What Mechanisms Underlie Diastolic Dysfunction in Heart Failure?

Abstract

Abstract-Abnormalities of diastolic function are common to virtually all forms of cardiac failure. However, their underlying mechanisms, precise role in the generation and phenotypic expression of heart failure, and value as specific therapeutic targets remain poorly understood. A growing proportion of heart failure patients, particularly among the elderly, have apparently preserved systolic function, and this is fueling interest for better understanding and treating diastolic abnormalities. Much of the attention in clinical and experimental studies has focused on relaxation and filling abnormalities of the heart, whereas chamber stiffness has been less well studied, particularly in humans. Nonetheless, new insights from basic and clinical research are helping define the regulators of diastolic dysfunction and illuminate novel targets for treatment. This review puts these developments into perspective with the major aim of highlighting current knowledge gaps and controversies. Key Words: myocardium Ⅲ dilated cardiomyopathy Ⅲ heart failure Ⅲ hypertrophy Ⅲ compliance Ⅲ diastole Ⅲ relaxation T he heart spends more than half its time in diastole (relaxing and then filling to prepare for the next ejection). Although abnormalities of diastolic function are well recognized and common to virtually all forms of heart failure, just how they affect basal and reserve function and their relative role in clinical heart failure remain unclear. There are a number of reasons for this. First, diastole assessment ideally requires invasive measurements that are nontrivial to obtain, whereas noninvasive surrogates often reported in clinical studies reflect integrative properties that lack specificity. Second, relatively few animal models recapitulate human diastolic disease, particularly chamber stiffening, which is often normal in murine models despite extensive matrix, myofibrillar, or signaling abnormalities. Third, there are few if any targeted treatments that can specifically test the impact of altering diastolic function on heart failure pathophysiology and outcome. Last, diastolic function has been less amenable to reductionist approaches given the potent roles that chamber geometry, loading (both intrinsic and extrinsic to myocytes), extracellular matrix, and myocardial perfusion all bring to bear.Another problem is that there is no single definition for diastolic dysfunction; many features can be altered, and any one change or their combination is typically called diastolic dysfunction, although the pathophysiology and functional significance varies greatly. Thus, the term is used to describe slowed force (or pressure) decay and cellular relengthening rates, increased (or decreased) early filling rates and deceleration, elevated or steeper diastolic pressure-volume (PV) relations, and filling-rate dependent pressure elevation (viscoelasticity). Clinically, the most common manifestation is an elevated end-diastolic pressure (EDP) and altered filling patterns, but neither of these identifies specific features of diastolic dys...

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