PMID- 28081822
OWN - NLM
STAT- MEDLINE
DCOM- 20170712
LR  - 20170922
IS  - 1558-3597 (Electronic)
IS  - 0735-1097 (Linking)
VI  - 69
IP  - 2
DP  - 2017 Jan 17
TI  - Diabetes Mellitus-Induced Microvascular Destabilization in the Myocardium.
PG  - 131-143
LID - S0735-1097(16)37030-9 [pii]
LID - 10.1016/j.jacc.2016.10.058 [doi]
AB  - 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 x 10(12) viral
      particles encoding vascular endothelial growth factor-A [VEGF-A] or thymosin beta
      4 [Tbeta4]) 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.Tbeta4 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.Tbeta4 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.Tbeta4 
      in a translational large animal model of hibernating myocardium.
CI  - Copyright (c) 2017 American College of Cardiology Foundation. Published by
      Elsevier Inc. All rights reserved.
FAU - Hinkel, Rabea
AU  - Hinkel R
AD  - 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 Universitat Munchen,
      Munich, Munich, Germany.
FAU - Howe, Andrea
AU  - Howe A
AD  - I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar,
      Technical University of Munich, Munich, Germany.
FAU - Renner, Simone
AU  - Renner S
AD  - Gene Center and Department of Veterinary Sciences, Ludwig Maximilian University
      of Munich, Munich, Germany; German Center for Diabetes Research (DZD),
      Neuherberg, Germany.
FAU - Ng, Judy
AU  - Ng J
AD  - I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar,
      Technical University of Munich, Munich, Germany.
FAU - Lee, Seungmin
AU  - Lee S
AD  - I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar,
      Technical University of Munich, Munich, Germany.
FAU - Klett, Katharina
AU  - Klett K
AD  - I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar,
      Technical University of Munich, Munich, Germany; Institute for Cardiovascular
      Prevention, Klinikum der Universitat Munchen, Munich, Munich, Germany.
FAU - Kaczmarek, Veronika
AU  - Kaczmarek V
AD  - I. Medizinische Klinik und Poliklinik, University Clinic Rechts der Isar,
      Technical University of Munich, Munich, Germany; Institute for Cardiovascular
      Prevention, Klinikum der Universitat Munchen, Munich, Munich, Germany.
FAU - Moretti, Alessandra
AU  - Moretti A
AD  - 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.
FAU - Laugwitz, Karl-Ludwig
AU  - Laugwitz KL
AD  - 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.
FAU - Skroblin, Philipp
AU  - Skroblin P
AD  - King's College London British Heart Foundation Centre, London, United Kingdom.
FAU - Mayr, Manuel
AU  - Mayr M
AD  - King's College London British Heart Foundation Centre, London, United Kingdom.
FAU - Milting, Hendrik
AU  - Milting H
AD  - Erich & Hanna Klessmann Institute, Heart and Diabetes Center North
      Rhine-Westphalia, Bad Oeynhausen, Germany.
FAU - Dendorfer, Andreas
AU  - Dendorfer A
AD  - Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of 
      Munich, Munich, Germany.
FAU - Reichart, Bruno
AU  - Reichart B
AD  - Walter-Brendel-Centre for Experimental Medicine, Ludwig Maximilian University of 
      Munich, Munich, Germany.
FAU - Wolf, Eckhard
AU  - Wolf E
AD  - Gene Center and Department of Veterinary Sciences, Ludwig Maximilian University
      of Munich, Munich, Germany; German Center for Diabetes Research (DZD),
      Neuherberg, Germany.
FAU - Kupatt, Christian
AU  - Kupatt C
AD  - 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.
LA  - eng
GR  - FS/13/2/29892/British Heart Foundation/United Kingdom
PT  - Journal Article
PL  - United States
TA  - J Am Coll Cardiol
JT  - Journal of the American College of Cardiology
JID - 8301365
RN  - 0 (Vascular Endothelial Growth Factor A)
RN  - 549LM7U24W (thymosin beta(4))
RN  - 61512-21-8 (Thymosin)
SB  - AIM
SB  - IM
MH  - Animals
MH  - Coronary Disease/*diagnosis/*physiopathology
MH  - Coronary Vessels/*physiopathology
MH  - Diabetes Mellitus, Experimental/diagnosis/physiopathology
MH  - Diabetic Angiopathies/*diagnosis/*physiopathology
MH  - Genetic Therapy
MH  - Heart Failure/diagnosis/physiopathology
MH  - Heart Transplantation
MH  - Humans
MH  - Microvessels/*physiopathology
MH  - Myocardial Stunning/drug therapy/physiopathology
MH  - *Myocardium
MH  - Neovascularization, Physiologic/drug effects
MH  - Stroke Volume/drug effects/physiology
MH  - Swine
MH  - Thymosin/administration & dosage
MH  - Translational Medical Research
MH  - Vascular Endothelial Growth Factor A/administration & dosage
OTO - NOTNLM
OT  - angiogenesis
OT  - chronic myocardial ischemia
OT  - gene therapy
OT  - thymosin beta4
EDAT- 2017/01/14 06:00
MHDA- 2017/07/14 06:00
CRDT- 2017/01/14 06:00
PHST- 2016/07/27 00:00 [received]
PHST- 2016/10/10 00:00 [revised]
PHST- 2016/10/12 00:00 [accepted]
PHST- 2017/01/14 06:00 [entrez]
PHST- 2017/01/14 06:00 [pubmed]
PHST- 2017/07/14 06:00 [medline]
AID - S0735-1097(16)37030-9 [pii]
AID - 10.1016/j.jacc.2016.10.058 [doi]
PST - ppublish
SO  - J Am Coll Cardiol. 2017 Jan 17;69(2):131-143. doi: 10.1016/j.jacc.2016.10.058.