title: Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium.
abstract: BACKGROUND
  Diabetes mellitus causes microcirculatory rarefaction and may impair the responsiveness of ischemic myocardium to proangiogenic factors.
  
  
  OBJECTIVE
  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 × 1012viral particles encoding vascular endothelial growth factor-A [VEGF-A] or thymosin beta 4 [Tβ4]) was applied regionally. CD31+ capillaries per high power field (c/hpf) and NG2+ pericyte coverage were analyzed. Global myocardial function (ejection fraction [EF] and left ventricular end-diastolic pressure) was assessed at days 28 and 56.
  
  
  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.
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Institute for Cardiovascular Prevention, Klinikum der Universität München, Munich, Munich, Germany.
authors.forename: Rabea
authors.initials: R
authors.lastname: Hinkel
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Howe
authors.affiliation: Gene Center and Department of Veterinary Sciences, Ludwig Maximilian University of Munich, Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Renner
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Judy
authors.initials: J
authors.lastname: Ng
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany.
authors.forename: Seungmin
authors.initials: S
authors.lastname: Lee
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; Institute for Cardiovascular Prevention, Klinikum der Universität München, Munich, Munich, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Klett
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; Institute for Cardiovascular Prevention, Klinikum der Universität München, Munich, Munich, Germany.
authors.forename: Veronika
authors.initials: V
authors.lastname: Kaczmarek
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Moretti
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany.
authors.forename: Karl-Ludwig
authors.initials: KL
authors.lastname: Laugwitz
authors.affiliation: King's College London British Heart Foundation Centre, London, United Kingdom.
authors.forename: Philipp
authors.initials: P
authors.lastname: Skroblin
authors.affiliation: King's College London British Heart Foundation Centre, London, United Kingdom.
authors.forename: Manuel
authors.initials: M
authors.lastname: Mayr
authors.affiliation: Erich & Hanna Klessmann Institute, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany.
authors.forename: Hendrik
authors.initials: H
authors.lastname: Milting
authors.affiliation: Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dendorfer
authors.affiliation: Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of Munich, Munich, Germany.
authors.forename: Bruno
authors.initials: B
authors.lastname: Reichart
authors.affiliation: Gene Center and Department of Veterinary Sciences, Ludwig Maximilian University of Munich, Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany.
authors.forename: Eckhard
authors.initials: E
authors.lastname: Wolf
authors.affiliation: I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany; DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany; Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of Munich, Munich, Germany. Electronic address: christian.kupatt@tum.de.
authors.forename: Christian
authors.initials: C
authors.lastname: Kupatt
mesh_terms: D000818:Animals; D003327:Coronary Disease / Q000175:diagnosis* / Q000503:physiopathology*; D003331:Coronary Vessels / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000175:diagnosis / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000175:diagnosis* / Q000503:physiopathology*; D015316:Genetic Therapy; D006333:Heart Failure / Q000175:diagnosis / Q000503:physiopathology; D016027:Heart Transplantation; D006801:Humans; D055806:Microvessels / Q000503:physiopathology*; D017682:Myocardial Stunning / Q000188:drug therapy / Q000503:physiopathology; D009206:Myocardium; D018919:Neovascularization, Physiologic / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects / Q000502:physiology; D013552:Swine; D013947:Thymosin / Q000008:administration & dosage; D057170:Translational Research, Biomedical; D042461:Vascular Endothelial Growth Factor A / Q000008:administration & dosage; D000099201:Thymosin beta(4)
chemical_list: D013947:Thymosin; D042461:Vascular Endothelial Growth Factor A; D000099201:Thymosin beta(4)
keywords: angiogenesis; chronic myocardial ischemia; gene therapy; thymosin β4