Chronic therapy for congestive heart failure with benazepril HCl, a new angiotensin converting enzyme inhibitor.

Benazepril HCl is an orally effective angiotensin converting enzyme (ACE) inhibitor previously shown to have significant acute hemodynamic benefits in patients with congestive heart failure. In this study, 21 patients with New York Heart Association Class III or IV congestive heart failure were treated with 2 to 15 mg of benazepril HCl as a single daily oral dose for 28 days to determine the clinical and hemodynamic value of chronic therapy. Each patient underwent clinical evaluation during the 28-day period, as well as invasive hemodynamic studies on the first two and last two days of the trial. Plasma ACE activity and aldosterone levels fell significantly and renin levels rose after therapy. Benazepril HCl produced significant (p less than 0.01) reductions in arterial pressure and systemic vascular resistance, with corresponding increases in cardiac output and decreases in pulmonary artery wedge pressure. Responses after 28 days of therapy were equivalent to those after the initial doses. Clinical effects included reduced rest, exertional and paroxysmal nocturnal dyspnea, as well as reduced peripheral edema. Only one patient developed symptomatic orthostatic hypotension. Thus, benazepril HCl, given once daily, is an effective and well tolerated oral agent for the chronic treatment of advanced congestive heart failure.

Use of hepatic vein catheterization in the evaluation of patients with anasarca.

In patients with anasarca, the relative importance of cardiac, pulmonary and/or hepatic dysfunction is often difficult to determine. Conventional use of the Swan-Ganz catheter helps to separate the contributions of right and left heart disease, but it is seldom used to evaluate liver dysfunction. This report describes passage of a Swan-Ganz catheter into the hepatic vein prior to pulmonary artery placement in 11 patients. Hepatic vein catheterization permitted wedged hepatic venography using contrast media and measurement of the wedged and free hepatic venous pressures. All 11 patients had pulmonary hypertension; three had cor pulmonale only, and the others had combinations of left and right heart failure. In addition, six patients had either a cirrhotic pattern on venography, or portal hypertension. Only three of these six patients had previous clinical evidence of liver disease. This study does not prove that identification of hepatic dysfunction by this method improves the outcome in such patients. However, this low risk modification of standard pulmonary artery catheterization provides additional information which is clinically useful in searching for and avoiding complications of cirrhosis, as well as offering a clearer understanding of pathophysiology in acute multisystem disease.

A multicenter study of the safety and efficacy of benazepril hydrochloride, a long-acting angiotensin-converting enzyme inhibitor, in patients with chronic congestive heart failure.

Benazepril hydrochloride is a nonsulfhydryl, long-acting angiotensin-converting enzyme inhibitor that is orally effective. This study was designed to determine the acute hemodynamic effects of this agent in patients with chronic congestive heart failure. Twenty-six patients with New York Heart Association class III or IV congestive heart failure and left ventricular ejection fractions less than 35%, cardiac indexes less than 2.1 L/min/m2, and pulmonary artery wedge pressures greater than 12 mm Hg were given 2 or 5 mg benazepril hydrochloride. All does produced significant (p less than 0.05) increases in cardiac output (26.7% to 31.6% above control) and heart rate (5.4% to 11.2% above control) and decreases in systemic (27.1% to 32.0% below control) and pulmonary (34.8% to 55.5% below control) vascular resistances, mean pulmonary (25.3% to 30.3% below control) and systemic (13.4% to 18.5% below control) arterial pressures, and pulmonary artery wedge pressure (46.9% to 51.1% below control). Twenty-four hours after an initial dose, systemic vascular resistance and pulmonary artery wedge pressures remained below control levels. Angiotensin-converting enzyme activity fell by 67.8% +/- 6.4%, with a 15.8% +/- 7.6% decline in aldosterone levels. Thus benazepril hydrochloride is an effective angiotensin-converting enzyme inhibitor that produces hemodynamic effects that persist for 24 hours after a single oral dose.

Instrumentation and practice standards for electrocardiographic monitoring in special care units. A report for health professionals by a Task Force of the Council on Clinical Cardiology, American Heart Association.

The proposed recommendations for continuous electrocardiographic monitoring systems represent goals for future development. Description of a technique in the report does not constitute an endorsement of its clinical use. Lead systems for ECG monitoring must adequately sense the cardiac electrical field and the leads should be standardized. Future monitors should be capable of simultaneously displaying and analyzing multiple leads. Recommendations for electrode placement and position of patient are made. Important parameters in each category of standards for instrumentation published in 1983 in the American National Standard for Cardiac Monitors, Heart Rate Meters, and Alarms are listed. Selected procedures proposed by the Association for the Advancement of Medical Instrumentation to inform users of minimally acceptable accuracy of computerized systems in a standardized manner are presented. Emphasis is placed on the importance of nursing and medical staff capabilities. Personnel qualifications and training as well as systems to assure and maintain quality of immediate ECG diagnosis are highlighted.

Effect of changes in the definition of ventricular tachycardia on the prevalence of complex ventricular ectopy.

The presence of ventricular tachycardia (VT) is commonly considered to represent a risk factor for sudden cardiac death as well as an indication for antiarrhythmic drug therapy. Although spontaneous VT is generally diagnosed by the presence of three or more consecutive ectopic beats, proposed criteria for induced VT require six or more complexes at rates exceeding 90 or 100 beats/min. To determine the clinical implications of a similar change in the diagnostic criteria for spontaneous VT, the authors examined 324 consecutive 24-hour ambulatory electrocardiograms. Of these, 111 (34.3%) had episodes of three or more ventricular premature beats. If six or more beats were required, only 34 (30.6%) would have been diagnosed as having VT. Requiring a minimum rate of 90 or 100 beats/min had less consequence, eliminating only 10 (9.0%) and 12 (10.8%) patients, respectively. Patients with only three to five beat runs had significantly fewer isolated premature beats (4,462.8 +/- 588.4 vs 7,158.1 +/- 1,688.1) and ventricular couplets (186.2 +/- 39.2 vs 294.3 +/- 74.4) per day, and slower average rates (142.1 +/- 4.6 vs 171.8 +/- 6.7 beats/min) during ventricular tachycardia than did those with runs of six or more beats. Thus, altering the definition of spontaneous VT has marked effects on the prevalence of this arrhythmia. Those patients excluded did, however, have a lower prevalence of associated electrocardiographic risk factors.

Efficacy of pentoxifylline in patients with stable angina pectoris.

Pentoxifylline, a methyl xanthine derivative, improves symptoms of peripheral vascular disease probably by reducing whole blood viscosity. The authors assessed the value of this agent in treating myocardial ischemia in 11 patients with angiographically documented coronary artery disease and stable angina pectoris. Maximal, symptom limited treadmill exercise stress tests were performed before and after six weeks of therapy with 1200 mg of pentoxifylline per day. Clinical symptoms proved in 9 [82%] of patients; none developed drug side effects. After therapy, mean total exercise time [7.7 +/- 1.3 vs 10.1 +/- 1.2 minutes], time to onset of angina [5.5 +/- 0.9 vs 7.9 +/- 1.0 minutes], heart rate at onset of angina [93.4 +/- 6.7 vs 112.0 +/- 10.5 beats/min] and rate at onset of ST depression [94.0 +/- 5.8 vs 115.9 +/- 7.4 beats/min] all increased significantly [p less than 0.05]. Mean maximum ST segment depression also decreased [1.6 +/- 0.3 vs 1.2 +/- 0.4mm], but the difference was not significant. Thus, pentoxifylline increases exercise performance in patients with angina pectoris and increases exercise capacity before development of of myocardial ischemia. It may, therefore, be a useful agent for treating ischemic heart disease.

Cardiovascular changes during transport of critically ill and postoperative patients.

We examined cardiovascular changes in 37 patients transported to an ICU after major general or vascular surgery (n = 14), open heart surgery (n = 13), or carotid endarterectomy (n = 10). Cardiovascular variables were also measured in a control group of 11 patients transported from an ICU for diagnostic or therapeutic procedures. All patients were followed for 30 min before transport until approximately 30 min after they arrived at their destinations. During this period, systolic BP and heart rate significantly increased only in patients recovering from major general/vascular surgery or carotid endarterectomy. These changes were apparently related to acute emergence from inhalational anesthesia (isoflurane plus nitrous oxide), since the other surgical patients were anesthetized with narcotic anesthesia, and the control group did not receive any anesthesia.

Adenosine and adenosine analogues are more toxic to chronic lymphocytic leukemia than to normal lymphocytes.

We compared the effect of adenosine and adenosine analogues on the phytohemagglutinin-induced proliferative response of blood lymphocytes from normal subjects and patients with chronic lymphocytic leukemia. As measured by the inhibition of thymidine or leucine incorporation, adenosine was more toxic to chronic lymphocytic leukemia (CLL) than to normal lymphocytes. This difference was not affected by the removal of adherent cells. The patients' B lymphocytes were more susceptible to adenosine toxicity than normal B lymphocytes. Similar responses were noted in T lymphocytes from both sources. Differential susceptibility was also observed with deoxyadenosine and adenosine analogues, including 5'deoxyadenosine. Uridine rescue from adenosine toxicity was observed for normal and CLL lymphocytes. In the presence of uridine, there was no difference in the residual inhibition of CLL as compared to normal lymphocytes. Intact CLL lymphocytes metabolized 14C-adenosine at a much lower rate than normal lymphocytes. While it appears that the greater toxicity of adenosine to CLL lymphocytes reflects the impaired catabolism of this nucleoside by these cells, evidence is presented that this is not the only mechanism underlying the differential susceptibility. These results may serve as the basis for further pharmacologic investigations of adenosine and adenosine deaminase inhibitors in chronic lymphocytic leukemia.

Insulin resistance and diabetes due to a genetic defect in insulin receptors.

A 14-yr-old woman presented with fasting hyperglycemia (269 mg/dl), fasting hyperinsulinemia (45 microU/ml), acanthosis nigricans, and insulin resistance. The patient's circulating insulin was normal by physical and biological criteria, and insulin receptor antibodies were not detected. Both the patient's in vivo dose-response curve for insulin-stimulated glucose transport in isolated adipocytes were shifted to the right and showed marked decreases in the maximal insulin response. Basal hepatic glucose output was significantly increased, and the in vivo dose-response curve for insulin-mediated suppression of basal hepatic glucose output was shifted to the right. Insulin binding to the patient's erythrocytes, monocytes, and adipocytes was markedly decreased. To confirm that the severe reduction in cellular insulin receptors was a primary rather than an acquired defect, similar studies were conducted using cultured fibroblasts. No detectable binding of insulin to these cells was observed. Further studies showed that the patient's mother and two sisters were hyperinsulinemic and insulin resistant, and had comparable, although less severe, changes in insulin binding. The patient was also demonstrated to have an insulin secretory defect both to both oral and iv glucose challenges. We thus conclude that this family demonstrates a genetic deficiency of insulin receptors, resulting in insulin resistance and, in this patient, severe diabetes mellitus.

Receptor and postreceptor defects contribute to the insulin resistance in noninsulin-dependent diabetes mellitus.

We have assessed the mechanisms involved in the pathogenesis of the insulin resistance associated with impaired glucose tolerance and Type II diabetes mellitus by exploring, by means of the euglycemic glucose-clamp technique, the in vivo dose-response relationship between serum insulin and the overall rate of glucose disposal in 14 control subjects; 8 subjects with impaired glucose tolerance, and 23 subjects with Type II diabetes. Each subject had at least three studies performed on separate days at insulin infusion rates of 40, 120, 240, 1,200, or 1,800 mU/M2 per min. In the subjects with impaired glucose tolerance, the dose-response curve was shifted to the right (half-maximally effective insulin level 240 vs. 135 microunits/ml for controls), but the maximal rate of glucose disposal remained normal. In patients with Type II diabetes mellitus, the dose-response curve was also shifted to the right, but in addition, there was a posal. This pattern was seen both in the 13 nonobese and the 10 obese diabetic subjects. Among these patients, an inverse linear relationship exists (r = -0.72) so that the higher the fasting glucose level, the lower the maximal glucose disposal rate. Basal rates of hepatic glucose output were 74 +/- 4, 82 +/- 7, 139 +/- 24, and 125 +/- 16 mg/M2 per min for the control subjects, subjects with impaired glucose tolerance, nonobese Type II diabetic subjects, and obese Type II diabetic subjects, respectively. Higher serum insulin levels were required to suppress hepatic glucose output in the subjects with impaired glucose tolerance and Type II diabetics, compared with controls, but hepatic glucose output could be totally suppressed in each study group. We conclude that the mechanisms of insulin resistance in patients with impaired glucose tolerance and in patients with Type II noninsulin-dependent diabetes are complex, and result from heterogeneous causes. (a) In the patients with the mildest disorders of carbohydrate homeostasis (patients with impaired glucose tolerance) the insulin resistance can be accounted for solely on the basis of decreased insulin receptors. (b) In patients with fasting hyperglycemia, insulin resistance is due to both decreased insulin receptors and postreceptor defect in the glucose mechanisms. (c) As the hyperglycemia worsens, the postreceptor defect in peripheral glucose disposal emerges and progressively increases. And (d) no postreceptor defect was detected in any of the patient groups when insulin's ability to suppress hepatic glucose output was measured.

Comparison of serum glucose, insulin, and glucagon responses to different types of complex carbohydrate in noninsulin-dependent diabetic patients.

We have studied the acute effects of oral ingestion of dextrose, rice, potato, corn, and bread on postprandial serum glucose, insulin, and glucagon responses in 20 diabetic subjects with nonketotic, noninsulin requiring fasting hyperglycemia. The carbohydrate loads were all calculated to contain 50 g of glucose. The data demonstrate that 1) dextrose and potato elicited similar postprandial serum glucose responses whereas rice and corn elicited lower responses, with bread intermediate; 2) postprandial insulin responses were relatively flat but rice ingestion led to significantly lower insulin responses than did potato; 3) urinary glucose excretion during the 3 h after carbohydrate ingestion was greatest following dextrose and least after rice and corn. In conclusion, there is a range in the magnitude of postprandial hyperglycemia after ingestion of different complex carbohydrates in diabetic patients with fasting hyperglycemia and emphasis on the use of the less hyperglycemic starches could be of therapeutic value in controlling hyperglycemia.

Mechanisms of insulin resistance in human obesity: evidence for receptor and postreceptor defects.

UNLABELLED: To assess the mechanisms of the insulin resistance in human obesity, we have determined, using a modification of the euglycemic glucose clamp technique, the shape of the in vivo insulin-glucose disposal dose-response curves in 7 control and 13 obese human subjects. Each subject had at least three euglycemic studies performed at insulin infusion rates of 15, 40, 120, 240, or 1,200 mU/M2/min. The glucose disposal rate was decreased in all obese subjects compared with controls (101 +/- 16 vs. 186 +/- 16 mg/M2/min) during the 40 mU/M2/min insulin infusion. The mean dose-response curve for the obese subjects was displaced to the right, i.e., the half-maximally effective insulin concentration was 270 +/- 27 microU/ml for the obese compared with 130 +/- 10 microU/ml for controls. In nine of the obese subjects, the dose-response curves were shifted to the right, and maximal glucose disposal rates (at a maximally effective insulin concentration) were markedly decreased, indicating both a receptor and a postreceptor defect. On the other hand, four obese patients had right-shifted dose-response curves but reached normal maximal glucose disposal rates, consistent with decreased insulin receptors as the only abnormality. When the individual data were analyzed, it was found that the lease hyperinsulinemic, least insulin-resistant patients displayed only the receptor defect, whereas those with the greatest hyperinsulinemia exhibited the largest post-receptor defect, suggesting a continuous spectrum of defects as one advances from mild to severe insulin resistance. When insulin's ability to suppress hepatic glucose output was assessed, hyperinsulinemia produced total suppresssion in all subjects. The dose-response curve for the obese subjects was shifted to the right, indicating a defect in insulin receptors. Insulin binding to isolated adipocytes obtained from the obese subjects was decreased, and a highly significant inverse linear relationship was demonstrated between insulin binding and the serum insulin concentration required for halfmaximal stimulation of glucose disposal. IN CONCLUSION: (a) decreased cellular insulin receptors contribute to the insulin resistance associated with human obesity in all subjects; (b) in the least hyperinsulinemic, insulin-resistant patients, decreased insulin receptors are the sole defect, whereas in the more hyperinsulinemic, insulin-resistant patients, the insulin resistance is the result of a combination of receptor and postreceptor abnormalities; (c) all obese patients were insensitive to insulin's suppressive effects on hepatic glucose output; this was entirely the result of decreased insulin receptors; no postreceptor defect in this insulin effect was demonstrated.