The effects of dobutamine on cardiac sympathetic activity in patients with congestive heart failure

OBJECTIVES: The goal of this work was to study the effects of short-term infusion of dobutamine on efferent cardiac sympathetic activity. BACKGROUND: Increased efferent cardiac sympathetic activity is associated with poor outcomes in the setting of congestive heart failure (CHF). Dobutamine is commonly used in the therapy of decompensated CHF. Dobutamine, through its effects on excitatory beta-receptors, may increase cardiac sympathetic activity. METHODS: Seven patients with normal left ventricular (LV) function and 13 patients with CHF were studied. A radiotracer technique was used to measure cardiac norepinephrine spillover (CANESP) before and during an intravenous infusion of dobutamine titrated to increase the rate of rise in LV peak positive pressure (+dP/dt) by 40%. RESULTS: Systemic arterial pulse pressure increased significantly in response to dobutamine in the normal LV function group (74 +/- 3 mm Hg to 85 +/- 3 mm Hg, p = 0.005) but remained unchanged in the CHF group. Dobutamine caused a significant decrease in LV end-diastolic pressure in the CHF group (14 +/- 2 mm Hg to 11 +/- 2 mm Hg, p = 0.02), an effect not observed in the normal LV group. In the normal LV function group, CANESP did not change in response to dobutamine (75 +/- 22 pmol/min vs. 72 +/- 22 pmol/min, p = NS). In contrast, dobutamine infusion was associated with a significant reduction in CANESP in patients with CHF (199 +/- 43 pmol/min to 128 +/- 30 pmol/min, p < 0.0009). CONCLUSIONS: Dobutamine infusion caused a significant sympatholytic response in patients with CHF. This sympathetic withdrawal response is probably related to reduction of LV filling pressures and/or activation of ventricular mechanoreceptors with dobutamine infusion.     

Atrial septostomy decreases sympathetic overactivity in pulmonary arterial hypertension

BACKGROUND: We have reported previously that the sympathetic nervous system is activated in patients with pulmonary arterial hypertension (PAH), and that this is only partly explained by a decrease in arterial oxygenation. Possible causes for increased muscle sympathetic nerve activity (MSNA) in patients with PAH include right atrial distension and decreased cardiac output. Both may be improved by atrial septostomy, but this intervention also further decreases arterial oxygenation. In the present study, we wanted to investigate the effect of atrial septostomy on MSNA in patients with PAH. METHODS: We recorded BP, heart rate (HR), arterial O2 saturation (SaO2), and MSNA before and after atrial septostomy in PAH patients (mean [+/- SE] age, 48 +/- 5 years) and in closely matched control subjects. Measurements were also performed after septostomy, while SaO2 was brought to the preprocedure level by supplemental O2 therapy. RESULTS: Compared to the control subjects (n = 10), the PAH patients (n = 11) had a lower mean BP (75 +/- 2 vs 96 +/- 3 mm Hg, respectively; p < 0.001), lower mean SaO2 (92 +/- 1% vs 97 +/- 0%, respectively; p < 0.001), increased mean HR (84 +/- 4 vs 68 +/- 3 beats/min; p < 0.01), and markedly increased mean MSNA (76 +/- 5 vs 29 +/- 2 bursts per minute; p < 0.001). Atrial septostomy decreased mean SaO2 (to 85 +/- 2%; p < 0.001) and mean MSNA (to 69 +/- 4 bursts per minute; p < 0.01), but did not affect HR or BP. Therapy with supplemental O2 did not affect MSNA, BP, or HR. The decrease in MSNA was correlated to the decrease in right atrial pressure (r = 0.62; p < 0.05). CONCLUSIONS: Atrial septostomy in PAH patients decreases sympathetic hyperactivity despite an associated decrease in arterial oxygenation, and this appears to be related to decreased right atrial distension.     

Nasal oxygen and muscle sympathetic nerve activity in heart failure

AIMS: To evaluate the effects of mild hyperoxia on sympathetic activity during quiet breathing in patients with chronic heart failure (CHF) and, hence, to investigate whether tonic activation of excitatory chemoreceptor afferents contributes to the elevated sympathetic activity in these patients. Sympathetic activation in patients with CHF may result in part from increased chemoreflex sensitivity. Previous studies using microneurography did not demonstrate deactivation of the chemoreceptors while the patients were breathing 100% O(2). However, 100% O(2) may decrease cardiac output, thereby offsetting the effects on the chemoreflexes. SETTING: University hospital. Patients and interventions: Ten patients with moderate-to-severe CHF (mean [+/-SD] age, 53.9 +/- 9.2 years; mean ejection fraction, 21.3 +/- 4.7%) were assigned to breathing 20 min of O(2) as well as room air (3 L/min) applied by nasal prongs. Muscle sympathetic nerve activity (MSNA) was evaluated by microneurography of the peroneal nerve. RESULTS: The application of O(2) resulted in an increase of arterial O(2) saturation but no significant change in MSNA during resting ventilation. Although voluntary apneas were no longer with O(2) (25.3 +/- 5.8 vs 32.6 +/- 8.6 s, respectively; p = 0.014), MSNA during the last 10 s of voluntary apnea was lower while breathing O(2) (63.5 +/- 15.0 vs 59.9 +/- 13.9 bursts per minute, respectively; p = 0.02). CONCLUSIONS: The increased MSNA in the patients studied could not be reduced by mild hyperoxia, suggesting that the tonic activation of chemoreflex afferents is unlikely to contribute to the elevated sympathetic activity. That nasal O(2) reduces MSNA during apnea may explain the beneficial effects of nocturnal O(2) therapy in CHF patients with Cheyne-Stokes respiration.     

Oxygen uptake/supply dependency. Effects of short-term dobutamine infusion

The present study explored the possibility of using a short-term dobutamine infusion to disclose oxygen uptake/supply dependency. The effects of a standard dose of 5 micrograms/kg/min of dobutamine on oxygen-derived variables were studied in 73 acutely ill patients with heart failure (n = 24) or sepsis (n = 49). In each group, patients were separated according to their blood lactate concentrations (either above or below 2 mEq/L). In all patient groups, dobutamine resulted in significant increases in cardiac output and oxygen transport. However, oxygen consumption increased significantly only in patients with elevated blood lactate levels (cardiac failure: from 108 +/- 26 to 131 +/- 25 ml/min/M2, n = 8, p less than 0.01; sepsis: from 139 +/- 44 to 167 +/- 68 ml/min/M2, n = 16, p less than 0.01) and not in the other patients (heart failure: from 121 +/- 29 to 115 +/- 31 ml/min/M2, n = 28, NS; sepsis: from 158 +/- 39 to 166 +/- 45 ml/min/M2, n = 21, NS). These data, therefore, indicate that dobutamine at the dose used does not increase oxygen consumption in critically ill patients unless there is coexistent tissue hypoxia reflected by increased blood lactate levels. A short-term dobutamine infusion can be used to disclose an oxygen uptake/supply dependency phenomenon.     

Comparative effects of volume loading, dobutamine, and nitroprusside in patients with predominant right ventricular infarction

To assess the value of volume loading and to determine the relative efficacy of dobutamine compared with nitroprusside therapy in acute right ventricular infarction (RVMI), 13 patients with clinical, hemodynamic, and radionuclide angiographic evidence of RVMI were evaluated. In 10 patients who had an initial pulmonary arterial wedge pressure less than 18 mm Hg, volume loading did not improve cardiac index (1.9 +/- 0.5 [SD] to 2.1 +/- 0.4 liters/min/m2), despite significant increases in mean right atrial pressure (11 +/- 2 to 15 +/- 2 mm Hg, p less than .001) and pulmonary arterial wedge pressure (10 +/- 4 to 15 +/- 2 mm Hg, p less than .001). Nine patients received dobutamine or nitroprusside in random order, while hemodynamic measurements and radionuclide angiograms were obtained simultaneously. Compared with nitroprusside, dobutamine produced a statistically significant increase in cardiac index (2.0 +/- 0.4 to 2.7 +/- 0.5 vs 2.1 +/- 0.4 to 2.3 +/- 0.5 liters/min/m2, p less than .001), stroke volume index (29 +/- 6 to 36 +/- 8 vs 29 +/- 6 to 30 +/- 6 ml/m2, p = .02), and right ventricular ejection fraction (30 +/- 8% to 42 +/- 7% vs 34 +/- 8% to 37 +/- 4%, p less than .01) by two-way analysis of variance. We conclude that volume loading does not improve cardiac index in patients with acute RVMI despite a rise in cardiac filling pressures and that infusion of dobutamine, after appropriate volume loading, produces a significant improvement in cardiac index and right ventricular ejection fraction over those after infusion of nitroprusside.     

Effects of cardiovascular drugs on oxygen consumption/oxygen delivery relationship in patients with congestive heart failure.

The oxygen consumption (VO2)/oxygen delivery (DO2) relationship was analyzed in ten patients with severe congestive heart failure (CHF) and normal blood lactate levels. First dobutamine and then enoximone, after a washout period, were administered to each patient to increase cardiac output by at least 15 percent. Similar increases in DO2 were obtained with both drugs: from 285 +/- 46 to 393 +/- 87 ml/min/m2 for dobutamine, and from 285 +/- 54 to 392 +/- 99 ml/min/m2 for enoximone. However, while VO2 did not change (132 +/- 24 vs 132 +/- 21 ml/min/m2) (VO2/DO2 independency) with a dobutamine infusion (mean dose of 10 +/- 2 micrograms/kg/min), a significant increase in VO2 from 134 +/- 22 to 157 +/- 21 ml/min/m2 was observed with a bolus infusion of enoximone (mean dose of 1.7 +/- 0.5 mg/kg). These results, observed in patients with CHF without patent oxygen debt, suggest that an artefactual VO2/DO2 dependency might be induced by the cardiovascular drug used to elevate DO2, probably because of a drug-induced oxygen demand increase.     

Calcium inhibits the cardiac stimulating properties of dobutamine but not of amrinone.

To contrast the effect of increasing blood calcium concentrations on the cardiovascular actions of intravenous beta-adrenergic agonists and phosphodiesterase inhibitors, 46 patients recovering from aortocoronary bypass surgery received either dobutamine or amrinone both in the presence and absence of a calcium infusion. Cardiac output, systemic arterial pressure, pulmonary arterial pressure, central venous pressure, pulmonary artery occlusion pressure, heart rate, and blood ionized calcium concentration were measured before and during infusions of dobutamine (2.5 and 5.0 micrograms/kg/min) and amrinone (0.75 mg/kg bolus + 10 micrograms/kg/min or 2.25 mg/kg bolus + 20 micrograms/kg/min). After the initial dobutamine infusion period, patients were randomly and blindly assigned to receive either a calcium or placebo infusion, and the dobutamine infusions were repeated. Because of the long duration of amrinone's actions, the amrinone maintenance infusion was continued while randomized, blinded infusion of either calcium or placebo was added. Dobutamine (5 micrograms/kg/min) increased cardiac output from 7.1 +/- 0.3 L/min to 9.1 +/- 0.4 L/min, and increased heart rate from 93 +/- 4 beats/min to 107 +/- 4 beats/min. Systemic vascular resistance decreased and stroke volume increased. Dobutamine had no significant effects on other hemodynamic values. Amrinone (2.25 mg/kg bolus + 20 micrograms/kg/min) increased cardiac output from 5.6 +/- 0.4 L/min to 6.9 +/- 0.5 L/min, and increased heart rate from 87 +/- 3 beats/min to 98 +/- 3 beats/min. Amrinone decreased mean arterial pressure, systemic vascular resistance, pulmonary artery occlusion pressure, central venous pressure, and pulmonary artery pressure. Calcium infusion increased arterial pressure (8 to 13 percent) but had no significant effects on any other hemodynamic parameters. Calcium reduced the increase in cardiac output produced by dobutamine by 30 percent, but it did not alter the cardiotonic actions of amrinone. Thus, calcium inhibits the cardiotonic actions of certain beta-adrenergic agonists, most likely by interfering with signal transduction through the beta-adrenergic receptor complex.     

Impact of 6 months of therapy with carvedilol on muscle sympathetic nerve activity in heart failure patients

BACKGROUND: The long-term effects of carvedilol on muscle sympathetic nerve activity (MSNA) and muscle blood flow at rest and exercise in patients with chronic heart failure (CHF) remain unknown. METHODS AND RESULTS: Twenty-six patients (New York Heart Association class II-III) were randomized to carvedilol or placebo. Blood pressure, heart rate, MSNA, and forearm vascular resistance (FVR) at rest and during isometric forearm exercise (10% and 30% maximal voluntary contraction) were assessed before and after 6 months. Seven patients did not complete the study. Paired data were obtained in 19 (carvedilol 12, placebo 7). Carvedilol significantly decreased MSNA levels and heart rate at rest (-13 +/- 2 versus 3 +/- 8 bursts/min, P = .0001 and -16 +/- 3 vs -4 +/- 6 bpm, P = .05, respectively) and peak exercise (30% = -20 +/- 5 versus -3 +/- 7 bursts/min, P = 0.05 and -19 +/- 4 versus -4 +/- 6 bpm, P = 0.03, respectively) when compared with placebo. Carvedilol did not change a magnitude of response of MSNA and heart rate during exercise (-10 +/- 3 versus -7 +/- 2 bursts/min, P = 0.7 and 11 +/- 3 versus 6 +/- 1, P = .6, respectively). FVR was unchanged by carvedilol. When MSNA was quantified by burst incidence, the strength of reduction in MSNA was attenuated but still greater than placebo. CONCLUSIONS: Carvedilol reduces MSNA in patients with CHF. Carvedilol does not reduce FVR at rest or during isometric exercise.     

Long-term prognostic value of dobutamine stress echocardiography in patients with atrial fibrillation

STUDY OBJECTIVE: To assess the long-term prognostic value of dobutamine stress echocardiography (DSE) for cardiac events (cardiac death, myocardial infarction, and late revascularization) in patients with atrial fibrillation (AF). METHODS: Baseline ECGs were studied in patients undergoing DSE between 1989 and 1998. Sixty-nine patients had AF before DSE. Prognostic value of DSE in these patients was compared with a control group who had sinus rhythm (n = 1,664). The presence of stress-induced ischemia was noted for every patient. The mean follow-up period was 35 months (range, 6 to 84 months). Data are presented as hazards ratio (HR) with 95% confidence interval (CI). RESULTS: Heart rate at rest was higher in patients with AF (77 +/- 15 beats/min vs 73 +/- 14 beats/min; p = 0.04); however, double product at peak stress was not different between patients with AF and sinus rhythm (17,602 vs 17,169, respectively; p = 0.46). In patients with AF, target heart rate was achieved at a lower dobutamine dose (33 +/- 8 microg/kg/min vs 35 +/- 9 microg/kg/min; p = 0.01). Cardiac arrhythmias occurred more frequently (12% vs 5%; p = 0.001) in patients with AF during DSE. During a follow-up period of 7 years, cardiac death occurred in 5 patients, myocardial infarction in 2 patients, and late revascularization in 10 patients. Prognostic value of DSE for all late cardiac events was similar in patients with AF (HR, 3.0; 95% CI, 0.9 to 9.5) and sinus rhythm (HR, 3.4; 95% CI, 2.7 to 4.3; p = 0.85). CONCLUSION: The prognostic value of DSE for late cardiac events is maintained in patients with AF.     

Long-term intermittent dobutamine infusion combined with oral amiodarone improves the survival of patients with severe congestive heart failure

STUDY OBJECTIVE: To evaluate the effects of long-term intermittent dobutamine infusion (IDI) with concomitant administration of low-dose amiodarone in patients with congestive heart failure (CHF) refractory to standard medical treatment. DESIGN: Prospective, interventional clinical trial. SETTING: Inpatient and outpatient heart failure clinic in a university teaching hospital. PATIENTS AND INTERVENTIONS: Twenty-two patients with CHF refractory to standard treatment who could be weaned from dobutamine therapy after an initial 72-h infusion were included in this study. The first 11 patients (group 1) were treated with IDI, 10 micromin, as needed (mean, once every 16 days, lasting for 12 to 48 h); the next 11 patients (group 2) received oral amiodarone, 400 mg/d, and IDI, 10 microg/kg/min, for 8 h every 7 days. MEASUREMENT AND RESULTS: There were no differences in baseline clinical, hemodynamic, and five biochemical characteristics between the two groups. The left ventricular ejection fraction was 13.5 +/- 4.5% in group 1 vs 15.5 +/- 4.9% in group 2 (mean +/- SD; p = 0.451); mean pulmonary capillary wedge pressure was 31.3 +/- 4.4 mm Hg vs 29.4 +/- 3.3 mm Hg (p = 0.316); serum creatinine was 1.9 +/- 0.4 mg/dL vs 1.6 +/- 0.5 mg/dL (p = 0.19); and serum Na was 139.6 +/- 6.2 mEq/L vs 138.4 +/- 3.1 mEq/L (p = 0.569). At 12 months of follow-up, 1 of 11 patients (9%) was alive in group 1 vs 6 of 11 patients (55%) in group 2 (p = 0.011). Furthermore, in group 2, the functional status improved significantly within the first 3 months of treatment, from New York Heart Association functional class IV to 2.63 +/- 0.5 (p = 0.0001). CONCLUSION: Long-term IDI in conjunction with amiodarone, added to conventional drugs, improved clinical status and survival of patients with severe CHF.     

Safety and efficacy of an accelerated dobutamine stress echocardiography protocol in the evaluation of coronary artery disease

Although dobutamine requires up to 10 minutes to achieve steady state, dobutamine stress echocardiography is routinely performed using stepwise increments at 3-minute intervals. Consequently, the full effect of any infusion rate is not attained before the dobutamine dose is advanced to the next level. This study sought to test the safety and efficiency of high-dose continuous dobutamine infusion. One hundred consecutive patients underwent an accelerated protocol using a constant infusion of 50 microg/kg/min. In the absence of a stress echocardiographic end point (>/=85% of maximal predicted heart rate, new wall motion abnormalities, hypotension, arrhythmia, or intolerable symptoms), dobutamine infusion was discontinued at 10 minutes. Hemodynamic responses and adverse effect profile were compared with 100 patients who underwent a standard stepwise dobutamine stress protocol. Peak heart rate (140 +/- 16 vs 140 +/- 19 beats/min, p = 0.95) and systolic blood pressure (169 +/- 32 vs 162 +/- 31 mm Hg, p = 0.08) were similar in both protocols. Accelerated dobutamine administration produced a rapid increase in heart rate (12.5 +/- 6.2 vs 5.7 +/- 2.6 beats/min, p <0.001), and a substantial reduction in test duration (6.4 +/- 2.4 vs 12.9 +/- 3.0 minutes, p <0.001). The mean weight-adjusted cumulative dobutamine dose was lower in the accelerated protocol group (320 +/- 111 vs 353 +/- 133 microg/kg, p = 0.016). No significant differences were noted between the 2 groups with respect to various side effects. These data demonstrate that a high-dose, single-stage dobutamine echocardiographic stress protocol is a feasible, well-tolerated alternative to standard dobutamine stress echocardiography, and results in a substantial reduction in test time while maintaining a low complication rate.     

Accelerated dobutamine stress testing: safety and feasibility in patients with known or suspected coronary artery disease

BACKGROUND: Dobutamine pharmodynamics require approximately 10 min to reach steady state. Despite this, standard dobutamine stress echo typically uses 3-min stages of advancing dobutamine doses because of safety concerns. HYPOTHESIS: In patients with a high pretest probability of coronary artery disease (CAD), a continuous infusion of high-dose dobutamine is a feasible and safe method for performing a dobutamine stress test. METHODS: Forty-seven consecutive patients (mean age 64 +/- 11 years) with 3.0 +/- 1.4 cardiac risk factors underwent dobutamine stress testing utilizing a single, high-dose (40 mcg/kg/min), continuous dobutamine infusion. The 40 mcg/kg/min infusion was continued for up to 10 min or until a test endpoint had been reached. If a test endpoint was not achieved, atropine (up to 1.0 mg) was added. RESULTS: Heart rate rose from 71 +/- 12 to 137 +/- 18 beats/min at peak (p<0.0001) with a concomitant change in systolic blood pressure (143 +/- 35 vs. 167 +/- 38 mmHg; p = 0.001) but no change in diastolic blood pressure (74 +/- 19 vs. 75 +/- 18 mmHg; p = NS). Target heart rate was achieved in 20 of 47 (43%) patients with accelerated dobutamine alone and in 34 of 47 (72%) with the addition of atropine. An average of 11.6 +/- 3.7 min was required to obtain target heart rate. Subjective sensations from the dobutamine occurred in 49% of patients (palpitations 21%, nausea 6%, chest pain 6%, headache 6%, dizziness 13%), mild arrhythmia in 48% of patients (ventricular premature beats 38%, supraventricular tachycardia 10%), and one patient had nonsustained ventricular tachycardia. CONCLUSION: A single, high-dose (40 mcg/kg/min) dobutamine-atropine protocol provides an efficient means of performing dobutamine stress echocardiography with a similar symptom profile as conventional dobutamine infusion protocols in patients with a high pretest probability of CAD. Randomized, controlled studies will be necessary to assess the sensitivity and specificity of this accelerated dobutamine echo protocol.     

Hemodynamic effects of levosimendan added to dobutamine in patients with decompensated advanced heart failure refractory to dobutamine alone

A 24-hour infusion of levosimendan was added to dobutamine in 18 patients (aged 63 +/- 9 years) hospitalized for management of decompensated New York Heart Association functional class IV heart failure refractory to a continuous 24-hour infusion of dobutamine (10 microg/kg/min) and furosemide (10 mg/hour); the primary study end point was a >or=40% increase in cardiac index and a >or=25% decrease in pulmonary capillary wedge pressure compared with pretreatment measurements.The primary end point was reached in one of the patients treated with dobutamine alone versus 7 patients (39%) treated with levosimendan and dobutamine combined (p = 0.008), whereas at 24 hours, the combined treatment was associated with a 0.76 +/- 0.78 L/min/m(2) (p = 0.001) mean increase in cardiac index and a 6.4 +/- 7.3 mm Hg (p = 0.002) mean decrease in pulmonary capillary wedge pressure compared with measurements obtained after 24 hours of dobutamine infusion alone. Symptoms were alleviated in all patients, and all but 3 were discharged from the hospital.     

Comparative vasoactive therapy for heart failure

Dopamine and dobutamine increase myocardial contractility by beta-adrenergic stimulation. Both agents provide significant support for decompensating congestive heart failure (CHF) patients. At the same time, both agents can have significant adverse effects. In 1981, it was reported that amrinone, a bipyridine derivative, produced hemodynamic changes similar to those of dobutamine. To confirm these results, the hemodynamic and clinical effects of amrinone were compared with those of dopamine and dobutamine in 15 consecutive patients with CHF. Although each drug improved maximal cardiac index to a similar extent, dopamine did not decrease pulmonary artery wedge pressure and caused a greater increase in heart rate. Dobutamine and amrinone conferred similar hemodynamic benefits: cardiac index improved from 2.4 +/- 0.2 to 3.4 +/- 0.2 liters/min/m2 with dobutamine and from 2.1 +/- 0.2 to 3.2 +/- 0.2 liters/min/m2 with amrinone. Pulmonary artery wedge pressure decreased similarly: from 19 +/- 2 to 13 +/- 1 mm Hg with dobutamine and from 18 +/- 2 to 12 +/- 1 mm Hg with amrinone. Dobutamine and amrinone produced similar modest decreases in mean arterial pressure and increments in heart rate. Dopamine was poorly tolerated; 5 patients developed such severe adverse reactions that this drug was discontinued prematurely. Dobutamine and amrinone were much better tolerated. Although amrinone caused asymptomatic tachycardia (heart rate increase greater than 20% over baseline) in 4 patients, no patient developed an adverse reaction warranting its premature termination.     

Cardiac nitric oxide production due to angiotensin-converting enzyme inhibition decreases beta-adrenergic myocardial contractility in patients with dilated cardiomyopathy

OBJECTIVES: This study tested the hypothesis that angiotensin-converting enzyme (ACE) inhibitors attenuate beta-adrenergic contractility in patients with idiopathic dilated cardiomyopathy (DCM) through nitric oxide (NO) myocardial signaling. BACKGROUND: The ACE inhibitors increase bradykinin, an agonist of NO synthase (NOS). Nitric oxide inhibits beta-adrenergic myocardial contractility in patients with heart failure. METHODS: The study patients were given the angiotensin-1 (AT-1) receptor antagonist losartan for one week. The hemodynamic responses to intravenous dobutamine were determined before and during intracoronary infusion of enalaprilat (0.2 mg/min) with and without the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA, 5 mg/min). RESULTS: In patients with DCM (n = 8), dobutamine increased the peak rate of rise of left ventricular pressure (+dP/dt) by 49 +/- 8% (p < 0.001) and ventricular elastance (Ecs) by 53 +/- 16% (p < 0.03). Co-infusion with enalaprilat decreased +dP/dt to 26 +/- 12% and Ecs to -2 +/- 17% above baseline (p < 0.05), and this anti-adrenergic effect was reversed by L-NMMA co-infusion (p < 0.05 vs. enalaprilat). In addition, intracoronary enalaprilat reduced left ventricular end-diastolic pressure (LVEDP), but not left ventricular end-diastolic volume, consistent with increased left ventricular distensibility. Infusion with L-NMMA before enalaprilat in patients with DCM (n = 5) prevented the reduction in +dP/dt, Ecs and LVEDP. In patients with normal left ventricular function (n = 5), enalaprilat did not inhibit contractility or reduce LVEDP during dobutamine infusion. CONCLUSIONS: Enalaprilat attenuates beta-adrenergic contractility and enhances left ventricular distensibility in patients with DCM, but not in subjects with normal left ventricular function. This response is NO modulated and occurs in the presence of angiotensin receptor blockade. These findings may have important clinical and pharmacologic implications for the use of ACE inhibitors, AT-1 receptor antagonists and their combination in the treatment of heart failure.     

Dobutamine echocardiographic study in patients with nonischemic dilated cardiomyopathy and prognostically borderline values of peak exercise oxygen consumption: 18-month follow-up study

OBJECTIVES: We sought to study the prognostic value of dobutamine echocardiography in patients with nonischemic dilated cardiomyopathy (DCM) and prognostically borderline values of peak oxygen consumption (VO2max) during exercise. BACKGROUND: Changes in echocardiographic variables assessed by dobutamine echocardiography can be used to evaluate the functional status of patients with chronic heart failure (CHF) and DCM. METHODS: In 27 consecutive patients (mean age 55 +/- 15 years) with VO2max values between 10 and 14 ml/kg body weight per min, a low infusion rate (10 microg/kg per min) dobutamine echocardiographic test was performed. The induced changes in echocardiographic variables were measured, and an 18-month follow-up study was done. RESULTS: At the end of the protocol, 9 patients (group I) had died from cardiac reasons, whereas the remaining 18 patients (group II) survived. After dobutamine infusion, the left ventricular end-systolic diameter (LVESD) was smaller in group II (6.22 +/- 0.94 cm) than in group I (6.99 +/- 0.76 cm; p < 0.05), whereas end-systolic wall stress (ESWS) was higher in group I (1030.66 +/- 193.98 g/cm2) than in group II (691.57 +/- 297.06 g/cm2; p < 0.05). The changes in LVESD and ESWS were greater in group I (0.75 +/- 0.36 cm and 463.11 +/- 159.87 g/cm2, respectively) than in group II (-0.04 +/- 0.36 cm and 83.16 +/- 291.74 g/cm2, respectively; p < 0.01 for both). CONCLUSIONS: In the "gray" zone of VO2max, dobutamine echocardiography seems to be a valuable prognostic indicator in patients with CHF and DCM.     

Oxidative stress does not modulate metabolic rate or skeletal muscle sympathetic activity with primary aging in adult humans

Support of resting metabolic rate (RMR) by the beta-adrenergic receptors of the sympathetic nervous system is attenuated with age and contributes to declines in RMR. This may be mediated by an age-associated increase in oxidative stress that can suppress beta-adrenergic responsiveness and/or modulate sympathetic activity. To address these issues, RMR was determined in 12 young (23 +/- 1 yr, mean +/- SE) and 21 older (68 +/- 3 yr) adults before and during systemic infusion of ascorbic acid [bolus, 0.06 g/kg fat free mass (FFM); drip, 0.02]. Ascorbic acid increased plasma concentrations similarly in young (72 +/- 5 to 1107 +/- 114 micro mol/liter) and older (70 +/- 6 to 1022 +/- 63 micro mol/liter) adults, and reduced (P = 0.001) plasma concentrations of isoprostanes (young, -82.8 +/- 47; older, -107 +/- 29 pg/ml). Baseline RMR(FFM) was lower (5719 +/- 215 vs. 6703 +/- 328 kJ/d; P = 0.001) and muscle sympathetic nerve activity (MSNA) was greater (MSNA, 28 +/- 2 vs. 23 +/- 3 bursts/min; P < 0.05) in older compared with young. However, neither RMR(FFM) (young, +117 +/- 63; older, +163 +/- 48 kJ/d; P = 0.14) or MSNA (young, 0 +/- 2; older, -1 +/- 1 bursts/min; P = 0.71) changed in either age group during ascorbic acid infusion compared with saline control. These results indicate that increased oxidative stress: 1) is not a mechanism contributing to decreases in RMR with primary aging; and 2) does not modulate MSNA in healthy adult humans.     

Safety profile and hemodynamic responses to beta-adrenergic stimulation by dobutamine in heart transplant patients

STUDY OBJECTIVE: Dobutamine stress echocardiography (DSE) has been used as a screening tool for coronary artery disease after heart transplantation and in the identification of patients at risk for development of cardiac events. However, the safety profile of high-dose dobutamine in heart transplant patients has not been systematically examined. Accordingly, we studied the safety profile and hemodynamic responses to escalating doses of dobutamine to determine the influence of denervation. DESIGN: We assessed the hemodynamic responses, heart rate (HR), and arterial BP indexes (mean arterial pressure, systolic BP [SBP], diastolic BP [DBP], and pulse pressure) to dobutamine in 87 heart transplant patients ([mean +/- SD] age, 51 +/- 1 years) and compared the results with 97 nontransplant patients (age, 63.0 +/- 1 years) who served as innervated control subjects. MEASUREMENTS AND RESULTS: The baseline HR (84 +/- 2 vs 69 +/- 1 beats/minute, respectively; p < 0.001) and peak HR response (144 +/- 2 vs 117 +/- 2 beats/minute, respectively; p < 0.001) were significantly higher in heart transplant patients than in the nontransplant patients. SBP was lower in heart transplant patients than in nontransplant patients at baseline (131 +/- 2 vs 138 +/- 2 mm Hg, respectively; p < 0.02) and at peak (150 +/- 3 vs 158 +/- 3 mm Hg, respectively; p < 0.03). However, baseline DBP was higher in transplant patients than in nontransplant patients (86 +/- 1 vs 77 +/- 1 mm Hg, respectively; p < 0.001). The decrease in DBP was similar in both groups (15 mm Hg). The dose-response curve for HR was shifted leftward in heart transplant patients. Heart transplant patients attained a higher absolute HR at each infusion stage and higher rates of increase, but the decrease in DBP was not significantly different in the two groups. CONCLUSIONS: These results show that there is augmented chronotropic response and expected decline in DBP in response to dobutamine infusion in heart transplant patients. This increase in myocardial oxygen demand and a decrease in coronary perfusion pressure may be important mechanisms in the development of ischemic abnormalities that are detectable as regional dysynergy on echocardiography.     

Wasting of the left ventricle in patients with cardiac cachexia: a cardiovascular magnetic resonance study

BACKGROUND: The "cachectic heart" has been described as a pathologic decrease in the size and mass of the heart, but no in vivo studies have shown changes in cardiac dimensions or left ventricular (LV) mass over time in chronic heart failure (CHF) associated with body wasting (cardiac cachexia). Cardiovascular magnetic resonance (CMR) has high reproducibility and is more sensitive than other techniques. METHODS: CMR studies of LV volumes and mass were performed at baseline and a mean of 15 months later in nine CHF patients with cardiac cachexia and 28 matched CHF controls without cachexia (mass index 23 +/- 1 vs. 29 +/- 5 kg/m2, P=0.0005). RESULTS: At baseline, LV end-diastolic volume (197 +/- 78 vs. 203 +/- 65 ml), end-systolic volume (131 +/- 75 vs. 126 +/- 63 ml), LV mass (213 +/- 44 vs. 222 +/- 62 g), and LV ejection fraction (38 +/- 19% vs. 40 +/- 16%) did not differ between cachectic patients and controls (all P>0.10). During follow-up, there was a significant decrease in LV mass in patients with cachexia (-16 g, P<0.05) and a trend to increase in LV mass in patients without cachexia (+7 g, P=0.12, comparison between groups: P=0.010). CONCLUSIONS: The direction of changes over time in LV mass differs in CHF patients with cachexia as compared with non-cachectic controls. A significant decrease in LV mass occurs in patients with cardiac cachexia. This study documents in vivo the occurrence of wasting of the left ventricle in patients with CHF who demonstrate general body wasting.     

Sympathetic nerve activity after thoracoscopic cardiac resynchronization therapy in congestive heart failure

BACKGROUND: Sympathetic benefits of thoracoscopic cardiac resynchronization therapy (TCRT) in congestive heart failure (CHF) are unknown. We determined cardiac hemodynamics, functional status, and muscle sympathetic nerve activity (MSNA) in a group of TCRT patients. We aimed to compare these patients with CHF patients with cardiac asynchrony (ASY) to substantiate the beneficial effects of TCRT. METHODS AND RESULTS: Eleven patients resynchronized by TCRT 6 +/- 1 months before study inclusion (SYN) and 10 matched ASY patients underwent blood pressure, heart rate, and MSNA recordings. All underwent functional status, cardiac index, and left ventricular ejection fraction (LVEF) assessments. SYN patients had shorter QRS duration and interventricular mechanical delays, longer 6 minute walking distance and lower New York Heart Association class (all P < .05) than ASY patients. MSNA of 56 +/- 2 bursts/min in ASY patients was higher than in SYN patients (48 +/- 3 bursts/min, P < .05). Cardiac index was higher in SYN patients than in ASY patients (2.8 +/- 0.2 versus 1.9 +/- 0.2 L.min.m2, P < .05, respectively). MSNA was highest in the patients with the lowest LVEF (r = -0.49, P < .05), cardiac index (r = -0.48, P < .05) and 6-minute walking distance (r = -0.50, P < .05). CONCLUSION: Lower sympathetic nerve activities in TCRT patients are related to more favorable cardiac indexes and six minute walking distances suggesting a sympathetic, hemodynamic, and functional improvement by TCRT.