Interrelationship of Multiple Endothelial Dysfunction Biomarkers with Chronic Kidney Disease.

The interrelationship of multiple endothelial biomarkers and chronic kidney disease (CKD) has not been well studied. We measured asymmetric dimethylarginine (ADMA), L-arginine, soluble intercellular adhesion molecule-1 (sICAM-1), soluble vascular adhesion molecule-1 (sVCAM-1), soluble E-selectin (sE-selectin), von Willebrand factor (vWF), flow-mediated dilation (FMD), and nitroglycerin-induced dilation (NID) in 201 patients with CKD and 201 community-based controls without CKD. Multivariable analyses were used to examine the interrelationship of endothelial biomarkers with CKD. The multivariable-adjusted medians (interquartile ranges) were 0.54 (0.40, 0.75) in patients with CKD vs. 0.25 (0.22, 0.27) µmol /L in controls without CKD (p<0.0001 for group difference) for ADMA; 67.0 (49.6, 86.7) vs. 31.0 (27.7, 34.2) µmol/L (p<0.0001) for L-arginine; 230.0 (171.6, 278.6) vs. 223.9 (178.0, 270.6) ng/mL (p=0.55) for sICAM-1; 981.7 (782.6, 1216.8) vs. 633.2 (507.8, 764.3) ng/mL (p<0.0001) for sVCAM-1; 47.9 (35.0, 62.5) vs. 37.0 (28.9, 48.0) ng/mL (p=0.01) for sE-selectin; 1320 (1044, 1664) vs. 1083 (756, 1359) mU/mL (p=0.008) for vWF; 5.74 (3.29, 8.72) vs. 8.80 (6.50, 11.39)% (p=0.01) for FMD; and 15.2 (13.5, 16.9) vs. 19.1 (17.2, 21.0)% (p=0.0002) for NID, respectively. In addition, the severity of CKD was positively associated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF and inversely associated with FMD and NID. Furthermore, FMD and NID were significantly and inversely correlated with ADMA, L-arginine, sVCAM-1, sE-selectin, and vWF. In conclusion, these data indicate that multiple dysfunctions of the endothelium were present among patients with CKD. Interventional studies are warranted to test the effects of treatment of endothelial dysfunction on CKD.

Circulating adipocytokines and chronic kidney disease.

BACKGROUND: Adipokines have been associated with atherosclerotic heart disease, which shares many common risk factors with chronic kidney disease (CKD), but their relationship with CKD has not been well characterized. METHODS: We investigated the association of plasma leptin, resistin and adiponectin with CKD in 201 patients with CKD and 201 controls without. CKD was defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m(2) or presence of albuminuria. Quantile regression and logistic regression models were used to examine the association between adipokines and CKD adjusting for multiple confounding factors. RESULTS: Compared to controls, adjusted median leptin (38.2 vs. 17.2 ng/mL, p<0.0001) and adjusted mean resistin (16.2 vs 9.0 ng/mL, p<0.0001) were significantly higher in CKD cases. The multiple-adjusted odds ratio (95% confidence interval) of CKD comparing the highest tertile to the lower two tertiles was 2.3 (1.1, 4.9) for leptin and 12.7 (6.5, 24.6) for resistin. Median adiponectin was not significantly different in cases and controls, but the odds ratio comparing the highest tertile to the lower two tertiles was significant (1.9; 95% CI, 1.1, 3.6). In addition, higher leptin, resistin, and adiponectin were independently associated with lower eGFR and higher urinary albumin levels. CONCLUSIONS: These findings suggest that adipocytokines are independently and significantly associated with the risk and severity of CKD. Longitudinal studies are warranted to evaluate the prospective relationship of adipocytokines to the development and progression of CKD.

Exercise-induced increases in oxidized low-density lipoprotein are associated with adverse outcomes in chronic heart failure.

BACKGROUND: Oxidative stress is an important pathophysiologic feature in chronic heart failure (CHF) and may in part result from the inability to counteract acute surges of circulating oxidant products. Oxidized low-density lipoprotein (oxLDL) is an emerging prognostic marker in CHF. Accordingly, we investigated the effect of exercise-induced oxidative stress on circulating levels of oxLDL and its association with clinical outcomes in CHF. METHODS AND RESULTS: Plasma levels of oxLDL and low-density lipoprotein cholesterol (LDL-c) were measured at rest and after maximal exercise in 48 subjects with CHF and 12 healthy controls. Subjects with CHF had a higher baseline oxLDL (77.7 +/- 3.2 U/L vs 57.9 +/- 5.0 U/L, P = .01) and a higher baseline oxLDL/LDL-c ratio (0.87 +/- 0.04 vs 0.49 +/- 0.04, P < or = .001). Exercise induced an increase in oxLDL in subjects with CHF (77.7 +/- 3.2 U/L to 85.3 +/- 3.0 U/L, P < or = .001) but not in controls (57.9 +/- 5.0 to 61.4 +/- 5.5, P = .17). In 39 subjects for whom follow-up data were available, an increase in oxLDL of more than 11.0 U/L was associated with an increased risk to meet a combined end point of death and need for ventricular assist device or heart transplant during a 19-month follow-up period (hazard ratio 8.6; 95% confidence interval 1.0-73.8, P = .05); this remained significant when adjusted for peak oxygen consumption, left ventricular ejection fraction, New York Heart Association class, sex, and age (hazard ratio 46.6, 95% confidence interval 1.5-1438.1, P = .02). CONCLUSION: Plasma oxLDL and the oxLDL/LDL-c ratio are elevated in subjects with CHF. Whether assessment of oxLDL during maximal exercise allows early identification of subjects at highest risk for adverse outcomes should be systematically investigated.

Randomized, double-blind comparison of acute beta1-blockade with 50 mg metoprolol tartrate vs 25 mg carvedilol in normal subjects.

Differential efficacy of immediate-release metoprolol tartrate and carvedilol in the treatment of congestive heart failure remains a subject of ongoing debate. The degree of beta1-blockade can be assessed by percentage reduction of exercise heart rate. Twelve healthy subjects underwent symptom-limited cardiopulmonary exercise testing repeated weekly and 2 hours after randomized, double-blind administration of 50 mg metoprolol tartrate vs 25 mg carvedilol. Baseline heart rate, heart rate at 40% and 70% peak O2 consumption, and maximal exercise were significantly blunted more by metoprolol tartrate than by carvedilol (P<.05 for all). Peak O2 consumption was significantly reduced by metoprolol tartrate (P<.03) but not by carvedilol (P=.054). The change in O2 consumption was significantly correlated with the degree of beta1-blockade (r =0.45; P<.05). In healthy subjects, a higher degree of beta1-blockade is achieved with 50 mg metoprolol tartrate compared with 25 mg carvedilol.

Association of heart rate recovery and maximum oxygen consumption in patients with chronic congestive heart failure.

BACKGROUND: Peak oxygen consumption (peak VO2) is one of the strongest predictors of mortality in patients with congestive heart failure (CHF). In contrast to measurements of peak VO2, which requires analysis of expired gases, heart rate recovery, defined as maximum heart rate minus heart rate at 1 minute after exercise, is easily obtained. The current study was undertaken to determine the association between peak VO2 and heart rate recovery in patients with CHF. METHODS: Retrospective data on VO2 and heart rate recovery were analyzed in 296 patients with CHF secondary to left ventricular systolic dysfunction (left ventricular ejection fraction [LVEF] <50%) who had undergone cardiopulmonary exercise testing (CPET). Patients exercised on a treadmill using a graded work rate protocol with the work increasing to a symptom-limited maximum. Peak oxygen consumption was defined as the highest value of oxygen uptake attained in the final 20 seconds of exercise when the respiratory exchange ratio was >1.0. RESULTS: Heart rate recovery and peak VO2 correlated moderately (r = 0.47, p < 0.001). The degree of correlation was similar in patients receiving beta-blockers (r = 0.47, p < 0.001) and those not receiving beta-blockers (r = 0.49, p < 0.001). CONCLUSIONS: Although heart rate recovery and peak VO2 correlated moderately, from a clinical standpoint, this finding is probably not strong enough to use heart rate recovery in lieu of peak VO2. This modest correlation of two independent predictors of outcome may suggest their usefulness when combined in a multivariate score.

Comparison of metabolic vasodilation in response to exercise and ischemia and endothelium-dependent flow-mediated dilation in African-American versus non-African-American patients with chronic heart failure.

Race-related disparities in response to therapy and clinical outcomes have been reported in patients with chronic heart failure (HF). Vascular dysfunction is an important determinant of therapeutic response and clinical outcomes in chronic HF, but race-related differences of vasodilator responses in those with chronic HF have not been previously characterized. We assessed metabolic vasodilation in response to exercise and ischemia and endothelium-dependent flow-mediated dilation in conduit and resistance vessels with strain gauge venous occlusion plethysmography and high-resolution ultrasound imaging in the forearm circulation of 69 African-American and 188 non-African-American patients with chronic HF. African-American patients had a higher prevalence of hypertension than non-African-American patients (59% vs 35%, p = 0.001) and higher mean arterial pressures despite similar HF treatment (93 +/- 2 vs 89 +/- 1 mm Hg, p = 0.045). Forearm vascular resistance in African-American patients was higher than that of non-African-American patients at rest (22.3 +/- 1.8 vs 16.2 +/- 0.8 U, p <0.001), during exercise (4.7 +/- 0.3 vs 3.8 +/- 0.2 U, p = 0.03), and after ischemia (2.0 +/- 0.3 vs 1.5 +/- 0.1 U, p = 0.04). Endothelium-dependent flow-mediated vasodilation was significantly decreased in African-American compared with non-African-American patients in conduit vessels (brachial artery flow-mediated dilation 0.77 +/- 0.43% vs 1.86 +/- 0.24%, p = 0.03) and resistance vessels (post-ischemic forearm hyperemia 110 +/- 11 vs 145 +/- 10 ml/min/100 ml, p = 0.035). Estimates of differences in race-related vasoreactivity did not substantially change and remained at significant or borderline significant levels after adjustment for hypertension. Impaired vasodilation may contribute to differences in therapeutic response and clinical outcomes in African-American patients with chronic HF.

Vascular endothelial dysfunction and mortality risk in patients with chronic heart failure.

BACKGROUND: Endothelial function is known to be impaired in subjects with chronic heart failure (CHF), but the association between endothelial function and subsequent mortality risk in CHF has not been previously reported. METHODS AND RESULTS: Biomarkers of endothelial function in the systemic arterial circulation (flow-mediated dilation [FMD] in the brachial artery) and the pulmonary circulation (exhaled nitric oxide [NO] production during submaximal exercise) were prospectively assessed in 259 subjects with New York Heart Association class II-III CHF. In subjects with FMD measurements (n=149), there were 12 deaths and 5 urgent transplantations over a median follow-up period of 841 days. In subjects with exhaled NO production measurements (n=110), there were 18 deaths and 1 urgent transplantation over a median follow-up period of 396 days. Both decreased FMD and decreased exhaled NO production were associated with increased risk of death or urgent transplantation after adjustment for other known CHF prognostic factors (age, etiology of CHF, functional class, left ventricular ejection fraction) in Cox multivariate proportional-hazards models (adjusted hazard ratio [HR] estimate for a 1% decrease in FMD=1.20; 95% confidence interval [CI], 1.03 to 1.45; P=0.027; adjusted HR estimate for a 1-ppb/min decrease in exhaled NO production=1.31, 95% CI, 1.01 to 1.69, P=0.04). CONCLUSIONS: Endothelial dysfunction in CHF, as assessed by FMD in the brachial artery and exhaled NO production during submaximal exercise, is associated with an increased mortality risk in subjects with both ischemic and nonischemic CHF.

Inhibition of angiotensin-converting enzyme and phosphodiesterase type 5 improves endothelial function in heart failure.

ACE (angiotensin-converting enzyme) inhibitors and PDE5 (phosphodiesterase type 5) inhibitors have each been reported to improve endothelial function in cardiovascular disease patients, but the comparative and combined effects of these two classes have not been studied previously. We sought to characterize the acute effects of ramipril alone, sildenafil alone, or their combination on endothelial function in patients with CHF (chronic heart failure). CHF subjects (n=64) were randomized to receive placebo, 10 mg of ramipril alone, 50 mg of sildenafil alone or a combination of ramipril and sildenafil in a double-blind manner. FMD (flow-mediated dilation) of the brachial artery was determined by high-resolution ultrasound imaging before and at 1, 2 and 4 h after administration of the study drug. Ramipril alone increased FMD at 4 h compared with placebo (+2.3+/-1.3%, P=0.02). Sildenafil alone increased FMD at 1, 2 and 4 h compared with placebo (+3.9+/-1.4, +4.6+/-1.8 and +3.7+/-1.3% respectively, all P<0.02). Sildenafil in combination with ramipril increased FMD at 1, 2 and 4 h when compared with placebo (+3.5+/-1.5, +4.5+/-1.8 and +4.8+/-1.3% respectively, all P<0.03). Ramipril and sildenafil both acutely improved FMD in patients with CHF, with additive effects evident at 4 h during combination therapy. Therefore further work to characterize chronic effects of combined ACE and PDE5 inhibition on endothelial function are warranted.

Relation of unrecognized hypervolemia in chronic heart failure to clinical status, hemodynamics, and patient outcomes.

Clinically unrecognized intravascular volume overload may contribute to worsening symptoms and disease progression in patients with chronic heart failure (CHF). The present study was undertaken to prospectively compare measured blood volume status (determined by radiolabeled albumin technique) with clinical and hemodynamic characteristics and patient outcomes in 43 nonedematous ambulatory patients with CHF. Blood volume analysis demonstrated that 2 subjects (5%) were hypovolemic (mean deviation from normal values -20 +/- 6%), 13 subjects (30%) were normovolemic (mean deviation from normal values -1 +/- 1%), and 28 subjects (65%) were hypervolemic (mean deviation from normal values +30 +/- 3%). Physical findings of congestion were infrequent and not associated with blood volume status. Increased blood volume was associated with increased pulmonary capillary wedge pressure (p = 0.01) and greatly increased risk of death or urgent cardiac transplantation during a median follow-up of 719 days (1-year event rate 39% vs 0%, p <0.01 by log-rank test). Systolic blood pressure was significantly lower in hypervolemic patients than in those with normovolemia or hypovolemia (107 +/- 2 vs 119 +/- 2 mm Hg, p = 0.008), and hypotension was independently associated with increased risk of hypervolemia in multivariate analysis (odds ratio 2.64 for a 10-mm Hg decrease in systolic blood pressure, 95% confidence interval 1.13 to 6.19, p = 0.025). These findings demonstrate that clinically unrecognized hypervolemia is frequently present in nonedematous patients with CHF and is associated with increased cardiac filling pressures and worse patient outcomes.

Comparative effects of carvedilol and metoprolol on regional vascular responses to adrenergic stimuli in normal subjects and patients with chronic heart failure.

BACKGROUND: Adrenergic receptor blockers used in the treatment of heart failure have distinct receptor affinity profiles. We hypothesized that alpha-adrenergic-blocking effects of carvedilol would limit vasoconstriction in response to adrenergic stimuli when compared with metoprolol. METHODS AND RESULTS: Forearm vascular resistance responses to isometric handgrip and cold pressor test were determined by plethysmography before and during adrenergic receptor blockade in prospective randomized trials. Acute effects were assessed in a crossover trial in normal subjects (single dose of 25 mg carvedilol, 100 mg metoprolol tartrate, and placebo). Chronic effects (25 mg carvedilol BID versus 200 mg extended-release metoprolol succinate daily for 6 months) were assessed in a parallel group trial of chronic heart failure subjects. In normal subjects, carvedilol decreased forearm vascular resistance responses to adrenergic stimuli when compared with metoprolol and placebo (isometric handgrip -3.5 U for carvedilol versus -1.2 U for metoprolol and -2.2 U for placebo, P=0.15; cold pressor test 3.1+/-8.9 U for carvedilol versus 9.0+/-2.7 U for metoprolol and 8.2+/-5.8 U for placebo, P<0.05). In heart failure subjects, vasomotor responses to isometric handgrip and cold pressor test did not differ between treatment groups. CONCLUSIONS: Acute administration of carvedilol attenuates the vasoconstriction response to adrenergic stimuli when compared with placebo and metoprolol in normal subjects, whereas chronic administration of carvedilol does not attenuate the vasoconstrictor response to adrenergic stimuli when compared with metoprolol in heart failure subjects. These data suggest that long-term benefits of carvedilol in heart failure are not mediated by alpha-adrenergic blockade.

Hemodilution is common in patients with advanced heart failure.

BACKGROUND: Anemia frequently occurs in chronic heart failure (CHF) patients and is associated with a poor prognosis. A low hematocrit may result from an increased plasma volume (hemodilution) or from reduced red blood cell volume (true anemia). The prevalence and clinical outcome of CHF patients with hemodilution is unknown. METHODS AND RESULTS: The prevalence of anemia and its effect on outcome was examined in 196 patients with CHF. The prevalence of hemodilution was assessed in a subset of 37 ambulatory anemic patients with I131-tagged albumin to measure red blood cell and plasma volume. Clinical outcome was monitored. Sixty-one percent of the CHF patients were anemic. The prevalence of anemia increased from 33% in patients with New York Heart Association class II heart failure to 68% in class IV CHF patients. Survival was reduced in anemic patients compared with patients with a normal hematocrit (P<0.05). In the subset of 37 anemic patients, 17 patients (46%) had hemodilution and 20 patients (54%) had a true anemia. Nine patients with hemodilution died or underwent urgent transplant compared with 4 patients in the true anemia group (P<0.04). CONCLUSION: Hemodilution is common in CHF patients. Anemia is associated with a poor prognosis in CHF. Patients with hemodilution tend to do worse than patients with true anemia, which suggests that volume overload may be an important mechanism contributing to the poor outcome in anemic CHF patients.

Effect of erythropoietin on exercise capacity in patients with moderate to severe chronic heart failure.

BACKGROUND: Patients with chronic heart failure (CHF) are frequently anemic. An increase in hemoglobin could enhance exercise performance by increasing oxygen delivery. We investigated the effect of erythropoietin (EPO) on exercise performance in anemic patients with CHF. METHODS AND RESULTS: Twenty-six anemic patients aged 57+/-11 years were randomized to receive EPO (15 000 to 30 000 IU per week) or placebo for 3 months. Parameters measured at baseline and end therapy included blood parameters (hemoglobin, hematocrit, plasma volume), exercise parameters (peak oxygen consumption [VO2], exercise duration, 6-minute walk), muscle aerobic metabolism (half-time of VO2 and near infrared recovery), and forearm vasodilatory function. EPO was well tolerated by all patients. Twelve patients in the EPO group felt improvement versus 1 in the placebo group (P<0.05). There were significant increases in hemoglobin (11.0+/-0.5 to 14.3+/-1.0 g/dL, P<0.05), peak VO2 (11.0+/-1.8 to 12.7+/-2.8 mL. min(-1) x kg(-1), P<0.05) and exercise duration (590+/-107 to 657+/-119 s, P<0.004) in the EPO group but no significant changes in the control group. Resting and hyperemic forearm vascular resistance and indices of the rate of muscle oxidative capacity were unchanged in both groups. CONCLUSION: EPO significantly enhances exercise capacity in patients with CHF. One mechanism of improvement in VO2 is increased oxygen delivery from increased hemoglobin concentration.

Partial reversal of cachexia by beta-adrenergic receptor blocker therapy in patients with chronic heart failure.

BACKGROUND: Cachexia is a common problem in chronic heart failure (CHF) that may be partly mediated by activation of the sympathetic nervous system. The effects of beta-adrenergic receptor blocker (BB) therapy on body weight in cachectic and noncachectic subjects with CHF has not been previously reported. METHODS AND RESULTS: Body weight and plasma norepinephrine, leptin, and insulin levels were measured in 27 subjects with CHF before and after 6 months of beta-adrenergic receptor blockade with carvedilol or long-acting metoprolol. Before BB therapy, baseline weight, plasma leptin, and plasma insulin levels did not differ between cachectic and noncachectic subjects. Baseline plasma norepinephrine levels were increased in cachectic subjects when compared with noncachectic subjects (930+/-248 pg/mL versus 503+/-109 pg/mL, P=.063). After 6 months of BB therapy, subjects with baseline cachexia demonstrated significantly greater weight gain (+5.2+/-9.6 versus +0.8+/-5.0 kg, P=.027), greater increase in plasma leptin levels (+3.7+/-3.9 versus +1.2+/-4.3 ng/mL, P=.030), and greater decrease in plasma norepinephrine levels (-374+/-261 versus -41+/-122 pg/mL, P=.012) when compared with noncachectic subjects. CONCLUSIONS: Six months of BB therapy with carvedilol or long-acting metoprolol is associated with differential effects on body weight and hormonal levels in cachectic and noncachectic subjects with CHF. Further work is needed to determine the role the sympathetic nervous system in the pathogenesis of cachexia in patients with CHF.

Effect of dexrazoxane on homocysteine-induced endothelial dysfunction in normal subjects.

OBJECTIVE: Dexrazoxane is an antioxidant prodrug that on hydrolysis is converted into an intracellular iron chelator. We hypothesized that the antioxidant effects of dexrazoxane would prevent homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. METHODS AND RESULTS: Ten healthy volunteers completed a randomized, double-blind, crossover study. Plasma homocysteine levels and brachial artery endothelium-dependent (flow-mediated dilation [FMD]) and endothelium-independent (sublingual nitroglycerin) responses were measured before and 4 hours after ingestion of L-methionine (100 mg/kg), preceded by intravenous administration of dexrazoxane (500 mg/m2) or placebo over 30 minutes. After placebo, oral methionine increased plasma homocysteine (from 5.1+/-0.4 micromol/L at baseline to 14.2+/-1.3 micromol/L at 4 hours, P<0.001) and decreased FMD (from 3.8+/-0.7% at baseline to 1.2+/-0.5% at 4 hours, P=0.02). Dexrazoxane did not change homocysteine concentrations after methionine administration (14.9+/-1.1 micromol/L at 4 hours, P=0.29 versus placebo) but did completely abrogate the homocysteine-induced reduction in FMD (from 3.5+/-0.5% at baseline to 5.9+/-1.1% at 4 hours, P<0.01 versus placebo). Endothelium-independent responses to sublingual nitroglycerin did not differ after the administration of placebo and dexrazoxane. CONCLUSIONS: Administration of the novel antioxidant agent dexrazoxane prevents homocysteine-induced impairment of vascular endothelial function in the brachial artery of healthy subjects.