Outcome in neonates with Ebstein's anomaly

AbstractThe presentation and outcome of 50 patients with neonatal Ebstein's anomaly seen from 1961 to 1990 were reviewed. The majority (88%) presented in the 1st 3 days of life; cyanosis (80%) was the most common presenting feature. Associated defects, present in 27 infants (54%), included pulmonary stenosis in 11 and atresia in 7. Nine patients (18%) died in the neonatal period; there were 15 late deaths (due to hemodynamic deterioration in 9, sudden death in 5 and a noncardiac cause in 1) at a mean age of 4.5 years (range 4 months to 19 years). Actuarial survival at 10 years was 61%.A new echocardiographic grade (1 to 4 in order of increasing severity of the defect) was devised with use of the ratio of the area of the right atrium and atrialized right ventricle to the area of the functional right ventricle and left heart chambers. Cardiac death occured in 0 of 4 infants with grade 1, 1 (10%) of 16 with grade 2, 4 (44%) of 9 with grade 3 and 5 (100%) of 5 with grade 4. In a multivariate analysis of clinical and investigational features at presentation, echocardiographic grade of severity was the best independent predictor of death.Neonates with Ebstein's anomaly have a high early mortality rate and those surviving the 1st month of life remain at high risk of late hemodynamic deterioration or sudden death. Echocardiographic grading of severity of the defect permits prognostic stratification

Apical ballooning syndrome complicated by acute severe mitral regurgitation with left ventricular outflow obstruction – Case report

BACKGROUND: Apical ballooning syndrome (or Takotsubo cardiomyopathy) is a syndrome of transient left ventricular apical ballooning. Although first described in Japanese patients, it is now well reported in the Caucasian population. The syndrome mimicks an acute myocardial infarction but is characterised by the absence of obstructive coronary disease. We describe a serious and poorly understood complication of Takotsubo cardiomyopathy. CASE PRESENTATION: We present the case of a 65 year-old lady referred to us from a rural hospital where she was treated with thrombolytic therapy for a presumed acute anterior myocardial infarction. Four hours after thrombolysis she developed acute pulmonary oedema and a new systolic murmur. It was presumed she had acute mitral regurgitation secondary to a ruptured papillary muscle, ischaemic dysfunction or an acute ventricular septal defect. Echocardiogram revealed severe mitral regurgitation, left ventricular apical ballooning, and systolic anterior motion of the mitral valve with significant left ventricular outflow tract gradient (60–70 mmHg). Coronary angiography revealed no obstructive coronary lesions. She had an intra-aortic balloon pump inserted with no improvement in her parlous haemodynamic state. We elected to replace her mitral valve to correct the outflow tract gradient and mitral regurgitation. Intra-operatively the mitral valve was mildly myxomatous but there were no structural abnormalities. She had a mechanical mitral valve replacement with a 29 mm St Jude valve. Post-operatively, her left ventricular outflow obstruction resolved and ventricular function returned to normal over the subsequent 10 days. She recovered well. CONCLUSION: This case represents a serious and poorly understood association of Takotsubo cardiomyopathy with acute pulmonary oedema, severe mitral regurgitaton and systolic anterior motion of the mitral valve with significant left ventricular outflow tract obstruction. The sequence of our patient's presentation suggests that the apical ballooning caused geometric alterations in her left ventricle that in turn led to acute and severe mitral regurgitation, systolic anterior motion of the mitral valve and left ventricular outflow tract obstruction. The left ventricular outflow tract obstruction and mitral regurgitation were corrected by mechanical mitral valve replacement. We describe a variant of Takotsubo cardiomyopathy with acute mitral regurgitation, systolic anterior motion of the mitral valve leaflet and left ventricular outflow tract obstruction of a dynamic nature

Multicentre randomised placebo-controlled trial of oral anticoagulation with apixaban in systemic sclerosis-related pulmonary arterial hypertension: the SPHInX study protocol

Introduction: Systemic sclerosis (SSc) is a severe and costly multiorgan autoimmune connective tissue disease characterised by vasculopathy and fibrosis. One of the major causes of SSc-related death is pulmonary arterial hypertension (PAH), which develops in 12–15% of patients with SSc and accounts for 30– 40% of deaths. In situ thrombosis in the small calibre peripheral pulmonary vessels resulting from endothelial dysfunction and an imbalance of anticoagulant and prothrombotic mediators has been implicated in the complex pathophysiology of SSc-related PAH (SSc- PAH), with international clinical guidelines recommending the use of anticoagulants for some types of PAH, such as idiopathic PAH. However, anticoagulation has not become part of standard clinical care for patients with SSc-PAH as only observational evidence exists to support its use. Therefore, we present the rationale and methodology of a phase III randomised controlled trial (RCT) to evaluate the efficacy, safety and cost-effectiveness of anticoagulation in SSc-PAH. Methods and analysis: This Australian multicentre RCT will compare 2.5 mg apixaban with placebo, in parallel treatment groups randomised in a 1:1 ratio, both administered twice daily for 3 years as adjunct therapy to stable oral PAH therapy. The composite primary outcome measure will be the time to death or clinical worsening of PAH. Secondary outcomes will include functional capacity, health-related quality of life measures and adverse events. A cost-effectiveness analysis of anticoagulation versus placebo will also be undertaken. Ethics and dissemination: Ethical approval for this RCT has been granted by the Human Research Ethics Committees of all participating centres. An independent data safety monitoring board will review safety and tolerability data for the duration of the trial. The findings of this RCT are to be published in open access journals.Alicia Calderone, Wendy Stevens, David Prior, Harshal Nandurkar, Eli Gabbay, Susanna M Proudman, Trevor Williams, David Celermajer, Joanne Sahhar, Peter K K Wong, Vivek Thakkar, Nathan Dwyer, Jeremy Wrobel, Weng Chin, Danny Liew, Margaret Staples, Rachelle Buchbinder, Mandana Nikpou

Treatment of obstructive sleep apnoea leads to improved microvascular endothelial function in the systemic circulation

Background: Obstructive sleep apnoea (OSA) is a common and potentially reversible cause of systemic hypertension. The mechanisms whereby OSA leads to hypertension and the effects of treatment on arterial function, however, are not well established. Microvascular arterial endothelial and smooth muscle function was assessed in subjects with OSA before and after treatment with continuous positive airways pressure (CPAP). Methods: Ten subjects of mean (SE) age 49 (8) years with at least moderately severe OSA had detailed forearm vascular reactivity studies before and after 3 months of CPAP treatment. The systemic circulation was assessed by measuring brachial artery pressure, flow and resistance responses to intra-arterial infusions of acetylcholine (ACh; an endothelium dependent vasodilator), sodium nitroprusside (SNP; an endothelium independent vasodilator), L-NMMA (a nitric oxide (NO) antagonist), and L-arginine (the substrate for NO). Results: Before CPAP, ACh and SNP infusions increased forearm blood flow in a dose dependent manner (p,0.01). After CPAP, endothelium dependent dilation to ACh was significantly increased (434 (23)% of baseline after CPAP v 278 (20)% before CPAP, p,0.001), whereas SNP induced dilation was unchanged. Resting NO production was higher after CPAP, evidenced by a significantly greater reduction in basal flow by L-NMMA (p = 0.05). L-Arginine reversed the effect of L-NMMA in all cases. Conclusion: In patients with OSA, treatment with CPAP improves baseline endothelial NO release and stimulates endothelium dependent vasorelaxation in the systemic circulation. This is a potential mechanism for improving systemic and vascular function in patients with OSA treated with CPAP

A critical role for Thioredoxin- Interacting protein in diabetes-related impairment of angiogenesis

Impaired angiogenesis in ischemic tissue is a hallmark of diabetes. Thioredoxin-interacting protein (TXNIP) is an exquisitely glucose-sensitive gene that is overexpressed in diabetes. As TXNIP modulates the activity of the key angiogenic cytokine vascular endothelial growth factor (VEGF), we hypothesized that hyperglycemia-induced dysregulation of TXNIP may play a role in the pathogenesis of impaired angiogenesis in diabetes. In the current study, we report that high glucose– mediated overexpression of TXNIP induces a widespread impairment in endothelial cell (EC) function and survival by reducing VEGF production and sensitivity to VEGF action, findings that are rescued by silencing TXNIP with small interfering RNA. High glucose–induced EC dysfunction was recapitulated in normal glucose conditions by overexpressing either TXNIP or a TXNIP C247S mutant unable to bind thioredoxin, suggesting that TXNIP effects are largely independent of thioredoxin activity. In streptozotocin-induced diabetic mice, TXNIP knockdown to nondiabetic levels rescued diabetes-related impairment of angiogenesis, arteriogenesis, blood flow, and functional recovery in an ischemic hindlimb. These findings were associated with in vivo restoration of VEGF production to nondiabetic levels. These data implicate a critical role for TXNIP in diabetes-related impairment of ischemia-mediated angiogenesis and identify TXNIP as a potential therapeutic target for the vascular complications of diabetes.Louise L. Dunn, Philippa J.L. Simpson, Hamish C. Prosser, Laura Lecce, Gloria S.C. Yuen, Andrew Buckle, Daniel P. Sieveking, Laura Z. Vanags, Patrick R. Lim, Renee W.Y. Chow, Yuen Ting Lam, Zoe Clayton, Shisan Bao, Michael J. Davies, Nadina Stadler, David S. Celermajer, Roland Stocker, Christina A. Bursill, John P. Cooke, and Martin K.C. N

Colchicine acutely suppresses local cardiac production of inflammatory cytokines in patients with an acute coronary syndrome

Background - Interleukin (IL)-1b, IL-18, and downstream IL-6 are key inflammatory cytokines in the pathogenesis of coronary artery disease. Colchicine is believed to block the NLRP3 inflammasome, a cytosolic complex responsible for the production of IL-1b and IL-18. In vivo effects of colchicine on cardiac cytokine release have not been previously studied. This study aimed to (1) assess the local cardiac production of inflammatory cytokines in patients with acute coronary syndromes (ACS), stable coronary artery disease and in controls; and (2) determine whether acute administration of colchicine inhibits their production. Methods and Results - Forty ACS patients, 33 with stable coronary artery disease, and 10 controls, were included. ACS and stable coronary artery disease patients were randomized to oral colchicine treatment (1 mg followed by 0.5 mg 1 hour later) or no colchicine, 6 to 24 hours prior to cardiac catheterization. Blood samples from the coronary sinus, aortic root (arterial), and lower right atrium (venous) were collected and tested for IL-1b, IL-18, and IL-6 using ELISA. In ACS patients, coronary sinus levels of IL-1b, IL-18, and IL-6 were significantly higher than arterial and venous levels (P=0.017, <0.001 and <0.001, respectively). Transcoronary (coronary sinus-arterial) gradients for IL-1b, IL-18, and IL-6 were highest in ACS patients and lowest in controls (P=0.077, 0.033, and 0.014, respectively). Colchicine administration significantly reduced transcoronary gradients of all 3 cytokines in ACS patients by 40% to 88% (P=0.028, 0.032, and 0.032, for IL-1b, IL-18, and IL-6, respectively). Conclusions - ACS patients exhibit increased local cardiac production of inflammatory cytokines. Short-term colchicine administration rapidly and significantly reduces levels of these cytokines.Gonzalo J. Martínez, Stacy Robertson, Jennifer Barraclough, Qiong Xia, Ziad Mallat, Christina Bursill, David S. Celermajer, Sanjay Pate