Therapeutic neovascularization with rAAV.Tβ4 improved ejection fraction in diabetic ischemic hearts (34.5%), but less efficiently than in wild-type hearts (44.8%).
Does therapeutic neovascularization with rAAV.Tβ4 or rAAV.VEGF-A improve myocardial vascularization and ejection fraction in diabetic models of chronic ischemia?
Diabetes mellitus causes microvascular destabilization and capillary rarefaction, which blunts the efficacy of therapeutic neovascularization with rAAV.Tβ4 in a large animal model of chronic ischemia.
Absolute Event Rate: 34.5% vs 44.8%
BACKGROUND: Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors. OBJECTIVES: This study sought to determine whether microvascular destabilization affects organ function and therapeutic neovascularization in diabetes mellitus. METHODS: The authors obtained myocardial samples from patients with end-stage heart failure at time of transplant, with or without diabetes mellitus. Diabetic (db) and wild-type (wt) pigs were used to analyze myocardial vascularization and function. Chronic ischemia was induced percutaneously (day 0) in the circumflex artery. At day 28, recombinant adeno-associated virus (rAAV) (5 × 10 RESULTS: Diabetic human myocardial explants revealed capillary rarefaction and pericyte loss compared to nondiabetic explants. Hyperglycemia in db pigs, even without ischemia, induced capillary rarefaction in the myocardium (163 ± 14 c/hpf in db vs. 234 ± 8 c/hpf in wt hearts; p < 0.005), concomitant with a distinct loss of EF (44.9% vs. 53.4% in nondiabetic controls; p < 0.05). Capillary density further decreased in chronic ischemic hearts, as did EF (both p < 0.05). Treatment with rAAV.Tβ4 enhanced capillary density and maturation in db hearts less efficiently than in wt hearts, similar to collateral growth. rAAV.VEGF-A, though stimulating angiogenesis, induced neither pericyte recruitment nor collateral growth. As a result, rAAV.Tβ4 but not rAAV.VEGF-A improved EF in db hearts (34.5 ± 1.4%), but less so than in wt hearts (44.8 ± 1.5%). CONCLUSIONS: Diabetes mellitus destabilized microvascular vessels of the heart, affecting the amplitude of therapeutic neovascularization via rAAV.Tβ4 in a translational large animal model of hibernating myocardium.
“It will be a while before this kind of therapy can be used in humans. But we were able to show for the first time in a transgenic large animal model, which closely models human type I diabetes mellitus, how diabetes damages the heart. That opens up new perspectives for treating patients. It also further reinforces our awareness of how important it is to diagnose diabetes early.”
Hinkel et al. (Sun,) conducted a other in End-stage heart failure and chronic myocardial ischemia in diabetes mellitus. rAAV.Tβ4 vs. rAAV.VEGF-A and wild-type controls was evaluated on Ejection fraction (EF). Therapeutic neovascularization with rAAV.Tβ4 improved ejection fraction in diabetic ischemic hearts (34.5%), but less efficiently than in wild-type hearts (44.8%).
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