Investigation of association of genetic variant rs3918242 of matrix metalloproteinase-9 with hypertension, myocardial infarction and progression of ventricular dysfunction in Irish Caucasian patients with diabetes: a report from the STOP-HF follow-up programme

Chris Watson, J Paul Spiers, Max Waterstone, Adam Russell-Hallinan, Joseph Gallagher, Kenneth McDonald, Cristin Ryan, John Gilmer, Mark Ledwidge, Chris Watson, J Paul Spiers, Max Waterstone, Adam Russell-Hallinan, Joseph Gallagher, Kenneth McDonald, Cristin Ryan, John Gilmer, Mark Ledwidge

Abstract

Background: Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. Progression to heart failure is usually preceded by ventricular dysfunction, linked to matrix metalloproteinase (MMP) mediated extracellular matrix changes. We hypothesise that the minor allele of genetic variant rs3918242 in the promoter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progression of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure.

Methods: We genotyped 498 diabetes patients participating in the St Vincent's Screening TO Prevent Heart Failure (STOP-HF) follow-up programme for the rs3918242 single nucleotide polymorphism and investigated associations with the co-primary endpoints hypertension and/or myocardial infarction using a dominant model. We also evaluated resulting cardiometabolic phenotype and progression of ventricular dysfunction and cardiac structural abnormalities over a median follow-up period of 3.5 years.

Results: The CT/TT genotype comprised 28.1% of the cohort and was associated with a twofold higher risk of myocardial infarction (17.9% vs 8.4%), a reduction in ejection fraction and greater left ventricular systolic dysfunction progression [adjusted OR = 2.56 (1.09, 6.01), p = 0.026] over a median follow-up of 3.5 years [IQR 2.6, 4.9 years]. Conversely, rs3918242 was not associated with hypertension, blood pressure, pulse pressure or left ventricular mass index at baseline or over follow up.

Conclusions: Diabetes patients with the minor T allele of rs3918242 in the STOP-HF follow up programme have greater risk of myocardial infarction, lower ejection fraction and greater progression of left ventricular systolic abnormalities, a precursor to heart failure. These data may support further work on MMP-9 as a biomarker of ventricular dysfunction and the investigation of MMP-9 inhibitors for heart failure prevention in diabetes, particularly in the post-infarction setting. ClinicalTrials.gov Identifier: NCT00921960.

Keywords: Diabetes; Genetics; Heart failure; Hypertension; Imaging; MMP-9; Myocardial infarction; Prevention; Single nucleotide polymorphism.

Conflict of interest statement

Dr Gallagher received payment for lectures from Merck, Servier Laboratories. Pfizer and Grunenthal and travel expenses to meeting from Merck. Prof. Ken McDonald is a named inventor on several patents relating to novel biomarkers of cardiovascular disease. He is also funded by an EU FP7 grant investigating biomarkers of cardiovascular disease and recently by the Health Research Board of Ireland. He had received honoraria from Pfizer, Alere, Menarini, Novartis, Servier and Abbott. Prof. Ledwidge reports board membership and shares in Solvotrin and is a named inventor on several relevant patents relating to absorption of iron, superaspirin effects of isosorbide prodrugs, compounds for treatment of heart failure and epigenetic regulation of cardiomyopathies. He is a Co-Investigator in the PARABLE study, which has received an unrestricted research grant from Novartis. He is principal investigator of the Genuity Science Genomics of Heart Failure study. He has also received honoraria and research grants from A Menarini, Servier and Abbott Diagnostics. No other conflicts of interest were reported.

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