M. Ord

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.

Right ventricular global longitudinal strain is an independent predictor of right ventricular function: a multimodality study of cardiac magnetic resonance imaging, real time three-dimensional echocardiography and speckle tracking echocardiography.

Accurate assessment of right ventricular (RV) systolic function is important, as it is an established predictor of mortality in cardiac and respiratory diseases. We aimed to compare speckle tracking–derived longitudinal deformation measurements with traditional two‐dimensional (2D) echocardiographic parameters, as well as real time three‐dimensional echocardiography (RT3DE) and cardiac magnetic resonance imaging (CMR)‐derived RV volumes and ejection fraction (EF).

Usefulness of the Charlson co-morbidity index to predict outcomes in patients >60 years old with aortic stenosis during 18 years of follow-up.

The present study assessed the effect of age and co-morbidity on the outcomes of mild, moderate, and severe aortic stenosis (AS) in patients aged >60 years during 18 years of follow-up. The outcomes evaluated were hemodynamic progression, a composite cardiac mortality or aortic valve replacement (AVR) end point, and all-cause mortality. Consecutive Department of Veterans Affairs patients (aged >60 years) with AS were prospectively enrolled from 1988 to 1994 and followed until 2008 (n = 239). The baseline demographic, co-morbidity, and echocardiographic parameters were recorded. At enrollment, the mean age was 74 ± 6 years, and 78% were men. The annualized mean aortic valve gradient progression was 4 ± 4, 6 ± 5, and 10 ± 8 mm Hg for mild, moderate, and severe AS, respectively (p <0.001). During a mean follow-up of 8 ± 5 years, 206 deaths (52% cardiac) and 91 AVRs were recorded. The AVR/cardiac mortality event rate at 1, 5, and 10 years was 2%, 26%, and 50% for mild AS, 13%, 63%, and 69% for moderate AS, and 66%, 95%, and 95% for severe AS (p <0.001). During the study period, 132 patients developed severe AS. The survival rate at 1, 5, and 10 years was 60 ± 7%, 14 ± 5%, and 5 ± 3% with conservative management and 98 ± 2%, 82 ± 4%, and 50 ± 5% after AVR, respectively (p <0.001). The independent predictors of all-cause mortality were the age-adjusted Charlson co-morbidity index (hazard ratio 1.24, p <0.001), AVR (hazard ratio 0.40, p <0.001), and grade of left ventricular dysfunction (hazard ratio 1.36, p = 0.01). In conclusion, the prognostic significance of AS is determined by the hemodynamic severity, left ventricular function, and the presence of symptoms, in the context of age and co-morbidities. The age-adjusted Charlson co-morbidity index provides crucial prognostic information to guide the surgical risk/benefit discussions for patients with severe AS.

Age adjusted Charlson Co-morbidity Index is an independent predictor of mortality over long-term follow-up in infective endocarditis.

BACKGROUND Infective endocarditis (IE) is associated with high morbidity and mortality. The epidemiology of IE is changing, affecting more elderly patients with increased medical comorbidities. We aimed to assess the ability of the age adjusted Charlson Co-morbidity Index (ACCI) to predict early and late outcomes. METHODS Between 1998 and 2010, adult patients with definite IE according to the modified Duke criteria were identified. The primary outcome was in-hospital and all-cause mortality. The secondary outcome was predictors of the primary outcome incorporating ACCI. RESULTS 148 patients with IE were followed up for a mean of 3.8 ± 3 years. The mean age was 57 ± 17 years and 66% were male. In-hospital mortality and all-cause mortality were 24 and 47% respectively. Comorbid conditions included diabetes mellitus (DM) (21%); ischaemic heart disease (16%); heart failure (HF) (14%); renal failure (eGFR <60 ml/min/1.73 m(2)) (19%); and anaemia (64%). The most common causative organism was Staphylococcus aureus (53%). ACCI was >3 in 59% of patients. Cardiac surgery was performed in 45% of patients. On Cox regression analysis, ACCI >3 (HR=3.0 [1.5-6.0], p<0.002), new onset HF (HR=2.2 [1.3-3.6], p<0.003), anaemia (HR=1.8 [1.1-3.2], p=0.04) and age-per decade (HR=1.4 [1.1-1.7]. p=0.004) were independently associated with all-cause mortality. ACCI >3 was the strongest predictor of in-hospital mortality (OR=8.4 [2.8-24], p<0.001). Of the individual ACCI components, prior HF, DM with complications and metastatic disease were independent predictors of all-cause mortality. CONCLUSION In-hospital and all-cause mortality of IE remain high. An ACCI >3 was a strong predictor of mortality, in addition to age, new HF and anaemia.

Prevalence, predictors and evolution of echocardiographically defined cardiac abnormalities in adults with type 1 diabetes: an observational cohort study☆ , ☆☆ ,★

AIMS/HYPOTHESIS The aims of this observational study were to determine the prevalence and predictors of an abnormal echocardiogram in adults with type 1 diabetes, and to assess the evolution of changes in a subset of subjects. METHODS Cardiac function and structure were prospectively investigated by comprehensive transthoracic echocardiographic techniques in asymptomatic adults with type 1 diabetes seen in the ambulatory care setting. RESULTS We recruited 136 subjects (mean age 39 years, SD 14 years) with a median diabetes duration of 21 years [25(th), 75(th) interquartile range; 11, 29]. An abnormal echocardiogram was present in 29% of subjects; diastolic dysfunction in 69%, left ventricular hypertrophy in 38% and systolic dysfunction in 10%. The independent predictors of an abnormal echocardiogram were age, with a 9-fold increase in those ≥40 years (OR 9.40 [95% CI 2.68-33.04], P <0.0001), and increased body mass index (BMI), with a 17% increase in risk (P=0.04). A second echocardiogram was available in 65 subjects (3.8±1.7 years later). The results showed that one in five with a normal first study had developed an abnormal second study, mainly diastolic dysfunction, with age being the only independent predictor of progression (P=0.006). CONCLUSIONS/INTERPRETATION Subclinical echocardiographic abnormalities are common in asymptomatic type 1 diabetes adults, and changes are progressive. The addition of an echocardiogram to complication surveillance programs in those with type 1 diabetes aged ≥40 years may represent a cost-effective way to screen for, and aggressively treat, occult cardiac disease.

Beta blocker use in subjects with type 2 diabetes mellitus and systolic heart failure does not worsen glycaemic control

BackgroundThe prognostic benefits of beta-blockers (BB) in patients with systolic heart failure (SHF) are known but despite this, in patients with diabetes they are underutilized. The aim of this study was to assess the effect of beta-blockers (BB) on glycaemic control in patients with Type 2 Diabetes (T2DM) and systolic heart failure (SHF) stratified to beta-1 selective (Bisoprolol) vs. nonselective BB (Carvedilol).MethodsThis observational, cohort study was conducted in patients with T2DM and SHF attending an Australian tertiary teaching hospitals heart failure services. The primary endpoint was glycaemic control measured by glycosylated haemoglobin (HbA1c) at initiation and top dose of BB. Secondary endpoints included microalbuminuria, changes in lipid profile and estimated glomerular filtration rate (eGFR).Results125 patients were assessed. Both groups were well matched for gender, NYHA class and use of guideline validated heart failure and diabetic medications. The mean treatment duration was 1.9 ± 1.1 years with carvedilol and 1.4 ± 1.0 years with bisoprolol (p = ns). The carvedilol group achieved a reduction in HbA1c (7.8 ± 0.21% to 7.3 ± 0.17%, p = 0.02) whereas the bisoprolol group showed no change in HbA1c (7.0 ± 0.20% to 6.9 ± 0.23%, p = 0.92). There was no significant difference in the change in HbA1c from baseline to peak BB dose in the carvedilol group compared to the bisoprolol group. There was a similar deterioration in eGFR, but no significant changes in lipid profile or microalbuminuria in both groups (p = ns).ConclusionBB use did not worsen glycaemic control, lipid profile or albuminuria status in subjects with SHF and T2DM. Carvedilol significantly improved glycemic control in subjects with SHF and T2DM and this improvement was non significantly better than that obtained with bisoprolol. BBs should not be withheld from patients with T2DM and SHF.

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.

Validation of rapid automated tissue synchronization imaging for the assessment of cardiac dyssynchrony in sinus and non-sinus rhythm.

AIMS Cardiac resynchronization therapy is showing benefits for an increasing number of indications but fails to predict response in up to 20-30% of subjects. Echocardiographically assessed dyssynchrony has been proposed as a potential stratifier but current methods are time-consuming and suffer poor reproducibility, thus limiting their clinical utility. This study compared the accuracy, time efficiency, and reproducibility of automated tissue synchronization imaging (Auto TSI) vs. established manual tissue velocity imaging (TVI) techniques for the assessment of intra-ventricular dyssynchrony in sinus and non-sinus rhythm. METHODS AND RESULTS Fifty consecutive stable systolic heart failure patients on optimal guideline-based medical therapy underwent intra-ventricular dyssynchrony assessment [time to peak velocity (Ts), septal to lateral delay (SLD), and dyssynchrony index (DI)] with TVI and Auto TSI techniques, enabling the assessment of agreement, time efficiency, and reproducibility. Statistical analyses included Pearsons correlation, Bland-Altmans statistics, and coefficient of reproducibility. There was excellent agreement between Auto TSI and TVI for the measurement of Ts [r=0.92, P<0.001, limits of agreement (LOA): -27.3 to 56.5 ms], SLD (r=0.94, P<0.001, LOA: -41 to 49 ms), and DI (r=0.89, P<0.001, LOA: -12.2 to 12.6 ms) which persisted irrespective of cardiac rhythm [Ts: sinus (n=32) r=0.93, P<0.001; non-sinus (n=18) r=0.91, P<0.001]. Automated TSI was more time efficient (3±1 vs. 14±2 min, P<0.001) and demonstrated superior reproducibility: intra-observer (5.5 vs. 9.6%) and inter-observer variability (9.5 vs. 13.4%). CONCLUSION Automated TSI enables rapid, reproducible intra-ventricular dyssynchrony assessment and overcomes some of the limitations of conventional techniques in sinus and non-sinus rhythm.

Electrical remodelling and response following cardiac resynchronization therapy: A novel analysis of intracardiac electrogram using a quadripolar lead

Cardiac resynchronization therapy (CRT) improves morbidity and mortality in patients with heart failure. Although structural remodelling correlates with improved long‐term outcomes, the role of electrical remodelling is poorly understood. This study aimed to evaluate electrical remodelling following CRT using a quadripolar left ventricular (LV) lead and to correlate this with structural remodelling.

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.