Effects of Eprosartan on Diastolic Function and Neurohormones in Patients with Hypertension and Diastolic Dysfunction

To compare the effects of an angiotensin receptor blocker(ARB)-based regimen versus a non-ARB based regimen on diastolic function and neurohormones in patients with hypertension and diastolic dysfunction. 97 patients with a systolic blood pressure (SBP) a parts per thousand yen140 mmHg, a left ventricular ejection fraction > 0.50, and echocardiographic evidence of diastolic dysfunction were randomly assignment to open-label treatment with eprosartan (with other anti-hypertensives; n = 47) or other anti-hypertensives alone (n = 50). Echocardiography, including tissue Doppler imaging (TDI), and neurohormones were done at baseline and after 6 months. Mean age was 65 (+/- 10) years and 64% was female. During 6 months of treatment, SBP decreased from 157 +/- 16 to 145 +/- 18 mmHg in the eprosartan group and from 158 +/- 17 to 141 +/- 18 mmHg in the control group (both p <0.001; p = ns between groups). Diastolic function was unaffected in both groups and there was no correlation between changes in SBP and changes in mean TDI (r = -0.06; p = 0.58). Aldosterone levels decreased in the eprosartan group, but other neurohormones remained largely unchanged. Change in SBP was however related to the change in NT-proBNP (r = 0.26; p = 0.019). Lowering blood pressure, either with eprosartan or other anti-hypertensives in hypertensive patients with diastolic dysfunction did not change diastolic function after 6 months of treatment, but was associated with a decrease of NT-proBNP

Advanced glycation end-products, a pathophysiological pathway in the cardiorenal syndrome

The prevalence of heart failure (HF) is increasing. A distinction is made between diastolic HF (preserved left ventricular ejection fraction (LVEF)) and systolic HF (reduced LVEF). Advanced glycation end-products (AGEs) are crystallized proteins that accumulate during ageing, but are particularly increased in patients with diabetes mellitus and in patients with renal failure. Through the formation of collagen crosslinks, and by interaction with the AGE-receptor, which impairs calcium handling and increases fibrosis, AGE-accumulation has pathophysiologically been associated with the development of diastolic and renal dysfunction. Interestingly, diastolic dysfunction is a frequent finding in elderly patients, diabetic patients and in patients with renal failure. Taken together, this suggests that AGEs are related to the development and progression of diastolic HF and renal failure. In this review, the role of AGEs as a possible pathophysiological factor that link the development and progression of heart and renal failure, is discussed. Finally, the role of AGE intervention as a possible treatment in HF patients will be discussed

Advanced glycation endproducts in chronic heart failure

Advanced glycation endproducts (AGEs) have been proposed as factors involved in the development and progression of chronic heart failure (CHF). Cross-linking by AGEs results in vascular and myocardial stiffening, which are hallmarks in the pathogenesis of CHE Additionally, stimulation of receptors by AGEs may affect endothelial function and myocardial calcium uptake and may perpetuate coronary sclerosis in CHE CHF is common in conditions with AGE accumulation, such as diabetes and renal failure. This review describes in detail the interrelation of plasma AGEs, renal function, and the severity and prognosis in clinical CHF patients with mild to moderate loss of renal function. This association is compared with the relation between tissue AGE accumulation (marked by skin autofluorescence) and diastolic dysfunction in renal failure. The evidence reviewed here provides support for the assumed role of AGES in determining the severity and prognosis of CHF, but also highlights the differences in this relation between plasma and tissue AGEs and between patients with and without advanced renal failure. Ongoing clinical intervention trials to reduce AGE accumulation in patients with CHF may elucidate the causal role of AGEs in the development and course of CHE</p

Advanced glycation endproducts in chronic heart failure

Advanced glycation endproducts (AGEs) have been proposed as factors involved in the development and progression of chronic heart failure (CHF). Cross-linking by AGEs results in vascular and myocardial stiffening, which are hallmarks in the pathogenesis of CHE Additionally, stimulation of receptors by AGEs may affect endothelial function and myocardial calcium uptake and may perpetuate coronary sclerosis in CHE CHF is common in conditions with AGE accumulation, such as diabetes and renal failure. This review describes in detail the interrelation of plasma AGEs, renal function, and the severity and prognosis in clinical CHF patients with mild to moderate loss of renal function. This association is compared with the relation between tissue AGE accumulation (marked by skin autofluorescence) and diastolic dysfunction in renal failure. The evidence reviewed here provides support for the assumed role of AGES in determining the severity and prognosis of CHF, but also highlights the differences in this relation between plasma and tissue AGEs and between patients with and without advanced renal failure. Ongoing clinical intervention trials to reduce AGE accumulation in patients with CHF may elucidate the causal role of AGEs in the development and course of CH

Effects of alagebrium, an advanced glycation end-product breaker, in patients with chronic heart failure: study design and baseline characteristics of the BENEFICIAL trial

Previous small open label studies have shown that the advanced glycation end-product (AGE) breaker alagebrium may improve cardiac function in patients with chronic heart failure (HF). We report the design, methods and baseline characteristics of a double-blind, placebo-controlled, randomized trial evaluating the efficacy and safety of alagebrium (BENEFICIAL) in patients with HF and a left ventricular ejection fraction (LVEF) <0.45. Patients with NYHA II-IV stable HF for at least 3 months were eligible for this study. One hundred and two patients were included in the study and randomized to either 200 mg alagebrium twice daily or placebo for a period of 36 weeks. The mean age of patients was 60 +/- 11 years, 78% were male, and 17% were diabetic. Mean peak VO(2) was 21.7 +/- 5.9 mL/min/kg, mean LVEF was 0.32 +/- 0.09. Diastolic function was worse (mean early tissue diastolic velocity (E') 4.6 +/- 1.7 vs. 6.1 +/- 2.0 cm/s; P <0.001) in patients with LVEF <0.35 compared to patients with LVEF between 0.35 and 0.45. The BENEFICIAL study is a proof-of-concept study that will provide new data on the efficacy and safety of the AGE crosslink breaker alagebrium in systolic HF patients. EudraCT number of this trial is NCT00516646

Effects of alagebrium, an advanced glycation endproduct breaker, on exercise tolerance and cardiac function in patients with chronic heart failure

Aims Advanced glycation endproducts (AGEs) have been associated with the development and progression of chronic heart failure (CHF). Advanced glycation endproducts-crosslink breakers might be of benefit in HF, but only small-scale and uncontrolled data are available. Our aim was to conduct a prospective, randomized, double-blind, placebo-controlled study to examine the effects of the AGE-breaker alagebrium on exercise capacity and cardiac function in patients with HF. Methods and results One hundred and two patients with HF (78% male, aged 62 +/- 11 years), and a left ventricular ejection fraction (LVEF) Conclusion In the present proof-of-concept study, the AGE-breaker alagebrium did not improve exercise tolerance in patients with HF and systolic dysfunction, and no changes were observed in a number of secondary endpoints. The present data therefore do not support earlier data which suggested a beneficial effect of alagebrium in systolic HF. Clinical Trial Registration Information: NCT00516646 (http://clinicaltrials.gov

Functional and Hemodynamic Cardiac Determinants of Exercise Capacity in Patients With Systolic Heart Failure

Decreased exercise capacity is the main symptom in patients with heart failure (HF). We assessed the association among noninvasively determined maximal cardiac output at exercise, systolic and diastolic cardiac functions at rest, and peak oxygen uptake (pVO(2)) exercise capacity in patients with congestive HF. We studied 102 patients 62 +/- 11 years of age with New York Heart Association class II to IV stable HF and left ventricular (LV) ejection fraction <45%. All patients underwent echocardiography and a treadmill cardiopulmonary exercise test for evaluation of pVO(2) corrected for fat-free mass. During the cardiopulmonary exercise test, cardiac output was estimated noninvasively and continuously using Nexfin HD. Fat-free mass-corrected pVO(2) was associated in an univariate linear regression analysis with peak exercise cardiac index (CI) (beta 0.511, p <0.001), LV end-diastolic pressure estimates (peak early diastolic filling velocity/early diastolic tissue velocity [E/e'], beta -0.363, p = 0.001), and right ventricular function (tricuspid annular plane systolic excursion, beta 0.393, p <0.001). In multivariate analysis peak exercise CI (beta 0.380, p = 0.001), but not cardiac output or LV ejection fraction at rest, was an independent predictor of pVO(2). Other independent predictors of pVO(2) were E/e' (beta -0.276, p = 0.009) and tricuspid annular plane systolic excursion (beta 0.392, p <0.001), also when adjusted for age and gender. In conclusion, peak CI is an independent predictor of fat-free mass-corrected pVO(2) in patients with systolic HF. Of all echocardiographic parameters at rest, right ventricular function and E/e' were independently and significantly associated with pVO(2), whereas LV ejection fraction at rest was not. (C) 2012 Elsevier Inc. All rights reserved. (Am J Cardiol 2012;110:1336-1341

Skin-autofluorescence, a measure of tissue advanced glycation end-products (AGEs), is related to diastolic function in dialysis patients

Background: Diastolic dysfunction is a frequent cause of heart failure. particularly in dialysis patients. Advanced glycation endproducts (AGEs) are increased in dialysis patients and are suggested to play a role in the development of diastolic dysfunction. The aim of our study was to assess whether AGE accumulation in dialysis patients is related to the presence of diastolic dysfunction. Methods and Results: Data were analyzed from 43 dialysis patients, age 58 +/- 15 years. of whom 65% were male. Diastolic function was assessed using tissue velocity imaging (TVI) oil echocardiography. Tissue AGE accumulation was measured using a validated skin-autofluorescence (skin-AF) reader. Plasma N-epsilon-(carboxymethyl)lysine (CML) and N-epsilon-(carboxyethyl)lysine (CEL) were measured by stable-isotope-dilution tandem mass spectrometry. Plasma pentosidine was measured by high-performance liquid chromatography. Skin-AF correlated with mean E'(r = -0.51, P <.001), E/A ratio(r = -0.39, P = .014). and E/E'(r = 0.38, P = .019). Plasnia AGEs were not significantly associated with diastolic function. Multivariable linear regression analysis revealed that 54% of the variance of average E' was explained by age (P = .007) dialysis type (P = 0.016), and skin-AF (P = .013). Conclusions: Tissue AGEs measured as skin-AF. but not plasma AGE levels, were related to diastolic function in dialysis patients. Although this May Support the concept that tissue AGEs explain part of the increased prevalence of diastolic dysfunction in these patients, the ambiguous relation between plasma and tissue AGEs needs further exploring