Sally S. Cutler

Contribution of Vasopressin to Vasoconstriction in Patients With Congestive Heart Failure: Comparison With the Renin-Angiotensin System and the Sympathetic Nervous System

Ten patients with advanced congestive heart failure were treated with an arginine vasopressin V1 antagonist during hemodynamic monitoring to determine the contribution of vasopressin to vasoconstriction in this disorder. The vasopressin antagonist caused a decrease in systemic vascular resistance in the three patients whose plasma vasopressin was greater than 4.0 pg/ml (average for the group was 2.4 +/- 0.6). Plasma vasopressin concentration correlated with the percent decrease of systemic vascular resistance (r = 0.70, p less than 0.025), serum sodium (r = 0.72, p less than 0.02) and serum creatinine (r = 0.85, p less than 0.005). To compare the relative roles of vasopressin, the renin-angiotensin system and the sympathetic nervous system, these patients also received captopril and phentolamine. Captopril decreased systemic vascular resistance by 20% (p less than 0.05), mostly in patients with high plasma renin activity. Levels of plasma renin activity ranged between 1 and 46 ng/ml per h (average 14.7 +/- 5.7) and correlated with serum sodium (r = 0.77, p less than 0.025), serum creatinine (r = 0.73, p less than 0.025) and right atrial pressure (r = 0.67, p less than 0.05). Phentolamine decreased systemic vascular resistance in all patients (average 34%, p less than 0.01), but the decrease did not correlate with the pretreatment norepinephrine concentration. Norepinephrine levels were elevated in all patients (694 +/- 110 pg/ml) and correlated with baseline stroke volume index (r = 0.75, p less than 0.025) and plasma renin activity (r = 0.67, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of the Time Saved by Prehospital Initiation of Reteplase for ST-Elevation Myocardial Infarction Results of the Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 Trial

OBJECTIVES The Early Retavase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 trial tested the feasibility of prehospital initiation of the bolus fibrinolytic reteplase (rPA) and determined the time saved by prehospital rPA in the setting of contemporary emergency cardiac care. BACKGROUND Newer bolus fibrinolytics have undergone only limited evaluation for prehospital administration. In addition, as door-to-drug times have decreased, the relevance of findings from prior trials of prehospital fibrinolysis has become less certain. METHODS Patients (n = 315) with ST-elevation myocardial infarction (STEMI) were enrolled in 20 emergency medical systems in North America. The time from emergency medical service (EMS) arrival to administration of a fibrinolytic was compared between study patients receiving prehospital rPA and sequential control patients from 6 to 12 months before the study who received a fibrinolytic in the hospital. RESULTS Acute myocardial infarction was confirmed in 98%. The median time from EMS arrival to initiation of rPA was 31 min (25th to 75th percentile, 24 min to 37 min). The time from EMS arrival to in-hospital fibrinolytic for 630 control patients was 63 min (25th to 75th percentile, 48 min to 89 min), resulting in a time saved of 32 min (p < 0.0001). By 30 min after first medical contact, 49% of study patients had received the first bolus of fibrinolytic compared with only 5% of controls (p < 0.0001). In-hospital mortality was 4.7%. Intracranial hemorrhage occurred in 1.0%. CONCLUSIONS Prehospital administration of rPA is a feasible approach to accelerating reperfusion in patients with STEMI. Valuable time savings can be achieved in the setting of contemporary transport and door-to-drug times and may translate into an improvement in clinical outcomes.

Decrease in systolic blood pressure during exercise testing: Reproducibility, response to coronary bypass surgery and prognostic significance

To investigate the reproducibility and prognostic significance of an exercise-induced decrease in systolic blood pressure, 47 patients were identified who manifested such a reduction below the pre-exercise standing level in a consecutive series of 436 patients who underwent treadmill exercise testing and cardiac catheterization during a 3 year period. The prevalence of this abnormal finding was 11 percent in the total group but 21 percent in the 124 patients with three vessel or left main coronary artery disease. Patients with an exercise-induced reduction in systolic blood pressure were more likely to be male, have typical angina pectoris with class III or IV functional limitation and to have had a prior myocardial infarction than were patients without this finding (p less than 0.05). Although no complications occurred during the exercise test of these 47 patients, the majority had severe ischemic responses and 14 (30 percent) showed complex repetitive ventricular arrhythmias. Of the 47 patients, 24 (group 1a) received medical treatment and 23 (group 1b) underwent coronary bypass surgery. On repeat exercise testing in 42 patients, a decrease in systolic blood pressure during exercise was consistently present in group 1a (17 of 20) but entirely absent (0 of 22) in group 1b (p less than 0.001). The mean treadmill time, peak heart rate and systolic blood pressure were not significantly different in the initial and on repeat exercise tests in patients in group 1a; however, in patients in group 1b, all of these variables were significantly higher in the repeat test (p less than 0.001). At a mean follow-up time of 37 months, the total cardiac mortality rate was 8 percent (2 of 24) in group 1a and 4 percent (1 of 23) in group 1b. It is concluded that a decrease in systolic blood pressure during exercise testing is highly reproducible and appears to be reversed by coronary bypass surgery.

Efficacy and safety of incremental doses of diltiazem for the treatment of stable angina pectoris

The safety and efficacy of incremental doses of diltiazem in treating angina pectoris were assessed in 20 patients with functional class II to III exertional angina. During an initial single-blind dose titration phase, dilitiazem produced a dose-related improvement in anginal frequency and exercise capacity. Weekly anginal attacks were reduced to 7.5 +/- 8.9, 5.6 +/- 7.8 and 4.9 +/- 7.3 on diltiazem, 120, 240 and 360 mg per day, respectively, as compared with 11.9 +/- 8.7 on placebo (all p less than 0.001). Treadmill time was significantly enhanced by high dose (360 mg per day) as compared with moderate dose (240 mg per day) diltiazem: 473 +/- 149 versus 424 +/- 146 seconds (p less than 0.05). Time to ischemic ST segment depression was similarly changed: 344 +/- 132 versus 298 +/- 142 seconds (p less than 0.05) by high dose as compared with moderate dose diltiazem. During a subsequent double-blind phase, high dose diltiazem significantly reduced weekly anginal frequency when compared with placebo: 3.1 +/- 3.0 versus 9.3 +/- 7.1 (p less than 0.001); and increased treadmill exercise time: 508 +/- 158 versus 418 +/- 172 seconds on placebo (p less than 0.05). Subjective and objective benefits of high dose diltiazem were sustained during a follow-up period of 6 months without major drug side effects.

Comparison of a 60- versus 90-minute determination of ST-segment resolution after thrombolytic therapy for acute myocardial infarction

Determination of ST-segment resolution 60 minutes after the administration of thrombolytic therapy allows accurate risk stratification for mortality and congestive heart failure. Patients with complete ST resolution at 60 minutes tended to be at lower risk for 30-day mortality than patients with complete ST resolution at 90 minutes.

Efficacy and Safety of Sustained-Release Diltiazem in Stable Angina Pectoris

The safety and efficacy of a sustained-release preparation of diltiazem (diltiazem-SR), with dose levels of 240 and 360 mg/day, were assessed in 18 patients with stable angina of effort. A double-blind, placebo-controlled, randomized, crossover protocol was used. Diltiazem-SR, when given twice daily, reduced the frequency of weekly anginal attacks from 9.3 +/- 10.4 with placebo to 3.7 +/- 4.7 with 240 mg/day and to 3.1 +/- 4.7 with 360 mg/day (both p less than 0.01 compared with placebo). Treadmill time was increased from 410 +/- 180 seconds during the placebo phase to 519 +/- 177 seconds during the 240-mg/day dose and to 506 +/- 182 seconds during the 360-mg/day dose of diltiazem-SR (both p less than 0.01 compared with placebo). The time to the onset of angina and ischemic ST-segment depression were similarly prolonged by both doses of diltiazem-SR. The beneficial effects of diltiazem-SR appeared partly due to a reduction in the heart rate during submaximal exercise. Diltiazem-SR is effective and safe for the treatment of angina of effort when given twice daily.

Treatment of stable angina of effort with verapamil: a double-blind, placebo-controlled randomized crossover study.

The effects of verapamil were assessed in 26 patients with stable exertional angina pectoris in a double-blind, placebo-controlled, randomized crossover protocol using serial treadmill tests. Verapamil, 480 mg/day, reduced anginal frequency from 5.6 ± 7.3 to 2.2 ± 3.9 attacks per week (p < 0.001) and nitroglycerin consumption from 3.4 ± 4.9 to 1.2 ± 2.5 tablets.per week (p < 0.05) compared with placebo. Treadmill time increased from 6.4 ± 2.1 minutes during the placebo phase to 7.5 ± 1.8 minutes during the verapamil phase (p < 0.001). Verapamils beneficial effect appeared to be related, in part, to a 10% reduction of the rate-pressure product at rest (p < 0.05) and a 12% reduction during submaximal exercise (p < 0.001). Verapamil also caused less marked ST-segment depressions at peak exercise (p < 0.05) at a similar rate-pressure product, suggesting a favorable redistribution of coronary blood flow to the ischemic zone. Side effects from verapamil were minimal, consisting mainly of constipation (six patients). Verapamil appears to be a safe and effective drug for treating angina of effort.

Hepatotoxicity Due to Treatment With Verapamil

Excerpt Verapamil hydrochloride (Isoptin; Knoll Pharmaceuticals, Whippany, New Jersey), a papaverine derivative currently being tested experimentally in the United States, is a calcium channel bloc...

Responsiveness of atrial natriuretic factor to reduction in right atrial pressure in patients with chronic congestive heart failure

In patients with congestive heart failure, atrial natriuretic factor may serve as a counter-regulatory hormone, offsetting the vasoconstrictive and volume-retentive effects of the sympathetic nervous system, the renin-angiotensin-aldosterone system and vasopressin. Indeed, the plasma levels of atrial natriuretic factor and the vasoconstrictor hormones are often simultaneously elevated in these patients. It is not known, however, whether atrial natriuretic factor remains responsive to sudden reductions in atrial pressure in patients with chronic heart failure, or is unresponsive like the vasoconstrictor systems. To examine this issue, the plasma concentrations of atrial natriuretic factor and the vasoconstrictor hormones were measured in 20 normal subjects and 12 patients with chronic congestive heart failure during incremental lower body negative pressure, an intervention that lowers atrial pressure. In the normal subjects, incremental lower body negative pressure at -10, -20 and -40 mm Hg decreased central venous pressure and pulse pressure. At maximal lower body negative pressure, plasma atrial natriuretic factor levels decreased from 51 +/- 5 to 27 +/- 3 pg/ml (p less than 0.01), whereas increases occurred in plasma levels of norepinephrine (194 +/- 11 to 385 +/- 70 pg/ml, p less than 0.01), renin activity (1.4 +/- 0.2 to 3.9 +/- 0.1 ng/ml per h, p less than 0.01) and vasopressin (1.3 +/- 0.1 to 6.4 +/- 2.4 pg/ml, p less than 0.05). In the patients with congestive heart failure, lower body negative pressure also reduced central venous pressure. Baseline plasma atrial natriuretic factor levels were markedly elevated, averaging 438 +/- 138 pg/ml, and decreased to 317 +/- 87 pg/ml at maximal lower body negative pressure (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Serial exercise testing after coronary artery bypass surgery.

To determine the duration of functional benefit from coronary bypass surgery, 111 patients with angina pectoris were serially evaluated by standard exercise testing prior to and for up to 4 years after surgery. Exercise testing 6 to 18 months after surgery showed greater heart rate-blood pressure product at peak work load, improved work capacity, and less symptomatic and electrocardiographic evidence of ischemia than was demonstrated preoperatively. Twenty patients were tested 37 to 48 months postoperatively and showed improved exercise performance in comparison with preoperative results, but the frequency of positive tests during this period no longer differed. Thus, improved exercise performance appears to persist for at least 4 years after coronary bypass surgery.