Alterations in Ventricular Function: Diastolic Heart Failure

Heart failure (HF) with preserved ejection fraction (EF; HFpEF) currently accounts for greater than 50% of all HF cases, and its prevalence relative to HF with reduced EF (HFrEF) continues to rise at a rate of 1% per year ( see also Chapter 39 ). By 2020, the prevalence of HFpEF is projected to exceed 8% of people older than 65 years of age, and the relative prevalences of HFpEF and HFrEF are predicted to be 69% and 31%, respectively, turning HFpEF into the most prevalent HF phenotype. Outcomes in patients with HFpEF and HFrEF are equally poor, with 5-year mortality rates up to 75% in both HF phenotypes. In contrast to HFrEF, modern HF pharmacotherapy did not improve outcome in HFpEF, which is related to incomplete understanding of HFpEF pathophysiology, patient heterogeneity, suboptimal trial designs, and lack of insight into primary pathophysiologic processes. Patients with HFpEF are frequently elderly females, and patients have a high prevalence of noncardiac comorbidities, which independently adversely affect myocardial structural and functional remodeling. Furthermore, although diastolic left ventricular (LV) dysfunction represents the dominant abnormality in HFpEF, numerous ancillary mechanisms are frequently present, which also negatively affects cardiovascular reserve. Over the past decade, clinical and translational research has led to improved insight into HFpEF pathophysiology and the importance of comorbidities and patient heterogeneity. Recently, a new paradigm for HFpEF has been proposed, which suggests that comorbidities drive myocardial dysfunction and remodeling in HFpEF through coronary microvascular inflammation. In the conceptual framework of HFpEF treatment, emphasis may need to shift from a “one-size-fits-all” strategy to an individualized approach based on phenotypic patient characterization and diagnostic and pathophysiologic stratification of myocardial disease processes. This chapter describes these novel insights from a pathophysiologic standpoint.

Physiology of Diastolic Filling and Compliance

Normal diastolic function allows adequate filling of the heart without an excessive increase in diastolic filling pressure both at rest and with exercise. LV relaxation starts at end-systole, and LV pressure falls rapidly when the LV expands, creating a left atrial (LA)-to-LV pressure gradient when LV diastolic pressure drops below LA pressure ( Fig. 11.1 A ). This accelerates blood out of the LA and produces rapid early diastolic LV filling, with the LA-to-LV pressure gradient being considered a measure of LV suction. Following filling of the LV, the pressure gradient from the LA to the LV apex decreases and then transiently reverses. The reversed mitral valve pressure gradient decelerates and then stops the rapid flow of blood into the LV in diastole. During the midportion of diastole (diastasis), the LA and LV pressures equilibrate and mitral flow nearly ceases. Late in diastole, atrial contraction produces a second LA-to-LV pressure gradient that again propels blood into the LV (see Fig. 11.1A ). After atrial systole, as the LA relaxes, its pressure decreases below LV pressure, causing the mitral valve to begin closing.

Invasive Measurement of Diastolic Function: Relaxation and Chamber Stiffness

Evidence of abnormal LV relaxation, filling, diastolic distensibility, and diastolic stiffness can be acquired invasively during cardiac catheterization. Ventricular pressure fall is the hemodynamic manifestation of myocardial relaxation, and the rate of global LV myocardial relaxation is reflected by the exponential course of isovolumic LV pressure fall (see Fig. 11.1B ). Isovolumic relaxation can be quantitated by calculating the peak instantaneous rate of LV pressure decline, peak (−)dP/dt, and the time constant of isovolumic LV pressure decline, tau (τ) (see Fig. 11.1B ). Tau is inversely related to the rate of LV pressure fall, becoming shorter when LV pressure fall accelerates and longer when LV pressure fall slows, such that τ greater than 48 milliseconds represents evidence for delayed relaxation. Another invasive approach that can be used to determine LV chamber stiffness and compliance is through measurement of LV pressure volume loops with the use of high-fidelity LV conductance catheters, which simultaneously measure LV pressure and LV volume ( Fig. 11.2A ). By changing preload (e.g., transient inferior vena caval occlusion) or afterload (e.g., administration of phenylephrine), a family of loops is obtained (see Fig. 11.2B ). The end-diastolic pressure-volume relationship (EDPVR), constructed by connecting the end-diastolic pressure-volume points of each loop, is nonlinear and defines the passive physical properties of the chamber with the myocardium in its most relaxed state. The end-systolic pressure-volume relationship (ESPVR), constructed by connecting the end-systolic pressure-volume points of each loop, defines a reasonably linear relationship that characterizes properties of the chamber with the myocardium in a state of maximal activation at a given contractile state (see Fig. 11.2B ). An important difference between HFrEF and HFpEF patients resides in these pressure-volume loops, with HFrEF being characterized by decreased contractility and downward and rightward displacement of the LV ESPVR (see Fig. 11.2C ), whereas HFpEF is characterized by preserved global contractility but impaired LV relaxation, elevated filling pressures, and increased stiffness with an upward and leftward shift of the LV EDPVR, representing raised LV end-diastolic pressure at any given LV end-diastolic volume (see Fig. 11.2C ). This steep LV EDPVR in patients with HFpEF seems the most important determinant for impaired exercise tolerance, with deficient early diastolic LV recoil, blunted LV lusitropic or chronotropic response, vasodilator incompetence, and deranged ventriculovascular coupling serving contributory roles. Elevated LV filling pressures constitute the hallmark of diastolic LV dysfunction, and filling pressures are considered elevated when the mean pulmonary capillary wedge pressure (PCWP) is greater than 12 mm Hg or when the LVEDP is greater than 16 mm Hg.