The phenotypic consequences of the increased cardiac mass and altered protein abundance and composition of the hypertrophied heart are considerable and depend upon the model utilized; the animal species; and the nature, intensity, and duration of the hypertrophic stimulus. Taken together, available clinical and animal studies suggest that functional alterations evolve along a continuum from normal chamber and myocyte function to abnormal chamber and normal myocyte function to abnormalities of both chamber and myocyte function Fig. 5-1).
The most typical electrical abnormality of the hypertrophied heart is prolongation of the duration of the action potential.64 Recent studies using the single-cell voltage-clamp technique have begun to elucidate the ionic mechanisms responsible for this phenomenon. In mild hypertrophy, increases in calcium and calcium-activated currents (including the NA+/Ca2+ exchanger) appear to be important. In severe hypertrophy, prolongation of the action potential is also determined importantly by a reduction in the potassium currents Ikl and Ito. The relations between these changes in membrane current properties of hypertrophied hearts and altered mechanical behavior at the myocyte and whole-heart level are not clearly understood at present. Hypertrophied myocardium is more likely than normal tissue to precipitate arrhythmias. The mechanisms for arrhythmogenesis are multifactorial and are operant at the tissue and cardiomyocyte levels. Increased dispersion of refractoriness and slowed conduction results from myocyte loss and fibrosis. Prolongation of the duration of the action potential increases the likelihood of early afterdepolarizations, which may result in triggered arrhythmias. Reduced coronary artery flow reserve and accelerated atherosclerosis of epicardial coronary vessels predispose toward ischemia-induced arrhythmias.65 In concert, these mechanisms contribute to the finding of cardiac hypertrophy as the most powerful predictor of cardiovascular mortality in the Framingham Study (see Chap. 1).
The application of molecular biological and molecular genetic approaches is providing increasing insight into the cellular mechanisms of arrhythmogenesis. Normal cardiomyocyte excitation and arrhythmogenesis involve voltage-dependent ion channels, mechanosensitive channels, sarcolemmal electrogenic transporters, and gap junctions. The latter are two channels or connexins that enable ion current flow between and among cardiomyocytes. Connexons are composed of a class of molecules called connexins. Isoform diversity of the connexins are determinants of ion conductance and sensitivity.66,67 The genes for each of the cardiomyocyte ion channels, transporters, and connexins have been cloned. Structure-function relations are being defined in vitro using site-directed mutagenesis and in vivo using loss of function or gain of function mutations in genetically engineered mice. In parallel, the abundance and/or function of the molecular determinants of excitability and arrhythmogenesis are beginning to be elucidated in animal models and human cardiovascular disease (see Chap. 23).
Genetic linkage analysis of familial arrhythmias and resultant identification of culprit gene defects of cardiomyocyte ion channels or channel modulators has provided complementary insight into the cellular mechanisms of arrhythmogenesis. The long-QT syndrome is now known to result from mutations in genes responsible for various outwardly rectifying potassium channels and the cardiomyocyte sodium channel.68-70 Analyses of other inherited arrhythmias are under way.
Mechanical function of the hypertrophied heart has been studied at the isolated myocyte, muscle, and chamber levels and in the intact circulation.71-73 The results of these studies have revealed variable alterations in the rate and extent of contraction and relaxation, in the amount of force development, and in resting muscle and chamber properties. In the intact circulation, altered systolic and diastolic function is a composite result of subcellular changes in the myocyte, changes in the extracellular matrix, altered chamber geometry and mass, altered ventricular-vascular coupling, and the modulatory effects of neural and hormonal influences.
The earliest changes in mechanical performance observed in isometrically contracting papillary muscles extracted from hypertrophied hearts consist of a prolongation of time to peak tension and relaxation, despite normal peak twitch tension normalized for cross-sectional area of the muscle.74 Afterloaded isotonically shortening papillary muscle preparations from hypertrophied hearts of a variety of animal species typically reveal a decrease in the force-velocity relationship and a depression of Vmax (the extrapolated maximal unloaded shortening velocity).75 Vmax has been directly related to the calcium-activated myosin ATPase activity. Both myosin and myofibrillar ATPase activity are typically depressed in hypertrophied myocardium. In small rodents, this is due to the transcriptionally mediated switch from 0(- to ft-MHC. In higher mammals including humans, the decreased myosin ATPase activity of the hypertrophied heart may be due to alterations in the troponin isoform composition76 or the posttranslational generation of a lower molecular variant of the ft-MHC.^
The dissociation between depressed rate-dependent indices of contraction and relaxation and normal maximal force development and extent of shortening in early cardiac hypertrophy has also been demonstrated in isolated cardiomyocytes and in the intact circulation of the nonhuman primate.7173 These results suggest the rate of cross-bridge cycling is reduced but that the effective number of active cross bridges per unit of myocardium is preserved in compensated cardiac hypertrophy. In decompensated hypertrophy, reduced absolute levels of force development and diminished contractility ultimately ensue.
In addition to alteration in excitation-contraction coupling and relaxation, the increased cardiac mass and changes in geometry significantly affect passive muscle and chamber properties of the hypertrophied heart. Concentric hypertrophy is characterized by an increased resting muscle and chamber stiffness, which results in an increase in pulmonary venous pressure for any given left ventricular volume. The resultant pulmonary congestion at rest or with exercise is an important determinant of symptoms in patients with hypertensive left ventricular hypertrophy or hypertrophic cardiomyopathy and normal or elevated ejection fraction. Pure volume overload hypertrophy, as occurs with mitral regurgitation, is typically associated with no change or a decrease in passive muscle or chamber stiffness. As a result, patients with chronic volume overload may remain asymptomatic for long periods despite appreciable increase in regurgitant fraction (see also Chaps. 56 and 57).
Clinicians have long recognized that myocardial blood flow may be abnormal in the hypertrophied heart, since such patients may have exertional angina, resting or exercise-induced electrocardiographic or perfusion abnormalities, or pathologic evidence of subendocardial fibrosis, despite the presence of angiographically normal epicardial coronary arteries.
Morphologic studies of hypertrophied hearts from experimental animals and patients with pressure-overload hypertrophy demonstrate that the ratio of capillaries to myocytes remains unchanged.77 Since myocyte cross-sectional area is increased, there is a resultant increase in nutrient diffusion distance in the hypertrophied heart. This anatomic change results in a reduced vasodilatory reserve in response to various stimuli in experimental and clinical studies.78 Myocardial blood flow and oxygen consumption per unit of myocardium are normal in compensated pressure overload-left ventricular hypertrophy, where wall stress has been normalized by an increase in wall thickness. The impairment in vasodilatory reserve produces evidence of ischemia during increased myocardial oxygen demand. In right ventricular pressure-overload hypertrophy, differences in perfusion between the ventricles result in increased right ventricular blood flow per unit of myocardial mass at rest and no increase in minimum coronary resistance of hypertrophied right ventricular myocardium.79
Few data are available regarding changes in the coronary circulation in experimental or clinical volume-overload hypertrophy. Most studies have reported normal resting flow values per unit of myocardial mass. In contrast to pressure overload, volume-overload hypertrophy has been associated with normal or mildly increased minimum coronary resistance and normal or mildly decreased coronary reserve.80 The coronary circulatory abnormalities associated with cardiac hypertrophy appear to be reversible with removal of the hypertrophic stimulus and resultant decreased chamber mass.81
Important recent studies have begun to elucidate the molecular and cellular mechanisms responsible for reversible functional consequences of ischemia and ischemia reperfusion. The syndrome of myocardial stunning, which refers to the variable period of regional or global myocardial hypofunction consequent to ischemia and reperfusion, is believed to involve two mechanisms. Either hydroxy-free radical generation, calcium overload, or both may be involved.82 Downstream effects of these two pathologic processes include activation of protein kinase C, tyrosine kinases, and stress-activated kinases. In addition, proteolytic degradation of troponin I has been observed and is associated with uncoupling of excitation from contraction due to reduced myofilament calcium sensitivity. Transgenic overexpression either of a PKC isoform or the proteolytic degradation product of troponin I in mice produces both myocardial dysfunction and reduced myofilament calcium sensitivity responsiveness.83
Brief repetitive periods of ischemia and reperfusion also produce a powerful cardioprotective effect against myocardial necrosis. This process, called ischemic preconditioning, is also associated with activation of similar signal transduction pathways. The precise mechanism(s) for reduced myocyte cell death from necrosis, apoptosis, or both are presently unclear. Hibernation or myocardial hypofunction associated with reduced steady-state coronary blood flow may, in fact, result from repetitive periods of stunning.
PREVIOUS | NEXT
Copyright ©2001-2002 The McGraw-Hill Companies. All rights reserved.
For further information about this site contact tech [email protected].
Last modified: September 12, 2001 .
(WJiL'ifirtit 4^'Jlii MrfJitjif-HUlfJ(*iipaniij
Was this article helpful?