Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality

Abstract

Background: A substantial proportion of patients with heart failure (HF) with preserved ejection fraction (HFpEF) present with normal natriuretic peptide (NP) levels. The pathophysiology and natural history for this phenotype remain unclear.

Methods and results: Consecutive subjects undergoing invasive cardiopulmonary exercise testing for unexplained dyspnoea at Mayo Clinic in 2006-18 were studied. Heart failure with preserved ejection fraction was defined as a pulmonary arterial wedge pressure (PAWP) ≥15 mmHg (rest) or ≥25 mmHg (exercise). Patients with HFpEF and normal NP [N-terminal of the pro-hormone B-type natriuretic peptide (NT-proBNP) < 125 ng/L] were compared with HFpEF with high NP (NT-proBNP ≥ 125 ng/L) and controls with normal haemodynamics. Patients with HFpEF and normal (n = 157) vs. high NP (n = 263) were younger, yet older than controls (n = 161), with an intermediate comorbidity profile. Normal NP HFpEF was associated with more left ventricular hypertrophy and worse diastolic function compared with controls, but better diastolic function, lower left atrial volumes, superior right ventricular function, and less mitral/tricuspid regurgitation compared with high NP HFpEF. Cardiac output (CO) reserve with exercise was preserved in normal NP HFpEF [101% predicted, interquartile range (IQR): 75-124%], but this was achieved only at the cost of higher left ventricular transmural pressure (LVTMP) (14 ± 6 mmHg vs. 7 ± 4 mmHg in controls, P < 0.001). In contrast, CO reserve was decreased in high NP HFpEF (85% predicted, IQR: 59-109%), with lower LVTMP (10 ± 8 mmHg) compared with normal NP HFpEF (P < 0.001), despite similar PAWP. Patients with high NP HFpEF displayed the highest event rates, but normal NP HFpEF still had 2.7-fold higher risk for mortality or HF readmissions compared with controls (hazard ratio: 2.74, 95% confidence interval: 1.02-7.32) after adjusting for age, sex, and body mass index.

Conclusion: Patients with HFpEF and normal NP display mild diastolic dysfunction and preserved CO reserve during exercise, despite marked elevation in filling pressures. While clinical outcomes are not as poor compared with patients with high NP, patients with normal NP HFpEF exhibit increased risk of death or HF readmissions compared with patients without HF, emphasizing the importance of this phenotype.

Keywords: Diastolic heart failure; Exercise tolerance; Mortality; Natriuretic peptides; Obesity.

Structured Graphical Abstract

As compared to control subjects without heart failure (black), patients with HFpEF and low NTproBNP levels (<125 ng/L, green) displayed increased risk for the combined endpoint of heart failure hospitalization or death, with greater reliance on an increase in left ventricular transmural pressure (LVTMP) to increase cardiac output during exercise. As compared to patients with HFpEF and lower NTproBNP, those with elevated NTproBNP (red) displayed the greatest risk for heart failure hospitalization or death, with more severely impaired cardiac output reserve, greater right ventricular (RV) remodeling, and higher prevalence of secondary (functional) mitral and tricuspid insufficiency.

Figure 1

(A) Left ventricular mass index, (B) left atrial volume index, (C) septal e′ velocity, and (D) septal E/e′ ratio in control subjects, patients with heart failure with preserved ejection fraction and N-terminal of the pro-hormone B-type natriuretic peptide <125 ng/L vs. ≥125 ng/L in sinus rhythm or <375 ng/L vs. ≥375 ng/L in atrial fibrillation. E, transmitral early velocity on pulsed-wave Doppler; e′, septal mitral annular early velocity on pulsed-wave tissue Doppler; HFpEF, heart failure with preserved ejection fraction; NT-proBNP, N-terminal of the pro-hormone B-type natriuretic peptide.

Figure 2

(A) Right ventricular dilation, (B) tricuspid annular plane systolic excursion, (C) mitral regurgitation, and (D) tricuspid regurgitation in control subjects, patients with heart failure with preserved ejection fraction and N-terminal of the pro-hormone B-type natriuretic peptide <125 ng/L vs. ≥125 ng/L in sinus rhythm or <375 ng/L vs. ≥375 ng/L in atrial fibrillation. HFpEF, heart failure with preserved ejection fraction; MR, mitral regurgitation; NT-proBNP, N-terminal of the pro-hormone B-type natriuretic peptide; RV, right ventricular; TAPSE, tricuspid annular plane systolic excursion; TR, tricuspid regurgitation.

Figure 3

(A) Mean pulmonary arterial pressure at rest; (B) pulmonary vascular resistance at rest; (C) mean pulmonary arterial pressure at peak exercise; and (D) pulmonary vascular resistance at peak exercise in control subjects, patients with heart failure with preserved ejection fraction and N-terminal of the pro-hormone B-type natriuretic peptide <125 ng/L vs. ≥125 ng/L in sinus rhythm or <375 ng/L vs. ≥375 ng/L in atrial fibrillation. HFpEF, heart failure with preserved ejection fraction; mPAP, mean pulmonary arterial pressure; NT-proBNP, N-terminal of the pro-hormone B-type natriuretic peptide; PVR, pulmonary vascular resistance.

Figure 4.

Freedom from all-cause mortality or heart failure readmission in control subjects; patients with heart failure with preserved ejection fraction and N-terminal of the pro-hormone B-type natriuretic peptide <125 ng/L vs. ≥125 ng/L. HFpEF, heart failure with preserved ejection fraction; NT-proBNP, N-terminal of the pro-hormone B-type natriuretic peptide.