Page 212 - Clinical Small Animal Internal Medicine

180 Section 3 Cardiovascular Disease

evidence that locally produced AT II plays a role in Wall stress pressure radius
VetBooks.ir cardiac remodeling under certain conditions. 2 wall thickness
While AT II directly increases systemic vascular resist-
ance to maintain blood pressure, it is also the primary
stimulus for aldosterone synthesis and release from the Normalization of wall stress serves as an adaptive
response to reduce myocardial oxygen consumption
adrenal glands. Aldosterone binds to mineralocorticoid while maintaining cardiac performance. Hence, if car-
receptors in the cytoplasm, followed by migration of the diac hypertrophy is capable of normalizing cardiac out-
complex into the nucleus. Within the nucleus, the aldos- put, the previously activated short‐term compensatory
terone–mineralocorticoid receptor complex promotes responses may be able to return to basal levels.
gene activation, transcription, and protein synthesis of Changes in myocardial workload produce rapid and
Na+/K+ exchangers along the luminal surface of the dis- dramatic responses from the molecular mechanisms that
tal tubule and collecting ducts to promote sodium and regulate protein synthesis. The isolated heart shows
water retention in exchange for potassium excretion. increased RNA and protein synthesis within two hours
Similar to the venoconstrictive effects of the sympathetic of a loading stimulus while the intact heart displays simi-
nervous system, aldosterone‐mediated water retention lar increases within 24 hours. This tight regulation
increases preload and enhances cardiac output via the between hemodynamic function and cardiac growth has
Starling mechanism. Additional rapidly acting, non- at least three signaling mechanisms: stretch-activated
genomically mediated actions of aldosterone continue to signals, agonists, such as AT II, catecholamines and
be investigated, including cellular ion regulation, altered endothelin‐1, that link to protein kinase C, and growth
cellular volume, negative inotropy, and cardiac hypertro- factors, including insulin‐like growth factor‐1, trans-
phy, fibrosis and remodeling. Increased potassium levels, forming growth factor‐beta, and platelet‐derived growth
corticotropin, catecholamines, endothelin‐1, arginine factor, that are linked to receptor tyrosine kinases. The
vasopressin, and reduced hepatic clearance are addi- mechanisms behind translation of these signals to car-
tional mechanisms that contribute to increased aldoster- diac hypertrophy are complex and continue to be eluci-
one activity.
dated, but seem linked to the family of mitogen‐activated
protein kinases.
Additional Compensatory Mechanisms The mechanisms Increased systolic wall stress, such as systemic hyper-
that maintain blood pressure and enhance preload tension or severe subaortic stenosis, necessitates increased
extend beyond the SNS and RAAS. Arginine vasopres- pressure generation by the left ventricle to overcome the
sin (AVP), also called antidiuretic hormone, is released forces opposing ejection. Laplace’s law dictates that nor-
from the pituitary in response to increased plasma malization of wall stress is achieved via increased left ven-
osmolality or hypovolemia. The SNS and RAAS also tricular wall thickness, termed concentric hypertrophy,
promote release of AVP. Vasoconstriction and weak ino- with sarcomeres replicating in parallel. The ventricular
tropic actions of AVP are mediated via adherence to V 1A radius remains normal or may actually decline secondary
receptors. Solute free water resorption is accomplished to encroachment of the thickened left ventricular walls.
via binding of AVP and V 2A receptors. Receptor activa- Increased diastolic wall stress, as observed with volume
tion triggers insertion of aquaporin‐2 channels into the overload secondary to mitral valve insufficiency, instead
luminal surface of the epithelial cells lining the distal promotes eccentric hypertrophy. This pattern of hyper-
tubule and collecting ducts, thereby providing enhanced trophy is characterized by sarcomeres replicating in series,
water retention. Endothelin‐1 is another modulator of producing a larger diameter and more spherical left
systemic arteriolar tone that acts via either ET A recep- ventricular chamber. The wall thickness increases only
tors, to promote vasoconstriction and positive inotropic modestly to try and maintain normal wall stress.
effects, or ET B receptors, to produce endothelial‐ Phases of the hypertrophic response have been detailed
dependent vasodilation.
for decades and include:
Long‐Term Adaptive Responses ● the initial stage of developing hypertrophy where
While augmentation of preload and afterload via the workload exceeds the output that is normal for the ini-
previously described mechanisms is able to maintain tial mass of the heart
cardiac output and perfusion pressure in the short term, ● compensatory hypertrophy where work‐induced
myocardial hypertrophy serves as the body’s long‐term growth of the myocardium normalizes wall stress
compensatory mechanism for cardiac dysfunction. ● an exhaustion phase characterized by cardiomyocyte
The concept of the afterload experienced by working death, myocardial fibrosis, and ventricular dilation
myocytes is more readily understood in terms of wall with decreasing work output per unit of cardiac mass
stress as described by Laplace’s law: leading to heart failure.