Eduardo R. Azevedo

Therapy with nitroglycerin increases coronary vasoconstriction in response to acetylcholine

OBJECTIVES The purpose of this study was to investigate whether therapy with nitroglycerin (GTN) would lead to abnormal coronary artery responses to the endothelium-dependent vasodilator acetylcholine. BACKGROUND Nitroglycerin therapy is associated with specific biochemical changes in the vasculature that may lead to increased vascular sensitivity to vasoconstrictors. METHODS Patients were randomized to continuous transdermal GTN, 0.6 mg/h (n = 8), or no therapy (n = 7), for 5 days prior to a diagnostic catheterization. Patients had similar risk factors for endothelial dysfunction. Quantitative angiography was performed in the morning to measure the mean luminal diameter of the left anterior descending coronary artery (LAD) in response to intracoronary acetylcholine (peak concentration, 10(-4) mol/liter). The transdermal preparation was removed from the GTN group, and 3 h later experimental procedures were repeated. RESULTS In the morning, the GTN group experienced greater coronary constriction in response to acetylcholine infusion than those not receiving GTN (-19.6+/-4.2 vs. -3.8+/-3.0%; p = 0.01). Three hours later, the GTN group continued to display greater constriction to acetylcholine (-24.1+/-5.9%) as compared to the non-GTN group (-1.8+/-4.8%). When the morning and afternoon responses to acetylcholine were compared, the increase in coronary constriction in the GTN group was greater than the change observed in the non-GTN group (p < 0.05). CONCLUSIONS This study demonstrates that therapy with GTN causes abnormal coronary vasomotor responses to the endothelium-dependent vasodilator acetylcholine, changes that were persistent for up to 3 hours after GTN discontinuation. This nitrate-associated vasomotor dysfunction has implications with respect to the development of nitrate tolerance and the potential for adverse events during nitrate withdrawal.

A high-sodium diet is associated with acute decompensated heart failure in ambulatory heart failure patients: a prospective follow-up study

BACKGROUND A low-sodium diet is an accepted treatment of patients with heart failure (HF), although minimal evidence exists on the appropriate amount of sodium intake for this population. Certain HF guidelines have liberalized dietary sodium recommendations, which actually exceed guidelines for healthy adults. OBJECTIVES We tested the hypothesis that high sodium intake is related to acute decompensated HF (ADHF) in ambulatory HF patients. Secondary outcomes included all-cause hospitalization and mortality. DESIGN We prospectively enrolled medically stable, ambulatory patients with systolic HF (n = 123; mean ± SD age: 60 ± 13 y) from 2 outpatient HF clinics from 2003 to 2007. Baseline estimates of dietary sodium and other nutrient intakes were obtained from two 3-d food records. RESULTS The median follow-up time was 3.0 y. Mean (±SD) sodium intakes were 1.4 ± 0.3, 2.4 ± 0.3, and 3.8 ± 0.8 g Na/d in the lower, middle, and upper tertiles, respectively. Cumulative ADHF event rates at 3 y were 12 ± 6%, 15 ± 7%, and 46 ± 11% in the low, middle, and upper tertiles, respectively (log-rank P = 0.001). For ADHF, the upper tertile was associated with an adjusted hazard ratio of 2.55 (95% CI: 1.61, 4.04; P < 0.001). Time-to-event probabilities were significant for mortality (log-rank P = 0.022) but not for all-cause hospitalization (log-rank P = 0.224). The high-sodium tertile was associated with an adjusted hazard ratio of 1.39 (95% CI: 1.06, 1.83; P = 0.018) for all-cause hospitalization and 3.54 (95% CI: 1.46, 8.62; P = 0.005) for mortality. CONCLUSIONS To our knowledge, this study provides the first prospective evidence that ambulatory HF patients who consume higher amounts of sodium are at greater risk of an ADHF event. These data provide support for more stringent sodium intake guidelines than those currently recommended for HF patients.

Reducing Cardiac Filling Pressure Lowers Norepinephrine Spillover in Patients With Chronic Heart Failure

BACKGROUND We studied the cardiac sympathetic response to selective unloading of cardiopulmonary baroreceptors in subjects with normal left ventricular (LV) function and congestive heart failure (CHF). METHODS AND RESULTS Eight patients with normal LV function (age 57+/-5 years, ejection fraction 58+/-2%) and 8 patients with CHF (age 60+/-2 years; ejection fraction 19+/-2%) were studied. Instrumentation consisted of an arterial line, a pulmonary artery catheter, and a coronary sinus thermodilution catheter. The radiotracer technique was used for measurement of cardiac norepinephrine spillover (CANESP) and total-body norepinephrine spillover. Lower-body negative pressure (LBNP) was applied at 2 levels: nonhypotensive and hypotensive LBNP. Nonhypotensive LBNP reduced filling pressures significantly in both groups. Arterial pressure did not change. This reduction in filling pressures caused a significant reduction in CANESP in the CHF group (from 167+/-53 to 125+/-37 pmol/min, P<0.05) but no change in the normal LV function group. Hypotensive LBNP caused a significant increase in CANESP in the normal group (73+/-13 vs 122+/-27 pmol/min, P<0.05) but no significant change in those with CHF. CONCLUSIONS We conclude that selective reduction in filling pressures lowers cardiac norepinephrine spillover in patients with CHF. These findings suggest that a goal of CHF management should be to reduce cardiac filling pressures while avoiding systemic hypotension.

Parasympathetic Control of Cardiac Sympathetic Activity Normal Ventricular Function Versus Congestive Heart Failure

BACKGROUND Muscarinic receptors on adrenergic nerve terminals attenuate norepinephrine release. The role of these receptors in the modulation of cardiac norepinephrine release in humans remains uncertain. METHODS AND RESULTS Twelve patients with normal left ventricular (LV) function and 18 with congestive heart failure (CHF) were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) in response to intracoronary acetylcholine (ACh, 5x10(-5) Mol), and in response to intracoronary atropine (12 micrograms/min). ACh did not affect CANESP in the group of subjects with normal LV function, but it caused a significant reduction in those with CHF [197 (150 to 302) versus 168 (87 to 288) pmol/min, P<0.05]. Atropine caused a significant increase in CANESP in those with normal LV function [47 (27 to 51) versus 64 (38 to 139) pmol/min, P<0.05], but no change was observed in the CHF group. CONCLUSIONS Therefore, in the setting of heart failure and sympathetic activation, muscarinic receptor stimulation decreases CANESP, an effect not observed in patients with preserved LV function. Blockade of muscarinic receptors with atropine increased CANESP in patients with normal LV function, suggesting that cardiac parasympathetic tone has inhibitory effects on cardiac sympathetic activity. This basal inhibition was not observed in CHF patients in response to atropine. The lack of basal parasympathetic inhibition of cardiac sympathetic activity may play a role in the pathogenesis of cardiac sympathetic activation in heart failure.

Inotropic and Sympathetic Responses to the Intracoronary Infusion of a β2-Receptor Agonist A Human In Vivo Study

BACKGROUND On the basis of the presence of beta2-receptors within the sympathetic nervous system, beta2-stimulation may increase cardiac sympathetic outflow. We addressed the hypothesis that sympathoexcitatory beta2-receptors are present in the human left ventricle. METHODS AND RESULTS The beta2-agonist salbutamol was infused into the left coronary artery in 3 groups of patients: group 1 (n=9, no beta-blocker therapy), group 2 (n=7, beta1-selective blockade with atenolol), and group 3 (n=6, nonselective beta-blockade with nadolol). Left ventricular +dP/dt in response to increasing concentrations of salbutamol was measured in all groups, and cardiac norepinephrine spillover was measured in group 1. There were no systemic hemodynamic changes in any group. Salbutamol resulted in a 44+/-6% increase in +dP/dt in group 1, a 25+/-6% increase in group 2 (P<0.05 versus group 1), and no increase in group 3. Salbutamol also resulted in a 124+/-37% increase in cardiac norepinephrine spillover in group 1 (P<0.05). CONCLUSIONS Evidence that salbutamol increased norepinephrine release from cardiac sympathetic nerves was provided by the observations that atenolol suppressed the salbutamol inotropic response, demonstrating that this response was mediated in part by beta1-receptors and that salbutamol also resulted in an increase in cardiac norepinephrine spillover. This result provides in vivo evidence, in humans, for the role of sympathoexcitatory cardiac beta2-receptors.

Nitroglycerin withdrawal increases endothelium-dependent vasomotor response to acetylcholine

OBJECTIVES We sought to determine whether nitroglycerin (NTG) withdrawal contributes to worsening of endothelial dysfunction and development of the rebound phenomenon during intermittent transdermal NTG therapy. BACKGROUND Intermittent transdermal NTG therapy is recommended to avoid the development of tolerance. However, this regimen may precipitate worsening angina in the NTG-free interval. METHODS Twenty patients were randomized to intermittent transdermal NTG (0.6 mg/h; NTG group) or no treatment (control group) five days before angiography. The risk factors for endothelial dysfunction were similar in both groups. After diagnostic angiography, the patients underwent quantitative angiography before and after intracoronary acetylcholine (ACh), 10(-4) mol/liter. Immediately after the morning study, the patch was removed from the NTG group, and 3 h later, the ACh infusion was repeated in both groups. All patients had mild to moderate coronary artery disease (CAD). RESULTS The diameter of the left anterior descending coronary artery at baseline was 2.0 +/- 0.1 mm in the control group and 2.6 +/- 0.1 mm in the NTG group (p < 0.05). Acetylcholine caused mild vasoconstriction in the control group in the morning and afternoon (2.7 +/- 5.3% and 2.4 +/- 3.9%, respectively; p = NS). The NTG group demonstrated mild vasoconstriction to ACh in the morning (3.2 +/- 2.8%; p = NS vs. control group). After patch removal, there was a significant increase in the magnitude ofvasoconstriction in the NTG group (11.6 +/- 3.9%, p = 0.04 vs. morning constriction). CONCLUSIONS These results confirm that NTG withdrawal increases the coronary vasomotor response to ACh in patients with mild CAD and suggests that the rebound phenomena may be secondary to the development of endothelial dysfunction after discontinuation of NTG therapy.

Lack of evidence for peripheral alpha1- adrenoceptor blockade during long-term treatment of heart failure with carvedilol

OBJECTIVES The purpose of this study was to determine whether carvedilols alpha(1)-adrenoceptor antagonism persists during long-term therapy of patients with congestive heart failure (CHF). BACKGROUND Carvedilol and metoprolol differ in that carvedilol also antagonizes beta(2)- and alpha(1)-adrenoceptors. We hypothesized that in contrast to metoprolol, carvedilol would increase calf vascular conductance (CVC), blunt neurally mediated vasoconstriction and attenuate neuroeffector transfer function gain. METHODS We randomized 36 patients with CHF (age 55 +/- 1 years, ejection fraction 19 +/- 1%, means +/- SE) to either drug. Blood pressure (BP), heart rate, muscle sympathetic nerve activity (MSNA) and CVC were assessed before and after four months of treatment. The variability of BP and MSNA was determined using fast Fourier transformation. RESULTS Paired data were obtained in 23 (carvedilol, 13; metoprolol, 10) subjects. Both beta-blockers decreased heart rate, but neither affected mean BP or CVC (carvedilol: 0.016 +/- 0.002 to 0.018 +/- 0.003 U; metoprolol: 0.020 +/- 0.002 to 0.020 +/- 0.004 U). Isometric handgrip exercise (30% of maximum) increased heart rate, mean BP and MSNA. The calf vasoconstrictor response to handgrip exercise was not affected by carvedilol (from 16 +/- 6 resistance U to 25 +/- 10 resistance U, NS). The gain of the transfer of oscillations in MSNA into BP under resting conditions was not attenuated by carvedilol. CONCLUSIONS Carvedilol did not increase CVC, blunt the calf vasoconstrictor response to handgrip or attenuate the gain of the neuroeffector transfer function, indicating the absence of functionally important peripheral alpha(1)-adrenoceptor antagonism during long-term treatment of CHF.

Cardiac and systemic sympathetic activity in response to clonidine in human heart failure

OBJECTIVES We studied the effects of clonidine on cardiac sympathetic activity and left ventricular function in patients with congestive heart failure (CHF). BACKGROUND Sympathetic activation has major prognostic implications in patients with heart failure. Clonidine, an imidazoline and alpha2-receptor agonist, has been shown to cause a reduction in generalized sympathetic activity. METHODS Nine patients with CHF (left ventricular ejection fraction 22+/-4% [mean+/-SEM]) received a 50 microg and 100 microg bolus of clonidine intravenously. Study measurements included right and left heart hemodynamics, cardiac output, rate of rise in left ventricular peak positive pressure (LV + dP/dt) and tau, along with cardiac and total body norepinephrine spillover. The radiotracer method was used for calculation of norepinephrine spillover. RESULTS Right and left heart filling pressures did not change in response to either dose of clonidine. Mean arterial pressure fell after the second dose of clonidine, from 94+/-8 to 82+/-6 mm Hg (p < 0.05). The LV + dP/dt was reduced from 737+/-53 to 629+/-43 mm Hg/s (p < 0.05). Clonidine also caused a significant increase in tau, as measured by the method of Weiss (65+/-3 vs. 74+/-4 ms, p < 0.01) and the direct pressure half-time technique (48+/-2 vs. 54+/-3 ms, p < 0.01). Cardiac norepinephrine spillover fell from 121+/-29 to 52+/-20 pmol/min in response to 100 microg of clonidine (p < 0.01 vs. control). CONCLUSIONS Despite a significant fall in arterial pressure, clonidine caused a marked reduction in sympathetic activity directed at the heart. The negative inotropic and lusitropic effects appear to be secondary to this reduction in sympathetic drive. Because increased cardiac and generalized sympathetic activity are strong predictors of an adverse outcome in patients with CHF, the role of centrally active sympathoinhibitory agents in the therapy of CHF deserves further exploration.

Biochemical, hemodynamic, and vascular evidence concerning the free radical hypothesis of nitrate Tolerance

Tolerance to nitroglycerin (NTG) may be due to increased superoxide anion production. Hemodynamic parameters and biochemical markers of free radical production were measured in 20 healthy male subjects at baseline, 3 h after acute transdermal NTG (0.6 mg/h), and after 5 days of continuous therapy. Transdermal NTG therapy was continued, and 2 days later all subjects received 2 g of oral vitamin C, or placebo, in a double-blind, randomized, crossover fashion. In another study of eight male subjects, forearm plethysmography was used to assess the venous responses to sublingual NTG at baseline, after 5 days of sustained transdermal NTG therapy (0.6 mg/h), and after 2 g of oral vitamin C or placebo. Systolic blood pressure decreased in response to acute transdermal NTG therapy but returned to normal after sustained NTG therapy, indicating the development of tolerance. The venous volume responses to sublingual NTG were significantly diminished after sustained therapy with transdermal NTG. Plasma lipid peroxidation products, 8-iso-PGF2 alpha, and vitamin C were unchanged by acute and sustained therapy with transdermal NTG. Vitamin C failed to restore either the hemodynamic or venous effects of NTG. These results do not support the hypothesis that nitrate therapy and tolerance is associated with increased free radical production.

The angiotensin II-receptor antagonist losartan does not prevent hemodynamic or vascular tolerance to nitroglycerin

Tolerance may involve increased production of angiotensin II. We tested the hypothesis that losartan would prevent the development of tolerance to continuous transdermal nitroglycerin (GTN). Twenty volunteers received losartan, 75 mg/day, or placebo in a randomized, double-blind, parallel fashion. After 1 week, continuous transdermal GTN, 0.6 mg/h, was given, in addition to losartan or placebo, to all volunteers for 1 week. Standing systolic blood pressure (SBP) and heart rate were measured, and forearm venous volume responses to sublingual GTN were evaluated. Measurements were made at baseline, after 1 week of losartan versus placebo, 3 h after initial therapy with transdermal GTN, and after 1 week of continuous transdermal GTN given in combination with losartan versus placebo. After sustained GTN therapy, SBP was unchanged from baseline in both groups, indicating that losartan did not prevent the development of tolerance. Tolerance also developed to the forearm venous volume responses and was not prevented by losartan. Therapy with an angiotensin II-receptor antagonist does not prevent the development of tolerance to continuous transdermal GTN.