The L-type calcium channels (LTCCs) function as the main entry points that convert myocyte membrane depolarization into calcium transients, which drive every heartbeat. There is increasing evidence to show that maladaptive remodeling of these channels is the cause of heart failure with reduced ejection fraction (HFrEF) and heart failure with preserved ejection fraction (HFpEF). Recent experimental, translational, and clinical studies have improved our understanding of the roles LTCC expression, micro-domain trafficking, and post-translational control have in disrupting excitation–contraction coupling, provoking arrhythmias, and shaping phenotype specific hemodynamic compromise. We performed a systematic search of the PubMed and Google Scholar databases (2015–2025, English) and critically evaluated 17 eligible publications in an effort to organize the expanding body of work. This review combines existing data about LTCC density and T-tubule architecture with β-adrenergic and Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) signaling and downstream sarcoplasmic reticulum crosstalk to explain how HFrEF presents with contractile insufficiency and how HFpEF shows diastolic calcium overload and stiffening. Additionally, we highlight the emerging therapeutic strategies aimed at restoring calcium homeostasis such as CaMKII inhibitors, ryanodine receptor type 2 (RyR2) stabilizers, and selective LTCC modulators without compromising systolic reserve. The review establishes LTCC dysregulation as a single mechanism that causes myocardial dysfunction while remaining specific to each phenotype, thus offering clinicians and researchers a complete reference for current concepts and future precision therapy approaches in heart failure.

Right heart failure (RHF) is a major cause of morbidity and mortality, often resulting from pulmonary arterial hypertension and characterized by impaired calcium (Ca²⁺) handling and maladaptive remodeling. Phosphodiesterase 9A (PDE9A), a cGMP-specific phosphodiesterase, has been proposed as a potential contributor to RHF pathogenesis by suppressing the cardioprotective cGMP–PKG signaling pathway—a conclusion largely extrapolated from left-sided heart failure models. This review examines existing evidence regarding PDE9A’s role in RHF, focusing on its effects on intracellular calcium cycling, fibrosis, hypertrophy, and contractile dysfunction. Data from preclinical models demonstrate that pathological stress upregulates PDE9A expression in cardiomyocytes, leading to diminished PKG activation, impaired SERCA2a function, RyR2 instability, and increased arrhythmogenic Ca²⁺ leak. Pharmacological or genetic inhibition of PDE9A restores cGMP signaling, improves calcium handling, attenuates hypertrophic and fibrotic remodeling, and enhances ventricular compliance. Early-phase clinical studies in heart failure populations suggest that PDE9A inhibitors are well tolerated and effectively augment cGMP levels, although dedicated trials in RHF are still needed. Overall, these findings indicate that targeting PDE9A may represent a promising therapeutic strategy to improve outcomes in RHF by directly addressing the molecular mechanisms underlying calcium mishandling and myocardial remodeling.