This e-Book is a comprehensive review of Cardiovascular Diseases: Causes, Risks and Management and related opportunities for Targeted Therapy written by Experts, Authors, Writers. The e-Book’s articles have been published on the Open Access Online Scientific Journal, since April 2012. All new articles on this subject, will continue to be incorporated, as published with periodical updates.

http://www.pharmaceuticalIntelligence.com The Open Access Online Journal 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.

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

Introduction to the Three Volume Series
Introduction to the Volumes
Introduction and key words to Each Chapter
Summary to each Chapter
Epilogue
Summary for the Volume

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 Series 1.1, 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 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

Introduction

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

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.
http://circ.ahajournals.org/doi/10.1161/CIRCULATIONAHA.109.886655

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

1.1 Vitamin C – Linus Pauling promoted an historic effort at identifying why heart attacks occur in certain mammals (including man). He tried blaming it on failure to self-manufacture vitamin C, but the data was flawed: Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C |Comments »

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

1.2 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. Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles |Comments »

Aviva Lev-Ari, PhD, RN

1.3 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. Cholesteryl Ester Transfer Protein (CETP) Inhibitor: Potential of Anacetrapib to treat Atherosclerosis and CAD |Comments »

Aviva Lev-Ari, PhD, RN

1.4 Expanding knowledge of the inflammatory and cellular mediatiors of atherosclerosis identifies mechanisms of the disease – any and all can be dysfunctional. Harnessing New Players in Atherosclerosis to Treat Heart Disease |Comments»

Aviva Lev-Ari, PhD, RN

References

[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, as gene products make the signals, receptors and building blocks that establish health and disease. However, the complete genome map is just a stepping stone, as it does not 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, vital follow-on steps 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 (remember: diseases generally come from a combination of nature and nurture).

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 — 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

2.2 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.

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)?On epigenetics (part II) — wildricegrains

2.3 First Epigenome in Europe Completed |Comments »

Prabodh Kandala, PhD

2.4 Unraveling retrograde signaling pathways |Comment »

Larry H Bernstein, MD, FACP

2.5 Targeted nucleases |Comments »

Larry H Bernstein, MD, FACP

VIEW VIDEOS – Courtesy of GenomeTVas 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

2.6 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. Genomic Model of Organogenesis: Computer Modeling of the Gene Regulatory Networks |Comment »

Larry H Bernstein, MD, FACP

2.7 Calcium signals activate muscle contraction, or protein transcription, depending on location of the signal. Ca2+ signaling: transcriptional control |Comments »

Larry H Bernstein, MD, FACP

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

Aviva Lev-Ari, PhD, RN

Chapter 3 Genomics Basis for Cardiovascular Diseases

2.9->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

2.10->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

2.11->3.3 Inhibitor RNA molecules that regulate gene expression have patent protection: RNA related IP Patents Awards

Aviva Lev-Ari, PhD, RN

2.12->3.4 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. Study Finds Low Methylation Regions Prone to Structural Mutation.

Aviva Lev-Ari, PhD, RN

2.13->3.5 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. Finding the Genetic Links in Common Disease: Caveats of Whole Genome Sequencing Studies.

Stephen J. Williams, Ph.D.

2.14->3.6 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. 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

2.15->3.7 The genetic basis for atherosclerosis and hardening (loss of elasticity) are multifactorial. 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

2.16->3.8 Naturally, genetic abnormalities that are manifest at birth are well recognized, even though the genetic abnormality often represents a spontaneous mutation. Congenital Heart Disease at Birth and into Adulthood: The Role of Spontaneous Mutations – The Genes and The Pathways

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 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

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

4.3 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 Decoding myocardial Ca2+ signals across multiple spatial scales: A role for sensitivity analysis

Eric A. Sobie

4.4 The mathematical models can describe in detail cardiac drug effects and basis for toxicities.
Leveraging Mathematical Models to Understand Population Variability in Response to Cardiac Drugs: Eric Sobie, PhD

Aviva Lev-Ari, PhD, RN

4.5 Whereas mathematical models are often designed to represent the median or general trend, they also may be used to highlight individuality. Exploiting mathematical models to illuminate electrophysiological variability between individuals.

Eric A. Sobie

4.6 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

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

5.2 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. 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

5.9 Models for disease may be constructed from simple biologic systems. 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).

1.5->6.1 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. An Important Marker of Hypertension in Young Adults |Comments » Manuela Stoicescu, MD, PhD

1.6->6.2 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. Arterial Hypertension in Young Adults: An Ignored Chronic Disease |Comments »

Manuela Stoicescu, MD, PhD

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

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 contributions credited to Dr. Mark Josephson.

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

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

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 usinglate 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

Introduction by Justin D Pearlman, MD. PhD, FACC

9.1 Identification of Biomarkers that are Related to the Actin Cytoskeleton

Larry H Bernstein, MD, FCAP

http://pharmaceuticalintelligence.com/2012/12/10/identification-of-biomarkers-that-are-related-to-the-actin-cytoskeleton/

9.2 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

http://pharmaceuticalintelligence.com/2013/08/26/role-of-calcium-the-actin-skeleton-and-lipid-structures-in-signaling-and-cell-motility/

9.3 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

http://pharmaceuticalintelligence.com/2013/09/02/renal-distal-tubular-ca2-exchange-mechanism-in-health-and-disease/

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

http://pharmaceuticalintelligence.com/2013/09/08/the-centrality-of-ca2-signaling-and-cytoskeleton-involving-calmodulin-kinases-and-ryanodine-receptors-in-cardiac-failure-arterial-smooth-muscle-post-ischemic-arrhythmia-similarities-and-differen/

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

http://pharmaceuticalintelligence.com/2013/08/26/heart-smooth-muscle-excitation-contraction-coupling-cytoskeleton-cellular-dynamics-and-ca2-signaling/

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

http://pharmaceuticalintelligence.com/2013/08/01/calcium-molecule-in-cardiac-gene-therapy-inhalable-gene-therapy-for-pulmonary-arterial-hypertension-and-percutaneous-intra-coronary-artery-infusion-for-heart-failure-contributions-by-roger-j-hajjar/

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

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

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

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

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

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

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

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

Calcium is another molecular signaler that controls muscle contraction. The need for supplements, medications, screening tests and interventions may best be optimized in the future according to your genetic individuality.

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

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

Aviva Lev-Ari, PhD, RN

10.2 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. 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

10.3 FDA Pending 510(k) for The Latest Cardiovascular Imaging Technology comment

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.

10.4 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

10.5 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

[Dr. Pearlman to add Summaries to each Chapter, Epilogue and Summary to

Volume One and transition paragraph on what to expect in Volume 2 and Volume 3]

This series represents a dynamic collection of articles covering the emerging new knowledge of the causes, risks and management of cardiovascular diseases, based on enormous contribution by many brilliant collaborating scientists. Your comments will promote further advances.

CHANGES MADE by Aviva:

On 5/28/2013 Aviva ADDED: 4.5 Genetics of Conduction Disease: Atrioventricular (AV) Conduction Disease (block): Gene Mutations – Transcription, Excitability, and Energy Homeostasis Aviva Lev-Ari, PhD, RN

On 4/15/2013: Aviva ADDED:

Chapter 6 Roles of the Mitochondria in Cardiovascular Diseases

6.1 Mitochondria and Cardiovascular Disease: A Tribute to Richard Bing Larry H Bernstein, MD, FACP 5.2 Mitochondrial Metabolism and Cardiac Function Larry H Bernstein, MD, FACP 5.3 Mitochondrial Dysfunction and Cardiac Disorders Larry H Bernstein, MD, FACP 5.4 Reversal of Cardiac mitochondrial dysfunction Larry H Bernstein, MD, FACP

[following your review/approval/denial with explanation/my final decision/ — removed every thing below this point

four articles added above,

1.10, 1.11, 2.7,

3.2 Cardiotoxicity and Cardiomyopathy Related to Drugs Adverse Effects Larry H Bernstein, MD, FACP

5.4 and Karra’s was

replaced by Larry in 2.6

ANY CHANGES BY Dr. PEARLMAN made from NOW on to be done in the ABOVE space NOT in the below space

Content BELOW THIS POINT

compared with above content

and to be

DELETED form HERE BY Dr. PEARLMAN

and to be placed in a DRAFT file as CVD 1

eBook:

Cardiovascular Diseases: Causes, Risks and Management

CVD 1: Causes of Cardiovascular Diseases

Justin D. Pearlman MD

ME PhD MA FACC, Editor

Pharmaceutical Intelligence

This volume 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. 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. 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 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, so, 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 mechanisms for deviations, and also because severe aberrancies 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 and behavior mediated exposures. 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 25% 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 Atherosclerosis Chapter 1.1: Atherosclerosis – The hardening of arteries Hardening of the arteries is described as atherosclerosis, or porridge-like wall changes with scarring, which leads to heart attacks, high blood pressure, stroke, and organ injury mediated by ischemia (insufficient nutrient blood supply). The causes are both nature (genetic) and nurture (behavior, diet). Specifics of the causes can guide diagnosis and management. Keywords: atheroma, plaque, lipoprotein, LDL, HDL, cholesterol, vitamin C, calcium VIEW VIDEOS – Courtesy of 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: 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 VIDEO: Atherosclerosis as an inflammatory deseaseInflammation In Atherosclerotic Plaque Formation — Nucleus Medical Media — Medical Sciences Animated Videos VIDEO: Angina animations — SpeakFromTheHeart.com Vitamin C – Linus Pauling An historic effort at identifying why heart attacks occur in certain mammals (including man) tried blaming it on failure to self-manufacture vitamin C, but the data was flawed: Linus Pauling: On Lipoprotein(a) Patents and On Vitamin C — Lev-Ari, A and Abir-Am PG Pharmaceutical Intelligence 1/18/2013 Small Dense LDL The data is much stronger about “bad” cholesterol (low-density lipoprotein or LDL), and the “baddest” of the bad, small low-density lipoproteins (sLDL): Artherogenesis: Predictor of CVD – the Smaller and Denser LDL Particles — Lev-Ari, A Pharmaceutical Intelligence 11/15/2012 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: Calcium (Ca) supplementation (>1400 mg/day): Higher Death Rates from all Causes and from Cardiovascular Disease in Women — Lev-Ari, A Pharmaceutical Intelligence 2/19/2013 The need for supplements, medications, screening tests and interventions may best be optimized in the future according to your genetic individuality. Personalized Cardiovascular Genetic Medicine at Partners HealthCare and Harvard Medical School — Lev-Ari, A Pharmaceutical Intelligence 2/25/2013 Models for disease may be constructed by simpler biologic systems. Engineered Microvessels Provide a 3-D Test Bed for Human Diseases — Kandala P Pharmaceutical Intelligence 5/30/ 2012 Hypertension One of the most common silent killers is hypertension (high blood pressure). It 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. An Important Marker of Hypertension in Young Adults |Comments » — Stoicescu M Pharmaceutical Intelligence 2/9/13 Arterial Hypertension in Young Adults: An Ignored Chronic Disease |Comment » — Stoicescu M Pharmaceutical Intelligence 2/9/13 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. Secondary Hypertension caused by Aldosterone-producing Adenomas caused by Somatic Mutations in ATP1A1 and ATP2B3 |Comment » — Lev-Ari, A Pharmaceutical Intelligence 2/25/2013 Differential Distribution of Nitric Oxide – A 3-D Mathematical ModelComments » — Sarkr A Pharmaceutical Intelligence 10/28/12 Chapter 1.2. 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, as gene products make the signals, receptors and building blocks that establish health and disease. However, the complete genome map is just a stepping stone, as it does not 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, vital follow-on steps to the determination of structures and function of the cardiovascular and other biologic systems. 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 — Brightstorm VIDEO: A Decade of the Human Genome — EducationaITV Genome sequencing of the Healthy — Bernstein LPharmaceutical Intelligence 3/2/13 VIDEO: The Genomic Landscape circa 2012 – Eric Green — GenomeTV VIDEO: Microarray Method for Genetic Testing — Ben Tripp Whole-Genome Sequencing Data will be Stored in Coriell’s Spin off For-Profit Entity — Lev-Ari, A Pharmaceutical Intelligence 1/30/13 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. 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) On epigenetics (part II) — wildricegrains First Epigenome inEurope Completed — Kandala P Pharmaceutical Intelligence 5/31/12 Unraveling retrograde signaling pathways —Bernstein LPharmaceutical Intelligence 3/2/13 Targeted nucleases —Bernstein LPharmaceutical Intelligence3/2/13 VIEW VIDEOS – Courtesy of 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 andGeneChanges — University of California TV Biologists create first predictive computational model of gene networksComment — Karra VS Pharmaceutical Intelligence 8/30/12 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 at Standford of the effects of natural selection (reproductive success impact) show how protein shape evolution can be predicted. Protein-folding Simulation: Stanford’s Framework for Testing and Predicting Evolutionary Outcomes in Living Organisms —Lev-Ari, A Pharmaceutical Intelligence 3/15/13

Genomics &

Genetics of Cardiovascular Disease Diagnoses: A Literature Survey of AHA’s Circulation Cardiovascular Genetics, 3/2010 – 3/2013 —Lev-Ari, A , Bernstein L Pharmaceutical Intelligence 3/7/13 1.3. Drug Toxicity 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 Bernstein L 3/15/13 Predicting Drug Toxicity for Acute Cardiac Events 1.4. 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). Keywords: arrhythmia, atrial fibrillation, atrial flutter, bigeminy, trigeminy,quadrigeminy, bradycardia, tachycardia, supraventricular, ventricular, arrest, escape, ectopy, parasystole

Sustaine

d Cardiac Atrial Fibrillation: Management Strategies by Director of the Arrhythmia Service and Electrophysiology Lab at The Johns Hopkins Hospital —Lev-Ari, A Pharmaceutical Intelligence 10/16/12

Cardiac Arrhythmias: A Risk for Extreme Performance Athletes

—Lev-Ari, A Pharmaceutical Intelligence 8/8/12

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) —Lev-Ari, A Pharmaceutical Intelligence 3/10/13

Reduction in Inappropriate Therapy and Mortality through ICD

Programming — aviralvatsa Pharmaceutical Intelligence 1/4/13 1.5. Lessons from Cardiovascular Imaging 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 ofSpontaneous Calcium Waves and Sparks of Fluo-4 loaded Cardiac Myocyte.avi Simulating the Human Heart Function requires World’s Fastest SupercomputerComment —Lev-Ari, A 10/24/12| FDA Pending 510(k) for The Latest Cardiovascular Imaging TechnologyComment —Lev-Ari, A 1/28/13 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. Minimally Invasive Structural CVD Repairs: FDA grants 510(k) Clearance to Philips’ EchoNavigator – X-ray and 3-D Ultrasound Image Fused. —Lev-Ari, A 3/7/13

Funding, Deals & Partnerships: BIOLOGICS & MEDICAL DEVICES; BioMed e-Series; Medicine and Life Sciences Scientific Journal – http://PharmaceuticalIntelligence.com

Causes of Cardiovascular Diseases

Risks of Cardiovascular Diseases

Management of Cardiovascular Diseases

List of Contributors

List of Movies by Chapter

Chapter 1: Atherosclerosis

Chapter 2: Genomics and Cardiovascular Diseases

Chapter 6: Roles of the Mitochondria in Cardiovascular Diseases

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

Introduction

Chapter 1

Atherosclerosis

Atherosclerosis – The Hardening of Arteries

Chapter 2

Genomics

Chapter 3

Genomics Basis for Cardiovascular Diseases

Chapter 4

Drug Toxicity and Cardiovascular Diseases

Chapter 5

Vascular Biology

Chapter 6

Hypertension

Chapter 7

Arrhythmia

Chapter 8

Roles of the Mitochondria in Cardiovascular Diseases

Chapter 9

Calcium Signaling in Electric Activity and in Myocardial Contraction

Chapter 10

Computing

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

Summary

CHANGES MADE by Aviva:

On 4/15/2013: Aviva ADDED:

Chapter 6

Roles of the Mitochondria in Cardiovascular Diseases

four articles added above,

1.10, 1.11, 2.7,

5.4

and Karra’s was

replaced by Larry in 2.6

ANY CHANGES BY Dr. PEARLMAN made from NOW on to be done in the ABOVE space NOT in the below space

Content BELOW THIS POINT

compared with above content

and to be

DELETED form HERE BY Dr. PEARLMAN

and to be placed in a DRAFT file as CVD 1

CVD 1: Causes of Cardiovascular Diseases

Summary

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