T. Lancefield

From gene to protein-experimental and clinical studies of ACE2 in blood pressure control and arterial hypertension.

Hypertension is a major risk factor for stroke, coronary events, heart and renal failure, and the renin-angiotensin system (RAS) plays a major role in its pathogenesis. Within the RAS, angiotensin converting enzyme (ACE) converts angiotensin (Ang) I into the vasoconstrictor Ang II. An “alternate” arm of the RAS now exists in which ACE2 counterbalances the effects of the classic RAS through degradation of Ang II, and generation of the vasodilator Ang 1-7. ACE2 is highly expressed in the heart, blood vessels, and kidney. The catalytically active ectodomain of ACE2 undergoes shedding, resulting in ACE2 in the circulation. The ACE2 gene maps to a quantitative trait locus on the X chromosome in three strains of genetically hypertensive rats, suggesting that ACE2 may be a candidate gene for hypertension. It is hypothesized that disruption of tissue ACE/ACE2 balance results in changes in blood pressure, with increased ACE2 expression protecting against increased blood pressure, and ACE2 deficiency contributing to hypertension. Experimental hypertension studies have measured ACE2 in either the heart or kidney and/or plasma, and have reported that deletion or inhibition of ACE2 leads to hypertension, whilst enhancing ACE2 protects against the development of hypertension, hence increasing ACE2 may be a therapeutic option for the management of high blood pressure in man. There have been relatively few studies of ACE2, either at the gene or the circulating level in patients with hypertension. Plasma ACE2 activity is low in healthy subjects, but elevated in patients with cardiovascular risk factors or cardiovascular disease. Genetic studies have investigated ACE2 gene polymorphisms with either hypertension or blood pressure, and have produced largely inconsistent findings. This review discusses the evidence regarding ACE2 in experimental hypertension models and the association between circulating ACE2 activity and ACE2 polymorphisms with blood pressure and arterial hypertension in man.

Impact of renal function in patients with multi-vessel coronary disease on long-term mortality following coronary artery bypass grafting compared with percutaneous coronary intervention

BACKGROUND Comorbidities, such as diabetes, affect revascularization strategy for coronary disease. We sought to determine if the degree of renal impairment affected long-term mortality after percutaneous coronary intervention (PCI) compared to coronary artery bypass grafting (CABG) in patients with multi-vessel coronary disease (MVD). METHODS AND RESULTS 8970 patients with MVD undergoing revascularization between 2004 and 2008, in two multi-center parallel PCI and CABG Australian registries were assigned to three groups based on their estimated glomerular filtration rate (eGFR)≥60 mL/min/1.73 m2 (n=1678:839), 30-59 mL/min/1.73 m2 (n=452:226) and <30 mL/min/1.73 m2 (n=74:37). We used 2:1 propensity matching to compare 3306 patients undergoing primary CABG versus PCI. Shock, myocardial infarction (MI)<24 h, previous CABG, valve surgery or PCI were exclusions. Long-term mortality (mean 3.1 years) was compared with Cox-proportional hazard-adjusted modeling. Observed long-term mortality rates (CABG vs. PCI) were 4.5% vs. 4.3% p=0.84, 12.8% vs. 17.3% p=0.12, and 23.0% vs. 40.5% p=0.05 in the three strata, respectively. In patients with eGFR≥60 mL/min/1.73 m2, long-term mortality between PCI and CABG (HR 0.99, 95% CI 0.65-1.49, p=0.95) was similar. However, amongst patients with eGFR 30-59 mL/min/1.73 m2, there was a significant mortality hazard with PCI (HR 2.00, 95% CI 1.32-3.04, p=0.001). In patients with eGFR<30 mL/min/1.73 m2, there was a trend for hazard with PCI (HR 1.66, 95% CI 0.80-3.46, p=0.17). CONCLUSION Long-term mortality in MVD patients with preserved renal function was very low and similar between PCI and CABG. However there was a long-term mortality hazard associated with PCI amongst patients with moderate renal impairment.

The Receptor for Advanced Glycation End Products (RAGE) Is Associated with Persistent Atrial Fibrillation

Objective Upregulation of the receptor for advanced glycation end products (RAGE) has been proposed as a pathophysiological mechanism underlying the development of atrial fibrillation (AF). We sought to investigate if soluble RAGE levels are associated with AF in Caucasian patients. Methods Patients (n = 587) were prospectively recruited and serum levels of soluble RAGE (sRAGE) and endogenous secretory RAGE (esRAGE) measured. The patients included 527 with sinus rhythm, 32 with persistent AF (duration >7 days, n = 32) and 28 with paroxysmal AF (duration <7 days, n = 28). Results Patients with AF were older and had a greater prevalence of heart failure than patients in sinus rhythm. Circulating RAGE levels were higher in patients with persistent AF [median sRAGE 1190 (724–2041) pg/ml and median esRAGE 452 (288–932) pg/ml] compared with paroxysmal AF [sRAGE 799 (583–1033) pg/ml and esRAGE 279 (201–433) pg/ml, p ≤ 0.01] or sinus rhythm [sRAGE 782 (576–1039) pg/ml and esRAGE 289 (192–412) pg/ml, p < 0.001]. In multivariable logistic regression analysis, independent predictors of persistent AF were age, heart failure, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% confidence interval (CI) 1.0–1.1, p = 0.001] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.1–1.4, p < 0.001]. Heart failure and age were the only independent predictors of paroxysmal AF. In AF patients, sRAGE [odds ratio 1.1 per 100 pg/ml, 95% CI 1.1–1.2, p = 0.007] and esRAGE [odds ratio 1.3 per 100 pg/ml, 95% CI 1.0–1.5, p = 0.017] independently predicted persistent compared with paroxysmal AF. Conclusions Soluble RAGE is elevated in Caucasian patients with AF, and both sRAGE and esRAGE predict the presence of persistent AF.

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.

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.