Matrix Metalloproteinase-2 Polymorphisms in Chronic Heart Failure: Relationship with Susceptibility and Long-Term Survival

Abstract

Circulating levels of matrix metalloproteinase-2 (MMP-2) predict mortality and hospital admission in heart failure (HF) patients. However, the role of MMP-2 gene polymorphisms in the susceptibility and prognosis of HF remains elusive. In this study, 308 HF outpatients (216 Caucasian- and 92 African-Brazilians) and 333 healthy subjects (256 Caucasian- and 77 African-Brazilians) were genotyped for the -1575G>A (rs243866), -1059G>A (rs17859821), and -790G>T (rs243864) polymorphisms in the MMP-2 gene. Polymorphisms were analyzed individually and in combination (haplotype), and positive associations were adjusted for clinical covariates. Although allele frequencies were similar in HF patients and controls in both ethnic groups, homozygotes for the minor alleles were not found among African-Brazilian patients. After a median follow-up of 5.3 years, 124 patients (40.3%) died (54.8% of them for HF). In Caucasian-Brazilians, the TT genotype of the -790G>T polymorphism was associated with a decreased risk of HF-related death as compared with GT genotype (hazard ratio [HR] = 0.512, 95% confidence interval [CI] 0.285–0.920). However, this association was lost after adjusting for clinical covariates (HR = 0.703, 95% CI 0.365–1.353). Haplotype analysis revealed similar findings, as patients homozygous for the -1575G/-1059G/-790T haplotype had a lower rate of HF-related death than those with any other haplotype combination (12.9% versus 28.5%, respectively; P = 0.010). Again, this association did not remain after adjusting for clinical covariates (HR = 0.521, 95% CI 0.248–1.093). Our study does not exclude the possibility that polymorphisms in MMP-2 gene, particularly the -790G>T polymorphism, might be related to HF prognosis. However, due to the limitations of the study, our findings need to be confirmed in further larger studies.

Relationship of polymorphisms in the tissue inhibitor of metalloproteinase (TIMP)-1 and -2 genes with chronic heart failure

“…In a previous study, we showed that high serum levels of MMP-9 are associated with carotid plaque vulnerability and stroke in patients who underwent endarterectomy 17 . In other studies, we also observed a lower rate of HF-related death in HF patients who carried the 2 G allele of the −1607 1 G/2 G polymorphism in the MMP-1 gene 18 , the TT genotype of the −790 G > T polymorphism in the MMP-2 gene 19 , or the 6 A allele of the −1171 5 A/6 A polymorphism in the MMP-3 gene 18 than patients with other genotypes. Considering our previous findings and the role of MMPs and TIMPs in HF pathogenesis, we decided to expand our study by investigating the association of TIMP gene variants with HF.…”

Matrix Metalloproteinases in Myocardial Infarction and Heart Failure

“…39 Interestingly, all three MMP-2 polymorphisms associate with heart failure related deaths only in Caucasians. 39 Similarly, the −790 T/G MMP-2 polymorphism, in addition to the −735 C/T polymorphism, also associates with chronic heart failure in patients from the Czech Republic. 40 How these polymorphisms effect heart failure related deaths is still unclear.…”

Matrix Metalloproteinases and Arterial Hypertension: Role of Oxidative Stress and Nitric Oxide in Vascular Functional and Structural Alterations

“…In fact, increased plasma levels of MMP-9 correlate with increased cardiovascular risk, myocardial infarct mortality, cardiac remodeling and dysfunction [ 112 , 113 , 114 , 115 , 116 ]. MMP-2 is also associated with cardiac failure, and both genetic polymorphisms commonly found in the MMP-2 gene [ 117 , 118 , 119 , 120 , 121 , 122 ] and increased plasma MMP-2 concentrations [ 123 , 124 , 125 , 126 , 127 , 128 ] are linked to heart failure. On the other hand, MMP-9 and its endogenous inhibitor, tissue inhibitor of metalloproteinase (TIMP)-1, when measured in serum, have been shown at increased concentrations.…”