Faculty Bibliography

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

Intravenous iron is commonly used in conjunction with erythropoietic agents to treat anemia in patients with chronic kidney disease. Iron has been proposed to promote oxidative stress and endothelial dysfunction in vascular tissues. We studied the acute effects of intravenous iron sucrose on homocysteine-induced endothelial dysfunction in the brachial artery of normal human subjects. In all, 40 healthy subjects received intravenous iron sucrose 100 mg or placebo over 30 min immediately before ingestion of 100 mg/kg of oral methionine in a double-blind, randomized study. Flow- and nitroglycerin-mediated dilation in the brachial artery, serum markers of iron stores, and homocysteine and nitrotyrosine levels were measured before and after study drug administration. Intravenous iron significantly increased transferrin saturation and non-transferrin-bound iron (NTBI) when compared with placebo. Flow-mediated dilation significantly decreased from baseline 1 h after administration of iron sucrose when compared with placebo (from 6.66+/-0.47 to 1.93+/-0.35% after iron sucrose vs from 6.00+/-0.40 to 5.61+/-0.46% after placebo, P<0.001), but did not differ between groups at 4 h (1.10+/-0.39 vs 1.33+/-0.51%). Nitroglycerin-mediated vasodilation, and homocysteine and 3-nitrotyrosine levels did not differ after administration of iron sucrose and placebo. Intravenous administration of iron sucrose in the setting of transient hyperhomocysteinemia induced by methionine ingestion significantly increased transferrin saturation and plasma levels of NTBI and significantly attenuated flow-mediated dilation in the brachial artery when compared with placebo. This potential mechanistic link between intravenous iron and endothelial dysfunction warrants further study of cardiovascular effects of intravenous iron in anemic chronic kidney disease populations

Erectile dysfunction (ED) is highly prevalent in patients with chronic heart failure (CHF) and is among the most distressing symptoms in this patient population. Although the safety and efficacy of phosphodiesterase 5 (PDE5) inhibitors in the management of ED have been evaluated in many cardiovascular disease populations, scant data are available in patients with CHF. In published studies, the short-term safety and efficacy of sildenafil in patients with stable mild-to-moderate CHF with ED appears to be comparable to that observed in other populations with cardiovascular disease. Evidence is not available on the effects of vardenafil or tadalafil in CHF. In addition to their benefits in the treatment of ED, preliminary studies suggest that PDE5 inhibitors enhance endothelial function in patients with CHF and have beneficial effects on pulmonary hemodynamics and exercise capacity in patients with pulmonary hypertension. Additional studies are needed to determine the therapeutic potential of this class of agents in these disease states

BACKGROUND: Iron is a pro-oxidant cofactor that may be linked to atherosclerosis progression. Reduction of body iron stores secondary to blood donation has been hypothesized to reduce coronary risk, but retrospective studies have yielded inconsistent findings. We sought to assess the effects of blood donation frequency on body iron stores and physiological and biochemical biomarkers of vascular function associated with atherosclerosis progression. METHODS AND RESULTS: Forty high-frequency voluntary blood donors (> or =8 donations in past 2 years) and 42 low-frequency blood donors (1 to 2 donations in past 2 years) aged 50 to 75 years were randomly selected from American Red Cross of Connecticut blood donor records. Flow-mediated dilation in the brachial artery, serum markers of iron stores, vascular inflammation and oxidative stress, and cardiac risk factors were assessed in all subjects. Serum ferritin was significantly decreased in high-frequency blood donors when compared with low-frequency blood donors (median values 17 versus 52 ng/mL; P<0.001), but hematocrit did not differ between groups. Flow-mediated dilation in the brachial artery was significantly greater in high-frequency donors when compared with low-frequency donors in univariate analysis (5.5+/-2.6% versus 3.8+/-1.6%; P=0.0003) and in multivariate analysis adjusting for cardiac risk factors and other potential confounders. Serum biomarkers of vascular inflammation did not differ between groups but 3-nitrotyrosine, a marker of oxidative stress, was decreased in high-frequency donors when compared with low-frequency donors. CONCLUSIONS: High-frequency blood donors had evidence of decreased body iron stores, decreased oxidative stress, and enhanced vascular function when compared with low-frequency donors. These findings support a potential link between blood donation and reduced cardiovascular risk that warrants further investigation in prospective outcome studies

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

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

Chronic heart failure (CHF) is an increasingly common cardiovascular disorder. Many patients who have CHF report moderate to marked decreases in the frequency of sexual activity, and up to 75% of patients report erectile dysfunction (ED). There are few controlled clinical data on the efficacy and safety of sildenafil citrate in men who have ED and CHF; thus, we evaluated these parameters in patients who had stable CHF. This was a double-blind, placebo-controlled, flexible-dose study. Men who had ED and stable CHF were randomized to receive sildenafil or placebo for 12 weeks. Primary outcomes were questions 3 and 4 of the International Index of Erectile Function. Secondary outcomes included the 5 functional domains of the International Index of Erectile Function, 2 global efficacy assessment questions, intercourse success rate, the Erectile Dysfunction Inventory of Treatment Satisfaction, and the Life Satisfaction Checklist. By week 12, patients who received sildenafil (n = 60) showed significant improvements on questions 3 and 4 compared with patients who received placebo (n = 72; p <0.002). Larger percentages of patients who received sildenafil reported improved erections (74%) and improved intercourse (68%) compared with patients who received placebo (18% and 16%, respectively). Intercourse success rates were 53% among patients who received sildenafil and 20% among those who received placebo. Patients who received sildenafil were highly satisfied with treatment and their sexual life compared with patients who received placebo. Sixty percent of patients who received sildenafil and 48% of patients who received placebo developed adverse events, including transient headache, facial flushing, respiratory tract infection, and asthenia. The incidence of events related to cardiovascular effects was low. Sildenafil is an effective and well-tolerated management of ED in men who have mild to moderate CHF