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Chapter 19: Congestive Heart Failure 265

systolic pressure volume relation (Figure 19.6). The sys- thirst, elicits vasopressin release from the pituitary,
tolic wall stress in mitral regurgitation may be less than induces endothelin I synthesis, and increases sympa-
in other causes of volume overload to the left ventricle thetic tone. Systemic vascular resistance is increased by
such as a patent ductus arteriosus or aortic insufficiency, imbalance of increased vasoconstrictors (ATII, vaso-
because blood leaks back into the low pressure left pressin, endothelin-I, norepinephrine) and decreased
atrium prior to opening of the aortic valve and essen- vasodilators including nitric oxide, natriuretic peptides,
tially “unloads” the left ventricle. This likely helps to and prostaglandins. The net effect of RAAS activation is
preserve systolic function until end-stage heart failure maintenance of systemic organ perfusion by increased
occurs in animals with mitral regurgitation. systemic vascular resistance and increased blood volume
through sodium and water retention, which occur
Compensatory Mechanisms in Heart Failure within several days of activation.
Increased blood volume (i.e., increased preload)
Acute compensatory mechanisms
in heart failure stretches the cardiomyocytes, which stimulates them to
replicate their sarcomeres end to end and elongate in a
Immediately following a cardiac insult, cardiac output process called eccentric hypertrophy. The left ventricle
and arterial blood pressure are reduced. Since the most chamber grows larger (i.e., increased end-diastolic
important priority of the cardiovascular system is to diameter and volume), which increases stroke volume
maintain adequate arterial blood pressure, the high and cardiac output. In chronic diseases of ventricular
pressure baroreceptors are immediately activated and volume overload (i.e., myocardial failure, valvular insuf-
cause a reflex neuroendocrine feedback to activate the ficiency, and left to right shunts), end-diastolic volume
sympathetic adrenergic system. Stimulation of cardiac can be increased by as much as 200%, but at the expense Congestive Heart Failure
beta receptors increases heart rate (positive chrono- of increased diastolic filling pressure and the develop-
tropic effect) and contractility (positive inotropic effect) ment of congestive heart failure. Volume overload also
to immediately increase cardiac output. Alpha adrener- leads to altered chamber geometry with increased sphe-
gic receptors in the arterial vascular bed are stimulated ricity, increased systolic wall stress, and annular dilation,
to cause vasoconstriction, and blood volume is shunted which worsen ventricular systolic function and exacer-
from the periphery to the central compartment. This bate valvular insufficiency.
acute response is necessary to increase cardiac output Except for the generation of renin by the kidney, all
and maintain perfusion to the critical organ beds of the components of RAAS are present at the myocardial level
heart, kidney, and brain. However, this immediate as well as in many other organs, and are capable of gen-
response is not able to compensate for more than a few erating high levels of ATII and aldosterone locally. Aside
days, and more chronic compensatory mechanisms are from cardiac ACE, other alternative pathways including
necessary for the animal to survive. After approximately chymase, ACE-2, cathepsins, and tonin convert ATI to
2–3 days of adrenergic activation, the beta receptors ATII. In fact, in dogs, cats, and humans, chymase is
become down-regulated and uncoupled, which blunts responsible for 90% of myocardial ATII formation
the positive inotropic and lusitropic (i.e., relaxation) (Balcells et al. 1997; Aramaki et al. 2003). Tissue RAAS
response of beta adrenergic stimulation. appears to be activated earlier in the course of cardiac
disease than circulating RAAS. This means that detec-
Chronic compensatory mechanisms tion of RAAS activation based on plasma neurohor-
in heart failure mone measurements may not reflect activation of RAAS
Activation of the renin angiotensin aldosterone system on a myocardial level. ATII and aldosterone induce myo-
occurs when there is reduced renal blood flow, reduced cardial hypertrophy and fibrosis, which appear to be
delivery of sodium to the macula densa, and beta adren- mediated by activation of the angiotensin II type 1
ergic stimulation of the juxtaglomerular apparatus. The receptor (AT1R) leading to increased transforming
classical system includes renin release from the juxtaglo- growth factor–β.
merular apparatus, which cleaves angiotensinogen in the
liver to angiotensin I, which is further cleaved by angio- Chronic deleterious effects
tensin converting enzyme (ACE) in the lungs or other of compensatory mechanisms
tissues to form the active hormone angiotensin II (ATII). Although the initial effects of the sympathetic nervous
ACE also inactivates vasodilators such as bradykinin. system activation are positive and life saving, chronically
ATII binds to the angiotensin II type 1 receptor (AT1R) there are deleterious effects that worsen cardiac dysfunc-
to exert powerful effects of vasoconstriction, increases tion and perpetuate progressive deleterious ventricular
aldosterone synthesis from the adrenal gland, stimulates remodeling. An autonomic imbalance occurs due to