Diabetes mellitus can reduce microvascular density and impair microvascular growth in the heart. This finding comes from a study that utilized human myocardial tissue from patients with end-stage heart failure, and a transgenic diabetic pig model to assess the effect of microvascular destabilization on function and therapeutic neovascularization.

Credit: V. Summersby/Macmillan Publishers Limited

The microvascular changes that occur in peripheral or retinal tissue of patients with diabetes have been well characterized, but how these structural changes impair function in the diabetic heart is less understood. To analyse capillary density and pericyte investment in this context, myocardial tissue specimens were collected from patients with end-stage heart failure with or without diabetes at time of transplantation. Capillary rarefaction and pericyte loss were observed in patients with diabetes, which were associated with reduced contractility in the papillary muscle, and increased left ventricular (LV) wall stiffness.

Myocardial vascularization and function were subsequently analysed in vivo using transgenic diabetic and wild-type pigs aged 5 months. Diabetic pig hearts showed capillary rarefaction and reduced pericyte investment, together with increased interstitial fibrosis and decreased LV systolic function compared with the wild-type hearts. To assess the microvascular changes in a setting of diabetes plus chronic ischaemia, the investigators subjected the diabetic pig hearts to regional ischaemia induced by gradual occlusion of the circumflex artery using a stent. Compared with age-matched, nondiabetic pigs, the hearts of the diabetic pigs had a higher degree of microcirculatory rarefaction and decreased pericyte investment. To correct for these changes, gene therapy was employed 28 days after stent placement; the myocardium was transduced with thymosin-β4 (Tβ4) using recombinant adeno-associated virus (rAAv) technology. rAAv.Tβ4 transduction significantly induced capillary growth and maturation in diabetic pigs, but to a lesser degree than in wild-type pigs. Furthermore, rAAv.Tβ4 transduction increased LV ejection fraction in the diabetic pigs, but again to a lesser extent than in wild-type pigs.

“Capillary loss and pericyte dropout have been well described in the retina, but are revealed for the first time in transgenic diabetic pig hearts and in hearts from patients with diabetes,” explain the investigators. “In the presence of [diabetes], balanced vascular gene therapy, targeting microvascular maturation, and macrovascular growth in addition to angiogenesis is effective”.