Page 230 - Basic _ Clinical Pharmacology ( PDFDrive )

216 SECTION III Cardiovascular-Renal Drugs

failure) may mediate negative inotropic effects. Excessive β activa- 100
tion can lead to leakage of calcium from the SR via RyR channels
and contributes to stiffening of the ventricles and arrhythmias.
2+
Reuptake of Ca into the SR by SERCA may also be impaired. 80
Prolonged β activation also increases caspases, the enzymes respon-
sible for apoptosis. Increased angiotensin II production leads to Normal range
increased aldosterone secretion (with sodium and water retention), 60
to increased afterload, and to remodeling of both heart and
vessels. Other hormones are released, including natriuretic peptide, LV stroke work (g-m/m 2 ) A + Ino
endothelin, and vasopressin (see Chapter 17). Of note, natriuretic 40 Depressed
peptides released from the heart and possibly other tissues include 1 2
N-terminal pro-brain natriuretic peptide (NT-proBNP), which Vaso B
has come into use as a surrogate marker for the presence and sever-
ity of heart failure. Within the heart, failure-induced changes have 20
been documented in calcium handling in the SR by SERCA and Shock
phospholamban; in transcription factors that lead to hypertro-
phy and fibrosis; in mitochondrial function, which is critical for 0 0 10 20 30 40
energy production in the overworked heart; and in ion channels,
especially potassium channels, which facilitate arrhythmogenesis, LV filling pressure (mm Hg)
a primary cause of death in heart failure. Phosphorylation of RyR FIGURE 13–4 Relation of left ventricular (LV) performance
2+
channels in the SR enhances and dephosphorylation reduces Ca to filling pressure in patients with acute myocardial infarction, an
release; studies in animal models indicate that the enzyme primarily important cause of heart failure. The upper line indicates the range
responsible for RyR dephosphorylation, protein phosphatase 1 (PP1), for normal, healthy individuals. At a given level of exercise, the heart
is up-regulated in heart failure. These cellular changes provide operates at a stable point, eg, point A. In heart failure, function is
many potential targets for future drugs. shifted down and to the right, through points 1 and 2, finally reach-
ing point B. A “pure” positive inotropic drug (+ Ino) would move the
The most obvious intrinsic compensatory mechanism is myo- operating point upward by increasing cardiac stroke work. A vasodila-
cardial hypertrophy. The increase in muscle mass helps maintain tor (Vaso) would move the point leftward by reducing filling pressure.
cardiac performance. However, after an initial beneficial effect, Successful therapy usually results in both effects. (Adapted, with permission,
hypertrophy can lead to ischemic changes, impairment of diastolic from Swan HJC, Parmley WW: Congestive heart failure. In: Sodeman WA Jr, Sodeman
filling, and alterations in ventricular geometry. Remodeling is the TM [editors]: Pathologic Physiology, 7th ed. Saunders, 1985. Copyright Elsevier.)
term applied to dilation (other than that due to passive stretch)
and other slow structural changes that occur in the stressed myo-
cardium. It may include proliferation of connective tissue cells as salt restriction and diuretic therapy in heart failure. Venodilator
well as abnormal myocardial cells with some biochemical charac- drugs (eg, nitroglycerin) also reduce preload by redistributing
teristics of fetal myocytes. Ultimately, myocytes in the failing heart blood away from the chest into peripheral veins.
die at an accelerated rate through apoptosis, leaving the remaining
myocytes subject to even greater stress. 2. Afterload: Afterload is the resistance against which the heart
must pump blood and is represented by aortic impedance and
Pathophysiology of Cardiac Performance systemic vascular resistance. As noted in Figure 13–2, as cardiac
output falls in chronic failure, a reflex increase in systemic vas-
Cardiac performance is a function of four primary factors: cular resistance occurs, mediated in part by increased sympa-
thetic outflow and circulating catecholamines and in part by
1. Preload: When some measure of left ventricular performance
such as stroke volume or stroke work is plotted as a function of activation of the renin-angiotensin system. Endothelin, a potent
left ventricular filling pressure or end-diastolic fiber length, the vasoconstrictor peptide, is also involved. This sets the stage for
resulting curve is termed the left ventricular function curve the use of drugs that reduce arteriolar tone in heart failure.
(Figure 13–4). The ascending limb (< 15 mm Hg filling pres- 3. Contractility: Heart muscle obtained by biopsy from patients
sure) represents the classic Frank-Starling relation described in with chronic low-output failure demonstrates a reduction in
physiology texts. Beyond approximately 15 mm Hg, there is a intrinsic contractility. As contractility decreases in the heart,
plateau of performance. Preloads greater than 20–25 mm Hg there is a reduction in the velocity of muscle shortening, the
result in pulmonary congestion. As noted above, preload is rate of intraventricular pressure development (dP/dt), and the
usually increased in heart failure because of increased blood stroke output achieved (Figure 13–4). However, the heart is
volume and venous tone. Because the function curve of the usually still capable of some increase in all of these measures of
failing heart is lower, the plateau is reached at much lower values contractility in response to inotropic drugs.
of stroke work or output. Increased fiber length or filling pres- 4. Heart rate: The heart rate is a major determinant of car-
sure increases oxygen demand in the myocardium, as described diac output. As the intrinsic function of the heart decreases
in Chapter 12. Reduction of high filling pressure is the goal of in failure and stroke volume diminishes, an increase in heart