BNP is "cardio-protective", STOP-HF study opens gates for next-gen therapeutics

B-type natriuretic peptide (BNP) possesses blood-pressure-lowering, antifibrotic, and aldosterone-suppressing properties. A recent analysis of STOP-HF study in Stage A and B heart failure patients shows that the carriers of the minor C allele of the BNP genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension, new-onset left ventricular systolic dysfunction, and hospitalization for major adverse cardiovascular events.

In this study, published in JACC: Basic to Translational Science, authors Cannone et al investigated the STOP-HF follow-up program by genotyping this cohort for rs198389 and analyzed BNP circulating levels along with the clinical characteristics related to rs198389 genotypes. They also performed a follow-up analysis that aimed to assess the risk of left ventricular dysfunction and, importantly, employed echocardiography to assess myocardial structure and function.

The major findings from the study are:

1. In a well phenotyped cohort of subjects at risk for HF (Stage A and B HF), from the STOP-HF study, the minor C allele of the BNP genetic variant rs198389 was associated with higher circulating levels of BNP, lower risk of hypertension, and—importantly—new-onset LVSD.

2. Further, in a 5-year follow-up study, carriers of the C allele also had a lower risk of major adverse cardiovascular events.

The study also has therapeutic implications, especially for the prevention of HF. At least 3 potential therapeutic approaches can be considered building on the protective properties of BNP and its molecular target pGC-A:

1. The use of neprilysin inhibition should be considered, which inhibits the degradation of native natriuretic peptides, thus increasing their circulating levels.

2. The use of chronically administered low dose BNP could be used in Stage A and B HF.

3. The use of novel small-molecule–positive allosteric modulators that serve to enhance receptors sensitivity to circulating endogenous peptides or hormones.

"On the other hand, the current results also beg for new avenues of investigation" comment Lanfear et al in an accompanying editorial. "Should the BNP threshold for intervention (in this case referral to cardiology) be different based on genotype? And if so, what should it be?"

"Could genetic screening be used as a first layer of population screening, informing in which patients and how often BNP levels should be obtained?", add Lanfear et al. The current analysis of a single variant is simplistic but offers proof of concept, and a glimpse of a possible future of primordial prevention of heart failure.

The single variant reported here seemed to help stratify risk within patients with Stage A/B HF; perhaps a more complete genomic assessment could identify patients at risk (and thus deserving of biomarker screening) even among those without established HF risk factors (preHF).

To summarise, In Stage A and B heart failure, the carriers of the minor C allele of the B-type natriuretic peptide (BNP) genetic variant rs198389 have higher circulating levels of BNP and are at decreased risk of hypertension and newonset left ventricular systolic dysfunction. Future studies are warranted to investigate the use of BNP-based therapy in the prevention of heart failure and the response according to rs198389 genotype.

Source: JACC: Basic to Translational Science: https://doi.org/10.1016/j.jacbts.2021.05.001