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Archive for the ‘Heart Transplant’ Category


cell-free DNA (cfDNA) tests could become the ultimate “Molecular Stethoscope” that opens up a whole new way of practicing Medicine

 

Reporter: Aviva Lev-Ari, PhD, RN

The first commercial application of cfDNA sequencing debuted in 2011. New blood tests can identify Down’s syndrome and similar genetic conditions during the first months of pregnancy by checking the fetal DNA in the bloodstream of a pregnant woman. (Anywhere from 10 to 15 percent of the DNA in a pregnant woman’s blood comes from the placenta, which is genetically similar to the fetus.) These maternal blood tests are fast replacing less-accurate procedures, such as ultrasound plus blood analysis.

More recently, researchers have started looking at cfDNA to develop so-called liquid biopsies, which analyze a tumor’s genetic makeup or look for evidence of a cancer recurrence. Tumors often spill DNA into the blood as they grow and divide, and because they are usually riddled with mutations, their scrambled DNA is clearly different from that found in normal DNA fragments. The first liquid biopsy test was launched only three years ago; although they are not yet part of routine care, the field is growing quickly. One company says it will give liquid biopsy tests to one million people in the next five years, and another has raised nearly $1 billion for its studies.

A similar cfDNA method is being tested for newly transplanted organs, which are at risk of being rejected by the recipient’s immune system. Currently, transplant doctors check a transplanted organ’s health by performing repeated biopsies, which are expensive and invasive. After a transplant small amounts of donor DNA from the new heart or kidney, for example, circulate in the blood as part of the normal process of cell birth and death. If the host immune system attacks the foreign organ, the proportion of donor DNA increases as more and more foreign cells die. One company, CareDx, already sells a test that picks up on that change for people who have had kidney transplants.

The researchers invented a way to boost the signal by reducing human DNA in blood samples. Their spin-off company, Karius, launched a test earlier this year to identify bacteria, fungi, viruses or parasites in hospitalized patients. It can spot infections in organs that are too dangerous for biopsies, including the lung and the brain, Kertesz says—and it is most useful for people with mystery infections or who are too sick to endure a surgery.

cell-free DNA tests in the future include stroke, or autoimmune conditions such as lupus

 

SOURCE

One Test May Spot Cancer, Infections, Diabetes and More

Researchers are starting to diagnose more ailments using DNA fragments found in the blood

https://www.scientificamerican.com/article/one-test-may-spot-cancer-infections-diabetes-and-more/

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SACHS FLYER 2014 CVD Title

Please see Further Titles at

https://pharmaceuticalintelligence.com/biomed-e-books/

Please see Further Information on the Sachs Associates 14th Annual Biotech in Europe Forum for Global Investing & Partnering at:

https://pharmaceuticalintelligence.com/2014/03/25/14th-annual-biotech-in-europe-forum-for-global-partnering-investment-930-1012014-%E2%80%A2-congress-center-basel-sachs-associates-london/

AND

http://www.sachsforum.com/basel14/index.html

why-is-twitter-s-logo-named-after-larry-bird--b8d70319daON TWITTER Follow at

@SachsAssociates

#Sachs14thBEF

@pharma_BI

@AVIVA1950 

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MedTech & Medical Devices for Cardiovascular Repair – Curations by Aviva Lev-Ari, PhD, RN


Aviva Lev-Ari, PhD, RN

Cardiovascular Medical Devices:

Cardiac Surgery, Cardiothoracic Surgical Procedures and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

 

Lev-Ari, A. 1/26/2014. Transcatheter Valve Competition in the United States: Medtronic CoreValve infringes on Edwards Lifesciences Corp. Transcatheter Device Patents

https://pharmaceuticalintelligence.com/2014/01/26/transcatheter-valve-competition-in-the-united-states-medtronic-corevalve-infringes-on-edwards-lifesciences-corp-transcatheter-device-patents/

 

Lev-Ari, A. 1/26/2014. Developments on the Frontier of Transcatheter Aortic Valve Replacement (TAVR) Devices

https://pharmaceuticalintelligence.com/2014/01/26/developments-on-the-frontier-of-transcatheter-aortic-valve-replacement-tavr-devices/

 

Larry H. Bernstein and
Aviva Lev-Ari 6/23/2013 Survivals Comparison of Coronary Artery Bypass Graft (CABG) and Percutaneous Coronary Intervention (PCI) / Coronary Angioplasty

https://pharmaceuticalintelligence.com/2013/06/23/comparison-of-cardiothoracic-bypass-and-percutaneous-interventional-catheterization-survivals/

 

Larry H Bernstein and Lev-Ari, A. 6/23/2013 First case in the US: Valve-in-Valve (Aortic and Mitral) Replacements with Transapical Transcatheter Implants – The Use of Transfemoral Devices.

https://pharmaceuticalintelligence.com/2013/06/23/valve-in-valve-replacements-with-transapical-transcatheter-implants/

Larry H Bernstein and  Lev-Ari, A. 6/17/2013 Transcatheter Aortic Valve Replacement (TAVR): Postdilatation to Reduce Paravalvular Regurgitation During TAVR with a Balloon-expandable Valve

https://pharmaceuticalintelligence.com/2013/06/17/postdilatation-to-reduce-paravalvular-regurgitation-during-transcatheter-aortic-valve-replacement/

Larry H Bernstein and Lev-Ari, A. 6/17/2013 Trans-apical Transcatheter Aortic Valve Replacement in a Patient with Severe and Complex Left Main Coronary Artery Disease (LMCAD)

https://pharmaceuticalintelligence.com/2013/06/17/management-of-difficult-trans-apical-transcatheter-aortic-valve-replacement-in-a-patient-with-severe-and-complex-arterial-disease/

Larry H Bernstein and Lev-Ari, A. 6/18/2013 Ventricular Assist Device (VAD): A Recommended Approach to the Treatment of Intractable Cardiogenic Shock

https://pharmaceuticalintelligence.com/2013/06/18/a-recommended-approach-to-the-treatmnt-of-intractable-cardiogenic-shock/

Larry H Bernstein and Lev-Ari, A.6/20/2013 Phrenic Nerve Stimulation in Patients with Cheyne-Stokes Respiration and Congestive Heart Failure

https://pharmaceuticalintelligence.com/2013/06/20/phrenic-nerve-stimulation-in-patients-with-cheyne-stokes-respiration-and-congestive-heart-failure/

Lev-Ari, A. 2/12/2013 Clinical Trials on transcatheter aortic valve replacement (TAVR) to be conducted by American College of Cardiology and the Society of Thoracic Surgeons

https://pharmaceuticalintelligence.com/2013/02/12/american-college-of-cardiologys-and-the-society-of-thoracic-surgeons-entrance-into-clinical-trials-is-noteworthy-read-more-two-medical-societies-jump-into-clinical-trial-effort-for-tavr-tech-f/

Lev-Ari, A. 12/31/2012 Renal Sympathetic Denervation: Updates on the State of Medicine

https://pharmaceuticalintelligence.com/2012/12/31/renal-sympathetic-denervation-updates-on-the-state-of-medicine/

Lev-Ari, A. 9/2/2012 Imbalance of Autonomic Tone: The Promise of Intravascular Stimulation of Autonomics

https://pharmaceuticalintelligence.com/2012/09/02/imbalance-of-autonomic-tone-the-promise-of-intravascular-stimulation-of-autonomics/

Lev-Ari, A. 8/13/2012 Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stentshttps://pharmaceuticalintelligence.com/2012/08/13/coronary-artery-disease-medical-devices-solutions-from-first-in-man-stent-implantation-via-medical-ethical-dilemmas-to-drug-eluting-stents/

Lev-Ari, A. 7/18/2012 Percutaneous Endocardial Ablation of Scar-Related Ventricular Tachycardia

https://pharmaceuticalintelligence.com/2012/07/18/percutaneous-endocardial-ablation-of-scar-related-ventricular-tachycardia/

Lev-Ari, A. 6/13/2012 Treatment of Refractory Hypertension via Percutaneous Renal Denervation

https://pharmaceuticalintelligence.com/2012/06/13/treatment-of-refractory-hypertension-via-percutaneous-renal-denervation/

Lev-Ari, A. 6/22/2012 Competition in the Ecosystem of Medical Devices in Cardiac and Vascular Repair: Heart Valves, Stents, Catheterization Tools and Kits for Open Heart and Minimally Invasive Surgery (MIS)

https://pharmaceuticalintelligence.com/2012/06/22/competition-in-the-ecosystem-of-medical-devices-in-cardiac-and-vascular-repair-heart-valves-stents-catheterization-tools-and-kits-for-open-heart-and-minimally-invasive-surgery-mis/

Lev-Ari, A. 6/19/2012 Executive Compensation and Comparator Group Definition in the Cardiac and Vascular Medical Devices Sector: A Bright Future for Edwards Lifesciences Corporation in the Transcatheter Heart Valve Replacement Market

https://pharmaceuticalintelligence.com/2012/06/19/executive-compensation-and-comparator-group-definition-in-the-cardiac-and-vascular-medical-devices-sector-a-bright-future-for-edwards-lifesciences-corporation-in-the-transcatheter-heart-valve-replace/

Lev-Ari, A. 6/22/2012 Global Supplier Strategy for Market Penetration & Partnership Options (Niche Suppliers vs. National Leaders) in the Massachusetts Cardiology & Vascular Surgery Tools and Devices Market for Cardiac Operating Rooms and Angioplasty Suites

https://pharmaceuticalintelligence.com/2012/06/22/global-supplier-strategy-for-market-penetration-partnership-options-niche-suppliers-vs-national-leaders-in-the-massachusetts-cardiology-vascular-surgery-tools-and-devices-market-for-car/

Lev-Ari, A. 7/23/2012 Heart Remodeling by Design: Implantable Synchronized Cardiac Assist Device: Abiomed’s Symphony

https://pharmaceuticalintelligence.com/2012/07/23/heart-remodeling-by-design-implantable-synchronized-cardiac-assist-device-abiomeds-symphony/

Lev-Ari, A. (2006b). First-In-Man Stent Implantation Clinical Trials & Medical Ethical Dilemmas. Bouve College of Health Sciences, Northeastern University, Boston, MA 02115

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Heart Metabolism or Metabolic Cardiology: The Role of Ribose (D-ribose) for the Ischemic Heart -The Work of John St. Cyr, M.D., Ph.D.

Reporter: Aviva Lev-Ari, PhD, RN

REVIEW

An interview with John St. Cyr, M.D., Ph.D. on Ribose : A Key to Heart Health and Energy

By Richard A. Passwater, Ph.D.

 

© Whole Foods Magazine

January 2005

Ribose : A Key to Heart Health and Energy

An interview with John St. Cyr, M.D., Ph.D.

By Richard A. Passwater, Ph.D.

SOURCE

http://www.drpasswater.com/nutrition_library/John_St_Cyr.html

 

John St. Cyr, M.D., Ph.D. — PATENTS:

Issued:

Suture removal device, USP5250052

Double layer prophylactic incorporating pharmacological fluid and spiral barrier layer, USP5623945

Compositions for increasing energy in vivo, USP6159942

Method for determining viability of a myocardial segment, USP6339716

Method for raising the hypoxic threshold, USP6218366

Use of ribose to prevent cramping and soreness in muscles, USP6159943

Compositions for increasing athletic performance in mammals, USP6429198

Dual lumen adjustable length cannulae for liquid perfusion or lavage, USP6692473

Method for treating acute mountain sickness, USP6511964

Compositions for increasing energy in vivo, USP6534480

Compositions for the storage of platelets, USP6790603

Compositions for enhancing the immune response, USP6663859

Composition methods for improving cardiovascular function, USP7553817

Rejuvenation of stored blood, USP7687468

 

John St. Cyr, M.D., Ph.D. — Pending applications:

Method for improving ventilatory efficiency, SN20050277598

Storage of blood SN20070111191

Ventilatory benefits of ribose in COPD, smoking, SN

Use of ribose in recovery from anesthesia, SN20070105787

Use of ribose to alleviate rhabdomyolysis and the side effects of statin drugs, SN20060135440

Use of ribose in first response to acute myocardial infarction, SN20100055206

Compositions and methods for improving cardiovascular function, SN20100009924

Use of ribose in lessening the clinical symptoms of aberrant firing of neurons, SN20090286750

Compositions for indoor tanning, SN20090232750

Compositions for improving and repairing skin, SN20090197819

Use of ribose for recovery from anesthesia, SN20090197818

Cosmetic use of D-ribose, SN20080312169

Method for improving ventilator efficiency SN20100099630

Method and compositions for improving pulmonary hypertension, SN20080146514

Storage of blood, SN20070111191

Compositions and methods for feeding poultry, SN201100221446

Use of D-ribose for fatigued subjects, SN20100189785

Fibrin sealants and platelet concentrates applied to effect hemostasis in the interface of an implantable medical device with body tissue, SN20060190017

Compositions for reducing the deleterious effects of stress and aging, SN20120045426

 

John St. Cyr, M.D., Ph.D. — Provisional patents:

Use of ribose in pre-slaughtering of animals

Rescue therapy for acute decompensated heart failure

Combination of D-ribose plus caffeine

Role of ribose in reducing joint swelling in mammals

Role of D-ribose in cardiac remodeling

Role of D-ribose in cachexia

Use of ribose in stem cells

Use of ribose in cardioplegia

Use of ribose for doping blood for cardioplegia

Surgical adhesive for bleeding situations

Metabolic approach with EECP

Role of ribose in mitral regurgitation

Compositions for the preservation of morphology in stored blood

Methods and nutritional supplements for improving the quality of meat

 

John St. Cyr, M.D., Ph.D. — Publications 2011 to 2013

This list does not include Publication #1 to #219

220. Shecterle LM, Wagner S, St.Cyr JA.  A sugar for congestive heart failure patients.  Ther Adv Cardiovasc Dis 5(2):95-97, 2011.

221. Perkowski D, Wagner S, Schneider JR, St.Cyr JA.  A targeted metabolic protocol with D-ribose for off pump coronary artery bypass procedures: A retrospective analysis.  Ther Adv Cardiovasc Dis 5(4):185-192, 2011.

222. Foker J, Berry J, Harvey B, Befera N, Tveter K, St.Cyr J, Bianco R.  Heart failure is initiated by and progresses because of normal responses of energy metabolism to stress.  Circ Res   , 2011.

223. Rakow N, Barka N, Gerhart R, Rothstein P, Green M, Schu C, Grassl E, St.Cyr JA, Kopcak MW, Jr.  Chronic aortic root pressure-loading assessment model.  J Invest Surg 25(2):137, 2012.

224. Shecterle LM, St.Cyr JA.  Chapter 11; Myocardial Ischemia: Alterations in myocardial cellular energy and diastolic function, a potential role for D-ribose. In: Novel Strategies in Ischemia Heart Disease. Lakshmanadoss U(Ed). InTech, Croatia.  219-228, 2012.

225. Addis P, Shecterle LM, St.Cyr JA.  Cellular protection during oxidative stress: a potential role for D-ribose and antioxidants.  Journal of Dietary Supplements 9(3):178-182, 2012.

226. Holsworth R, Shecterle L, St.Cyr J, Sloop G.  Letter to the Editor.  Importance of monitoring blood viscosity during cardiopulmonary bypass.  Perfusion 28(1):91-2, 2013.

227. Seifert JG, Frost J, ST.Cyr JA.  Recovery benefits of a heat and moisture exchange mask when performing sprint exercise in cold temperature environments.  Aviation, Space and Environmental Medicine.    , 2013.

228. Seifert JG, McNair M, DeClercq P, St.Cyr JA.  A heat and moisture mask attenuates cardiovascular stress during cold air exposure.  Ther Adv Cardiovasc Dis 7(3):123-129, 2013.

229. Holsworth R, Cho Y, Weldman J, Sloop G, St.Cyr, J.  Cardiovascular benefits of phlebotomy: Relationship to changes in hemorheological variables.  Perfusion,   2013.

 

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Myocardial Infarction: The New Definition After Revascularization

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 7/31/2014

Myocardial Ischemia Symptoms

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/29/myocardial-ischemia-symptoms/

 

VIEW VIDEO

Gregg Stone, MD

Co-DIrector, Medical Research & Education Division Cardiovascular Research Foundation

http://www.medpagetoday.com/Cardiology/MyocardialInfarction/42256?xid=nl_mpt_DHE_2013-10-15&goback=%2Egmr_4346921%2Egde_4346921_member_5795830612724035588#%21

Primary source: Journal of the American College of Cardiology
Source reference: Moussa I, et al “Consideration of a new definition of clinically relevant myocardial infarction after coronary revascularization: an expert consensus document from the Society for Cardiovascular Angiography and Interventions (SCAI)” J Am Coll Cardiol2013; 62: 1563-1570.

Additional source: Journal of the American College of Cardiology
Source reference:White H “Avatar of the universal definition of periprocedural myocardial infarction” J Am Coll Cardiol 2013; 62: 1571-1574.

Moussa reported that he had no conflicts of interest.

Stone is a consultant for Boston Scientific, Eli Lilly, Daiichi Sankyo, and AstraZeneca. The other authors reported relationships with Guerbet, The Medicines Company, Bristol-Myers Squibb/Sanofi, Merck, Maya Medical, AstraZeneca, Abbott Vascular, Regado Biosciences, Janssen Pharma, Lilly/Daiichi Sankyo, St. Jude Medical, Medtronic, Terumo, Bridgepoint/Boston Scientific, Gilead, Boston Scientific, Eli Lilly, and Daiichi Sankyo.

White is co-chairman for the Task Force for the Universal Definiton of Myocardial Infarction; has received research grants from sanofi-aventis, Eli Lilly, The Medicines Company, the NIH, Pfizer, Roche, Johnson & Johnson, Schering-Plough, Merck Sharpe & Dohme, AstraZeneca, GlaxoSmithKline, Daiichi Sankyo Pharma Development, and Bristol-Myers Squibb; and has served on advisory boards for AstraZeneca, Merck Sharpe & Dohme, Roche, and Regado Biosciences.

WASHINGTON, DC — A “clinically meaningful” definition of MI following PCI or CABG is urgently needed to replace the arbitrarily chosen “universal definition” proposed in recent years that has no relevance to patients and may be muddying clinical-trial results. Those are the conclusions of a new expert consensus document released Monday by the Society of Cardiovascular Angiography and Interventions (SCAI)[1].

The notion of a “universal definition of MI” was first proposed in 2000 and updated in 2007 and 2012. The 2012 document defines a PCI-related MI as an increase in cardiac troponin (cTn) of more than five times the upper limit of normal (ULN) during the first 48 hours postprocedure plus specific clinical or ECG features. Post-CABG, the definition is a cTn increase of >10 times the ULN, plus different clinical or ECG features.

The problem, lead author Dr Issam Moussa (Mayo Clinic, Jacksonville, FL) told heartwire , is that these cutoffs were arbitrarily chosen and not based on any hard evidence that these biomarker levels spelled a poor prognosis. Moreover, “overnight, the rate of MI went from 5% following these procedures to 20% to 30%!” he said.

The SCAI committee, in its new document, focuses on post-PCI procedures and highlights the importance of acquiring baseline cardiac biomarkers and differentiating between patients with elevated baseline CK-MB (or cTn) in whom biomarker levels are stable or falling, as well as those in whom it hasn’t been established whether biomarkers are changing.

SCAI’s Proposed Clinically Meaningful MI Definitions

Group Definition
Normal baseline CK-MB CK-MB rise of >10x ULN or >5x ULN with new pathologic Q-waves in at least 2 contiguous leads or new persistent left bundle branch block
OR
In the absence of baseline CK-MB, a cTn rise of >70x ULN or a rise of>35 ULN plus new pathologic Q-waves in at least 2 contiguous leads or new persistent left bundle branch block
Elevated baseline biomarkers that are stable or falling A CK-MB or cTn rise that is equal (by an absolute increment) to the definitions described for patients with normal CK-MB at baseline.
Elevated baseline biomarkers that have not been shown to be stable or falling A CK-MB or cTn rise that is equal (by an absolute increment) to the definitions described for patients with normal CK-MB at baseline
Plus
New ST-segment elevation or depression
Plus
New-onset or worsening heart failure or sustained hypotension or other signs of a clinically relevant MI.

Moussa is quick to emphasize that these new clinically meaningful definitions have limited evidence to support them—and most of what exists supports CK-MB definitions, not cTn—but that the new document is based on the best scientific evidence available.

“We don’t want to come out with a definitive statement” saying this is the final word on MI definitions,” he stressed. “There is more science that needs to be done and there remains more uncertainty. We framed this to be inclusive and also to open the field for discussion.”

His hope is that this will lead to important changes in how patients are managed and money is spent. Currently, patients with clinically meaningless biomarker elevations may become unnecessarily panicked over news that they’ve had a “heart attack,” while hospital stays may be extended and further tests ordered on the basis of these results.

Moussa et al’s proposal also has important implications for clinical trials, he continued. Currently, for studies that include periprocedural MIs as an individual end point or as part of a composite end point, the very high number of biomarker-defined “MIs” collected in the trial could potentially overwhelm the true impact of any given therapy. “You are really using an end point that is truly not relevant to patients. . . . This could really affect the whole hypothesis.”

He’s expecting some push-back from cardiologists and academics, particularly those who championed the need for the universal definition in the first place, but believes most people will welcome a clinically meaningful definition.

“I think many in the medical community will accept this because they have not really been using the universal definition in their day-to-day practice anyhow.” What’s more, the National Cardiovascular Data Registry (NCDR) does not include the reporting of MI postangiography, in part because of concerns that the universal definition of MI overestimates the true incidence of this problem. “I think many in the community will look at this definition as more reflective of the true incidence of MI after angioplasty, and if it’s accepted, they are more likely to report it to databases like NCDR and use it to reflect quality-of-care processes.”

http://www.medscape.com/viewarticle/812533?nlid=35983_2105&src=wnl_edit_medp_card&uac=93761AJ&spon=2

  • ESC/ACCF/AHA/WHF Expert Consensus Document

Circulation.2012; 126: 2020-2035  Published online before print August 24, 2012,doi: 10.1161/​CIR.0b013e31826e1058

Third Universal Definition of Myocardial Infarction

  1. Kristian Thygesen;
  2. Joseph S. Alpert;
  3. Allan S. Jaffe;
  4. Maarten L. Simoons;
  5. Bernard R. Chaitman;
  6. Harvey D. White
  7. the Writing Group on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Universal Definition of Myocardial Infarction
  1. *Corresponding authors/co-chairpersons: Professor Kristian Thygesen, Department of Cardiology, Aarhus University Hospital, Tage-Hansens Gade 2, DK-8000 Aarhus C, Denmark. Tel: +45 7846-7614; fax: +45 7846-7619: E-mail: kristhyg@rm.dk. Professor Joseph S. Alpert, Department of Medicine, Univ. of Arizona College of Medicine, 1501 N. Campbell Ave., P.O. Box 245037, Tucson AZ 85724, USA, Tel: +1 520 626 2763, Fax: +1 520 626 0967, E-mail: jalpert@email.arizona.edu. Professor Harvey D. White, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92024, 1030 Auckland, New Zealand. Tel: +64 9 630 9992, Fax: +64 9 630 9915, E-mail: harveyw@adhb.govt.nz.

Table of Contents

  • Abbreviations and Acronyms. . . . . . . . . . . . . . . . . . . .2021

  • Definition of Myocardial Infarction. . . . . . . . . . . . . . .2022

  • Criteria for Acute Myocardial Infarction. . . . . . . . . . . .2022

  • Criteria for Prior Myocardial Infarction. . . . . . . . . . . .2022

  • Introduction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2022

  • Pathological Characteristics of Myocardial Ischaemia and Infarction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .2023

  • Biomarker Detection of Myocardial Injury With Necrosis. . .2023

  • Clinical Features of Myocardial Ischaemia and Infarction. . .2024

  • Clinical Classification of Myocardial Infarction. . . .2024
    • Spontaneous Myocardial Infarction (MI Type 1). . . .2024

    • Myocardial Infarction Secondary to an Ischaemic Imbalance (MI Type 2). . . . . . . . . . . . . . . . . . . . . . . .2024

    • Cardiac Death Due to Myocardial Infarction (MI Type 3). .2025

    • Myocardial Infarction Associated With Revascularization Procedures (MI Types 4 and 5). . . . . . . . . . . . . . . . . . …

New Definition for MI After Revascularization

Published: Oct 14, 2013 | Updated: Oct 15, 2013

By Todd Neale, Senior Staff Writer, MedPage Today
Reviewed by Zalman S. Agus, MD; Emeritus Professor, Perelman School of Medicine at the University of Pennsylvania and Dorothy Caputo, MA, BSN, RN, Nurse Planner

The Society for Cardiovascular Angiography and Interventions (SCAI) has released a new definition for myocardial infarction (MI) following coronary revascularization aimed at identifying only those events likely to be related to poorer patient outcomes.

In the new criteria — published as an expert consensus document inCatheterization and Cardiovascular Interventions and the Journal of the American College of Cardiology — creatine kinase-myocardial band (CK-MB) is the preferred cardiac biomarker over troponin, and much greater elevations are required to define a clinically relevant MI compared with the universal definition of MI proposed in 2007 and revised in 2012.

Also, the new definition uses the same biomarker elevation thresholds to identify MIs following both percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG), whereas the universal definition has different thresholds for events following the two procedures.

“What we’ve really tried to emphasize in this classification scheme is the primary link between biomarker elevations and prognosis,” according to Gregg Stone, MD, of Columbia University Medical Center and the Cardiovascular Research Foundation in New York City, one of the authors of the document.

“In the universal definition of MI, they even acknowledged that their criteria were arbitrary,” Stone said in an interview. “We’ve tried to reduce the arbitrariness of the cutoff values that we selected so that the researcher, academician, clinician, hospital administrator, etc., can be confident that these levels that we’re recommending are the ones that are associated with a worse prognosis for patients suffering periprocedural complications.”

The Change

The existing universal definition for MI defines events following PCI according to an increase in cardiac troponin to greater than five times the 99th percentile upper reference limit (URL) within 48 hours when baseline levels are normal, with confirmation by electrocardiogram (ECG), imaging, or symptoms.

For CABG-related MI, the increase must be more than 10 times the 99th percentile URL within 48 hours when baseline levels are normal, with confirmation by ECG, angiography, or imaging.

But, Stone and colleagues wrote, the relationship between that degree of troponin elevation after a revascularization procedure and prognosis is not as strong as the association between a CK-MB elevation and patient outcomes.

Using a small elevation in troponin to define a post-procedure MI could find myocardial necrosis that is unlikely to be associated with poor clinical outcomes, which could have far-reaching implications, they wrote.

“Widespread adoption of an MI definition not clearly linked to subsequent adverse events such as mortality or heart failure may have serious consequences for the appropriate assessment of devices and therapies, may affect clinical care pathways, and may result in misinterpretation of physician competence,” they wrote.

To address that issue, the expert panel convened by SCAI sought to define clinically relevant MI after PCI or CABG.

A clinically relevant MI is defined in the new document based on an increase of at least 10 times the upper limit of normal in the level of CK-MB within 48 hours after a revascularization procedure when baseline levels are normal.

When the CK-MB level is not available, then an increase in troponin I or T of at least 70 times the upper limit of normal can be used to define a clinically relevant MI, according to the authors.

However, if an ECG shows new pathologic Q-waves in at least two contiguous leads or a new persistent left bundle branch block, then the thresholds can be lowered to at least five times and at least 35 times the upper limit of normal for CK-MB and troponin, respectively.

Further guidance is provided for identifying clinically relevant post-procedure MIs when the cardiac biomarker levels are elevated at baseline.

Dueling Definitions

Co-chairman of the Task Force for the Universal Definition of Myocardial Infarction, Harvey White, DSc, of Auckland City Hospital in Auckland, New Zealand, noted some limitations of the new definition, including the lack of a requirement for ischemic symptoms.

“Ischemic symptoms have always been a basic tenet of the diagnosis of MI, and it should be no different for a [PCI-related] MI,” he wrote in an accompanying editorial.

In addition, with the use of such large elevations in biomarker levels in the new definition, “there will be very few PCI-related events identified, and an opportunity to improve patient outcomes may be lost,” he wrote.

Troponin should remain the preferred biomarker over CK-MB, White argued, pointing to variability in and analytical issues with CK-MB assays, the need for sex-specific cutoffs for CK-MB levels, the need for higher thresholds of CK-MB to determine abnormalities because all individuals have circulating levels of the biomarker, and the reduced sensitivity and specificity of CK-MB.

Also, he said, CK-MB is becoming increasingly unavailable at medical centers.

“With CK-MB becoming obsolete, troponin will become the gold standard, and CK-MB will no longer have a role in defining PCI injury and infarction in clinical practice,” White wrote.

Stone admitted that troponin ultimately might be preferable to CK-MB because of its greater specificity, although the evidence does not yet support it.

“I think there’s a general desirability to move to troponins, although when you look at the data that’s out there it’s much stronger correlating CK-MB elevations to subsequent prognosis,” he said. “I think a lot of the troponin elevations are just noise or troponins are just too sensitive.”

Room for Both?

White noted in his editorial that “the rationale for the SCAI definition has been well articulated by its authors and may be appropriate in an individual trial, but it should not supplant the universal definition of MI,” he wrote.

When asked whether the new definition would replace the universal definition, Stone said there is a place for both sets of criteria.

“We would propose the clinically relevant definition be the one that is used to make most substantial decisions right now, [such as] trade-offs between efficacy and safety for new drugs and devices, in judging hospital systems and physicians, etc.,” he said. “But I do think there’s value in both, and they will both continue to evolve over time as new data becomes evident.”

http://www.medpagetoday.com/Cardiology/MyocardialInfarction/42256?xid=nl_mpt_DHE_2013-10-15&goback=%2Egmr_4346921%2Egde_4346921_member_5795830612724035588#%21 

Articles citing 

Third Universal Definition of Myocardial Infarction

  • Improved long-term clinical outcomes in patients with ST-elevation myocardial infarction undergoing remote ischaemic conditioning as an adjunct to primary percutaneous coronary interventionEur Heart J. 2013;0:eht369v1-eht369

  • The role of myeloperoxidase (MPO) for prognostic evaluation in sensitive cardiac troponin I negative chest pain patients in the emergency departmentEuropean Heart Journal: Acute Cardiovascular Care. 2013;2:203-210,
  • Coronary artery bypass grafting or percutaneous revascularization in acute myocardial infarction?Interact CardioVasc Thorac Surg. 2013;0:ivt381v1-ivt381,
  • Ischemic Conditioning as an Adjunct to Percutaneous Coronary InterventionCirc Cardiovasc Interv. 2013;6:484-492,
  • High sensitivity cardiac troponin in patients with chest painBMJ. 2013;347:f4222,
  • Chest Pain and Palpitations: Taking a Closer LookCirculation. 2013;128:271-277,
  • An Updated Definition of Stroke for the 21st Century: A Statement for Healthcare Professionals From the American Heart Association/American Stroke AssociationStroke. 2013;44:2064-2089,
  • Factors Influencing the 99th Percentile of Cardiac Troponin I Evaluated in Community-Dwelling Individuals at 70 and 75 Years of AgeClin. Chem.. 2013;59:1068-1073,
  • Detection and management of asymptomatic myocardial injury after noncardiac surgeryEuropean Journal of Preventive Cardiology.2013;0:2047487313494294v1-2047487313494294,
  • Postoperative Troponin Screening: A Cardiac Cassandra?Circulation. 2013;127:2253-2256,
  • Remote Ischemic Preconditioning Improves Outcome at 6 Years After Elective Percutaneous Coronary Intervention: The CRISP Stent Trial Long-term Follow-upCirc Cardiovasc Interv. 2013;6:246-251,
  • Outcomes for Clinical Studies Assessing Drug and Revascularization Therapies for Claudication and Critical Limb Ischemia in Peripheral Artery DiseaseCirculation. 2013;127:1241-1250,
  • Prevalence, Incidence, and Implications of Silent Myocardial Infarctions in Patients With Diabetes MellitusCirculation. 2013;127:965-967,
  • 2013 ACCF/AHA Key Data Elements and Definitions for Measuring the Clinical Management and Outcomes of Patients With Acute Coronary Syndromes and Coronary Artery Disease: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Clinical Data Standards (Writing Committee to Develop Acute Coronary Syndromes and Coronary Artery Disease Clinical Data Standards)Circulation. 2013;127:1052-1089,
  • Clin. Chem.. 2013;59:574-576,
  • Percutaneous Coronary Intervention Versus Optimal Medical Therapy for Prevention of Spontaneous Myocardial Infarction in Subjects With Stable Ischemic Heart DiseaseCirculation. 2013;127:769-781,
  • Frequency of Myocardial Infarction and Its Relationship to Angiographic Collateral Flow in Territories Supplied by Chronically Occluded Coronary ArteriesCirculation. 2013;127:703-709,
  • The Power of More Than OneCirculation. 2013;127:665-667,
  • The curious life of the biomarkerJournal of the American Dental Association. 2013;144:126-128,
  • Persistent Increases in Cardiac Troponin Concentrations As Measured with High-Sensitivity Assays after Acute Myocardial InfarctionClin. Chem.. 2013;59:443-445,
  • 2013 ACCF/AHA Guideline for the Management of ST-Elevation Myocardial Infarction: A Report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice GuidelinesCirculation. 2013;127:e362-e425,

Read Full Post »

Alternative Designs for the Human Artificial Heart: Patients in Heart Failure – Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community


Alternative Designs for the Human Artificial Heart: Patients in Heart Failure –  Outcomes of Transplant (donor)/Implantation (artificial) and Monitoring Technologies for the Transplant/Implant Patient in the Community

Authors and Curators: Larry H Bernstein, MD, FCAP and Justin D Pearlman, MD, PhD, FACC

and

Article Curator and Reporter: Aviva Lev-Ari, PhD, RN

When the heart fails to function adequately, whether from large or multiple myocardial infarctions (tissue death/scarring) or from permanent inflammatory, toxic, microvascular or infectious muscle injury, it has two modes of failure: forward failure = inadequate pumping of blood to tissues, and backward failure = inadequate withdrawal of blood from the lungs, resulting in pulmonary congestion and elevated back-pressures which cause fluid to seep into air spaces (pulmonary edema) interfering with oxygen uptake. When the heart cannot be repaired, replacement is considered. Additional pumps may be placed in parallel and/or in series with the heart to assist circulation of blood. A heart from another patient (usually a patient deemed brain dead from trauma) or from a baboon may be transplanted to replace the ailing heart, or may be placed in tandem with the ailing heart, or the heart and lungs may be replaced together (heart-lung transplant). Additional options include the intra-aortic balloon pump, the Impella catheter pump, other ventricular assist devices. There is far greater demand for heart transplants than there are available suitable organs, so work continues on alternatives. Additional reasons to seek alternatives include the complications of transplantation. Transplantation requires shutting down the body defenses against foreign materials, called immune suppression, but the immune defense system protects against cancer and infection, so a one in five of the transplant patients succomb to cancer or infection, while others die of rejection due to insufficient suppression of the autoimmune system. Artificial materials exist that do not trigger autoimmune defenses, thereby avoiding that major issue, but energizing the pump, providing sufficient circulatory support and avoiding damage to the blood have been major hurdles.

This article has the following FIVE Parts:

Part I.  Alternative Models of Artificial Hearts, US and Europe

By Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

Part  II.  Comparison of the Cardiac Operations involved in an Organ Transplant of a Donor’s Heart vs Implantation of an Artificial Heart

By Justin D Pearlman, MD, PhD, FACC 

Part III. Comparative Analysis of Transplant Clinical Outcomes based on Data in:

Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

By Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN 

Part IV.  Imaging Technologies in use for Clinical Monitoring of Patients with Heart Transplant: Donor Human Heart and Artificial Heart

By Justin D Pearlman, MD, PhD, FACC 

Part V. The Failure of a Heart Transplant – Pathology and Autopsy Findings

by Larry H Bernstein, MD, FCAP

Conclusions

by Larry H Bernstein, MD, FCAP

 

Part I

Alternative Models of Artificial Hearts, US and Europe

By Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

 

Latest Innovations in Alternative Models of Artificial Hearts, US and Europe

by Aviva Lev-Ari, PhD, RN

UPDATED on 12/29/2013

Total Artificial Heart Manufacturer SynCardia Secures $14M in Growth Financing

December 17, 2013

Total Artificial Heart Manufacturer SynCardia Secures $14M in Growth Financing

$10M Financed by SWK of Dallas with $4M from Athyrium Opportunities Fund

A $14 million infusion of funding will allow SynCardia Systems, Inc. to respond to the rapid growth in the number of Total Artificial Heart implants and SynCardia Certified Centers that has occurred since 2010. As of Dec. 16, 2013, there were 155 implants of the SynCardia Total Artificial Heart, making 2013 another record-breaking year.

TUCSON, Ariz., Dec. 17, 2013 /PRNewswire/ — Privately held SynCardia Systems, Inc. announced today that it had raised $14 million to fund the rapid growth of the only approved medical device that eliminates the symptoms and source of end-stage heart failure, the SynCardia temporary Total Artificial Heart. The SynCardia Total Artificial Heart is the world’s first and only FDA, Health Canada and CE (Europe) approved Total Artificial Heart.

“SWK is very pleased to provide SynCardia this new capital in order to help further the growth of the company’s Total Artificial Heart,” Brett Pope, CEO of SWK Holdings Corporation, says of its $10-million financing. “We are very gratified to help expand the availability of this lifesaving device.”

“In 2013 we are setting another record for SynCardia Heart implants, nearly double what was then our 2011 record-breaking year of 81 implants,” says Michael Garippa, President and CEO of SynCardia. “As of Dec. 16, 155 SynCardia Total Artificial Hearts have been implanted this year.”

The financing positively affects the development of the new, smaller 50cc version of the approved 70cc SynCardia Total Artificial Heart, the availability of the Freedom portable driver and the use of SynCardia technology for destination therapy.

“We are pleased to support SynCardia’s continued clinical and commercial successes,” says Laurent Hermouet, a partner at Athyrium. “This latest financing will help reinforce SynCardia’s supply chain and manufacturing capabilities ahead of new product launches and increased production levels.”

The $4 million provided by Athyrium Capital Management in last week’s funding supplemented $15 million in long-term growth capital it provided to SynCardia in March 2013.

Wedbush PacGrow Life Sciences acted as exclusive placement agent for the offering.

The new financing allows SynCardia to accelerate the development and launch of its 50cc Total Artificial Heart* through an FDA-approved clinical study. Together, the 50cc and 70cc sizes of the Total Artificial Heart will fit almost all women and men, as well as many pediatric patients. With this expanded product line, SynCardia anticipates the tripling of the market size and sales potential for the SynCardia Total Artificial Heart.

The funds also will help the company meet the increasing demand for the Freedom portable drivers. In a letter dated Oct. 21, 2013, the FDA determined that the Freedom PMA supplement is approvable with the submission of additional information. The 13.5-pound wearable Freedom driver, which powers the SynCardia Heart while giving patients nearly unrestricted mobility, is already approved by Health Canada and has a CE Mark for Europe.

SynCardia is an innovative, 85-employee company focused on advanced medical technology targeting the NYHA Class IV heart failure market. There are 93 SynCardia Certified Centers worldwide where the SynCardia Heart is immediately available with an additional 35 hospitals undergoing the company’s four-phase certification program. As of Dec. 16, 2013, there have been 1,262 total implants of the SynCardia Total Artificial Heart worldwide.

SWK Holdings Corporation is a specialized finance company with a focus on the global healthcare sector. SWK partners with ethical product marketers and royalty holders to provide flexible financing solutions at an attractive cost of capital to create long-term value for both SWK’s business partners and its investors. SWK believes its financing structures achieve an optimal partnership for companies, institutions and inventors seeking capital for expansion or capital and estate planning by allowing its partners to monetize future cash flow with minimal dilution to their equity stakes. Additional information on the life science finance market is available on the company’s website at http://www.swkhold.com.

Athyrium Capital Management, LLC is an asset management company formed in 2008 to focus on investment opportunities in the global healthcare sector. Athyrium invests across all healthcare verticals including biopharma, medical devices and products and healthcare services, and partners with management teams to implement creative financing solutions to companies’ capital needs. The Athyrium team has substantial investment experience in the healthcare sector across a wide range of asset classes, including public equity, private equity, fixed income, royalties and other structured securities. Athyrium has over $600 million under management as of Sept. 30, 2013. The firm’s investors include public and corporate pension funds, charitable endowments, insurance companies, funds-of-funds, family offices and university endowments. For more information, please visit http://www.athyrium.com.

*The 50cc Total Artificial Heart is designed for use as a bridge to transplant in patients of smaller stature, including women and adolescents. It has been designated as a Humanitarian Use Device (HUD) by the FDA for destination therapy in adults and as a bridge to transplant in pediatric patients. Prior to clinical study, an Investigational Device Exemption (IDE) application that includes each indication must be approved by the FDA.
** CAUTION – The Freedom portable driver is an investigational device, limited by United States law to investigational use.
About the SynCardia temporary Total Artificial Heart
For additional information, please visit: http://www.syncardia.com
Like SynCardia on Facebook
Follow SynCardia on Twitter – @SynCardia
Connect with SynCardia on LinkedIn

SOURCE

SynCardia Systems, Inc.

Read more: Total Artificial Heart Manufacturer SynCardia Secures $14M in Growth Financing – FierceMedicalDevices http://www.fiercemedicaldevices.com/press-releases/total-artificial-heart-manufacturer-syncardia-secures-14m-growth-financing#ixzz2otlLCH8I
Subscribe at FierceMedicalDevices

UPDATED on 12/23/2013

First Carmat artificial heart implanted in human in France

http://medcitynews.com/2013/12/first-artificial-heart-implanted-human/

UPDATED on 3/27/2014

Carmat Investigates Death of First Artificial Heart Recipient

Posted in Cardiovascular by Stephen Levy on March 18, 2014

French artificial heart maker Carmat says it will not perform another human implant until it has determined the cause of death of the first patient fitted with the device.

That first patient, a 76-year-old man suffering from terminal heat failure, died March 2. He received the implanted artificial heart 75 days before, on December 18. The Georges Pompidou European Hospital in Paris, where the implantation was performed, announced the death.

 

Carmat
Artificial heart internals (Courtesy Carmat)

Alain Carpentier, MD, the inventor of the heart, told the Journal du Dimanche on March 16 that the heart had stopped after a short circuit, although the exact reasons behind the death were still unknown.

“We are trying to understand where this electronic problem came from and why,” Carpentier told the French weekly. “Our engineers are working night and day to understand, and they will find (the reason).”

Velizy Villacoublay, France–based Carmat said in a news release on March 17 that it is continuing to analyze the data from the first implanted prosthesis. The company further stated that it will continue the clinical trial once it has obtained the results of the data from the first implantation.

Reuters reports that Philippe Pouletty, director general of Truffle Capital, one of Carmat’s main shareholders, told i>Tele television, “Patients are still being chosen, but of course we will wait to hear a little more on the causes of the death of the first patient before transplanting another artificial heart.”

The company explained that its detailed analysis of the data is still being carried out. More than 4000 pieces of data are recorded every second, it said. These include inputs from the artificial heart itself, its control console, and their respective power supplies.

Also of great interest are the very complex interactions between the weakened heart of the patient and the prosthesis. At the current time, Carmat says, there is no single explanation, only hypotheses that will be substantiated or not in the coming weeks by in-house and external experts. The results of the analyses of the first implantation, and the subsequent implantations, will be reviewed by the Data and Safety Monitoring Board (DSMB).

From the company’s point of view, the first implantation was a success. The patient survived for 74 days within the framework of a trial where the benchmark for success was 30 days. Carmat says that the approved medical centers are continuing to assess next patients for the ongoing clinical trial.

Pouletty said that the data analysis would be complete within “a few weeks.” The company has previously stated that if it passed this first safety test, it intends to fit the device into about 20 more patients with less severe heart failure later this year. It hopes to apply for CE Marking to market its device in Europe by 2015.

Stephen Levy is a contributor to Qmed and MPMN.

SOURCE

http://www.qmed.com/news/carmat-investigates-death-first-artificial-heart-recipient?cid=nl.qmed02

 

UPDATED on 3/6/2014

Artificial heart patient in France dies – Frenchman died 75 days after surgery

Thomson Reuters Posted: Mar 04, 2014 5:11 PM ET Last Updated: Mar 04, 2014 5:12 PM ET

The first patient fitted with an artificial heart made by the French company Carmat has died, the hospital that had performed the transplant in December has announced.

Carmat artificial heartCarmat’s bioprosthetic device is designed to replace the real heart for as much as five years, mimicking nature’s work using biological materials and sensors. (Benoit Tessier/Reuters)

The 76-year-old man died on Sunday, 75 days after the operation, the Georges Pompidou European Hospital in Paris said in a statement, adding that the cause of his death could not be known for sure at this stage.

When he was fitted with the device, the man was suffering from terminal heart failure, when the sick heart can no longer pump enough blood to sustain the body, and was said to have only a few weeks, or even days, to live.

Carmat’s bioprosthetic device is designed to replace the real heart for as much as five years, mimicking nature’s work using biological materials and sensors. It aims to help the thousands of patients who die each year while awaiting a donor, and reducing the side-effects associated with transplants.

“Carmat wishes to pay tribute to the courage and the pioneering role of this patient and his family, as well as the medical team’s dedication,” a company spokeswoman said.

She stressed that it was premature to draw any conclusions on Carmat’s artificial heart at this stage.

Three more patients in France with terminal heart failure are due to be fitted with the device. The clinical trial will be considered a success if the patients survive with the implant for at least a month.

If it passes the test, Carmat has said it would fit the device into about 20 patients with less severe heart failure.

Extending life

“The doctors directly involved in the post-surgical care wish to highlight the value of the lessons learned from this first clinical trial, with regard to the selection of the patient, his surveillance, the prevention and treatment of difficulties encountered,” the hospital said in its statement.

An in-depth analysis of the medical and technical data gathered since the patient’s operation will be needed to establish the cause of his death, the hospital added.

Carmat estimates around 100,000 patients in the United States and Europe could benefit from its artificial heart, a market worth more than $12 billion.

Among Carmat’s competitors for artificial heart implants are privately-held SynCardia Systems and Abiomed, both of the United States.

SynCardia’s artificial heart is the only one approved both in the United States and the European Union and has been implanted in more than 1,200 patients to keep them waiting for a heart from a matching donor. The longest a patient has lived with the device is just under four years prior to a transplant.

Carmat’s heart is designed to serve not as a bridge to transplant but as a permanent implant, extending life for terminally ill patients who cannot hope for a real organ, generally because they are too old and donors too scarce.

Carmat’s shares, which have risen nearly five-fold since floating on the Paris stock market in 2010, closed at 95 euros before Monday’s news, giving the company a market capitalization of around 407 million euros

SOURCE

 

December 20, 2013 12:11 pm by 

healthy heartPARIS (Reuters) – France’s Carmat said on Friday it had carried out the first human implantation of its artificial heart.The operation, performed on Wednesday at the Georges Pompidou European Hospital in Paris, went smoothly, Carmat said in a statement, adding that the patient was being monitored in the intensive care unit but was awake and talking.(Reporting by Natalie Huet; editing by Mark John)

Read more: http://medcitynews.com/2013/12/first-artificial-heart-implanted-human/#ixzz2oLlFRyDG

An artificial heart from a French company is to be tested in patients in four countries.

ArtificialHeart

By ANNE EISENBERG
Published: July 13, 2013 – The New York Times, Novelties

SCIENTISTS have long searched for a durable artificial heart that can work as efficiently as the one supplied by nature.

Carmat

Cow tissue will be used on surfaces of membranes — represented by elliptical shapes in this rendering — that touch the blood.

Now Carmat, a company based in Paris, has designed an artificial heart fashioned in part from cow tissue. The device, soon to be tested in patients with heart failure, is regulated by sensors, software and microelectronics.  Its power will come from two external, wearable lithium-ion batteries.

Fifteen years in development, the heart has been approved for clinical trials at cardiac surgery centers in Belgium, Poland, Saudi Arabia and Slovenia, where staff members are receiving training and patients are being screened, said Dr. Piet Jansen, medical director at Carmat.

In France, where the device is not yet cleared for human implantation, regulators have requested more animal tests, Dr. Jansen said; those tests are continuing.

Artificial hearts aren’t new, of course, but the Carmat heart is unusual in its design, said Dr. Joseph Rogers, an associate professor at Duke University and medical director of its cardiac transplant and mechanical circulatory support program. Surfaces in the new heart that touch human blood are made from cow tissue instead of artificial materials like plastic that can cause problems like clotting.

“The way they’ve incorporated biological surfaces for any place that contacts blood is a really nice advantage,” Dr. Rogers said. “If they have this design right, this could be a game changer.” He added that it could lessen the need for anticoagulation medicines. (Dr. Rogers has no financial connections to Carmat.)

This is the first artificial heart to use cow-derived materials — specifically, tissue from the pericardial sac that surrounds the heart. Biological tissue has been used in earlier mechanical blood pumps only in valves, Dr. Rogers said.

Thousands of people in the United States need a replacement heart, said Dr. Lynne Warner Stevenson, a professor at Harvard Medical School and director of the cardiomyopathy and heart-failure program at Brigham and Women’s Hospital in Boston. “It’s estimated that if we had enough donor hearts to go around, 100,000 to 150,000 people in the United States with heart failure would benefit,” she said. “Transplants work best, but we have only 2,000 or so adult hearts” that are available each year, she said. “It’s a huge problem.”

There are long-established options for patients while they await transplants, Dr. Stevenson said, including installing an artificial heart made by SynCardia until a donor heart is available.

When the natural heart is partly damaged or diseased, patients might keep it and have a mechanical aid implanted to bolster blood flow. Such pumps — especially those that aid the left side of the heart (LVAD)— are in wide use both as a bridge to a transplant and for lifetime therapy.

A totally artificial heart for extended use would be of great value, but it’s far too early to know if the Carmat heart, as yet untried in humans, will be that device. “The whole history of mechanical devices is that people thought they had devices where blood wouldn’t clot. But they didn’t,” Dr. Stevenson said.

Dr. Jansen said that the cost of the Carmat heart would be about $200,000 and that he did not expect it to be brought to market in Europe before the end of 2014. Once the company gains momentum with its European clinical studies, he said, it plans to start working through the regulatory process in the United States.

The Carmat heart has two chambers, each divided by a membrane. That membrane has cow tissue on one side — the side that is in contact with blood — and polyurethane on the other side, which touches the miniaturized pumping system of motors and hydraulic fluids that changes the membrane’s shape. (The motion of the membrane pushes the blood out to the body.) The embedded electronics and software adjust the rate of blood flow. Patients can wear the batteries under the arm in a holster, or in a belt, among other options.

Cow tissue is also used for the heart’s artificial valves, which were created by Dr. Alain Carpentier, a cardiac surgeon and a pioneer of heart valve repair who is also a co-founder of Carmat and its scientific director. Such valves have been used in heart-valve replacement surgery for decades. The cow tissue is chemically treated so that it is sterile and biologically inert.

The heart’s design and development relied heavily on aerospace testing strategies by EADS, the European Aeronautic Defense and Space Company, one of Carmat’s backers, Dr. Jansen said. Even so, duplicating the durability of a human heart will not be easy, said Dr. Robert Kormos, director of the artificial heart program at the University of Pittsburgh Medical Center and co-director of its heart transplant program.

“We can test these pumps on the bench in the laboratory, and in animals, but there is no true long-term data until you implant them in people for trials,” he said.

DR. JANSEN said that one design requirement for the heart was that it last five years. The company has been doing bench tests to see whether the new heart will stand up to that level of wear and tear. “Whether it lasts five years in the patient we will have to prove clinically,” he said.

Dr. Stevenson of Harvard is optimistic about the new device.

“Innovation is what we need,” she said. “This new device is exciting. I applaud the pioneers who developed it, and the patients and families who will go down this path for the first time.”

A version of this article appeared in print on July 14, 2013, on page BU3 of the New York edition with the headline: The Artificial Heart Is Getting a Bovine Boost.

SOURCE
An American designed Artificial Heart by ABIOMED, the Symphony model, assists in remodeling of heart tissue cells by design, as described in

Mechanical Circulatory Assist Devices as a Bridge to Heart Transplantation or as “Destination Therapy“: Options for Patients in Advanced Heart Failure

By Larry H Bernstein, MD, FCAP

A total artificial heart (TAH) is a device that replaces the two ventricles of the heart. Those who benefit from a TAH usually have end-stage heart failure. Since the condition is so severe that the heart can’t pump enough blood to meet the body’s needs, all treatments, except heart transplant, have failed.

The TAH is attached the atria, and mechanical valves are between the TAH and the atria functioning like the heart’s valves, controlling the flow of blood in pulmonary and systemic circulation.

Currently, the two types of TAHs are the CardioWest and the AbioCor. The main difference between these TAHs is that the CardioWest is connected to an outside power source.  The CardioWest has tubes that, through holes in the abdomen, run from inside the chest to an outside power source.

CardioWest Total Artificial Heart

Figure A shows a CardioWest TAH. Tubes exit the body and connect to a machine that powers the TAH and controls how it works.

Cardiowest_TAHt_Photo

The AbioCor TAH is completely contained inside the chest. A battery powers this TAH, and the battery is charged through the skin with a special magnetic charger. Energy from the external charger reaches the internal battery through an energy transfer device called transcutaneous energy transmission, or TET. An implanted TET device is connected to the implanted battery. An external TET coil is connected to the external charger. Also, an implanted controller monitors and controls the pumping speed of the heart.

AbioCor Total Artificial Heart

Figure B shows an AbioCor TAH and the internal devices that control how it works.

Abiomed_AB5000

A TAH usually extends life for months beyond what is expected with end-stage heart failure. It can keep one alive while waiting for a donor heart.  It is a challenge for surgeons to implant, and it can cause complications.  TAHs are devices used only in a small number of people.

There is a Difference Between Artificial Heart & Ventricular Assist Device

(see Michael Paul Maupin, eHow Contributor)

http://www.ehow.com/facts_6713118_difference-_amp_-ventricular-assist-devices.html#ixzz2a5BH465n

A ventricular assist device (VAD) utilizes the patient’s own heart, and it operates as a bridge device until a donor heart is procured for transplant. A TAH replaces a patient’s explanted heart.  The VAD is grafted onto a patient’s left ventricle, boosting the impaired ventricular function.  A VAD is either continuous or pulsatile in function. In a continuous VAD, blood is circulated through the heart like water through a hose.  A pulsatile VAD more mimics the expulsion of blood in rhythmic patterns.

http://www.ehow.com/facts_6713118_difference-_amp_-ventricular-assist-devices.html#ixzz2a5Bcbszh

On the other hand, an artificial heart completely replaces the human heart. The device functions in every way a healthy human heart would in the absence of cardiac disease.  The TAH creates the same pattern of squeeze-and-release seen in a real heart.

http://www.ehow.com/facts_6713118_difference-_amp_-ventricular-assist-devices.html#ixzz2a5Bn6xaR

As of 2010, the longest any human being has lived with an artificial heart is 21 months. In comparison, documentation exists in which a VAD recipient was still enjoying a vigorous quality of life after seven years.

Read more: http://www.ehow.com/facts_6713118_difference-_amp_-ventricular-assist-devices.html#ixzz2a5C1cPFV

The SynCardia temporary Total Artificial Heart

(An artificial heart displayed at the London Science Museum)

200px-Artificial-heart-london

http://www.wikipedia.com/Artificial Heart

An artificial heart is a device is typically used to bridge the time to heart transplantation, or to permanently replace the heart in case heart transplantation is impossible. The first artificial heart to be successfully implanted in a human was the Jarvik-7, designed and implemented by Robert Jarvik in 1982, but the first two patients to receive these hearts survived 112 (4 m) and 620 (21 m) days beyond their surgeries, respectively.[1]

Jarvik-7

It has already been stated that a TAH is distinct from a VAD, both used to support a failing heart. It is also distinct from a cardiopulmonary bypass machine, which is an external device used to provide the functions of both the heart and lungs, and it is used for only a few hours during cardiac bypass surgery.

Origin and Development of the Heart-Lung Bypass

A synthetic replacement for the severely failing heart would be expected to lower the need for heart transplants, because the demand for organs always greatly exceeds supply.  However, the first devices had problems with reactivity to synthetic materials and power supplies. For example, the Jarvik models were not created of a material that the human body would accept. This problem was improved when Dayton, Ohio’s Ival O. Salyer, along with various colleagues, developed a polymer material that the human body would not necessarily reject.

Prior to Jarvik-7, 41-year-old Henry Opitek made medical history in 1952 at Harper Hospital, Wayne State University in Detroit, Michigan when Dr. Forest Dewey Dodrill used the Dodrill-GMR heart machine to bypass Henry Opitek’s left ventricle for 50 minutes while he repaired the mitral valve. [2][3]  In this case In Dr. Dodrill’s post-operative report, he notes, “To our knowledge, this is the first instance of survival of a patient when a mechanical heart mechanism was used to take over the complete body function of maintaining the blood supply of the body while the heart was open and operated on.”[4]  A heart-lung machine was used in 1953 during a successful open heart surgery by Dr. John Heysham Gibbon, the inventor, who  performed the operation with the heart-lung substitute (distinct from an artificial heart substitute).

Designs of total artificial hearts

A precursor to the modern artificial heart pump was built by doctors William Sewell and William Glenn of the Yale School of Medicine in 1949 using an assortment of parts, and successfully bypassed the heart of a dog for more than an hour.[5]

The first patent for an artificial heart was held by Paul Winchell invented and Dr. Henry Heimlich (of the Heimlich Maneuver), which preceded the Jarvik heart.  On December 12, 1957, Dr. Willem Johan Kolff, the world’s most prolific inventor of artificial organs, implanted an artificial heart into a dog at Cleveland Clinic before he relocated to Salt Lake City, Utah, where there was established an Institute for artificial organs.  There, more than 200 physicians, engineers, students and faculty at the University of Utah Division of Artificial Organs developed, tested and improved Dr. Kolff’s artificial heart. To help manage his many endeavors, Dr. Kolff assigned project managers. Each project was named after its manager. Graduate student Robert Jarvik was the project manager for the artificial heart, which was subsequently renamed the Jarvik 7.

In 1958, Domingo Liotta initiated the studies of TAH replacement at Lyon, France, and in 1959–60 at the National University of Córdoba, Argentina. He presented his work at the meeting of the American Society for Artificial Internal Organs held in Atlantic City in March 1961. At that meeting, Dr. Liotta described the implantation of three types of orthotopic (inside the pericardial sac) TAHs in dogs, each of which used a different source of external energy: an implantable electric motor, an implantable rotating pump with an external electric motor, and a pneumatic pump.[6][7]

In 1964, the National Institutes of Health started the Artificial Heart Program, with the goal of putting a man-made organ into a human by the end of the decade.[8]  The first success followed in February 1966, when Dr. Adrian Kantrowitz performed the world’s first permanent implantation of a partial mechanical heart (left ventricular assist device) at Maimonides Medical Center, Brooklyn, NY.[9]  He relocated to Detroit’s Sinai and Wayne Stae University.

In 1981, Dr. William DeVries submitted a request to the FDA to implant the Jarvik 7 into a human being. On December 2, 1982, Dr. Kolff implanted the Jarvik 7 artificial heart into Barney Clark, who was suffering from severe congestive heart failure. With Clark tethered to an external 400 lb pneumatic compressor, he suffered prolonged periods of confusion, a number of instances of bleeding, and asked several times to be allowed to die.[10]

Total Artificial Heart (TAH)

On April 4, 1969, Domingo Liotta and Denton A. Cooley replaced a dying man’s heart with a mechanical heart inside the chest at The Texas Heart Institute in Houston as a bridge for a transplant. The patient woke up and recovered well. After 64 hours, the pneumatic-powered artificial heart was removed and replaced by a donor heart. However thirty-two hours after transplantation, the patient died of what was later proved to be an acute pulmonary infection, extended to both lungs, caused by fungi, most likely caused by an immunosuppressive drug complication.[11]

The original prototype of Liotta-Cooley artificial heart used in this historic operation is prominently displayed in the Smithsonian Institution’s National Museum of American History “Treasures of American History” exhibit in Washington, D.C..[12]

Permanent Pneumatic Total Artificial Heart (TAH)

The eighty-fifth clinical use of an artificial heart designed for permanent implantation rather than a bridge to transplant occurred in 1982 at the University of Utah. Artificial kidney pioneer Dr. Willem Johan Kolff started the Utah artificial organs program in 1967.[13] There, physician-engineer Dr. Clifford Kwan-Gett invented two components of an integrated pneumatic artificial heart system: a ventricle with hemispherical diaphragms that did not crush red blood cells (a problem with previous artificial hearts) and an external heart driver that inherently regulated blood flow without needing complex control systems.[14]   Dr. Robert Jarvik combined several modifications of the original: an ovoid shape to fit inside the human chest, a more blood-compatible polyurethane developed by biomedical engineer Dr. Donald Lyman, and a fabrication method by Kwan-Gett that made the inside of the ventricles smooth and seamless to reduce dangerous stroke-causing blood clots.[16]

Today, the modern version of the Jarvik 7 is known as the SynCardia temporary CardioWest Total Artificial Heart. It has been implanted in more than 800 people as a bridge to transplantation.

Artificial Heart   Cardiowest TAH-t (improvement of Jarvik-7)

In the mid-1980s, artificial hearts were powered by dishwasher-sized pneumatic power sources whose lineage went back to Alpha-Laval milking machines and required two catheters to cross the abdominal wall to carry the pneumatic pulses to the implanted heart. The National Heart, Lung, and Blood Institute opened a competition for implantable electrically powered artificial hearts funding  Cleveland Clinic in Cleveland, Ohio; the College of Medicine of Pennsylvania State University (Penn State Hershey Medical Center) in Hershey, Pennsylvania; and AbioMed, Inc. of Danvers, Massachusetts.

Abiomed_AB5000

Polymeric trileaflet valves ensure unidirectional blood flow with a low pressure gradient and good longevity. State-of-the-art transcutaneous energy transfer eliminates the need for electric wires crossing the chest wall.

AbioCor

The first AbioCor to be surgically implanted in a patient was on July 3, 2001.[17] The AbioCor is made of titanium and plastic with a weight of two pounds, and its internal battery can be recharged with a transduction device that sends power through the skin.[17] The internal battery lasts for a half hour, and a wearable external battery pack lasts for four hours.[18] The FDA announced on September 5, 2006, that the AbioCor, intended for critically ill patients who can not receive a heart transplant[19]  could be implanted after the device had been tested on 15 patients.[19]  But limitations of the current AbioCor are that its size makes it suitable for only about 50% of the male population, and its useful life is only 1–2 years.[20]  AbioMed designed a smaller, more stable heart, the AbioCor II, by combining its valved ventricles with the control technology and roller screw developed at Penn State. This pump, which should be implantable in most men and 50% of women with a life span of up to five years,[20] had animal trials in 2005, and the company hoped to get FDA approval for human use in 2008.[21]

Intrathoracic Pump (LVAD)

On July 19, 1963, E. Stanley Crawford and Domingo Liotta implanted the first clinical Left Ventricular Assist Device (LVAD) at The Methodist Hospital in Houston, Texas, in a patient who had a cardiac arrest after surgery. The patient survived for four days under mechanical support but did not recover from the complications of the cardiac arrest.

On April 21, 1966, Michael DeBakey and Liotta implanted the first clinical LVAD in a paracorporeal position (where the external pump rests at the side of the patient) at The Methodist Hospital in Houston, in a patient experiencing cardiogenic shock after heart surgery. The patient developed neurological and pulmonary complications and died after few days of mechanical support. In October 1966, DeBakey and Liotta implanted the paracorporeal Liotta-DeBakey LVAD in a new patient who recovered well and was discharged from the hospital after 10 days, marking the first successful use of an LVAD for postcardiotomy shock.

Recent developments

In June 1996, a 46-year-old Taiwanese American Mr. Yao ST received the world’s first total artificial heart implantation done by Dr. Jeng Wei at Cheng-Hsin General Hospital[26] in the Republic of China (Taiwan). This technologically advanced pneumatic Phoenix-7 Total Artificial Heart was manufactured by a Taiwanese dentist Kelvin K. Cheng, a Chinese physican T. M. Kao and colleagues at the Taiwan TAH Research Center in Tainan, Republic of China (Taiwan). With this experimental artificial heart, the patient’s BP was maintained at 90-100/40-55 mmHg and cardiac output at 4.2-5.8 L/min. After 15 days of bridging, Mr. Yao received combined heart and kidney transplantation. As of March 2013, he is still very well and is currently living in San Francisco, USA. Mr. Yao ST is the world first successful combined heart and kidney transplantation patient after bridging with total artificial heart.[27]

In August 2006, an artificial heart was implanted into a 15-year-old girl at the Stollery Children’s Hospital in Edmonton, Alberta. It was intended to act as a temporary fixture until a donor heart could be found. Instead, the artificial heart (called a Berlin Heart) allowed for natural processes to occur and her heart healed on its own. After 146 days, the Berlin Heart was removed, and the girl’s heart was able to function properly on its own.[22]

On December 16, 2011 the Berlin Heart, a ventricular assist intended for children age 16 and under, gained U.S. FDA approval. The device has since been successfully implanted in several children including a 4-year-old Honduran girl at Children’s Hospital Boston.[23]

In 2012, a study published in the New England Journal of Medicine compared the Berlin Heart to extracorporeal membrane oxygenation (ECMO) and concluded that “a ventricular assist device available in several sizes for use in children as a bridge to heart transplantation [such as the Berlin Heart] was associated with a significantly higher rate of survival as compared with ECMO.”[24] The study’s primary author, Dr. Charles D. Fraser, Jr., surgeon in chief at Texas Children’s Hospital, explained: “With the Berlin Heart, we have a more effective therapy to offer patients earlier in the management of their heart failure. ..This is a giant step forward.” [25]

Total artificial heart (TAH) invention abroad

On October 27, 2008, French professor and leading heart transplant specialist Alain F. Carpentier announced that a fully implantable artificial heart will be ready for clinical trial by 2011 and for alternative transplant in 2013. It was developed and will be manufactured by him, biomedical firm CARMAT SA, and venture capital firm Truffle Capital. The prototype uses embedded electronic sensors and is made from chemically treated animal tissues, called “biomaterials”, or a “pseudo-skin” of biosynthetic, microporous materials.[28] According to an interview of the professor Alain Carpentier in Paris (2011), a number of leading cardiac clinics already conducted successful partial replacement of the organic components of the artificial heart, for example, replacing valves, large vessels, atria, ventricles. In addition to cardio-surgery, there is the medico-psychological aspect of an artificial heart. A quarter of patients in the postoperative period after prosthetic valvular surgery developed specific psychopathological symptoms, which later received the name Skumin syndrome in 1978. It is possible that a similar problem will be discovered when conducting large-scale operations to implant an artificial heart.[29]

Another U.S. team with a prototype called 2005 MagScrew Total Artificial Heart, including Japan and South Korea researchers are racing to produce similar projects.[30][31][32]

In August 2010, 50-year-old Angelo Tigano of Fairfield, New South Wales, Australia, had his failing heart removed in a five-hour operation and it was replaced with the SynCardia temporary Total Artificial Heart by surgeon Dr Phillip Spratt, head of the heart transplant unit at St Vincent’s Hospital, Sydney.[33]

On 12 March 2011, an experimental artificial heart was implanted in 55-year-old Craig Lewis at The Texas Heart Institute in Houston by Drs. O. H. Frazier and William Cohn. The device is a combination of two modified HeartMate II pumps that is currently undergoing bovine trials.[34]

On 9 June 2011, 40 year old Matthew Green was implanted with the SynCardia temporary Total Artificial Heart in a seven hour operation at Papworth Hospital. He was the first Briton to leave hospital supported by an artificial Heart on 2 August 2011.[35]

A centrifugal pump[36][37] or an axial-flow pump[38][39] can be used as an artificial heart, resulting in the patient being alive without a pulse.

Imachi et al. described a centrifugal artificial heart which alternately pumps the pulmonary circulation and the systemic circulation, causing a pulse.[40]

Heart Assist Devices

Patients who have some remaining heart function but who can no longer live normally may be candidates for ventricular assist devices (VAD), which do not replace the human heart but complement it by taking up much of the function.

The first Left Ventricular Assist Device (LVAD) system was created by Domingo Liotta at Baylor College of Medicine in Houston in 1962.[41]

Another VAD, the Kantrowitz CardioVad, designed by Adrian Kantrowitz boosts the native heart by taking up over 50% of its function.[42] Additionally, the VAD can help patients on the wait list for a heart transplant. In a young person, this device could delay the need for a transplant by 10–15 years, or even allow the heart to recover, in which case the VAD can be removed.[42] The artificial heart is powered by a battery that needs to be changed several times while still working.

The first heart assist device was approved by the FDA in 1994, and two more received approval in 1998.[43] While the original assist devices emulated the pulsating heart, newer versions, such as the Heartmate II,[44] developed by The Texas Heart Institute of Houston, provide continuous flow. These pumps (which may be centrifugal or axial flow) are smaller and potentially more durable and last longer than the current generation of total heart replacement pumps. A major advantage of a VAD is that the patient keeps the natural heart, which may provide enough support to keep the patient alive until a solution to the problem is implemented.

Impella 2.5 cardiac assist device in LV

Suffering from end-stage heart failure, former Vice President Dick Cheney underwent a procedure in July 2010 to have a VAD implanted at INOVA Fairfax Hospital, in Fairfax Virginia. In 2012, he received a heart transplant at age 71 after 20 months on a waiting list.

REFERENCES

1^ American Heart Association. The Mechanical Heart celebrates 50 lifesaving years. 22 10 2002. 9 Feb 2008 <http://www.americanheart.org/presenter.jhtml;jsessionid=EFNP3NSFUBXLICQFCXQCDSQ?identifier=3005888>

2^ Stephenson, Larry W, et al. “The Michigan Heart: The World’s First Successful Open Heart Operation?” Journal of Cardiac Surgery 17.3 (2002): 238–246.

3^ Lavietes, Stuart. William Glenn, 88, Surgeon Who Invented Heart Procedure, The New York Times, March 17, 2003. Accessed May 21, 2009.

4^ Artificial Heart in the chest: Preliminary report. Trans. Amer. Soc. Inter. Organs, 1961, 7:318

5^ Ablation experimentale et replacement du coeur par un coer artificial intra-thoracique. Lyon Cirurgical, 1961, 57:704

6^ Sandeep Jauhar, M.D., Ph.D.: The Artificial Heart. New England Journal of Medicine (2004): 542–544.

7^ http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2676518/, NCBI In Memoriam Dr. Adrian Kantrowitz

8^ Barron H. Lerner, MD, PhD (December 1, 2007). “The 25th Anniversary of Barney Clark’s Artificial Heart”. Celebrity Health. HealthDiaries.com. Retrieved 15 November 2010.

9^ Orthotopic cardiac prosthesis for two-staged cardiac replacement. Am J Cardio 1969; 24:723–730.

10^ “Treasures of American History”, National Museum of American History

11^ Spare Parts: Organ Replacement in American Society. Renee C. Fox and Judith P. Swazey. New York: Oxford University Press; 1992, pp. 102–104

12^ Kwan-Gett CS, Van Kampen KR, Kawai J, Eastwood N, Kolff WJ. “Results of total artificial heart implantation in calves.” Journal of Thoracic and Cardiovascular Surgery. 1971 Dec; 62(6):880–889.

13^ “Winchell’s Heart”. Time. March 12, 1973. Retrieved April 25, 2010.

14^ Kolff

15^ a b “Patient gets first totally implanted artificial heart”. CNN.com. 2001-07-03. Archived from the original on 7 June 2008. Retrieved 2008-07-13.

16^ “AbioCor FAQs”. AbioMed. Archived from the original on 3 July 2008. Retrieved 2008-07-13.

17^ a b “FDA Approves First Totally Implanted Permanent Artificial Heart for Humanitarian Uses”. FDA.gov. 2006-09-05. Retrieved 2008-07-13.

18^ a b “Will We Merge With Machines?”. popsci.com. 2005-08-01. Archived from the original on 19 July 2008. Retrieved 2008-07-13.

19^ “14th Artificial Heart Patient Dies: A Newsmaker Interview With Robert Kung, PhD”. medscape.com. 2004-11-11. Retrieved 2008-07-13.

20^ Capital Health: One year later: Berlin Heart bridges patient back to health (August 28, 2007), Capital Health, Edmonton (archived from [1] the original) on 2007-10-01).

21^ approved Berlin Heart helps patients waiting for a transplant (December 30, 2011), Children’s Hospital Boston.

22^ http://www.nejm.org/doi/pdf/10.1056/NEJMoa1014164

23^ http://www.texaschildrens.org/About-Us/News/Berlin-Heart-NEJM-2012/

24^ Cheng-Hsin General Hospital

25^ J. Wei, K. K. Cheng, D. Y. Tung, C. Y. Chang, W. M. Wan, Y. C. Chuang: Successful Use of Phoenix-7 Total Artificial Heart. Transplantation Proceedings, 1998, 30:3403-4

26^ The Carmat Heart,- The technology behind the prosthesis

27^ “About artificial heart”. Heart For Your Soul. Retrieved 2011-02-19.

28^ Total artificial heart to be ready by 2011: research team, news.yahoo.com

29^ Scientists develop artificial heart that beats like the real thing, timesonline.co.uk

30-^ Total artificial heart to be ready by 2011: research team, afp.google.com

31^ Sydney man receives Total Artificial Heart, dailyTelegraph.com.au

32^ Berger, Eric. “New artificial heart ‘a leap forward'”. Houston Chronicle. Retrieved 23 March 2011.

33^ “Plastic heart gives dad Matthew Green new lease of life”. BBC News. August 2, 2011.

34^ Black, Rosemary (January 5, 2011). “Former vice president Dick Cheney now has no pulse”. Daily News (New York).

35^ http://www.scribd.com/doc/21241693/Pulseless-Pumps-Artificial-Hearts

36^ The pulseless life

37^ Dan Baum: No Pulse: How Doctors Reinvented The Human Heart. 2012-02-29.

38^ ‘#A new pulsatile total artificial heart using a single centrifugal pump., K. Imachi, T. Chinzei, Y. Abe, K. Mabuchi, K. Imanishi, T. Yonezawa, A. Kouno, T. Ono, K. Atsumi, T. Isoyama, et al.. Institute of Medical Electronics, Faculty of Medicine, University of Tokyo, Japan.

39^ Prolonged Assisted circulation after cardiac or aortic surgery. Prolonged partial left ventricular bypass by means of intracorporeal circulation. This paper was finalist in The Young Investigators Award Contest of the American College of Cardiology. Denver, May 1962 Am. J. Cardiol. 1963, 12:399–404

40^ a b Mitka, Mike. “Midwest Trials of Heart-Assist Device.” Journal of the American Medical Association 286.21 (2001): 2661.

41^ FDA APPROVES TWO PORTABLE HEART-ASSIST DEVICES at FDA.gov

42^ An Artificial Heart That Doesn’t Beat at TechnologyReview.com

How does an artificial heart work?

The development and operation of these life-saving devices requires understanding and application of a combination of biology, materials science and physics.
Institute of Physics website  http://www.physics.org/article-questions.asp?id=74

The artficial heart

Image: Syncardia Systems

The right atrium collects blood and the right ventricle then pumps it to the lungs where it is oxygenated. The blood is then picked up by the left atrium and distributed around the body and brain by the left ventricle. Each side of the heart has a pair of valves – one pair per lung – controlling the flow of blood.

Artificial hearts can now completely, if temporarily, replace the ventricles and valves with a device made of plastic or other man-made materials, which does the job of pumping blood around.

The type of artificial heart made by Syncardia Systems, works by using a pump carried externally in a backpack – previously, patients would have to be connected to a large, immobile pump and would not have the freedom to move around.

Cardiowest_TAHt_Photo

The NHS Choices website explains that tubes connecting the heart to the pump “send pulses of air into two expandable, balloon-like sacs in the artificial ventricles, forcing out blood in much the same way that a beating heart would”.

Other models such as that produced by AbioMed use an internal pump and battery, which can be charged via transcutaneous energy transmission – a method of transferring power under the skin without having to penetrate it, thereby decreasing the chance of infection.

Energy transmission

In the artificial hearts produced by AbioMed, an electronics package is implanted in the abdomen of the recipient of the transplant to monitor and control the pumping of the heart.

Power is supplied from an external source to components under the skin, without penetrating it, using inductive electromagnetic coupling – the same principle as used by transformers to transfer electricity between different circuits, as in the national grid.

At their simplest, systems of transcutaneous energy transmission will use an external power supply connected to an external coil of wire, generating a magnetic field in it. This, in turn, produces an induced voltage in a second coil implanted under the skin, and a rectifier is used to change this alternating current into direct current that can be used to power the electronics of the heart and its controller.

Though simple in theory, in practice there are complications that arise from the need to keep the two coils aligned correctly as the patient moves, in delivering the correct level of power so that there is no excess dissipated as heat to potentially damage surrounding tissue in the patient’s body, and in making the components small enough to be carried around without too much discomfort.

Monitoring blood flow

A replacement heart needs to be able to monitor the flow of blood to regulate its pumping and ensure that the correct amount of blood is delivered around the body.

Quicker pumping is required when the transplant recipient is more active, whereas the opposite is true while he or she is resting.

Blood-flow monitors make use of ultrasound – they bounce high-frequency sound waves off blood cells coming out of the heart, the volume and speed can be measured using similar basic principles to those behind radar.

Ultrasound is used because it can monitor the flow of blood without having to be in contact with it.

Appropriate materials

Artificial hearts need to be made of light but durable materials – the Syncardia version is plastic whereas that made by AbioMed is a combination of titanium and a specially developed polyurethane, called ‘Angioflex’.

Although the Abiomed heart is designed to have as few moving parts as possible, those that it does have are made from Angioflex and are tested to ensure that they are safe for contact with blood and capable of withstanding beating 100 000 times a day for years on end.

Materials scientists can develop substances with specific properties by manipulating the constituent elements and the way in which they are processed. Materials are characterised using various techniques from condensed-matter physics including electron microscopy, x-ray diffraction and neutron diffraction.

Because they were still quite large, the first devices produced were limited to around half the male population – those with the largest chest cavities. A newer, smaller, model is intended to extend their availability to smaller people.

An artificial heart being produced by the French medical company Carmat and expected to be available by 2013 will use chemically treated animal tissue to help avoid rejection by the host’s immune system. Aerospace engineers from Airbus were also involved in its development.

Artificial hearts combine, and improve upon, many existing physics ideas to produce a piece of technology that saves lives – although they are currently only approved as a stopgap until a donor heart can be found.

Expressions of Experience: Heart Assist Devices

Video interview with O. H. “Bud” Frazier, MD; Chief, Center for Cardiac Support; Director, Cardiovascular Surgery Research; and Co-Director, Cullen Cardiovascular Research Laboratories, at Texas Heart Institute.

 O. H. “Bud” Frazier, MD, on his inspiration for developing treatments for heart failure at the Texas Heart Institute.

The Texas Heart Institute is a world leader in the development, testing and application of heart assist devices. Our goal for the surgical research conducted here is to develop and determine the best assist device to use for each individual patient. Devices may be referred to as mechanical assist devices, ventricular assist devices (VAD), left ventricular assist devices (LVAD), total artificial hearts (TAH), or simply heart pumps.

January 23, 2013

Keeping hearts pumping   Dr. Bud Frazier and Dr. Billy Cohn with heart pump BiVacor. [Photo credit Mayra Beltran, Houston Chronicle]

Doctors push the limits of heart-pump technology in an effort to save lives. Dr. Bud Frazier often tells a story about when he was a medical student in the 1960s . . . Frazier had this thought: If I can keep a man alive with my hand, why can’t we make a pump that we can pull off of the shelf to do the same thing? Dr. Billy Cohn, another physician who works at the cutting edge of heart pump technology, likes to use the history of human flight as an analogy for the evolution in his field. Experimenters in both domains had to give up the idea of bio-mimicry to advance the technology. “It is similar to when man first tried to build a flying machine with flapping wings that mimic the birds. It is obvious now that fixed wings were the way to go,” he says. “We think it is the same with the nonpulsatile pump, which, because it has only one moving part, is much more durable.” – Houston Chronicle [Photo credit Mayra Beltran]

January 13, 2013

BiVACOR artificial heart device

Australian engineer Daniel Timm’s revolutionary device to be developed at THI. “I think we’re beyond the Kitty Hawk stage with this,” – Drs. Bud Frazier and Billy Cohn. Read Eric Berger’s Houston Chronicle article.

November 20, 2012

FDA Approves HeartWare LVAD for HF

The FDA gave the green light for the HeartWare Ventricular Assist System as a bridge to heart transplantation in patients with heart failure. “The miniaturized device with an integrated inflow cannula is placed within the pericardial sac . . . simplifying the surgical insertion,” said O.H. “Bud” Frazier, MD, of Texas Heart Institute. Read the full story from medpagetoday.com.

Drs. Bud Frazier & Billy Cohn TEDMED 2012

Is this the future of artificial hearts?

At TEDMED 2012, Bud Frazier and Billy Cohn of the Texas Heart Institute preview a continuous-flow heart pump with minimal parts that works via a screw pump. Watch the VIDEO.

Cameron Engineers, THI researchers collaborate on heart pump

Engineers and scientists at Cameron Manufacturing & Engineering have worked with THI researchers in developing a new heart pump. On March 1, 2012, Cameron donated $500,000 to Texas Heart Institute at St. Luke’s Episcopal Hospital to develop a prototype heart pump which could save countless lives.

Can Tiny Heart Pump Limit Heart Muscle Damage after STEMI?

Interventional cardiologists affiliated with THI at St. Luke’s recently implanted the first two patients in the nation with a tiny heart pump in a feasibility trial to determine the pump’s potential to limit damage to heart muscle following a STEMI (ST-elevation myocardial infarction). Read the full news release to learn about the FDA-approved trial and the first enrolled patients. (November 2011)

Miniature Heart Pump: Smaller May Be Better!

Dr. William “Billy” Cohn discusses recent advances in left ventricular assist devices (LVADs) and other mechanical circulatory blood pumps as they get smaller and more adaptable to individual patients. View the video of his presentation at the Pumps & Pipes Conference (15 minutes, December 2010).

Video: Artificial hearts giving hope, saving lives. (August 19, 2011)

imeplla-LD-video

Companion 2 and Freedom Drivers

C2 Driver Supports Total Artificial Heart Patients in the Hospital Until They Are Stable and Eligible for the Freedom® Portable Driver

The Companion 2 Driver, which can be docked in the Hospital Cart or Caddy, powers the SynCardia Total Artificial Heart from implant until the patient’s condition stabilizes. Once stable, patients who are eligible can be switched to the smaller, wearable Freedom® portable driver. The Companion 2 Driver, which can be docked in the Hospital Cart or Caddy, powers the SynCardia Total Artificial Heart from implant until the patient’s condition stabilizes. Once stable, patients who are eligible can be switched to the smaller, wearable Freedom® portable driver.

The Companion 2 (C2) Driver System, which powers the SynCardia temporary Total Artificial Heart in the hospital, was selected as the Silver Winner in the Critical-Care and Emergency Medicine Products category of the Medical Design Excellence Awards (MDEA) held on June 19 in Philadelphia.

“It is a tremendous honor to have one of our products selected as a winner for the second consecutive year,” said Michael Garippa, SynCardia Chairman/CEO/President. “Our Freedom® portable driver, the world’s first wearable power supply for the Total Artificial Heart, was selected as the Bronze Winner in the same category last year. These drivers support Total Artificial Heart patients from implant with the C2 through discharge with the Freedom.”

Once stable, patients who are eligible can be switched to the 13.5-pound Freedom portable driver. Patients who meet discharge criteria can then leave the hospital and wait for a matching donor heart at home and in their communities.

The Medical Design Excellence Awards are the industry’s premier design awards competition and is the only awards program exclusively recognizing contributions and advances in the design of medical products. Entries were evaluated on the basis of their design and engineering features, including innovative use of materials, user-related functions that improve healthcare delivery and change traditional medical attitudes or practices, features that provide enhanced benefits to the patient, and the ability to overcome design and engineering challenges to meet clinical objectives.

About the SynCardia temporary Total Artificial Heart

The SynCardia Total Artificial Heart is currently approved as a bridge to transplant for people suffering from end-stage heart failure affecting both sides of the heart (biventricular failure). There have been more than 1,200 implants of the Total Artificial Heart, accounting for more than 315 patient years of life on the device. It is the only device that eliminates the symptoms and source of end-stage biventricular failure. The TAH provides immediate, safe blood flow of up to 9.5 liters per minute through each ventricle. This high volume of blood flow helps speed the recovery of vital organs, helping make the patient a better transplant candidate.

Artificial Heart Devices used at Barnes-Jewish Hospital Washington University, St. Louis

The cardiac surgeons at the Barnes-Jewish & Washington University Heart & Vascular Center are one of the leading heart surgery teams in the nation. Our permanent and temporary artificial heart devices can dramatically improve symptoms of late-stage heart failure, and sometimes even provide long-term treatment.

Mechanical Circulatory Support

The field of mechanical circulatory support in the management of patients with heart failure has seen significant advances over the past few years.  The heart failure program at Washington University and Barnes-Jewish Hospital utilizes the latest technology for both temporary and long-term mechanical support of the heart failure patient.

Temporary Support

Patients that experience severe symptoms of heart failure that cannot be stabilized with medical therapy may require a temporary support device. These implantable devices are usually placed in a cardiac catheterization lab by interventional cardiologists and/or cardiac surgeons. Temporary support devices typically serve to stabilize the patient until long-term mechanical support can be introduced. These devices include:

  • intra-aortic balloon pump
  • Impella 2.5, 4.0 and 5.0
  • TandemHeart
  • Thoratec CentriMag

Long-Term Mechanical Support

Patients may require long-term circulatory support either as a bridge to a heart transplant (bridge-to-transplant, or BTT) or as long-term treatment of heart failure in non-transplant candidates (destination therapy, or DT).  The mechanical assist device program at Barnes-Jewish & Washington University Heart & Vascular Center is one of the largest programs in the country. The program has a multidisciplinary group of dedicated specialists to ensure excellent outcomes in this patient population. Currently available devices include both left ventricular assist devices (LVAD) and the total artificial heart:

  • HeartMate II
  • HeartWare HVAD
  • Syncardia Total Artificial Heart 

The cardiac surgeons at the Barnes-Jewish & Washington University Heart & Vascular Center are one of only 13 surgical teams in the country to implant the CardioWest™ temporary Total Artificial Heart (TAH-t) as a bridge-to-transplantation in specific heart transplant candidates.

The CardioWest™ TAH-t is an improved version of the Jarvik-7 Artificial Heart, which was first implanted in 1982. This unique technology allows us to treat patients who would not survive without full circulatory support.  The CardioWest™ TAH-t completely replaces the patient’s diseased heart with a goal of restoring normal blood pressure, increasing cardiac output and giving organs such as the kidney and liver a chance to recover. As a result, patients become better candidates for transplantation.  The program is currently involved in testing the Freedom portable driver which will allow patients to leave the hospital following implantation of the TAH.

cardiowest_tah

An American designed Artificial Heart by ABIOMED, the Symphony model, assists in remodeling of heart tissue cells by design, as described in

Impella_Thumb_small  5.0 for heart failure

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device:Abiomed’s Symphony

Table IABT vs Impella

SOURCE

Heart Remodeling by Design – Implantable Synchronized Cardiac Assist Device:Abiomed’s Symphony

Part  II  

Comparison of the Cardiac Operations involved in an Organ Transplant of a Donor’s Heart vs Implantation of an Artificial Heart

By Justin D Pearlman, MD, PhD, FACC 

A heart donor is a patient deemed brain dead who had forethought (a designation on the driver’s license) or a designated decision-maker (Healthcare Proxy) elected to make the heart available to help save another person’s life. Every tissue in the body has proteins that render a unique signature or “smell” and every patient has a limited set of markers it will accept without a fight (the histocompatibility complex, and in particular, the human leukocyte antigen).  The immune system is a major part of the body’s defenses against infection and abnormal tissues (cancer) which consists of cells trained to attack foreign protein chemistry and/or mark it for destruction with anti-bodies.

I. Heart Transplant of a Human Donor

The steps for heart transplant include:

(1) demonstration of need,

(2) identification of suitable donors,

(3) surviving while waiting for a suitable donor,

(4) surviving the removal of the damaged heart or heart and lungs to make room for the replacement (accomplished with a bypass pump),

(5) survival of the donor heart (or heart and lungs) pending preparation of the patient for receipt of the transplant,

(6) inserting the donor heart (or heart and lungs),

(7) taking the patient off the bypass pump and directing circulation through the transplant,

(8) recovery and healing,

(9) establishing and maintaining sufficient immune suppression to avoid rejection of the transplant,

(10) monitoring for functional losses or rejection.

(11) monitoring for cancer or infection,

(12) resuming enjoyment of life. Each year in the United states 800 patients die waiting for a transplant, while 2300 receive transplants.

The first heart transplant is credited to Vladimer Demikhov when he transplanted dog hearts in 1946; Dr. Shumway reported successful transplantation of the heart in 1966, and Dr. Christiaan Barnard performed the operation successfully on humans in 1967 (that patient lived 18 days). Replacing the heart with a donor heart is called orthotopic (true location) heart transplantation.  Durability of a transplant improved markedly with the approval of the immune suppression medication ciclosporineNOVA has created a shockwave video demonstrating the heart transplant operation: view video.

The actual transplantation requires only five or six lines of sutures (stitches):

  • inferior and superior vena cava (venous input to the right ventricle),
  • the main (or left and right) pulmonary arteries (delivery of blood from right ventricle to the lungs),
  • the upper half of the original left atrium to route the 3-5 pulmonary veins to the left ventricle (return of blood from the lungs), and the
  • aorta (to route blood from the left ventricle to the brain and body).

The donor heart harvesting typically includes a segment of the superior and inferior vena cava which feed

  • the right atrium,
  • the four pulmonary veins which feed the left atrium, and
  • a portion of the pulmonary artery, and
  • the aorta.

The heart is chilled to minimized its metabolic demands while it is disconnected and transferred.

The recipient heart explantation (removal of the bad heart) after the patient is supported by a bypass pump involves:

  • cannulation (tubing placement) into the aorta,
  • the superior vena cava and
  • the inferior vena cava, then
  • explantation leaving the posterior aspect of the left atrium and the posterolateral aspect of the right atrium in the recipient patient.

The left and right pulmonary veins of the donor are divided and the veins are threaded into the retained portion of the recipient left atrium. The inferor vena cava, superior vena cava, pulmonary artery, and aorta are respectively anastomosed (sewed onto the truncated portion of the corresponding native vessels end-to-end). Clots and air are flushed out and the patient is taken off bypass pump.

II. Artificial Heart:  Implant of an Assist Device

Implantation of ventricular assist device or an artificial heart is easier than a heart transplant, but it has been challenging to match nature’s ability to place the pump and keep it powered and regulated. Also durability is a major issue. The most common ventricular assist device, the intra-aortic balloon pump, is a temporizing tool to sustain a patient for just a few days while alternatives are evaluated and pursued.The steps for implanting a ventricular assist pump can be as simple as:

(1) cleaning and applying antiseptics to the skin,

(2) placing a needle in the femoral artery at the groin area,

(3) threading a wire into the artery,

(4) threading a series of hollow tubes over the wire (dilators) and leaving the largest in place (introducer),

(5) threading a catheter-pump  through the introducer and up the aorta to the desired location,

(6) synchronizing the pump the the cardiac cycle by electrocardiogram.

If the device is an intra-aortic balloon pump (IABP) then the device is advanced to the aortic arch so that an inflatable balloon expands and contracts within the aorta from the aortic arch down to just above the renal arteries. The IABP is designed to deflate when the heart contracts (systole), to make space for blood ejecting from the failing heart (afterload reduction), then inflate when the heart relaxes (diastole), effectively converting a blood pressure of 120/80 to 80/120. The coronary arteries are stressed during systole and receive their blood supply during diastole, so the diastolic augmentation (inflation of the balloon during heart relaxation) markedly improves blood delivery to the coronary arteries, which is very helpful when the coronary arteries are diseased and not well suited for immediate repair. The actions of the balloon damage blood cells and can rupture the aorta. The blood cell damage activates clotting, so full anticoagulation is required.
If the device is an Impella catheter pump, then the distal end (farthest into the patient) crosses the aortic valve into the left ventricle to draw blood from there and deliver it beyond the heart in the descending aorta.
 The ins and outs of the IABP. Shows diastole and systole. The IABP rapidly shuttles helium gas in and out of the balloon, which is located in the descending aorta. The balloon is inflated at the onsetImpellaIABP  www.fda.gov/MedicalDevices/Safety                           Impella  www.abiomed.com

Devices draw their input from

  • arterial blood (aorta or femoral artery)
  • venous blood (vena cava), or
  • a puncture wound created in the apex of the left ventricle of the heart

The next example of a ventricular assist device to consider during open heart surgery, is the bypass pump that is used during most cardiovascular surgeries, and in particular during heart or heart-lung transplant. The bypass pump relies on a tube (cannula) placed in a large source of deoxygenated blood

  • the right atrium,
  • the inferior vena cava or
  • the femoral vein

to draw its input blood from there (diverting it from the heart), and a second cannula placed in a large artery (the aorta or the femoral artery) for output. The blood passes out of the patient (extra-corporeal) to a very large mechanical pump, that typically consists of compressible tubing and rollers to minimize trauma to the blood, passing the red cells of the blood by membranes that enable uptake of oxygen. Despite the attempts not to damage the blood, blood does get damaged, so full anti-coagulation is required. The anti-coagulation consists of intravenous heparin to bind the coagulation factors. When the patient comes off the pump, the heparinization of the blood is counteracted by intravenous protamine sulfate. Also the blood is cooled because low temperatures slow down metabolism and make the cells of the body less needy during the sub-optimal circulation support. Cooled blood has increased viscosity, offset by dilution of the blood with saline (Normal Saline, isotonic solution,  w/v of NaCl, about 300 mOsm/L or 9.0 g per liter). As the pump takes over circulation, the blood supply to the heart is clamped off (cross-clamp), at which point the surgeon can work to repair the heart (valve repair, valve replacement, aorta graft, coronary grafts) or replace the heart or heart and lungs.

Artificial hearts are extensions of the concepts above, and differ primarily in

  • how the pump in energized and
  • how the pump is regulated.

An artificial heart is designed for long term use so it must be more gentle on the blood. In Part I: Alternative Models of Artificial Hearts, US and Europe, in this article, we reported on the Latest Innovations in Alternative Models of Artificial Hearts, the Carmat Heart, it is unusual in its design, said Dr. Joseph Rogers, an associate professor at Duke University and medical director of its cardiac transplant and mechanical circulatory support program. Surfaces in the new heart that touch human blood are made from cow tissue instead of artificial materials like plastic that can cause problems like clotting, it will decrease the anticoagulation dependence by design.

Artificial hearts  must accommodate changes in demands of the body, not just in the chilled low metabolic state imposed by cardiovascular surgeons. The demands of the heart are measured by oxygen consumption in units of metabolic equivalents (METS) where 1 MET represents basal metabolism (awake at rest). MET values of activities range from 0.9 (sleeping) to 23 or more (running at 14 miles/hour = 22.5 km/hour). Thus, the artificial heart should be capable of increasing its output 2300% without damage the blood cells or running out of power. The goal of long term use generally is met by linking to an external power supply that is considered portable (on wheels), or in some cases, wearable

In contrast to Transplant of a human donor’s heart, described above, we present below the procedure for implantation of:

  • Left Ventricular Assist Device (LVAD)
  • Right Ventricular Assist Device (RVAD)
  • Bi-Ventricular Assist Device (BiVAD)
  • Total artificial heart
Heartmate II (Thoratec, Pleasanton, CA). HeartHeartmate II (Thoratec, Pleasanton, CA).  http://thenatureofhiking.com/heartless-man.html#.UiPybNKsh8E
A left ventricular assist device has two aims:
(1) reduce the work on an ailing heart and
(2) boost the forward circulation to the brain and other vital organs.
Those goals require access to the aorta and/or the left ventricle. Most LVAD devices use the apex of the left ventricle (LV) to draw blood into the pump and they deliver the blood to the aorta (for example, Heartmate II (Thoratec, Pleasanton, CA). Thus an LVAD has the following components:
(A) Input conduit,
(B) Pump,
(C) Control lines and power drive lines (may be bundled or separate),
(D) Outflow conduit and
(E) Controller and power source (may be bundled or separate, generally external).
The connections require opening the chest to gain access to the LV apex for (A) and the aorta for (E). A cannula (hollow tube conduit) is inserted through incisions in each, and secured to those two targets. The other ends of those tubes can exit the chest wall through holes created for the purpose, but a short path to the outside invites infection. Therefore longer tunnels may be created to provide a longer passage beneath the skin for body defenses against infection, or a tunnel may be created alongside the esophagus down alongside the stomach so the pump can sit in the abdomen.  Power and control for the pump (C) may require a tunnel to the surface to reach (E) (length provides greater opportunity for the skin to defend against infection), or energy transfer may be accomplished by magnetic induction (a loop of wire below the skin paired with a loop outside the patient, well aligned) and control can also be wireless.

Complications related to Open Heart Surgery

Early complications include
  • perioperative hemorrhage,
  • air embolism, and
  • ventricular failure.
Late complications include
  • infection,
  • thromboembolism, and
  • device failure.  If the power drive is connected to a power line, the patient is tethered. Alternatively, the power may be provided by a battery pack that the patient may wear or wheel alongside.

Open Heart Surgery and Reoperative Sternotomy

The e-Reader is recommended to review the Authors’ article on this topic:

Pearlman, JD and A. Lev-Ari 7/23/2013 Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Similar to the intra-aortic balloon pump, the role of the LVAD does not require access to the left ventricle. Both goals (afterload reduction and improved forward circulation) can be accomplished in the aorta: the afterload on the left ventricle can be reduced by removing volume from the aorta during contraction of the ailing heart (systole), thereby facilitating its forward emptying. Next, both
  • perfusion of the heart and
  • promotion of circulation
can be boosted by delivering volume to the aorta during relaxation of the ailing heart (diastole).
Alternatively, there is experimentation with a continuous pump rather than mimicking the pulsation of the native heart.
A Right ventricular assist device (RVAD) draws blood from either the right atrium or the right ventricle and delivers it to the pulmonary artery. Otherwise, it has the same components and the analogous surgical requirements.
A Biventricular assist device (BiVAD) is used when neither ventricle can perform adequately. It consists of the two devices, LVAD plus RVAD, with opportunity to share components (may share the controller system, the power drive system, and even share a single pump with two circulation channels can serve as RVAD plus LVAD).

III. Implant of a Total Artificial Heart

  • A total artificial heart is similar to a BiVAD except for the option that it can replace most of the native heart instead of connecting in tandem to it
  • If a total artificial heart is placed in tandem, the procedure is basically the same as for an RVAD plus and LVAD.
  • If the total artificial heart replaces the native heart, the surgery is very similar to the heart transplant procedure explained above, plus handling for
– pump placement,
– power drive, and
– controller as for LVAD.
As a heart replacement,
  • the native right atrium connects to the right intake of the total artificial heart,
  • the main pulmonary artery connects to the right output,
  • the native left atrium connects to the left input, and
  • the aorta connects to the left output.
The so-called “heartless man”  walked more than 400 miles (six miles every day) after a SynCardia Total Artificial Heart was placed, powered by a Freedom(R) portable backpack device.

REFERENCES

  1. Shumway NE, Lower RR, Stofer RC. Transplantation of the heart. Adv Surg 1966;2:265-84.
  2. Gilles Dreyfus G, Jebara V, Mihaileanu S, Carpentier AF.  Total orthotopic heart transplantation: An alternative to the standard technique. The Annals of Thoracic Surgery Volume 52, Issue 5 , Pages 1181-1184, November 1991
  3. Angermann CE, Spes CH, Tammew A, et al. Anatomic characteristics and valvular function of the transplanted heart:
    transthoracic versus transoesophageal echocardiographic findings. J Heart Transplant 1990;9:331-8.
  4. Griepp RB, Ergin MA. The history of experimental heart transplantation. J Heart Transplant. 1984;3:145.
  5. Copeland JG, Emery RW, Levinson MM, et al. Selection of patients for cardiac transplantation. Circulation. Jan 1987;75(1):2-9. [Medline].
  6. Ramakrishna H, Jaroszewski DE, Arabia FA. Adult cardiac transplantation: A review of perioperative management Part – I. Ann Card Anaesth. Jan-Jun 2009;12(1):71-8. [Medline]
  7. Hill JD. Bridging to cardiac transplantation. Ann Thorac Surg. Jan 1989;47(1):167-71. [Medline].
  8. Portner PM, Oyer PE, Pennington DG, et al. Implantable electrical left ventricular assist system: bridge to transplantation and the future. Ann Thorac Surg. Jan 1989;47(1):142-50. [Medline].
  9. Holman WL, Kormos RL, Naftel DC, Miller MA, Pagani FD, Blume E, et al. Predictors of death and transplant in patients with a mechanical circulatory support device: a multi-institutional study. J Heart Lung Transplant. Jan 2009;28(1):44-50. [Medline].
  10. Overcast TD, Evans RW, Bowen LE, et al. Problems in the identification of potential organ donors. Misconceptions and fallacies associated with donor cards. JAMA. Mar 23-30 1984;251(12):1559-62.[Medline].
  11. Reichart B, Brandl U. 40 years of heart transplantation and the DFG-Transregio Research Group Xenotransplantation. Xenotransplantation. Sep 2008;15(5):293-294. [Medline].
  12. Moriguchi J, Davis S, Jocson R, Esmailian F, Ardehali A, Laks H, et al. Successful use of a pneumatic biventricular assist device as a bridge to transplantation in cardiogenic shock. J Heart Lung Transplant. Oct 2011;30(10):1143-7. [Medline].
  13. Kilic A, Conte JV, Shah AS, Yuh DD. Orthotopic Heart Transplantation in Patients With Metabolic Risk Factors. Ann Thorac Surg. Feb 2 2012;[Medline].
  14. Arnaoutakis GJ, George TJ, Allen JG, Russell SD, Shah AS, Conte JV, et al. Institutional volume and the effect of recipient risk on short-term mortality after orthotopic heart transplant. J Thorac Cardiovasc Surg. Jan 2012;143(1):157-67, 167.e1. [Medline].
  15. Lee I, Localio R, Brensinger CM, Blumberg EA, Lautenbach E, Gasink L, et al. Decreased post-transplant survival among heart transplant recipients with pre-transplant hepatitis C virus positivity. J Heart Lung Transplant. Nov 2011;30(11):1266-74. [Medline].
  16. Caves PK, Stinson EB, Billingham M, Shumway NE. Percutaneous transvenous endomyocardial biopsy in human heart recipients. Experience with a new technique. Ann Thorac Surg. Oct 1973;16(4):325-36.[Medline].
  17. Hunt J, Lerman M, Magee MJ, et al. Improvement of renal dysfunction by conversion from calcineurin inhibitors to sirolimus after heart transplantation. J Heart Lung Transplant. Nov 2005;24(11):1863-7.[Medline].
  18. Pedotti P, Mattucci DA, Gabbrielli F, Venettoni S, Costa AN, Taioli E. Analysis of the complex effect of donor’s age on survival of subjects who underwent heart transplantation. Transplantation. Oct 27 2005;80(8):1026-32. [Medline].
  19. Griffith BP, Hardesty RL, Deeb GM, et al. Cardiac transplantation with cyclosporin A and prednisone. Ann Surg. Sep 1982;196(3):324-9. [Medline].
  20. Ye F, Ying-Bin X, Yu-Guo W, Hetzer R. Tacrolimus versus cyclosporine microemulsion for heart transplant recipients: a meta-analysis. J Heart Lung Transplant. Jan 2009;28(1):58-66. [Medline].
  21. Khan MS, Mery CM, Zafar F, Adachi I, Heinle JS, Cabrera AG, et al. Is mechanically bridging patients with a failing cardiac graft to retransplantation an effective therapy? Analysis of the United Network of Organ Sharing database. J Heart Lung Transplant. Aug 17 2012;[Medline].
  22. Hofflin JM, Potasman I, Baldwin JC, et al. Infectious complications in heart transplant recipients receiving cyclosporine and corticosteroids. Ann Intern Med. Feb 1987;106(2):209-16. [Medline].
  23. Tambur AR, Pamboukian SV, Costanzo MR, et al. The presence of HLA-directed antibodies after heart transplantation is associated with poor allograft outcome. Transplantation. Oct 27 2005;80(8):1019-25.[Medline].
  24. Kfoury AG, Renlund DG, Snow GL, Stehlik J, Folsom JW, Fisher PW, et al. A clinical correlation study of severity of antibody-mediated rejection and cardiovascular mortality in heart transplantation. J Heart Lung Transplant. Jan 2009;28(1):51-7. [Medline].
  25. Sweeney MS, Macris MP, Frazier OH, et al. The treatment of advanced cardiac allograft rejection. Ann Thorac Surg. Oct 1988;46(4):378-81. [Medline].
  26. Ford MA, Almond CS, Gauvreau K, Piercey G, Blume ED, Smoot LB, et al. Association of graft ischemic time with survival after heart transplant among children in the United States. J Heart Lung Transplant. Nov 2011;30(11):1244-9. [Medline].

Part III

Comparative Analysis of Transplant Clinical Outcomes based on Data in: Heart Transplant (HT) Indication for Heart Failure (HF): Procedure Outcomes and Research on HF, HT @ Two Nation’s Leading HF & HT Centers

By Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN 

 

Procedures Outcomes of Heart Transplant (HT) Indication for Heart Failure (HF)Center for Heart Failure @Cleveland Clinic, and Transplant Center @Mayo Clinic

Center for Heart Failure @Cleveland Clinic: Institution Profile

The treatment of heart failure requires a specialized multidisciplinary approach to manage the overall patient care plan.   The Kaufman Center for Heart Failure Team brings together clinicians that specialize in cardiomyopathies and ischemic heart failure for patients with:

  • All types of heart failure
  • Dilated Cardiomyopathy
  • Restrictive Cardiomyopathy
  • Arrhythmogenic Right Ventricular Dysplasia (ARVD)

Heart Failure – National Hospital Quality Measures
Cleveland Clinic, 2011 (N = 1,163) 96.9%
UHC Top Decile, 2011 99.2%
SOURCE
University Health System Consortium (UHC) Comparative Database, January through November 2011 discharges.

The Centers for Medicare and Medicaid Services (CMS) calculates two heart failure outcome measures:

  • all-cause mortality and
  • all-cause readmission rates,

each based on Medicare claims and enrollment information.

Heart Failure All-Cause 30-Day Mortality (N = 762)  July 2008 – June 2011
Cleveland Clinic 9.2%
National Average 11.6%
Heart Failure All-Cause 30-Day Readmission (N = 1,)  July 2008 – June 2011
Cleveland Clinic 27.3%
National Average 24.7%
SOURCE:
hospitalcompare.hhs.gov

The results for risk-adjusted all-cause mortality is 2% lower than the National Average and 30-day risk-adjuted readmission rates for 2008-2011 are 2% higher than the National Average.  There is no definitive information provided to explain the higher readmission rate.  One might consider that they take most difficult referrals.  The heart failure risk-adjusted readmission rate is higher than the national average; and both differences are statistically significant. To further reduce this rate, a multidisciplinary team was tasked with improving transitions from hospital to home or post-acute care facility. Specific initiatives have been implemented in each of these focus areas: communication, education and follow-up.  There is no data for comparing 1-month, 1-year, and 3-year survivals.
http://my.clevelandclinic.org/Documents/outcomes/2011/outcomes

Additional Cleveland Clinic Data is provided related to Pre- and Post-operative conditions

Preoperative patient characteristics

Prob

Diabetes mellitus 499 (21.5%) 61 (26.4%)

0.084

Congestive heart failure 758 (32.6%) 89 (38.5%)

0.069

III-IV 1830 (78.8%) 184 (84.0%)

Previous operation No injury (2324) Injury (231) P

CABG 1375 (59.2%) 162 (70.1%)

0.001

Current operation No injury (2324) Injury (231) P

CABG 897 (38.6%) 104 (45.0%)

0.056

Aortic valve surgery 1020 (43.9%) 118 (51.1%)

0.036

Tricuspid valve surgery 414 (17.8%) 52 (22.5%)

0.078

Aortic surgery 232 (10.0%) 37 (16.0%)

0.004

Postoperative results

No injury (2324) —  Injury (231) – P

PRCs 4.5  7.2 6.5  8.9

0.046

ICU stay (h) 102.3  228.6 146.3 +/- 346.9

<.001

Reoperation for bleeding 127 (5.5%) 21 (9.1%)

0.024

Sepsis 86 (3.7%) 16 (6.9%)

0.017

Stroke 56 (2.4%) 11 (4.8%)

0.033

Prolonged ventilation 505 (21.7%) 97 (42.0%)

<.001

Pneumonia 123 (5.3%) 25 (10.8%)

<.001

ARDS 32 (1.4%) 8 (3.5%)

0.015

Postoperative renal failure 237 (10.2%) 51 (22.1%)

<.001

Multisystem failure 45 (1.9%) 13 (5.6%)

<.001

Hospital death 151 (6.5%) 43 (18.6%)

<.001

Cleveland Clinic
LVAD mortality 2007-2011   5%
VAD mortality   2011
Obs 10%  Exp   17.5%  N 56
HF- NHQM
2010    1194    93.9%
2011    1163    96.9%
UHC Top decile, 2011   99.2%

Transplant Center @ Mayo Clinic: Alternative Solutions to Treatment of Heart Failure.  Mayo Clinic performs has pre-eminent adult and pediatric transplant programs.

Success Measures   2009-2011

1 mo

1 year

3 year

Heart Transplant Patient Survival — Adult
Mayo – Phoenix, AZ (n=40)

97.50%

94.63%

82.22%

Mayo – Jacksonville, FL (n=61)

95.08%

91.50%

81.82%

Saint Marys Hospital – Rochester, MN (n=48)

95.83%

95.83%

82.61%

National Average

95.89%

90.21%

81.79%

Heart Transplant – Children
Saint Marys Hospital – Rochester, MN (n=5)

100%

100%

60%

Adult Heart Organ (Graft)
Mayo – Phoenix, AZ (n=41)

97.56%

94.77%

82.22%

Mayo – Jacksonville, FL (n=61)

95.08%

91.50%

80.00%

Mayo -Rochester, MN (n=49)

93.88%

93.88%

82.61%

National Average

95.71%

89.91%

80.92%

Standards for Comparison:  SRTR function, data acquisition, analysis, and reporting.

Curator: Larry H Bernstein, MD and Curator: Aviva Lev-Ari, PhD, RN
Source: Program Specific Reprting, by S Everson [SRTR]

http://srtr.transplant.hrsa.gov/

The Scientific Registry of Transplant Recipients

supports the ongoing evaluation of solid organ transplantation in the United States. SRTR designs and carries out data analyses and maintains two websites to disseminate organ transplant information.

This site is srtr.transplant.hrsa.gov. Here you will find the OPTN/SRTR Annual Data Report, which publishes organ transplant statistics and is produced each year by SRTR staff and staff of the national Organ Procurement and Transplantation Network (OPTN).

At www.srtr.org, you will find older (pre-2010) annual data reports, current and past reports on organ procurement organizations and transplant programs, and information for researchers (including additional data tables and information about SRTR data and statistical methods).

Both sites aim to inform transplant programs, organ procurement organizations, policy makers, transplant professionals, transplant recipients, organ donors and donor families, and the general public about the current state of solid organ transplantation in the US.

SRTR also helps facilitate transplant research by providing access to data for qualified researchers interested in studying various aspects of solid organ transplantation.

The SRTR supports ongoing evaluation of the scientific and clinical status of solid organ transplantation and it provides data on all solid organ transplants and donations in the United States with oversight and funding from the Health Resources and Services Administration (HRSA), a division of the US Department of Health and Human Services, and is admionitered by the Chronic Disease Research Group of the Minneapolis Medical Research Foundation.
How SRTR differs from the Organ Procurement and Transplantation Network (OPTN).
Program-Specific Reports and their intended audience.
  1. Timeline and cohort selection.
  2. Patients who are lost to follow-up: censoring and extra ascertainment.
  3. Expected survival and risk-adjustment.
  4. Comparison points: norms versus targets.
Interpretation of survival statistics: what is important to whom? 
SRTR Products and Responsibilities: Inferential Analyses to Support Policymaking and Patient Care
*Analytic support for policy committees (OPTN, Advisory Committee on Organ Transplantation [ACOT]).
*OPTN/SRTR Annual Report.
Publications
*Report to Congress.
Journal articles and scientific presentations.
Public release data files for researchers.
*Program-specific analyses (Program-Specific Reports, Organ Procurement Organization [OPO] reports, etc).
Inferential requests.
Primary data from OPTN, supplemented with other sources.
*legislatively mandated
^Primary data source is the transplant center, submitting data through the OPTN system. Includes WL and organ allocation, tiedi, match runs.
  1. Range of other data here are incorporated either on a person-level matching basis or on an aggregate basis for comparison.
  2. Primary data source is the transplant center, submitting data through the OPTN system. Includes WL and organ allocation, tiedi, match runs.
  3. Range of other data here are incorporated either on a person-level matching basis or on an aggregate basis for comparison.
  4. Primary data source is the transplant center, submitting data through the OPTN system. Includes WL and organ allocation, tiedi, match runs.
  5. Range of other data here are incorporated either on a person-level matching basis or on an aggregate basis for comparison.
  6. National Death Index is not be used for analyses, but is used to evaluate completeness of extra ascertainment.
Each month, the SRTR receives an updated version of all data submitted by transplant centers, organ procurement organizations, and histocompatibility laboratories, along with data produced by the OPTN itself regarding organ offers, match runs, and the like.  Data linkages are used to add patient-level data, and additional ascertainment of mortality events is provided via linkage to the Social Security Death Master File.   Analysis files optimized for research are created and merged with analysis variables from the National Center for Health Statistics and the annual survey of the American Hospital Association to produce a set of Standard Analysis Files.  These are the data files used for SRTR analyses.
Regularly scheduled analyses are produced, including those available to the public such as the center-specific reports of transplant programs and OPOs, reports to the OPTN Membership and Professional Standards Committee, and the standardized insurance request for information data reports.  Program-Specific Reporting (http://www.srtr.org) uses different formats for different audiences. Feedback from centers enables data fixes and data quality improvements to occur over time.
Additional research is presented in the form of journal articles, the SRTR Report on the State of Transplantation published each year in the American Journal of Transplantation, conference proceedings, reports to OPTN and ACOT committees, an Annual Report published on the web and on CD, and a Biennial Report to Congress.  The same Standard Analysis Files that are used by SRTR are available to all researchers and can be obtained via submission of an analysis plan and completion of a Data Use Agreement.
Using SRTR-calculated center-specific statistics provides several advantages – for each audience of the CSR — over having each center self-report these characteristics:
  • Uniform methodology: The SRTR provides a uniform methodology of calculation. These methods are standard and accepted within the statistical and medical communities, however they are not the only ones available.
  • Audited data collection: All data on which these statistics are based are audited by the OPTN. The United Network for Organ Sharing (UNOS), the contractor for the OPTN, works to ensure the accuracy and reliability of these data.
  • Extra ascertainment of mortality: The SRTR helps find information about patients who become lost-to-follow-up that may be unavailable to transplanting centers, or very difficult to find.
  • Risk adjustment: Comparison of outcomes should be based on risk-adjusted models that account for the types of patients treated. Without national data, it is impossible for centers to calculate risk-adjusted comparison points.

Program-Specific Reporting –  different formats for different audiences: What we choose to focus on 

 

 Percent survival at one year, three years.

  1. What choices do our patients have?
  2. How well are we doing?

*Report Contents – Focus on patient outcomes

 Report Tables [10-11]– 
  1. Graft and patient survival rates compared with expected values
  2. Updated every 6 months (January, July).
  3. Patient and graft survival tables report 1-month, 1-year, and 3-year outcomes for 2.5-year cohorts of recipients.

Calculating Survival

 

Transplant Month Follow-up Group A: Transplant > 1 Y Group B:Transplant 6-12 Mo All
Months 0-6 Transplants
Deaths
100
10
100
14
200
24
Survival 90% 86% 88%
Months 7-12 At-Risk
Deaths
Survival
90
18
80%
Not yet observed,
Use 80%
.88*.80 = 70.4%or  (72 + 68.8)/2 = 70.4
1 Year Survival .90 * .80 = 72% .86*.80 = 68.8%

Incomplete Data and Loss to Follow-Up

  • Censoring (Kaplan Meier/Cox) works only if “lost” patients have similar failure rates as followed patients (unbiased).
  • Censoring can produce unstable estimates for small samples
  • NDI study indicates that the SRTR identifies > 99% of deaths
  • Observed rates are compared with rates that would be expected based on characteristics of recipients and donors at each center.
  • Allows fair comparison among centers that treat different types of patients
  • Is the difference we see between the observed survival of 87.78% and the expected rate of 89.41% large enough to be meaningful? The answer may depend perspective.

The percent surviving at one year is only 2% lower than expected, an apparently small difference. However, the same difference appears more consequential when comparing the percent died that implied by subtracting survival percents from 100: the percent of patients who had died by the end of the first year was a full 15% higher than expected. Finally, in our example center that performed 90 transplants during a 2.5-year period, the count of deaths observed during follow-up was 30% higher, accounting for 2.5 deaths more than we would expect during time these patients were followed.

The difference between each of these is stark. The first change from a 2% difference to a 15% difference reflects the change in denominator: a small percentage point difference is a much smaller fraction of survival (usually a large number at one year) than of mortality (usually a small number). Several years after transplant, when survival rates may be close to 50%, the contrast would not be as evident.

The difference between the percent died and death count is more subtle: the expected number of deaths is calculated according to the time that patients are followed after transplant, so a patient whose follow-up ends immediately after transplant – for any reason, including death — is smaller than the expected number of deaths for a patient who died after ten months. Therefore, this last statistic accounts for the difference between a patient who survives only briefly during follow-up, and one who survives nearly the entire period, despite the fact that they have both died in the end-of-period accounting of “percent died”.

Survival time -expected deaths

Risk Adjustment

What rate would be expected for patients at this center if their outcomes were comparable to national outcomes for similar patients?
“Similar” defined by characteristics that affect the rate, such as:

  • Demographics
  • Etiology
  • Severity of illness

Differences between observed and expected outcomes are not due to these adjustment factors.

*notion of a “similar” patient: have in-common characteristics that may influence the outcome –
include basic demographic factors such as age, etiology of disease, and the patient’s severity of illness.

journal.pmed.0020133.g001  Global Mortality and Burden of Disease Attributable to Cardiovascular Diseases and Their Major Risk Factors for People 30 y of Age and Older

278px-Preventable_causes_of_death
Causes_of_death_by_age_group

Adjusted odds ratios comparing the results of CABG and PCI-stenting in the various prespecified subsets.

50-Graph-4-33_2012  Hospitalization Rates for Heart Failure, Ages 45–64 and 65 and Older, U.S., 1971–2010

48-Graph-4-30_2012  Age-Adjusted Prevalence of Cardiovascular Disease Risk Factors in Adults, U.S., 1961–2011

Risk-Adjustment Models

Each risk-adjustment model is published one month in advance of the PSRs (Figure 5). These tables serve not only as a list of all characteristics incorporated, but also tell the reader:

  1. The beta, or calculated coefficient, tells what was the effect of that characteristic on expected risk of dying or failed transplant?
  2. The standard error and p-value tell how much random variance there was around this estimate, and how sure we are that there is a real effect of this characteristic.
  3. Models are repeated for a series of three different cohorts of transplants, allowing a comparison of how stable the coefficients are across time.
  4. The index of concordance, for each model, tells the percent of variation in the order of events (deaths or graft failures) that is accurately predicted by the model. A index of 100% would suggest that the model perfectly predicts the order of events; 50% would suggest that the order is random with regard to predictors.

*Odds Ratio >1 = Failure/Death More Likely = Lower Expected;
Odds Ratio <1 = Failure/Death Less Likely = Higher Expected

Adjusting for Age

Nationally: Average survival, 85%.

  • 50% of patients are young with 95% survival.
  • 50% of patients are old with 75% survival.

Center A treats only older patients, 80% survival:
Center survival of 80% worse than national average of 85%.
100% are older patients with expected 75% survival.
Center A patients have better expected survival compared with similar patients nationwide
Center X Treats More Older Recipients than the National Average

more older recipients

Adjustment: Account for Case Mix

The older recipient age at Center X (along with other factors) gives Center X an expected 13.1% deaths, compared with the national average of 9.5%.
Use ratio of observed/expected deaths.

Adjustment: Random Variation

Obs/Exp Deaths: Center X = 1.1 (0.88-1.37); National Ave = 1.0
The confidence interval for Center X, reflecting random variation in this measure over time, overlaps the national average.
Do not flag Center X.

Concepts: Actionable, Important, and Significant

The first principle in these criteria is that all comparisons should be based on observed and expected events during the time a patient is actually followed either by the center or, in the case of patient survival, by extra ascertainment; no imputed survival should be used. They should also account for the difference in outcomes between a patient who dies in the 1st week after transplant versus 51st week.
The following criteria, applied by the MPSC, are based on comparison of counts of observed and expected deaths (graft failures) as presented in “Deaths during follow-up period”. To be identified for further review by the MPSC, differences between observed and expected must meet all of the following criteria:
Actionable: the magnitude of the problem, in terms of potential lives saved, should be sufficient to take action
  1. MPSC Criteria: Observed (O) – Expected (E) greater than 3, O – E > 3
  2. Interpretation: 3 excess deaths per 2-year transplant cohort
Important: a clinically significant pattern, suggesting that it may be changeable, indicated by a high fraction of excess deaths
  1. MPSC Criteria: Standardized Mortality Ratio (SMR) > 1.5; O / E > 1.5
  2. Interpretation: 50% more deaths than expected
Significant: it should be unlikely that the difference occurred by random chance alone
  1. MPSC Criteria: one-sided p-value less than .05
  2. Interpretation: there is less than a 5 percent chance that a poor outcome occurred by simple random variation

Important: More than 3 excess deaths

more than 3 excess deaths

Actionable: More than 50% excess deaths

more than s 50% excess deaths

excess deaths unlikely due to hance

MPSC Flagging Boundaries

1-s2.0-S0194599809003301-gr1    action statement may be classified as an option, recommendation, or strong recommendation

Part IV

Imaging Technologies in use for Clinical Monitoring of Patients with Heart Transplant: Donor Human Heart and Artificial Heart

By Justin D Pearlman, MD, PhD, FACC

Imaging of the heart monitors success and viability of the transplanted heart in terms of

what fraction of the contents of each ventricle moves out of the heart (ejection fraction),

  • what volumes the heart sees
  1. end-diastolic volume, or EDV, and
  2. end-diastolic diameter, or
  3. LVIDd,
  4. end systolic volume or ESV),
  5. how well the walls move (wall motion) and
  6. wall thickening analysis,
  • tissue character
  1. visual evidence for changes in the heart muscle,
  2. perfusion (delivery of nutrient blood supply to the heart muscle), and
  3. various means to detect coronary artery disease (obstructions to blood delivery to the heart muscle).

Clinical tools for imaging the heart include:

  1. The major tool – ultrasound (echocardiography),
  2. cardiac magnetic resonance (CMR),
  3. computed xray tomography (CT),
  4. catheterization with xray imaging (coronary angiography and ventriculography),
  5. metabolic marker distribution by positron emission tomography (PET), and
  6. radioactive marker distribution (nuclear imaging, SPECT).

Ultrasound applies alternating current to a piezoelectric crystal (lead zirconate) to produce compressions and expansions of material as a wave pattern that relies on tissue elastic properties to propagate into the tissue, reflecting back when the wave encounters a change of properties (acoustic impedance mismatch). Display of signal versus time on an oscilloscope (like an ECG monitor) constitutes “A-mode”(amplitude) display, whereby the distance between peaks corresponds to distances along the path that can report thickness of the left ventricle, and diameter of the left ventricular cavity. Time translates to distance because the speed of sound through tissue is fairely constant, ~1540 meters/second. Collapsing the peaks to bright dots represents the same data in “B-mode” (brightness) which reduces the data to a line of variable intensity with bright dots marking changes in tissue (e.g., muscle versus blood). Attaching a position sensor to the handle of the sound source (the transducer) enabled plotting the B-mode signal on a 2D screen to indicate the position of the sound beam. Gynecologists showed that a steady sweep of the transducer (C-mode, composite) then generated 2D images that delineated the shape of a fetal head, and as quality improved, the gender prior to birth. The invention of phased-array crystal sets (multiple sources electrically activated sequentially with specific timing) enabled generation of a composite beam that is electronically swept in an arc with no mechanically moving parts. That is now the main method of ultrasound imaging, called phased-array sector scanning. More advanced phased arrays sweep in a 2D pattern to generate 3D imaging (4D or dynamic 3D, when you include repeating over time).

The e-Reader is encourage to review Cardiovascular Imaging Chapters in each of the three volumes.

For new technological developments in achieving Optimal PCI Outcomes and for Visual Tools for Characterization of endovascular tissue affecting Coronary Circulation, review the following article:

Coronary Circulation Combined Assessment: Optical Coherence Tomography (OCT), Near-Infrared Spectroscopy (NIRS) and Intravascular Ultrasound (IVUS) – Detection of Lipid-Rich Plaque and Prevention of ACS

Part V

The Failure of a Heart Transplant – Pathology and Autopsy Findings

by Larry H Bernstein, MD, FCAP 

Section A.  SRTR Graft and Patient Survival Data

Table 1.  Transplant Survivals, 2011, and related conditions

Activities    2011 Numbers
Deceased donor transplants (n=number) 2,322
Adult graft survival (based on 4595  transplants) 89.91 (%)
Adult patient survival (based on 4449 transplants) 90.21 (%)
Pediatric graft survival (based on 886  transplants) 90.74 (%)
Pediatric patient survival (based on 829  transplants) 91.31 (%)
Primary Disease (%) of Waitlist
Cardiomyopathy 49.4
Coronary Artery Disease 34.7
Retransplant/Graft Failure   4.4
Valvular Heart Disease   1.7
Congenital Heart Disease   8.4

Table 2.  Recipient Condition at Transplant (%)

Not Hospitalized 54.0
Hospitalized 14.6
ICU 31.0
No Support Mechanism 25.2
Devices 42.4
Other Support Mechanism 32.2

Table 3.  Donor Characteristics

Cause of Death (%)
Stroke 20.9
MVA 23.4
Other 55.7
Age (years)
18-34 48.8
35-49 24.5
12-17 9.4
Cold ischemic time 1.5-4.5 h 85.3

Table 4.  Graft and Patient Survival

Survival by… time since transplant
1 mo 1 yr 3 yrs
Adult (Age 18+)
Graft survival (%)   95.7   89.9   80.9
# failures

197

442

847

Patient survival (%)   95.9   90.2   81.8
# deaths

183

415

783

Pediatric (Age < 18)
Graft Survival (%)   96.3   90.7   82.0
Graft Failures

  33

  80

151

Patient Survival (%)

  96.4

  91.3

 82.93

Deaths

  30

  70 134

* 07/01/2006 and 12/31/2008 for the 3 Year Model

Table 4.    Risk Model Documentation – Adult, Three−Year Graft Survival

Characteristic Level Estimate Std. Err. P−Value
Bilirubin at Transplant mg/dL 0.0364 0.008 <0.0001
Dialysis at Transplant Yes 0.8026 0.169 <0.0001
Donor Age 0−17 −0.5789 0.140 <0.0001
18−34 −0.3098 0.074 <0.0001
Ischemic Time hrs 0.1298 0.033 <0.0001
Previous Transplant Yes 0.4251 0.157 0.0069
Recipient DX Cardiomyopathy −0.1933 0.078 0.0130
Recipient Age 18-34 0.2806 0.110 0.0107
65+ 0.2694 0.101 0.0074
Recipient Race Black 0.4104 0.086 <0.0001
Recipient SCrea >1 & <=1.5 mg/dL 0.0115 0.086 0.8933
>1.5 mg/dL 0.4316 0.095 <0.0001
Recipient on VAD Yes 0.2777 0.086 0.0013
Recipient on Vent Yes 0.7014 0.169 <0.0001

* SRTR Program−Specific Report   July 12, 2012

Table 5.  Risk Model Documentation  Adult, Three−Year Patient Survival

Characteristic Level Estimate Std. Err. P−Value
Donor Age 0−17 −0.4758 0.1452 0.0010
18−34 −0.3066 0.0764 0.0001
Ischemic Time hrs 0.1400 0.0344 <0.0001
Most Recent CPRA/PRA% 0.0039 0.0019 0.0359
Recipient Age 18−34 0.3041 0.1157 0.0086
65+ 0.3089 0.1013 0.0023
Recipient DX Cardiomyopathy −0.2151 0.0809 0.0078
Congen Heart Dis 0.5504 0.2085 0.0083
Recipient Race Black 0.4942 0.0895 <0.0001
Recipient SCrea >1 and <=1.5 0.0245 0.0887 0.7827
>1.5 mg/dL 0.5053 0.0991 <0.0001
Recipient on VAD Yes 0.2559 0.0816 0.0017
Recipient on Vent Yes 0.7340 0.1852 0.0001

Note the following: 

1. The most common transplant recipients in adults are cardiomyopathy and CAD, and congenital heart disease in children.
2.  recipient on VAD or on vantilator is significant
3.  ischemic time for donor heart is usually 1.5-4.5 hours, but longer time has an effect on graft and patient survival
4. Recipient serum creatinine exceeding 1.5 mg/dl is unfavorable, but considering BMI and age related renal nephron loss, eGFR would be a better measure.5.  African-American has an effect, but it is not at all clear whether sickle cell trait or disease is a factor.
6. Half the recipients are not hospitalized, and they might coincide with no or other support.

Section B.  Special Concerns

Topic 1

Cellular repopulation of myocardial infarction in patients with sex-mismatched heart transplantation
Source: Georg-August-University G€ottingen.  c2004, Eur Soc Cardiol

Recent studies have suggested that human extracardiac progenitor cells are capable of differentiating into cardiomyocytes. In animal studies, myocardial infarction attracted bone marrow stem cells and enhanced their differentiation into cardiomyocytes.
Myocardial infarction enhances the invasion of extracardiac progenitor cells and their  regeneration of endothelial cells. However, a significant differentiation into cardiomyocytes as a physiological mechanism of postischaemic regeneration does not occur in transplanted patients.

Topic 2

Five-year follow-up of hepatitis C-naïve heart transplant recipients who received hepatitis C-positive donor hearts.
G S Gudmundsson, K Malinowska, J A Robinson, B A Pisani, J C Mendez, B K Foy, G M Mullen
Advanced Heart Failure/Heart Transplant Program, Loyola University, Maywood, Illinois, USA.
Transplantation Proceedings (impact factor: 1). 07/2003; 35(4):1536-8.
Source: PubMed

Due to the risk of transmission of hepatitis C virus, the use of hepatitis C seropositive donors in heart transplantation is controversial. The transmission rate of hepatitis C in this patient population is estimated to range from 67% to 80%. Long-term clinical outcomes of heart transplant recipients of hepatitis C-positive donor hearts are not well described. We report the 5-year long-term outcome of seven hepatitis C-naïve heart transplant recipients who received hepatitis C-positive donor hearts.

Seven hearts transplant recipients, six men and one woman were included in our study. After a mean follow-up of 63.3 +/- 20.4 months (range 28.2 to 85.9), four of seven (57.1%) patients are hepatitis C-negative, have normal liver function tests, and no clinical evidence of hepatitis. Three of seven (43%) have been diagnosed with hepatitis C by liver biopsy or the HCV-RNA reverse transcriptase polymerase chain reaction at a mean follow-up of 35.1 months (18.8 months posttransplantation). One had an accelerated course of hepatitis that was ultimately fatal, one was successfully treated with interferon, and the third died from other causes than liver injury. Overall, the 5-year survival was 71.4%.

Topic 3

Cryptococcus neoformans Infection in Organ Transplant Recipients: Variables Influencing Clinical Characteristics and Outcome
Shahid Husain, Marilyn M. Wagener, and Nina Singh
Veterans Affairs Medical Center and University of Pittsburgh
Thomas E. Starzl Transplantation Institute, Pittsburgh, Pennsylvania, USA
Emerging Infectious Diseases 376 Vol. 7, No. 3, May–June 2001

Unique clinical characteristics and other variables influencing the outcome of Cryptococcus neoformans infection in organ transplant recipients have not been well defined. From a review of published reports, we found that C. neoformans infection was documented in 2.8% of organ transplant recipients (overall death rate 42%). The type of primary immunosuppressive agent used in transplantation influenced the predominant clinical manifestation of cryptococcosis. Patients receiving tacrolimus were significantly less likely to have central nervous system involvement (78% versus 11%, p =0.001) and more likely to have skin, soft-tissue, and osteoarticular involvement (66% versus 21%, p = 0.006) than patients receiving nontacrolimus-based immunosuppression. Renal failure at admission was the only independently significant predictor of death in these patients (odds ratio 16.4, 95% CI 1.9–143, p = 0.004). Hypotheses based on these data may elucidate the pathogenesis and may ultimately guide the management of C. neoformans infection in organ transplant recipients.

Patients were 12 to 67 years of age (median 44 years); 78% were male. The mean incidence of C. neoformans infection was 2.8 per 100 transplants (0.3 to 5.3 per 100). The overall incidence was 2.4% in liver, 2.0% in lung, 3.0% in heart, and 2.8% in renal transplant recipients. Of 127 transplant recipients who could be evaluated, 100 (79%) had azathioprine as the primary immunosuppressive agent, 9 (7%) had tacrolimus, 11 (9%) had cyclosporine, and 7 (6%) had cyclosporine and azathioprine. Of these 127 patients, 78 were also receiving prednisone in various dosages. The incidence of cryptococcosis was 4.5 per 100 transplants in patients who received tacrolimus, 2.4 per 100 transplants in patients who received cyclosporine, and 3.4 per 100 transplants in patients who received azathioprine. These rates did not differ significantly. Rejection episodes preceding cryptococcal infection were documented in 17 (25%) of 67 patients; rejection had occurred a median of 7 months (from 5 days to 49 months) before onset of infection.

Cryptococcosis occurred a median of 1.6 years (from 2 days to 12 years) after transplantation. Overall, 14 (15%) of 94 cases occurred within 3 months, 10 (11%) of 94 in 3 to 6 months, 15 (16%) of 94 in 6 to 12 months, and 55 (59%) of 94 >12 months after transplantation.  The median time to onset after transplantation was 35 months for kidney, 25 months for heart, 8.8 months for liver, and 3 months for lung transplant recipients (p = 0.001). Overall, cryptococcosis developed in 100% of the lung, 75% of the liver, 33% of the heart, and 30% of the kidney transplant recipients within 12 months of transplantation (p = 0.002).

Topic 4

Diagnostic Accuracy of Mortality on a Population of Heart Transplant Patients
M AMUCHÁSTEGUI, AE CONTRERAS, O SALOMONE, A DILLER, et al.
Hospital Privado Centro Médico de Córdoba
REV ARGENT CARDIOL 2008;76:292-294.

Although morbidity and mortality rates in heart transplant have been extensively analyzed, most mortality studies and mortality registries in heart transplant patients are based on clinical data.
Between January 1990 and January 2005 all dead transplant patients were included. The final diagnosis of the cause of death was confirmed with necropsy or biopsy of a solid organ. The causes of death assessed were early graft failure, cellular rejection, graft vascular disease, neoplasms and others.
Seventy three patients underwent heart transplantation during the study period. Thirty one patients died. The cause of death was certified in 61% of cases by 12 necropsies and 7 solid organ biopsies.

  • Cellular rejection greater than grade III was the most frequent cause of death.
  • Histopathology studies differed from the clinically suspected cause of death in 12.9% of cases.

Clinical and pathological information derived from post mortem studies is an indicator of the reality of our practice and constitutes an underlying mainstay for understanding transplant patients and for their further management; in this sense, performing necropsies is of vital importance for these patients.

Topic 5

How do Heart Failure patients die?
S. Orn and K. Dickstein
Central Hospital in Rogaland, Stavanger, Norway
European Heart Journal Supplements (2002) 4 (Supplement D), D59-D65
http://eurheartjsupp.oxfordjournals.org/

Approximately 90% of heart failure patients die from cardiovascular causes. Fifty per cent die from progressive heart failure, and the remainder die suddenly from arrhythmias and ischaemic events. Autopsy reveals the presence of an acute ischaemic event inapproximately 50% of sudden deaths and in 35% of all deaths among patients with ischaemic heart failure.

An accurate description of the cause and mode of death is important if we are to elucidate the mechanisms that are operative in the heart failure population.

At present, the most accurate data on mode of death are obtained from large randomized heart failure trials. They indicate that current treatment strategies for heart failure prolong life expectancy, but have relatively little impact on the proportion of heart failure patients who die from cardiovascular causes. The ultimate goal of intervention is to shift the balance toward more deaths from non-cardiovascular causes. (Eur Heart J Supplements 2002; 4 (Suppl D): D59-D65)
The heterogeneity of the heart failure population is reflected in the different ways in which these patients die.

  • Some deteriorate progressively, whereas others
  • die after acute episodes of decompensation.
  • Others die suddenly and unexpectedly, and some (relatively few)
  • die from noncardiac causes.

Before the angiotensin-converting enzyme (ACE) inhibitor era, it was estimated that

  • 90% of the total deaths in heart failure patients were from cardiovascular causes,
  • 49% were related to worsening heart failure,
  • 22% to arrhythmias and
  • 11% to acute myocardial infarction[S].

It is conventional to categorise death according to mode and cause of death.

  • Cause of death addresses the mechanisms by which death occurs, such as arrhythmia, acute myocardial infarction or progressive heart failure (Table 1).
  • Mode of death is perhaps easier to categorise.
  • Mode and cause of death are not the same, although they are often used interchangeably.

Sudden death has various underlying causes, such as

  • arrhythmia,
  • acute myocardial infarction,
  • pulmonary embolism,
  • myocardial or aortic rupture, and
  • stroke.

Sudden cardiac death is defined as natural death due to cardiac causes, heralded by abrupt loss of consciousness within 1 h of the onset of acute symptoms[2].

In order to avoid confusion in terminology, some clinical trials subclassify death without using the term ’cause of death’ and end-point committees focus instead on mode and place of death (Table 1)[31]. However, although it is more difficult to classify cause of death than mode of death, it is nevertheless productive to examine the causes of death among heart failure patients. The cause of death reflects the underlying pathophysiology of the disease, and helps us to understand the mechanisms responsible for its progression. Unravelling the mechanisms that lead to death is clinically relevant and may reveal potential new treatment targets. Effective treatment may alter the cause of death, and should ideally shift the operative mechanism from cardiovascular to noncardiovascular. Most of our knowledge of the cause and mode of death in heart failure comes from the

  • large randomized mortality trials and from
  • official death registries.

However, both of these sources of information have their problems.

A simplified classification of heart failure deaths

  • Cardiovascular
  • Non-cardiovascular
  • Cardiac
  • Myocardial infarction
  • Progressive heart failure
  • Other cardiac
  • Sudden death
  • Non-cardiac
  • Stroke
  • Other
  • Procedure-related

Conclusions

by Larry H Bernstein, MD, FCAP 

Part I

Leading Causes of Death

Number of Deaths – Leading Causes

Heart disease

597,689

Cancer

574,743

Chronic Lung Disease

138,080

Stroke

129,476

Accidents

120,859

Alzheimer’s

83,494

Diabetes

69,071

Kidney disease

50,476

Influenza and Pneumonia

50,097

Suicide

38,364

*National Vital Statistics Report (NVSR) “Deaths: Final Data for 2010.”   MortalityData@cdc.gov.

WHO Leading Causes of Death

Low income countries

Deaths (mil)

% of deaths

Lower respiratory infections

1.05

11.3

Diarrheal diseases

0.76

8.2

HIV/AIDS

0.72

7.8

Ischemic heart disease

0.57

6.1

Malaria

0.48

5.2

High-income countries

Deaths (mil)

% of deaths

Ischemic heart disease

1.42

15.6

Cerebrovascular disease

0.79

8.7

Bronchioepithelial cancers

0.54

5.9

Alzheimer and dementias

0.37

4.1

Pneumonias

0.35

3.8

High-income countries

Deaths (mil)

% of deaths

Ischemic heart disease

5.27

13.7

Stroke

4.91

12.8

COPD

2.79

7.2

Lower respiratory infections

2.07

5.4

Diarrheal diseases

1.68

4.4

World

Deaths (mil)

% of deaths

Ischaemic heart disease

7.25

12.8

Stroke

6.15

10.8

Pneumonias

3.46

6.1

COPD

3.28

5.8

Diarrheal diseases

2.46

4.3

HIV/AIDS

1.78

3.1

Q: What is the number one cause of death throughout the world?
Cardiovascular diseases kill more people each year than any others. In 2008, 7.3 million people died of ischaemic heart disease, 6.2 million from stroke or another form of cerebrovascular disease.

Q: Isn’t smoking a top cause of death?
Tobacco use is a major cause of many of the world’s top killer diseases – including cardiovascular disease, chronic obstructive lung disease and lung cancer.

Deaths across the globe: an overview

Imagine a diverse international group of 1000 individuals representative of the women, men and children from all over the globe who died in 2008. Of those 1000 people,

  • 159 would have come from high-income countries,
  • 677 from middle-income countries and
  • 163 from low-income countries.

What would be the top 10 causes of their deaths?
Low income countries
http://who.int/entity/mediacentre/factsheets/fs310_graph3.gif
Middle income countries
http://who.int/entity/mediacentre/factsheets/fs310_graph3.gif
High income countries
http://who.int/entity/mediacentre/factsheets/fs310_graph3.gif

Note: In this fact sheet, we use low-, middle- and high-income categories as defined by the World Bank. Countries are grouped based on their 2009 gross national income. See World health statistics 2011 for more information.

SOURCE

World health statistics 2011

Part II

Advances in Imaging Technology

This document discusses the advances in cardiac surgery assisted by rapid advances in cardiac imaging technology over the last 15 years.  This portion concentrates on the treatments for advanced and disabling congestive heart failure as the age expectancy has increased to a range of early 8th and mid-9th decade, depending on patient related comorbidities, nutrition and activity status.  Many of the patients who require a heart transplant have coincident metabolic syndrome, advanced coronary artery circulation compromise, and/or atherosclerotic disease at the aortic arch.  The advances in cardiothoracic technique has enabled a parallel advance in ventricular assist devices and a total artificial heart, which has allowed the maintenance of patients on waitlists until a suitable donor can be found, which is usually under a 5 year period.  The ventricular assist device is selected for those patients who have sufficient reserve of left ventricular function. The cardiac and cardiosurgical advances have been advanced by the development of vastly improved imaging for both diagnosis and for enabling safety of procedures.

Cardiac magnetic resonance imaging is a noninvasive technique for assessing heart structure and function without the need for ionizing radiation. Its ability to precisely outline regions of myocardial ischemia and infarction gives it an important role in guiding interventional cardiologists in revascularization. Its ability to characterize and precisely quantify abnormal regurgitant flow volumes or abnormal shunts also makes it a valuable tool for many noncoronary interventions. The evidence is sufficient to show that cardiac magnetic resonance in guiding complex therapies in the catheter laboratory, as well as practical issues that need to be addressed to allow the application of this powerful tool to an increasing number of patients.  But this advantage extends as well to the transplantation arena.1 (Cardiac magnetic resonance imaging for the interventional cardiologist. GA Figtree, JLønborg, SM Grieve, MR Ward, RBhindi. University of Sydney, Sydney, Australia.  PubMed 02/2011; 4(2):137-48.  http://dx.doi.org/10.1016/j.jcin.2010.09.026.)

Further, A novel approach to three-dimensional (3D) visualization of high quality, respiratory compensated cardiac magnetic resonance (MR) data is presented with the purpose of assisting the cardiovascular surgeon and the invasive cardiologist in the pre-operative planning2. Developments included:

(1) optimization of 3D, MR scan protocols;
(2) dedicated segmentation software;
(3) optimization of model generation algorithms;
(4) interactive, virtual reality visualization.

The approach is based on a tool for interactive, real-time visualization of 3D cardiac MR datasets in the form of 3D heart models displayed on virtual reality equipment. This allows the cardiac surgeon and the cardiologist to examine the model as if they were actually holding it in their hands. To secure relevant examination of all details related to cardiac morphology, the model can be re-scaled and the viewpoint can be set to any point inside the heart. Finally, the original, raw MR images can be examined on line as textures in cut-planes through the heart models3. (A new virtual reality approach for planning of cardiac interventions. T S Sørensen, SV Therkildsen, P Makowski, JL Knudsen, EM Pedersen. University of Aarhus Abogade 34, 8200 N, Arhus, Denmark. PubMed 07/2001; 22(3):193-214.

In addition, TeraRecon, (www.terarecon.com), the largest dedicated provider of advanced visualization and decision support solutions for medical imaging, showcased iNtuitionREVIEW™, a powerful new multi-modality, multi-monitor review and collaboration tool at the 24th European Congress Of Radiology4, held at the Austria Center, Vienna, Austria, March 8th-11th 2013. iNtuitionREVIEW is part of the iNtuition™ solution suite for advanced image management and quantitative decision support.

iNtuition has always complemented PACS with advanced functionality to resolve specialized use cases and workflow challenges not adequately addressed by existing PACS solutions.  Features relevant to this discussion are:

  • Time-Volume Analysis – Enhanced support for Cardiac MRI image acquisitions
  • 3D/4D Visualization – Enhanced TAVI (transcatheter valve implantation) analysis
  • Lesion-Specific Analysis – Support for research into downstream impact of stenosis

Editorial5: Seeing the heart; the success story of cardiac imaging
European Heart Journal 2000; 21(16): 1281–1288
http://dx.doi.org/10.1053/euhj.2000.2299

In 1896 a large audience at the Wurzburg Physical Medical Society attended a lecture and a demonstration, published a paper in 1895 ‘Eine Neue Art von Strahlen’ in the Annals of the Society. He showed an image of the hand of the famous anatomist F. Von Kolliker (1817– 1905). He was awarded the first Nobel prize laureate in Physics in 1901.  FH Williams (1852–1936) began lecturing on the use of X-rays in visualization of the heart. In his paper ‘A method for more fully determining the outline of the heart by means of a fluoroscope together with otheruses of this instrument in medicine, he laid the basis for quantitative cardiac measurements from the chest X-ray.

To make angiocardiography of the heart possible, the feasibility of human cardiac catheterization had to be demonstrated. In 1929 W. Forssman (1904–1979) introduced ‘. . . a well oiled 65 cm long ureteral catheter’ into his antecubital vein to reach the right atrium. Soon thereafter he performed the first cardiac angiocardiogram on himself using 20 cc of 25% sodium iodide. Forssman shared the Nobel Prize for Medicine with A. Cournard and D. Richards in 1956.

The modern era of cardiac X-ray imaging began after the Second World War. G. Hounsfield of EMI Ltd tested their mathematical solutions and constructed the first clinical CT, which was installed in the Atkinson Morle Hospital in London in 1971 for brain scanning. This instrument revolutionized radiological imaging. Electronic and computer developments resulted in the image intensifier in 1952, which was a critical tool for analysing internal cardiac anatomy and the performing of selective coronary arteriography. Cormack and Hounsfield received the Nobel Prize for Physiology in 1979.  Subsequent major advances have been the dramatic increase in the speed of scanning and image reconstruction and improved image quality as a result of faster and more sophisticated computers. At the Mayo Clinic, dynamic volume scanning was achieved in 1975 with the dynamic spatial reconstructor which is based on multiple X-ray sources  and multiplex detectors for scanning the heart using the mathematical principles of CT.  Fast computed tomography, or electron beam tomography of the heart, was introduced by D. Boyd and co-workers in 1979 at Imatron. Contrary to the conventional CT scanner, this instrument has no moving parts and can acquire an image in as little as 50 ms, obviating the need for ECG-gating. By successively steering a small focal spot size electron beam at four tungsten target rings, producing a moving beam 180o about the patient, with a 180o ring of detectors, the heart is imaged virtually free of motion artifacts.

The existence of ultrasound was recognized by L. Spallanzani (1729–1799). He demonstrated that bats who are blind navigate by means of echo reflection using inaudible sound. In 1880, Jacques and Pierre Curie discovered the piezo-electric effect, a peculiar phenomenon observed in certain quartz crystals, which were the basis of early ultrasound systems and were later replaced by ferroelectric materials. The first suggestion that submerged objects could be located by echo-reflection probably came after theTitanic disaster in 1912. During World War I, P.Langevin (1872–1946) conceived the idea in 1917 of using a piezo-electric quartz crystal as both transmitter and receiver, and this ultimately led to the development of sonar which was completed with the invention of the cathode ray tube, extensively used in World War II for ship navigation and remote submarine detection.  In 1950, the German W. D. Keidel, also using an echo-transmission technique, performed the first cardiac examinations in an attempt to measure cardiac output.

In the late 1960s, the fibreoptic recorder, a spin-off from space technology, was introduced allowing the M-mode recording of all structures along the ultrasound beam: this constituted the definitive breakthrough in echocardiography. Today, M-mode echocardiography remains an important part of a complete cardiac ultrasound examination because of its high temporal resolution.  J Griffith and W Henry introduced the mechanical sector-scanner in 1974, in the same year that FL Thurstone and OT.von Ramm constructed their electronic phased-array scanner. Today, phased-array scanners are the most widely available tomographic imaging instruments with a tremendous impact on cardiac diagnosis. Recently, new computer technologies have enabled the development of volume-rendered data which display tissue information possible even in real-time.   The mono- and biplane electronic phased-array probes developed by J. Souquet in 1982 and his multiplane probe in 1985 represented the definitive clinical breakthrough of transoesophageal echocardiography.

The pulsed-wave Doppler technique allowed depth selection for blood flow velocity interrogation, but the major step forward for its clinical acceptance was its combination with imaging: the duplex scanner, reported by F. E. Barber et al. in 1974[35]. This development ultimately led to the integration of pulsed-wave Doppler with two-dimensional phased-array systems and allowed blood flow to be studied at selected regions within the image plane. The Bernouilli equation is now the cornerstone for Doppler assessment of cardiac haemodynamics and was published by the Dutch born D. Bernouilli (1700–1782) in his treatise ‘Hydrodynamica’ in 1738.  The rapid progress in interventional cardiology renewed the interest in imaging devices, allowing circumferential imaging of the arterial wall under the endothelial surface. Both mechanical single-element and multi-element electronic systems are now increasingly used.

De Hevesy introduced the red cell blood volume measurement and the1284 anniversary ‘dilution principle’ in humans using the first man-made radioisotope 32P produced by the cyclotron in Berkeley, a milestone invention by EO Lawrence in 1931 for which he received the Nobel Prize in 1939. With the cyclotron it was now possible to artificially produce radiopharmaceuticals and radionuclides, which became increasingly available for clinical research. Diagnostic nuclear imaging techniques can be divided into four general groups, depending on localization, dilution, flow or diffusion and biochemical and metabolic properties. Most of these basic principles were first demonstrated by de Hevesy using cyclotron-produced radioisotopes and techniques that he had described many years before—he should therefore be considered the ‘father of nuclear medicine’. It was the introduction of technetium-99m which spurred on the growth of nuclear medicine because of its ideal properties for gamma camera imaging, its short half life and the possibility of producing it in a hospital radiopharmacy. There are now radiopharmaceuticals labelled with 99mTc for almost every application in nuclear medicine. However, the clinical application of nuclear imaging required both counting and detection of radioisotope emissions. Modern counting equipment dates back to 1908 when H Geiger made his first electron counting tube, the precursor of the 1928 Geiger counter. The major breakthrough in radioisotope emission detection was the development of the scintillation scanner by B. Cassen in Los Angeles in 1949, an instrument rapidly followed by refinements. The scintillation camera was designed by Anger based on a concept proposed by DE Copeland and EW Benjamin and was followed by the electronic gamma camera in 1952, which is still the basis of the scintillation camera used today.

Single photon emission tomography (SPET) is based on the pioneering work of Kuhl and Edwards and the first clinical system became available in 1953. However, digital computer technology was necessary for emission tomography as we use it today and put the ‘C’ in SPECT. Tomographic capabilities have proved invaluable in the clinical use of nuclear imaging of the heart. Clinical application rapidly followed technical advances. Although Wren et al. laid the foundation of PET in 1951 it was Sweet and Brownell of Massachusetts General Hospital who conceived the idea of positron imaging which relies on the annihilation radiation emitted at 180o when positrons and electrons meet. PET has a clinical role in defining myocardial viability in patients with ischemic left  ventricular dysfunction who may benefit from revascularization rather than transplantation. It allows the sympathetic nervous system to be studied as regards the development of a number of cardiac disorders by receptor imaging. Although PET was developed before SPECT, it is less accessible because it requires direct access to a cyclotron to produce the short-lived positron emitting tracers and a radiopharmaceutical laboratory, which is not required for SPECT.

F Bloch et al. at Stanford and E Purcell et al. at Harvard in 1946 published a paper on the nuclear magnetic resonance (NMR) phenomenon in bulk matter for which they received the Nobel Prize in Physics in 1952. Initially, the major limitation to NMR spectroscopy in intact living systems was the small bore of the superconducting magnets. In the early 1980s, the Oxford Instrument Company started to produce superconducting magnets with increasing bores and extremely uniform and intense magnetic fields allowing the whole human body to be studied.  The major advantages of MRI are that contrary to ultrasound, the images are not degraded by overlying bony structures, that there is a high natural contrast between flowing blood and soft tissue, the wide field of view, and that cross-sections of the heart can be obtained in any arbitrary orientation. The ideal cardiovascular imaging technique would provide the cardiologist with integrated information on structure function, myocardial characteristics, perfusion and metabolism. Potentially, magnetic resonance imaging offers all this and will probably become the one-stop non-invasive diagnostic test of cardiology.

Real-time dynamic display of registered 4D cardiac MR and ultrasound images using a GQ Zhanga,

Huanga, R Eagleson,G. Guiraudona, and TM Peters

University of Western Ontario, London, ON, Canada

In minimally invasive image-guided surgical interventions, different imaging modalities, such as magnetic resonance imaging (MRI) or computed tomography (CT), and real-time three-dimensional (3D) ultrasound (US), can provide complementary, multi-spectral image information. Multimodality dynamic image registration is a well-established approach that permits real-time diagnostic information to be enhanced by placing lower-quality real-time images within a high quality anatomical context. For the guidance of cardiac procedures, it would be valuable to register dynamic MRI or CT with intraoperative US. However, in practice, either the high computational cost prohibits such real-time visualization of volumetric multimodal images in a real-world medical environment, or else the resulting image quality is not satisfactory for accurate guidance during the intervention. Modern graphics processing units (GPUs) provide the programmability, parallelism and increased computational precision to begin to address this problem.

The Use of Rapid Prototyping in Clinical Applications

G Biglino, S Schievano and AM Taylor
UCL Institute of Cardiovascular Sciences, London
http://www.intechopen.com

Rapid prototyping broadly indicates the fabrication of a three-dimensional (3D) model from a computer-aided design (CAD), traditionally built layer by layer according to the 3D input (Laoui & Shaik, 2003). Rapid prototyping has also been indicated as solid free-form, computer-automated or layer manufacturing (Rengier et al., 2008). The development of this technique in the clinical world has been rendered possible by the concomitant advances in all its three fundamental steps:

1. Medical imaging (data acquisition),
2. Image processing (image segmentation and reconstruction by means of appropriate software) and
3. Rapid prototyping itself (3D printing).

Particular advantages in this discussion are:

1. Customised implants: Instead of using a standard implant and adapting it to the implantation site during the surgical procedure, rapid prototyping enables the fabrication of patient-specific implants, ensuring better fitting and reduced operation time.

2.  Microelectromechanical systems (MEMS): These are micro-sized objects that are fabricated by the same technique as integrated circuits. MEMS can have different. applications, including diagnostics (used in catheters, ultrasound intravascular diagnostics, angioplasty, ECG), pumping systems, drug delivery systems, monitoring, artificial organs, minimally invasive surgery.

Example: Stages of rapid prototyping in a clinical setting. From left to right: data acquisition (in this case with magnetic resonance (MR) imaging), image processing, 3D volume reconstruction with appropriate software (in this case, Mimics®, Materialise, Leuven, Belgium) and final 3D model printed in a transparent resin.

Despite its clinical use to the present day is still somewhat limited, considering the potential and flexibility of this technique, it is likely that applications of rapid prototyping such as individual patient care and academic research will be increasingly utilised (Rengier et al., 2010).

Nuclear Cardiology — In the Era of the Interventional Cardiology

B Baskot, I Ivanov, D Kovacevic, S Obradovic, N Ratkovic and M Zivkovic
Chap 10, InTech.  http://dx.doi.org/10.5772/55484

The strength and breadth of nuclear cardiology lie in its great potential for future creative growth. This growth involves the development of new biologically derived radiopharmaceuticals, advanced imaging techologies, and a broad/based set of research and clinical applications involving diagnosis, functional categorization, prognosis, evaluation of therapeutic interventions, and the ability to deal with many of the major investigative issues in contemporary cardiology such as myocardial hibernation, stunning, and viability. The past decade has been characterized by major advances in nuclear cardiology that have greatly enhanced the clinical utility of the various radionuclide techniques used for the assessment of regional myocardial perfusion and regional and global left ventricular function under resting and stress conditions. Despite the emergence of alternative noninvasive techniques for the diagnosis of coronary aretry disease (CAD) and the assessment of prognosis of viability, such as ergo- stress tests, stress echocardiography, the use and application of nuclear cardiology techniques have continued to increase.

For many years, planar imaging and SPECT with 201Tl (201 Thalium) constituted the only scintigraphic techniques available for detecting CAD and assessing prognosis in patients undergoing stress perfusion imaging. The major limitation of 201Tl scintigraphy is the high false/positive rate observed in many laboratories, which is attributed predominantly to image attenuation artefact and variants of normal that are interpreted as defects consequent to a significant coronary artery stenoses.

In recent years, new 99mTc (technetium) labeled perfusion agents have been introduced into clinical practice to enhance the specificity of Single Photon Emission Cumputed Tomography (SPECT) and to provide additional information regarding and global left ventricular systolic function via ECG gating of images [3, 4, 8]. It was immediately apparent that the quality of images obtained with these 99mTc-labeled radionuclides was superior to that images obtained with 201Tl because of the more favorable psysical characteristic of 99mTc imaging with gamma camera. Perhaps most importantly, 99mTc imaging allows easy gated acquisition, permitting simultaneous evaluation of regional systolic thickening, global left ventricular function (LVEF), and myocardial perfusion. One the most significant avdances in myocardial perfusion imaging in the past decade is the development of quantitative SPECT perfusion imaging.

Indications for nuclear cardiology procedures

CAD is still the single greatest cause of death of men and women in the world, despite a declining total death rate. The reduction of the morbidity and mortality due to CAD is thus primary importance. The first step in evaluating patients for CAD involves the assessment of the presence of traditional risk factors. Symptoms suggestive of CAD, in addition to other risk factors, drive decisions for further testing.
In patients able to exercise, the diagnostic accuracy of stress myocardial perfusion imaging (MPI) is significantly higher than the ETT alone and provides greater risk stratification for predicting the future cardiac events.

Nuclear cardiology –practical applications

  • ETT exercise treadmill test
  • DIP-ECHO dipyridamole echocardiography
  • DOB-ECHO dobutamine echocardiography
  • DIP- MIBI dipyridamole myocardial perfusion imaging with Tc-99m MIBI
  • DOB-MIBI dobutamine myocardial perfusion imaging with Tc-99m MIBI

Evaluating and determination CULPRIT lesion, an indication for interventional cardiology


One of the most powerfull uses of MPI is the evaluation of the risk for future events in patients with suspected or known CAD. Over the years, MPI has evolved as an essential tool in the evaluation and assessment of patient prior to coronary revascularization. It has a dual role. Prior to coronary angiography, MPI is extremely useful in documenting ischemia and determining the functional impact of single or multiple lesions subsequently identified. Despite some limitations in the setting of multivessel disease, MPI remains the test of choice for identifying the lesion responsible for the ischemic symptoms.  The primary objective of those study is to determine and localize the culprit lesion. The authors introduce parameters SRS (summary reversible score) and ISRS (index of summary reversible score), under the angiographically detected coronary narrowing ≥75% for the least one coronary artery. Coronary angiography, considered the “gold standard” for the diagnosis of CAD, often does not provide information about the physiologic significance of atherosclerotic lesions, especially in borderline lesions. More importantly, it does not provide a clear marker of risk of adverse events, especially in patients with moderate disease severity.  The presence of normal scintigraphic MPI study at a high level of stress ( ≥ 85 % of maximum predicted heart rate) or proper pharmacologic stress carries a very benign prognosis, with mortality rate less than 0.5% per year. This finding has been reproduced in many studies. Iskander and Iskandiran, pooling the results of SPECT imaging from more than 12000 patients in 14 studies, demonstrated that the events rate (death/MI) for patients with normal MPI finding is 0.6%, whereas abnormal study carries 7.4% per year event rate, a 12-fold increase.

The size and severity of the perfusion abnormality provide powerful prognostic information and has been shown to directly relate to outcome. MPI perfusion imaging and determination of culprit lesion is more predicitble of cardiac events than coronary angiography. As MPI imaging may identify those patients at high risk for subsequent cardiac events, perfusion imaging may be used to help guide further testing and revascularization procedures. Myocardial perfusion imaging provides information on the extent and location  of myocardial ischemia. The assessment of jeopardized myocardium may be performed and provides a measure of the relative value of PTCA in terms of the amount of jeopardized myocardium. The location of the stenosis may dictate the area at risk: extent and severity of perfusion defects were significantly smaller in patients with proximal compared with distal coronary artery occlusions.

The aim of the study Baskot at al.(*)  was to determine and localize culprit lesion by MPI in cases of angiographically detected coronary narrowing ≥ 75% of at least one coronary artery. In the study four hundred and thirty-seven [437] patients were studied. Angiographically detected significant coronary narrowing (≥ 75% luminal stenosis) was found in all before PCI. All the patients were submitted to MPI 99mTc-MIBI, with pharmacologic dipyridamole stress protocol with concomitant low level bicycle exercise 50 W (DipyEX). We measured relative uptake 99mTc-MIBI for each myocardial segment using short-axis tomogram study. A 5-point scoring system was used to assess the difference between uptake degree in stress and rest studies for the same segment, and we created two indices: Sum reversible score (SRS), Index of sum reversibility score (ISRS). In the results a total 1311 vascular territories (7429 segments) were analyzed before elective percutaneous coronary intervention (ePCI). Overall sensitivity, specificity and accuracy using SRS were 89.7%, 86, 7%, and 88, 2%, with a positive predictive value of 92, 7%. Overall sensitivity, specificity and accuracy using ISRS were 92.8%, 89.1%, and 92.3%, and the positive predictive value was 93.7%.

Pathophysiology and investigation of coronary artery disease

Ever D Grech
University of Manitoba, Winnipeg
BMJ 2003;326:1027–30

In affluent societies, coronary artery disease causes severe disability and more death than any other disease, including cancer. It manifests as angina, silent ischemia, unstable angina, myocardial infarction, arrhythmias, heart failure, and sudden death.  Coronary artery disease is almost always due to atheromatous narrowing and subsequent occlusion of the vessel. A mature plaque is composed of two constituents, each associated with a particular cell population. The lipid core is mainly released from necrotic “foam cells”—monocyte derived macrophages, which migrate into the intima and ingest lipids. The connective tissue matrix is derived from smooth muscle cells, which migrate from the media into the intima, where they proliferate and change their phenotype to form a fibrous capsule around the lipid core.

Stress echocardiography

Stress induced impairment of myocardial contraction is a sensitive marker of ischemia and precedes electrocardiographic changes and angina. Cross sectional echocardiography can be used to evaluate regional and global left ventricular impairment during ischaemia, which can be induced by exercise or an intravenous infusion of drugs that increase myocardial contraction and heart rate (such as dobutamine) or dilate coronary arterioles (such as dipyridamole or adenosine).

Radionuclide myocardial perfusion imaging

Thallium-201 or technetium-99m (99mTc-sestamibi, 99mTc-tetrofosmin) is injected intravenously at peak stress, and its myocardial distribution relates to coronary flow. Images are acquired with a gamma camera. This test can distinguish between reversible and irreversible ischemia (the latter signifying infarcted tissue). Although it is expensive and requires specialised equipment, it is useful in patients whose exercise test is non-diagnostic or whose exercise ability is limited.

A multigated acquisition (MUGA) scan assesses left ventricular function and can reveal salvageable myocardium in patients with chronic coronary artery disease. It can be performed with either thallium scintigraphy at rest or metabolic imaging with fluorodeoxyglucose by means of either positron emission tomography (PET) or single photon emission computed tomography (SPECT).

Intravascular ultrasound (IVUS)

In contrast to angiography, which gives a two dimensional luminal silhouette with little information about the vessel wall, intravascular ultrasound provides a cross sectional, three dimensional image of the full circumference of the artery. It allows precise measurement of plaque length and thickness and minimum lumen diameter, and it may also characterise the plaque’s composition. It is often used to clarify ambiguous angiographic findings and to identify wall dissections or thrombus. It is most useful during percutaneous coronary intervention, when target lesions can be assessed before, during, and after the procedure and at follow up. The procedure can also show that stents which seem to be well deployed on angiography are, in fact, suboptimally expanded.

Interventional Cardiology for Structural Heart Disease

Georgios Parcharidis
Hellenic J Cardiol 2012; 53: 403-404

Many questions arise from this “explosion” of new technologies. Is all this enthusiasm justified and supported by robust scientific evidence? Which is the best way to implement these new treatment options? What is the role of “traditional” surgical treatment? How can we decide which patient should be treated percutaneously and which surgically? What level of training and experience should an interventional cardiologist (or a centre) have in order to perform structural and/or congenital heart disease interventions?

With regard to the scientific evidence, it should be noted that, currently, the number of randomized clinical trials and the duration of follow up is quite limited. Thus, great caution should be exercised in patient selection and planning for these complex procedures. In addition, careful data collection and, ideally, inclusion in a patient registry would increase surveillance and, therefore, patient safety.

Notably, for the majority of structural and congenital heart diseases, surgery is still considered the “gold standard”. It is now globally accepted that decision making for patients with cardiovascular disease should be done in the context of a “Heart Team”, with close collaboration between cardiologists, cardiothoracic surgeons, anesthesiologists, imaging specialists and, occasionally, other specialists. Some patients will benefit more from transcatheter interventions whereas others will do better with surgery. Based on specific criteria, the role of the Heart Team is to identify (and treat) those patients.

PET vs. SPECT: Will PET Dominate Over the Next Decade?

DAIC  July/August 2013  pp28-31.  www. DIcardiology.com

The future success of PET may be grounded in its inherently better image resolution. In cardiac scanning, it has generally been reported that PET offers a resolution of 5 to 7 mm, compared with a cardiac SPECT resolution of 12 to 15 mm. Better performance has allowed data to emerge suggesting that as many as one in 10 scans interpreted as normal on SPECT would have been abnormal if done on PET due to the presence of unseen microvascular, triple-vessel disease. PET’s superior diagnostic capability is achieved partly through advances in hardware, particularly quantification, which leverages numerical precision to identify global perfusion defects in the heart that otherwise might be hidden from qualitative SPECT scans.

A big difference between the two technologies is the half-life of the isotope that each radiopharmaceutical tracer uses. SPECT tracers have a relatively long half-life (technetium-99m has a half-life of six hours), whereas rubidium-82 is only 75 seconds. This short half-life is a limitation of the current front-line cardiac PET radiotracer, which does not leave much room for error when imaging and presents the inability to do exercise stress testing. New iterative reconstruction (IR) software such as UltaSPECT is improving SPECT image quality by boosting the signal-to-noise ratio. Just as in CT scans, IR can also help reduce dose by enhancing lower-quality scans.

Part III

Heart Failure Patients

Heart Failure Complicating Non–ST-Segment Elevation Acute Coronary Syndrome -Timing, Predictors, and Clinical Outcomes

MC Bahit, RD Lopes, RM Clare, LK Newby,KS Pieper, et al.
J Am Coll Cardiol HF 2013;1(3): 223–9This study sought to describe the occurrence and timing of heart failure (HF), associated clinical factors, and 30-day outcomes in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS). Using pooled patient-level data from 7 clinical trials from 1994 to 2008, we describe the occurrence and timing of HF,associated clinical factors, and 30-day outcomes in NSTE-ACS patients. HF at presentation was defined as Killip classes II to III; patients with Killip class IV or cardiogenic shock were excluded. New in-hospital cases of HF included new pulmonary edema. After adjusting for baseline variables, we created logistic regression models to identify clinical factors associated with HF at presentation and to determine the association between HF and 30-day mortality.Of 46,519 NSTE-ACS patients, 4,910 (10.6%) had HF at presentation. Of the 41,609 with no HF at presentation, 1,194 (2.9%) developed HF during hospitalization. A total of 40,415 (86.9%) had no HF at any time. Patients presenting with or developing HF during hospitalization were older, more often female, and had a higher risk of death at 30 days than patients without HF (adjusted odds ratio [OR]: 1.74; 95% confidence interval: 1.35 to 2.26). Older age, higher presenting heart rate, diabetes, prior myocardial infarction (MI), and enrolling MI were significantly associated with HF during hospitalization. In this large cohort of NSTE-ACS patients, presenting with or developing HF during hospitalization was associated with an increased risk of 30-day mortality.

Outcomes Following Heart Transplantation among Those Bridged with VAD

Jeffrey Shuhaiber MD
University of Cincinnati and Cincinnati Children’s Hospital
www.intechopen.com

Clinical assessment of outcome for post heart transplant recipients who were bridged with ventricular assist device is essential for service evaluation, device evaluation and audit. We will review the clinical outcomes measured so far in the field of heart transplant recipients who were bridged with VAD. In this chapter we will review the ongoing methods of assessment of outcomes for transplant recipients bridged by VAD and discuss the potential challenges facing the clinicians. We will finalize with brief conclusions and future directions.

Survival following heart transplantation: Does VAD Type matter?

There have been many clinical studies comparing outcomes following heart transplantation. Only one has been done in a multicenter fashion with clinically relevant as well as a robust risk-adjustment. In 2006 we asked the question- does survival differ between those who did and did not receive the left ventricular assist device (LVAD) following heart transplantation? And in summary we found that survival following heart transplantation for patients who received an LVAD prior to transplantation was comparable to those who did not receive an LVAD. The results of this study were published as lead research article in the British Medical Journal earlier this year (Shuhaiber).

We reviewed all patients above 18 years of age who received heart transplants registered in the United Network for Organ Sharing (UNOS) Registry from 1996 to 2004. The study included 2786 status 1/1A/1B heart transplant patients. We used the entry data for all patients who received LVAD pulsatile device. Our study design included a prospective cohort study in which post-transplant survival between patients who received an LVAD and those who did not receive an LVAD was compared.

1:1 propensity score matching analysis was also performed. Comparisons of survival distributions were made using the Kaplan-Meier method and the risk ratios were estimated using Cox proportional model. Our primary outcomes as well as risks and exposures included survival following heart transplantation in heart transplant recipients who did or did not receive ventricular assist device. The strength of the study was in adopting a robust statistical methodology that can adequately control for confounding variables. A stratified  propensity score analysis of data revealed that the risk of death following heart transplantation in an LVAD patient was not significantly different from those who did not have an LVAD within each stratum (see table for estimated hazard ratios and their 95% confidence intervals). A 1:1 propensity score matching analysis also revealed no significant difference in post heart transplant survival between the two groups (hazard ratio = 1.18, 95% CIs=0.75 to1.86). The propensity score matching was performed in order to control potential selection biases that can lead to a false association (or false lack of association) between LVAD and survival.

Part IV

Mechanical Heart Devices

The treatment of heart failure at end stage myocardial function has depended on having patients on waiting lists until the time that a donor heart becomes available.  Waiting times are within 1.5 to 4.5 years.  This required the development for mechanical support until a suitable donor is found.  The expectation for future devices will be that suitable mechanical heart assist devices for selected patients will possibly alleviate the need for a donor heart.

There are two main types of mechanical assist devices.  One type ios actually a total artificial heart, and the other is an assist that in complementary to the still functioning weak left ventricle.  The VAD was just discussed in the preceding discussion.  It has a pump that is attached to the atria and the pump controls the flow of blood through the pulmonary circulation.  This device is extremely important for patients who have sufficient LV function to not require a TAH.

The total artificial heart  (TAH) has been dominated by use of either of two models – the Syncardia temporary artificial heart, and the AbiCor.  The difference between them is that one has an externalization outside the thorax to an electrical source.  The Syncardia model is a modern day improvement of Jarvik-7.
The controlled flow is a miniature motor that has a rotor that moves the blood forward.  Of course, it presents a problem with respect to blood cell damage and anemia.  One of the innovations to the blood flow control has been that it flows without a heart beat.  The most significant innovation is the entry into the market of a new model, the Carmat, from France.  The Carmat would reduce the hemolysis that is associated with the flow of RBCs along a synthetic lining.  How?  It has the blood in contact with a cow skin lining.

Part V

Heart Transplant


The heart transplant is a technique that has been mastered at a number of excellent cardiothoracic surgical sites, and the facilities are being replaced by Hybrid Units that accommodate cardiology and surgical interventions. This brings to fruition the concept of a “Heart Team”.  The procedure has risks of complication, either in the patient condition, or in environmental, or other factors the surgeon has no control over.

These factors include, associated comorbidities, such as

  • diabetes mellitus
  • Late NYHF Stage 4
  • Late stage renal disease
  • mismatch of Graft vs Host
  • infection

Other related articles published on this Open Access Online Scientific Journal, include the following: 

Pearlman, JD and A. Lev-Ari, Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

https://pharmaceuticalintelligence.com/2013/07/23/cardiovascular-complications-of-multiple-etiologies-repeat-sternotomy-post-cabg-or-avr-post-pci-pad-endoscopy-andor-resultant-of-systemic-sepsis/

Larry H Bernstein, Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/

Pearlman, JD and A. Lev-Ari  Cardiac Resynchronization Therapy (CRT) to Arrhythmias: Pacemaker/Implantable Cardioverter Defibrillator (ICD) Insertion

https://pharmaceuticalintelligence.com/2013/07/22/cardiac-resynchronization-therapy-crt-to-arrhythmias-pacemakerimplantable-cardioverter-defibrillator-icd-insertion/

Lev-Ari, A.  3D Cardiovascular Theater – Hybrid Cath Lab/OR Suite, Hybrid Surgery, Complications Post PCI and Repeat Sternotomy

https://pharmaceuticalintelligence.com/2013/07/19/3d-cardiovascular-theater-hybrid-cath-labor-suite-hybrid-surgery-complications-post-pci-and-repeat-sternotomy/

Read Full Post »


Cardiovascular Complications: Death from Reoperative Sternotomy after prior CABG, MVR, AVR, or Radiation; Complications of PCI; Sepsis from Cardiovascular Interventions

Author, Introduction and Summary: Justin D Pearlman, MD, PhD, FACC

and

Article Curator: Aviva Lev-Ari, PhD, RN

The Curator recommends the e-Reader to read the following book on Surgical Complications:

Complications
“Essential Reading For Anyone Involved In Medicine”–Amazon.com –  2002

Cardiovascular Complications:

I. Reoperative Sternotomy after prior CABG, MVR, AVR, or radiation therapy

IIa. PCI, and

IIb. PAD Endovascular Interventions: Carotid Artery Endarterectomy

III. Incidence of Sepsis (circulation infection with serious consequences)

UPDATED 11/2/2013

As minimally interventional techniques improve, patients are offered a choice of invasive surgical remedies or less invasive procedures (video assisted, robotic, or percutaneous). The decision should not rest on the size of the scar or even the up front risk and discomfort, but rather should weigh all aspects of the risks and benefits. In addition to the risks and benefits for the current problem, one should also consider why the problem occurred and its likelihood of recurrence. Open chest surgery has a clear disadvantage when it comes to recurrences, as the scars from first surgery interfere with second surgery. Opening the chest (sternotomy) for a second or third time poses elevated risks analyzed herein. This article reviews data from major centers addressing the risks from repeat sternotomy and from minimally invasive cardiovascular surgeries. Any invasion of the body elevates risk of infection, which can lead to sepsis and possible death, so that risk is also addressed.

I. Risk of Injury During Repeat Sternotomy for CABG or Aortic Valve Replacement, Open Heart Surgery

II. Complications After Percutaneous Coronary intervention (PCI) and endovascular surgery for Peripheral Artery Disease (PAD)

  • (a) Post PCIand 
  • (b) PAD Endovascular Interventions: Carotid Artery Endarterectomy

III. Cardiac Failure During Systemic Sepsis

This article addresses specific reports of complications but does not cover numerous other complications that may occur, such as lung collapse, cardiogenic shock, blood loss, local infection, emboli, thrombus, stroke.

I. Risk of Injury During Open Heart Surgery after prior Coronary Artery Bypass Grafting (CABG), Aortic Valve Replacement, Mitral Valve Replacement, or Radiation Therapy 

Conclusions of a Study conducted @Mayo Clinic on Reoperative (Repeat) Sternotomy (opening of the chest through the sternum):

Chan B. Park, MD,a,b Rakesh M. Suri, MD,a Harold M. Burkhart, MD,a Kevin L. Greason, MD,a

Joseph A. Dearani, MD,a Hartzell V. Schaff, MD,a and Thoralf M. Sundt III, MDa

Identifying patients at particular risk of injury during repeat sternotomy: Analysis of 2555 cardiac reoperations

Authors Affiliations: From the Division of Cardiovascular Surgery,

a Mayo Clinic, Rochester, Minn; and the Department of Thoracic and Cardiovascular Surgery,

b St. Paul’s Hospital, The Catholic University of Korea, Seoul, Korea.

Disclosures: None.

Read at the 90th Annual Meeting of The American Association for Thoracic Surgery, Toronto, Ontario, Canada, May 1–5, 2010. Received for publication April 6, 2010; revisions received July 19, 2010; accepted for publication July 30, 2010.

doi:10.1016/j.jtcvs.2010.07.086

Particular attention to protective strategies should be considered during reoperative sternotomy among patients with multiple previous sternotomies, previous mediastinal radiotherapy, and those with patent internal thoracic artery grafts. (J Thorac Cardiovasc Surg 2010;140:1028-35)

Of the 2555 patients,

  • 1537 (60%) had undergone previous coronary artery bypass grafting,
  • 700 (27%) previous mitral valve surgery, and
  • 643 (25%) previous aortic valve replacement (AVR).
  • 61 (2%) had prior mediastinal radiotherapy, and
  • 424 (17%) had more than one previous sternotomy.

 Injury Analysis – 9% events in 231 Patient in the study

In 231 patients, 267 injuries (9.0%) occurred.

Injury occurred

  • during sternotomy in 87 patients (33%) and
  • during prepump dissection in 135 (51%).

Hospital mortality rate was

6.5% among those without injury and

18.5% among those with injury (P < .001);

25% when injury occurred during sternal division

Injuries were more common

1. after previous coronary artery bypass grafting

  • 11% with previous coronary artery bypass grafting vs
  • 7% without, (P = .0012)

but not

  • previous aortic valve surgery,
  • previous mitral valve surgery, or
  • previous aorta surgery.

2.  Injury was also more common when the current operation was aortic valve replacement (AVR)

  • 10% with AVR vs
  • 8% without, (P = .04) or

3.  aorta surgery

  • 14% vs
  • 8% (P = .004).

Predicted injury by multivariate analysis –

Injury was an independent risk factor of hospital death (odds ratio, 2.6).

4.   previous radiotherapy (odds ratio, 4.9)

5.  a greater number of previous sternotomies (odds ratio 1.7), and

6.  a patent internal thoracic artery (odds ratio, 1.8)

J Thorac Cardiovasc Surg. 2010 Nov;140(5):1028-35. doi: 10.1016/j.jtcvs.2010.07.086.

Identifying patients at particular risk of injury during repeat sternotomy: analysis of 2555 cardiac reoperations.

Source

Division of Cardiovascular Surgery, Mayo Clinic, Rochester, MN 55905, USA.

Abstract

OBJECTIVES:

A variety of protective strategies during repeat sternotomy been proposed; however, it remains unclear for which patients they are warranted.

METHODS:

We identified adults undergoing repeat median sternotomy for routine cardiac surgery at our institution between January 1, 1996, and December 31, 2007. The operative notes and perioperative outcomes were reviewed.

RESULTS:

Of the 2555 patients, 1537 (60%) had undergone previous coronary artery bypass grafting, 700 (27%) previous mitral valve surgery, and 643 (25%) previous aortic valve replacement (AVR). Sixty-one patients (2%) had prior mediastinal radiotherapy, and 424 (17%) had more than one previous sternotomy. In 231 patients, 267 injuries (9.0%) occurred. Injury occurred during sternotomy in 87 patients (33%) and during prepump dissection in 135 (51%). The hospital mortality rate was 6.5% among those without injury and 18.5% among those with injury (P < .001); when injury occurred during sternal division, the mortality rate was 25%. Injuries were more common after previous coronary artery bypass grafting (11% with previous coronary artery bypass grafting vs 7% without, P = .0012) but not previous AVR, mitral valve surgery, or aortic surgery. Injury was also more common when the current operation was AVR (10% with AVR vs 8% without, P = .04) or aortic surgery (14% vs 8%, P = .004). On multivariate analysis, previous radiotherapy (odds ratio, 4.9), a greater number of previous sternotomies (odds ratio 1.7), and a patent internal thoracic artery (odds ratio, 1.8) predicted injury. Injury was an independent risk factor of hospital death (odds ratio, 2.6).

CONCLUSIONS:

Particular attention to protective strategies should be considered during reoperative sternotomy among patients with multiple previous sternotomies, previous mediastinal radiotherapy, and those with patent internal thoracic artery grafts.

Copyright © 2010 The American Association for Thoracic Surgery. Published by Mosby, Inc. All rights reserved.

Comment in

TABLE 2. Hospital mortality according to Timing of Injury

Timing Mortality rate with injury P value

  • Re-entry 19/76 (25.0%) <.001
  • Prepump 20/121 (16.5%) <.001
  • Cardiopulmonary bypass (CPB)  3/14 (21.4%) .05
  • Aortic CrossClamp (ACC 1/11) (9.1%) .85
  • Closing 5/17 (29.4%) <.001

TABLE 1. Preoperative patient characteristics

Characteristic No injury (n 1/4 2324) Injury (n 1/4 231) P value

Age (y) 66.9  12.4 67.7  11.5 .509

Men 1583 (68.1%) 167 (72.3%) .192

Diabetes mellitus 499 (21.5%) 61 (26.4%) .084

Hypertension 1536 (66.2%) 158 (68.4%) .490

Hypercholesterolemia 1656 (71.4%) 171 (74.0%) .395

Myocardial infarction 633 (27.3%) 68 (29.4%) .480

Congestive heart failure 758 (32.6%) 89 (38.5%) .069

NYHA .064

I-II 492 (21.2%) 37 (16.0%)

III-IV 1830 (78.8%) 184 (84.0%)

Previous operation No injury (n 1/4 2324) Injury (n 1/4 231) P value

CABG 1375 (59.2%) 162 (70.1%) .001

Aortic valve surgery 586 (25.2%) 57 (24.7%) .857

Mitral valve surgery 645 (27.8%) 55 (23.8%) .200

Tricuspid valve surgery 64 (2.8%) 9 (3.9%) .320

Aorta surgery 167 (7.2%) 20 (8.7%) .413

Current operation No injury (n 1/4 2324) Injury (n 1/4 231) P value

CABG 897 (38.6%) 104 (45.0%) .056

Aortic valve surgery 1020 (43.9%) 118 (51.1%) .036

Mitral valve surgery 821 (35.3%) 80 (34.6%) .833

Tricuspid valve surgery 414 (17.8%) 52 (22.5%) .078

Aortic surgery 232 (10.0%) 37 (16.0%) .004

DISCUSSION

The results of the present study have confirmed the significant risk of cardiovascular injury during reoperative cardiac surgery. The death rate from such injury can be 10-30%, particularly  when occurring during division of the sternum. These risks are greatest among patients with multiple previous sternotomies or prior chest radiotherapy.

Current PROTOCOL at Virginia University, now suggested to be considered for adoption @Mayo Clinic:

The Mayo Clinic’s Authors write: Our findings are more consistent with those reported by Roselli and colleagues.2 The explanation of these institutional differences is unclear, although a number of practice differences are likely present between these institutions in terms of both patient substrate and surgical practice. Compared with the series from the University of Virginia, the Mayo series we have reported represents a greater percentage of total cases performed at the institution (13.5% vs 7.8%), with a somewhat greater percentage of those reoperations being for CABG (41% vs 60%). In the Mayo series, a lower percentage were first-time repeat sternotomies (83% vs 90%) and a greater percentage were the fourth time or more (2.7% vs 1.1%).

The incidence of previous radiotherapy in the University of Virginia series was not reported.

It is also unclear to what degree the differences in surgical practice, including the role of the assistant surgeons in performing the repeat sternotomy, could account for these differences. In the present retrospective study, we were unable to demonstrate an effect of experience or expertise in either the occurrence of injury or the outcome. However, it is clear to all practicing surgeons that, when injury occurs, the judgment and expertise of the operating surgeon is critical to expeditious institution of CPB or other ‘‘rescue’’ maneuvers.

Perhaps of more practical value and broad applicability, however, is the standardized approach to repeat sternotomy advocated by the group at the University of Virginia, including routine preoperative CT scanning if the procedure is the third or fourth sternotomy and insertion of a femoral arterial line by which emergent percutaneous arterial inflow cannulation can be accomplished, if necessary. In their series, emergent institution of CPB using the femoral route was instituted in 1.8% of reoperative patients, constituting 19% of the patients with injury. Most notably, in their series, no deaths occurred among these patients. Serious consideration should be given to adopting such protocols.

Our high mortality rate associated with SVG injury during sternotomy, however, supports the  recommendation by others to carefully assess the course of bypass grafts by preoperative angiography. Routine preoperative CT imaging of all patients with more than one previous sternotomy has been advocated by Morishita and colleagues,3 with a demonstrable reduction in operative complications. Roselli and colleagues2 identified a lack of preparative imaging as the most common ‘‘lapse’’ in the preventive strategy among patients with injury. Our data suggest that CT scanning might be particularly helpful in the subset of patients with multiple previous sternotomies or radiotherapy and would support the institution of a policy of routine scanning for these patients.

FIGURE 1. Hospital mortality according to emergent cardiopulmonary bypass (CPB) in The Journal of Thoracic and Cardiovascular Surgery c November 2010, pp. 1032

TABLE 5. Postoperative results

No injury (n 1/4 2324) —  Injury (n 1/4 231) — P value

Postoperative transfusion (U)

PRCs 4.5  7.2 6.5  8.9 .046

ICU stay (h) 102.3  228.6 146.3 +/- 346.9 <.001

Reoperation for bleeding 127 (5.5%) 21 (9.1%) .024

Sepsis 86 (3.7%) 16 (6.9%) .017

Stroke 56 (2.4%) 11 (4.8%) .033

Prolonged ventilation 505 (21.7%) 97 (42.0%) <.001

Pneumonia 123 (5.3%) 25 (10.8%) <.001

ARDS 32 (1.4%) 8 (3.5%) .015

Postoperative renal failure 237 (10.2%) 51 (22.1%) <.001

Multisystem failure 45 (1.9%) 13 (5.6%) <.001

Perioperative MI 9 (0.4%) 2 (0.9%) .289

Hospital death 151 (6.5%) 43 (18.6%) <.001

Abbreviations:

IABP, intra-aortic balloon pump; ICU, intensive care unit; ARDS, acute respiratory

distress syndrome; MI, myocardial infarction.

SOURCE
The Journal of Thoracic and Cardiovascular Surgery c November 2010, pp. 1032

Independent predictors for injury during repeat median sternotomy

The structures injured and the timing of injury in our study were similar to those reported by Roselli and colleagues.2  Bypass grafts were the most commonly injured and, perhaps in contrast to expectations, most injuries occurred during dissection, not during sternal division. Unlike their study, however, we found injury during sternal division to carry a greater mortality risk. We observed a remarkably high mortality rate associated with injury to the right ventricle, as did Roselli and colleagues.2  This may be particularly true in the presence of pulmonary hypertension, when attempts to repair the injury are hampered by inadequate access, progressive tearing of the ventricle secondary to traction injury, and what can be a relatively thin and friable free wall. The incidence of injury to the Internal thoracic artery (ITA) in our series (4.9%) was comparable to the 4.4%–5.3% reported by other investigators.11-14 Because the ITA was damaged more often during prepump dissection (20.7%) than during re-entry (11.5%), these data support the trend to avoid dissecting and isolating the ITA during AVR after previous CABG.12,13

FOUR CONCLUSIONS

1. On the basis of these data, we would advocate preoperative axial CT imaging to define the proximity of cardiovascular structures to the sternum of patients who have undergone more than one previous sternotomy and those who have undergone radiotherapy because these patients statistically have the greatest risk of injury.

2. We would also advocate considering percutaneous or open access of the femoral vessels, if not the institution of CPB, before sternotomy in these same patients, as well as those with significant pulmonary hypertension.

3. Because injury is common during prepump dissection, we support a philosophy of leaving patent ITA grafts undisturbed by attempts to gain control during AVR after previous CABG.

4. Finally, given the mortality rate associated with graft injury, patients with previous CABG should be considered for graft angiography or high-resolution CT.

Summary 

This is a very important study  on the Outcomes and the Complications involved in Cardiac Surgery @Mayo Clinic.

Study’s Objectives: A variety of protective strategies during repeat sternotomy been proposed; however, it remains unclear for which patients they are warranted.

Authors @Mayo Clinic reported:

We were unable to definitively assess the effect of any specific protective strategies on the incidence of injury. Because we do not have standardized or uniform prospective institutional policies in this regard, it was not possible to account for the confounding factor of the clinician’s judgment in the decision to use these strategies in particularly highrisk patients.

Our high mortality rate associated with saphenous vein graft (SVG) injury during sternotomy, however, supports the  recommendation by others to carefully assess the course of bypass grafts by preoperative angiography. Routine preoperative CT imaging of all patients with more than one previous sternotomy has been advocated by Morishita and colleagues,3 with a demonstrable reduction in operative complications.

The reader is advised to review another article Co-Curated by us on the following related study by Mayo Clinic researches, This article examines 10-year to 15-year survivals from arterial bypass grafts using arterial vs saphenous venous grafts.

CABG Survival in Multivessel Disease Patients: Comparison of Arterial Bypass Grafts vs Saphenous Venous Grafts

The conclusions in this article are:

In patients undergoing isolated coronary artery bypass graft surgery with LIMA to left anterior descending artery,

  • arterial grafting of the non-left anterior descending vessels conferred a survival advantage at 15 years compared with Saphenous Venous grafting (SVG).

It is still unproven whether these results apply to higher-risk subgroups of patients.

Related study

Coronary Artery Disease – Medical Devices Solutions: From First-In-Man Stent Implantation, via Medical Ethical Dilemmas to Drug Eluting Stents,

REFERENCES

1. Sabik JF III, Blackstone EH, Houghtaling PL,Walts PA, LytleBW. Is reoperation

still a risk factor in coronary artery bypass surgery? Ann Thorac Surg. 2005;80:

1719-27.

2. Roselli EE, Pettersson GB, Blackstone EH, Brizzio ME, Houghtaling PL,

Lauck R, et al. Adverse events during reoperative cardiac surgery: Frequency,

characterization, and rescue. J Thorac Cardiovasc Surg. 2008;135:316-23.

3. Morishita K, Kawaharada N, Fukada J, Yamada A, Masaru T, Kuwaki K, et al.

Three or more median sternotomies for patients with valve disease: Role of computed

tomography. Ann Thorac Surg. 2003;75:1476-81.

4. Luciani N, Anselmi A, De Geest R, Martinelli L, Perisano M, Possati G. Extracorporeal

circulation by peripheral cannulation before redo sternotomy: Indications

and results. J Thorac Cardiovasc Surg. 2008;136:572-7.

5. Potter DD, Sundt TM III, Zehr KJ, Dearani JA, Daly RC, Mullany CJ, et al. Risk

of repeat mitral valve replacement for failed mitral valve prostheses. Ann Thorac

Surg. 2004;78:67-72.

6. Potter DD, Sundt TM III, Zehr KJ, Dearani JA, Daly RC, Mullany CJ, et al. Operative

risk of reoperative aortic valve replacement. J Thorac Cardiovasc Surg.

2005;129:94-103.

7. Sundt TM III, Murphy SF, Barzilai B, Schuessler RB, Mendeloff EN,

Huddleston CB, et al. Previous coronary artery bypass grafting is not a risk factor

for aortic valve replacement. Ann Thorac Surg. 1997;64:651-7.

8. Ellman PI, Smith RL, Girotti ME, Thompson PW, Peeler BB, Kern JA, et al. Cardiac

injury during resternotomy does not affect perioperative mortality. JAm Coll

Surg. 2008;206:993-9.

9. Chang ASY, Smedira NG, Chang CL, Benavides MM, Myhre U, Feng J, et al.

Cardiac surgery after mediastinal radiation: Extent of exposure influences outcome.

J Thorac Cardiovasc Surg. 2007;133:404-13.

10. Schmuziger M, Christenson JT, Maurice J, Mosimann E, Simonet F, Velebit V.

Reoperative myocardial revascularization: An analysis of 458 reoperations and

2645 single operations. Cardiovasc Surg. 1994;2:623-9.

11. Gillinov AM, Casselman FP, Lytle BW, Blackstone EH, Parsons EM, Loop FD,

et al. Injury to a patent left internal thoracic artery graft at coronary reoperation.

Ann Thorac Surg. 1999;67:382-6.

12. Byrne JG, Karavas AN, Filsoufi F, Mihaljevic T, Aklog L, Adams DH, et al. Aortic

valve surgery after previous coronary artery bypass grafting with functioning

internal mammary artery grafts. Ann Thorac Surg. 2002;73:779-84.

13. Smith RL, Ellman PI, Thompson PW, Girotti ME, Mettler BA, Ailawadi G, et al.

Do you need to clamp a patent left internal thoracic artery—Left anterior descending

graft in reoperative cardiac surgery? Ann Thorac Surg. 2009;87:742-7.

14. Coltharp WH, Decker MD, Lea JWIV, Petracek MR, Glassford DM,

Thormas CS, et al. Internal mammary artery graft at reoperation: Risks, benefits,

and methods of preservation. Ann Thorac Surg. 1991;52:225-9.

15. O’Brien MF, Harrocks S, Clarke A, Garlick B, Barnett AG. How to do safe sternal

reentry and the risk factors of redo cardiac surgery: A 21-year review with

zero major cardiac injury. J Cardiac Surg. 2002;17:4-13.

16. Klein G. Naturalistic decision making. Human Factors. 2008;50:456-60.

II. Complications After Percutaneous Coronary intervention (PCI) and endovascular surgery for Peripheral Artery Disease (PAD)

(a) after prior PCI, and

(b) after prior PAD Endovascular Interventions: Carotid Artery Endarterectomy

II(a)  PCI  After Prior PCI – Major occurring Complications include the following:

 

  • Hematoma (a firm collection of blood greater than 2 cm around or in the proximity of the access site).
  • Pseudoaneurysm / dissection,
  • A-V fistula and ischemic leg were also considered along with
  • Retroperitoneal bleed. Retroperitoneal bleeding was defined by any amount of bleeding in the retroperitoneum diagnosed by computer tomography.
  • Inflammation of the Lower extremity on the side of the access site to the femoral artery

UPDATED 11/2/2013

VIEW VIDEO

Impact of Intra-procedural Stent Thrombosis during Percutaneous Coronary Intervention: Insights from the CHAMPION PHOENIX Trial ONLINE FIRST

Philippe Généreux, MD1; Gregg W. Stone, MD1; Robert A. Harrington, MD4; C. Michael Gibson, MD5; Ph. Gabriel Steg, MD6; Sorin J. Brener, MD10; Dominick J. Angiolillo, MD, PhD11; Matthew J. Price, MD12; Jayne Prats, PhD13; Laura LaSalle, MPH2; Tiepu Liu, MD, PhD12; Meredith Todd, B.Sc12; Simona Skerjanec, Pharm.D12; Christian W. Hamm, MD14; Kenneth W. Mahaffey, MD4; Harvey D. White, DSc15; Deepak L. Bhatt, MD, MPH16
J Am Coll Cardiol. 2013;():. doi:10.1016/j.jacc.2013.10.022

Abstract

Objective  We sought to evaluate the clinical impact of intra-procedural stent thrombosis (IPST), a relatively new endpoint.

Background  In the prospective, double-blind, active-controlled CHAMPION PHOENIX trial, cangrelor significantly reduced periprocedural and 30-day ischemic events in patients undergoing percutaneous coronary intervention (PCI), including IPST.

Methods  An independent core laboratory blinded to treatment assignment performed a frame-by-frame angiographic analysis in 10,939 patients for the development of IPST, defined as new or worsening thrombus related to stent deployment anytime during the procedure. Adverse events were adjudicated by an independent, blinded clinical events committee.

Results  IPST developed in 89 patients (0.8%), including 35/5470 (0.6%) and 54/5469 (1.0%) in the cangrelor and clopidogrel arms, respectively (OR [95%CI] = 0.65 [0.42,0.99], p=0.04). Compared to patients without IPST, IPST was associated with a marked increase in composite ischemia (death, myocardial infarction [MI], ischemia-driven revascularization, or new onset out-of-lab stent thrombosis [ARC]) at 48 hours and at 30 days (29.2% vs. 4.5% and 31.5% vs. 5.7%, P<0.0001 for both). After controlling for potential confounders, IPST remained a strong predictor of all adverse ischemic events at both time points.

Conclusion  In the large-scale CHAMPION PHOENIX trial, the occurrence of IPST was strongly predictive of subsequent adverse cardiovascular events. The potent intravenous ADP antagonist cangrelor substantially reduced IPST, contributing to its beneficial effects at 48 hours and 30 days.

Clinical trial info  CHAMPION PHOENIX; NCT01156571

Bleeding and Vascular Complications at the Femoral Access Site Following Percutaneous Coronary Intervention (PCI): An Evaluation of Hemostasis Strategies

Author(s):

Dale R. Tavris, MD, MPH1, Yongfei Wang, MS2, Samantha Jacobs, BS1, Beverly Gallauresi, MPH, RN1, Jeptha Curtis, MD2, John Messenger, MD3, Frederic S. Resnic, MD, MSc4, Susan Fitzgerald, MS, RN5

Authors Affiliation

From the 1US Food and Drug Administration (FDA), Silver Spring, Maryland, 2Yale University, New Haven, Connecticut, 3University of Colorado, Boulder, Colorado, 4Brigham and Women’s Hospital, Boston, Massachusetts, and 5the American College of Cardiology, Bethesda, Maryland.

Abstract: Background. Previous research found at least one vascular closure device (VCD) to be associated with excess vascular complications, compared to manual compression (MC) controls, following cardiac catheterization. Since that time, several more VCDs have been approved by the Food and Drug Administration (FDA). This research evaluates the safety profiles of current frequently used VCDs and other hemostasis strategies. Methods. Of 1089 sites that submitted data to the CathPCI Registry from 2005 through the second quarter of 2009, a total of 1,819,611 percutaneous coronary intervention (PCI) procedures performed via femoral access site were analyzed. Assessed outcomes included bleeding, femoral artery occlusion, embolization, artery dissection, pseudoaneurysm, and arteriovenous fistula. Seven types of hemostasis strategy were evaluated for rate of “any bleeding or vascular complication” compared to MC controls, using hierarchical multiple logistic regression analysis, controlling for demographic factors, type of hemostasis, several indices of co-morbidity, and other potential confounding variables. Rates for different types of hemostasis strategy were plotted over time, using linear regression analysis.Results. Four of the VCDs and hemostasis patches demonstrated significantly lower bleeding or vascular complication rates than MC controls: Angio-Seal (odds ratio [OR], 0.68; 95% confidence interval [CI], 0.65-0.70); Perclose (OR, 0.54; CI, 0.51-0.57); StarClose (OR, 0.77; CI, 0.72-0.82); Boomerang Closure Wire (OR, 0.63; CI, 0.53-0.75); and hemostasis patches (OR, 0.70; CI, 0.67-0.74). All types of hemostasis strategy, including MC, exhibited reduced complication rates over time. All trends were statistically significant except one. Conclusions. This large, nationally representative observational study demonstrated better safety profiles for most of the frequently used VCDs, compared to MC controls.

J INVASIVE CARDIOL 2012;24(7):328-334

Key words: hemostasis patch, mechanical compression, vascular closure device

Problems and Complications of the Transradial Approach for Coronary Interventions: A Review

The Journal of invasive Cardiology

Elizabeth Bazemore, BS and J. Tift Mann, III, MD

The benefits of the transradial approach have clearly been documented in numerous studies in the past ten years.1–9 Access site bleeding complication rates are lower and early ambulation results in a significant reduction in patient morbidity and a lower total procedure cost.3,4 Both patients undergoing the procedure and staff caring for these patients overwhelmingly prefer the transradial approach.10
As a result of these benefits, there has been an increase in the use of the radial artery for interventional procedures worldwide in the past several years. This experience has led to an understanding of the problems and complications that can result from the transradial approach. The purpose of the present manuscript is to review these issues.
Radial artery occlusion. Although this complication is a major concern, the consequences of radial artery occlusion are usually benign. The dual blood supply to the hand is an extremely protective mechanism (Figure 1). Hand ischemia with necrosis has occurred following prolonged cannulation of the radial artery for hemodynamic monitoring in critically ill patients; however, this complication has not been reported thus far after transradial coronary procedures.
The absence of ischemic complications is largely the result of the original recommendation by Kiemeneij that the transradial procedure be performed only in patients with a documented patent ulnar artery and palmar arch.1 This has traditionally been evaluated using the Allen’s test, but ultrasound, Doppler, and plethysmography prior to the procedure are more accurate methods.11
Plethysmography is probably the simplest and most effective method. A pulse oximetry test is performed with the probe placed on the patient’s thumb (Figure 2). The persistence of waveform and high oximetry readings after digital occlusion of the radial artery is very strong evidence that the patient will have sufficient collateral flow to prevent hand ischemia if the radial artery should become occluded as a result of the procedure. Barbeau has demonstrated the reappearance of the waveform and a high oximetry reading two minutes after initial negative results.11 This delayed recruitment of collaterals may be an additional explanation for the absence of hand ischemia with radial occlusion.
Several variables influence the incidence of radial artery occlusion. Adequate anticoagulation is extremely important. This is usually not an issue in patients undergoing interventional procedures, but the incidence of radial occlusion was as high as 30% in patients receiving only 1,000 units of heparin during diagnostic catheterization.12 The incidence of radial occlusion is reduced significantly by administering at least 5,000 units of heparin during the procedure.12,13 Due to this risk of radial occlusion, we tend to reserve the use of the radial artery for interventional procedures and “look-see” diagnostic catheterization. Elective diagnostic catheterizations are performed transradially only when there is an increased risk of femoral complications.
Catheter size has been shown to be an important predictor of post-procedure radial artery occlusion. Saito has studied the ratio of the radial artery internal diameter to the external diameter of the arterial sheath.14 The incidence of occlusion was 4% in patients with a ratio of greater than 1, as compared to 13% in those with a ratio of less than 1. Radial procedures have traditionally been performed using 6 Fr catheters, and most patients have an internal radial artery diameter larger than the 2.52 mm external 6 Fr sheath diameter.14 The incidence of radial occlusion following 6 Fr procedures is less than 5%, but the rate increases with larger sheath sizes.4,13 Virtually all interventional procedures can now be performed through large-bore, 6 Fr guide catheters, and larger-sized catheters are rarely necessary. For straightforward procedures, 5 Fr guide catheters may be utilized and are particularly useful in smaller women.
When the radial artery is utilized for hemodynamic monitoring in critically ill patients, the incidence of radial occlusion is significantly higher in patients with cannulation times greater than 24 hours, as compared to those under 20 hours.15 Since catheters are virtually always removed at the conclusion of a catheterization or interventional procedure, the time of cannulation may not be a factor. However, prolonged post-procedure compression times, particularly with high pressure using a mechanical device, may be a factor. We use sufficient pressure only to achieve hemostasis and try to remove the device as quickly as possible. Even in patients with intensive anticoagulation, it is rarely necessary to maintain mechanical compression for longer than one to two hours. A compression dressing using non-occlusive pressures can then be applied.
In summary, post-procedure radial occlusion occurs only in a small percentage of patients and is virtually always asymptomatic because of the dual blood supply to the hand. Patients with generalized vascular disease, diabetes mellitus, and those undergoing repeat procedures are more susceptible. The incidence can be minimized with appropriate anticoagulation, proper sheath selection, and avoiding prolonged high-pressure compression following the procedure.
Non-occlusive radial artery injury. Recent studies have demonstrated that permanent radial artery injury without occlusion may occur following transradial intervention in some patients. Mean radial artery internal diameter as measured by ultrasound was smaller in patients undergoing repeat transradial interventional procedures as compared to the initial procedure.16 This smaller diameter was not present on the day following the procedure, but developed during a mean follow up of 4.5 months. Wakeyama et al. demonstrated with intravascular ultrasound that this progressive narrowing is due to intimal hyperplasia, presumably induced by trauma from the cannulation sheath or catheter.17 The studies in our laboratory show that this hyperplasia is usually segmental rather than diffuse and is not present in all patients with a previous transradial procedure (Figure 3). The incidence of subsequent intimal hyperplasia in patients undergoing radial procedures is yet to be determined.
The ramifications of this injury are important not only in patients undergoing repeat interventional procedures, but also in patients in whom the radial artery may be used as a conduit for coronary artery bypass surgery. At our center, this is not an issue as most procedures are performed from the right radial artery and surgeons use the left radial artery for bypass graft purposes. At present, it would seem prudent not to use a radial artery that previously has been used for a catheterization as a bypass graft.
Radial artery spasm. Much of the morbidity of the transradial procedure is related to vasospasm induced by the introduction of a sheath or catheter into the radial artery. The vessel has a prominent medial layer that is largely dominated by alpha-1 adenoreceptor function.18 Thus, increased levels of circulating catecholamines are a cause of radial artery spasm. Local anesthesia and adequate sedation to control anxiety during catheter insertion are important preventative measures.
It has been demonstrated in isolated radial artery ring segments that nitroglycerin and verapamil are effective agents in preventing arterial spasm.19 Indeed, a vasodilator cocktail consisting of 3–6 mg of verapamil injected intra-arterially prior to sheath insertion is extremely effective in preventing radial artery spasm. The effect of the drug is immediate and significant arterial dilatation can be seen within minutes of its administration (Figure 4).
Intra-arterial verapamil and nitroglycerin have virtually eliminated vasospasm as a cause of significant morbidity of the procedure. It is now possible to perform transradial procedures using short sheaths and arm discomfort generally occurs only in patients with very small or tortuous radial arteries, particularly if guide catheter manipulation is excessive.
Spasm distal to the access site may be a cause of access failure. Occasionally, guide wire or guide catheter induced focal spasm may occur in a tortuous segment. Angiographic visualization of these areas is important as they generally respond to repeat verapamil administration and can be traversed with an angled hydrophilic coated guide wire. A soft-tipped coronary guide wire may also be used to cross these areas (Figure 5).
Sheath-induced spasm is also minimized by the use of sheaths with hydrophilic coating. Kiemeneij has documented that both patient discomfort and the force required to remove a sheath as measured by an automatic pull-back device was significantly less with hydrophilic coated sheaths as opposed to non-coated sheaths.20
Local access bleeding. The most important benefit of transradial procedures is the elimination of access site bleeding complications.1–4 The radial artery puncture site is located over bone and can easily be compressed with minimal pressure. Thus, bleeding from the radial access site can virtually always be prevented. Although manual pressure from an experienced operator is the ideal method to obtain hemostasis, several compression devices have been developed in an attempt to maximize operator and staff efficiency. Local hematomas may occur as a result of improper device application or device failure. It is important to emphasize that compression of the radial artery both proximally and distally to the puncture site must be performed because of retrograde flow from the palmar arch collaterals.
Forearm hematoma. Bleeding may occur from a site in the radial artery remote from the access site. The most common cause is perforation of a small side branch by the guide wire in patients receiving a platelet glycoprotein IIb/IIIa inhibitor (Figure 6). Avulsion of a small radial recurrent artery arising from a radial loop is another important cause of this syndrome.21,22 Hydrophilic guidewires preferentially select this small arterial remnant in patients with a radial loop and forceful advancement of the guide catheter can result in avulsion of the vessel. Radial artery perforation has been described in 1% of patients although in our experience the incidence is substantially lower. A low threshold to perform a radial artery arteriogram when any resistance to guide wire or catheter insertion is encountered will help prevent this complication.
Recognition of this bleeding remote from the access site is important as hemostatic pressure must be applied to an area other than the access site. Hemostasis is usually easily accomplished by the application of an Ace bandage to the forearm. A blood pressure sphygmomanometer may also be utilized. The latter is inflated to systolic pressure and then gradually released over a period of one to two hours. Sealing of a perforation with a long sheath is also an option, but this is rarely necessary.22
Compartment syndrome is the most dreaded complication of radial artery hemorrhage. A large hematoma causes hand ischemia due to pressure-induced occlusion of both the radial and ulnar arteries. Fasciotomy with hematoma evacuation must be performed as an emergency procedure to prevent chronic ischemic injury. This complication is rare, occurring only once in our early experience; it should always be preventable.

Access failure. Failure to cannulate the radial artery using a 20 gauge needle and a 0.025 mm straight Terumo guide wire occurs in less than 5% of patients with an experienced operator. The importance of adequate patient sedation and local anesthesia in the prevention of radial artery spasm has previously been emphasized. In addition, meticulous attention to detail is important as the probability of failure increases as the number of unsuccessful attempts to puncture the artery increases. It should be emphasized that the puncture site is proximal to the styloid process of the radius bone. The radial artery distally usually bifurcates and becomes less superficial and attempting to puncture the vessel too distally is a common cause of access failure (Figure 7).
The radial loop is the most common congenital anomaly of the radial artery and may be a cause of access failure. It occurs in 1–2% of patients and may be unilateral or bilateral.21 Wide loops can occasionally be traversed with hydrophilic guidewires and 5 Fr catheters without excessive patient discomfort.23 However, in most cases, it is preferable to consider an alternative access site.
Radial arteries that are smaller than 2 mm in diameter are difficult to access. These are generally seen in smaller women and patients with previous radial procedures. The use of a 5 Fr guide in this situation may be an option. However, complex or difficult procedures cannot be performed through a 5 Fr guide catheter.
Miscellaneous complications. Pseudoaneurysm formation may rarely occur at the radial artery access site. This is usually easily managed with thrombin injection and/or mechanical compression. However, surgery may be required. Radial artery avulsion due to intense spasm has been described but this complication should virtually never occur using contemporary techniques. Sterile abscesses rarely occur with the use of hydrophilic coated sheaths.24
Conclusion. The radial artery is an excellent access site for coronary interventions. Although technically more challenging with a definite learning curve, there are significant advantages to this approach. Complications are infrequent and many are preventable with careful technique.

 http://www.invasivecardiology.com/article/3821

J Invasive Cardiol. 2010 Apr;22(4):175-8.

Vascular complications after percutaneous coronary intervention following hemostasis with the Mynx vascular closure device versus the AngioSeal vascular closure device.

Source

Department Cardiology, New York Medical College, Macy Pavilion, Valhalla, NY 10595, USA.

Abstract

We investigated the prevalence of vascular complications after PCI following hemostasis in 190 patients (67% men and 33% women, mean age 64 years) treated with the AngioSeal vascular closure device (St. Jude Medical, Austin, Texas) versus 238 patients (67% men and 33% women, mean age 64 years) treated with the Mynx vascular closure device (AccessClosure, Mountain View, California).

RESULTS:

Death, myocardial infarction or stroke occurred in none of the 190 patients (0%) treated with the AngioSeal versus none of 238 patients (0%) treated with the Mynx. Major vascular complications occurred in 4 of 190 patients (2.1%) treated with the AngioSeal versus 5 of 238 patients (2.1%) treated with the Mynx (p not significant). Major vascular complications in patients treated with the AngioSeal included removal of a malfunctioning device (1.1%), hemorrhage requiring intervention (0.5%) and hemorrhage with a loss of > 3g Hgb (0.5%). The major vascular complications in patients treated with the Mynx included retroperitoneal bleeding requiring surgical intervention (0.8%), pseudoaneurysm with surgical repair (0.8%) and hemorrhage with a loss of > 3g Hgb (0.4%). These complications were not significantly different between the two vascular closure devices (p = 0.77). Minor complications included hematoma > 5 cm (0.5%, n = 1) within the AngioSeal group, as well as procedure failure requiring > 30 minutes of manual compression after device deployment, which occurred in 7 out of 190 patients (3.7%) treated with the AngioSeal versus 22 of 238 patients with the Mynx (9.2%) (p = 0.033).

CONCLUSIONS:

Major vascular complications after PCI following hemostasis with vascular closure devices occurred in 2.1% of 190 patients treated with the AngioSeal vascular closure device versus 2.1% of 238 patients treated with the Mynx vascular closure device (p not significant). The Mynx vascular closure device appears to have a higher rate of device failure.

Comment in

http://www.ncbi.nlm.nih.gov/pubmed/20351388

Z Kardiol. 2005 Jun;94(6):392-8.

Incications and complications of invasive diagnostic procedures and percutaneous coronary interventions in the year 2003. Results of the quality control registry of the Arbeitsgemeinschaft Leitende Kardiologische Krankenhausarzte (ALKK).

Source

Herzzentrum Ludwigshafen, Bremserstrasse 79, 67063 Ludwigshafen, Germany. Uwe.Zeymer@t-online.de

Abstract

BACKGROUND:

The ALKK registry contains about 20% of the invasive and interventional cardiological procedures performed in Germany.

METHODS:

In 2003 a total of 82,282 consecutive diagnostic invasive and 30,689 interventional procedures from 75 hospitals were centrally collected and analyzed.

RESULTS:

The main indication for an invasive diagnostic procedure was coronary artery disease in 92.5% of cases, myocardial disease in 1.6%, impaired left ventricular function in 4.0%, valve disease in 4% and other indications in 1.9%. An acute coronary syndrome was present in 25% of the patients. The rate of severe complications in patients with a lone diagnostic invasive procedure was low (<0.5%). The indication for percutaneous coronary intervention (n=30,689) was stable angina in 44.1%, ST elevation myocardial infarction in 22.3%, non ST elevation myocardial infarction in 14.8%, unstable angina in 10.0%, silent ischemia in 2.2%, prognostic in 5.2% of patients. The majority of interventions were performed directly after the diagnostic procedure (n=23,887=78.6%). The intervention was successful in 94.6% of cases. Stent implantation was performed in 77.2%, with 1 stent in 88.4%, two stents in 7.6% and 3 or more stents in 3.3%. A drug-eluting stent was implanted in 3.6% of the cases. The complication rate after PCI was influenced by the indication for the intervention. The in-hospital mortality in patients with cardiogenic shock was 33%, while in patients with stable angina, silent ischemia and prognostic indication only 0.2% died.

CONCLUSION:

There is an increase of invasive diagnostic and interventional procedures in patients with acute coronary syndromes, with 47% of PCIs performed in these patient. PCIs were performed in 75% of the cases directly after the diagnostic procedure. The rate of stent implantation seems to have reached a plateau at around 80%, while drug-eluting stents were implanted only in a minority of cases. The complication rate is mainly dependent on the clinical presentation of the patients and the indication for PCI.

http://www.ncbi.nlm.nih.gov/pubmed/15940439

Coronary arterial complications after percutaneous coronary intervention in Behçet’s disease

Authors: Kinoshita T, Fujimoto S, Ishikawa Y, Yuzawa H, Fukunaga S, Toda M, Wagatsuma K, Akasaka Y, Ishii T, Ikeda T

Published Date February 2013 Volume 2013:4 Pages 9 – 12

DOI: http://dx.doi.org/10.2147/RRCC.S41240,

Published: 05 February 2013
Toshio Kinoshita,1 Shinichiro Fujimoto,Yukio Ishikawa,2 Hitomi Yuzawa,1 Shunji Fukunaga,1Mikihito Toda,3 Kenji Wagatsuma,3 Yoshikiyo Akasaka,2 Toshiharu Ishii,2 Takanori Ikeda1
1Department of Cardiovascular Medicine, 2Department of Pathology, 3Division of Interventional Cardiology, Toho University Faculty of Medicine, Ohta City, Tokyo, Japan

Abstract: Behçet’s disease is a multisystemic vascular inflammatory disease, but concurrent cardiac diseases, such as acute myocardial infarction, are rare. Several complications may arise after coronary intervention for coronary lesions that interfere with treatment, and the incidence of coronary arterial complications due to invasive therapy remains unclear. Further, the long-term outcomes in patients with Behçet’s disease after stenting for acute myocardial infarction have not been described. The present report describes a 35-year-old Japanese man with Behçet’s disease who developed acute myocardial infarction. A coronary aneurysm developed at the stenting site of the left anterior descending coronary artery, along with stenosis in the left anterior descending segment proximal to the site. Although invasive therapy was considered, medication including immunosuppressants was selected because of the high risk of vascular complications after invasive therapy. The coronary artery disease has remained asymptomatic for the 4 years since the patient started medication. This case underscores the importance of considering the incidence of coronary arterial complications and of conservative treatment when possible.

Keywords: Behçet’s disease, myocardial infarction, coronary arterial complications, percutaneous coronary intervention, immunosuppressants

http://www.dovepress.com/coronary-arterial-complications-after-percutaneous-coronary-interventi-peer-reviewed-article-RRCC-recommendation1

REFERENCES

  1. Marso SP, Amin AP, House JA, et al; on behalf of the National Cardiovascular Data Registry. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA. 2010;303(21):2156-2164.
  2. Heart Disease and Stroke Statistics — 2011 Update. American Heart Association, 2011.
  3. Tavris DR, Gallauresi BA, Dey S, Brindis R, Mitchel K. Risk of local adverse events by gender following cardiac catheterization. Pharmacoepidemiol Drug Saf. 2007;16(2):125-131.
  4. United States Food and Drug Administration (US FDA). Manufacturer and user facility device experience; MAUDE Database, 2001: Accessed atwww.accessdata.fda.gov/scripts/cdrh/cfdocs/cfmaude/TextResults.cfm
  5. Tavris DR, Dey S, Gallauresi B, et al. Risk of local adverse events following cardiac catheterization by hemostasis device use — phase II. J Invasive Cardiol. 2005;17(12):644-650.
  6. An initiative of the American College of Cardiology Foundation, the NCDR, National Cardiovascular Data Registry, is a comprehensive, outcomes-based suite of registries focused on quality improvement. www.ncdr.com. 
  7. Applegate RJ, Sacrinty MT, Kutcher MA, et al. Propensity score analysis of vascular complications after diagnostic cardiac catheterization and percutaneous coronary intervention 1998-2003. Catheter Cardiovasc Interv. 2006;67(4):556-562.
  8. Applegate RJ, Sacrinty M, Kutcher MA, et al. Vascular complications with newer generations of Angio-Seal vascular closure devices. J Interv Cardiol. 2006;19(1):67-74.
  9. Applegate RJ, Sacrinty MT, Kutcher MA, et al. Propensity score analysis of vascular complications after diagnostic cardiac catheterization and percutaneous coronary intervention using thrombin hemostatic patch-facilitated manual compression. J Invasive Cardiol. 2007;19(4):164-170.
  10. Sulzbach-Hoke LM, Ratcliffe SJ, Kimmel SE, et al. Predictors of complications following sheath removal with percutaneous coronary intervention. J Cardiovasc Nurs. 2010;25(3):E1-E8.
  11. Legrand V, Doneux P, Martinez C, et al. Femoral access management: comparison between two different vascular closure devices after percutaneous coronary intervention. Acta Cardiol. 2005;60(5):482-488.
  12. Hermiller JB, Simonton C, Hinohara T, et al. The StarClose Vascular Closure System: interventional results from the CLIP study. Catheter Cardiovasc Interv. 2006;68(5):677-683.
  13. Martin JL, Pratsos A, Magargee E, et al. A randomized trial comparing compression, Perclose Proglide and Angio-Seal VIP for arterial closure following percutaneous coronary intervention: the CAP trial. Catheter Cardiovasc Interv. 2008;71(1):1-5.
  14. Deuling JH, Vermeulen RP, Anthonio RA, et al. Closure of the femoral artery after cardiac catheterization: a comparison of Angio-Seal, StarClose, and manual compression. Catheter Cardiovasc Interv. 2008;71(4):518-523.
  1. Wong SC, Bachinsky W, Cambier P, et al; ECLIPSE Trial Investigators. A randomized comparison of a novel bioabsorbable vascular closure device versus manual compression in the achievement of hemostasis after percutaneous femoral procedures: the ECLIPSE (Ensure’s Vascular Closure Device Speeds Hemostasis Trial). JACC Cardiovasc Interv. 2009;2(8):785-793.
  2. Arora N, Matheny ME, Sepke C, Resnic FS. A propensity analysis of the risk of vascular complications after cardiac catheterization procedures with the use of vascular closure devices. Am Heart J. 2007;153(4):606-611.
  3. Castillo-Sang M, Tsang AW, Almaroof B, et al. Femoral artery complications after cardiac catheterization: a study of patient profile. Ann Vasc Surg. 2010;24(3):328-335.
  4. Sanborn TA, Ebrahimi R, Manoukian SV, et al. Impact of femoral vascular closure devices and antithrombotic therapy on access site bleeding in acute coronary syndromes: the Acute Catheterization and Urgent Intervention Triage Strategy (ACUITY) trial. Circ Cardiovasc Interv. 2010;3(1):57-62.
  5. Iqtidar AF, Li D, Mather J, McKay RG. Propensity matched analysis of bleeding and vascular complications associated with vascular closure devices vs standard manual compression following percutaneous coronary intervention. Conn Med. 2011;75(1):5-10.
  6. Marso SP, Amin AP, House JA, et al; National Cardiovascular Data Registry. Association between use of bleeding avoidance strategies and risk of periprocedural bleeding among patients undergoing percutaneous coronary intervention. JAMA. 2010;303(21):2156-2164.
  7. Ahmed B, Piper WD, Malenka D, et al. Significantly improved vascular complications among women undergoing percutaneous coronary intervention: a report from the Northern New England Percutaneous Coronary Intervention Registry. Circ Cardiovasc Interv. 2009;2(5):423-429.
  8. Trimarchi S, Smith DE, Share D, et al; BMC2 Registry. Retroperitoneal hematoma after percutaneous coronary intervention: prevalence, risk factors, management, outcomes, and predictors of mortality: a report from the BMC2 (Blue Cross Blue Shield of Michigan Cardiovascular Consortium) registry. JACC Cardiovasc Interv. 2010;3(8):845-850.
  9. Vaitkus PT. A meta-analysis of percutaneous vascular closure devices after diagnostic catheterization and percutaneous coronary intervention. J Invasive Cardiol. 2004;16(5):243-246.
  10. Koreny M, Riedmuller E, Nikfardjam M, et al. Arterial puncture closing devices compared with standard manual compression after cardiac catheterization — systematic review and meta-analysis. JAMA. 2004;291(3):350-357.
  11. Nikolsky E, Mehran R, Halkin A, et al. Vascular complications associated with arteriotomy closure devices in patients undergoing percutaneous coronary procedures: a meta-analysis. J Am Coll Cardiol. 2004;44(6):1200-1209.
  12. Biancari F, D’Andrea V, Di Marco C, et al. Meta-analysis of randomized trials on the efficacy of vascular closure devices after diagnostic angiography and angioplasty. Am Heart J. 2010;159(4):518-531.
  13. Tavris DR, Dey S, Gallauresi B, et al. Risk of local adverse events following cardiac catheterization by hemostasis device use — phase II. J Invasive Cardiol. 2005;17(12): 644-650.

Frequency and Costs of Ischemic and Bleeding Complications After Percutaneous Coronary Interventions: Rationale for New Antithrombotic Therapy

Journal of Invasive Cardiology

http://www.invasivecardiology.com/article/2489

Author(s):

Mauro Moscucci, MD

Recent advances in catheter technology and antithrombotic therapy have led to a continuous improvement in outcomes of percutaneous coronary intervention (PCI). These improved outcomes have been associated with broadening of the indications for PCI, with an exponential growth in number of procedures performed, but they have also been paralleled by incremental procedure costs. The estimated costs of PCI currently range from $8,000–$13,000.1 With over 800,000 cases performed each year in the United States (US) alone, this represents over $10 billion annually for the US Healthcare System.2 Roughly half of these costs are incurred by the Center for Medicare and Medicaid Services (CMS, formerly known as the Health Care Financing Administration).3 Total costs of PCI include disposable equipment used during the procedure (balloons, catheters, stents, etc.), cardiac catheterization laboratory overhead and depreciation, nursing and pharmacy costs, laboratory costs and physician services. In addition, factors that have been found to be associated with increased PCI costs include the use of special devices such as atherectomy or vascular closure devices, the use of multiple stents, the use of platelet glycoprotein (GP) IIb/IIIa inhibitors, and the presence of certain patient demographic characteristics including advanced age, gender and other comorbidities.1,4,5 Finally, complications related to the procedure have been identified in several studies as the single most significant contributor to increased costs of PC.5–7

Methods to reduce the cost of PCI include re-use of balloon catheters,8 percutaneous revascularization performed at the same time as diagnostic catheterization,9 reduced anticoagulation, the use of new devices or pharmacological interventions to reduce restenosis and complications, and the use of competitive bidding for cardiac cath lab supplies.10 For example, the evolution of anticoagulation therapy in stented patients from a regime of post-procedural heparin and warfarin to one of thienopyridines and aspirin,11 and the subsequent reduction of length of stay from 4 days in 1995 to 2 days in 2000, have helped keep total procedure costs down.12 In addition, a reduction in complication rates appears to be a key target for cost reduction efforts. In support of this statement, in the economic assessment of the Evaluation of 7E3 for the Prevention of Ischemic Complications (EPIC) trial in high-risk patients, Mark et al. identified bleeding complications, urgent and non-urgent coronary artery bypass graft surgery (CABG), and urgent and non-urgent percutaneous transluminal coronary angioplasty (PTCA) as important correlates of incremental costs.7 Unfortunately, standard aggressive antithrombotic therapy aimed toward a reduction of ischemic complications is often associated with an increase in bleeding complications. In the analysis of the EPIC trial, the benefits of abciximab in decreasing procedure costs through a reduction of ischemic complications were offset by drug acquisition costs and by an increase in bleeding complications.7 Thus, with ischemic complications becoming more rare as a result of improvement in PCI technology and more aggressive antithrombotic therapy, bleeding has become a rather common and costly complication of PCI, with a blood transfusion estimated to add up to $8,000 to the cost of care for the PCI patient.13

Based on these premises, it appears that the next challenge in the care of PCI patients will be to determine how to continue to prevent ischemic complications without increasing the risk of bleeding. This paper examines the frequency of PCI complications in both recent clinical trials and actual practice, discusses the costs of complications, and explores improvements in patient management and particularly changes in anticoagulation therapy that might impact total costs of PCI.

Complication rates in clinical trials

Ischemic complications in clinical trials. Despite advances in PCI technology and adjunctive pharmacotherapy, data from clinical trials indicate that ischemic complications still occur in 5–15% of patients.14–19 Typically, clinical trials define ischemic complications as a combination of death, myocardial infarction (MI; both Q-wave and non-Q wave) and either urgent or any target vessel revascularization (TVR). Different definitions of MI or revascularization can make comparisons across trials difficult. However, comparisons may still be possible through the application of strict meta-analysis methodology. A recent meta-analysis combined data from 6 double-blind PCI trials conducted predominantly in North America between 1993 and 1998.20 A total of 16,546 patients were enrolled in these trials (Table 1). Protocols and case report forms for trials included in the analysis were compared to ensure reasonable consistency of study methods, patient management, data reporting and data structure. Integration of the databases from the trials enabled a direct comparison of key event rates at 7 days, using standard classifications and criteria for severity. The meta-analysis showed that the use of high-dose heparin (175 U/kg) was associated with significantly less frequent clinical ischemic events (8.1%) than lower doses of heparin (100 U/kg; 10.3%). In this same meta-analysis, event rates in patients treated with low-dose heparin (70 U/kg) plus a GP IIb/IIIa inhibitor was 6.5%.20 Although not included in this meta-analysis, it is worth noting that the incidence of death, MI and revascularization in the ESPRIT trial was 9.3% in patients treated with low-dose heparin alone (60 U/kg).21

Bleeding complications in clinical trials. In clinical trials of antiplatelet and anti-thrombotic therapy in PCI, bleeding complications are generally defined using either thrombolysis in myocardial infarction (TIMI)22 or global utilization of streptokinase or tPA outcomes (GUSTO)23 criteria (Table 2). Rates of major bleeding in clinical trials using these criteria are generally less than 2% (Table 3).14–19,21,24,25 However, these restrictive definitions may not capture all clinically significant bleeding. For example, neither the TIMI nor the GUSTO major bleeding definition includes the need for a blood transfusion as part of the criteria. Thus, a broader measure of bleeding using a combination of both major and minor bleeding defined by TIMI or GUSTO criteria appears more likely to be representative of bleeding rates in clinical practice.

In the meta-analysis of contemporary PCI trials, TIMI criteria were used to classify hemorrhagic events, permitting direct comparisons between trials. In the high-dose heparin group, the combination of TIMI major and minor bleeding occurred in 10.5% of patients compared with a rate of 10.7% in the low-dose heparin group, while the bleeding rate was 14.3% in patients receiving a combination of GP IIb/IIIa inhibitors and low-dose heparin.

As shown in Table 3, when both TIMI major and minor bleeding are combined in contemporary PCI trials, bleeding complications average 4–14%, depending on patient characteristics and the drug regime used. In addition, when transfusions are included in the definition, the frequency of bleeding complications increases substantially. For example, in NICE-3, bleeding complications were 10.5% when transfusions were included in the criteria, but only 2% of the patients experienced TIMI major bleeding.26

Notably, the only adjunctive anti-thrombotic agent shown to reduce both ischemic and bleeding complications in PCI is bivalirudin. In the Bivalirudin Angioplasty Trial,27 the risk of bleeding was decreased 62% in the bivalirudin group compared with high-dose heparin. The combined rate of TIMI major and TIMI minor bleeding in bivalirudin patients (n = 2,161) was found to be 4.3% in the meta-analysis of contemporary PCI trials with a corresponding ischemic event rate of 6.6%.20

Complications in practice

Ischemic complications in practice. Rates of ischemic complications in clinical practice are difficult to determine. Although several investigators have published data from multicenter databases, these data tend to be 3–5 years old by the time manuscripts are in print. Since trends in the published literature do show continued reduction in PCI complications over time, the frequency of complications noted in these publications may overestimate the actual rate of complications in clinical practice today. In addition, rates of complications can vary widely across institutions due to differences in practice patterns, definitions, operator skills and resource utilization. For example, in the Society for Cardiac Angiography and Interventions (SCA&I) registry, stent use among laboratories varied from 29–95%.28 Others have found lower complication rates in patients whose procedure was performed by a high-volume operator or in a high-volume institution.29 We identified 6 published reports of PCI complications in clinical practice reporting a variety of ischemic outcomes.1,28–31

Saucedo et al. prospectively collected data on 900 patients undergoing successful elective stent placement in native coronary arteries between January 1994 and December 1995.30 The purpose of this study was to evaluate the incidence and long-term clinical consequences of patients with creatine kinase (CK) myocardial isoenzyme band (CK-MB) elevations after stenting. By design, all patients in this observational study had a successful procedure defined as an increase of > 20% in luminal diameter with final percent diameter stenosis of < 50%, without the occurrence of any major complications (death, Q-wave MI and CABG). Nevertheless, 26.4% of patients had CK-MB elevations 1–5 times the upper limit of normal (ULN) and 8.5% had CK-MB elevations > 5 times ULN. In total, 3.9% of patients required a repeat diagnostic catheterization for recurrent ischemia and 1.2% required urgent target vessel revascularization. In this study, patients requiring the use of GP IIb/IIIa inhibitors were excluded.

The Northern New England group (NNE) collected data on 14,498 patients undergoing PCI between 1994 and 1996.29 In this study, outcomes included the in-hospital occurrence of death; emergency CABG (eCABG) or non-eCABG; or new MI (defined as chest pain, diaphoresis, dyspnea or hypotension associated with the development of new Q-waves or ST-T wave changes and a rise in CK to at least twice normal with a positive CK-MB). Overall, death occurred in 1.2% of patients, CABG in 2.6% (0.8% eCABG and 1.8% non-eCABG), and MI in 2%. Stents were used in 22% of patients enrolled in this registry.

In the National Cardiovascular Network database (NCN), Batchelor et al. reported complications of PCI in 109,708 patients who underwent PCI between 1994 and 1997.31 In this observational study, in-hospital mortality was defined as the occurrence of death after the procedure, MI was defined as the appearance of new Q-waves in 2 contiguous leads on a 12-lead electrocardiogram (ECG) for up to 30 days post-PCI, and repeat revascularization was defined as the need for CABG or additional PCI prior to discharge. In this study, death occurred in 1.3% of patients, Q-wave MI in 1.4% and repeat revascularization in 4.5%. Half of the patients underwent stenting in this study. Notably, this database did not record myocardial enzymes or the use of GP IIb/IIIa inhibitors.

Aronow and colleagues observed outcomes in a cohort of consecutive registry patients undergoing coronary stent placement between 1995 and 1997.32 A total of 373 patients underwent PCI during this time period, with death occurring in 9 patients (2.4%), CABG in 3 (0.8%) and MI in 19 (5.1%, including both QWMI and NQWMI). Repeat diagnostic catheterization was performed in 3.2% of patients and repeat PCI in 0.8%.

The SCA&I registry evaluated outcomes in 16,811 patients undergoing either balloon angioplasty (n = 6,121) or stenting (n = 10,690) between July 1996 and December 1998.28 In this observational analysis, 12.9% of patients received a GP IIb/IIIa inhibitor, 87% of patients enrolled in the database underwent PCI between 1997 and 1998, and 60% of the stent patients were enrolled in 1998. Outcomes reported included in-hospital death (occurring at any time during the hospitalization) and eCABG, defined as CABG occurring immediately after PCI. Death occurred in 0.4% of patients and eCABG in 0.5%.

Finally, Cohen and others recorded in-laboratory complications in 26,421 patients at 70 different centers undergoing PCI in 1998.1 In-laboratory complications were rare, with death occurring in 0.17%, cardiac arrest in 0.32%, stroke in 0.03%, ventricular fibrillation or tachycardia in 0.94%, abrupt closure in 0.71%, and eCABG in 0.53%. Overall, 72% of patients received stents and 20% received GP IIb/IIIa inhibitors.

In addition to published reports of PCI complications, data from unpublished sources can be used to determine outcomes in a more contemporary cohort of patients undergoing PCI.33 The MQ-Profile (MQ-Pro) Database [Cardinal Information Corporation (CIC), Marlborough, Massachusetts] is maintained by CIC, which sells and distributes software to US acute-care hospitals for the collection of detailed clinical and administrative data. Data from 5,373 PCI procedures performed between July 1, 1998 and June 30, 1999 were obtained from the database using International Classification of Diseases 9th Edition (ICD-9) procedure codes for PCI (36.01, 36.02, 36.05). Demographic, clinical and economic data were collected on each patient using a combination of database retrieval and chart review. In this analysis, death was defined as discharge disposition of “deceased”, MI as the presence of ECG changes consistent with MI (new Q-waves or ST-segment changes) or an increase in CK-MB of at least 2 times the testing facility’s ULN. CABG was identified by the presence of ICD-9 procedure code 36.1 and repeat PCI by either code 36.01, 36.02, or 36.05. Failed PCI was defined by the term “failed PTCA” in chart notes (for patients without a previous history of PCI) and recurrent ischemia documented by ECG changes. Death occurred in 2.0% of patients, MI in 3.1%, CABG in 1.3% and repeat PCI in 5.5%. Translated into a combined endpoint similar to those used in clinical trials, the rate of death/MI/revascularization was 11.9%.

Data from these published and unpublished observations of contemporary PCI practice indicate that while in-laboratory ischemic complications are exceedingly rare, in-hospital ischemic complications still occur in a substantial number of patients. Using an approximation of outcomes from these published and unpublished reports, mortality averages 1%, Q-wave MI occurs in 2% of patients, NQWMI in 6%, CABG in 2% and repeat PCI occurs in 3–5% of patients. It is important to underscore that although most deaths following PCI are due to underlying comorbidities (i.e., acute MI, cardiogenic shock, etc.) rather than to the procedure itself, few deaths still occur as a complication of the procedure.34,35 Extrapolated to the estimated PCI population of 800,000 cases per year, then 8,000 people will die and 64,000 will experience an MI. In addition, approximately 16,000 will require CABG and as many as 40,000 will need a repeat PCI before hospital discharge.

II(b) PAD Endovascular Interventions: Carotid Artery Endarterectomy

  • Original Contributions

Medical Complications Associated With Carotid Endarterectomy

Stroke.1999; 30: 1759-1763  doi: 10.1161/​01.STR.30.9.1759

  1. Maurizio Paciaroni, MD;
  2. Michael Eliasziw, PhD;
  3. L. Jaap Kappelle, MD;
  4. Jane W. Finan, BScN;
  5. Gary G. Ferguson, MD;
  6. Henry J. M. Barnett, MD;
  7. for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Collaborators

+Author Affiliations


  1. From the John P. Robarts Research Institute (M.P., M.E., L.J.K., J.W.F., H.J.M.B) and the Departments of Epidemiology and Biostatistics (M.E.) and Clinical Neurological Sciences (M.E., G.G.F., H.J.M.B.), University of Western Ontario, London, Ontario, Canada.
  1. Correspondence to Dr H.J.M. Barnett, John P. Robarts Research Institute, PO Box 5015, 100 Perth Dr, London, ON N6A 5K8, Canada. E-mail barnett@rri.on.ca

Abstract

Background and Purpose—Carotid endarterectomy (CE) has been shown to be beneficial in patients with symptomatic high-grade (70% to 99%) internal carotid artery stenosis. To achieve this benefit, complications must be kept to a minimum. Complications not associated with the procedure itself, but related to medical conditions, have received little attention.

Methods—Medical complications that occurred within 30 days after CE were recorded in 1415 patients with symptomatic stenosis (30% to 99%) of the internal carotid artery. They were compared with 1433 patients who received medical care alone. All patients were in the North American Symptomatic Carotid Endarterectomy Trial (NASCET).

Results—One hundred fifteen patients (8.1%) had 142 medical complications: 14 (1%) myocardial infarctions, 101 (7.1%) other cardiovascular disorders, 11 (0.8%) respiratory complications, 6 (0.4%) transient confusions, and 10 (0.7%) other complications. Of the 142 complications, 69.7% were of short duration, and only 26.8% prolonged hospitalization. Five patients died: 3 from myocardial infarction and 2 suddenly. Medically treated patients experienced similar complications with one third the frequency. Endarterectomy was ≈1.5 times more likely to trigger medical complications in patients with a history of myocardial infarction, angina, or hypertension (P<0.05).

Conclusions—Perioperative medical complications were observed in slightly fewer than 1 of every 10 patients who underwent CE. The majority of these complications completely resolved. Most complications were cardiovascular and occurred in patients with 1 or more cardiovascular risk factors. In this selected population, the occurrence of perioperative myocardial infarction was uncommon.

Key Words:

The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Endarterectomy Trial showed unequivocal benefit of carotid endarterectomy (CE) in symptomatic patients with high-grade internal carotid artery (ICA) stenosis (70% to 99%).1 2 The parallel study dealing with symptomatic patients with moderate-grade stenosis (30% to 69%) showed benefits of CE only in a carefully selected group of patients.3 Currently, CE is the most common elective peripheral vascular procedure, which in 1997 was performed in ≈130 000 patients in the United States.4

Despite benefit in the long term, CE may cause complications either by the operation itself or by concomitant medical conditions. The challenge for the future is to reduce the perioperative risk as much as possible. The incidence and type of complications that are directly related to the surgical procedure have been the subject of many reports,5 6 7 8 910 whereas medical complications that are not directly caused by the procedure have received less attention. The aim of the present study is to describe the incidence and type of medical complications that occurred in patients randomized into NASCET and to determine their association with baseline risk factors.

Subjects and Methods

The methods of the NASCET have been described in detail elsewhere.1 11 Briefly, NASCET was a randomized clinical trial designed to compare the benefit of best medical therapy alone with best medical therapy plus CE in patients with recent transient or nondisabling neurological deficit caused by cerebral or retinal ischemia in the territory of the ICA. Among the exclusions were patients with recent history (6 months) of myocardial infarction, unstable angina pectoris, atrial fibrillation, recent congestive heart failure, and valvular heart disease. For inclusion, the ICA had to have a 30% to 99% stenosis as assessed by selective carotid angiography and to be technically suitable for CE. Baseline evaluations included a detailed medical history and complete physical and neurological examination.

Surgeons were invited to join NASCET if the center had a documented CE stroke and death rate of ≤6% in a minimum of 50 consecutive cases over a 2-year period. Surgery was completed at the earliest opportunity after randomization, and patients underwent a second complete physical and neurological examination 30 days after surgery. All medical and surgical complications that caused transient or permanent disability within the 30-day period were recorded.

Medical complications consisted of myocardial infarction (based on ECG and cardiac enzyme changes), arrhythmia (requiring antiarrhythmic medication), congestive heart failure, angina pectoris, hypertension (diastolic blood pressure >100 mm Hg requiring intravenous medication), hypotension (systolic pressure <90 mm Hg requiring administration of vasopressor agent), sudden death, respiratory problems (pneumonia, atelectasis, pulmonary edema, or exacerbation of chronic obstructive pulmonary disease), renal failure (doubling of preoperative urea and/or creatinine), depression, and confusion (requiring restraint). Complications were considered mild if they were transient and did not prolong hospital stay, moderate if they were transient but caused delay in hospital discharge, and severe if they were associated with permanent disability or death.

In the present study, patients were excluded from the analyses if they had serious complications that were directly attributable to the surgical procedure, such as those due to anesthesia, thrombosis at the operative site, wound hematomas requiring surgical intervention, or deficits from a vagus nerve injury interfering with swallowing. These surgical complications are described in detail elsewhere.12 For comparative purposes, a list of complications that occurred in the medically treated arm of NASCET was compiled for the 32-day period after randomization (ie, the 30-day period plus the average 2 days that lapsed from randomization to CE in the surgical arm). In both the surgical and medical arms, patients were censored at the time of a stroke, since the subsequent medical complications are commonly the result of the stroke.

Cox proportional hazards regression modeling was used to identify baseline factors that increased the risk of perioperative medical complications. Adjusted hazard rates and adjusted hazard ratios were used to summarize the results. The estimated hazard ratio (or relative hazard) is a measure of association that can be interpreted as a relative risk. Hazard ratios with corresponding probability value of <0.05 were considered statistically significant. Adjusted hazard rates were obtained from the regression model by using the mean value for a factor being adjusted.

The modeling strategy consisted of initially fitting a “full” model, which included all factors. A “final” model was determined by eliminating all factors that were not significantly predictive of the medical complications, using a backward selection approach. The “change-in-estimate” strategy was used to determine whether the remaining factors in the final model were independent risk factors. A factor was considered an independent risk factor if the change in hazard ratios between the full and final models was <10%.

Results

A total of 1436 eligible patients were randomized to the surgical arm and 1449 to the medical arm of the NASCET. In the surgical arm, 21 patients were not operated on for various reasons.12 In the medical arm 16 patients crossed over to surgical therapy within 30 days, leaving 1433 patients for analysis. CE was performed in 1415 patients (328 patients with severe stenosis and 1087 with moderate stenosis). Of the 1415, 59 (4.2%) patients had serious surgical complications that excluded them from further analyses, and 115 (8.1%) had medical complications (Table 1). Of the 142 complications, 69.7% were mild, 26.8% were moderate, and 3.5% were severe. Twenty patients had ≥2 complications. No patient had pulmonary embolus, renal failure, or depression requiring medication. Cardiovascular disorders were >4 times as common as all other conditions combined. All 5 severe complications were fatal and were caused by cardiovascular disorders: 3 patients had fatal myocardial infarction, and 2 patients died suddenly. Of the patients with fatal myocardial infarction, 2 patients had massive myocardial infarctions on the day of surgery. In the other patient, CE was prolonged (7 hours) because of intraoperative occlusion of the ICA. Twenty-four hours after CE, the patient had a myocardial infarction followed by cardiac arrest, leaving the patient in a vegetative state. The patient died 2 months later. Two patients died suddenly on days 3 and 6 after CE, and both had a history of previous myocardial infarction. All patients with fatal medical complications were male, and all had multiple cardiovascular risk factors.

http://stroke.ahajournals.org/content/30/9/1759.full

REFERENCES

  1. North American Symptomatic Carotid Endarterectomy Trial (NASCET). Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–453.
  2. European Carotid Surgery Trialists’ Collaborative Group. MRC European Carotid Surgery Trial: interim results for symptomatic patients with severe (70–99%) or with mild (0–29%) carotid stenosis. Lancet. 1991;337:1235–1243.
  3. Barnett HJM, Taylor DW, Eliasziw M, Fox AJ, Ferguson GG, Haynes RB, Rankin RN, Clagett GP, Hachinski VC, Sackett DL, Thorpe KE, Meldrum HE, for the North American Symptomatic Carotid Endarterectomy Trial Collaborators. Benefit of carotid endarterectomy in patients with symptomatic moderate or severe stenosis. N Engl J Med. 1998;339:1415–1425.
  4. Kozak LJ, Owings MF. Ambulatory and inpatient procedures in the United States, 1995. National Center for Health Statistics. Vital Health Stat 13. 1998;135:1–116.
  5. Hertzer NR. Early complications of carotid endarterectomy: incidence, diagnosis, and management. In: Moore WS, ed. Surgery for Cerebrovascular Disease. Philadelphia, Pa: WB Saunders Co; 1996:625–649.
  6. Fode NC, Sundt TM, Robertson JT, Peerless SJ, Shields CB. Multicenter retrospective review of results and complications of carotid endarterectomy in 1981.Stroke. 1986;17:370–375.
  7. Goldstein LB, Moore WS, Robertson JT, Chaturvedi S. Complication rates for carotid endarterectomy: a call to action. Stroke. 1997;28:889–890.
  8. Young B, Moore WS, Robertson JT, Toole JF, Ernst CB, Cohen SN, Broderick JP, Dempsey RJ, Hosking JD. An analysis of perioperative surgical mortality and morbidity in the Asymptomatic Carotid Atherosclerosis Study. Stroke.1996;27:2216–2224.
  9. McCrory DC, Goldstein LB, Samsa GP, Oddone EZ, Landsman PB, Moore WS, Matchar DB. Predicting complications of carotid endarterectomy. Stroke.1993;24:1285–1291.
  10. Rothwell PM, Slattery J, Warlow CP. Clinical and angiographic predictors of stroke and death from carotid endarterectomy: systemic review. BMJ.1997;315:1571–1517.
  11. North American Symptomatic Carotid Endarterectomy Trial (NASCET) Steering Committee. North American Symptomatic Carotid Endarterectomy Trial: methods, patient characteristics, and progress. Stroke. 1991;22:711–720.
  12. Ferguson GG, Barnett HJM, Eliasziw M, Finan JW, Clagett GP, Barnes R, Barr H, Wallace C, for the North American Symptomatic Carotid Endarterectomy Trial (NASCET) Collaborators. North American Symptomatic Carotid Endarterectomy Trial (NASCET): surgical results in 1415 patients. Stroke. In press.
  13. Hertzer NR, Young JR, Beven EG, Graor RA, O’Hara PJ, Ruschaupt WF, deWolfe VG, Maljovec LC. Coronary angiography in 506 patients with extracranial cerebrovascular disease. Arch Intern Med. 1985;145:849–852.
  14. Mangano DT. Perioperative cardiac morbidity. Anesthesiology. 1990;72:153–184.
  15. Goldstein LB, McCrory DC, Landsman PB, Samsa GP, Auncukiewicz M, Oddone EZ, Matchar DB. Multicenter review of preoperative risk factors for carotid endarterectomy in patients with ipsilateral symptoms. Stroke. 1994;24:1116–1121.
  16. Musser DJ, Nicholas GG, Reed JF III. Death and adverse cardiac events after carotid endarterectomy. J Vasc Surg. 1994;19:615–622.
  17. Urbinati S, Di Pasquale G, Andreoli A, Lusa AM, Carini G, Grazi P, Labanti G, Passarelli P, Corbelli C, Pinelli G. Preoperative non-invasive coronary risk stratification in candidates for carotid endarterectomy. Stroke. 1994;25:2022–2027.
  18. Adams HP Jr, Brott TG, Crowell RM, Furlan AJ, Gomez CR, Grotta J, Helgason CM, Marler JR, Woolson RF, Zivin JA, Feinberg W, Mayberg M. Guidelines for the management of patients with acute ischemic stroke: a statement for healthcare professionals from a special writing group of the Stroke Council, American Heart Association. Stroke. 1994;25:1901–1914.
  19. Feinberg WM, Albers GW, Barnett HJ, Biller J, Caplan LR, Carter LP, Hart RG, Hobson RW II, Kronmal RA, Moore WS, Robertson JT, Adams HP, Mayberg M. Guidelines for the management of transient ischemic attacks: from the Ad Hoc Committee on Guidelines for the Management of Transient Ischemic Attacks of the Stroke Council of the American Heart Association. Circulation. 1994;89:2950–2965.
  20. Hankey GJ, Warlow CP. Cost-effective investigation of patients with suspected transient ischaemic attacks. J Neurol Neurosurg Psychiatry. 1992;55:171–176.
  21. Wong JH, Findlay JM, Suarez-Almazor ME. Regional performance of carotid endarterectomy: appropriateness, outcomes, and risk factors for complications.Stroke. 1997;28:891–898.
  22. Holton P, Wood JB. The effect of bilateral removal of the carotid bodies and denervation of the carotid sinuses in two human subjects. J Physiol (Lond).1965;181:365–378.
  23. Lilly MP, Brunner MJ, Wehberg KE, Rudolphi DM, Queral LA. Jugular venous vasopressin increases during carotid endarterectomy after cerebral reperfusion. J Vasc Surg. 1992;16:1–9.
  24. Smith BL. Hypertension following carotid endarterectomy: the role of cerebral renin production. J Vasc Surg. 1984;1:623–627.
  25. Eliasziw M, Spence JD, Barnett HJM. Carotid endarterectomy does not affect long-term blood pressure: observations from the NASCET. Cerebrovasc Dis.1998;8:20–24.
  26. Solomon RA, Loftus CM, Quest DO, Correll JW. Incidence and etiology if intracerebral hemorrhage following carotid endarterectomy. J Neurosurg.1986;64:29–34.
  27. Hafner DH, Smith RB, King OW, Perdue GD, Stewart MT, Rosenthal D, Jordan WD. Massive intracerebral hemorrhage following carotid endarterectomy. Arch Surg.1987;122:305–307.
  28. Piepgras DG, Morgan MK, Sundt TM, Yanagihara T, Mussman LM. Intracerebral hemorrhage after carotid endarterectomy. J Neurosurg. 1988;68:532–536.
  29. Jansen C, Sprengers AM, Moll FL, Vermeulen FE, Hamerlijnck RP, van Gijn J, Ackerstaff RG. Prediction of intracerebral hemorrhage after carotid endarterectomy by clinical criteria and intraoperative transcranial Doppler monitoring. Eur J Vasc Surg. 1994;8:303–308.
  30. Chambers BR, Smidt U, Koh O. Hyperperfusion post-endarterectomy.Cerebrovasc Dis. 1994;4:32–37.
  31. Penn AA, Schomer DF, Steinberg GK. Imaging studies of cerebral hyperperfusion after carotid endarterectomy: case report. J Neurosurg. 1995;83:133–137.
  32. Baptista MV, Maeder P, Dewarrat A, Bogousslavsky J. Conflicting images.Lancet. 1998;351:414.

Intraoperative use of dextran is associated with cardiac complications after carotid endarterectomy.

J Vasc Surg. 2013 Mar;57(3):635-41. doi: 10.1016/j.jvs.2012.09.017. Epub 2013 Jan 18.

Source

Section of Vascular and Endovascular Surgery, Boston University Medical Center, Boston, MA, USA. Alik.Farber@bmc.org

Abstract

OBJECTIVE:

Although dextran has been theorized to diminish the risk of stroke associated with carotid endarterectomy (CEA), variation exists in its use. We evaluated outcomes of dextran use in patients undergoing CEA to clarify its utility.

METHODS:

We studied all primary CEAs performed by 89 surgeons within the Vascular Study Group of New England database (2003-2010). Patients were stratified by intraoperative dextran use. Outcomes included perioperative death, stroke, myocardial infarction (MI), and congestive heart failure (CHF). Group and propensity score matching was performed for risk-adjusted comparisons, and multivariable logistic and gamma regressions were used to examine associations between dextran use and outcomes.

RESULTS:

There were 6641 CEAs performed, with dextran used in 334 procedures (5%). Dextran-treated and untreated patients were similar in age (70 years) and symptomatic status (25%). Clinical differences between the cohorts were eliminated by statistical adjustment. In crude, group-matched, and propensity-matched analyses, the stroke/death rate was similar for the two cohorts (1.2%). Dextran-treated patients were more likely to suffer postoperative MI (crude: 2.4% vs 1.0%; P = .03; group-matched: 2.4% vs 0.6%; P = .01; propensity-matched: 2.4% vs 0.5%; P = .003) and CHF (2.1% vs 0.6%; P = .01; 2.1% vs 0.5%; P = .01; 2.1% vs 0.2%; P < .001). In multivariable analysis of the crude sample, dextran was associated with a higher risk of postoperative MI (odds ratio, 3.52; 95% confidence interval, 1.62-7.64) and CHF (odds ratio, 5.71; 95% confidence interval, 2.35-13.89).

CONCLUSIONS:

Dextran use was not associated with lower perioperative stroke but was associated with higher rates of MI and CHF. Taken together, our findings suggest limited clinical utility for routine use of intraoperative dextran during CEA.

J Vasc Surg. 2008 Nov;48(5):1139-45. doi: 10.1016/j.jvs.2008.05.013. Epub 2008 Jun 30.

Factors associated with stroke or death after carotid endarterectomy in Northern New England.

Source

Section of Vascular Surgery Dartmouth-Hitchcock Medical Center, Lebanon, NH 03765, USA. philip.goodney@hitchcock.org

Abstract

OBJECTIVE:

This study investigated risk factors for stroke or death after carotid endarterectomy (CEA) among hospitals of varying type and size participating in a regional quality improvement effort.

METHODS:

We reviewed 2714 patients undergoing 3092 primary CEAs (excluding combined procedures or redo CEA) at 11 hospitals in Northern New England from January 2003 through December 2007. Hospitals varied in size (25 to 615 beds) and comprised community and teaching hospitals. Fifty surgeons reported results to the database. Trained research personnel prospectively collected >70 demographic and clinical variables for each patient. Multivariate logistic regression models were used to generate odds ratios (ORs) and prediction models for the 30-day postoperative stroke or death rate.

RESULTS:

Across 3092 CEAs, there were 38 minor strokes, 14 major strokes, and eight deaths (5 stroke-related) < or =30 days of the index procedure (30-day stroke or death rate, 1.8%). In multivariate analyses, emergency CEA (OR, 7.0; 95% confidence interval [CI], 1.8-26.9; P = .004), contralateral internal carotid artery occlusion (OR, 2.8; 95% CI, 1.3-6.2; P = .009), preoperative ipsilateral cortical stroke (OR, 2.4; 95% CI, 1.1-5.1; P = .02), congestive heart failure (OR, 1.6; 95% CI, 1.1-2.4, P = .03), and age >70 (OR, 1.3; 95% CI, 0.8-2.3; P = .315) were associated with postoperative stroke or death. Preoperative antiplatelet therapy was protective (OR, 0.4; 95% CI, 0.2-0.9; P = .02). Risk of stroke or death varied from <1% in patients with no risk factors to nearly 5% with patients with > or =3 risk factors. Our risk prediction model had excellent correlation with observed results (r = 0.96) and reasonable discriminative ability (area under receiver operating characteristic curve, 0.71). Risks varied from <1% in asymptomatic patients with no risk factors to nearly 4% in patients with contralateral internal carotid artery occlusion (OR, 3.2; 95% CI, 1.3-8.1; P = .01) and age >70 (OR, 2.9; 95% CI, 1.0-4.9, P = .05). Two hospitals performed significantly better than expected. These differences were not attributable to surgeon or hospital volume.

CONCLUSION:

Surgeons can “risk-stratify” preoperative patients by considering the variables (emergency procedure, contralateral internal carotid artery occlusion, preoperative ipsilateral cortical stroke, congestive heart failure, and age), reducing risk with antiplatelet agents, and informing patients more precisely about their risk of stroke or death after CEA. Risk prediction models can also be used to compare risk-adjusted outcomes between centers, identify best practices, and hopefully, improve overall results.

III. Cardiac Failure During Systemic Sepsis

CHANGES IN HEART FUNCTION DURING SEPSIS

The patient with sepsis has severely altered physiology in a number of ways, which can influence cardiac function. Firstly, there is a

  • Loss of intravascular volume due to excessive third space loss that results in a decrease in preload. Systemic vascular resistance is decreased which results in a fall in afterload. In addition,
  • end diastolic volumes often increase and
  • ejection fraction falls. However, many of these changes are overcome by an
  • increase in heart rate that may result in an increase in cardiac output. However, it should be remembered that even in the presence of high cardiac outputs it is usually always possible to demonstrate
  • ventricular dysfunction in patients with sepsis. Echocardiographic studies consistently confirm that there is decreased left ventricular systolic function in humans with sepsis.

In addition, there have been many studies in animals and a few in humans which have confirmed the presence of

  • diastolic dysfunction – particularly in those patients that go on to die from sepsis.

In the presence of adequate fluid resuscitation there is an increase in end diastolic volume and this is probably a normal response to a decrease in contractility. However, in the non-survivors of sepsis there is a normal or low end diastolic volume that is the result of a decrease in ventricular diastolic compliance. Thus, there is a decreased end diastolic volume at the same filling pressure.

During sepsis, a

  • decrease in contractility results in a shift to the right of the end-systolic pressure / volume curve and if this is not compensated for results in a
  • decrease in stroke volume and cardiac output.

When patients with sepsis are appropriately fluid resuscitated there is an

  • increase in end diastolic pressure that increases stroke volume. In addition, the
  • decrease in afterload will also increase stroke volume and will prevent a decrease in ejection fraction.

Alas, because there is a decrease in systolic contractility it would be expected that there would also be a decrease in diastolic stiffness which would allow cardiac output to be maintained despite the relatively low filling pressures. However, if this diastolic compliance change does not occur (as in the nonsurvivors of sepsis) then it is apparent  that the ability of the ventricle to generate a stroke volume is impaired at both ends of the curve.

The cause of the altered cardiac function in sepsis remains unknown although there are many theoretical explanations. Clearly, one of the most important mechanisms which can be readily corrected is hypovolaemia.

  • Myocardial oedema may contribute to a decrease in contractility.
  • Increased circulating catecholamines can result in a decrease in diastolic compliance, particularly important since these agents are often used to improve myocardial contractility.
  • Increased intrathoracic pressure caused by positive pressure ventilation can also result in decreased diastolic compliance. In addition, many of the
  • mediators of the inflammatory response, including products of activated endothelial cells and polymorphonuclear leucocytes (e.g. nitric oxide, tumour necrosis factor and interleukins 1 and 2) have all been postulated as negative inotropes and negative lusitropes.

Another, as yet, unidentified agent which is believed to be released from the splanchnic bed –

  • myocardial depressant factor – is postulated to play a role.

Treatments aimed at correcting the effects of these various inflammatory mediators may be eventually found but until these approaches have been proven to be beneficial the septic patient will continue to be managed according to the physiological principles outlined by Starling.

http://www.rcsed.ac.uk/RCSEDBackIssues/journal/vol46_1/4610005.htm

Sepsis and the Heart – Cardiovascular Involvement in General Medical Conditions

  1. M.W. Merx, MD;
  2. C. Weber, MD

+Author Affiliations


  1. From the Department of Medicine (M.W.M.), Division of Cardiology, Pulmonary Diseases and Vascular Medicine and the Institute of Molecular Cardiovascular Research (IMCAR) at the University Hospital (C.W.), RWTH Aachen University, Aachen, Germany.
  1. Correspondence to Marc W. Merx, MD, Medizinische Klinik I, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mailmmerx@ukaachen.de), or Christian Weber, MD, Institut für Kardiovaskuläre Molekularbiologie, Universitätsklinikum der RWTH Aachen, Pauwelstraße 30, 52057 Aachen, Germany (e-mail cweber@ukaachen.de).
Circulation.2007; 116: 793-802doi: 10.1161/​CIRCULATIONAHA.106.678359

Abstract

Sepsis is generally viewed as a disease aggravated by an inappropriate immune response encountered in the afflicted individual. As an important organ system frequently compromised by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear to date. There is currently no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis; however, in septic patients with coexistent and possibly undiagnosed coronary artery disease, regional myocardial ischemia or infarction secondary to coronary artery disease may certainly occur.

A circulating myocardial depressant factor in septic shock has long been proposed, and potential candidates for a myocardial depressant factor include

  • cytokines,
  • prostanoids, and
  • nitric oxide, among others.
  • Endothelial activation and
  • induction of the coagulatory system also contribute to the pathophysiology in sepsis.

Prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. The purpose of this review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches.

Key Words:

Sepsis, defined by consensus conference as “the systemic inflammatory response syndrome (SIRS) that occurs during infection,”1 is generally viewed as a disease aggravated by the inappropriate immune response encountered in the affected individual (for review, see Hotchkiss and Karl2 and Riedemann et al,3). The Table gives the current criteria for the establishment of the diagnosis of systemic inflammatory response syndrome, sepsis, and septic shock.1,4 Morbidity and mortality are high, resulting in sepsis and septic shock being the 10th most common cause of death in the United States.5 The incidence of sepsis and sepsis-related deaths appears to be increasing by 1.5% per year.6 In a recent study,6 the total national hospital cost invoked by severe sepsis in the United States was estimated at approximately $16.7 billion on the basis of an estimated severe sepsis rate of 751 000 cases per year with 215 000 associated deaths annually. A recent study from Britain documented a 46% in-hospital mortality rate for patients presenting with severe sepsis on admission to the intensive care unit.7

Current Criteria for Establishment of the Diagnosis of SIRS, Sepsis, and Septic Shock1,4

As an important organ system frequently affected by sepsis and always affected by septic shock, the cardiovascular system and its dysfunction during sepsis have been studied in clinical and basic research for more than 5 decades. In 1951, Waisbren was the first to describe cardiovascular dysfunction due to sepsis.8 He recognized a hyperdynamic state with full bounding pulses, flushing, fever, oliguria, and hypotension. In addition, he described a second, smaller patient group who presented clammy, pale, and hypotensive with low volume pulses and who appeared more severely ill. With hindsight, the latter group might well have been volume underresuscitated, and indeed, timely and adequate volume therapy has been demonstrated to be one of the most effective supportive measures in sepsis therapy.9

Under conditions of adequate volume resuscitation, the profoundly reduced systemic vascular resistance typically encountered in sepsis10 leads to a concomitant elevation in cardiac index that obscures the myocardial dysfunction that also occurs. However, as early as the mid-1980s, significant reductions in both stroke volume and ejection fraction in septic patients were observed despite normal total cardiac output.11 Importantly, the presence of cardiovascular dysfunction in sepsis is associated with a significantly increased mortality rate of 70% to 90% compared with 20% in septic patients without cardiovascular impairment.12 Thus, myocardial dysfunction in sepsis has been the focus of intense research activity. Although a number of mediators and pathways have been shown to be associated with myocardial depression in sepsis, the precise cause remains unclear.

The purpose of the present review is to delineate some characteristics of septic myocardial dysfunction, to assess the most commonly cited and reported underlying mechanisms of cardiac dysfunction in sepsis, and to briefly outline current therapeutic strategies and possible future approaches. This review is not intended to be all inclusive.

Characteristics of Myocardial Dysfunction in Sepsis

Using portable radionuclide cineangiography, Calvin et al13 were the first to demonstrate myocardial dysfunction in adequately volume-resuscitated septic patients with decreased ejection fraction and increased end-diastolic volume index. Adding pulmonary artery catheters to serial radionuclide cineangiography, Parker and colleagues11 extended these observations with the 2 major findings that (1) survivors of septic shock were characterized by increased end-diastolic volume index and decreased ejection fraction, whereas nonsurvivors typically maintained normal cardiac volumes, and (2) these acute changes in end-diastolic volume index and ejection fraction, although sustained for several days, were reversible. More recently, echocardiographic studies have demonstrated impaired left ventricular systolic and diastolic function in septic patients.14–16 These human studies, in conjunction with experimental studies ranging from the cellular level17 to isolated heart studies18,19 and to in vivo animal models,20–22 have clearly established decreased contractility and impaired myocardial compliance as major factors that cause myocardial dysfunction in sepsis.

Notwithstanding the functional and structural differences between the left and right ventricle, similar functional alterations, as discussed above, have been observed for the right ventricle, which suggests that right ventricular dysfunction in sepsis closely parallels left ventricular dysfunction.23–26 However, the relative contribution of the right ventricle to septic cardiomyopathy remains unknown.

Myocardial dysfunction in sepsis has also been analyzed with respect to its prognostic value. Parker et al,27 reviewing septic patients on initial presentation and at 24 hours to determine prognostic indicators, found a heart rate of <106 bpm to be the only cardiac parameter on presentation that predicted a favorable outcome. At 24 hours after presentation, a systemic vascular resistance index >1529 dyne · s−1 · cm−5 · m−2, a heart rate <95 bpm or a reduction in heart rate >18 bpm, and a cardiac index >0.5 L · min−1 · m−2 suggested survival.27 In a prospective study, Rhodes et al28 demonstrated the feasibility of a dobutamine stress test for outcome stratification, with nonsurvivors being characterized by an attenuated inotropic response. The well-established biomarkers in myocardial ischemia and heart failure, cardiac troponin I and T, as well as B-type natriuretic peptide, have also been evaluated with regard to sepsis-associated myocardial dysfunction. Although B-type natriuretic peptide studies have delivered conflicting results in septic patients (for review, see Maeder et al29), several small studies have reported a relationship between elevated cardiac troponin T and I and left ventricular dysfunction in sepsis, as assessed by echocardiographic ejection fraction30–33 or pulmonary artery catheter–derived left ventricular stroke work index.34 Cardiac troponin levels also correlated with the duration of hypotension35 and the intensity of vasopressor therapy.34In addition, increased sepsis severity, measured by global scores such as the Simplified Acute Physiology Score II (SAPS II) or the Acute Physiology And Chronic Health Evaluation II score (APACHE II), was associated with increased cardiac troponin levels,31,33 as was poor short-term prognosis.32,33,35,36 Despite the heterogeneity of study populations and type of troponin studied, the mentioned studies were univocal in concluding that elevated troponin levels in septic patients reflect higher disease severity, myocardial dysfunction, and worse prognosis. In a recent meta-analysis of 23 observational studies, Lim et al37 found cardiac troponin levels to be increased in a large percentage of critically ill patients. Furthermore, in a subset of studies that permitted adjusted analysis and comprised 1706 patients, this troponin elevation was associated with an increased risk of death (odds ratio, 2.5; 95% CI, 1.9 to 3.4, P<0.001)37; however, the underlying mechanisms clearly require further research.

Thus, it appears reasonable to recommend inclusion of cardiac troponins in the monitoring of patients with severe sepsis and septic shock to facilitate prognostic stratification and to increase alertness to the presence of cardiac dysfunction in individual patients. However, it remains to be shown whether risk stratification based on cardiac troponins can identify patients in whom aggressive therapeutic regimens might reap the greatest benefit and so translate into a survival benefit.

Mechanisms Underlying Myocardial Dysfunction in Sepsis

Cardiac depression during sepsis is probably multifactorial (Figure). Nevertheless, it is important to identify individual contributing factors and mechanisms to generate worthwhile therapeutic targets. As a consequence, a vast array of mechanisms, pathways, and disruptions in cellular homeostasis have been examined in septic myocardium.

Figure

View larger version:

Synopsis of potential underlying mechanisms in septic myocardial dysfunction. MDS indicates myocardial depressant substance.

Global Ischemia

An early theory of myocardial depression in sepsis was based on the hypothesis of global myocardial ischemia; however, septic patients have been shown to have high coronary blood flow and diminished coronary artery–coronary sinus oxygen difference.38 As in the peripheral circulation, these alterations can be attributed to disturbed flow autoregulation or disturbed oxygen utilization.39,40 Coronary sinus blood studies in patients with septic shock have also demonstrated complex metabolic alterations in septic myocardium, including increased lactate extraction, decreased free fatty acid extraction, and decreased glucose uptake.41 Furthermore, several magnetic resonance studies in animal models of sepsis have demonstrated the presence of normal high-energy phosphate levels in the myocardium.42,43 It has also been proposed that myocardial dysfunction in sepsis may reflect hibernating myocardium.44 To reach this conclusion, Levy et al44 studied a murine cecal ligation and double-puncture model and observed diminished cardiac performance, increased myocardial glucose uptake, and deposits of glycogen in a setting of preserved arterial oxygen tension and myocardial perfusion. Although all of the above-mentioned findings reflect important alterations in coronary flow and myocardial metabolism, mirroring effects observed in peripheral circulation during sepsis, there is no evidence supporting global ischemia as an underlying cause of myocardial dysfunction in sepsis. However, in septic patients with coexistent and possibly undiagnosed coronary artery disease (CAD), regional myocardial ischemia or infarction secondary to CAD may certainly occur. The manifestation of myocardial ischemia due to CAD might even be facilitated by the volatile hemodynamics in sepsis, as well as by the generalized microvascular dysfunction so frequently observed in sepsis.45 Additional CAD-aggravating factors encountered in sepsis encompass generalized inflammation and the activated coagulatory system. Furthermore, the endothelium plays a prominent role in sepsis (see below), but little is known of the impact of preexisting, CAD-associated endothelial dysfunction in this context. In a postmortem study of 21 fatal cases of septic shock, previously undiagnosed myocardial ischemia at least contributed to death in 7 of the 21 cases (all 21 patients were males, with a mean age of 60.4 years).46 It certainly appears prudent to remain wary of CAD complications while treating sepsis, especially in patients with identifiable risk factors and in view of the ever-increasing mean age of intensive care unit patients and including septic patients.

Myocardial Depressant Substance

A circulating myocardial depressant factor in septic shock was first proposed more than 50 years ago.47 Parrillo et al48 quantitatively linked the clinical degree of septic myocardial dysfunction with the effect the serum, taken from respective patients, had on rat cardiac myocytes, with clinical severity correlating well with the decrease in extent and velocity of myocyte shortening. These effects were not seen when serum from convalescent patients whose cardiac function had returned to normal was applied or when serum was obtained from other critically ill, nonseptic patients.48 In extension of these findings, ultrafiltrates from patients with severe sepsis and simultaneously reduced left ventricular stroke work index (<30 g · m−1 · m−2) displayed cardiotoxic effects and contained significantly increased concentrations of interleukin (IL)-1, IL-8, and C3a.49Recently, Mink et al50 demonstrated that lysozyme c, a bacteriolytic agent believed to originate mainly from disintegrating neutrophilic granulocytes and monocytes, mediates cardiodepressive effects during Escherichia coli sepsis and, importantly, that competitive inhibition of lysozyme c can prevent myocardial depression in the respective experimental sepsis model. Additional potential candidates for myocardial depressant substance include other cytokines, prostanoids, and nitric oxide (NO). Some of these will be discussed below.

Cytokines

Infusion of lipopolysaccharide (LPS, an obligatory component of Gram-negative bacterial cell walls) into both animals and humans51 partially mimics the hemodynamic effects of septic shock.51,52 However, only a minority of patients with septic shock have detectable LPS levels, and the prolonged time course of septic myocardial dysfunction and the chemical characteristics of LPS are not consistent with LPS representing the sole myocardial depressant substance.48,53 Tumor necrosis factor-α (TNF-α) is an important early mediator of endotoxin-induced shock.54 TNF-α is derived from activated macrophages, but recent studies have shown that TNF-α is also secreted by cardiac myocytes in response to sepsis.55 Although application of anti-TNF-α antibodies improved left ventricular function in patients with septic shock,56 subsequent studies using monoclonal antibodies directed against TNF-α or soluble TNF-α receptors failed to improve survival in septic patients.57–59 IL-1 is synthesized by monocytes, macrophages, and neutrophils in response to TNF-α and plays a crucial role in the systemic immune response. IL-1 depresses cardiac contractility by stimulating NO synthase (NOS).60 Transcription of IL-1 is followed by delayed transcription of IL-1 receptor antagonist (IL-1-ra), which functions as an endogenous inhibitor of IL-1. Recombinant IL-1-ra was evaluated in phase III clinical trials, which showed a tendency toward improved survival61 and increased survival time in a retrospective analysis of the patient subgroup with the most severe sepsis62; however, to date, this initially promising therapy has failed to deliver a statistically significant survival benefit. IL-6, another proinflammatory cytokine, has also been implicated in the pathogenesis of sepsis and is considered a more consistent predictor of sepsis than TNF-α because of its prolonged elevation in the circulation.63 Although cytokines may very well play a key role in the early decrease in contractility, they cannot explain the prolonged duration of myocardial dysfunction in sepsis, unless they result in the induction or release of additional factors that in turn alter myocardial function, such as prostanoids or NO.64,65

Prostanoids

Prostanoids are produced by the cyclooxygenase enzyme from arachidonic acid. The expression of cyclooxygenase enzyme-2 is induced, among other stimuli, by LPS and cytokines (cyclooxygenase enzyme-1 is expressed constitutively).66 Elevated levels of prostanoids such as thromboxane and prostacyclin, which have the potential to alter coronary autoregulation, coronary endothelial function, and intracoronary leukocyte activation, have been demonstrated in septic patients.67 Early animal studies with cyclooxygenase inhibitors such as indomethacin yielded very promising results.68,69Along with other positive results, these led to an important clinical study involving 455 septic patients who were randomized to receive intravenous ibuprofen or placebo.70Unfortunately, that study did not demonstrate improved survival for the treatment arm. Similarly, a more recent, smaller study on the effects of lornoxicam failed to provide evidence for a survival benefit through cyclooxygenase inhibition in sepsis.71 Animal studies aimed at elucidating possible benefits of isotype-selective cyclooxygenase inhibition have so far produced conflicting results.72,73

Endothelin-1

Endothelin-1 (ET-1; for an in-depth review of endothelin in sepsis, see Gupta et al74) upregulation has been demonstrated within 6 hours of LPS-induced septic shock.75Cardiac overexpression of ET-1 triggers an increase in inflammatory cytokines (among others, TNF-α, IL-1, and IL-6), interstitial inflammatory infiltration, and an inflammatory cardiomyopathy that results in heart failure and death.76 The involvement of ET-1 in septic myocardial dysfunction is supported by the observation that tezosentan, a dual endothelin-A and endothelin-B receptor antagonist, improved cardiac index, stroke volume index, and left ventricular stroke work index in endotoxemic shock.77 However, higher doses of tezosentan exhibited cardiotoxic effects and led to increased mortality.77Although ET-1 has been demonstrated to be of pathophysiological importance in a wide array of cardiac diseases through autocrine, endocrine, or paracrine effects, its biosynthesis, receptor-mediated signaling, and functional consequences in septic myocardial dysfunction warrant further investigation to assess the therapeutic potential of ET-1 receptor antagonists.

Nitric Oxide

NO exerts a plethora of biological effects in the cardiovascular system.78 It has been shown to modulate cardiac function under physiological and a multitude of pathophysiological conditions. In healthy volunteers, low-dose NO increases LV function, whereas inhibition of endogenous NO release by intravenous infusion of the NO synthase (NOS) inhibitor NG-monomethyl-L-arginine reduced the stroke volume index.79 Higher doses of NO have been shown to induce contractile dysfunction by depressing myocardial energy generation.80 The absence of the important NO scavenger myoglobin (Mb) in Mb knockout mice results in impaired cardiac function that is partially reversible by NOS inhibition.81 Endogenous NO contributes to hibernation in response to myocardial ischemia by reducing oxygen consumption and preserving calcium sensitivity and contractile function.82 NO also represents a potent modulator of myocardial ischemia/reperfusion injury. However, as in sepsis-related NO research, the reported effects of NO on ischemia/reperfusion injury are inconsistent owing to a multitude of confounding experimental factors.83

Sepsis leads to the expression of inducible NOS (iNOS) in the myocardium,84,85 followed by high-level NO production, which in turn importantly contributes to myocardial dysfunction, in part through the generation of cytotoxic peroxynitrite, a product of NO and superoxide (for an excellent review, see Pacher et al86). In iNOS-deficient mice, cardiac function is preserved after endotoxin challenge.87 Nonspecific NOS inhibition restores cardiac output and stroke volume after LPS injection.88 Strikingly, in septic patients, infusion of methylene blue, a nonspecific NOS inhibitor, improves mean arterial pressure, stroke volume, and left ventricular stroke work and decreases the requirement for inotropic support but, unfortunately, does not alter outcome.89 An interesting study comparing the inhibition of NO superoxide and peroxynitrite in cytokine-induced myocardial contractile failure found peroxynitrite to indeed be the most promising therapeutic target.90 It has also been proposed that the constitutively expressed mitochondrial isoform of NOS (mtNOS), the expression of which can be augmented by induction, controls rates of oxidative phosphorylation by inhibiting various steps of the respiratory chain.91 Although this hypothesis would provide a plausible explanation for the reduced coronary oxygen extraction observed during sepsis (see above), the effects of sepsis on expression of mtNOS and NO generation remain to be explored. Furthermore, the constitutively expressed endothelial NOS (eNOS), previously neglected in the context of sepsis, has been shown to be an important regulator of iNOS expression, resulting in a more stable hemodynamic status in eNOS-deficient mice after endotoxemia.92 Very recently, a functional NOS in red blood cells (rbcNOS) was identified that regulates deformability of erythrocyte membranes and inhibits activation of platelets.93 With both effect targets thus far demonstrated for rbcNOS lying at the core of microvascular dysfunction in sepsis, this discovery opens a whole new window to NO-related sepsis research. Given the existence of different NOS isoforms and their various modulating interactions, dose-dependent NO effects, and the precise balance of NO, superoxide, and thus peroxynitrite generated in subcellular compartments, further advances in our understanding of the complex NO biology and its derived reactive nitrogen species hold the promise of revealing new, more specific and effective therapeutic targets.

Adhesion Molecules

Surface-expression upregulation of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 has been demonstrated in murine coronary endothelium and cardiomyocytes after LPS and TNF-α stimulation.94 After cecal ligation and double puncture, myocardial intercellular adhesion molecule-1 expression increases in rats.95Vascular cell adhesion molecule-1 blockade with antibodies has been shown to prevent myocardial dysfunction and decrease myocardial neutrophil accumulation,94,96 whereas both knockout and antibody blockade of intercellular adhesion molecule-1 ameliorate myocardial dysfunction in endotoxemia without affecting neutrophil accumulation.94 In addition, neutrophil depletion does not protect against septic cardiomyopathy, which suggests that the cardiotoxic potential of neutrophils infiltrating the myocardium is of lesser importance in this context.94 Other aspects of adhesion molecules are discussed in conjunction with possible statin effects below.

The e-Reader is advised to consider the following expansion on the subject matter carrying the discussion to additional related clinical issues:

Advanced Topics in Sepsis and the Cardiovascular System at its End Stage

Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2013/08/18/advanced-topics-in-sepsis-and-the-cardiovascular-system-at-its-end-stage/

Therapeutic Approaches: The Present and the Future

A detailed discussion of therapeutic options in septic patients would clearly be beyond the scope of this review, and readers are kindly referred to the multiple excellent reviews published on the subject (eg, Hotchkiss and Karl,2 Annane et al,4 and Dellinger et al97). Although a number of preventive measures, such as prophylactic antibiotics, maintenance of normoglycemia, selective digestive tract decontamination, vaccines, and intravenous immunoglobulin, have shown benefit in distinct patient populations, preventive strategies with a broader aim remain elusive. Once sepsis is manifest (see the Table for criteria), prompt and adequate antibiotic therapy accompanied by surgical removal of the infectious focus, if indicated and feasible, is the mainstay and also the only strictly causal line of therapy. In the presence of severe sepsis and septic shock, supportive treatment in addition to causal therapy is mandatory. Supportive therapy encompasses early and goal-directed fluid resuscitation,9 vasopressor and inotropic therapy, red blood cell transfusion, mechanical ventilation, and renal support when indicated. It is very likely beneficial to monitor cardiac performance in these patients. A wide array of techniques are available for this purpose, ranging from echocardiography to pulmonary catheters, thermodilution techniques, and pulse pressure analysis.98 Because none of these techniques have demonstrated superiority, physicians should use the method with which they are most familiar. Whichever method is chosen, it should be applied frequently to tailor supportive therapy to the individual patient and to achieve the “gold standard” of early goal-directed therapy. In recent years, several attempts have been made to therapeutically address myocardial dysfunction in sepsis. Although the combination of norepinephrine as vasopressor and dobutamine as inotropic agent is probably the most frequently applied in septic shock, there is currently no evidence to recommend one catecholamine over the other.97 In human endotoxemia, epinephrine has been demonstrated to inhibit proinflammatory pathways and coagulation activation, as well as to augment antiinflammatory pathways,99,100 whereas no immunomodulatory or coagulant effects could be demonstrated for dobutamine in a similar setting.101 Isoproterenol has recently been applied successfully in a small group of patients with septic shock, no known history of CAD, and inappropriate mixed venous oxygen concentration despite correction of hypoxemia and anemia.102 In a cecal ligation and double-puncture model of sepsis, the β-blocker esmolol given continuously after sepsis induction improved myocardial oxygen utilization and attenuated myocardial dysfunction,103 which suggests that therapeutic strategies proven in ischemic heart failure might also hold promise in septic cardiomyopathy. However, the optimal mode of β-receptor stimulation (or indeed inhibition) to limit myocardial dysfunction remains a wide-open field for inspired investigation.

Given the generally accepted view of sepsis as a disease largely propelled by an inappropriate immune response, numerous basic research and clinical trials have been undertaken to curb the lethal toll of sepsis through modulation of this uncontrolled immune response.2,3 To date, activated protein C104 and low-dose hydrocortisone105 have emerged as the only inflammation-modulating substances that have been confirmed to be of benefit in patients with severe sepsis and septic shock. Over the past years, increasing evidence has accumulated that suggests that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase, or statins, have therapeutic benefits independent of cholesterol lowering, termed “pleiotropic” effects. These have added a wide scope of potential targets for statin therapy that range from decreasing renal function loss106 and lowering mortality in patients with diastolic heart failure107 to prevention and treatment of stroke,108 to name just a few. These pleiotropic effects include antiinflammatory and antioxidative properties, improvement of endothelial function, and increased NO bioavailability and thus might contribute to the benefit observed with statin therapy. Notably, these important immunomodulatory effects of statins have been demonstrated to be independent of lipid lowering109 and appear to be mediated via interference with the synthesis of mevalonate metabolites (nonsteroidal isoprenoid products). Blockade of the mevalonate pathway has been shown to suppress T-cell responses,110 reduce expression of class II major histocompatibility complexes on antigen presenting cells,109 and inhibit chemokine synthesis in peripheral blood mononuclear cells.111 Furthermore, CD11b integrin expression and CD11b-dependent adhesion of monocytes have been found to be attenuated by the initiation of statin treatment in hypercholesterolemic patients.112 In this context, Yoshida et al113 have reported that statins reduce the expression of both monocytic and endothelial adhesion molecules, eg, the integrin leukocyte function-associated antigen-1 (LFA-1), via an inhibition of Rho GTPases, in particular their membrane anchoring by geranylation. In addition, mechanisms for antiinflammatory actions of statins have been revealed that are not related to the isoprenoid metabolism. For instance, Weitz-Schmidt et al114 have identified that some statins act as direct antagonists of LFA-1 owing to their capacity to bind to the regulatory site in the LFA-1 i-domain. In addition to these multifaceted antiinflammatory effects, statins may interfere with activation of the coagulation cascade, as illustrated by the suppression of LPS-induced monocyte tissue factor in vitro.115 Beyond their immunomodulatory functions, statins have been shown to exert direct antichlamydial effects during pulmonary infection with Chlamydia pneumoniae in mice,116 and a recent report suggests the benefit of statins may also extend to viral pathogens.117

Given the strong impact of statins on inflammation, statins might represent a welcome enforcement in the battle against severe infectious diseases such as sepsis. Consequently, several investigators have evaluated the role of statins in the prevention and treatment of sepsis. In a retrospective analysis, Liappis et al118 demonstrated a reduced overall and attributable mortality in patients with bacteremia who were treated concomitantly with statins. Pretreatment with simvastatin has been shown to profoundly improve survival in a polymicrobial murine model of sepsis by preservation of cardiovascular function and inhibition of inflammatory alterations.19 Encouraged by these findings, the same model was used to successfully treat sepsis in a clinically feasible fashion, ie, treatment was initiated several hours after the onset of sepsis. With different statins (atorvastatin, pravastatin, and simvastatin) being effective, the therapeutic potential of statins in sepsis appears to be a class effect.22 Recently, Steiner et al119observed that pretreatment with simvastatin can suppress the inflammatory response induced by LPS in healthy human volunteers. Furthermore, in a prospective observational cohort study in patients with acute bacterial infections performed by Almog et al,120previous treatment with statins was associated with a considerably reduced rate of severe sepsis and intensive care unit admissions. A total of 361 patients were enrolled in that study, and 82 of these patients had been treated with statins for at least 4 weeks before their admission. Severe sepsis developed in 19% of patients in the no-statin group compared with only 2.4% in patients who were taking statins. The intensive care unit admission rates were 12.2% for the no-statin group and 3.7% for the statin group. Because of the number of patients enrolled, the study was not powered to detect differences in mortality, although the large effect on sepsis rate and intensive care unit admission were at least suggestive. As the most recent development in this field, Hackam et al121 have produced an impressive observational study by initial evaluation of 141 487 cardiovascular patients, which resulted in a well-paired and homogenous study cohort of 69 168 patients after propensity-based matching. Drawing from this solid base, Hackam and coauthors were able to support the conclusion that statin therapy is associated with a considerably decreased rate of sepsis (hazard ratio, 0.81; 95% CI, 0.72 to 0.90), severe sepsis (hazard ratio, 0.83; 95% CI, 0.70 to 0.97), and fatal sepsis (hazard ratio, 0.75; 95% CI, 0.61 to 0.93). This protective effect prevailed at both high and low statin doses and for several clinically important subpopulations, such as diabetic and heart failure patients.

As has been suggested previously,122 statins might provide cumulative benefit by reducing mortality from cardiovascular and infectious diseases such as sepsis. However, statins may have detrimental effects in distinct subsets of patients. Therefore, caution should prevail, and the use of statins in patients with sepsis must be accompanied by meticulous monitoring of unexpected side effects and well-designed randomized, controlled clinical trials.

Beyond an apparent rationale for randomized trials on statins in sepsis, it is notable that the results with other immunomodulatory approaches in sepsis have yielded rather limited success. For instance, use of the anti-TNF antibody F(ab′)2 fragment afelimomab led to a significant but rather modest reduction in risk of death and to improved organ-failure scores in patients with severe sepsis and elevated IL-6 levels.123 Moreover, a selective inhibitor of group IIA secretory phospholipase A2 failed to improve clinical outcome for patients with severe sepsis, with a negative trend most pronounced among patients with cardiovascular failure.124 Hence, because none of the available strategies proven to be effective in sepsis are designed specifically to target myocardial dysfunction, one might conclude that strategies that preferentially address cardiac morbidity in sepsis may be a promising area for investigation. For instance, lipoteichoic acid, a major virulence factor in Gram-positive sepsis, causes cardiac depression by activating myocardial TNF-α synthesis via CD14 and induces coronary vascular disturbances by activating thromboxane 2 synthesis. It thus contributes to cardiac depression and may therefore be a worthwhile and cardiac-specific target.125 The implications of intensified efforts in the search for successful novel approaches to the treatment of myocardial dysfunction in sepsis may be considerable with regard to improved patient care that results in reduced mortality. This is of major significance in view of the substantial economic consequences of increasing sepsis morbidity in an aging population.

REFERENCES

in Circulation.2007; 116: 793-802 doi: 10.1161/​CIRCULATIONAHA.106.678359

  1. Bone RC, Balk RA, Cerra FB, Dellinger RP, Fein AM, Knaus WA, Schein RMH, Sibbald WJ. Definitions for sepsis and organ failure and guidelines for the use of innovative therapies in sepsis. Chest1992; 101: 1644–1655.
  2. Hotchkiss RS, Karl IE. The pathophysiology and treatment of sepsis. N Engl J Med2003; 348: 138–150.
  3. Riedemann NC, Guo R, Ward PA. Novel strategies for the treatment of sepsis.Nat Med2003; 9: 517–524.
  4. Annane D, Bellissant E, Cavaillon JM. Septic shock. Lancet2005; 365: 63–78.
  5. Martin GS, Mannino DM, Eaton S, Moss M. The epidemiology of sepsis in the United States from 1979 through 2000. N Engl J Med2003; 348: 1546–1554.
  6. Angus DC, Linde-Zwirble WT, Lidicker J, Clermont G, Carcillo J, Pinsky MR. Epidemiology of severe sepsis in the United States: analysis of incidence, outcome, and associated costs of care. Crit Care Med2001; 29: 1303–1310.
  7. Padkin A, Goldfrad C, Brady AR, Young D, Black N, Rowan K. Epidemiology of severe sepsis occurring in the first 24 hrs in intensive care units in England, Wales, and Northern Ireland. Crit Care Med2003; 31: 2332–2338.
  8. Waisbren BA. Bacteremia due to gram-negative bacilli other than the Salmonella: a clinical and therapeutic study. AMA Arch Intern Med1951; 88: 467–488.
  9. Rivers E, Nguyen B, Havstad S, Ressler J, Muzzin A, Knoblich B, Peterson E, Tomlanovich M; Early Goal-Directed Therapy Collaborative Group. Early goal-directed therapy in the treatment of severe sepsis and septic shock. N Engl J Med.2001; 345: 1368–1377.
  10. Bone RC. Gram-negative sepsis: background, clinical features, and intervention.Chest1991; 100: 802–808.
  11. Parker MM, Shelhamer JH, Bacharach SL, Green MV, Natanson C, Frederick TM, Damske BA, Parrillo JE. Profound but reversible myocardial depression in patients with septic shock. Ann Intern Med1984; 100: 483–490.
  12. Parrillo JE, Parker MM, Natanson C, Suffredini AF, Danner RL, Cunnion RE, Ognibene FP. Septic shock in humans: advances in the understanding of pathogenesis, cardiovascular dysfunction, and therapy. Ann Intern Med1990; 113:227–242.
  13. Calvin JE, Driedger AA, Sibbald WJ. An assessment of myocardial function in human sepsis utilizing ECG gated cardiac scintigraphy. Chest1981; 80: 579–586.
  14. Jafri SM, Lavine S, Field BE, Bahorozian MT, Carlson RW. Left ventricular diastolic function in sepsis. Crit Care Med1990; 18: 709–714.
  15. Munt B, Jue J, Gin K, Fenwick J, Tweeddale M. Diastolic filling in human severe sepsis: an echocardiographic study. Crit Care Med1998; 26: 1829–1833.
  16. Poelaert J, Declerck C, Vogelaers D, Colardyn F, Visser CA. Left ventricular systolic and diastolic function in septic shock. Intensive Care Med1997; 23: 553–560.
  17. Ren J, Ren BH, Sharma AC. Sepsis-induced depressed contractile function of isolated ventricular myocytes is due to altered calcium transient properties. Shock.2002; 18: 285–288.
  18. McDonough KH, Smith T, Patel K, Quinn M. Myocardial dysfunction in the septic rat heart: role of nitric oxide. Shock1998; 10: 371–376.
  19. Merx MW, Liehn EA, Janssens U, Lütticken R, Schrader J, Hanrath P, Weber C. HMG-CoA reductase inhibitor simvastatin profoundly improves survival in a murine model of sepsis. Circulation2004; 109: 2560–2565.
  20. Natanson C, Fink MP, Ballantyne HK, Mac Vittie TJ, Conklin JJ, Parrillo JE. Gram-negative bacteremia produces both severe systolic and diastolic cardiac dysfunction in a canine model that simulates human septic shock. J Clin Invest.1986; 78: 259–270.
  21. Stahl TJ, Alden PB, Ring WS, Madoff RC, Cerra FB. Sepsis-induced diastolic dysfunction in chronic canine peritonitis. Am J Physiol Heart Circ Physiol1990;258: H625–H633.
  22. Merx MW, Liehn EA, Graf J, van de Sandt A, Schaltenbrand M, Schrader J, Hanrath P, Weber C. Statin treatment after onset of sepsis in a murine model improves survival. Circulation2005; 112: 117–124.
  23. Vincent JL, Thirion M, Brimioulle S, Lejeune P, Kahn RJ. Thermodilution measurement of right ventricular ejection fraction with a modified pulmonary artery catheter. Intensive Care Med1986; 12: 33–38.
  24. Dhainaut JF, Brunet F, Monsaillier JF, Villemant D, Devaux JY, Konno M, De Gournay JM, Armaganidis A, Iotti G, Huyghebaert MF. Bedside evaluation of right ventricular performance using a rapid computerized thermodilution method. Crit Care Med1987; 15: 148–152.
  25. Dhainaut JF, Lanore JJ, de Gournay JM, Huyghebaert MF, Brunet F, Villemant D, Monsallier JF. Right ventricular dysfunction in patients with septic shock.Intensive Care Med1988; 14: 488–491.
  26. Parker MM, McCarthy KE, Ognibene FP, Parrillo JE. Right ventricular dysfunction and dilatation, similar to left ventricular changes, characterize the cardiac depression of septic shock in humans. Chest1990; 97: 126–131.
  27. Parker MM, Shelhamer JH, Natanson C, Alling DW, Parrillo JE. Serial cardiovascular variables in survivors and nonsurvivors of human septic shock: heart rate as an early predictor of prognosis. Crit Care Med1987; 15: 923–929.
  28. Rhodes A, Lamb FJ, Malagon I, Newman PJ, Grounds RM, Bennett ED. A prospective study of the use of a dobutamine stress test to identify outcome in patients with sepsis, severe sepsis, or septic shock. Crit Care Med1999; 27: 2361–2366.
  29. Maeder M, Fehr T, Rickli H, Ammann P. Sepsis-associated myocardial dysfunction: diagnostic and prognostic impact of cardiac troponins and natriuretic peptides. Chest2006; 129: 1349–1366.
  30. Fernandes CJ, Akamine N, Knobel E. Cardiac troponin: a new serum marker of myocardial injury in sepsis. Intensive Care Med1999; 25: 1165–1168.
  31. ver Elst KM, Spapen HD, Nguyen DN, Garbar C, Huyghens LP, Gorus FK. Cardiac troponins I and T are biological markers of left ventricular dysfunction in septic shock. Clin Chem2000; 46: 650–657.
  32. Ammann P, Fehr T, Minder EI, Gunter C, Bertel O. Elevation of troponin I in sepsis and septic shock. Intensive Care Med2001; 27: 965–969.
  33. Mehta NJ, Khan IA, Gupta V, Jani K, Gowda RM, Smith PR. Cardiac troponin I predicts myocardial dysfunction and adverse outcome in septic shock. Int J Cardiol.2004; 95: 13–17.
  34. Turner A, Tsamitros M, Bellomo R. Myocardial cell injury in septic shock. Crit Care Med1999; 27: 1775–1780.
  35. Arlati S, Brenna S, Prencipe L, Marocchi A, Casella GP, Lanzani M, Gandini C. Myocardial necrosis in ICU patients with acute non-cardiac disease: a prospective study. Intensive Care Med2000; 26: 31–37.
  36. Spies C, Haude V, Fitzner R, Schroder K, Overbeck M, Runkel N, Schaffartzik W. Serum cardiac troponin T as a prognostic marker in early sepsis. Chest1998;113: 1055–1063.
  37. Lim W, Qushmag I, Devereaux PJ, Heels-Ansdell D, Lauzier F, Ismaila AS, Crowther MA, Cook DJ. Elevated cardiac troponin measurements in critically ill patients. Arch Intern Med2006; 166: 2446–2454.
  38. Cunnion RE, Schaer GL, Parker MM, Natanson C, Parrillo JE. The coronary circulation in human septic shock. Circulation1986; 73: 637–644.
  39. Herbertson MJ, Werner HA, Russell JA, Iversen K, Walley KR. Myocardial oxygen extraction ratio is decreased during endotoxemia in pigs. J Appl Physiol.1995; 79: 479–486.
  40. Powell RJ, Machiedo GW, Rush BF, Dikdan G. Oxygen free radicals: effect on red cell deformability in sepsis. Crit Care Med1991; 19: 732–735.
  41. Dhainaut JF, Huyghebaert MF, Monsallier JF, Lefevre G, Dall’Ava-Santucci J, Brunet F, Villemant D, Carli A, Raichvarg D. Coronary hemodynamics and myocardial metabolism of lactate, free fatty acids, glucose, and ketones in patients with septic shock. Circulation1987; 75: 533–541.
  42. Solomon MA, Correa R, Alexander HR, Koev LA, Cobb JP, Kim DK, Roberts WC, Quezado ZM, Scholz TD, Cunnion RE, Hoffman WD, Bacher J, Yatsiv I, Danner RL, Banks SM, Ferrans VJ, Balaban RS, Natanson C. Myocardial energy metabolism and morphology in a canine model of sepsis. Am J Physiol Heart Circ Physiol1994; 266: H757–H768.
  43. Van Lambalgen AA, van Kraats AA, Mulder MF, Teerlink T, van den Bos GC. High-energy phosphates in heart, liver, kidney, and skeletal muscle of endotoxemic rats. Am J Physiol Heart Circ Physiol1994; 266: H1581–H1587.
  44. Levy RJ, Piel DA, Acton PD, Zhou R, Ferrari VA, Karp JS, Deutschman CS. Evidence of myocardial hibernation in the septic heart. Crit Care Med2005; 33:2752–2756.
  45. Hinshaw LB. Sepsis/septic shock: participation of the microcirculation: an abbreviated review. Crit Care Med1996; 24: 1072–1078.
  46. Hoffmann R. Tissue Doppler echocardiography: already of clinical significance? Z Kardiol2002; 91: 677–684.
  47. Wiggers CJ. Myocardial depression in shock: a survey of cardiodynamic studies.Am Heart J1947; 33: 633–650.
  48. Parrillo JE, Burch C, Shelhamer JH, Parker MM, Natanson C, Schuette W. A circulating myocardial depressant substance in humans with septic shock: septic shock patients with a reduced ejection fraction have a circulating factor that depresses in vitro myocardial cell performance. J Clin Invest1985; 76: 1539–1553.
  49. Hoffmann JN, Werdan K, Hartl WH, Jochum M, Faist E, Inthorn D. Hemofiltrate from patients with severe sepsis and depressed left ventricular contractility contains cardiotoxic compounds. Shock1999; 13: 174–180.
  50. Mink SN, Jacobs H, Duke K, Bose D, Cheng ZQ, Light RB. N,N′,N″-triacetylglucosamine, an inhibitor of lysozyme, prevents myocardial depression in Escherichia coli sepsis in dogs. Crit Care Med2004; 32: 184–193.
  51. Suffredini AF, Fromm RE, Parker MM, Brenner M, Kovacs JA, Wesley RA, Parrillo JE. The cardiovascular response of normal humans to the administration of endotoxin. N Engl J Med1989; 321: 280–287.
  52. Danner RL, Elin RJ, Hosseini JM, Wesley RA, Reilly JM, Parrillo JE. Endotoxemia in human septic shock. Chest1991; 99: 169–175.
  53. Reilly JM, Cunnion RE, Burch-Whitman C, Parker MM, Shelhamer JH, Parrillo JE. A circulating myocardial depressant substance is associated with cardiac dysfunction and peripheral hypoperfusion (lactic acidemia) in patients with septic shock. Chest1989; 95: 1072–1080.
  54. Sharma AC, Motew SJ, Farias S, Alden KJ, Bosmann HB, Law WR, Ferguson JL. Sepsis alters myocardial and plasma concentrations of endothelin and nitric oxide in rats. J Mol Cell Cardiol1997; 29: 1469–1477.
  55. Horton JW, Maass D, White J, Sanders B. Nitric oxide modulation of TNF-alpha-induced cardiac contractile dysfunction is concentration dependent. Am J Physiol Heart Circ Physiol2000; 278: H1955–H1965.
  56. Vincent JL, Bakker J, Marecaux G, Schandene L, Kahn RJ, Dupont E. Administration of anti-TNF antibody improves left ventricular function in septic shock patients: results of a pilot study. Chest1992; 101: 810–815.
  57. Fisher CJ, Agosti JM, Opal SM, Lowry SF, Balk RA, Sadoff JC, Abraham E, Schein RM, Benjamin E; the Soluble TNF Receptor Sepsis Study Group. Treatment of septic shock with the tumor necrosis factor receptor:Fc fusion protein. N Engl J Med1996; 334: 1697–1702.
  58. Abraham E, Glauser MP, Butler T, Garbino J, Gelmont D, Laterre PF, Kudsk K, Bruining HA, Otto C, Tobin E, Zwingelstein C, Lesslauer W, Leighton A; Ro 45-2081 Study Group. p55 Tumor necrosis factor receptor fusion protein in the treatment of patients with severe sepsis and septic shock: a randomized controlled multicenter trial. JAMA1997; 277: 1531–1538.
  59. Abraham E, Anzueto A, Gutierrez G, Tessler S, San Pedro G, Wunderink R, Dal Nogare A, Nasraway S, Berman S, Cooney R, Levy H, Baughman R, Rumbak M, Light RB, Poole L, Allred R, Constant J, Pennington J, Porter S; NORASEPT II Study Group. Double-blind randomised controlled trial of monoclonal antibody to human tumour necrosis factor in treatment of septic shock. Lancet1998; 351: 929–933.
  60. Francis SE, Holden H, Holt CM, Duff GW. Interleukin-1 in myocardium and coronary arteries of patients with dilated cardiomyopathy. J Mol Cell Cardiol1998;30: 215–223.
  61. Opal SM, Fisher CJ Jr, Dhainaut JF, Vincent JL, Brase R, Lowry SF, Sadoff JC, Slotman GJ, Levy H, Balk RA, Shelly MP, Pribble JP, LaBrecque JF, Lookabaugh J, Donovan H, Dubin H, Baughman R, Norman J, DeMaria E, Matzel K, Abraham E, Seneff M; Interleukin-1 Receptor Antagonist Sepsis Investigator Group. Confirmatory interleukin-1 receptor antagonist trial in severe sepsis: a phase III, randomized, double-blind, placebo-controlled, multicenter trial. Crit Care Med1997; 25: 1115–1124.
  62. Fisher CJ Jr, Dhainaut JF, Opal SM, Pribble JP, Balk RA, Slotman GJ, Iberti TJ, Rackow EC, Shapiro MJ, Greenman RL; Phase III rhIL-1ra Sepsis Syndrome Study Group. Recombinant human interleukin 1 receptor antagonist in the treatment of patients with sepsis syndrome: results from a randomized, double-blind, placebo-controlled trial. JAMA1994; 271: 1836–1843.
  63. Damas P, Ledoux D, Nys M, Vrindts Y, De Groote D, Franchimont P, Lamy M. Cytokine serum level during severe sepsis in human IL-6 as a marker of severity.Ann Surg1992; 215: 356–362.
  64. Schulz R, Nava E, Moncada S. Induction and potential biological relevance of a Ca2+-independent nitric oxide synthase in the myocardium. Br J Pharmacol1992;105: 575–580.
  65. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hattler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide.Science1992; 257: 387–389.
  66. Liu SF, Newton R, Evans TW, Barnes PJ. Differential regulation of cyclo-oxygenase-1 and cyclo-oxygenase-2 gene expression by lipopolysaccharide treatment in vivo in the rat. Clin Sci (Lond)1996; 90: 301–306.
  67. Reines HD, Halushka PV, Cook JA, Wise WC, Rambo W. Plasma thromboxane concentrations are raised in patients dying with septic shock. Lancet1982; 2: 174–175.
  68. Fletcher JR, Ramwell PW. Modification, by aspirin and indomethacin, of the haemodynamic and prostaglandin releasing effects of E. coli endotoxin in the dog.Br J Pharmacol1977; 61: 175–181.
  69. Parratt JR, Sturgess RM. E. coli endotoxin shock in the cat; treatment with indomethacin. Br J Pharmacol1975; 53: 485–488.
  70. Bernard GR, Wheeler AP, Russel JA, Schein R, Summer WR, Steinberg KP, Fulkerson WJ, Wright PE, Christmann BW, Dupont WD, Higgins SB, Swindell BB; The Ibuprofen in Sepsis Study Group. The effects of ibuprofen on the physiology and survival of patients with sepsis. N Engl J Med1997; 336: 912–918.
  71. Memis D, Karamanlioglu B, Turan A, Koyuncu O, Pamukcu Z. Effects of lornoxicam on the physiology of severe sepsis. Crit Care2004; 8: R474–R482.
  72. Tunctan B, Altug S, Uludag O, Demirkay B, Abacioglu N. Effects of cyclooxygenase inhibitors on nitric oxide production and survival in a mice model of sepsis. Pharmacol Res2003; 48: 37–48.
  73. Reddy RC, Chen GH, Tateda K, Tsai WC, Phare SM, Mancuso P, Peters-Golden M, Standiford TJ. Selective inhibition of COX-2 improves early survival in murine endotoxemia but not in bacterial peritonitis. Am J Physiol Lung Cell Mol Physiol.2001; 281: L537–L543.
  74. Gupta A, Brahmbhatt S, Kapoor R, Loken L, Sharma AC. Chronic peritoneal sepsis: myocardial dysfunction, endothelin and signaling mechanisms. Front Biosci.2005; 10: 3183–3205.
  75. Shindo T, Kurihara H, Kurihara Y, Morita H, Yazaki Y. Upregulation of endothelin-1 and adrenomedullin gene expression in the mouse endotoxin shock model. J Cardiovasc Pharmacol1998; 31: S541–S544.
  76. Yang LL, Gros R, Kabir MG, Sadi A, Gotlieb AI, Husain M, Stewart DJ. Conditional cardiac overexpression of endothelin-1 induces inflammation and dilated cardiomyopathy in mice. Circulation2004; 109: 255–261.
  77. Konrad D, Oldner A, Rossi P, Wanecek M, Rudehill A, Weitzberg E. Differentiated and dose-related cardiovascular effects of a dual endothelin receptor antagonist in endotoxin shock. Crit Care Med2004; 32: 1192–1199.
  78. Schulz R, Rassaf T, Massion PB, Kelm M, Balligand JL. Recent advances in the understanding of the role of nitric oxide in cardiovascular homeostasis. Pharmacol Ther2005; 108: 225–256.
  79. Rassaf T, Poll LW, Brouzos P, Lauer T, Totzeck M, Kleinbongard P, Gharini P, Andersen K, Schulz R, Heusch G, Modder U, Kelm M. Positive effects of nitric oxide on left ventricular function in humans. Eur Heart J2006; 27: 1699–1705.
  80. Kelm M, Schafer S, Dahmann R, Dolu B, Perings S, Decking UK, Schrader J, Strauer BE. Nitric oxide induced contractile dysfunction is related to a reduction in myocardial energy generation. Cardiovasc Res1997; 36: 185–194.
  81. Merx MW, Godecke A, Flogel U, Schrader J. Oxygen supply and nitric oxide scavenging by myoglobin contribute to exercise endurance and cardiac function.FASEB J2005; 19: 1015–1017.
  82. Heusch G, Post H, Michel MC, Kelm M, Schulz R. Endogenous nitric oxide and myocardial adaptation to ischemia. Circ Res2000; 87: 146–152.
  83. Schulz R, Kelm M, Heusch G. Nitric oxide in myocardial ischemia/reperfusion injury. Cardiovasc Res2004; 61: 402–413.
  84. Preiser JC, Zhang H, Vray B, Hrabak A, Vincent JL. Time course of inducible nitric oxide synthase activity following endotoxin administration in dogs. Nitric Oxide2001; 5: 208–211.
  85. Khadour FH, Panas D, Ferdinandy P, Schulze C, Csont T, Lalu MM, Wildhirt SM, Schulz R. Enhanced NO and superoxide generation in dysfunctional hearts from endotoxemic rats. Am J Physiol Heart Circ Physiol2002; 283: H1108–H1115.
  86. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev2007; 87: 315–424.
  87. Ullrich R, Scherrer-Crosbie M, Bloch KD, Ichinose F, Nakajima H, Picard MH, Zapol WM, Quezado ZM. Congenital deficiency of nitric oxide synthase 2 protects against endotoxin-induced myocardial dysfunction in mice. Circulation2000; 102:1440–1446.
  88. Hwang TL, Yeh CC. Hemodynamic and hepatic microcirculational changes in endotoxemic rats treated with different NOS inhibitors. Hepatogastroenterology.2003; 50: 188–191.
  89. Kirov MY, Evgenov OV, Evgenov NV, Egorina EM, Sovershaev MA, Sveinbjornsson B, Nedashkovsky EV, Bjertanaes LJ. Infusion of methylene blue in human septic shock: a pilot, randomized, controlled study. Crit Care Med2001; 29:1860–1867.
  90. Ferdinandy P, Danial H, Ambrus I, Rothery RA, Schulz R. Peroxynitrite is a major contributor to cytokine-induced myocardial contractile failure. Circ Res2000;87: 241–247.
  91. Elfering SL, Sarkela TM, Giulivi C. Biochemistry of mitochondrial nitric-oxide synthase. J Biol Chem2002; 277: 38079–38086.
  92. Connelly L, Madhani M, Hobbs AJ. Resistance to endotoxic shock in endothelial nitric-oxide synthase (eNOS) knock-out mice: a pro-inflammatory role for eNOS-derived NO in vivo. J Biol Chem2005; 280: 10040–10046.
  93. Kleinbongard P, Schulz R, Rassaf T, Lauer T, Dejam A, Jax TW, Kumara I, Gharini P, Kabanova S, Ozuyaman B, Schnurch H-G, Gödecke A, Weber A-A, Robenek M, Robenek H, Bloch W, Rosen P, Kelm M. Red blood cells express a functional endothelial nitric oxide synthase. Blood2006; 107: 2943–2951.
  94. Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Harken AH, Meng X. ICAM-1 and VCAM-1 mediate endotoxemic myocardial dysfunction independent of neutrophil accumulation. Am J Physiol Regul Integr Comp Physiol.2002; 283: R477–R486.
  95. Neviere R, Guery B, Mordon S, Zerimech F, Charre S, Wattel F, Chopin C. Inhaled NO reduces leukocyte-endothelial cell interactions and myocardial dysfunction in endotoxemic rats. Am J Physiol Heart Circ Physiol2000; 278:H1783–H1790.
  96. Raeburn CD, Calkins CM, Zimmerman MA, Song Y, Ao L, Banerjee A, Meng X, Harken AH. Vascular cell adhesion molecule-1 expression is obligatory for endotoxin-induced myocardial neutrophil accumulation and contractile dysfunction.Surgery2001; 130: 319–325.
  97. Dellinger RP, Carlet JM, Masur H, Gerlach H, Calandra T, Cohen J, Gea-Banacloche J, Keh D, Marshall JC, Parker MM, Ramsay G, Zimmerman JL, Vincent JL, Levy MM. Surviving sepsis campaign guidelines for management of severe sepsis and septic shock. Crit Care Med2004; 32: 858–873.
  98. Hollenberg SM, Ahrens TS, Annane D, Astiz ME, Chalfin DB, Dasta JF, Heard SO, Martin C, Napolitano LM, Susla GM, Totaro R, Vincent JL, Zanotti-Cavazzoni S. Practice parameters for hemodynamic support of sepsis in adult patients: 2004 update. Crit Care Med2004; 32: 1928–1948.
  99. van der Poll T, Coyle SM, Barbosa K, Braxton CC, Lowry SF. Epinephrine inhibits tumor necrosis factor-alpha and potentiates interleukin 10 production during human endotoxemia. J Clin Invest1996; 97: 713–719.
  100. van der Poll T, Levi M, Dentener M, Jansen PM, Coyle SM, Braxton CC, Buurman WA, Hack CE, ten Cate JW, Lowry SF. Epinephrine exerts anticoagulant effects during human endotoxemia. J Exp Med1997; 185: 1143–1148.
  101. Lemaire L, de Kruif M, Giebelen IA, Levi M, van der Poll T, Heesen M. Dobutamine does not influence inflammatory pathways during human endotoxemia.Crit Care Med2006; 34: 1365–1371.
  102. Leone M, Boyadjiev I, Boulos E, Antonini F, Visintini P, Albanese J, Martin C. A reappraisal of isoproterenol in goal-directed therapy of septic shock. Shock2006;26: 353–357.
  103. Suzuki T, Morisaki H, Serita R, Yamamoto M, Kotake Y, Ishizaka A, Takeda J. Infusion of the beta-adrenergic blocker esmolol attenuates myocardial dysfunction in septic rats. Crit Care Med2005; 33: 2294–2301.
  104. Bernard GR, Vincent JL, Laterre PF, LaRosa SP, Dhainaut JF, Lopez-Rodriguez A, Steingrub JS, Garber GE, Helterbrand JD, Ely EW, Fisher CJ Jr; Recombinant Human Protein C Worldwide Evaluation in Severe Sepsis (PROWESS) Study Group. Efficacy and safety of recombinant human activated protein C for severe sepsis. N Engl J Med2001; 344: 699–709.
  105. Annane D. Corticosteroids for septic shock. Crit Care Med2001; 29: S117–S120.
  106. Tonelli M, Isles C, Craven T, Tonkin A, Pfeffer MA, Shepherd J, Sacks FM, Furberg C, Cobbe SM, Simes J, West M, Packard C, Curhan GC. Effect of pravastatin on rate of kidney function loss in people with or at risk for coronary disease. Circulation2005; 112: 171–178.
  107. Fukuta H, Sane DC, Brucks S, Little WC. Statin therapy may be associated with lower mortality in patients with diastolic heart failure: a preliminary report.Circulation2005; 112: 357–363.
  108. Zhang L, Zhang ZG, Ding GL, Jiang Q, Liu X, Meng H, Hozeska A, Zhang C, Li L, Morris D, Zhang RL, Lu M, Chopp M. Multitargeted effects of statin-enhanced thrombolytic therapy for stroke with recombinant human tissue-type plasminogen activator in the rat. Circulation2005; 112: 3486–3494.
  109. Kwak B, Mulhaupt F, Myit S, Mach F. Statins as a newly recognized type of immunomodulator. Nat Med2000; 6: 1399–1402.
  110. Kurakata S, Kada M, Shimada Y, Komai T, Nomoto K. Effects of different inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, pravastatin sodium and simvastatin, on sterol synthesis and immunological functions in human lymphocytes in vitro. Immunopharmacology1996; 34: 51–61.
  111. Romano M, Diomede L, Sironi M, Massimiliano L, Sottocorno M, Polentarutti N, Guglielmotti A, Albani D, Bruno A, Fruscella P, Salmona M, Vecchi A, Pinza M, Mantovani A. Inhibition of monocyte chemotactic protein-1 synthesis by statins. Lab Invest2000; 80: 1095–1100.
  112. Weber C, Erl W, Weber KS, Weber PC. HMG-CoA reductase inhibitors decrease CD11b expression and CD11b-dependent adhesion of monocytes to endothelium and reduce increased adhesiveness of monocytes isolated from patients with hypercholesterolemia. J Am Coll Cardiol1997; 30: 1212–1217.
  113. Yoshida M, Sawada T, Ishii H, Gerszten RE, Rosenzweig A, Gimbrone MA Jr, Yasukochi Y, Numano F. HMG-CoA reductase inhibitor modulates monocyte-endothelial cell interaction under physiological flow conditions in vitro: involvement of Rho GTPase-dependent mechanism. Arterioscler Thromb Vasc Biol2001; 21:1165–1171.
  114. Weitz-Schmidt G, Welzenbach K, Brinkmann V, Kamata T, Kallen J, Bruns C, Cottens S, Takada Y, Hommel U. Statins selectively inhibit leukocyte function antigen-1 by binding to a novel regulatory integrin site. Nat Med2001; 7: 687–692.
  115. Colli S, Eligini S, Lalli M, Camera M, Paoletti R, Tremoli E. Vastatins inhibit tissue factor in cultured human macrophages: a novel mechanism of protection against atherothrombosis. Arterioscler Thromb Vasc Biol1997; 17: 265–272.
  116. Erkkila L, Jauhiainen M, Laitinen K, Haasio K, Tiirola T, Saikku P, Leinonen M. Effect of simvastatin, an established lipid-lowering drug, on pulmonary Chlamydia pneumoniae infection in mice. Antimicrob Agents Chemother2005; 49: 3959–3962.
  117. del Real G, Jimenez-Baranda S, Mira E, Lacalle RA, Lucas P, Gomez-Mouton C, Alegret M, Pena JM, Rodriguez-Zapata M, Alvarez-Mon M, Martinez A, Manes S. Statins inhibit HIV-1 infection by down-regulating Rho activity. J Exp Med2004;200: 541–547.
  118. Liappis AP, Kan VL, Rochester CG, Simon GL. The effect of statins on mortality in patients with bacteremia. Clin Infect Dis2001; 33: 1352–1357.
  119. Steiner S, Speidl WS, Pleiner J, Seidinger D, Zorn G, Kaun C, Wojta J, Huber K, Minar E, Wolzt M, Kopp CW. Simvastatin blunts endotoxin-induced tissue factor in vivo. Circulation2005; 111: 1841–1846.
  120. Almog Y, Shefer A, Novack V, Maimon N, Barski L, Eizinger M, Friger M, Zeller L, Danon A. Prior statin therapy is associated with a decreased rate of severe sepsis. Circulation2004; 110: 880–885.
  121. Hackam DG, Mamdani M, Li P, Redelmeier DA. Statins and sepsis in patients with cardiovascular disease: a population-based cohort analysis. Lancet2006; 367:413–418.
  122. Merx MW, Weber C. Statins: a preventive strike against sepsis in patients with cardiovascular disease? Lancet2006; 367: 372–373.
  123. Panacek EA, Marshall JC, Alberson TE, Johnson DH, Johnson S, MacArthur RD, Miller M, Barchuk WT, Fischkoff S, Kaul M, Teoh L, Van Meter L, Daum L, Lemeshow S, Hicklin G, Doig C. Efficacy and safety of the monoclonal anti-tumor necrosis factor antibody F(ab′)2 fragment afelimomab in patients with severe sepsis and elevated interleukin-6 levels. Crit Care Med2004; 32: 2173–2182.
  124. Zeiher BG, Steingrub J, Laterre PF, Dmitrienko A, Fukiishi Y, Abraham E; EZZI Study Group. LY315920NA/S-5920, a selective inhibitor of group IIA secretory phospholipase A2, fails to improve clinical outcome for patients with severe sepsis.Crit Care Med2005; 33: 1741–1748.
  125. Grandel U, Hopf M, Buerke M, Hattar K, Heep M, Fink L, Bohle RM, Morath S, Hartung T, Pullamsetti S, Schermuly RT, Seeger W, Grimminger F, Sibelius U. Mechanisms of cardiac depression caused by lipoteichoic acids from Staphylococcus aureus in isolated rat hearts. Circulation2005; 112: 691–698.
    SOURCE

Circulation.2007; 116: 793-802doi: 10.1161/​CIRCULATIONAHA.106.678359

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https://pharmaceuticalintelligence.com/2013/07/08/becoming-a-cardiothoracic-surgeon-an-emerging-profile-in-the-surgery-theater-and-through-scientific-publications/

Pearlman, JD and A. Lev-Ari  7/4/2013 Fractional Flow Reserve (FFR) & Instantaneous wave-free ratio (iFR): An Evaluation of Catheterization Lab Tools (Software Validation) for Ischemic Assessment (Diagnostics) – Change in Paradigm: The RIGHT vessel not ALL vessels

https://pharmaceuticalintelligence.com/2013/07/04/fractional-flow-reserve-ffr-instantaneous-wave-free-rario-ifr-an-evaluation-of-catheterization-lab-tools-for-ischemic-assessment/

Lev-Ari, A. 7/1/22013 Endovascular Lower-extremity Revascularization Effectiveness: Vascular Surgeons (VSs), Interventional Cardiologists (ICs) and Interventional Radiologists (IRs)

https://pharmaceuticalintelligence.com/2013/07/01/endovascular-lower-extremity-revascularization-effectiveness-vascular-surgeons-vss-interventional-cardiologists-ics-and-interventional-radiologists-irs/

Lev-Ari, A. 6/10/2013 No Early Symptoms – An Aortic Aneurysm Before It Ruptures – Is There A Way To Know If I Have it?

https://pharmaceuticalintelligence.com/2013/06/10/no-early-symptoms-an-aortic-aneurysm-before-it-ruptures-is-there-a-way-to-know-if-i-have-it/

Lev-Ari, A. 6/9/2013 Congenital Heart Disease (CHD) at Birth and into Adulthood: The Role of Spontaneous Mutations

https://pharmaceuticalintelligence.com/2013/06/09/congenital-heart-disease-at-birth-and-into-adulthood-the-role-of-spontaneous-mutations-the-genes-and-the-pathways/

Lev-Ari, A. 6/3/2013 Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

https://pharmaceuticalintelligence.com/2013/06/03/clinical-indications-for-use-of-inhaled-nitric-oxide-ino-in-the-adult-patient-market-clinical-outcomes-after-use-therapy-demand-and-cost-of-care/

Lev-Ari, A. 6/2/2013 Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings

https://pharmaceuticalintelligence.com/2013/06/02/inhaled-nitric-oxide-in-adults-with-acute-respiratory-distress-syndrome/

Pearlman, JD and A. Lev-Ari 5/24/2013 Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

Pearlman, JD and A. Lev-Ari 5/22/2013 Acute and Chronic Myocardial Infarction: Quantification of Myocardial Perfusion Viability – FDG-PET/MRI vs. MRI or PET alone

https://pharmaceuticalintelligence.com/2013/05/22/acute-and-chronic-myocardial-infarction-quantification-of-myocardial-viability-fdg-petmri-vs-mri-or-pet-alone/

Lev-Ari, A. 5/17/2013 Synthetic Biology: On Advanced Genome Interpretation for Gene Variants and Pathways: What is the Genetic Base of Atherosclerosis and Loss of Arterial Elasticity with Aging

https://pharmaceuticalintelligence.com/2013/05/17/synthetic-biology-on-advanced-genome-interpretation-for-gene-variants-and-pathways-what-is-the-genetic-base-of-atherosclerosis-and-loss-of-arterial-elasticity-with-aging/

Justin D Pearlman, HL Bernstein and A. Lev-Ari 5/15/2013 Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

https://pharmaceuticalintelligence.com/2013/05/15/diagnosis-of-cardiovascular-disease-treatment-and-prevention-current-predicted-cost-of-care-and-the-promise-of-individualized-medicine-using-clinical-decision-support-systems-2/

Pearlman, JD and A. Lev-Ari 5/11/2013 Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus

https://pharmaceuticalintelligence.com/2013/05/11/arterial-elasticity-in-quest-for-a-drug-stabilizer-isolated-systolic-hypertension-caused-by-arterial-stiffening-ineffectively-treated-by-vasodilatation-antihypertensives/

Pearlman, JD and A. Lev-Ari 5/7/2013 On Devices and On Algorithms: Arrhythmia after Cardiac Surgery Prediction and ECG Prediction of Paroxysmal Atrial Fibrillation Onset

https://pharmaceuticalintelligence.com/2013/05/07/on-devices-and-on-algorithms-arrhythmia-after-cardiac-surgery-prediction-and-ecg-prediction-of-paroxysmal-atrial-fibrillation-onset/

Pearlman, JD and A. Lev-Ari 5/4/2013 Cardiovascular Diseases: Decision Support Systems for Disease Management Decision Making

https://pharmaceuticalintelligence.com/2013/05/04/cardiovascular-diseases-decision-support-systems-for-disease-management-decision-making/

Lev-Ari, A. 5/3/2013 Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

https://pharmaceuticalintelligence.com/2013/05/03/gene-meis1-regulates-the-hearts-ability-to-regenerate-after-injuries/

Lev-Ari, A. 4/30/2013 Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

https://pharmaceuticalintelligence.com/2013/04/30/prostacyclin-and-nitric-oxide-adventures-in-vascular-biology-a-tale-of-two-mediators/

Lev-Ari, A. 4/28/2013 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

Lev-Ari, A. 4/25/2013 Economic Toll of Heart Failure in the US: Forecasting the Impact of Heart Failure in the United States – A Policy Statement From the American Heart Association

https://pharmaceuticalintelligence.com/2013/04/25/economic-toll-of-heart-failure-in-the-us-forecasting-the-impact-of-heart-failure-in-the-united-states-a-policy-statement-from-the-american-heart-association/

Lev-Ari, A. 4/24/2013 Harnessing New Players in Atherosclerosis to Treat Heart Disease

https://pharmaceuticalintelligence.com/2013/04/25/harnessing-new-players-in-atherosclerosis-to-treat-heart-disease/

Lev-Ari, A. 4/25/2013 Revascularization: PCI, Prior History of PCI vs CABG

https://pharmaceuticalintelligence.com/2013/04/25/revascularization-pci-prior-history-of-pci-vs-cabg/

Lev-Ari, A. 4/7/2013 Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

https://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

Lev-Ari, A. 4/4/2013 Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

https://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

Lev-Ari, A. 4/3/2013 Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

https://pharmaceuticalintelligence.com/2013/04/03/fight-against-atherosclerotic-cardiovascular-disease-a-biologics-not-a-small-molecule-recombinant-human-lecithin-cholesterol-acyltransferase-rhlcat-attracted-astrazeneca-to-acquire-alphacore/

Lev-Ari, A. 3/31/2013 High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

https://pharmaceuticalintelligence.com/2013/03/31/high-density-lipoprotein-hdl-an-independent-predictor-of-endothelial-function-artherosclerosis-a-modulator-an-agonist-a-biomarker-for-cardiovascular-risk/

Lev-Ari, A. 3/10/2013 Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI

https://pharmaceuticalintelligence.com/2013/03/10/acute-chest-painer-admission-three-emerging-alternatives-to-angiography-and-pci/

Lev-Ari, A. and L H Bernstein 3/7/2013 Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

https://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

Lev-Ari, A. 2/28/2013 The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

Lev-Ari, A. 2/27/2013 Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

Lev-Ari, A. 12/29/2012. Coronary artery disease in symptomatic patients referred for coronary angiography: Predicted by Serum Protein Profiles

https://pharmaceuticalintelligence.com/2012/12/29/coronary-artery-disease-in-symptomatic-patients-referred-for-coronary-angiography-predicted-by-serum-protein-profiles/

Bernstein, HL and Lev-Ari, A. 11/28/2012. Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

Lev-Ari, A. 11/13/2012 Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

https://pharmaceuticalintelligence.com/2012/11/13/peroxisome-proliferator-activated-receptor-ppar-gamma-receptors-activation-pparγ-transrepression-for-angiogenesis-in-cardiovascular-disease-and-pparγ-transactivation-for-treatment-of-dia/

Lev-Ari, A. 10/19/2012 Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

https://pharmaceuticalintelligence.com/2012/10/19/clinical-trials-results-for-endothelin-system-pathophysiological-role-in-chronic-heart-failure-acute-coronary-syndromes-and-mi-marker-of-disease-severity-or-genetic-determination/

Lev-Ari, A. 10/4/2012 Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

Lev-Ari, A. 10/4/2012 Inhibition of ET-1, ETA and ETA-ETB, Induction of NO production, stimulation of eNOS and Treatment Regime with PPAR-gamma agonists (TZD): cEPCs Endogenous Augmentation for Cardiovascular Risk Reduction – A Bibliography

https://pharmaceuticalintelligence.com/2012/10/04/inhibition-of-et-1-eta-and-eta-etb-induction-of-no-production-and-stimulation-of-enos-and-treatment-regime-with-ppar-gamma-agonists-tzd-cepcs-endogenous-augmentation-for-cardiovascular-risk-reduc/

Lev-Ari, A. 8/29/2012 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/

Lev-Ari, A. 8/28/2012 Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

Lev-Ari, A. 8/27/2012 Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

Lev-Ari, A. 8/24/2012 Vascular Medicine and Biology: CLASSIFICATION OF FAST ACTING THERAPY FOR PATIENTS AT HIGH RISK FOR MACROVASCULAR EVENTS Macrovascular Disease – Therapeutic Potential of cEPCs

https://pharmaceuticalintelligence.com/2012/08/24/vascular-medicine-and-biology-classification-of-fast-acting-therapy-for-patients-at-high-risk-for-macrovascular-events-macrovascular-disease-therapeutic-potential-of-cepcs/

Lev-Ari, A. 7/19/2012 Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

https://pharmaceuticalintelligence.com/2012/07/19/cardiovascular-disease-cvd-and-the-role-of-agent-alternatives-in-endothelial-nitric-oxide-synthase-enos-activation-and-nitric-oxide-production/

Lev-Ari, A. 4/30/2012 Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

https://pharmaceuticalintelligence.com/2012/04/30/93/

Lev-Ari, A. 5/29/2012 Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

https://pharmaceuticalintelligence.com/2012/05/29/445/

Lev-Ari, A. 7/2/2012 Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

https://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

 

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