Molecular Mechanisms of L-Type Calcium Channel Dysregulation in Heart Failure

Abstract

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.

Keywords: Ca2⁺/calmodulin-dependent protein kinase II (CaMKII); L-type calcium channel (LTCC); T-tubule remodeling; calcium handling; excitation–contraction coupling; heart failure.

Figure 1

Schematic representation of L-type calcium channel (LTCC) behavior in normal, HFrEF, and HFpEF cardiomyocytes. (A) Normal cardiomyocyte showing organized T-tubules and tightly coupled LTCC–RyR2 interactions for efficient systolic Ca²⁺ release and diastolic reuptake. (B) HFrEF cardiomyocyte with disrupted T-tubules, increased LTCC–RyR2 distance, downregulated LTCC expression, maladaptive phosphorylation, and delayed Ca²⁺ reuptake—leading to systolic dysfunction and arrhythmogenesis. (C) HFpEF cardiomyocyte with preserved or increased LTCC expression, intact T-tubules, elevated diastolic Ca²⁺, and blunted β-adrenergic responsiveness—leading to preserved EF but impaired relaxation. The figure illustrates phase-specific Ca²⁺ flux, LTCC gating, kinase signaling, and EC coupling efficiency across phenotypes. Abbreviations: LTCC, L-type calcium channel; RyR2, ryanodine receptor 2; SERCA, sarcoplasmic reticulum Ca²⁺-ATPase; PLB, phospholamban; CaMKII, calcium/calmodulin-dependent protein kinase II; β-AR, beta-adrenergic receptor; PKA, protein kinase A; cAMP, cyclic AMP; HFrEF, heart failure with reduced ejection fraction; HFpEF, heart failure with preserved ejection fraction; EADs, early afterdepolarizations.