Heart failure with preserved ejection fraction: pathophysiology, diagnosis, and treatment

Abstract

Half of patients with heart failure (HF) have a preserved left ventricular ejection fraction (HFpEF). Morbidity and mortality in HFpEF are similar to values observed in patients with HF and reduced EF, yet no effective treatment has been identified. While early research focused on the importance of diastolic dysfunction in the pathophysiology of HFpEF, recent studies have revealed that multiple non-diastolic abnormalities in cardiovascular function also contribute. Diagnosis of HFpEF is frequently challenging and relies upon careful clinical evaluation, echo-Doppler cardiography, and invasive haemodynamic assessment. In this review, the principal mechanisms, diagnostic approaches, and clinical trials are reviewed, along with a discussion of novel treatment strategies that are currently under investigation or hold promise for the future.

Figures

Figure 1

Extracellular matrix and cardiomyocytes determine myocardial stiffness and interact via matricellular proteins.

Figure 2

Steps of collagen type 1 synthesis and degradation. PCP, procollagen type I carboxy-terminal proteinase; PNP, procollagen type I N-terminal proteinase; PICP, PINP, carboxy-terminal and amino-terminal propeptides; MMP, matrix metalloproteinase.

Figure 3

Compared with normal controls (A and B), the slope of the end-systolic pressure–volume relationship (end-systolic elastance; Ees, dotted lines) is increased in heart failure with preserved ejection fraction (HFpEF) (C and D). This leads to exaggerated increases and decreases in blood pressure for the same change in afterload (A and C) or preload (B and D) in HFpEF, accounting for the greater predilection for hypertensive crisis and/or hypotension and azotemia with over-diuresis or overly vigorous vasodilation.

Figure 4

(A) Combined ventricular–arterial stiffening in heart failure with preserved ejection fraction may lead to dramatic elevations in blood pressure with afterload increase (red arrow). This feeds back to increase LV end-diastolic pressures (arrowhead), by altering the slope or position of the diastolic pressure–volume relation, and/or (B) by prolonging LV pressure decay during isovolumic relaxation (arrowhead).

Figure 5

(A) Chamber volumes and EF are similar at rest in heart failure (HF) with preserved ejection fraction (HFpEF) (red) and controls (blue), but HFpEF patients are less able to enhance preload volume (end-diastolic volume, EDV) and also contract to as low an end-systolic volume (ESV) during exercise stress. These impairments are related to diastolic, systolic, and vasodilator reserve dysfunction, which contribute to impaired stroke volume (SV) responses with exercise in HFpEF. (B) Despite less enhancement of EDV with exercise, there is a much larger increase in LV filling pressures, measured as LV end-diastolic pressure (arrow) or pulmonary wedge pressure (red). (C) Chronotropic response during submaximal and peak workload is impaired in HFpEF (red) compared with controls (blue) and the extent of chronotropic impairment is associated with more severely depressed aerobic capacity (D). Peripheral vascular function is also impaired in HFpEF, which may be related to impaired endothelium-dependent vasodilation, measured as the increase in peripheral arterial blood flow after upper arm cuff occlusion (E). These figures were created based upon previously published data in Borlaug et al.,

Figure 6

Contrasting outcomes of trials using similar compounds in HFnEF and HFrEF. For ARB and ACEI, a neutral outcome is observed in HFnEF but a positive in HFrEF. Conversely, for statins, a positive outcome is observed in HFrEF but a neutral in HFnEF. †P< 0.0001; ‡P< 0.01.