Page 214 - Clinical Small Animal Internal Medicine

182 Section 3 Cardiovascular Disease

reticulum, or its resequestration into the sarcoplasmic ventricular eccentric hypertrophy/remodeling with
VetBooks.ir reticulum may exert profoundly negative consequences increased ECM turnover via an increase in the matrix
metalloproteinases (MMPs)/tissue inhibitors of matrix
on cardiac performance. Myocytes from humans with
heart failure exhibit a prolonged action potential with a
2+
blunted rise in intracellular Ca during depolarization metalloproteinases (TIMPs) ratio. The MMPs degrade
collagen and other matrix components while the TIMPs
and a slowed rate of decline during repolarization. Slower either inhibit or prevent MMP activation. Isoform shifts
2+
Ca delivery to the contractile proteins during systole and from type I to type III collagen further contribute to a net
2+
excessive cytosolic Ca during diastole may contribute to degradation of collagen with resultant chamber dilation
both systolic and diastolic dysfunction. The failing myo- and progressive wall thinning.
cardium also displays a negative force–frequency relation- During the compensated phase, the remodeling
ship. Rather than progressive increases in ventricular contributes to increased ventricular compliance with pre-
contractility with increasing heart rate, humans with heart served systolic function. Ultimately, the progression to
failure have little or no increase in contractility with decompensated failure is complex and includes a combi-
increased frequency of stimulation. This alteration is pre- nation of ECM degradation and profibrotic synthesis
2+
sumably related to impaired Ca cycling between the sar- mediated concomitantly at different subcellular locations
coplasmic reticulum and the cytosol. and within different regions of the ventricle.
Calcium conductance, release, and resequestration are
critical components of normal cardiac function and Alterations in Cardiac Metabolism
numerous pumps and channels are responsible for coor- The heart requires a high rate of adenosine triphosphate
dinating events. Studies in failing human myocardium (ATP) hydrolysis because of its continuous mechanical
have found that mRNA and protein levels of SERCA, work and therefore requires a constant supply of oxygen
2+
voltage‐dependent Ca channels, and the calcium and fuel. Oxidation of fatty acids (FA) accounts for
release channel on the sarcoplasmic reticulum are approximately 70–90% of ATP production in the fasted
2+
reduced. Alterations in proteins responsible for Ca state while glucose utilization increases in the fed state.
cycling in dogs have also been identified. Therefore, Because of the fundamental roles metabolism and ATP
altered expression or function of these proteins may neg- generation have in maintenance of cardiac structure and
atively impact systolic and diastolic function. function, it is reasonable to hypothesize that alterations
in cardiac metabolism have a role in the pathophysiology
Changes within the Extracellular Matrix of heart failure. Studies in animal models and humans
Ventricular remodeling is a key feature of heart failure with advanced heart failure and systolic dysfunction
regardless of the underlying cardiac disease or underly- have reported a decrease in the phosphocreatine/ATP
ing phenotype (e.g., volume overload, pressure overload, ratio, ATP content, and ATP movement through creatine
primary cardiomyopathy). Changes within the ventricu- kinase. It is uncertain whether these alterations serve as
lar geometry and function must be viewed as a summa- a primary contributor to the progressive nature of heart
tion of events occurring at the level of the cardiomyocyte, failure or are simply an adaptation to decreased ventric-
the vascular compartment, and within the extracellular ular function, but significant mitochondrial changes are
matrix (ECM). Although once only viewed as scaffold- present in various models of cardiac hypertrophy and
ing, there is now growing recognition that the ECM failure.
mediates mechanical and biological signals that contrib- Decreased cardiac energy production may be second-
ute to the progression of heart failure. ary to impaired substrate use or altered mitochondrial
Regulation and turnover of the ECM is a complex pro- function. Studies of heart failure with systolic dysfunc-
cess dictated by mechanical stress, neurohormonal acti- tion have identified reduced mRNA and protein expres-
vation, inflammation, and oxidative stress. Accelerated sion of FA transporters with reduced cardiac FA
growth of both the myocyte and ECM produced by pres- utilization and ATP production. Studies of glucose oxi-
sure overload yield left ventricular concentric hypertrophy. dation are variable with reports of decreased, unchanged
Left ventricular thickening negatively impacts both of or increased glucose uptake. Varying results likely
the fundamental processes that dictate diastolic func- depend on the stage and type of disease, but these results
tion – active relaxation and passive stiffness. Shifting may also be influenced via the channeling of pyruvate
isoforms and phosphorylation sites of cytoskeletal proteins into anaplerotic pathways. Flux of pyruvate through ana-
(e.g., titin) can impair myocyte relaxation and hamper plerotic pathways appears to be a hallmark of metabolic
active relaxation/early cardiac filling. Accumulation of remodeling and reduces its availability for oxidation and
collagen within the ECM increases ventricular stiffness, energy production by pyruvate dehydrogenase.
thus reducing myocardial compliance and impairing Nicotinamide adenine dinucleotide phosphate (NADPH)
passive ventricular filling. Volume overload triggers left is also consumed by induction of anaplerotic pathways