Sympathetic activation by sildenafil.

BACKGROUND: Sildenafil citrate is an effective and widely prescribed therapy for erectile dysfunction. Little is known about the effects of sildenafil on neural control of the circulation or about the effects of sildenafil on neurocirculatory stress responses. METHODS AND RESULTS: We studied 14 normal volunteers (age 32+/-7 years) who were randomized in a double-blind crossover fashion to receive a single oral dose of sildenafil 100 mg or placebo on 2 separate study days. Blood pressure, heart rate, forearm vascular resistance, muscle sympathetic nerve activity, and plasma catecholamines were measured at baseline and at 30 and 60 minutes after sildenafil and after placebo administration. The effects of sildenafil and placebo on neural and circulatory responses to stressful stimuli (sustained handgrip, maximal forearm ischemia, mental stress, and the cold pressor test) were also evaluated. Blood pressure, heart rate, and forearm vascular resistance after sildenafil and placebo were similar. However, muscle sympathetic nerve activity increased strikingly after sildenafil (by 141+/-26%, mean+/-SEM) compared with placebo (3+/-8%) (P=0.006); plasma norepinephrine levels also increased by 31+/-5% after sildenafil administration (P=0.004). Sympathetic nerve traffic during mental, physical, and cold stresses was 2- to 8-fold higher after sildenafil than with placebo (P<0.05). CONCLUSIONS: Sildenafil causes a marked increase in sympathetic activation, evident both at rest and during stressful stimuli. Sympathetic activation by sildenafil may have implications for understanding cardiovascular events associated with sildenafil use.

Independent association between plasma leptin levels and heart rate in heart transplant recipients.

BACKGROUND: Leptin, the protein product of the ob gene, has been linked to a faster heart rate in animal and human studies. The interaction between leptin and heart rate in the denervated heart is not known. Therefore, we studied the relationship between plasma leptin levels and heart rate in heart transplant recipients. METHODS AND RESULTS: We studied 32 male patients (mean age, 56.5+/-9.3 years; range, 41 to 74 years) after orthotopic heart transplantation. All subjects underwent a physical examination, anthropometric measurements, blood chemistry analysis, and office blood pressure measurements. A blood sample was collected from each subject while fasting. In univariate analysis, heart rate was related to leptin levels (r=0.47, P=0.007) but heart rate was not related to systolic or diastolic blood pressure, mean arterial pressure, body mass index, or catecholamines. Leptin levels were only strongly associated with heart rate and body mass index (r=0.73, P<0.0001). In multivariate analysis, heart rate was independently and positively associated with leptin levels (F=2.61, P=0.017). We also observed a strong, independent association between leptin levels and body mass index (F=5.8, P<0.00001). CONCLUSIONS: We show an independent association between leptin levels and heart rate in heart transplant recipients. We speculate that this may be due, in part, to a direct effect of leptin on heart rate, conceivably mediated through cardiac leptin receptors.

Impairment of endothelium-dependent vasodilation of resistance vessels in patients with obstructive sleep apnea.

BACKGROUND: Patients with obstructive sleep apnea (OSA) experience repetitive episodic hypoxemia with consequent sympathetic activation and marked blood pressure surges, each of which may impair endothelial function. We tested the hypothesis that patients with OSA have impaired endothelium-dependent vasodilation, even in the absence of overt cardiovascular disease. METHODS AND RESULTS: We studied 8 patients with OSA (age 44+/-4 years) and 9 obese control subjects (age 48+/-3 years). Patients with OSA were newly diagnosed, never treated for OSA, on no medications, and free of any other known diseases. All obese control subjects underwent complete overnight polysomnographic studies to exclude occult OSA. Resistance-vessel function was tested by use of forearm blood flow responses to intra-arterial infusions of acetylcholine (a vasodilator that stimulates endothelial release of nitric oxide), sodium nitroprusside (an exogenous nitric oxide donor), and verapamil (a calcium channel blocker). Conduit-vessel function was also evaluated by ultrasonography. Brachial artery diameter was measured under baseline conditions, during reactive hyperemia (with flow increase causing endothelium-dependent dilatation), and after sublingual administration of nitroglycerin (an endothelium-independent vasodilator). Patients with OSA had a blunted vasodilation in response to acetylcholine (P:<0.007), but responses to sodium nitroprusside and verapamil were not significantly different from those of control subjects. No significant difference in conduit-vessel dilation was evident between OSA patients and obese control subjects. CONCLUSIONS: Patients with OSA have an impairment of resistance-vessel endothelium-dependent vasodilation. This may be implicated in the pathogenesis of hypertension and heart failure in this condition.

Effect of acute and antecedent hypoglycemia on sympathetic neural activity and catecholamine responsiveness in normal rats.

Adrenergic responsiveness to acute hypoglycemia is impaired after prior episodes of hypoglycemia. Although circulating epinephrine responses are blunted, associated alterations in adrenal sympathetic nerve activity (SNA) have not been reported. We examined adrenal nerve traffic in normal conscious rats exposed to acute insulin-induced hypoglycemia compared with insulin with (clamped) euglycemia. We also examined adrenal SNA and catecholamine responses to insulin-induced hypoglycemia in normal conscious rats after two antecedent episodes of hypoglycemia (days -2 and -1) compared with prior episodes of sham treatment. Acute insulin-induced hypoglycemia increased adrenal sympathetic nerve traffic compared with insulin administration with clamped euglycemia (165 +/- 12 vs. 118 +/- 21 spikes/s [P < 0.05]; or to 138 +/- 8 vs. 114 +/- 10% of baseline [P < 0.05]). In additional experiments, 2 days of antecedent hypoglycemia (days -2 and -1) compared with sham treatment significantly enhanced baseline adrenal SNA measured immediately before subsequent acute hypoglycemia on day 0 (180 +/- 11 vs. 130 +/- 12 spikes/s, respectively; P < 0.005) and during subsequent acute hypoglycemia (229 +/- 17 vs. 171 +/- 16 spikes/s; P < 0.05). However, antecedent hypoglycemia resulted in a nonsignificant reduction in hypoglycemic responsiveness of adrenal SNA when expressed as percent increase over baseline (127 +/- 5% vs. 140 +/- 14% of baseline). Antecedent hypoglycemia, compared with sham treatment, resulted in diminished epinephrine responsiveness to subsequent hypoglycemia. Norepinephrine responses to hypoglycemia were not significantly altered by antecedent hypoglycemia. In summary, prior hypoglycemia in normal rats increased adrenal sympathetic tone, but impaired epinephrine responsiveness to acute hypoglycemia. Hence, these data raise the intriguing possibility that increased sympathetic tone resulting from antecedent hypoglycemia downregulates subsequent epinephrine responsiveness to hypoglycemia. Alternatively, it is possible that the decrease in epinephrine responsiveness after antecedent hypoglycemia could be the result of reduced adrenal sympathetic nerve responsiveness.

Status of antithrombotic therapy for patients with atrial fibrillation in university hospitals.

BACKGROUND: The risk of stroke in patients with atrial fibrillation can be significantly reduced with antithrombotic therapy. Despite this, many physicians remain hesitant to prescribe warfarin sodium or aspirin therapy for patients with atrial fibrillation. OBJECTIVE: To assess the use of antithrombotic therapy in patients with atrial fibrillation at 6 academic hospitals in the United States. METHODS: Records were reviewed from consecutive hospital admissions of 309 patients with atrial fibrillation at 6 members of the University Health System Consortium, Oak Brook, III, which is a member driven alliance of 70 academic health centers in the United States. Risk factors for stroke, contraindications to anticoagulant therapy, and use of antithrombotic therapy at admission and discharge were recorded. RESULTS: The mean age of patients was 71.6 years, 54% had chronic, 22% paroxysmal, and 24% new-onset atrial fibrillation. Eighty-two percent of the patients had cardiovascular risk factors that have been associated with increased risk of stroke. At least 1 relative contraindication to anticoagulant therapy was present in 44%. At the time of admission. 32% of the patients with previously diagnosed atrial fibrillation (n = 235) were receiving warfarin (or warfarin plus aspirin), 31% were receiving aspirin alone, and 36% were receiving no antithrombotic therapy. At discharge (n = 230), 41% of these patients were taking warfarin (or warfarin plus aspirin) and 36% were taking aspirin. Forty-four percent of the patients with risk factors for stroke and no contraindications to anticoagulation (n = 134) were discharged on a regimen of warfarin (or warfarin plus aspirin), 34% were discharged on a regimen of aspirin, and 22% received no antithrombotic therapy. CONCLUSIONS: About half of the patients with atrial fibrillation admitted to these academic hospitals had clinical risk factors that are associated with increased risk of stroke and no contraindications to anticoagulation. Antithrombotic therapy was underused in these patients.

Baroreflex control of sympathetic nerve activity and heart rate in obstructive sleep apnea.

-Patients with obstructive sleep apnea are at increased risk for hypertension. The mechanisms underlying this increased risk are not known. We tested the hypothesis that obstructive sleep apnea, independent of factors such as hypertension, obesity, and age, is characterized by impairment of baroreflex sensitivity. We measured muscle sympathetic nerve activity (MSNA) and heart rate responses to activation and deactivation of baroreceptors in newly diagnosed, never treated, normotensive patients with obstructive sleep apnea. These responses were compared with those obtained in healthy control subjects closely matched for age, body mass index, and blood pressure. Heart rate and MSNA changes during infusion of phenylephrine (baroreceptor activation) were similar in the control subjects and patients with sleep apnea. Infusion of nitroprusside (baroreceptor deactivation) elicited similar decreases in mean arterial pressure (MAP) but lesser MSNA increases in patients with sleep apnea than in control subjects. Calculation of DeltaMSNA/DeltaMAP ratio revealed that baroreflex regulation of sympathetic activity for similar blood pressure changes was diminished in patients with sleep apnea in comparison to normal control subjects (P=0.01). However, increases in heart rate during nitroprusside infusion were comparable in both groups. Sympathetic, blood pressure and heart rate responses to the cold pressor test were also similar in the 2 groups. Our results indicate that normotensive patients with sleep apnea have a selective impairment of the sympathetic response to baroreceptor deactivation but not to baroreceptor activation or to the cold pressor test. The impairment of baroreflex sympathetic modulation in patients with sleep apnea is not accompanied by any impairment of baroreflex control of heart rate.

Leptin interacts with heart rate but not sympathetic nerve traffic in healthy male subjects.

OBJECTIVE: Administration of leptin to animals increases sympathetic nerve activity and heart rate. We therefore tested the hypothesis that plasma leptin is linked independently to muscle sympathetic nerve activity (MSNA) and heart rate in healthy humans. METHODS: We measured plasma leptin, plasma insulin, body mass index (BMI), percent body fat, waist: hip ratio, MSNA, heart rate and blood pressure in 88 healthy individuals (50 men and 38 women). RESULTS: In men, plasma leptin concentration correlated significantly with BMI (r = 0.75, P < 0.001), percent body fat (r = 0.70, P< 0.001), waist: hip ratio (r = 0.69, P < 0.001), insulin (r = 0.37, P = 0.009), and age (r = 0.38, P = 0.006). Only BMI and waist: hip ratio were linked independently to plasma leptin concentration (r = 0.78, P < 0.001). Plasma leptin concentrations also correlated with heart rate (r = 0.39, P = 0.006) and mean arterial pressure (MAP; r = 0.38, P = 0.007), but not with MSNA (r = 0.17, P = 0.24). After adjustment for BMI and waist: hip ratio, plasma leptin concentration correlated significantly only with heart rate (r = 0.29, P = 0.04), and not with MAP (r = 0.21, P = 0.14). Individuals were divided into high-leptin and low-leptin subgroups on the basis of plasma leptin concentrations adjusted for BMI and waist: hip ratio. Those with high leptin concentrations had significantly faster heart rates than those with low leptin. MAP and MSNA were similar in both subgroups. No relationship between leptin and either heart rate or MSNA was evident in women. CONCLUSIONS: In normal men, heart rate, but not MSNA, is linked to plasma leptin concentration. This sex-specific relationship between heart rate and plasma leptin is independent of plasma insulin, BMI, waist:hip ratio and percentage body fat.

Recent weight gain in patients with newly diagnosed obstructive sleep apnea.

OBJECTIVE: Patients with obstructive sleep apnea are often obese. Obesity may contribute to both sleep apnea itself and to the cardiovascular risk associated with sleep apnea. Weight loss in obese patients with sleep apnea may alleviate symptoms and decrease the severity of sleep apnea. Whether patients with obstructive sleep apnea are indeed predisposed to recent weight gain, as compared with similarly obese subjects without sleep apnea, is not known. PATIENTS AND METHODS: We compared 1-year weight histories in 53 male and female patients newly diagnosed with obstructive sleep apnea, compared with 24 controls matched for gender, age, body mass index, and percent body fat. Sleep apnea patients had never been treated. Control subjects were proven to be free of sleep-disordered breathing by overnight polysomnography. RESULTS: Patients with obstructive sleep apnea (n = 53) had a significant recent weight gain of 7.4 +/- 1.5 kg compared with a weight loss of 0.5 +/- 1.7 kg (P = 0.001) in similarly obese controls (n = 24). Male patients with obstructive sleep apnea (n = 28) had a history of significant weight gain (6.8 +/- 2.3 kg) over the year preceding the study compared with male control subjects (n = 13), in whom average weight fell by 0.58 +/- 2.4 kg (P = 0.03). Female patients (n = 25) with obstructive sleep apnea had an 8.0 +/- 1.9 kg weight gain compared with female controls (n = 11) who had a history of weight loss of 0.46 +/- 2.6 kg (P = 0.02). CONCLUSION: These findings support the concept that patients with obstructive sleep apnea may be susceptible to increasing obesity in the period preceding the diagnosis of obstructive sleep apnea.

The effects of short-term passive smoke exposure on endothelium-dependent and independent vasodilation.

OBJECTIVE: There is limited information on the mechanisms mediating the deleterious effects of passive smoke exposure. Cross-sectional studies indicate that nonsmokers exposed chronically to passive smoke have impaired endothelium mediated vasodilation. We tested the hypothesis that acute exposure to sidestream (passive) smoke impairs endothelium-dependent vasodilation in healthy nonsmokers. METHODS AND RESULTS: We studied 12 healthy nonsmokers (aged 27 +/- 5 years, nine men and three women). We obtained measurements of blood pressure, heart rate, and bilateral forearm blood flow (FBF). Each individual was studied twice, following a randomized, placebo-controlled design. The effects of passive smoke were studied on one day and the effects of vehicle (room air) on a separate day. Acetylcholine (ACh) and sodium nitroprusside (SNP) were infused into the left brachial artery before and after 15 min of exposure to either passive smoke (carbon monoxide concentration between 20 and 40 p.p.m.) or vehicle (room air). The order of ACh and SNP, and smoke or vehicle, was randomized between individuals. Smoke exposure increased carboxyhemoglobin from 0.5 +/- 0.1 % to 0.8 +/- 0.1% (P= 0.002). Neither passive smoke nor vehicle changed baseline measurements of heart rate, blood pressure and forearm vascular resistance (FVR). The vasodilatory responses to ACh and SNP were very similar, both before and after exposure to passive smoke and before and after vehicle. CONCLUSION: Our data demonstrate that acute exposure to passive smoke does not alter either endothelium-dependent or independent vasodilatory responses in healthy nonsmoking individuals. Hence, impaired endothelial vasodilatory responses in nonsmokers chronically exposed to passive smoke most likely reflect chronic functional and/or structural changes in responses to cigarette smoke, rather than the acute effects of cigarette smoke toxicity on endothelial function.

Effects of obstructive sleep apnea on endothelin-1 and blood pressure.

OBJECTIVE: To evaluate blood pressure and humoral vasoconstrictor responses to recurrent episodes of obstructive sleep apnea and the effects of therapy by means of continuous positive airway pressure. PATIENTS AND METHODS: We prospectively evaluated overnight changes in hemodynamics, oxygen saturation, the apnea-hypopnea index, circulating endothelin-1, norepinephrine and plasma renin activity in 22 patients with severe obstructive sleep apnea before and after successful therapy using continuous positive airway pressure therapy (three measurements). Measurements of endothelin-1 and blood pressure were also obtained on three occasions, at similar times, in 12 healthy control subjects without sleep disturbances. RESULTS: Mean arterial pressure and endothelin-1 concentrations increased significantly after 4 h of untreated obstructive sleep apnea, and decreased after 5 h of continuous positive airway pressure. Changes in endothelin-1 levels were correlated with changes in mean arterial pressure (r = 0.44, P < 0.02) and with changes in oxygen saturation (r = 0.37, P < 0.05). Norepinephrine levels and plasma renin activity did not change significantly in patients with obstructive sleep apnea, and were not correlated with changes in blood pressure or oxygen saturation. In controls, blood pressure measurements at similar times during the night showed changes directionally opposite to that seen in obstructive sleep apnea, while endothelin-1 levels remained unchanged. CONCLUSIONS: Sleep apnea elicits increases in blood pressure and endothelin-1, with reductions in both after treatment. Vasoconstrictor and mitogenic effects of endothelin-1 may be implicated in increased cardiovascular risk in patients with obstructive sleep apnea.

Racial and gender differences in endothelin-1.

In summary, ET-1 levels were significantly increased in black men compared with white men. This racial difference could have important research implications if increased ET-1 levels are linked to left ventricular hypertrophy and other cardiovascular diseases, and it may serve as a foundation for future studies.

Serum nifedipine concentrations and response of patients with pulmonary hypertension.

In patients with primary pulmonary hypertension who respond to nifedipine during acute drug testing, there is a significant linear correlation of serum nifedipine concentration with pulmonary artery pressure and resistance. Although most demonstrate an initial response at readily attainable nifedipine concentrations with conventional dosages, a subset of patients seem to display delayed or incomplete oral absorption; these results may facilitate the clinical use of nifedipine in patients with primary pulmonary hypertension.

Lack of effect of alpha- and beta-adrenergic inhibition on forearm glucose uptake despite differences in forearm blood flow in healthy humans.

Insulin has both sympathoexcitatory and vasodilatory actions. It is unclear how these interact to affect muscular glucose uptake. The current study was designed to determine the systemic and local contributions of alpha- and beta-adrenergic activity to muscle glucose uptake. Forearm blood flow (FBF, plethysmography), arterial-venous glucose difference (AV-diff), and forearm glucose uptake (FGU) were measured during a 40-mU/m(2)/min insulin infusion with 120 minutes of euglycemia in 6 normal subjects (age, 28.8 +/- 4.9 years, mean +/- SD). Each subject was studied 5 times, once each with intravenous propranolol (IV PROP, 80 microg/min), intravenous phentolamine (IV PHEN, 500 microg/min), intra-arterial propranolol (IA PROP, 25 microg/min), intra-arterial phentolamine (IA PHEN, 12 microg/min/100 mL forearm tissue), and saline (SAL). FBF did not change during insulin with SAL, IA PROP, or IV PROP, but increased during insulin with IA PHEN and IV PHEN (P <.05). Despite the increased glucose delivery during insulin plus IA PHEN and IV PHEN, FGU did not differ between study sessions at any time during the insulin infusion. This was due to the lower AV-diff during insulin with IA PHEN and IV PHEN compared to the other studies (P <.05). AV-diff negatively correlated with FBF at the end of the insulin infusion (P <.001) for all studies. In normal humans, inhibition of basal sympathetic activity does not alter muscular glucose uptake. The increased insulin-induced vasodilation during alpha-adrenergic inhibition suggests that insulin-induced sympathetic activation prevents excess vasodilation. This inhibition does not alter glucose uptake because changes in flow are counterbalanced by changes in glucose extraction.

Comparison of intravenous diltiazem and verapamil for the acute treatment of atrial fibrillation and atrial flutter.

STUDY OBJECTIVES: To compare the efficacy and safety of intravenous diltiazem and verapamil in controlling ventricular rate in patients with atrial fibrillation or flutter, and to evaluate the effects of these agents on left ventricular systolic function. DESIGN: Prospective, randomized, double-blind, crossover study. SETTING: University-affiliated hospital and Veterans Administration hospital. PATIENTS: Seventeen men with atrial fibrillation or flutter with a ventricular rate of 120 beats/minute or higher and a systolic blood pressure of 100 mm Hg or greater. INTERVENTIONS: Patients received up to two intravenous boluses of either diltiazem or verapamil, followed by an 8-hour continuous infusion if a therapeutic response was achieved (phase I). After a washout period, patients who responded were crossed over to receive the other drug in a similar fashion (phase II). MEASUREMENTS AND MAIN RESULTS: At the end of each infusion, the patient's ejection fraction was assessed by gated angiography. Of the 17 men initially randomized, 8 successfully completed both phases I and II. In these patients, baseline mean (+/- SD) ventricular rates before treatment with intravenous diltiazem and verapamil were 138 +/- 15 and 132 +/- 9 beats/minute, respectively (NS). At 2 minutes after the initial bolus dose, the mean ventricular rate decreased to 100 +/- 13 beats/minute in the diltiazem group compared with 114 +/- 17 beats/minute in those receiving verapamil (p < 0.05). Mean ventricular rates of 96 +/- 11 and 97 +/- 9 beats/minute were maintained during the 8-hour continuous infusion of diltiazem and verapamil, respectively (NS). On completion of the bolus dose(s) and during continuous infusions, there were no significant differences in blood pressures between the groups. Mean ejection fractions were 35.6 +/- 13.6% and 35.5 +/- 15.4% in the diltiazem and verapamil groups, respectively (NS). For the 17 patients, the mean maximum percentage decreases in blood pressure were not significantly different between groups. However, three patients developed symptomatic hypotension, all of whom were randomized to receive verapamil initially. CONCLUSION: Intravenous diltiazem and verapamil are comparable in terms of efficacy and effect on systolic function in patients with rapid atrial fibrillation and flutter. However, hypotension may limit therapy with verapamil in some patients.

Prescribing trends and pharmacoeconomic considerations in the treatment of arrhythmias. Focus on atrial fibrillation and flutter.

Considerable progress has been made regarding the treatment of atrial fibrillation and atrial flutter. However, controversies still exist with respect to the therapy of choice for ventricular rate control, requirements for long term preventive therapy, and the place of surgical and ablation alternatives. Surrounding these controversies also lies a paucity of pharmacoeconomic studies, which limits delineation of the most cost-effective therapy for patients with atrial fibrillation and atrial flutter. This article reviews prescribing trends in the US for antiarrhythmic agents, and the available pharmacoeconomic studies that have specifically addressed the treatment of atrial fibrillation and atrial flutter.

Treatment of hypertension in patients with diabetes.

Approximately 3 million Americans have the dual diagnosis of hypertension and diabetes. Both conditions are associated with and are risk factors for cardiovascular events, nephropathy, and retinopathy. When these conditions coexist, the prevalence, progression, and severity of these adverse outcomes are dramatically enhanced. For these reasons, hypertension should be treated aggressively and early in the diabetic patient to curtail the morbidity and mortality associated with these disease states. To this end, a number of consensus statements have been formulated and promulgated in an effort to increase the awareness of this condition and to provide guidelines by which optimal care may be afforded to patients. In addition, specific patient and drug-related factors and conditions should be considered so patients can be committed to the optimal therapeutic plan. The outcome to attain optimal blood pressure should be mirrored by efforts to obtain glycemic and lipidemic control. By the implementation and optimization of effective therapeutic measures, which have the least amount of impact on the patient's concomitant disease states and body chemistry, positive differences in outcomes may be realized in this population.