Is hyperhomocysteinemia a causal factor for heart failure? The impact of the functional variants of MTHFR and PON1 on ischemic and non-ischemic etiology

Background: Hyperhomocysteinemia was found to be uniformly associated with the development of heart failure (HF) and HF mortality; however, it is uncertain whether this relation is causative or not. We used Mendelian randomization to examine the associations of the methylene tetrahydrofolate gene (MTHFR) and paraoxonase 1 gene (PON1) variants as a proxy for lifelong exposure to high Hcy and Hcy-thiolactone concentrations with the development of HF in men aged <= 60 years and the occurrence of adverse effects at one-year follow-up. Methods: The study enrolled 172 men with HF: 117 with ischemic etiology (iHF) related to coronary artery disease (CAD) and 55 with non-ischemic etiology (niHF) related to dilated cardiomyopathy (DCM). The reference group of 329 CAD patients without HF and the control group of 384 men were also analyzed. Results: Hyperhomocysteinemia (OR = 2.0, P < 0.05) and the MTHFR 677TT/1298AA, 677CC/1298CC genotypes (OR = 1.6, P = 0.03) were associated with HF regardless of its etiology, especially among normotensives (OR = 4.6, P = 0.001 and OR = 2.3, P = 0.003, respectively). In niHF, the PON1 162AA (OR = 2.3, P = 0.03) and 575AG+GG (OR = 0.46, P = 0.01) genotypes also influenced the risk. The interaction between HDLC < 1 mmol/L and the PON1 575GG genotype was found to influence the risk of iHF (OR = 7.2, P = 0.009). Hyperhomocysteinemia improved the classification of niHF patients as 'high-risk' by 10.1%. Ejection fraction < 30% and DCM increased the probability of HF death or re-hospitalization within one year. Conclusion: Our results provide evidence that hyperhomocysteinemia is a causal factor for niHF in DCM, while dysfunctional HDL could contribute to the pathogenesis of iHF. (C) 2016 Elsevier Ireland Ltd. All rights reserved.