Showing papers by "Institute of Chartered Accountants of Nigeria published in 2014"

EIF2AK4 mutations cause pulmonary veno-occlusive disease, a recessive form of pulmonary hypertension

Abstract: Pulmonary veno-occlusive disease (PVOD) is a rare and devastating cause of pulmonary hypertension that is characterized histologically by widespread fibrous intimal proliferation of septal veins and preseptal venules and is frequently associated with pulmonary capillary dilatation and proliferation. PVOD is categorized into a separate pulmonary arterial hypertension-related group in the current classification of pulmonary hypertension. PVOD presents either sporadically or as familial cases with a seemingly recessive mode of transmission. Using whole-exome sequencing, we detected recessive mutations in EIF2AK4 (also called GCN2) that cosegregated with PVOD in all 13 families studied. We also found biallelic EIF2AK4 mutations in 5 of 20 histologically confirmed sporadic cases of PVOD. All mutations, either in a homozygous or compound-heterozygous state, disrupted the function of the gene. These findings point to EIF2AK4 as the major gene that is linked to PVOD development and contribute toward an understanding of the complex genetic architecture of pulmonary hypertension.

Heart failure with preserved ejection fraction: a clinical dilemma

Abstract: Heart failure with preserved ejection fraction (HFpEF) is now recognized as a major and growing public health problem worldwide. Yet significant uncertainties still surround its pathophysiology and treatment, leaving clinicians in a dilemma regarding its optimal management. Whether HFpEF and heart failure with reduced ejection fraction (HFrEF) are two distinct entities or two ends of a common spectrum remains a matter of debate. In particular, the lack of benefit observed with renin-angiotensin system blockers has raised questions regarding our understanding of the pathophysiology of HFpEF. New paradigms including a prominent role of co-morbidities, inflammation, endothelial dysfunction, and pro-hypertrophic signalling pathways have been proposed. Recent proof-of-concept trials using a phosphodiesterase inhibitor, a mineralocorticoid receptor antagonist, an angiotensin receptor/neprilysin inhibitor, a soluble guanylate cyclase stimulator, or a sino atria, if current blocker provide important insight for the development of novel therapeutic strategies in HFpEF.

Mechanical ventilation during extracorporeal membrane oxygenation.

Abstract: The timing of extracorporeal membrane oxygenation (ECMO) initiation and its outcome in the management of respiratory and cardiac failure have received considerable attention, but very little attention has been given to mechanical ventilation during ECMO. Mechanical ventilation settings in non-ECMO studies have been shown to have an effect on survival and may also have contributed to a treatment effect in ECMO trials. Protective lung ventilation strategies established for non-ECMO-supported respiratory failure patients may not be optimal for more severe forms of respiratory failure requiring ECMO support. The influence of positive end-expiratory pressure on the reduction of the left ventricular compliance may be a matter of concern for patients receiving ECMO support for cardiac failure. The objectives of this review were to describe potential mechanisms for lung injury during ECMO for respiratory or cardiac failure, to assess the possible benefits from the use of ultra-protective lung ventilation strategies and to review published guidelines and expert opinions available on mechanical ventilation-specific management of patients requiring ECMO, including mode and ventilator settings. Articles were identified through a detailed search of PubMed, Ovid, Cochrane databases and Google Scholar. Additional references were retrieved from the selected studies. Growing evidence suggests that mechanical ventilation settings are important in ECMO patients to minimize further lung damage and improve outcomes. An ultra-protective ventilation strategy may be optimal for mechanical ventilation during ECMO for respiratory failure. The effects of airway pressure on right and left ventricular afterload should be considered during venoarterial ECMO support of cardiac failure. Future studies are needed to better understand the potential impact of invasive mechanical ventilation modes and settings on outcomes.

Maximizing the Power of Principal-Component Analysis of Correlated Phenotypes in Genome-wide Association Studies

Abstract: Many human traits are highly correlated. This correlation can be leveraged to improve the power of genetic association tests to identify markers associated with one or more of the traits. Principal component analysis (PCA) is a useful tool that has been widely used for the multivariate analysis of correlated variables. PCA is usually applied as a dimension reduction method: the few top principal components (PCs) explaining most of total trait variance are tested for association with a predictor of interest, and the remaining components are not analyzed. In this study we review the theoretical basis of PCA and describe the behavior of PCA when testing for association between a SNP and correlated traits. We then use simulation to compare the power of various PCA-based strategies when analyzing up to 100 correlated traits. We show that contrary to widespread practice, testing only the top PCs often has low power, whereas combining signal across all PCs can have greater power. This power gain is primarily due to increased power to detect genetic variants with opposite effects on positively correlated traits and variants that are exclusively associated with a single trait. Relative to other methods, the combined-PC approach has close to optimal power in all scenarios considered while offering more flexibility and more robustness to potential confounders. Finally, we apply the proposed PCA strategy to the genome-wide association study of five correlated coagulation traits where we identify two candidate SNPs that were not found by the standard approach.

Residual macrovascular risk in 2013: what have we learned?

Abstract: Cardiovascular disease poses a major challenge for the 21st century, exacerbated by the pandemics of obesity, metabolic syndrome and type 2 diabetes. While best standards of care, including high-dose statins, can ameliorate the risk of vascular complications, patients remain at high risk of cardiovascular events. The Residual Risk Reduction Initiative (R3i) has previously highlighted atherogenic dyslipidaemia, defined as the imbalance between proatherogenic triglyceride-rich apolipoprotein B-containing-lipoproteins and antiatherogenic apolipoprotein A-I-lipoproteins (as in high-density lipoprotein, HDL), as an important modifiable contributor to lipid-related residual cardiovascular risk, especially in insulin-resistant conditions. As part of its mission to improve awareness and clinical management of atherogenic dyslipidaemia, the R3i has identified three key priorities for action: i) to improve recognition of atherogenic dyslipidaemia in patients at high cardiometabolic risk with or without diabetes; ii) to improve implementation and adherence to guideline-based therapies; and iii) to improve therapeutic strategies for managing atherogenic dyslipidaemia. The R3i believes that monitoring of non-HDL cholesterol provides a simple, practical tool for treatment decisions regarding the management of lipid-related residual cardiovascular risk. Addition of a fibrate, niacin (North and South America), omega-3 fatty acids or ezetimibe are all options for combination with a statin to further reduce non-HDL cholesterol, although lacking in hard evidence for cardiovascular outcome benefits. Several emerging treatments may offer promise. These include the next generation peroxisome proliferator-activated receptorα agonists, cholesteryl ester transfer protein inhibitors and monoclonal antibody therapy targeting proprotein convertase subtilisin/kexin type 9. However, long-term outcomes and safety data are clearly needed. In conclusion, the R3i believes that ongoing trials with these novel treatments may help to define the optimal management of atherogenic dyslipidaemia to reduce the clinical and socioeconomic burden of residual cardiovascular risk.

Impact of fluid balance on outcome of adult patients treated with extracorporeal membrane oxygenation

Abstract: To assess the relationship between early daily fluid balance (FB) and 90-day outcome in adult patients treated with extracorporeal membrane oxygenation (ECMO). Retrospective observational study. Tertiary referral centre for ECMO. 115 patients treated with ECMO for refractory heart failure and 57 patients treated with ECMO for refractory respiratory failure. We analysed the association between early daily FB versus hospital and 90-day mortality using multivariable logistic regression model, Cox proportional-hazards model and propensity score. We obtained detailed demographic, clinical, and biochemical data, daily FB, and continuous renal replacement days. Fifty-seven per cent of patients had acute kidney injury (AKI) at ECMO initiation, and 60 % (n = 103) of patients received continuous renal replacement therapy (CRRT) during ECMO course, beginning at a median of 1 (0–3.5) days after ECMO initiation. Overall 90-day mortality was 24 %. Survivors exhibited lower daily FB from day 3 to day 5. After adjustments, Acute Physiology and Chronic Health Evaluation (APACHE) III, CRRT during the first 3 days, major bleeding event at day 1 and positive FB on day 3 were independent predictors of 90-day mortality. Positive FB at ECMO day 3 remained an independent predictor of hospital and 90-day mortality, regardless of the statistical model used or the inclusion of a propensity score to have positive FB. Positive FB at ECMO day 3 is an independent predictor of 90-day mortality. Further interventional studies aimed at testing the value of strategy of tight control of FB during the early ECMO period are now warranted.

Considerations for pre-clinical models and clinical trials of pluripotent stem cell-derived cardiomyocytes.

Abstract: Pluripotent stem cells (PSCs) represent an appealing source from which to develop cell replacement therapies. Different initiatives have been launched to promote their development toward clinical applications. This article will review the main questions that should be considered before translating PSC-derived cardiomyocytes into clinical investigations, including the development of good manufacturing practice-level PSC lines, the development of efficient protocols to generate pure populations of cardiac myocytes, and the development of techniques to improve the retention and survival rate of transplanted cells.

Human CalDAG-GEFI gene (RASGRP2) mutation affects platelet function and causes severe bleeding

Abstract: The nature of an inherited platelet disorder was investigated in three siblings affected by severe bleeding. Using whole-exome sequencing, we identified the culprit mutation (cG742T) in the RAS guanyl-releasing protein-2 (RASGRP2) gene coding for calcium- and DAG-regulated guanine exchange factor-1 (CalDAG-GEFI). Platelets from individuals carrying the mutation present a reduced ability to activate Rap1 and to perform proper αIIbβ3 integrin inside-out signaling. Expression of CalDAG-GEFI mutant in HEK293T cells abolished Rap1 activation upon stimulation. Nevertheless, the PKC- and ADP-dependent pathways allow residual platelet activation in the absence of functional CalDAG-GEFI. The mutation impairs the platelet's ability to form thrombi under flow and spread normally as a consequence of reduced Rac1 GTP-binding. Functional deficiencies were confined to platelets and megakaryocytes with no leukocyte alteration. This contrasts with the phenotype seen in type III leukocyte adhesion deficiency caused by the absence of kindlin-3. Heterozygous did not suffer from bleeding and have normal platelet aggregation; however, their platelets mimicked homozygous ones by failing to undergo normal adhesion under flow and spreading. Rescue experiments on cultured patient megakaryocytes corrected the functional deficiency after transfection with wild-type RASGRP2. Remarkably, the presence of a single normal allele is sufficient to prevent bleeding, making CalDAG-GEFI a novel and potentially safe therapeutic target to prevent thrombosis.

Adipocyte Size Threshold Matters: Link with Risk of Type 2 Diabetes and Improved Insulin Resistance After Gastric Bypass

Abstract: Context: Adipocyte volume has been associated with insulin resistance and type 2 diabetes. Objective: Our purpose was to identify an adipocyte volume threshold linked with increased insulin resistance risk, and to examine its association with insulin resistance improvement after bariatric surgery. Setting and Design: We investigated two cohorts of Caucasian women, candidates for bariatric surgery, from two institutional centers in France (age 42.0 ± 11.5 years; body mass index, 47.6 ± 6.9 kg/m2) and Germany (age 41.3 ± 11.2 years; body mass index, 49.5 ± 8.1 kg/m2). 38% of the subjects had gastric bypass surgery and were followed for 6 months after the intervention. We defined a group of subjects with type 2 diabetes or at risk of type 2 diabetes (DRD) and investigated the relations between adipocyte volume and this status before and after surgery. Results: In both cohorts, subjects with DRD presented enlarged adipocytes (France, P = 3×10−4; Germany, P =3×10−10) and we were able to determine thresholds in...

Dietary Patterns Differently Associate with Inflammation and Gut Microbiota in Overweight and Obese Subjects

Abstract: Background: Associations between dietary patterns, metabolic and inflammatory markers and gut microbiota are yet to be elucidated. Objectives: We aimed to characterize dietary patterns in overweight and obese subjects and evaluate the different dietary patterns in relation to metabolic and inflammatory variables as well as gut microbiota. Design: Dietary patterns, plasma and adipose tissue markers, and gut microbiota were evaluated in a group of 45 overweight and obese subjects (6 men and 39 women). A group of 14 lean subjects were also evaluated as a reference group. Results: Three clusters of dietary patterns were identified in overweight/obese subjects. Cluster 1 had the least healthy eating behavior (highest consumption of potatoes, confectionary and sugary drinks, and the lowest consumption of fruits that was associated also with low consumption of yogurt, and water). This dietary pattern was associated with the highest LDL cholesterol, plasma soluble CD14 (p = 0.01) a marker of systemic inflammation but the lowest accumulation of CD163+ macrophages with anti-inflammatory profile in adipose tissue (p = 0.05). Cluster 3 had the healthiest eating behavior (lower consumption of confectionary and sugary drinks, and highest consumption of fruits but also yogurts and soups). Subjects in this Cluster had the lowest inflammatory markers (sCD14) and the highest anti-inflammatory adipose tissue CD163+ macrophages. Dietary intakes, insulin sensitivity and some inflammatory markers (plasma IL6) in Cluster 3 were close to those of lean subjects. Cluster 2 was in-between clusters 1 and 3 in terms of healthfulness. The 7 gut microbiota groups measured by qPCR were similar across the clusters. However, the healthiest dietary cluster had the highest microbial gene richness, as evaluated by quantitative metagenomics. Conclusion: A healthier dietary pattern was associated with lower inflammatory markers as well as greater gut microbiota richness in overweight and obese subjects.

The SPOTLIGHT virtual audit tool: a valid and reliable tool to assess obesogenic characteristics of the built environment

Abstract: Background: A lack of physical activity and overconsumption of energy dense food is associated with overweight and obesity. The neighbourhood environment may stimulate or hinder the development and/or maintenance of a healthy lifestyle. To improve research on the obesogenicity of neighbourhood environments, reliable, valid and convenient assessment methods of potential obesogenic characteristics of neighbourhood environments are needed. This study examines the reliability and validity of the SPOTLIGHT-Virtual Audit Tool (S-VAT), which uses remote sensing techniques (Street View feature in Google Earth) for desk-based assessment of environmental obesogenicity. Methods: A total of 128 street segments in four Dutch urban neighbourhoods – heterogeneous in socio-economic status and residential density – were assessed using the S-VAT. Environmental characteristics were categorised as walking related items, cycling related items, public transport, aesthetics, land use-mix, grocery stores, food outlets and physical activity facilities. To assess concordance of inter- and intra-observer reliability of the Street View feature in Google Earth, and validity scores with real life audits, percentage agreement and Cohen's Kappa (k) were calculated. Results: Intra-observer reliability was high and ranged from 91.7% agreement (k = 0.654) to 100% agreement (k = 1.000) with an overall agreement of 96.4% (k = 0.848). Inter-observer reliability results ranged from substantial agreement 78.6% (k = 0.440) to high agreement, 99.2% (k = 0.579), with an overall agreement of 91.5% (k = 0.595). Criterion validity was substantial to high for most of the categories ranging from 87.3% agreement (k = 0.539) to 99.9% agreement (k = 0.887) with an overall score of 95.6% agreement (k = 0.747). Conclusion: These study results suggest that the S-VAT is a highly reliable and valid remote sensing tool to assess potential obesogenic environmental characteristics.

The effects of gastrointestinal surgery on gut microbiota: potential contribution to improved insulin sensitivity.

Abstract: Bariatric surgery induces weight loss and major improvement in insulin-resistance through many mechanisms some of which are weight independent. It is now well acknowledged that gut microbiota is involved in the development of obesity and its related metabolic diseases, at least in mice. However, its causal role in human obesity progression remains to be demonstrated. Few studies now pointed at changes in microbiota composition after bariatric surgery, suggesting links between gut microbiota switch and metabolic improvement observed after surgery. As such new potential mechanisms of actions have been proposed. The aim of this review is to describe microbiota modifications observed after bariatric surgery and its potential relationships with improved insulin resistance. We here list some hypotheses, which will need further demonstration.

Efficacy and safety of ivabradine in patients with chronic systolic heart failure according to blood pressure level in SHIFT.

Abstract: Aims Low systolic blood pressure (SBP) is associated with poor outcomes in heart failure and complicates management. In a post hoc analysis, we investigated the efficacy and safety of ivabradine in the SHIFT population divided by tertiles of baseline SBP. Methods and Results The analysis comprised 2110 patients with SBP <115 mmHg, 1968 with 115≤ SBP <130 mmHg, and 2427 with SBP ≥130 mmHg. Patients with low SBP were younger, had lower ejection fraction, and were less likely to be at target beta-blocker dose than patients in the other SBP groups. Ivabradine was associated with a similar relative risk reduction of the composite outcome in the three SBP groups [SBP <115 mmHg, hazard ratio (HR) = 0.84, 95% confidence interval (CI) 0.72–0.98; 115≤ SBP <130 mmHg, HR = 0.86, 95% CI 0.72 to 1.03; SBP ≥130 mmHg, HR = 0.77, 95% CI 0.66 to 0.92; P interaction = 0.68]. Similar results were found for cardiovascular mortality (P interaction = 0.91), hospitalization because of heart failure (P interaction = 0.79), all-cause mortality (P interaction = 0.90), and heart failure mortality (P interaction = 0.18). There was no evidence for a difference in safety profile according to SBP group. Conclusion The efficacy and safety of ivabradine is independent of SBP. This may have implications for the management of HF patients with low SBP and elevated heart rate.

Maximal exercise limitation in functionally overreached triathletes: role of cardiac adrenergic stimulation

Abstract: Functional overreaching (F-OR) induced by heavy load endurance training programs has been associated with reduced heart rate values both at rest and during exercise. Because this phenomenon may reflect an impairment of cardiac response, this research was conducted to test this hypothesis. Thirty-five experienced male triathletes were tested (11 control and 24 overload subjects) before overloading (Pre), immediately after overloading (Mid), and after a 2-wk taper period (Post). Physiological responses were assessed during an incremental cycling protocol to volitional exhaustion, including catecholamines release, oxygen uptake (Vo2), arteriovenous O2 difference, cardiac output (Q), and systolic (SBP) and diastolic blood pressure (DBP). Twelve subjects of the overload group developed signs of F-OR at Mid (decreased performance with concomitant high perceived fatigue), while 12 others did not [acute fatigue group (AF)]. Vo2max was reduced only in F-OR subjects at Mid. Lower Q and SBP values with greater arteriovenous O2 difference were reported in F-OR subjects at all exercising intensities, while no significant change was observed in the control and AF groups. A concomitant decrease in epinephrine excretion was reported only in the F-OR group. All values returned to baseline at Post. Following an overload endurance training program leading to F-OR, the cardiac response to exhaustive exercise is transiently impaired, possibly due to reduced epinephrine excretion. This finding is likely to explain the complex process of underperformance syndrome experienced by F-OR endurance athletes during heavy load programs.

Genome-Wide Association Study for Circulating Tissue Plasminogen Activator Levels and Functional Follow-Up Implicates Endothelial STXBP5 and STX2

Abstract: Objective— Tissue plasminogen activator (tPA), a serine protease, catalyzes the conversion of plasminogen to plasmin, the major enzyme responsible for endogenous fibrinolysis. In some populations, elevated plasma levels of tPA have been associated with myocardial infarction and other cardiovascular diseases. We conducted a meta-analysis of genome-wide association studies to identify novel correlates of circulating levels of tPA. Approach and Results— Fourteen cohort studies with tPA measures (N=26 929) contributed to the meta-analysis. Three loci were significantly associated with circulating tPA levels ( P <5.0×10−8). The first locus is on 6q24.3, with the lead single nucleotide polymorphism (SNP; rs9399599; P =2.9×10−14) within STXBP5 . The second locus is on 8p11.21. The lead SNP (rs3136739; P =1.3×10−9) is intronic to POLB and <200 kb away from the tPA encoding the gene PLAT . We identified a nonsynonymous SNP (rs2020921) in modest linkage disequilibrium with rs3136739 ( r 2=0.50) within exon 5 of PLAT ( P =2.0×10−8). The third locus is on 12q24.33, with the lead SNP (rs7301826; P =1.0×10−9) within intron 7 of STX2 . We further found evidence for the association of lead SNPs in STXBP5 and STX2 with expression levels of the respective transcripts. In in vitro cell studies, silencing STXBP5 decreased the release of tPA from vascular endothelial cells, whereas silencing STX2 increased the tPA release. Through an in silico lookup, we found no associations of the 3 lead SNPs with coronary artery disease or stroke. Conclusions— We identified 3 loci associated with circulating tPA levels, the PLAT region, STXBP5 , and STX2. Our functional studies implicate a novel role for STXBP5 and STX2 in regulating tPA release. # Significance {#article-title-31}

Mechanisms of exertional dyspnoea in pulmonary veno-occlusive disease with EIF2AK4 mutations

Abstract: To the Editor: Dyspnoea curtails daily-living activities in patients with pulmonary veno-occlusive disease (PVOD) [1, 2] and pulmonary arterial hypertension (PAH) [3–5]. It is a common clinical observation that PVOD patients may experience greater dyspnoea than PAH patients during daily activities [1, 2]. However, this clinical feature and its putative underlying mechanisms have not yet been explored. Cardiopulmonary exercise testing (CPET) is well suited for understanding mechanisms underlying dyspnoea during exercise both in research and clinical settings [4, 5]. In the present study, we hypothesised that the perceived clinical difference between PVOD and PAH regarding exertional dyspnoea would be reflected by a different physiological response to CPET. Building on recent advances obtained with CPET in PAH patients [4], we set out to evaluate the relationship between exertional dyspnoea and the physiological response to CPET in eight PVOD patients presenting with recessive mutations in EIF2AK4 , compared with 16 idiopathic or heritable PAH patients. We studied eight clinically stable patients referred to the French Reference Center for Pulmonary Hypertension (Le Kremlin-Bicetre, France) for management of PAH [6, 7]. Using whole-exome sequencing, we detected recessive mutations in the major gene linked to PVOD development, EIF2AK4 (also called GCN2 ), that co-segregated with PVOD in eight patients studied, as recently described [8]. 16 clinically stable patients with diagnosed idiopathic or heritable PAH [9] and without other concomitant diseases were also evaluated. Pulmonary function tests, cycle ergometer symptom-limited incremental CPET, and measurements at rest and at peak exercise of arterial oxygen tension ( P aO2) and arterial carbon dioxide tension ( P aCO2), the physiological dead space ( V D)/tidal volume ( V T) ratio, and the alveolar–arterial oxygen tension gradient ( P A–aO2) and …

Medication Cost is Significantly Reduced After Roux-en-Y Gastric Bypass in Obese Patients

Abstract: Background This study aims to determine the influence of Roux-en-Y gastric bypass (RYGB) on medication-related costs.

Physiopathology of necrobiotic xanthogranuloma with monoclonal gammopathy

Abstract: Rationale Xanthomatosis associated with monoclonal gammopathy includes hyperlipidaemic xanthoma (HX), normolipidaemic xanthoma (NX) and necrobiotic xanthogranuloma (NXG). All three pathologies are characterized by skin or visceral lesions related to cholesterol accumulation, monoclonal immunoglobulin (MIg) and hypocomplementemia. The pathophysiology underlying NXG remains unknown although the involvement of MIg is suspected. Objective To provide further insights into the pathophysiology of NXG, we evaluated the plasma lipid phenotype, mechanisms involved in cellular cholesterol accumulation and role of MIg in an analysis of blood and plasma markers of inflammation in 16 patients with xanthomatosis [NXG (n = 8) and NX (n = 8)] associated with monoclonal IgG relative to the relevant controls. Results The lipid profile of patients with NXG was characterized by a low HDL-C phenotype and an abnormal distribution of HDL particles. Sera from patients with NXG induced cholesterol accumulation in human macrophages. This accumulation was due in part to a significant reduction in the HDL capacity to promote cholesterol efflux from macrophages, which was not found in the case of NX. The MIg of NXG and NX patients was tested positively by ELISA to recognize a large spectrum of lipoproteins. High plasma levels of pro-inflammatory cytokines (TNFα and IL-6), soluble cytokine receptors (sIL-6R, sTNFRI and sTNFRII), adhesion molecules (VCAM-1 and ICAM-1) and chemokines (MCP-1, IL-8 and MIP-1α) were observed in both patients with NXG and NX, revealing a specific xanthoma inflammatory signature which was inversely correlated with plasma levels of anti-inflammatory HDL. However, patients with NXG were distinguished by elevated levels of IL-15 and a marked increase in the rate of intermediate CD14++CD16+ monocytes. Conclusion This study revealed that NXG is characterized by impaired macrophage lipid homeostasis associated with a systemic inflammatory profile that may result from the interaction of MIg and lipoproteins.

Prognostic value of liver fibrosis and steatosis biomarkers in type‐2 diabetes and dyslipidaemia

Abstract: SummaryBackground In cardiometabolic disorders, non-alcoholic fatty liver disease is frequent and presumably associated with increased mortality and cardiovascular risk. Aim To evaluate the prognostic value of non-invasive biomarkers of liver fibrosis (FibroTest) and steatosis (SteatoTest) in patients with type-2 diabetes and/or dyslipidaemia. Methods A total of 2312 patients with type-2 diabetes and/or dyslipidaemia were included and prospectively followed up for 5–15 years. The cardiovascular Framingham-risk score was calculated; advanced fibrosis and severe steatosis, were defined by FibroTest >0.48 and SteatoTest >0.69, respectively, as previously established. Results During a median follow-up of 12 years, 172 patients (7.4%) died. The leading causes of mortality were cancer (31%) and cardiovascular-related death (20%). The presence of advanced fibrosis [HR (95% CI)] [2.98 (95% CI 1.78–4.99); P < 0.0001] or severe steatosis [1.86 (1.34–2.58); P = 0.0002] was associated with an increased risk of mortality. In a multivariate Cox model adjusted for confounders: the presence of advanced fibrosis was associated with overall mortality [1.95 (1.12–3.41); P = 0.02]; advanced fibrosis at baseline [n = 50/677; 1.92 (1.04–3.55); P = 0.04] and progression to advanced fibrosis during follow-up [n = 16/127; 4.8 (1.5–14.9); P = 0.007] were predictors of cardiovascular events in patients with type-2 diabetes. In patients with a Framingham-risk score ≥20%, the presence of advanced fibrosis was predictive of cardiovascular events [2.24 (1.16–4.33); P < 0.05]. Conclusions Liver biomarkers, such as FibroTest and SteatoTest, have prognostic values in patients with metabolic disorders. FibroTest has prognostic value for predicting overall survival in patients with type-2 diabetes and/or dyslipidaemia. In type-2 diabetes, FibroTest predicted cardiovascular events and improved the Framingham-risk score.

Complex Brugada syndrome inheritance in a family harbouring compound SCN5A and CACNA1C mutations

Abstract: Brugada syndrome (BrS) is characterized by ST-segment elevation in the right precordial leads and is associated with increased risk of sudden cardiac death. We have recently reported families with BrS and SCN5A mutations where some affected members do not carry the familial mutation. We evaluated the involvement of additional genetic determinants for BrS in an affected family. We identified three distinct gene variants within a family presenting BrS (5 individuals), cardiac conduction defects (CCD, 3 individuals) and shortened QT interval (4 individuals). The first mutation is nonsense, p.Q1695*, lying within the SCN5A gene, which encodes for NaV1.5, the α-subunit of the cardiac Na(+) channel. The second mutation is missense, p.N300D, and alters the CACNA1C gene, which encodes the α-subunit CaV1.2 of the L-type cardiac Ca(2+) channel. The SCN5A mutation strictly segregates with CCD. Four out of the 5 BrS patients carry the CACNA1C variant, and three of them present shortened QT interval. One of the BrS patients carries none of these mutations but a rare variant located in the ABCC9 gene as well as his asymptomatic mother. Patch-clamp studies identified a loss-of-function of the mutated CaV1.2 channel. Western-blot experiments showed a global expression defect while increased mobility of CaV1.2 channels on cell surface was revealed by FRAP experiments. Finally, computer simulations of the two mutations recapitulated patient phenotypes. We report a rare CACNA1C mutation as causing BrS and/or shortened QT interval in a family also carrying a SCN5A stop mutation, but which does not segregate with BrS. This study underlies the complexity of BrS inheritance and its pre-symptomatic genetic screening interpretation.

Left atrial volume predicts abnormal exercise left ventricular filling pressure.

Abstract: Aims Latent heart failure at rest can be observed in a number of patients upon exercise. Considering left atrial (LA) remodelling as the reflection of the cumulative effects of the LV filling pressure (FP) over time, our aim was to investigate whether the LA volume would predict abnormal exercise LVFP. Methods and results Ninety patients (58.6 ± 10.8 years, 74 men) underwent exercise echocardiography. The LA maximal volume was measured by the Simpson method and indexed to body surface area. LVFP was assessed by the ratio between early peak diastolic velocities of mitral inflow and the septal annular mitral plane (E/e′). Exercise E/e′ >13 was used as a threshold to define abnormal LVFP. Indexed LA volume was correlated with E/e′ at rest (r = 0.37, P = 0.003), but the correlation was better with exercise E/e′ (r = 0.54, P 13; compared with the rest of the population, these patients were older and achieved a milder effort. LA volume index >33 mL/m2 predicted an abnormal exercise LVFP with a 91% sensitivity and a 78% specificity. None of the patients with an LA volume index 13. Conclusion Exercise LVFP is a determinant of LA size. LA volume index seems to be helpful for predicting abnormal exercise LVFP. The potential use of LA remodelling to identify the patients benefitting most from exercise echocardiography should be investigated in larger studies.

Effects of High-Protein Diet and/or Resveratrol Supplementation on the Immune Response of Irradiated Rats

Abstract: We investigated the effects of a high-protein diet and resveratrol supplementation on immune cells changes induced by abdominal irradiation in rats. Female Wistar rats were divided into 5 groups: 1) control diet, 2) control diet with irradiation 3) 30% high-protein diet with irradiation, 4) normal diet with resveratrol supplementation and irradiation, and 5) 30% high-protein diet with resveratrol supplementation and irradiation. We measured blood protein and albumin concentrations, lipid profiles, white blood cell (WBC) counts, proinflammatory cytokine production, and splenocyte proliferation in rats that had been treated with a 17.5 Gy dose of radiation 30 days prior. A high-protein diet affected plasma total cholesterol and very low density lipoprotein-cholesterol levels, which were increased by the radiation treatment. In addition, the lymphocyte percentage and immunoglobulin M (IgM) concentration were increased, and the neutrophil percentage was decreased in rats fed a high-protein diet. Resveratrol supplementation decreased the triglyceride (TG) level, but increased the IgM concentration and splenocyte proliferation. Proinflammatory cytokine production was lower in rats fed a high-protein diet supplemented with resveratrol than in rats fed a control diet. The results of the present study indicate that high-protein diets, with or without resveratrol supplementation, might assist with recovery from radiation-induced inflammation by modulating immune cell percentages and cytokine production.