Four-Volume Series on Four-Volume Series on Cardiovascular Diseases:

Causes, Risks and Management

Dr. Pearlman, MD, PhD, FACC

Editor 

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

This Series is positioned as Academic Textbooks for Training Residents in Cardiology and Texts for CEU Courses in Cardiology 

[Hardcover, Softcover, e-Books]

• CVD 1: Causes of Cardiovascular Diseases
• CVD 2: Risk Assessment of Cardiovascular Diseases
• CVD 3: Management of Cardiovascular Diseases
• CVD 4: Cardiac Imaging 

VOLUME THREE

Management of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

jdpmdphd@gmail.com

Cover image: [STORY]

List of Contributors

Justin D. Pearlman MD ME PhD MA FACC, Editor and Author of the

• Introduction to the Three-Volume Series
• Introduction to each Volume
• Introduction and key words to Each Chapter
• Summary to each Chapter
• Summary and Epilogue to each volume
• Summary for the Three-Volume Series

Articles:

Larry Bernstein, MD, FACP

2.3, 3.3, 3.7, 3.11, 5.1, 5.2, 5.3, 9.6, 9.7

Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Books Series

1.1, 1.1.7 1.2, 1.2.8 1.6, 1.8, 1.9, 1.13, 1.14, 1.15, 1.16,, 2.1, 2.2, 2.4, 2.5, 2.6,2.7, 3.2, 3.3, 3.4, 3.6, 3.8, 3.9, 3.10, 3.12, 3.13, 3.14, 3.15, 3.16, 3.17, 3.18, 4.1, 4.2, 4.3, 4.4, 4.5, 4.6, 4.7, 4.8, 4.9, 4.10, 4.11, 4.12, 4.13, 4.14, 4.15,4.16, 5.1, 5.2, 5.3, 5.4, 5.5

Sudipta Saha, PhD

1.3, 1.4, 1.5, 1.10

Ritu Saxena, PhD

1.11, 1.12

McNally E, MacLeod H, Dellefave L

1.7

Prabodh Kandala. PhD

3.5

Tilda Barliya, PhD

3.1

List of Videos by Chapter

VIEW VIDEOS – Courtesy of YouTube as well as the individual sponsors of the links cited below.

Chapter 1.1: Therapeutic Genomics

VIDEO: The heart of the matter: genomics and cardiovascular disease – Leslie Biesecker

VIDEO: Pharmacogenomics (2010)

VIDEO: My Health Chat – Innovation in Heart Care & Genomic Medicine

VIDEO: A new approach to genome modification

VIDEO: David Valle The Human Genome and Individualized Medicine

Chapter 2: Computer Guidance of Therapy

VIDEO: Cardiac Surgery Simulation – Graphics Hardware meets Congenital Heart Disease

VIDEO: Cardiac Defibrillation video – Animation by Cal Shipley, MDTrial Image Inc.

VIDEO: SPY Imaging: Quality in Heart Bypass Surgery

VIDEO: Inova Heart and Vascular Institute: New ‘Hybrid’ Operating Room

VIDEO: Real-Time Interactive MRI for Guiding Cardiovascular Surgical Interventions

VIDEO: UH Research: Robot- Assisted Heart Surgery

VIDEO: Pericardiocentesis subxyphoid video – Animation by Cal Shipley, MD Trial Image Inc.

VIDEO: Augmented Reality and Image Guided Robotic Surgery: Luc Soler, M.D

Chapter 3: Drug Therapy

VIDEO: Treat Arteriosclerosis

VIDEO: Nanorobotic atherosclerotic plaque removal

VIDEO: Coronary artery stents in Atherosclerosis

e-Table of Contents

Chapter 1

Cardiovascular Disorders and Therapy Modalities

1.1: Genomics as a Therapy Source

1.2: Regenerative Cell and Molecular Biology

1.3: Therapeutics Levels in Molecular Cardiology

Chapter 2

Healthcare Reform

2.1 Selection PENDING

2.2 Selection PENDING

2.3 Content Creation Pending

2.4 Content Creation Pending

Chapter 3

Computer Visualization Technology in Use for Cardiovascular Disease Diagnosis and Therapy Delivery

3.1 to 3.9

Chapter 4

Pharmacological Agents in Cardiovascular Treatment of Disease

4.1: Agents and Delivery Modalities

4.2: Hypertension Therapy

4.3: Anticoagulation Therapy and Related Readings to the Blood Thinning Process

Chapter 5

Invasive Procedures by Surgery versus Catheterization (PCI)

5.1: Cardiothoracic Surgery

5.2: Catheter Interventions

5.3: Comparison of outcomes: surgery versus catheter intervention

5.4: Transcatheter (Percutaneous) Valves

5.5: Transcatheter (Percutaneous) Pumps

5.6: Peripheral Vascular Disease in PCI and in Surgery

5.7: Cardiovascular Invasive Interventions: Denervation of the Renal Artery

5.8: Hybrid Operating Rooms and Catheterization Suites

5.9: Heart & Heart-Lung Transplant

Chapter 6

Electric System of the heart: Pacemakers & Implantable Cardioverter Defibrillators (ICD)

6.1 to 6.3

Chapter 7

Cardiovascular Biomaterials Technology

7.1 t0 7.5

Chapter 8

Cardiovascular Translational Medicine: Treatment Modalities & Technology

8.1 to 8.3

Chapter 9

Calcium Signaling Control of Ryanopathy:

Calcium Roles in Impaired Cardiac Muscle Contraction

9.1 to 9.5

Chapter 10

Mitochondria

Chapter 11

Cardiovascular Translational Medicine

Introduction

All the Sections in italics below represent the voice of the Editor, Justin D. Pearlman MD ME PhD MA FACC


The three volume set of Cardiovascular Diseases: Causes, Risks and Management presents a fresh look at the leading causes of death and disability, which happen to revolve around the heart and blood vessels. Volume ONE addresses the causes of problems with the heart and blood vessels. Volume TWO addresses how to predict harm by identifying risks, to enable pursuit of opportunities to prevent injury (one in four people develop serious cardiovascular problems). Volume THREE addresses how to manage cardiovascular risks and abnormal conditions to minimize, slow down the progression, or even reverse the harm. These categories have significant overlap: the causes stimulate methods of risk assessment, which in turn expand the opportunities for effective management of disease status. Therefore, these volumes address interrelated themes, and the reader should consider all three vantages to understanding the rapidly evolving changes in cardiovascular disease causes, risks, and management. As cardiovascular diseases remain the leading causes of death and disability, there is intense effort expanding and correcting the current concepts and evidence basis for best practices in research and clinical applications. The unique format of this series enables continual updates and feedback from experts world wide to bring you fresh insights and stimulate you to benefit and contribute.

This volume presents fascinating new data relating to the management of cardiovascular diseases. The opportunities to halt progression, mitigate and even reverse harm take many forms: replace missing signals, suppress excessive signals, provide cells to replace or repair damage, compensate for over or under activity with complementary functions, or intervene mechanically. While it is often quite effective to intervene at the source of a problem, effective treatments have often been devised that act downstream from the cause, interrupting or countermanding the cascade of consequences. For example, ion channels may cause sinus arrest, leading to failure to activate heart contractions in a timely fashion. Pacemakers do not correct the malfunctioning sinus node, but rather act downstream to provide an alternative means to activate timely heart contractions. Currently pacemakers do not aim to bridge into the specialized conduction system of the heart, rather they directly activate distal muscle. Consequently the activation sequence is distinct and is not as well synchronized, resulting in a wobbling motion of the heart called dysynchrony. In extreme, the distinct activation pattern of dysynchrony can lower the effectiveness of each heart beat (reduced stroke volume and reduced ejection fraction). More advanced pacemakers initiate contraction from two different locations (left and right ventricle) at staggered times aimed to produce a more synchronized net contraction timing. If a patient has an intact specialized conduction system, pacing to activate that system produces a more normal synchronized contraction of heart muscle. Atrial pacemakers have that effect, but often disease requiring pacemakers includes not only sinus node dysfunction but also abnormal conduction. Theory has to be tested to evaluate reliability and extent of benefit. Solutions that cover a wide range of abnormalities are generally easiest to apply, whereas solutions that are very specific often have better results.

Chapter 1

Cardiovascular Disorders and Therapy Modalities

1.1: Genomics as a Therapy Source

As the mysteries of the human genome products are unraveled, we learn more and more about key components. As we learn more details about the controlling biologic functions we can expand our ability to decide about manipulating them responsibly and predict the consequences.

VIEW VIDEOS – Courtesy of YouTube as well as the individual sponsors of the links cited below.

VIDEO: The heart of the matter: genomics and cardiovascular disease – Leslie Biesecker

VIDEO: Pharmacogenomics (2010)

VIDEO: My Health Chat – Innovation in Heart Care & Genomic Medicine

VIDEO: A new approach to genome modification

VIDEO: David Valle on The Human Genome and Individualized Medicine

Genomics studies the blueprints which constitute the genetic underpinnings of biology. Proteomics studies the structure and function of the protein gene products. Proteins provide structure, function, receptors, and signals.

1.1.1 How genes are linked to disease: Genomic Endocrinology and its Future

Sudipta Saha, PhD

A research team at Northwestern University has developed automated proteomics (automated means to determine the structure and function of proteins).

1.1.2 A Protease for ‘Middle-down’ Proteomics

Ritu Saxena, PhD

Tools are now available to determine personal gene maps (targeted custom genotyping). Knowledge of your own gene expression can determine if you over- or under- produce specific gene product therapeutic targets, or if you are a slow or fast metabolizer (destroyer) of specific medications, offering a shortcut to the trial and error process of finding effective treatment medicine choices and dosing by enabling personalized prioritization of therapeutic options.

1.1.3 Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School

Aviva Lev-Ari, PhD, RN

1.1.4 The Way With Personalized Medicine: Reporters’ Voice at the 8th Annual Personalized Medicine Conference, 11/28-29, 2012, Harvard Medical School, Boston, MA

Aviva Lev-Ari, PhD, RN

One by one, the genetic basis for specific diseases are elucidated, yielding new therapeutic options. Some patients with syncope (fainting) have a gene for abnormal fat in the outflow tract (exit channel) of the right ventricle of the heart, which promotes life-threatening arrhythmias.

1.1.5 Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant.

Aviva Lev-Ari, PhD, RN

1.1.6 Congestive Heart Failure & Personalized Medicine: Two-gene Test predicts response to Beta Blocker Bucindolol

Aviva Lev-Ari, PhD, RN

Gene therapy can be delivered to the lungs by inhalation (nebulizer), and to the heart by catheters. Both routes are being applied therapeutically to modify how cells handle calcium. Calcium is used by muscle cells to control the timing and strength of muscle contraction. In the heart, calcium controls the strength of each heartbeat, among other roles. In the muscles in the wall of pulmonary blood vessels, calcium concentrations influence pulmonary vascular pressure. High pressure in the lungs impedes transit of blood from the right ventricle to the left ventricle which can lead to death. Thus hallmarks of heart failure and of pulmonary hypertension include change in the intracellular handling of calcium. Correction of the deficit in serca2a may improve calcium redistribution in both of those diseases.

1.1.7 Calcium Molecule in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD.

Aviva Lev-Ari, PhD, RN

1.2: Regenerative Cell and Molecular Biology

The continual advances in stem cell research are exciting because they offer the possibility of replacing defective systems, for example, by generating a replacement vascular subsystem instead of undergoing bypass surgery. One of the biologic controllers is Thymosin beta 4 (Tβ4) which plays an essential role in cardiac and blood vessel development and regeneration. Understanding the roles and controls of thymosin offers promise of enabling physician control of new blood vessel development (angiogenesis and vasculogenesis), which can solve the problem of blocked arteries which cause heart attacks, strokes, renal failure, and limb loss. Stimulating new vessel development can mimic the biologic behavior of the lucky few who develop new vessels, or collaterals, as a natural bypass system, without requiring a surgeon to provide a blood supply to avoid or limit heart attacks.

1.2.1 Stem Cell Research — The Frontier at the Technion in Israel

Aviva Lev-Ari, PhD, RN

1.2.2 Blood vessel-generating stem cells discovered

Ritu Saxena, PhD

1.2.3 Heart Renewal by pre-existing Cardiomyocytes: Source of New Heart Cell Growth Discovered

Aviva Lev-Ari, PhD, RN

Research presented in CELL (Wu et al.) and in Nature (Smart et al.) suggests that the small protein fragment thymosin β4 (Tβ4) can inhibit myocardial apoptosis (cell death), promote vasculogenesis (stimulate vessel growth), and activate endogenous cardiac progenitors (stem cells) by reminding the adult heart how to apply its embryonic program. The protein fragment that promotes these benefits may be marketed as RegeneRx.

There is continual progress tracing the path from stem cells to new blood supply. A single cell is parent to three cell lines vital to cardiovascular development or regeneration.

1.2.4 The Heart: Vasculature Protection – A Concept-based Pharmacological Therapy including THYMOSIN

Aviva Lev-Ari, PhD, RN

1.2.5 Innovations in Bio instrumentation for Measurement of Circulating Progenetor Endothelial Cells in Human Blood.

Sudipta Saha, PhD

1.2.6 Endothelial Differentiation and Morphogenesis of Cardiac Precursor

Sudipta Saha, PhD

1.2.7 Cardiovascular Outcomes: Function of circulating Endothelial Progenitor Cells (cEPCs): Exploring Pharmaco-therapy targeted at Endogenous Augmentation of cEPCs

Aviva Lev-Ari, PhD, RN

1.2.8 Calcium Cycling (ATPase Pump) in Cardiac Gene Therapy: Inhalable Gene Therapy for Pulmonary Arterial Hypertension and Percutaneous Intra-coronary Artery Infusion for Heart Failure: Contributions by Roger J. Hajjar, MD

Aviva Lev-Ari, PhD, RN

1.3: Therapeutics Levels in Molecular Cardiology

1.3.1 Arteriogenesis and Cardiac Repair: Two Biomaterials – Injectable Thymosin beta4 and Myocardial Matrix Hydrogel

Aviva Lev-Ari, PhD, RN

1.3.2 Human Embryonic-Derived Cardiac Progenitor Cells for Myocardial Repair

Sudipta Saha, PhD

1.3.3 Heart patients’ skin cells turned into healthy heart muscle cells

Aviva Lev-Ari, PhD, RN

Stimulation of cell and molecular changes does not always require medications or surgery. The complex biologic systems that control cell distribution (chemotaxis) and modulations of cellular and system functions (regulation) can be improved by taking a hike.

1.3.4 Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia, DM, and possibly CAD

Aviva Lev-Ari, PhD, RN

In addition to simple exercise (e.g. a fast walk 30 minutes daily), you may also be able to promote health by spiritual, sonic and other means of signaling your cells, and you may learn how to operate your life better by lessons learned from cellular systems. A best selling text presents arguments that the cells of your body offer important life lessons and may respond to spiritural and other cues.

1.3.5 Secrets of Your Cells: Discovering Your Body’s Inner Intelligence (Sounds True, on sale May 1, 2013) by Sondra Barrett

Aviva Lev-Ari, PhD, RN

Chapter 2

Healthcare Reform

The Affordable Care Act (“ObamaCare”) has numerous forums arguing its strengths and weaknesses. Much of the discussion of benefits focus on broadened access and potentially improved prevention and efficiency, whereas concerns center on unintended or undesirable consequences, such as employers dropping fulltime employment offerings, physicians and whole hospitals losing their patients, insufficient time per patient, reduced therapeutic choices, uncertainty about what options remain covered, decreased personal responsibility, reduced quality of care to meet the expanded coverage and changes in coverage that may impede care choices. Regardless of the outcome of those debates, it is healthy to continue to explore a wider range of ideas for improvements in health care delivery.

The concept of “universal insurance” blurs the potential distinctions between true insurance, government provided safety nets and control of healthcare. Blurring those roles invokes the danger of leveling healthcare into a monolithic system, curtailing innovation and discouraging pioneering efforts at superlative care as part of cost cutting and leveling. An obvious alternative to universal insurance is obviating any need for insurance, by providing a free care safety network, and outlawing overcharging those without insurance, so that the role of insurance converts to an optional value-added service, like valet parking. That change in the role and impact of insurance could be achieved at virtually no taxpayer cost, simply by capping the difference in charges for insured versus uninsured. Insurance does not lower the costs of care any more than competition does, and insurance often limits competition.

Hand in hand with the exploration of changing how we pay for healthcare is exploration of changing how we deliver healthcare. Some claim there are no alternatives, but in fact there are many other ways to improve healthcare delivery without severe impairments of choice.

An evolving strategy for new health care delivery models is an analogy to the pit crew that puts racing cars back on the track when cars have needs for repair. A team of people with far less skill required than for a broadly trained mechanic provides very specialized and highly coordinated roles to set common problems right with high efficiency. Thus one can encourage deployment of a new level of healthcare workers – health technicians and/or trained volunteers – each with a narrow focus – to provide inexpensive superlative care. For example, instead of always seeing a doctor or nurse, you might meet with a team of technologists, one trained just to implement a physician selected management approach to blood sugar, another to manage lipids, another weight, another blood pressure – such teams could potentially handle the majority of patient issues better than a single primary care physician. We call this model “parallel care” whereby a supervised team of health technicians works in parallel to meet healthcare objectives, freeing the physician to manage far more with far less individual effort. It takes the model of physician assistants and nurse practitioners to a markedly broadened level.

Dr. Atul Gawande wrote books about the improvements achieved by teamwork and checklists (Complications, Better, and The Checklist Manifesto), and more recently is lecturing about how a “pit crew” model of healthcare can solve the problem of not being able to afford what doctors do.

VIEW VIDEOS – Courtesy of YouTube as well as the individual sponsors of the links cited below.

VIDEO: What Doctors worry about. Dr. Atul Gawande.

A simple model of applying a stitch in time to lower cost and improve effectiveness tried deploying a healthcare system instead of a sick care system, by expanding the ability of physicians to prescribe preventions that include basic health impact necessities such as food and housing. Dr. Jack Geiger founded a community health facility that prescribed food, but government interfered. The current affordable care act forces any free clinic that also utilizes medicare to cease and desist provision of free care because the law requires that they CANNOT compete by providing care less expensive than medicare.

VIDEO: Surgical Teams’ “CHECK LIST” developed @ Harvard Medical School with Boeing Guidance Dr. Atul Gawande.

VIDEO: What if our healthcare system kept us healthy? Attorney Rebecca Onie.

Confusion about the impact of the Affordable Care Act (“ObamaCare”) has affected business planning and hiring practices, with some companies putting plans on hold, freezing new hiring.

2.1 Affordable Care Act became law in 2010, Cardiologists’ Practice Management Decisions Unclear

Aviva Lev-Ari, PhD, RN

Chapter 3

Computer Visualization Technology for Cardiovascular

Diagnosis and Therapy

Computer use is ubiquitous, and a natural extension is its use in medical diagnostics and therapy. In addition to computer use for electronic medical records (EMR) and for value added process, efficiency and quality improvement computer services, e.g., Missive (c), computing plays an important and expanding role in imaging and image processing. As imaging improves in real-time, high-resolution, and higher value tissue characterization, computer assisted guidance from imaging is becoming as or more useful than direct observation for guidance of interventions. Animation and vector graphics are useful methods for such guidance, both to provide just-in-time review of procedural details (education) and to provide co-registered (superimposed) coordinated information for positioning and therapeutic targeting.

VIEW VIDEOS – Courtesy of YouTube as well as the individual sponsors of the links cited below.

VIDEO: Cardiac Defibrillation video – Animation by Cal Shipley, MDTrial Image Inc.

VIDEO: Real-Time Interactive MRI for Guiding CardiovascularSurgical Interventions

VIDEO: UH Research: Robot- Assisted Heart Surgery

VIDEO: Pericardiocentesis subxyphoid video – Animation by Cal Shipley, MD Trial Image Inc.

VIDEO: Augmented Reality and Image Guided Robotic Surgery: Luc Soler, M.D

VIDEO: Nanorobotic atherosclerotic plaque removal

3.1 The FDA announced a partnership with a new nonprofit organization—the Medical Device Innovation Consortium (MDIC) —to advance regulatory science in the medical technology arena, e.g., promoting advanced cardiovascular imaging.

Aviva Lev-Ari, PhD, RN

Decisions about management of cardiovascular disease can get complex, and computer models may be useful. The following article discusses cost-benefit analysis, decision trees, and computer decision support systems, with specific examples.

3.2 Clinical Decision Support Systems for Management Decision Making of Cardiovascular Diseases

Justin D Pearlman, MD, PhD and Aviva Lev-Ari, PhD, RN

3.3 The Roll of Medical Imaging in Personalized Medicine

Dror Nir, PhD

3.3 The potential contribution of informatics to healthcare is more than currently estimated

Larry H. Bernstein, MD, FACP

3.4 Expected New Trends in Cardiology and Cardiovascular Medical Devices

Aviva Lev-Ari, PhD, RN

3.5 New Definition of MI Unveiled, Fractional Flow Reserve (FFR)CT for Tagging Ischemia

Aviva Lev-Ari, PhD, RN

The adequacy of coronary arteries (blood supply to the heart) to adapt to challenges is measured as fractional flow reserve (FFR). That measurement use to require catheterization, but now FFR can be estimated from CT imaging.

3.6 Emerging Clinical Applications for Cardiac CT: Plaque Characterization, SPECT Functionality, Angiogram’s and Non-Invasive FFR

Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

Therapeutic endpoints for treatment of atherosclerosis have relied on lipid blood tests, but benefits of statins occur in patients with normal “target” levels prior to therapy. Some have argued the benefits relate not only to changes in blood lipids but also anti-inflammatory effects of statins. Carotid intimal thickness by high frequency ultrasound has been offered as an alternative method to guide sucess of halting and/or reversing plaque build up in arteries. The following article aims to offer another method which can be applied to coronary arteries, the aorta, and other vessels not reachable by surface high frequency ultrasound.

3.7 Advanced CT Reconstruction: Plaque Estimation Algorithm for Fewer Errors and Semiautomation

Aviva Lev-Ari, PhD, RN

Minimally invasive imaging (computed tomography instead of arterial catheterization cinefluoroscopy) provides lower quality images at similar or higher radiation and similar or higher contrast agent load without the opportunity for concurrent intervention. However, it does provide 3D data, does not require arterial catheterization with risks of vessel damage, is faster and easier, and there is progress reducing the radiation hazard.

3.8 CT Angiography (CCTA) Reduced Medical Resource Utilization compared to Standard Care reported in JACC

Aviva Lev-Ari, PhD, RN

3.9 Acute Chest Pain/ER Admission: Three Emerging Alternatives to Angiography and PCI – Corus CAD, hs cTn, CCTA

Aviva Lev-Ari, PhD, RN

Chapter 4

Pharmacological Agents in Cardiovascular Treatment of Disease

4.1: Agents and Delivery Modalities

VIEW VIDEOS – Courtesy of YouTube as well as the individual sponsors of the links cited below.

VIDEO: Treat Arteriosclerosis

New systems to delivery medication through the skin can provide steady adequate levels of medications that might otherwise require taking a pill every 5 minutes.

4.1.1 Introduction to Transdermal Drug Delivery (TDD) system and nanotechnology

Tilda Barliya, PhD

4.1.2 Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Larry H. Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN

Cardiac Endothelial Progenitor Cells (cEPCs) build new blood vessels, and may be used to help repair or replace blocked arteries, like a salamander can replace damaged or lost limbs.
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4.1.3 Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Aviva Lev-Ari, PhD, RN

4.1.4 Too Much Vitamin D Can Be as Unhealthy as Too Little

Prabodh Kandala, PhD

4.1.5 Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and Cardiovascular Disease in Women

Aviva Lev-Ari, PhD, RN

Endocarditis represents an infection of the heart, usually focused on or near an injured heart valve where disordered flow creates a tissue injury that facilitates infection..

4.1.6 Treatment for Infective Endocarditis

Larry H Bernstein, MD, FACP

4.2: Hypertension Therapy

Hypertension (high blood pressure) stresses the heart and vessels, leading to thickening of the heart and vessels as well as damage to the lining (endothelium), elevation of the pressures needed to fill the heart, and eventually heart failure and other complications. Many patients have blood pressure problems that are difficult to control or have variations in pressure throughout the day so that a good blood pressure in the doctor’s office in the morning may not abolish the risk of on-going damage. Often two or three different targets of therapy are warranted, customized to the cause and response. For patient convenience, multiple arms of treatment may be combined into a single pill, but it may be best to start with separate pills to optimize the dose of each, then see if that corresponds to a manufactured combination. Pharmacists stopped making combinations for the individual, but pharmacies are offering stock combination pills for popular combinations as long as all components are available from a single vendor.

4.2.1 Triple Antihypertensive Combination Therapy Significantly Lowers Blood Pressure in Hard-to-Treat Patients with Hypertension and Diabetes

Aviva Lev-Ari, PhD, RN

4.2.2 Renal Denervation Safe in Real-World Setting: Preliminary results from the Global SYMPLICITY registry

Aviva Lev-Ari, PhD, RN

4.2.3 Resident-cell-based Therapy in Human Ischaemic Heart Disease: Evolution in the PROMISE of Thymosin beta4 for Cardiac Repair

Aviva Lev-Ari, PhD, RN

4.2.4 Bystolic’s generic Nebivolol – positive effect on circulating Endothelial Proginetor Cells endogenous augmentation

Aviva Lev-Ari, PhD, RN

4.2.5 Statins’ Nonlipid Effects on Vascular Endothelium through eNOS Activation

Larry Bernstein, MD, FACP

4.2.6 Fight against Atherosclerotic Cardiovascular Disease: A Biologics not a Small Molecule – Recombinant Human lecithin-cholesterol acyltransferase (rhLCAT) attracted AstraZeneca to acquire AlphaCore

Aviva Lev-Ari, PhD, RN

4.2.7 Outcomes in High Cardiovascular Risk Patients: Prasugrel (Effient) vs. Clopidogrel (Plavix); Aliskiren (Tekturna) added to ACE or added to ARB

Aviva Lev-Ari, PhD, RN

Nitric oxide controls blood vessel dilation. Inhaled as a gas, it targets pulmonary arterioles associated with ventilated areas of the lung. The delivery makes it “selective” for areas that merit dominance of circulation for gas exchange. Not all areas of the lung have the same perfusion – gravity alone imposes that. If the lungs ventilate a region of lung that is not well perfused that effort does not contribute efficiently to oxygenation. Moreover, the flip side, perfusion of a region of lung that is not ventilated well creates shunting – passage of deoxygenated blood through the lung to reduce the oxygen saturation of the blood exiting the lungs. This issue is known clinically as V/Q mismatch. Inhaled nitric oxide – iNO – can correct a mismatch of ventilation and perfusion by redistributing blood flow the the well ventilated areas. The ventilation-perfusion match is vital not only for the uptake of oxygen, but also for the exhalation of the metabolic waste product carbondioxide. Thus iNO offers potentially life-saving benefits for patients with severe hypoxia, patients with acutely severe pulmonary hypertension interfering with blood transit from the lungs to the left ventricle, and also for patients acutely not getting rid of carbondioxide. Oxygen and carbondioxide exchange are vital and timely. Just 2-3 days of high oxygen requirements >50% FIO2 promotes fibrosis (scarring) in the air-exchange tissues and permanent impairment. The benefits iNO offers may best be served by early pulsed therapy – clinical trials that apply iNO after multiple days of life threatening impairment not surprisingly have failures. Unnecessarily sustained treatments can promote toxic byproducts including nitrogendioxide and met-hemoglobin.

4.2.8: Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use of iNO in the Institutional Market, Therapy Demand and Cost of Care vs. Existing Supply Solutions

Aviva Lev-Ari, PhD, RN

4.3: Anticoagulation Therapy and Related Readings to the Blood Thinning Process

4.3.1 Xarelto (Rivaroxaban): Anticoagulant Therapy gains FDA New Indications and Risk Reduction for: (DVT) and (PE), while in use for Atrial fibrillation increase in Gastrointestinal (GI) Bleeding Reported

Aviva Lev-Ari, PhD, RN

4.3.2 Cardiovascular Risk: C-Reactive Protein BioMarker and Plasma Fibrinogen

Aviva Lev-Ari, PhD, RN

4.3.4 PCI Outcomes, Increased Ischemic Risk associated with Elevated Plasma Fibrinogen not Platelet Reactivity

Aviva Lev-Ari, PhD, RN

4.3.5 PLATO Trial on ACS: BRILINTA (ticagrelor) better than Plavix® (clopidogrel bisulfate): Lowering chances of having another heart attack Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment What is the role of plasma viscosity in hemostasis and vascular disease risk?

Aviva Lev-Ari, PhD, RN

4.3.6 What is the role of plasma viscosity in hemostasis and vascular disease risk?

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

4.3.7 High-Density Lipoprotein (HDL): An Independent Predictor of Endothelial Function & Atherosclerosis, A Modulator, An Agonist, A Biomarker for Cardiovascular Risk

Aviva Lev-Ari, PhD, RN

Chapter 5

Invasive Procedures by Surgery versus Catheterization

Coronary artery disease (blockages in blood supply) causes heart attacks by two methods: (1) severe narrowing that provides insufficient nutrition and oxygen to a region of heart muscle compared to its needs (hence the tissue commits a form of hara-kari called apoptosis), or (2) unstable plaque that can crack, cause localized hemorrhage into the wall of a coronary artery, and clot, suddenly stopping blood supply to a region of heart muscle. The blood supply to the heart consists of the left main (LM, a short vessel that promptly branches to the left anterior descending (LAD), and the left circumflex (LCX)), and the right coronary (RCA) which often gives rise to the posterior descending artery (PDA) (10% of patients get PDA blood supply as an extension of the LCX). Based on the normal branching pattern of blood supply to the heart, these lesions may cause heart attacks affecting different regions:

SOURCE for FIGURE:
Robin Smithuis and Tineke Wilems
Radiology department of the Rijnland Hospital Leiderdorp and the University Medical Centre Groningen, the Netherlands.

• septum (anterior 2/3 of the interventricular septum, LAD),
• apex (distal LAD),
• anterior (mid LAD),
• pan-anterior (proximal LAD or LM),
• lateral (LCX),
• inferior wall (PDA, RCA or LCX) and
• right ventricle (RCA).

As one in four people eventually suffers a heart attack (myocardial infarction, death of heart muscle), and a third die from that, there have been great efforts at prevention. Heart attacks can be prevented by

(1) not smoking,

(2) small waist (<35 inches for women, <40 inches for men),

(3) prevent or control diabetes,

(4) control lipids/cholesterol.

Additional benefits have been demonstrated from fish oil (controversy about inconsistent association with prostate cancer not withstanding), alcohol (1/2 to 2 drinks daily elevates apoproteins and HDL which reverses lipid deposits in arterial walls), and statins even if LDL is not high, and possibly from red wine or grape congeners. All of these aim to prevent the development of blockages. Once blockages do develop, one may consider balloon angioplasty to open the obstruction, bare metal stent to keep it propped open, drug-eluting stent to inhibit reactive tissue growth, or bypass surgery.

While heart surgery is the primary means to improve quality and quantity of life from severe valve disease, there is a momentum building for less invasive competition analogous to the catheter approach to coronary artery disease.

5.1: Cardiothoracic Surgery

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VIDEO: Cardiac Surgery Simulation – Graphics Hardware meets Congenital Heart Disease

VIDEO: SPY Imaging: Quality in Heart Bypass Surgery

The major cardiovascular surgeries include (1) coronary artery bypass grafting (CABG), (2) heart valve repair or replacement, (3) repair of a defect in the heart or a blood vessel, (4) reconstructions to compensate for a congenital defect, (5) insertion of a device to modify electric, pump or blood pressure control activities. Surgery on blood vessels outside the chest constitutes a separate specialty distinct from cardiothorasic .

The word bypass in relation to CABG has two meanings: (1) a bypass route to delivery blood around a narrow or obstructed segment, and (2) use of a bypass pump that circumvents the pumping role of the heart and the oxygenation role of the lungs so that the heart may be stopped for several hours with minimal interruption of delivery of oxygenated blood to the brain and the rest of the body (the brain does not tolerate >5-10 minutes interruption unless it is chilled). Venous blood is diverted to the bypass pump which oxygenates the blood.

Cardiothoracic Surgery at Tertiary Academic Hospitals in the US

by Larry H Bernstein, MD, FCAP

The following articles are a review of a decade of cardiovascular surgery and interventional cardiology at the Presbyterian Hospital, Columbia University Medical Center and Weill Cornell Medical Center.

This section includes analysis of morbidity and mortality, including 10 year survival rates for coronary artery bypass grafts (CABG heart surgery) versus percutaneous catheter interventions (PCI), presented along with discussion of deficiencies inherent in such studies, and conclusions. The first major comparison addresses CABG vs Plain Old Balloon Angioplasty (POBA), showing similar survival rates at 10 years for patients qualifying for either procedure. The high rate of restenosis observed in PCI, requiring a second procedure, declined substantially in the time since the initial comparisons as a result of technological innovations in stent design and in diameter of insertion device. The comparisons involve moving targets, as drug-eluting stents (DES) continue to improve. These studies involve 10,000 matched patients.

Mortality rates were adjusted using Cox proportional hazards method, adjusting for

• severity of disease
• comorbidity
• LAD only
• multiple vessel disease

As most patients are presented the options of catheter interventions versus bypass surgery, the results impact patient shared decision-making. An early study of CABG versus medical therapy was biased in favor of medical therapy, achieved by stringent exclusion criteria eliminating large percentage of patients with left main CAD and an ejection fraction of < 0.40. Many of these patient would have crossed over to CABG. The study was done prior to advances in medical therapy, as well as advances in imaging, myocardial protection, anesthesia, and LIMA.

5.1.1 Becoming a Cardiothoracic Surgeon: An Emerging Profile in the Surgery Theater and through Scientific Publications

Aviva Lev-Ari, PhD, RN

Comparison of the 10-year and 15-year survivals after CABG demonstrated benefit from a change in graft sources used at the Mayo Clinic and widely adapted by others: vascular grafts from the left internal mammary artery (LIMA) instead of just leg veins, for multiple grafts (up to 3), LIMA-to-LAD plus grafts using LIMA or radial artery vs LIMA/saphenous vein (SV).

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

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

5.1.3 Call for the abandonment of the Off-pump CABG surgery (OPCAB) in the On-pump / Off-pump Debate, +100 Research Studies

Aviva Lev-Ari, PhD, RN

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.

5.1.4 Cardiovascular Complications: Death from Reoperative Sternotomy After Prior CABG, MVR, AVR, or Radiation; Complications of PCI & PAD Endovascular Interventions; Sepsis from Cardiovascular Interventions

Justin D Pearlman and Aviva Lev-Ari, PhD, RN

5.2: Catheter Interventions

Arterial access typically starts by passing a needle through skin into an access artery, such as the femoral artery in the groin, or the radial artery at the wrist or brachial artery at the inside of the elbow. A wire is passed through the needle (Seldinger technique) to serve as a guide wire conducting hollow items into the artery. Once the wire is in place the needle is pulled off over the wire while the wire remains threaded into the artery, then the needle is replaced by plastic tubing, called an introducer, threaded over the guide wire. Large diameter tubing may require surgical cut down into the artery, and subsequent arterial repair (there are mechanical inserts that facilitate artery wall closure and repair). What occurs next depends on the target of treatment. To diagnose coronary artery obstructions, there are different designs of catheters consisting of long hollow tubing pre-shaped to catch the entrance of the left or right coronary arteries. To place a balloon across a lesion within a coronary artery is more challenging, so a longer thin guide wire is threaded down the catheter through the lesion, and a new catheter is threaded over that wire to place a balloon, and later a balloon with a stent on it, centered in the lesion, for deployment.

For percutaneous access (path starting by skin penetration into a blood vessel) to replace the aortic valve, the path is very similar to that for coronary arteries: femoral artery, up the aorta, around the arch of the aorta, to the aortic root. In theory, the mitral valve could be reached by passing through the aortic valve across the left ventricle, to the mitral valve, but the submitral apparatus would be hard to navigate. Alternatively, one may use venous access: femoral vein to inferior vena cava to right atrium, then pass through the foramen ovale (a trap door between right and left atria, normally closed after birth) into the left atrium, to the mitral valve, with no interference from the submitral (left ventrcular) apparatus of chordae and papilllary muscles.

Once the catheter is in place, it can be used to perform a number of procedures including

• coronary angiography
• flow reserve measurement
• balloon angioplasty (dilation and cracking of obstructions)
• stent placement
• balloon septostomy (creating an opening in the interatrial septum, to modify circulation impeded by congenital abnormalities)
• embolization to occlude a vessel or to inject alcohol to kill obstructive musle
• localize delivery of a thrombolytic or anti-spasm medication or angiogenesis or vasculogenesis or stem cell therapies
• percutaneous closure of a septal defect
• electrophysiology study
• ablation of dysfunctional electro-conductive pathways or arrhythmia riggers
• valvuloplasty
• valve placement
• aneurysm repair tube graft

The decision to intervene on a vascular lesion considers:

• length of the abnormal segment
• flow reserve (physiologic impact)
• patient age and co-morbidities (ailments)
• extent of calcification
• renal function
• pathway to the lesion
• branch anatomy that may be affected by the planned intervention

There has been considerable controversy about the role of catheterization (percutaneous catheter intervention or PCI) as an alternative to coronary artery bypass surgery (CABG). PCI has clearly been vital when applied within the first hour of a discrete coronary occlusion (heart attack) and may be as valuable even out to 12 or more hours, particularly with incomplete injuries (“stuttering heart attack”). Both PCI and CABG relieve chest pain due to impaired blood supply to the heart (ischemia). CABG provides alternate routes for blood delivery competing with the diseased segments, while PCI repairs (recanulates) selected obstructed segments of coronary arteries. PCI is faster and may be repeated far more often in the future of a given patient (CABG is generally limited to 2-3 per lifetime due to scar tissues). Benefits on life expectancy have been more challenging to demonstrate. While early comparisons demonstrated advantage of surgery for diabetics and patients with 3 vessel obstruction or left main obstruction or equivalent, the continual changes in technique for both surgery and PCI require updated comparisons. PCI has evolved from plain old balloon angioplasty (POBA), which lead to early restenosis (recurrence of narrowing in the arterial channel) and/or thrombosis (clot formation), requiring repeated interventions often within 6 months. Stents (wire cages to keep the vessels open) addressed the early restenosis problem, but reaction to the metal results in another mechanism for early failure: endotherial tissue in-growth (in-stent stenosis) as well as more frequent thrombosis. Use of stronger antiplatelet medications (e.g., aspirin plus clopidogrel) reduced the thrombosis issue, and addition of medications in the stent to block endothelial growth (drug-eluting stents, DES) reduced the problem with in-stent stenosis but prolonged the problem with thrombosis.

As a general clinical rule, the aspirin and clopidogrel interfere with platelet function sufficient to put off any surgeries – the anti-platelet treatment after stent is deemed uninterruptable for 1-2 months after a bare metal stent, and 6-12 months after a drug-eluting stent, with fading benefit thereafter over 2 years (then aspirin alone can suffice). Genetic studies identified that some patients are not protected by clopidogrel plus aspirin, so further studies investigate alternatives such as prasugrel and ticagrelor. Clopidogrel is a thienopyridine which selectively and irreversibly inhibits the platelet adenosine 5’-diphosphate (ADP) P2Y12 receptor, further inhibiting platelet aggregation (the “white” component of blood clots) over aspirin alone. The Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) trial, randomly assigned 12,562 patients with acute coronary syndrome (ACS) to receive clopidogrel (300 mg loading followed by 75 mg once daily) or placebo in addition to aspirin for 3 to 12 months; after an average follow-up of 9 months, the major adverse cardiovascular event rate (MACE= death from cardiovascular causes, myocardial infarction or stroke) occurred in 9.3% vs 11.4%, respectively (P < 0.001), due to fewer myocardial infarctions in those treated with clopidogrel (5.2% vs 6.7%, P < 0.001). Prasugrel is a thienopyridine ADP receptor inhibitor, which irreversibly binds to the P2Y12 receptor. In comparison to clopidogrel, prasugrel acts more quickly, more consistently, and more potently, and its value was examined in the Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel-TRITON-TIMI 38. Analysis of 13,608 patients treated with Prasugrel 60 mg loading dose and a 10 mg daily maintenance dose versus clopidogrel 300 mg loading dose and a 75 mg daily maintenance dose showed prasugrel more was effective than clopidogrel in reducing MACE (9.9% vs 12.1%, P < 0.001), due to fewer myocardial infarctions (7.3% vs 9.5%, P < 0.001), but at the cost of increased major bleeds (2.5% of those treated with prasugrel vs 1.7% of those treated with clopidogrel, P = 0.001, with CABG-related major bleeding 0.4% vs 0.1%, P = 0.001). Ticagrelor is a reversible inhibitor of platelet P2Y12-subtype ADP receptor, which means a switch of plans to CABG need not be delayed for the 9 days it takes permanent platelet inhibition to wear off. The Platelet Inhibition and Patient Outcomes (PLATO) study randomized 18,624 patients with ACS to 180 mg loading dose, then 90 mg twice dailyof ticagrelor vs 300-600 mg loading dose, then 75 mg daily of clopidogrel for 12 months. The risk of MACE was reduced by ticagrelor (9.8% vs 11.7%, P < 0.001), due to reduced death from all causes (4.5% vs 5.9%, P < 0.001), death from vascular causes (4.0% vs 5.1%, P = 0.001), myocardial infarction (5.8% vs 6.9%, P = 0.005), and stent thrombosis (1.3% vs 1.9%,P = 0.009), at a cost of increased major bleeding (2.8% vs 2.2%, P = 0.030).

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VIDEO: Coronary artery stents in Atherosclerosis

In an uncommon reversal of opinion, the combined forces of the American Heart Association (AHA) and the American College of Cardiology (ACC) reviewed compelling data and reversed a prior assessment on the need for an on-site cardiovascular surgery support for sites offering interventional cardiac catheterization. The data show that sites offering the intervention without a surgeon achieve better results that sites that ship patients out for the interventions, and that the risk without on-site thoracic surgery backup is negligible.

5.2.1 AHA, ACC Change in requirement for surgical support: Class IIb -> Class IIa Level of Evidence A: Supports Nonemergent PCI without Surgical Backup (Change of class IIb, level of Evidence B).

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

Improvements in stents