490
U N I T 5
Circulatory Function
heart failure.
5,6,8
Both cardiac sympathetic tone and
catecholamine (epinephrine and norepinephrine) lev-
els are elevated during the late stages of most forms of
heart failure. By direct stimulation of heart rate and
cardiac contractility, regulation of vascular tone, and
enhancement of renal sodium and water retention, the
sympathetic nervous system initially helps to maintain
perfusion of the various body organs.
Although the sympathetic nervous system response
is meant to maintain blood pressure and cardiac out-
put, it quickly becomes maladaptive and contributes
to the deterioration of heart function. An increase in
sympathetic activity can lead to tachycardia, vaso-
constriction, and cardiac arrhythmias. Acutely, tachy-
cardia significantly increases the workload of the
heart, thus increasing myocardial oxygen demand and
leading to cardiac ischemia, myocyte damage, and
decreased contractility (inotropy). An increase in sys-
temic vascular resistance causes an increase in cardiac
afterload and ventricular wall stress. By promoting
arrhythmias, the catecholamines released with sympa-
thetic nervous system stimulation also may contrib-
ute to the high rate of sudden death seen with heart
failure. Other sympathetic mediated effects include
decreased renal perfusion and additional augmenta-
tion of the renin-angiotensin-aldosterone system, as
well as decreased blood flow to skin, muscle, and
abdominal organs.
12
Renin-Angiotensin-Aldosterone Mechanism
One of the most important effects of lowered cardiac
output in heart failure is a reduction in renal blood flow
and glomerular filtration rate, which leads to sodium
and water retention by way of aldosterone production.
With decreased renal blood flow, there is a progressive
increase in renin secretion by the kidneys with parallel
increases in circulating levels of angiotensin II.
10–13
The
increased concentration of angiotensin II contributes
directly to generalized and excessive vasoconstriction,
as well as facilitating norepinephrine release and inhibit-
ing reuptake of norepinephrine by the sympathetic ner-
vous system.
8
Angiotensin II also provides a powerful
stimulus for aldosterone production by the adrenal cor-
tex (see Chapter 18).
Aldosterone increases tubular reabsorption of
sodium, with an accompanying increase in water reten-
tion. Because aldosterone is metabolized in the liver, its
levels are further increased when heart failure causes
liver congestion. Angiotensin II also increases the
level of antidiuretic hormone (ADH), which serves as
a vasoconstrictor and inhibitor of water excretion (see
Chapter 8). In addition to their individual effects on
sodium and water balance, angiotensin II and aldoste-
rone are also involved in regulating the inflammatory
and reparative processes that follow tissue injury.
10
However, the sustained expression of aldosterone may
stimulate fibroblast and collagen deposition, resulting
in ventricular hypertrophy as well as fibrosis within the
vasculature and myocardium, and thereby contributing
to reduced vascular compliance and increased ventricu-
lar stiffness.
10
Natriuretic Peptides
The heart muscle produces and secretes a family of
related peptide hormones, called the
natriuretic peptides
(NPs), which have potent diuretic, natriuretic, vascular
smooth muscle, and other neurohumoral actions that
affect cardiovascular function. Two of the four known
NPs most commonly associated with heart failure are
atrial natriuretic peptide and B-type natriuretic pep-
tide.
10,14
As the name indicates, atrial natriuretic peptide
(ANP) is released from atrial cells in response to atrial
stretch, pressure, or fluid overload. B-type natriuretic
peptide (BNP), so named because it was originally found
in extracts of the porcine brain, is primarily secreted by
the ventricles as a response to increased ventricular pres-
sure or fluid overload. Although the NPs are not secreted
from the same chambers in the heart, they have very sim-
ilar functions. In response to increased chamber stretch
and pressure, they promote rapid and transient natriure-
sis and diuresis through an increase in the glomerular
filtration rate and an inhibition of tubular sodium and
water reabsorption. The NPs also facilitate complex
interactions with the neurohormonal system, inhibiting
the sympathetic nervous system, the renin-angiotensin-
aldosterone system, and the antidiuretic hormone
(ADH), also known as vasopressin. Circulating levels of
both ANP and BNP are elevated in persons with heart
failure. The concentrations are well correlated with
the extent of ventricular dysfunction, increasing up to
30-fold in persons with advanced heart disease.
14
Assays
of BNP are used clinically in the diagnosis of heart fail-
ure and to predict the severity of the condition.
Endothelins
The endothelins, released from the endothelial cells
throughout the circulation, are potent vasoconstrictors.
Like angiotensin II, endothelin can also be synthesized
and released by a variety of cell types, such as cardiac
myocytes. There are three endothelin (ET) peptides (ET-1,
ET-2, and ET-3).
10,15
In addition to vasoconstrictor actions,
the endothelins induce vascular smooth muscle cell pro-
liferation and cardiac myocyte hypertrophy and fibrosis;
increase the release of ANP, aldosterone, and catechol-
amines; and exert antinatriuretic effects on the kidneys.
They also have been shown to have a negative inotropic
action in patients with heart failure.
15
Plasma ET-1 levels
also correlate directly with pulmonary vascular resistance,
and it is thought that ET-1 may play a role in mediating
pulmonary hypertension in persons with heart failure.
10
Myocardial Hypertrophy and Remodeling
The development of myocardial hypertrophy constitutes
one of the principal mechanisms by which the heart com-
pensates for an increase in workload.
10,16
Although ven-
tricular hypertrophy improves the work performance of
the heart, it is also an important risk factor for subsequent
cardiac morbidity and mortality. Inappropriate hypertro-
phy and remodeling can result in changes in structure (i.e.,
muscle mass, chamber dilation) and cardiac function (i.e.,
impaired systolic or diastolic function) that often lead to
further pump dysfunction and hemodynamic overload.
