The endothelin antagonist bosentan: Hemodynamic effects during normoxia and hypoxic pulmonary hypertension in pigs

AbstractIn this study, we investigated the hemodynamic effects and receptor-blocking properties of the nonselective endothelin antagonist bosentan in pigs during normoxia and acute hypoxia. Hypoxic pulmonary hypertension was induced by decreasing the fraction of inhaled oxygen to 0.1. In a control group of pigs, hemodynamic parameters proved to be stable through 2 hours of hypoxia. Infusions of endothelin-1, endothelin-3, and sarafotoxin 6c into the pulmonary artery resulted in pulmonary and systemic vasoconstriction during normoxia, whereas endothelin administration during hypoxic pulmonary hypertension resulted in pulmonary vasodilation. After administration of bosentan, the vasopressor effect of endothelin-1 during normoxia was significantly attenuated and the pulmonary vasodilatory effect of endothelin-1 during hypoxia was reduced. Furthermore, the development of hypoxic pulmonary hypertension was significantly reduced by bosentan. In contrast, bosentan did not influence the pulmonary vasopressor response to the thromboxane mimic U-46619. We therefore conclude that vasopressor endothelin receptors seem to be activated by endogenous endothelin released during hypoxia, leading to an increase in the pulmonary vascular tone. (J THORAC CARDIOVASC SURG 1996;112:890-7

Relationship between CAD Risk Genotype in the Chromosome 9p21 Locus and Gene Expression. Identification of Eight New ANRIL Splice Variants

BACKGROUND: Several genome-wide association studies have recently linked a group of single nucleotide polymorphisms in the 9p21 region with cardiovascular disease. The molecular mechanisms of this link are not fully understood. We investigated five different expression microarray datasets in order to determine if the genotype had effect on expression of any gene transcript in aorta, mammary artery, carotid plaque and lymphoblastoid cells. METHODOLOGY/PRINCIPAL FINDINGS: After multiple testing correction, no genes were found to have relation to the rs2891168 risk genotype, either on a genome-wide scale or on a regional (8 MB) scale. The neighbouring ANRIL gene was found to have eight novel transcript variants not previously known from literature and these varied by tissue type. We therefore performed a detailed probe-level analysis and found small stretches of significant relation to genotype but no consistent associations. In all investigated tissues we found an inverse correlation between ANRIL and the MTAP gene and a positive correlation between ANRIL and CDKN2A and CDKN2B. CONCLUSIONS/SIGNIFICANCE: Investigation of relation of the risk genotype to gene expression is complicated by the transcript complexity of the locus. With our investigation of a range of relevant tissue we wish to underscore the need for careful attention to the complexity of the alternative splicing issues in the region and its implications to the design of future gene expression studies

Continuous surgical multi-level extrapleural block for video-assisted thoracoscopic surgery: a retrospective study assessing its efficacy as pain relief following lobectomy and wedge resection [version 1; peer review: 2 approved]

Background: Video-assisted thoracoscopic surgery (VATS) causes less postoperative pain than thoracotomy; however, adequate analgesia remains vital. As part of a multi-modal postoperative analgesia, a continuous surgeon-placed extrapleural block catheter is an option. The aim of this retrospective study was to evaluate the analgesic efficacy of a continuous extrapleural block as part of a multimodal analgesic regimen after VATS in general, and VATS lobectomy and wedge resection in particular. Methods: Case records for patients having undergone VATS surgery and been provided a multi-level continuous extrapleural block with an elastomeric pump infusing levobupivacaine 2.7 mg/ml at a rate of 5 ml/h during 2015 and 2016 were reviewed. Pain (Numeric Rating Scale) at rest and mobilisation as well as opioid requirement (daily, postoperative days 0-3, as well as accumulated) were analysed.    Results: In all, 454 records were reviewed: 150 wedge resections, 264 lobectomies and 40 miscellaneous cases. At rest, pain was mild median NRS rated 3-3-1-1 for postoperative day (POD) 0 to 3, during movement, pain was rated moderate during POD 0 and 1 and mild the remaining days (median NRS 4-4-3-3 for POD 0-3). The proportion of patients exhibiting mild pain at rest increased from 55% on POD 0 to 81 % on POD 3. The percentage of patients experiencing severe pain at rest decreased from 15% to 6%. Median oxycodone consumption was 10 mg per day for POD 1-3. Pain after VATS wedge resection was significantly lower at POD 1 and 3 compared to pain after VATS lobectomy. Conclusion: We found a continuous surgeon-placed extrapleural catheter block to be a valuable and seemingly safe addition to our multimodal procedure specific analgesia after VATS. Whether the efficacy of the block can be improved by increasing local anaesthetic and/or adding adjuncts warrants further investigation

Introducing intravascular microdialysis for continuous lactate monitoring in patients undergoing cardiac surgery:a prospective observational study

Introduction: Lactate is a marker of hypoperfusion and may be used for risk assessment in critically ill patients. Although evidence suggests that repeated lactate measurements are of clinical interest, how and when lactate should be analyzed is controversial. Intravascular microdialysis provides a novel method for the continuous monitoring of lactate, which may be clinically beneficial in critically ill patients. Methods: Circulating lactate levels were continuously monitored in 80 patients undergoing cardiac surgery using either a separate single-lumen microdialysis catheter or a triple-lumen central venous catheter with an integrated microdialysis function. The catheter was placed with the tip positioned in the superior vena cava. Arterial blood gas samples were taken every hour to obtain reference values, and the lactate levels were analyzed in a blood gas analyzer. Results: A total of 1,601 paired microdialysis-arterial blood gas lactate samples were obtained. Bland-Altman analysis showed a bias (mean difference) +/- limits of agreement (+/- 1.96 SD) of 0.02 +/- 0.42 mmol/L. The regression coefficient was 0.98 (P = 0.0001). Conclusions: Central venous microdialysis is an accurate and reliable method for continuous blood lactate monitoring in patients undergoing cardiac surgery. The system may be useful for early lactate-guided therapy in critically ill patients

Cardiac expression of the microsomal triglyceride transport protein protects the heart function during ischemia

Aims: The microsomal triglyceride transport protein (MTTP) is critical for assembly and secretion of apolipoprotein B (apoB)-containing lipoproteins and is most abundant in the liver and intestine. Surprisingly, MTTP is also expressed in the heart. Here we tested the functional relevance of cardiac MTTP expression. Materials and methods: We combined clinical studies, advanced expression analysis of human heart biopsies and analyses in genetically modified mice lacking cardiac expression of the MTTP-A isoform of MTTP. Results: Our results indicate that lower cardiac MTTP expression in humans is associated with structural and perfusion abnormalities in patients with ischemic heart disease. MTTP-A deficiency in mice heart does not affect total MTTP expression, activity or lipid concentration in the heart. Despite this, MTTP-A deficient mice displayed impaired cardiac function after a myocardial infarction. Expression analysis of MTTP indicates that MTTP expression is linked to cardiac function and responses in the heart. Conclusions: Our results indicate that MTTP may play an important role for the heart function in conjunction to ischemic events

Genome-wide association analysis of self-reported events in 6135 individuals and 252 827 controls identifies 8 loci associated with thrombosis

Thrombotic diseases are among the leading causes of morbidity and mortality in the world. To add insights into the genetic regulation of thrombotic disease, we conducted a genome-wide association study (GWAS) of 6135 self-reported blood clots events and 252 827 controls of European ancestry belonging to the 23andMe cohort of research participants. Eight loci exceeded genome-wide significance. Among the genome-wide significant results, our study replicated previously known venous thromboembolism (VTE) loci near the F5, FGA-FGG, F11, F2, PROCR and ABO genes, and the more recently discovered locus near SLC44A2 In addition, our study reports for the first time a genome-wide significant association between rs114209171, located upstream of the F8 structural gene, and thrombosis risk. Analyses of expression profiles and expression quantitative trait loci across different tissues suggested SLC44A2, ILF3 and AP1M2 as the three most plausible candidate genes for the chromosome 19 locus, our only genome-wide significant thrombosis-related locus that does not harbor likely coagulation-related genes. In addition, we present data showing that this locus also acts as a novel risk factor for stroke and coronary artery disease (CAD). In conclusion, our study reveals novel common genetic risk factors for VTE, stroke and CAD and provides evidence that self-reported data on blood clots used in a GWAS yield results that are comparable with those obtained using clinically diagnosed VTE. This observation opens up the potential for larger meta-analyses, which will enable elucidation of the genetics of thrombotic diseases, and serves as an example for the genetic study of other diseases

Expression of ceramide-metabolising enzymes in subcutaneous and intra-abdominal human adipose tissue

WOS:000310235100001Peer reviewe

Predictors of Bicuspid Aortic Valve-Associated Aortopathy in Childhood: A Report From the MIBAVA Consortium

BACKGROUND: Bicuspid aortic valve (BAV) is the most prevalent congenital heart defect affecting 1% to 2% of the population. It is associated with ascending aorta dilatation. Valve morphology, aortic stenosis (AS), and aortic insufficiency (AI) have been proposed as potential risk factors; however, evaluating their role is difficult, as these factors are inherently related. The aim of this study was to determine whether BAV morphology and dysfunction are independent determinants for ascending aorta dilatation in pediatric patients. METHODS: A multicenter, retrospective, cross-sectional study of pediatric BAV patients followed since 2004 was performed. Imaging data were assessed for BAV morphology, severity of AS and AI, history of coarctation, and aortic dimensions. Associations were determined using multivariable regression analysis. A subset of patients undergoing aortic interventions (balloon dilation or Ross) were assessed longitudinally. RESULTS: Data were obtained from 2122 patients (68% male; median age 10.2 years). Fifty percent of patients had ascending aorta dilatation. Right and noncoronary cusp fusion, increasing AS and AI, and older age were independently associated with ascending aorta dilatation. A history of coarctation was associated with less ascending aorta dilatation. In patients with neither AS nor AI, 37% had ascending aorta dilatation (4% severe). No complications related to aortic dilatation occurred in this cohort. Aortic CONCLUSIONS: In this large pediatric cohort of patients with BAV, valve morphology, AS, and AI are independently associated with ascending aorta dilatation, suggesting that hemodynamic factors influence aortopathy. However, even in BAVs with no AS or AI, there is significant ascending aorta dilatation independent of valve morphology. Interventions that led to changes in degree of AI and AS did not seem to influence change in aortic dimensions. The current BAV cohort can be used as a reference group for expected changes in aortic dimensions during childhood

Multi-Organ Expression Profiling Uncovers a Gene Module in Coronary Artery Disease Involving Transendothelial Migration of Leukocytes and LIM Domain Binding 2: The Stockholm Atherosclerosis Gene Expression (STAGE) Study

Environmental exposures filtered through the genetic make-up of each individual alter the transcriptional repertoire in organs central to metabolic homeostasis, thereby affecting arterial lipid accumulation, inflammation, and the development of coronary artery disease (CAD). The primary aim of the Stockholm Atherosclerosis Gene Expression (STAGE) study was to determine whether there are functionally associated genes (rather than individual genes) important for CAD development. To this end, two-way clustering was used on 278 transcriptional profiles of liver, skeletal muscle, and visceral fat (n = 66/tissue) and atherosclerotic and unaffected arterial wall (n = 40/tissue) isolated from CAD patients during coronary artery bypass surgery. The first step, across all mRNA signals (n = 15,042/12,621 RefSeqs/genes) in each tissue, resulted in a total of 60 tissue clusters (n = 3958 genes). In the second step (performed within tissue clusters), one atherosclerotic lesion (n = 49/48) and one visceral fat (n = 59) cluster segregated the patients into two groups that differed in the extent of coronary stenosis (P = 0.008 and P = 0.00015). The associations of these clusters with coronary atherosclerosis were validated by analyzing carotid atherosclerosis expression profiles. Remarkably, in one cluster (n = 55/54) relating to carotid stenosis (P = 0.04), 27 genes in the two clusters relating to coronary stenosis were confirmed (n = 16/17, P<10$^{−27and−30}$). Genes in the transendothelial migration of leukocytes (TEML) pathway were overrepresented in all three clusters, referred to as the atherosclerosis module (A-module). In a second validation step, using three independent cohorts, the A-module was found to be genetically enriched with CAD risk by 1.8-fold (P<0.004). The transcription co-factor LIM domain binding 2 (LDB2) was identified as a potential high-hierarchy regulator of the A-module, a notion supported by subnetwork analysis, by cellular and lesion expression of LDB2, and by the expression of 13 TEML genes in Ldb2–deficient arterial wall. Thus, the A-module appears to be important for atherosclerosis development and, together with LDB2, merits further attention in CAD research

Auxilin is a novel susceptibility gene for congenital heart block which directly impacts fetal heart function

Objective: Neonatal lupus erythematosus (NLE) may develop after transplacental transfer of maternal autoantibodies with cardiac manifestations (congenital heart block, CHB) including atrioventricular block, atrial and ventricular arrhythmias, and cardiomyopathies. The association with anti-Ro/SSA antibodies is well established, but a recurrence rate of only 12%–16% despite persisting maternal autoantibodies suggests that additional factors are required for CHB development. Here, we identify fetal genetic variants conferring risk of CHB and elucidate their effects on cardiac function. Methods: A genome-wide association study was performed in families with at least one case of CHB. Gene expression was analysed by microarrays, RNA sequencing and PCR and protein expression by western blot, immunohistochemistry, immunofluorescence and flow cytometry. Calcium regulation and connectivity were analysed in primary cardiomyocytes and cells induced from pleuripotent stem cells. Fetal heart performance was analysed by Doppler/echocardiography. Results: We identified DNAJC6 as a novel fetal susceptibility gene, with decreased cardiac expression of DNAJC6 associated with the disease risk genotype. We further demonstrate that fetal cardiomyocytes deficient in auxilin, the protein encoded by DNAJC6, have abnormal connectivity and Ca2+ homoeostasis in culture, as well as decreased cell surface expression of the Cav1.3 calcium channel. Doppler echocardiography of auxilin-deficient fetal mice revealed cardiac NLE abnormalities in utero, including abnormal heart rhythm with atrial and ventricular ectopias, as well as a prolonged atrioventricular time intervals. Conclusions: Our study identifies auxilin as the first genetic susceptibility factor in NLE modulating cardiac function, opening new avenues for the development of screening and therapeutic strategies in CHB.publishedVersio