Effect of acetylcholinesterase inhibition with pyridostigmine on cardiac parasympathetic function in sedentary adults and trained athletes.

Heart rate variability and postexercise heart rate recovery are used to assess cardiac parasympathetic tone in human studies, but in some cases these indexes appear to yield discordant information. We utilized pyridostigmine, an acetylcholinesterase inhibitor that selectively augments the parasympathetic efferent signal, to further characterize parasympathetic regulation of rest and postexercise heart rate. We measured time- and frequency-domain indexes of resting heart rate variability and postexercise heart rate recovery in 10 sedentary adults and 10 aerobically trained athletes after a single oral dose of pyridostigmine (30 mg) and matching placebo in randomized, double-blind, crossover trial. In sedentary adults, pyridostigmine decreased resting heart rate [from 66.7 (SD 12.6) to 58.1 beats/min (SD 7.6), P = 0.005 vs. placebo] and increased postexercise heart rate recovery at 1 min [from 40.7 (SD 10.9) to 45.1 beats/min (SD 8.8), P = 0.02 vs. placebo]. In trained athletes, pyridostigmine did not change resting heart rate or postexercise heart rate recovery when compared with placebo. Time- and frequency-domain indexes of resting heart rate variability did not differ after pyridostigmine versus placebo in either cohort and were not significantly associated with postexercise heart rate recovery in either cohort. The divergent effects of pyridostigmine on resting and postexercise measures of cardiac parasympathetic function in sedentary subjects confirm that these measures characterize distinct aspects of cardiac parasympathetic regulation. The lesser effect of pyridostigmine on either measure of cardiac parasympathetic tone in the trained athletes indicates that the enhanced parasympathetic tone associated with exercise training is at least partially attributable to adaptations in the efferent parasympathetic pathway.

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.

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.

Treatment of anemia in patients with chronic heart failure.

Anemia occurs frequently in chronic heart failure (CHF) patients and is associated with increased morbidity and mortality risk. Clinical trials with recombinant human erythropoietin in patients with chronic kidney disease and concomitant structural heart disease have demonstrated beneficial effects on ventricular remodeling but variable effects on clinical outcome. Preliminary clinical trials in patients with CHF demonstrate that erythropoietin therapy is well-tolerated and associated with short-term clinical benefits. The optimum target hemoglobin, erythropoietin dosing regimen, and role of iron supplementation in patients with CHF are not known. Darbepoetin alfa is a glycosylated derivative of erythropoietin with a prolonged half-life that may allow less frequent dosing in CHF populations. Additional studies are needed to determine the safety and efficacy of long-term erythropoietic therapy in CHF patients.

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.