Objective: Peroxisome proliferator-activated receptors (PPARs), key transcriptional regulators of lipid and energy metabolism in cardiomyocytes, have recently been proposed to modulate cardiovascular pathophysiological responses in experimental models. However, there is little information about the functional activity of PPARs in human heart failure. Aims: To investigate PPAR-a and -g expression and activity, and the association with ET-1 production and fibrosis, in cardiac biopsies from patients with end-stage heart failure due to ischemic cardiomyopathy (ICM) in comparison and from non-failing donor hearts. All samples were obtained during cardiac transplantation. Methods and results: Morphological analysis (by Masson trichrome and image analysis) did not detect fibrosis in the left atrium from nonfailing donors (NFLA) or from ICM patients (FLA). However, left ventricles from failing hearts (FLV) contained a greater number of fibrotic areas (NFLA: 3.21 T1.15, FLA: 1.63 T 0.83, FLV: 14.5 T 3.45%; n = 9, P < 0.05). By RT-PCR, preproET-1 expression was similar in the nonfailing and failing atrium but was significantly higher in the ventricles from failing hearts (NFLA: 1.00 T 0.06, FLA: 1.08 T 0.11, FLV: 1.74 T 0.19; n = 9, P < 0.05). PPAR-a and PPAP-g mRNA (by RT-PCR) and protein (by Western blot) levels were higher in the ventricles from failing hearts compared with the atrium from failing and non-failing hearts. Electrophoretic mobility shift assays showed that PPAR-a and PPAP-g were not activated in the ventricles (NFLA: 1.00 T 0.11, FLA: 1.89 T 0.24, FLV: 0.95 T 0.07; n = 9, P < 0.05). Conclusions: These data suggest that PPAR-a and PPAP-g are selectively activated in the atria from ICM patients and might be functionally important in the maintenance of atrial morphology.

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Background To evaluate whether a genetic risk score (GRS) improves the prediction of recurrent events in young non-diabetic patients presenting with an acute myocardial infarction and identifies a more aggressive form of atherosclerosis in this population. Methods and results We performed a prospective study including 81 consecutive non-diabetic patients aged below 55 y.o. presenting with an acute myocardial infarction (48±6 y.o., 89% male). A comprehensive study including serum biomarkers, genetic testing and cardiac CT was performed. We studied the association of a GRS composed of 11 genetic variants with a primary composite end-point (all-cause mortality, recurrent acute coronary syndrome, and cardiac re-hospitalisation). After a median follow-up of 4.1 (3.5 - 4.4) years 24 recurrent events were documented. A significantly higher prevalence of 9 out of 11 risk alleles was noted compared with general population. The GRS was significantly associated with recurrent events, especially when baseline LDL-cholesterol levels were elevated. Compared with the low-risk GRS category, the multivariate-adjusted hazard ratio for recurrent events for the intermediate-risk GRS category was 10.2 (95% CI 1.1–100.3, p=0.04) and for the high-risk GRS was 20.7 (2.4–181.0, p=0.006) when LDL-C ≥2.8 mmol/L. Inclusion of the GRS improved the C statistic (ΔC statistic =0.086), the continuous Net Reclassification Index (30%) and the Integrated Discrimination Improvement (0.05) compared with a multivariate clinical risk model. Cardiac CT detected coronary calcified atherosclerosis and numerous plaques but it had a limited value for prediction of recurrences. No association was observed between extracellular matrix metabolism biomarkers and GRS or recurrent events in this population. Cox regression analysis between GRS terciles and LDL-C Univariate analysis Multivariate analysis* HR (95% CI) p-value HR (95% CI) p-value* Low GRS 1 1 Intermediate GRS 2.0 (0.7–5.8) 0.21 LDL-C≤110 mg/dL (≤2.8 mmol/L) 1.0 (0.3–4.0) >110 mg/dL (>2.8 mmol/L) 10.2 (1.1–100.3) 0.04 High GRS 3.0 (1.0–9.2) 0.05 LDL-C≤110 mg/dL (≤2.8 mmol/L) 0.3 (0.1–1.9) >110 mg/dL (>2.8 mmol/L) 20.7 (2.4–181.0) 0.006 *Multivariate model adjusted for GRACE risk score and LDL-C and interaction. There was a strong interaction between GRS terciles and LDL-C (p<0.01). Recurrent events based on genetic risk Conclusions A multilocus genetic risk score identified non-diabetic young patients at increased risk for recurrent events after a myocardial infarction. The significance of LDL-cholesterol in relation to genetic predisposition for recurrences merits further evaluation. Acknowledgement/Funding Instituto de Salud Carlos III (PI12/0564, PI14/01152 and PI15/00667), the CIBERCV and the Spanish Society of Cardiology (2015/CC)