The metabolic syndrome (MetS) is a cluster of cardiovascular risk factors that include obesity, insulin resistance, dyslipidemia, and hypertension, and is characterized by substantial inflammation. The increase in cardiovascular morbidity and mortality due to MetS precedes development of occlusive vascular lesions, and may conceivably be linked to direct impact on the myocardial microcirculation. Understanding the mechanisms by which MetS affects the heart would facilitate development of strategies for monitoring and management of target organ injury in MetS, but the nature and mechanisms of the cardiac effects of MetS have not been fully elucidated. Importantly, however, novel imaging techniques for studying the myocardial microcirculation, and swine models that mimic human cardiovascular physiology and pathophysiology, now provide a unique opportunity to serially assess the effects of MetS on myocardial microvascular function and structure. The hypothesis underlying this proposal is that MetS elicits myocardial microvascular rarefaction and remodeling, which are partly mediated by inflammation through monocyte chemoattractant protein-1 (MCP-1), and that consequent microvascular loss interferes with compensatory mechanisms meant to protect the heart from ischemic insults. To test this hypothesis we will utilize obese swine, a unique large animal model with a naturally occurring constellation of features of the MetS, and a combination of powerful imaging techniques both in vivo and in vitro. Multi-detector computed tomography (CT) will be used to quantify non-invasively myocardial regional perfusion, ischemia, and microvascular integrity, in conjunction with blood oxygen level- dependent magnetic resonance imaging assessment of myocardial oxygenation in response to increased cardiac demand. Micro-CT will then be used to reconstruct myocardial microvessels in situ, and assess their permeability and myocardial lipid accumulation. Furthermore, chronic blockade of MCP-1 will establish the role of inflammation and MCP-1 as a central mechanism underlying the cardiac effects of MetS.
Three Specific Aims will implement powerful and novel tools to test the following hypotheses: 1). MetS exacerbates myocardial microvascular dysfunction and loss by inducing myocardial inflammation, oxidative stress, and altered growth factor expression;2). Micro-vascular rarefaction and remodeling are functionally consequential and exacerbate myocardial ischemia during ischemic insult (like chronic coronary artery obstruction), but would be improved by a change of diet or administration of vascular endothelial growth factor;3). Inflammation and MCP-1 contribute to microvascular alterations induced by MetS. Elucidation of the mechanisms involved in early deleterious effects of MetS at the level of the myocardial microcirculation would advance our understanding of the pathogenesis of cardiac injury during the evolution of MetS, in a manner potentially applicable to humans. Indeed, these studies may shed light into and have a substantial ramification for designing preventive and diagnostic measures for management of MetS patients.

Public Health Relevance

Understanding the mechanisms by which the metabolic syndrome affects the heart, and developing strategies for its early identification, treatment, and prevention, present a major challenge for health care professionals facing an epidemic of overweight and sedentary lifestyle. The proposed studies could contribute towards our understanding of the cardiovascular effects of the metabolic syndrome, and towards development of imaging strategies for assessment of its evolution and mechanisms.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL077131-08
Application #
8403984
Study Section
Special Emphasis Panel (ZRG1-SBIB-P (04))
Program Officer
OH, Youngsuk
Project Start
2004-06-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2014-12-31
Support Year
8
Fiscal Year
2013
Total Cost
$356,022
Indirect Cost
$120,402
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Zhang, Xin; Gibson, Matthew E; Li, Zi-Lun et al. (2016) Autophagy Portends the Level of Cardiac Hypertrophy in Experimental Hypertensive Swine Model. Am J Hypertens 29:81-9
Collin, Julia; Gössl, Mario; Matsuo, Yoshiki et al. (2015) Osteogenic monocytes within the coronary circulation and their association with plaque vulnerability in patients with early atherosclerosis. Int J Cardiol 181:57-64
Sun, Dong; Eirin, Alfonso; Zhu, Xiang-Yang et al. (2015) Experimental coronary artery stenosis accelerates kidney damage in renovascular hypertensive swine. Kidney Int 87:719-27
Ebrahimi, Behzad; Rihal, Naveen; Woollard, John R et al. (2014) Assessment of renal artery stenosis using intravoxel incoherent motion diffusion-weighted magnetic resonance imaging analysis. Invest Radiol 49:640-6
Reriani, Martin; Flammer, Andreas J; Li, Jing et al. (2014) Microvascular endothelial dysfunction predicts the development of erectile dysfunction in men with coronary atherosclerosis without critical stenoses. Coron Artery Dis 25:552-7
Guddeti, Raviteja R; Matsuo, Yoshiki; Matsuzawa, Yasushi et al. (2014) Ischemic cardiomyopathy is associated with coronary plaque progression and higher event rate in patients after cardiac transplantation. J Am Heart Assoc 3:
Zhang, Xin; Li, Zi-Lun; Crane, John A et al. (2014) Valsartan regulates myocardial autophagy and mitochondrial turnover in experimental hypertension. Hypertension 64:87-93
Choi, Byoung-Joo; Matsuo, Yoshiki; Aoki, Tatsuo et al. (2014) Coronary endothelial dysfunction is associated with inflammation and vasa vasorum proliferation in patients with early atherosclerosis. Arterioscler Thromb Vasc Biol 34:2473-7
Eirin, Alfonso; Ebrahimi, Behzad; Zhang, Xin et al. (2014) Mitochondrial protection restores renal function in swine atherosclerotic renovascular disease. Cardiovasc Res 103:461-72
Lerman, Lilach O (2014) Imaging: BOLD assessment--effects of RAAS inhibition in CKD. Nat Rev Nephrol 10:247-8

Showing the most recent 10 out of 130 publications