Evidence Supporting the Existence of a Distinct Obese Phenotype of Heart Failure With Preserved Ejection Fraction

Abstract

Background: Heart failure (HF) with preserved ejection fraction (HFpEF) is a heterogeneous syndrome. Phenotyping patients into pathophysiologically homogeneous groups may enable better targeting of treatment. Obesity is common in HFpEF and has many cardiovascular effects, suggesting that it may be a viable candidate for phenotyping. We compared cardiovascular structure, function, and reserve capacity in subjects with obese HFpEF, those with nonobese HFpEF, and control subjects.

Methods: Subjects with obese HFpEF (body mass index ≥35 kg/m²; n=99), nonobese HFpEF (body mass index <30 kg/m²; n=96), and nonobese control subjects free of HF (n=71) underwent detailed clinical assessment, echocardiography, and invasive hemodynamic exercise testing.

Results: Compared with both subjects with nonobese HFpEF and control subjects, subjects with obese HFpEF displayed increased plasma volume (3907 mL [3563-4333 mL] versus 2772 mL [2555-3133 mL], and 2680 mL [2380-3006 mL]; P<0.0001), more concentric left ventricular remodeling, greater right ventricular dilatation (base, 34±7 versus 31±6 and 30±6 mm, P=0.0005; length, 66±7 versus 61±7 and 61±7 mm, P<0.0001), more right ventricular dysfunction, increased epicardial fat thickness (10±2 versus 7±2 and 6±2 mm; P<0.0001), and greater total epicardial heart volume (945 mL [831-1105 mL] versus 797 mL [643-979 mL] and 632 mL [517-768 mL]; P<0.0001), despite lower N-terminal pro-B-type natriuretic peptide levels. Pulmonary capillary wedge pressure was correlated with body mass and plasma volume in obese HFpEF (r=0.22 and 0.27, both P<0.05) but not in nonobese HFpEF (P≥0.3). The increase in heart volumes in obese HFpEF was associated with greater pericardial restraint and heightened ventricular interdependence, reflected by increased ratio of right- to left-sided heart filling pressures (0.64±0.17 versus 0.56±0.19 and 0.53±0.20; P=0.0004), higher pulmonary venous pressure relative to left ventricular transmural pressure, and greater left ventricular eccentricity index (1.10±0.19 versus 0.99±0.06 and 0.97±0.12; P<0.0001). Interdependence was enhanced as pulmonary artery pressure load increased (P for interaction <0.05). Compared with those with nonobese HFpEF and control subjects, obese patients with HFpEF displayed worse exercise capacity (peak oxygen consumption, 7.7±2.3 versus 10.0±3.4 and12.9±4.0 mL/min·kg; P<0.0001), higher biventricular filling pressures with exercise, and depressed pulmonary artery vasodilator reserve.

Conclusions: Obesity-related HFpEF is a genuine form of cardiac failure and a clinically relevant phenotype that may require specific treatments.

Keywords: exercise; heart failure; hypertension, pulmonary; obesity; pericardium.

Figure 1. Body mass, cardiac remodeling and relationships between NT-proBNP and LV filling pressures

(A, B) Increased body mass was associated with larger RV size and total heart volume. (C) Pulmonary capillary wedge pressure (PCWP) was directly correlated with NT-proBNP in all HFpEF subjects, but the relationship was shifted upward in obese HFpEF, indicating a higher PCWP for any value of NT-proBNP as compared to non-obese HFpEF. (D) In contrast, the correlations between left ventricular transmural pressure (LVTMP) and NT-proBNP did not differ in obese and non-obese HFpEF. HFpEF indicates heart failure with preserved ejection fraction; RV, right ventricular.

Figure 2. Correlations between left ventricular filling pressures, adiposity and plasma volume

Elevations in left heart filling pressures were related to greater body mass (A) and plasma volume (B) in obese HFpEF, but not in non-obese HFpEF. Abbreviations as in Figure 1.

Figure 3. Exercise capacity and hemodynamic reserve is reduced in obese HFpEF

(A) Compared to controls, increase in cardiac index was lower in both non-obese and obese HFpEF but similar between the groups. (B) The efficiency of translating metabolic work (VO₂) to external ergometric work (cycling Watts) was lower in obese HFpEF as compared to both non-obese HFpEF and controls. (C) Peak VO₂ was inversely correlated with body mass. (D) Peak exercise pulmonary artery mean pressure (mPAP) was higher in obese HFpEF than in both non-obese HFpEF and controls. This was explained by impaired pulmonary vasodilation with exercise in obese HFpEF as compared to both non-obese HFpEF and controls, evidenced by greater decreases in PA compliance index (PACI) and less reduction in pulmonary vascular resistance index (PVRI) (E–F). Error bars indicate SEM. *p<0.05 vs. controls, †p<0.05 vs. non-obese HFpEF. Abbreviations as in Figure 1.

Figure 4. Pericardial restraint and ventricular interdependence are enhanced in obese HFpEF

(A) Compared to non-obese HFpEF and control subjects, obese HFpEF displayed greater total epicardial heart volume. (B) Representative short-axis echocardiographic images of the mitral valve and mid cavity levels at end-diastole in obese HFpEF. The septum becomes flattened and less convex to the RV at end-diastole, indicative of enhanced ventricular interaction. (C–D) This was further supported by higher LV eccentricity index and right atrial pressure (RAP)/PCWP ratio in obese HFpEF as compared to non-obese HFpEF and control subjects. *p<0.05 vs. controls; and †p<0.05 vs. non-obese HFpEF. LV indicates left ventricular; and other abbreviation as in Figure 1.

Figure 5. Interactions between pericardial restraint, pulmonary artery pressures and filling pressures in obese HFpEF

(A–B) Compared to non-obese HFpEF, LV eccentricity index was greater in obese HFpEF for any given value of PA systolic pressure both at end-diastole and systole, suggesting that septal distortion in obese HFpEF was not simply related to more RV afterload mismatch. (C) The increase in RAP (which approximates pericardial pressure) relative to oxygen consumption (VO₂) was greater in obese HFpEF than in both non-obese HFpEF and control subjects with exercise. (D) The PCWP required to achieve any given distending LV pressure (transmural pressure, LVTMP) was shifted upward in obese HFpEF. See text for details. *p<0.05 vs. controls; and †p<0.05 vs. non-obese HFpEF. Abbreviations as in Figures 1, 3, and 4.