222
CARDIOVASCULAR PHYSIOLOGY CONCEPTS
muscle and leads to increased oxygen extrac-
tion (increased arterial-venous oxygen differ-
ence), enhanced lactic acid production (and a
lower anaerobic threshold), and muscle fatigue
at lower workloads. The increase in blood
volume, although helping to maintain stroke
volume at rest through the Frank-Starling
mechanism, decreases the reserve capacity of
the heart to increase preload during exercise.
Physiologic Basis for Therapeutic
Intervention
Therapeutic goals in the pharmacologic treat-
ment of heart failure include (1) reducing the
clinical symptoms of edema and dyspnea; (2)
improving cardiovascular function to enhance
organ perfusion and increase exercise capac-
ity; and (3) reducing mortality.
Four pharmacologic approaches are taken
to achieve these goals. The first approach is
to reduce venous pressure to decrease edema
and help relieve the patient of dyspnea. Diu-
retics are routinely used to reduce blood vol-
ume by increasing renal excretion of sodium
and water. Drugs that dilate the venous vascu-
lature (e.g., ACE inhibitors) also can reduce
venous pressure. Judicious use of these drugs
to decrease blood volume and venous pres-
sure does not significantly reduce stroke
volume because
the Frank-Starling curve
associated with systolic failure is relatively
flat at left ventricular end-diastolic pressures
above 15 mm Hg (see Fig. 9.8).
The second approach is to use drugs that
reduce afterload on the ventricle by dilating
the systemic vasculature. Drugs such as ACE
inhibitors and ARBs have proven to be use-
ful in this regard for patients with chronic
heart failure. Decreasing the afterload on the
ventricle can significantly enhance stroke
volume and ejection fraction, which sec-
ondarily
reduces
ventricular
end-diastolic
volume (preload). Because arterial vasodila-
tors enhance cardiac output in heart failure
patients, the reduction in systemic vascular
resistance does not usually lead to an unac-
ceptable fall in arterial pressure. Vasodilators
also have the benefit of decreasing myocardial
oxygen demand.
The third approach is to use drugs that
stimulate ventricular inotropy. A commonly
used drug is digoxin, which inhibits the
Na+
/K+-ATPase and thereby increases intra-
cellular calcium (see Chapter 2). This drug,
however, has not been shown to reduce
mortality
associated
with
heart
failure.
Drugs that stimulate Pj-adrenoceptors (e.g.,
dobutamine)
or inhibit cAMP-dependent
phosphodiesterase
(e.g.,
milrinone)
are
sometimes used as inotropic agents (see
Chapter 3). With the exception of digoxin,
inotropic drugs are used only in acute
heart failure and end-stage failure because
their long-term use has been shown to be
deleterious to the heart.
The fourth therapeutic approach involves
using beta-blockers.
Although this might
seem
counterintuitive,
many
clinical
tri-
als have clearly demonstrated the efficacy of
some beta-blockers (e.g., carvedilol and meto-
prolol). The mechanism of their efficacy is not
clear, but it is known that long-term sympa-
thetic activation of the heart is deleterious.
Therefore, beta-blockers probably work by
reducing the deleterious actions of long-term
sympathetic activation. Beta-blockers (as well
as ACE inhibitors) provide long-term benefit
through ventricular remodeling (e.g., reduc-
ing ventricular
hypertrophy
or
dilation).
Furthermore, P-blockers significantly reduce
mortality in heart failure.
It should be noted that vasodilators, ino-
tropic drugs, and P-blockers are nearly always
used in combination with a diuretic.
CASE 9-3
A patient is diagnosed with dilated
cardiomyopathy. The echocardiogram
shows substantial left ventricular
dilation (end-diastolic volume is
240 mL) and an ejection fraction
of 20%; the arterial pressure is
115/70 mm Hg. Calculate the stroke
volume and end-systolic volume. How
would combined therapy with an ACE
inhibitor and diuretic alter ventricular
volumes, ejection fraction, and arterial
pressure?
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