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Essential Cardiology: Principles and Practice, 3rd Edition, blends molecular, cellular, and physiologic concepts with current clinical practice and provides up-to-date information on all major aspects of cardiovascular disease. Fully revised by an international panel of leading authorities in the field, it is an authoritative resource for cardiologists, internists, residents, and students. The book presents the clinical examination of the patient, including diagnostic testing and cutting-edge radiologic imaging; pathogenesis and treatment of various types of cardiac abnormalities; the needs of special populations, including pregnant, elderly, and renal-compromised patients; cardiovascular gene and cell therapy; and preventive cardiology. It includes new chapters on cardiovascular disease in women; diabetes and the cardiovascular system; and cancer therapy-induced cardiomyopathy. The Third Edition also focuses on the substantial advances in anti-platelet and anticoagulant therapy; new modalities of cardiac imaging; new anti-arrhythmic drugs; and a sophisticated understanding of vascular biology and atherogenesis.

Inhoudsopgave

Voorwerk

1. Multivariable Evaluation of Candidates for Cardiovascular Disease

Abstract
A preventive approach to the management of atherosclerotic cardiovascular disease (CVD) is needed. It is the leading cause of death in the USA and across most of the world. Those fortunate enough to survive can seldom be restored to full function. Extensive epidemiologic research and clinical trials have identified modifiable predisposing risk factors which, when corrected, can reduce the likelihood of its occurrence. Because CVD is a multifactorial disease with the risk factors interacting multiplicatively over time to promote it, these risk factors need to be assessed jointly. To accomplish this, multivariate risk prediction functions (algorithms) which estimate the probability of cardiovascular events conditional on the burden of specified risk factors have been produced to facilitate evaluation of candidates for CVD in need of preventive management.
Over six decades, the Framingham Study and other epidemiological studies have identified modifiable CVD risk factors that have a strong dose-dependent and independent relationship to the rate of development of atherosclerotic CVD. They include classes of risk factors such as atherogenic personal traits, lifestyles that promote them, and innate susceptibility. Most of the relevant risk factors are easy to assess during an office visit and include systolic blood pressure, blood lipids (total and HDL cholesterol) diabetes status, and current smoking. These risk factors in addition to age and sex are the standard CVD risk factors that are basic components in most risk prediction functions.
We summarize the data that established the standard risk factors. We then present the justification and need for multivariate evaluation and prediction functions along with some history. We illustrate the above using examples of existing functions. Then we discuss the evaluation of the performance of the functions and the validity and transportability of existing functions. We end with the discussion of adding new variables (novel biomarkers) to risk prediction.
Ralph B. D’Agostino, William B. Kannel

2. Molecular and Cellular Basis of Myocardial Contractility

Abstract
Cardiac contraction is brought about by interactions between actin and myosin that are regulated by tropomyosin, troponin I, troponin T, and troponin C. Contraction is activated by a process called excitation-contraction coupling that is initiated by plasma membrane depolarization and ends when calcium is delivered to the cytosol for binding to troponin C. Most of this activator calcium is derived from intracellular stores within the sarcoplasmic reticulum; a smaller amount enters from the extracellular fluid. The heart relaxes when calcium is pumped out of the cytosol into the sarcoplasmic reticulum by an ATP-dependent calcium pump and into the extracellular fluid by a sodium/calcium exchanger and a plasma membrane calcium pump.
Arnold M. Katz

3. Ventricular Function

Abstract
The basic cardiac events of the Wiggers’ Cycle are three fold: left ventricular contraction, left ventricular relaxation, and left ventricular filling. Physiologically, systole starts at the beginning of isovolumic contraction when the LV pressure exceeds the atrial pressure. Contractility is a complex concept, with alternate names such as the inotropic state or a contractile state. At a molecular level, increased contractility is enhanced interaction between calcium ions and the contractile proteins. Contractility increases as part of the response to β-adrenergic stimulation. Contractility is independent of the preload and afterload. Starling’s law in modern terms states that increased end-diastolic muscle fiber interaction increases the force and rate of muscular contraction. As the heart muscle is stretched, the interfilament distance decreases and, hypothetically there is an increase rate of change from the weak to the strong binding state with increased contractile activity. The enhanced heart rate (HR) and stroke volume (SV) increase the cardiac output (CO = SV × HR). Thus, exercise increases the heart rate, venous return, and the contractile activity of the heart. The latter is measured at the increase in the inotropic index, dP/dt max. The relaxation phase of the heart, diastole, can be divided into four phases, the first being the isovolumic filling phase, the second being the phase of early rapid filling, and the third the phase of slow filling with the final fourth atrial booster phase accounting for a small percentage. In hypertrophic hearts, increased thickness of the left ventricular leads to impaired diastolic relaxation and shortness of breath. In left heart contractile failure, there are numerous molecular defects in the left ventricle which lead to impaired interaction between calcium ions and the contractile proteins.
Lionel H. Opie

4. Vascular Function

Abstract
The vasculature is a dynamic system that is continually undergoing change by adapting to mechanical, hemodynamic, and humoral changes. Central to these processes are vascular smooth muscle cells (VSMC) that constitute the bulk of the vascular media. VSMCs are regulated by many factors that promote contraction, dilation, growth, fibrosis, calcification, and inflammation, which impact on vascular functional and structural changes. Acute regulation of vascular diameter involves activation/deactivation of the contractile machinery, triggered primarily by an increase in intracellular free calcium concentration. Vasoactive agents, such as Ang II, ET-1, bradykinin, and neurotransmitters, regulate vascular function and in pathological conditions contribute to vascular dysfunction and vascular remodeling. Emerging evidence indicates an important role for reactive oxygen species in the regulation of vascular function. Moreover, factors secreted by adipocytes (adipokines) may directly impact on vascular contraction, dilation, growth, and inflammation. Molecular processes underlying these events are complex and involve small G proteins, phospholipases, protein kinase C, mitogen-activated protein kinases, tyrosine kinases, and RhoA–Rho kinase, among others. This chapter addresses mechanisms regulating vascular function (contraction/dilation) and highlights some processes contributing to vascular structural changes (remodeling). Some important vasoactive agents are described, and implications in vascular dysfunction and cardiovascular disease are discussed.
Rhian M. Touyz, Augusto C. Montezano, Clive Rosendorff

5. Thrombosis

Abstract
Hemostasis is a preventative mechanism for blood loss after vessel injury, while thrombosis describes the pathogenic formation of thrombi. The precise balance of procoagulant and anticoagulant mechanisms keeps blood in a fluid state while circulating, yet can rapidly respond to vascular injury through clot formation. The initial formation of the platelet plug is classically termed “primary hemostasis,” while propagation of the coagulation cascade is termed “secondary hemostasis.”
After vessel injury, platelets adhere to the exposed subendothelium via von Willebrand factor and glycoprotein (GP) Ib-IX-V on the platelet surface. Platelets become activated and secrete a number of molecules including ADP and thromboxane A2, which are platelet agonists themselves leading to further platelet activation. Platelet recruitment and aggregation occurs through binding of platelet GPIIbIIIa receptors to fibrinogen leading to formation of the platelet plug. Tissue factor (TF) in the exposed subendothelium also binds to factor VIIa with formation of the TF-FVIIa complex. The TF-FVIIa complex initiates the coagulation cascade with the ultimate production of thrombin, which is a potent agonist for platelet activation.
Chronic atherosclerotic lesions are associated with plaque formation, which, when ruptured, exposes blood to collagen and to TF in the macrophages of atheroma. There are distinct hemostatic factors in the platelet and coagulation systems that modulate atherosclerosis and have an effect on atherothrombosis. A systemic inflammatory environment leads to a proatherogenic endothelium, independent of vessel wall injury. Atherogenic mediators include cytokines, adhesion molecules like P-selectin, and TF.
Given our thorough understanding of primary and secondary hemostasis, numerous antiplatelet and anticoagulant drugs have been synthesized. This chapter reviews in detail the mechanism of action and properties of the various agents used in clinical practice and some newer experimental agents.
Farzana R. Bacchus, Mark Crowther

6. The History and Physical Examination of the Cardiovascular System

Abstract
In this chapter, we outline the general approach to the patient with known or suspected cardiovascular disease with specific emphasis on the history and physical examination. Time constraints challenge the development of a detailed history, yet a properly obtained patient narrative can serve to guide the examination and subsequent diagnostic testing. Special attention should be given to the family history as genetic testing and personalized medicine grow in importance. A general examination that includes assessment of the major organ systems, coupled with specific attention to the venous and arterial waveforms, as well as inspection, palpation, and auscultation of the heart, makes for a complete cardiovascular evaluation. This chapter provides a guide to recognizing and applying the findings on physical examination to the diagnosis and assessment of a variety of cardiovascular disorders. The history and physical examination constitute the foundation of the doctor-patient relationship and should serve as the springboard for diagnosis and management.
Rajat Gupta, Patrick O’Gara

7. Electrocardiography

Abstract
Electrocardiography, one of the most useful tools in the field of cardiology, offers an electrical snapshot of the heart that can potentially reveal information about physiological conditions in the human body. As such, the physician must clearly understand the elements of the electrocardiogram (ECG) from the generation of the normative tracing to the significance of changes in that tracing during various clinical situations. This chapter presents the ECG in its entirety, beginning with the derivation of the leads, axis, and standardization of the recording. The chapter can basically be broken down into four sections: the basics of electrocardiographic generation; description and illustration of the waves and intervals, including the physiology behind each and examples of pathological alterations; myocardial infarction and its differential diagnosis; and other commonly encountered medical scenarios and their respective influence on the ECG. The fourth section of the chapter includes discussion of drug effects of digoxin, metabolic abnormalities, pulmonary diseases, acute pericarditis, pericardial effusion, central nervous system disorders, the preexcitation syndrome, and congenital and acquired heart disease. Updated sections of the chapter in the most recent edition expand upon the early repolarization pattern/J-wave and the prolonged as well as the congenitally shortened QT interval.
Tara L. DiMino, Alexander Ivanov, James F. Burke, Peter R. Kowey

8. Echocardiography

Abstract
Echocardiography is the most commonly used cardiac imaging technique. It has the advantages of portability, safety, and overall accuracy in evaluation of ventricular systolic and diastolic function, cardiac chamber sizes, regional wall motion abnormalities (both at rest and with stress imaging), valvular pathology, and pericardial disease. This chapter discusses the utility and limitations of transthoracic, transesophageal, and Doppler echocardiographic imaging.
Daniel G. Blanchard, Anthony N. DeMaria

9. Exercise Testing

Abstract
Exercise testing is an important part of the clinical evaluation of cardiovascular status. In this chapter, we will review the different protocols, indications, and contraindications for this testing. The diagnostic, as well as prognostic, use of exercise testing are explained, with reference to the current ACC/AHA guidelines. The two major exercise test scores—the Duke treadmill and VA predictive score—each provide important prognostication tools for patient care. The chapter includes how to calculate each score and provides an example of using the Duke nomogram with the important variable of age added. The exercise stress test is also compared to other methods of stress testing, such as nuclear perfusion and echocardiogram examinations. Patient characteristics such as beta-blocker use, digoxin use, gender, age, and symptoms require consideration, but do not preclude exercise stress testing. The exercise test is relatively inexpensive, noninvasive, and readily available. It provides both diagnostic and prognostic information and can also help determine functional capacity and degree of disability.
Abhimanyu (Manu) Uberoi, Shirin Zarafshar, Victor Froelicher

10. Radiology of the Heart

Abstract
The chest radiograph is the first imaging study performed in patients suspected of having cardiac disease. This chapter discusses the role of the chest radiograph in the diagnosis of cardiac disease in adults, with an emphasis on both normal cardiovascular anatomy and pathology in a variety of diseases. Cross-sectional imaging is correlated with plain film images to illustrate important anatomic points. Thorough knowledge of mediastinal interfaces and the cardiac borders will help to determine if pathology is present. There are many frequently occurring cardiovascular conditions with specific and often diagnostic imaging findings on the plain chest radiograph. The conditions that will be discussed include aortic stenosis and insufficiency, mitral stenosis and acute mitral regurgitation, pericardial calcification suggesting constriction, and the plain film alterations found in atrial septal defect and other intracardiac defects.
Christopher M. Walker, Gautham P. Reddy, Robert M. Steiner

11. Cardiac Catheterization

Abstract
Diagnostic cardiac catheterization is recommended whenever it is clinically important to define the presence or severity of a suspected cardiac lesion that cannot be evaluated adequately by noninvasive techniques. Because the risk of a major complication from cardiac catheterization is less than 1 % with mortality of less than 0.08 %, there are few patients who cannot be studied safely in an active laboratory. Intracardiac pressure measurements and coronary arteriography are procedures that can be performed with reproducible accuracy best by invasive catheterization. Identification of coronary artery disease and assessment of its extent and severity are the most common indications for cardiac catheterization in adults. The information obtained is crucial to optimize the selection of mechanical or medical therapy. In addition, dynamic coronary vascular lesions, such as spasm, myocardial bridging, and plaque rupture with thrombosis, can be identified. The consequences of coronary heart disease, such as ischemic mitral regurgitation and left ventricular (LV) dysfunction, can be defined. Cardiac catheterization should be considered a diagnostic test used in combination with complementary noninvasive tests. This allows catheterization to be directed and simplified without obtaining redundant anatomic information that is reliably available through echocardiography and cardiac magnetic resonance. There is no true absolute contraindication to cardiac catheterization other than refusal of the competent patient. The procedure can be successfully performed even in the most critically ill patient with a relatively low risk.
Nirat Beohar, Mark J. Ricciardi, Charles J. Davidson

12. Nuclear Imaging in Cardiovascular Medicine

Abstract
Nuclear cardiovascular imaging uses various radioisotopes labeled to suitable molecules to noninvasively image various biological phenomena in the intact human body under various physiological conditions. In cardiovascular medicine, we can study myocardial perfusion, function, and metabolism at rest and with exercise or pharmacological stress. Myocardial perfusion imaging is perhaps the most powerful and widely used noninvasive test for diagnosing, risk stratification, and evaluating the progress of patients with coronary artery disease. A number of advances have been made recently in the techniques and instrumentation used for myocardial perfusion imaging, to improve its diagnostic accuracy and patient comfort and reduce radiation exposure to the patients. Single-photon emission tomography (SPECT) is the conventional technique for nuclear imaging. However, positron emission tomography (PET) is increasingly being used. PET imaging offers better resolution and better image quality and less susceptibility to technical artifacts compared to SPECT imaging. A number of new molecular imaging techniques are currently under development. These techniques use novel radiopharmaceuticals and offer the possibility of noninvasive imaging of several complex biological phenomena such as myocardial ischemia; atheroma, vascular inflammation, and vascular remodeling; angiogenesis, stem cell and gene therapy, and gene expression; and myocardial injury, repair, and remodeling.
Diwakar Jain, Barry L. Zaret

13. Cardiovascular Magnetic Resonance and Multidetector Computed Tomography

Abstract
The advanced imaging technologies, cardiovascular computed tomography (using X-ray), and cardiovascular magnetic resonance (using magnetic and radio frequency or RF fields) generally provide more comprehensive and frequently unique clinical information compared with other technologies. They are not used routinely, but rather for specific indications. Since they are more technically advanced, they are more expensive and require additional knowledge for proper acquisition and interpretation. The strength of CCT resides in its ability to provide excellent imaging quality of the large- and medium-sized coronary arteries using IV-administered contrast medium. While CCT utilizes X-rays, the radiation dose is drastically decreasing with improving technology. The strengths of CMR are the ability to visualize morphology, function, perfusion, viability, and metabolism without ionizing radiation, although sometimes requiring IV gadolinium contrast agent. These two technologies have received relatively recent Nobel prizes (one for CT and three for MRI), and both continue to improve with the advent of new software and hardware. This chapter provides a background for most of the commonly employed applications of computed tomography and magnetic resonance imaging of the heart.
Gabriel Vorobiof, Norman Elliot Lepor, Mark Doyle, Hee-Won Kim, Gerald M. Pohost

14. Choosing Appropriate Imaging Techniques

Abstract
There is no single algorithm for choosing among myriad cardiac imaging tests. Suspected or confirmed epicardial coronary artery stenoses are typically evaluated directly by X-ray angiography in settings where revascularization is under consideration or when the pretest likelihood of disease is sufficiently high to warrant bypassing less invasive indirect testing of coronary perfusion (i.e., treadmill stress electrocardiography, stress echocardiography, or myocardial perfusion imaging.) As the pathophysiologic model of acute coronary syndromes continues to evolve, more attention will focus on early detection of nonstenotic but high-risk “vulnerable” atheromatous plaques. CT, cardiac MRI, intravascular ultrasound, and nuclear imaging techniques will continue to evolve for the purpose of coronary plaque characterization and risk stratification.
Myocardial and valvular disorders, including myocardial tissue abnormalities and systolic and diastolic dysfunction, are best imaged by techniques that provide both structural and functional (i.e., hemodynamic) information. While 2-D echocardiography with Doppler imaging is currently the standard for assessing myocardial and valvular function, cardiac MR techniques may develop into a new “gold standard” for measuring systolic function. 3-D echocardiography has great potential. Invasive measurement of intracardiac pressures by right heart catheterization is reserved for cases in which noninvasive testing yields inconclusive results or results discrepant with clinical findings.
Martin E. Goldman, Anthony F. Yu

15. Electrophysiology of Cardiac Arrhythmias

Abstract
Abnormalities in the initiation and propagation of cardiac impulses result in a variety of arrhythmias. The cardiac action potential consists of five phases that are determined by channels that allow ions to flow passively down their electrochemical gradients, as well as by a series of energy-dependent ion pumps, thereby leading to cardiac contraction.
Sodium, potassium, calcium, and chloride ions are principally responsible for the membrane potential (phase 4). Phase 0 marks the initiation of the action potential. In nodal cells, the pacemaker current, If, initiates each cycle. In “nonpacemaker” tissue, If is absent. In these cells, phase 0 is triggered when the cell membrane is depolarized by adjacent cells. Phase 1 consists of rapid membrane repolarization. This is achieved by inactivation of the inward Na+ current and activation of a transient outward current, Ito. Phase 2, the plateau phase, is characterized by a small change in membrane potential generated by the L-type calcium channel, ICa–L. Rapid repolarization of the cell occurs during phase 3. ICa–L is inactivated in a time-dependent fashion, thus decreasing the flow of cations into the cell, while several outward potassium currents become active. This results in a net outward positive current and a negative transmembrane potential.
The mechanisms of cardiac arrhythmias can be divided into three categories: (1) abnormal or enhanced automaticity, (2) triggered activity, and (3) reentry. This chapter reviews each of these mechanisms, along with the common clinical correlates of each.
Sei Iwai, Steven M. Markowitz, Bruce B. Lerman

16. Treatment of Cardiac Arrhythmias

Abstract
The treatment of arrhythmias involves consideration of patient symptoms, the clinical situation in which the arrhythmia arises, the natural history of a given arrhythmia, and the relative likelihood of success of different pharmacologic and invasive options such as device implantation, catheter ablation, or surgery. With advances in implantable cardiac devices and catheter ablation, the options for arrhythmia treatment have expanded significantly, and a basic understanding of these procedures is necessary to properly counsel patients on arrhythmia management. It is also important to understand the basic pharmacology of antiarrhythmic drugs, their indications, and their potential side effects and relative contraindications. An algorithmic approach to decision making while also taking into account individual patient preference and clinician experience is key. Thus, a structured approach to considering the different treatment modalities available for arrhythmias, when certain therapies may be reasonable, and how they may be implemented must be taken in the context of constantly evolving epidemiologic understanding and technological advances.
Suraj Kapa, Francis E. Marchlinski

17. Syncope

Abstract
Syncope is a syndrome in which a relatively brief and self-limited period of loss of consciousness is triggered by transient insufficiency of oxygen delivery to the brain; most often, spontaneously reversible systemic hypotension leading to insufficient cerebral blood flow is at fault. Syncope falls within a larger set of conditions in which there is real or apparent transient loss of consciousness (TLOC). However, not all TLOC is syncope. Thus, a TLOC episode should not be considered syncope if a medical intervention is required to reverse the loss of consciousness. Similarly, if cerebral dysfunction is not due to insufficient cerebral nutrient flow, the loss of consciousness or apparent loss of consciousness should not be termed syncope. Finally, many patients complain of less-specific symptoms such as “dizziness” or “lightheadedness.” Most often, these latter symptoms are not related to syncope either clinically or pathophysiologically but nevertheless often find their way into the “syncope clinic” and require evaluation. A wide range of conditions may be responsible for initiating syncope. In any case, whether the underlying problem is “innocent” or potentially life-threatening, syncope may lead to physical injury, accidents that put the affected individual and others at risk, and economic loss. The physician’s key tasks are to establish a confident causal diagnosis and provide appropriate advice regarding treatment and prognosis. To be successful, it is important to develop an organized approach to the assessment of the syncope patient. The initial patient evaluation, particularly a detailed medical history, is crucial. Subsequently, carefully selected diagnostic tests can be chosen to confirm the clinical suspicion. This chapter focuses on clinical management (diagnosis and treatment) of syncope. Whenever possible, the recommendations provided here are adapted from the European Society of Cardiology Syncope Task Force guidelines.
Venkata Krishna Puppala, Scott Sakaguchi, Oana Dickinson, David G. Benditt

18. Pathophysiology of Heart Failure

Abstract
This chapter outlines our current understanding of the syndrome of heart failure and the pathophysiological abnormalities triggered by the underlying cardiac dysfunction. Many mechanisms are activated in an attempt to compensate for depressed cardiac performance. Objective cardiac measurements, however, may correlate poorly with the clinical manifestations of the heart failure syndrome – the body’s response varies markedly from one patient to another and over time. Many of these responses take place within the heart, at the anatomical, cellular, molecular, and genetic levels. In addition, a variety of systemic responses also occur, including activation of the sympathetic, renin–angiotensin–aldosterone, and natriuretic peptide systems; increased peripheral vascular resistance; cytokine activation; and skeletal muscle dysfunction. Such changes are frequently accompanied by renal dysfunction, anemia, and sleep-disordered breathing. In general, the heart failure syndrome comprises a gradual decline in cardiac function, and once symptoms develop the decline becomes more rapid, eventually resulting in death. This decline may be stepwise, as in myocardial infarction, or progressive as in hypertensive or valve disease. At any stage, sudden cardiac death may occur, secondary to arrhythmia. A better understanding of the pathophysiology of the syndrome had opened up new avenues for therapy.
Martin R. Cowie, Philip A. Poole-Wilson

19. Treatment of Congestive Heart Failure

Abstract
The goals of heart failure treatment include both symptomatic improvement and prolongation of life. These goals are not necessarily concordant. Related to this problem is the observation that the acute actions of an intervention may be very different than the chronic effects. When treating heart failure, therefore, one must understand the immediate and long-term desires of a particular patient and the immediate and long-term consequences of one’s therapy. The result is an uncomfortable use of acute treatments known to have adverse consequences when given for a prolonged period and chronic treatments which are counterintuitive. Fortunately, however, congestive heart failure has been well investigated with multiple large studies demonstrating the multiple consequences of many of our standard interventions.
Stephen S. Gottlieb

20. Congenital Heart Disease

Abstract
Congenital heart disease (CHD) is defined as a cardiovascular defect that is present since birth. Due to substantial medical and surgical advances, the majority of patients with CHD now survive into adulthood and form an exponentially growing population of more than 1,000,000 in the USA. Despite improved survival, it has become apparent that timely interventions are reparative and not curative with significant sequelae and residual hemodynamic lesions in most cases. The complexity of the anatomy and physiology of patients with CHD presents physicians with challenges that are unique to this population. Thus, familiarization with the principles of management of patients with CHD is essential. This book chapter provides an introduction to the most prevalent CHD lesions and summarizes specific issues which are topical to adult patients with CHD.
Matina Prapa, Dimitra Krexi, Anselm Uebing, Michael A. Gatzoulis

21. Pathogenesis of Atherosclerosis

Abstract
Atherosclerotic vascular disease is a leading cause of death and disability throughout the USA and other industrialized nations and consumes enormous fiscal resources. Atherosclerosis involves the development of a plaque composed of variable amounts of atherogenic lipoproteins, extracellular matrix (collagen, proteoglycans, glycosaminoglycans), calcium, vascular smooth muscle cells, inflammatory and immune cells (chiefly monocyte-derived macrophages, T lymphocytes, mast cells, dendritic cells), and new blood vessels. Atherosclerosis represents a chronic inflammatory response to vascular injury triggered by a variety of risk factors that injure endothelium and promote lipoprotein infiltration, retention, and modification, combined with leukocyte entry, retention, proliferation, and activation. Atherosclerosis predisposes to arterial thrombosis and acute arterial occlusion when plaque disruption leads to activation of the clotting cascade in the vasculature. Ultimately, most lethal and significant occlusive cardiovascular events result from plaque disruption leading to thrombosis. Disruption of plaques is believed to result from inflammation and immune activation in the plaque leading to matrix degradation and inadequate repair. Inflammation plays a crucial role in the initiation, progression, and eventual destabilization of atherosclerotic plaques. Disruption-prone plaques generally contain large necrotic lipid core with adventitial remodeling, plaque cap inflammation, increased neovascularity, and intraplaque hemorrhage.
Prediman K. Shah

22. Coronary Blood Flow and Myocardial Ischemia

Abstract
This chapter reviews coronary flow regulation in normal and pathophysiological states. Under normal conditions, the heart maximally extracts oxygen and as a result, increases in oxygen demand are met by proportionate increases in coronary blood flow. Mechanisms responsible for the regulation of coronary resistance in the microcirculation include metabolic, myogenic, and flow-dependent resistance vessel control. There is substantial vasodilator reserve in the normal heart such that, in the presence of an epicardial coronary stenosis, local vasodilation decreases vascular resistance and autoregulates flow at the normal level as coronary pressure falls. As stenosis severity increases, however, flow reserve is exhausted and the subendocardium becomes vulnerable to reversible ischemia during increased myocardial oxygen demands. When ischemia is severe and prolonged following a total coronary occlusion, irreversible myocyte injury develops leading to a wave front of myocardial necrosis that extends from subendocardium to subepicardium. When ischemia is brief (as in angina), myocardial function remains depressed after flow normalizes indicative of myocardial stunning. Repetitive reversible ischemia leads to persistent dysfunction followed by intrinsic adaptive responses characteristic of hibernating myocardium. These protect the heart from irreversible injury and acute stunning at the expense of producing chronically depressed but reversible contractile dysfunction. A thorough understanding of coronary physiology and myocardial ischemia is essential in the management of patients with coronary artery disease.
Brian R. Weil, John M. Canty

23. Risk Factors and Prevention, Including Hyperlipidemia

Abstract
Improvements in control of cardiovascular risk factors, combined with advances in the pharmacologic and surgical management of patients with atherosclerotic vascular disease, have resulted in an age-adjusted decline in cardiovascular morbidity and mortality. This chapter reviews the major cardiovascular risk factors with a special emphasis on dyslipidemia. Non-modifiable risk factors include age, gender, and family history, and their impact can be lessened by lifestyle modifications to address obesity, hypertension, and dyslipidemia. In addition to dyslipidemia, hypertension and cigarette smoking are the major modifiable risk factors whose optimization has been shown to substantially reduce risk for cardiovascular disease. Dyslipidemia can be manifested as abnormalities in plasma levels of triglyceride-rich lipoproteins, low-density lipoprotein (LDL) cholesterol, or high-density lipoprotein (HDL) cholesterol. The National Cholesterol Education Program issues guidelines for the screening, diagnosis, and treatment of dyslipidemia. Risk assessment incorporates Framingham scoring and the presence of major risk factors to determine the necessity and intensity of pharmacologic therapy. Lifestyle modifications, including increased physical activity and dietary improvements, are key to reducing cardiovascular risk in both primary and secondary prevention. Drug therapy should be targeted at the lipid phenotype. Agents predominantly affecting LDL cholesterol include bile acid sequestrants, statins, and ezetimibe, while those that have a primary effect on triglyceride and HDL cholesterol levels are nicotinic acid and fibric acid derivatives. This chapter concludes with a discussion of cardiovascular risk factors in elderly and pediatric patients, women, individuals with obesity or metabolic syndrome, and patients with diabetes.
Antonio M. Gotto, John A. Farmer

24. Stable Angina

Abstract
In the USA, it is estimated that there are more than 13 million people with coronary artery disease (CAD). Beyond a thorough history and physical, there are several diagnostic tests used to detect CAD. If indicated, medications with different mechanistic behaviors are used to prevent cardiac injury and provide symptomatic relief. In addition to medical therapy, revascularization plays a significant function in treatment. The roles of coronary artery bypass surgery (CABG) and percutaneous coronary intervention (PCI) have evolved over the past several decades. The decision to pursue revascularization and the type of procedure to perform depends on the amount of ischemic burden. Additionally, if a patient continues to have symptoms despite optimal medical therapy, revascularization should be considered. Finally, exercise is a key component in treating CAD. Every patient should be instructed to perform exercise training to supplement medical therapy and revascularization procedures for optimal treatment.
Sachin Mehta, Neal Kleiman

25. Unstable Angina and Non-ST Segment Elevation Myocardial Infarction (Acute Coronary Syndromes)

Abstract
Acute coronary syndrome (ACS) and the sequelae that stem from this disease process affect millions of patients every year. In addition to a comprehensive history and physical examination, biochemical markers have been developed to aid in diagnosing ACS. Once the diagnosis has been established, there is a medley of medications that are used commonly in the treatment of unstable angina. These medications include anti-ischemic, vasodilator, antiplatelet, antithrombotic, and statin therapies. Increasingly, newer agents within each drug class are being developed and utilized. Beyond medical therapy, revascularization is frequently performed and is very efficacious in treating ACS. The timing, extent, and type of revascularization are individualized to each patient and are determined by the clinical, local, and anatomical nature of the patient’s underlying coronary artery disease.
Sachin Mehta, Neal Kleiman

26. ST-Segment Elevation Myocardial Infarction

Abstract
ST-segment elevation myocardial infarction (STEMI) remains an important cause of morbidity and mortality in industrialized nations, and advances are continually being made in this realm. From primary and secondary prevention to prehospital care, acute reperfusion therapy, adjunctive medical therapy, and management of complications, innovative treatments and systems are constantly reshaping the landscape of STEMI care. Increasingly, attention is being placed on the quality of acute MI care, with recognition that improvement in processes of care can directly lead to better patient outcomes. This chapter provides up-to-date knowledge of the pathophysiologic mechanisms, diagnostic modalities, therapeutic strategies, and potential complications of STEMI that health-care providers caring for these patients need to know.
Jonathan R. Enriquez, James A. de Lemos

27. Cardiopulmonary Resuscitation

Abstract
Out-of-hospital cardiac arrest claims the lives of approximately 382,800 adult Americans each year. The majority of these victims have underlying structural heart disease, usually in the form of coronary atherosclerosis. Out-of-hospital cardiac arrest occurring in public places is usually caused by a chance arrhythmic event that is triggered by an interaction between structural heart abnormalities and transient, functional electrophysiological disturbances. In such cases, the single most important determinant of survival is the time interval from initiation of the cardiac arrest until defibrillation. Waveform capnography, regionalized post-resuscitation care with therapeutic hypothermia, bundled goal-directed therapy, and frequent EEG (preferably continuous) recording are now important American Heart Association CPR Guideline recommendations.
Joseph P. Ornato

28. Cardiac Rehabilitation and Secondary Prevention After Acute MI

Abstract
Cardiac rehabilitation programs for patients following an acute MI originally consisted of early ambulation and moderate-intensity physical activity in the hospital and following discharge in order to counter the debilitating effects of bed rest. They subsequently have evolved into comprehensive, multifaceted, physician-supervised programs targeted not only at improving the patient’s functional capacity but also for preventing recurrent (secondary) coronary and other cardiovascular events. These cardiac rehabilitation/secondary prevention programs (CRSPP) currently include, in addition to supervised exercise training, intense risk factor modification, patient and family education about coronary heart disease, psychosocial counseling and support, and, if necessary, vocational and occupational counseling. CRSPP in addition to improving the patient’s functional capacity, and hence quality of life, have been shown by meta-analyses of randomized trials to reduce fatal and nonfatal cardiovascular recurrent events as well as all-cause mortality. The purpose of this chapter is to review the evolution of such programs, the research-based evidence of their benefits, and their recommended components and personnel.
Arthur S. Leon

29. Rheumatic Fever and Valvular Heart Disease

Abstract
Although the incidence of rheumatic fever has declined dramatically in developed countries in the last few decades, it continues to be a major cause of morbidity and mortality in the developing world. There is no test specific for the diagnosis in rheumatic fever, and the diagnosis relies heavily on clinical findings and a few simple investigations.
Those with a history of or established rheumatic fever are at increased risk of recurrence, and thus, a lower threshold for the diagnosis of recurrence has been established. Secondary prophylaxis has proven to be the most cost-effective strategy for the prevention of recurrence. Especially in high-risk settings and in more severe valvular heart disease, a longer period, in some cases even lifelong, of prophylaxis is advocated according to the new WHO guidelines.
Mitral stenosis is almost exclusively due to rheumatic heart disease. Medical management, percutaneous balloon valvuloplasty, and valve replacement strategies are discussed. Pure MR is uncommon in rheumatic heart disease. Mitral valve repair or replacement is indicated in patients with severe MR and NYHA III or IV. Asymptomatic or mildly symptomatic patients can be managed medically provided LVEF and symptoms get monitored, and they are referred for surgery if the EF falls toward 60 % or the end-systolic dimension reaches 45 mm.
Aortic stenosis requires surgery when symptoms occur. Patients with severe aortic regurgitation should also be offered valve replacement when they become symptomatic. Those with severe AR who do not experience symptoms require careful evaluation and follow-up of their left ventricular ejection fractions and end-systolic and end-diastolic diameters to determine when surgery would be warranted.
Tricuspid disease is often overlooked as the symptoms of the left-sided lesion may predominate. It is almost always associated with mitral valve disease and adds a dimension of complexity to the treatment as well as an unfavorable impact on prognosis.
In many cases multiple valves are involved, and this has a profound impact on the assessment, by any modality, of the severity of each individual valve lesion.
Blanche J. Cupido, Patrick J. Commerford

30. Infective Endocarditis

Abstract
The incidence and clinical manifestations of infective endocarditis (IE) have remained stable over the past four decades. The epidemiology and consequently the microbiology of IE have changed dramatically during this time period. As a result of modern healthcare using invasive technology, including the implantation of intracardiac devices (prosthetic valves, pacemakers, implanted defibrillators), 25–35 % of IE is healthcare associated and occurs in older patients with multiple comorbidities resulting in increased risk of death. From 13 to 22 % of IE involves prosthetic valves (PVE) and 6 to 13 % involves cardiac implanted electrical devices. Extensive injection drug abuse in our society has become another major predisposition accounting for 10 % of cases. Because of these two predispositions, Staphylococcus aureus, with its increased virulence and significant association with embolic complications, valve destruction, and increased mortality, has become the single most common organism causing IE. Antimicrobial therapy has evolved to address increased resistance among classical organisms causing IE and increased awareness of adverse events result from treatment. Newer regimens include short-course combination therapy for penicillin-susceptible viridans streptococcal native valve IE (NVE). The role of gentamicin in treating left-sided S. aureus NVE has been questioned; double beta-lactam therapy for Enterococcus faecalis and daptomycin for right-sided S. aureus IE are new regimens. The indications for surgical treatment have been clarified by more sophisticated statistical analyses and as has the population wherein early (first week) valve replacement will reduce mortality. It has become clear that reduced mortality resulting from valve surgery is not fully recognized until 6 months have elapsed from initial hospitalization. Lastly, the approach to prevention of IE has been markedly truncated. Prophylaxis in the United States is currently recommended for only 4 groups of patients identified as those at greatest risk of morbidity and mortality from IE and is advised only in association with dental and respiratory tract procedures, while in the United Kingdom, prophylaxis is no longer recommended for anyone.
Adolf W. Karchmer

31. Hypertension: Mechanisms and Diagnosis

Abstract
Hypertension, defined as an arterial blood pressure (BP) of ≥140/90 mmHg, affects one in three US adults and is a major independent risk factor for myocardial infarction, stroke, and renal failure. Only 43 % of the total hypertensive population has their BP controlled to goal (<140/90 mmHg). Pre-hypertension refers to a BP of 120–139/80–89 mmHg and also increases cardiovascular risk, compared with normal BP (<120/80 mmHg). Definitions are provided for the terms essential hypertension, secondary hypertension, refractory (resistant) hypertension, pseudohypertension, white coat hypertension, masked hypertension, and hypertensive crisis. This chapter deals with definitions, measurement of BP, the initial workup of the hypertensive patient, target-organ damage (vascular hypertrophy, left ventricular hypertrophy, myocardial infarction, stroke, encephalopathy, chronic kidney disease, and retinopathy), hypertensive emergency and urgency, and risk factor profiling. The section on the pathogenesis of primary hypertension deals with genetic factors, increased cardiac output, excessive dietary sodium, renal sodium retention, increased activity of the renin–angiotensin system, increased sympathetic activity, increased peripheral resistance, abnormal cell membrane ion transport, endothelial function, and insulin resistance and hyperinsulinemia. Causes of secondary hypertension include renal artery stenosis, renal parenchymal disease, pheochromocytoma, and abnormalities of adrenocortical function.
Clive Rosendorff

32. Hypertension Therapy

Abstract
With an increase in life expectancy and obesity, the number of patients needing therapy to reduce their hypertension will continue to increase. In the USA in 2012, fewer than half of hypertensive patients are being adequately treated. In order to improve the management of hypertension, the use of more effective and intensive lifestyle modifications and antihypertensive drugs is needed. The appropriate application of these treatments is addressed in this chapter.
Norman M. Kaplan, Odelia Cooper, Ronald G. Victor

33. Cardiomyopathies and Myocarditis

Abstract
Cardiomyopathies are diseases of the heart muscle characterized by abnormal chamber size, wall thickness, or functional contractile abnormalities such as systolic or diastolic dysfunction. They include a variety of myocardial disorders that manifest with various structural and functional phenotypes and are frequently genetic. Primary cardiomyopathies consist of disorders that are confined to the heart muscle and are genetic, mixed, and acquired, while secondary cardiomyopathies are caused by myocardial damage from a systemic disease process. The World Health Organization/International Society and Federation of Cardiology task force on the definition and classification of cardiomyopathies has defined five subtypes of cardiomyopathy: dilated, hypertrophic, restrictive, arrhythmogenic right ventricular dysplasia, and unclassified cardiomyopathies. In 2008, the European Society of Cardiology’s working group on myocardial and pericardial diseases presented an update to the WHO/ISFC classification in which cardiomyopathy was defined as “A myocardial disorder in which the heart muscle is structurally and functionally abnormal in the absence of coronary artery disease, hypertension, valvular disease and congenital heart disease sufficient to explain the observed myocardial abnormality.” Dilated cardiomyopathy is the most common cause, compromising 90 % of cases. Each type of cardiomyopathy has unique etiologies and properties. Treatment is usually directed toward the underlying cause.
Colleen M. Harrington, Edward K. Kasper

34. Pericardial Disease

Abstract
The clinical diagnosis of acute pericarditis is based on chest pain, a pericardial friction rub and ECG changes (ST-segment elevation acutely, low voltage by effusion). Effusions can be detected best by echocardiography. Echocardiography or magnetic resonance imaging (MRI) is essential to detect concomitant myocarditis, valvular abscesses in endocarditis or aortic dissection. Idiopathic pericarditis describes our inability to define the exact aetiology, which is often viral or autoreactive. For their diagnosis, pericardiocentesis, pericardioscopy, pericardial or epicardial biopsy are essential. Polymerase chain reaction (PCR) can assess the causative microbial agent in fluid or peri- and epicardial biopsy. Autoreactive or malignant processes are detected by cytology, histopathology and immunological methods. Whereas bacterial pericarditis has become rare in Western countries, it is still a major problem in other parts of the world, e.g. for tuberculous pericarditis. Pericardiocentesis is indicated for cardiac tamponade, which occurs most frequently in neoplastic pericarditis, and in suspected purulent effusions or in larger effusion of unknown aetiology. If carried out with fluoroscopy, the halo phenomenon can guide pericardiocentesis. Aortic dissection is a contraindication for pericardiocentesis but an indication for surgery as in cardiac trauma or postinfarction myocardial rupture. Loculated effusions may require surgery or pericardiocenteses guided by echocardiography or thoracoscopy. In neoplastic effusion, intrapericardial instillation of cisplatin or thiotepa can prevent recurrences, but not the final outcome. In autoreactive effusions, intrapericardial instillation of triamcinolone is recommended to avoid the side effects of systemic corticosteroid therapy. Nonsteroidal antiphlogistics are the mainstay of acute symptomatic treatment, whereas colchicine is given in recurrent and protracted forms of acute pericarditis for longer time periods or when the effusion is too small for puncture. In constrictive pericarditis, the expansion of the ventricles is impaired due to the stiff or chronically inflamed, mostly thickened pericardium. Then pericardiectomy is to be carried out. It should not be performed too early to avoid operating for transient constriction, but also not too late to avoid myocardial fibrosis and/or atrophy.
Bernhard Maisch

35. Pulmonary Vascular Disease

Abstract
A wide variety of disorders affect the pulmonary vasculature including pulmonary hypertension (PH) and pulmonary embolism (PE). Increased understanding of the pathophysiological basis of PH has led to a reclassification, incorporating multiple etiological factors including heritable forms. Accurate classification of PH subtypes relies on a detailed clinical and diagnostic evaluation, with right heart catheterization a requirement for definitive diagnosis. Recently developed therapies have been shown to provide clinical benefit in selected patients with PH.
Significant progress has also been made in PE. Technological improvements in diagnostics, most notably in computed tomography pulmonary angiography (CTPA), have led to increased and more accurate detection of PE. Algorithms based on risk stratification and clinical probabilities have been refined to assist clinicians in the diagnosis and treatment of this frequently complex condition. Treatment with anticoagulation and thrombolytic therapy has evolved. Outpatient management is now increasingly recognized as a viable option.
This chapter will focus on two of the most widely encountered manifestations of pulmonary vascular disease – PH and PE. In addition to discussing the etiology, epidemiology, diagnosis, and treatment of these diseases, the chapter highlights recently published evidence-based guidelines.
Eoin P. Judge, Dermot O’Callaghan, Sean P. Gaine

36. Diseases of the Aorta

Abstract
Diseases of the aorta can affect any segment of the aorta or its branch vessels, may exhibit diverse and at times nonspecific protean manifestations, and might be chronic and indolent but also have the potential to present with acutely lethal consequences. Accordingly, it is imperative that both internists and cardiologists are familiar with principles of emergent management of aortopathies as well as of screening for these conditions, since detection and prophylactic treatment of diseases of the aorta will generally improve patient outcomes. Aortic aneurysms represent dilatation of all three layers of the vessel wall and may cause mass effects or progress toward dissection and/or rupture. Acute aortic dissections require prompt diagnosis and expert medical and interventional management. Endovascular techniques have become an adjunct to traditional open surgical repairs and may be utilized for select patient populations and scenarios, though comparative and long-term outcomes of the endovascular approach remain under investigation. Genetic and molecular techniques are elucidating novel pathophysiologic bases underlying diseases of the aorta and may reveal future therapeutic targets that can prevent or reverse aortopathy.
David M. Dudzinski, Eric M. Isselbacher

37. Cardiovascular Disease in Women

Abstract
Cardiovascular disease (CVD) is the leading cause of death in women. Clear gender differences exist in the incidence, prevalence, presentation, diagnosis, treatment, and prognosis of cardiovascular diseases. Over the past 15 years, robust efforts focused on the evidence-based prevention and treatment of CVD in women have resulted in a steeper decrease in cardiovascular (CV) mortality rates in women compared to men beginning in 2000. The prominent decline in female CV mortality rates is a new phenomenon, as decreases in male CV mortality rates outpaced those in women during the 1980s and 1990s. Historically, women have been underrepresented in clinical trials investigating cardiovascular diseases. Over the past decade, the representation of women in clinical trials has improved, and nuanced treatment approaches and prevention strategies have resulted from the dedicated study of gender differences. The traditional CV research focus has been on obstructive coronary disease and the development and complications of ischemic heart disease in men. Research has shown multiple layers of complexity in the etiology and pathophysiology of cardiovascular diseases in women differing from those predominating in men. Investigation has also shown a relationship between the hormonal fluctuations women experience throughout life and the development of ischemic heart disease and arrhythmias. Therefore, cardiovascular disease processes in women should not be equated to those traditionally encountered in the male population, and these differences should alter the physicians’ approach to the female patient.
Benjamin D. Mackie, Nanette Kass Wenger

38. Pregnancy and Heart Disease

Abstract
Although women with heart disease are rare in the obstetric population, they are the main cause of maternal mortality and morbidity. During pregnancy large hemodynamic changes take place. In developing countries, rheumatic heart disease is still a major problem. While in the developed countries congenital heart disease is most often encountered, but acquired heart diseases such as aortic dissection and acute coronary syndrome cause the highest maternal mortality rates.
Specific Cardiac Disease. Congenital cardiology covers a wide spectrum of heart diseases, ranging from simple shunts lesions to very rare and complex disorders. Patients with unrepaired lesions, cyanotic lesions, diminished systemic ventricular function, complex congenital heart disease, left ventricular outflow tract obstruction, and mechanical valves are at highest risk of complications during pregnancy. Although other conditions such as peripartum cardiomyopathy, Marfan syndrome, and pulmonary arterial hypertension are also associated with high maternal mortality and compromised pregnancy outcome.
Management. Pre-pregnancy evaluation should focus on identifying and quantifying the risk to the mother and on the outcomes of the potential pregnancy. Current medication use should be discussed and if necessary changed, since some medication may be harmful for the unborn child. The most common cardiac complications in pregnant patients with heart disease are arrhythmias and heart failure. The balance between maternal and fetal outcome should always be considered in treatment choices and should be discussed with the future parents. Generally, vaginal delivery is preferred in women with adequate cardiac output. Neonatal outcome is strongly correlated with maternal outcome.
T. P. E. Ruys, Mark R. Johnson, J. W. Roos-Hesselink

39. Heart Disease in the Elderly

Abstract
Aging is associated with multiple changes throughout the cardiovascular system that substantively impact the incidence, prevalence, clinical presentation, response to treatment, and prognosis of all adult cardiovascular disorders. This chapter reviews the epidemiology of cardiovascular disease in older adults and the effects of normal aging on the cardiovascular system. This is followed by a discussion of traditional and nontraditional cardiovascular risk factors in older adults. The remainder of the chapter reviews current evidence and recommendations for the management of acute and chronic coronary artery disease, valvular disorders, heart failure, and heart rhythm disorders in the elderly. This chapter concludes with a brief discussion of ethical issues and end-of-life care in older patients with cardiovascular disease.
Michael W. Rich

40. Cardiovascular Complications in Patients with Renal Disease

Abstract
Chronic kidney disease includes both patients with a low glomerular filtration rate (GFR) and those with a normal GFR and abnormal albumin excretion in their urine. The former make up approximately 4 % of the adult population and the latter an additional 3–4 %. Both a low GFR and the presence of abnormal amount of albumin in the urine indicate that the patient is at higher risk not only of progressive kidney disease but that they are also at much greater risk of cardiovascular disease. Fortunately the condition can be identified through screening of renal function, urine albumin, and blood pressure measurement. Therapy to reduce global cardiovascular risk should include control of blood pressure, treatment with the maximal recommended dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker, aggressive LDL lowering, management of diabetes, as well as lifestyle changes including diet, exercise, and smoking cessation. Together these therapies represent “optimal medical therapy” and are particularly effective when managed by an interprofessional and interdisciplinary team. For the practicing clinician, the finding of a low GFR or abnormal albuminuria should constitute an “action item” for pursuing the evaluation and diagnosis of potentially unsuspected cardiac involvement and the initiation of multimodal therapy to lower cardiovascular and renal risk.
Sheldon W. Tobe, Haowei (Linda) Sun, Murray Epstein

41. Diabetes and the Cardiovascular System

Abstract
Diabetes has become a worldwide epidemic. The majority of patients with diabetes ultimately die from complications of cardiovascular disease. The mechanisms underlying macrovascular disease in diabetes are incompletely understood but likely involve inflammation and alterations of the endothelium and vascular smooth muscle. An increasing proportion of patients hospitalized with acute coronary syndromes will have diabetes. These patients tend to have worse outcomes and are less likely to receive guideline-based therapy. Prevention of cardiovascular disease in both type 1 and type 2 diabetes is an area of increasing focus and complexity. Both diabetes and prediabetes commonly carry with them cardiovascular risk factors including dyslipidemia, hypertension, hyperglycemia, obesity, and sedentary lifestyle. Intensive glucose control has not been shown to improve macrovascular outcomes in patients with diabetes. A number of explanations for this counterintuitive data have been proposed, and ongoing studies are needed for further clarification. New antidiabetic drugs and therapeutic strategies are being pursued, including their effects on macrovascular outcomes. Multifactorial risk factor modification appears to be particularly effective in preventing cardiovascular events, underscoring the critical need for careful management of risk factors in patients with diabetes.
Paul Cohen, Jorge Plutzky

42. Cancer Therapy-Induced Cardiomyopathy

Abstract
Modern advances in cancer treatment have resulted in a steady improvement in life expectancy in cancer patients. However, cardiovascular toxicity is one of the most devastating complications threatening to offset the substantive reductions in cancer-related morbidity and mortality that has been achieved with novel chemotherapeutic agents. Cardiologists and oncologists must collaborate closely to provide effective cancer therapy to kill cancer cells while minimizing toxicity to the cardiovascular system. Structural, functional, or biochemical indicators of cardiac injury are emerging as potential markers for early detection of cardiotoxicity. Imaging modalities such as tissue Doppler imaging, strain imaging, and cardiac magnetic resonance imaging have shown promise in earlier detection of cardiotoxicity. Biomarkers such as troponin I may also play an adjunctive role in earlier recognition of cardiotoxicity and identifying high-risk patients. There have been significant advances in the understanding of the mechanisms of cancer therapy-induced cardiotoxicity. These new pathways have been instrumental in the testing of preventive therapies. Several agents have been investigated in their ability to protect normal cardiac tissue during cancer therapy. These include dexrazoxane, angiotensin-converting enzyme inhibitors, and beta-blockers. However, further studies are warranted to clarify the efficacy, safety, and cancer treatment-related effects of these agents. Once clinical signs or symptoms of cardiac dysfunction develop, the patients should be promptly treated with standard heart failure therapy, and offending agents should be stopped. In some patients, cancer therapy may be resumed following the restoration of cardiac function. Close collaboration between the cardiologists and oncologists will herald in a new era where cancer patients will have a healthy heart to enjoy life after cancer therapy.
Peter Kim, Pimprapa Vejpongsa, Edward T. H. Yeh

43. Assessment of Patients with Heart Disease for Fitness for Noncardiac Surgery

Abstract
The basic tenet in preoperative evaluation remains that information regarding the extent and stability of disease will effect patient management and lead to improved outcome. The history should focus on cardiovascular risk factors and symptoms or signs of unstable cardiac disease states. Six independent predictors of complications have been identified: high-risk type of surgery, history of ischemic heart disease, history of congestive heart failure, history of cerebrovascular disease, preoperative treatment with insulin, and preoperative serum creatinine >2.0 mg/day, with increasing cardiac complication rates noted with increasing number of risk factors. In 2009, the American College of Cardiology/American Heart Association produced guidelines which include an algorithm to determine the indication for further diagnostic evaluation which incorporates clinical risk, surgical procedure risk, and exercise capacity. Current evidence suggests that further risk stratification in this group of patients considered at intermediate risk based on clinical history alone was unnecessary as long as perioperative beta-blockers were used, while those patients with left main disease may benefit from testing. The current evidence does not support the use of percutaneous coronary interventions beyond established indications for nonoperative patients, while advocates continuing aspirin therapy in all patients with a coronary stent and discontinuing clopidogrel for as short a time interval as possible. With respect to perioperative medical therapy, current evidence supports the continuation of beta-blockers and statins.
Lee A. Fleisher, Joseph S. Savino

44. Cardiovascular Gene Therapy

Abstract
Gene therapy is rapidly evolving as an effective therapeutic strategy for patients suffering from various forms of cardiovascular disease. Since the conceptualization of gene therapy, the scientific and clinical community has learned a great deal from the successes and, unfortunately, failures of previous gene therapy clinical trials over the past decades. Cardiovascular gene therapy has benefitted from recent advancements in vector technology, design and vector delivery modalities. Nonviral and viral vectors including plasmids, retrovirus, lentivirus, adenovirus, and adeno-associated virus each have unique cellular transduction mechanisms and expression profiles. Due to the exclusive qualities of each vector, the selection and development of vectors for cardiovascular gene therapy is critically dependent on the specific cardiac pathology. In addition, how these vectors are delivered to the heart greatly affects myocardial transduction and clinical outcomes. It is necessary to employ the proper vector and delivery modality that can safely and efficiently transduce the myocardium with well-validated transgenes shown to protect against acute ischemia, arrhythmias, hypertrophy, or ventricular failure. Gene therapies targeting the β-adrenergic pathway, calcium regulatory mechanisms, angiogenesis, or the CXCL12/CXCR4 axis have shown promise both preclinically and in human clinical trials. The current state of the art of cardiovascular gene therapy as well as clinically significant molecular targets is reviewed as this promising strategy enters the clinical realm.
Thomas J. LaRocca, Roger J. Hajjar

45. Cardiovascular Cell Therapy

Abstract
The concept of the heart as a terminally differentiated organ incapable of replacing damaged myocytes has been at the center of cardiovascular research and therapeutic development for the last 50 years. The progressive decline in myocyte number as a function of age and the formation of scarred tissue following myocardial infarction have been interpreted as irrefutable proofs of the postmitotic characteristic of the heart. Emerging evidence supports a more dynamic view of the heart, in which cell death and renewal are vital components of the remodeling process that governs cardiac homeostasis, aging, and disease. In a recent study, myocyte regeneration in the physiologically aging heart was found to occur at previously unexpected levels. From 20 to 100 years of age, the myocyte compartment is replaced completely 15 times in women and 11 times in men, and essentially none of the myocytes present at birth is preserved in the young adult, middle-aged, and senescent heart. The identification of dividing myocytes raises the important question concerning the origin of the newly formed cells. In vitro and in vivo findings strongly suggest that replicating myocytes correspond to transit-amplifying cells derived from the lineage determination of primitive cells, supporting the notion that cardiomyogenesis is controlled by activation and differentiation of stem cells. Investigators in several laboratories concur with the notion that the myocardium is an organ permissive for tissue regeneration mediated by exogenous and/or endogenous progenitors. In this chapter, we will focus on the cell classes that are currently employed in clinical studies for the treatment of cardiac diseases.
Annarosa Leri, Jan Kajstura, Marcello Rota, Piero Anversa

46. Preventive Cardiology

Abstract
The Framingham Risk Score has been endorsed by the National Cholesterol Education Program (NCEP) to assess the 10-year risk of coronary heart disease (CHD). Updated evidence-based guidelines may also include lifetime CHD risk and/or the integration of other factors associated with increased risk (i.e., chronic renal insufficiency). The field of preventive cardiology continues to evolve as the prevalence of CHD risk factors in the population change. In this day and age when obesity and type 2 diabetes mellitus have become epidemic, never has the need for identifying areas for CHD prevention been greater. This chapter will highlight results of recently completed clinical trials and the associated advances made toward reducing primary and secondary CHD risk.
Temilolu O. Aje, Michael Miller

47. Peripheral Arterial Disease

Abstract
Atherosclerotic peripheral arterial disease (PAD) refers to a range of non-coronary arterial vascular syndromes with progressive stenosis, occlusion, or aneurysmal dilation, most commonly affecting the lower extremity. Lower extremity PAD involves occlusive disease of the aorta, iliac, femoral, and more distal arteries. Patients with PAD typically carry a substantial burden of systemic atherosclerotic disease. Like other manifestations of atherosclerosis, the prevalence of PAD is related to hyperlipidemia, diabetes mellitus, hypertension, tobacco smoking, age, gender, and heredity. Clinical manifestations associated with lower extremity PAD include decrements in functional capacity and quality of life, intermittent claudication, and possibly limb loss. In addition, patients with PAD face an increased risk of vascular events including myocardial infarction (MI), stroke, and mortality.
The principles of management for patients with PAD involve measures directed at protecting affected tissues, preserving functional capacity, avoiding disease progression and arterial thrombosis, restoring blood flow, and preventing mortality. Treatment includes local measures, risk factor modification, drug therapy for claudication, and antithrombotic agents. If symptoms persist with conservative therapy, more invasive measures can be taken including atherectomy, balloon angioplasty, stenting, and surgery to overcome arterial obstruction and improve clinical outcomes.
Giovina Lara Bomba, Jonathan L. Halperin

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