Aims: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by major fibro-fatty replacement of the right ventricle (RV). We hypothesized that changes in peroxisome proliferator-activated receptor (PPAR) signalling contributed to myocardium fatty accumulation and contractile dysfunction in ARVC.
Methods and results: Real-time quantitative reverse transcriptase-polymerase chain reaction and western blotting were used to assess cardiac expression of PPARalpha and gamma and two of their downstream target genes--medium-chain acyl-CoA dehydrogenase (MCAD) and phosphoenolpyruvate carboxykinase (PEPCK)--in both RV and left ventricle (LV) from five controls and five ARVC patients. In vitro motility assays were used to analyse functional properties of myosin. In the RV, sliding velocity was nearly two-fold lower in ARVC than in controls, whereas a 10% reduction in velocity values was noted between ARVC and non-failing myocardium in the LV. In controls, PPARalpha and MCAD mRNA and protein levels were higher in the RV compared with the LV. In ARVC, the expression of PPARalpha and MCAD mRNA and/or proteins was decreased in both RV and LV. RV from ARVC was also characterized by a dramatic activation of the PPARgamma pathway, as attested by the increase in PPARgamma mRNA and protein (500 and 270%, respectively, each P < 0.001) and by the induction of PEPCK gene. In contrast, the LV of ARVC heart exhibited no changes in the expression of the PPARgamma regulatory pathway compared with control.
Conclusion: ARVC is associated with major disturbances in the PPARalpha and PPARgamma signalling pathway in the RV that may contribute to intracellular lipid overload and severe myosin dysfunction.