M. Anthony Schork

Blood pressure dependent and independent effects of antihypertensive treatment on clinical events in the VALUE Trial

The Valsartan Antihypertensive Long-term Use Evaluation (VALUE) trial was designed to test whether, for the same achieved blood pressures, regimens based on valsartan or amlodipine would have differing effects on cardiovascular endpoints in high risk hypertension. But inequalities in blood pressure, favouring amlodipine, throughout the multiyear trial precluded comparison of outcomes. A technique of serial median matching, applied at 6 months when treatment adjustments intended to achieve control of blood pressure were complete, created 5006 valsartan-amlodipine patient pairs matched exactly for systolic blood pressure, age, sex, and the presence or absence of previous coronary disease, stroke, or diabetes. Subsequent combined cardiac events, myocardial infarction, stroke, and mortality were almost identical in the two cohorts, but admission to hospital for heart failure was significantly lower with valsartan. Reaching blood pressure control (systolic <140 mm Hg) by 6 months, independent of drug type, was associated with significant benefits for subsequent major outcomes; the blood pressure response after just 1 month of treatment predicted events and survival.

A Prospective Randomized Clinical Trial of Intracoronary Streptokinase versus Coronary Angioplasty for Acute Myocardial Infarction

We randomly assigned 56 patients who presented within 12 hours of their first symptoms of acute myocardial infarction to treatment with either intracoronary streptokinase or coronary angioplasty. The mean (+/- SD) duration of symptoms (3.0 +/- 1.2 hours in the group treated with angioplasty vs. 3.6 +/- 1.8 in the group treated with streptokinase; P not significant) and time to recanalization (4.1 +/- 1.4 hours vs. 4.8 +/- 1.7 hours; P not significant) were similar in both groups. Coronary recanalization was achieved in 83 percent of the patients treated with angioplasty and in 85 percent of those treated with streptokinase (P not significant). Residual luminal stenosis in the coronary artery was significantly decreased after angioplasty, as compared with streptokinase therapy (43 +/- 31 percent of patients vs. 83 +/- 17; P less than 0.001). Residual stenosis of 70 percent or more was present in 4 percent of the angioplasty-treated patients and in 83 percent of the streptokinase-treated patients (P less than 0.01). Ventricular function after therapy was assessed by serial contrast ventriculograms. Increases in both global ejection fraction (8 +/- 7 percent vs. 1 +/- 6; P less than 0.001) and regional wall motion (+1.32 +/- 1.32 SD vs. +0.59 +/- 0.79 SD; P less than 0.05) were greater for the angioplasty group. We conclude that angioplasty and streptokinase produce similar rates of early coronary reperfusion during evolving transmural myocardial infarction. However, angioplasty is significantly more effective in alleviating the underlying coronary stenoses, and this may result in more effective preservation of ventricular function after therapy.

Decrease in cortisol reverses human hippocampal atrophy following treatment of Cushing’s disease

BACKGROUND Decreased hippocampal volume is observed in patients with Cushings syndrome and other conditions associated with elevated cortisol levels, stress, or both. Reversibility of hippocampal neuronal atrophy resulting from stress occurs in animals. Our study investigated the potential for reversibility of human hippocampal atrophy. METHODS The study included 22 patients with Cushings disease. Magnetic resonance brain imaging was performed prior to transsphenoidal microadenomectomy and again after treatment. RESULTS Following treatment, hippocampal formation volume (HFV) increased by up to 10%. The mean percent change (3.2 +/- 2.5) was significantly greater (p < .04) than that of the comparison structure, caudate head volume (1.5 +/- 3.4). Increase in HFV was significantly associated with magnitude of decrease in urinary free cortisol (r = -.61, p < .01). This relationship strengthened after adjustments for age, duration of disease, and months elapsed since surgery (r = -.70, p < .001). There was no significant correlation between caudate head volume change and magnitude of cortisol decrease. CONCLUSIONS Changes in human HFV associated with sustained hypercortisolemia are reversible, at least in part, once cortisol levels decrease. While many brain regions are likely affected by hypercortisolemia, the human hippocampus exhibits increased sensitivity to cortisol, affecting both volume loss and recovery.

Functional units, chewing, swallowing, and food avoidance among the elderly

PURPOSE The number of teeth in the dentition was compared with the number and types of dental functional units (opposing tooth pairs) to correlate the number of functional units with complaints about chewing and swallowing in the elderly. MATERIAL AND METHODS Complaints of oral pharyngeal function and food avoidance practices were compared with the number and types of functional units. A convenience sample of 602 elderly subjects (468 men, 134 women, mean age 70 years) were interviewed and examined dentally. RESULTS Functional unit measures, which included functional arrangement of the teeth and the number and type of teeth present, were found to be more discriminatory and descriptive of masticatory potential than the more number of teeth. Elderly persons (> or = 60 years of age) with reduced numbers of functional units tended to report difficulty chewing, avoidance of stringy foods (including meat), crunchy foods (including vegetables), and dry solid foods (including breads), and difficulty in swallowing. Removable prostheses did not appear to prevent these consequences and, at least in this elderly population, did not appear to be equivalent to natural teeth in terms of masticatory potential. CONCLUSIONS It is possible that compromised dental function results in the swallowing of poorly chewed food, food avoidance patterns, dietary inadequacies, and systemic changes favoring illness, reduced vigor, debilitation, and shortened life expectancy. Emphasis should be placed on maintaining natural teeth whenever possible.

Elevated cortisol levels in Cushing's disease are associated with cognitive decrements

Objective The objective of this study was to use Cushing’s disease as a unique human model to elucidate the cognitive deficits resulting from exposure to chronic stress-level elevations of endogenous cortisol. Methods Forty-eight patients with a first episode of acute, untreated Cushing’s disease and 38 healthy control subjects were studied. Results Scores for four of five verbal IQ subtests were significantly lower in patients with Cushing’s disease; their scores were significantly lower for only one nonverbal performance IQ subtest (block design). Verbal, but not visual, learning and delayed recall at 30 minutes were significantly decreased among patients with Cushing’s disease. Although verbal delayed recall was significantly lower in these patients, the retention index (percentage), which compares the amount of initially learned material to that recalled after the delay, was not significantly decreased. There was no significant association between depression scores and cognitive performance. A higher degree of cortisol elevation was associated with poorer performance on several subtests of learning, delayed recall, and visual-spatial ability. Conclusions Chronically elevated levels of glucocorticoids have deleterious effects on particular domains of cognition. Verbal learning and other verbal functions seem more vulnerable than nonverbal functions. The results suggest that both the neocortex and hippocampus are affected.

Effects of valsartan compared to amlodipine on preventing type 2 diabetes in high-risk hypertensive patients: The VALUE trial

Context Type 2 diabetes is emerging as a major health problem, which tends to cluster with hypertension in individuals at high risk of cardiovascular disease. Objective To test for the first time the hypothesis that treatment of hypertensive patients at high cardiovascular risk with the angiotensin-receptor blocker (ARB) valsartan prevents new-onset type 2 diabetes compared with the metabolically neutral calcium-channel antagonist (CCA) amlodipine. Design Pre-specified analysis in the VALUE trial. Follow-up averaged 4.2 years. The risk of developing new diabetes was calculated as an odds ratio (OR) with 95% confidence intervals (CI) for different definitions of diabetes. Patients A sample of 9995 high-risk, non-diabetic hypertensive patients. Interventions Valsartan or amlodipine with or without add-on medication [hydrochlorothiazide (HCTZ) and other add-ons, excluding other ARBs, angiotensin-converting enzyme (ACE) inhibitors, CCAs]. Main outcome measure New diabetes defined as an adverse event, new blood-glucose-lowering drugs and/or fasting glucose > 7.0 mmol/l. Results New diabetes was reported in 580 (11.5%) patients on valsartan and in 718 (14.5%) patients on amlodipine (OR 0.77, 95% CI 0.69–0.87, P < 0.0001). Using stricter criteria (without adverse event reports) new diabetes was detected in 495 (9.8%) patients on valsartan and in 586 (11.8%) on amlodipine (OR 0.82, 95% CI 0.72–0.93, P = 0.0015). Conclusion Compared with amlodipine, valsartan reduces the risk of developing diabetes mellitus in high-risk hypertensive patients.

Prostacyclin protects ischemic reperfused myocardium in the dog by inhibition of neutrophil activation.

Prostacyclin (PGI2) and the stable PGI2 analogue SC39902 (6,9 alpha-epoxy,5S-fluoro-11 alpha, 15S-dehydroxyprosta-6,13E-dien-1-oic acid, sodium salt) were studied in anesthetized open-chest dogs subjected to 90 minutes of left circumflex coronary artery (LCCA) occlusion and 6 hours of reperfusion. PGI2 (50 ng/kg/min, infused into the left atrium) reduced infarct mass by 59% compared to control, but SC39902 (1.5 micrograms/kg/min) failed to produce a significant reduction in infarct size. Both PGI2 and SC39902 reduced mean arterial blood pressure, heart rate, and rate-pressure product to the same extent. Regional myocardial blood flow measured with radiolabelled tracer microspheres did not demonstrate an increase in regional blood flow to the ischemic myocardium during the 90 minutes of LCCA occlusion in the PGI2 and control treatment groups. Canine neutrophils were isolated from whole blood and activated with opsonized zymosan. PGI2 produced a concentration-dependent inhibition of neutrophil activation as measured by superoxide production in vitro, whereas SC39902 failed to effectively inhibit neutrophil activation. Neutrophil migration into inflammatory skin lesions was effectively attenuated when dogs were pretreated with PGI2 (50 ng/kg/min, intravenously). Therefore, it is suggested that the cytoprotective effect of PGI2 during myocardial ischemia and reperfusion is related to an inhibition of neutrophil migration and the production of cytotoxic activated oxygen species.

Prospective, double-blind, placebo-controlled trial of low-dose amiodarone in patients with severe heart failure and asymptomatic frequent ventricular ectopy

Sudden cardiac death is a common cause of mortality in patients with congestive heart failure. To determine if low-dose amiodarone could reduce sudden death among these patients, a prospective, placebo-controlled, double-blind pilot trial was conducted. One hundred one patients with ejection fractions less than 30%, New York Heart Association class III or IV symptoms, and frequent but asymptomatic spontaneous ventricular ectopy (Lown class II to V) were randomly assigned to treatment with low-dose amiodarone (400 mg/day for 4 weeks and then 200 mg/day) or placebo. Mean follow-up was 357 days (range 4 to 1009 days). Side effects were infrequent and there was no difference in the incidence of side effects between the treatment groups. The frequency of spontaneous ventricular ectopy in the group receiving amiodarone fell from 4992 +/- 1240 beats/24 hours at baseline to 1135 +/- 494 beats/24 hours after 1 month of treatment (p = 0.02) and remained low after 6 months, while there was no change in ventricular ectopy among the patients receiving placebo. Despite the reduction in ectopy, there was no improvement in mortality or decrease in the incidence of sudden death. One-year mortality by Kaplan-Meier analysis was 28% in the group receiving amiodarone and 19% in the group receiving placebo (p = NS). One-year mortality in patients with greater than 75% reduction in ventricular ectopy after 1 month of treatment was 31% versus 17% in patients with less than or equal to 75% ectopic suppression (p = NS).(ABSTRACT TRUNCATED AT 250 WORDS)

Cushing's syndrome after treatment: changes in cortisol and ACTH levels, and amelioration of the depressive syndrome.

Twenty-three patients with pituitary adrenocorticotropic hormone (ACTH)-dependent Cushings syndrome were studied before and after treatment. The relationship between the amelioration of the depressive syndrome and changes in cortisol and ACTH levels was investigated. There was a significant difference in mean change in 24-hour urinary free cortisol (UFC) excretion for changes in the depressed mood score from first to last visit. There were also significant correlations between decreases in UFC and decreases in both the depressed mood score and the modified Hamilton depression score. These relationships were not found for ACTH. Furthermore, with cortisol decreased to normal levels, continued high ACTH levels did not prevent improvement in depressed mood. The possibility that cortisol may also play a role in the pathogenesis and/or maintenance of the mood disorder in psychiatric patients is discussed.

Intraaortic balloon pumping 1967 through 1982: Analysis of complications in 733 patients

Between June 1967 and December 1982, 872 attempts at intraaortic balloon pumping (IABP) were made in 733 patients. Nearly 75% of the patients were men; the proportion of women has increased in recent years. The principal indication for IABP support initially was cardiogenic shock, but over the years, preoperative support, weaning from cardiopulmonary bypass and unstable angina have become the primary indications. Complications of IABP were classified and distributed by severity (minor: I [15%] and II [26%]; major: III [3%] and IV [1%]) and type ([vascular [22%], infectious [22%], and bleeding [7%]). Vascular complication rates were higher in women (32 vs 18%; p = 0.0001), in diabetic patients (32 vs 20%, p = 0.003), and in hypertensive patients (27 vs 20%, p = 0.02). These did not vary with the duration of IABP support (range of duration 0 to 76 days). The rate of infectious complications was related to location where IABP was performed (coronary care unit 26%, operating room 12%). The rate of fever and bacteremia increased significantly with duration of IABP support, but the rate of local wound infection did not. In conclusion, most IABP complications are minor, resolve after balloon removal, are related to vascular status of the patient and, with the exception of bacteremia, are independent of IABP duration.