eGFR <15 mL/min/1.73 m² increased LVH risk by OR 4.69; Slc10a6 inhibition by betulinic acid reduced myocardial hypertrophy in CKD mice.
Does reduced eGFR correlate with an increased risk of ventricular remodeling in CAD patients, and does Slc10a6 inhibition improve myocardial hypertrophy in CKD?
Renal insufficiency in CAD patients is strongly associated with ventricular remodeling, and preclinical data suggest Slc10a6 inhibition may serve as a novel therapeutic target for cardiorenal syndrome.
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Abstract Background Chronic Kidney Disease (CKD) affects 15-20% of adults worldwide, with cardiovascular disease being the leading complication, causing over 50% of deaths in CKD patients. CKD leads to pathological ventricular remodeling, including left ventricular hypertrophy (LVH) and heart failure, which increases cardiovascular risk. Despite growing clinical attention to cardiorenal syndrome, the mechanisms underlying these changes remain unclear. Objective This study investigates the relationship between estimated glomerular filtration rate (eGFR) and ventricular remodeling in patients with coronary artery disease (CAD) and explores the potential mechanisms of renal insufficiency-induced ventricular remodeling at both the clinical and animal model levels. Methods A total of 4,225 CAD patients from five tertiary hospitals in China were enrolled and categorized by eGFR levels. Logistic regression and restricted cubic spline (RCS) analyses were used to assess the correlation between eGFR and the risks of left ventricular hypertrophy, systolic dysfunction, and diastolic dysfunction. A 5/6 nephrectomy (Nx) mouse model was established to study renal dysfunction-induced ventricular remodeling, and echocardiography, histological staining, and RT-PCR were used to assess cardiac changes. Human heart tissue from stage 5 CKD patients undergoing heart transplantation was analyzed for Slc10a6 expression and compared with samples from non-CKD heart transplant patients. The effect of Slc10a6 inhibition using betulinic acid in CKD mice was also evaluated. Results Among CAD patients, the prevalence of LVH, systolic dysfunction, and diastolic dysfunction was 34.6%, 26.2%, and 33.7%, respectively. As eGFR decreased, the risk of these conditions increased, with eGFR 15 mL/min per 1.73 m² associated with the highest risk (OR: 4.69, 2.93, 6.47). In the 5/6Nx mouse model, cardiac hypertrophy and dysfunction were observed, alongside upregulation of Slc10a6 expression. Stage 5 CKD patients exhibited significantly higher Slc10a6 expression in heart tissue compared to non-CKD patients. Uremic toxins like indoxyl sulfate (IS) and dehydroepiandrosterone sulfate (DHEAS) induced myocardial hypertrophy and Slc10a6 upregulation. Slc10a6 inhibition alleviated IS-induced myocardial hypertrophy and inhibited IS transport. Betulinic acid effectively reduced myocardial hypertrophy in CKD mice. Conclusions Renal insufficiency in CAD patients is significantly associated with higher risks of LVH, systolic dysfunction, and diastolic dysfunction. Stage 5 CKD patients exhibit increased Slc10a6 expression in heart tissue. Slc10a6 regulates CKD-induced myocardial hypertrophy through uremic toxin transport and fatty acid metabolism. Inhibition of Slc10a6 improves myocardial hypertrophy in CKD mice, suggesting its potential as a therapeutic target in cardiorenal syndrome.
Zhang et al. (Sat,) reported a other. eGFR <15 mL/min/1.73 m² increased LVH risk by OR 4.69; Slc10a6 inhibition by betulinic acid reduced myocardial hypertrophy in CKD mice.