Wednesday, April 2, 2025
4/2/2025
Human Cardiorenal Syndrome - PROJECT SUMMARY The broad objective of the current application is to advance our understanding of 2 major clinical phenotypes of heart failure with preserved ejection fraction (HFpEF): 1) HFpEF with volume overload in the presence of chronic kidney diseases (HFpEF-CKD) and 2) HFpEF with exercise induced (HFpEF-EI) dyspnea, to elucidate the differences in the pathophysiological mechanisms, to identify biomarkers to differentiate the two clinical phenotypes and to develop novel therapies for individualization of treatment. 50% of patients with heart failure (HF) have preserved EF. Pathophysiological heterogeneity in HFpEF is substantial, ranging from chronic kidney diseases, diabetes, obesity, hypertension, etc. There is no FDA approved therapy for HFpEF (LVEF>55%) which may be due to the heterogeneous underlying pathophysiological causes. Recently, the NHLBI Research Priorities for HFpEF Working Group emphasized the need for phenotyping of patients with HFpEF so as to classify patients into phenotypically homogeneous subpopulations, to understand pathophysiological mechanisms and to facilitate individualization of treatment. Sacubatril/valsartan is a dual angiotensin receptor (AT1) blocker and neprilysin (NEP) inhibitor which is approved for management of HFrEF. However, the PARAGON Study failed to demonstrate significant clinical benefit in HFpEF patients. This may be because NP are very low in some subgroups of HFpEF, thus negating the actions of NEP inhibition and therefore, Sacubatril/valsartan effectively functions as an AT1blocker, which has previously been shown to be not beneficial in HFpEF. Therefore, we hypothesized that the endogenous NP levels (specifically ANP) are low in those with exercise induced dyspnea as compared to those with CKD and extravascular fluid overload. Hence, those with HFpEF-EI may not respond to Sacubatril/valsartan but will respond to exogenous NPs administration, while those with HFpEF-CKD will respond to Sacubatril/valsartan due to increased endogenous NPs. MANP is a novel particulate-guanylyl-cyclase A (pGC-A) receptor activator designed at the Mayo Clinic which is more potent than ANP in promoting natriuresis, inhibiting aldosterone with greater activation of cGMP and longer half-life. Our Specific Aims: Specific Aim 1: To perform high definition phenotyping of HFpEF-CKD and HFpEF-EI, defining the differential cardiorenal and humoral response to acute saline volume expansion (VE) Specific Aim 2: To determine the effects of neprilysin and angiotensin receptor inhibition with Sacubatril/valsartan on the cardiorenal and humoral response to acute VE in HFpEF-CKD and HFpEF-EI. Specific Aim 3: To determine the effects of MANP on the cardiorenal and humoral response to acute VE in HFpEF-CKD and HFpEF-EI. The impact of our proposed studies is high as it will advance our knowledge of the integrated cardiorenal and humoral physiology in patients with HFpEF-CKD and HFpEF-EI, and to test novel diagnostic and therapeutic strategies specific for HFpEF-CKD and HFpEF-EI, thus advancing a precision medicine approach in HFpEF.
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