Patients with systolic dysfunction have reduced myocardial contractility evidenced by a low EF and a reduced dP/dt during ventricular systole. The dP/dt is a measure of inotropy—how quickly the ventricle can develop a forceful contraction. The nature of the impaired contractility is only partially understood; however, myocyte loss, mechanical derangements of myocardial cells, and dysregulation of neurohormones are believed to be critical elements.10

Impaired contractility attributable to myocardial infarction (MI) is a common cause of heart failure.¹¹ MI, with cell death and loss of contractile elements, reduces the heart’s contractile force. The degree of pump failure is related to the amount of heart muscle lost. In patients with heart failure, myocardial cells are also subject to high rates of apoptosis or programmed cell death. Apoptosis can be triggered by excessive stimulation by certain neurohormones and by ischemia. Over time, the loss of myocardial cells contributes to reduced contractility. In severe systolic HF, the EF may fall below 15% or 20%. In general, the prognosis worsens as EF decreases. Symptomatic patients with systolic heart failure often have impaired diastolic function, which is associated with a higher mortality rate.⁷

Inadequate supplies of oxygen to the contracting cells may impair contractility because each myosin cross-bridge cycle requires a molecule of adenosine triphosphate (ATP). When ATP production is low, fewer cross-bridge cycles are completed with each contraction, which results in a reduced EF.

β₁-Receptor down-regulation is thought to be an important mechanism of impaired systolic function. Chronic overexcitation of cardiac β₁ receptors by sympathetic neurotransmitters (e.g., norepinephrine) leads to a reduction in the number of β₁ receptors, and results in a myocardium that is less responsive to sympathetic stimulation and adrenergic drug therapy. β₁-Receptor blocking agents have been shown to improve EF and also to reduce mortality, which lend support to the view that chronic excessive sympathetic nervous system (SNS) activation is detrimental to cardiac function.^12–14

Coronary artery disease and hypertension are the two main causes of diastolic dysfunction, just as they are the primary causes of systolic failure. Why the same disease processes result in different cardiac dynamics in different individuals is not known. Some patients have isolated systolic failure, whereas others have isolated diastolic failure. Some patients exhibit both abnormal systolic and diastolic function. HF with normal EF is more common in women, the elderly, and those with no history of MI.7 Diastolic failure is a disorder of myocardial relaxation. In this condition, the left ventricle is excessively noncompliant and does not fill effectively. Two separate functional processes occur during the diastolic relaxation phase: The first is an energy-requiring process (lusitropy) that removes free calcium ions from the cytoplasm by pumping them back into the sarcoplasmic reticulum and across the cell membrane into the extracellular fluid. Removal of calcium ions inhibits cross-bridge formation and allows the thick and thin filaments of the sarcomere to passively slide apart. Ischemia, with subsequent ATP deficiency, interferes with the efficiency of calcium ion removal and can impair the active phase of diastolic relaxation.

The second process is passive stretch of the ventricular myocardium to accommodate filling. Passive compliance of the ventricle can be decreased by deposition of fibrin and collagen during scar formation or by hypertrophic thickening of the ventricular wall. Both active and passive processes may be impaired together and are difficult to distinguish clinically.

The hallmark of HF with normal EF is that the patient exhibits clinical manifestations of HF, including low cardiac output, pulmonary congestion, and edema formation, but has a normal EF (usually defined as greater than 50%), indicating absence of significant systolic impairment.^8,9 Because prognosis and treatment recommendations may differ, an echocardiogram to measure EF is recommended in all patients with HF to determine the presence of isolated diastolic dysfunction from systolic failure.^11,13 A comparison of the left ventricular pressure-volume loop in systolic and diastolic dysfunction is shown in Figure 19-1. Systolic failure is characterized by higher than normal diastolic volume and low EF, whereas the pressure-volume loop in diastolic failure indicates poor compliance with a lower diastolic volume at a higher than normal pressure.

Sympathetic activation is a very effective means for increasing cardiac output in an acute process, such as volume depletion. However, in heart failure, sympathetic activation becomes a chronic process that is ultimately deleterious. A major problem with excessive sympathetic activation is that afterload on the left ventricle can be increased significantly. A high afterload increases cardiac workload and may decrease stroke volume. Therefore, treatment of high blood pressure is important to improve cardiac function in patients with HF.8

Drugs that block β₁ receptors have been advocated in the management of HF to inhibit the cardiac effects of sympathetic activation. Many clinicians had been reluctant to use β-blockers in patients with HF because these drugs are negative inotropes and have the potential to reduce cardiac output. In HF, where cardiac output is already low, the use of a negative inotrope would seem to be contraindicated. However, several randomized clinical trials have reported an improved mortality rate in patients receiving certain β₁-blockers, and they are now recommended as standard therapy in most HF guidelines.^6,13 Long-term SNS stimulation of the heart may contribute to heart failure progression and remodeling of the cardiac tissue. Remodeling is a process of myocyte loss, hypertrophy of remaining cells, and interstitial fibrosis (Figure 19-3). The remodeled tissue is less functional and may predispose to worsening failure and cardiac dysrhythmias.

Increased preload in the cardiac chambers is initially a consequence of reduced EF with a resultant increase in residual end-systolic volume. Subsequently, decreased cardiac output to the kidney reduces glomerular filtration, resulting in fluid conservation. In addition, the renin-angiotensin-aldosterone system (RAAS) is activated because of reduced blood flow to the kidney and SNS activation of the juxtaglomerular cells. Angiotensin II (AII) and aldosterone enhance sodium and water reabsorption by the kidney, contributing to an elevated blood volume. Increased preload is a compensatory mechanism that enhances the ability of the myocardium to contract forcefully. An enlarged chamber volume causes the myocardial fibers to lengthen during diastole, which results in greater fiber shortening during contraction (Frank-Starling mechanism).12 The diastolic length of the muscle fibers is thought to determine the number of effective cross-bridge cycles that can be accomplished during systole.¹⁰ Thus, up to a point, an increase in the volume or preload of the heart will result in a greater force of contraction (Figure 19-4). The cardiac function curve flattens out at a certain point, and minimal benefit is obtained despite increasing preload. Patients with systolic failure have a cardiac function curve that is flat and shifted to the right of normal. Thus, they require a higher preload to achieve a given stroke volume. However, patients with HF often retain so much volume that their hearts are functioning on the flat part of the curve. These patients benefit from preload reduction, which will decrease systemic and pulmonary congestive symptoms and cardiac workload with little or no reduction in cardiac output. Diuretics are commonly used to achieve moderate preload reduction.

Hypertrophy of cardiac muscle cells is the third mechanism of compensation and generally takes much longer to occur than preload enhancement or sympathetic activation. Hypertrophy appears to result, in part, from a chronic elevation of myocardial wall tension.10 Wall tension may be high as a result of increased diastolic blood volume (high preload) or as a consequence of high systolic pressures generated in the chamber (to overcome high afterload). The relationship between myocardial wall tension and intrachamber pressure and diameter is described by the law of Laplace: tension = (transmural pressure × radius)/wall thickness. When the ventricular chamber enlarges and pressures increase, more tension is created in the ventricular muscle wall (Figure 19-5). The development of high systolic pressures in the ventricle may be necessary to overcome a high afterload, such as occurs with arterial hypertension and aortic valve stenosis. The hypertrophy of contractile elements in the myocardium increases the heart’s pumping force and helps to reduce the wall tension of the heart toward normal levels. In general, an increase in chamber diameter because of excessive preload is thought to contribute to eccentric hypertrophy in which the muscle fibers elongate.^7,10 High afterload results in concentric hypertrophy in which the muscle fibers grow in diameter and thicken the ventricular wall (Figure 19-6).

Neurohormones, which include norepinephrine (NE) and angiotensin (Ang II), also have hypertrophic effects on the heart. Circulating Ang II levels are higher than normal in HF because of poor kidney perfusion, which triggers production of Ang II through the RAAS. In heart failure, Ang II is also produced locally in the heart. Ang II binds to the angiotensin type 1 (AT1) receptor on cardiac myocytes to activate genes in various growth pathways. Initially, hypertrophy may help the heart compensate for acute loss of myocardial tissue from MI or help maintain cardiac function during chronic hypertension. But over time, the signals that promote hypertrophy are thought to trigger a type of ventricular remodeling that contributes to progression of heart failure. Pathologic remodeling includes loss of myocardial cells through apoptosis and production of fibrous changes in the heart that stiffen the ventricles and contribute to diastolic failure (Figure 19-7). In addition to NE and Ang II, a number of immune cytokines have been implicated in cardiac remodeling.^7,11,12

Evidence for a role of Ang II in remodeling comes from drug studies in which Ang II production is inhibited or the actions of Ang II are blocked at the AT1 receptor. An important enzyme in the pathway of Ang II production is angiotensin-converting enzyme (ACE). Drugs called ACE inhibitors (ACEIs) have been developed to inhibit the activity of this enzyme and prevent formation of Ang II. Another drug class, angiotensin type 1 receptor blockers (ARBs), binds to this Ang II receptor and blocks the intracellular actions of Ang II. ARBs were developed as a more selective means of RAAS inhibition, and to improve the safety and tolerability profile of ACE inhibitors. Both ACE inhibitors and ARBs have been shown to significantly reduce HF mortality, and both drug classes are used as standard therapy in HF.1,4,6 In general, ARBs are prescribed if a patient is intolerant of ACE inhibitors.

In summary, enhanced preload and cardiac hypertrophy may allow a heart to compensate for reduced ventricular function for an extended period. Unfortunately, these compensatory mechanisms, which serve to restore cardiac output to the tissues, also result in an increase in myocardial work and oxygen requirements and appear to cause pathologic remodeling. Progression and decompensation may occur when the primary disease plus the superimposed burdens of compensation overwhelm the heart’s ability to generate adequate contractile force. The focus of therapy for HF is to maintain a state of compensation by minimizing cardiac work while optimizing cardiac output and preventing or delaying ventricular remodeling.

Left-sided heart failure is most often associated with left ventricular infarction and systemic hypertension.7,8 The backward effects of left-sided heart failure may produce dramatic clinical symptoms attributable to pulmonary dysfunction (Figure 19-9). Ineffective pumping of the left ventricle results in an accumulation of blood within the pulmonary circulation. As hydrostatic pressure builds within the pulmonary veins and capillaries, fluid is forced from the capillaries into interstitial and alveolar spaces, causing edema. Pulmonary congestion and edema are associated with a number of clinical findings (Figure 19-10). Dyspnea, or breathlessness, occurs early in the progression of left-sided heart failure and may be considered the cardinal symptom. Difficulty breathing may be exacerbated by activity (dyspnea on exertion), lying down (orthopnea and paroxysmal nocturnal dyspnea), and blood volume expansion from excessive salt or fluid intake. Orthopnea and paroxysmal nocturnal dyspnea are due in part to a redistribution of blood volume from the periphery to the heart when the individual lies down. The failing left ventricle is unable to effectively pump extra volume, and pulmonary congestion is worsened. The severity of orthopnea may be quantified by the degree of head elevation (e.g., number of pillows) used to relieve dyspnea. Paroxysmal nocturnal dyspnea refers to intermittent attacks of severe dyspnea during the night and is a most distressing form of orthopnea. The individual experiences a feeling of suffocation and panic at not being able to overcome the dyspnea. Sitting or standing helps to relieve the dyspnea because blood pools in the extremities, reducing pulmonary hydrostatic pressure and congestion.

Elevated LAP is a common finding in left-sided heart failure because of excessive blood volume and the compensatory responses of atrial dilation and hypertrophy. Atrial pressure can be estimated by inserting a balloon-tipped catheter (Swan-Ganz) into the pulmonary artery. If LAP acutely increases to 25 mm Hg (normal is 4 to 12 mm Hg), increased capillary filtration leads to pulmonary edema. Patients with chronic elevations in LAP associated with chronic HF are more resistant to developing acute pulmonary edema, and may not experience symptoms until pressures approach 40 mm Hg.7 On x-ray, findings of fluid overload include an enlarged heart and engorged pulmonary capillaries and lymphatic vessels.

Acute cardiogenic pulmonary edema is a life-threatening condition associated with left ventricular failure that severely impairs gas exchange, producing dramatic signs and symptoms. The patient exhibits severe dyspnea and anxiety, and a bolt-upright posture is usually assumed in order to maximize respiratory effort. Bubbly crackles may be heard all the way up the lung from the bases to the apices, and pink frothy sputum may be expectorated or well up from the trachea into the nose and mouth. Anxiety and hypoxemia contribute to tachycardia, which may worsen the pumping efficiency of the failing heart. Cyanosis and symptoms of tissue hypoxia are usually apparent. The immediate treatment is aimed at reducing the fluid volume in the lungs and supporting oxygenation.

Because the right and left ventricles function in series, left ventricular failure eventually increases the workload on the right ventricle. Consequently, the right ventricle may fail. The etiology of right ventricular failure must include all the causes of left ventricular failure. Isolated right ventricular failure is rare and is usually a consequence of right ventricular infarction or pulmonary disease. Only 3% of MIs occur in the right ventricle; however, right ventricular infarctions are often poorly tolerated and difficult to manage.7 Pulmonary disorders that result in increased pulmonary vascular resistance impose a high afterload on the right ventricle. The resultant right ventricular hypertrophy, called cor pulmonale, may progress to right ventricular failure as the lung disease worsens.

Any lung disorder that decreases the total cross-sectional area of the lung vasculature can increase pulmonary vascular resistance and produce right ventricular strain. Hypoxemia, for example, causes the pulmonary arterioles to constrict, which increases pulmonary resistance. Constriction or blockage of the vascular bed, such as occurs with pulmonary hypertension or pulmonary embolus, similarly reduces the cross-sectional area of the pulmonary vasculature and leads to increased pulmonary resistance. If the increase in pulmonary resistance and right ventricular workload occurs gradually, the right ventricle can compensate by increasing preload and hypertrophy. However, the thin musculature of the right ventricle has limited ability to adjust to acute changes in workload, as would occur with a right ventricular infarction or large pulmonary embolus.

As with left-sided heart failure, congestion of blood occurs behind the failing right ventricle because of inefficiency of the pump. The backward effects of right-sided heart failure are due to congestion in the systemic venous system (Figure 19-11). Systemic venous congestion results in impaired function of the liver, portal system, spleen, kidneys, peripheral subcutaneous tissues, and brain (Figure 19-12).

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