Abstract
BackgroundHypertension 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.MethodsWe 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.ResultsThe 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.ConclusionsDiabetes 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
Highlights
Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes
matrix metalloproteinase (MMP)-9 increase in cardiovascular disease can be driven by multiple factors, one of which is via promoter-activating single nucleotide polymorphisms (SNPs)
Rs3918242 is associated with coronary atherosclerosis and outcome in heart failure [22, 23], the association between rs391824 genotype, hypertension, myocardial infarction and progression of left ventricular dysfunction has not been evaluated in diabetes without heart failure
Summary
Hypertension and/or myocardial infarction are common causes of heart failure in Type 2 diabetes. We hypothesise that the minor allele of genetic variant rs3918242 in the pro‐ moter region of the MMP-9 gene is associated with hypertension and/or myocardial infarction, with resultant progres‐ sion of dysfunctional cardiac remodelling in patients with diabetes without symptomatic heart failure. The most common clinical precursors to heart failure in diabetes are hypertension and myocardial infarction, causing ventricular dysfunction and extracellular matrix (ECM) changes with diabetes-related arterial and myocardial remodelling [3,4,5,6]. Nih.gov/snp/?term=rs3918242) near the promoter region of the MMP-9 gene has been associated with increased circulating levels of MMP-9 and with higher frequencies of vascular disease, especially in type 2 diabetes [18, 19]. Rs3918242 is associated with coronary atherosclerosis and outcome in heart failure [22, 23], the association between rs391824 genotype, hypertension, myocardial infarction and progression of left ventricular dysfunction has not been evaluated in diabetes without heart failure
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