In mouse models of Cantú syndrome, KATP channel gain-of-function reduced systemic vascular resistance and elevated renin-angiotensin signaling, driving high-output cardiac hypertrophy.
Does renin-angiotensin system blockade with captopril or losartan reduce cardiac hypertrophy in mouse models of Cantú syndrome?
In Cantú syndrome mouse models, high-output cardiac hypertrophy is driven by compensatory renin-angiotensin system activation secondary to vascular smooth muscle hypo-excitability, and can be reversed by ACE inhibitors or ARBs.
Abstract Dramatic cardiomegaly arising from gain-of-function (GoF) mutations in the ATP-sensitive potassium (KATP) channels genes, ABCC9 and KCNJ8, is a characteristic feature of Cantú syndrome (CS). How potassium channel over-activity results in cardiac hypertrophy, as well as the long-term consequences of cardiovascular remodeling in CS, is unknown. Using genome-edited mouse models of CS, we therefore sought to dissect the pathophysiological mechanisms linking KATP channel GoF to cardiac remodeling. We demonstrate that chronic reduction of systemic vascular resistance in CS is accompanied by elevated renin–angiotensin signaling, which drives cardiac enlargement and blood volume expansion. Cardiac enlargement in CS results in elevation of basal cardiac output, which is preserved in aging. However, the cardiac remodeling includes altered gene expression patterns that are associated with pathological hypertrophy and are accompanied by decreased exercise tolerance, suggestive of reduced cardiac reserve. Our results identify a high-output cardiac hypertrophy phenotype in CS which is etiologically and mechanistically distinct from other myocardial hypertrophies, and which exhibits key features of high-output heart failure (HOHF). We propose that CS is a genetically-defined HOHF disorder and that decreased vascular smooth muscle excitability is a novel mechanism for HOHF pathogenesis.
McClenaghan et al. (Wed,) conducted a other in Cantú syndrome. KATP channel gain-of-function mutations was evaluated on Pathophysiological mechanisms of cardiac remodeling. In mouse models of Cantú syndrome, KATP channel gain-of-function reduced systemic vascular resistance and elevated renin-angiotensin signaling, driving high-output cardiac hypertrophy.