Abstract 4365934: Investigating causal links and molecular pathways that govern organ dysfunction in cardiovascular and chronic kidney disease

Abstract

Cardiac and renal dysfunction are tightly linked, with each accelerating the other and undermining cardiovascular–kidney–metabolic health. Renal impairment is now recognized as a pivotal intermediary between metabolic risk factors and cardiovascular disease, particularly heart failure (HF). Recent single-cell RNA sequencing data has revealed shared inflammatory and fibrotic programs in both organs, yet the cellular and molecular drivers of their combined pathology remain incompletely defined. In the present study we integrated clinical and preclinical data to uncover pathways involved in mediating cardiac and renal dysfunction. Using the ICELL8 cx platform, we generated snRNA-seq libraries from frozen left ventricular (LV) tissue of healthy donors, HF patients, and HF + chronic kidney disease (CKD) patients (n=10/group, males and females, 30–70 years). We profiled 25,122 nuclei in total and snRNA sequencing identified 10 distinct cell populations with endothelial cells forming the bulk of cell types detected followed by fibroblasts and myeloid cells. Differential gene expression analysis highlighted pronounced transcriptional changes in endothelial cells, fibroblasts, myeloid cells, and pericytes. Compared to healthy donors, both diseased groups showed marked depletion of endothelial cells and pericytes that was more pronounced in HF + CKD patient samples, suggesting vascular dysfunction. Next, to establish causal associations between cardiac and renal dysfunction, we characterized 2 mouse models to study the impact of HF on renal function and CKD on cardiac function. The transverse aortic constriction (TAC) mouse model of HF (n = 15/group) displayed severe systolic dysfunction (ejection fraction 27.9 % vs 63.9 %; cardiac output 16.3 vs 23.3 mL/min), and persistent LV hypertrophy (198.5 vs 108.8 mg) via echocardiography. Kidney function measurements showed a progressive decline in GFR at 12 weeks post-surgery and reaching significance at 16 weeks post-surgery (946.6 vs 1 263 µL/min/100 g). Conversely, in the adenine model of CKD (n = 10/group), a sharp fall in GFR (194.9 vs 975.5 µL/min/100 g) was accompanied by a modest reduction cardiac output (13.3 vs 18.7 mL/min), and a compensatory rise in ejection fraction (74.7 % vs 67.2 %). Together, these integrated human and mouse datasets provide a detailed picture of cardiorenal pathophysiology and reveal alterations to cardiac endothelial and stromal cells in response to impaired renal function.