Reduced exercise tolerance in CHF may be related to factors other than impaired skeletal muscle oxidative capacity

BACKGROUND: We sought to determine whether skeletal muscle oxidative capacity, fiber type proportions, and fiber size, capillary density or muscle mass might explain the impaired exercise tolerance in chronic heart failure (CHF). Previous studies are equivocal regarding the maladaptations that occur in the skeletal muscle of patients with CHF and their role in the observed exercise intolerance.Methods and results Total body O(2) uptake (VO(2peak)) was determined in 14 CHF patients and 8 healthy sedentary similar-age controls. Muscle samples were analyzed for mitochondrial adenosine triphosphate (ATP) production rate (MAPR), oxidative and glycolytic enzyme activity, fiber size and type, and capillary density. CHF patients demonstrated a lower VO(2peak) (15.1+/-1.1 versus 28.1+/-2.3 mL.kg(-1).min(-1), P<.001) and capillary to fiber ratio (1.09+/-0.05 versus 1.40+/-0.04; P<.001) when compared with controls. However, there was no difference in capillary density (capillaries per square millimeter) across any of the fiber types. Measurements of MAPR and oxidative enzyme activity suggested no difference in muscle oxidative capacity between the groups. CONCLUSIONS: Neither reductions in muscle oxidative capacity nor capillary density appear to be the cause of exercise limitation in this cohort of patients. Therefore, we hypothesize that the low VO(2peak) observed in CHF patients may be the result of fiber atrophy and possibly impaired activation of oxidative phosphorylation.     

Production and role of extracellular guanosine cyclic 3', 5' monophosphate in sodium uptake in human proximal tubule cells

The present study was designed to determine the capability of human renal proximal tubule (RPT) to generate and export guanosine cyclic 3', 5' monophosphate (cGMP) in response to direct stimulation of soluble guanylyl cyclase by nitric oxide (NO) donors. In addition, we investigated whether cGMP extrusion from human RPT cells is required for inhibition of cellular sodium uptake. RPT cells were cultured from fresh human kidneys (normotensive subjects, n=4, mean age 65+/-4.7 years, 3 men, 1 woman; hypertensive patients, n=6, mean age 64+/-6.1 years, 4 men, 2 women) after unilateral nephrectomy. The fluorescence dye Sodium Green was employed to determine cytoplasmic Na+ concentration. In the presence of the Na+/K+ ATPase inhibitor ouabain, fluorescence was monitored at the appropriate wavelength (excitation 485 nm, emission 535 nm). Nitric oxide donor, S-nitroso-N-acetylpenicillamine (SNAP, 10(-4) M), increased both intracellular and extracellular cGMP (from 1.26+/-0.21 to 88.7+/-12.6 pmol/mg protein and from 0.58+/-0.10 to 9.24+/-1.9 pmol/mL, respectively, P<0.01) and decreased cellular Na+ uptake by 37.4+/-6.8% (P<0.05) compared with control. The effects of SNAP on cGMP production were similar in normotensive and hypertensive subjects. The increases in intracellular and extracellular cGMP concentration because of SNAP were blocked completely by soluble guanylyl cyclase inhibitor ODQ (1-H-[1,2,4] oxadiazolo [4,2-alpha] quinoxalin-1-one). Probenecid, an organic anion transport inhibitor, augmented the SNAP (10(-6) M)-induced increase in intracellular cGMP accumulation (from 4.9+/-0.9 to 9.8+/-1.5 pmol/mg protein, P<0.05), abrogated the SNAP-induced increase in extracellular cGMP extrusion (from 1.07+/-0.4 to 0.37+/-0.1 pmol/L, P<0.05) and blocked the SNAP-induced reduction in cellular Na+ uptake. Neither intracellular nor extracellular cGMP were influenced by l-arginine, the metabolic precursor of NO, or N(G)-nitro-L-arginine methyl ester, an inhibitor of NO synthase. After exogenous administration of cGMP (10(-5) M) or its membrane-permeable analogue 8-Br-cGMP (10(-5) M), only 8-Br-cGMP crossed the cell membrane to increase intracellular cGMP (from 1.36+/-0.19 to 289.7+/-29.4 pmol/mg protein, P<0.01). However, both cGMP and 8-Br-cGMP were effective in decreasing cellular Na+ uptake. In conclusion, human RPT cells contain soluble guanylyl cyclase and are able to generate and export cGMP in response to NO. Because human RPT cells do not themselves contain constitutive NO synthase, the NO-generating cGMP must be derived from sources outside the human RPT. The cGMP cellular export system is critical in the regulation of RPT cellular Na+ absorption in humans.     

Risk of Extraesophageal Malignancy in Patients with Adenocarcinoma Arising in Barrett's Esophagus

Objectives : It has been suggested that the presence of Barrett's mucosa is a marker for potential malignancy in other organs. Our objective was to study subjects with adenocarcinoma of the esophagus arising in Barrett's epithelium. Methods : We reviewed the medical records of patients with esophageal adenocarcinoma, with esophageal squamous cell carcinoma, and with no esophageal pathology and recorded the occurrence of extrae-sophageal malignancies and the heavy use of tobacco and alcohol. Results : The prevalence of extraesophageal malignancies was not higher in patients with esophageal adenocarcinoma (15%) than in patients in either control group (14% each). Patients with either type of cancer of the esophagus had higher rates of tobacco and alcohol use than normal controls (tobacco: p = 0.02 and/7 < 0.01 for adenocarcinoma and squamous cell carcinoma, respectively, vs. normal controls; alcohol:/; < 0.01 for each esophageal malignancy vs . normal controls). The rate of tobacco and alcohol use was higher in patients with esophageal squamous cell carcinoma than in those with adenocarcinoma, but only the difference in alcohol consumption was statistically significant ( p < 0.01). Conclusion : Patients with adenocarcinoma of the esophagus are not at higher risk for development of extraesophageal malignancy. This observation applies to both those with and without underlying Barrett's epithelium. Alcohol and tobacco use appear to be related to the malignant transformation of esophageal epithelium.     

Circulating immune complexes in Hodgkin's disease

Levels of circulating immune complexes (CIC) in the serum of patients with Hodgkin's disease were measured by the Raji cell radioimmunoassay. Elevated levels of immune complexes (mean value of 49 μg/ml ± 21 SE) were detected in 20 of 40 (50 per cent) untreated patients. After treatment, the level of CIC was normal (< 15 μg/ml) in 39 of 41 patients. Recurrent disease developed in two of the 39 patients with normal post-treatment levels of CIC and in one of the two patients with elevated post-treatment levels during the follow-up period of six months to six years. Elevated levels of CIC were detected in patients with Hodgkin's disease in stages I, II and III but not in stage IV. No significant correlations were found in the frequency of elevated levels of CIC or the values observed, and the presence or absence of symptoms (fever, sweats, weight loss) or the histologic subtype of the tumor. Our data indicate that the measurement of CIC by the sensitive and specific Raji cell assay may prove useful in the management of patients with Hodgkin's disease. In particular, serial measurement of the level of CIC could be employed to monitor the response to treatment and to detect recurrent diseases.     

Prediction of mortality in community-living frail elderly people with long-term care needs

OBJECTIVES: To develop and validate a prognostic index for mortality in community‐living, frail elderly people. DESIGN: Cohort study of Program of All‐Inclusive Care for the Elderly (PACE) participants enrolled between 1988 and 1996. SETTING: Eleven PACE sites, a community‐based long‐term care program that cares for frail, chronically ill elderly people who meet criteria for nursing home placement. PARTICIPANTS: Three thousand eight hundred ninety‐nine PACE enrollees. The index was developed in 2,232 participants and validated in 1,667. MEASUREMENTS: Time to death was predicted using risk factors obtained from a geriatric assessment performed by the PACE interdisciplinary team at the time of enrollment. Risk factors included demographic characteristics, comorbid conditions, and functional status. RESULTS: The development cohort had a mean age of 79 (68% female, 40% white). The validation cohort had a mean age of 79 (76% female, 65% white). In the development cohort, eight independent risk factors of mortality were identified and weighted, using Cox regression, to create a risk score: male sex, 2 points; age (75–79, 2 points; 80–84, 2 points; ≥85, 3 points); dependence in toileting, 1 point; dependence in dressing (partial dependence, 1 point; full dependence, 3 points); malignant neoplasm, 2 points; congestive heart failure, 3 points; chronic obstructive pulmonary disease, 1 point; and renal insufficiency, 3 points. In the development cohort, respective 1‐ and 3‐year mortality rates were 6% and 21% in the lowest‐risk group (0–3 points), 12% and 36% in the middle‐risk group (4–5 points), and 21% and 54% in the highest‐risk group (>5 points). In the validation cohort, respective 1‐ and 3‐year mortality rates were 7% and 18% in the lowest‐risk group, 11% and 36% in the middle‐risk group, and 22% and 55% in the highest‐risk group. The area under the receiver operating characteristic curve for the point score was 0.66 and 0.69 in the development and validation cohorts, respectively. CONCLUSION: A multidimensional prognostic index was developed and validated using age, sex, functional status, and comorbidities that effectively stratifies frail, community‐living elderly people into groups at varying risk of mortality.     

Identification and differentiation of surgically correctable hypertension due to primary aldosteronism.

During a protocol study for the evaluation of patients with primary aldosteronism, a variety of diagnostic studies were employed in an attempt to identify patients with primary aldosteronism and to differentiate patients with adrenal adenoma from patients with idiopathic adrenal hyperplasia. In this study, we are able to demonstrate the utility of (1) absent postural increase in plasma aldosterone concentration, (2) adrenal scanning and (3) normalization of blood pressure with spironolactone therapy in identifying patients with primary aldosterone excess who have an adrenal adenoma, surgical removal of which results in eliminating their hypertension.     

Rapid adrenocorticotropic hormone test in practice. Retrospective review

Retrospective analysis of the rapid adrenocorticotropic hormone (ACTH) test in a large adult population shows a marked interdependence of the basal cortisol concentration, peak cortisol concentration, and increase in cortisol concentration. Repetition of the rapid ACTH test in the same patient does not improve diagnostic accuracy. A significant number of falsely abnormal rapid ACTH test results were observed (in comparison to continuous ACTH infusion as a reference test). This supports the use of the rapid ACTH test as a screening test, but not as a diagnostic test for adrenocortical failure. It is proposed that a peak cortisol level greater than or equal to 20 micrograms/dl (550 nmol/liter) is a sufficient single criterion for normal adrenal function as assessed by the rapid ACTH test.     

Experience with the Gianturco-Roubin stent for abrupt vessel closure complicating percutaneous transluminal coronary angioplasty

Background: Emergency coronary artery bypass grafting (CABG) has previously been the only option in the treatment of refractory abrupt vessel closure complicating percutaneous transluminal coronary angioplasty (PTC A), and has been associated with high rates of morbidity and mortality. Intracoronary stenting now provides an alternative to emergency CABG. Aim: To assess our initial experience with emergency coronary artery stenting as a new technique. Methods: Retrospective case study review with clinical and angiographic follow-up. Results: The Gianturco-Roubin (GR) stent was deployed in 13 patients in whom PTCA was complicated by abrupt vessel closure refractory to standard balloon techniques. Indications for PTCA were unstable angina (six), stable angina (six) and acute myocardial infarction (MI) (one). The arteries stented included left anterior descending (LAD) artery lesions (eight) and right coronary artery lesions (five). Two patients required urgent CABG, one due to failed stent deployment and one for inadequate control of vessel dissection. In seven of the stented patients the creatine kinase rose to greater than twice the upper limit or normal. Three patients had subacute thrombotic occlusion at seven to 19 days post stent deployment, managed with intravenous thrombolysis or repeat PTCA. At seven months follow-up, 11 patients were free of angina, two patients had Canadian Heart Association class II angina and there were no deaths. Eleven patients had repeat angiography at mean six months post stent. Five patients had evidence of restenosis managed with repeat PTCA in four and CABG in one. Conclusions: The GR stent is an effective alternative to urgent CABG in the treatment of refractory abrupt vessel closure complicating PTCA.     

Fetal expression of the angiotensinogen gene

To determine whether the angiotensinogen (Ao) gene is expressed in multiple organs of the fetal rat and the changes associated with maturation, fetal (15-20 days of gestation), newborn (1-10 days old), and adult (90 days old) rat tissues were subjected to Northern analysis and hybridization with a full length Ao complementary DNA (cDNA). Whereas Ao messenger RNA (mRNA) was undetectable in fetal livers, Ao sequences were readily detectable 1 h after birth and reached a peak at 24 h of birth. Levels remained elevated at 5 and 10 days after birth to decrease slightly at 90 days of postnatal life. Poly A+ enriched liver RNA was subjected to a similar analysis demonstrating that fetal liver Ao mRNA levels were 50-fold less than the corresponding adult levels. In contrast to the finding in the fetal liver, Ao mRNA was found in fetal brown fat, brains, and kidneys. We conclude that 1) Expression of the Ao gene is developmentally regulated in a tissue-specific manner; 2) Unlike the adult animal, the liver may not be the primary source of Ao in the fetus; 3) Alternate sources of Ao synthesis include fetal brown fat, brain, and kidneys.     

Understanding how breast cancer patients use risk information from genomic tests

We sought to examine how patients’ treatment decisions incorporate potentially conflicting information from standard clinical indicators (e.g., tumor size) and genomic tests for breast cancer recurrence risk. Participants were 77 early stage breast cancer survivors who previously received genomic testing. They read six hypothetical vignettes that varied recurrence risk indicated by standard tests (low or high risk) coupled with the genomic test (low, intermediate or high risk). For each vignette, women reported their perceived recurrence risk and treatment preferences. Test results indicating high recurrence risk increased perception of risk and preference for chemotherapy (p < .001 for all). Perceived risk explained (i.e., mediated) the effect of test results on chemotherapy preferences. When test results conflicted, women gave more weight to genomic over standard test results. Hypothetical genomic test results had the intended effect of influencing women’s perceptions of recurrence risk and interest in chemotherapy.