Further Study Needed to Better Understand HFpEF, Normal NT-proBNP Relationship

Patients with heart failure (HF) with preserved ejection fraction (HFpEF) who presented for this study analysis with normal levels of N-terminal prohormone B-type natriuretic peptide (NT-proBNP) and unexplained dyspnea were shown to have higher risks of both mortality and readmission for HF, according to investigators.

Although their risks of these outcomes were still lower than those among patients with HFpEF and high levels of NT-proBNP, the prospective cohort study findings published in European Heart Journal indicate a clear need for more precise identification of this HF phenotype, and its associated cardiac and hemodynamic changes, to optimize clinical knowledge and treatment. Patients who underwent invasive hemodynamic testing—at rest and while exercising—at Mayo Clinic Rochester’s catheterization laboratory between February 2006 and March 2018 who had both recorded NT-proBNP levels and New York Heart Association functional class II to III dyspnea were included in the final analysis.

Outcomes were compared among patients with HFpEF and normal (n = 157) or high (n = 263) NT-proBNP and patients without HFpEF (n = 161). A majority of each group were women (57%, 60%, and 55%, respectively), and the most common comorbidites were hypertension (92%, 95%, and 63%) and obesity (79%, 57%, and 32%).

“To our knowledge, the present study shows for the first time that patients with HFpEF and normal NP display an increased risk of adverse outcome compared with controls with noncardiac dyspnoea,” the authors wrote. “These 2 patient groups are difficult to distinguish by NP levels or echocardiography, but the present data show the importance of correctly identifying patients with this specific phenotype who also require treatment, even as they are often excluded from clinical trials.”

Overall, compared with controls, more participants with normal NT-proBNP levels had elevated left ventricular (LV) hypertrophy (58% vs 38%) and concentric remodeling (43% vs 30%), their mean (SD) LV mass (195 [58] vs 166 [47] g) was higher, and their cardiac output reserve was deemed significantly worse (101% [range, 75%-124%] vs 112% [range, 91%-135%]).

“Patients with HFpEF and normal NP displayed significant hemodynamic abnormalities that were apparent at rest and became more pronounced during exercise,” the authors wrote.

In addition, the normal NT-proBNP/HFpEF cohort had a mean (SD) left ventricular transmural pressure (LVTMP) almost twice that of controls, at 14 (6) vs 7 (4) mm Hg, and a combined elevated risk of death or hospitalization (HR, 2.74; 95% CI, 1.02-7.32) even after adjusting for age, sex, and body mass index. This group also had higher overall blood pressure but a lower overall heart rate.

Still, they also had better diastolic function, superior right ventricular function, and lower left atrial volume and mitral/tricuspid regurgitation vs the persons with high NT-proBNP levels, despite having an older mean age, more comorbidities, and greater use of diuretics and β-blockers.

Additional study findings show the following:

• Natriuretic peptide levels had strong correlations with total pulmonary resistance, pulmonary vascular resistance, and mean pulmonary arterial wedge pressure (PAWP) (all P < .001).
• During peak exercise effort, LVTMP increased the most in the study participants with HFpEF and normal NT-proBNP levels vs the control group (P = .188) and those with high NT-proBNP levels (P < .001): 104% (range, 43%-263%) vs 100% (range, 25%-200%) and 40% (range, –18% to 143%).
• NT-proBNP levels had strong correlations with reduced cardiac output during exercise, higher pulmonary vascular resistance, and mean PAWP (all P < .001).
• 10% of study participants died, and 8% required hospitalization due to HF.
• Those with low NT-proBNP levels had an overall 62% lower risk of all-cause mortality/HF hospitalization vs patients with high NT-proBNP levels (HR, 0.38; 95% CI, 0.22-0.65) and a 59% reduced risk after adjusting for age, sex, and body mass index (HR, 0.41; 95% CI, 0.24-0.72).
• Those with low NT-proBNP levels had an overall 328% greater risk of all-cause mortality/HF hospitalization vs controls (HR, 4.28; 95% CI, 1.29-8.33) and a 174% greater risk after adjusting for age, sex, and body mass index (HR, 2.74; 95% CI, 1.02-7.32).

For this study, HFpEF had a maximum ejection fraction of 50% and maximum resting and exercised-induced PAWP of 15 and 25 mm Hg, respectively. A normal NT-proBNP level was below 125 ng/L and a high level, 125 ng/L and above.

The authors highlighted their results are novel because they are the first to show a greater risk of adverse cardiac outcomes between patients with normal NT-proBNP level and a control group who has dyspnea but of the noncardiac kind, as well as that this group has their own “unequivocal cardiac and vascular abnormalities.”

“This is important because these 2 patient groups are difficult to distinguish by NP levels or echocardiography,” the authors wrote. “But the present data show the importance of correctly identifying patients with this specific phenotype who also require treatment. Indeed, the present data raise serious questions with the practice of using NP levels as a necessary component to establish the diagnosis of HF.”

To make further progress in understanding the unique cardiac disease characteristics of patients with HFpEF and a normal NT-proBNP level and to better tailor treatment, future studies should investigate the longitudinal course of cardiac changes among these individuals and compare outcomes with those with high levels of NT-proBNP.

Reference

Verbrugge FH, Omote K, Reddy YNV, Sorimachi H, Obokata M, Borlaug BA. Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur Heart J. Published online February 9, 2022. doi:10.1093/eurheartj/ehab911