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Drugs Used in Heart Failure - Bertram G. Katzung, MD, PhD, & William W. Parmley, MD

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Introduction

Heart failure occurs when cardiac output is inadequate to provide the oxygen needed by the body. It is a highly lethal condition, with a 5-year mortality rate conventionally said to be about 50%. The most common cause of heart failure in the USA is coronary artery disease. Two major types of failure may be distinguished. In systolic failure, the mechanical pumping action (contractility) and the ejection fraction of the heart are reduced. In diastolic failure stiffening and loss of adequate relaxation plays a major role in reducing cardiac output and ejection fraction may be normal. Because other cardiovascular conditions are now being treated more effectively (especially myocardial infarction), more patients are surviving long enough for heart failure to develop, making this one of the cardiovascular conditions that is actually increasing in prevalence.

Although it is believed that the primary defect in early heart failure resides in the excitation-contraction coupling machinery of the heart, the clinical condition also involves many other processes and organs, including the baroreceptor reflex, the sympathetic nervous system, the kidneys, angiotensin II and other peptides, aldosterone, and apoptosis of cardiac cells. Recognition of these factors has resulted in evolution of a variety of treatment strategies (Table 13-1).

Clinical research has shown that therapy directed at noncardiac targets is more valuable in the long-term treatment of heart failure than traditional positive inotropic agents (cardiac glycosides [digitalis]). Careful clinical trials have shown that angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers, b blockers, aldosterone receptor antagonists, and combined hydralazine-nitrate therapy are the only agents in current use that actually prolong life in patients with chronic heart failure. Positive inotropic drugs, on the other hand, can be very helpful in acute failure. They also reduce symptoms in chronic failure.

Control of Normal Cardiac Contractility

The vigor of contraction of heart muscle is determined by several processes that lead to the movement of actin and myosin filaments in the cardiac sarcomere (Figure 13-1). Ultimately, contraction results from the interaction of activator calcium (during systole) with the actin-troponin-tropomyosin system, thereby releasing the actin-myosin interaction. This calcium is released from the sarcoplasmic reticulum (SR). The amount released depends on the amount stored in the SR and on the amount of trigger calcium that enters the cell during the plateau of the action potential.

A. SENSITIVITY OF THE CONTRACTILE PROTEINS TO CALCIUM
The determinants of calcium sensitivity, ie, the curve relating the shortening of cardiac myofibrils to the cytoplasmic calcium concentration, are incompletely understood, but several types of drugs can be shown to affect it in vitro. Levosimendan is the most recent example of a drug that increases calcium sensitivity (it may also inhibit phosphodiesterase) and reduces symptoms in models of heart failure.

B. THE AMOUNT OF CALCIUM RELEASED FROM THE SARCOPLASMIC RETICULUM
A small rise in free cytoplasmic calcium, brought about by calcium influx during the action potential, triggers the opening of ryanodine-sensitive calcium channels (RyR2) in the membrane of the cardiac SR and the rapid release of a large amount of the ion into the cytoplasm in the vicinity of the actin-troponin-tropomyosin complex. The amount released is proportional to the amount stored in the SR and the amount of trigger calcium that enters the cell through the cell membrane. (Ryanodine is a potent negative inotropic plant alkaloid that interferes with the release of calcium through cardiac SR channels.)

C. THE AMOUNT OF CALCIUM STORED IN THE SARCOPLASMIC RETICULUM
The SR membrane contains a very efficient calcium uptake transporter, known as the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA). This pump maintains free cytoplasmic calcium at very low levels during diastole by pumping calcium into the SR. The amount of calcium sequestered in the SR is thus determined, in part, by the amount accessible to this transporter. This in turn is dependent on the balance of calcium influx (primarily through the voltage-gated membrane calcium channels) and calcium efflux, the amount removed from the cell (primarily via the sodium-calcium exchanger, a transporter in the cell membrane).

D. THE AMOUNT OF TRIGGER CALCIUM
The amount of trigger calcium that enters the cell depends on the availability of membrane calcium channels (primarily the L type) and the duration of their opening. As described in Chapters 6 and 9, sympathomimetics cause an increase in calcium influx through an action on these channels. Conversely, the calcium channel blockers (see Chapter 12) reduce this influx and depress contractility.

E. ACTIVITY OF THE SODIUM-CALCIUM EXCHANGER
This antiporter uses the sodium gradient to move calcium against its concentration gradient from the cytoplasm to the extracellular space. Extracellular concentrations of these ions are much less labile than intracellular concentrations under physiologic conditions. The sodium-calcium exchanger's ability to carry out this transport is thus strongly dependent on the intracellular concentrations of both ions, especially sodium.

F. INTRACELLULAR SODIUM CONCENTRATION AND ACTIVITY OF NA+/K+ ATPASE
Na+/K+ ATPase, by removing intracellular sodium, is the major determinant of sodium concentration in the cell. The sodium influx through voltage-gated channels, which occurs as a normal part of almost all cardiac action potentials, is another determinant although the amount of sodium that enters with each action potential is much less than 1% of the total intracellular sodium. As described below, Na+/K+ ATPase appears to be the primary target of cardiac glycosides.

 Figure 13-1. Schematic diagram of a cardiac muscle sarcomere, with sites of action of several drugs that alter contractility (numbered structures). Site 1 is Na+/K+ ATPase, the sodium pump. Site 2 (NaxC) is the sodium/calcium exchanger. Site 3 is the voltage-gated calcium channel. Site 4 (SERCA) is a calcium transporter that pumps calcium into the sarcoplasmic reticulum (SR). Site 5 (RyR) is a calcium channel in the membrane of the SR that is triggered to release stored calcium by activator calcium. Site 6 is the actin-troponin-tropomyosin complex at which activator calcium brings about the contractile interaction of actin and myosin. 0 

Pathophysiology of Heart Failure

Heart failure is a syndrome with multiple causes that may involve the right ventricle, the left ventricle, or both. Cardiac output in heart failure is usually below the normal range. Systolic dysfunction, with reduced cardiac output and significantly reduced ejection fraction (< 45%), is typical of acute failure, especially that resulting from myocardial infarction. Diastolic dysfunction often occurs as a result of hypertrophy and stiffening of the myocardium, and although cardiac output is reduced, ejection fraction may be normal. Heart failure due to diastolic dysfunction does not usually respond optimally to positive inotropic drugs.

Rarely, "high-output" failure may occur. In this condition, the demands of the body are so great that even increased cardiac output is insufficient. High-output failure can result from hyperthyroidism, beriberi, anemia, and arteriovenous shunts. This form of failure responds poorly to the drugs discussed in this chapter and should be treated by correcting the underlying cause.

The primary signs and symptoms of all types of heart failure include tachycardia, decreased exercise tolerance, shortness of breath, peripheral and pulmonary edema, and cardiomegaly. Decreased exercise tolerance with rapid muscular fatigue is the major direct consequence of diminished cardiac output. The other manifestations result from the attempts by the body to compensate for the intrinsic cardiac defect.

Neurohumoral (extrinsic) compensation involves two major mechanisms previously presented in Figure 6-7: the sympathetic nervous system and the reninangiotensin-aldosterone hormonal response. Some of the pathologic as well as beneficial features of these compensatory responses are illustrated in Figure 13-2. The baroreceptor reflex appears to be reset, with a lower sensitivity to arterial pressure, in patients with heart failure. As a result, baroreceptor sensory input to the vasomotor center is reduced even at normal pressures; sympathetic outflow is increased, and parasympathetic outflow is decreased. Increased sympathetic outflow causes tachycardia, increased cardiac contractility, and increased vascular tone.

While the increased preload, force, and heart rate initially increase cardiac output, increased arterial tone results in increased afterload and decreased ejection fraction, cardiac output, and renal perfusion. After a relatively short time, complex down-regulatory changes in the b1-adrenoceptor-G protein-effector system take place that result in diminished stimulatory effects. Beta2 receptors are not down-regulated and may develop increased coupling to the IP3-DAG cascade. It has also been suggested that cardiac b3 receptors (which do not appear to be down-regulated in failure) may mediate negative inotropic effects. Excessive beta activation can lead to leakage of calcium from the SR via RyR2 channels and contributes to stiffening of the ventricles and arrhythmias. Increased angiotensin II production leads to increased aldosterone secretion (with sodium and water retention), to increased afterload, and to remodeling of both heart and vessels (discussed below). Other hormones may also be released, including natriuretic peptide and endothelin (see Chapter 17).

The most important intrinsic compensatory mechanism is myocardial hypertrophy. This increase in muscle mass helps maintain cardiac performance. However, after an initial beneficial effect, hypertrophy can lead to ischemic changes, impairment of diastolic filling, and alterations in ventricular geometry. Remodeling is the term applied to dilation (other than that due to passive stretch) and other slow structural changes that occur in the stressed myocardium. It may include proliferation of connective tissue cells as well as abnormal myocardial cells with some biochemical characteristics of fetal myocytes. Ultimately, myocytes in the failing heart die at an accelerated rate through apoptosis, leaving the remaining myocytes subject to even greater stress.

The severity of heart failure is usually described according to a scale devised by the New York Heart Association. Class I failure is associated with no limitations on ordinary activities and symptoms that occur only with greater than ordinary exercise. Class II is characterized by slight limitation of ordinary activities, which result in fatigue and palpitations with ordinary physical activity. Class III failure results in no symptoms at rest, but fatigue, etc, with less than ordinary physical activity. Class IV is associated with symptoms even when the patient is at rest.

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