The role of advanced glycation end-products and their receptor on outcome in heart failure patients with preserved and reduced ejection fraction.

INTRODUCTION: Advanced glycation end products (AGEs) are increased in patients with heart failure (HF). We studied the predictive value of plasma AGEs N(ε)-(carboxymethyl)lysine (CML), pentosidine, and the soluble form of its receptor (sRAGE) in a large HF population. METHODS: In 580 patients hospitalized with HF, plasma AGEs were measured before discharge when patients were clinically stable. Patients were followed for a period of 18 months. Primary end point was a composite of death and HF admissions. CML was determined by liquid chromatography mass spectrometry, pentosidine by high-performance liquid chromatography and sRAGE by sequential sandwich immunoassay. RESULTS: Mean age was 71 ± 11 years, 62% were men, and mean left ventricular ejection fraction was 0.32 ± 0.14. At baseline, mean CML level was 2.16 ± 0.73 µmol/L, median pentosidine was 0.043 (0.030-0.074) µmol/L, and median sRAGE level was 2.92 (1.90-4.59) ng/mL. CML and pentosidine levels were independently related to the composite end-point (HR, 1.20 per SD; 95% CI,1.05-1.37; P = .01 and HR, 1.15 per SD; 95% CI, 1.00-1.31; P = .045, respectively) and HF hospitalization (HR, 1.27 per SD; 95% CI, 1.10-1.48; P = .001 and HR, 1.27 per SD; 95% CI, 1.10-1.47; P = .001, respectively). Furthermore, CML levels were independently related to increased mortality (P = .006). Whereas sRAGE levels were univariately predictive for outcome, in multivariate models sRAGE did not reach statistical significance. DISCUSSION: In HF patients, both CML and pentosidine predict HF hospitalization and the combined primary end-point (mortality or HF-hospitalization), whereas sRAGE did not predict events. In addition, CML was significantly and independently associated with a higher risk for mortality.

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.

Effects of eprosartan on diastolic function and neurohormones in patients with hypertension and diastolic dysfunction.

OBJECTIVE: 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. METHODS: 97 patients with a systolic blood pressure (SBP) > or =140 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. RESULTS: 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). CONCLUSION: 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.

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 end-products (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) on 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). Plasma 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.

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 CHF. Additionally, stimulation of receptors by AGEs may affect endothelial function and myocardial calcium uptake and may perpetuate coronary sclerosis in CHF. 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 CHF.

Advanced glycation end-products (AGEs) and heart failure: pathophysiology and clinical implications.

Advanced glycation end-products (AGEs) are molecules formed during a non-enzymatic reaction between proteins and sugar residues, called the Maillard reaction. AGEs accumulate in the human body with age, and accumulation is accelerated in the presence of diabetes mellitus. In patients with diabetes, AGE accumulation is associated with the development of cardiac dysfunction. Enhanced AGE accumulation is not restricted to patients with diabetes, but can also occur in renal failure, enhanced states of oxidative stress, and by an increased intake of AGEs. Several lines of evidence suggest that AGEs are related to the development and progression of heart failure in non-diabetic patients as well. Preliminary small intervention studies with AGE cross-link breakers in heart failure patients have shown promising results. In this review, the role of AGEs in the development of heart failure and the role of AGE intervention as a possible treatment for heart failure are discussed.

Accumulation of advanced glycation end products, measured as skin autofluorescence, in renal disease.

Advanced glycation end products (AGEs) accumulate during renal failure and dialysis. Kidney transplantation is thought to reverse this accumulation by restoring renal function. Using a noninvasive and validated autofluorescence reader, we evaluated AGE levels in 285 transplant recipients (mean age, 52 years; range, 41 to 60 years), 32 dialysis patients (mean age, 56 years; range, 43 to 65 years), and 231 normal control subjects (mean age, 51 years; range, 40 to 65 years). Measurements in transplant recipients were performed for a mean of 73 months (range, 32 to 143 months) after transplantation. Dialysis patients were on dialysis therapy for a mean of 42 months (range, 17 to 107 months). Fluorescence was significantly increased in dialysis patients compared with normal control subjects (2.8 vs. 2.0 arbitrary units [a.u.], P < .0001). Although fluorescence levels were significantly decreased in transplant recipients compared with dialysis patients (2.5 vs. 2.8 a.u., P < .0001), fluorescence in transplant recipients was higher than in controls (2.5 vs. 2.0 a.u., P < .0001). In transplant recipients, fluorescence correlated positively with the duration of dialysis prior to transplantation (R = 0.21, P < .0001), and negatively with creatinine clearance (R = -0.34, P < .0001). No correlation was found between time after transplantation and fluorescence in transplant recipients (R = -0.10, P = .10). Fluorescence in dialysis patients was positively correlated with duration of dialysis (R = 0.36, P = .042). Our results, like those of others, suggest that kidney transplantation does not fully correct increased AGE levels found in dialysis patients. The increased AGE levels in kidney transplant recipients cannot be explained by the differences in renal function alone. The availability of a simple, noninvasive method (AGE-Reader) to measure AGE accumulation may be used to monitor AGE accumulation in a clinical setting as well as in a study setting.

Advanced glycation end products in kidney transplant patients: a putative role in the development of chronic renal transplant dysfunction.

Chronic renal transplant dysfunction is one of the leading causes of graft failure in kidney transplantation. A complex interplay of both alloantigen-related and alloantigen-unrelated risk factors is believed to underlie its development. We propose that advanced glycation end products (AGEs) are involved in the development of chronic renal transplant dysfunction. AGE formation is associated with different alloantigen-unrelated risk factors for chronic renal transplant dysfunction, such as recipient age, diabetes, proteinuria, hypertension, and hyperlipidemia. In vitro studies have shown that AGEs induce the expression of various mediators associated with chronic renal transplant dysfunction. Furthermore, AGE-induced renal damage has been found in multiple experimental studies. This renal damage shows similarity to the damage found in chronic renal transplant dysfunction. Together, several lines of evidence support a role of AGEs in the development of chronic renal transplant dysfunction and suggest that preventive therapy with AGE inhibitors may be helpful in preserving renal function in transplant recipients.

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.

Tissue advanced glycation end products are associated with diastolic function and aerobic exercise capacity in diabetic heart failure patients.

AIMS: Advanced glycation end products (AGEs) are increased in patients with diabetes and are associated with diastolic dysfunction through the formation of collagen crosslinks in the heart. The association among AGEs, diastolic function, and aerobic capacity in heart failure (HF) patients with and without diabetes is, however, unknown. We therefore studied the association among tissue AGEs, diastolic function, and aerobic capacity in patients with HF with or without diabetes. METHODS AND RESULTS: In chronic HF patients (with and without left ventricular systolic dysfunction), tissue AGEs [skin autofluorescence (AF)], diastolic function (echocardiographic mean E' and E/E'), and aerobic capacity [peak oxygen uptake (VO(2)) on cardiopulmonary exercise testing] were obtained. A total of 49 diabetics and 156 non-diabetics were included. Diabetics were older and had more cardiovascular risk factors, but left ventricular ejection fractions (LVEF) were similar. Tissue AGEs were higher in diabetics compared with non-diabetics (2.8 ± 0.8 vs. 2.3 ± 0.7 a.u.; P < 0.001). Furthermore, there was a correlation between tissue AGEs and mean E' (r = -0.30; P < 0.001, after adjustment for age, r = -0.21; P = 0.004). Aerobic capacity was significantly lower in diabetic patients with HF (peak VO(2): 17.4 ± 5.1 vs. 21.7 ± 6.1 mL/min/kg; P = 0.001), even after adjustment for age and LVEF. Peak VO(2) was related to skin AF (P = 0.03), independent of age, diabetes, LVEF, and New York Heart Association functional class. CONCLUSION: Patients with diabetes and HF have similar LVEF but poorer exercise capacity compared with non-diabetic HF patients. Our data suggest that these findings might be explained by the observed association among tissue AGE levels, diastolic function, and exercise capacity.

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) ≤0.45, were randomized to either 200 mg alagebrium twice daily or placebo. After 36 weeks, the primary efficacy end-point peak VO(2) had changed by (mean ± SEM) -2.1 ± 0.5 mL/min/kg in alagebrium vs. -0.5 ± 0.7 mL/min/kg in placebo-treated patients (P= 0.06). No significant changes were observed in a number of secondary end-points, including diastolic function (mean E': P= 0.32; E/E': P= 0.81), systolic function (LVEF: P= 0.43), AGE accumulation (skin-autofluorescence: P= 0.42), N-terminal pro brain natriuretic peptide, P= 0.20); New York Heart Association functional class (P= 0.73), patient global assessment (P= 0.32), physicians global assessment (P= 0.76), and the Minnesota Living with Heart Failure Questionnaire score (P= 0.38). Overall alagebrium was reasonably well tolerated. 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).

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

AIMS: 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)

Advanced glycation end-products, anti-hypertensive treatment and diastolic function in patients with hypertension and diastolic dysfunction.

AIMS: To investigate the relationship between advanced glycation end-products (AGEs) and diastolic function and the response to blood pressure treatment in patients with hypertension and diastolic dysfunction. METHODS AND RESULTS: Data were analysed from 97 patients (aged 65 +/- 10 years, 36% male) who were randomly assigned to 6 months open-label treatment with either eprosartan on top of other anti-hypertensive drugs (n = 47) or other anti-hypertensive drugs alone (n = 50). Tissue AGE accumulation was measured using a validated skin-autofluorescence (skin-AF) reader (n = 26). Plasma N(epsilon)-(carboxymethyl)lysine (CML), N(epsilon)-(carboxyethyl)lysine (CEL), and pentosidine were measured by LC-MS/MS and HPLC. Diastolic function was assessed using echocardiography. Blood pressure was reduced from 157/91 to 145/84 mmHg (P < 0.001) in the eprosartan group and from 158/91 to 141/83 mmHg (P < 0.001) in the control group. No effect of eprosartan was found on AGE levels. In patients with baseline skin-AF < median, E/A ratio (P = 0.04) and the mean peak early-diastolic filling velocity (E') improved (P = 0.001). In contrast, in patients with skin-AF levels > median, E/A ratio (P = 0.84) and mean E' (P = 0.32) remained unchanged. CONCLUSION: Although eprosartan did not decrease levels of AGEs, patients with lower skin-AF at baseline showed a larger improvement in diastolic function in response to either anti-hypertensive treatment compared with patients with higher skin-AF.

Skin-autofluorescence is an independent predictor of graft loss in renal transplant recipients.

BACKGROUND: Skin-autofluorescence (skin-AF) noninvasively measures the tissue accumulation of advanced glycation end products (AGEs). AGEs are nephrotoxic and potential effectors of cardiovascular mortality. We investigated whether skin-AF predicted graft loss after kidney transplantation. METHODS: A total of 302 renal transplant recipients were enrolled at a median time of 6.1 (2.6-12.1) years after transplantation and were subsequently followed up for first occurrence of graft loss (i.e., graft failure or all-cause mortality) for 5.2 (4.6-5.4) years. The association of baseline skin-AF with graft loss was investigated with univariable and multivariable Cox-regression and receiver-operator-characteristic curve analyses. RESULTS: Baseline skin-AF was 2.7+/-0.8 arbitrary units. Skin-AF predicted graft loss in a univariable Cox regression analysis (Hazard ratios 2.40 [1.75-3.29], P<0.001) and in a multivariable model (Hazard ratios 1.83 [1.22-2.75], P=0.003), adjusted for other identified risk-factors, including patient age, creatinine clearance, protein excretion, high sensitivity C-reactive protein (hsCRP), and human leukocyte antigen-DR mismatching. The area under the receiver-operator-characteristic curve for skin-AF as predictor of graft loss was significantly different from 0.5. Skin-AF was also a significant predictor of graft failure and mortality as separate end points. CONCLUSIONS: We conclude that skin-AF is an independent predictor of graft loss in kidney transplant recipients. Although skin-AF is not a direct measurement for AGEs, we believe that our results do support the hypothesis that accumulation of AGEs in renal transplant recipients contributes to the development of graft loss.

Clinical and prognostic value of advanced glycation end-products in chronic heart failure.

AIMS: Advanced glycation end-products (AGEs) have been proposed as a novel factor involved in the development and progression of chronic heart failure (CHF). We aimed to determine whether plasma levels of N(epsilon)-(carboxymethyl)lysine (CML) and N(epsilon)-(carboxyethyl)lysine (CEL), two well-known AGEs, are related to the severity and prognosis of CHF. METHODS AND RESULTS: A total of 102 CHF patients, aged 58 +/- 12 years, with an average left ventricular ejection fraction of 28 +/- 9% were followed for 1.7 (1.2-1.9) years. NYHA functional class and NT-pro-BNP were used as estimates of the severity of CHF. CML and CEL were determined by LC-MS/MS. CML levels were associated with NYHA functional class (P < 0.001) and NT-pro-BNP levels (P < 0.001). Survival analysis for the combined end-point of death, heart transplantation, ischaemic cardiovascular event, and hospitalization for heart failure revealed that CML levels predicted outcome, even after adjustment for age, gender, aetiology of CHF, identified risk modifiers, and several known predictors of outcome in CHF. The predictive value of CML subsided after correction for renal function. CEL was not associated with the severity or prognosis of CHF. CONCLUSION: Plasma AGEs, in particular CML levels, are related to the severity and prognosis of CHF. The fact that the relation between CML and prognosis subsided after correction for renal function may suggest that AGE accumulation in renal failure explains part of the prognostic value of renal function in CHF. However, further investigation is warranted to exclude the possibility that CML is just an innocent marker of renal function.

Risk factors for chronic transplant dysfunction and cardiovascular disease are related to accumulation of advanced glycation end-products in renal transplant recipients.

BACKGROUND: Accumulation of advanced glycation end-products (AGEs) has been implicated in the pathogenesis of chronic transplant dysfunction and cardiovascular disease in renal transplant recipients. We aimed to investigate which factors are associated with tissue AGE accumulation in renal transplant recipients. METHODS: The AGE accumulation was assessed using a validated skin-autofluorescence reader (AFR) in 285 consecutive renal transplant recipients (57% male, aged 50+/-12 years) visiting the outpatient clinic at a median (interquartile range) time of 73 (32-143) months after transplantation. Furthermore, various transplant- and recipient-related factors of interest were collected. RESULTS: Average skin-autofluorescence of lower arm and leg was 2.7+/-0.8 a.u. Skin-autofluorescence was positively determined by recipient age, systolic blood pressure, smoking, high-sensitivity C-reactive protein, duration of pre-transplant dialysis, and negatively by plasma vitamin C levels, creatinine clearance at baseline, and change in creatinine clearance since one year after transplantation in linear multivariate regression analysis. Together, these factors explained 41% of the variance of skin-autofluorescence. CONCLUSIONS: Skin-autofluorescence was associated with several risk factors for cardiovascular disease and chronic renal transplant dysfunction. These results are in line with the hypothesis that AGEs play a role in the pathogenesis of these conditions in renal transplant recipients. Prospective studies are required to investigate whether the AFR can be used as a simple, non-invasive tool to identify and monitor patients at risk for chronic renal transplant dysfunction and cardiovascular disease.

Skin autofluorescence, a measure of cumulative metabolic stress and advanced glycation end products, predicts mortality in hemodialysis patients.

Tissue advanced glycation end products (AGE) are a measure of cumulative metabolic stress and trigger cytokines driven inflammatory reactions. AGE are thought to contribute to the chronic complications of diabetes and ESRD. Tissue autofluorescence is related to the accumulation of AGE. Therefore, skin autofluorescence (AF) may provide prognostic information on mortality in hemodialysis (HD) patients. Skin AF was measured noninvasively with an AF reader at baseline in 109 HD patients. Overall and cardiovascular mortality was monitored prospectively during a period of 3 yr. The AF reader was validated against AGE contents in skin biopsies from 29 dialysis patients. Forty-two of the 109 (38.5%) HD patients died. Cox regression analysis showed that AF was an independent predictor of overall and cardiovascular mortality (for overall mortality odds ratio [OR] 3.9), as were pre-existing cardiovascular disease (CVD; OR 3.1), C-reactive protein (OR 1.1), and serum albumin (OR 0.3). Multivariate analysis revealed that 65% of the variance in AF could be attributed to the independent effects of age, dialysis and renal failure duration, presence of diabetes, triglycerides levels, and C-reactive protein. AF was also independently linked to the presence of CVD at baseline (OR 8.8; P < 0.001). AF correlated with collagen-linked fluorescence (r = 0.71, P < 0.001), pentosidine (r = 0.75, P < 0.001), and carboxy(m)ethyllysine (both r = 0.45, P < 0.01). Skin AF is a strong and independent predictor of mortality in ESRD. This supports a role for AGE as a contributor to mortality and CVD and warrants interventions specifically aimed at AGE accumulation.