Lipid Metabolism as a Therapeutic Target in Arrhythmogenic Cardiomyopathy: Emerging Therapeutic Implications of Lipid-Lowering Therapy.

Arrhythmogenic cardiomyopathy (ACM) is a hereditary myocardial disorder characterized by progressive replacement of ventricular myocardium with fibro-fatty tissue, leading to life-threatening ventricular arrhythmias and heart failure. Historically, management has focused on arrhythmia suppression and prevention of sudden cardiac death (SCD). However, recent advances in understanding disease mechanisms have redefined ACM as a structural-metabolic cardiomyopathy. Central to this evolving paradigm is the "adipogenic switch", driven by desmosomal dysfunction, impaired Wnt/β-catenin signaling, and activation of the peroxisome proliferator-activated receptor gamma (PPARγ) pathway. Emerging evidence highlights the critical role of metabolic dysregulation, specifically the oxidized low-density lipoprotein (oxLDL)/cluster of differentiation 36 (CD36)/PPARγ axis, in driving disease progression. Elevated oxLDL levels correlate with greater phenotypic severity, increased ventricular fat infiltration, and a higher arrhythmic risk. Translational models demonstrate that high-fat diets exacerbate the ACM phenotype, whereas lipid-lowering interventions, particularly statins, show potential to arrest fibro-fatty remodeling. In addition to the primary inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase associated with statins, these medications exert pleiotropic effects, including attenuation of systemic inflammation, stabilization of the intercalated disc via Rho GTPase modulation, and reduction of oxidative stress. Clinical data from non-ischemic dilated cardiomyopathy (NIDCM) suggest that lipophilic statins such as atorvastatin, may confer significant mortality and antiarrhythmic benefits by stabilizing the myocardial electrical substrate. The ongoing SEARCH trial (NCT06922994) represents a landmark effort to translate these insights into clinical practice. Using high-dose atorvastatin and sensitive primary endpoints, such as right ventricular free wall longitudinal strain, this study aimed to determine whether lipid-lowering therapy can function as a true disease-modifying intervention in ACM. The integration of lipid-lowering agents into the therapeutic armamentarium for ACM could enable a transition toward precision medicine, contingent upon successful clinical validation. If clinical trials confirm the efficacy of these agents in slowing myocardial substrate decay, this approach could redefine the management of ACM, including the use of targeted molecular strategies to preserve myocardial identity and electrical stability.