Physiologic basis and pathophysiologic implications of the diastolic properties of the cardiac muscle

Abstract

Although systole was for long considered the core of cardiac function, hemodynamic performance is evenly dependent on appropriate systolic and diastolic functions. The recognition that isolated diastolic dysfunction is the major culprit for approximately fifty percent of all heart failure cases imposes a deeper understanding of its underlying mechanisms so that better diagnostic and therapeutic strategies can be designed. Risk factors leading to diastolic dysfunction affect myocardial relaxation and/or its material properties by disrupting the homeostasis of cardiomyocytes as well as their relation with surrounding matrix and vascular structures. As a consequence, slower ventricular relaxation and higher myocardial stiffness may result in higher ventricular filling pressures and in the risk of hemodynamic decompensation. Thus, determining the mechanisms of diastolic function and their implications in the pathophysiology of heart failure with normal ejection fraction has become a prominent field in basic and clinical research.

Figure 1

Schematic representation of the end-diastolic pressure-volume relationship (EDPVR) in the absence (a) or presence (b) of diastolic dysfunction. The dashed segment of the EDPVR represents the pressure-volume interval in which an individual remains hemodynamically stable. In (b), the steeper EDPVR narrows the ventricular pressure-volume interval and increases the individual's susceptibility to hemodynamic decompensation.

Figure 2

Progressive increase in myocardial (a) and collagen-based stiffness (b) during physiologic cardiac growth as well as HF or HF-associated pathological conditions. The increase in myocardial stiffness can be paralleled by a concordant increase in the expression of the stiff titin isoform N2B (c) or by a compensatory increase in the expression of the compliant titin isoform N2BA (d). Relative hypophosphorylation of the stiff N2B titin also accounts for an increase in myocardial stiffness in HF, especially in HFNEF (e) (P-N2B: phosphorylated N2B; P-N2BA: phosphorylated N2BA).