FIGURE 13–4 Relation of left ventricular (LV) performance to filling pressure in patients with acute myocardial infarction, an important cause of heart failure. The upper line indicates the range for normal, healthy individuals. At a given level of exercise, the heart operates at a stable point, eg, point A. In heart failure, function is shifted down and to the right, through points 1 and 2, finally reaching point B. A “pure” positive inotropic drug (+ Ino) would move the operating point upward by increasing cardiac stroke work. A vasodilator (Vaso) would move the point leftward by reducing filling pressure. Successful therapy usually results in both effects. (Adapted, with permission, from Swan HJC, Parmley WW: Congestive heart failure. In: Sodeman WA Jr, Sodeman TM [editors]: Pathologic Physiology, 7th ed. Saunders, 1985. Copyright Elsevier.) salt restriction and diuretic therapy in heart failure. Venodilator drugs (eg, nitroglycerin) also reduce preload by redistributing blood away from the chest into peripheral veins.
2.
Afterload: Afterload is the resistance against which the heart must pump blood and is represented by aortic impedance and systemic vascular resistance. As noted in Figure 13–2, as cardiac output falls in chronic failure, a reflex increase in systemic vascular resistance occurs, mediated in part by increased sympathetic outflow and circulating catecholamines and in part by activation of the renin-angiotensin system. Endothelin, a potent vasoconstrictor peptide, is also involved. This sets the stage for the use of drugs that reduce arteriolar tone in heart failure.
3.
Contractility: Heart muscle obtained by biopsy from patients with chronic low-output failure demonstrates a reduction in intrinsic contractility. As contractility decreases in the heart, there is a reduction in the velocity of muscle shortening, the rate of intraventricular pressure development (dP/dt), and the stroke output achieved (Figure 13–4). However, the heart is usually still capable of some increase in all of these measures of contractility in response to inotropic drugs.
4.
Heart rate: The heart rate is a major determinant of cardiac output. As the intrinsic function of the heart decreases in failure and stroke volume diminishes, an increase in heart rate—through sympathetic activation of β adrenoceptors— is the first compensatory mechanism that comes into play to maintain cardiac output. However, tachycardia limits diastolic filling time and coronary flow, further stressing the heart. Thus, bradycardic drugs may benefit patients with high heart rates.
Although digitalis is not the first drug and never the only drug used in heart failure, we begin our discussion with this group because other drugs used in this condition are discussed in more detail in other chapters.
Digitalis is the name of the genus of plants that provide most of the medically useful cardiac glycosides, eg, digoxin. Such plants have been known for thousands of years but were used erratically and with variable success until 1785, when William Withering, an English physician and botanist, published a monograph describing the clinical effects of an extract of the purple foxglove plant (Digitalis purpurea, a major source of these agents).
All of the cardiac glycosides, or cardenolides—of which digoxin is the prototype—combine a steroid nucleus linked to a lactone ring at the 17 position and a series of sugars at carbon 3 of the nucleus. Because they lack an easily ionizable group, their solubility is not pH-dependent. Digoxin is obtained from Digitalis lanata, the white foxglove, but many common plants (eg, oleander, lily of the valley, milkweed, and others) contain cardiac glycosides with similar properties.