Reversal of diuretic-induced secondary hyperaldosteronism and hypokalemia by enalapril (MK-421): A new angiotensin-converting enzyme inhibitor

The study reported here prospectively evaluated the prevention of diuretic-induced secondary hyperaldosteronism and hypokalemia by a converting enzyme inhibitor, enalapril (MK 421). Eighteen normal subjects were randomized into three groups: (1) a HCTZ group (hydrochlorothiazide (HCTZ) 50 mg/day); (2) a MK-421 group (MK-421 10 mg/day); and (3) a HCTZ + MK-421 group [HCTZ 50 mg/day plus MK-421 10 mg/day]. Following a five-day control and a 28-day treatment period, the HCTZ group demonstrated an attenuated but persistent secondary hyperaldosteronism and hypokalemia, the MK-421 group manifested a gradual decline in aldosterone secretion, and the HCTZ + MK-421 group had a delayed but effective correction of secondary hyperaldosteronism and hypokalemia at 28 days but not before. In conclusion, MK-421 reversed diuretic-induced secondary hyperaldosteronism and hypokalemia after 28 days of hydrochlorothiazide therapy. Therefore, converting enzyme inhibitors, such as enalapril, provide useful adjunctive therapy in diuretic-treated patients, but potassium supplementation may be required before the start of four weeks of combined therapy.     

Discordance of plasma DHEA-S, DHEA, and cortisol responses with various ACTH regimens

The origin and time course of ACTH-stimulated adrenal androgens are controversial. Since previous protocols have used differing ACTH preparations and routes of administration, we sought to compare plasma DHEA and DHEA-S responses to four ACTH regimens. Fourteen young men underwent the following five three-day study periods: (1) placebo, (2) alpha 1-24 ACTH, 400 micrograms intravenously (IV); (3) alpha 1-39 ACTH, 400 micrograms intramuscularly (IM); (4) alpha 1-18 (D-Ser1, Lys17, Lys18) ACTH, 400 micrograms IM; and (5) alpha 1-18 ACTH, 400 micrograms IV. alpha 1-18 ACTH IV had the most potent and prolonged corticotropic effect, listing more than 24 hours, as measured by plasma cortisol, 17-OHCS, and cortisol secretion rates. alpha 1-39 ACTH and alpha 1-18 ACTH IM were corticotropic up to 12 hours, and alpha 1-24 ACTH IV was corticotropic only up to one hour. Plasma DHEA rose acutely at one hour with all of the ACTH regimens (P less than 0.05). This response was correlated with cortisol (r = 0.62, P less than 0.01) and reflected the relative corticotropic potency of each of the ACTH regimens. Plasma DHEA-S, on the other hand, did not rise acutely at one hour with any of the regimens. DHEA-S did rise at 12 hours with three of the ACTH regimens (alpha-1-24, alpha 1-39, alpha 1-18 IM), but this response was not synchronous with cortisol (r = 0.14, P = NS).(ABSTRACT TRUNCATED AT 250 WORDS)     

The superiority of the metyrapone test versus the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome

Differentiating the cause of Cushing's syndrome traditionally has depended upon measuring the response of 24-hour urine samples of cortisol or glucocorticoid metabolites to the high-dose (8 mg per day) dexamethasone test. The metyrapone test, however, is more convenient because it is a shorter test and requires the obtainment of serum samples, which can be collected more simply and more reliably than 24-hour urine samples. The usefulness of these two tests has not been adequately evaluated in a large series of patients with Cushing's syndrome. This study prospectively evaluated the accuracy of the dexamethasone and metyrapone tests in determining the cause of Cushing's syndrome in a series of 25 unselected patients. The diagnostic accuracy of these tests was calculated as follows: diagnostic accuracy = true positives and true negatives/study population X 100. Results of this study demonstrated that the metyrapone test was more accurate than the dexamethasone test in differentiating Cushing's disease from adrenocortical neoplasm (diagnostic accuracy, 100 percent versus 81 percent). All patients with Cushing's disease had a normal postmetyrapone 11-deoxycortisol concentration (greater than 10 micrograms/dl), while all patients with adrenocortical neoplasm had a suppressed 11-deoxycortisol concentration (less than 10 micrograms/dl). Thus, this study demonstrates that the metyrapone test is superior to the high-dose dexamethasone test in the differential diagnosis of Cushing's syndrome.     

Primary empty sella syndrome, ACTH hypersecretion, and normal adrenocortical function. Report of two cases

Although the primary empty sella syndrome (PESS) is associated with normal endocrine function or subtle pituitary insufficiency, pituitary hormone hypersecretion associated with PESS has also been recognized. ACTH hypersecretion and primary empty sella syndrome have previously been reported in patients with either Cushing's disease or Addison's disease. This report describes two unique patients with ACTH hypersecretion, primary empty sella syndrome, and normal cortisol dynamics. The investigators speculate that this association may have resulted from infarction of hyperplastic adenohypophyseal corticotrophes due to production of an ACTH peptide with reduced biologic activity. These two cases emphasize that primary empty sella syndrome may be associated with ACTH hypersecretion and normal adrenocortical function.     

New mineralocorticoids and adrenocorticosteroids in hypertension.

Alterations in steroidogenesis have been demonstrated in experimental and human hypertension. It is highly likely that increased secretion of the nonaldosterone mineralocorticoid deoxycorticosterone (DOC) and 18-hydroxy-11-deoxycorticosterone (18-OH-DOC) may initiate or perpetuate hypertension, or both. It is possible that 16 beta-hydroxydehydroeplandrosterone (16beta-OH-DHEA) directly induces the hypertensive process in animals. The significance of the findings of increased secretion of 16 alpha, 18-dihydroxy-11-deoxycorticosterone (16alpha, 18-diOH-DOC) and dehydroepiandrosterone sulfate (DHEA-S) cannot now be appreciated. Neither has been examined experimentally for its ability to induce hypertension, and the former compound is not a mineralocorticoid. It does possess the curious property of increasing mineralocorticoid activity of other steroids, by altering either their metabolism or mode of action. Variations in the mineralocorticoid hypertensive syndrome or, more aptly, the steroid hypertensive syndrome could account for the hypertension in a substantial portion of patients with reduced plasma renin activity.     

Adverse acute and chronic effects of electrical defibrillation and cardioversion on implanted unipolar cardiac pacing systems

Six cases are presented in which a transient or chronic rise in the stimulation threshold of a permanently implanted unipolar pacemaker resulted in the loss of effective pacing after therapeutic defibrillation or cardioversion. Although damage to the pulse generator may still occur, leading to a loss of function as demonstrated in a seventh patient, improvements in the internal protection circuits of the present generation of pacemakers makes this less likely while possibly predisposing to endocardial burns and increased fibrosis at the electrode-endocardial interface. The theoretical explanations for this phenomenon are discussed, along with recommendations for the prospective and retrospective management of the pacemaker patient who requires defibrillation or cardioversion.     

Derivation of systolic time intervals from doppler measurement of temporal arterial blood flow

The carotid pulse method of recording systolic time intervals is limited by significant motion-induced artifact, making it unsuitable for studying patients during exercise. As an approach to overcoming this limitation, a new method utilizing the blood velocity profile of the superficial temporal artery measured by Doppler ultrasound has been developed. When compared with the values obtained from the conventional carotid pulse method, Doppler-derived left ventricular election time and preejection period showed excellent correlation (r = 0.99 for both) and the Doppler-derived measurements showed little intra- or interobserver variability. Studies performed during treadmill exercise showed that in 8 of 10 subjects, suitable tracings could be recorded through stage 3 of the Bruce protocol, confirming the enhanced stability of the technique compared with the carotid pulse method.     

Role of percutaneous transluminal coronary angioplasty in the treatment of unstable angina: Report from the national heart, lung, and blood institute percutaneous transluminal coronary angioplasty and coronary artery surgery study registries

The acute and long-term consequences of PTCA performed in patients with unstable angina was determined in 442 patients with 1-vessel CAD who were enrolled in the NHLBI PTCA Registry. These patients were compared with 214 similar patients in the PTCA Registry with stable angina and with 330 patients with unstable angina from the NHLBI CASS Registry who underwent CABG. The 3 groups had similar baseline characteristics. The immediate angiographic success after PTCA was not different between patients with stable and those with unstable angina. The in-hospital mortality rate was 0.9 % for the PTCA group with unstable angina and 0.47% for the PTCA group with stable angina. The combined 18-month mortality and MI rate was low in both groups (10.8 and 9.5%, respectively). No differences were observed in the mortality and MI rates between patients with unstable angina treated surgically or with PTCA. Both revascularization procedures markedly reduced symptoms of angina. Ninety-two percent of the PTCA group reported improvement in their angina, whereas 80 % of the surgical group had a reduction in angina (p < 0.05). The results from this observational study suggest that PTCA can be performed as safely and successfully in patients with unstable angina as in those with stable angina. PTCA compares favorably with CABG in patients with unstable angina in that the procedure is associated with low mortality and morbidity rates, while marked improvement in symptoms can be expected. Thus, PTCA could be considered an alternative to CABG in patients with unstable angina who have the appropriate anatomic characteristics.     

Angiotensin inhibition in severe heart failure: Acute central and limb hemodynamic effects of captopril with observations on sustained oral therapy

The systemic, pulmonary, and limb circulatory responses to the angiotensin-converting enzyme inhibitor, captopril, were determined in 10 patients with severe, chronic heart failure. Immediate effects include sustained reductions in arterial pressure and pulmonary capillary wedge pressure and improvement in cardiac output, as reported with other vasodliator drugs. Calf vascular resistance did not change despite substantial lowering of total systemic vascular resistance, indicating that arteriolar dilatation occurred on a selective basis. Transient reduction in mean right atrial pressure paralleled slight calf venodillatation, but effects upon the resistance vasculature predominated. Plasma renin activity and norepinephrine concentrations increased after therapy in the acute phase as plasma aldosterone levels consistently fell. During maintenance oral treatment over 7 to 15 months (median, 11.5 months), patients displayed symptomatic benefit, improved functional capacity, and greater exercise tolerance. No major adverse reactions developed. These findings suggest that angiotensin converting enzyme inhibition with captopril in congestive heart failure patients improves cardiocirculatory function through selective arteriolar dilatation. The reordering of regional blood flow which appears to result from release of angiotensin-mediated vasoconstriction, as well as the suppression of aldosterone, may underlle the prolonged benefit observed in these patients. This oral vasodilator appears to represent an effective adjunct for the treatment of advanced, chronic heart failure refractory to conventional measures.     

Verapamil therapy for stable exertional angina pectoris

Clinical and exercise responses to therapy with the calcium-channel blocking agent verapamil were assessed in 26 patients with stable exertional angina pectoris using a double-blind, placebo-controlled, randomized crossover study design. Verapamil, 480 mg daily, reduced the frequency of angina attacks (5.6 +/- 7.3 to 2.2 +/- 3.0 attacks per week, p less than 0.001) and number of nitroglycerin tablets consumed (3.4 +/- 4.9 to 1.2 +/- 2.5 tablets per week, p less than 0.05), and increased exercise duration (6.4 +/- 2.1 to 7.5 to 1.8 minutes, p less than 0.001) (all data are mean +/- standard deviation). These changes were significantly better than those seen with placebo. These beneficial effects of verapamil were related to significant reduction in the heart rate-systolic blood pressure product during submaximal exercise. Adverse effects from verapamil were few and consisted primarily of constipation in 6 patients. A total of 193 patients had been entered in 6 independent clinical trials, which have compared verapamil with placebo for the treatment of stable exertional angina pectoris, using a similar study design. The combined evidence from all these studies indicates that verapamil is a highly effective and safe drug for the treatment of stable effort-related angina pectoris.     

Effect of antiplatelet therapy on restenosis after experimental angioplasty

Restenosis is recognized as a common complication of PTCA and can limit the long-term benefit of this procedure. To study the effect of antiplatelet agents in preventing restenosis, 25 New Zealand rabbits had bilateral iliac stenoses created by balloon deendothelialization and a 2% cholesterol diet for 6 weeks. After angiographic delineation of the iliac atherosclerosis, successful angioplasty was performed in all rabbits, with an average increase in luminal diameter of 0.9 mm (81%). Seven rabbits received aspirin (32 mg/day) plus dipyridamole (25 mg/day) and 9 received sulfinpyrazone (100 mg/ day); 9 were given no antiplatelet drugs and served as controls. After 4 weeks of drug therapy and a continued atherogenic diet, angiography was repeated and the rabbits were killed for histologic examination. The angiographic luminal diameter was similar for these groups both before and immediately after angioplasty. However, the luminal diameter 4 weeks later was significantly larger in both the aspirin plus dipyridamole and the sulfin-pyrazone groups compared with the control rabbits (1.3 ± 0.6 and 1.8 ± 0.5 mm vs 0.7 ± 0.6 mm, respectively, p < 0.05). Histologic examination revealed intraluminal clot in 4 of 9 control rabbits and in none of the drug-treated rabbits. Also, less intimal thickening was evident. In conclusion, aspirin plus dipyridamole and sulfinpyrazone inhibited angiographic restenosis after transluminal angioplasty in this experimental model. These findings support the use of antiplatelet agents in clinical angioplasty and suggest that platelet aggregation at the angioplasty site may promote restenosis.     

Randomized withdrawal from nifedipine: Placebo-controlled study in patients with coronary artery spasm

A multicenter randomized double-blind withdrawal study was conducted to compare the efficacy of nifedipine to that of placebo in vasospastic angina. Following a 2-week single-blind nifedipine baseline period, during which nifedipine was maintained at prestudy levels, 38 patients, 19 taking placebo and 19 continuing nifedipine therapy, either completed a 4-week randomized phase or were prematurely withdrawn because of therapeutic failure. During the randomized phase, an increase in median anginal frequency (2.8 attacks/wk, p < 0.003) and nitroglycerin usage (0.5 tablets/wk, p < 0.03) occurred only in the placebo group. The randomized phase was prematurely terminated because of anginal exacerbation in 7 of 19 placebo patients (37%) (only 1 patient receiving nifedipine [p = 0.02] experienced anginal exacerbation). Double-blind therapy was judged effective in 16 patients (84%) receiving nifedipine and in 3 patients (16%) receiving placebo (p < 0.001). Nifedipine was well tolerated. This study establishes the efficacy of nifedipine in the treatment of variant angina and validates previous clinical experience.     

Electrocardiogram of the athlete: An analysis of 289 professional football players

The electrocardiogram (EGG) of athletes reflects physiologic cardiovascular adaptations that occur in well-conditioned individuals. To more clearly define electrocardiographic changes seen in predominantly power-trained athletes, the ECGs of 289 apparently healthy professional football players were analyzed in detail. The players, aged 21 to 35 years, one-third of whom were black, had a mean body surface area of 2.24 m², a mean heart rate at rest of 56 ± 9 beats/min (with 77% (223) having a rate of less than 60 beats/min), and a mean P axis of 30 ± 25 °. A wide QRS-T angle (>60 °) was present in 14% (41 players) of the group. The mean PR interval was 0.18 ± 0.02 second (>0.21 in 9% [26 players]). Although two-thirds of the players had a QRS duration of 0.10 second, only 1 had right bundle branch block and none had left bundle branch block. The sum of S in lead V₁ plus R in lead V₅ averaged 37 ± 9 mm, with 35% (101 players) demonstrating voltage criteria for left ventricular hypertrophy. The S + R value varied inversely with weight (r = ?0.27, p < 0.002). The maximum T height in any lead had a mean of 8.6 ± 3 mm, with 22% (64 players) having a T height ≥11 mm. U waves were universally present. ST-T changes mimicking ischemia were noted in 39 of 289 players (13%), 22 (58%) of whom were black (p < 0.001). The maximal J-point elevation in any lead averaged 1.9 ± 0.9 mm. These findings confirm that the ECGs of power-trained athletes show changes similar to those of endurance-trained athletes. These changes most likely reflect the increased vagal tone and ventricular mass observed in conditioned athletes. Large body size masks the voltage changes expected with increased left ventricular mass. Ischemic-like ST-T-wave deviations were found predominantly in black athletes.     

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.     

Cardiokymography during exercise testing: A new device for the detection of coronary artery disease and left ventricular wall motion abnormalities

The cardiokymograph (CKG) is a device that has been shown to reflect left ventricular (LV) wall motion abnormalities. Its accuracy in detecting coronary artery disease (CAD) during treadmill exercise testing was assessed in 204 consecutive patients undergoing coronary arteriography. Of the 188 patients with a technically adequate CKG, 146 (78%) had significant CAD. The sensitivity and specificity were similar for both the exercise electrocardiogram (ECG) (66% and 86%, respectively) and the exercise CKG (73% and 95%, respectively). An abnormal exercise CKG was significantly more common In patients with 3-vessel CAD than in those with 1-vessel disease (97% versus 52%, respectively;p < 0.001) and in patients with left anterior descending disease than in those without (85% versus 26%, respectively; p < 0.001). Seventy patients showed both an abnormal exercise ECG and CKG; all had CAD and 86% had multivessel CAD. Forty-eight patients demonstrated a normal exercise ECG and CKG; 29% had CAD but only 6% had multivessel CAD. Among 55 patients who had simultaneous exercise radionuclide ventriculography, new septal or apical wall motion abnormalities were found in 79% (23 of 29) of patients with an abnormal CKG compared with 19% (5 of 26) of patients with a normal CKG (p < 0.001). Thus, the CKG during exercise testing accurately reflects LV wall motion abnormalities and can be used to improve the diagnostic accuracy of exercise testing as an additional marker of myocardial ischemia.