Page 211 - Clinical Small Animal Internal Medicine

18 Pathophysiology of Heart Failure 179

consistent with CM in 16 cats (15.5%). Eleven of the 16 IP3 transiently increases smooth muscle cytosolic
VetBooks.ir cats with cardiomyopathy did not have an auscultable calcium, thereby initiating the contractile cycle while
DAG activates protein kinase C and is thought to
murmur. None of the 16 cats exhibited left atrial enlarge-
ment, and hence their risk of cardiac‐related complica-
quent increased vascular tone promotes arterial vaso-
tions was presumably low. But this study highlights that induce sustained vascular contraction. The subse-
many asymptomatic animals have underlying heart dis- constriction to maintain systemic blood pressure and
ease and may have active maladaptive compensatory enhanced venoconstriction to promote increased
mechanisms and cardiac remodeling even in the absence venous return. Augmented preload contributes to
of clinical signs. enhanced length‐dependent activation and cardiac
output via the previously described Starling’s law of
Phase 2 – Compensatory Phase the heart.
With a reduction in cardiac output, the body depends on
a number of short‐ and long‐term compensatory mecha- Renin‐Angiotensin‐Aldosterone System Decreased renal
nisms to maintain perfusion pressure to vital organs. The perfusion pressure also stimulates the renin‐angiotensin‐
principal short‐term compensatory mechanisms, acti- aldosterone system (RAAS). The RAAS is complementary
vated within seconds to minutes, include activation of to the SNS wherein it provides a hemostatic mechanism
several neurohormonal systems and subsequent utiliza- for blood pressure through maintenance of sodium bal-
tion of the Frank–Starling mechanism. These short‐term ance and intravascular volume. Additional stimuli for the
mechanisms promote the long‐term adaptive response RAAS include reduced sodium delivery to the macula
which is myocardial remodeling/hypertrophy. Each of densa and increased adrenergic activity.
these mechanisms has inherent limitations and as the Renin, released from the juxtaglomerular apparatus,
disease progresses, their once beneficial properties cleaves angiotensinogen to the decapeptide angiotensin I.
become detrimental. Angiotensin converting enzyme (ACE) cleaves the C‐ter-
minal dipeptide from angiotensin I, forming the potent
Short‐Term Adaptive Responses vasoconstrictor angiotensin II (AT II). Similar to alpha‐1
Sympathetic Nervous System Baroreceptors in the receptors, AT II promotes vascular smooth muscle con-
carotid sinus and aortic arch, along with cardiopulmo- traction and maintenance of blood pressure via IP3 and
nary baroreceptors, cardiovascular low‐threshold poly- DAG. ACE is also capable of cleaving the C‐terminal
modal receptors, and peripheral chemoreceptors, dipeptide from the vasodilatory substance bradykinin,
are responsible for the sympathetic nervous system hence making it inactive. Therefore, ACE appears to be a
(SNS) outflow to the heart and peripheral circulation. regulator between vasoconstrictive/sodium retaining and
Hypotension, whether related to dehydration, blood loss vasodilatory/natriuretic mechanisms. Although all their
or cardiovascular disease, will enhance release of norepi- roles have not been elucidated, four receptors for AT II
nephrine from terminal neurons to the sinoatrial and have been identified and classified as AT 1 , AT 2 , AT 3 , and
atrioventricular nodes and cardiomyocytes, and increase AT 4 receptor subtypes. Critical activities of AT II beyond
release of epinephrine and norepinephrine into the potent vasoconstriction include stimulation of aldoster-
circulation from the adrenal gland. The catecholamines one release, potentiation of presynaptic norepinephrine
bind to cardiac beta‐receptors and increase cytosolic release, stimulation of antidiuretic hormone release,
cAMP levels via G‐protein coupling to increase contrac- promotion of renal tubular sodium resorption, and car-
tility, heart rate, the rate of ventricular relaxation, and diomyocyte necrosis, apoptosis, and ventricular fibrosis.
the speed of impulse conduction through the heart. Understanding of the RAAS continues to evolve with
Beta‐receptor stimulation also produces hyperpolariza- identification of a new homolog of ACE, called ACE 2,
tion of the pacemaker cells (possibly via increased and additional biologically active metabolites of AT II,
activity of the sodium–potassium pump), reducing the including the angiotensin‐(1‐7) peptide. Additional enzy-
membrane potential into the range of funny current (I f ) matic pathways, including chymase, cathepsin G, elastase,
activation. Increased conductance of sodium through tonin, and tissue plasminogen activator, have been
the funny channels further enhances the heart rate identified although their role in maintenance of blood
response to sympathetic activation. pressure and the pathophysiologic alterations that con-
The release of norepinephrine from the terminal tribute to heart failure is uncertain. In addition to the
neurons of the systemic vasculature results in vaso- conventional circulating RAAS, all its constituents are
constriction via activation of postsynaptic alpha‐1 also found in a variety of tissues, including the brain,
receptors. Occupancy of the receptor promotes break- myocardium, vasculature, kidney, and adipose tissue.
down of phosphatidylinositol, via phospholipase C, to The importance of tissue RAAS is likely organ, species,
inositol triphosphate (IP3) and diacylglycerol (DAG). and disease dependent although there is growing