Sharon Grant

Association of ACE2 Genetic Variants With Blood Pressure, Left Ventricular Mass, and Cardiac Function in Caucasians With Type 2 Diabetes

BACKGROUND Cardiovascular disease is common in diabetes, and is associated with activation of the renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE)2 is a recently described member of the RAS, and this study investigated whether ACE2 polymorphisms are associated with hypertension, left ventricular (LV) mass, and cardiac function in type 2 diabetes. METHODS Variants in ACE2 (rs1978124, rs2074192, rs4240157, rs4646156, rs4646188) were examined in 503 Caucasian subjects with type 2 diabetes. As ACE2 is located on the X chromosome, analyses were performed separately for men and women. Hypertension was defined by a history of hypertension, and/or antihypertensive medications or blood pressure (BP) >130/80 mm Hg. LV mass and systolic function (ejection fraction) were assessed by transthoracic echocardiography. RESULTS In men, hypertension was more prevalent with the ACE2 rs2074192 C allele (P = 0.023), rs4240157 G allele (P = 0.016) and rs4646188 T allele (P = 0.006). In men, the rs1978124 A allele was associated with a significantly lower ejection fraction compared to the G allele (62.3 ± 13.3 vs. 67.2 ± 10.9%, P = 0.002). This association remained significant after covariate adjustment for age, body mass index, hypertension, antihypertensive treatment, and BP. In women, the prevalence of hypertension was higher (P = 0.009) with the rs4240157 G allele, and the rs1978124 A allele was associated with significantly higher LV mass (P = 0.008). CONCLUSIONS In Caucasians with type 2 diabetes, genetic variation in ACE2 is associated with hypertension and reduced systolic function in men, and hypertension and increased LV mass in women.

The CTGF gene −945 G/C polymorphism is not associated with cardiac or kidney complications in subjects with type 2 diabetes

BackgroundConnective tissue growth factor (CTGF) has been implicated in the cardiac and kidney complications of type 2 diabetes, and the CTGF − 945 G/C polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF − 945 G/C promoter variant with cardiac complications (left ventricular (LV) hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in type 2 diabetes.MethodsThe CTGF − 945 G/C polymorphism (rs6918698) was examined in 495 Caucasian subjects with type 2 diabetes. Cardiac structure and function were assessed by transthoracic echocardiography. Kidney function was assessed using estimated glomerular filtration rate (eGFR) and albuminuria, and CKD defined as the presence of kidney damage (decreased kidney function (eGFR <60 ml/min/1.73 m2) or albuminuria).ResultsThe mean age ± SD of the cohort was 62 ± 14 years, with a body mass index (BMI) of 31 ± 6 kg/m2 and median diabetes duration of 11 years [25th, 75th interquartile range; 5, 18]. An abnormal echocardiogram was present in 73% of subjects; of these, 8% had LVH alone, 74% had diastolic dysfunction and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of subjects. There were no significant associations between the CTGF − 945 G/C polymorphism and echocardiographic parameters of LV mass or cardiac function, or kidney function both before and after adjustment for covariates of age, gender, BMI, blood pressure and hypertension. CTGF − 945 genotypes were not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, nor with CKD.ConclusionsIn Caucasians with type 2 diabetes, genetic variation in the CTGF − 945 G/C polymorphism is not associated with cardiac or kidney complications.

Effects of indomethacin on epidermal growth factor-induced renal responses in sheep.

1. The effects of indomethacin (an inhibitor of prostaglandin synthesis) on the renal responses to epidermal growth factor (EGF) were investigated in conscious sheep.

795 Are Advanced Glycation End Products Associated with Elevated Filling pressures in Diabetes

Background: Pre-clinical diastolic dysfunction is common in diabetes. The parameter, E/e[Combining Acute Accent] has emerged as a powerful variable in the assessment of diastolic function; E/e[Combining Acute Accent] is the ratio of the early mitral inflow (E) to septal mitral annular velocity (e[Combining Acute Accent]) in diastole, and is a continuous variable that correlates with increased left ventricular filling pressure. In retrospective studies in diabetes, E/e[Combining Acute Accent]>15 predicted mortality and heart failure (HF). As advanced glycation end products (AGEs) accelerate collagen crosslinking and contribute to myocardial stiffening, this study investigated if serum and urinary AGEs are associated with elevated filling pressures in diabetes. Methods: We recruited 137 patients with diabetes attending a diabetes clinic as part of a routine surveillance program. Patients with LVEF<50%, macrovascular disease and history of HF were excluded. A transthoracic echocardiogram was performed and elevated filling pressures defined as E/e[Combining Acute Accent]>15. N-carboxymethyllysine AGE-modified proteins were measured in serum and urine using an ELISA. Data are presented as mean ± SD for parametric data and geometric mean (25, 75th quartile) for non-parametric data. Results: Mean ± SD age was 61 ± 13y (58% male), BMI 31 ± 6 kg/m2, HbA1c 7.6 ± 1%, median diabetes duration 14(8,23)y and a low eGFR<60 ml/min/1.73m2 occurred in 14%. Table. No title available. An elevated E/e’ was associated with higher serum AGEs after correcting for age, gender, BMI, eGFR and diabetes duration (P = 0.004). Conclusions: This is the first study to show increased serum AGEs are associated with subclinical elevated filling pressures in patients with diabetes. Serum AGEs may be a useful biomarker of diastolic dysfunction and a potential therapeutic target for treatment with crosslink breakers.

932 ECHOCARDIOGRAPHIC CARDIAC DISEASE IN ADULTS WITH TYPE 1 DIABETES

Background: Patients with type 1 diabetes (T1DM) are at increased risk of cardiac death. This study assessed the prevalence and predictors of echocardiographically determined cardiac abnormalities in adults with T1DM. Methods: Cardiac structure and function were assessed by transthoracic echocardiography in 193 T1DM patients attending a Diabetes Clinic as part of a complication surveillance program. Predictors of an abnormal echocardiogram were identified using logistic regression analysis. Results: The mean (±SD) age was 44±15y and median diabetes duration, 18y [25th, 75th interquartile range; 9, 27]. An abnormal echocardiogram was present in 34%; of these 42% had left ventricular hypertrophy (LVH), 77% had diastolic dysfunction; and 6% had systolic ± diastolic dysfunction. Those with an abnormal echocardiogram were significantly older with a higher BMI, longer duration of diabetes, and were more likely to have hypertension, micro- and macro-vascular disease, and reduced creatinine clearance (all, p<0.05). The risk of an abnormal echocardiogram increased 13-fold in those aged >40y [odds ratio (OR) 13.6 (95% CIs, 2.7-68.5), p=0.002), 5-fold with diabetes duration >10y [OR 5.3 (1.1-24.8), p=0.03] and 3-fold if hypertension was present (p=0.047). Increased BMI (p=0.04) and reduced creatinine clearance (p=0.02) were also associated with the risk of an abnormal echocardiogram. Micro- and macro-vascular complications were not independent predictors of an abnormal echocardiogram. Conclusion: One third of patients with T1DM have an abnormal echocardiogram. It is known that LVH and systolic dysfunction are associated with adverse outcomes, but further studies are needed to determine the prognostic significance of diastolic dysfunction in this population.

925 ARE ADVANCED GLYCATION END PRODUCTS ASSOCIATED WITH MACROVASCULAR DISEASE IN TYPE 2 DIABETES MELLITUS

Background: Macrovascular disease remains a significant cause of morbidity and mortality in type 2 diabetes (T2DM). Advanced glycation end products (AGEs) are implicated in the pathogenesis and progression of diabetic renal complications, but their role in cardiovascular disease (CVD) is not clear. This study investigated whether AGEs are associated with macrovascular complications in T2DM. Methods: We recruited 182 patients with T2DM attending a Diabetes Clinic. Serum N-carboxymethyllysine AGE-modified proteins were measured using an ELISA. Macrovascular disease was defined as documented coronary artery disease, cerebrovascular disease or peripheral vascular disease (n = 70). Results: Patients with macrovascular disease were older (age 70±10 vs 65±11y), more likely to be male (76 vs 55%), with dyslipidaemia (97 vs 81%) and impaired renal function (eGFR<60 ml/min/1.73m2, 43 vs 21%)(mean±SD, all P<0.05), compared to those without macrovascular disease. Systolic blood pressure, BMI, HbA1c, diabetes duration and smoking were similar in the 2 groups. AGEs were elevated in patients with macrovascular disease (geometric mean [25th, 75th interquartile range] 3662 [2508, 4027] vs 3183 [2664, 4616] &mgr;mol/mol/lysine, P=0.036). In logistic regression analysis, age, male gender, dyslipidaemia and AGEs were associated with macrovascular disease. Serum AGEs were associated with a 7-fold increased risk of macrovascular disease (OR 7.3; 95%CI 1.1, 48.7; P=0.041). Conclusions: Elevated serum AGEs are strongly associated with macrovascular disease in T2DM. It is unknown if increased AGEs are a cause or a consequence of CVD, and whether drugs that target AGEs such as cross-link breakers represent a novel treatment strategy for CVD in diabetes.

603 THE CTGF GENE -945 G/C POLYMORPHISM IS NOT ASSOCIATED WITH ECHOCARDIOGRAPHICALLY DETERMINED CARDIAC DISEASE OR CHRONIC KIDNEY DISEASE IN TYPE 2 DIABETES

Background: Connective tissue growth factor (CTGF) mediates tissue fibrosis and has been implicated in the cardiac and kidney complications of type 2 diabetes (T2DM). The CTGF -945 G/C promoter polymorphism is associated with susceptibility to systemic sclerosis, a disease characterised by tissue fibrosis. This study investigated the association of the CTGF -945 G/C polymorphism with echocardiographically determined cardiac disease (left ventricular hypertrophy (LVH), diastolic and systolic dysfunction) and chronic kidney disease (CKD) in T2DM. Methods: The CTGF -945 G/C promoter polymorphism was genotyped in 495 Caucasian subjects with T2DM. Cardiac structure and function were assessed by transthoracic echocardiography. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73m2and/or the presence of albuminuria. Results: The mean age ± SD of the cohort was 62 ± 14 years; BMI was 31 ± 6 kg/m2, median diabetes duration was 11 years [25th, 75th interquartile range; 5, 18] and hypertension was present in 82% of the cohort. An abnormal echocardiogram was present in 73% of subjects; of these 8% had LVH alone, 74% had diastolic dysfunction, and 18% had systolic ± diastolic dysfunction. CKD was present in 42% of the study cohort. Both before and after adjustment for the covariates of age, gender, BMI, blood pressure and hypertension, the CTGF -945 G/C polymorphism was not associated with the cardiac complications of LVH, diastolic or systolic dysfunction, or with CKD. Conclusion: The CTGF -945 G/C polymorphism is not associated with echocardiographically determined cardiac disease or CKD in subjects with T2DM.

INTERACTION BETWEEN EPIDERMAL GROWTH FACTOR AND ARGININE VASOPRESSIN IN RENAL MEDULLARY MEMBRANES

1. Epidermal growth factor is a potent mitogen that causes natriuresis, diuresis and inhibition of arginine vasopressin‐induced water reabsorption.