Heart failure occurs when the cardiac output is inadequate to
provide the oxygen needed by the body. Heart failure is a highly
lethal condition, with a 5-year mortality rate conventionally said
to be about 50%. In systolic failure, cardiac 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, although the ejection fraction
may be normal. Because other cardiovascular conditions such as myocardial
infarction are now being treated more effectively, more patients
are surviving long enough to develop heart failure. Thus, heart
failure is increasing in prevalence. Although research suggests
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, and death of cardiac cells. The most common cause
of heart failure in the United States is coronary artery disease.
This chapter reviews normal cardiac contractility and the pathophysiology
and major clinical manifestations of heart failure. Drugs used to
treat heart failure include positive inotropic agents, vasodilators,
diuretics, and several miscellaneous drug classes (Figure 9–1).
The positive inotropic agents increase the contractility of the
heart, whereas the vasodilators and miscellaneous drugs have effects
at both cardiac and noncardiac sites. Several drugs acting at noncardiac
sites, such as the vasculature, kidneys, and central nervous system,
have been discussed in Chapters 6, 7, and 8.
Drugs used in the treatment of heart failure. Several
pharmacologic classes have a combination of physiologic effects
and do not fall into a single category. ACE = angiotensin-converting
enzyme inhibitors; PDE = phosphodiesterase. Spironolactone
is a potassium-sparing diuretic that inhibits the aldosteronereceptor
in the collecting tubules of the kidney and nonrenal tissue sites.
The force 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 9–2). During systole, contraction results from the interaction of calcium with the
actin-troponin-tropomyosin system, thereby releasing the actin-myosin
interaction from inhibition. The calcium involved in this interaction
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 action
Schematic diagram of a cardiac muscle sarcomere, with
the sites of action of several drug classes that alter contractility
(numbered structures). Site 1 is Na+/K+–ATPase,
the sodium pump. Site 2 is the Na-Ca2+ exchanger.
Site 3 is the voltage-gated calcium channel. Site 4 is a calcium
transporter that pumps ...
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