Development of a Screening Platform to Assess Myocardial Energy Efficiency for Heart Failure Mitigation

Heart failure is a growing global health crisis, exacerbated by aging populations worldwide, including in Japan. Despite advances in medical treatment, the prevalence of heart failure continues to rise, posing severe challenges to healthcare systems and economic and social infrastructures. Heart failure leads to a vicious cycle of increased cardiac energy consumption and functional decline, underscoring the importance of cardiac energy metabolism abnormalities in disease progression. However, real-time monitoring of myocardial energy metabolism, particularly ATP dynamics, has been technically difficult. We developed a novel mouse model (AVID mouse) expressing FRET-based ATP sensor enabling in vivo visualization of rapid ATP fluctuations. Using isolated cardiomyocytes from both wild-type and heart failure AVID mice, we established a method to measure myocardial energy efficiency in real time by calculating the ratio of ATP consumption to contraction. Administration of the selective cardiac myosin activator Omecamtiv Mecarbil (2 nM, 1 hour) significantly improved energy efficiency by approximately 15%. Longitudinal analysis demonstrated that energy efficiency in heart failure mice decreased with increasing heart weight-to-body weight ratio, reflecting cardiac hypertrophy and dysfunction. This methodology enables screens for pharmacological agents that improve myocardial energy efficiency, offering potential for novel therapeutic strategies to inhibit heart failure progression.