Background: Cardiometabolic Heart Failure with Preserved Ejection Fraction (HFpEF) represents a common clinical endpoint of structural and metabolic diseases which impair myocardial diastolic relaxation by increased myocardial stiffness. The disease mechanisms are poorly understood and the therapeutic options for HFpEF are currently limited. In the realm of cardiac disease, calcium/calmodulin-dependent protein kinase II (CAMK2D) has been recognized for its detrimental role. Notably, CAMK2D-dependent activation by reactive oxygen species (ROS) has been demonstrated. Given that myocardial redox perturbations are a critical aspect of HFpEF pathophysiology, it suggests a potential contributory role of CaMKII in the development and progression of cardiometabolic HFpEF.
Methods and Results: In the current study, 12-week-old tamoxifen-induced cardiac specific Camk2d/Camk2g double knockout (DKO) mice in a C57BL/6N background, and their control counterparts, were exposed to a high-fat diet combined with 0.5% N(ω)-nitro-L-arginine methyl ester (HFD+L-NAME) for 9 weeks, with each group comprising 10 mice. Remarkably, DKO mice exhibited resistance to the hallmarks of cardiometabolic syndrome following the 9-week HFD+L-NAME regimen. This resistance was characterized by a increase in body weight (30% in DKO vs. 59% in control mice), improved glucose tolerance, and enhanced exercise capacity (460 m vs.107 m in treadmill test in control mice) compared to controls. Echocardiographic analysis further revealed a significant mitigation of diastolic dysfunction in DKO mice compared to the controls (E/e′ ratio of 26 in DKO vs. 36 in control mice). These findings suggest that cardiac specific deletion of cardiac Camk2 effectively prevents the development of cardiac and systemic complications of cardiometabolic HFpEF. Interestingly, DKO mice exhibited reduced weight gain not only under the HFD/L- NAME challenge but also when maintained on a standard diet, indicating a yet not recognized fundamental role for cardiac CaMKII in regulating systemic metabolic homeostasis. Transcriptomic analyses of adipose tissue revealed increased expression of key lipolytic signaling markers, including Adrb3 and PGC-1α, along with a trend toward elevated levels of adipokines such as Adipoq in cardiac CaMKII deficient mice. These findings point to a heart–adipose tissue communication axis influenced by cardiac CAMK2 activity, which deserves further investigations.
Conclusion: Our research demonstrates that cardiac CAMK2 is required not only for cardiac complications of the cardiometabolic syndrome but also for obesity. Notably, the observed reduction in body weight gain—even under standard dietary conditions— highlights a potential heart-to-peripheral-organ signaling axis that warrants deeper investigations. Clinically, these findings emphasize that cardiac-targeted therapies of HFpEF may improve systemic metabolism. Targeting CAMK2 pathways could thus offer novel, far-reaching therapeutic strategies for this complex cardiometabolic disorder.
