Agrawal, Vineet

Background: Heart failure (HF) is a complex syndrome marked by adverse cardiac remodeling and natriuretic peptide (NP) deficiency, which drives disease progression despite current therapies. NPs exert cardioprotective effects via particulate guanylate cyclase receptors GC-A and GC-B, which generate cGMP. Activation of GC-A by ANP or BNP induces arteriodilation, natriuresis, antihypertrophic effects, and inhibits the renin-angiotensin-aldosterone system, while GC-B activation by CNP mediates antifibrotic, lusitropic, venodilatory, and anti-inflammatory actions. Existing drugs target either GC-A or GC-B, but none target both. We developed RT-A1, a unimolecular peptide activating both GC-A and GC-B, hypothesizing it will attenuate myocardial remodeling in a preclinical model of HF with preserved systolic function. Methods: RT-A1 was engineered by rational drug design. HEK293 cells expressing human GC-A or GC-B, human cardiac myocytes (CMs) and fibroblasts (CFs) were treated with RT-A1 (10-100nM) and cGMP was measured. In vivo, mice underwent mild transverse aortic constriction (TAC) or sham surgery. After 3 weeks, LV hypertrophy (LVH) was confirmed by echo. TAC mice were then randomized to vehicle (Veh) or RT-A1 (50pmol/kg/min) via subcutaneous osmotic pumps for 3 weeks. Endpoints included LV/body weight ratio, myocyte cross-sectional area (CSA), plasma cGMP, and RNA-seq. Data are mean±SEM. P<0.05 was significant. Results: RT-A1 dose-dependently increased cGMP in HEK293 cells expressing GC-A or GC-B, confirming dual activation, and elevated cGMP in human CMs and CFs. TAC induced significant LV wall thickening with preserved systolic function versus sham. After three weeks, RT-A1 normalized LV/body weight (3.14±0.14 vs. 3.82±0.29, P=0.03) and reduced myocyte CSA (348±16 vs. 506±17, P=0.0005) compared to Veh. Plasma cGMP was higher in TAC+RT-A1 versus TAC+Veh (85±8 vs 54±8 pmol/ml, P=0.01), confirming target engagement. RNA-seq showed reduced LV BNP expression and downregulation of hypertrophy, fibrosis, and inflammation pathways with RT-A1 treatment vs. Veh following TAC. Conclusions: RT-A1 is a novel dual GC-A/GC-B peptide activator that elevates plasma cGMP and reduces adverse cardiac remodeling in experimental HF by downregulating hypertrophy, fibrosis, and inflammation pathways. Dual GC-A/GC-B activation via RT-A1 represents a promising anti-remodeling therapeutic strategy for HF with preserved systolic function warranting further study.

BACKGROUND: Greater left atrial size is associated with a higher incidence of cardiovascular disease and mortality, but the full spectrum of diagnoses associated with left atrial enlargement in sex-stratified clinical populations is not well known. Our study sought to identify genetic risk mechanisms affecting left atrial diameter (LAD) in a clinical cohort. METHODS: Using Vanderbilt deidentified electronic health record, we studied 6163 females and 5993 males of European ancestry who had at least 1 LAD measure and available genotyping. A sex-stratified polygenic score was constructed for LAD variation and tested for association against 1680 International Classification of Diseases code–based phenotypes. Two-sample univariable and multivariable Mendelian randomization approaches were used to assess etiologic relationships between candidate associations and LAD. RESULTS: A phenome-wide association study identified 25 International Classification of Diseases code–based diagnoses in females and 11 in males associated with a polygenic score of LAD (false discovery rate q<0.01), 5 of which were further evaluated by Mendelian randomization (waist circumference [WC], atrial fibrillation, heart failure, systolic blood pressure, and coronary artery disease). Sex-stratified differences in the genetic associations between risk factors and a polygenic score for LAD were observed (WC for females; heart failure, systolic blood pressure, atrial fibrillation, and WC for males). By multivariable Mendelian randomization, higher WC remained significantly associated with larger LAD in females, whereas coronary artery disease, WC, and atrial fibrillation remained significantly associated with larger LAD in males. CONCLUSIONS: In a clinical population, we identified, by genomic approaches, potential etiologic risk factors for larger LAD. Further studies are needed to confirm the extent to which these risk factors may be modified to prevent or reverse adverse left atrial remodeling and the extent to which sex modifies these risk factors.