Plasma norepinephrine and atrial natriuretic peptide in heart failure: influence of felodipine in the third Vasodilator Heart Failure Trial. V-HeFT III investigators.

BACKGROUND: Reflex activation of the sympathetic nervous system by short-acting dihydropyridine calcium channel antagonists has been reported to harm hypertensive patients. Different neurohormonal profiles and their response to treatment may influence the effectiveness of dihydropyridine vasodilator treatment of heart failure. METHODS: Four hundred fifty men with left ventricular (LV) systolic dysfunction were administered standard heart failure treatment and felodipine extended release (ER) or placebo in the Vasodilator Heart Failure Trial III (V-HeFT III). Plasma norepinephrine (PNE) levels, atrial natriuretic peptide (ANP) levels, exercise capacity, LV ejection fraction (EF), cardiac dimensions and function, and arrhythmia frequency were measured. Hospital-free survival for baseline neurohormonal classes was assessed. RESULTS: Distributions of ANP and PNE levels at baseline in patients with heart failure of ischemic and nonischemic causes were virtually identical. ANP levels at baseline were inversely related to LVEF (r = -0.39; P = .0001), exercise duration (r = -0.19; P = .0001), and peak oxygen consumption (r = -0.27; P = .008) and directly related to LV (r = 0.23; P = .0006) and right ventricular dilatation (r = 0.23; P = .0008). The increase in ANP levels between baseline and 3 months (P = .02) and 1 year (P = .03) was significantly less in the felodipine-ER group than in the placebo group, but PNE levels did not differ between treatment groups. Hospital-free survival was directly related to baseline ANP (P = .0002) and PNE levels (P = .004). All-cause mortality was related to baseline PNE levels (P = .02) but not baseline ANP levels. CONCLUSION: Levels of ANP and PNE hormones are related to LV dysfunction, exercise performance, and hospital-free survival in heart failure and PNE levels are related to all-cause mortality. Treatment with felodipine ER did not adversely affect survival in any neurohormone subclass.

Racial differences in response to therapy for heart failure: analysis of the vasodilator-heart failure trials. Vasodilator-Heart Failure Trial Study Group.

BACKGROUND: Heart failure in blacks has been associated with a poorer prognosis than in whites. In such diseases as hypertension, blacks show pathophysiological differences and respond differently to some therapies than whites. The aim of this study is to evaluate the clinical characteristics and response to therapy of black compared with white patients with heart failure. METHODS AND RESULTS: In the first Vasodilator-Heart Failure Trial (V-HeFT I), 180 black male patients were compared with 450 white male patients for baseline characteristics, prognosis, and response to therapy. In V-HeFT II, the same comparisons were made for 215 black and 574 white male patients, including an analysis stratified by the presence or absence of a history of hypertension. In both trials, black patients had a lower incidence of coronary artery disease, greater incidence of previous hypertension, and a greater cardiothoracic ratio (P < .05) than white patients. In V-HeFT II, plasma norepinephrine levels were significantly less in blacks; plasma renin activity was less only in blacks with a history of hypertension. Overall mortality or hospitalization for congestive heart failure did not differ between blacks and whites in the placebo group in V-HeFT I. However, the mortality of black patients receiving hydralazine plus isosorbide dinitrate (H-I) was reduced (P = .04) in V-HeFT I, whereas white patients showed no difference from placebo. In V-HeFT II, only white patients showed a mortality reduction from enalapril therapy compared with H-I therapy (P = .02). Whites also showed evidence of greater blood pressure reduction and enhanced regression of cardiac size in response to enalapril. When stratified by history of hypertension in V-HeFT II, only whites with a history of hypertension, who had greater renin levels, showed significant mortality reduction with enalapril compared with H-I therapy. Hospitalization rates did not differ between treatment groups in either study. CONCLUSION: Whites and blacks showed differences in cause, neurohormonal stimulation, and pharmacological response in heart failure. This retrospective analysis suggests angiotensin-converting enzyme inhibitors are particularly effective in whites, and the H-I combination can be equally effective in blacks. Prospective trials involving large numbers of black patients are needed to further clarify their response to therapy.

Augmented short- and long-term hemodynamic and hormonal effects of an angiotensin receptor blocker added to angiotensin converting enzyme inhibitor therapy in patients with heart failure. Vasodilator Heart Failure Trial (V-HeFT) Study Group.

BACKGROUND: ACE inhibitors may not adequately suppress deleterious levels of angiotensin II in patients with heart failure. An angiotensin receptor blocker added to an ACE inhibitor may exert additional beneficial effects. METHODS AND RESULTS: Eighty-three symptomatic stable patients with chronic heart failure receiving long-term ACE inhibitor therapy were randomly assigned to double-blind treatment with valsartan 80 mg BID, valsartan 160 mg BID, or placebo while receiving their usual ACE inhibitor therapy. Studies were performed before and after the first dose of the test drug and again after 4 weeks of therapy. A single dose of lisinopril was administered during study days to ensure sustained ACE inhibition. Compared with placebo, the first dose of valsartan 160 mg resulted in a significantly greater reduction in pulmonary capillary wedge pressure at 3, 4, and 8 hours and during the prespecified 4- to 8-hour interval after the dose and in systolic blood pressure at 2, 3, 6, 8, and 12 hours and 4 to 8 hours after the dose. A pressure reduction from valsartan 80 mg did not achieve statistical significance. After 4 weeks of therapy, net reductions in 0-hour trough pulmonary capillary wedge pressure (-4.3 mm Hg; P=0. 16), pulmonary artery diastolic pressure (-4.7 mm Hg; P=0.013), and systolic blood pressure (-6.8 mm Hg; P=0.013) were observed in the valsartan 160 mg group compared with placebo. After 4 weeks of therapy, plasma aldosterone was reduced by valsartan 80 mg BID (-52. 1 pg/mL; P=0.001) and 160 mg BID (-47.8 pg/mL; P<0.001) compared with placebo, and there was a trend for a reduction in plasma norepinephrine (-97 pg/mL; P=0.10). Seventy-four of the 83 patients completed the trial. CONCLUSIONS: Physiologically active levels of angiotensin II persist during standard long-term ACE inhibitor therapy.

Transcription analysis of two disparate rRNA operons in the halophilic archaeon Haloarcula marismortui.

The genome of the halophilic archaeon Haloarcula marismortui contains two rRNA operons designated rrnA and rrnB. Genomic clones of the two operons and their flanking regions have been sequenced, and primary transcripts and processing intermediates derived from each operon have been characterized. The 16S, 23S, and 5S genes from the two operons were found to differ at 74 of 1,472 positions, 39 of 2,922 positions, and 2 of 122 positions, respectively. This degree of sequence divergence for multicopy (paralogous) rRNA genes was 10- to 50-fold or more higher than anticipated. The two operons exhibit other profound differences that include (i) the presence in rrnA and the absence in rrnB of tRNAAla and tRNACys genes in the intergenic and distal regions, respectively, (ii) divergent 5' flanking sequences, and (iii) distinct pathways for processing and maturation of 16S rRNA. Processing and maturation of 16S and 23S rRNA from rrnA operon transcripts and of 23S rRNA from rrnB operon transcripts follow the canonical halophilic pathway, whereas maturation of 16S rRNA from rrnB operon transcripts follows an unusual and different pathway that is apparently devoid of any 5' processing intermediate.

Effect of the calcium antagonist felodipine as supplementary vasodilator therapy in patients with chronic heart failure treated with enalapril: V-HeFT III. Vasodilator-Heart Failure Trial (V-HeFT) Study Group.

BACKGROUND: Despite therapy with diuretics, ACE inhibitors and digoxin morbidity and mortality in heart failure remain high and might respond favorably to an additional vasodilator. METHODS AND RESULTS: Male patients (n=450) with chronic heart failure (cardiac dysfunction and impaired exercise performance) on optimal current therapy (97% enalapril, 89% diuretics) were randomly assigned to double-blind treatment with felodipine extended release (5 mg BID) or placebo for 3 to 39 months (average, 18 months). Felodipine significantly reduced blood pressure and, at 3 months, increased ejection fraction (2.1% versus -0.1% units in the placebo group, P=.001) and reduced plasma atrial natriuretic peptide levels (-2.9 versus 26.9 pg/mL in the placebo group, P=.01) but did not improve exercise tolerance, quality of life, or the need for hospitalization. During long-term follow-up, the favorable effects on ejection fraction and atrial peptide did not persist, but felodipine prevented worsening exercise tolerance and quality of life. In the felodipine and placebo groups, mortality (13.8% versus 12.8%, respectively) and hospitalization (43% versus 42%) rates were similar, and a higher incidence of peripheral edema was the only apparent side effect of felodipine therapy. CONCLUSIONS: Felodipine exerts a well-tolerated additional sustained vasodilator effect in patients with heart failure treated with enalapril, but the only possible long-term benefit was a trend for better exercise tolerance and less depression of quality of life in the second year of treatment. The drug appears to be safe but not clearly efficacious in patients with heart failure.

Gas vesicle formation in halophilic Archaea.

Gas vesicles are intracellular, microbial flotation devices that consist of mainly one protein, GvpA. The formation of halobacterial gas vesicles occurs along a complex pathway involving 14 different gvp genes that are clustered in a genomic region termed the "vac region". Various vac regions found in Halobacterium salinarum (p-vac and c-vac), Haloferax mediterranei (mc-vac), and Natronobacterium vacuolatum (nv-vac) have been investigated. Except for the latter vac region, the arrangement of the gvp genes is identical. Single gvp genes have been mutated to study the effect on gas vesicle synthesis in transformants and to determine their possible function. Each vac region exhibits a characteristic transcription pattern, and regulatory steps have been observed at the DNA, RNA, and protein level, indicating a complex regulatory network acting during gas vesicle gene expression.

Rationale and design of the third vasodilator-heart failure trial (V-HeFT III): felodipine as adjunctive therapy to enalapril and loop diuretics with or without digoxin in chronic congestive heart failure. V-HeFT III investigators.

Therapy with angiotensin-converting enzyme inhibitors and nonselective vasodilators (hydralazine and isosorbide dinitrate) has become accepted treatment in patients with symptomatic, chronic congestive heart failure (CHF), and has been demonstrated in large clinical trials to ameliorate symptoms, improve exercise performance, and reduce cardiac mortality. Nevertheless, the management of patients with CHF remains a therapeutic challenge. The second Vasodilator-Heart Failure Trial (V-HeFT II) showed that the average 2-year mortality with enalapril (18%) was significantly lower than that with hydralazine-isosorbide dinitrate (25%) but, somewhat surprisingly, the nonspecific vasodilators produced significantly more improvement in exercise performance and left ventricular function. Such data suggest that improvement in symptoms, hemodynamics, and survival may not be afforded by the use of a single class of vasodilator therapy, but might be optimized by the combined use of different agents. This report describes the rationale and design of V-HeFT III, a multicenter, prospective, randomized, double-blind, placebo-controlled trial comparing the effects of chronic oral extended-release felodipine (felodipine ER) 2.5 to 5 mg twice daily, when added to a stable regimen of enalapril and loop diuretics, with or without digoxin, on exercise performance, morbidity, and mortality in patients with New York Heart Association functional class II to III CHF followed for a minimum of 12 weeks. Felodipine is a second-generation dihydropyridine calcium antagonist with a high degree of vascular selectivity which, in the doses used in this study, exerts its systemic arterial effect by decreasing peripheral vascular resistance without producing negative inotropic effects. The results of V-HeFT III may shed important light on the role of additive vasodilator therapy in the management of patients with CHF.

Interobserver discordance in the classification of mechanisms of death in studies of heart failure.

Studies of the mechanism of death in heart failure are dependent on the reliability and validity of classification of deaths as pump failure or arrhythmias (sudden). Two recent trials differed in that the Vasodilator Heart Failure Trial II (V-HeFT II) reported a higher incidence of sudden death than the Studies of Left Ventricular Dysfunction Treatment Trial (SOLVD) and an effect of enalapril on sudden death was not observed in SOLVD. A similar classification system was used in the two studies, but deaths in V-HeFT were classified centrally from a narrative summary, whereas deaths in SOLVD were classified in the field by individual investigators. To examine reliability, 10 narratives used to classify V-HeFT deaths were independently classified by 21 SOLVD investigators. In only 5 of 10 cases did 75% of SOLVD investigators agree with the V-HeFT classification. In no deaths were all SOLVD investigators in agreement on classification. Although V-HeFT classified 5 of 10 cases as sudden death, 16 of 21 SOLVD investigators classified less than 5 deaths as sudden and 1 classified none as sudden. The kappa statistic for interobserver agreement of 0.22 (P < or = .01) indicated interobserver agreement only slightly better than chance agreement. Therefore, the incidence of sudden death in heart failure is critically dependent on the bias of the investigator. Central classification will minimize inconsistencies, but it does not solve the problem that the mechanism of death is difficult to assign. Total mortality may be the only reliable endpoint in heart failure trials.

Hydralazine and isosorbide dinitrate combination improves exercise tolerance in heart failure. Results from V-HeFT I and V-HeFT II. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: To better define the effects of long-term vasodilator therapy on exercise performance in chronic congestive heart failure, we compared placebo with prazosin and with the combination of hydralazine and isosorbide dinitrate (Hyd-Iso) in 642 men over a 5-year period in V-HeFT I. METHODS AND RESULTS: Patients were randomized (double-blind) to 20 mg of prazosin daily or 300 mg of hydralazine plus 160 mg daily of isosorbide dinitrate or placebo. We compared enalapril (20 mg daily), a converting enzyme inhibitor, with Hyd-Iso in 804 men over another 5-year period in V-HeFT II: Background therapy in both trials consisted of digitalis and diuretics. Serial bicycle ergometric exercise was performed with gas exchange measurements during progressive incremental work rates to a symptom-limited peak end point. Gas exchange anaerobic threshold (ATge) measurement was performed in the second trial. In V-HeFT I, an increase in peak VO2 with Hyd-Iso compared with placebo approached significance at 2 months (p < 0.16) and was significant (p < 0.04) at 1 year. In V-HeFT II, Hyd-Iso significantly increased peak VO2 compared with enalapril (p < 0.01 at 3 months, p < 0.02 at 6 months and 2 years). The changes in ATge measurements were not statistically different between the two treatment groups in V-HeFT II: CONCLUSIONS: Combination therapy with Hyd-Iso was more effective in increasing peak VO2 than placebo, prazosin, or enalapril in patients with mild-to-moderate congestive heart failure. Long-term data were confounded by mortality and other events, which may have led to an underestimate of the benefits of Hyd-Iso over placebo and an underestimate of the long-term benefits of enalapril on exercise performance. Therefore, short-term improvement in exercise performance is a suitable therapeutic end point, but long-term studies should more appropriately assess mortality.

Functional capacity in heart failure. Comparison of methods for assessment and their relation to other indexes of heart failure. The V-HeFT VA Cooperative Studies Group.

BACKGROUND: Left ventricular (LV) dysfunction plays a primary role in the pathogenesis of congestive heart failure and correlates with prognosis, but a strong quantitative relation between exercise performance and indexes of LV function has not been demonstrated. We examined the relation between LV ejection fraction at rest, oxygen consumption at peak exercise (VO2), patient and physician assessments of clinical severity, and other clinical attributes in 804 patients with moderate heart failure. METHODS AND RESULTS: Ejection fraction correlated weakly with VO2, and mean ejection fraction was related to severity of symptoms. There was a statistical association between the patient's self-assessed quality of life questionnaire score and the physician-assigned New York Heart Association (NYHA) functional class; NYHA class was statistically associated with exercise performance. To identify other factors that might influence exercise capacity, comparisons of clinical attributes were made between patients grouped by VO2 within each stratum of LV function. Exercise performance was inversely related to plasma norepinephrine levels within the ejection fraction < 25% stratum. The percentage of patients reaching their anaerobic threshold was not different between groups, yet the peak heart rate increased with VO2 within all strata. Elevated venous pressure and cardiomegaly were inversely related to exercise performance. CONCLUSIONS: Clinical scales based on physician and patient assessment of symptoms were statistically associated with exercise capacity but do not accurately predict individual exercise performance. The strong association of heart rate response to exercise performance suggests that the variability of the chronotropic response to exercise contributes to differences in exercise capacity among patients with a similar degree of LV dysfunction.

A comparison of enalapril with hydralazine-isosorbide dinitrate in the treatment of chronic congestive heart failure.

BACKGROUND: To define better the efficacy of vasodilator therapy in the treatment of chronic congestive heart failure, we compared the effects of hydralazine and isosorbide dinitrate with those of enalapril in 804 men receiving digoxin and diuretic therapy for heart failure. The patients were randomly assigned in a double-blind manner to receive 20 mg of enalapril daily or 300 mg of hydralazine plus 160 mg of isosorbide dinitrate daily. The latter regimen was identical to that used with a similar patient population in the effective-treatment arm of our previous Vasodilator-Heart Failure Trial. RESULTS: Mortality after two years was significantly lower in the enalapril arm (18 percent) than in the hydralazine-isosorbide dinitrate arm (25 percent) (P = 0.016; reduction in mortality, 28.0 percent), and overall mortality tended to be lower (P = 0.08). The lower mortality in the enalapril arm was attributable to a reduction in the incidence of sudden death, and this beneficial effect was more prominent in patients with less severe symptoms (New York Heart Association class I or II). In contrast, body oxygen consumption at peak exercise was increased only by hydralazine-isosorbide dinitrate treatment (P less than 0.05), and left ventricular ejection fraction, which increased with both regimens during the 2 years after randomization, increased more (P less than 0.05) during the first 13 weeks in the hydralazine-isosorbide dinitrate group. CONCLUSIONS: The similar two-year mortality in the hydralazine-isosorbide dinitrate arms in our previous Vasodilator-Heart Failure Trial (26 percent) and in the present trial (25 percent), as compared with that in the placebo arm in the previous trial, (34 percent) and the further survival benefit with enalapril in the present trial (18 percent) strengthen the conclusion that vasodilator therapy should be included in the standard treatment for heart failure. The different effects of the two regimens (enalapril and hydralazine-isosorbide dinitrate) on mortality and physiologic end points suggest that the profile of effects might be enhanced if the regimens were used in combination.

Marked spontaneous improvement in ejection fraction in patients with congestive heart failure.

PURPOSE: The overall prognosis for patients with congestive heart failure is poor. Defining specific populations that might demonstrate improved survival has been difficult. We therefore examined our patient database for patients with congestive heart failure who demonstrated sustained improvement in left ventricular function and associated resolution of signs and symptoms of congestive heart failure. PATIENTS AND METHODS: We identified 11 patients with severe congestive heart failure (average ejection fraction 21.9 +/- 4.23% (+/- SD) who developed spontaneous, marked improvement over a period of follow-up lasting 4.25 +/- 1.49 years. All 11 patients were initially symptomatic with exertional dyspnea and fatigue for a minimum duration of 3 months. They form a subset of a larger group of 97 patients with chronic congestive heart failure that we have followed with sequential ejection fraction measurements. All 11 patients were treated with digitalis diuretics, and either converting-enzyme inhibitors or a combination of isosorbide dinitrate and hydralazine. Ten of the 11 patients had a history consistent with chronic alcoholism, and each reportedly abstained from alcohol during follow-up. RESULTS: During the follow-up period, the average ejection fraction improved in 11 patients from 21.9 +/- 4.23% to 56.64 +/- 10.22%. Late follow-up indicates an average ejection fraction of 52.6 +/- 8.55% for the group. Congestive heart failure resolved in each case. CONCLUSIONS: We conclude that selected patients with severe congestive heart failure can markedly improve their left ventricular function in association with complete resolution of heart failure. This appears to be particularly evident in those patients with chronic alcoholism who subsequently abstain.

Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure: influence of prerandomization variables on the reduction of mortality by treatment with hydralazine and isosorbide dinitrate.

The Veterans Administration Cooperative Study on Vasodilator Therapy of Heart Failure was designed to determine whether vasodilator drugs could alter the survival of patients with chronic congestive heart failure treated with digoxin and diuretics. Among the 642 patients entered into the study, 273 were randomly assigned to placebo, 186 were randomly assigned to the combination of hydralazine and isosorbide dinitrate, and 183 patients were randomly assigned to prazosin; all patients were followed for periods ranging from 6 months to 5.7 years. Treatment with hydralazine-nitrate produced a 28% reduction in mortality compared with that in patients receiving placebo (95% confidence interval, 3% to 46%), whereas prazosin exerted no apparent beneficial effect. Data were further examined to determine if any baseline variables had an impact on the response to treatment. Mortality in the placebo group was higher in those with coronary artery disease, with a history of antiarrhythmic drug use, and with values lower than the median for ejection fraction and exercise tolerance. A reduction in mortality with hydralazine-isosorbide dinitrate was observed in all of the above pairs of subgroups as well as in those above and below 60 years of age and those with and without a history of hypertension or excess alcohol ingestion. The benefit of hydralazine and isosorbide dinitrate was particularly prominent in younger patients with a lower ejection fraction and those with a history of hypertension and without an alcoholic history.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of vasodilator therapy on mortality in chronic congestive heart failure. Results of a Veterans Administration Cooperative Study.

To evaluate the effects of vasodilator therapy on mortality among patients with chronic congestive heart failure, we randomly assigned 642 men with impaired cardiac function and reduced exercise tolerance who were taking digoxin and a diuretic to receive additional double-blind treatment with placebo, prazosin (20 mg per day), or the combination of hydralazine (300 mg per day) and isosorbide dinitrate (160 mg per day). Follow-up averaged 2.3 years (range, 6 months to 5.7 years). Mortality over the entire follow-up period was lower in the group that received hydralazine and isosorbide dinitrate than in the placebo group. This difference was of borderline statistical significance. For mortality by two years, a major end point specified in the protocol, the risk reduction among patients treated with both hydralazine and isosorbide dinitrate was 34 percent (P less than 0.028). The cumulative mortality rates at two years were 25.6 percent in the hydralazine--isosorbide dinitrate group and 34.3 percent in the placebo group; at three years, the mortality rate was 36.2 percent versus 46.9 percent. The mortality-risk reduction in the group treated with hydralazine and isosorbide dinitrate was 36 percent by three years. The mortality in the prazosin group was similar to that in the placebo group. Left ventricular ejection fraction (measured sequentially) rose significantly at eight weeks and at one year in the group treated with hydralazine and isosorbide dinitrate but not in the placebo or prazosin groups. Our data suggest that the addition of hydralazine and isosorbide dinitrate to the therapeutic regimen of digoxin and diuretics in patients with chronic congestive heart failure can have a favorable effect on left ventricular function and mortality.

Relative attenuation of sympathetic drive during exercise in patients with congestive heart failure.

Patients with congestive heart failure have been considered to have augmented sympathetic drive both at rest and during dynamic exercise. The augmentation observed during exercise may be related to the state of near exhaustion experienced by patients with heart failure at relatively low work loads. To compare the response of the sympathetic nervous system to exercise in normal subjects and patients with heart failure when they are working in a comparable physiologic frame of reference, the data for both groups can be expressed as percent peak oxygen consumption achieved (percent peak VO2) rather than as a function of absolute oxygen consumption (VO2). Ten healthy control subjects and 31 patients with chronic clinical class II and III heart failure were studied during upright maximal bicycle exercise. Eighteen of the 31 patients had primary cardiomyopathy and 13 had ischemic cardiomyopathy. The average ejection fraction at rest was 24 +/- 10% (+/- SD) in the group with heart failure. Heart rate, systolic blood pressure, VO2 and plasma norepinephrine levels were measured at rest and throughout exercise. When the data were expressed as a function of percent peak VO2 achieved, patients with heart failure demonstrated a flatter slope (p = 0.004) than normal in the response of plasma norepinephrine to exercise, indicating a relative blunting of sympathetic drive. This was accompanied by attenuated heart rate (p = 0.001) and blood pressure (p less than 0.001) responses. These differences were not apparent when the data are expressed as a function of absolute VO2.(ABSTRACT TRUNCATED AT 250 WORDS)

Response of plasma norepinephrine and epinephrine to dynamic exercise in patients with congestive heart failure.

The activity of the sympathetic nervous system is increased at rest in patients with congestive heart failure. To determine whether this augmentation is carried over during dynamic upright exercise, 14 patients with congestive heart failure were stressed maximally during upright bicycle ergometry. Plasma norepinephrine and epinephrine levels were measured in the basal upright (sitting) posture before and during maximal exercise. The results were compared with those in six healthy control subjects before and during maximal exercise. Plasma norepinephrine increased during exercise from a mean (+/- standard error of the mean) of 650 +/- 95 to 1,721 +/- pg/ml in the group with heart failure. This increase was significantly less (p less than 0.001) than that in the control group (from 318 +/- 36 to 3,230 +/- 418 pg/ml). However, for equivalent levels of total body oxygen consumption (VO2), the group with heart failure had higher levels of plasma norepinephrine than the control group. Plasma epinephrine was similar in the two groups in the basal upright position (92 +/- 18 and 92 +/- 26 pg/ml), but it increased more during exercise in the normal subjects (743 +/- 210 pg/ml) than in the group with heart failure (167 +/- 67 pg/ml) (p less than 0.001). The percent increase in norepinephrine correlated with the percent change in VO2 in the group with heart failure (r = 0.62, p less than 0.02), but the percent change in epinephrine did not. There is, therefore, a disturbance in the sympathetic nervous system during exercise in patients with congestive heart failure. Although norepinephrine increases in such patients to a greater extent than in normal subjects at lower levels of exercise, the extremely high levels of norepinephrine and epinephrine generated by normal subjects during maximal upright exercise do not occur in patients with heart failure.

Clinical application of sodium nitroprusside.

The potent vasodilator sodium nitroprusside has been used to treat hypertensive emergencies and to improve the hemodynamics of chronic heart failure and acute myocardial infarction. As the use of this seemingly beneficial agent appears to be increasing, personnel caring for patients should be familiar with nitroprusside in order to use it properly and safely. We have reviewed the pharmacology, mode of mixing and administering, monitoring requirements, and indications of nitroprusside so it may be used with maximal benefit and minimal risk.