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CLINICAL RESEARCH

Relationship Between Increasing Body Weight, Insulin Resistance, Inflammation, Adipocytokine Leptin, and Coronary Circulatory Function

Thomas H. Schindler, MD^_*, Jerson Cardenas, MD^_*, John O. Prior, MD, PhD^_*, Alvaro D. Facta, MD^_*, Michael C. Kreissl, MD^_*, Xiao-Li Zhang, MD, PhD^_*, James Sayre, PhD^_*, Magnus Dahlbom, PhD^_*, Julio Licinio, MD and Heinrich R. Schelbert, MD, PhD^_*,_*

^_* Department of Molecular and Medical Pharmacology
Department of Psychiatry and Biobehavioral Science and Medicine/Endocrinology, David Geffen School of Medicine at UCLA, University of California at Los Angeles, Los Angeles, California

Manuscript received August 6, 2005; revised manuscript received September 30, 2005, accepted October 10, 2005.

^_* Reprint requests and correspondence: Dr. Heinrich H. Schelbert, Department of Molecular and Medical Pharmacology, David Geffen School of Medicine at UCLA, 10833 Le Conte Avenue, 23-120 CHS, Box 173517, Los Angeles, California 90095-1735 (Email: hschelbert{at}mednet.ucla.edu).

OBJECTIVES: We sought to evaluate effects of obesity, insulin resistance, and inflammation on coronary circulatory function and its relationship to leptin plasma levels.

BACKGROUND: It is not known whether obesity, commonly paralleled by insulin resistance, inflammation, and leptin, is independently associated with coronary circulatory dysfunction.

METHODS: Myocardial blood flow (MBF) responses to cold pressor test (CPT) and pharmacologic vasodilation was measured with positron emission tomography and ¹³N-ammonia. Study participants were divided into three groups based on their body mass index (BMI, kg/m²): control, 20 BMI <25 (n = 19); overweight, 25 BMI <30 (n = 21); and obese, BMI >30 (n = 32).

RESULTS: Body mass index was significantly correlated to the Homeostasis Model Assessment Index of insulin resistance and C-reactive protein levels (r = 0.60 and r = 0.47, p < 0.0001). Compared with control subjects, endothelium-related change in MBF (MBF) to CPT progressively declined in overweight and obese groups (0.32 ± 0.09 vs. 0.21 ± 0.19 and 0.07 ± 0.16 ml/g/min; p < 0.03 and p < 0.0001). The dipyridamole-induced total vasodilator capacity was significantly lower in obese than in control subjects (1.77 ± 0.51 vs. 2.04 ± 0.37 ml/g/min, p < 0.02). On multivariate analysis, BMI (p < 0.012) and age (p < 0.035) were significant independent predictors of MBF. Finally, only in the obese group leptin plasma levels significantly correlated with MBF (r = 0.37, p < 0.036).

CONCLUSIONS: Increased body weight is independently associated with abnormal coronary circulatory function that progresses from an impairment in endothelium-related coronary vasomotion in overweight individuals to an impairment of the total vasodilator capacity in obese individuals. The findings that elevated leptin plasma levels in patients that are obese might exert beneficial effects on the coronary endothelium to counterbalance the adverse effects of increases in body weight on coronary circulatory function should be tested.

Abbreviations and Acronyms   ANOVA = analysis of variance   BMI = body mass index   CAD = coronary artery disease   CPT = cold pressor test   CRP = C-reactive protein   CVR = coronary vascular resistance   ECG = electrocardiogram   HDL = high-density lipoprotein   HOMA = Homeostasis Model Assessment   LDL = low-density lipoprotein   MBF = myocardial blood flow   PET = positron emission tomography   ROS = reactive oxygen species   RPP = rate-pressure product   WHR = waist-hip ratio

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