Leaders in Pharmaceutical Business Intelligence (LPBI) Group

Four-Volume Series on Cardiovascular Diseases:

Causes, Risks and Management

Dr. Pearlman, MD, PhD, FACC

Editor  

Leaders in Pharmaceutical Business Intelligence (LPBI) Group

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

[Hardcover, Softcover, e-Books].

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

VOLUME ONE

Causes of Cardiovascular Diseases

Justin D. Pearlman MD PhD MA FACC, Editor

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

jdpmdphd@gmail.com

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Other Volumes on Cardiovascular Diseases by same Editor

VOLUME TWO

Risks of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

VOLUME THREE

Management of Cardiovascular Diseases

Justin D. Pearlman MD ME PhD MA FACC, Editor

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VOLUME FOUR

Cardiac Imaging

Justin D. Pearlman MD ME PhD MA FACC, Editor

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Aviva Lev-Ari, PhD, RN

Editor-in-Chief BioMed E-Book Series

Leaders in Pharmaceutical Business Intelligence (LPBI) Group, Boston

avivalev-ari@alum.berkeley.edu

 

Cover image: The editor produced this image by applying dynamic magnetic resonance imaging to a patient with a patent foramen ovale. The 3D reconstruction shows blood movement in chambers of the heart, which includes a narrow funnel of shunt flow between left and right atrial chambers through an opening in a flap of tissue that normally seals a trap door called the foramen ovale. The foramen ovale provides a bypass of the lungs in utero.

List of Contributors

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

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

Articles: 9.4, 9.5, 9.7, 9.8, 9.9

Larry Bernstein, MD, FACP 2.1,2.4, 2.5, 2.6, 2.7, 2.9, 3.1, 3.2, 4.3, 4.4, 4.5, 4.6, 7.1,7.2,7.3, 7.4, 9.15, 9.16

Aviva Lev-Ari, PhD, RN, Editor-in-Chief, BioMed e-Books Series1.1, 1.2, 1.3, 1.4, 1.7, 2.1, 2.2, 2.8, 2.9, 2.10,2.11,2.12,2.14,2.15,2.16, 3.3, 4.1, 4.3, 4.6, 4.7, 4.8, 6.1, 6.2, 6.3, 6.4, 6.5, 7.5, 8.1, 8.2, 8.3,8.4, 8.5

Anamika Sarkar, PhD 4.2

Prabodh Kandala, PhD 2.3, 4.9

Aviral Vatsa, PhD, MBBS 4.3, 6.4

Manuela Stoicescu, MD, PhD 1.5, 1.6

Ritu Saxena, PhD 6.5, 6.6

Stephen J. Williams, PhD 2.13, 3.3, 3.4, 3.5

Eric A. Sobie 3.3, 3.4, 3.5

List of Movies by Chapter

Chapter 1: Atherosclerosis

VIDEO: What is Atherosclerosis? Dr. Prodigious.

VIDEO: What is atherosclerosis? MEDICAL

VIDEO: How cholesterol clogs your arteries (atherosclerosis) — Technicom3D France

VIDEO: Pathophysiology of Atherosclerosis— Dr. Andrew Wolf

VIDEO:Atherosclerosis —

VIDEO:Atherosclerosis – Part 1

VIDEO:Atherosclerosis – Part 2?— MedFlux?— Khan Academy

VIDEO: Biology of progression of atherosclerosis — Ahmad Rusydi Jamaludin

VIDEO: Heart Attack due to Atherosclerosis — Nucleus Medical Media

VIDEO: Atherosclerosis as an inflammatory desease — Nucleus Medical Media

VIDEO: Inflammation In Atherosclerotic Plaque Formation — Medical Sciences Animated Videos

VIDEO: Angina animations —

VIDEO: SpeakFromTheHeart.com

Chapter 2: Genomics and Cardiovascular Diseases

VIDEO: Human Genome Project animation — PVDK

VIDEO: Human Genome Project –Prof. Eric Lander

VIDEO: Human Genome Project II — Prof. Eric Lander

VIDEO: Human Genome Project — Brightstorm

VIDEO: A Decade of the Human GenomeEducationaITV

VIDEO: The Genomic Landscape circa 2012 – Eric Green GenomeTV

VIDEO: Microarray Method for Genetic Testing — Ben Tripp

VIDEO: The Ghost In Your Genes (Documentary)

VIDEO: EducationalChannel

VIDEO: On epigenetics (part I)

VIDEO: On epigenetics (part II) — wildricegrains

VIDEO: Introduction to Gene Network — GeneNetwork.org

VIDEO: Gene Networks – NJN News Science & Technology Report — New Jersey Network (NJN)

VIDEO: Gene network that builds tissues — National Institute for Medical Research (NIMR)

VIDEO: Human Gene Regulation Signaling Networks and GeneChanges — University of California TV

Chapter 6: Roles of the Mitochondria in Cardiovascular Diseases

VIDEO: Cardiac Function and Vital Signs video – Animation by Cal Shipley, MD Trial Image Inc.

VIDEO: Cardiac Catheterization video – Trial Image Inc. Animation by Cal Shipley, MD

VIDEO: Aortic dissection and cardiac tamponade video -Trial ImageInc. Animation by Cal Shipley, MD

VIDEO: Cardiac tamponade – traumatic – Trial Image Inc. Medical Animation by Cal Shipley, MD

VIDEO: Shock – cardiac, septic, hypovolemic – Trial Image Inc. Medical Animation by Cal Shipley, MD –

VIDEO: Confocal Image Sequence of Spontaneous Calcium Waves and Sparks of Fluo-4 loaded Cardiac Myocyte.avi

Chapter 11: Cardiovascular Translational Medicine

VIDEO: Translational Medicine: From Better Ideas to Better Health Dr. Robert M. Califf

VIDEO: What is Translational Medicine.

VIDEO: Translational Medicine. Prof. Richard Aspinall

VIDEO: Biobanking and the Future of Translational Medicine. Part 1 Part 2 Part 3 Dr, Gyorgy Marko-Varga

VIDEO: Translational Medicine. Prof. Richard Aspinall

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

Introduction

Author: Justin D. Pearlman MD ME PhD MA FACC

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

This is Volume ONE which presents fascinating new data relating to the etiology (causes) of cardiovascular diseases. Risk assessment and management of cardiovascular diseases are addressed in volume 2 and volume 3. The full list of cardiovascular diseases stems quite simply from looking at all cardiovascular structures and functions, for each can have deviant design and/or function. The blood pressure can be to high (hypertension) or too low (hypotension). The heart can be too big (cardiomegaly) or too small (hypoplastic heart), too stiff (diastolic failure, restrictive cardiomyopathy, constrictive cardiomyopathy) or too soft (aneurysm). The heart can pump too much (high output failure) or too little (low output failure). The heartbeat rhythm may be too slow (bradycardia) or too fast tachycardia). In addition to too much or too little, there are numerous other ways to invoke Murphy’s law. For example there are hundreds arrhythmias (abnormal rhythm mechanisms). Despite the theoretically infinite ways structure and function can go wrong, the number of treatable conditions is relatively small, partly because biology provides a limited number of viable mechanisms for deviations, and also because severe aberrancies of design do not achieve life. Mechanisms for abnormal structure or function include: congenital, developmental, neoplastic, metabolic, inflammatory,infectious, extrinsic (injury), and degenerative. The basic causes of disease are nature and nurture, i.e., genetic or epigenic predisposition (nature) versus behavior mediated exposures (nurture).

Teleologically the genetic issues may be labeled “maladaptive” in the sense that in certain circumstances the genetically programmed organic functions cause more harm than benefit. For example, when a patient develops heart failure and reduces blood delivery to the kidneys, the kidneys fight back by retaining sodium desperately, and by sending signals to stimulate thirst. Whether or not it is “well-intentioned” the kidneys make the problem worse, as the retained salt water volume overloads the beleaguered failing heart, so the heart dilates and develops worsening mitral valve leakage, thus delivering even less forward to the kidneys, while in addition the lungs get wetter and struggle to take up sufficient oxygen. On the nurture side, the patients intake of salt has major impact on this harmful chain of events, which can be counteracted by disciplined behavior (salt restriction, optimal use of diuretics).

As we learn more about the details of the body’s signals and receptors, we can manufacture medications to counteract the “maladaptive genetics” as well as learn about additional behavior changes that may mitigate or even reverse each disease state. The reason for the quotation marks about “maladaptive genetics” is that the genetic and homeostatic systems may in fact be truly adaptive to the overriding population reproductive success that drives gene pool prevalence, as that drive may include promoting death of the elderly to make room for the young and not compete for their resources. Some of the most fascinating enigmas relate to the teleology of disease. For example why do we have complex systems that disassemble circulating cholesterol lipoproteins only to reassemble them within the wall of blood vessels, where they lead to endothelial (vessel lining) disruption, thrombosis, and vessel occlusion. Such arterial wall damage is the leading mechanism of strokes and heart attacks.

As part of my PhD research I documented that these lipids are liquid crystals which transition between solid and liquid at body temperature (37C) under the influence of the concentration of triglycerides. One could posit a protective effect against vessel dilation, at a large cost. Similarly, is inflammation a defense mechanism gone awry? Inflammation is a component of the damage to blood vessels, but patients who take an anti-inflammatory medication for more than 18 months have a 50% risk of developing a new arterial blockage. These are complex systems, and we simply do not know enough about them. As you read through the discoveries and ideas in the following sections, consider their value in clarifying many aspects of health and disease, including causation, assessment, management, and also edification of the complex systems, their purposes, and their “maladaptive” impact and the checks and balances.

Content links by Key Words

Atherosclerosis, vitamin C – Linus Pauling Small Dense LDL, Calcium supplements, Personal Genetics, Hypertension

Chapter 1

Atherosclerosis

Chapter 1 addresses the mechanisms underlying impaired blood delivery due to cholesterol build up in artery walls. The blockages slow or stop arterial traffic by one of three mechanisms: progressive narrowing of the flow channel, spasm of muscles in the arterial wall, or sudden obstruction caused by cracking, bleeding into the plaque, and clotting (thrombosis). Reduced blood delivery through arteries by any of these mechanisms injures the downstream tissues that depend on fresh continual blood supply. Loss of blood supply to the brain causes strokes, to the heart causes angina (chest pain), ischemia (impaired function due to poor blood supply expressed as weakness and as abnormal rhythms), and myocardial infarction (heart attacks), to the kidneys causes renal failure, and to the extremities it causes pain (claudication) and possible limb loss (gangrene necessitating amputation). This chapter describes the disease process, reviews the pathology and physiology, explains the biologic mechanisms of its progression, including the role of inflammation, and demonstrates how that leads to its devastating consequences. Hardening of the arteries is described as atherosclerosis, or porridge-like wall changes associated with scarring, which produce the blockages that cause heart attacks, high blood pressure, stroke, and organ injury mediated by ischemia (insufficient nutrient blood supply). The determinants of who suffers from this disease are both nature (genetic) and nurture (behavior, diet). Specifics of the causes can guide diagnosis and management.

Atherosclerosis – The Hardening of Arteries

1.1 Arterial Stiffness and Cardiovascular Events. The Framingham Heart Study. GF Mitchell, Shih-Jen Hwang, RS Vasan, MG Larson, et al. Circulation. 2010;121:505-511.

Keywords: atheroma, plaque, lipoprotein, LDL, HDL, cholesterol, vitamin C, calcium

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

VIDEO: What is Atherosclerosis? — Dr. Prodigious.

VIDEO: MEDICAL – How cholesterol clogs your arteries (atherosclerosis)?— Technicom3D, France

VIDEO: Pathophysiology of Atherosclerosis?— Dr. Andrew Wolf

VIDEO: Atherosclerosis Atherosclerosis – Part 1 Atherosclerosis – Part 2?— MedFlux?— Khan Academy

VIDEO: Biology of progression of atherosclerosis — Ahmad Rusydi Jamaludin

VIDEO: Heart Attack due to Atherosclerosis — Nucleus Medical Media Atherosclerosis as an inflammatory disease — Nucleus Medical Media

VIDEO: Inflammation In Atherosclerotic Plaque Formation — Medical Sciences Animated

VIDEO: Angina animations — SpeakFromTheHeart.com

Regarding heart attacks, the major cause of death, and Vitamin C – Linus Pauling promoted an historic effort at identifying why heart attacks occur in certain mammals (including man). He tried blaming the cause of heart attacks (myocardial infarctions) on failure to self-manufacture vitamin C, but the data was flawed:

1.2 Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C

Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD

The data is much stronger about “bad” cholesterol (low-density lipoprotein or LDL), and the “baddest” of the bad, small low-density lipoproteins (sLDL). Every 1% elevation of cholesterol confers a 2% increase in early mortality. Total cholesterol includes good (protective) cholesterol HDL, and bad (harmful) cholesterols LDL and VLDL.

1.3 Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles
Aviva Lev-Ari, PhD, RN

CTEP, the enzyme responsible for chemical exchanges between triglycerides (dietary simple carbohydrate intake) and good cholesterol (HDL) can contribute to hardening of arteries. Conversely genetically low activity of CETP can confer longevity. CTEP mediates lowering of HDL due to dietary excesses of bread and other carbohydrates by chemical interactions triggered by high triglyceride levels.

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

Aviva Lev-Ari, PhD, RN

Expanding knowledge of the inflammatory and cellular mediatiors of atherosclerosis identifies mechanisms of the disease – any and all can be dysfunctional.

1.5 Harnessing New Players in Atherosclerosis to Treat Heart Disease

Aviva Lev-Ari, PhD, RN

Reference
[1] Bertazzo, S. et al. Nano-analytical electron microscopy reveals fundamental insights into human cardiovascular tissue calcification. Nature Materials 12, 576-583 (2013).

Chapter 2

Genomics

Understanding the causes of cardiovascular diseases logically starts with the genetic code that specifies the designs for the structures and function. These may be inherited from your parents, or may differ from either parent due to spontaneous mutations. Congenital heart disease comprises many different abnormalities, primarily of structure. For example valves and tubular pathways may be malformed, and connections may be deviant. Connections not normally present are known as shunts. The completion of the human genome map was a major accomplishment enabling complete enumeration of all the possibilities. Genes specify the codes for gene products that make the structural elements, signals, receptors and other building blocks that establish health and disease. However, the complete genome map is just a stepping stone, as it does not completely explain why, where, or how the gene products are regulated and interact. Epigenetics picks up on the issues of gene expression, product modifications and assembly. Epigenetics is the scientific focus that characterizes the vital follow-on steps from genetic code to the determination of structures and function of the cardiovascular and other biologic systems. This chapter explores what is known about the human genome and how it determines the nature of health versus cardiovascular disease Diseases generally come from a combination of nature and nurture – this chapter focuses on nature.

Keywords: genome, epigenics, microarray, signaling pathways, nucleases, protein folding

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

VIDEO: Human Genome Project animation — PVDK

VIDEO: Human Genome Project I — Prof. Eric Lander – Harvey Prize 2012

VIDEO: Human Genome Project II — Prof. Eric Lander

VIDEO: Human Genome Project I — Brightstorm

VIDEO: A Decade of the Human Genome — EducationaITV

2.1 Genome sequencing of the Healthy

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

VIDEO: The Genomic Landscape circa 2012 – Eric Green — GenomeTV Microarray Method for Genetic Testing — Ben Tripp

The genome provides blueprints for all the gene products used by the body, as well as others that are not used. The same blueprints are found in virtually all cells of your body, but cells in different tissues have distinct functions. Epigenetics studies the inherited control of expression of gene products which differs for different tissues.

2.2 Whole-Genome Sequencing Data will be Stored in Coriell’s Spin off For-Profit Entity

Aviva Lev-Ari, PhD, RN

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

VIDEO: The Ghost In Your Genes (Documentary) — EducationalChannel

VIDEO: On epigenetics (part I)

VIDEO: On epigenetics (part II)
— wildricegrains

2.3 First Epigenome in Europe Completed

Prabodh Kandala, PhD

2.4 Unraveling retrograde signaling pathways

Larry H Bernstein, MD, FACP

2.5 Targeted nucleases

Larry H Bernstein, MD, FACP

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

VIDEO: Introduction to Gene Network — GeneNetwork.org

VIDEO: Gene Networks – NJN News Science & Technology Report — New Jersey Network (NJN)

VIDEO: Gene network that builds tissues — National Institute for Medical Research (NIMR)

VIDEO: Human Gene Regulation Signaling Networks and GeneChanges – University of California TV

Genes (DNA) code for gene products (proteins) but the biological impact depends not only on the sequence of amino acids in the gene product but also depends on the expression (how many copies of the protein product are produced where), the post-processing and assembly (what parts are changed or cleaved off, what other proteins join with it) and protein folding (the folded shape determines what parts are exposed, what parts are internalized, and the resultant shape can determine enzymatic activity as well as membrane pore activity (transport channels). Computer simulation performed at Stanford on the effects of natural selection (reproductive success impact) show how protein shape evolution can be predicted.

2.6 Genomic Model of Organogenesis: Computer Modeling of the Gene Regulatory Networks

Larry H Bernstein, MD, FACP

Calcium signals activate muscle contraction, or protein transcription, depending on location of the signal.

2.7 Ca2+ signaling: transcriptional control

Larry H Bernstein, MD, FACP

Proteins serve as structural elements, ion channels, enzymes, and in each of these roles, the folded shape of the chain of amino acids is a critical factor.

2.8 Protein-folding Simulation: Stanford’s Framework for Testing and Predicting Evolutionary Outcomes in Living Organisms – Work by Marcus Feldman

Aviva Lev-Ari, PhD, RN

Chapter 3

Genomics Basis for Cardiovascular Diseases

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

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

3.2 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

Aviva Lev-Ari, PhD, RN

3.3 Inhibitor RNA molecules that regulate gene expression have patent protection: RNA related IP Patents Awards

Aviva Lev-Ari, PhD, RN

Applying Murphy’s law (what can go wrong will go wrong) is a helpful guide to identifying the causes of cardiovascular disease, but not sufficient. Fatal mutations often do not reach clinical attention. Some areas of the genome are more prone to mutation (spontaneous variation) than others.

3.4 Study Finds Low Methylation Regions Prone to Structural Mutation.

Aviva Lev-Ari, PhD, RN

Even though we have a complete human genome map and we identify genetic abnormalities in pathways that should affect particular diseases, the association with disease runs only 20-40% in practice for common conditions, and special methods such as exome sequencing are needed for rare conditions where the number of cases found may be just one.

3.5 Finding the Genetic Links in Common Disease: Caveats of Whole Genome

Stephen J. Williams, Ph.D.

Genetic defects in the coding for heart muscle causes abnormal thickening, fiber orientation, and wall stiffness classified as “hypertrophic cardiomyopathy.” Screening by echocardiography to estimate wall thickness may miss early stages of the disease, detectable by cardiac magnetic resonance.

3.6 Echo vs Cardiac Magnetic Resonance Imaging (CMRI): CMRI may be a useful adjunct in Hypertrophic Cardiomyopathy (HCM) family screening in higher risk.

Aviva Lev-Ari, PhD, RN

The genetic bases for atherosclerosis and hardening (loss of elasticity) are multifactorial.

3.7 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

Aviva Lev-Ari, PhD, RN

Naturally, genetic abnormalities that are manifest at birth are well recognized, even though the genetic abnormality often represents a spontaneous mutation.

3.8 Congenital Heart Disease at Birth and into Adulthood: The Role of Spontaneous Mutations – The Genes and The Pathways

Aviva Lev-Ari, PhD, RN

Chapter 4

Drug Toxicity and Cardiovascular Diseases

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 by 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

4.1 Predicting Drug Toxicity for Acute Cardiac Events

Larry H Bernstein, MD, FACP

4.2 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.

4.3 Decoding myocardial Ca2+ signals across multiple spatial scales: A role for sensitivity analysis. J Mol Cell Cardiol 2013 58;92-9.” href=”http://www.ncbi.nlm.nih.gov/pubmed/23026728″ target=”_blank”>sensitivity analysis

Aviva Lev-Ari, PhD, RN

The mathematical models can describe in detail cardiac drug effects and basis for toxicities.

4.4 Leveraging Mathematical Models to Understand Population Variability in Response to Cardiac Drugs: Eric Sobie, PhD

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.

4.5 Exploiting mathematical models to illuminate electrophysiological variability between individuals.

Eric A. Sobie, PhD

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.

4.6 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.

4.7 Lexapro may improve heart health – eMaxHealth

Chapter 5

Vascular Biology

The cardiovascular system is spread over a larger territory – the entire body. Coordination of functions requires signals be sent by either the nervous system or in the blood. A very small molecule, nitric oxide, controls dilation or contraction of muscular blood vessels, to adjust flow impedance, blood pressure, target tissue perfusion, and workload on the heart.

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

Aviva Lev-Ari, PhD, RN

Artery walls use a simple molecule, nitric oxide, as a signal to adjust the diameter of each vessel appropriately for the variable demands of blood delivery.

5.2 Differential Distribution of Nitric Oxide – A 3-D Mathematical Model Comments »

Anamika Sarkar, PhD

5.3 Perspectives on Nitric Oxide in Disease Mechanisms

Aviral Vatsa, PhD and Larry H. Bernstein, MD, FACP

5.4 Interaction of Nitric Oxide and Prostacyclin in Vascular Endothelium

Larry H. Bernstein, MD, FACP

5.5 Endothelial Function and Cardiovascular Disease

Larry H Bernstein, MD, FACP

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

Aviva Lev-Ari, PhD, RN

Models for disease may be constructed from simple biologic systems.

5.7 Engineered Microvessels Provide a 3-D Test Bed for Human Diseases

Prabodh Kandala, PhD

Chapter 6

Hypertension

Hypertension: One of the most common silent killers is hypertension (high blood pressure).

Hypertension is not just a disease of the elderly – children and young adults can have narrowing in the renal arteries or other preconditions that cause severe elevation of blood pressure initially with no symptoms. Unchecked, hypertension makes the heart thicken and become stiff (diastolic failure). Arteries also thicken. Thickened damaged arteries can block off with blood clots, resulting in inadequate delivery of blood (ischemia), or they can fissure (crack) and leak harmful materials directly into tissues (hemorrhage). Serious complications include strokes, heart attacks, heart failure, renal failure, limb ischemia and limb loss.

6.1 An Important Marker of Hypertension in Young Adults

Manuela Stoicescu, MD, PhD

Hormones modulate how salt is handled in the body. Salt controls the “central volume” of circulation of fluids within blood vessels. Excess volume for the expandable space makes pressure rise.

6.2 Arterial Hypertension in Young Adults: An Ignored Chronic Disease

Manuela Stoicescu, MD, PhD

6.3 Secondary Hypertension caused by Aldosterone-producing Adenomas caused by Somatic Mutations in ATP1A1 and ATP2B3

Aviva Lev-Ari, PhD, RN

Chapter 7

Arrhythmia

Arrhythmia literally means without rhythm, but in practice refers to any abnormal heart mechanism controlling rhythm, including those that are regular or patterned (hence technically, not without rhythm). Purists may use the term “dysrhythmia” instead. The normal heart rhythm starts near the junction of the superior vena cava and the right atrium in specialized pacing cells called the sino-atrial node (sinus node, SA node). Electrochemical signals propagate like tumbling dominoes through the atria and activate another specialized rhythm control center (a waiting station) called the atrio-ventricular node (AV node). From there, after a delay to allow time for blood to fill the ventricles from the contracting atria, the electrochemical signal passes to the ventricles by way of specialized conduction tissue (His bundle). These pathways and the electrochemical signals in heart muscle can fail, form short-circuits that produce fast rhythms, or excite too easily, as a few of many reasons for arrhythmia. The study of rhythm forms the sub-specialty electrophysiology, with many contributors.

7.1 credited to Dr. Mark Josephson.

Keywords: arrhythmia, atrial fibrillation, atrial flutter, bigeminy, trigeminy, quadrigeminy, bradycardia, tachycardia, supraventricular, ventricular, arrest, escape, ectopy, parasystole

7.1 Oxidized Calcium Calmodulin Kinase and Atrial Fibrillation

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

7.2 Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

Aviva Lev-Ari, PhD, RN

7.3 Dilated Cardiomyopathy: Decisions on implantable cardioverter-defibrillators (ICDs) using left ventricular ejection fraction (LVEF) and Midwall Fibrosis: Decisions on Replacement using late gadolinium enhancement cardiovascular MR (LGE-CMR)

Aviva Lev-Ari, PhD, RN

7.4 Reduction in Inappropriate Therapy and Mortality through ICD Programming

Aviral Vatsa, PhD, MBBS

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

Aviva Lev-Ari, PhD, RN

Chapter 8

Roles of the Mitochondria in Cardiovascular Diseases

8.1 Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing

Larry H Bernstein, MD, FACP

8.2 Mitochondrial Metabolism and Cardiac Function

Larry H Bernstein, MD, FACP

8.3 Mitochondrial Dysfunction and Cardiac Disorders

Larry H Bernstein, MD, FACP

8.4 Reversal of Cardiac mitochondrial dysfunction

Larry H Bernstein, MD, FACP

8.5 Mitochondria: More than just the “powerhouse of the cell”

Ritu Saxena, Ph.D. Consultants: Aviva Lev-Ari, PhD, RN and Pnina G. Abir-Am, PhD

8.6 Mitochondrial dynamics and cardiovascular diseases

Ritu Saxena, PhD

Chapter 9

Calcium Signaling in Electric Activity and in Myocardial Contraction

Calcium is an ion used by cells for numerous distinct signaling roles, depending on the cell type and calcium location. Calcium mediates muscle activation, but also can interfere with efficiency of mitrochondria converting oxygen to chemical energy mediators. Thus administration of calcim chloride or calcium gluconate to a patient can temporarily increase the strength of muscle contraction, in a non-sustainable manner.

While learning about the roles, controls and biologic events involving calcium, it is helpful to keep in mind the desire to identify markers of disease states (in preparation for the focus of CVD 2) and the opportunities for designing and implementing helpful interventions (in preparation for the focus of CVD 3). When a patient’s brain is in imminent danger of permanent injury due to inadequate cardiac strength of contraction, an intervention increasing calicium and its impact on heart muscle contration can offer a timely rescue. Therefore, it is important to understand not only the myriad roles of calcium in the body, but also the timing, consequences, response to interventions, and the chain of compensatory changes at various times in response to the changes instigated.

As patients develop heart failure, calcium increases in the storage area known as the sarcoplasmic reticulum. High levels of calcium there are akin to fetal phenotype. Calcium also contributes to the electrochemical signaling of cardiac and other muscles (the “action potential”). The kidneys have distinctive management of calicum as well.

Generally the role of calcium is mediated by special protein structures called ion channels – tubular conditional tunnels or gated passageways that enable transfer of the double charged ions from one area to another at controlled times, conditions, and rates, often only to be transferred back a short time later.

9.1 Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

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

9.2 Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

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

9.4 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

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

9.5 Heart, Vascular Smooth Muscle, Excitation-Contraction Coupling (E-CC), Cytoskeleton, Cellular Dynamics and Ca2 Signaling

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

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

Aviva Lev-Ari, PhD, RN

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

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

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

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

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

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

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

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

In general, one can only expect partial improvement from “one size fits all” diagnosis and therapy. We are all genetically unique. Examination of each individual’s genetics may enable as alternatve to trial and error approaches possibly individualized therapy targeted to your specific genetic constitution.

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

Aviva Lev-Ari, PhD, RN

Calcium supplements: Health-oriented patients often take supplements aiming to correct genetic predispositions. The word “vitamin” means vital in minimal amounts. High doses of supplements can be harmful.

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

Aviva Lev-Ari, PhD, RN

9.13 Critical Gene in Calcium Reabsorption: Variants in the KCNJ and SLC12A1 genes – Calcium Intake and Cancer Protection

Aviva Lev-Ari, PhD, RN

9.14 MGH’s Largest-ever Genetic Study of Five Psychiatric Disorders: Variation in SNPs in Two Genes involved in Calcium-Channel Signaling

Aviva Lev-Ari, PhD, RN

9.15 Role of Calcium, the Actin Skeleton, and Lipid Structures in Signaling and Cell Motility

Larry H Bernstein, MD, FCAP

9.16 Renal Distal Tubular Ca2+ Exchange Mechanism in Health and Disease

Larry H Bernstein, MD, FCAP

Chapter 10

Computing

VIDEO: Cardiac Function and Vital Signs video – Animation by Cal Shipley, MD Trial Image Inc.

VIDEO: Cardiac Catheterization video – Trial Image Inc. Animation by Cal Shipley, MD

VIDEO: Aortic dissection and cardiac tamponade video -Trial ImageInc. Animation by Cal Shipley, MD

VIDEO: Cardiac tamponade – traumatic – Trial Image Inc. Medical Animation by Cal Shipley, MD

VIDEO: Shock – cardiac, septic, hypovolemic – Trial Image Inc. Medical Animation by Cal Shipley, MD –

VIDEO: Confocal Image Sequence of Spontaneous Calcium Waves and Sparks of Fluo-4 loaded Cardiac Myocyte.avi

Computer forecasting has value not only in modeling the individual patient to predict response to changes in nature, nurture, and management. Computer forecasting is also vital in identifying the priorities for investment in disease prevention and more efficient management.

10.1 Simulating the Human Heart Function requires World’s Fastest Supercomputer

Aviva Lev-Ari, PhD, RN

10.2 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

Aviva Lev-Ari, PhD, RN

Imaging modalities (methods) are based on various physical principles of energy interactions with matter (materials). Thus imaging can be based on sound waves (ultrasound, echocardiography), ionizing radiation (xrays, radionuclide imaging, SPECT imaging, PET imaging, CT scan), magnetization (MRI), optics (infrared, fluorescent, white light transillumination and backscatter) to name the most common. Different imaging methods may be combined to pursue Sir Isaac Newton’s observation that one can see farther by standing on the shoulders of giants.

10.3 Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused

Aviva Lev-Ari, PhD, RN

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

Aviva Lev-Ari, PhD, RN

Chapter 11:

Cardiovascular Translational Medicine

VIDEO: Translational Medicine: From Better Ideas to Better Health Dr. Robert M. Califf

VIDEO: What is Translational Medicine.

VIDEO: Translational Medicine. Prof. Richard Aspinall

VIDEO: Biobanking and the Future of Translational Medicine. Part 1 Part 2 Part 3 Dr, Gyorgy Marko-Varga

VIDEO: Translational Medicine. Prof. Richard Aspinall

Translational medicine is a mindset that focuses on linkage between scientific discovery and improved healthcare. Translational medicine constitutes an applied science that promotes the rapid development of methods, discoveries and investigations to patient applications, comparative human trials, evidence-based practice guidelines, widespread practice, and confirmed public benefit (improved outcomes and public health measures). Major areas of focus in translational medicine include:

• Communication
• Coordination of care
• Meaningful use of electronic records systems
• Pharma
• Devices
• Comparative effectiveness
• Influencing widespread practice
• Guideline adherence
• Accountability for better outcomes
• Healthcare reform

With respect to etiology or causes of cardiovascular disease, the human genome project provides a stellar example of opportunity to link the elucidated road map for all genes and gene products to explanations of the rate-controlling elements of biologic pathways underlying maladaptive states and dysfunction. Such investigations identify molecular and cellular causes of cardiovascular diseases, and point to opportunities for intervention. At the other end of the healthcare spectrum, careful analyses of healthcare practices identifies system causes for poor outcomes. Whether the cause of undesirable outcomes is nature (genetic) or nurture (exposures), inherent, volitional (abuses) or iatrogenic (system failures), identifying the causes in the context of translational medicine offers opportunities for improvement, individual and public benefit.

Summary

The causes (etiology) of cardiovascular diseases stem from the genetic code and its expression as gene products interacting with environmental factors. The curated material in this volume presented examples of the linkages already established. In addition, it illustrates methods of discovery and classification that serve as models for future advances. The human genome has been fully mapped, but the epigenetics of how the genetic blueprint plays out in structurallly and functionally impaired systems requires continued study along the lines presented above. There are many non-viable variations that have no hope of survival. Disease focuses on viable but dysfunctional states.

The genetics of disease require viability plus recognizable shortfalls. The viable defects explain the nature component of disease causation. Environmental exposures constitute the nurture component. These two major factors interact strongly because our nature is naturally selected to survive and utilize nurture. The combination of nature and nurture explains survival and reproductive success. It the process struggles and shortfalls are labelled as disease.

For every disease, there are corresponding biologic and imaging indicators of disease status, the subject of CVD 2. For every disease status, there are opportunities to intervene in order to halt progressive deterioration, reverse, or prevent illness manifestations, the subject of CVD 3. The combination of 1) recognizing disease, 2) quantifying disease status, and 3) intervening for benefit constitute the core goals of medicine.