Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

Rabea Hinkel; Andrea Hoewe; Simone Renner; Judy Ng; Seungmin Lee; Katharina Klett; Veronika Kaczmarek; Alessandra Moretti; Karl Ludwig Laugwitz; Philipp Skroblin; Manuel Mayr; Hendrik Milting; Andreas Dendorfer; Bruno Reichart; Eckhard Wolf; Christian Kupatt

doi:10.1016/j.jacc.2016.10.058

Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

Rabea Hinkel, Andrea Hoewe, Simone Renner, Judy Ng, Seungmin Lee, Katharina Klett, Veronika Kaczmarek, Alessandra Moretti, Karl Ludwig Laugwitz, Philipp Skroblin, Manuel Mayr, Hendrik Milting, Andreas Dendorfer, Bruno Reichart, Eckhard Wolf, Christian Kupatt^*

^*Corresponding author for this work

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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.

Original language	English
Pages (from-to)	131-143
Number of pages	13
Journal	Journal of the American College of Cardiology
Volume	69
Issue number	2
Early online date	9 Jan 2017
DOIs	https://doi.org/10.1016/j.jacc.2016.10.058
Publication status	Published - 17 Jan 2017

Keywords

angiogenesis
chronic myocardial ischemia
gene therapy
thymosin β4

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jacc.2016.10.058

Diabetes Mellitus-induced Microvascular_HINKEL_Accepted12October2016_GREEN AAM (CC-BY-NC-ND)Accepted author manuscript, 5.15 MBLicence: CC BY-NC-ND

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Hinkel, R., Hoewe, A., Renner, S., Ng, J., Lee, S., Klett, K., Kaczmarek, V., Moretti, A., Laugwitz, K. L., Skroblin, P., Mayr, M., Milting, H., Dendorfer, A., Reichart, B., Wolf, E., & Kupatt, C. (2017). Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium. Journal of the American College of Cardiology, 69(2), 131-143. https://doi.org/10.1016/j.jacc.2016.10.058

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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. 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.",

keywords = "angiogenesis, chronic myocardial ischemia, gene therapy, thymosin β4",

author = "Rabea Hinkel and Andrea Hoewe and Simone Renner and Judy Ng and Seungmin Lee and Katharina Klett and Veronika Kaczmarek and Alessandra Moretti and Laugwitz, {Karl Ludwig} and Philipp Skroblin and Manuel Mayr and Hendrik Milting and Andreas Dendorfer and Bruno Reichart and Eckhard Wolf and Christian Kupatt",

year = "2017",

month = jan,

day = "17",

doi = "10.1016/j.jacc.2016.10.058",

language = "English",

volume = "69",

pages = "131--143",

journal = "Journal of the American College of Cardiology",

issn = "0735-1097",

publisher = "Elsevier USA",

number = "2",

}

Hinkel, R, Hoewe, A, Renner, S, Ng, J, Lee, S, Klett, K, Kaczmarek, V, Moretti, A, Laugwitz, KL, Skroblin, P , Mayr, M, Milting, H, Dendorfer, A, Reichart, B, Wolf, E & Kupatt, C 2017, 'Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium', Journal of the American College of Cardiology, vol. 69, no. 2, pp. 131-143. https://doi.org/10.1016/j.jacc.2016.10.058

TY - JOUR

T1 - Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

AU - Hinkel, Rabea

AU - Hoewe, Andrea

AU - Renner, Simone

AU - Ng, Judy

AU - Lee, Seungmin

AU - Klett, Katharina

AU - Kaczmarek, Veronika

AU - Moretti, Alessandra

AU - Laugwitz, Karl Ludwig

AU - Skroblin, Philipp

AU - Mayr, Manuel

AU - Milting, Hendrik

AU - Dendorfer, Andreas

AU - Reichart, Bruno

AU - Wolf, Eckhard

AU - Kupatt, Christian

PY - 2017/1/17

Y1 - 2017/1/17

N2 - 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.

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 × 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.

KW - angiogenesis

KW - chronic myocardial ischemia

KW - gene therapy

KW - thymosin β4

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U2 - 10.1016/j.jacc.2016.10.058

DO - 10.1016/j.jacc.2016.10.058

M3 - Article

SN - 0735-1097

VL - 69

SP - 131

EP - 143

JO - Journal of the American College of Cardiology

JF - Journal of the American College of Cardiology

IS - 2

ER -

Diabetes Mellitus–Induced Microvascular Destabilization in the Myocardium

Abstract

Keywords

UN SDGs

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