Rabea Hinkel1, Andrea Howe2, Simone Renner3, Judy Ng2, Seungmin Lee2, Katharina Klett4, Veronika Kaczmarek4, Alessandra Moretti5, Karl-Ludwig Laugwitz5, Philipp Skroblin6, Manuel Mayr6, Hendrik Milting7, Andreas Dendorfer8, Bruno Reichart8, Eckhard Wolf3, Christian Kupatt9. 1. 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. 2. I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar, Technical University of Munich, Munich, Germany. 3. Gene Center and Department of Veterinary Sciences, Ludwig Maximilian University of Munich, Munich, Germany; German Center for Diabetes Research (DZD), Neuherberg, Germany. 4. 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. 5. 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. 6. King's College London British Heart Foundation Centre, London, United Kingdom. 7. Erich & Hanna Klessmann Institute, Heart and Diabetes Center North Rhine-Westphalia, Bad Oeynhausen, Germany. 8. Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of Munich, Munich, Germany. 9. 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.
Abstract
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 × 1012 viral 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.
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 × 1012 viral 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: Hernán Mejía-Rentería; Nina van der Hoeven; Tim P van de Hoef; Julius Heemelaar; Nicola Ryan; Amir Lerman; Niels van Royen; Javier Escaned Journal: Int J Cardiovasc Imaging Date: 2017-05-13 Impact factor: 2.357
Authors: Maximilian Kleinert; Christoffer Clemmensen; Susanna M Hofmann; Mary C Moore; Simone Renner; Stephen C Woods; Peter Huypens; Johannes Beckers; Martin Hrabe de Angelis; Annette Schürmann; Mostafa Bakhti; Martin Klingenspor; Mark Heiman; Alan D Cherrington; Michael Ristow; Heiko Lickert; Eckhard Wolf; Peter J Havel; Timo D Müller; Matthias H Tschöp Journal: Nat Rev Endocrinol Date: 2018-01-19 Impact factor: 43.330