Genetic markers of repolarization and arrhythmic events after acute coronary syndromes.

BACKGROUND: There is a genetic contribution to the risk of ventricular arrhythmias in survivors of acute coronary syndromes (ACS). We wished to explore the role of 33 candidate single nucleotide polymorphisms (SNPs) in prolonged repolarization and sudden death in patients surviving ACS. METHODS: A total of 2,139 patients (1680 white ethnicity) surviving an admission for ACS were enrolled in the prospective Coronary Disease Cohort Study. Extensive clinical, echocardiographic, and neurohormonal data were collected for 12 months, and clinical events were recorded for a median of 5 years. Each SNP was assessed for association with sudden cardiac death (SCD)/cardiac arrest (CA) and prolonged repolarization at 3 time-points: index admission, 1 month, and 12 months postdischarge. RESULTS: One hundred six SCD/CA events occurred during follow-up (6.3%). Three SNPs from 3 genes (rs17779747 [KCNJ2], rs876188 [C14orf64], rs3864180 [GPC5]) were significantly associated with SCD/CA in multivariable models (after correction for multiple testing); the minor allele of rs17779747 with a decreased risk (hazard ratio [HR] 0.68 per copy of the minor allele, 95% CI 0.50-0.92, P = .012), and rs876188 and rs386418 with an increased risk (HR 1.52 [95% CI 1.10-2.09, P = .011] and HR 1.34 [95% CI 1.04-1.82, P = .023], respectively). At 12 months postdischarge, rs10494366 and rs12143842 (NOS1AP) were significant predictors of prolonged repolarization (HR 1.32 [95% CI 1.04-1.67, P = .022] and HR 1.30 [95% CI 1.01-1.66, P = .038], respectively), but not at earlier time-points. CONCLUSION: Three SNPs were associated with SCD/CA. Repolarization time was associated with variation in the NOS1AP gene. This study demonstrates a possible role for SNPs in risk stratification for arrhythmic events after ACS.

The obesity paradox in heart failure patients with preserved versus reduced ejection fraction: a meta-analysis of individual patient data.

BACKGROUND: In heart failure (HF), obesity, defined as body mass index (BMI) ≥30 kg m(-2), is paradoxically associated with higher survival rates compared with normal-weight patients (the 'obesity paradox'). We sought to determine if the obesity paradox differed by HF subtype (reduced ejection fraction (HF-REF) versus preserved ejection fraction (HF-PEF)). PATIENTS AND METHODS: A sub-analysis of the MAGGIC meta-analysis of patient-level data from 14 HF studies was performed. Subjects were divided into five BMI groups: <22.5, 22.5-24.9 (referent), 25-29.9, 30-34.9 and ≥35 kg m(-2). Cox proportional hazards models adjusted for age, sex, aetiology (ischaemic or non-ischaemic), hypertension, diabetes and baseline blood pressure, stratified by study, were used to examine the independent association between BMI and 3-year total mortality. Analyses were conducted for the overall group and within HF-REF and HF-PEF groups. RESULTS: BMI data were available for 23 967 subjects (mean age, 66.8 years; 32% women; 46% NYHA Class II; 50% Class III) and 5609 (23%) died by 3 years. Obese patients were younger, more likely to receive cardiovascular (CV) drug treatment, and had higher comorbidity burdens. Compared with BMI levels between 22.5 and 24.9 kg m(-2), the adjusted relative hazards for 3-year mortality in subjects with HF-REF were: hazard ratios (HR)=1.31 (95% confidence interval=1.15-1.50) for BMI <22.5, 0.85 (0.76-0.96) for BMI 25.0-29.9, 0.64 (0.55-0.74) for BMI 30.0-34.9 and 0.95 (0.78-1.15) for BMI ≥35. Corresponding adjusted HRs for those with HF-PEF were: 1.12 (95% confidence interval=0.80-1.57) for BMI <22.5, 0.74 (0.56-0.97) for BMI 25.0-29.9, 0.64 (0.46-0.88) for BMI 30.0-34.9 and 0.71 (0.49-1.05) for BMI ≥35. CONCLUSIONS: In patients with chronic HF, the obesity paradox was present in both those with reduced and preserved ventricular systolic function. Mortality in both HF subtypes was U-shaped, with a nadir at 30.0-34.9 kg m(-2).

Hyperuricaemia and gout in New Zealand rural and urban Maori and non-Maori communities.

BACKGROUND: There are few current data on the prevalence of hyperuricaemia and gout in New Zealand, particularly among the indigenous Maori population. AIMS: To determine the prevalence of gout and hyperuricaemia in rural and urban Maori and non-Maori community samples and describe the treatment and comorbidities of participants with gout. METHODS: Participants aged 20-64 years were recruited by random selection from the electoral roll. Maori samples were selected from among those identified as being of Maori descent on the roll and who self-identified as being of Maori ethnicity at interview. Personal medical history, blood pressure, anthropometrics, fasting lipids, glucose, HbA1c and urate were recorded. RESULTS: There were 751 participants. Mean serum urate (SU) was 0.30 mmol/L (0.06-0.69 mmol/L). Maori had a significantly higher prevalence of hyperuricaemia (SU > 0.40 mmol/L) compared with non-Maori (17.0% vs 7.5%, P = 0.0003). A total of 57 participants had a history of gout, with a higher prevalence in Maori compared with non-Maori (10.3% vs 2.3%, P < 0.0001). Of the participants, 18/57 (31.6%) with gout were receiving urate-lowering therapy, but in 38.9%, SU was >0.36 mmol/L. Participants with gout were more likely to have metabolic syndrome, diabetes, cardiac disease or hypertension. CONCLUSIONS: Gout and hyperuricaemia were more prevalent in Maori, and participants with gout were more likely to have comorbidities. There was not a higher overall adjusted cardiovascular disease risk in Maori participants with gout. Despite the high prevalence of gout, management remains suboptimal.

Role of echocardiographic left ventricular mass and carotid intima-media thickness in the cardiovascular risk assessment of asymptomatic patients with type 2 diabetes mellitus.

BACKGROUND: Standard cardiovascular (CV) risk assessment may underestimate risk in people with type 2 diabetes mellitus (T2DM). Cardiac and vascular imaging to detect subclinical disease may augment risk prediction. This study investigated the association between CV risk, left ventricular hypertrophy (LVH) and carotid intima-media thickness (CIMT) in patients with T2DM free of CV symptoms. METHODS: People with T2DM without known CV disease were recruited from general practice. The 5-year risk of CV events was calculated using an adjusted Framingham equation and the prevalence of LVH and abnormal CIMT across bands of CV risk assessed. In those at intermediate risk, the number needed to scan (NNS) to reclassify one person to high risk was calculated across the group and compared in those above and below 55 years. The association between LV mass and CIMT was also assessed. RESULTS: Mean age 57 years (SD11), 51% female. Median 5-year CV risk 14.3% (interquartile range 10.3, 19.5), 51% had LVH (American Society of Echocardiography criteria) and 31% an abnormal CIMT (age and sex criteria). In the 52% at intermediate risk, 37% had LVH and 36% an abnormal CIMT. The NNS was 1.7 using both imaging techniques, 2.7 using cardiac imaging alone or 2.8 using vascular imaging alone. Almost twice as many people >55 years had an abnormal CIMT than those <55 years. CONCLUSIONS: Cardiac and vascular imaging to detect subclinical disease can be used to augment prediction of CV risk in people with T2DM at intermediate risk. The value of reclassifying risk is as yet unproven and requires outcome data from intervention studies.

Hapten-specific stimulation of secondary B cells independent of T cells.

Treatment of spleen cell suspensions from immunized mice with anti-theta serum and complement before transfer to nonimmune irradiated recipients reduced the degree of in vitro stimulation by hapten-homologous carrier complexes by 90%, but did not decrease at all the number of isolated precursor cells stimulated by hapten on heterologous carriers. Thus, secondary B cells can be stimulated by low concentrations of multiply substituted hapten-carrier complexes in the apparent complete absence of specific T cells.

Atrial fibrillation and the risk of death in patients with heart failure: a literature-based meta-analysis.

BACKGROUND: Heart failure (HF) and atrial fibrillation (AF) are common, associated with significant morbidity and mortality, and frequently coexist. It is uncertain from published data if the presence of AF in patients with HF is associated with an incremental adverse outcome. The aim of this study was to combine the results of all studies investigating prognosis for patients with HF and AF compared with those in sinus rhythm (SR) to asses the mortality risk associated with this arrhythmia. METHODS: Electronic databases were searched (Biological Abstracts, Current Contents, EMBASE, Medline, Medline In-progress, PubMed and Scopus), to 31 December 2006, using the key words congestive heart failure, heart failure, ventricular dysfunction, atrial fibrillation, atrial flutter, sinus rhythm, prognosis, outcome, death and hospitalization. Bibliographies of retrieved publications were hand searched. Studies were eligible if they included a HF population and if outcomes were reported by cardiac rhythm (AF or SR). Studies were reviewed by predetermined protocol (including quality assessment). Data were pooled using a random effects model. RESULTS: Twenty studies were included (from 3380 initially identified) representing 32946 patients (10819 deaths). Nine randomized controlled trials (RCT) were included. The prevalence of AF was 15%, crude mortality rates were 46% (AF) and 33% (SR). The odds ratio for death was 1.33 (95% confidence interval (CI) 1.12-1.59) for AF compared with SR. Eleven observational studies were included. The prevalence of AF was 23%, crude mortality rates were 38% (AF) and 25% (SR). The odds ratio for death was 1.57 (95% CI 1.20-2.05) for AF compared with SR. CONCLUSION: This meta-analysis demonstrates that AF is associated with worse outcomes for patients with HF compared with those with SR. Further research is required to determine whether the adverse outcome associated with AF is related to the arrhythmia itself, or to variables, such as HF severity, patient age and comorbidity.

A copper(II)-selective chelator ameliorates left-ventricular hypertrophy in type 2 diabetic patients: a randomised placebo-controlled study.

AIMS/HYPOTHESIS: Cu(II)-selective chelation with trientine ameliorates cardiovascular and renal disease in a model of diabetes in rats. Here, we tested the hypothesis that Cu(II)-selective chelation might improve left ventricular hypertrophy (LVH) in type 2 diabetic patients. METHODS: We performed a 12 month randomised placebo-controlled study of the effects of treatment with the Cu(II)-selective chelator trientine (triethylenetetramine dihydrochloride, 600 mg given orally twice daily) on LVH in diabetic patients (n = 15/group at baseline) in an outpatient setting wherein participants, caregivers and those assessing outcomes were blinded to group assignment. Using MRI, we measured left ventricular variables at baseline, and at months 6 and 12. The change from baseline in left ventricular mass indexed to body surface area (LVM(bsa)) was the primary endpoint variable. RESULTS: Diabetic patients had LVH with preserved ejection fraction at baseline. Trientine treatment decreased LVM(bsa) by 5.0 +/- 7.2 g/m(2) (mean +/- SD) at month 6 (when 14 trientine-treated and 14 placebo-treated participants were analysed; p = 0.0056 compared with placebo) and by 10.6 +/- 7.6 g/m(2) at month 12 (when nine trientine-treated and 13 placebo-treated participants were analysed; p = 0.0088), whereas LVM(bsa) was unchanged by placebo treatment. In a multiple-regression model that explained ~75% of variation (R (2) = 0.748, p = 0.001), cumulative urinary Cu excretion over 12 months was positively associated with trientine-evoked decreases in LVM(bsa). CONCLUSIONS/INTERPRETATION: Cu(II)-selective chelation merits further exploration as a potential pharmacotherapy for diabetic heart disease. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ACTRN 12609000053224 FUNDING: The Endocore Research Trust; Lottery Health New Zealand; the Maurice and Phyllis Paykel Trust; the Foundation of Research, Science and Technology (New Zealand); the Health Research Council of New Zealand; the Ministry of Education (New Zealand) through the Maurice Wilkins Centre for Molecular Biodiscovery; and the Protemix Corporation.

Independent prognostic importance of a restrictive left ventricular filling pattern after myocardial infarction: an individual patient meta-analysis: Meta-Analysis Research Group in Echocardiography acute myocardial infarction.

BACKGROUND: Restrictive mitral filling pattern (RFP), the most severe form of diastolic dysfunction, is a predictor of outcome after acute myocardial infarction (AMI). Low power has precluded a definite conclusion on the independent importance of RFP, especially when overall systolic function is preserved. We undertook an individual patient meta-analysis to determine whether RFP is predictive of mortality independently of LV ejection fraction (LVEF), end-systolic volume index, and Killip class in patients after AMI. METHODS AND RESULTS: Twelve prospective studies (3396 patients) assessing the relationship between prognosis and Doppler echocardiographic LV filling pattern in patients after AMI were included. Individual patient data from each study were extracted and collated into a single database for analysis. RFP was associated with higher all-cause mortality (hazard ratio, 2.67; 95% CI, 2.23 to 3.20; P<0.001) and remained an independent predictor in multivariate analysis with age, gender, and LVEF. The overall prevalence of RFP was 20% but was highest (36%) in the quartile of patients with lowest LVEF (<39%) and lowest (9%) in patients with the highest LVEF (>53%; P<0.0001). RFP remained significant within each quartile of LVEF, and no interaction was found for RFP and LVEF (P=0.42). RFP also predicted mortality in patients with above- and below-median end-systolic volume index (1575 patients) and in different Killip classes (1746 patients). Importantly, when diabetes, current medication, and prior AMI were included in the model, RFP remained an independent predictor of outcome. CONCLUSIONS: Restrictive filling is an important independent predictor of mortality after AMI regardless of LVEF, end-systolic volume index, and Killip class.

Independence of restrictive filling pattern and LV ejection fraction with mortality in heart failure: an individual patient meta-analysis.

BACKGROUND: The Doppler echocardiographic restrictive mitral filling pattern (RFP) is an important prognostic indicator in patients with heart failure (HF), but the interaction between RFP, left ventricular ejection fraction (LVEF) and filling pattern remains uncertain. AIMS: To determine whether the RFP is predictive of mortality independently of LVEF in patients with HF. METHODS: Online databases were searched to identify studies assessing the relationship between prognosis and LV filling pattern in patients with HF. Individual patient data from 18 studies (3540 patients) were extracted and collated at the MeRGE Coordinating Centre (The University of Auckland). RESULTS: Overall, RFP was associated with higher all-cause mortality than the non-restrictive filling pattern: hazard ratio 2.42 (95% CI 2.06, 2.83). In multivariable analysis the RFP, LVEF, NYHA class and age were independent predictors of mortality. The prevalence of the RFP was inversely related to LVEF but remained a predictor of mortality even in those patients with preserved LVEF. CONCLUSIONS: The restrictive mitral filling pattern is a powerful predictor of mortality, independent of LVEF and age, in patients with HF. Doppler-derived LV filling patterns are an accessible marker from echocardiography that can readily be incorporated in risk stratification of all patients with HF.

Histomorphological changes after renal X-ray arteriography using iodine and gadolinium contrast media in an ischemic porcine model.

BACKGROUND: Gadolinium contrast media (Gd-CM) are regarded as non-nephrotoxic or considerably less nephrotoxic than iodine contrast media (I-CM), and have therefore come to be used as a substitute for I-CM in patients with renal insufficiency in a variety of radiographic examinations. PURPOSE: To investigate renal histomorphological changes caused by Gd-CM in comparison with I-CM after renal X-ray arteriography in an ischemic porcine model,and to evaluate these changes in relation to the nephrotoxicity of the CM used. MATERIAL AND METHODS: Test solutions: gadopentetate, gadodiamide, iohexol, gadobutrol,iopromide, iodixanol, mannitol, and saline. The experiments were performed on 152 animals. Each pig was randomized to receive one test solution injected into the balloon occluded(10 min) right renal artery. The kidneys were evaluated histomorphologically.The severity of histomorphological changes was graded subjectively: 15 minimal, 25 mild, 35 moderate, and 4=marked. RESULTS: The main histological changes were 1) proximal tubular and glomerular necrosis,2) hemorrhage/congestion of the cortex, medulla, and glomeruli, 3) proximal tubular vacuolation, and 4) protein-filled tubules in the cortex and medulla. Necrosis and hemorrhage/congestion were more frequent after injections with gadopentetate, mannitol solution iso-osmotic to gadopentetate, and gadobutrol compared to all other groups(P<0.001). The degree of necrosis and hemorrhage/congestion was related to the degree of impairment of renal function, but inversely related to vacuolation and tubular protein filling. CONCLUSION: In ischemic porcine kidneys, the histomorphological changes caused by Gd-CM are similar to those caused by I-CM. Vacuolation appears to be independent of the osmolality and viscosity of the CM, and does not seem to be an indicator of renal impairment. "High-osmolal" Gd-CM are more nephrotoxic than "low- and iso-osmolal" I-CM when compared in equal volumes of concentrations, resulting in equal X-ray attenuation.

Serum IGF-I levels are similar in Samoan, Maori and European populations despite differences in body composition.

OBJECTIVE: To determine if serum IGF-I concentrations are similar in healthy adult subjects from the Samoan, Maori and European populations in New Zealand. DESIGN: Serum IGF-I concentration was measured in 75 healthy adults, aged 18-50 years, of Samoan (n=23), Maori (n=22) and European (n=30) descent. Body composition was assessed using standard anthropomorphic measures. In addition all subjects had body composition assessed by Dual energy X-ray absorptiometry (DXA). RESULTS: Weight, body mass index (BMI), and fat mass were significantly greater in Maori and Samoan subjects than European subjects (ANOVA p=0.006, p=0.0003, p=0.03, respectively). However, serum IGF-I concentration was similar between the groups (European 186.8 SEM 14.9 microg/l, Maori 204.8 SEM 17.1 microg/l, Samoan 180.0 SEM 17.5 microg/l, p=0.58). IGF-I levels were similar between ethnic groups after adjustment (ANCOVA) for age, sex or BMI (p=0.5) or age, sex and fat mass (p=0.44). In multivariate analysis the only independent predictor of IGF-I was age (p<0.001) and explained 22% of the variance in IGF-I level. CONCLUSIONS: Serum IGF-I concentrations were similar in Maori, Samoan and European population groups in New Zealand, despite significant differences in anthropomorphic variables and body composition.

Prognostic significance of anaemia in patients with heart failure with preserved and reduced ejection fraction: results from the MAGGIC individual patient data meta-analysis.

BACKGROUND: Anaemia is common among patients with heart failure (HF) and is an important prognostic marker. AIM: We sought to determine the prognostic importance of anaemia in a large multinational pooled dataset of prospectively enrolled HF patients, with the specific aim to determine the prognostic role of anaemia in HF with preserved and reduced ejection fraction (HF-PEF and HF-REF, respectively). DESIGN: Individual person data meta-analysis. METHODS: Patients with haemoglobin (Hb) data from the MAGGIC dataset were used. Anaemia was defined as Hb < 120 g/l in women and <130 g/l in men. HF-PEF was defined as EF ≥ 50%; HF-REF was EF < 50%. Cox proportional hazard modelling, with adjustment for clinically relevant variables, was undertaken to investigate factors associated with 3-year all-cause mortality. RESULTS: Thirteen thousand two hundred and ninety-five patients with HF from 19 studies (9887 with HF-REF and 3408 with HF-PEF). The prevalence of anaemia was similar among those with HF-REF and HF-PEF (42.8 and 41.6% respectively). Compared with patients with normal Hb values, those with anaemia were older, were more likely to have diabetes, ischaemic aetiology, New York Heart Association class IV symptoms, lower estimated glomerular filtration rate and were more likely to be taking diuretic and less likely to be taking a beta-blocker. Patients with anaemia had higher all-cause mortality (adjusted hazard ratio [aHR] 1.38, 95% confidence interval [CI] 1.25-1.51), independent of EF group: aHR 1.67 (1.39-1.99) in HF-PEF and aHR 2.49 (2.13-2.90) in HF-REF. CONCLUSIONS: Anaemia is an adverse prognostic factor in HF irrespective of EF. The prognostic importance of anaemia was greatest in patients with HF-REF.

Beta-blockers in heart failure: promising or proved?

Despite recent improvements in the management of congestive heart failure, the prognosis of many patients with this condition remains poor. The level of neurohormonal activation appears to be predictive of survival, and clinical studies indicate that inhibition of overactivated neurohormonal systems may be beneficial. Activation of the renin-angiotensin-aldosterone system is well documented in heart failure, and angiotensin-converting enzyme inhibition now has an established role in treatment based on evidence of hemodynamic, symptomatic and mortality benefit. Sympathetic nervous system activation also occurs as a compensatory mechanism in heart failure but with long-term deleterious effects. Increasing evidence suggests that beta-adrenergic blockade can produce hemodynamic and symptomatic improvement in heart failure of idiopathic or ischemic etiology. Trials of beta-adrenergic blocking agents in patients after myocardial infarction suggest a beneficial effect on mortality, even among those with heart failure. However, there remains uncertainty as to how generalizable are the results from the postinfarction trials, particularly in the current therapeutic environment with routine angiotensin-converting enzyme inhibitor therapy. Appropriately powered randomized, controlled trials are required to determine precisely the balance of benefit and risk resulting from long-term beta-blocker therapy in patients with heart failure of ischemic and other etiology.

Left ventricular remodeling with carvedilol in patients with congestive heart failure due to ischemic heart disease. Australia-New Zealand Heart Failure Research Collaborative Group.

OBJECTIVES: The aim of this study, a substudy of the Australia-New Zealand trial of carvedilol in patients with heart failure due to ischemic heart disease, was to determine the effects of this treatment on left ventricular size and function with the use of quantitative two-dimensional (2D) echocardiography. BACKGROUND: Beta-adrenergic blocking drugs have been shown to improve left ventricular ejection fraction in patients with heart failure due to either ischemic heart disease or idiopathic dilated cardiomyopathy. However, the effects of such treatment on left ventricular size remain uncertain. METHODS: One hundred twenty-three patients from 10 centers in New Zealand and Australia participated in the 2D echocardiographic substudy. Echocardiography was performed before randomization and was repeated after 6 and 12 months of treatment. Left ventricular end-diastolic and end-systolic volumes were measured from apical four- and two-chamber views with the use of a modified Simpson's rule method. RESULTS: After 12 months, heart rate was 8 beats/min lower in the carvedilol than in the placebo group, whereas left ventricular end-diastolic and end-systolic volumes were increased in the placebo group but reduced in the carvedilol group. At 12 months, left ventricular end-diastolic volume index was 14 ml/m2 less in the carvedilol than in the placebo group (p = 0.0015); left ventricular end-systolic volume index was 15.3 ml/m2 less (p = 0.0001), and left ventricular ejection fraction was 5.8% greater (p = 0.0015). CONCLUSIONS: In patients with heart failure due to ischemic heart disease, carvedilol therapy for 12 months reduced left ventricular volumes, increased left ventricular ejection fraction and prevented progressive left ventricular dilation. These changes demonstrate a beneficial effect of carvedilol on left ventricular remodeling in heart failure. The observed changes may explain in part the improved clinical outcomes produced by treatment with carvedilol.

Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: prognostic utility and prediction of benefit from carvedilol in chronic ischemic left ventricular dysfunction. Australia-New Zealand Heart Failure Group.

OBJECTIVES: We sought to assess plasma concentrations of the amino (N)-terminal portion of pro-brain natriuretic peptide (N-BNP) and adrenomedullin for prediction of adverse outcomes and responses to treatment in 297 patients with ischemic left ventricular (LV) dysfunction who were randomly assigned to receive carvedilol or placebo. BACKGROUND: Although neurohormonal status has known prognostic significance in heart failure, the predictive power of either N-BNP or adrenomedullin in chronic ischemic LV dysfunction has not been previously reported. METHODS: Plasma N-BNP and adrenomedullin were measured in 297 patients with chronic ischemic (LV) dysfunction before randomization to carvedilol or placebo, added to established treatment with a converting enzyme inhibitor and loop diuretic (with or without digoxin). The patients' clinical outcomes, induding mortality and heart failure events, were recorded for 18 months. RESULTS: Above-median N-BNP and adrenomedullin levels conferred increased risks (all p < 0.001) of mortality (risk ratios [95% confidence intervals]: 4.67 [2-10.9] and 3.92 [1.76-8.7], respectively) and hospital admission with heart failure (4.7 [2.2-10.3] and 2.4 [1.3-4.5], respectively). Both of these predicted death or heart failure independent of age, New York Heart Association functional class, LV ejection fraction, previous myocardial infarction or previous admission with heart failure. Carvedilol reduced the risk of death or heart failure in patients with above-median levels of N-BNP or adrenomedullin, or both, to rates not significantly different from those observed in patients with levels below the median value. CONCLUSIONS: In patients with established ischemic LV dysfunction, plasma N-BNP and adrenomedullin are independent predictors of mortality and heart failure. Carvedilol reduced mortality and heart failure in patients with higher pre-treatment plasma N-BNP and adrenomedullin.

Acute encephalopathy, streptococcal infection, and cryoglobulinemia.

A 9-year-old girl had an acute encephalopathic illness characterized by disordered consciousness, seizures, and multiple cortical deficits. The acute illness was associated with serologic evidence of an antecedent streptococcal infection and the presence of a mixed cryoglobulin with specific antistreptococcal antibody activity. Although the patient had no other evidence of a systemic or central nervous system vasculitis, computerized tomography demonstrated changes compatible with a vasculitic process. Treatment with corticosteroids was associated with resolution of the cryoglobulinemia and complete clinical recovery.

An enzyme linked immunosorbent assay for leucocyte and platelet antibodies.

An enzyme linked immunosorbent assay (ELISA) method for the detection of antibodies to platelets and leucocytes is presented. The method can be used for large numbers of samples. The method is objective when photometers are used. Approximately 50% of all cases of possible autoimmune thrombocytopenic purpura (A.T.P.) and unexplained neutropenia showed positive results. The results obtained using ELISA and standard tests for leucocyte and platelet antibodies are compared. The ELISA tests may also detect immune complexes.

HER-2/neu (erbB-2) and the cell cycle.

Signaling by the HER-2 proto-oncogene product results in the activation of several biochemical pathways, which in turn modulate the expression and function of cell cycle regulators. These alterations of cell cycle regulatory molecules may be critical for the conception and maintenance of the transformed phenotype conferred by HER-2 gene amplification and overexpression. On the other hand, blockade of HER-2 function with a therapeutic intent will require the reversal of these effects on cell cycle regulatory molecules in order for these interventions to be effective. Data is presented to suggest that the G1 cyclin D1 and the cyclin-dependent kinase inhibitor p27KIP1 may be involved in subversion of the G1/S traverse by signaling pathways activated by HER-2 function.

Left ventricular mass correlates with fat-free mass but not fat mass in adults.

BACKGROUND: Left ventricular mass is associated with body size, obesity and blood pressure. Echocardiography is routinely used to estimate this parameter, which is usually indexed to body surface area to allow comparisons to be made between individuals and groups of different body size. However, in obese subjects, using left ventricular mass indexed to body surface area may inappropriately normalize left ventricular mass. OBJECTIVES: The aim of this study was to investigate the relationships between left ventricular mass and body composition and to determine the best determinants of left ventricular mass. SUBJECTS AND METHODS: Echocardiography and dual-energy X-ray absorptiometry were performed in 106 subjects under primary care. Half were hypertensive subjects and the others were normotensive age- and sex-matched control subjects. Univariate correlations were studied between left ventricular mass and height, height1.5, height2.7, weight, body surface area, body mass index, waist: hip ratio, fat-free mass, bone mineral content and fat mass. Stepwise multiple linear regression was performed to determine the best determinants of left ventricular mass. RESULTS: Fat-free mass was correlated with left ventricular mass (r = 0.53, P = 0.0001) and was the only independent predictor of left ventricular mass (R2 = 0.30, P= 0.0001) by multivariate analysis. Fat mass did not correlate with left ventricular mass (r= -0.005, P= 0.96). Other measures of body size, including body surface area, waist: hip ratio, bone mineral content, weight, height, height 1.5, height2.7 and body mass index all were correlated with, but were not independent determinants of, left ventricular mass. CONCLUSIONS: Left ventricular mass is independently determined by fat-free mass but by no other measures of body size or composition. Specifically, left ventricular mass was neither correlated with nor determined by fat mass. None of the other measures of body size determined left ventricular mass. It may be more appropriate to index left ventricular mass to fat-free mass rather than to measures of body size which include fat mass.

Esophageal motor abnormalities in children and adolescents with scleroderma and mixed connective tissue disease.

To determine the frequency and nature of esophageal motor abnormalities in children and adolescents with scleroderma syndromes and mixed connective tissue disease, esophageal manometry was performed on seven patients with progressive systemic sclerosis, four patients with mixed connective tissue disease, and two patients with linear scleroderma. A total of 73% of patients with progressive systemic sclerosis and mixed connective tissue disease had symptoms of esophageal dysfunction. A significant association between the presence of Raynaud phenomenon and esophageal symptoms was noted. Esophageal motor abnormalities were detected in 73% of patients with progressive systemic sclerosis and mixed connective tissue disease; these abnormalities were characterized by decreased lower esophageal sphincter pressure and abnormal peristalsis in the distal two thirds of the esophageal body. They resemble those described among adults with progressive systemic sclerosis and mixed connective tissue disease but were not related to disease duration or to the presence of Raynaud phenomenon. Patients with linear scleroderma did not have esophageal symptoms and demonstrated only nonspecific motor abnormalities that did not worsen during several years of follow-up.