RATIONALE: Identifying genetic markers for heterogeneous complex diseases such as heart failure is challenging, and requires prohibitively large cohort sizes in genome-wide association studies (GWAS) in order to meet the stringent threshold of genome-wide statistical significance. On the other hand, chromatin quantitative trait loci (QTL), elucidated by direct epigenetic profiling of specific human tissues, may contribute towards prioritising sub-threshold variants for disease-association. OBJECTIVE: Here, we captured non-coding genetic variants by performing epigenetic profiling for enhancer H3K27ac ChIP-seq in 70 human control and end-stage failing hearts. METHODS AND RESULTS: We have mapped a comprehensive catalogue of 47,321 putative human heart enhancers and promoters. 3,897 differential acetylation peaks (FDR 5%) pointed to pathways altered in heart failure (HF). To identify cardiac histone acetylation QTLs (haQTLs), we regressed out confounding factors including HF disease status, and employed the G-SCI test to call out 1,680 haQTLs (FDR 10%). RNA-seq performed on the same heart samples proved a subset of haQTLs to have significant association also to gene expression (expression QTLs), either in cis (180), or through long range interactions (81), identified by Hi-C and HiChIP performed on a subset of hearts. Furthermore, a concordant relationship between the gain or disruption of transcription factor (TF) binding motifs, inferred from alternative alleles at the haQTLs, implied a surprising direct association between these specific TF and local histone acetylation in human hearts. Finally, 62 unique loci were identified by colocalisation of haQTLs with the sub-threshold loci of heart-related GWAS datasets. CONCLUSIONS: Disease and phenotype-association for 62 unique loci are now implicated. These loci may indeed mediated their effect through modification of enhancer H3K27-acetylation enrichment and their corresponding gene expression differences.