Renal denervation calms inflammasome-driven heart stiffness in a new multi-hit HFpEF mouse model

Heart failure with preserved ejection fraction (HFpEF) accounts for over half of heart failure hospitalizations and is expected to dominate as populations age, yet drugs that work in reduced-EF heart failure have largely failed here. One obstacle is that HFpEF arises from several overlapping problems, including aging, metabolic stress, hypertension, inflammation and sympathetic nervous system overactivity, and simple animal models capture only some of them.

The authors built a '3-hit' mouse model: 18-month-old male C57BL/6J mice given a high-fat diet plus L-NAME (a nitric oxide synthase inhibitor) for 5 weeks. They compared it with young controls, aged chow-fed mice and young 2-hit mice (diet plus L-NAME). They then tested three interventions, each in 24 mice (n=6 per group): bilateral renal denervation (surgical nerve stripping plus phenol), the P2X7 antagonist A438079, and the NLRP3 inhibitor MCC950, the latter two delivered by osmotic pump for 2 weeks. Assessments included echocardiography, tail-cuff blood pressure, treadmill exhaustion testing, histology, electron microscopy, RNA-seq and proteomics, oxidative stress markers, and cytokine ELISAs. Mechanistic experiments used H9c2 cells and neonatal rat cardiomyocytes stimulated with 5 mM ATP, with P2X7 knockdown or antagonism.

Both the 2-hit and 3-hit mice gained weight and developed higher blood glucose and blood pressure. They kept a normal ejection fraction but showed raised E/e′ ratios (diastolic dysfunction) and thicker posterior walls. The full text provided to us was truncated after the early model-characterization results, so the following intervention results are drawn from the abstract. The 3-hit mice also had cardiomyocyte hypertrophy, interstitial fibrosis, reduced exercise capacity, elevated inflammatory cytokines, increased myocardial ATP, activated P2X7/NLRP3 signaling, oxidative stress and pyroptosis. Renal denervation lowered systemic and myocardial norepinephrine, suppressed inflammasome activation, reduced fibrosis and cell size, improved E/e′ and exercise capacity, and reduced oxidative stress and myocardial injury. A438079 and MCC950 each improved diastolic function and exercise capacity and reduced fibrosis and hypertrophy. In cardiomyocytes, ATP increased mitochondrial ROS, inflammasome activation, cytokine release and cell injury, partly reversed by P2X7 knockdown or blockade.

Taken together, the data suggest that sympathetic overactivity can drive a cardiac ATP-P2X7-NLRP3 inflammatory loop that contributes to HFpEF, and that interrupting it at the nerve, receptor or inflammasome level can improve diastolic function in mice. This may help identify patients with high sympathetic tone as candidates for renal denervation or inflammasome-targeted therapy.

Caveats are substantial. Only male mice were used, group sizes were small (n=6), and the model is an approximation of human HFpEF. Reversal of effects in cells was only partial, and the cell experiments used a high 5 mM ATP dose. Renal denervation was performed at the start of disease induction, so it tests prevention rather than treatment of established HFpEF. Human efficacy remains untested.