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Abstract: Objective: To investigate whether cardiac expression of the nuclear peroxisome proliferator-activated receptor α (PPARα) is altered in patients with hypertensive heart disease (HHD). Methods: We studied endomyocardial septal biopsies from 24 patients with essential hypertension divided into three groups: 6 without left ventricular hypertrophy (LVH) (HT group), 10 with LVH (LVH group), and 8 with LVH and heart failure (HF) (HF group). The expression of two PPARα isoforms (the native active and the truncated inhibitory) was analyzed by Western blot and reverse transcription polymerase chain reaction (RT–PCR), and two PPARα target genes were evaluated by RT–PCR. Histomorphological features were evaluated in a second myocardial sample from LVH and HF groups. Results: Whereas the expression of native PPARα protein was lower (p <0.05) in LVH and HF groups than in the HT group, truncated PPARα protein was overexpressed (p <0.001) in the HF group as compared with LVH and HT groups. The mRNA expression of native and truncated PPARα was similar in the three groups of hypertensives. In addition, a progressive decrease (p for trend<0.05) in the two PPARα target genes mRNA expression was observed among HT, LVH and HF groups. The amount of truncated PPARα protein correlates directly with cardiomyocytes apoptosis and inversely with cardiomyocytes density in patients with HHD. In addition, the expression of truncated PPARα protein was directly correlated with left ventricular volumes, and inversely with ejection fraction in all hypertensives. Conclusions: These findings suggest that post-transcriptional regulation of PPARα isoforms is altered in patients with HHD, namely in those developing HF. An excess of the truncated inhibitory isoform may be involved in hypertensive left ventricular failure and remodeling. [Copyright &y& Elsevier]