Global cardiovascular reserve dysfunction in heart failure with preserved ejection fraction

Abstract

Objectives: The purpose of this study was to comprehensively examine cardiovascular reserve function with exercise in patients with heart failure and preserved ejection fraction (HFpEF).

Background: Optimal exercise performance requires an integrated physiologic response, with coordinated increases in heart rate, contractility, lusitropy, arterial vasodilation, endothelial function, and venous return. Cardiac and vascular responses are coupled, and abnormalities in several components may interact to promote exertional intolerance in HFpEF.

Methods: Subjects with HFpEF (n = 21), hypertension without heart failure (n = 19), and no cardiovascular disease (control, n = 10) were studied before and during exercise with characterization of cardiovascular reserve function by Doppler echocardiography, peripheral arterial tonometry, and gas exchange.

Results: Exercise capacity and tolerance were reduced in HFpEF compared with hypertensive subjects and controls, with lower VO(2) and cardiac index at peak, and more severe dyspnea and fatigue at matched low-level workloads. Endothelial function was impaired in HFpEF and in hypertensive subjects as compared with controls. However, blunted exercise-induced increases in chronotropy, contractility, and vasodilation were unique to HFpEF and resulted in impaired dynamic ventricular-arterial coupling responses during exercise. Exercise capacity and symptoms of exertional intolerance were correlated with abnormalities in each component of cardiovascular reserve function, and HFpEF subjects were more likely to display multiple abnormalities in reserve.

Conclusions: HFpEF is characterized by depressed reserve capacity involving multiple domains of cardiovascular function, which contribute in an integrated fashion to produce exercise limitation. Appreciation of the global nature of reserve dysfunction in HFpEF will better inform optimal design for future diagnostic and therapeutic strategies.

Figure 1. Assessment of Endothelial Function

[A] Increases in peripheral arterial tonometry (PAT) amplitude with reactive hyperemia are diminished in HFpEF and hypertensives compared with controls, consistent with endothelial dysfunction. [B] Mean reactive hyperemia index (log RHI) is reduced in HFpEF and hypertensives compared with control. [C] Compared with controls, endothelial dysfunction was more prevalent in HFpEF (42% of subjects; p<0.05) and tended to be more common in hypertensives (28% of subjects, p=0.056).

Figure 2. Contractile, Vascular and Coupling Reserve with low-level exercise (20W)

[A-C] Compared with both controls (blue) and hypertensives (green), contractile reserve was blunted in HFpEF (red) at 20W, evidenced by blunted increases end-systolic elastance (Ees), preload recruitable stroke work (PRSW), and peak power index (PWRI). [D,E] Vasodilation (reduction in arterial elastance, Ea; and systemic vascular resistance index, SVRI) was also impaired in HFpEF. [F] These deficits led to abnormal ventricular-arterial coupling responses (i.e. less reduction in Ea/Ees ratio) in HFpEF compared with controls and hypertensives.

Figure 3. Global Reserve Dysfunction

[A] HFpEF subjects displayed a greater number of abnormalities in cardiovascular reserve function than hypertensives and normal controls, and hypertensives had more abnormalities than healthy controls. [B] The presence of a greater number of reserve abnormalities was associated with more severely depressed exercise capacity. Numbered colored bars indicate total number of subjects in each grouping for controls (blue), hypertensives (green) and HFpEF subjects (red). P value reflects 1-way ANOVA testing relationship of number of abnormalities versus peak VO₂.