Abstract 6250: Haptoglobin Genotype Is a Determinant of the Severity of Diabetic Cardiomyopathy and Affects Survival and Cardiac Remodeling after Myocardial Infarction in Diabetic Mice
Introduction: Diabetic cardiomyopathy is primarily related to impaired coronary microcirculation and changes in the composite and physical properties of the myocardial extra cellular matrix (ECM) leading to decreased ventricular compliance and congestive heart failure. Haptoglobin (Hp) 2–2 genotype is an independent risk factor for heart failure and death after myocardial infarction (MI) in individuals with Diabetes mellitus (DM). It was previously shown that Hp is involved in coronary collateralization and arterial remodeling by mediating ECM breakdown and cell migration. We hypothesized that Hp genotype would play a role in the progression of diabetic cardiomyopathy and cardiac remodeling after MI in diabetic mice.
Methods: The Hp 2 allele exists only in man. Wild type C57Bl/6 mice carry the Hp 1 allele with a high homology to the human 1 allele. We genetically engineered a murine Hp 2 allele and targeted its insertion by homologous recombination to the murine Hp locus to create Hp 2 mice. DM was induced by intra-peritoneal injection of streptozotocin. MI was produced by occlusion of the left anterior descending artery in diabetic mice carrying the Hp 1 or 2 allele. MI size was determined with TTC staining. Left ventricular (LV) function and dimensions were assessed by 2-dimentional echocardiography.
Results: In the absence of diabetes, Hp 1 and Hp 2 mice have a similar LV dimensions and function, yet, 10 weeks after the induction of DM Hp 2 mice had a significant larger LV end diastolic area (LVEDA) compared to Hp 1 mice (0.12±0.01 cm2 vs. 0.10±0.01 cm2, p=0.01). MI size was similar in diabetic Hp 1 and Hp 2 mice 24 hours after MI (46.9±5.5 vs. 50.2±2.1, respectively). However, diabetic Hp 2 mice had a higher mortality rate than diabetic Hp 1 mice 30 days after MI (RR 2.83; 95% CI 1.06 –7.34, P<0.04). Mortality was similar in sham operated mice. LVEDA was significantly increased in Hp 2 mice compared to Hp 1 mice 30 days after MI (0.19±0.01 cm2 vs. 0.15±0.01 cm2, p=0.012).
Conclusion: In diabetic mice the Hp 2 genotype is associated with exacerbated cardiomyopathy and increased mortality and more severe cardiac remodeling 30 days after MI.