The acute response of plasma norepinephrine, renin activity, and arginine vasopressin to short-term nitroprusside and nitroprusside withdrawal in patients with congestive heart failure

Activation of the sympathetic nervous system, manifested by an increase in heart rate and circulating plasma norepinephrine, can occur in normal subjects when they are given vasodilators. The extent to which this activation occurs in patients with congestive heart failure (CHF) and whether this activation could account for the hemodynamic rebound sometimes observed following abrupt withdrawal of nitroprusside in such patients are unclear. We prospectively and retrospectively studied the effects of nitroprusside on plasma norepinephrine in 38 patients with CHF to determine if acute vasodilator therapy activates this vasoconstrictor system during or following such treatment. Thirty-six of these patients also had plasma renin activity (PRA) measured and plasma arginine vasopressin was measured in 12 patients. Baseline supine plasma norepinephrine (714 +/- 72 pg/ml, +/- SEM), PRA (15 +/- 2 ng/ml/hr), and arginine vasopressin (10 +/- 1 pg/ml) were increased at least twofold in the CHF patients. Nitroprusside (96 +/- 11 micrograms/min) was infused for 63 +/- 5 minutes after achieving an optimal hemodynamic response: cardiac index increased (2.01 +/- 0.08 to 2.67 +/- 0.1 L/min/m2, p less than 0.001), pulmonary artery wedge pressure decreased (25 +/- 1 to 16 +/- 1 mm Hg, p less than 0.001), mean arterial pressure decreased (83 +/- 1 to 72 +/- 1 mm Hg, p less than 0.001), and heart rate was unchanged. Plasma norepinephrine (632 +/- 43 pg/ml), PRA (18 +/- 3 ng/ml/hr), and arginine vasopressin (11 +/- 1 pg/ml) did not change significantly for the group during peak effect of the vasodilator.(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 < 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 (V?O₂), 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 < 0.001). The percent increase in norepinephrine correlated with the percent change in V?O₂ in the group with heart failure (r = 0.62, p < 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.     

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)     

Ventricular arrhythmias in patients with rest angina: correlation with ST segment changes and extent of coronary atherosclerosis

Major ventricular arrhythmias occurring concurrently with myocardial ischemia are presumed to be the most frequent mechanism for sudden cardiac death. Two hundred eighteen catheterized patients with angina pectoris at rest were reviewed to identify clinical, ECG, and arteriographic features that might correlate with the presence of serious ventricular arrhythmias occurring during episodes of rest pain. Ventricular arrhythmias during episodes of rest pain were significantly more common in patients who manifested transient ST segment elevation in the anterior leads and in patients with marked transient ST segment shifts (greater than 5 mm). Ventricular arrhythmias during episodes of rest pain were not more common in patients with extensive coronary artery disease.     

Beneficial hemodynamic effects of intravenous diazoxide in refractory congestive heart failure

Despite the growing popularity of vasodilator therapy for acute and chronic congestive heart failure (CHF), no single agent has been uniformly effective and well tolerated. Therefore, we investigated the acute hemodynamic response to diazoxide, a potent and long-acting arteriolar dilator, in nine patients with severe CHF refractory to conventional treatment and, in seven of nine, other vasodilators. Diazoxide was administered intravenously in successive 300 mg infusions, each over 10 minutes, until a satisfactory response in cardiac output occurred or a fall in arterial blood pressure or increase in heart rate was noted. The mean dose of diazoxide was 670 mg (range 450 to 900 mg). Systemic vascular resistance fell immediately, by a maximum of 44%. Arterial pressure was not changed significantly, but cardiac and stroke volume indices rose by 64% and 49%, respectively, from 2.0 ± 0.5 to 3.3 ± 0.6 L/min/m² and from 24 ± 10 to 36 ± 9 ml/m² (each p < 0.001). Pulmonary capillary wedge pressure declined more gradually, by a mean of 8 mm at 4 and 6 hours after drug infusion. This hemodynamic improvement was sustained for a mean of 9.7 hours (range 6 to 12 hours). Our findings indicate that intravenous diazoxide may be useful in the management of acute heart failure and that a trial of oral diazoxide in chronic normotensive CHF is warranted.     

Regional hemodynamic effects of beta-adrenergic blockade with propranolol in the unanesthetized primate

The effects of equal doses of d- and dl-propranolol on systemic and regional hemodynamics were studied in the unanesthetized rhesus monkey using the radioactive microsphere technique. No changes in systemic hemodynamics were seen with d-propranolol, but dl-propranolol significantly decreased the cardiac output (?25 per cent), heart rate (?18 per cent), and stroke volume (?9 per cent), and increased the total peripheral resistance (+40 per cent). During the dl-propranolol infusion the cardiac output was preferentially distributed to the brain with a small decrease in the fraction received by the liver. Flow to all organs except the brain was diminished during dl-propranolol, and the decrease was proportionate to the change in cardiac output. No change in distribution of flow was seen with d-propranolol and total flow to all organs was unchanged from control, with the exception of an increase in flow to the skin. This comparison of d- and dl-propranolol indicates that the effects of dl-propranolol are due to beta-adrenergic blockade rather than a non-specific effect of the drug.     

Comparative systemic and regional hemodynamic effects of dopamine and dobutamine.

Dopamine and dobutamine are sympathomimetic amines with divergent peripheral vascular actions. The renal, mesenteric, and femoral vascular and total systemic hemodynamic effects of these amines were compared in pentobarbital-anesthetized dogs. Both agents increased myocardial contractility. Infusion rates of dopamine greater than 5 mug per kilogram per minute increased mean aortic pressure. Dobutamine increased mean aortic pressure. Dobutamine in creased the systolic pressure but did not alter mean aortic pressure. Dobutamine increased cardiac output more than dopamine. Dopamine infusions up to 10 mug per kilogram per minute increased renal and mesenteric blood flow and decreased vascular resistance. Dobutamine had negligible effects on the renal or mesenteric blood flow but produced dose-related increases in femoral blood flow. Dopamine did not significantly alter femoral hemodynamics. These results more clearly define the systemic and regional vascular hemodynamic effects of these agents.     

Effects of vasodilators on pulmonary hemodynamics and gas exchange in left ventricular failure

Nitroprusside (NP) has been shown to improve left ventricular function in patients with congestive heart failure, but despite an increased cardiac output and decreased pulmonary capillary pressure, arterial oxygen tension (P_aO₂) may fall. In order to determine the mechanism of this hypoxemia, and to determine if similar effects occur with non-parenteral vasodilators, hemodynamic, respiratory, and blood gas responses to NP, hydralazine (H), and hydralazine combined with isiosorbide dinitrate (H+N) were studied in 10 patients with left ventricular failure. At the dosages used, all three drug regimens increased cardiac output equivalently, but pulmonary vascular responses differed. NP and H+N decreased mean pulmonary artery pressure, pulmonary wedge pressure, and pulmonary arteriolar resistance, while H did not. NP decreased P_aO₂ by 10.4 mm. Hg (p < .01) and H+N decreased it by 5.3 mm. Hg (p < .06) while H did not alter P_aO₂. Arteriolar-alveolar oxygen gradient increased with NP (150 ± 39 per cent, p < .01) and with H+N (73 ± 23 per cent, p < .01) but not H alone (51 ± 16 per cent). Similarly, per cent change in venous admixture increased on NP (28.7 ± 3.3 to 38.5 ± 3.1 per cent, p < .01) and H+N (28.1 ± 3.3 to 36.8 ± 3.5 per cent, p < .01) but not H alone (28.1 ± 3.3 to 31.5 ± 4.1 per cent). There was no increase in arterial carbon dioxide tension or change in pulmonary function studies with any of the drugs. Due to the increase in cardiac output, oxygen delivery index (cardiac output times arterial oxygen content) increased with each regimen despite the changes in P_aO₂. Changes in arteriolar-alveolar oxygen gradient correlate with the changes in pulmonary arteriolar resistance. Thus vasodilators which have prominent pulmonary vascular effects can decrease P_aO₂ in patients with congestive heart failure, and this effect is most likely due to increasing ventilation-perfusion inequities.     

Comparative effects of oral verapamil and propranolol on exercise-induced myocardial ischemia and energetics in patients with coronary artery disease: Single-blind placebo crossover evaluation using radionuclide ventriculography

Using multiple-gated equilibrium cardiac blood pool imaging and single-blind placebo crossover protocol, the effects of oral verapamil (VRP) (480 mg/day) were compared to those of oral propranolol (PRP) (320 mg/day) on the left ventricular ejection fraction (LVEF) and regional wall motion (RWM) abnormalities at rest and during supine bicycle exercise in 15 patients with coronary artery disease (CAD). During exercise on placebo before VRP the mean LVEF fell from the resting value of 0.54 ± 0.09 to 0.47 ± 0.12 (p < 0.05); on VRP (plasma level 283 ± 150 ng/dl and noverapamil 220 ± 97 ng/dl) the corresponding values were 0.54 ± 0.11 and 0.53 ± 0.13 (NS). On placebo before PRP, exercise reduced LVEF from 0.54 ± 0.13 to 0.48 ± 0.14 (p < 0.05); on PRP (plasma level 144 ± 59 ng/dl) the resting LVEF was 0.54 ± 0.11 and exercise LVEF 0.52 ± 0.13 (NS). Both drugs reduced the exercise-induced RWM (interoapical) abnormality and ST segment depression but the changes were only significant (p < 0.05) in the case of VRP. PRP attenuated the exercise-induced increase in heart rate by 24.5% (p < 0.005), in systolic blood pressure by 13.4% (p < 0.001), in diastolic pressure by 8.7% (p < 0.005), and in rate-pressure product by 34.5% (p < 0.001). VRP reduced the exercise heart rate response by 10.3% (p < 0.001), systolic pressure by 4.6% (NS), diastolic pressure by 7.9% (p < 0.005), and rate-pressure product by 14.6% (p < 0.001). These data suggest that VRP and PRP exhibit comparable potency in reducing the ischemic consequences of exercise stress in CAD patients. In the case of PRP, the beneficial effect was accountable in terms of reduction in oxygen demand; in the case of VRP, additional mechanisms such as those involving myocardial metabolism or primary changes in perfusion may be involved.     

Regional myocardial perfusion at rest and during intracoronary papaverine in patients with coronary artery disease

Regional myocardial perfusion was measured in 32 patients with the xenon-133 washout technique at rest and after 5 mg of intracoronary papaverine. Areas of decreased perfusion and/or decreased vasodilation were identified visually from computer-generated functional images. The locations of arteries and stenoses, obtained from identically positioned cineangiograms, were overlaid on the functional images. Perfusion rates for 62 myocardial regions were calculated and correlated with the percentage of stenosis. There was no association between degree of stenosis and perfusion at rest. Regional myocardial perfusion increased after papaverine in regions supplied by coronary arteries without stenoses (0% to 25%), 88.6 ± 4.7 ml/min/100 gm. This increase was significantly greater (p < 0.001) than the increase in regions supplied by 51% to 75% stenoses (23.7 ± 6.3 ml/min/100 gm), or 76% to 99% stenoses (12.9 ± 6.3 ml/min/100 gm), or 100% stenoses (2.5 ± 3.8 ml/min/100 gm). Thus there was an inverse relationship between the increase in myocardial perfusion stimulated by papaverine and the degree of coronary artery stenosis measured angiographically. In regions supplied by two stenoses in series, vasodilation produced less of an increase than a single stenosis of a similar degree.     

Effect of propafenone in patients with stable ventricular arrhythmias

Thirty patients with clinically significant ventricular ectopy were treated with propafenone, a new potent antiarrhythmic agent with membrane stabilizing action. Patients had a minimum mean of greater than 30 ventricular premature beats per hour documented by continuous 48-hour ambulatory ECG recording. Twenty-five patients qualified as responders, defined as greater than 85% reduction of ventricular ectopy compared to baseline, and completed a double-blind placebo-crossover phase. Significant reduction in single ventricular ectopy per hour, paired ventricular ectopy per hour, and ventricular tachycardia beats per hour were observed. Almost total abolition of ventricular tachycardia and paired ventricular ectopy was achieved. Side effects were minimal and well tolerated. A significant prolongation of the PR interval occurred. QRS prolongation and prolongation of the corrected QT interval was observed in some patients, with new left bundle branch block developing in two patients. Long-term efficacy and safety studies will be necessary to determine the ultimate role of this new agent in the selection of antiarrhythmic therapy, but these inital results are encouraging.     

Bacteremia following dental cleaning in patients with and without penicillin prophylaxis

The rate, type, and magnitude of bacteremia were studied in 56 patients undergoing dental cleaning with and without penicillin prophylaxis. Sixty-one percent of patients without penicillin prophylaxis were bacteremic 5 minutes following the procedure. Although a significant decrease in detectable bacteremia occurred in patients receiving penicillin prophylaxis, the recovery of streptococci was not significantly different in the two groups. Using the present sample of patients as a basis for statistical inference, the true rate of bacteremia in such patients could be between 41% and 79% with 95% certainty. The magnitude of bacteremia was low and positive quantitative pour plates occurred at 5 minutes and only in patients without penicillin prophylaxis. Of the 71 total bacterial isolates, 53 (74.6%) were anaerobes and 18 (25.4%) were aerobes. This study indicates that parenteral penicillin prophylaxis for dental cleaning decreased detectable bacteremia rates significantly and could be recommended for patients with valvular heart disease who are known to be vulnerable to endocarditis.     

Acute effects of captopril on cardiopulmonary hemodynamics and renin-angiotensin-aldosterone and bradykinin profile in hypertension

Hemodynamic variables were measured and plasma renin activity (PRA), angiotensin II (AII), aldosterone, and bradykinin assays performed in 21 hypertensive men on regular diet and thiazide diuretics before and 60 to 90 minutes after 25 mg oral captopril. Heart rate, right and left ventricular filling pressures, mean cardiac index (CI), and pulmonary vascular resistance (PVR) remained unchanged. The mean intra-arterial pressure (MAP) fell from 140 +/- 5 to 116 +/- 6 mm Hg (p less than 0.001) correlating with reduction of systemic vascular resistance (SVR) (r = 0.87, p less than 0.001), control PRA (r = 0.59, p less than 0.01), and All levels (r = 0.72, p less than 0.005) but not with control bradykinin or its postcaptopril rise (p less than 0.01). The fall in SVR correlated with reduction in plasma All (r = 0.80, p less than 0.001) and aldosterone concentrations (r = 0.53, p less than 0.05). Of four patients (19%) with precipitous fall in MAP after captopril, three needed volume expansion for circulatory support. We conclude: (1) All reduction by captpril and not bradykinin potentiation explains most of the agent's hemodynamic response in hypertensive circulation, (2) endogenous All may have a supportive role for SVR and possibly for CI but not for PVR, and (3) extra precaution is warranted while captopril is being started in patients taking diuretics.     

Predicting oxygen uptake from treadmill testing in normal subjects and coronary artery disease patients

In order to evaluate the clinical practice of estimating oxygen uptake from treadmill time, patients with coronary heart disease and normal subjects had their oxygen uptake measured during treadmill testing. Continuous expired gas analysis was performed in order to see if the gas exchange anaerobic threshold could explain the difference between measured and estimated oxygen uptake. Below the gas exchange anaerobic threshold, normal subjects and patients had similar oxygen uptakes for a given workload. However, at workloads above this threshold, patients had approximately 1 MET lower oxygen uptake than normal subjects. Regression equations relating treadmill time to oxygen uptake are specific to groups of patients or individuals due to differences in anaerobic threshold. In addition, the use of standard workloads to predict aerobic capacity depends on the rate at which oxygen uptake obtains a steady state value. These findings must be considered in clinical practice when attempting to estimate aerobic capacity from treadmill testing.     

Reassessment of vasodilator therapy in angina: Effects of oral isosorbide dinitrate and hydralazine on exercise tolerance in patients receiving propranolol

Nitrates, predominantly venodilators, are commonly used in the treatment of angina pectoris, whereas hydralazine, a potent systemic and coronary arterial vasodllator, is usually contraindicated. Hydralazine might be useful in therapy of angina H tachycardia could be prevented by beta adrenergic blockade. Consequently, treadmill exercise tolerance was determined in 20 patients with chronic stable angina during treatment with oral propranolol, 60 mg four times daily (control), propranolol plus 20 mg of oral isosorbide dinitrate, propranolol plus 100 mg of oral hydralazine, and all three drugs combined. The mean heart rate at rest in patients recelving propranolol was 54.0 ± 1.7 beats/min (mean ± standerd error of the mean). It increased 6.8 beats/min with the additlon of hydralazine (p < 0.005) and 7.2 beats/min with Isosorbide dlnitrate and hydralazine comblned (p < 0.005), but was unchanged with Isosorbide dinitrarate alone. Systoilc blood pressure decreased 13.5 mm Hg with Isosorbide dinitrate (p < 0.05) and 28.3 mm Hg with Isosorbide dinitrate and hydralazine combined (p < 0.005), but did not change significantly with hydralazine alone (average decrease 4.1 mm Hg). The mean duration of exercise increased by 24.1 seconds with Isosorbide dinitrate (p < 0.05), and almost twice that (42.4 seconds longer than the control value) with Isosorbide dinitrate and hydralazine (p < 0.005). With hydralazine alone, exercise duration was decreased by 24.7 seconds (p < 0.05). Rate-pressure product at symptom-tolerated maximal exercise was unchanged with Isosorbide dinitrarate or hydralazine alone, but lower than the control value with the two agents combined. It Is concluded that Isosorbide dinitrate Improves exercise tolerance in patients with angina who are being treated with propranolol, but hydralazine remains detrlmental despite the use of the beta blocking agent. However, when Isosorbide dinitrate is combined with hydralazine, the detrimental effects of hydralazine on exercise tolerance are reversed.     

Alternating bundle branch block

Mechanisms postulated for alternating bundle branch block are incomplete-and cycle-length-dependent-block in both the right and left bundle branches. A patient with severe longstanding cardiac conduction disease who developed alternating bundle branch block during treatment for advanced ischemic heart disease and malignant ventricular arrhythmia is presented. In this patient alternation was induced by atrial premature beats as well as spontaneous and pacemaker induced premature ventricular beats. Right bundle branch block which followed a premature atrial beat resulted from the longer refractory period of the right bundle. The maintenance of right bundle branch block at long cycle lengths was presumed to be due to continuous retrograde reentry. This was terminated when a pause following a premature beat allowed functional recovery of the right bundle branch. This patient died suddenly at home with a functioning pacemaker, demonstrating the high risk of death from ventricular dysrhythmia in the post myocardial infarction patient with a new conduction defect.