In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the β-adrenergic response to isoproterenol was depressed in both pathologies. Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

Heart failure (HF) presents a significant clinical challenge, with current treatments mainly easing symptoms without stopping disease progression. The targeting of calcium (Ca²⁺) 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 Ca²⁺ 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 (Ca²⁺ binding to Troponin C) and k_off (its dissociation) to fully comprehend how changes in Ca²⁺ sensitivity impact heart function. Additionally, we examine how increased Ca²⁺ 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 Ca²⁺ sensitivity could revolutionize anti-arrhythmic approaches, reshaping the HF treatment landscape. In conclusion, we emphasize the need for precision in therapeutic approaches targeting Ca²⁺ sensitivity and call for comprehensive research into the complex interactions between Ca²⁺ regulation, myofilament sensitivity, and their clinical manifestations in HF.

Congenital heart disease (CHD), the most common congenital anomaly, remains a significant lifelong burden despite advancements in medical and surgical interventions. Induced pluripotent stem cells (iPSCs) have emerged as a groundbreaking platform in CHD research, offering patient-specific models to investigate the genetic, epigenetic, and molecular mechanisms driving the disease. Utilizing technologies such as CRISPR/Cas9 gene editing, cardiac organoids, and high-throughput screening, iPSCs enable innovative strategies in disease modeling, precision drug discovery, and regenerative therapies. However, clinical translation faces challenges related to immaturity, differentiation variability, large-scale feasibility, and tumorigenicity. Addressing these barriers will require standardized protocols, bioengineering solutions, and interdisciplinary collaboration. This review examines the critical role of iPSCs in advancing CHD research and care, demonstrating their potential to revolutionize treatment through patient-specific, regenerative approaches. By addressing current limitations and advancing iPSC technology, the field is positioned to pave the way for precision-based CHD therapies for this lifelong condition.