Zhiqian Gao

Influence of Duration of Diabetes, Glycemic Control, and Traditional Cardiovascular Risk Factors on Early Atherosclerotic Vascular Changes in Adolescents and Young Adults with Type 2 Diabetes Mellitus

BACKGROUND Carotid intima-media thickness (IMT) provides a mechanism for detecting early atherosclerosis. Little information is available concerning carotid IMT and the progression of atherosclerosis in adolescents and young adults with type 2 diabetes mellitus. OBJECTIVE We sought to determine the factors that contribute to early changes in carotid IMT in youth with type 2 diabetes mellitus and to identify any predictors of increased carotid IMT. METHODS Demographic, anthropometric, laboratory data and carotid imaging were obtained in 129 youth of mixed ethnicity, ages 10-23 yr. Associations of carotid IMT outcomes and risk variables were analyzed by regression analysis. Logistic regression was performed to elucidate independent determinants that predict a worse carotid IMT. RESULTS Carotid IMT increased with higher glycosylated hemoglobin (HbA1c) levels and longer duration of diabetes. Regression modeling showed that HbA1c and duration of diabetes in the presence of traditional cardiovascular risk factors (male sex, LDL cholesterol, and blood pressure) were independent determinants of carotid IMT. Logistic regression analysis demonstrated that each 1% increase in HbA1c or each year increase in duration of type 2 diabetes mellitus is associated with approximately 30% increased odds of a thicker carotid IMT. CONCLUSIONS Poorer glycemic control and longer disease duration have independent adverse effects on carotid IMT in youth with type 2 diabetes mellitus. These adverse effects appear to be more prominent in males. Developing effective strategies to improve blood glucose control in youth with type 2 diabetes mellitus is essential to prevent or limit the development and progression of atherosclerotic cardiovascular disease.

Myocardial Fibrosis Burden Predicts Left Ventricular Ejection Fraction and Is Associated With Age and Steroid Treatment Duration in Duchenne Muscular Dystrophy

Background Patients with Duchenne muscular dystrophy exhibit progressive cardiac and skeletal muscle dysfunction. Based on prior data, cardiac dysfunction in Duchenne muscular dystrophy patients may be influenced by myocardial fibrosis and steroid therapy. We examined the longitudinal relationship of myocardial fibrosis and ventricular dysfunction using cardiac magnetic resonance in a large Duchenne muscular dystrophy cohort. Methods and Results We reviewed 465 serial cardiac magnetic resonance studies (98 Duchenne muscular dystrophy patients with ≥4 cardiac magnetic resonance studies) for left ventricular ejection fraction (LVEF) and presence of late gadolinium enhancement (LGE), a marker for myocardial fibrosis. LVEF was modeled by examining LGE status, myocardial fibrosis burden (as assessed by the number of LGE‐positive left ventricular segments), patient age, and steroid treatment duration. An age‐only model demonstrated that LVEF declined 0.58±0.10% per year. In patients with both LGE‐negative and LGE‐positive studies (n=51), LVEF did not decline significantly over time if LGE was absent but declined 2.2±0.31% per year when LGE was present. Univariate modeling showed significant associations between LVEF and steroid treatment duration, presence of LGE, and number of LGE‐positive left ventricular segments; multivariate modeling showed that LVEF declined by 0.93±0.09% for each LGE‐positive left ventricular segment, whereas age and steroid treatment duration were not significant. The number of LGE‐positive left ventricular segments increased with age, and longer steroid treatment duration was associated with lower age‐related increases. Conclusion Progressive myocardial fibrosis, as detected by LGE, was strongly correlated with the LVEF decline in Duchenne muscular dystrophy patients. Longer steroid treatment duration was associated with a lower age‐related increase in myocardial fibrosis burden.

Cross-Sectional and Longitudinal Assessment of Aortic Root Dilation and Valvular Anomalies in Hypermobile and Classic Ehlers-Danlos Syndrome

OBJECTIVES To delineate the prevalence of cardiac findings in hypermobile and classic Ehlers-Danlos syndrome and provide longitudinal analysis of aortic root growth. STUDY DESIGN A retrospective chart review was conducted, and data were analyzed for cross-sectional prevalence of aortic dilation and valvular anomalies. The clinical implications of aortic root growth were determined by assessment of progression of aortic root measurements over time and clinical symptoms. RESULTS Patients whose first echocardiogram was obtained in late childhood or adulthood were less likely to have aortic dilation (P < .002) than those whose first echocardiogram was obtained in early childhood. Longitudinally, seven individuals had dilated aortas before age 14, and only one individual continued to show dilation after age 14 (P = .0143). No patient with a normal aortic root in childhood had development of dilation in adulthood. Fifteen of the 252 patients (6.0%) had mitral valve prolapse (MVP), although only one patient (0.4%) had MVP that was mild to moderate. CONCLUSIONS Although aortic root size and MVP are increased in patients with these types of Ehlers-Danlos syndrome, they tend to be of little clinical consequence. Echocardiography may still be warranted as part of cardiovascular assessment, but decreased frequency of screening is recommended especially in symptom-free adults.

Prediabetes: The Effects on Arterial Thickness and Stiffness in Obese Youth

OBJECTIVE Adults with prediabetes are at increased risk to develop cardiovascular disease. Whether prediabetes in adolescents is associated with early markers of cardiovascular disease is not known. We sought to 1) compare the cardiovascular risk profiles among adolescents and young adults with prediabetes with those with normal glucose tolerance and 2) determine whether prediabetes is independently associated with noninvasive measures of arterial thickness and stiffness. RESEARCH DESIGN AND METHODS We studied 102 obese youth with prediabetes and 139 obese youth with normal glucose tolerance in a cross-sectional study. Prediabetes or at increased diabetes risk was diagnosed by a fasting blood glucose level of ≥100 to 125 mg/dL, 2-hour oral glucose tolerance test value of ≥140 to 199 mg/dL, or a hemoglobin A1c (HbA1c) value of ≥5.7% to 6.4%. Arterial thickness and stiffness were measured by carotid intima-media thickness (IMT), augmentation index, pulse wave velocity, and brachial distensibility (BrachD). RESULTS Nearly 50% of youth were diagnosed with prediabetes by HbA1c. Youth with prediabetes had worse metabolic profiles with higher BMI z score, systolic blood pressure, and fasting insulin; increased carotid IMT; and lower BrachD compared with normal glucose-tolerant youth (P < .05). Multivariate regression analysis found prediabetes was a significant determinant of internal carotid IMT and BrachD (P < .05). After excluding youth diagnosed by HbA1c, the prediabetes group was borderline significant for internal carotid IMT (.1 > P ≥ .05) only. CONCLUSIONS Youth with prediabetes have worse cardiometabolic risk factors and evidence of increased arterial thickness and stiffness. Interventions to prevent prediabetes are crucial to reduce the development of early arterial disease.

Racial differences in arterial stiffness among adolescents and young adults with type 2 diabetes

Shah AS, Dolan LM, Gao Z, Kimball TR, Urbina EM. Racial differences in arterial stiffness among adolescents and young adults with type 2 diabetes.

Clustering of Risk Factors: A Simple Method of Detecting Cardiovascular Disease in Youth

OBJECTIVE: Cardiovascular risk assessment is an accepted practice in adults and correlates with early changes in carotid structure and function. Its clinical use in pediatrics is less common. We sought to determine whether a simple method of clustering cardiovascular risks could detect early atherosclerotic changes in youth. In addition, we compared risk clustering with the accepted Patholobiological Determinants of Atherosclerosis in Youth score to assess its utility for predicting early vascular disease. PATIENTS AND METHODS: We collected demographic, anthropometric, laboratory, and vascular measures in a cross-sectional study. The study population (n = 474; mean age: 18 years) was divided into low-risk (0–1) or high-risk (≥2) groups on the basis of the number of cardiovascular risk factors present at evaluation. Group differences and vascular outcomes were compared. General linear models were used to compare clustering cardiovascular risks with the Patholobiological Determinants of Atherosclerosis in Youth score. RESULTS: The high-risk group had higher vascular thickness and stiffness compared with the low-risk group (P < .05). Regression models found that clustering cardiovascular risks is associated with abnormal vascular structure and function after adjustment for age, race, and gender. The Patholobiological Determinants of Atherosclerosis in Youth score also is associated with abnormal vascular structure and function but with lower R2 values (P < .05). CONCLUSIONS: Cardiovascular risk clustering is a reliable tool for assessing abnormal vascular function. Its simplicity, compared with the Patholobiological Determinants of Atherosclerosis in Youth score, provides an advantageous tool for the practicing clinician to identify those youth who are at higher risk for early cardiovascular disease.

Dystrophin Genotype–Cardiac Phenotype Correlations in Duchenne and Becker Muscular Dystrophies Using Cardiac Magnetic Resonance Imaging

Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.

Adiposity has no direct effect on carotid intima-media thickness in adolescents and young adults: Use of structural equation modeling to elucidate indirect & direct pathways

BACKGROUND Carotid intima-media thickness (cIMT) is associated with CV events in adults. Thicker cIMT is found in youth with CV risk factors including obesity. Which risk factors have the most effect upon cIMT in youth and whether obesity has direct or indirect effects is not known. We used structural equation modeling to elucidate direct and indirect pathways through which obesity and other risk factors were associated with cIMT. METHODS We collected demographics, anthropometrics and laboratory data on 784 subjects age 10-24 years (mean 18.0 ± 3.3 years). Common, bulb and internal carotid cIMT were measured by ultrasound. Multivariable regression analysis was performed to assess independent determinants of cIMT. Analyses were repeated with structural equation modeling to determine direct and indirect effects. RESULTS Multivariable regression models explained 11%-22% of variation of cIMT. Age, sex and systolic blood pressure (BP) z-score were significant determinants of all cIMT segments. Body mass index (BMI) z-score, race, presence of type 2 diabetes mellitus (T2DM), hemoglobin A1c (HbA1c) and non-HDL were significant for some segments (all p = 0.05). The largest direct effect on cIMT was age (0.312) followed by BP (0.228), Blood glucose control (0.108) and non-HDL (0.134). BMI only had a significant indirect effect through blood glucose control, BP & non-HDL. High sensitivity C-reactive protein (CRP) had a small indirect effect through blood glucose control (all p = 0.05). CONCLUSIONS Age and BP are the major factors with direct effect on cIMT. Glucose and non-HDL were also important in this cohort with a high prevalence of T2DM. BMI only has indirect effects, through other risk factors. Traditional CV risk factors have important direct effects on cIMT in the young, but adiposity exerts its influence only through other CV risk factors.

Assessing endothelial dysfunction in adolescents and young adults with type 1 diabetes mellitus using a non-invasive heat stimulus

Microvascular dysfunction is a key event in the development of atherosclerosis, which predates the clinical manifestations of vascular disease including stroke and myocardial infarction. Dysfunction of the microvasculature can be measured as a decreased microperfusion in response to heat.

Endothelial Function and Arterial Stiffness Relate to Functional Outcomes in Adolescent and Young Adult Fontan Survivors

Background Fontan survivors demonstrate diminished vascular function and functional outcomes, but the relationships between these measures have not been established. Methods and Results We performed a cross‐sectional study of 60 Fontan survivors (52% male) with a mean age of 13.9±4.1 years and mean Fontan duration of 9.9±4.2 years. Multimodality assessment of endothelial function (reactive hyperemia index and flow‐mediated dilation) and arterial stiffness (augmentation index and baseline pulse amplitude) was performed with peripheral arterial tonometry and brachial flow‐mediated dilation. Aerobic capacity was determined using cardiopulmonary exercise testing; mean peak and percentage of predicted oxygen consumption (VO2) were 27.8±7.6 mL/kg per minute and 71.0±21.2%, respectively. Quality of life and physical activity were assessed using the Pediatric Quality of Life Inventory (PedsQL) and the Physical Activity Questionnaire. Vascular measures served as predictor variables, whereas functional measures served as outcome variables. In all cases, worse vascular measures were associated with worse functional measures. Flow‐mediated dilation–derived reactive hyperemia index (P<0.05) was positively associated with VO2 at anaerobic threshold. Peripheral arterial tonometry–derived baseline pulse amplitude (P<0.05) was negatively associated with the ratio of minute ventilation to carbon dioxide at anaerobic threshold. Flow‐mediated dilation–derived reactive hyperemia index and peripheral arterial tonometry–derived augmentation index (P<0.05) were positively and negatively associated, respectively, with peak VO2. Maximum flow‐mediated dilation (P<0.05) was positively associated with Physical Activity Questionnaire score. Peripheral arterial tonometry–derived augmentation index and baseline pulse amplitude (P<0.05) were negatively associated with parent‐reported PedsQL total and physical heath summary scores. Conclusions Increased arterial stiffness and decreased endothelial function are associated with lower aerobic capacity, physical activity, and quality of life in adolescent and young adult Fontan survivors. Understanding the cause–effect relationship between vascular function and functional outcomes is an important next step.