[Show abstract][Hide abstract] ABSTRACT: Endothelin-1 (ET-1) is a potent vasoconstrictor that increases vascular tone in the resistance vessels of subjects with hypertension. It is unclear whether endogenous ET-1 affects resistance-vessel function equally in patients with other cardiovascular risk factors. Vasoconstriction to ET-1 is mediated principally via the endothelin-A (ETA) receptor on vascular smooth muscle cells. Accordingly, we used an ETA-specific antagonist, BQ-123, to test the hypothesis that endogenous ET-1 increases vascular resistance selectively in subjects with hypertension compared with other risk factors. BQ-123 was infused at 100 nmol/min for 80 minutes into the brachial artery of 10 subjects with hypertension (mean+/-SEM arterial pressure, 106+/-5 mm Hg), 12 subjects with hypercholesterolemia (mean+/-SEM total cholesterol, 7.1+/-0.2 mmol/L), 10 active smokers (mean+/-SEM, 42+/-11 pack-years), and 11 healthy, age-matched individuals. Forearm blood flow (FBF) was measured by venous occlusion plethysmography. BQ-123 dilated resistance arterioles in hypertensive subjects, with FBF's increasing by 46+/-7% from baseline (P<0.001). BQ-123 increased FBF to a lesser extent in hypercholesterolemic (24+/-5%, P<0.001) and healthy (20+/-8%, P=0.007) individuals but did not affect FBF significantly in smokers (10+/-8%, P=0.185). The vasodilator response in hypertensive subjects, but not in hypercholesterolemic patients or smokers, was significantly greater than that in healthy individuals (P=0.012). Endogenous ET-1, acting via the ETA receptor, increases resistance-vessel tone in subjects with hypertension more than in subjects with hypercholesterolemia or in smokers. These results indicate that ET-1 contributes more to the pathophysiology of hypertension than of other risk factors in subjects without overt atherosclerosis.
[Show abstract][Hide abstract] ABSTRACT: We sought to test the hypothesis that patients with decompensated heart failure (HF) lose a compensatory process whereby nitric oxide (NO) maintains pulmonary vascular tone.
Exhaled nitric oxide (eNO) partially reflects vascular endothelial NO release. Levels of eNO are elevated in patients with compensated HF and correlate inversely with pulmonary artery pressures (PAP), reflecting pulmonary vasodilatory activity.
We measured the mean mixed expired NO content of a vital-capacity breath using chemiluminescence in patients with compensated HF (n = 30), decompensated HF (n = 7) and in normal control subjects (n = 90). Pulmonary artery pressures were also measured in patients with HF. The eNO and PAP were determined sequentially during therapy with intravenous vasodilators in patients with decompensated HF (n = 7) and in an additional group of patients with HF (n = 13) before and during administration of milrinone.
The eNO was higher in patients with HF than in control subjects (9.9 +/- 1.1 ppb vs. 6.2 +/- 0.4 ppb, p = 0.002) and inversely correlated with PAP (r = -0.81, p < 0.00001). In marked contrast, patients with decompensated HF exhibited even higher levels of eNO (20.4 +/- 6.2 ppb) and PAP, but there was a loss of the inverse relationship between these two variables. During therapy (7.3 +/- 6 days) with sodium nitroprusside and diuresis, hemodynamics improved, eNO concentrations fell (11.2 +/- 1.2 ppb vs. before treatment, p < 0.05), and the relationship between eNO and PAP was restored. After milrinone, eNO rose proportionally with decreased PAP (p < 0.05).
Elevated eNO may reflect a compensatory circulatory mechanism in HF that is lost in patients with clinically decompensated HF. The eNO may be an easily obtainable and quantifiable measure of the response to therapy in advanced HF.
Journal of the American College of Cardiology 10/2002; 40(6):1114-9. · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The contribution of endothelin to resting pulmonary vascular tone and hypoxic pulmonary vasoconstriction in humans is unknown. We studied the hemodynamic effects of BQ-123, an endothelin type A receptor antagonist, on healthy volunteers exposed to normoxia and hypoxia. Hemodynamics were measured at room air and after 15 min of exposure to hypoxia (arterial PO(2) 99.8 +/- 1.8 and 49.4 +/- 0.4 mmHg, respectively). Measurements were then repeated in the presence of BQ-123. BQ-123 decreased pulmonary vascular resistance (PVR) 26% and systemic vascular resistance (SVR) 21%, whereas it increased cardiac output (CO) 22% (all P < 0.05). Hypoxia raised CO 28% and PVR 95%, whereas it reduced SVR 23% (all P < 0.01). During BQ-123 infusion, hypoxia increased CO 29% and PVR 97% and decreased SVR 22% (all P < 0.01). The pulmonary vasoconstrictive response to hypoxia was similar in the absence and presence of BQ-123 [P = not significant (NS)]. In vehicle-treated control subjects, hypoxic pulmonary vasoconstriction did not change with repeated exposure to hypoxia (P = NS). Endothelin contributes to basal pulmonary and systemic vascular tone during normoxia, but does not mediate the additional pulmonary vasoconstriction induced by acute hypoxia.
[Show abstract][Hide abstract] ABSTRACT: This study was designed to determine whether therapy with vasodilators and diuretics, designed to normalize loading conditions in decompensated heart failure (HF), reduces neurohormonal activation in the short term. BACKGROUND; Elevated vasoactive neurohormone levels in chronic HF have adverse prognostic impact and may be targeted by specific therapies.
Endothelin-1, catecholamines, renin, aldosterone, angiotensin and atrial natriuretic peptides (ANP, N-ANP and BNP) were measured in 34 patients with advanced HF before and after hemodynamically guided therapy with vasodilators and diuretics. The therapy was designed to reduce filling pressures and systemic vascular resistance (SVR) without inotropic therapy. Blood was drawn before therapy (A), after initial diuretic and nitroprusside therapy to optimize hemodynamics (B, mean 1.4 days) and after transition to an oral regimen designed to maintain improved hemodynamics (C, mean 3.4 days).
Mean pulmonary wedge pressure fell from 31 to 18 mm Hg, right atrial pressure from 15 to 8 mm Hg, and SVR from 1,780 to 1,109 dynes/s/cm(-5). Cardiac index increased from 1.7 to 2.6 l/min/m(2) without intravenous inotropic agents (all p < or = 0.05). Average endothelin levels declined by 30%, from 7.7 to 5.5 pg/ml, and remained low at time point C, 5.2 pg/ml (p < 0.01). Norepinephrine was 858 at time A, 817 at time B, and fell by time C to 608 pg/ml (p < or = 0.05). The mean plasma BNP level fell by 26% after only 1.4 days and by 53% at time C (p < 0.001).
Neurohormonal activation rapidly decreases after short-term therapy tailored to decrease severely elevated filling pressures and SVR without inotropic agents. Therapy designed to address neurohormonal activation should include therapy to improve severe resting hemodynamic compromise.
Journal of the American College of Cardiology 05/2002; 39(10):1623-9. · 15.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This study sought to determine to what extent the 6-min walk (6MW) distance in advanced heart failure predicts aerobic capacity and provides comparable information regarding survival. Peak oxygen uptake ( VO(2)) and the 6MW both describe function and predict outcome over a wide range of heart failure, but their determinants and implications may differ within a narrower clinical spectrum. This study compared 6MW with aerobic capacity both at peak exercise and during low-level cycling.
Both the 6MW and symptom-limited cycle ergometry were performed by 307 patients of whom 264 patients additionally performed 6 min of 20-W cycling to estimate aerobic capacity during sustained low-level activity. In the first 198 patients, multivariate analysis of survival was performed with the 6MW and peak VO (2). Patients achieved the 6MW of 393 +/- 104 m and peak VO (2) of 14 +/- 5 mL/kg per minute. Although low peak VO (2) was more likely with the shorter 6MW, the relation was weak within peak VO (2) range of 10 to 20 mL/kg per minute (n = 213, 69% of patients, r = 0.28). During 20-W exercise, VO (2) was 9.2 +/- 2.0 mL/kg per minute, with respiratory exchange ratio poorly correlated with the 6MW. In contrast to peak VO (2), the 6MW in meters did not predict survival. Division into short, medium, and long walks, however, supplemented simple clinical description.
Although helpful in broader populations for identification of patients with obvious clinical compromise, the 6MW distance is not a surrogate for peak VO (2) in assessing aerobic capacity or prognosis for individuals with advanced heart failure.