Series A: e-Books on Cardiovascular Diseases
Series A Content Consultant: Justin D Pearlman, MD, PhD, FACC
VOLUME THREE
Etiologies of Cardiovascular Diseases:
Epigenetics, Genetics and Genomics
http://www.amazon.com/dp/B018PNHJ84
Larry H Bernstein, MD, FCAP, Senior Editor, Author and Curator
and
Aviva Lev-Ari, PhD, RN, Editor and Curator
Image Source: Google Images
Aviva Lev-Ari, PhD, RN
Editor-in-Chief BioMed e-Series of e-Books
Leaders in Pharmaceutical Business Intelligence, Boston
avivalev-ari@alum.berkeley.edu
Other e-Books in the BioMedicine e-Series
Series A: e-Books on Cardiovascular Diseases
Content Consultant: Justin D Pearlman, MD, PhD, FACC
Volume One: Perspectives on Nitric Oxide
Sr. Editor: Larry Bernstein, MD, FCAP, Editor: Aviral Vatsa, PhD and Content Consultant: Stephen J Williams, PhD
available on Kindle Store @ Amazon.com
http://www.amazon.com/dp/B00DINFFYC
Volume Two: Cardiovascular Original Research: Cases in Methodology Design for Content Co-Curation
Curators: Justin D Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP, Aviva Lev-Ari, PhD, RN
- Causes
- Risks and Biomarkers
- Therapeutic Implications
Volume Three: Etiologies of CVD: Epigenetics, Genetics & Genomics
Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
- Causes
- Risks and Biomarkers
- Therapeutic Implications
Volume Four: Therapeutic Promise: CVD, Regenerative & Translational Medicine
Curators: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
- Causes
- Risks and Biomarkers
- Therapeutic Implications
Volume Five: Pharmaco-Therapies for CVD
Volume Curators: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
- Causes
- Risks and Biomarkers
- Therapeutic Implications
Volume Six: Interventional Cardiology and Cardiac Surgery for Disease Diagnosis and Guidance of Treatment
Volume Curators: Justin D Pearlman, MD, PhD, FACC and Aviva Lev-Ari, PhD, RN
- Causes
- Risks and Biomarkers
- Therapeutic Implications
In addition to the Seven Volumes of SERIES A: Cardiovascular Diseases, Not included in SERIES A is a Three Volume Series by Dr. Pearlman, Editor, on Cardiovascular Diseases, positioned as Academic Textbooks for Training Residents in Cardiology and Texts for CEU Courses in Cardiology [Hardcover, Softcover, e-Books].
- CVD 1: Causes of Cardiovascular Diseases
- CVD 2: Risk Assessment of Cardiovascular Diseases
- CVD 3: Management of Cardiovascular Diseases
- CVD 4: Volume Seven: Cardiac Imaging
Series B: e-Books on Genomics & Medicine
Content Consultant: Larry H Bernstein, MD, FCAP
Volume 1: Genomics and Individualized Medicine
Sr. Editor: Stephen J Williams, PhD
Editors: Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Volume 2: Latest in Genomics Methodologies for Therapeutics: Gene Editing, NGS & BioInformatics, Simulations and the Genome Ontology
Editors: Stephen J Williams, PhD and TBA
Volume 3: Institutional Leadership in Genomics
Editors: Aviva Lev-Ari, PhD, RN and TBA
Series C: e-Books on Cancer & Oncology
Content Consultant: Larry H Bernstein, MD, FCAP
Volume 1: Cancer and Genomics
Sr. Editor: Stephen J Williams, PhD
Editors: Ritu Saxena, PhD, Tilda Barliya, PhD
Volume 2: Cancer Therapies: Metabolic, Genomics, Interventional, Immunotherapy and Nanotechnology in Therapy Delivery
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Guest Authors: Stephen J Williams, PhD, Dror Nir, PhD and Tilda Barliya, PhD, Demet Sag, PhD
Volume 3: Cancer Patients’ Resources on Therapies
Sr. Editor: TBA
Series D: e-Books on BioMedicine
Content Consultant: Larry H Bernstein, MD, FCAP
Volume 1: Metabolic Genomics & Pharmaceutics
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Volume 2: Infectious Diseases
Editor: TBA
Volume 3: Immunology and Therapeutics
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Series E: Patient-centered Medicine
Content Consultant: Larry H Bernstein, MD, FCAP
Volume 1: The VOICES of Patients, HealthCare Providers, Care Givers and Families: Personal Experience with Critical Care and Invasive Medical Procedures
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Volume 2: Medical Scientific Discoveries for the 21st Century & Interviews with Scientific Leaders
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Volume 3: Milestones in Physiology & Discoveries in Medicine and Genomics
Author, Curator and Editor: Larry H Bernstein, MD, FCAP
Volume 4: Medical 3D BioPrinting – The Revolution in Medicine
Our DOMAINS in Scientific Media
I. Pharmaceutical: Biologics, Small Molecules, Diagnostics
II. Life Sciences: Genomics and Cancer Biology
III. Patient-centered Medicine: Focus on #1: Cardiovascular, #2: Cancer, #3: Physiology Metabolomics, Immunology
IV. Biomedicine, BioTech, and MedTech (Medical Devices)
V. HealthCare: Patient-centered Medicine and Personalized/Precision Medicine
Open Access Online Journal
http://www.pharmaceuticalIntelligence.com
is a scientific, medical and business, multi-expert authoring environment for information syndication in several domains of Life Sciences, Medicine, Pharmaceutical and Healthcare Industries, BioMedicine, Medical Technologies & Devices. Scientific critical interpretations and original articles are written by PhDs, MDs, MD/PhDs, PharmDs, Technical MBAs as Experts, Authors, Writers (EAWs) on an Equity Sharing basis.
List of Contributors
Justin D. Pearlman MD ME PhD MA FACC
1.3.3, 2.1.8.5, 2.2.3.2, 2.2.3.3
1.1, 1.3.1, 1.3.3, 1.3.4, 1.4.2, 2.1.2.1, 2.1.2.2, 2.1.2.3, 2.1.3.5, 2.1.4.1, 2.1.5.3, 2.1.5.4, 2.1.6.1, 2.1.6.3, 2.1.6.4, 2.1.6.5, 2.1.7.1, 2.1.7.2, 2.1.7.3, 2.1.7.4, 2.1.7.5, 2.1.8.1, 2.1.8.2, 2.1.8.4, 2.1.8.5, 2.1.8.6, 2.1.8.7, 2.1.8.8, 2.1.8.9, 2.1.8.10, 2.2.1.4, 2.2.2.1, 2.2.2, 2.2.2.3, 2.2.2.4, 2.2.2.5, 2.2.2.6, 2.2.2.10, 2.2.4.7, 2.2.4.8, 2.2.4.10, 2.2.4.11, 2.2.5.1, 2.2.5.2, 2.2.5.4, 2.2.5.5, 2.2.5.6, 2.3.1, 2.3.2, 2.3.3, 2.3.4, 2.3.5, 2.3.6, 2.3.7, 2.3.8, 2.4.2, 2.4.7, 2.4.8, 2.4.12, 2.4.13, 2.5.1, 2.5.2, 3.1.1, 3.3.6.1, 3.3.6.2, 3.3.7.6, 4.4.1, 4.4.2
1.2, 1.3.1, 1.3.2, 1.3.3, 1.3.4, 1.3.5, 1.3.6, 1.4.1, 1.5, 2.1.1.1, 2.1.1.2, 2.1.1.3, 2.1.2.4, 2.1.2.5, 2.1.2.6, 2.1.2.7, 2.1.2.8, 2.1.2.9, 2.1.2.11, 2.1.2.12, 2.1.3.1, 2.1.3.2, 2.1.3.3, 2.1.3.4, 2.1.3.6, 2.1.3.7, 2.1.4.2, 2.1.5.1, 2.1.5.2, 2.1.5.5, 2.1.5.6, 2.1.5.7, 2.1.5.8, 2.1.6.1, 2.1.6.3, 2.1.6.4, 2.1.7.1, 2.1.7.2, 2.1.8.3, 2.1.8.5, 2.1.9.1, 2.2.1.3, 2.2.1.5, 2.2.1.6, 2.2.2.1, 2.2.2.2, 2.2.2.7, 2.2.2.8, 2.2.2.9, 2.2.3.1, 2.2.3.2, 2.2.3.3, 2.2.3.6, 2.2.3.7, 2.2.4.1, 2.2.4.2, 2.2.4.3, 2.2.4.4, 2.2.4.5, 2.2.4.6, 2.2.4.7, 2.2.4.9, 2.2.5.1, 2.2.5.3, 2.2.5.7, 2.3.1, 2.3.5, 2.3.6, 2.3.7, 2.4.1, 2.4.3, 2.4.4, 2.4.6, 2.4.9, 2.4.10, 2.4.11, 2.5.4, 2.5.6, 2.6.1, 2.6.2, 3.3.1.1, 3.3.1.2, 3.3.1.3, 3.3.2.1, 3.3.2.2, 3.3.3.1, 3.3.3.2, 3.3.3.3, 3.3.4.1, 3.3.4.2, 3.3.4.3, 3.3.4.4, 3.3.5.1, 3.3.6.1, 3.3.6.3, 3.3.6.4, 3.3.6.5, 3.3.6.6, 3.3.7.1, 3.3.7.2, 3.3.7.3, 3.3.7.4, 3.3.7.5, 3.3.8.1, 3.3.8.2, 3.3.9.1, 3.3.9.2, 3.3.9.3, 3.3.9.4, 3.3.10.1, 4.2, 4.1.1, 4.5.1, 4.5.2, 4.5.3, 4.5.4, 4.5.5, 4.5.6, 4.5.7
Stephen J Williams, PhD, Author and Curator
1.3.4, 2.3.5, 3.1.1
Tilda Barliya, PhD, Author and Curator
2.6.4
Sudipta Saha, PhD, Author and Curator
2.6.3
Ritu Saxena, PhD, Author and Curator
2.4.5
Manuela Stoicescu, MD, PhD – PI and Author
2.2.3.4, 2.2.3.5
Aviral Vatsa, PhD, Author and Curator
2.4.14
Eric Sobie, PhD – PI and Author, ASSOCIATE PROFESSOR Pharmacology and Systems Therapeutics, Mount Sinai Hospital
2.5.3, 2.5.5
LIST of VIDEOS
- Sandra Aamodt: Why dieting doesn’t usually work (2013)
Talkshttps://archive.org/details/SandraAamodt_2013G
[ourtesy TED Talks]
- Evidence based Medicine: Advocacy on Plant-based Diet and Cardiovascular Wellness
http://www.youtube.com/watch?v=AYTf0z_zVs0
[Courtesy youtube.com]
- Implementing Biomarker Programs Paul Ridker ― GenomeTV
http://toxcafe.com/musicvideo.php?vid=2f6ea79f5
[Courtesy GenomeTV]
electronic Table of Contents (eTOCs)
Introduction to Volume Three
PART 1
Genomics and Medicine
1.1 Genomics and Medicine: The Physician’s View
1.2 Ribozymes and RNA Machines – Work of Jennifer A. Doudna
1.3 Genomics and Medicine: Contributions of Genetics and Genomics to Cardiovascular Disease Diagnoses
1.4 Genomics Orientations for Individualized Medicine, Volume One
1.4.1 CVD Epidemiology, Ethnic subtypes Classification, and Medication Response Variability: Cardiology, Genomics and Individualized Heart Care: Framingham Heart Study (65 y-o study) & Jackson Heart Study (15 y-o study)
1.4.2 What comes after finishing the Euchromatic Sequence of the Human Genome?
1.5 Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data
PART 2
Epigenetics – Modifiable Factors Causing Cardiovascular Diseases
2.1 Diseases Etiology
2.1.1 Environmental Contributors Implicated as Causing Cardiovascular Diseases
2.1.2 Diet: Solids, Fluid Intake and Nutraceuticals
2.1.3 Physical Activity and Prevention of Cardiovascular Diseases
2.1.4 Psychological Stress and Mental Health: Risk for Cardiovascular Diseases
2.1.5 Correlation between Cancer and Cardiovascular Diseases
2.1.6 Medical Etiologies for Cardiovascular Diseases: Evidence-based Medicine – Leading DIAGNOSES of Cardiovascular Diseases, Risk Biomarkers and Therapies
2.1.7 Signaling Pathways
2.1.8 Proteomics and Metabolomics
2.1.9 Sleep and Cardiovascular Diseases
2.2 Assessing Cardiovascular Disease with Biomarkers
2.2.1 Issues in Genomics of Cardiovascular Diseases
2.2.2 Endothelium, Angiogenesis, and Disordered Coagulation
2.2.3 Hypertension BioMarkers
2.2.4 Inflammatory, Atherosclerotic and Heart Failure Markers
2.2.5 Myocardial Markers
2.3 Therapeutic Implications: Focus on Ca(2+) signaling, platelets, endothelium
2.3.1 The Centrality of Ca(2+) Signaling and Cytoskeleton Involving Calmodulin Kinases and Ryanodine Receptors in Cardiac Failure, Arterial Smooth Muscle, Post-ischemic Arrhythmia, Similarities and Differences, and Pharmaceutical Targets
2.3.2 EMRE in the Mitochondrial Calcium Uniporter Complex
2.3.3 Platelets in Translational Research 2: Discovery of Potential Anti-platelet Targets
2.3.4 The Final Considerations of the Role of Platelets and Platelet Endothelial Reactions in Atherosclerosis and Novel Treatments
2.3.5 Nitric Oxide Synthase Inhibitors (NOS-I)
2.3.6 Resistance to Receptor of Tyrosine Kinase
2.3.7 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation
2.3.8 Advanced Topics in Sepsis and the Cardiovascular System at its End Stage
2.4 Comorbidity of Diabetes and Aging
2.4.1 Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients
2.4.2 Pathophysiological Effects of Diabetes on Ischemic-Cardiovascular Disease and on Chronic Obstructive Pulmonary Disease (COPD)
2.4.3 Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)
2.4.4 Mitochondrial Mechanisms of Disease in Diabetes Mellitus
2.4.5 Mitochondria: More than just the “powerhouse of the cell”
2.4.6 Pathophysiology of GLP-1 in Type 2 Diabetes
2.4.7 Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets
2.4.8 CaKMII Inhibition in Obese, Diabetic Mice leads to Lower Blood Glucose Levels
2.4.9 Protein Target for Controlling Diabetes, Fractalkine: Mediator cell-to-cell Adhesion though CX3CR1 Receptor, Released from cells Stimulate Insulin Secretion
2.4.10 Peroxisome proliferator-activated receptor (PPAR-gamma) Receptors Activation: PPARγ transrepression for Angiogenesis in Cardiovascular Disease and PPARγ transactivation for Treatment of Diabetes
2.4.11 CABG or PCI: Patients with Diabetes – CABG Rein Supreme
2.4.12 Reversal of Cardiac Mitochondrial Dysfunction
2.4.13 BARI 2D Trial Outcomes
2.4.14 Overview of new strategy for treatment of T2DM: SGLT2 inhibiting oral antidiabetic agents
2.5 Drug Toxicity and Cardiovascular Diseases
2.5.1 Predicting Drug Toxicity for Acute Cardiac Events
2.5.2 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects
2.5.3 Decoding myocardial Ca2+ signals across multiple spatial scales: A role for sensitivity analysis
2.5.4. Leveraging Mathematical Models to Understand Population Variability in Response to Cardiac Drugs: Eric Sobie, PhD
2.5.5 Exploiting mathematical models to illuminate electrophysiological variability between individuals.
2.5.6 Clinical Effects and Cardiac Complications of Recreational Drug Use: Blood pressure changes, Myocardial ischemia and infarction, Aortic dissection, Valvular damage, and Endocarditis, Cardiomyopathy, Pulmonary edema and Pulmonary hypertension, Arrhythmias, Pneumothorax and Pneumopericardium
2.6 Male and Female Hormonal Replacement Therapy: The Benefits and the Deleterious Effects on Cardiovascular Diseases
2.6.1 Testosterone Therapy for Idiopathic Hypogonadotrophic Hypogonadism has Beneficial and Deleterious Effects on Cardiovascular Risk Factors
2.6.2 Heart Risks and Hormones (HRT) in Menopause: Contradiction or Clarification?
2.6.3 Calcium Dependent NOS Induction by Sex Hormones: Estrogen
2.6.4 Role of Progesterone in Breast Cancer Progression
PART 3
Determinants of Cardiovascular Diseases Genetics, Heredity and Genomics Discoveries
Introduction
3.1 Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
3.1.1 Aneuploidy and Carcinogenesis
3.2 Functional Characterization of Cardiovascular Genomics: Disease Case Studies @ 2013 ASHG
3.3 Leading DIAGNOSES of Cardiovascular Diseases covered in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013
3.3.1: Heredity of Cardiovascular Disorders
3.3.3: Hypertention and Atherosclerosis
3.3.5: Aging: Heart and Genetics
3.3.7: Hyperlipidemia, Hyper Cholesterolemia, Metabolic Syndrome
3.3.8: Stroke and Ischemic Stroke
3.3.9: Genetics and Vascular Pathologies and Platelet Aggregation, Cardiac Troponin T in Serum
3.3.10: Genomics and Valvular Disease
3.4 Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease
PART 4
Individualized Medicine Guided by Genetics and Genomics Discoveries
4.1 Preventive Medicine: Cardiovascular Diseases
4.1.1 Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges
4.2 Gene-Therapy for Cardiovascular Diseases
4.2.1 Genetic Basis of Cardiomyopathy
4.3 Congenital Heart Disease/Defects
4.4 Cardiac Repair: Regenerative Medicine
4.4.1 A Powerful Tool For Repairing Damaged Hearts
4.4.2 Modified RNA Induces Vascular Regeneration After a Heart
4.5 Pharmacogenomics for Cardiovascular Diseases
4.5.1 Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study
4.5.2 Statin-Induced Low-Density Lipoprotein Cholesterol Reduction: Genetic Determinants in the Response to Rosuvastatin
4.5.3 SNPs in apoE are found to influence statin response significantly. Less frequent variants in PCSK9 and smaller effect sizes in SNPs in HMGCR
4.5.4 Voltage-Gated Calcium Channel and Pharmacogenetic Association with Adverse Cardiovascular Outcomes: Hypertension Treatment with Verapamil SR (CCB) vs Atenolol (BB) or Trandolapril (ACE)
4.5.5 Response to Rosuvastatin in Patients With Acute Myocardial Infarction: Hepatic Metabolism and Transporter Gene Variants Effect
4.5.6 Helping Physicians identify Gene-Drug Interactions for Treatment Decisions: New ‘CLIPMERGE’ program – Personalized Medicine @ The Mount Sinai Medical Center
4.5.7 Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?
Summary & Epilogue to Volume Three
PART 1
Genomics and Medicine
Introduction to Volume Three
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
- the ubiquitous elevations in the population
- 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.
1.1: Genomics and Medicine: The Physician’s View
Larry H Bernstein, MD, FCAP
1.2 Ribozymes and RNA Machines – Work of Jennifer A. Doudna
Aviva Lev-Ari, PhD, RN
1.3: Genomics and Medicine: Contributions of Genetics and Genomics to Cardiovascular Disease Diagnoses
Part 3 of this e-Book represents Curations on Genetics and Genomics of Cardiovascular Diseases. In Part 1, Subsection 1.3, a focus on Conduction and Cardiac Contractility is presented.
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Justin Pearlman, MD, PhD, FACC, Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
1.3.4 Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility – Part II
Larry H. Bernstein, MD, FCAP, Stephen Williams, PhD and Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
1.3.6 Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock
Aviva Lev-Ari, PhD, RN
1.4 Genomics Orientations for Individualized Medicine, Volume One
Larry H Bernstein, MD, FCAP, Senior Editor, Stephen J. Williams, PhD, Editor and Aviva Lev-Ari, PhD, RN, Editor and Editor-in-Chief, BioMed E-Book Series
Aviva Lev-Ari, PhD, RN
1.4.2 What comes after finishing the Euchromatic Sequence of the Human Genome?
Larry H Bernstein, MD, FCAP
1.5: Genomics in Medicine – Establishing a Patient-Centric View of Genomic Data
Aviva Lev-Ari, PhD, RN
PART 2
Epigenetics
Modifiable Factors Causing Cardiovascular Diseases
2.1 Disease Etiologies
2.1.1 Environmental Contributors Implicated as Causing Cardiovascular Diseases
- Causes
The Health Consequences of Smoking—50 Years of Progress: A Report of the Surgeon General
Tue, Jan 21, 2014, SurgeonGeneral.gov
This is the 32nd tobacco-related Surgeon General’s report issued since 1964. It highlights 50 years of progress in tobacco control and prevention, presents new data on the health consequences of smoking, and discusses opportunities that can potentially end the smoking epidemic in the United States. Scientific evidence contained in this report supports the following facts:
The century-long epidemic of cigarette smoking has caused an enormous, avoidable public health catastrophe in the United States.
- Since the first Surgeon General’s report on smoking and health was published 50 years ago, more than 20 million Americans have died because of smoking.
- If current rates continue, 5.6 million Americans younger than 18 years of age who are alive today are projected to die prematurely from smoking-related disease.
- Most of the 20 million smoking-related deaths since 1964 have been adults with a history of smoking; however, 2.5 million of those deaths have been among nonsmokers who died from diseases caused by exposure to secondhand smoke.
- More than 100,000 babies have died in the last 50 years from Sudden Infant Death Syndrome, complications from prematurity, complications from low birth weight, and other pregnancy problems resulting from parental smoking.
- The tobacco epidemic was initiated and has been sustained by the tobacco industry, which deliberately misled the public about the risks of smoking cigarettes.
Despite significant progress since the first Surgeon General’s report, issued 50 years ago, smoking remains the single largest cause of preventable disease and death in the United States.
- Smoking rates among adults and teens are less than half what they were in 1964; however, 42 million American adults and about 3 million middle and high school students continue to smoke.
- Nearly half a million Americans die prematurely from smoking each year.
- More than 16 million Americans suffer from a disease caused by smoking.
- On average, compared to people who have never smoked, smokers suffer more health problems and disability due to their smoking and ultimately lose more than a decade of life.
- The estimated economic costs attributable to smoking and exposure to tobacco smoke continue to increase and now approach $300 billion annually, with direct medical costs of at least $130 billion and productivity losses of more than $150 billion a year.
The scientific evidence is incontrovertible: inhaling tobacco smoke, particularly from cigarettes, is deadly. Since the first Surgeon General’s Report in 1964, evidence has linked smoking to diseases of nearly all organs of the body.
- In the United States, smoking causes 87 percent of lung cancer deaths, 32 percent of coronary heart disease deaths, and 79 percent of all cases of chronic obstructive pulmonary disease (COPD).
- One out of three cancer deaths is caused by smoking.
- This report concludes that smoking causes colorectal and liver cancer and increases the failure rate of treatment for all cancers.
- The report also concludes that smoking causes diabetes mellitus, rheumatoid arthritis and immune system weakness, increased risk for tuberculosis disease and death, ectopic (tubal) pregnancy and impaired fertility, cleft lip and cleft palates in babies of women who smoke during early pregnancy, erectile dysfunction, and age-related macular degeneration.
- Secondhand smoke exposure is now known to cause stroke
sin nonsmokers. - This report finds that in addition to causing multiple serious diseases, cigarette smoking diminishes overall health status, impairs immune function, and reduces quality of life.
Smokers today have a greater risk of developing lung cancer than did smokers in 1964.
- Even though today’s smokers smoke fewer cigarettes than those 50 years ago, they are at higher risk of developing lung cancer.
- Changes in the design and composition of cigarettes since the 1950s have increased the risk of adenocarcinoma of the lung, the most common type of lung cancer.
- Evidence suggests that ventilated filters may have contributed to higher risks of lung cancer by enabling smokers to inhale more vigorously, thereby drawing carcinogens contained in cigarette smoke more deeply into lung tissue.
- At least 70 of the chemicals in cigarette smoke are known carcinogens. Levels of some of these chemicals have increased as manufacturing processes have changed.
For the first time, women are as likely to die as men from many diseases caused by smoking.
- Women’s disease risks from smoking have risen sharply over the last 50 years and are now equal to men’s for lung cancer, COPD, and cardiovascular diseases. The number of women dying from COPD now exceeds the number of men.
- Evidence also suggests that women are more susceptible to develop severe COPD at younger ages.
- Between 1959 and 2010, lung cancer risks for smokers rose dramatically. Among female smokers, risk increased 10-fold. Among male smokers, risk doubled.
Proven tobacco control strategies and programs, in combination with enhanced strategies to rapidly eliminate the use of cigarettes and other combustible, or burned, tobacco products, will help us achieve a society free of tobacco-related death and disease.
- The goal of ending tobacco-related death and disease requires additional action.
- Evidence-based tobacco control interventions that are effective continue to be underused. What we know works to prevent smoking initiation and promote quitting includes hard-hitting media campaigns, tobacco excise taxes at sufficiently high rates to deter youth smoking and promote quitting, easy-to-access cessation treatment and promotion of cessation treatment in clinical settings, smoke-free policies, and comprehensive statewide tobacco control programs funded at CDC-recommended levels.
- Death and disease from tobacco use in the United States is overwhelmingly caused by cigarettes and other burned tobacco products. Rapid elimination of their use will dramatically reduce this public health burden.
- New “end-game” strategies have been proposed with the goal of eliminating tobacco smoking. Some of these strategies may prove useful for the United States, particularly reduction of the nicotine yield of tobacco products to non-addictive levels.
SOURCES
- Biomarkrs
- Therapies
2.1.1.3 2014 Winter in New England: The Effect of Record Cold Temperatures on Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN
2.1.2 Diet: Solids, Fluid Intake and Nutraceuticals
- Causes
- Biomarkrs
- Therapies
Diet, Obesity and Weight Management
Larry H Bernstein, MD, FCAP
2.1.2.2 Food Insecurity in Africa and GMOs
Larry H. Bernstein, MD, FCAP
2.1.2.3 Cardiovascular Risk Reduction in Diabetes in Sub-Saharan Africa
Larry H. Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
2.1.2.10 Plant-based Nutrition
Caldwell Esselstyn, MD of the famed Cleveland Clinic gives a FULL 62 minute talk from the 2003 VegSource Healthy Lifestyle Expo.
Dr. Esselstyn’s ongoing 21-year study shows that you CAN reverse heart disease and save your life. Of 20 patients sent home to die by their cardiologists in 1989, every one is still alive and healthy today, and heart-disease free, even though together they had had a total of 63 cardiac events before entering his study.
This talk and many other life-saving presentations are available on DVD from the VegSource store at https://secure2.vegsource.com/catalog/
VIEW VIDEO – Evidence based Medicine: Advocacy on Plant-based Diet and Cardiovascular Wellness
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.1.3 Physical Activity and Prevention of Cardiovascular Diseases
- Causes
- Biomarkrs
- Therapies
2.1.3.1 In Two-thirds of Waking Hours Older Women are Sedentary
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.1.3.3 Cardiac Arrhythmias: A Risk for Extreme Performance Athletes
Aviva Lev-Ari, PhD, RN
2.1.3.4 Preventive Medicine Philosophy: Exercise vs. Drug, IF More of the First THEN Less of the Second
Aviva Lev-Ari, PhD, RN
2.1.3.5 Heart Rate Variability (HRV) as a Tool
Larry H. Bernstein, MD, FCAP
2.1.3.6 Is it Hypertension or Physical Inactivity: Cardiovascular Risk and Mortality – New results in 3/2013
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.1.4 Psychological Stress and Mental Health: Risk for Cardiovascular Diseases
- Causes
- Biomarkrs
2.1.4.1 Burden of Depressive Disorders
Larry H Bernstein, MD, FCAP
- Therapies
2.1.4.2 Voices from the Cleveland Clinic: Five Super Stress-busting Foods
Aviva Lev-Ari, PhD, RN
2.1.5 Correlation between Cancer and Cardiovascular Diseases
- Causes
2.1.5.1 Reuben Shaw, Ph.D., a geneticist and researcher at the Salk Institute: Metabolism Influences Cancer
Aviva Lev-Ari, PhD, RN
2.1.5.2 Heart Tumors: Etiology and Classification
Aviva Lev-Ari, PhD, RN
2.1.5.3 Amyloidosis with Cardiomyopathy
Larry H Bernstein, MD, FACP
- Biomarkrs
2.1.5.4 Stabilizers that prevent Transthyretin-mediated Cardiomyocyte Amyloidotic Toxicity
Larry H. Bernstein, MD, FCAP
2.1.5.5 Cancer Symptom Science: On the Mechanisms underlying the Expression of Cancer-related Symptoms
Aviva Lev-Ari, PhD, RN
- Therapies
Aviva Lev-Ari, PhD, RN
2.1.5.7 Radiation and Chemotherapy Therapy: The Pharmacological Risk for Developing Cardiovascular Disease
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.1.6 Medical Etiologies for Cardiovascular Diseases: Evidence-based Medicine – Leading DIAGNOSES of Cardiovascular Diseases, Risk Biomarkers and Therapies
Material is covering articles in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013. The Diagnoses covered include the following topics – relevant to this discussion
- MicroRNA in Serum as Biomarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
- Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy
- Heredity of Cardiovascular Disorders
Explanations for Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN and Larry H. Bernstein, MD, FCAP
The implications of heredity extend beyond serving as a platform for genetic analysis, influencing diagnosis, prognostication, and treatment of both index cases and relatives, and enabling rational targeting of genotyping resources.
This review covers acquisition of a family history, evaluation of heritability and inheritance patterns, and the impact of inheritance on subsequent components of the clinical pathway.
SOURCE
Circulation: Cardiovascular Genetics.2011; 4: 701-709. http://dx.doi.org/10.1161/CIRCGENETICS.110.959379
2.1.6.2 Large-Scale Candidate Gene Analysis in Whites and African Americans Identifies IL6R Polymorphism in Relation to Atrial Fibrillation – The National Heart, Lung, and Blood Institute’s Candidate Gene Association Resource (CARe) Project
RB Schnabel, KF Kerr, SA Lubitz, EL Alkylbekova, et al.
SOURCE
Circulation: Cardiovascular Genetics.2011; 4: 557-564 http://dx.doi.org/10.1161/CIRCGENETICS.110.959197
2.1.6.3 Genomics-Based Classification
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.1.6.4 Targeting Untargetable Proto-oncogenes
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.1.6.5 Zebrafish Study Tool
Larry H. Bernstein, MD, FCAP
2.1.7 Signaling Pathways
2.1.7.1 Contributions to Cardiomyocyte Interactions and Signaling
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.1.7.2 Leptin Signaling in Mediating the Cardiac Hypertrophy associated with Obesity
Larry H Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.1.7.3 Sensors and Signaling in Oxidative Stress
Larry H. Bernstein, MD, FCAP
2.1.7.4 Inhibition of the Cardiomyocyte-Specific Kinase TNNI3K Oxidative Stress
Larry H Bernstein, MD, FCAP
2.1.7.5 Triggering of Plaque Disruption and Arterial Thrombosis
Larry H Bernstein, MD, FCAP
2.1.8 Proteomics and Metabolomics
2.1.8.1 The Role of Tight Junction Proteins in Water and Electrolyte Transport
Larry H Bernstein, MD, FCAP
2.1.8.2 Selective Ion Conduction
Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
Larry H. Bernstein, MD, FCAP
Larry H Bernstein, MD, FCAP, Aviva Lev-Ari, PhD, RN, Justin Pearlman, MD, PhD, FACC
2.1.8.6 Platelets in Translational Research - Part 1
Larry H Bernstein, MD, FCAP
2.1.8.7 Vegan Diet is Sulfur Deficient and Heart Unhealthy
Larry H Bernstein, MD, FCAP
2.1.8.8 Transthyretin and Lean Body Mass in Stable and Stressed State
Larry H Bernstein, MD, FCAP
2.1.8.9 Effect of Dietary Magnesium Intake on Insulin Resistance
Larry H Bernstein, MD, FCAP
2.1.8.10 Cocoa and Heart
Larry H Bernstein, MD, FCAP
VIDEO: Implementing Biomarker Programs Paul Ridker ― GenomeTV
VIEW VIDEO
http://toxcafe.com/musicvideo.php?vid=2f6ea79f5
(Eugene Braunwald, Prof of Medicine, HMS; Discovered the importance of hsCRP with R Nadai [now editor, Clinical Chemistry]) Headed the trial demonstrating value of hsCRP for patients without cholesterol abnormalities – and recommends use of statins because of risk identified.
Predictive Cardiovascular and Circulation BiomarkersBiomarkers are chemistry analytes measured in plasma, serum or whole blood that potentially identify injury or risk for injury. They may be measured in the laboratory or at the bedside (point of care technology). They may be measured as an enzyme (CK isoenzyme MB), a protein (troponins I & T), or as a micro RNA (miRNA). In the last decade the discovery and use of cardiac biomarkers has moved toward very small quantities, even 100 times below the picogram range using Quanterix Simoa, compared with an enzyme immunoassay.
Biomarkers are indicators of predisposition to, or emerging disease status that may provide diagnosis and also prognosis (flow of knowledge) that can guide therapeutic compensations to prevent or mitigate complications and future adverse events.
2.1.9 Sleep and Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN
2.2 Assessing Cardiovascular Disease with Biomarkers
Introduction on the Diagnostic Value of Cardiac Biomarkers
Larry H Bernstein, MD, FACP
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)
2.2.1 Issues in Genomics of Cardiovascular Diseases – MicroRNA in Serum as Biomarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
2.2.1.1 Increased MicroRNA-1 and MicroRNA-133a Levels in Serum of Patients With Cardiovascular Disease Indicate Myocardial Damage
Y Kuwabara, Koh Ono, T Horie, H Nishi, K Nagao, et al.
SOURCE: Circulation: Cardiovascular Genetics. 2011; 4: 446-454 http://dx.doi.org/10.1161/CIRCGENETICS.110.958975
2.2.1.2 Circulating MicroRNA-208b and MicroRNA-499 Reflect Myocardial Damage in Cardiovascular Disease
MF Corsten, R Dennert, S Jochems, T Kuznetsova, Y Devaux, et al.
SOURCE: Circulation: Cardiovascular Genetics. 2010; 3: 499-506 http://dx.doi.org/10.1161/CIRCGENETICS.110.957415
2.2.1.3 15 Novel Risk Loci for Coronary Artery Disease: found by International Consortium
Aviva Lev-Ari, PhD, RN
2.2.1.4 Biomarkers. Diagnosis and Management
Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.2.2: Endothelium, Angiogenesis, and Disordered Coagulation
2.2.2.1 What is the Role of Plasma Viscosity in Hemostasis and Vascular Disease Risk?
Larry H Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN
2.2.2.2 Special Considerations in Blood Lipoproteins, Viscosity, Assessment and Treatment
Larry H Bernstein, MD, FACP and Aviva Lev-Ari, PhD, RN
Larry H Bernstein, MD, FCAP
2.2.2.4 A future for plasma metabolomics in cardiovascular disease assessment
Larry H Bernstein, MD, FCAP
2.2.2.5 Nitric Oxide Function in Coagulation – Part II
Larry H Bernstein, MD, FACP
2.2.2.6 Nitric Oxide, Platelets, Endothelium and Hemostasis (Coagulation Part II)
Larry H Bernstein, MD, FACP
Aviva Lev-Ari, PhD, RN
Endothelium Inflammatory Biomarkers
2.2.2.8 Cardiovascular Risk: C-Reactive Protein BioMarker and Plasma Fibrinogen
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.2.2.10 Importance of high sensitivity C-reactive protein (hs-CRP)
Larry H Bernstein, MD, FCAP
2.2.3 Hypertension BioMarkers
2.2.3.1 Hypertension – JNC 8 Guideline: Henry R. Black, MD, Michael A. Weber, MD and Raymond R. Townsend, MD
Aviva Lev-Ari, PhD, RN
Justin D. Pearlman, MD, PhD and Aviva Lev-Ari, PhD, RN
2.2.3.3 Hypertension and Vascular Compliance: 2013 Thought Frontier – An Arterial Elasticity Focus
Justin D. Pearlman, MD, PhD and Aviva Lev-Ari, PhD, RN
Plasma Renin Level Reports the Amount of Hormonal Vasoconstriction, which, in excess, can cause Severe Elevation of Blood Pressure.
2.2.3.4 Arterial Hypertension in Young Adults: An Ignored Chronic Problem
Manuela Stoicescu, MD, PhD
2.2.3.5 An Important Marker of Hypertension in Youth
Manuela Stoicescu, MD, PhD
2.2.3.6 IF Elevated Pediatric Blood Pressure THEN High Adult Arterial Stiffness
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.2.4 Inflammatory, Atherosclerotic and Heart Failure Markers
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.2.4.3 Voice from the Cleveland Clinic: On the New Lipid Guidelines and On the ACC/AHA Risk Calculator
Aviva Lev-Ari, PhD, RN
2.2.4.4 Atherogenesis: Predictor of CVD the Smaller and Denser LDL Particles
Aviva Lev-Ari, PhD, RN
2.2.4.5 Recombinant Human Lecithin-Cholesterol Acyltransferase (rhLCAT): New Biomarker for Atherosclerosis
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.2.4.7 The Cardiorenal Syndrome in Heart Failure: Cardiac? Renal? syndrome?
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.2.4.8 Identification of Biomarkers that are Related to the Actin Cytoskeleton
Larry H Bernstein, MD, FCAP
2.2.4.9 Publications on Heart Failure by Prof. William Gregory Stevenson, M.D.
Aviva Lev-Ari, PhD, RN
2.2.4.10 Is there a role for Galectin-3 in the management of heart failure?
Larry H Bernstein, MD, FCAP
2.2.4.11 Natriuretic Peptides in Evaluating Dyspnea and Congestive Heart Failure
Larry H Bernstein, MD, FCAP
2.2.5 Myocardial Markers
2.2.5.1 Dealing with the Use of the High Sensitivity Troponin (hs cTn) Assays
Larry H Bernstein MD FACP and Aviva Lev-Ari, PhD, RN
New assays can measure cardiac Troponin in the single digit range of nanograms per liter (picograms per milliliter). Troponin is a protein that belongs inside heart muscle cells, so elevated levels in blood implicate heart injury. However, healthy patients may have elevated levels, sometimes explainable from slowed renal clearance or cross-reactive antibodies, but often not explained and yet with no evidence of heart attack. There is a bias: health services reward diagnosis of myocardial injury, and Troponin elevation can be declared a “Non-STEMI” myocardial injury or myocardial infarction to earn such credits. Then a “validation” study that looks at hospital discharge diagnosis will see a high predictive value of elevated Troponin and “myocardial injury” which may be circular.
2.2.5.2 Amyloidosis with Cardiomyopathy
Larry H Bernstein, MD, FACP
Amyloidosis inserts abnormal proteins into tissues in the heart, that results in an insidious decline cardiac function marked by increased stiffness (requiring high filling pressures that wet the lungs) and decreased contractility or inotropy (pumping ability). resulting in poor circulation of nutrients to tissues and organs. Amyoloidosis is suspected when imaging shows thickened heart muscle and thickened valves with reduced function, but thickened muscle also occurs as a reaction to incomplete control of elevated blood pressures, as well as by other infiltrative disorders.
Aviva Lev-Ari, PhD, RN
2.2.5.4 More on the Performance of High Sensitivity Troponin T and with Amino Terminal Pro BNP in Diabetes
Larry H. Bernstein, MD, FCAP
2.2.5.5 Recent Insights into the High Sensitivity Troponins for Acute Coronary Syndromes
Larry H Bernstein, MD, FCAP
2.2.5.6 Is there a role for serum copeptin measurement?
Larry H. Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
2.3. Therapeutic Implications: Focus on Ca(2+) signaling, platelets, endothelium
Larry H Bernstein, MD, FCAP, and Aviva Lev-Ari, PhD, RN
2.3.2 EMRE in the Mitochondrial Calcium Uniporter Complex
Larry H. Bernstein, MD, FCAP
2.3.3 Platelets in Translational Research 2: Discovery of Potential Anti-platelet Targets
Larry H. Bernstein, MD, FCAP
Larry H. Bernstein, MD, FCAP
2.3.5 Nitric Oxide Synthase Inhibitors (NOS-I)
Larry H Bernstein, MD, FCAP, Stephen J. Williams, PhD, and Aviva Lev-Ari, PhD, RN
2.3.6 Resistance to Receptor of Tyrosine Kinase
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.3.7 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation
Larry H. Bernstein, MD, FCAP and Aviva Lev-Ari, PhD, RN
2.3.8 Advanced Topics in Sepsis and the Cardiovascular System at its End Stage
Larry H Bernstein, MD, FCAP
2.4 Comorbidity of Diabetes and Aging in Cardiovascular Diseases
- Causes
Aviva Lev-Ari, PhD, RN
Larry H. Bernstein, MD, FCAP
- Biomarkers
2.4.3 Risks of Hypoglycemia in Diabetics with Chronic Kidney Disease (CKD)
Aviva Lev-Ari, PhD, RN
2.4.4 Mitochondrial Mechanisms of Disease in Diabetes Mellitus
Aviva Lev-Ari, PhD, RN
2.4.5 Mitochondria: More than just the “powerhouse of the cell”
Ritu Saxena, PhD
2.4.6 Pathophysiology of GLP-1 in Type 2 Diabetes
Aviva Lev-Ari, PhD, RN
- Therapies
2.4.7 Developments in the Genomics and Proteomics of Type 2 Diabetes Mellitus and Treatment Targets
Larry H Bernstein, MD, FCAP
2.4.8 CaKMII Inhibition in Obese, Diabetic Mice leads to Lower Blood Glucose Levels
Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
2.4.11 CABG or PCI: Patients with Diabetes – CABG Rein Supreme
Aviva Lev-Ari, PhD, RN
2.4.12 Reversal of Cardiac Mitochondrial Dysfunction
Larry H Bernstein, MD, FCAP
2.4.13 BARI 2D Trial Outcomes
Larry H Bernstein, MD, FCAP
2.4.14 Overview of new strategy for treatment of T2DM: SGLT2 inhibiting oral antidiabetic agents
Aviral Vatsa, PhD, MBBS
2.5 Drug Toxicity and Cardiovascular Diseases
The Voice of Content Consultant: Justin D. Pearlman, MD, PhD, FACC
Numerous medications can have toxic effects on the heart. Amphetamines, for example, cause a catechol toxicity cardiomyopathy which can result in severe decrease in the strength of contraction (contractility) measured in imaging as a very low ejection fraction (EF). The development of a large weak heart can occur quite quickly not only from amphetamines but also from endogenous (internal) hormones in response to stress (takotsubo cardiomyopathy, catechol toxicity). Cocaine can cause coronary artery spasms that choke blood supply to the heart, possibly resulting in myocardial infarction (heart attack permanent damage). Chemotherapy medications can weaken the heart also, and commonly that damage is irreversible from fibrosis (diffuse scar formation). A variety of tests may be used to identify cardiac toxicity early in the design and early evaluation of medications.
Keywords: drug toxicity
2.5.1 Predicting Drug Toxicity for Acute Cardiac Events
Larry H Bernstein, MD, FACP
2.5.2 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects
Larry H Bernstein, MD, FACP
Calicium is a mediator of electric and mechanical signaling in the heart and basic metabolism. Excess calcium blocker can cause complete heart block and death, interfere with basic metabolic and motor functions, halt gastrointestinal motility and more. Mathemetical modeling can describe the normal dynamics of calicium movement
2.5.3 Decoding myocardial Ca2+ signals across multiple spatial scales: A role for sensitivity analysis
Eric A. Sobie, PhD
The mathematical models can describe in detail cardiac drug effects and basis for toxicities.
Aviva Lev-Ari, PhD, RN
Whereas mathematical models are often designed to represent the median or general trend, they also may be used to highlight individuality.
2.5.5 Exploiting mathematical models to illuminate electrophysiological variability between individuals.
Eric A. Sobie, PhD
Aviva Lev-Ari, PhD, RN
The Voice of Content Consultant: Justin D. Pearlman, MD, PhD, FACC
Methamphetamines and cocaine are common street drugs with adverse effects on the heart. Teenagers and young adults die from the reversible cardiomyopathy of the catechol-toxic effects which weaken the heart so severely that the stagnant circulation forms blood clots. Normally, each heart beat ejects more than half of the blood in the left ventricle (ejection fraction (EF) >50%) but the editor has cared for patients who dropped their EF below 10% from these drugs. Blood clots in the left ventricle constitute grave danger because simply standing up can dislodge the clot to pass out into circulation to block blood flow to vital tissues. A blood clot to a coronary artery (10% of cardiac output) results in a heart attack (myocardial infarction). A blood clot to the brain results in a stroke (cerebral infarction). A massive stroke or massive heart attack result in death.
Cocaine promotes contraction and spasm of blood vessels, which can choke off blood supply to the heart and cause a myocardial infarction (MI) even without a blood clot. Mose beta-blocker medications are contraindicated in patients who use cocaine. Prescribing a common beta-blocker blood pressure medication, such as metoprolol, for example, increases the risk for a heart attack for a patient who uses cocaine. Exceptions to this rule are carvedilol and acebutelol which have both alpha and beta blocking effects. The reason for the increased risk in cocaine users relates to the fundamental way the body regulates its functions – homeostasis (maintenance of balance of power). The control of blood vessel “tone” (muscle tension modulating blood pressure and circulation) is controlled by a push-pull balance between activities of alpha and beta chemical receptors. Medically blocking just the beta receptors results in “unopposed alpha” which promotes constriction. Medication effects to block a receptor are mitigated by homeostatic feedback.
Say you are a passenger in an airplane who does not want to hear chatter so you put in earplugs. The earplugs act as blockers, analogous to the beta-blocker medication. A fellow passenger who wants your attention determines you are hard of hearing, so he speaks louder. The sound is reduced by the earplugs, but a bit less due to the increase in loudness. That mitigating response is typical in biology. There are multiple regulatory systems which assess status and react, either with positive or negative feedback (accelerators or brakes). Medications do not have unbridled impact, but rather, change begets resistance.
Thus use of a beta-blocker invokes offsetting feedback that stimulates catechol release. The rise in circulating catechols lessens the beta blockade and also overdrives the alpha tone. In combination with cocaine, the risk of vessel spasm and cutoff of blood flow is thereby elevated. Hence, use of beta-blockers without concomittant alpha-blocking is contraindicated in cocaine users.
Cocaine-induced coronary-artery vasoconstriction. [N Engl J Med. 1989] – PubMed – NCBI
Emotional stress, caffeine, hectic lifestyle, behavioural addictions can also cause or contribute to catechol toxicity.
Hence emotional stabilizers can contribute to cardiovascular health.
Lexapro may improve heart health – eMaxHealth
2.6 Male and Female Hormonal Replacement Therapy: The Benefits and the Deleterious Effects on Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN
2.6.2 Heart Risks and Hormones (HRT) in Menopause: Contradiction or Clarification?
Aviva Lev-Ari, PhD, RN
2.6.3 Calcium Dependent NOS Induction by Sex Hormones: Estrogen
Sudipta Saha, Ph.D.
2.6.4 Role of Progesterone in Breast Cancer Progression
Tilda Barliya PhD
PART 3
Determinants of Cardiovascular Diseases
Genetics, Heredity and Genomics Discoveries
Introduction
3.1 Why cancer cells contain abnormal numbers of chromosomes (Aneuploidy)
3.2 Functional Characterization of Cardiovascular Genomics: Disease Case Studies @ 2013 ASHG
All Cardiovascular Disease Cases presented below are described in the link, below
- Human Syndromic Atrioventricular Septal Defect
- Left Ventricular Noncompaction – Model in Zebrafish
- Genetics of Cerebral Small Vessel Disease
- Genetics & Brugada Syndrome
- Mutations, Vasculopathy with Fever and Early Onset Strokes
- Genetics of Atherosclerotic Plaque in Patients with Chronic Coronary Artery Disease
- Genetics of influence IL-18 regulation in patients with Acute Coronary Syndrome
- Thoracic Aortic Aneurysmal Genes
Cardiovascular Genetics: Functional Characterization and Clinical Applications @ 2013 Annual Conference of American Society of Human Genetics in Boston, 10/22-26, 2013
3.3 Leading DIAGNOSES of Cardiovascular Diseases covered in Circulation: Cardiovascular Genetics, 3/2010 – 3/2013
The Diagnoses covered include the following:
- Preventative Cardiology
- MicroRNA in Serum as Bimarker for Cardiovascular Pathologies: acute myocardial infarction, viral myocarditis, diastolic dysfunction, and acute heart failure
- Genetic Determinants of Potassium Sensitivity and Hypertension
- Heart and Aging Research in Genomic Epidemiology: 1700 MIs and 2300 coronary heart disease events among about 29 000 eligible patients
- Genomics of Ventricular arrhythmias, A-Fib, Right Ventricular Dysplasia, Cardiomyopathy
- Genetics of CVD and Hyperlipidemia, Hyper Cholesterolemia, Metabolic Syndrome
- Genetics and Vascular Pathologies and Platelet Aggregation, Cardiac Troponin T in Serum
- Genomics and Valvular Disease
- Heredity of Cardiovascular Disorders Inheritance
SOURCE
Introduction by Larry H. Bernstein, MD, FCAP
The curation of this large amount of material in 10 categories begins with a first chapter on preventative cardiology, which has had much public attention for the last decade. Much of the concern with preventive cardiology has emphasized diet and exercise. There is much to be said about this in articles not yet written. However, there are several decades of research on the amino acid composition of foods, and the essential fatty acids, that indicates an essential balance between proinflammatory and antiinflammatory fatty acids in polyunsaturated fatty acids, and of the harmful effects of saturated fats. There is also much to be said of essential amino acids, and in particular, those essential for methylation processes, and sulfur metabolism.
The next eight chapters are all concerned with genomics in cardiovascular disease. This is in no small part a follow up on the completion of the genetic code in 2003, a seminal event. Let us look at these in clusters.
[1] microRNA in serum is now considered for a biomarker for cardiovascular disease. It can be measured at very low levels, but we don’t yet know where it fits. It might be more revealing once we understand the adaptive mechanism in development of congestive heart failure, renal hypertension, and post-genomic events.
[2] It appears to me that potassium sensitivity and hypertension approached from the genomic side is more complicate. Why is that? The kidney excretes a sodium load and in metabolic acidosis, the serum potassium rises with a metabolic acidemia that can’t be compensated by the respiratory loss of CO2 through the carbonic anhydrase mechanism.
[3] Heart and aging research is a rich area for work on the long term post-genomic changes, and it involves a large population base.
[4][5] The genomics of cardiac dysrrhytmias and cardiomyopathies will open new doors into our understanding of the mechanisms of these diseases, and perhaps find therapeutic targets. There has been a large volume of work on lipid synthesis, the role of the liver in generating apolipoproteins, and this has new answers on the way. The most important feature, not readily accepted is the measurement of particles, which has now been done by a monoclonal antibody. Metabolic syndrome brings together adipose tissue metabolism, endocrine and changes in CRP and IL-1.
[6] Vascular pathologies and coagulation, hyperviscosity has had an enormous increase in intensity of research. The concept of plaque rupture to account for all AMIs is being modified, and the high sensitivity cardio-specific troponins have become the most widely use test.
[7] The genomics of valvular disease fits with the increased surgical procedures for valvular disease related to atheroschlerosis and advent of minimally invasive surgical procedures for the reapir and replacement of valves, procedure called TAVR vs. Openhealrt surgery for valve replacement.
[8] Inherited cardiovascular disease is an older family of disorders, going back to Victor McKusik, and also the “Blue Baby” operation, both at Johns Hopkins.
[9] Pharmacogenomics is a vary active field of investigation and has uncovered inter-individual differences in handling Warfarin as a starter.
3.3.1: Heredity of Cardiovascular Disorders
Aviva Lev-Ari, PhD, RN
3.3.1.2 Common Heart Failure: Clinical Considerations of Heritable Factors
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.2: Myocardial Damage
Aviva Lev-Ari, PhD, RN
3.3.2.2 Myocardial Damage in Cardiovascular Disease: Circulating MicroRNA-208b and MicroRNA-499
Aviva Lev-Ari, PhD, RN
3.3.3: Hypertention and Atherosclerosis
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.3.3 Genetics of Aortic and Carotid Calcification: The Role of Serum Lipids
Aviva Lev-Ari, PhD, RN
3.3.4: Ethnic Variation in Cardiac Structure and Systolic Function
3.3.4.1 Genetics of Hypertension in African Americans – Gene Association Study
Aviva Lev-Ari, PhD, RN
3.3.4.2 Atrial Fibrillation: IL6R Polymorphism in Whites and African Americans
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.5: Aging: Heart and Genetics
Aviva Lev-Ari, PhD, RN
3.3.6: Genetics of Heart Rhythm
3.3.6.1 Genetic Analysis of Atrial Fibrillation
Larry H Bernstein, MD, FCAP and Aviva-Lev Ari, PhD, RN
3.3.6.2 Genetics, Myocardium, and Heart Rhythm
Larry H Bernstein, MD, FCAP
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.6.5 Conduction and Arrhythmias: Genetics and Genomics
Aviva Lev-Ari, PhD, RN
3.3.6.6 Atrioventricular (AV) Conduction Disease (block): Human Mutations affecting the Voltage Clock
Aviva Lev-Ari, PhD, RN
3.3.7: Hyperlipidemia, Hyper Cholesterolemia, Metabolic Syndrome
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.7.3 Resuscitation From Sudden Cardiac Arrest: Common Variation in Fatty Acid Genes
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.7.6 CaKMII Inhibition in Obese, Diabetic Mice leads to Lower Blood Glucose Levels
Larry H Bernstein, MD, FCAP
3.3.8: Stroke and Ischemic Stroke
3.3.8.1 Genomics of Incident Ischemic Stroke Events, Stroke and Cardiovascular Disease
Aviva Lev-Ari, PhD, RN
3.3.8.2 The Role of Sibling Kinship, Sex, and Age of Ischemic Stroke Onset: The Familial Component
Aviva Lev-Ari, PhD, RN
3.3.9: Genetics and Vascular Pathologies and Platelet Aggregation
Aviva Lev-Ari, PhD, RN
3.3.9.2 Abdominal Aortic Aneurysm: Matrix Metalloproteinase-9 Genotype as a Potential Genetic Marker
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
3.3.10: Genomics and Valvular Disease
3.3.10.1 Elastin Arteriopathy: The Genetics of Supravalvular Aortic Stenosis
Aviva Lev-Ari, PhD, RN
3.4 Commentary on Biomarkers for Genetics and Genomics of Cardiovascular Disease
Author: Larry H Bernstein, MD, FCAP
PART 4
Individualized Medicine Guided by Genetics and Genomics Discoveries
4.1 Preventive Medicine: Cardiovascular Diseases
4.1.1 Personal Genomics for Preventive Cardiology Randomized Trial Design and Challenges
Aviva Lev-Ari, PhD, RN
4.2 Gene-Therapy for Cardiovascular Diseases
Aviva Lev-Ari, PhD, RN
Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School
Center for Personalized Genetic Medicine, Partners HealthCare and Harvard Medical School
OLD SOURCE:
NEW SOURCE:
Mass General Brigham Training Program in Precision & Genomic Medicine
https://cgm.massgeneral.org/training-program/
Reporter: Aviva Lev-Ari, PhD, RN
4.2.1 Genetic Basis of Cardiomyopathy
Original gene identification for Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant
McNally E, MacLeod H, Dellefave L. Arrhythmogenic Right Ventricular Dysplasia/Cardiomyopathy, Autosomal Dominant. 2005 Apr 18 [Updated 2009 Oct 13]. In: Pagon RA, Bird TD, Dolan CR, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-.
Summary
Disease characteristics. Autosomal dominant arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) is characterized by progressive fibrofatty replacement of the myocardium that predisposes to ventricular tachycardia and sudden death in young individuals and athletes. It primarily affects the right ventricle; with time, it may also involve the left ventricle. The presentation of disease is highly variable even within families, and affected individuals may not meet established clinical criteria. The mean age at diagnosis is 31 years (±13; range: 4-64 years).
Available from:
http://www.ncbi.nlm.nih.gov/books/NBK1131/
- Unexplained Hypertrophy Panel (LAMP2 & PRKAG2)
- Fabry Disease – GLA Gene Sequencing
- Transthyretin Amyloidosis – TTR Gene Sequencing
Disease Backgrounds
4.2.1.1 Hypertrophic cardiomyopathy (HCM) is characterized by unexplained left ventricular hypertrophy (LVH) in a non-dilated ventricle. With a prevalence estimated to be ~1/500 in the general population, HCM is the most common monogenic cardiac disorder. To date, over 1000 variants have been identified in genes causative of HCM, most of which affect the sarcomere, the contractile unit of the cardiac muscle. In addition, defects in genes involved in storage diseases, such as LAMP2, PRKAG2 and GLA, typically cause systemic disease but may also result in predominant cardiac manifestations, which can mimic hypertrophic cardiomyopathy (HCM). For additional information about HCM, please visit GeneReviews.
4.2.1.2 Dilated cardiomyopathy (DCM) is characterized by ventricular chamber enlargement and systolic dysfunction with normal left ventricular wall thickness. The estimated prevalence of DCM is 1/2,500 and about 20-35% of cases have a family history showing a predominantly autosomal mode of inheritance. To date, over 40 genes have been demonstrated to cause DCM, encoding proteins involved in the sarcomere, Z-disk, nuclear lamina, intermediate filaments and the dystrophin-associated glycoprotein complex. Variants in some genes cause additional abnormalities: LMNA variants are frequently found in DCM that occurs with progressive conduction system disease. Variants in the TAZ gene cause Barth syndrome, an X-linked cardioskeletal myopathy in infants. In addition, variants in several genes (including LMNA, DES, SGCD, TCAP and EMD) can cause DCM in conjunction with skeletal myopathy. For additional information about DCM, please visit GeneReviews.
4.2.1.3 Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is estimated to affect approximately 1/5,000 individuals in the general population, about half of which have a family history. The disease is characterized by replacement of myocytes by fatty or fibrofatty tissue, mainly in the right ventricle. The resulting manifestations are broad and include ventricular tachyarrhythmias and sudden death in young individuals and athletes. ARVC is typically inherited in an autosomal dominant fashion with incomplete penetrance and variable expressivity and to date, 5 ARVC genes (DSP, DSC2, DSG2, PKP2, TMEM43) have been identified, all but one (TMEM43) encode components of the desmosome. For more information about ARVC, please visit GeneReviews.
4.2.1.4 Catecholaminergic polymorphic ventricular tachycardia (CPVT) is typically characterized by exercise induced syncope due to ventricular tachycardia in individuals without structural heart disease. Two CPVT genes are known to date (RYR2 – autosomal dominant; CASQ2 – autosomal recessive). For more information about CPVT, please visit GeneReviews.
4.2.1.5 Left ventricular noncompaction (LVNC) has recently been established as a specific type of cardiomyopathy and is characterized by a spongy appearance of the left ventricular myocardium, resulting from an arrest in normal cardiac development. LVNC can be found in isolation or in association with other cardiomyopathies (HCM, DCM) as well as congenital cardiac abnormalities. The population prevalence is not known but LVNC is reported in ~0.014% of echocardiograms. LVNC is often familial and the genetic spectrum is beginning to emerge although it is not yet well defined. LVNC genes reported to date include ACTC, DTNA, LDB3, MYBPC3, MYH7, TAZ, and TNNT2 (Montserrat 2007, Klaassen 2008; Kaneda 2007, Zaragoza 2007; reviewed in: Maron 2006, Finsterer 2009). For more information about LVNC, please visit OMIM.org.
For any additional information, please contact us at 617-768-8500 or lmm@partners.org.
SOURCE:
http://pcpgm.partners.org/lmm/tests/cardiomyopathy
Genes: 51 genesMethodology: A combination of next generation sequencing technology and Sanger sequencingAnalytical Sensitivity:Substitutions: 100% (95%CI=98.5-100)Small InDels: 95% (95%CI=83-99)Clinical Sensitivity: See below.Additional Links:Genetic Basis of Cardiomyopathy Booklet |
4.3 Congenital Heart Disease/Defects
Medical Diagnosis based on Genetics and Genomics
Price | TAT | CPT Codes | |
Congenital Heart Disease Panel A (GATA4, NKX2-5, JAG1) – lmCHD-pnlA_L | |||
$1,300 | 4 wks | 81479 | |
ELN (Elastin) Gene Sequencing – lmELN-a_L | |||
$1,300 | 4 wks | 81479 | |
GATA4 Gene Sequencing – lmGATA4-a_L | |||
$750 | 3 wks | 81479 | |
JAG1 Gene Sequencing – lmJAG1-a_L | |||
$1,100 | 3 wks | 81407 | |
NKX2-5 Gene Sequencing – lmNKX2-5-a_L | |||
$600 | 3 wks | 81479 |
SOURCE
Genetic Basis of Cardiomyopathy Booklet
Lakdawala NK, Funke BH, Baxter S, Cirino A, Roberts AE, Judge DP, Johnson N, Mendelsohn NJ, Morel C, Care M, Chung WK, Jones C, Psychogios A, Duffy E, Rehm HL, White E, Seidman JG, Seidman CE, Ho CY. Genetic Testing for Dilated Cardiomyopathy in Clinical Practice. J Card Fail. 2012 Apr;18(4):296-303. doi: 10.1016/j.cardfail.2012.01.013. Epub 2012 Feb 15.
http://www.ncbi.nlm.nih.gov/pubmed/22464770
Neri PM, Pollard SE, Volk LA, Newmark L, Varugheese M, Baxter S, Aronson SJ, Rehm HL, Bates DW. Usability of a Novel Clinician Interface for Genetic Results. J Biomed Inform. 2012 Oct;45(5):950-7. doi: 10.1016/j.jbi.2012.03.007. Epub 2012 Apr 12.
4.4 Cardiac Repair: Regenerative Medicine
4.4.1 A Powerful Tool For Repairing Damaged Hearts
Larry H Bernstein, MD, FCAP
4.4.2 Modified RNA Induces Vascular Regeneration After a Heart Attack
Larry H Bernstein, MD, FCAP
4.5 Pharmacogenomics for Cardiovascular Diseases
4.5.1 Blood Pressure Response to Antihypertensives: Hypertension Susceptibility Loci Study
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
Aviva Lev-Ari, PhD, RN
4.5.7 Is Pharmacogenetic-based Dosing of Warfarin Superior for Anticoagulation Control?
Aviva Lev-Ari, PhD, RN
Summary & Epilogue
Volume Three
Larry H Bernstein, MD, FCAP
- Genomics and Medicine
- Epigenetics – Modifyable Factors Causing CVD
- Determinants of CVD – Genetics, Heredity and Genomics Discoveries
- Individualized Medicine Guided by Genetics and Genomics Discoveries
- rapidly evolving science of genomics
- aided by analytical and computational tools for the identification of nucleotide substitutions, or combinations of them
- cardiovascular diseases,
- hypercoagulable state,
- atherosclerosis,
- microvascular disease,
- endothelial disruption, and
- type-2DM, to name a few.
- essentially because the involvement of the circulation is systemic in nature.
Part 1
- the necessity of a patient-centric approach to patient-care.
- the height of a series of discoveries elucidating key metabolic pathways.
- carbohydrate,
- protein, and
- lipid metabolism,
- Tay Sachs, or
- Transthyretin-Associated amyloidosis.
- multifactorial non-linear traits of great complexity and
- cardiovascular disease,
- cancer,
- microbial,
- plant,
- prion, and
- metabolic diseases.
- the identification of genomic targets
- that are either involved in transcription or
- are involved with cellular control mechanisms for targeted pharmaceutical development.
- codevelop with new drugs,
- biomarkers that are indicators of toxicity or
- of drug effectiveness.
- this portion of the genome is not identified in transcription of proteins.
- an essential role in the regulation of nuclear and cytoplasmic activities.
- changes in Van der Waal forces and internucleotide distances lead to
- conformational changes that could have an effect on cell activity.
Part 2
- 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.
- may be modifiable, and they
- may be highly influenced by environmental factors, such as
-
- smoking and environmental toxins,
- diet,
- physical activity, and
- neutraceuticals.
- 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.
- 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.
- 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.
- for identifying and classifying types of disease pathobiology, and
- for following treatment measures
Part 3
Part 4
- the pursuit of cardiovascular disease prevention.
- in the pharmacogenomics for cardiovascular diseases, with
-
- volyage-gated calcium-channels, and
- ApoE in the statin response.
This volume is a splendid example representative of the entire Epigenetics, Genetics and Genomics collection on cardiovascular diseases.
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