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BACKGROUND: Youth-onset type 2 diabetes (Y-T2D) is associated with increased risk for coronary atherosclerotic disease, but the timing of the earliest pathological features and evidence of cardiac endothelial dysfunction have not been evaluated in this population. Magnetic resonance imaging functional imaging may detect early and direct endothelial dysfunction in the absence of classical risk factors (severe hyperglycemia, hypertension, and hyperlipidemia). Using cardiac magnetic resonance imaging functional imaging, we evaluated peripheral and coronary endothelial artery structure and function in young adults with Y-T2D diagnosed ≤5 years compared with age-matched healthy peers. We isolated and characterized plasma-derived small extracellular vesicles and evaluated their effects on inflammatory and signaling biomarkers in healthy human coronary artery endothelial cells to validate the imaging findings. METHODS: Right coronary wall thickness, coronary artery flow-mediated dilation, and brachial artery flow-mediated dilation were measured at baseline and during isometric handgrip exercise using a 3.0T magnetic resonance imaging. Human coronary artery endothelial cells were treated with Y-T2D plasma-derived small extracellular vesicles. Protein expression was measured by Western blot analysis, oxidative stress was measured using the redox-sensitive probe dihydroethidium, and nitric oxide levels were measured by 4-amino-5-methylamino-2',7'-difluororescein diacetate. RESULTS: Y-T2D (n=20) had higher hemoglobin A1c and high-sensitivity C-reactive protein, but similar total and LDL (low-density lipoprotein)-cholesterol compared with healthy peers (n=16). Y-T2D had greater coronary wall thickness (1.33±0.13 versus 1.22±0.13 mm; P=0.04) and impaired endothelial function: coronary artery flow-mediated dilation (-3.1±15.5 versus 15.9±17.3%; P<0.01) and brachial artery flow-mediated dilation (6.7±14.7 versus 26.4±15.2%; P=0.001). Y-T2D plasma-derived small extracellular vesicles reduced phosphorylated endothelial nitric oxide synthase expression and nitric oxide levels, increased reactive oxygen species production, and elevated ICAM (intercellular adhesion molecule)-mediated inflammatory pathways in human coronary artery endothelial cells. CONCLUSIONS: Coronary and brachial endothelial dysfunction was evident in Y-T2D who were within 5 years of diagnosis and did not have severe hyperglycemia or dyslipidemia. Plasma-derived small extracellular vesicles induced markers of endothelial dysfunction, which corroborated accelerated subclinical coronary atherosclerosis as an early feature in Y-T2D. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02830308.
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Purpose To assess early subclinical coronary artery disease (CAD) burden and its relation to myocardial function in asymptomatic persons living with HIV (PLWH) who are at low risk for cardiovascular disease (CVD). Materials and Methods In this prospective, HIPAA-compliant study (ClinicalTrials.gov NCT01656564 and NCT01399385) conducted from April 2010 to May 2013, 74 adult PLWH without known CVD and 25 matched healthy controls underwent coronary MRI to measure coronary vessel wall thickness (VWT) and echocardiography to assess left ventricular function. Univariable and multivariable linear regression analyses were used to evaluate statistical associations. Results For PLWH, the mean age was 49 years ± 11 (SD), and the median Framingham risk score was 3.2 (IQR, 0.5-6.6); for matched healthy controls, the mean age was 46 years ± 8 and Framingham risk score was 2.3 (IQR, 0.6-6.1). PLWH demonstrated significantly greater coronary artery VWT than did controls (1.47 mm ± 0.22 vs 1.34 mm ± 0.18; P = .006) and a higher left ventricular mass index (LVMI) (77 ± 16 vs 70 ± 13; P = .04). Compared with controls, PLWH showed altered association between coronary artery VWT and both E/A (ratio of left ventricular-filling peak blood flow velocity in early diastole [E wave] to that in late diastole [A wave]) (P = .03) and LVMI (P = .04). In the PLWH subgroup analysis, coronary artery VWT increase was associated with lower E/A (P < .001) and higher LVMI (P = .03), indicating restricted diastolic function. In addition, didanosine exposure was associated with increased coronary artery VWT and decreased E/A ratio. Conclusion Asymptomatic low-CVD-risk PLWH demonstrated increased coronary artery VWT in association with impaired diastolic function, which may be amenable to follow-up studies of coronary pathogenesis to identify potential effects on the myocardium and risk modification strategies. Keywords: Coronary Vessel Wall Thickness, Diastolic Function, HIV, MRI, Echocardiography, Atherosclerosis Clinical trial registration nos. NCT01656564 and NCT01399385 Supplemental material is available for this article. © RSNA, 2024.