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Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Posted in Acute Myocardial Infarction, Biological Networks, Gene Regulation and Evolution, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Curation, De novo synthesis, Diabetes Mellitus, Discovery process, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Endothelial cells, Epigenetics and Cardiovascular Risks, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical Devices R&D and Inventions, Molecular Genetics & Pharmaceutical, Na-K transport, Na-K-ATPase, Nitric Oxide in Health and Disease, Nutrition, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Proteomics, Regenerative Biology and Medicine, Resident-cell-based, Stem Cells for Regenerative Medicine, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on April 27, 2014| Leave a Comment »

Introduction to e-Series A: Cardiovascular Diseases, Volume Four Part 2: Regenerative Medicine

Author and Curator: Larry H Bernstein, MD, FCAP

and

Curator: Aviva Lev-Ari, PhD, RN

This document is entirely devoted to medical and surgical therapies that have made huge strides in

  • simplification of interventional procedures,
  • reduced complexity, resulting in procedures previously requiring surgery are now done, circumstances permitting, by medical intervention.

This revolution in cardiovascular interventional therapy is regenerative medicine.  It is regenerative because it is largely driven by

  • the introduction into the impaired vasculature of an induced pleuripotent cell, called a stem cell, although
  • the level of differentiation may not be a most primitive cell line.

There is also a very closely aligned development in cell biology that extends beyond and including vascular regeneration that is called synthetic biology.  These developments have occurred at an accelerated rate in the last 15 years. The methods of interventional cardiology were already well developed in the mid 1980s.  This was at the peak of cardiothoracic bypass surgery.

Research on the endothelial cell,

  • endothelial cell proliferation,
  • shear flow in small arteries, especially at branch points, and
  • endothelial-platelet interactions

led to insights about plaque formation and vessel thrombosis.

Much was learned in biomechanics about the shear flow stresses on the luminal surface of the vasculature, and there was also

  • the concomitant discovery of nitric oxide,
  • oxidative stress, and
  • the isoenzymes of nitric oxide synthase (eNOS, iNOS, and nNOS).

It became a fundamental tenet of vascular biology that

  • atherogenesis is a maladjustment to oxidative stress not only through genetic, but also
  • non-genetic nutritional factors that could be related to the balance of omega (ω)-3 and omega (ω)-6 fatty acids,
  • a pro-inflammatory state that elicits inflammatory cytokines, such as, interleukin-6 (IL6) and c-reactive protein(CRP),
  • insulin resistance with excess carbohydrate associated with type 2 diabetes and beta (β) cell stress,
  • excess trans- and saturated fats, and perhaps
  • the now plausible colonic microbial population of the gastrointestinal tract (GIT).

There is also an association of abdominal adiposity,

  • including the visceral peritoneum, with both T2DM and with arteriosclerotic vessel disease,
  • which is presenting at a young age, and has ties to
  • the effects of an adipokine, adiponectin.

Much important work has already been discussed in the domain of cardiac catheterization and research done to

  • prevent atheroembolization.and beyond that,
  • research done to implant an endothelial growth matrix.

Even then, dramatic work had already been done on

  • the platelet structure and metabolism, and
  • this has transformed our knowledge of platelet biology.

The coagulation process has been discussed in detailed in a previous document.  The result was the development of a

  • new class of platelet aggregation inhibitors designed to block the activation of protein on the platelet surface that
  • is critical in the coagulation cascade.

In addition, the term long used to describe atherosclerosis, atheroma notwithstanding, is “hardening of the arteries”.  This is particularly notable with respect to mid-size arteries and arterioles that feed the heart and kidneys. Whether it is preceded by or develops concurrently with chronic renal insufficiency and lowered glomerular filtration rate is perhaps arguable.  However, there is now a body of evidence that points to

  • a change in the vascular muscularis and vessel stiffness, in addition to the endothelial features already mentioned.

This has provided a basis for

  • targeted pharmaceutical intervention, and
  • reduction in salt intake.

So we have a  group of metabolic disorders, which may alone or in combination,

  • lead to and be associated with the long term effects of cardiovascular disease, including
  • congestive heart failure.

This has been classically broken down into forward and backward failure,

  • depending on decrease outflow through the aorta (ejection fraction), or
  • decreased venous return through the vena cava,

which involves increased pulmonary vascular resistance and decreased return into the left atrium.

This also has ties to several causes, which may be cardiac or vascular. This document, as the previous, has four pats.  They are broadly:

  1. Stem Cells in Cardiovascular Diseases
  2. Regenerative Cell and Molecular Biology
  3. Therapeutics Levels In Molecular Cardiology
  4. Research Proposals for Endogenous Augmentation of circulating Endothelial Progenitor Cells (cEPCs)

As in the previous section, we start with the biology of the stem cell and the degeneration in cardiovascular diseases, then proceed to regeneration, then therapeutics, and finally – proposals for augmenting therapy with circulating endogenous endothelial progenitor cells (cEPCs).

 

context

stem cells

 

theme

regeneration

 

 

 

 

theme

Therapeutics

 

theme

augmentation

 

 

 

 

 

 

 

 

 

 

Key pathways involving NO

Key pathways involving NO

 

 

 

 

stem cell lin28

stem cellLlin28

1479-5876-10-175-1-l translational research with feedback loops

Tranlational Research -Lab to Bedside

 

 

Read Full Post »

Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN

Posted in Acute Myocardial Infarction, Anemia in CVD Patients, Atherogenic Processes & Pathology, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Chronic Thromboembolic Pulmonary Hypertension (CTEPH) and Pulmonary Arterial Hypertension (PAH), Circulating Progenitor Cells, Coagulation Therapy and Internal Bleeding, Competition in regenerative stem cell science, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Curation, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Drug Toxicity, Electrophysiology, Epigenetics and Cardiovascular Risks, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, HTN, HTN in Youth, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical Industry Competitive Intelligence, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Regenerative Biology and Medicine, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Resident-cell-based, Spontaneous Coronary Artery Dissection (SCAD), Stem Cells for Regenerative Medicine, Systemic Inflammatory Response Related Disorders, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science on April 17, 2014| Leave a Comment »

Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN, 2006 – 4/2018

 

+120 articles listed below cover the following topics:

  • National Trends: Cardiovascular-related Hospital stay, Cost of Treatment & Societal Burden
  • Introduction to Drug Types: De Novo Brand, Generic, Biologics, Biosimsilars
  • Anti-Inflammatory & Systemic Inflammatory
  • Anti-thrombotic Drug Class & Novel Oral Anticoagulants (NOACs)
  • Pharmaco-Genetics response to Congenital and Spontaneous Mutations: new drugs and new biomarkers for Atherosclerosis, Genetic-related Novel Anti-Cholesterol, Lipids, LDL, HDL, Hypertriglyceridemia Hyperlipidemia
  • Epigenetics, Gender differences and Life Style: DM, Obesity, Hormonal Markers, Diets, Chrono-therapeutics
  • BP Management: Genetics & Human Adaptive Immunity
  • Anti-arrhythmic Drugs – Atrial Fibrillation (AF) & Silent Cerebral Infarctions
  • MI, Acute Coronary Syndrome (ACS) and Heart Failure (HF)
  • Calcium &Cardiovascular Diseases: Contractile Dysfunction, Calcium as Neurotransmitter Sensor
  • Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)
  • Vascular Biology, Atherosclerosis and Molecular Cardiology

 

A new mechanism of action to attack in the treatment of coronary artery disease (CAD), Novartis developed Ilaris (canakinumab), a human monoclonal antibody targeting the interleukin-1beta innate immunity pathway

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/04/06/a-new-mechanism-of-action-to-attack-in-the-treatment-of-coronary-artery-disease-cad-novartis-developed-ilaris-canakinumab-a-human-monoclonal-antibody-targeting-the-interleukin-1beta-innate-i/

 

Advantages and Disadvantages of Novel Oral Anticoagulants (NOACs)

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/20/advantages-and-disadvantages-of-novel-oral-anticoagulants-noacs/

 

Acute Coronary Syndrome (ACS): Strategies in Anticoagulant Selection: Diagnostics Approaches – Genetic Testing Aids vs. Biomarkers (Troponin types and BNP)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/13/acute-coronary-syndrome-acs-strategies-in-anticoagulant-selection-diagnostics-approaches-genetic-testing-aids-vs-biomarkers-troponin-types-and-bnp/

 

Cholesterol Lowering Novel PCSK9 drugs: Praluent [Sanofi and Regeneron] vs Repatha [Amgen] – which drug cuts CV risks enough to make it cost-effective?

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/12/cholesterol-lowering-novel-pcsk9-drugs-praluent-sanofi-and-regeneron-vs-repatha-amgen-which-drug-cuts-cv-risks-enough-to-make-it-cost-effective/

 

Higher BMI (Obesity Marker): Earlier onset of incident CVD followed by Shorter overall Survival – Men and women of all ages

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/03/05/higher-bmi-obesity-marker-earlier-onset-of-incident-cvd-followed-by-shorter-overall-survival-men-and-women-of-all-ages/

 

ODYSSEY Outcomes trial evaluating the effects of a PCSK9 inhibitor, alirocumab, on major cardiovascular events in patients with an acute coronary syndrome to be presented at the American College of Cardiology meeting on March 10.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/odyssey-outcomes-trial-evaluating-the-effects-of-a-pcsk9-inhibitor-alirocumab-on-major-cardiovascular-events-in-patients-with-an-acute-coronary-syndrome-to-be-presented-at-the-america/

 

Sex and Gender Connections: Heart and Brain Disease in Women

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/28/sex-and-gender-connections-heart-and-brain-disease-in-women/

 

In 2018 Cardiovascular PharmacoTherapy Market: Anti-thrombotic Drug Class Segment will continue to bring in the biggest profit and dominate production

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/in-2018-cardiovascular-pharmacotherapy-market-anti-thrombotic-drug-class-segment-will-continue-to-bring-in-the-biggest-profit-and-dominate-production/

 

Cost per Inpatient Hospital Stay: Five cardiovascular issues ranked in the top 10 – #1 Heart valve disorders, #2 Acute myocardial infarction (heart attack), #4 Coronary atherosclerosis, #7 Septicemia, #10 Acute cerebrovascular disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/27/cost-per-inpatient-hospital-stay-five-cardiovascular-issues-ranked-in-the-top-10-1-heart-valve-disorders-2-acute-myocardial-infarction-heart-attack-4-coronary-atherosclerosis/

 

There may be a genetic basis to CAD and that CXCL5 may be of therapeutic interest

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/02/09/there-may-be-a-genetic-basis-to-cad-and-that-cxcl5-may-be-of-therapeutic-interest/

 

FDA Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/fda-approval-marks-first-presentation-of-bivalirudin-in-frozen-premixed-ready-to-use-formulation/

 

What Level of Blood Pressure (BP) should be Treated? Comments on the New Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2018/01/24/what-level-of-blood-pressure-bp-should-be-treated-comments-on-the-new-guidelines/

 

FDA approval on 12/1/2017 of Amgen’s evolocumb (Repatha) a PCSK9 inhibitor for the prevention of heart attacks, strokes, and coronary revascularizations in patients with established cardiovascular disease

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/12/01/fda-approval-on-12-1-2017-of-amgens-evolocumb-repatha-a-pcsk9-inhibitor-for-the-prevention-of-heart-attacks-strokes-and-coronary-revascularizations-in-patients-with-established-cardiovascular-di/

 

Long-term Canakinumab Treatment Lowering Inflammation Independent of Lipid Levels for Residual Inflammatory Risk Benefit – Personalized Medicine for Recurrent MI, Strokes and Cardiovascular Death

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/21/long-term-canakinumab-treatment-lowering-inflammation-independent-of-lipid-levels-for-residual-inflammatory-risk-benefit-personalized-medicine-for-recurrent-mi-strokes-and-cardiovascular-death/

 

Daily Highlights at 2017 American Heart Association Annual Meeting Scientific Sessions

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/daily-highlights-at-2017-american-heart-association-annual-meeting-scientific-sessions/

 

2017 Guideline for the Prevention, Detection, Evaluation and Management of High Blood Pressure in Adults – A REPORT OF THE American College of Cardiology/ American Heart Association Task Force on Clinical Practice Guidelines

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/14/2017-guideline-for-the-prevention-detection-evaluation-and-management-of-high-blood-pressure-in-adults-a-report-of-the-american-college-of-cardiology-american-heart-association-task-force-on-clin/

 

2017 American Heart Association Annual Meeting: Sunday’s Science at #AHA17 – Presidential Address

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/11/13/2017-american-heart-association-annual-meeting-sundays-science-at-aha17-presidential-address/

 

Systemic Inflammatory Diseases as Crohn’s disease, Rheumatoid Arthritis and Longer Psoriasis Duration May Mean Higher CVD Risk

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/10/09/systemic-inflammatory-diseases-as-crohns-disease-rheumatoid-arthritis-and-longer-psoriasis-duration-may-mean-higher-cvd-risk/

 

Shaun Coughlin from UCSF Cardiovascular Research Center to cardio group for the Novartis Institute for Biomedical Research in Cambridge, MA

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/08/17/shaun-coughlin-from-ucsf-cardiovascular-research-center-to-cardio-group-for-the-novartis-institute-for-biomedical-research-in-cambridge-ma/

 

In Europe, BigData@Heart aim to improve patient outcomes and reduce societal burden of atrial fibrillation (AF), heart failure (HF) and acute coronary syndrome (ACS).

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/in-europe-bigdataheart-aim-to-improve-patient-outcomes-and-reduce-societal-burden-of-atrial-fibrillation-af-heart-failure-hf-and-acute-coronary-syndrome-acs/

 

SNP-based Study on high BMI exposure confirms CVD and DM Risks – no associations with Stroke

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/07/10/snp-based-study-on-high-bmi-exposure-confirms-cvd-and-dm-risks-no-associations-with-stroke/

 

Tweets by @pharma_BI and @AVIVA1950 at World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/05/tweets-by-pharma_bi-and-aviva1950-at-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

 

e-Proceedings for Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

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

https://pharmaceuticalintelligence.com/2017/05/05/e-proceedings-for-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma/

REAL TIME Highlights and Tweets: Day 1,2,3: World Medical Innovation Forum – CARDIOVASCULAR • MAY 1-3, 2017, BOSTON, MA

Author and Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/05/03/deliverables-day-123-world-medical-innovation-forum-cardiovascular-%E2%80%A2-may-1-3-2017-boston-ma-httpsworldmedicalinnovation-orgagenda-highlights-of-live-day-1-world-medical/

 

Expedite Use of Agents in Clinical Trials: New Drug Formulary Created – The NCI Formulary is a public-private partnership between NCI, part of the National Institutes of Health, and pharmaceutical and biotechnology companies

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2017/01/12/expedite-use-of-agents-in-clinical-trials-new-drug-formulary-created-the-nci-formulary-is-a-public-private-partnership-between-nci-part-of-the-national-institutes-of-health-and-pharmaceutical-and/

 

Reversing Heart Disease: Combination of PCSK9 Inhibitors and Statins – Opinion by Steven Nissen, MD, Chairman of Cardiovascular Medicine at Cleveland Clinic

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/12/29/reversing-heart-disease-combination-of-pcsk9-inhibitors-and-statins-opinion-by-steven-nissen-md-chairman-of-cardiovascular-medicine-at-cleveland-clinicopinion-on-reversing-heart-disease-combinat/

 

Coronary Heart Disease Research: Sugar Industry influenced national conversation on heart disease – Adoption of Low Fat Diet vs Low Carbohydrates Diet

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/09/17/coronary-heart-disease-research-sugar-industry-influenced-national-conversation-on-heart-disease-adoption-of-low-fat-diet-vs-low-carbohydrates-diet/

 

Pathophysiology in Hypertension: Opposing Roles of Human Adaptive Immunity

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/19/pathophysiology-in-hypertension-opposing-roles-of-human-adaptive-immunity/

 

PCSK9 inhibitors: Reducing annual drug prices from more than $14 000 to $4536 would be necessary to meet a $100 000 per QALY threshold per JAMA

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/17/pcsk9-inhibitors-reducing-annual-drug-prices-from-more-than-14%E2%80%AF000-to-4536-would-be-necessary-to-meet-a-100%E2%80%AF000-per-qaly-threshold-per-jama/

 

The presence of any Valvular Heart Disease (VHD) did not influence the comparison of Dabigatran [Pradaxa, Boehringer Ingelheim] with Warfarin

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/08/16/the-presence-of-any-valvular-heart-disease-vhd-did-not-influence-the-comparison-of-dabigatran-pradaxa-boehringer-ingelheim-with-warfarin/

 

Resveratrol, an antioxidant found in red wine presented since 2003 presented for its potential to lower risk for cardiovascular disease and neurodegeneration by increasing cell survival and slowing aging: 2014 Study – Diet rich in resveratrol offers no health boost

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/07/25/resveratrol-an-antioxidant-found-in-red-wine-2014-study-resveratrol-offers-no-health-boost/

 

Amgen’s Corlanor® can help Reduce the Risk of Hospitalization for Patients with worsening Heart Failure

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/05/04/amgens-corlanor-can-help-reduce-the-risk-of-hospitalization-for-patients-with-worsening-heart-failure/

 

Effectiveness of Anti-arrhythmic Drugs: Amiodarone and Lidocaine, for treating sudden cardiac arrest, increasing likelihood of Patients Surviving Emergency Transport to Hospital

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/04/04/effectiveness-of-anti-arrhythmic-drugs-amiodarone-and-lidocaine-for-treating-sudden-cardiac-arrest-increasing-likelihood-of-patients-surviving-emergency-transport-to-hospital/

 

Efficacy and Tolerability of PCSK9 Inhibitors by Patients with Muscle-related Statin Intolerance – New Cleveland Clinic study published in JAMA 4/2016

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

https://pharmaceuticalintelligence.com/2016/04/03/efficacy-and-tolerability-of-pcsk9-inhibitors-by-patients-with-muscle-related-statin-intolerance-new-cleveland-clinic-study-published-in-jama-42016/

 

Triglycerides: Is it a Risk Factor or a Risk Marker for Atherosclerosis and Cardiovascular Disease ? The Impact of Genetic Mutations on (ANGPTL4) Gene, encoder of (angiopoietin-like 4) Protein, inhibitor of Lipoprotein Lipase

Reporters, Curators and Authors: Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/03/13/triglycerides-is-it-a-risk-factor-or-a-risk-marker-for-atherosclerosis-and-cardiovascular-disease-the-impact-of-genetic-mutations-on-angptl4-gene-encoder-of-angiopoietin-like-4-protein-that-in/

 

In One-Hour: A Diagnosis of Heart Attack made possible by one Blood Test

Reporter: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2016/01/14/in-one-hour-a-diagnosis-of-heart-attack-made-possible-by-one-blood-test/

 

Heart-Failure–Related Mortality Rate: CDC Reports comparison of 2000, 2012, 2014  – the decease is steadily reversed

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2016/01/05/heart-failure-related-mortality-rate-cdc-reports-comparison-of-2000-2012-2014-the-decease-is-steadily-reversed/

 

PCSK9: A Recent Discovery in Understanding Cholesterol Regulation @ AMGEN Cardiovascular

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/08/04/pcsk9-a-recent-discovery-in-understanding-cholesterol-regulation-amgen-cardiovascular/

 

Praluent – FDA approved as Cholesterol-lowering Medicine for Patient non responsive to Statin due to Genetic origin of Hypercholesterolemia

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/27/praluent-fda-approved-as-cholesterol-lowering-medicine-for-patient-non-responsive-to-statin-due-to-genetic-origin-of-hypercholesterolemia/

 

Atherosclerosis: What is New in Biomarker Discovery

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/07/01/atherosclerosis-what-is-new-in-biomarker-discovery/

 

Cangrelor wins Clopidogrel (Plavix): reduction of Risk of a composite of all-cause mortality, myocardial infarction, ischemia driven revascularization, and stent thrombosis

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/cangrelor-wins-clopidogrel-plavix-reduction-of-risk-of-a-composite-of-all-cause-mortality-myocardial-infarction-ischemia-driven-revascularization-and-stent-thrombosis/

 

Sets of co-expressed Genes influence Blood Pressure Regulation: Genome-wide Association and mRNA expression @US National Heart, Lung, and Blood Institute

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2015/04/16/sets-of-co-expressed-genes-influence-blood-pressure-regulation-genome-wide-association-and-mrna-expression-us-national-heart-lung-and-blood-institute/

 

HDL-C: Target of Therapy – Steven E. Nissen, MD, MACC, Cleveland Clinic vs Peter Libby, MD, BWH

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/07/hdl-c-target-of-therapy-steven-e-nissen-md-macc-cleveland-clinic-vs-peter-libby-md-bwh/

 

Atrial Fibrillation and Silent Cerebral Infarctions: A Meta Analysis Study and Literature Review

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/11/04/atrial-fibrillation-and-silent-cerebral-infarctions-a-meta-analysis-study-and-literature-review/

 

Intracranial Vascular Stenosis: Comparison of Clinical Trials: Percutaneous Transluminal Angioplasty and Stenting (PTAS) vs. Clot-inhibiting Drugs: Aspirin and Clopidogrel (dual antiplatelet therapy) – more Strokes if Stenting

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/15/intracranial-vascular-stenosis-comparison-of-clinical-trials-percutaneous-transluminal-angioplasty-and-stenting-ptas-vs-clot-inhibiting-drugs-aspirin-and-clopidogrel-dual-antiplatelet-therapy/

 

Hypertension: It is Autoimmunity that Underlies its Development in Humans

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/08/hypertension-it-is-autoimmunity-that-underlies-its-development-in-humans/

 

OPINION LEADERSHIP on Cardiovascular Diseases

Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation

  • Cardiovascular Diseases, Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation. On Amazon.com since 11/30/2015

http://www.amazon.com/dp/B018Q5MCN8

 Epilogue to Volume Two

Author and Curator: Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Series of e-Books

https://pharmaceuticalintelligence.com/2014/07/31/opinion-leadership-on-cardiovascular-diseases/

 

Risk of Major Cardiovascular Events by LDL-Cholesterol Level (mg/dL): Among those treated with high-dose statin therapy, more than 40% of patients failed to achieve an LDL-cholesterol target of less than 70 mg/dL.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/07/29/risk-of-major-cardiovascular-events-by-ldl-cholesterol-level-mgdl-among-those-treated-with-high-dose-statin-therapy-more-than-40-of-patients-failed-to-achieve-an-ldl-cholesterol-target-of-less-th/

 

Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease: Views by Larry H Bernstein, MD, FCAP

Commissioned article, Author: Larry H Bernstein, MD, FCAP

https://pharmaceuticalintelligence.com/2014/07/16/commentary-on-biomarkers-for-genetics-and-genomics-of-cardiovascular-disease-views-by-larry-h-bernstein-md-fcap/

 

Coagulation Therapy: Leading New Drugs – Efficacy Comparison

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/coagulation-therapy-leading-new-drugs-efficacy-comparison/

 

Apixaban (Eliquis): Mechanism of Action, Drug Comparison and Additional Indications

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/05/10/apixaban-eliquis-mechanism-of-action-drug-comparison-and-additional-indications/

 

Boston Heart Diagnostics (BHD) offers Statin Induced Myopathy (SLCO1B1) Genotype test and genetic tests targeting ApoE, Factor V Leiden, prothrombin (Factor II), and CYP2C19

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/boston-heart-diagnostics-bhd-offers-statin-induced-myopathy-slco1b1-genotype-test-and-genetic-tests-targeting-apoe-factor-v-leiden-prothrombin-factor-ii-and-cyp2c19/

 

@@@ Cardiovascular Diseases and Pharmacological Therapy: Curations by Aviva Lev-Ari, PhD, RN

Curator: Aviva Leve-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/04/17/cardiovascular-diseases-and-pharmacological-therapy-curations-by-aviva-lev-ari-phd-rn/

 

Richard Lifton, MD, PhD of Yale University & Howard Hughes Medical Institute: Recipient of 2014 Breakthrough Prizes Awarded in Life Sciences for the Discovery of Genes and Biochemical Mechanisms that cause Hypertension

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/03/03/richard-lifton-md-phd-of-yale-university-and-howard-hughes-medical-institute-recipient-of-2014-breakthrough-prizes-awarded-in-life-sciences-for-the-discovery-of-genes-and-biochemical-mechanisms-tha/

 

Differences in Health Services Utilization and Costs between Antihypertensive Medication Users Versus Nonusers in Adults with Diabetes and Concomitant Hypertension from Medical Expenditure Panel Su…

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/28/differences-in-health-services-utilization-and-costs-between-antihypertensive-medication-users-versus-nonusers-in-adults-with-diabetes-and-concomitant-hypertension-from-medical-expenditure-panel-su-2/

 

2014 Epidemiology and Prevention, Nutrition, Physical Activity and Metabolism Conference: San Francisco, Ca. Conference Dates: San Francisco, CA 3/18-21, 2014

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/26/2014-epidemiology-and-prevention-nutrition-physical-activity-and-metabolism-conference-san-francisco-ca-conference-dates-san-francisco-ca-318-21-2014/

 

2014 High Blood Pressure Research Conference, 9/9 – 9/12, 2014 — Hilton SF Union Square, San Francisco, CA

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/24/2014-high-blood-pressure-research-conference-99-912-2014-hilton-sf-union-square-san-francisco-ca/

 

Females and Non-Atherosclerotic Plaque: Spontaneous Coronary Artery Dissection – New Insights from Research and DNA Ongoing Study

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/female-and-non-atherosclerotic-plaque-spontaneous-coronary-artery-dissection-new-insights-from-research-and-dna-ongoing-study/

 

Hypertension – JNC 8 Guideline: Henry R. Black, MD, Michael A. Weber, MD and Raymond R. Townsend, MD

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/12/hypertension-jnc-8-guideline-henry-r-black-md-michael-a-weber-md-and-raymond-r-townsend-md/

 

Why Don’t You Trust Generic Drugs as Much as Brand Name …

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/10/why-dont-you-trust-generic-drugs-as-much-as-brand-name/

 

National Trends, 2005 – 2011: Adverse-event Rates Declined among Patients Hospitalized for Acute Myocardial Infarction or Congestive Heart Failure

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/04/national-trends-2005-2011-adverse-event-rates-declined-among-patients-hospitalized-for-acute-myocardial-infarction-or-congestive-heart-failure/

 

Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/

 

Prolonged Wakefulness: Lack of Sufficient Duration of Sleep as a Risk Factor for Cardiovascular Diseases – Indications for Cardiovascular Chrono-therapeutics

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/02/02/prolonged-wakefulness-lack-of-sufficient-duration-of-sleep-as-a-risk-factor-for-cardiovascular-diseases-indications-for-cardiovascular-chrono-therapeutics/

 

Testosterone Therapy for Idiopathic Hypogonadotrophic Hypogonadism has Beneficial and Deleterious Effects on Cardiovascular Risk Factors

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/30/testosterone-therapy-for-idiopathic-hypogonadotrophic-hypogonadism-has-beneficial-and-deleterious-effects-on-cardiovascular-risk-factors/

 

Calcium and Cardiovascular Diseases: A Series of Twelve Articles in Advanced Cardiology

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/28/calcium-and-cardiovascular-diseases-a-series-of-twelve-articles-in-advanced-cardiology/

 

Acute Myocardial Infarction: Curations of Cardiovascular Original Research – A Bibliography

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/acute-myocardial-infarction-curations-of-cardiovascular-original-research-a-bibliography/

 

On-Hours vs Off-Hours: Presentation to ER with Acute Myocardial Infarction – Lower Survival Rate if Off-Hours

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/22/on-hours-vs-off-hours-presentation-to-er-with-acute-myocardial-infarction-lower-survival-rate-if-off-hours/

 

2014 Winter in New England: The Effect of Record Cold Temperatures on Cardiovascular Diseases

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/2014-winter-in-new-england-the-effect-of-record-cold-temperatures-on-cardiovascular-diseases/

 

Voices from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/21/voices-from-the-cleveland-clinic-on-the-new-lipid-guidelines-and-on-the-accaha-risk-calculator/

 

Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/19/is-it-hypertension-or-physical-inactivity-cardiovascular-risk-and-mortality-new-results-in-32013/

 

Regeneration: Cardiac System (cardiomyogenesis) and Vasculature (angiogenesis)

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/15/regeneration-cardiac-system-and-vasculature

 

Conceived: NEW Definition for Co-Curation in Medical Research

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/01/04/conceived-new-definition-for-co-curation-in-medical-research/

 

The Young Surgeon and The Retired Pathologist: On Science, Medicine and HealthCare Policy – The Best Writers Among the WRITERS

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/12/10/the-young-surgeon-and-the-retired-pathologist-on-science-medicine-and-healthcare-policy-best-writers-among-the-writers/

 

Diabetes-risk Forecasts: Serum Calcium in Upper-Normal Range (>2.5 mmol/L) as a New Biomarker

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/09/25/diabetes-risk-forecasts-serum-calcium-in-upper-normal-range-2-5-mmoll-as-a-new-biomarker/

 

Do Novel Anticoagulants Affect the PT/INR? The Cases of XARELTO (rivaroxaban) or PRADAXA (dabigatran)

Curators: Lal, V., Justin D. Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/23/do-novel-anticoagulants-affect-the-ptinr-the-cases-of-xarelto-rivaroxaban-and-pradaxa-dabigatran/

 

Calcium-Channel Blocker, Calcium Release-related Contractile Dysfunction (Ryanopathy) and Calcium as Neurotransmitter Sensor

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/16/calcium-channel-blocker-calcium-as-neurotransmitter-sensor-and-calcium-release-related-contractile-dysfunction-ryanopathy/

 

Disruption of Calcium Homeostasis: Cardiomyocytes and Vascular Smooth Muscle Cells: The Cardiac and Cardiovascular Calcium Signaling Mechanism

Curators: Larry H. Bernstein, MD FCAP, Justin D. Pearlman, MD, PhD, FACC, and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/09/12/disruption-of-calcium-homeostasis-cardiomyocytes-and-vascular-smooth-muscle-cells-the-cardiac-and-cardiovascular-calcium-signaling-mechanism/

 

Synaptotagmin functions as a Calcium Sensor: How Calcium Ions Regulate the fusion of vesicles with cell membranes during Neurotransmission

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

https://pharmaceuticalintelligence.com/2013/09/10/synaptotagmin-functions-as-a-calcium-sensor-how-calcium-ions-regulate-the-fusion-of-vesicles-with-cell-membranes-during-neurotransmission/

 

Cardiac Contractility & Myocardium Performance: Ventricular Arrhythmias and Non-ischemic Heart Failure – Therapeutic Implications for Cardiomyocyte Ryanopathy (Calcium Release-related Contractile Dysfunction) and Catecholamine Responses

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD FCAP and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/08/28/cardiac-contractility-myocardium-performance-ventricular-arrhythmias-and-non-ischemic-heart-failure-therapeutic-implications-for-cardiomyocyte-ryanopathy-calcium-release-related-contractile/

 

Cardiovascular Original Research: Cases in Methodology Design for Content Curation and Co-Curation

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/07/29/cardiovascular-original-research-cases-in-methodology-design-for-content-curation-and-co-curation/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/07/09/research-programs-george-m-linda-h-kaufman-center-for-heart-failure-cleveland-clinic/

 

Congenital Heart Disease (CHD) at Birth and into Adulthood: The Role of Spontaneous Mutations

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/06/09/congenital-heart-disease-at-birth-and-into-adulthood-the-role-of-spontaneous-mutations-the-genes-and-the-pathways/

 

Clinical Indications for Use of Inhaled Nitric Oxide (iNO) in the Adult Patient Market: Clinical Outcomes after Use, Therapy Demand and Cost of Care

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

Inhaled Nitric Oxide in Adults: Clinical Trials and Meta Analysis Studies – Recent Findings

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/06/02/inhaled-nitric-oxide-in-adults-with-acute-respiratory-distress-syndrome/

 

Imaging Biomarker for Arterial Stiffness: Pathways in Pharmacotherapy for Hypertension and Hypercholesterolemia Management

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

https://pharmaceuticalintelligence.com/2013/05/24/imaging-biomarker-for-arterial-stiffness-pathways-in-pharmacotherapy-for-hypertension-and-hypercholesterolemia-management/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

Diagnosis of Cardiovascular Disease, Treatment and Prevention: Current & Predicted Cost of Care and the Promise of Individualized Medicine Using Clinical Decision Support Systems

Curators: Justin D. Pearlman, MD, PhD, FACC, Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN

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/

 

Gene, Meis1, Regulates the Heart’s Ability to Regenerate after Injuries.

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/05/03/gene-meis1-regulates-the-hearts-ability-to-regenerate-after-injuries/

 

Prostacyclin and Nitric Oxide: Adventures in Vascular Biology – A Tale of Two Mediators

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/30/prostacyclin-and-nitric-oxide-adventures-in-vascular-biology-a-tale-of-two-mediators/

 

Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/28/genetics-of-conduction-disease-atrioventricular-av-conduction-disease-block-gene-mutations-transcription-excitability-and-energy-homeostasis/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

Harnessing New Players in Atherosclerosis to Treat Heart Disease

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/25/harnessing-new-players-in-atherosclerosis-to-treat-heart-disease/

 

Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/07/cholesteryl-ester-transfer-protein-cetp-inhibitor-potential-of-anacetrapib-to-treat-atherosclerosis-and-cad/

 

Hypertriglyceridemia concurrent Hyperlipidemia: Vertical Density Gradient Ultracentrifugation a Better Test to Prevent Undertreatment of High-Risk Cardiac Patients

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/04/04/hypertriglyceridemia-concurrent-hyperlipidemia-vertical-density-gradient-ultracentrifugation-a-better-test-to-prevent-undertreatment-of-high-risk-cardiac-patients/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

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/ 

 

Genomics & Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013

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

https://pharmaceuticalintelligence.com/2013/03/07/genomics-genetics-of-cardiovascular-disease-diagnoses-a-literature-survey-of-ahas-circulation-cardiovascular-genetics-32010-32013/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/02/28/the-heart-vasculature-protection-a-concept-based-pharmacological-therapy-including-thymosin/

 

Thymosin References

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/02/27/thymosin-references/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2013/02/27/arteriogenesis-and-cardiac-repair-two-biomaterials-injectable-thymosin-beta4-and-myocardial-matrix-hydrogel/

 

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

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2013/01/10/pci-outcomes-increased-ischemic-risk-associated-with-elevated-plasma-fibrinogen-not-platelet-reactivity/

 

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

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/12/23/heart-renewal-by-pre-existing-cardiomyocytes-source-of-new-heart-cell-growth-discovered/

 

Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment

Curators: Larry H. Bernstein and Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/11/28/special-considerations-in-blood-lipoproteins-viscosity-assessment-and-treatment/

 

Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

Cardiovascular Risk Inflammatory Marker: Risk Assessment for Coronary Heart Disease and Ischemic Stroke – Atherosclerosis.

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/30/cardiovascular-risk-inflammatory-marker-risk-assessment-for-coronary-heart-disease-and-ischemic-stroke-atherosclerosis/

 

Clinical Trials Results for Endothelin System: Pathophysiological role in Chronic Heart Failure, Acute Coronary Syndromes and MI – Marker of Disease Severity or Genetic Determination?

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

Sustained Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/10/16/sustained-cardiac-atrial-fibrillation-management-strategies-by-director-of-the-arrhythmia-service-and-electrophysiology-lab-at-the-johns-hopkins-hospital/

 

Endothelin Receptors in Cardiovascular Diseases: The Role of eNOS Stimulation

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/10/04/endothelin-receptors-in-cardiovascular-diseases-the-role-of-enos-stimulation/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

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/

Positioning a Therapeutic Concept for Endogenous Augmentation of cEPCs — Therapeutic Indications for Macrovascular Disease: Coronary, Cerebrovascular and Peripheral

Curator: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/29/positioning-a-therapeutic-concept-for-endogenous-augmentation-of-cepcs-therapeutic-indications-for-macrovascular-disease-coronary-cerebrovascular-and-peripheral/ 

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/08/28/cardiovascular-outcomes-function-of-circulating-endothelial-progenitor-cells-cepcs-exploring-pharmaco-therapy-targeted-at-endogenous-augmentation-of-cepcs/

 

Endothelial Dysfunction, Diminished Availability of cEPCs, Increasing CVD Risk for Macrovascular Disease – Therapeutic Potential of cEPCs

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/08/27/endothelial-dysfunction-diminished-availability-of-cepcs-increasing-cvd-risk-for-macrovascular-disease-therapeutic-potential-of-cepcs/

 

Vascular Medicine and Biology: Classification of Fast Acting Therapy for Patients at High Risk for Macrovascular Events – Macrovascular Disease – Therapeutic Potential of cEPCs

Curator: Aviva Lev-Ari, PhD, RN

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/

 

 

Ethical Considerations in Studying Drug Safety — The Institute of Medicine Report

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/23/ethical-considerations-in-studying-drug-safety-the-institute-of-medicine-report/

 

Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

Reporter: Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2012/08/08/cardiac-arrhythmias-a-risk-for-extreme-performance-athletes/

 

Biosimilars: Intellectual Property Creation and Protection by Pioneer and by Biosimilar Manufacturers

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-intellectual-property-creation-and-protection-by-pioneer-and-by-biosimilar-manufacturers/

 

Biosimilars: Financials 2012 vs. 2008

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/30/biosimilars-financials-2012-vs-2008/

 

Biosimilars: CMC Issues and Regulatory Requirements

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/29/biosimilars-cmc-issues-and-regulatory-requirements/

 

Cardiovascular Disease (CVD) and the Role of agent alternatives in endothelial Nitric Oxide Synthase (eNOS) Activation and Nitric Oxide Production

Curator: Aviva Lev-Ari, PhD, RN 

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/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/04/30/93/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/05/29/445/

 

Macrovascular Disease – Therapeutic Potential of cEPCs: Reduction Methods for CV Risk

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/02/macrovascular-disease-therapeutic-potential-of-cepcs-reduction-methods-for-cv-risk/

 

Mitochondria Dysfunction and Cardiovascular Disease – Mitochondria: More than just the “powerhouse of the cell”

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/09/mitochondria-more-than-just-the-powerhouse-of-the-cell/

 

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

Curator: Aviva Lev-Ari, PhD, RN 

https://pharmaceuticalintelligence.com/2012/07/16/bystolics-generic-nebivolol-positive-effect-on-circulating-endothilial-progrnetor-cells-endogenous-augmentation/

Lev-Ari, A. Heart Vasculature (2007) Regeneration and Protection of Coronary Artery Endothelium and Smooth Muscle: A Concept-based Pharmacological Therapy of a Combined Three Drug Regimen.

Bouve College of Health Sciences, Northeastern University, Boston, MA 02115

 

Lev-Ari, A. & Abourjaily, P. (2006a) “An Investigation of the Potential of circulating Endothelial Progenitor Cells (cEPC) as a Therapeutic Target for Pharmacologic Therapy Design for Cardiovascular Risk Reduction.”

  • Part I: Macrovascular Disease – Therapeutic Potential of cEPCs – Reduction methods for CV risk.
  • Part II:(2006b) Therapeutic Strategy for cEPCs Endogenous Augmentation: A Concept-based Treatment Protocol for a Combined Three Drug Regimen.
  • Part III: (2006c)Biomarker for Therapeutic Targets of Cardiovascular Risk Reduction by cEPCs Endogenous Augmentation using New Combination Drug Therapy of Three Drug Classes and Several Drug Indications.

Northeastern University, Boston, MA 02115

 

Curator: Medical Research – 557 articles in Books

Editorial & Publication of Articles in e-Books by Leaders in Pharmaceutical Business Intelligence: Contributions of Aviva Lev-Ari, PhD, RN

https://pharmaceuticalintelligence.com/2014/10/16/editorial-publication-of-articles-in-e-books-by-leaders-in-pharmaceutical-business-intelligence-contributions-of-aviva-lev-ari-phd-rn/

 

 

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ACC 2014: Clinical Trials on Bivalirudin: Questions on Bleeding and Outcomes

Posted in Acute Myocardial Infarction, Cardiac and Cardiovascular Surgical Procedures, Coagulation Therapy and Internal Bleeding, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, PCI, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Stents & Tools, Valves & Tools on April 8, 2014| Leave a Comment »

Clinical Trials on Bivalirudin: Questions on Bleeding and Outcomes

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 1/24/2018

Baxter Announces FDA Approval of Ready-to-Use Cardiovascular Medication Bivalirudin

Approval marks first presentation of bivalirudin in frozen, premixed, ready-to-use formulation

https://www.dicardiology.com/product/baxter-announces-fda-approval-ready-use-cardiovascular-medication-bivalirudin?eid=333021707&bid=1983307

 

UPDATED on 2/16/2015

 

Maybe those early stent thrombosis rates with bivalirudin (Angiomax) aren’t so high after all, the Swedish Coronary Angiography and Angioplasty Register suggested.

SOURCE

http://www.medpagetoday.com/Cardiology/Strokes/50048?isalert=1&uun=g99985d3527R5099207u&utm_source=breaking-news&utm_medium=email&utm_campaign=breaking-news&xid=NL_breakingnews_2015-02-16

 

UPDATED on 4/15/2014

Listen to AUDIO: Dr. Harrington, Stanford Medical Center and Dr. Ohman, Duke Medical Center

http://www.medscape.com/viewarticle/823352?nlid=54703_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

Medscape Medical News from the

This coverage is not sanctioned by, nor a part of, the American College of Cardiology.

Bivalirudin Bleeding? More Questions: NAPLES III, BRAVE 4, and BRIGHT

April 04, 2014

RELATED LINKS
  • DRUG & REFERENCE INFORMATION

WASHINGTON, DC — There are mounting questions over whether bivalirudin (Angiomax, the Medicines Company) does indeed reduce major bleeding in the setting of contemporary primary PCI, compared with unfractionated heparin (UFH), without routine GPIIb/IIIa inhibition and when newer antiplatelet drugs are used. Presented at the American College of Cardiology 2014 Scientific Sessions earlier this week, controversial results from the large, single-center, randomized HEAT-PPCI trial showed no differences in bleeding but an increase in stent thrombosis with bivalirudin compared with heparin, when GPIIb/IIIa inhibitors were used just for bailout in both arms.

Two other trials, also presented at ACC 2014, appear to support those controversial findings: NAPLES III and BRAVE 4. A third trial, BRIGHT, presented in China, however, went in the other direction.

BRAVE 4 Results

BRAVE 4, like HEAT-PPCI, was a primary-PCI trial, designed to demonstrate that the “synergistic effects” of prasugrel (Effient, Lily/Daiichi-Sankyo) plus bivalirudin on ischemic events and bleeding complications would be superior to clopidogrel plus UFH in STEMI patients. Senior author Dr Stefanie Schulz(Deutsches Herzzentrum, Munich, Germany) and coauthors (the results were presented by Dr Gert Richardt [Herzzentrum Bad Segeberg, Germany]) chose an end point of net clinical outcome (defined as all-cause death, recurrent MI, unplanned revascularization of the infarct-related artery, definite stent thrombosis, stroke, or major bleeding at 30 days, using theHORIZONS-AMI definition). In one arm, a 60-mg loading dose of prasugrel plus an IV bolus of bivalirudin 0.75 mg/kg was followed by an infusion of 1.75 mg/kg. In the other, clopidogrel was given at 600 mg, then heparin was given as a 70- to 100-IU/kg bolus.

The investigator-initiated trial, conducted at three German centers, was originally designed to enroll over 1200 patients; the trial was stopped early, however, due to slow recruitment, with just 548 patients enrolled. As with HEAT-PPCI, GPIIb/IIIa inhibitors were used only when an operator decided they were needed with either drug. All but one patient underwent a transfemoral PCI.

At 30 days, there were no differences in the rate of primary composite end point. The secondary ischemic end point and secondary bleeding end point were also no different.

“We were not able to demonstrate a difference in net clinical outcome between prasugrel plus bivalirudin and clopidogrel plus heparin in STEMI patients,” Richardt concluded. “Neither the composite of ischemic complications nor bleeding were favorably affected by prasugrel plus bivalirudin. The results, however, must be interpreted [cautiously] in view of the premature termination of the trial.”

To heartwire , study coauthor Dr Robert Byrne noted that the actual event rate in the study was higher than the predicted event rate used for the power calculations in the study design, although these don’t fully compensate for the low patient numbers.

Given the premature discontinuation of the study, “the message we took was that when we use a primary composite end point, we didn’t see any difference between a newer antithrombotic approach with prasugrel and bivalirudin and an older combination, clopidogrel and heparin.”

NAPLES III: Results

In NAPLES III, Dr Carlo Briguori (Clinica Mediterranea, Naples, Italy) and colleagues compared bivalirudin with UFH in 830 elective transfemoral-PCI patients deemed to be at a high risk of bleeding (risk score >10). UFH was given in a bolus of 70 U/kg IV prior to the start of the PCI, followed by 20 U/kg if activated clotting times (ACTs) dropped below 250. Bivalirudin was given at 0.75 mg/kg IV prior to the procedure, followed by an infusion of 1.75 mg/kg per hour for the procedure duration, with additional 0.3 mg/kg if ACTs dropped below 250.

For the primary end point of in-hospital major bleeding (defined according to REPLACE 2 criteria) there were no differences between groups, including no differences by entry-site or non–entry-site bleeds, and no differences using different bleeding definitions. Major and minor bleeds combined were also no different between groups. For a range of secondary end points, including MI, stent thrombosis, and revascularization at both 30 days and one year, no differences emerged.

“In patients at high risk of bleeding undergoing elective PCI through the femoral approach, the use of bivalirudin does not reduce the rate of in-hospital major bleeding compared with UFH,” Briguori concluded.

Entry-site bleeding—seen in two and seven UFH and bivalirudin-treated patients, respectively “still represents an important issue,” he added. “A radial approach should be routinely used in this subgroup of patients.”

BRIGHTer News From China

Speaking with heartwire earlier this week about HEAT-PPCI,Dr Gregg Stone (Columbia University, New York, NY) emphasized that he did not think the results of any single-center randomized trial should inform the guidelines. “They should just be hypothesis-generating,” he said.

“There have been three large multicenter trials testing bivalirudin against heparin or heparin and GPIIb/IIIa inhibitors,” and these have all supported a lower risk of bleeding with bivalirudin.

Stone also flagged another large, “high-quality study” that he only learned about the previous week, while chairing a session at the China Interventional Therapeutics meeting in Shanghai.

According to a copy of the slide set obtained by heartwire , BRIGHT trial enrolled 2194 patients at 82 sites, comparing bivalirudin with heparin alone or heparin plus GPIIb/IIIa inhibitors. At 30 days, net adverse cardiovascular results were significantly reduced in the bivalirudin vs UFH/GPIIb/IIIa-inhibitor arms and narrowly missed being statistically significantly reduced in the bivalirudin vs UFH-monotherapy arms. A similar pattern was seen for all bleeding events, with 50% to 60% reductions in the bivalirudin-treated patients vs the heparin monotherapy and heparin/GPIIb/IIIa-inhibitor groups (p of 0.041 and 0.001, respectively).

The reductions in bleeding compared with both heparin arms are much more “consistent with what we’ve seen in EuroMAX , HORIZONS-AMI , and the registry series,” Stone said.

Why the Bleeds?

Stone, to heartwire , emphasized a point he also made during the HEAT-PPCI trial, that he did not believe the bivalirudin-treated patients were adequately dosed and questioned whether that dose was adjusted for renal insufficiency. One indicator of suboptimal dosing, he said, was the high use of bailout GPIIb/IIIa-inhibitors in HEAT: 13.5% in the bivalirudin-treated patients and 15.5% in the heparin-treated group.

By way of comparison, bailout GPIIb/IIIa inhibitor use was 3% in the prasugrel/bivalirudin group and 6% in the clopidogrel/heparin group in BRAVE 4. It was just 0.5% and 1.3% for the bivalirudin and UFH groups, respectively, in NAPLES III, although that lower use is to be expected in an elective-angioplasty population.

To heartwire , Byrne agreed that the ACC trials have raised questions about the bleeding advantage of bivalirudin in the contemporary PCI setting but stressed that it’s important with all of these trials to focus on the primary outcomes.

That said, “When you look at bleeding in BRAVE 4, as a secondary end point, we also didn’t see a difference.” One explanation, aside from the discretionary use of GPIIb/IIIa inhibitors, may be the use of more potent ADP-receptor antagonists, prasugrel and ticagrelor (Brilinta, AstraZeneca), which may “cancel out the bleeding benefit” of bivalirudin in modern-day PCI. Of note, clopidogrel was used in almost 100% of patients in BRIGHT.

Byrne says most operators at his institution are primarily using heparin, not bivalirudin, although they’ve only just stopped randomizing patients into BRAVE 4. “We are more comfortable with the lower doses of heparin based on ISAR REACT 3A ,” he noted. Byrne and his colleagues are also already enrolling patients into ISAR-REACT 5 , a 4000-patient trial randomizing ACS patients to heparin plus either ticagrelor or prasugrel. This is another investigator-initiated trial that Byrne notes neither drug maker was interested in funding.

Byrne, Richardt, and Briguori all disclosed having no conflicts of interest in their presentations. Stone was the PI for HORIZONS-AMI, for which he disclosed consulting fees and grant support from the Medicines Company, and ACUITY, for which he disclosed both consulting and lecturing fees. He currently discloses consulting fees/honoraria from Reva, Guided Delivery Systems, Velomedix, Osprey, Inspire MD, Miracor, CSI, Eli Lilly/Daiichi Sankyo, and Boston Scientific; holding a partnership/principal in Access Closure, Biostar I and II funds, Micardia, VNT, Medfocus I, II, and Accelerati funds, Arstasis, and Caliber; and research grants from InfraReDx and TherOx.

 

 

SOURCE

http://www.medscape.com/viewarticle/823119?nlid=53983_2562&src=wnl_edit_medp_card&uac=93761AJ&spon=2

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Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Posted in Coagulation Therapy and Internal Bleeding on February 4, 2014| Leave a Comment »

Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Reporter: Aviva Lev-Ari, PhD, RN

 

UPDATED on 4/28/2014

A pharmacogenetic versus a clinical algorithm for warfarin dosing.

N Engl J Med. 2013 Dec 12;369(24):2283-93. doi: 10.1056/NEJMoa1310669. Epub 2013 Nov 19.

Kimmel SE1, French B, Kasner SE, Johnson JA, Anderson JL, Gage BF, Rosenberg YD, Eby CS, Madigan RA, McBane RB, Abdel-Rahman SZ, Stevens SM,Yale S, Mohler ER 3rd, Fang MC, Shah V, Horenstein RB, Limdi NA, Muldowney JA 3rd, Gujral J, Delafontaine P, Desnick RJ, Ortel TL, Billett HH, Pendleton RC, Geller NL, Halperin JL, Goldhaber SZ, Caldwell MD, Califf RM, Ellenberg JH; COAG Investigators.

Collaborators (198)

Author information

Abstract

BACKGROUND:

The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.

METHODS:

We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.

RESULTS:

At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], -0.2; 95% confidence interval, -3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.

CONCLUSIONS:

Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

(Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.).

Comment in

SOURCE 

http://www.ncbi.nlm.nih.gov/pubmed/24251361

What is the clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin?

“Anticoagulation Control” defined: higher percentage of time in the therapeutic INR range than was standard dosing. It was achieved in an European Study and not conferred in an American Study, see below the two studies.

 

A Randomized Trial of Genotype-Guided Dosing of Warfarin

Munir Pirmohamed, Ph.D., F.R.C.P., Girvan Burnside, Ph.D., Niclas Eriksson, Ph.D., Andrea L. Jorgensen, Ph.D., Cheng Hock Toh, M.D., Toby Nicholson, F.R.C.Path., Patrick Kesteven, M.D., Christina Christersson, M.D., Ph.D., Bengt Wahlström, M.D., Christina Stafberg, M.D., J. Eunice Zhang, Ph.D., Julian B. Leathart, M.Phil., Hugo Kohnke, M.Sc., Anke H. Maitland-van der Zee, Pharm.D., Ph.D., Paula R. Williamson, Ph.D., Ann K. Daly, Ph.D., Peter Avery, Ph.D., Farhad Kamali, Ph.D., and Mia Wadelius, M.D., Ph.D. for the EU-PACT Group

N Engl J Med 2013; 369:2294-2303 December 12, 2013DOI: 10.1056/NEJMoa1311386

BACKGROUND

The level of anticoagulation in response to a fixed-dose regimen of warfarin is difficult to predict during the initiation of therapy. We prospectively compared the effect of genotype-guided dosing with that of standard dosing on anticoagulation control in patients starting warfarin therapy.

METHODS

We conducted a multicenter, randomized, controlled trial involving patients with atrial fibrillation or venous thromboembolism. Genotyping for CYP2C9*2, CYP2C9*3, and VKORC1 (−1639G→A) was performed with the use of a point-of-care test. For patients assigned to the genotype-guided group, warfarin doses were prescribed according to pharmacogenetic-based algorithms for the first 5 days. Patients in the control (standard dosing) group received a 3-day loading-dose regimen. After the initiation period, the treatment of all patients was managed according to routine clinical practice. The primary outcome measure was the percentage of time in the therapeutic range of 2.0 to 3.0 for the international normalized ratio (INR) during the first 12 weeks after warfarin initiation.

RESULTS

A total of 455 patients were recruited, with 227 randomly assigned to the genotype-guided group and 228 assigned to the control group. The mean percentage of time in the therapeutic range was 67.4% in the genotype-guided group as compared with 60.3% in the control group (adjusted difference, 7.0 percentage points; 95% confidence interval, 3.3 to 10.6; P<0.001). There were significantly fewer incidences of excessive anticoagulation (INR ≥4.0) in the genotype-guided group. The median time to reach a therapeutic INR was 21 days in the genotype-guided group as compared with 29 days in the control group (P<0.001).

CONCLUSIONS

Pharmacogenetic-based dosing was associated with a higher percentage of time in the therapeutic INR range than was standard dosing during the initiation of warfarin therapy.

(Funded by the European Commission Seventh Framework Programme and others; ClinicalTrials.gov number, NCT01119300.)

SOURCE

A Pharmacogenetic versus a Clinical Algorithm for Warfarin Dosing

Stephen E. Kimmel, M.D., Benjamin French, Ph.D., Scott E. Kasner, M.D., Julie A. Johnson, Pharm.D., Jeffrey L. Anderson, M.D., Brian F. Gage, M.D., Yves D. Rosenberg, M.D., Charles S. Eby, M.D., Rosemary A. Madigan, R.N., M.P.H., Robert B. McBane, M.D., Sherif Z. Abdel-Rahman, Ph.D., Scott M. Stevens, M.D., Steven Yale, M.D., Emile R. Mohler, III, M.D., Margaret C. Fang, M.D., Vinay Shah, M.D., Richard B. Horenstein, M.D., Nita A. Limdi, Pharm.D., Ph.D., James A.S. Muldowney, III, M.D., Jaspal Gujral, M.B., B.S., Patrice Delafontaine, M.D., Robert J. Desnick, M.D., Ph.D., Thomas L. Ortel, M.D., Ph.D., Henny H. Billett, M.D., Robert C. Pendleton, M.D., Nancy L. Geller, Ph.D., Jonathan L. Halperin, M.D., Samuel Z. Goldhaber, M.D., Michael D. Caldwell, M.D., Ph.D., Robert M. Califf, M.D., and Jonas H. Ellenberg, Ph.D. for the COAG Investigators

N Engl J Med 2013; 369:2283-2293 December 12, 2013DOI: 10.1056/NEJMoa1310669

BACKGROUND

The clinical utility of genotype-guided (pharmacogenetically based) dosing of warfarin has been tested only in small clinical trials or observational studies, with equivocal results.

METHODS

We randomly assigned 1015 patients to receive doses of warfarin during the first 5 days of therapy that were determined according to a dosing algorithm that included both clinical variables and genotype data or to one that included clinical variables only. All patients and clinicians were unaware of the dose of warfarin during the first 4 weeks of therapy. The primary outcome was the percentage of time that the international normalized ratio (INR) was in the therapeutic range from day 4 or 5 through day 28 of therapy.

RESULTS

At 4 weeks, the mean percentage of time in the therapeutic range was 45.2% in the genotype-guided group and 45.4% in the clinically guided group (adjusted mean difference, [genotype-guided group minus clinically guided group], −0.2; 95% confidence interval, −3.4 to 3.1; P=0.91). There also was no significant between-group difference among patients with a predicted dose difference between the two algorithms of 1 mg per day or more. There was, however, a significant interaction between dosing strategy and race (P=0.003). Among black patients, the mean percentage of time in the therapeutic range was less in the genotype-guided group than in the clinically guided group. The rates of the combined outcome of any INR of 4 or more, major bleeding, or thromboembolism did not differ significantly according to dosing strategy.

CONCLUSIONS

Genotype-guided dosing of warfarin did not improve anticoagulation control during the first 4 weeks of therapy.

(Funded by the National Heart, Lung, and Blood Institute and others; COAG ClinicalTrials.gov number, NCT00839657.)

SOURCE

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

 

Pharmocogenomics is a Multidirectional Street

Demet Sag, PhD

http://pharmaceuticalintelligence.com/2014/04/28/pharmocogenomics-is-a-multidirectional-street/

 

Pharmacogenomics – A New Method for Druggability

Demet Sag, PhD

http://pharmaceuticalintelligence.com/2014/04/28/pharmacogenomics-a-new-method-for-druggability/

 

Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/02/04/is-pharmacogenetic-based-dosing-of-warfarin-superior-for-anticoagulation-control/

 

Clinical Trials on Bivalirudin: Questions on Bleeding and Outcomes

Aviva Lev-Ari, PhD, RN

http://pharmaceuticalintelligence.com/2014/04/08/acc-2014-clinical-trials-on-bivalirudin-questions-on-bleeding-and-outcomes/

 

 

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Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Posted in Atherogenic Processes & Pathology, Best evidence, Biological Networks, Gene Regulation and Evolution, Biomarkers & Medical Diagnostics, Ca2+ triggered activation, Calcium Signaling, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Congenital Heart Disease, Curation, Cytoskeleton, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Experimental validation, Explanatory, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Human Immune System in Health and in Disease, Immunodiagnostics, International Global Work in Pharmaceutical, Medical and Population Genetics, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Nutrigenomics, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Research, Translational Science, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , on January 6, 2014| Leave a Comment »

Summary of Genomics and Medicine: Role in Cardiovascular Diseases

Author: Larry H. Bernstein, MD, FCAP

The articles within Chapters and Subchapters you have just read have been organized into four interconnected parts.
  1. Genomics and Medicine
  2. Epigenetics – Modifyable Factors Causing CVD
  3. Determinants of CVD – Genetics, Heredity and Genomics Discoveries
  4. Individualized Medicine Guided by Genetics and Genomics Discoveries
The first part established the
  • rapidly evolving science of genomics
  • aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
that have a significant association with the development of
  • cardiovascular diseases,
  • hypercoagulable state,
  • atherosclerosis,
  • microvascular disease,
  • endothelial disruption, and
  • type-2DM, to name a few.
These may well be associated with increased risk for stroke and/or peripheral vascular disease in some cases,
  • essentially because the involvement of the circulation is systemic in nature.

Part 1

establishes an important connection between RNA and disease expression.  This development has led to
  • the necessity of a patient-centric approach to patient-care.
When I entered medical school, it was eight years after Watson and Crick proposed the double helix.  It was also
  • the height of a series of discoveries elucidating key metabolic pathways.
In the period since then there have been treatments for some of the important well established metabolic diseases of
  • carbohydrate,
  • protein, and
  • lipid metabolism,
such as –  glycogen storage disease, and some are immense challenges, such as
  • Tay Sachs, or
  • Transthyretin-Associated amyloidosis.
But we have crossed a line delineating classical Mendelian genetics to
  • multifactorial non-linear traits of great complexity and
involving combinatorial program analyses to resolve.
The Human Genome Project was completed in 2001, and it has opened the floodgates of genomic discovery.  This resulted in the identification of
genomic alterations in
  • cardiovascular disease,
  • cancer,
  • microbial,
  • plant,
  • prion, and
  • metabolic diseases.
This has also led to
  • the identification of genomic targets
  • that are either involved in transcription or
  • are involved with cellular control mechanisms for targeted pharmaceutical development.
In addition, there is great pressure on the science of laboratory analytics to
  • codevelop with new drugs,
  • biomarkers that are indicators of toxicity or
  • of drug effectiveness.
I have not mentioned the dark matter of the genome. It has been substantially reduced, and has been termed dark because
  • this portion of the genome is not identified in transcription of proteins.
However, it has become a lightning rod to ongoing genomic investigation because of
  • an essential role in the regulation of nuclear and cytoplasmic activities.
Changes in the three dimensional structure of these genes due to
  • changes in Van der Waal forces and internucleotide distances lead to
  • conformational changes that could have an effect on cell activity.

Part 2

is an exploration of epigenetics in cardiovascular diseases.  Epigenetics is
  • the post-genomic modification of genetic expression
  • by the substitution of nucleotides or by the attachment of carbohydrate residues, or
  • by alterations in the hydrophobic forces between sequences that weaken or strengthen their expression.
This could operate in a manner similar to the conformational changes just described.  These changes
  • may be modifiable, and they
  • may be highly influenced by environmental factors, such as
    1. smoking and environmental toxins,
    2. diet,
    3. physical activity, and
    4. neutraceuticals.
While neutraceuticals is a black box industry that evolved from
  • the extraction of ancient herbal remedies of agricultural derivation
    (which could be extended to digitalis and Foxglove; or to coumadin; and to penecillin, and to other drugs that are not neutraceuticals).

The best examples are the importance of

  • n-3 fatty acids, and
  • fiber
  • dietary sulfur (in the source of methionine), folic acid, vitamin B12
  • arginine combined with citrulline to drive eNOS
  • and of iodine, which can’t be understated.
In addition, meat consumption involves the intake of fat that contains

  • the proinflammatory n-6 fatty acid.

The importance of the ratio of n-3/n-6 fatty acids in diet is not seriously discussed when

  • we look at the association of fat intake and disease etiology.
Part 2 then leads into signaling pathways and proteomics. The signaling pathways are
  • critical to understanding the inflammatory process, just as
  • dietary factors tie in with a balance that is maintained by dietary intake,
    • possibly gut bacteria utilization of delivered substrate, and
    • proinflammatory factors in disaease.
These are being explored by microfluidic proteomic and metabolomic technologies that were inconceivable a half century ago.
This portion extended into the diagnosis of cardiovascular disease, and
  • elucidated the relationship between platelet-endothelial interaction in the formation of vascular plaque.
It explored protein, proteomic, and genomic markers
  1. for identifying and classifying types of disease pathobiology, and
  2. for following treatment measures.

Part 3

connected with genetics and genomic discoveries in cardiovascular diseases.

Part 4

is the tie between life style habits and disease etiology, going forward with
  • the pursuit of cardiovascular disease prevention.
The presentation of walking and running, and of bariatric surgery (type 2DM) are fine examples.
It further discussed gene therapy and congenital heart disease.  But the most interesting presentations are
  • in the pharmacogenomics for cardiovascular diseases, with
    1. volyage-gated calcium-channels, and
    2. ApoE in the statin response.

This volume is a splendid example representative of the entire collection on cardiovascular diseases.

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Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Posted in Atherogenic Processes & Pathology, Best evidence, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Congenital Heart Disease, Cytoskeleton, Diabetes Mellitus, Diagnostic Immunology, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Evidence-based decision-making, Experimental validation, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, HTN, Human Immune System in Health and in Disease, Immunodiagnostics, Innovation in Immunology Diagnostics, International Global Work in Pharmaceutical, Medical and Population Genetics, Metabolomics, Molecular Genetics & Pharmaceutical, Myocardial metabolism, Myocardial ischemia, myocardial perfusion, Myocardial adenine nucleotide metabolism, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Pre-Clinical Animal Model Development, Proteomics, Regulated Clinical Trials: Design, Methods, Components and IRB related issues, Statistical Methods for Research Evaluation, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Theoretic convergence, Translational Effectiveness, Translational Research, Translational Science, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on January 5, 2014| Leave a Comment »

Introduction to Genomics and Epigenomics Roles in Cardiovascular Diseases

Author and Curator: Larry H Bernstein, MD, FCAP

This introduction is to a thorough evaluation of a rich source of research literature on the genomic influences, which may have variable strength in the biological causation of atherosclerosis, microvascular disease, plaque formation, not necessarily having expressing, except in a multivariable context that includes the environment, dietary factors, level of emotional stress, sleep habits, and the daily activities of living for affected individuals.  The potential of genomics is carried in the DNA, copied to RNA, and this is most well studied in the micro RNAs (miRNA).  The miRNA has been explored for the appearance in the circulation of specific miRNAs that might be associated with myocyte or endothelial cell injury, and they are also being used as targets for therapeutics by the creation of silencing RNAs (siRNA).  The extent to which there is evidence of success in these studies is limited, but is being translated from animal studies to human disease.  There is also a long history of the measurement of  circulating enzymes and isoenzymes (alanine amino transferase, creatine kinase, and lactate dehydrogenase, not to leave out the adenylate kinase species specific to myocardium), and more recently the release of troponins I and T, and the so far still not fully explored ischemia modified albumin, or of miRNAs for the diagnosis of myocardial infarction.

There is also a significant disagreement about the value of measuring high sensitivity C reactive protein (hs-CRP), which has always been a marker for systemic inflammatory disease, in both chronic rheumatic and infectious diseases having a broad range, so that procalcitonin has appeared to be better for that situation, and for early diagnosis of sepsis. The hs-CRP has been too easily ignored because of

1. the ubiquitous elevations in the population
2. the expressed concerns that one might not be inclined to treat a mild elevation without other risk factors, such as, LDL cholesterolemia, low HDL, absent diabetes or obesity.  Nevertheless, hs-CRP raises an reasonable argument for preventive measures, and perhaps the use of a statin.

There has been a substantial amount of work on the relationship of obesity to both type 2 diabetes mellitus (T2DM) and to coronary vascular disease and stroke.  Here we bring in the relationship of the vascular endothelium, adipose tissue secretion of adiponectin, and platelet activation.  A whole generation of antiplatelet drugs addresses the mechanism of platelet activation, adhession, and interaction with endothelium.   Very interesting work has appeared on RESISTIN, that could bear some fruit in the treatment of both obesity and T2DM.

It is important to keep in mind that epigenomic gene rearrangements or substitutions occur throughout life, and they may have an expression late in life.  Some of the known epigenetic events occur with some frequency, but the associations are extremely difficult to pin down, as well as the strength of the association.  In a population that is not diverse, epigenetic changes are passed on in the population in the period of childbearing age.  The establishment of an epigenetic change is diluted in a diverse population.  There have been a number of studies with different findings of association between cardiovascular disease and genetic mutations in the Han and also in the Uyger Chinese populations, which are distinctly different populations that is not part of this discussion.

This should be sufficient to elicit broad appeal in reading this volume on cardiovascular diseases, and perhaps the entire series.  Below is a diagram of this volume in the series.

PART 1 – Genomics and Medicine
Introduction to Genomics and Medicine (Vol 3)
Genomics and Medicine: The Physician’s View
Ribozymes and RNA Machines
Genomics and Medicine: Genomics to CVD Diagnoses
Establishing a Patient-Centric View of Genomic Data
VIDEO:  Implementing Biomarker Programs ­ P Ridker PART 2 – Epigenetics – Modifiable
Factors Causing CVD
Diseases Etiology
   Environmental Contributors
Implicated as Causing CVD
   Diet: Solids and Fluid Intake
and Nutraceuticals
   Physical Activity and
Prevention of CVD
   Psychological Stress and
Mental Health: Risk for CVD
   Correlation between
Cancer and CVD
PART 3  Determinants of CVD – Genetics, Heredity and Genomics Discoveries
Introduction
    Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
     Functional Characterization of CV Genomics: Disease Case Studies @ 2013 ASHG
     Leading DIAGNOSES of CVD covered in Circulation: CV Genetics, 3/2010 – 3/2013
     Commentary on Biomarkers for Genetics and Genomics of CVD
PART 4 Individualized Medicine Guided by Genetics and Genomics Discoveries
    Preventive Medicine: Cardiovascular Diseases
    Walking and Running: Similar Risk Reductions for Hypertension, Hypercholesterolemia,
DM, and possibly CAD
http://pharmaceuticalintelligence.com/2013/04/04/walking-and-running-similar-risk-reductions-for-hypertension-hypercholesterolemia-dm-and-possibly-cad/
    Prevention of Type 2 Diabetes: Is Bariatric Surgery the Solution?
http://pharmaceuticalintelligence.com/2012/08/23/prevention-of-type-2-diabetes-is-bariatric-surgery-the-solution/
Gene-Therapy for CVD
Congenital Heart Disease/Defects
   Medical Etiologies: EBM – LEADING DIAGNOSES, Risks Pharmacogenomics for Cardio-
vascular Diseases
   Signaling Pathways     Response to Rosuvastatin in
Patients With Acute Myocardial Infarction:
Hepatic Metabolism and Transporter Gene
Variants Effect
http://pharmaceuticalintelligence.com/2014/
01/02/response-to-rosuvastatin-in-patients-
with-acute-myocardial-infarction-hepatic-
metabolism-and-transporter-gene-variants-effect/
   Proteomics and Metabolomics      Voltage-Gated Calcium Channel and Pharmaco-
genetic Association with Adverse Cardiovascular
Outcomes: Hypertension Treatment with Verapamil
SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
http://pharmaceuticalintelligence.com/2014/01/02/
voltage-gated-calcium-channel-and-pharmacogenetic-
association-with-adverse-cardiovascular-outcomes-
hypertension-treatment-with-verapamil-sr-ccb-vs-
atenolol-bb-or-trandolapril-ace/
      SNPs in apoE are found to influence statin response
significantly. Less frequent variants in
PCSK9 and smaller effect sizes in SNPs in HMGCR
http://pharmaceuticalintelligence.com/2014/01/02/snps-in-apoe-are-found-to-influence-statin-response-significantly-less-frequent-variants-in-pcsk9-and-smaller-effect-sizes-in-snps-in-hmgcr/

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Diagnostic Value of Cardiac Biomarkers

Posted in Atherogenic Processes & Pathology, Best evidence, Ca2+ triggered activation, Calmodulin Kinase and Contraction, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Coagulation Therapy and Internal Bleeding, Curation, Diabetes Mellitus, Disease Biology, Small Molecules in Development of Therapeutic Drugs, Drug Delivery Platform Technology, Evidence-based decision-making, Evolutionary cognition, Frontiers in Cardiology and Cardiovascular Disorders, Genomic Testing: Methodology for Diagnosis, Immunodiagnostics, Inferential analysis, Medical and Population Genetics, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Molecular Genetics & Pharmaceutical, Nephrology, Nutritional Supplements: Atherogenesis, lipid metabolism, Personalized and Precision Medicine & Genomic Research, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Proteomics, Quality Assurance, Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, tagged , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , on January 4, 2014| Leave a Comment »

Diagnostic Value of Cardiac Biomarkers

Author and Curator: Larry H Bernstein, MD, FCAP 

These presentations covered several views of the utilization of cardiac markers that have evolved for over 60 years.  The first stage was the introduction of enzymatic assays and isoenzyme measurements to distinguish acute hepatitis and acute myocardial infarction, which included lactate dehydrogenase (LD isoenzymes 1, 2) at a time that late presentation of the patient in the emergency rooms were not uncommon, with the creatine kinase isoenzyme MB declining or disappeared from the circulation.  The world health organization (WHO) standard definition then was the presence of two of three:

1. Typical or atypical precordial pressure in the chest, usually with radiation to the left arm

2. Electrocardiographic changes of Q-wave, not previously seen, definitive; ST- elevation of acute myocardial injury with repolarization;
T-wave inversion.

3. The release into the circulation of myocardial derived enzymes –
creatine kinase – MB (which was adapted to measure infarct size), LD-1,
both of which were replaced with troponins T and I, which are part of the actomyosin contractile apparatus.

The research on infarct size elicited a major research goal for early diagnosis and reduction of infarct size, first with fibrinolysis of a ruptured plaque, and this proceeded into the full development of a rapidly evolving interventional cardiology as well as cardiothoracic surgery, in both cases, aimed at removal of plaque or replacement of vessel.  Surgery became more imperative for multivessel disease, even if only one vessel was severely affected.

So we have clinical history, physical examination, and emerging biomarkers playing a large role for more than half a century.  However, the role of biomarkers broadened.  Patients were treated with antiplatelet agents, and a hypercoagulable state coexisted with myocardial ischemic injury.  This made the management of the patient reliant on long term followup for Warfarin with the international normalized ratio (INR) for a standardized prothrombin time (PT), and reversal of the PT required transfusion with thawed fresh frozen plasma (FFP).  The partial thromboplastin test (PPT) was necessary in hospitalization to monitor the heparin effect.

Thus, we have identified the use of traditional cardiac biomarkers for:

1. Diagnosis
2. Therapeutic monitoring

The story is only the beginning.  Many patients who were atypical in presentation, or had cardiovascular ischemia without plaque rupture were problematic.  This led to a concerted effort to redesign the troponin assays for high sensitivity with the concern that the circulation should normally be free of a leaked structural marker of myocardial damage. But of course, there can be a slow leak or a decreased rate of removal of such protein from the circulation, and the best example of this would be the patient with significant renal insufficiency, as TnT is clear only through the kidney, and TNI is clear both by the kidney and by vascular endothelium.  The introduction of the high sensitivity assay has been met with considerable confusion, and highlights the complexity of diagnosis in heart disease.  Another test that is used for the diagnosis of heart failure is in the class of natriuretic peptides (BNP, pro NT-BNP, and ANP), the last of which has been under development.

While there is an exponential increase in the improvement of cardiac devices and discovery of pharmaceutical targets, the laboratory support for clinical management is not mature.  There are miRNAs that may prove valuable, matrix metalloprotein(s), and potential endothelial and blood cell surface markers, they require

1. codevelopment with new medications
2. standardization across the IVD industry
3. proficiency testing applied to all laboratories that provide testing
4. the measurement  on multitest automated analyzers with high capability in proteomic measurement  (MS, time of flight, MS-MS)

nejmra1216063_f1 Atherosclerotic Plaques Associated with Various Presentations               nejmra1216063_f2 Inflammatory Pathways Predisposing Coronary Arteries to Rupture and Thrombosis.        atherosclerosis progression

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Genomics and Medicine: The Physician’s View

Posted in Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, CANCER BIOLOGY & Innovations in Cancer Therapy, Cardiomyopathy, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cerebrovascular and Neurodegenerative Diseases, Coagulation Therapy and Internal Bleeding, Evidence-based decision-making, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Expression, Genomic Testing: Methodology for Diagnosis, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, HealthCare IT, Hematopoiesis, Infectious Disease & New Antibiotic Targets, Infectious Disease Immunodiagnostics, Innovation in Immunology Diagnostics, Liver & Digestive Diseases Research, Medical and Population Genetics, Molecular Genetics & Pharmaceutical, Myelodysplasia, Myelofibrosis, Neurodegenerative Diseases, Origins of Cardiovascular Disease, Personalized and Precision Medicine & Genomic Research, Pharmaceutical Analytics, Pharmaceutical R&D Investment, Pharmacogenomics, Pharmacologic toxicities, Population Health Management, Genetics & Pharmaceutical, Pre-Clinical Animal Model Development, Prescription Drugs Costs, Regenerative Biology and Medicine, Stem Cells for Regenerative Medicine, Translational Effectiveness, Translational Science, tagged , , , , , , , , , , , , on January 3, 2014| Leave a Comment »

Genomics and Medicine: The Physician’s View

Author and Curator: Larry H. Bernstein, MD, FCAP

 

Genomics has had a rapid growth of research into variability of human genetics in both healthy populations in the study of population migration, and in the study of genetic sequence alterations that may increase the risk of expressed human disease.  This is the case for cardiology, cancer, inflammtory conditions, and gastrointestinal diseases. For the most part, genomics research in the last decade has shed light on potential therapeutic targets, but the identification of drug toxicities in late phase trials has been associated with a 70 percent failure rate in bringing new drugs to the market.   Despite good technologies for investigative studies, initial work is carried out on animals and then the transferrability of the work from a “model” to man has to be assured.  That is the first issue of concern.

Secondly, there is a well considered reluctance on the part of experienced and well prepared physicians to be “early” adopters to newly introduced drugs, with the apprehension that unidentified clinical problems can be expected to be unmasked.  It is, however, easier to consider when a new drug belongs to an established class of medications, and it has removed known adverse effects.  In this case, the adverse effects are known side effects, but not necessarily serious drug reactions that would preclude use.

A third consideration is the cost of drug development, and the cost of development is passed on to the healthcare organization in the purchasing cost. We can rest assured that the Pharmacy and Therapeutics Review Committee will not cease meeting on a regular schedule anytime soon.  Further, how do the drug failures become embedded in the cost of the pharmaceutical budget passed on to the recipient.  Historically, insurance is an actuarial discipline.  But in the lifetime of an individual, they are bound to see a physician for acute or chronic medical attention.  Only the timing cannot be predicted.  As a result, dealing with the valid introduction of new medications is a big concern for both the public and the private insurer.

How does this compute for the physician provider.  The practice of medicine is not quickly adaptive, as the physician’s primary concern is to do no harm.   Genomics testing is not widely available, and it is for the most part not definitive for diagnostic purposes as things stand today.  It may provide assessment of risk, or of survival expectation.  The physician uses a step by step assessment, using the patient and family history, a focused physical exam, laboratory and radiology, proceeding to other more specialized exams.  Much of the laboratory testing is based on the appearance in the circulation of changes in blood chemistry of the nature of electrolytes, circulating cells in the blood and of the blood forming organ, proteins, urea and uric acid.  They are not exquisitely sensitive, but they might be sufficient for their abnormal concentrations appearing at the time the patient presents with a complaint. What tests are ordered is determioned by a need for relevant information to make a medical decision.

The relevant questions are:

1. acuity of symptoms and signs.
2. actions to be taken.
3. tests that are needed to clarify the examination findings.

once a provisional diagnosis is obtained, referrals, additional testing, and medication orders are provided based on the assessment.

Where does genetic testing fit into this? At this point, it will only be used

  1. to confirm a restricted list of diagnoses that have a high association with the condition, and
  2. only with the participation of a medical geneticist, when
  3. profiling the patient and other members of the family is required.

10d0de1 Vitruvian Man by Leonardo da Vinci

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The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Posted in Accountable Care Organizations, Affordable Care Act, Anemia, Atherogenic Processes & Pathology, Best evidence, Bio Instrumentation in Experimental Life Sciences Research, Biomarkers & Medical Diagnostics, Biomedical Measurement Science, Ca2+ triggered activation, Ca2+ triggered activation, Calcium Signaling, Cardiac & Vascular Repair Tools Subsegment, Cardiac and Cardiovascular Surgical Procedures, Cardiac muscle regeneration, Cardiomyopathy, Cardiovascular Pharmacogenomics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, Curation, Curation methodology, Cytoskeleton, Diabetes Mellitus, Electrophysiology, Evidence-based decision-making, Experimental validation, Federal Budget Appropriations, Frontiers in Cardiology and Cardiovascular Disorders, Health Economics and Outcomes Research, Health Law & Patient Safety, Healthcare costs and reimbursement, Healthcare Reform, Historical relevance, HTN, HTN in Youth, Indigent Nutrition, Interviews with Scientific Leaders, Ionic Transporters Na+, K, Medical Devices R&D and Inventions, Medical Imaging Technology, Image Processing/Computing, MRI, CT, Nuclear Medicine, Ultra Sound, Medicare and Medicaid, Na-K transport, Na-K-ATPase, Nephrology, Nitric Oxide in Health and Disease, Nutrition, Nutritional Supplements: Atherogenesis, lipid metabolism, Origins of Cardiovascular Disease, Pharmaceutical Analytics, Pharmacogenomics, Pharmacologic toxicities, Pharmacotherapy of Cardiovascular Disease, Population Health Management, Genetics & Pharmaceutical, Population Health Management, Nutrition and Phytochemistry, Prescription Drugs Costs, Regenerative Biology and Medicine, Resident-cell-based, Skilled Nursing Facilities, Stem Cells for Regenerative Medicine, Stents & Tools, Synaptic vesicle, Systematic Error (Bias), Systemic Inflammatory Response Related Disorders, Technology Advance Assessment of, Technology Capital Expenses, Technology Transfer: Biotech and Pharmaceutical, Translational Effectiveness, Translational Science, Uninsured and Underinsured, Valves & Tools, tagged , , , , , , , , , , , , , , , , , , , , , , , , , on January 1, 2014| Leave a Comment »

The Cost to Value Conundrum in Cardiovascular Healthcare Provision

Author: Larry H. Bernstein, MD, FCAP

Article ID #98: The Cost to Value Conundrum in Cardiovascular Healthcare Provision. Published on 1/1/2014

WordCloud Image Produced by Adam Tubman

I write this introduction to Volume 2 of the e-series on Cardiovascular Diseases, which curates the basic structure and physiology of the heart, the vasculature, and related structures, e.g., the kidney, with respect to:

1. Pathogenesis
2. Diagnosis
3. Treatment

Curation is an introductory portion to Volume Two, which is necessary to introduce the methodological design used to create the following articles. More needs not to be discussed about the methodology, which will become clear, if only that the content curated is changing based on success or failure of both diagnostic and treatment technology availability, as well as the systems needed to support the ongoing advances.  Curation requires:

  • meaningful selection,
  • enrichment, and
  • sharing combining sources and
  • creation of new synnthesis

Curators have to create a new perspective or idea on top of the existing media which supports the content in the original. The curator has to select from the myriad upon myriad options available, to re-share and critically view the work. A search can be overwhelming in size of the output, but the curator has to successfully pluck the best material straight out of that noise.

Part 1 is a highly important treatment that is not technological, but about the system now outdated to support our healthcare system, the most technolog-ically advanced in the world, with major problems in the availability of care related to economic disparities.  It is not about technology, per se, but about how we allocate healthcare resources, about individuals’ roles in a not full list of lifestyle maintenance options for self-care, and about the important advances emerging out of the Affordable Care Act (ACA), impacting enormously on Medicaid, which depends on state-level acceptance, on community hospital, ambulatory, and home-care or hospice restructuring, which includes the reduction of management overhead by the formation of regional healthcare alliances, the incorporation of physicians into hospital-based practices (with the hospital collecting and distributing the Part B reimbursement to the physician, with “performance-based” targets for privileges and payment – essential to the success of an Accountable Care Organization (AC)).  One problem that ACA has definitively address is the elimination of the exclusion of patients based on preconditions.  One problem that has been left unresolved is the continuing existence of private policies that meet financial capabilities of the contract to provide, but which provide little value to the “purchaser” of care.  This is a holdout that persists in for-profit managed care as an option.  A physician response to the new system of care, largely fostered by a refusal to accept Medicaid, is the formation of direct physician-patient contracted care without an intermediary.

In this respect, the problem is not simple, but is resolvable.  A proposal for improved economic stability has been prepared by Edward Ingram. A concern for American families and businesses is substantially addressed in a macroeconomic design concept, so that financial services like housing, government, and business finance, savings and pensions, boosting confidence at every level giving everyone a better chance of success in planning their personal savings and lifetime and business finances.

http://macro-economic-design.blogspot.com/p/book.html

Part 2 is a collection of scientific articles on the current advances in cardiac care by the best trained physicians the world has known, with mastery of the most advanced vascular instrumentation for medical or surgical interventions, the latest diagnostic ultrasound and imaging tools that are becoming outdated before the useful lifetime of the capital investment has been completed.  If we tie together Part 1 and Part 2, there is ample room for considering  clinical outcomes based on individual and organizational factors for best performance. This can really only be realized with considerable improvement in information infrastructure, which has miles to go.  Why should this be?  Because for generations of IT support systems, they are historically focused on billing and have made insignificant inroads into the front-end needs of the clinical staff.

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Platelet Endothelial Aggregation Receptor-1 (PEAR1) Gene to be most strongly associated with Dual Antiplatelet Therapy Response: Genetic Determinants of Variable Response to Aspirin (alone and in combination with Clopidogrel)

Posted in Atherogenic Processes & Pathology, Cardiac and Cardiovascular Surgical Procedures, Cardiovascular Pharmacogenomics, Cardiovascular Research, Cell Biology, Signaling & Cell Circuits, Chemical Genetics, Coagulation Therapy and Internal Bleeding, Computational Biology/Systems and Bioinformatics, FDA Regulatory Affairs, Frontiers in Cardiology and Cardiovascular Disorders, Genome Biology, Genomic Testing: Methodology for Diagnosis, HTN, Medical and Population Genetics, Origins of Cardiovascular Disease, PCI, Personalized and Precision Medicine & Genomic Research, Pharmacotherapy of Cardiovascular Disease, Stents & Tools, Valves & Tools, tagged , , , , , , on December 30, 2013| Leave a Comment »

Platelet Endothelial Aggregation Receptor-1 (PEAR1) Gene to be most strongly associated with Dual Antiplatelet Therapy Response: Genetic Determinants of Variable Response to Aspirin (alone and in combination with Clopidogrel)

Reporter: Aviva Lev-Ari, PhD, RN

4 Genetic Variation in PEAR1 is Associated with Platelet Aggregation and Cardiovascular Outcomes

Joshua P. Lewis1, Kathleen Ryan1, Jeffrey R. O’Connell1, Richard B. Horenstein1,Coleen M. Damcott1, Quince Gibson1, Toni I. Pollin1, Braxton D. Mitchell1, Amber L. Beitelshees1, Ruth Pakzy1, Keith Tanner1, Afshin Parsa1, Udaya S. Tantry2, Kevin P. Bliden2, Wendy S. Post3, Nauder Faraday3, William Herzog4, Yan Gong5, Carl J. Pepine6, Julie A. Johnson5, Paul A. Gurbel2 and Alan R. Shuldiner7*

Author Affiliations

1University of Maryland School of Medicine, Baltimore, MD

2Sinai Hospital of Baltimore, Baltimore, MD

3Johns Hopkins University School of Medicine, Baltimore, MD

4Sinai Hospital of Baltimore & Johns Hopkins University School of Medicine, Baltimore, MD

5University of Florida College of Pharmacy, Gainesville, FL

6University of Florida College of Medicine, Gainesville, FL

7University of Maryland School of Medicine & Veterans Administration Medical Center, Baltimore, MD

↵* University of Maryland School of Medicine & Veterans Administration Medical Center, Baltimore, MD ashuldin@medicine.umaryland.edu

Abstract

Background-Aspirin or dual antiplatelet therapy (DAPT) with aspirin and clopidogrel is standard therapy for patients at increased risk for cardiovascular events. However, the genetic determinants of variable response to aspirin (alone and in combination with clopidogrel) are not known.

Methods and Results-We measured ex-vivo platelet aggregation before and after DAPT in individuals (n=565) from the Pharmacogenomics of Antiplatelet Intervention (PAPI) Study and conducted a genome-wide association study (GWAS) of drug response. Significant findings were extended by examining genotype and cardiovascular outcomes in two independent aspirin-treated cohorts: 227 percutaneous coronary intervention (PCI) patients, and 1,000 patients of the International VErapamil SR/trandolapril Study (INVEST) GENEtic Substudy (INVEST-GENES). GWAS revealed a strong association between single nucleotide polymorphisms on chromosome 1q23 and post-DAPT platelet aggregation. Further genotyping revealed rs12041331 in the platelet endothelial aggregation receptor-1 (PEAR1) gene to be most strongly associated with DAPT response (P=7.66×10-9). In Caucasian and African American patients undergoing PCI, A-allele carriers of rs12041331 were more likely to experience a cardiovascular event or death compared to GG homozygotes (hazard ratio = 2.62, 95%CI 0.96-7.10, P=0.059 and hazard ratio = 3.97, 95%CI 1.10-14.31, P=0.035 respectively). In aspirin-treated INVEST-GENES patients, rs12041331 A-allele carriers had significantly increased risk of myocardial infarction compared to GG homozygotes (OR=2.03, 95%CI 1.01-4.09, P=0.048).

Conclusions – Common genetic variation in PEAR1 may be a determinant of platelet response and cardiovascular events in patients on aspirin, alone and in combination with clopidogrel.

Clinical Trial Registration Information-clinicaltrials.gov; Identifiers:NCT00799396 and NCT00370045

SOURCE:

http://www.ncbi.nlm.nih.gov/pubmed/23392654

http://circgenetics.ahajournals.org/content/6/2/184.short?rss=1

Circulation: Cardiovascular Genetics.2013; 6: 184-192 Published online before print February 7, 2013,doi: 10.1161/​CIRCGENETICS.111.964627

 

 

 

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