Heart Failure and Cardiogenic Shock

Heart Failure and Cardiogenic Shock

Laurie A. Soine


Heart failure (HF) is a pathophysiologic state in which an abnormality of cardiac function is responsible for inadequate systemic perfusion. HF is not an event or disease but rather a constellation of signs and symptoms that represent the final pathway of a heterogeneous group of diseases, the end result of most cardiovascular disease states.1 The extent and severity by which cardiac function is impaired varies greatly. It is the primary reason people over the age of 65 are hospitalized in the United States.2,3 Three-month rehospitalization rates for recurrent failure are as high as 79%.3

The prevalence of the syndrome of HF has increased dramatically throughout the world over the last decade, attributable to both the general aging of the worlds’ population and advances in the treatment of acute cardiac disease. Over 5 million people carry the diagnosis, with approximately 550,000 new cases diagnosed annually.4 While the syndrome of HF has been extensively researched and intensively studied, it remains a significant and growing health problem in the United States and worldwide. There is an increasing incidence of HF in the aging population, with a prevalence of approximately 10% by age 70 years. For HF occurring in the absence of myocardial infarction (MI), the lifetime risk is 1 in 9 for men and 1 in 6 for women; the increase in HF is largely attributable to hypertension.5 The American Heart Association estimates that greater than $33 billion is spent on the syndrome of HF annually.4

As many as 20 million people in the United States who have asymptomatic impairment of cardiac function are likely to develop symptoms of HF within 5 years.4 In the past decade, experimental and clinical studies have demonstrated altered neurohormonal activity as a major pathophysiologic component of HF. The quality of life, exercise capacity, and perhaps the life expectancy of patients with HF can be altered by the introduction of appropriate medical and nursing interventions.

This chapter reviews major physiologic and pathophysiologic concepts of chronic HF as a basis for understanding its underlying causes as well as its clinical and physical findings. Emphasis also is placed on the various diagnostic tests, the vast array of pharmacologic agents, and medical and nursing interventions in the adult patient with ventricular dysfunction. With this knowledge, the nurse is able to develop and implement a plan of care, to identify patients at risk for developing the syndrome, and to optimize the functional capacity and outcome of patients living with the syndrome of HF. Although pharmacologic agents are reviewed in this chapter, refer to current sources of information for specifics of use and dose.

Historic Perspective

The understanding of the syndrome of HF has evolved dramatically in the last 100 years. Advances in our understanding of the syndrome have evolved secondary to the tools available to detect and mark the disease progression. During the nineteenth century the altered architecture of the failing heart was implicated as the cause of patient’s symptoms. In 1832, James Hope first described backward failure as the failure that results as the ventricle fails to pump its volume, causing blood accumulation and subsequent increase in ventricular, atrial, and venous pressures. A primary cause of backward failure was mechanical cardiac obstruction. The term forward failure, proposed by MacKenzie in 1913, was applied to a situation in which the primary pathologic process was decreased cardiac output, which ultimately leads to a decrease in vital organ perfusion, and to water and sodium retention.6 MacKenzie was the first to propose that intrinsic myocardial abnormalities lead to the death of patients with this syndrome.7 By the mid-1920s Starling and colleagues revolutionized the understanding of the syndrome with their animal studies describing the effect of alterations in pressure and flow on myocardial performance. This work formed the basis upon which the syndrome was understood until almost the end of the twentieth century. The hemodynamic derangement secondary to pressure and flow abnormalities became the accepted paradigm, explaining the therapeutic interventions of the time. If pressure and volume where the two components of myocardial contractility—causing reduced cardiac output, therapeutic interventions were aimed at accurately assessing and altering hemodynamics. While we now know that cardiac hemodynamics play a role in the syndrome of HF, therapeutic intervention targeted at normalization of hemodynamic derangement did not translate to improved outcomes in patients.

Advances in cellular biochemistry and biophysics in the 1970s to 1980s lead to a widening of the lens through which the complexity and progression of the HF syndrome emerged. Patients with HF were noted to have markedly elevated levels of stress hormones such as norepinephirine. These discoveries led some to hypothesize that while myocardial dysfunction begins the syndrome, progression and subsequent death of the patients may be attributable to dramatic neurohormonal abnormalities. By the early 1990s studies of medications aimed at altering the neurohormonal milieu within the body solidly supported the neurohormonal/neuroendocrine hypothesis that remains the target of many of our current interventions.8 However, by the turn of the twentieth century advances in the ability to measure molecular changes in myocytes has lead to an ever complex understanding of the collection of complex genetic and molecular disorders that lead to and perpetuate the syndrome.

Etiologies and Definitions

HF is a complex clinical syndrome manifested by shortness of breath, fatigue, and characterized by abnormalities of left ventricular
(LV) function and neurohormonal regulation.1 Any disorder that places the heart under an increased volume or pressure load or that produces primary damage or an increased metabolic demand on the myocardium may result in HF (Table 24-1). Over the last decade there has been a primary shift in the etiology of HF with coronary artery disease (CAD) surpassing hypertension or valvular heart disease.5 As treatment modalities for both the acute and chronic treatment of CAD improve, the number of patients living with CAD grows.


Abnormal Volume Load

Abnormal Pressure Load

Myocardial Abnormalities

Filling Disorders

Increased Metabolic Demand

Aortic valve incompetence
Mitral valve incompetence
Tricuspid valve incompetence
Left-to-right shunts
Secondary hypervolemia

Aortic stenosis
Hypertrophic cardiomyopathy
Coarctation of the aorta

Coronary heart disease
Toxic disorders
Administration of cardiac depressants agents or salt-retaining drugs

Mitral stenosis
Tricuspid stenosis
Cardiac tamponade
Restrictive pericarditis
Restrictive cardiomyopathy

Paget’s disease
Arteriovenous fistulas
Pulmonary emboli
Systemic emboli

Ventricular dysfunction begins with injury. It is vital for the clinician to identify the underlying and the precipitating causes of HF. CAD is the underlying cause of HF in two thirds of patients with systolic dysfunction. Hypertension is implicated in both systolic and diastolic dysfunctions. Arrhythmias are common in patients with underlying structural heart disease; and they commonly precipitate an acute decompensation in patients with stable HF. These arrhythmias may take the form of tachyarrhythmias (most commonly atrial fibrillation), marked bradycardia, degrees of heart block, and abnormal intraventricular conduction, such as left bundle-branch block or ventricular arrhythmias. Other precipitating factors include systemic infections, anemias, and pulmonary emboli that all place increased metabolic and hemodynamic demand on the heart. Administration of cardiac depressants or salt-retaining drugs may precipitate HF; examples may include corticosteroids, nondihydropyridine calcium-channel antagonists, and nonsteroidal anti-inflammatory drugs (NSAIDs). Alcohol is a potent myocardial depressant and may be responsible for the development of cardiomyopathy. Inappropriate reduction in therapy is perhaps the most common cause of decompensation in a previously compensated patient, with reduction in pharmacological therapy or dietary excess of sodium.

Stages of HF

The writing committee of the American College of Cardiology and the American Heart Association (ACC/AHA) Task Force decided to emphasize the evolution and progression of HF in their most recent revision of the guidelines.1 This classification recognizes that HF, like CAD, has established risk factors, that the progression of HF has asymptomatic and symptomatic phases, and that treatments prescribed at each stage can reduce morbidity and mortality. Four stages of HF were identified. Stage A identifies the patient who is at high risk but has no structural heart disease; stage B refers to a patient with structural heart disease but no symptoms of HF; stage C denotes the patient with structural heart disease and current or previous symptoms of HF; and stage D describes the patient with end-stage disease that requires special interventions (Fig. 24-1). The importance of this staging system arises from the fact that, while treatment options for HF have advanced in the last decade, once myocyte, myocardial, and systemic changes have begun, the only treatment option is altering the trajectory of the syndrome as cure is seldom an option.

As the understanding of the mechanisms underlying both the development and progression of the syndrome have evolved, much attention of late has been placed on identifying the factors that put patients at risk for developing the syndrome (Table 24-2). While it is not surprising that advancing age, history of CAD, MI, or hypertension are associated with developing HF, a robust association has been seen in patients with both Type II diabetes mellitus (DM)9,10 and obesity, and the subsequent syndrome of HF. The worldwide epidemic of Type II DM and obesity make them potentially modifiable targets to reduce incidence of HF.

The clinical manifestations of acute and chronic failure depend on how rapidly the syndrome of HF develops. Acute HF may be the initial manifestation of heart disease but is more commonly an acute exacerbation of a chronic cardiac condition. The marked decrease in LV function may be caused by acute MI or acute valvular dysfunction. The events occur so rapidly that the sympathetic nervous system compensation is ineffective, resulting in the rapid development of pulmonary edema and circulatory collapse (cardiogenic shock). Chronic HF develops over time and is usually the end result of an increasing inability of physiologic mechanisms to compensate.

Low and High Cardiac Output Syndromes

In response to high blood pressure and hypovolemia, low cardiac output syndrome can appear. The word syndrome implies that the failure represents a reaction rather than a primary pathologic process. Low cardiac output syndrome is evidenced by impaired peripheral circulation and peripheral vasoconstriction.

Figure 24-1 Stages in the development of heart failure/recommended therapy by stage. (From Hunt, S. A., Abraham, W. T., Chin, M. H., et al. [2005]. ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines [Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure]: Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation, 112[12], e154-e235.) CM, cardiomyopathy; ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin II receptor blocker; LVH, left ventricular hypertrophy

Any condition that causes the heart to work harder to supply blood may be categorized as high cardiac output syndrome. High cardiac output states require an increased oxygen supply to the peripheral tissues, which can occur only with an increased cardiac output. Reduced systemic vascular resistance (SVR) is characteristic of this condition; it augments peripheral circulation and venous return, which in turn increases stroke volume and cardiac output. High cardiac output states may be caused by increased metabolic requirements, as seen in hyperthyroidism, fever, and pregnancy, or may be triggered by hyperkinetic conditions such as arteriovenous fistulas, anemia, and beriberi. While the terms low-output and high-output syndromes are not commonly used in practice, recognizing that processes occur is important.

Pathogenesis and Pathophysiology

While the root of HF is altered myocardial function, a host of compensatory systemic responses lead to the subsequent progressive clinical syndrome (Fig. 24-2). Altered myocardial function, ventricular remodeling, altered hemodynamics, neurohormonal
and cytokine activation, and vascular and endothelial dysfunction. Multiple alterations in organ and cellular physiology contribute to HF under various circumstances. Adaptive and maladaptive processes affect the myocardium, kidneys, peripheral vasculature, smooth and skeletal muscle, and multiple reflex control mechanisms.11 Our understanding of the mechanism behind both the development and progression has evolved dramatically over the last decade (Fig. 24-3).


Major Risk Factors

Toxic Precipitants

Minor Risk Factors

Asymptomatic LV dysfunction
Increased LV mass
Age, male gender
Hypertension, LVH
Myocardial infarction
Valvular heart disease

Chemotherapy (anthracyclines, cyclophosphamide, 5-FU, trastuzumab)

Sleep-disordered breathing
Chronic renal disease
Sedentary lifestyle
Low socioeconomic status
Psychological stress

5-FU, 5-florouracil; LV, left ventricle; LVH, left ventricle hypertrophy; NSAIDs, nonsteroidal anti-inflammatory agents.

Adapted from Schocken, D. D., Benjamin, E. J., Fonarow, G. C., et al. [2008]. Prevention of heart failure. A scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation, Table 1.

Changes in myocardial architecture due to injury result in myocardial contractile dysfunction. The changes in architecture come about by alterations in cardiac myocyte biology, and in myocardial and ventricular structures. Ventricular contractile dysfunction leads to altered systemic perfusion. Alterations in systemic perfusion result in neuroendocrine activation resulting in progressive alterations in myocardial architecture and contractile function. In short, myocardial injury leads to altered systemic perfusion causing neuroendorine changes that result in further ventricular dysfunction. The remainder of this section examines more closely each of the steps in this process. It is important to recognize that understanding the interplay between each of these steps is a dynamic and rapidly expanding venture.

Histologically there are four prominent features of the failing heart: (1) hypertrophy of the myocytes, (2) fibrosis, (3) myocyte disarray (or unordered appearance), and (4) apoptosis. These histological processes occur secondary to myocardial ischemia, infarction, or hemodynamic overload.12 Ventricular hypertrophy is defined by an increase in ventricular mass attributable to increase in the volume of cardiac cells. The increase in ventricular mass is due to an increase in the size of the myocytes, increased number of fibroblasts, and an increase in the extracellular matrix proteins (collagen and fibronectin).

Myocyte Pathophysiology

The primary goal in preventing and ultimately managing HF is protection and preservation of the myocyte. Cardiac myocytes cease replicating and dividing early in life. Myocardial insult and injury occurs as decades progress, and the compensatory adaptation often leads to dysfunction. Preventing myocyte hypertrophy, injury, and death becomes the primary goal in altering the trajectory of the syndrome of HF. Understanding the changes that occur within the cardiac myocyte provides insight into the syndrome.

Increased pressure or volume reactivates growth factors present in the embryonic heart but dormant in the adult heart. This fetal gene expression stimulates the hypertrophy of the myocytes and the synthesis and degradation of the extracellular matrix. There is some evidence that extracellular matrix degradation may elicit side-to-side slippage or disarray of myocytes, perhaps caused by dissolution of collagen struts that normally hold cells together, whereas reparative and reactive fibrosis may represent a secondary event resulting in a stiffer ventricle. Myocyte slippage may also be caused by myocyte loss.13

Hypertrophied myocytes have alterations in contractile protein synthesis and calcium cycling. Force within the myocyte is a result of the interaction of myosin and actin. Myocyte hypertrophy alters the synthesis of myocin proteins from α-myosin heavy chain toward β-myosin heavy chain. This shift in the myosin subunit alters the kinetics by which it binds to actin resulting in contraction. Initially, this change produces an energetically favorable state, but chronically this state is unsustainable and failure occurs. Altered expression or alignment of contractile proteins within sarcomeres is important, as increasing mutations in sarcomeric proteins have been linked to inherited cardiomyopathic processes. Alteration in expression and function of the contractile proteins is signaled by mechanical wall stress, angiotensin II (AT), norepinephrine (NE), endothelin (ET), tumor necrosis factor-alpha (TNF-α), inflammatory interleukins, and intracellular calcium signaling. There are changes in the sarcomeric proteins that lead to decreased contraction velocity, reduced stroke volume, and increased ventricular volume.7,11

Ventricular contraction and relaxation is a dynamic process controlled by the uptake of calcium by the sarcoplasmic reticulum and the efflux of calcium within the myocyte.11, 12, 13 Myocyte hypertrophy impacts several intracellular proteins involved in calcium cycling. The most consistent change is a significant downregulation of expression and activity of the sarcoplasmic reticulum calcium ATP-ase (SERCA) pump. While the role of SERCA in calcium handling within the myoctye is complex and remains the topic of study, the net result is a reduction in the availability of peak systolic calcium, and an elevation and prolongation in diastolic calcium, resulting in reduced systolic contraction and delayed diastolic relaxation.

The paracrine function of the heart is markedly altered in HF. Paracrine action is the release of a locally acting endocrine substance, a system in which the target cells are close to the signaling cells. The signal transduction system in the failing myocardium is profoundly altered. The failing myocardium is induced to secrete both atrial and b-type natriuretic peptides (ANP and BNP, respectively).

Actual myocyte loss may also occur by one of two mechanisms: apoptosis or necrosis. Apoptosis is a programmed cell death that is energy-dependent, producing cell dropout. Apoptosis is a highly regulated process that causes the cell to shrink, yielding cell fragments that are surrounded by plasma membrane. This process does not invoke an inflammatory or fibrotic response. Apoptosis is stimulated by hypoxia, AT II, TNF-α, myocyte calcium overload, and mitochondrial or cell injury.14 Two forms of apoptosis appear to affect the course of postinfarction remodeling: ischemicdriven apoptosis at the site of the infarction and load-dependent or receptor-dependent apoptosis at sites remote from the ischemic areas.15 Necrosis or accidental cell death occurs when the myocyte is deprived of oxygen or energy. Energy starvation of the myocyte results from an increase in energy demand and a reduced capacity for energy production.11 The inflammatory response that is induced by overload elevates circulating levels of cytokines that in turn release reactive oxygen species and free radicals. Calcium overload increases energy expenditure and slows energy production. All these processes lead to the loss of cellular membrane integrity, causing the cell to swell and eventually burst. This loss of cellular membrane integrity releases proteolytic enzymes that cause cellular disruption. The release of cell contents initiates an inflammatory reaction that leads to scarring and fibrosis. Myocyte necrosis may be localized, as in an MI, or diffuse, as from myocarditis or idiopathic cardiomyopathy.6,7 The vicious cycle of the overloaded heart is depicted in Figure 24-4.

Figure 24-2 Sequence of events in heart failure. An increased load or myocardial abnormality leads to myocardial failure and eventually heart failure, resulting in increased sympathetic activity, increased activity of the renin-angiotensin-aldosterone system, pulmonary and peripheral congestion and edema, and decreased cardiac output reserve. Both the atrial natriuretic and b-type natriuretic plural-peptides are also released in response to increased plasma volume. (From Francis, G. S., Gassler, J. P., & Sonneblick, E. H. [2001]. Pathophysiology and diagnosis of heart failure. In J. W. Hurst [Ed.], The heart [10th ed.]. New York: McGraw-Hill.)

Figure 24-3 The evolution of HF along AHA/ACC guidelines for the diagnosis and management of HF clinical stages. (From Schocken, D. D., Benjamin, E. J., Fonarow, G. C. , et al. [2008]. Prevention of heart failure. A scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation, CIRCULATIONAHA. 107.188965.)

Figure 24-4 Energy starvation contributes to several vicious cycles that cause myocyte necrosis by increasing energy utilization and decreasing energy production. Reduced turnover of the calcium pumps of the sarcoplasmic reticulum and plasma membrane, the Na/Ca exchanger, and the sodium pump impair calcium removal from the cytosol. The resulting increase in cytosolic calcium inhibits actomyosin dissociation, which in addition to impairing relaxation increases energy utilization and so worsens the energy starvation. Aerobic energy production is also inhibited when cytosolic calcium is taken up by the mitochondria, which uncouples oxidative phosphorylation. The resulting increase in cytosolic calcium amplifies these vicious cycles and can lead to necrosis of the energy-starved cells. (From Katz, A. M., & Konstam, M. A. [2008]. Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins; adapted from Katz, A. M. [2006]. Physiology of the heart [4th ed.]. Philadelphia: Lippincott Williams & Wilkins.)

Ventricular Remodeling

Myocardial remodeling in the failing myocardium involves complex events at the molecular and cellular levels.16 When the heart is presented with an increased workload by either pressure or volume overload, or by myocardial abnormality, a number of physiologic alterations are evoked in an attempt to maintain normal cardiac pumping function. Myocardial contractility (inotropy) and relaxation (lusitropy) are impaired in patients with HF. In addition, systemic hemodynamics, which include both preload and afterload, and ventricular architecture (shape, cavity size, and wall thickness) determine ejection and filling of a failing heart (Fig. 24-5).7 As diastolic filling increases, ventricular dilatation occurs in response to maladaptive growth response and remodeling of the damaged or chronically overloaded heart. Renal compensatory mechanisms cause sympathetic stimulation, thus increasing the end-diastolic volume or preload. The Frank-Starling response is immediately activated as a consequence of increased diastolic volume. According to the Frank-Starling law, length-dependent changes in contractile performance during diastole increases the force of contraction during systole. The increased preload augmenting contractility is the major mechanism by which the ventricles
maintain an equal output as their stroke volumes vary.7,11 It may be useful to consider normal and impaired myocardial function within the framework of the Frank-Starling mechanism, as illustrated by analysis of LV function curves (Fig. 24-6). Cardiac output or cardiac index (CI) is used as a measure of ventricular work; LV end-diastolic pressure or pulmonary artery wedge pressure (PAWP) is used as a reflection of preload. The normal relation between ventricular end-diastolic volume and ventricular work is shown in Figure 24-6 by curve 1. Optimal contractility occurs at a diastolic volume of 12 to 18 mm Hg. If the heart is physiologically stressed, as occurs in acute MI, the initial drop in cardiac output stimulates the sympathetic nervous system. An increase in sympathetic tone elevates heart rate and contractility, illustrated in Figure 24-6 by curve 2. As the cardiac workload increases and myocardial dysfunction persists, HF progresses. HF progression is reflected by further elevation of end-diastolic volume (preload) and ventricular dilatation. This increased preload, in turn, may further contribute to depressed ventricular contractility and the development of congestive symptoms (Fig. 24-6, curve 3).17

Figure 24-5 Patterns of ventricular hypertrophy and remodeling in various forms of cardiomyopathy. (From Katz, A. M., & Konstam, M. A. [2008]. Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins; adapted from Konstam, M. A. [2003]. Systolic and diastolic dysfunction in heart failure? Time for a new paradigm. Journal of Cardiac Failure, 9[1], 1-3.)

Figure 24-6 Left ventricular function curves. Curve 1: Normal function curve, with a normal cardiac output at optimal filling pressures. Curve 2: Cardiac hyperfunction, with an increased cardiac output at optimal filling pressures. Curve 3: Compensated heart failure, with normal cardiac outputs at higher filling pressures. Curve 4: Decompensated heart failure, with a decrease in cardiac output and elevated filling pressures. Curve 5: Cardiogenic shock, with extremely depressed cardiac output and marked increase in filling pressures. (Adapted from Michaelson, C. R. [1983]. Congestive heart failure [p. 61]. St. Louis: CV Mosby.)

The normal left ventricle is able to adjust to large changes in aortic impedance (afterload) with small changes in output, in part by calling on the Frank-Starling response and, perhaps, by augmenting the contractile force as an intrinsic property of the normal myocardium. In contrast, the damaged left ventricle loses this compensatory ability and becomes sensitive to even small changes in impedance.18 Because increased activity of the sympathetic nervous system or the renin-angiotensin-aldosterone system (RAAS) results in vasoconstriction of the small arteries and arterioles, increased impedance of LV filling is imposed, decreasing the stroke volume and cardiac output. Because HF is characterized by heightened activity of these neurohormonal vasoconstrictor systems, a positive-feedback loop can be generated in which impaired pump performance increases impedance to LV ejection, further impairing pump performance.

Changes in the composition of the myocardium occur in response to injury or overload and result in structural remodeling, divided into both cellular and noncellular changes. Several of the cellular changes have be discussed in the prior section and include changes within the cardiomyocytes (hypertrophy, apoptosis, and necrosis) but several alterations in other cell types, such as fibroblasts, vascular smooth muscle cells, monocytes and macrophages, also contribute to ventricular remodeling. Noncellular components of the myocardium likewise contribute to remodeling. There is an increase in interstitial deposition of collagen fibers and an increase in perivascular deposition of collagen, leading to thickening of the walls of the small intramyocardial arteries and arterioles.

Throughout the body there is a fine balance of synthesis and degradation. Fibroblasts within the myocardium produce collagen. Excesses in ventricular collagen are thought to be caused by both an increase in collagen synthesis by the myofibroblasts and an associated reduction in collagenase activity.19 The balance of synthesis and degradation of myocardial fibrosis is complex. But it is intriguing that many of the substances known to be elevated in patients with HF are highly profibrotic and include angiotensin II, ET, NE, aldosterone, and interleukin-6. In contrast many substances that facilitate degradation seem to be lacking in patients with HF, including bradykinin, prostaglandins, and TNF-α.11 Thus, myocardial fibrosis, which accounts for a large part of the structural changes seen in patients with HF, may be the consequence of the loss of regulation that exists between synthesis and degradation.

Neurotransmitters such as NE, secreted at sympathetic nerve junctions within the myocardium, attempt to help the myocardium meet the increasing demands of the body. β-Receptors located within the myocardium serve as the portal to activation. Stimulation of β1-receptors leads to increased heart rate, contractility, and speed of relaxation. Myocardial injury leads to neurohormonal activation that prompts a dramatic reduction of both the number and function of β-receptors within the myocardium, resulting in impaired signal transduction and disturbances in myocellular calcium metabolism.

The metabolism of the failing myocardium likewise is altered adversely. In fact, the hyperadrenergic state of HF initiates a metabolic vicious cycle. The principal energy source in a normal myocardium is free fatty acids, but in hypertrophic states, switches to glucose utilization. Myocardial energy generation and utilization may have a profound effect on cellular energy levels. Altered myocardial carbohydrate metabolism and related insulin resistance are currently variables of interest in abnormal myocardial energetics.

Ventricular volume overload and increased diastolic wall stress lead to replication of sarcomeres, elongation of myocytes, and ventricular dilatation or eccentric hypertrophy. Maladaptive growth and changing myocyte phenotype leads to myocyte thickening (seen in diastolic dysfunction and concentric hypertrophy) and myocyte elongation (seen in systolic dysfunction and eccentric hypertrophy).20 These large, genetically abnormal cells cannot contract as efficiently as normal cells (Fig. 24-7).

Concentric and eccentric hypertrophy impair ventricular filling. Decreased cavity size, as seen in concentric hypertrophy, decreases compliance and thus impedes venous return. Eccentric hypertrophy, which increases end-diastolic volume and pressure,
is also accompanied by a decrease in compliance.12 Mechanisms responsible for diastolic dysfunction include hypertrophy, as described, which causes an increase in passive chamber stiffness (decreased compliance) and decreased active relaxation. Decreased levels of activity of SERCA (sarco/endoplasmic reticulum calcium ATPase) to remove calcium from the cytosol and increased levels of phospholamban (a SERCA inhibitory protein) lead to a net effect of impaired relaxation. This same net effect is seen in myocardial ischemia, abnormal ventricular loading (e.g., in hypertrophic or dilated cardiomyopathy), asynchrony, abnormal flux of calcium ions, and hypothyroidism. Of interest, SERCA decreases with age, coincident with impaired diastolic dysfunction.6,21 Wall stiffness and associated decreased compliance is increased with age and is caused, in part, by diffuse fibrosis. Decreased compliance is also noted in patients with focal scar or aneurysm after MI. Infiltrative cardiomyopathies (e.g., amyloidosis) can also increase wall stiffness. Pericardial constriction or tamponade causes mechanical increased resistance to filling of part or all of the heart.20 Interactions with LV hypertrophy (LVH), ischemia, and diastolic dysfunction create a vicious cycle in which LVH predisposes to ischemia, the ischemia causes impairment of relaxation in the heart with LVH, and the severity of subendocardial ischemia worsens. Several mechanisms appear to lower subendocardial perfusion pressure. Coronary vascular remodeling occurs with increased medial thickness and perivascular fibrosis. The increased LV mass and inadequate vascular growth results in a loss of coronary vasodilator reserve so that there is a limited ability to increase myocardial perfusion in response to an increased oxygen demand. In addition, increased diastolic pressure exerts a compressive force against the subendocardium and restricts subendocardial perfusion.20

Figure 24-7 Phenotype change of the heart at the cellular and organ levels. Normal muscle can grow in a physiologic way, as seen in the athlete’s heart. Concentric hypertrophy can result from pressure overload; eccentric hypertrophy due to volume overload, or dilated cardiomyopathy. (Adapted from Drexler, H., & Hasenfuss, G. [2001]. Physiology of the normal and failing heart. In M. Crawford, & J. P. Di-Marco [Eds.], Cardiology. London: Mosby.)

Altered Systemic Perfusion Results in Neuroendocrine Activation

The major elements of the neuroendocrine response may be described as activation of the sympathic nervous system, RAAS, and inflammatory systems. While each of these homeostatic mechanisms represents a beneficial short-term response to impaired cardiac function, they also are associated with detrimental maladaptive long-term consequences (Table 24-3).7

The systemic response to a decrease in cardiac output accelerates heart rate, vasoconstricts arteries and veins, increases the ejection fraction and, by promoting salt and water retention by the kidneys, increases blood volume. Salt and water retention, vasoconstriction, and cardiac stimulation are mediated by signaling molecules that play a regulatory and counter-regulatory role in HF (Table 24-4). The various mediators evoke similar and often overlapping responses. When a regulatory signal turns on a process, counter-regulatory signals are released to turn off the process.7,22

Activation of the Sympathetic Nervous System.

The most important stimulus for vasoconstriction in HF is sympathetic activation that releases catecholamines. Plasma levels of NE become elevated. NE binds to α1-adrenergic receptors increasing vascular tone to raise SVR (afterload) and mean systemic filling pressure, thereby augmenting venous return or preload (Fig. 24-8).23

In HF, stimulation of the sympathetic nervous system represents the most immediately responsive mechanism of compensation. Stimulation of the β-adrenergic receptors in the heart causes an elevation in heart rate and contractility to raise stroke volume and cardiac output. Sympathetic over-activity in HF may exert adverse effects on the structure and function of the myocardium
by the process of remodeling. Myocardial remodeling involves hypertrophy and apoptosis of myocytes, regression to a cellular phenotype, and changes in the nature of the extracellular matrix.11,23



Short-Term Adaptive

Long-Term Maladaptive


Adaptive Response

Maladaptive Consequences

Salt and water retension

↑ Preload, maintain cardiac output

Edema, anasarca, pulmonary congestion


↑ Afterload, maintain blood pressure

↓ Cardiac output, ↑ energy expenditure, cardiac necrosis

Cardiac β-adrenergic drive

↑ Contractility, ↑Relaxation

↑ Cytosolic calcium (arrhythmias, sudden death

↑ Heart rate

↑ Cardiac energy demand (cardiac necrosis)




Antimicrobial, antihelminthic

Cachexia (skeletal catabolism)

Adaptive hypertophy

Skeletal muscle myopathy


Adaptive Hypertrophy

Maladaptive Hypertrophy

Transcriptional activation

Cell thickening (normalize wall stress, maintain cardiac output)

Cell elongation (dilation, remodeling, increased wall stress)

More sarcomeres


↑ Sarcomere number

↑ Cardiac energy demand (cardiac myocyte necrosis)

Adapted from Katz, A. M., & Konstam, M. A. (2008). Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins.

Attenuating the myocardial response to NE is an important counter-regulatory change in patients with HF. Chronic sympathetic stimulation inhibits β-receptor synthesis and reduces the ability of the β-receptor to respond to the stimulus of NE. β-Receptor downregulation reduces the amount of receptors available to bind to NE. Mechanisms responsible for β1-receptor downregulation help protect the failing heart from the adverse effects of sustained sympathetic stimulation.


I. Signaling Molecules Whose Major Role is Regulatory


Catecholamines (peripheral effect)

Renin-angiotensin-aldosterone system (angiotensin II)

Arginine vasopressin or ADH



Retention of fluid by kidneys


Stimulation of cell growth and proliferation

Increased contractility, relaxation, heart rate

II. Signaling Molecules Whose Major Role is Counter Regulatory


Catecholamines (peripheral effect)


Atrial natriuretic peptide

Nitric oxide



Reduced fluid retention by the kidneys


Decreased cardiac contractility, relaxation, heart rate

Inhibition of cell growth and proliferation

Adapted from Katz, A. M., & Konstam, M. A. (2008). Heart failure: Pathophysiology, molecular biology and clinical management. Philadelphia: Lippincott Williams & Wilkins.

Activation of the RAAS.

The RAAS plays an important role in HF; AT has a vast range of biologic activities (Fig. 24-9). In addition to stimulating aldosterone, AT is a potent vasoconstrictor.11 There are four recognized AT receptor sites, but the AT1 receptors, which predominate in adult hearts, exert their regulatory effects in myocytes: vasoconstriction, increased myocardial contractility,
cell growth (hypertrophy), and apoptosis (programmed cell death). The AT2 receptor, a “fetal phenotype,” promotes counter-regulatory effects, including vasodilatation and decrease in growth and proliferation of cells. The AT1 receptor is downregulated in patients with HF.24

Figure 24-8 Increased sympathetic activity may contribute to the pathophysiology of HF by multiple mechanisms. (B-AR, postsynaptic β-adrenergic receptor; RAS, renin-angiotensin system. (Adapted from Floras, J. S. [1993]. Clinical aspects of sympathetic activation and parasympathetic withdrawal in heart failure. Journal of American College of Cardiology, 22[4, Suppl. A], 72A-84A.)

Figure 24-9 The renin-angiotensin-aldosterone system is activated in patients with heart failure. Multiple stimuli may contribute to renal release of renin into the systemic circulation, including increased sympathetic efferent activity, decreased tubular sodium delivery, reduced renal perfusion, and diuretic therapy. Natriuretic peptides (ANP, BNP), and vasopressin (ADH) (striped arrows) may inhibit release of renin. Angiotensin I is converted to angiotensin II, which is a potent vasoconstrictor; it promotes sodium reabsorption by increasing aldosterone secretion, and by a direct effect on the tubules, stimulates water intake by acting on the thirst center. (Adapted from Paganelli, W. C., Craeger, M. A., & Dzau, V. J. [1986]. Cardiac regulation of renal function. In T. O. Cheung [Ed.], International textbook of cardiology. New York: Bergamman Press.)

ADH is a pituitary hormone that plays a central role in regulation of plasma osmolality and free water clearance. It is released into the circulation in response to hyperosmolarity and AT. It causes vasoconstriction via vasopressin 1 receptors (Fig. 24-10).6 ET is also a potent vasoconstrictor, which is stimulated by ADH, catecholamines, AT, and growth factors. Two ET receptor sites, ET-A and ET-B, have been identified. The ET-A elicits, in addition to peripheral vasoconstriction, an increase in inotropy, fluid retention, and growth or hypertrophy. The ET-B receptor is less well understood, although it can mediate vasoconstriction and also a vasodilator effect through increased levels of nitric oxide (NO) and prostaglandins. Plasma ET correlates directly with PA pressures and PA resistance and may play a role in pulmonary hypertension seen in patients with HF.11 Counter-regulatory mediators that cause vasodilatation include the natriuretic peptides, NO, bradykinin, dopamine, and some of the prostaglandins, all of which act directly to relax arteriolar smooth muscle. NO, a free-radical gas initially known as endothelial-derived relaxing factor, is synthesized by the vascular endothelium. Inability of the endothelium to respond to vasodilator stimulus of NO may contribute to the exercise intolerance in patients with HF. Bradykinin and related peptides are vasodilators. Bradykinin is a substrate for angiotensin-converting enzyme (ACE) that is also responsible for the production of AT. In addition, bradykinin also inhibits maladaptive growth.6,7 Adrenomedullin is a peptide with vasodilating and natriuretic properties. It also has positive inotropic effects. The clinical importance of these effects on HF is not fully established.25 Dopamine, which is a precursor to NE, is a catecholamine that has central and peripheral effects. At low concentrations, dopamine relaxes smooth muscle; this vasodilatation lowers peripheral resistance and dilates renal blood vessels. Prostaglandin synthesis is stimulated by NE, AT, and ADH. The vasodilators are prostacyclin (PGI2) and prostaglandin E2. Because they are short-lived, they act locally to exert their effects, either released from one cell to work on another (paracrine effect) or binding to the same cell that released the prostaglandin (autocrine effect). In patients with HF, these counter-regulatory effects are often overwhelmed by the vasoconstrictor response.11

Renal compensation is triggered initially by a decrease in kidney perfusion, which decreases glomerular filtration rate (GFR) and activates the RAAS, resulting in an increased SVR and increased sodium and water absorption.22 Under normal physiologic conditions these pathways act in concert to maintain volume status, vascular tone, and optimize cardiac output. However, chronic activation of these systems leads to worsening of the syndrome.26 Mediators of the selective vasoconstrictor response include NE, ADH, AT, and ET.27 Aldosterone, a steroid hormone, increases tubular sodium reabsorption along with AT and NE. ADH acts on the collecting ducts to promote water reabsorption. In early HF, catecholamine, ADH, and ET play the major role in stimulating aldosterone secretion.23 In patients with advanced HF, the most important stimulus for aldosterone release is AT, whose levels are increased with diuretic therapy.22

Natriuretic peptides are counter-regulatory mediators produced in the body. This family of peptides includes ANP, BNP, and clearance natriuretic peptide (CNP). The heart itself produces ANP and BNP. ANP is stored mainly in the right atria, and an increase in atrial distending pressure, however produced, leads to the release of ANP. BNP, identified initially in the brain, is synthesized in the ventricles and is released in response to increased ventricular pressure.27 CNP is produced in blood vessels and in the brain. CNP appears to act primarily as a clearance receptor that regulates levels of the peptides and reduces vascular resistance
but has no natriuretic property. Both ANP and BNP promote vasodilatation and sodium excretion.28 They may also attenuate sympathetic tone, RAAS activity (see Fig. 24-9), ADH, and the growth or hypertrophy of the ventricle.6,11 All three peptides are elevated in HF29 (see Fig. 24-10).

Figure 24-10 Arginine vasopressin (ADH) is a peptide released from the posterior pituitary gland. Angiotensin II and osmoreceptors stimulate vasopressin release; the natriuretic peptides (ANP, BNP) inhibit vasopressin secretion. Vasopressin causes vasoconstriction, renal reabsorption of water, and renal secretion of renin. (Cusco, J. A. & Creager, M. A. [1999]. Neurohumoral, renal, and vascular adjustments in heart failure. In W. S. Colucci & E. Braunwald (Eds.), Atlas of heart failure. Cardiac function and dysfunction [2nd ed.]. Philadelphia: Blackwell Science.)

The syndrome of HF is more accurately a syndrome of concomitant cardiac and renal dysfunction, each accelerating the progression of the other. Renal dysfunction in patients with HF is common and is an independent risk factor for morbidity and mortality.30,31 Studies have demonstrated that for every 0.5 mg/dL increase in serum creatinine there is an associated 7% risk of death.26 Interestingly, renal dysfunction is equally prevalent in patients with HF with either preserved or reduced ejection fractions.32 What is not known is whether worsening renal function itself leads to increased morbidity and mortality or if it is a marker of more severe cardiac and renal diseases.


Local and systemic inflammation plays an important role in HF, particularly in regard to disease progression.33 Cytokines are signaling peptides whose actions include cell growth and cell death through direct toxic effects on the heart and peripheral circulation. The proinflammatory or “stress-activated” cytokines include TNF-α and some interleukins (e.g., IL-1α, IL-6, IL-8, IL-12). The cardiac myocytes themselves are capable of synthesizing these proinflammatory cytokines in response to various forms of cardiac injury.34 The local inflammatory response can appear within minutes of an abnormal stress. Local inflammation of the cytokines and other mediators includes deleterious effects of LV remodeling, which include myocyte hypertrophy, alteration in fetal gene expression, contractile defects, and progressive myocyte loss through apoptosis. In addition, there may be promotion of LV remodeling through alterations of the extracellular matrix. A number of studies have shown that the local proinflammatory molecules are activated as early as New York Heart Association (NYHA) class I, which is before some of the classic neurohormonal responses, that tend to be activated in the latter stages (NYHA II thru IV). There are important signaling interactions between the RAAS and the sympathetic nervous system, along with the proinflammatory cytokines.35

Activation of the systemic inflammatory response is found in advanced HF. Cardiac cachexia and skeletal muscle myopathy, which contributes to the fatigue and muscle weakness seen in HF, is a part of the systemic inflammatory response; the elevation of the proinflammatory cytokines correlates with the severity of the syndrome. The knowledge of the role of inflammation remains incomplete. As with the hemodynamic defence reaction, the inflammatory response may be initially beneficial, but when sustained becomes deleterious.

Systolic and Diastolic Dysfunction

HF is commonly subdivided into two entities. Patients with symptoms of HF and a reduction in left ventricular ejection fraction (LVEF) (<0.50) are classified as having systolic dysfunction. Patients with symptoms and preserved LVEF are classified as having diastolic dysfunction. While these labels are somewhat useful in describing the pattern of LV dysfunction, they grossly oversimplify the underlying pathophysiology. In fact, there is little pathophysiologic evidence to support this subdivision. Instead HF might best be thought of as a continuous spectrum of closely related clinical entities. As our understanding grows of the dynamic and complex processes that result in effective myocardial contractility, this distinction may no longer be appropriate.36

Table 24-5 describes the clinical features of HF in patients with reduced and preserved LVEFs. Interestingly, survival of patients with clinical HF symptoms is similar regardless of whether LVEF is reduced or preserved.37

HF With Reduced LVEF.

Systolic dysfunction is determined by an impaired pump function with LVEF less than 0.50 and an enlarged end-diastolic chamber volume. The ventricle is dilated, often thin-walled, and may be eccentrically hypertrophied. Systolic dysfunction can be regional, as in MI, or global, as in dilated cardiomyopathy.16 The principal clinical manifestations of LV systolic dysfunction result from inadequate cardiac output and fluid retention. Systolic dysfunction is thought to account for approximately 50% of patients with symptoms of HF.38 The etiology is most commonly secondary to long-standing chronic ischemic heart disease attributable to CAD.

HF With Preserved LVEF.

Diastolic HF implies normal systolic function in the presence of clinical HF, and is characterized by an increased resistance to filling, with one or both ventricles becoming stiff or noncompliant. Diastolic dysfunction is related to reduction in early LV relaxation compromising the transfer of blood from the atrium into the ventricle. It is typically characterized by
delayed ventricular relaxation most commonly due to distortion of the ventricular chamber and prolongation of the ventricular ejection. Advances in imaging of the myocardium both with echocardiograms and functional MRI have led to increased understanding of the factors that lead to diastolic dysfunction. Qualitatively, ventricle walls are thick, there is an increase in left atrial (LA) size and reduction in mitral annulus motion.36 LA volume is often viewed as a morphologic expression of LV diastolic dysfunction. When the mitral valve is open during diastole, the LA is exposed to the loading pressures of the LV. As the LA is chronically exposed to the increased filling pressure of LV, remodeling occurs and results in increased LA size and volume.39


HF with Reduced LVEF

HF with Preserved LVEF


More men than women

More women than men

Age (years)




MI or idiopathic DCM


Clinical progress

Persistent HF

Often episodic HF

↑ LV volumes



LV hypertrophy





Less common

Mitral inflow pattern



Peak mitral annular systolic velocity

Greatly reduced

Moderately reduced

Peak mitral annular early diastolic velocity

Greatly reduced

Moderately reduced

LA pressure



LA volume



AF, atrial fibrillation; ARP, abnormal relaxation pattern; DCM, dilated cardiomyopathy; HTN, hypertension; DM, diabetes; LA, left atrium; RFP, restricted filling pattern; MI, myocardial infarction.

Adapted from Sanderson, J. E. (2007). Heart failure with a normal ejection fraction. Heart, 93(2), 155-158. Table 1.

The LV has passive compliance or elastic property that characterizes wall stiffness. Diastolic function can be impaired by four types of lusitropic abnormalities: slowed relaxation with decreased rate of pressure fall (-dP/dt) during isovolumetric relaxation, delayed filling during early diastole, incomplete relaxation with reduced filling throughout diastole, and decreased compliance or increased stiffness in late diastole. These changes cause abnormal pressure-volume relationships and produce a higher pressure for any given volume. The pressure is transmitted backwards to the atria, and the pulmonary, and systemic circulation, as noted by elevated pulmonary pressures and decreased cardiac output, leading to dyspnea and fatigue during exercise.7

LV failure is caused by diastolic dysfunction in up to 40% of cases. The etiology is most commonly secondary to long-standing systemic hypertension, but CAD; diabetes; obesity; sleep disorders; hypertrophic, infiltrative, and restrictive cardiomyopathies; and primary valve disorders also can lead to diastolic HF.20 Pure diastolic dysfunction has also been observed immediately after cardiac surgery.20 Changes that occur in the cardiovascular system as a result of aging have a greater impact on diastolic function than on systolic function. Consistency of the association of female sex with HF and preserved LV function across numerous subgroups of patients implies that sex itself is an important determinant of LV adaptation, regardless of the underlying pathophysiologic process.40,41 The major consequence of diastolic failure relates to elevation of ventricular filling pressures, causing pulmonary and/or systemic congestion.

During the past 20 years, the role of diastolic dysfunction has been increasingly recognized. The different pathophysiologic processes behind systolic and diastolic dysfunction affect prognosis and treatment and are addressed in the following sections.20

Left-Sided HF

Left-sided HF, associated with elevated pulmonary venous pressure and decreased cardiac output, appears clinically as breathlessness, weakness, fatigue, dizziness, confusion, pulmonary congestion, hypotension, and death.

Weakness or fatigue is precipitated by decreased perfusion to the muscles. Abnormalities of skeletal muscle histology and biochemistry also play a role, along with deficient endothelial function. Patients describe a feeling of heaviness in their arms and legs, and there is a reduction in exercise capacity. Cardiac cachexia is a severe complication of HF and is considered a terminal manifestation. Circulating cytokines are known to be important in tissue catabolism.

Decreased cerebral perfusion caused by low cardiac output leads to changes in mental status, such as restlessness, insomnia, nightmares, or memory loss. Anxiety, agitation, paranoia, and feelings of impending doom may develop as the syndrome progresses.

During the course of HF, pulmonary congestion progresses through three stages: stage 1, early pulmonary congestion; stage 2, interstitial edema; and stage 3, alveolar edema.27 During the early phase, little measurable increase in interstitial lung fluid is noted. There are few clinical manifestations during this phase.

Interstitial edema usually occurs when the PAWP exceeds 18 mm Hg, leading to a net filtration of fluid into the interstitial space. Clinical manifestations of interstitial edema are varied. Engorged pulmonary vessels, elevated PA pressure, and reduced lung compliance cause increased exertional dyspnea.22 If LV function is severely impaired, orthopnea or a nonproductive cough may be present. Paroxysmal nocturnal dyspnea may also occur because of postural redistribution of blood flow that increases venous return and pulmonary vascular pressure when the patient is in a recumbent position. Congestion of the bronchial mucosa that increases airway resistance and the work of breathing may also contribute to paroxysmal nocturnal dyspnea.
Pulmonary crackles are first noted over the lung bases, and as the PAWP increases, they progress toward the apices.

Stage 3 occurs when the PAWP rises to 25 to 28 mm Hg, causing rapid movement of fluid out of the intravascular and interstitial spaces into the alveoli. As the edema progresses, the alveoli no longer remain open because of the large fluid accumulation. At this point, the alveolar-capillary membrane is disrupted, fluid invades the large airways, and the patient describes or exhibits frothy, pinktinged sputum. Acute pulmonary edema is a catastrophic indicator of HF. These pulmonary congestion stages are broad categories. The correlation between a patient’s PCWP and clinical symptoms is highly variable and most likely dependent upon the duration of illness and individual compensatory mechanisms.

Right-Sided HF

Right-sided HF, associated with increased systemic venous pressure, gives rise to the clinical signs of jugular venous distension, hepatomegaly, dependent peripheral edema, and ascites.22 Dependent ascending peripheral edema is a manifestation in which edema begins in the lower legs and ascends to the thighs, genitalia, and abdominal wall. Patients may notice their shoes fitting tightly or marks left on the feet from their shoes or socks. Weight gain is what most patients recognize; consistent self-weighing in the morning helps to detect subtle changes in fluid status. An adult may retain 10 to 15 lb (4 to 7 L) of fluid before edema occurs.

Congestive hepatomegaly characterized by a large, tender, pulsating liver, and ascites also occurs. Liver engorgement is caused by venous engorgement, whereas ascites results from transudation of fluid from the capillaries into the abdominal cavity. Gastrointestinal symptoms such as nausea and anorexia may be a direct consequence of the increased intra-abdominal pressure.

Another finding related to fluid retention is diuresis at rest. When at rest, the body’s metabolic requirements are decreased, and cardiac function improves. This decreases systemic venous pressure, allowing edema fluid to be mobilized and excreted. Recumbency also increases renal blood flow and GFR, also increasing diuresis. Table 24-6 lists the various subjective and objective indicators for LV and right ventricular (RV) failure.

Diagnosis and Clinical Manifestations

The predominant symptoms of HF are breathlessness or dyspnea and fatigue. Orthopnea and paroxysmal nocturnal dyspnea occur in the more advanced stages of HF. For more detail, refer to “Part III/Assessment of Heart Disease.”


A careful history is important to ascertain possible causes of HF and identify patients at increased risk for HF. The history should include past medical history and a thorough review of systems. Table 24-7 lists the vital elements in a thorough history, including a history of CAD, hypertension, valvular heart disease, congenital heart defects, or diabetes. Other endocrine abnormalities include a history of thyroid disease or a family history of cardiomyopathy or CAD should be explored. Ascertain if the patient is using possible toxic agents, such as alcohol or cocaine, or has been exposed to radiation or chemotherapy. Patients with a history of central sleep apnea may also have impaired autonomic control and increased cardiac arrhythmias.42 Precipitating factors for HF should be assessed, such as anemia, infection, or pulmonary embolism. Obtaining a description of a patient’s exercise capacity and ability to perform activities of daily living may be useful in assessing their degree of limitation. Patients who describe symptoms of presyncope or syncope should be evaluated for arrhythmias, because atrial fibrillation and ventricular arrhythmias are commonly found in this patient population. Sudden death is responsible for up to 40% to 50% of fatal events in HF.43 In patients with decompensation of existing HF, dietary or medication noncompliance, or exacerbating mediations (like NSAIDs) should be investigated.


Left Ventricular Failure

Right Ventricular Failure

Subjective Findings


Lower extremity heaviness


Abdominal distention

Fatigue and weakness

Gastric distress

Memory loss and confusion

Anorexia, nausea





Objective Findings

Weight gain

Weight gain


Neck vein pulsations and distention

Decreased S1

Increased jugular venous pressure (increased central venous pressure)

S3 and S4 gallops

Crackles (rales)


Pleural effusion



Positive hepatojugular reflux

Pulsus alternans


Increased pulmonary artery wedge pressure

Decreased cardiac index

Increased systemic vascular resistance

Physical Examination

A major goal in assessing the patient with HF is to determine the type and severity of the underlying disease causing HF and the extent of the HF syndrome. Physical examination of the patient with HF focuses on the cardiovascular and pulmonary systems, as well as relevant aspects of the integumentary and gastrointestinal systems (See Chapter 10.)

Cardiovascular Assessment.

Determination of the rate, rhythm, and character of the pulse is important in patients with HF. The pulse rate is usually elevated in response to a low cardiac output. Pulsus alternans (alternating pulse) is characterized by an altering strong and weak pulse with a normal rate and interval. Pulsus alternans is associated with altered functioning of the LV causing variance in LV preload. An irregular pulse is usually indicative of an arrhythmia. Increased heart size is common in patients with HF. This cardiac enlargement is detected by precordial palpation, with the apical impulse displaced laterally to the left and downward. In patients with HF, there maybe a third heart sound (S3) that is associated with a reduced EF and impaired diastolic function as determined by the peak filling rate.44 A fourth heart sound (S4) may occur, although it is not in itself a sign of failure but rather a reflection of decreased ventricular compliance associated with ischemic heart disease, high blood pressure, or hypertrophy. When the heart rate is rapid, these two diastolic sounds may merge
into a single loud sound or summation gallop. Patients with HF frequently have a murmur of mitral regurgitation, which radiates to the axilla. Jugular venous pulses are a means of estimating venous pressure. The a and v waves rise as the mean right atrial (RA) pressure rises. The hepatojugular reflux is also associated with HF.


Patient History to Include

Family History to Include


Predisposition to atherosclerotic disease



Sudden cardiac death

Valvular heart disease


Coronary or peripheral vascular disease

Conduction system disease



Rheumatic fever

Cardiomyopathy (unexplained HF)

Mediastinal irradiation

Skeletal myopathies

History or symptoms of sleep disorders

Exposure to cardiotoxic agents

Current or past heavy alcohol consumption


Collagen vascular disease

Thyroid disease



Adapted from Hunt, S. A., Abraham, W. T., Chin, M. H., et al. (2005). ACC/AHA 2005 Guideline Update for the Diagnosis and Management of Chronic Heart Failure in the Adult: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): Developed in Collaboration With the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: Endorsed by the Heart Rhythm Society. Circulation, 112(12), e154-e235. Table 2.

Pulmonary Assessment.

Persistently elevated PA pressures result in the transudation of fluid from the capillaries into the interstitial spaces and, eventually, into the alveolar spaces. The accumulated fluid may result in pulmonary crackles. Initially, the crackles are heard at the most dependent portions of the lungs; but later, as pulmonary congestion increases, crackles become diffuse and are heard over the entire chest.44 Respiratory rate and pattern reflect the severity of the pulmonary compromise, with rapid breathing (tachypnea) or periodic respiratory (Cheyne-Stokes) being noted.42

Integumentary Assessment.

Patients with HF often present with dependent edema. It is most often detected in the feet, ankles, or sacral area. Color and temperature of the skin are also assessed, with major findings being pallor, decreased temperature, cyanosis, and diaphoresis. Cardiac cachexia, with a decrease in tissue mass, may be evident in patients with long-standing HF. Cachexia is defined as a documented, unintentional, nonedematous weight loss of 5 kg or more with a body mass index of less than 24 kg/m2.

Gastrointestinal Assessment.

Characteristically, HF results in hepatomegaly. The liver span is increased and the liver is usually palpable well below the right costal margin. An enlarged spleen may also be palpated in advanced HF.

Imaging and Laboratory Studies

Transthoracic Doppler two-dimensional echocardiography coupled with Doppler flow studies is the single most valuable tool and is of particular benefit for specifically assessing ventricular mass, chamber size, valvular changes, pericardial effusion, and systolic and diastolic dysfunctions.1 (See Chapter 13.) Systolic dysfunction is defined as an EF less than 0.35 to 0.40. Diastolic dysfunction appears with concentric LV hypertrophy, LA enlargement, an EF of 0.45 to 0.55, a reduced rate of LV filling, and a prolonged time to peak filling.45,46 Studies have shown LV mass/volume were increased in diastolic dysfunction but not in systolic dysfunction.18,40,47 Radionuclide studies are a precise and reliable measurement of EF and have also become important in providing clues to the presence and cause of HF.1 Myocardial perfusion studies are also a valuable tool in assessing myocardial ischemia, myocardial infarction and myocardial viability to help determine patients who might benefit from revascularization.1,47 (See Chapter 14.)

Cardiac catheterization/coronary arteriography is used in patients with angina or large areas of ischemic or hibernating myocardium, and is also the best quantitative evaluation of diastolic dysfunction and shows an increase in PAWP or LV end-diastolic pressure.1,48 (See Chapter 20.)

A number of routine laboratory tests useful in the evaluation of HF, including a chest radiograph, should also be included to assess the size of the heart and the pulmonary vascular markings (Chapter 12). The electrocardiogram (ECG) is not helpful in assessing the presence or degree of HF, but it demonstrates patterns of ventricular hypertrophy, arrhythmias, and any degree of myocardial ischemia, injury, or infarction (Chapter 15).

Laboratory tests include blood chemistries, complete blood count, and urinalysis (Chapter 11). Measurement of hemoglobin and hematocrit is useful to exclude anemia in patients with HF.1 Anemia was found to be a common factor in patients with HF and an independent prognostic factor for mortality.31,49 Electrolyte imbalances in HF reflect complications of failure as well as the use of diuretics and other drug therapy. Disturbances in sodium, potassium, and magnesium are particularly significant. In patients with severe HF, an increase in total-body water dilutes body fluid and is reflected by a decrease in the serum sodium. Diuretics may also contribute to low serum sodium. Hypokalemia, or low serum potassium level, and low serum magnesium may occur as the result of the use of diuretics such as thiazides and furosemides, because these diuretics may lead to excessive excretion of potassium and magnesium. Hyperkalemia, or elevated potassium level, may occur secondary to depressed effective renal blood flow and low GFR.

Any impairment of kidney function may be reflected by elevated blood urea nitrogen, creatinine, and uric acid.31 Elevated levels of bilirubin, aspartate aminotransferase and lactate dehydrogenase result from hepatic congestion. Urinalysis may reveal proteinuria, red blood cells, and high specific gravity. Thyroid-stimulating hormone in patients with unexplained HF may also be helpful. Elevated serum glucose (diabetes) and lipid abnormalities are risk factors, and these should also be measured.9

In patients with decompensation of HF, arterial blood gases usually show a decrease in PaO2 (partial pressure of oxygen in arterial blood; hypoxemia) and a low PaCO2 (partial pressure of carbon dioxide in arterial blood). In the clinical situation of HF, the alveoli become filled with fluid, causing a decrease in PaO2, whereas the compensatory attempt to increase the PaO2 by hyperventilating causes a decrease in the PaCO2, resulting in a mild respiratory alkalosis. Later changes caused by decreased peripheral perfusion result in a build-up of lactic acid, causing metabolic acidosis (Chapter 7).

Measurement of BNP has become a recent laboratory value that is measured as a means to identify patients with elevated LV filling
pressures. It is increased in patients with systolic and diastolic dysfunction, and although it cannot distinguish between the two dysfunctions, it is being widely investigated as a biochemical marker for morbidity and mortality.50, 51, 52 It is very helpful in differentiating dyspnea caused by HF from other causes. The normal level of BNP is less than 100 pg/mL (Fig. 24-11).

Figure 24-11 BNP values for the different subclasses of LV dysfunction. Normal BNP levels are less than 100 pg/mL. (From Maisel, A. S., Koon, J., Krishnaswamy, P., et al. [2001]. Utility of B-natriuretic peptide as a rapid, point-of-care test for screening patients undergoing echocardiography to determine left ventricular dysfunction. American Heart Journal, 141[3], 369.)

Although not a general test for HF, plasma homocysteine has been recently associated with an increased risk of vascular disease. There is some evidence that increased plasma homocysteine level independently predicts risk of the development of HF in adults without previous MI.53


Despite many advances in the treatment of HF in the last decade it remains a highly lethal syndrome, with more than 50,000 deaths reported annually in the United States.54 Most patients with HF will die from the syndrome. The mode of death is typically either secondary to progressive LV dysfunction with systemic malperfusion or via a sudden arrhythmic event. Two-year mortality rates of approximately 20% and 6-year rates of 50% have been reported in population-based studies.55 A large community-based cohort study revealed that the number of new cases of HF has not declined over the past 20 years but survival has. The incidence of HF was highest among men and survival after onset was worse in men. However, the largest survival gains over the last 20 years were seen in the men and younger patients, with less improvement in women and patients over the age of 75.56

While complex algorithms and computer tools have been created and tested in the last few years to aid in estimating prognosis,57 it is important to remember that likelihood of survival can only be determined in populations not in individuals. A large, population-based study examined the association between application of the AHA/ACC HF staging system and survival. The following 5-year survival rates in patients were determined: stage 0, 99%; stage A, 97%; stage B, 96%; stage C, 75%; and stage D, 20%.58 Historically, mortality has been linked to NYHA functional class (i.e., patient’s symptoms); newer algorithms include laboratory measures and quantitative data regarding LV status. Clinical factors associated with a lower survival rates include older age; hyponatremia, decreased hematocrit; widened QRS; and worsening LVEF, NYHA functional class, peak exercise oxygen uptake (VO2 max), and renal function.43 While studies have demonstrated an association between elevated circulating neurohormones (BNP, ET, and NE) and outcome, neurohormonal levels are not used commonly in the clinical area to predict survival. Sudden cardiac death (SCD; Chapter 27) remains an ever-present risk. It is estimated that approximately 50% of patients with systolic dysfunction will die of a sudden tachycardic or bradycardiac rhythm. Predicting SCD in this population has proven difficult; thus, primary prevention measures, such as implantation of implantable cardioverter defibrillators (ICDs) is indicated in patients with LVEF less than 0.35.59

As imperfect as the ability to predict the outcome for individual patients, candid discussions regarding prognosis must occur between providers, families, and patients such that expectations can be aligned and plans made. As the tools to detect, quantify, diagnose, and treat the syndrome of HF improve, the life trajectory of patients has improved.43

Approach to Treatment

Patients with LV dysfunction often present with exercise intolerance, shortness of breath, and/or fluid retention. Incidental findings of dysfunction also may be found in asymptomatic patients. All patients presenting with HF should undergo a detailed evaluation to: (1) determine the type of cardiac dysfunction, (2) uncover correctable causative factors, (3) determine prognosis, and (4) guide treatment. Recognition of signs and symptoms resulting from an inadequate cardiac output and from systemic and pulmonary congestion is accomplished through a careful history, physical examination, routine laboratory analyses, and diagnostic studies.1

There are various principles that guide management of HF. The first and most important step begins with early identification of patients who we know to be at risk for developing the syndrome. The first step is identification and correction of the underlying pathogenic processes, as appropriate, such as aggressive medical management of hypertension, coronary revascularization procedures for CAD or surgical correction of structural abnormalities.1 The second step is the removal of the compounding or precipitating causes, such as infection, arrhythmia, and pulmonary emboli. The third step is the treatment and control of HF. Therapy for HF is directed at reducing the workload of the heart and manipulating the various factors that determine cardiac performance, such as contractility, heart rate, preload, and afterload. The greatest advance has been in agents that inhibit harmful neurohormonal systems that are activated in support of the failing heart, specifically the RAAS and sympathetic nervous system.60 Treatment of HF is based on the manner in which the patient clinically presents, which may encompass the extremes from asymptomatic LV failure to acute cardiogenic shock.

HF ranges clinically from acute cardiogenic shock, acute decompensation of chronic HF, to compensated chronic HF. The goal of therapy is support of pump function, which may include positive inotropic agents, vasodilator therapy, and/or, if extremely severe, mechanical devices. In the case of ischemia caused by CAD,
treatment of the underlying process is the management goal. The combination of ischemia and LV dysfunction carries a poor prognosis, and it is this patient group that may benefit from revascularization by percutaneous coronary intervention techniques (Chapter 23) or urgent cardiac surgery (Chapter 25).

Systolic Dysfunction

Coronary heart disease, hypertension, and dilated cardiomyopathy are the most commonly identified causes of LV systolic dysfunction. The writing committee of the ACC/AHA1 based the therapy guidelines on the four stages of evolution of HF (Fig. 24-1). Stage A includes patients who are at high risk for HF but do not have LV dysfunction. Treatment is aimed at risk factor modification, including management of hypertension, diabetes and lipids, cessation of smoking, and counseling to avoid alcohol and illicit drugs. Patients are encouraged to exercise on a regular basis. Obesity increases the risk of diabetes and hypertension, and steps should be taken to promote strategies to maintain optimal weight. An angiotensin-converting enzyme inhibitor (ACE-I) is indicated in patients with a history of atherosclerotic vascular disease, hypertension, or diabetes.

Stage B includes patients who are asymptomatic but who have LV systolic dysfunction and are at significant risk for HF. All of stage A therapies are needed, with the addition of an ACE-I and β-adrenergic blockers unless contraindicated. Valve replacement or repair should be undertaken in patients with hemodynamically significant valvular stenosis or regurgitation.

Stage C includes patients with LV dysfunction with current or previous symptoms and who need to be treated with all measures used for stages A and B. They should be managed routinely with four types of drugs: a diuretic, an ACE-I, a β-adrenergic blocker agent, and digitalis. For those patients with an intolerance to ACE inhibitors, an angiotensin receptor blocker (ARB) can be used. For those patients with renal insufficiency or angioedema, a hydralazine/nitrate combination can be substituted. The use of an aldosterone antagonist (i.e., spironolactone) for NYHA Classes III and IV symptoms should be considered. Avoid the use of antiarrhythmics, NSAIDs, and most calcium-channel blockers. Calcium-channel blockers are not of proven benefit for patients with systolic dysfunction and may be harmful. Such risks may not extend to the use of longer-acting calcium-channel blockers (e.g., amlodipine), which currently are undergoing further evaluation. Nonpharmacologic therapies include a 2 to 3 g sodium diet, encouragement of physical activity with possible referral for cardiac rehabilitation and exercise training, and administration of influenza and pneumococcal vaccines.

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