Abstract
Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca(2+)) regulation is emerging as a key area for innovative HF treatments that could significantly alter disease outcomes and enhance cardiac function. In this review, we aim to explore the implications of altered Ca(2+) sensitivity, a key determinant of cardiac muscle force, in HF, including its roles during systole and diastole and its association with different HF types-HF with preserved and reduced ejection fraction (HFpEF and HFrEF, respectively). We further highlight the role of the two rate constants k(on) (Ca(2+) binding to Troponin C) and k(off) (its dissociation) to fully comprehend how changes in Ca(2+) sensitivity impact heart function. Additionally, we examine how increased Ca(2+) sensitivity, while boosting systolic function, also presents diastolic risks, potentially leading to arrhythmias and sudden cardiac death. This suggests that strategies aimed at moderating myofilament Ca(2+) sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca(2+) sensitivity and call for comprehensive research into the complex interactions between Ca(2+) regulation, myofilament sensitivity, and their clinical manifestations in HF.