Diabetic patients are at high risk of a range of comorbid complications, including cardiovascular disease (CVD). The increased risk of cardiovascular events seen in patients with type 2 diabetes is associated with a cluster of risk factors for cardiovascular and metabolic disorders that tend to coexists in these patients. Despite successful implementation of evidence based strategies, many individuals are not identified as high risk before their first event and others continue to experience cardiovascular events despite optimal management. While much of this risk is attributable to the presence of conventional risk factors, such as hyperglycemia, hyperlipidemia, hypertension, a substantial burden of this risk remains unexplained. Inflammatory mediators and growth factors are increasingly recognized as playing important roles in the development of atherosclerosis. Therefore the overall objective of this proposal focuses on performing longitudinal assessment to define the role and contribution of a novel biomarker, connective tissue growth factor (CTGF), in the initiation/ progression of macrovascular and microvascular disease in subjects with type 2 diabetes and to determine whether increases in CTGF in the presence of microvascular disease will predict development of macrovascular disease. Our preliminary findings, based on cross-sectional data generated from a cohort of type 2 diabetic patients, suggest that the occurrence of cardiovascular events is independently linked to elevations in CTGF level. Our results demonstrate that diabetic patients with a prior history of myocardial infarction (MI) or coronary artery disease (CAD) have significantly higher levels of plasma CTGF than patients who have not had a prior cardiovascular event. We also uncovered a strong association between circulating levels of plasma CTGF and retinopathy ETDRS scores as well as albumin excretion rate (AER) in these type 2 diabetic subjects. In addition, our findings demonstrate that CTGF expression is induced in aorta of ApoE-/- knockout mice with atherosclerosis compared to control mice. Therefore, based on the preliminary data we generated, we hypothesize that higher levels of circulating CTGF reflect ongoing vascular damage from hypertension, endothelial dysfunction and inflammation, and that elevated CTGF levels will predict greater risk for future cardiovascular events and progressive retinopathy and nephropathy. To test our hypothesis we propose the following specific aims: 1) Determine whether plasma CTGF levels predict future cardiovascular events and progressive retinopathy and nephropathy in individuals with type 2 diabetes. 2) Determine the role and contribution of CTGF to the initiation and progression of diabetic vascular disease. The proposed studies should establish CTGF as a pathologically-important risk factor for diabetic vascular disease that will form the basis for defining new targets for interventional therapy.

Public Health Relevance

Diabetes is associated with a number of metabolic and inflammatory risk factors that contribute to the development of micro- and macrovascular complications. The risk factors and mechanisms that contribute to the development of diabetic complications are not adequately defined. The longitudinal studies proposed in this application will provide a unique opportunity to identify new risk markers that predict development and progression of macrovascular disease in type 2 diabetic patients and will form the basis for new therapeutic approaches to prevent diabetic complications.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Clinical and Integrative Cardiovascular Sciences Study Section (CICS)
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Maric-Bilkan, Christine
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Medical University of South Carolina
Internal Medicine/Medicine
Schools of Medicine
United States
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Hunt, Kelly J; Jaffa, Miran A; Garrett, Sara M et al. (2018) Plasma Connective Tissue Growth Factor (CTGF/CCN2) Levels Predict Myocardial Infarction in the Veterans Affairs Diabetes Trial (VADT) Cohort. Diabetes Care 41:840-846
Jaffa, Miran A; Gebregziabher, Mulugeta; Garrett, Sara M et al. (2018) Analysis of longitudinal semicontinuous data using marginalized two-part model. J Transl Med 16:301
Nokkari, Amaly; Abou-El-Hassan, Hadi; Mechref, Yehia et al. (2018) Implication of the Kallikrein-Kinin system in neurological disorders: Quest for potential biomarkers and mechanisms. Prog Neurobiol 165-167:26-50
Jaffa, Miran A; Luttrell, Deirdre; Schmaier, Alvin H et al. (2016) Plasma Prekallikrein Is Associated With Carotid Intima-Media Thickness in Type 1 Diabetes. Diabetes 65:498-502
Jaffa, Miran A; Jaffa, Ayad A (2016) Joint Modeling of Covariates and Censoring Process Assuming Non-Constant Dropout Hazard. Stat Methods Appt 25:251-267
Jaffa, Miran A; Gebregziabher, Mulugeta; Luttrell, Deirdre K et al. (2016) Multivariate Generalized Linear Mixed Models With Random Intercepts To Analyze Cardiovascular Risk Markers in Type-1 Diabetic Patients. J Appl Stat 43:1447-1464
Wilson, Parker C; Fitzgibbon, Wayne R; Garrett, Sara M et al. (2015) Inhibition of Sphingosine Kinase 1 Ameliorates Angiotensin II-Induced Hypertension and Inhibits Transmembrane Calcium Entry via Store-Operated Calcium Channel. Mol Endocrinol 29:896-908
Nokkari, Amaly; Mouhieddine, Tarek H; Itani, Muhieddine M et al. (2015) Characterization of the Kallikrein-Kinin System Post Chemical Neuronal Injury: An In Vitro Biochemical and Neuroproteomics Assessment. PLoS One 10:e0128601
Jaffa, Miran A; Gebregziabher, Mulugeta; Jaffa, Ayad A (2015) Analysis of multivariate longitudinal kidney function outcomes using generalized linear mixed models. J Transl Med 13:192
Abou Msallem, J; Chalhoub, H; Al-Hariri, M et al. (2015) Mechanisms of bradykinin-induced expression of connective tissue growth factor and nephrin in podocytes. Am J Physiol Renal Physiol 309:F980-90

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