Adverse hemodynamic and clinical effects of encainide in severe chronic heart failure

STUDY OBJECTIVE: To evaluate the hemodynamic effects of the antiarrhythmic drug, encainide, in patients with severe chronic heart failure. DESIGN: Unblinded, before-after study. SETTING: Referral center for patients with heart failure. PATIENTS: Thirty patients with severe chronic heart failure and a left ventricular ejection fraction less than 40%. INTERVENTIONS: Invasive hemodynamic measurements were done (using a balloon-tipped thermodilution catheter) before and for 3 hours after a single oral dose of 50 mg of encainide. MEASUREMENTS AND MAIN RESULTS: Ninety to one hundred and twenty minutes after its administration, encainide produced a significant deterioration in cardiac performance, as reflected by a fall in cardiac index from 2.3 to 1.8 L/min.m2 body surface (mean change 0.5 +/- 0.1; P less than 0.001), a fall in stroke work index from 26 to 18 g.m/m2 (mean change 8 +/- 2; P less than 0.001), and an increase in left ventricular filling pressure from 19 to 22 mm Hg (mean change 3 +/- 2; P less than 0.05). These deleterious hemodynamic effects were accompanied by worsening symptoms of heart failure in 8 of the 30 patients. Serum levels of encainide and its metabolites, O-desmethylencainide and 3-methoxy-O-desmethylencainide, were within the therapeutic range in most patients. CONCLUSIONS: Encainide can cause adverse hemodynamic and clinical effects in patients with severe chronic heart failure.     

Functional renal insufficiency during long-term therapy with captopril and enalapril in severe chronic heart failure

Renal function was evaluated in 104 patients with severe chronic heart failure whom we treated with captopril or enalapril. Seventy patients showed no change or an improvement in renal function (group A), and 34 patients developed functional renal insufficiency (group B). Before converting-enzyme inhibition, group B patients received higher doses of furosemide (p less than 0.02) and had lower central venous pressures (p less than 0.05) than group A patients. After 1 to 3 months of converting-enzyme inhibition, an excessive reduction in left ventricular filling pressure (to less than 15 mm Hg) or mean arterial pressure (to less than 60 mm Hg) was noted in 28 of 34 (82%) patients in group B but in only 22 of 70 patients in group A (31%) (p less than 0.001). At the end of the study, drug-induced azotemia resolved after a reduction in the dosage of diuretics, despite unaltered treatment with captopril and enalapril. Hence, the deterioration of renal function after converting-enzyme inhibition in heart failure is not a toxic or immunologic reaction to therapy but results from specific hemodynamic events that can be ameliorated by sodium repletion.     

Role of endothelin in the exercise intolerance of chronic heart failure

In conclusion, plasma levels of the endothelialderived vasoconstrictor endothelin-1 (but not those of other neurohormonal vasoconstrictor factors), measured during exercise correlated closely with objective variables of exercise capacity in patients with heart failure. These findings suggest that endothelin-1 may contribute to exercise intolerance in patients with heart failure, perhaps by limiting the ability of the peripheral vasculature to dilate during exercise.     

Effect of combined supplementation with vitamin E and alpha-lipoic acid on myocardial performance during in vivo ischaemia-reperfusion

Reactive oxygen species (ROS) contribute significantly to myocardial ischaemia-reperfusion (I-R) injury. Recently the combination of the antioxidants vitamin E (VE) and alpha-lipoic acid (alpha-LA) has been reported to improve cardiac performance and reduce myocardial lipid peroxidation during in vitro I-R. The purpose of these experiments was to investigate the effects of VE and alpha-LA supplementation on cardiac performance, incidence of dysrhythmias and biochemical alterations during an in vivo myocardial I-R insult. Female Sprague-Dawley rats (4-months old) were assigned to one of the two dietary treatments: (1) control diet (CON) or (2) VE and alpha-LA supplementation (ANTIOXID). The CON diet was prepared to meet AIN-93M standards, which contains 75 IU VE kg-1 diet. The ANTIOXID diet contained 10 000 IU VE kg(-1) diet and 1.65 g alpha-LA kg(-1) diet. After the 14-week feeding period, significant differences (P<0.05) existed in mean myocardial VE levels between dietary groups. Animals in each experimental group were subjected to an in vivo I-R protocol which included 25 min of left anterior coronary artery occlusion followed by 10 min of reperfusion. No group differences (P>0.05) existed in cardiac performance (e.g. peak arterial pressure or ventricular work) or the incidence of ventricular dysrhythmias during the I-R protocol. Following I-R, two markers of lipid peroxidation were lower (P<0.05) in the ANTIOXID animals compared with CON. These data indicate that dietary supplementation of the antioxidants, VE and alpha-LA do not influence cardiac performance or the incidence of dysrhythmias but do decrease lipid peroxidation during in vivo I-R in young adult rats.     

Primitive Neuroectodermal Tumors of the Central Nervous System

Controversial issues relating to the pathobiology and classification of central nervous system primitive neuroectodermal tumors (PNETs) have plagued neuropathologists for more than 70 years. Hypotheses advanced in the mid-1920's have remained as fixed concepts in contemporary literature, largely consequent to repetitious support by a small number of neuropathologists despite a growing body of information discrediting these ideas from neuroembryologists, oncologists, neuroscien-tists and pathologists.
Attention has largely focused upon PNETs arising in the cerebellum (commonly known as medul-loblastomas [MBs]), because about 80% of central nervous system (CNS) PNETs originate in this site. It has been asserted that the 20% which do not are biologically different, although most individuals agree that the histological features of PNETs that occur in different sites throughout the CNS are indistinguishable from those growing in the cerebellum.
The historical aspects of this controversy are examined in the face of evidence that there is, in fact, a unique class of CNS tumors which should appropriately be regarded as primitive neuroectodermal in nature. Specifically, a number of different approaches to the problem have yielded data supporting this hypothesis. These approaches include the identification of patterns of expression among a variety of cellular antigens (demonstrated by the use of immunopathological techniques), molecular analyses of cell lines derived from these tumors, experimental production of PNETs and molecular genetic analyses.
Differences of opinion among surgeons, oncologists and radiotherapists are typically resolved by conducting cooperative studies of patients with these tumors who are diagnosed and treated at multiple centers.     

Race and the response to adrenergic blockade with carvedilol in patients with chronic heart failure

BACKGROUND: The benefits of angiotensin-converting-enzyme inhibitors and beta-blockers may be smaller in black patients than in patients of other races, but it is unknown whether race influences the response to carvedilol in patients with chronic heart failure. METHODS: In the U.S. Carvedilol Heart Failure Trials Program, 217 black and 877 nonblack patients (in New York Heart Association class II, III, or IV and with a left ventricular ejection fraction of no more than 0.35) were randomly assigned to receive placebo or carvedilol (at doses of 6.25 to 50 mg twice daily) for up to 15 months. The effects of carvedilol on ejection fraction, clinical status, and major clinical events were retrospectively compared between black and nonblack patients. RESULTS: As compared with placebo, carvedilol lowered the risk of death from any cause or hospitalization for any reason by 48 percent in black patients and by 30 percent in nonblack patients. Carvedilol reduced the risk of worsening heart failure (heart failure leading to death, hospitalization, or a sustained increase in medication) by 54 percent in black patients and by 51 percent in nonblack patients. The ratios of the relative risks associated with carvedilol for these two outcome variables in black as compared with nonblack patients were 0.74 (95 percent confidence interval, 0.42 to 1.34) and 0.94 (95 percent confidence interval, 0.43 to 2.05), respectively. Carvedilol also improved functional class, ejection fraction, and the patients' and physicians' global assessments in both the black patients and the nonblack patients. For all these measures of outcome and clinical status, carvedilol was superior to placebo within each racial cohort (P<0.05 in all analyses), and there was no significant interaction between race and treatment (P> 0.05 in all analyses). CONCLUSIONS: The benefit of carvedilol was apparent and of similar magnitude in both black and nonblack patients with heart failure.     

Isochromosome 17q in primitive neuroectodermal tumors of the central nervous system

We have prepared karyotypes from 22 primitive neuroectodermal tumors (PNETs) from pediatric patients ranging in age from 10 months to 16 years. Twenty-one cases were newly diagnosed, primary, posterior fossa tumors. One case was a recurrent tumor in a patient previously treated with radiation. Cytogenetic results were obtained from direct preparations and/or short-term (1-10 day) culture. Three tumors had apparently normal karyotypes. Nineteen tumors demonstrated numerical and/or structural abnormalities. The most frequent structural chromosomal changes were deletions and nonreciprocal translocations. Four tumors contained double minutes. Several chromosomes appear to be nonrandomly involved in PNETs. These include chromosomes 5, 6, 11, 16, 17, and a sex chromosome. The most consistent change, however, was an i(17q), present in one-third (8/22) of the cases. Strikingly, in three of these eight tumors, the i(17q) was the only structural abnormality observed. An i(17q) is not specific for pediatric PNETs, as it is also seen in leukemias and other solid tumors. However, in PNETs it may be a primary change related to tumor development and/or progression. Clinically, there was no correlation of the cytogenetic findings with histologic features of the tumors, size of the tumor, extent of metastasis, or surgical resection.