Topic: Congenital

Abstract

The association between pulmonary hypertension and stroke: A systematic review and meta-analysis.

Shah TG, Sutaria JM, Vyas MV
Background
Pulmonary hypertension is associated with atrial fibrillation and paradoxical embolism. Yet, the association between pulmonary hypertension and stroke has not been well studied.
Methods
We reviewed Medline and Embase from inception to December 1, 2018, to identify observational studies reporting prevalence of stroke in adult patients with pulmonary hypertension. We sought studies that included patients with pulmonary hypertension secondary to any etiology except left heart failure, and excluded studies that reported rates of perioperative stroke. We conducted random effects meta-analyses to obtain pooled prevalence of stroke in patients with pulmonary hypertension, and pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without.
Results
We included 14 studies including 32,523 participants of which 2976 (9.2%) had pulmonary hypertension, and 727 (2.2%) had a stroke. The pooled prevalence of stroke in patients with pulmonary hypertension was 8.0% [95% confidence interval (CI), 5.1%-10.9%, I 91.9]. The pooled unadjusted odds ratio of stroke in patients with pulmonary hypertension compared to those without was 1.46 (95% CI, 1.07-1.99, I 55.6, n = 7 studies).
Conclusion
Stroke is a major non-cardiac morbidity in patients with pulmonary hypertension, requiring further evaluation to determine its etiology, and measures to reduce its risk.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:21-24
Shah TG, Sutaria JM, Vyas MV
Int J Cardiol: 14 Nov 2019; 295:21-24 | PMID: 31402157
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Abstract

Dimethylarginine dimethylaminohydrolase 1 deficiency aggravates monocrotaline-induced pulmonary oxidative stress, pulmonary arterial hypertension and right heart failure in rats.

Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y

Patients with pulmonary arterial hypertension (PAH) and right ventricular (RV) failure have a poor clinical outcome, but the mechanisms of PAH and RV failure development are not totally clear. PAH is associated with reduced NO bioavailability and increased endogenous NOS inhibitor asymmetric dimethylarginine (ADMA). Dimethylarginine dimethylaminohydrolase-1 (DDAH1) plays a critical role in ADMA degradation. Here we generated a novel DDAH1 deficiency rat strain using the CRISPR-Cas9 technique, and studied the effect of DDAH1 dysfunction on monocrotaline-induced PAH, lung vascular remodeling and RV hypertrophy. DDAH1 knockout resulted in abolished DDAH1 expression in various tissues, and significant increases of plasma and lung ADMA content. DDAH1 knockout has no detectable effect on cardiac and lung structure, and LV function under control conditions in rats. However, DDAH1 knockout significantly aggravated monocrotaline-induced lung and RV oxidative stress, lung vascular remodeling and fibrosis, pulmonary hypertension and RV hypertrophy in rats. DDAH1 KO resulted in significantly greater increases of plasma and lung ADMA content under control conditions. In the wild type rats monocrotaline resulted in significant increases of plasma and lung ADMA contents and reduction of lung eNOS protein content and these changes were more marked in DDAH1 KO rats. Together, our results demonstrated that DDAH1 plays an important role in attenuating monocrotaline-induced lung oxidative stress, pulmonary hypertension and RV hypertrophy in rats.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 14 Nov 2019; 295:14-20
Wang D, Li H, Weir EK, Xu Y, Xu D, Chen Y
Int J Cardiol: 14 Nov 2019; 295:14-20 | PMID: 31402164
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Abstract

CMR feature tracking left ventricular strain-rate predicts ventricular tachyarrhythmia, but not deterioration of ventricular function in patients with repaired tetralogy of Fallot.

Hagdorn QAJ, Vos JDL, Beurskens NEG, Gorter TM, ... Berger RMF, Willems TP
Background
Myocardial strain has been shown to predict outcome in various cardiovascular diseases, including congenital heart diseases. The aim of this study was to evaluate the predictive value of cardiac magnetic resonance (CMR) feature-tracking derived strain parameters in repaired tetralogy of Fallot (rTOF) patients for developing ventricular tachycardia (VT) and deterioration of ventricular function.
Methods
Patients with rTOF who underwent CMR investigation were included. Strain and strain-rate of both ventricles were assessed using CMR feature tracking. The primary outcome was a composite of the occurrence of sustained VT or non-sustained VT requiring invasive therapy. The secondary outcome was analyzed in patients that underwent a second CMR after 1.5 to 3.5 years. Deterioration was defined as reduction (≥10%) in right ventricular (RV) ejection fraction, reduction (≥10%) in left ventricular (LV) ejection fraction or increase (≥30 mL/m) in indexed RV end-diastolic volume compared to baseline.
Results
172 patients (median age 24.3 years, 54 patients <18 years) were included. Throughout a median follow-up of 7.4 years, 9 patients (4.5%) experienced the primary endpoint of VT. Multivariate Cox-regression analysis showed that LV systolic circumferential strain-rate was independently predictive of primary outcome (p = 0.023). 70 patients underwent a serial CMR, of whom 14 patients (20%) showed ventricular deterioration. Logistic regression showed no predictive value of strain and strain-rate parameters.
Conclusions
In patients with rTOF, LV systolic circumferential strain-rate is an independent predictor for the development of VT. Ventricular strain parameters did not predict deterioration of ventricular function in the studied population.

Copyright © 2019 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Nov 2019; 295:1-6
Hagdorn QAJ, Vos JDL, Beurskens NEG, Gorter TM, ... Berger RMF, Willems TP
Int J Cardiol: 14 Nov 2019; 295:1-6 | PMID: 31402156
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Abstract

Sarcopenia is common in adults with complex congenital heart disease.

Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Background
Adults with complex congenital heart disease (CHD) have reduced aerobic capacity and impaired muscle function. We therefore hypothesized that patients have a lower skeletal muscle mass and higher fat mass than controls.
Methods
Body composition was examined with full body Dual-Energy x-ray Absorptiometry (DXA) in 73 patients with complex CHD (mean age 35.8 ± 14.3, women n = 22) and 73 age and sex matched controls. Patients fulfilling criteria for low skeletal muscle mass in relation to their height and fat mass were defined as sarcopenic.
Results
Male patients (n = 51) were shorter (177.4 ± 6.6 cm vs. 180.9 ± 6.7 cm, p = 0.009) and weighed less (76.0 ± 10.8 kg vs. 82.0 ± 12.4 kg, p = 0.01) than controls. Also, patients had a lower appendicular lean mass-index (ALM-index) (7.57 ± 0.97 kg/mvs. 8.46 ± 0.90 kg/m, p < 0.001). Patients\' relative tissue fat mass (27.9 ± 7.0% vs. 25.4 ± 8.6%, p = 0.1) did not differ. Forty-seven percent of the men (n = 24) were classified as sarcopenic. Female patients (n = 22) were also shorter (163.5 ± 8.7 cm vs. 166.7 ± 5.9 cm, p = 0.05) but had a higher BMI (25.7 ± 4.2 vs. 23.0 ± 2.5, p = 0.02) than controls. Patients also had a lower ALM-index (6.30 ± 0.75 vs. 6.67 ± 0.55, p = 0.05), but their relative body fat mass (40.8 ± 7.6% vs. 32.0 ± 7.0%, p < 0.001) were higher. Fifty-nine percent of the women (n = 13) were classified as sarcopenic.
Conclusions
The body composition was altered toward lower skeletal muscle mass in patients with complex CHD. Approximately half of the patients were classified as sarcopenic. Contrary to men, the women had increased body fat and a higher BMI. Further research is required to assess the cause, possible adverse long-term effects and whether sarcopenia is preventable or treatable.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:57-62
Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Int J Cardiol: 30 Nov 2019; 296:57-62 | PMID: 31230936
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Abstract

Heart failure risk predictions in adult patients with congenital heart disease: a systematic review.

Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ

To summarise existing heart failure (HF) risk prediction models and describe the risk factors for HF-related adverse outcomes in adult patients with congenital heart disease (CHD). We performed a systematic search of MEDLINE, EMBASE and Cochrane databases from January 1996 to December 2018. Studies were eligible if they developed multivariable models for risk prediction of decompensated HF in adult patients with CHD (ACHD), death in patients with ACHD-HF or both, or if they reported corresponding predictors. A standardised form was used to extract information from selected studies. Twenty-five studies met the inclusion criteria and all studies were at moderate to high risk of bias. One study derived a model to predict the risk of a composite outcome (HF, death or arrhythmia) with a c-statistic of 0.85. Two studies applied an existing general HF model to patients with ACHD but did not report model performance. Twenty studies presented predictors of decompensated HF, and four examined patient characteristics associated with mortality (two reported predictors of both). A wide variation in population characteristics, outcome of interest and candidate risk factors was observed between studies. Although there were substantial inconsistencies regarding which patient characteristics were predictive of HF-related adverse outcomes, brain natriuretic peptide, New York Heart Association class and CHD lesion characteristics were shown to be important predictors. To date, evidence in the published literature is insufficient to accurately profile patients with ACHD. High-quality studies are required to develop a unique ACHD-HF prediction model and confirm the predictive roles of potential risk factors.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 30 Oct 2019; 105:1661-1669
Wang F, Harel-Sterling L, Cohen S, Liu A, ... Paradis G, Marelli AJ
Heart: 30 Oct 2019; 105:1661-1669 | PMID: 31350277
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Abstract

Advanced Heart Failure Therapies for Adults With Congenital Heart Disease: JACC State-of-the-Art Review.

Givertz MM, DeFilippis EM, Landzberg MJ, Pinney SP, Woods RK, Valente AM

In the contemporary era, nearly 85% of children with congenital heart disease will reach adulthood. Despite optimal medical and surgical treatment, many will experience a progressive decline in cardiopulmonary function leading to advanced heart failure. These patients present unique anatomic and physiological challenges to the care team, and unlike adults with acquired heart disease who progress to severe heart failure, advanced treatment options such as mechanical circulatory support and cardiac transplant may be limited. Severe ventricular dysfunction and/or pulmonary hypertension may not be amenable to corrective repair. Heart transplantation with or without mechanical circulatory support may be the only option for highly selected patients. The aim of this review is to describe advanced heart failure therapies for adults with congenital heart disease, including the general approach to evaluation and management, pre- and post-operative care, anticipated short- and long-term outcomes, and future directions for clinical care and research.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 04 Nov 2019; 74:2295-2312
Givertz MM, DeFilippis EM, Landzberg MJ, Pinney SP, Woods RK, Valente AM
J Am Coll Cardiol: 04 Nov 2019; 74:2295-2312 | PMID: 31672187
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Abstract

Defects in the Exocyst-Cilia Machinery Cause Bicuspid Aortic Valve Disease and Aortic Stenosis.

Fulmer D, Toomer K, Guo L, Moore K, ... Norris RA, Lipschutz JH
Background
Bicuspid aortic valve (BAV) disease is a congenital defect that affects 0.5% to 1.2% of the population and is associated with comorbidities including ascending aortic dilation and calcific aortic valve stenosis. To date, although a few causal genes have been identified, the genetic basis for the vast majority of BAV cases remains unknown, likely pointing to complex genetic heterogeneity underlying this phenotype. Identifying genetic pathways versus individual gene variants may provide an avenue for uncovering additional BAV causes and consequent comorbidities.
Methods
We performed genome-wide association Discovery and Replication Studies using cohorts of 2131 patients with BAV and 2728 control patients, respectively, which identified primary cilia genes as associated with the BAV phenotype. Genome-wide association study hits were prioritized based onvalue and validated through in vivo loss of function and rescue experiments, 3-dimensional immunohistochemistry, histology, and morphometric analyses during aortic valve morphogenesis and in aged animals in multiple species. Consequences of these genetic perturbations on cilia-dependent pathways were analyzed by Western and immunohistochemistry analyses, and assessment of aortic valve and cardiac function were determined by echocardiography.
Results
Genome-wide association study hits revealed an association between BAV and genetic variation in human primary cilia. The most associated single-nucleotide polymorphisms were identified in or near genes that are important in regulating ciliogenesis through the exocyst, a shuttling complex that chaperones cilia cargo to the membrane. Genetic dismantling of the exocyst resulted in impaired ciliogenesis, disrupted ciliogenic signaling and a spectrum of cardiac defects in zebrafish, and aortic valve defects including BAV, valvular stenosis, and valvular calcification in murine models.
Conclusions
These data support the exocyst as required for normal ciliogenesis during aortic valve morphogenesis and implicate disruption of ciliogenesis and its downstream pathways as contributory to BAV and associated comorbidities in humans.



Circulation: 14 Oct 2019; 140:1331-1341
Fulmer D, Toomer K, Guo L, Moore K, ... Norris RA, Lipschutz JH
Circulation: 14 Oct 2019; 140:1331-1341 | PMID: 31387361
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Abstract

Transcatheter Mitral Valve Replacement in Patients with Heart Failure and Secondary Mitral Regurgitation: From COAPT Trial.

Asch FM, Grayburn PA, Siegel RJ, Kar S, ... Weissman NJ,
Background
In the COAPT trial among patients with heart failure (HF) and moderate-to-severe (3+) or severe (4+) secondary mitral regurgitation (SMR), patients treated with the transcatheter mitral valve replacement (TMVR) had reduced rates of HF hospitalization and mortality compared with guideline-directed medical therapy (GDMT) alone.
Objectives
To describe the echocardiographic patient qualification process for COAPT, baseline echocardiographic characteristics, changes over time, and the interaction between treatment group and echocardiographic parameters on clinical outcomes.
Methods
A novel echocardiographic algorithm was implemented for grading MR severity during the screening process. Standardized echocardiograms were obtained at baseline and during regular follow-up intervals through 2 years, and analyzed by a core laboratory.
Results
A total of 614 patients were randomized to TMVR plus maximally- tolerated GDMT or GDMT alone. Mean baseline left ventricular ejection fraction (LVEF) was 31.3±9.3%, LV end-diastolic volume was 192.7±71 ml, and effective regurgitant orifice area was 0.41±0.15 cm. The beneficial effect of TMVR compared with GDMT alone was consistent in all echocardiographic subgroups, independent of the severity of LV dysfunction, LV dilatation, pulmonary hypertension, severity of tricuspid regurgitation or individual MR characteristics. The LVEF decreased and the LV volumes progressively increased in both groups during follow-up, although less after TMVR (P<0.05).
Conclusions
HF patients in the COAPT trial with 3+ or 4+ SMR, selected using strict echocardiographic criteria, benefitted from TMVR with reduced 2-year rates of death and HF hospitalization. Strict application of these echocardiographic criteria should enable the COAPT results to be translated to clinical practice.

Copyright © 2019. Published by Elsevier Inc.

J Am Coll Cardiol: 19 Sep 2019; epub ahead of print
Asch FM, Grayburn PA, Siegel RJ, Kar S, ... Weissman NJ,
J Am Coll Cardiol: 19 Sep 2019; epub ahead of print | PMID: 31574303
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Abstract

Right Atrial Mechanisms of Atrial Fibrillation in a Rat Model of Right Heart Disease.

Hiram R, Naud P, Xiong F, Al-U\'datt D, ... Tardif JC, Nattel S
Background
Conditions affecting the right heart, including diseases of the lungs and pulmonary circulation, promote atrial fibrillation (AF), but the mechanisms are poorly understood.
Objectives
This study sought to determine whether right heart disease promotes atrial arrhythmogenesis in a rat model of pulmonary hypertension (PH) and, if so, to define the underlying mechanisms.
Methods
PH was induced in male Wistar rats with a single intraperitoneal injection of 60 mg/kg of monocrotaline, and rats were studied 21 days later when right heart disease was well developed. AF vulnerability was assessed in vivo and in situ, and mechanisms were defined by optical mapping, histochemistry, and biochemistry.
Results
Monocrotaline-treated rats developed increased right ventricular pressure and mass, along with right atrial (RA) enlargement. AF/flutter was inducible in 32 of 32 PH rats (100%) in vivo and 11 of 12 (92%) in situ, versus 2 of 32 (6%) and 2 of 12 (17%), respectively, in control rats (p < 0.001 vs. PH for each). PH rats had significant RA (16.1 ± 0.5% of cross-sectional area, vs. 3.0 ± 0.6% in control) and left atrial (LA: 11.8 ± 0.5% vs. 5.4 ± 0.8% control) fibrosis. Multiple extracellular matrix proteins, including collagen 1 and 3, fibronectin, and matrix metalloproteinases 2 and 9, were up-regulated in PH rat RA. Optical mapping revealed significant rate-dependent RA conduction slowing and rotor activity, including stable rotors in 4 of 11 PH rats, whereas no significant conduction slowing or rotor activity occurred in the LA of monocrotaline-treated rats. Transcriptomic analysis revealed differentially enriched genes related to hypertrophy, inflammation, and fibrosis in RA of monocrotaline-treated rats versus control. Biochemical results in PH rats were compared with those of AF-prone rats with atrial remodeling in the context of left ventricular dysfunction due to myocardial infarction: myocardial infarction rat LA shared molecular motifs with PH rat RA.
Conclusions
Right heart disease produces a substrate for AF maintenance due to RA re-entrant activity, with an underlying substrate prominently involving RA fibrosis and conduction abnormalities.

Copyright © 2019 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Sep 2019; 74:1332-1347
Hiram R, Naud P, Xiong F, Al-U'datt D, ... Tardif JC, Nattel S
J Am Coll Cardiol: 10 Sep 2019; 74:1332-1347 | PMID: 31488271
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Abstract

Usefulness of ventilatory gas analysis for the non-invasive evaluation of the severity of chronic thromboembolic pulmonary hypertension.

Akizuki M, Sugimura K, Aoki T, Kakihana T, ... Shimokawa H, Kohzuki M
Background
Chronic thromboembolic pulmonary hypertension (CTEPH) is characterized by organic thrombotic obstructions in the pulmonary arteries with reduced pulmonary vascular reserve. This study aimed to examine whether postural changes in ventilatory gas analysis parameters are useful for assessing pulmonary hemodynamics in patients with CTEPH.
Methods
A total of 44 patients with newly diagnosed CTEPH (CTEPH group), 33 patients with improved CTEPH (mean pulmonary arterial pressure [mPAP] <25 mm Hg), and 25 controls were enrolled. Patients with improved CTEPH referred to patients without residual PH who were previously diagnosed with CTEPH and already received optimal therapies. Various pulmonary function parameters were examined in supine and sitting positions, and postural changes were calculated (Δ[supine - sitting]). In 32 patients with CTEPH, we examined hemodynamic and ventilatory gas analysis parameters before the first balloon pulmonary angioplasty (BPA) and during follow-up.
Results
Patients with CTEPH had significantly lower supine end-tidal carbon dioxide pressure (PCO) and ΔPCO than controls (both P < 0.001), and these parameters were significantly correlated with mPAP (R = 0.507, P < 0.0001 and R = 0.470, P < 0.001, respectively). Supine PCO and ΔPCO were significantly lower in patients with improved CTEPH than in controls (both P < 0.001). Hemodynamic and echocardiographic parameters were comparable in both groups. Furthermore, significant correlation between the change in mPAP and change in supine PCO by BPA was noted (R = 0.478, P < 0.001).
Conclusion
These results indicate that postural changes in ventilatory gas analysis parameters are useful and non-invasive method for the evaluation of mPAP, which is one of the hemodynamic parameters of CTEPH severity.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Nov 2019; 296:149-154
Akizuki M, Sugimura K, Aoki T, Kakihana T, ... Shimokawa H, Kohzuki M
Int J Cardiol: 30 Nov 2019; 296:149-154 | PMID: 31350036
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Abstract

Identification of Emetine as a Therapeutic Agent for Pulmonary Arterial Hypertension: Novel Effects of an Old Drug.

Siddique MAH, Satoh K, Kurosawa R, Kikuchi N, ... Tokuyama H, Shimokawa H
Objective
Excessive proliferation and apoptosis resistance are special characteristics of pulmonary artery smooth muscle cells (PASMCs) in pulmonary arterial hypertension (PAH). However, the drugs in clinical use for PAH target vascular dilatation, which do not exert adequate effects in patients with advanced PAH. Here, we report a novel therapeutic effect of emetine, a principal alkaloid extracted from the root of ipecac clinically used as an emetic and antiprotozoal drug. Approach and Results: We performed stepwise screenings for 5562 compounds from original library. First, we performed high-throughput screening with PASMCs from patients with PAH (PAH-PASMCs) and found 80 compounds that effectively inhibited proliferation. Second, we performed the repeatability and counter assay. Finally, we performed a concentration-dependent assay and found that emetine inhibits PAH-PASMC proliferation. Interestingly, emetine significantly reduced protein levels of HIFs (hypoxia-inducible factors; HIF-1α and HIF-2α) and downstream PDK1 (pyruvate dehydrogenase kinase 1). Moreover, emetine significantly reduced the protein levels of RhoA (Ras homolog gene family, member A), Rho-kinases (ROCK1 and ROCK2 [rho-associated coiled-coil containing protein kinases 1 and 2]), and their downstream CyPA (cyclophilin A), and Bsg (basigin) in PAH-PASMCs. Consistently, emetine treatment significantly reduced the secretion of cytokines/chemokines and growth factors from PAH-PASMCs. Interestingly, emetine reduced protein levels of BRD4 (bromodomain-containing protein 4) and downstream survivin, both of which are involved in many cellular functions, such as cell cycle, apoptosis, and inflammation. Finally, emetine treatment ameliorated pulmonary hypertension in 2 experimental rat models, accompanied by reduced inflammatory changes in the lungs and recovered right ventricular functions.
Conclusions
Emetine is an old but novel drug for PAH that reduces excessive proliferation of PAH-PASMCs and improves right ventricular functions.



Arterioscler Thromb Vasc Biol: 30 Oct 2019; 39:2367-2385
Siddique MAH, Satoh K, Kurosawa R, Kikuchi N, ... Tokuyama H, Shimokawa H
Arterioscler Thromb Vasc Biol: 30 Oct 2019; 39:2367-2385 | PMID: 31533472
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Abstract

Structures of a RAG-like transposase during cut-and-paste transposition.

Liu C, Yang Y, Schatz DG

Transposons have had a pivotal role in genome evolution and are believed to be the evolutionary progenitors of the RAG1-RAG2 recombinase, an essential component of the adaptive immune system in jawed vertebrates. Here we report one crystal structure and five cryo-electron microscopy structures of Transib, a RAG1-like transposase from Helicoverpa zea, that capture the entire transposition process from the apo enzyme to the terminal strand transfer complex with transposon ends covalently joined to target DNA, at resolutions of 3.0-4.6 Å. These structures reveal a butterfly-shaped complex that undergoes two cycles of marked conformational changes in which the \'wings\' of the transposase unfurl to bind substrate DNA, close to execute cleavage, open to release the flanking DNA and close again to capture and attack target DNA. Transib possesses unique structural elements that compensate for the absence of a RAG2 partner, including a loop that interacts with the transposition target site and an accordion-like C-terminal tail that elongates and contracts to help to control the opening and closing of the enzyme and assembly of the active site. Our findings reveal the detailed reaction pathway of a eukaryotic cut-and-paste transposase and illuminate some of the earliest steps in the evolution of the RAG recombinase.



Nature: 12 Nov 2019; epub ahead of print
Liu C, Yang Y, Schatz DG
Nature: 12 Nov 2019; epub ahead of print | PMID: 31723264
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Abstract

Leptin Restores Endothelial Function via Endothelial PPARγ-Nox1-Mediated Mechanisms in a Mouse Model of Congenital Generalized Lipodystrophy.

Bruder-Nascimento T, Faulkner JL, Haigh S, Kennard S, ... Chen W, Belin de Chantemèle EJ

Leptin is the current treatment for metabolic disorders associated with acquired and congenital generalized lipodystrophy (CGL). Although excess leptin levels have been associated with vascular inflammation and cardiovascular disease in the context of obesity, the effects of chronic leptin treatment on vascular function remain unknown in CGL. Here, we hypothesized that leptin treatment will improve endothelial function via direct vascular mechanisms. We investigated the cardiovascular consequences of leptin deficiency and supplementation in male gBscl2 ( gene-deficient) mice-a mouse model of CGL. CGL mice exhibited reduced adipose mass and leptin levels, as well as impaired endothelium-dependent relaxation. Blood vessels from CGL mice had increased NADPH Oxidase 1 (Nox1) expression and reactive oxygen species production, and selective Nox1 inhibition restored endothelial function. Remarkably, chronic and acute leptin supplementation restored endothelial function via a PPARγ-dependent mechanism that decreased Nox1 expression and reactive oxygen species production. Selective ablation of leptin receptors in endothelial cells promoted endothelial dysfunction, which was restored by Nox1 inhibition. Lastly, we confirmed in aortic tissue from older patients undergoing cardiac bypass surgery that acute leptin can promote signaling in human blood vessels. In conclusion, in gBscl2 mice, leptin restores endothelial function via peroxisome proliferator activated receptor gamma-dependent decreases in Nox1. Furthermore, we provide the first evidence that vessels from aged patients remain leptin sensitive. These data reveal a new direct role of leptin receptors in the control of vascular homeostasis and present leptin as a potential therapy for the treatment of vascular disease associated with low leptin levels.



Hypertension: 27 Oct 2019:HYPERTENSIONAHA11913398; epub ahead of print
Bruder-Nascimento T, Faulkner JL, Haigh S, Kennard S, ... Chen W, Belin de Chantemèle EJ
Hypertension: 27 Oct 2019:HYPERTENSIONAHA11913398; epub ahead of print | PMID: 31656096
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Abstract

Decreased OLA1 (Obg-Like ATPase-1) Expression Drives Ubiquitin-Proteasome Pathways to Downregulate Mitochondrial SOD2 (Superoxide Dismutase) in Persistent Pulmonary Hypertension of the Newborn.

Schultz A, Olorundami OA, Teng RJ, Jarzembowski J, ... Konduri GG, Afolayan AJ

Persistent pulmonary hypertension of the newborn (PPHN) is a failure of pulmonary vascular resistance to decline at birth rapidly. One principal mechanism implicated in PPHN development is mitochondrial oxidative stress. Expression and activity of mitochondrial SOD2 (superoxide dismutase) are decreased in PPHN; however, the mechanism remains unknown. Recently, OLA1 (Obg-like ATPase-1) was shown to act as a critical regulator of proteins controlling cell response to stress including Hsp70, an obligate chaperone for SOD2. Here, we investigated whether OLA1 is causally linked to PPHN. Compared with controls, SOD2 expression is reduced in distal-pulmonary arteries (PAs) from patients with PPHN and fetal-lamb models. Disruptions of thegene reproduced PPHN phenotypes, manifested by elevated right ventricular systolic pressure, PA-endothelial cells apoptosis, and PA-smooth muscle cells proliferation. Analyses of SOD2 protein dynamics revealed higher ubiquitinated-SOD2 protein levels in PPHN-lambs, suggesting dysregulated protein ubiquitination. OLA1 controls multiple proteostatic mechanisms and is overexpressed in response to stress. We demonstrated that OLA1 acts as a molecular chaperone, and its activity is induced by stress. Strikingly, OLA1 expression is decreased in distal-PAs from PPHN-patients and fetal-lambs. OLA1 deficiency enhanced CHIP affinity for Hsp70-SOD2 complexes, facilitating SOD2 degradation. Consequently, mitochondrial HO formation is impaired, leading to XIAP (X-linked inhibitor of apoptosis) overexpression that suppresses caspase activity in PA-smooth muscle cells, allowing them to survive and proliferate, contributing to PA remodeling. In-vivo, o downregulated SOD2 expression, induced distal-PA remodeling, and right ventricular hypertrophy. We conclude that decreased OLA1 expression accounts for SOD2 downregulation and, therefore, a therapeutic target in PPHN treatments.



Hypertension: 29 Sep 2019; 74:957-966
Schultz A, Olorundami OA, Teng RJ, Jarzembowski J, ... Konduri GG, Afolayan AJ
Hypertension: 29 Sep 2019; 74:957-966 | PMID: 31476900
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Impact:
Abstract

HIMF (Hypoxia-Induced Mitogenic Factor) Signaling Mediates the HMGB1 (High Mobility Group Box 1)-Dependent Endothelial and Smooth Muscle Cell Cross Talk in Pulmonary Hypertension.

Lin Q, Fan C, Gomez-Arroyo J, Van Raemdonck K, ... Yamaji-Kegan K, Johns RA
Objective
HIMF (hypoxia-induced mitogenic factor; also known as FIZZ1 [found in inflammatory zone-1] or RELM [resistin-like molecule-α]) is an etiological factor of pulmonary hypertension (PH) in rodents, but its underlying mechanism is unclear. We investigated the immunomodulatory properties of HIMF signaling in PH pathogenesis. Approach and Results: Gene-modified mice that lacked HIMF (KO [knockout]) or overexpressed HIMF human homolog of resistin (hResistin) were used for in vivo experiments. The pro-PH role of HIMF was verified in HIMF-KO mice exposed to chronic hypoxia or sugen/hypoxia. Mechanistically, HIMF/hResistin activation triggered the HMGB1 (high mobility group box 1) pathway and RAGE (receptor for advanced glycation end products) in pulmonary endothelial cells (ECs) of hypoxic mouse lungs in vivo and in human pulmonary microvascular ECs in vitro. Treatment with conditioned medium from hResistin-stimulated human pulmonary microvascular ECs induced an autophagic response, BMPR2 (bone morphogenetic protein receptor 2) defects, and subsequent apoptosis-resistant proliferation in human pulmonary artery (vascular) smooth muscle cells in an HMGB1-dependent manner. These effects were confirmed in ECs and smooth muscle cells isolated from pulmonary arteries of patients with idiopathic PH. HIMF/HMGB1/RAGE-mediated autophagy and BMPR2 impairment were also observed in pulmonary artery (vascular) smooth muscle cells of hypoxic mice, effects perhaps related to FoxO1 (forkhead box O1) dampening by HIMF. Experiments in EC-specific hResistin-overexpressing transgenic mice confirmed that EC-derived HMGB1 mediated the hResistin-driven pulmonary vascular remodeling and PH.
Conclusions
In HIMF-induced PH, HMGB1-RAGE signaling is pivotal for mediating EC-smooth muscle cell cross talk. The humanized mouse data further support clinical implications for the HIMF/HMGB1 signaling axis and indicate that hResistin and its downstream pathway may constitute targets for the development of novel anti-PH therapeutics in humans.



Arterioscler Thromb Vasc Biol: 09 Oct 2019:ATVBAHA119312907; epub ahead of print
Lin Q, Fan C, Gomez-Arroyo J, Van Raemdonck K, ... Yamaji-Kegan K, Johns RA
Arterioscler Thromb Vasc Biol: 09 Oct 2019:ATVBAHA119312907; epub ahead of print | PMID: 31597444
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Impact:
Abstract

Methamphetamine Use and Cardiovascular Disease.

Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, ... Traylor JG, Orr AW

While the opioid epidemic has garnered significant attention, the use of methamphetamines is growing worldwide independent of wealth or region. Following overdose and accidents, the leading cause of death in methamphetamine users is cardiovascular disease, because of significant effects of methamphetamine on vasoconstriction, pulmonary hypertension, atherosclerotic plaque formation, cardiac arrhythmias, and cardiomyopathy. In this review, we examine the current literature on methamphetamine-induced changes in cardiovascular health, discuss the potential mechanisms regulating these varied effects, and highlight our deficiencies in understanding how to treat methamphetamine-associated cardiovascular dysfunction.



Arterioscler Thromb Vasc Biol: 30 Aug 2019; 39:1739-1746
Kevil CG, Goeders NE, Woolard MD, Bhuiyan MS, ... Traylor JG, Orr AW
Arterioscler Thromb Vasc Biol: 30 Aug 2019; 39:1739-1746 | PMID: 31433698
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Abstract

ALDH2 (Aldehyde Dehydrogenase 2) Protects Against Hypoxia-Induced Pulmonary Hypertension.

Zhao Y, Wang B, Zhang J, He D, ... Wei S, Chen Y
Objective
Hypoxia-induced pulmonary hypertension (HPH) increases lipid peroxidation with generation of toxic aldehydes that are metabolized by detoxifying enzymes, including ALDH2 (aldehyde dehydrogenase 2). However, the role of lipid peroxidation and ALDH2 in HPH pathogenesis remain undefined. Approach and Results: To determine the role of lipid peroxidation and ALDH2 in HPH, C57BL/6 mice, ALDH2 transgenic mice, and ALDH2 knockout (ALDH2) mice were exposed to chronic hypoxia, and recombinant tissue-specific ALDH2 overexpression adeno-associated viruses were introduced into pulmonary arteries via tail vein injection for ALDH2 overexpression. Human pulmonary artery smooth muscle cells were used to elucidate underlying mechanisms in vitro. Chronic hypoxia promoted lipid peroxidation due to the excessive production of reactive oxygen species and increased expression of lipoxygenases in lung tissues. 4-hydroxynonenal but not malondialdehyde level was increased in hypoxic lung tissues which might reflect differences in detoxifying enzymes. ALDH2 overexpression attenuated the development of HPH, whereas ALDH2 knockout aggravated it. Specific overexpression of ALDH2 using AAV1-ICAM (intercellular adhesion molecule) 2p-ALDH2 and AAV2-SM22αp-ALDH2 viral vectors in pulmonary artery smooth muscle cells, but not endothelial cells, prevented the development of HPH. Hypoxia or 4-hydroxynonenal increased stabilization of HIF (hypoxia-inducible factor)-1α, phosphorylation of Drp1 (dynamin-related protein 1) at serine 616, mitochondrial fission, and pulmonary artery smooth muscle cells proliferation, whereas ALDH2 activation suppressed the latter 3.
Conclusions
Increased 4-hydroxynonenal level plays a critical role in the development of HPH. ALDH2 attenuates the development of HPH by regulating mitochondrial fission and smooth muscle cell proliferation suggesting ALDH2 as a potential new therapeutic target for pulmonary hypertension.



Arterioscler Thromb Vasc Biol: 11 Sep 2019:ATVBAHA119312946; epub ahead of print
Zhao Y, Wang B, Zhang J, He D, ... Wei S, Chen Y
Arterioscler Thromb Vasc Biol: 11 Sep 2019:ATVBAHA119312946; epub ahead of print | PMID: 31510791
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Abstract

Formation and Resolution of Pial Microvascular Thrombosis in a Mouse Model of Thrombotic Thrombocytopenic Purpura.

Adili R, Holinstat M
Objective
Microvascular thrombosis is the hallmark pathology of thrombotic thrombocytopenic purpura (TTP), a rare life-threatening disease. Neurological dysfunction is present in over 90% of patients with TTP, and TTP can cause long-lasting neurological damage or death. However, the pathophysiology of microvascular thrombosis in the brain is not well studied to date. Here, we investigate the formation and resolution of thrombosis in pial microvessels. Approach and Results: Using a cranial intravital microscopy in well-established mouse models of congenital TTP induced by infusion of recombinant VWF (von Willebrand factor), we found that soluble VWF, at high concentration, adheres to the endothelium of the vessel wall, self-associates, and initiates platelet adhesion resulting in the formation of pial microvascular thrombosis in ADAMTS13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13) mice. Importantly, VWF-mediated pial microvascular thrombosis occurred without vascular injury to the brain, and thrombi consisted of resting platelets adhered onto ultra-large VWF without fibrin in the brain in rVWF (recombinant VWF) challenged ADAMTS13 mice. Prophylactic treatment with recombinant ADAMTS13 (BAX930) effectively prevented the onset of the VWF-mediated microvascular thrombosis and therapeutic treatment with BAX930 acutely resolved the preexisting or growing thrombi in the brain of ADAMTS13 mice after rVWF challenge. The absence of platelet activation and fibrin formation within VWF-mediated thrombi and efficacy of BAX930 was confirmed with an endothelial-driven VWF-mediated microvascular thrombosis model in mice.
Conclusions
Our results provide important insight into the initiation and development of microvascular thrombi in mouse models that mimics TTP and indicate that rADAMTS13 could be an effective interventional therapy for microvascular thrombosis, the hallmark pathology in TTP.



Arterioscler Thromb Vasc Biol: 30 Aug 2019; 39:1817-1830
Adili R, Holinstat M
Arterioscler Thromb Vasc Biol: 30 Aug 2019; 39:1817-1830 | PMID: 31340669
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Abstract

Safety and pharmacokinetics of dolutegravir in pregnant mothers with HIV infection and their neonates: A randomised trial (DolPHIN-1 study).

Waitt C, Orrell C, Walimbwa S, Singh Y, ... Lamorde M, Khoo S
Background
The global transition to use of dolutegravir (DTG) in WHO-preferred regimens for HIV treatment is limited by lack of knowledge on use in pregnancy. Here we assessed the relationship between drug concentrations (pharmacokinetics, PK), including in breastmilk, and impact on viral suppression when initiated in the third trimester (T3).
Methods and findings
In DolPHIN-1, HIV-infected treatment-naïve pregnant women (28-36 weeks of gestation, age 26 (19-42), weight 67kg (45-119), all Black African) in Uganda and South Africa were randomised 1:1 to dolutegravir (DTG) or efavirenz (EFV)-containing ART until 2 weeks post-partum (2wPP), between 9th March 2017 and 16th January 2018, with follow-up until six months postpartum. The primary endpoint was pharmacokinetics of DTG in women and breastfed infants; secondary endpoints included maternal and infant safety and viral suppression. Intensive pharmacokinetic sampling of DTG was undertaken at day 14 and 2wPP following administration of a medium-fat breakfast, with additional paired sampling between maternal plasma and cord blood, breastmilk and infant plasma. No differences in median baseline maternal age, gestation (31 vs 30 weeks), weight, obstetric history, viral load (4.5 log10 copies/mL both arms) and CD4 count (343 vs 466 cells/mm3) were observed between DTG (n = 29) and EFV (n = 31) arms. Although DTG Ctrough was below the target 324ng/mL (clinical EC90) in 9/28 (32%) mothers in the third trimester, transfer across the placenta (121% of plasma concentrations) and into breastmilk (3% of plasma concentrations), coupled with slower elimination, led to significant infant plasma exposures (3-8% of maternal exposures). Both regimens were well-tolerated with no significant differences in frequency of adverse events (two on DTG-ART, one on EFV-ART, all considered unrelated to drug). No congenital abnormalities were observed. DTG resulted in significantly faster viral suppression (P = 0.02) at the 2wPP visit, with median time to <50 copies/mL of 32 vs 72 days. Limitations related to the requirement to initiate EFV-ART prior to randomisation, and to continue DTG for only two weeks postpartum.
Conclusion
Despite low plasma DTG exposures in the third trimester, transfer across the placenta and through breastfeeding was observed in this study, with persistence in infants likely due to slower metabolic clearance. HIV RNA suppression <50 copies/mL was twice as fast with DTG compared to EFV, suggesting DTG has potential to reduce risk of vertical transmission in mothers who are initiated on treatment late in pregnancy.
Trial registration
clinicaltrials.gov NCT02245022.



PLoS Med: 30 Aug 2019; 16:e1002895
Waitt C, Orrell C, Walimbwa S, Singh Y, ... Lamorde M, Khoo S
PLoS Med: 30 Aug 2019; 16:e1002895 | PMID: 31539371
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Abstract

Role of the lymphatic vasculature in cardiovascular medicine.

Telinius N, Hjortdal VE

The lymphatic vasculature has traditionally been considered important for removal of excessive fluid from the interstitial space, absorption of fat from the intestine and the immune system. Advances in molecular medicine and imaging have provided us with new tools to study the lymphatics. This has revealed that the vessels are actively involved in regulation of immune cell trafficking and inflammation. We now know much about how new lymphatic vessels are created (lymphangiogenesis) and that this is important in, for example, wound healing and tissue repair. The best characterised pathway for lymphangiogenesis is the vascular endothelial growth factor C (VEGF-C)/VEGFR3 pathway. Over recent years, there has been an increasing interest in the role of the lymphatics in cardiovascular medicine. Preclinical studies have shown that lymphangiogenesis and immune cell trafficking play a role in cardiovascular conditions such as atherosclerosis, recovery after myocardial infarction and rejection of cardiac allografts. Targeting the VEGF-C/VEGFR3 pathway can be beneficial in these conditions. The clinical spectrum of lymphatic abnormalities and lymphoedema is wide and overlaps with congenital heart disease. Important long-term complications to the Fontan circulation involves the lymphatics. New and improved imaging modalities has improved our understanding and management of these patients. Lymphatic leaks and flow abnormalities can be successfully treated, minimally invasively, with percutaneous embolisation. Future research will prove if the preclinical findings that point to a role of the lymphatics in several cardiovascular conditions will result in new treatment options.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 03 Oct 2019; epub ahead of print
Telinius N, Hjortdal VE
Heart: 03 Oct 2019; epub ahead of print | PMID: 31585946
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Abstract

Isolated nocturnal and isolated daytime hypertension associate with altered cardiovascular morphology and function in children with chronic kidney disease: findings from the Cardiovascular Comorbidity in Children with Chronic Kidney Disease study.

Düzova A, Karabay Bayazit A, Canpolat N, Niemirska A, ... Wühl E,
Introduction
Prevalence of isolated nocturnal hypertension (INH) and isolated daytime hypertension (IDH) is around 10% in adults. Data in children, especially in chronic kidney disease (CKD), are lacking. The aim of this cross-sectional multicenter cohort study was to define the prevalence of INH and IDH and its association with cardiovascular morphology and function, that is, pulse wave velocity (PWV), carotid intima-media thickness (cIMT), or left ventricular mass index (LVMI) in children with CKD.
Methods
Ambulatory blood pressure (BP) monitoring profiles were analyzed in 456 children with CKD stages III-V participating in the Cardiovascular Comorbidity in Children with Chronic Kidney Disease Study (64.3% males, 71.3% congenital anomaly of the kidney and urinary tract, age 12.5 ± 3.2 years, estimated glomerular filtration rate 29 ± 12 ml/min per 1.73 m). Baseline PWV, cIMT, and LVMI were compared in normotension, INH, IDH, or sustained 24-h hypertension.
Results
Prevalence of sustained hypertension was 18.4%, of INH 13.4%, and of IDH 3.7%. PWV SDS (SD score) and cIMT SDS were significantly higher in sustained hypertension and INH, and PWV SDS was significantly higher in IDH, compared with normotension. LVMI was significantly increased in sustained hypertension, but not in INH or IDH. Determinants of INH were smallness for gestational age, older age, higher height SDS and parathyroid hormone, and shorter duration of CKD. In logistic regression analysis, day/night-time hypertension or ambulatory BP monitoring pattern (normal, INH, IDH, sustained hypertension) were independently associated with cardiovascular outcome measures: elevated night-time BP was associated with increased cIMT, PWV, and left ventricular hypertrophy; INH was associated with cIMT.
Conclusion
INH is present in almost one out of seven children with predialysis CKD; INH and nocturnal hypertension in general are associated with alterations of arterial morphology and function.



J Hypertens: 30 Oct 2019; 37:2247-2255
Düzova A, Karabay Bayazit A, Canpolat N, Niemirska A, ... Wühl E,
J Hypertens: 30 Oct 2019; 37:2247-2255 | PMID: 31205198
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Abstract

Pulmonary hypertension in patients with a subaortic right ventricle: prevalence, impact and management.

Van De Bruaene A, Toh N, Hickey EJ, Benson L, ... Williams WG, Roche SL
Objective
This study sought to determine the prevalence, predictors, prognostic relevance and evolution of pulmonary hypertension (PH) (mean pulmonary artery pressure ≥25 mm Hg) in adult patients with a subaortic right ventricle (RV) in a biventricular circulation (2V-RV).
Methods
We analysed retrospective data from patients with 2V-RV undergoing cardiac catheterisation in our centre between 2000 and 2018. Echocardiographic assessment of subpulmonary ventricular pressures (left ventricular systolic pressure (LVSP)), age and B-type natriuretic peptide (BNP) were assessed as PH screening tools. Kaplan-Meier curves examined time to a composite outcome of death, transplant or ventricular assist device (VAD). Data from repeat catheterisations were analysed to evaluate PH changes over time, including the effects of therapy.
Results
A total of 141 patients (median age 39 (IQR 33-45) years, 68% men) underwent 191 cardiac catheterisations. At baseline, 55% had PH (isolated postcapillary 24%, combined precapillary and postcapillary 26% and precapillary 5%). BNP (area under the curve 0.80; 95% CI 0.72 to 0.88; p<0.0001), but not age at catheterisation or echocardiographic estimates of LVSP were associated with the presence of PH. The absence of PH and BNP <100 pg/mL discriminated a subgroup at very low risk during short-term (2.5 (1.3-3.9) years) follow-up (p<0.0001). Diuretics, milrinone and VAD improved haemodynamics over time.
Conclusion
PH is prevalent in patients with 2V-RV even when asymptomatic. It is difficult to identify by echocardiography and most importantly, is strongly associated with adverse outcomes. PH affects prognosis and transplant options for this patient group and yet is often amenable to treatment. Awareness of these results ought to lower the threshold for invasive haemodynamic assessment and may change the management of failing patients with 2V-RV.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 29 Sep 2019; 105:1471-1478
Van De Bruaene A, Toh N, Hickey EJ, Benson L, ... Williams WG, Roche SL
Heart: 29 Sep 2019; 105:1471-1478 | PMID: 31053610
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Abstract

ADAMTS8 Promotes the Development of Pulmonary Arterial Hypertension and Right Ventricular Failure -A Possible Novel Therapeutic Target.

Omura J, Satoh K, Kikuchi N, Satoh T, ... Okada Y, Shimokawa H

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling with aberrant pulmonary artery smooth muscle cells (PASMCs) proliferation, endothelial dysfunction, and extracellular matrix remodeling.Right ventricular (RV) failure is an important prognostic factor in PAH. Thus, we need to elucidate a novel therapeutic target in both PAH and RV failure.We performed microarray analysis in PASMCs from patients with PAH (PAH-PASMCs) and controls. We found a disintegrin and metalloproteinase with thrombospondin motifs 8 (ADAMTS8), a secreted protein specifically expressed in the lung and the heart, was up-regulated in PAH-PASMCs and the lung in hypoxia-induced pulmonary hypertension (PH) in mice. To elucidate the role of ADAMTS8 in PH, we used vascular smooth muscle cell-specific ADAMTS8-knockout mice (ADAMTS). Hypoxia-induced PH was attenuated in ADAMTS mice compared with controls. ADAMTS8 overexpression increased PASMC proliferation with downregulation of AMP-activated protein kinase (AMPK). In contrast, deletion of ADAMTS8 reduced PASMC proliferation with AMPK upregulation. Moreover, deletion of ADAMTS8 reduced mitochondrial fragmentation under hypoxia in vivo and in vitro. Indeed, PASMCs harvested from ADAMTSΔSM22 mice demonstrated that phosphorylated dynamin-related protein 1 (DRP-1) at Ser637 was significantly up-regulated with higher expression of pro-fusion genes ( and ) and improved mitochondrial function. Moreover, recombinant ADAMTS8 induced endothelial dysfunction and matrix metalloproteinase activation in an autocrine/paracrine manner. Next, to elucidate the role of ADAMTS8 in RV function, we developed a cardiomyocyte-specific ADAMTS8 knockout mice (ADAMTS8). ADAMTS8 mice showed ameliorated RV failure in response to chronic hypoxia. In addition, ADAMTS8 mice showed enhanced angiogenesis and reduced RV ischemia and fibrosis. Finally, high-throughput screening revealed that mebendazole, which is used for treatment of parasite infections, reduced ADAMTS8 expression and cell proliferation in PAH-PASMCs and ameliorated PH and RV failure in PH rodent models.These results indicate that ADAMTS8 is a novel therapeutic target in PAH.



Circ Res: 25 Sep 2019; epub ahead of print
Omura J, Satoh K, Kikuchi N, Satoh T, ... Okada Y, Shimokawa H
Circ Res: 25 Sep 2019; epub ahead of print | PMID: 31556812
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Abstract

Cell atlas of the fetal human heart and implications for autoimmune-mediated congenital heart block.

Suryawanshi H, Clancy R, Morozov P, Halushka MK, Buyon JP, Tuschl T
Aims
Investigating human heart development and applying this to deviations resulting in disease is incomplete without molecular characterization of the cell types required for its normal functioning. We investigated fetal human heart single-cell transcriptomes from midgestational healthy and anti-Ro associated congenital heart block (CHB) samples, respectively.
Methods and results
Three healthy fetal human hearts (19th-22nd week of gestation) and one fetal heart affected by autoimmune-associated CHB (21st week of gestation) were subjected to enzymatic dissociation using the Langendorff preparation to obtain single cell suspensions followed by 10x Genomics- and Illumina-based single cell RNA-sequencing (scRNA-seq). In addition to the myocytes, fibroblasts, immune cells, and other minor cell types, previously uncharacterized diverse subpopulations of endothelial cells were identified in the human heart. Differential gene expression analysis revealed increased and heterogeneous interferon responses in varied cell types the CHB heart compared to the healthy controls. In addition, we also identified matrisome transcripts enriched in CHB stromal cells that potentially contributing to extracellular matrix deposition and subsequent fibrosis.
Conclusion
These data provide an information-rich resource to further understanding of human heart development, which, as illustrated by comparison to a heart exposed to a maternal autoimmune environment, can be leveraged to provide insight into the pathogenesis of disease.
Translational perspective
This study provides a single cell transcriptomic atlas of cells obtained from healthy second trimester fetal hearts to further understand human heart development and impart insight into autoimmune associated congenital heart block. In addition to myocytes and fibroblasts, previously uncharacterized subpopulations of endothelial cells were identified. Leveraging an unprecedented opportunity, healthy heart transcriptomes were compared to an age matched anti-SSA/Ro exposed fetal heart with third degree block in which no maternal medications were taken. Differential gene expression analysis revealed a remarkable interferon response in many cell types of the diseased heart. In addition, matrisome transcripts were enriched in the stromal cells likely contributing to the extracellular matrix deposition and thereby fibrosis, a signature lesion of heart block. Thus, targeting the interferon pathway merits therapeutic consideration.

© The Author(s) 2019. Published by Oxford University Press on behalf of the European Society of Cardiology.

Cardiovasc Res: 06 Oct 2019; epub ahead of print
Suryawanshi H, Clancy R, Morozov P, Halushka MK, Buyon JP, Tuschl T
Cardiovasc Res: 06 Oct 2019; epub ahead of print | PMID: 31589297
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Abstract

Growth differentiation factor-15 as candidate predictor for mortality in adults with pulmonary hypertension.

Geenen LW, Baggen VJM, Kauling RM, Koudstaal T, ... Roos-Hesselink JW, van den Bosch AE
Objective
Despite its predictive value for mortality in various diseases, the relevance of growth differentiation factor-15 (GDF-15) as prognostic biomarker in pulmonary hypertension (PH) remains unclear. This study investigated the association between GDF-15 and outcomes in adults with PH.
Methods
This is a single-centre prospective observational cohort study. All adults with PH were included at the day of their diagnostic right heart catheterisation between 2012 and 2016. PH due to left heart disease was excluded. Venous blood sampling was performed and included GDF-15 and N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurements. Kaplan-Meier curves and Cox regression analysis were used to investigate the association between GDF-15 and a composite endpoint of death or lung transplantation. We adjusted for age and NT-proBNP in multivariable analysis. Reference values were established by GDF-15 measurements in healthy controls.
Results
GDF-15 was measured in 103 patients (median age 59.2 years, 65% women, 51% pulmonary arterial hypertension). GDF-15 was elevated in 76 patients (74%). After a median follow-up of 3.4 (IQR 2.3-4.6) years, 32 patients (31.1%) reached the primary endpoint. Event-free survival 2 years after diagnosis was 100% in patients with normal GDF-15 versus 72.4% in patients with elevated GDF-15 (p=0.007). A significant association was found between GDF-15 and the primary endpoint (HR per twofold higher value 1.77, 95% CI 1.39 to 2.27, p<0.001), also after adjustment for age and NT-proBNP (HR 1.41, 95% CI 1.02 to 1.94, p=0.038).
Conclusions
High GDF-15 levels are associated with an increased risk of death or transplant in adults with PH, independent of age and NT-proBNP. As non-specific biomarker, GDF-15 could particularly be useful to detect low-risk patients.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 05 Sep 2019; epub ahead of print
Geenen LW, Baggen VJM, Kauling RM, Koudstaal T, ... Roos-Hesselink JW, van den Bosch AE
Heart: 05 Sep 2019; epub ahead of print | PMID: 31492701
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Abstract

A Multicentre study of anticoagulation in operable chronic thromboembolic pulmonary hypertension.

Bunclark K, Newnham M, Chiu YD, Ruggiero A, ... Pepke-Zaba J, Toshner M
Background
Chronic thromboembolic pulmonary hypertension (CTEPH) is an uncommon complication of acute pulmonary emboli necessitating lifelong anticoagulation. Despite this, little data exists on the safety and efficacy of Vitamin K Antagonists (VKAs) in CTEPH and none for Direct Oral Anticoagulants (DOACs).
Objectives
To evaluate outcomes and complication rates in CTEPH following Pulmonary Endarterectomy (PEA) for individuals receiving VKAs or DOACs.
Methods
Consecutive CTEPH patients undergoing PEA between 2007 and 2018 were included in a retrospective analysis. Post-operative outcomes, recurrent venous thromboembolism (VTE) and bleeding events were obtained from patient medical records.
Results
794 individuals were treated with VKAs and 206 with DOACs following PEA. Mean observation period was 612 (SD: 702) days. Significant improvements in haemodynamics and functional status were observed in both groups following PEA (p < 0.001). Major bleeding events were equivalent (p = 1) in those treated with VKAs (0.67%/person-year) and DOACs (0.68%/person-year). VTE recurrence was proportionately higher (p = 0.008) with DOACs (4.62%/person-year) than VKAs (0.76%/person-year), although survival did not differ.
Conclusions
Post-PEA functional and haemodynamic outcomes appear unaffected by anticoagulant choice. Bleeding events were similar, but recurrent VTE rates significantly higher in those receiving DOACs. Our study provides a strong rationale for prospective registry data and/or studies to evaluate the safety of DOACs in CTEPH.

© 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 25 Sep 2019; epub ahead of print
Bunclark K, Newnham M, Chiu YD, Ruggiero A, ... Pepke-Zaba J, Toshner M
J Thromb Haemost: 25 Sep 2019; epub ahead of print | PMID: 31557382
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Impact:
Abstract

Towards Precision Medicine With Human iPSCs for Cardiac Channelopathies.

Wu JC, Garg P, Yoshida Y, Yamanaka S, ... Knollmann BC, Schwartz PJ

Long-QT syndrome, a frequently fatal inherited arrhythmia syndrome caused by genetic variants (congenital) or drugs (acquired), affects 1 in 2000 people worldwide. Its sentinel event is often sudden cardiac death, which makes preclinical diagnosis by genetic testing potentially life-saving. Unfortunately, clinical experience with genetic testing has shown that it is difficult to correctly identify genetic variants as disease causing. These current deficiencies in accurately assigning pathogenicity led to the discovery of increasing numbers of rare variants classified as variant of uncertain significance. To overcome these challenges, new technologies such as clustered regularly interspaced short palindromic repeats (CRISPR) genome editing can be combined with human induced pluripotent stem cell-derived cardiomyocytes to provide a new approach to decipher pathogenicity of variants of uncertain significance and to better predict arrhythmia risk. To that end, the overarching goal of our network is to establish the utility of induced pluripotent stem cell-based platforms to solve major clinical problems associated with long-QT syndrome by determining how to (1) differentiate pathogenic mutations from background genetic noise, (2) assess existing and novel variants associated with congenital and acquired long-QT syndrome, and (3) provide genotype- and phenotype- guided risk stratification and pharmacological management of long-QT syndrome. To achieve these goals and to further advance the use of induced pluripotent stem cells in disease modeling and drug discovery, our team of investigators for this Leducq Foundation Transatlantic Networks of Excellence proposal will work together to (1) improve differentiation efficiency, cellular maturation, and lineage specificity, (2) develop new assays for high throughput cellular phenotyping, and (3) train young investigators to clinically implement patient-specific genetic modeling.



Circ Res: 29 Aug 2019; 125:653-658
Wu JC, Garg P, Yoshida Y, Yamanaka S, ... Knollmann BC, Schwartz PJ
Circ Res: 29 Aug 2019; 125:653-658 | PMID: 31465267
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Abstract

A novel secreted-cAMP pathway inhibits pulmonary hypertension via a feed-forward mechanism.

Jones C, Bisserier M, Bueno-Beti C, Bonnet G, ... Hajjar RJ, Sassi Y
Aims
Cyclic adenosine monophosphate (cAMP) is the predominant intracellular second messenger that transduces signals from Gs-coupled receptors. Intriguingly, there is evidence from various cell types that an extracellular cAMP pathway is active in the extracellular space. Herein, we investigated the role of extracellular cAMP in the lung and examined whether it may act on pulmonary vascular cell proliferation and pulmonary vasculature remodeling in the pathogenesis of pulmonary hypertension (PH).
Methods and results
The expression of cyclic AMP-metabolizing enzymes was increased in lungs from patients with PH as well as in rats treated with monocrotaline and mice exposed to Sugen/hypoxia. We report that inhibition of the endogenous extracellular cAMP pathway exacerbated Sugen/hypoxia-induced lung remodeling. We found that application of extracellular cAMP induced an increase in intracellular cAMP levels and inhibited proliferation and migration of pulmonary vascular cells in vitro. Extracellular cAMP infusion in two in vivo pulmonary hypertension models prevented and reversed pulmonary and cardiac remodeling associated with PH. Using protein expression analysis along with luciferase assays, we found that extracellular cAMP acts via the A2R/PKA/CREB/p53/Cyclin D1 pathway.
Conclusions
Taken together, our data reveal the presence of an extracellular cAMP pathway in pulmonary arteries that attempts to protect the lung during PH, and suggest targeting of the extracellular cAMP signaling pathway to limit pulmonary vascular remodeling and PH.
Translational perspective
Lungs samples from patients with clinical PAH and from animals with PH display increased cyclic AMP-metabolizing enzymes expression levels. Our results indicate that an endogenous extracellular cAMP pathway is activated during PH and attempts to counteract vascular remodeling. Additionally, our study demonstrates that extracellular-cAMP inhibits chronic hypoxia-induced PH in mice and MCT-induced PH in rats by activating the A2R/PKA/CREB/p53/Cyclin D1 pathway. Importantly, PAH patients display an inactive PKA/CREB/p53/Cyclin D1 pathway that could be stimulated by extracellular-cAMP. Targeting the extracellular cAMP pathway may represent a novel therapeutic approach for the treatment of pulmonary arterial hypertension.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions please email: [email protected]

Cardiovasc Res: 13 Sep 2019; epub ahead of print
Jones C, Bisserier M, Bueno-Beti C, Bonnet G, ... Hajjar RJ, Sassi Y
Cardiovasc Res: 13 Sep 2019; epub ahead of print | PMID: 31529026
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Impact:
Abstract

Characterization of -Mutated Rat, a Novel Model of Pulmonary Hypertension.

Lambert M, Capuano V, Boet A, Tesson L, ... Humbert M, Antigny F
Rationale
Pulmonary arterial hypertension is a severe lethal cardiopulmonary disease. Loss of function mutations in(potassium channel subfamily K member 3) gene, which encodes an outward rectifier K channel, have been identified in pulmonary arterial hypertension patients.
Objective
We have demonstrated that KCNK3 dysfunction is common to heritable and nonheritable pulmonary arterial hypertension and to experimental pulmonary hypertension (PH). Finally, KCNK3 is not functional in mouse pulmonary vasculature.
Methods and results
Using CRISPR/Cas9 technology, we generated a 94 bp out of frame deletion in exon 1 ofgene and characterized these rats at the electrophysiological, echocardiographic, hemodynamic, morphological, cellular, and molecular levels to decipher the cellular mechanisms associated with loss of KCNK3. Using patch-clamp technique, we validated our transgenic strategy by demonstrating the absence of KCNK3 current in freshly isolated pulmonary arterial smooth muscle cells from -mutated rats. At 4 months of age, echocardiographic parameters revealed shortening of the pulmonary artery acceleration time associated with elevation of the right ventricular systolic pressure. -mutated rats developed more severe PH than wild-type rats after monocrotaline exposure or chronic hypoxia exposure. -mutation induced a lung distal neomuscularization and perivascular extracellular matrix activation. Lungs of -mutated rats were characterized by overactivation of ERK1/2 (extracellular signal-regulated kinase1-/2), AKT (protein kinase B), SRC, and overexpression of HIF1-α (hypoxia-inducible factor-1 α), survivin, and VWF (Von Willebrand factor). Linked with plasma membrane depolarization, reduced endothelial-NOS expression and desensitization of endothelial-derived hyperpolarizing factor, -mutated rats presented predisposition to vasoconstriction of pulmonary arteries and a severe loss of sildenafil-induced pulmonary arteries relaxation. Moreover, we showed strong alteration of right ventricular cardiomyocyte excitability. Finally, -mutated rats developed age-dependent PH associated with low serum-albumin concentration.
Conclusions
We established the first -mutated rat model of PH. Our results confirm that KCNK3 loss of function is a key event in pulmonary arterial hypertension pathogenesis. This model presents new opportunities for understanding the initiating mechanisms of PH and testing biologically relevant therapeutic molecules in the context of PH.



Circ Res: 12 Sep 2019; 125:678-695
Lambert M, Capuano V, Boet A, Tesson L, ... Humbert M, Antigny F
Circ Res: 12 Sep 2019; 125:678-695 | PMID: 31347976
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Impact:
Abstract

Knock-in mice bearing constitutively active αIIb(R990W) mutation develop macrothrombocytopenia with severe platelet dysfunction.

Akuta K, Kiyomizu K, Kashiwagi H, Kunishima S, ... Miyata T, Tomiyama Y
Background
To date, several mutations that induce constitutive activation of integrin αIIbβ3 have been identified in congenital macrothrombocytopenia. Of these, αIIb(R995W) is the most prevalent mutation observed in Japanese patients with αIIbβ3-related congenital macrothrombocytopenia.
Objective and methods
The present study aimed to explore the effects of constitutive activation of the αIIb(R995W) mutation on platelet production, morphology, and function. We generated αIIb(R990W) knock-in (KI) mice corresponding to human αIIb(R995W).
Results
Platelet counts of heterozygous (Hetero) and homozygous (Homo) KI mice were decreased by ~10% and ~25% relative to those of wild-type (WT) mice, respectively, with increase in platelet size. Decrease in absolute reticulated platelet numbers in steady state, delayed recovery from thrombocytopenia induced by anti-platelet antibody and impaired response to exogenous thrombopoietin administration suggested impaired platelet production in KI mice. WT and KI mice showed no significant differences in the number of megakaryocytes and ploidy of megakaryocytes, whereas proplatelet formation was significantly impaired in Homo mice. We observed a slight but significant reduction in platelet lifespan in Homo mice. The Homo mice showed dramatic reduction in αIIbβ3 expression in platelets, which was accompanied by severe in vivo and in vitro platelet dysfunction.
Conclusion
The αIIb(R990W) KI mice developed macrothrombocytopenia, which was primarily attributed to impaired proplatelet formation. In addition, Homo KI mice showed marked downregulation in αIIbβ3 expression in platelets with severe impaired platelet function, similar to Glanzmann thrombasthenia.

© 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 05 Nov 2019; epub ahead of print
Akuta K, Kiyomizu K, Kashiwagi H, Kunishima S, ... Miyata T, Tomiyama Y
J Thromb Haemost: 05 Nov 2019; epub ahead of print | PMID: 31691484
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Abstract

Management of the adult Fontan patient.

Rodriguez FH, Book WM

Adults with congenital heart disease who underwent the Fontan operation to palliate single ventricle heart defects-by direct connection of caval venous return to the pulmonary circulation-have improved survival due to advancements in surgical and interventional techniques. However, cardiac and non-cardiac comorbidities often coexist, complicating management, and contributing to premature morbidity and mortality. Cardiac issues include heart failure symptoms related to systolic and diastolic dysfunction, atrial and ventricular arrhythmias and systemic atrioventricular valve regurgitation. Structural issues may be related to obstruction of the Fontan pathway, or to branch pulmonary artery stenosis, both of which exacerbate symptoms. Non-cardiac complications in adults involve hepatic congestion, fibrosis and cirrhosis, hepatocellular carcinoma, chronic kidney disease, stroke, venous stasis, lymphatic issues and involvement of other organ systems. \'Fontan failure\' refers to circulatory dysfunction, either cardiac, non-cardiac, or both, diagnosed after exclusion or treatment of reversible contributors such as structural issues and arrhythmias. Counselling about reproductive health, mental health, perioperative management and overall wellness are paramount for patients\' well-being. Fontan patients are typically managed in highly specialised adult congenital heart centres, but may present to cardiologists or other practitioners with cardiac and non-cardiac emergencies or urgencies, sometimes after being out of care. In this review, we discuss the management of the adult Fontan patient, including surveillance, cardiac and non-cardiac complications, reproductive health, and advanced therapies.

© Author(s) (or their employer(s)) 2019. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 28 Oct 2019; epub ahead of print
Rodriguez FH, Book WM
Heart: 28 Oct 2019; epub ahead of print | PMID: 31662332
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Abstract

A Glanzmann thrombasthenia family associated with a TUBB1-related macrothrombocytopenia.

Guillet B, Bayart S, Pillois X, Nurden P, Caen JP, Nurden AT
Background
Macrothrombocytopenia (MTP) is a rare but enigmatic complication of Glanzmann thrombasthenia (GT), an inherited bleeding disorder caused by the absence of platelet aggregation due to deficiencies of the αIIbβ3 integrin.
Objectives
We report a family with type I GT and a prolonged bleeding time but unusually associated with congenital mild thrombocytopenia and platelet size heterogeneity with giant forms.
Methods and results
Sanger sequencing of DNA from the propositus identified 2 heterozygous ITGB3 gene mutations: p.P189S and p.C210S both of which prevent αIIbβ3 expression and are causative of GT but without explaining the presence of enlarged platelets. High-throughput screening led to the detection of a predicted disease-causing heterozygous mutation in the TUBB1 gene: p.G146R, encoding β1-tubulin, a component of the platelet cytoskeleton and a gene where mutations are a known cause of MTP.
Conclusions
Family screening confirmed that this rare phenotype results from oligogenic inheritance while suggesting that the GT phenotype dominates clinically.

© 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 28 Sep 2019; epub ahead of print
Guillet B, Bayart S, Pillois X, Nurden P, Caen JP, Nurden AT
J Thromb Haemost: 28 Sep 2019; epub ahead of print | PMID: 31565851
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Abstract

Pharmacological activation of IKr in models of long QT Type 2 risks overcorrection of repolarization.

Perry MD, Ng CA, Mangala MM, Ng TYM, ... Hill AP, Vandenberg JI
Aims
Current treatment for congenital long QT syndrome Type 2 (cLQTS2), an electrical disorder that increases the risk of life-threatening cardiac arrhythmias, is aimed at reducing the incidence of arrhythmia triggers (beta-blockers) or terminating the arrhythmia after onset (implantable cardioverter-defibrillator). An alternative strategy is to target the underlying disease mechanism, which is reduced rapid delayed rectifier current (IKr) passed by Kv11.1 channels. Small molecule activators of Kv11.1 have been identified but the extent to which these can restore normal cardiac signalling in cLQTS2 backgrounds remains unclear. Here, we examined the ability of ICA-105574, an activator of Kv11.1 that impairs transition to the inactivated state, to restore function to heterozygous Kv11.1 channels containing either inactivation enhanced (T618S, N633S) or expression deficient (A422T) mutations.
Methods and results
ICA-105574 effectively restored Kv11.1 current from heterozygous inactivation enhanced or expression defective mutant channels in heterologous expression systems. In a human-induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model of cLQTS2 containing the expression defective Kv11.1 mutant A422T, cardiac repolarization, estimated from the duration of calcium transients in isolated cells and the rate corrected field potential duration (FPDc) in culture monolayers of cells, was significantly prolonged. The Kv11.1 activator ICA-105574 was able to reverse the prolonged repolarization in a concentration-dependent manner. However, at higher doses, ICA-105574 produced a shortening of the FPDc compared to controls. In vitro and in silico analysis suggests that this overcorrection occurs as a result of a temporal redistribution of the peak IKr to much earlier in the plateau phase of the action potential, which results in early repolarization.
Conclusion
Kv11.1 activators, which target the primary disease mechanism, provide a possible treatment option for cLQTS2, with the caveat that there may be a risk of overcorrection that could itself be pro-arrhythmic.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Cardiovasc Res: 12 Sep 2019; epub ahead of print
Perry MD, Ng CA, Mangala MM, Ng TYM, ... Hill AP, Vandenberg JI
Cardiovasc Res: 12 Sep 2019; epub ahead of print | PMID: 31628797
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Impact:
Abstract

Sex-specific differences in chronic thromboembolic pulmonary hypertension. Results from the European CTEPH registry.

Barco S, Klok FA, Konstantinides SV, Dartevelle P, ... Delcroix M, Lang IM
Background
Women are more susceptible than men to several forms of pulmonary hypertension, but have better survival. Sparse data are available on chronic thromboembolic pulmonary hypertension (CTEPH).
Methods
We investigated sex-specific differences in the clinical presentation of CTEPH, performance of pulmonary endarterectomy (PEA), and survival.
Results
Women constituted one-half of the study population of the European CTEPH registry (N = 679) and were characterized by a lower prevalence of some cardiovascular risk factors, including prior acute coronary syndrome, smoking habit, and chronic obstructive pulmonary disease, but more prevalent obesity, cancer, and thyroid diseases. The median age was 62 (interquartile ratio, 50-73) years in women and 63 (interquartile ratio, 53-70) in men. Women underwent PEA less often than men (54% vs 65%), especially at low-volume centers (48% vs 61%), and were exposed to fewer additional cardiac procedures, notably coronary artery bypass graft surgery (0.5% vs 9.5%). The prevalence of specific reasons for not being operated, including patient\'s refusal and the proportion of proximal vs distal lesions, did not differ between sexes. A total of 57 (17.0%) deaths in women and 70 (20.7%) in men were recorded over long-term follow-up. Female sex was positively associated with long-term survival (adjusted hazard ratio, 0.66; 95% confidence interval, 0.46-0.94). Short-term mortality was identical in the two groups.
Conclusions
Women with CTEPH underwent PEA less frequently than men, especially at low-volume centers. Furthermore, they had a lower prevalence of cardiovascular risk factors and were less often exposed to additional cardiac surgery procedures. Women had better long-term survival.

© 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 02 Sep 2019; epub ahead of print
Barco S, Klok FA, Konstantinides SV, Dartevelle P, ... Delcroix M, Lang IM
J Thromb Haemost: 02 Sep 2019; epub ahead of print | PMID: 31479557
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Impact:
Abstract

Safety analysis of rFVIIa with emicizumab dosing in congenital hemophilia A with inhibitors: Experience from the HAVEN clinical program.

Levy GG, Asikanius E, Kuebler P, Benchikh El Fegoun S, Esbjerg S, Seremetis S
Background
Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program.
Objective
Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab.
Methods
The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed.
Results
The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 ± 20 μg/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials.
Conclusion
rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information.

© 2019 F. Hoffman La-Roche AG. Journal of Thrombosis and Haemostasis published by Wiley Periodicals Inc. on behalf of International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 30 Aug 2019; 17:1470-1477
Levy GG, Asikanius E, Kuebler P, Benchikh El Fegoun S, Esbjerg S, Seremetis S
J Thromb Haemost: 30 Aug 2019; 17:1470-1477 | PMID: 31124272
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Impact:
Abstract

Ultra-High-Density Mapping Supplemented with Global Chamber Activation Identifies Non-cavo-tricuspid Dependent Intra-atrial Reentry Conduction Isthmuses in Adult Congenital Heart Disease.

Moore JP, Buch E, Gallotti RG, Shannon KM
Objective
To evaluate the role of ultra-high definition mapping for conduction isthmus (CI) characterization in adult congenital heart disease (ACHD).
Background
Catheter ablation remains suboptimal for ACHD with atypical intra-atrial reentrant tachycardias (IART) that can be challenging to define using existing mapping technology.
Methods
An ultra-high-density mapping system was selectively employed over a 1-year period for procedures involving non-cavo-tricuspid isthmus (CTI) dependent-IART. A global activation histogram (GAH) was assessed for ability to predict ablation targets. Procedural characteristics were compared to a group of matched controls.
Results
Twenty patients (mean age 43 ± 15, 70% male) underwent 20 procedures targeting 34 tachycardias during the study period. Diagnoses included single ventricle (8), tetralogy of Fallot (2), left heart obstruction (3), Ebstein\'s anomaly (2) atrial septal defect (2), Mustard operation (2), and Rastelli (1). Prior catheter ablation/Maze operation had been performed in 12 (60%). The median time per map was 21 minutes (interquartile range [IQR] 16 - 32), representing 14,834 points per map [IQR 9,499 - 43,191] (p<0.001 vs. controls). Review of GAH maps showed lower trough values were associated with more favorable IART CI characteristics (p≤0.001 for all). Acute success was achieved in 19/20 (95%) procedures, with tachycardia termination during the first lesion in 8 cases (p=0.02 vs. controls). There was one recurrence during 0.6 years follow-up.
Conclusions
Ultra-high-density mapping supplemented with the GAH tool was effective for CI identification in a cohort of complex ACHD patients. Catheter ablation was more efficient compared to controls, suggesting precise CI characterization using this technology. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 22 Oct 2019; epub ahead of print
Moore JP, Buch E, Gallotti RG, Shannon KM
J Cardiovasc Electrophysiol: 22 Oct 2019; epub ahead of print | PMID: 31646694
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Impact:
Abstract

Elevated thrombin generation in patients with congenital disorder of glycosylation and combined coagulation factor deficiencies.

Pascreau T, de la Morena-Barrio ME, Lasne D, Serrano M, ... Corral J, Borgel D
Background
Congenital disorders of glycosylation are rare inherited diseases affecting many different proteins. The lack of glycosylation notably affects the hemostatic system and leads to deficiencies of both procoagulant and anticoagulant factors.
Objective
To assess the hemostatic balance in patients with multiple coagulation disorders by using a thrombin generation assay.
Method
We performed conventional coagulation assays and a thrombin generation assay on samples from patients with congenital disorder of glycosylation. The thrombin generation assay was performed before and after activation of the protein C system by the addition of soluble thrombomodulin.
Results
A total of 35 patients were included: 71% and 57% had low antithrombin and factor XI levels, respectively. Protein C and protein S levels were abnormally low in 29% and 26% of the patients, respectively, whereas only 11% displayed low factor IX levels. Under baseline conditions, the thrombin generation assay revealed a significantly higher endogenous thrombin potential and thrombin peak in patients, relative to controls. After spiking with thrombomodulin, we observed impaired involvement of the protein C system. Hence, 54% of patients displayed a hypercoagulant phenotype in vitro. All the patients with a history of stroke-like episodes or thrombosis displayed this hypercoagulant phenotype.
Conclusion
A thrombin generation assay revealed a hypercoagulant in vitro phenotype under baseline condition; this was accentuated by impaired involvement of the protein C system. This procoagulant phenotype may thus reflect the risk of severe vascular complications. Further research will have to determine whether the thrombin generation assay is predictive of vascular events.

© 2019 French National Institute of Health and Medical Research. © 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 30 Oct 2019; 17:1798-1807
Pascreau T, de la Morena-Barrio ME, Lasne D, Serrano M, ... Corral J, Borgel D
J Thromb Haemost: 30 Oct 2019; 17:1798-1807 | PMID: 31271700
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Impact:
Abstract

Interstitial Macrophage-Derived Thrombospondin-1 Contributes to Hypoxia-Induced Pulmonary Hypertension.

Kumar R, Mickael C, Kassa B, Sanders L, ... Tuder RM, Graham BB
Aims
TGF-β signaling is required for chronic hypoxia-induced pulmonary hypertension (PH). The activation of TGF-β by thrombospondin-1 (TSP-1) contributes to the pathogenesis of hypoxia-induced PH. However, neither the cellular source of pathologic TSP-1 nor the downstream signaling pathway that link activated TGF-β to PH have been determined. In this study, we hypothesized that circulating monocytes, which are recruited to become interstitial macrophages, are the major source of TSP-1 in hypoxia-exposed mice, and TSP-1 activates TGF-β with increased Rho kinase signaling, causing vasoconstriction.
Methods and results
Flow cytometry revealed that a specific subset of interstitial macrophages is the major source of pathologic TSP-1 in hypoxia. Intravenous depletion and parabiosis experiments demonstrated that these cells are circulating prior to recruitment into the interstitium. Rho kinase mediated vasoconstriction was a major downstream target of active TGF-β. Thbs1 deficient bone marrow protected against hypoxic-PH by blocking TGF-β activation and Rho kinase-mediated vasoconstriction.
Conclusions
In hypoxia-challenged mice, bone marrow derived and circulating monocytes are recruited to become interstitial macrophages which express TSP-1, resulting in TGF-β activation and Rho kinase-mediated vasoconstriction.
Translational perspectives
Inflammation contributes to the pathogenesis of many forms of pulmonary hypertension, but blocking inflammation has not been a successful therapeutic strategy to date. Here we found that mice with experimental hypoxia-induced pulmonary hypertension have recruitment of circulating, classical monocytes into the lungs, and that these cells express the protein thrombospondin-1 that causes activation of TGF-β and results in Rho-kinase mediated vasoconstriction. These data suggest that more precise targeting of inflammation, such as blocking specific cells like monocytes or cytokines like TGF-β, would be a more effective future therapeutic approach for pulmonary hypertension etiologies where these pathways underlie disease pathogenesis.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions please email: [email protected]

Cardiovasc Res: 08 Nov 2019; epub ahead of print
Kumar R, Mickael C, Kassa B, Sanders L, ... Tuder RM, Graham BB
Cardiovasc Res: 08 Nov 2019; epub ahead of print | PMID: 31710666
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Impact:
Abstract

Hybrid transcatheter pulmonary valve replacement with a SAPIEN S3 valve after pulmonary artery banding via left lateral thoracotomy.

Serfas JD, Turek J, Haney J, Krasuski RA, Fleming GA

For many patients with repaired congenital heart disease, the need for reintervention on dysfunctional right ventricular outflow tracts is pervasive. Many such patients are poor candidates for both transcatheter pulmonary valve replacement and cardiopulmonary bypass, and hybrid surgical and transcatheter procedures have evolved to meet this need. We present two cases of hybrid pulmonary valve replacement involving pulmonary artery band placement via left anterior thoracotomy followed by transvenous placement of a SAPIEN S3 valve without prestenting. This approach avoids cardiopulmonary bypass as well as redo sternotomy and will likely see an increase in utilization in the future.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 06 Nov 2019; epub ahead of print
Serfas JD, Turek J, Haney J, Krasuski RA, Fleming GA
Catheter Cardiovasc Interv: 06 Nov 2019; epub ahead of print | PMID: 31696653
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Impact:
Abstract

Pulmonary Vascular Distensibility and Early Pulmonary Vascular Remodeling in Pulmonary Hypertension.

Singh I, Oliveira RKF, Naeije R, Rahaghi FN, ... Systrom DM, Waxman AB
Background
Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects.
Methods
A PV distensibility coefficient α (%/mm Hg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption.
Results
The α coefficient decreased from 1.35 ± 0.58%/mm Hg in control subjects and 1.1 ± 0.48%/mm Hg in patients with passive HFpEF to 0.62 ± 0.32%/mm Hg in exercise PH, 0.54 ± 0.27%/mm Hg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed.
Conclusions
PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity.

Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chest: 29 Sep 2019; 156:724-732
Singh I, Oliveira RKF, Naeije R, Rahaghi FN, ... Systrom DM, Waxman AB
Chest: 29 Sep 2019; 156:724-732 | PMID: 31121149
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Impact:
Abstract

Whole-genome sequencing of triple-negative breast cancers in a population-based clinical study.

Staaf J, Glodzik D, Bosch A, Vallon-Christersson J, ... Borg Å, Nik-Zainal S

Whole-genome sequencing (WGS) brings comprehensive insights to cancer genome interpretation. To explore the clinical value of WGS, we sequenced 254 triple-negative breast cancers (TNBCs) for which associated treatment and outcome data were collected between 2010 and 2015 via the population-based Sweden Cancerome Analysis Network-Breast (SCAN-B) project (ClinicalTrials.gov ID:NCT02306096). Applying the HRDetect mutational-signature-based algorithm to classify tumors, 59% were predicted to have homologous-recombination-repair deficiency (HRDetect-high): 67% explained by germline/somatic mutations of BRCA1/BRCA2, BRCA1 promoter hypermethylation, RAD51C hypermethylation or biallelic loss of PALB2. A novel mechanism of BRCA1 abrogation was discovered via germline SINE-VNTR-Alu retrotransposition. HRDetect provided independent prognostic information, with HRDetect-high patients having better outcome on adjuvant chemotherapy for invasive disease-free survival (hazard ratio (HR) = 0.42; 95% confidence interval (CI) = 0.2-0.87) and distant relapse-free interval (HR = 0.31, CI = 0.13-0.76) compared to HRDetect-low, regardless of whether a genetic/epigenetic cause was identified. HRDetect-intermediate, some possessing potentially targetable biological abnormalities, had the poorest outcomes. HRDetect-low cancers also had inadequate outcomes: ~4.7% were mismatch-repair-deficient (another targetable defect, not typically sought) and they were enriched for (but not restricted to) PIK3CA/AKT1 pathway abnormalities. New treatment options need to be considered for now-discernible HRDetect-intermediate and HRDetect-low categories. This population-based study advocates for WGS of TNBC to better inform trial stratification and improve clinical decision-making.



Nat Med: 29 Sep 2019; epub ahead of print
Staaf J, Glodzik D, Bosch A, Vallon-Christersson J, ... Borg Å, Nik-Zainal S
Nat Med: 29 Sep 2019; epub ahead of print | PMID: 31570822
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Impact:
Abstract

A 12-Year-Old Girl With Dyspnea and Unilateral Interlobular Septal Thickening.

Chen Y, Xiao Y, Zhang Y, Zhu G, Dou R, Gu H
Case presentation
A 12-year-old girl was admitted to the hospital for exercise intolerance and radiographic abnormalities. She presented with a 5-year history of shortness of breath during intense exercise and did not undergo any medical evaluation. She felt that her symptoms had progressed with fever and right chest pain 2 months prior to admission. She was diagnosed with pneumonia by her chest CT scan, which revealed a small right hemithorax, interlobular septal thickening, and ground-glass opacity of the right lung (Fig 1A), and was treated with antibiotics. She soon became afebrile, but still felt shortness of breath during intense exercise. Then, a contrast-enhanced CT scan of the chest (not shown) showed the right lung still had interlobular septal thickening, and the right pulmonary artery was smaller than the left. There were no systemic symptoms, including skin rash and arthralgia. Family history showed her grandparents were cousins and her father had congenital dysarthria.

Copyright © 2019. Published by Elsevier Inc.

Chest: 30 Aug 2019; 156:e57-e61
Chen Y, Xiao Y, Zhang Y, Zhu G, Dou R, Gu H
Chest: 30 Aug 2019; 156:e57-e61 | PMID: 31511161
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Impact:
Abstract

Metabolic Remodeling in the Pressure-Loaded Right Ventricle: Shifts in Glucose and Fatty Acid Metabolism-A Systematic Review and Meta-Analysis.

Koop AC, Bossers GPL, Ploegstra MJ, Hagdorn QAJ, ... Silljé HHW, Bartelds B

Background Right ventricular (RV) failure because of chronic pressure load is an important determinant of outcome in pulmonary hypertension. Progression towards RV failure is characterized by diastolic dysfunction, fibrosis and metabolic dysregulation. Metabolic modulation has been suggested as therapeutic option, yet, metabolic dysregulation may have various faces in different experimental models and disease severity. In this systematic review and meta-analysis, we aimed to identify metabolic changes in the pressure loaded RV and formulate recommendations required to optimize translation between animal models and human disease. Methods and Results Medline and EMBASE were searched to identify original studies describing cardiac metabolic variables in the pressure loaded RV. We identified mostly rat-models, inducing pressure load by hypoxia, Sugen-hypoxia, monocrotaline (MCT), pulmonary artery banding (PAB) or strain (fawn hooded rats, FHR), and human studies. Meta-analysis revealed increased Hedges\' g (effect size) of the gene expression of GLUT1 and HK1 and glycolytic flux. The expression of MCAD was uniformly decreased. Mitochondrial respiratory capacity and fatty acid uptake varied considerably between studies, yet there was a model effect in carbohydrate respiratory capacity in MCT-rats. Conclusions This systematic review and meta-analysis on metabolic remodeling in the pressure-loaded RV showed a consistent increase in glucose uptake and glycolysis, strongly suggest a downregulation of beta-oxidation, and showed divergent and model-specific changes regarding fatty acid uptake and oxidative metabolism. To translate metabolic results from animal models to human disease, more extensive characterization, including function, and uniformity in methodology and studied variables, will be required.



J Am Heart Assoc: 04 Nov 2019; 8:e012086
Koop AC, Bossers GPL, Ploegstra MJ, Hagdorn QAJ, ... Silljé HHW, Bartelds B
J Am Heart Assoc: 04 Nov 2019; 8:e012086 | PMID: 31657265
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Impact:
Abstract

Predictors of Late Mortality in D-Transposition of the Great Arteries After Atrial Switch Repair: Systematic Review and Meta-Analysis.

Venkatesh P, Evans AT, Maw AM, Pashun RA, ... Bacha E, Singh HS

Background Existing data on predictors of late mortality and prevention of sudden cardiac death after atrial switch repair surgery for D-transposition of the great arteries (D-TGA) are heterogeneous and limited by statistical power. Methods and Results We conducted a systematic review and meta-analysis of 29 observational studies, comprising 5035 patients, that reported mortality after atrial switch repair with a minimum follow-up of 10 years. We also examined 4 additional studies comprising 105 patients who reported rates of implantable cardioverter-defibrillator therapy in this population. Average survival dropped to 65% at 40 years after atrial switch repair, with sudden cardiac death accounting for 45% of all reported deaths. Mortality was significantly lower in cohorts that were more recent and operated on younger patients. Patient-level risk factors for late mortality were history of supraventricular tachycardia (odds ratio [OR] 3.8, 95% CI 1.4-10.7), Mustard procedure compared with Senning (OR 2.9, 95% CI 1.9-4.5) and complex D-TGA compared with simple D-TGA (OR 4.4, 95% CI 2.2-8.8). Significant risk factors for sudden cardiac death were history of supraventricular tachycardia (OR 4.7, 95% CI 2.2-9.8), Mustard procedure (OR 2.2, 95% CI 1.1-4.1), and complex D-TGA (OR 5.7, 95% CI 1.8-18.0). Out of a total 124 implantable cardioverter-defibrillator discharges over 330 patient-years in patients with implantable cardioverter-defibrillators for primary prevention, only 8% were appropriate. Conclusions Patient-level risk of both mortality and sudden cardiac death after atrial switch repair are significantly increased by history of supraventricular tachycardia, Mustard procedure, and complex D-TGA. This knowledge may help refine current selection practices for primary prevention implantable cardioverter-defibrillator implantation, given disproportionately high rates of inappropriate discharges.



J Am Heart Assoc: 04 Nov 2019; 8:e012932
Venkatesh P, Evans AT, Maw AM, Pashun RA, ... Bacha E, Singh HS
J Am Heart Assoc: 04 Nov 2019; 8:e012932 | PMID: 31642369
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Impact:
Abstract

Successful engraftment of gene-corrected hematopoietic stem cells in non-conditioned patients with Fanconi anemia.

Río P, Navarro S, Wang W, Sánchez-Domínguez R, ... Sevilla J, Bueren JA

Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date. Mutations in FANCA account for more than 60% of FA cases worldwide. Clinically, FA is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.



Nat Med: 30 Aug 2019; 25:1396-1401
Río P, Navarro S, Wang W, Sánchez-Domínguez R, ... Sevilla J, Bueren JA
Nat Med: 30 Aug 2019; 25:1396-1401 | PMID: 31501599
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Impact:
Abstract

Early and Late Effects of Cardiac Resynchronization Therapy in Adult Congenital Heart Disease.

Yin Y, Dimopoulos K, Shimada E, Lascelles K, ... Babu-Narayan SV, Li W

Background There are limited data about cardiac resynchronization therapy (CRT) in adult congenital heart disease. We aimed to assess early and late outcomes of CRT among patients with adult congenital heart disease. Methods and Results We retrospectively studied 54 patients with adult congenital heart disease (median age, 46 years; range, 18-73 years; 74% men) who received CRT implantation (biventricular paced >90%) between 2004 and 2017. Clinical and echocardiographic data were analyzed at baseline and early (mean±SD: 1.8±0.8 years) and late (4.7±0.8 years) follow-up after CRT. Compared with baseline, CRT was associated with significant improvement at early follow-up in New York Heart Association functional class, QRS duration, and cardiothoracic ratio (<0.05 for all); improvement in New York Heart Association class was sustained at late follow-up. Among patients with a systemic left ventricle (LV; n=39), there was significant increase in LV ejection fraction and reduction in LV end-systolic volume at early and late follow-up (<0.05 for both). For patients with a systemic right ventricle (n=15), there was a significant early but not late reduction in systemic right ventricular basal and longitudinal diameters. Eleven patients died, and 2 had heart transplantation unrelated to systemic ventricular morphological characteristics. Thirty-five patients (65%) responded positively to CRT, but only baseline QRS duration was predictive of a positive response. Conclusions CRT results in sustained improvement in functional class, systemic LV size, and function. Patients with a systemic LV and prolonged QRS duration, independent of QRS morphological characteristics, were most likely to respond to CRT.



J Am Heart Assoc: 04 Nov 2019; 8:e012744
Yin Y, Dimopoulos K, Shimada E, Lascelles K, ... Babu-Narayan SV, Li W
J Am Heart Assoc: 04 Nov 2019; 8:e012744 | PMID: 31657270
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Abstract

Neonatal Risk in Children of Women With Congenital Heart Disease: A Cohort Study With Focus on Socioeconomic Status.

Kloster S, Tolstrup JS, Olsen MS, Johnsen SP, ... Nielsen DG, Ersbøll AK

Background We hypothesized that women with congenital heart disease (CHD) are at increased risk of giving birth preterm, including very and moderately preterm and giving birth to infants small for gestational age (SGA). We aimed to investigate this in a nation-wide study with focus on the potential modifying effect of socioeconomic status. Methods and Results We performed a cohort study using Danish nation-wide registers between 1997 and 2014. The exposure, maternal CHD, was subdivided into simple, moderate and complex based on severity of defects. Outcomes were preterm birth and SGA. Cox regression was used to estimate hazard ratios (HR). A total of 933 149 births including 3745 births among women with CHD were studied. The risk of giving birth preterm and SGA were higher among women with CHD as compared with women without CHD; for example, adjusted hazard ratios of preterm birth according to severity: simple 1.33 (95% CI, 1.11-1.59), moderate 1.45 (95% CI, 1.14-1.83) and complex 3.26 (95% CI, 2.41-4.40). Same pattern was seen for very and moderately preterm births and SGA. Education was a strong predictor of both preterm birth and SGA but did not modify the association between maternal congenital heart disease and preterm birth (=0.38) or SGA (=0.99). Conclusions Women with CHD were at increased risk of preterm birth both, moderately and very preterm, as well as giving birth to infants SGA. Education was a strong predictor of both preterm birth and SGA but the association between CHD and risk of preterm birth and SGA was independent of educational level.



J Am Heart Assoc: 04 Nov 2019; 8:e013491
Kloster S, Tolstrup JS, Olsen MS, Johnsen SP, ... Nielsen DG, Ersbøll AK
J Am Heart Assoc: 04 Nov 2019; 8:e013491 | PMID: 31656122
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Abstract

A reference genome for pea provides insight into legume genome evolution.

Kreplak J, Madoui MA, Cápal P, Novák P, ... Wincker P, Burstin J

We report the first annotated chromosome-level reference genome assembly for pea, Gregor Mendel\'s original genetic model. Phylogenetics and paleogenomics show genomic rearrangements across legumes and suggest a major role for repetitive elements in pea genome evolution. Compared to other sequenced Leguminosae genomes, the pea genome shows intense gene dynamics, most likely associated with genome size expansion when the Fabeae diverged from its sister tribes. During Pisum evolution, translocation and transposition differentially occurred across lineages. This reference sequence will accelerate our understanding of the molecular basis of agronomically important traits and support crop improvement.



Nat Genet: 30 Aug 2019; 51:1411-1422
Kreplak J, Madoui MA, Cápal P, Novák P, ... Wincker P, Burstin J
Nat Genet: 30 Aug 2019; 51:1411-1422 | PMID: 31477930
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Abstract

An 82-Year-Old Man With Sleep-Onset Insomnia, Breathing Arrest, and Heart Failure.

de la Motte T, Schwab M, Schultze T, Witte OW, Rupprecht S
Case presentation
An 82-year-old man presented with 6 months of difficulties of falling asleep. He described a feeling of fading breath culminating in breathing arrest when he becomes drowsy. These recurrent events prevented him from falling asleep. Symptoms would only appear when he went to sleep but not during wakefulness. Medical history comprised several episodes of acute decompensated heart failure due to supraventricular tachyarrhythmia with need for hospitalization during the last 2 years. He additionally had two-vessel coronary artery disease with myocardial infarction, pulmonary hypertension, chronic atrial fibrillation, peripheral arterial disease, and chronic kidney disease (stage 3). Medication included diuretics, sodium bicarbonate, angiotensin II receptor antagonist, beta-blocker, statin, clopidogrel, and phenprocoumon without sedatives or analgesics.

Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chest: 30 Oct 2019; 156:e95-e98
de la Motte T, Schwab M, Schultze T, Witte OW, Rupprecht S
Chest: 30 Oct 2019; 156:e95-e98 | PMID: 31699235
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Abstract

Arrhythmia Mechanisms and Outcomes of Ablation in Pediatric Patients With Congenital Heart Disease.

Houck CA, Chandler SF, Bogers AJJC, Triedman JK, ... de Groot NMS, Abrams DJ
Background
In contrast to the adult population with congenital heart disease (CHD), arrhythmia mechanisms and outcomes of ablation in pediatric patients with CHD in recent era have not been studied in detail. Aims of this study were to determine arrhythmia mechanisms and to evaluate procedural and long-term outcomes in pediatric patients with CHD undergoing catheter ablation.
Methods
Consecutive patients <18 years of age with CHD undergoing catheter ablation over an 11-year period (2007-2018) were included. Procedural outcome included complete or partial success, failure or empirical ablation. Long-term outcome included arrhythmia recurrence and burden according to a 12-point clinical arrhythmia severity score.
Results
The study population consisted of 232 patients (11.7 years [0.01-17.8], 33.5 kg [2.2-130.1]). The most common diagnoses were Ebstein\'s anomaly (n=44), septal defects (n=39), and single ventricle (n=36). Arrhythmia mechanisms included atrioventricular reentry tachycardia (n=104, 90 patients), atrioventricular nodal reentry tachycardia (n=33, 29 patients), twin atrioventricular nodal tachycardia (n=3, 2 patients), macroreentrant atrial tachycardia (n=59, 56 patients), focal atrial tachycardia (n=33, 25 patients), ventricular ectopy (n=10, 8 patients), and ventricular tachycardia (n=15, 13 patients). Fifty-six arrhythmias (39 patients) were undefined. Outcomes included complete success (n=189, 81%), partial success (n=7, 3%), failure (n=16, 7%), or empirical ablation (n=20, 9%). Over 3.6 years (0.3-10.7) arrhythmia recurred in 49%. Independent of arrhythmia recurrence, arrhythmia scores decreased from 4 (0-10) at baseline to 0.5 (0-8) at 4 years follow-up (<0.001). In 23/51 repeat procedures (45%), a different arrhythmia substrate was found. Overall adverse event rate was 9.4%, although only 1.6% (n=4) were of major severity and 0.8% (n=2) of moderate severity.
Conclusions
Pediatric patients with CHD demonstrate a broad spectrum of arrhythmia mechanisms. Despite recurrence and emergence of novel mechanisms after a successful procedure, ablation can be performed safely and successfully resulting in decreased arrhythmia burden.



Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007663
Houck CA, Chandler SF, Bogers AJJC, Triedman JK, ... de Groot NMS, Abrams DJ
Circ Arrhythm Electrophysiol: 30 Oct 2019; 12:e007663 | PMID: 31722541
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Abstract

Ventricular Arrhythmia Risk Prediction in Repaired Tetralogy of Fallot using Personalized Computational Cardiac Models.

Shade JK, Cartoski MJ, Nikolov P, Prakosa A, ... Spevak PJ, Trayanova NA
Background
Adults with repaired Tetralogy of Fallot (rTOF) are at increased risk of ventricular tachycardia (VT) due to fibrotic remodeling of the myocardium. However, the current clinical guidelines for VT risk stratification and subsequent ICD deployment for primary prevention of sudden cardiac death in rTOF remain inadequate.
Objective
To determine the feasibility of using a rTOF-specific virtual-heart approach to identify patients stratified incorrectly as being at low VT risk by current clinical criteria.
Methods
This multi-center retrospective pilot study included seven adult rTOF patients who were considered low-risk for VT based on clinical criteria. Patient-specific computational heart models were generated from the LGE-MRI, incorporating the individual distribution of rTOF fibrotic remodeling in both ventricles. Simulations of rapid pacing determined VT inducibility. Model creation and simulations were performed by operators blinded to clinical outcome.
Results
Two patients in the study experienced clinical VT. The virtual hearts constructed from LGE-MRI scans of seven rTOF patients predicted correctly reentrant VT in the models from VT-positive patients and no arrhythmia in those from VT-negative patients. There were no statistically significant differences in clinical criteria commonly used to assess VT risk, including QRS duration and age, between patients who did and did not experience clinical VT.
Conclusions
This study demonstrates the feasibility of image-based virtual-heart modeling in patients with congenital heart disease and structurally abnormal hearts. It highlights the potential of the methodology to improve VT risk stratification in patients with rTOF.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 03 Oct 2019; epub ahead of print
Shade JK, Cartoski MJ, Nikolov P, Prakosa A, ... Spevak PJ, Trayanova NA
Heart Rhythm: 03 Oct 2019; epub ahead of print | PMID: 31589989
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Abstract

Contemporary epidemiology of infective endocarditis in patients with congenital heart disease: A UK prospective study.

Cahill TJ, Jewell PD, Denne L, Franklin RC, ... Orchard E, Prendergast BD
Objectives
Infective endocarditis is a life-threatening complication of congenital heart disease (CHD), but there are few studies concerning the contemporary risk profile, preceding invasive procedures and outcomes in this patient population. The aim of this study was to investigate the epidemiology of infective endocarditis (IE) in patients with CHD.
Methods
Cases of IE in children and adults with CHD were prospectively recorded as part of the UK National Institute for Cardiovascular Outcomes Research (NICOR) National Congenital Heart Disease Audit. Patients were entered into the database between April 2008 and March 2016.
Results
Eight hundred episodes of IE were recorded in 736 patients with CHD. Sixty-five patients (9%) were infants (aged <1 year), 235 (32%) were children (aged 1-15 years), and 436 (59%) were adults (aged >15 years). The most common diagnoses were Tetralogy of Fallot (n = 150, 22.8%), ventricular septal defect (n = 129, 19.6%) and bicuspid aortic valve (n = 70, 10.7%). Dental procedures preceded 67 of 635 episodes (11%) of IE, and non-dental invasive procedures preceded 177 of 644 episodes (27.4%). The most common causative organisms were streptococci, accounting for 40% of cases. Overall in-hospital mortality was 6.7%. On multivariable analysis, adverse factors associated with in-hospital mortality were staphylococcal infection and presence of an underlying atrioventricular septal defect.
Conclusions
Infective endocarditis in patients with CHD is an ongoing clinical challenge. In contemporary practice in tertiary congenital centers, 1 of 15 patients do not survive to hospital discharge. Streptococci remain the most common causative organism, and antecedent dental or medical procedures were undertaken in a significant minority in the 3 months before diagnosis. The presence of an atrioventricular septal defect or staphylococcal infection is associated with significantly increased risk of early mortality.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am Heart J: 30 Aug 2019; 215:70-77
Cahill TJ, Jewell PD, Denne L, Franklin RC, ... Orchard E, Prendergast BD
Am Heart J: 30 Aug 2019; 215:70-77 | PMID: 31299559
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Abstract

Right ventricular systolic to diastolic duration ratio: A novel predictor of outcome in adult idiopathic pulmonary arterial hypertension.

McCabe C, Vranesic II, Verdes MC, Kempny A, ... Wort SJ, Li W
Background
The systolic to diastolic (SD) duration ratio reflects global RV performance in pulmonary arterial hypertension (PAH) yet limited data exists on its application to adult non-congenital PAH. We measured SD ratios on echocardiogram in idiopathic PAH (IPAH) to establish its response to pulmonary vasodilator therapy and prognostic value at diagnosis and follow up.
Methods
Incident patients with IPAH undergoing echocardiogram, haemodynamic and exercise assessments were identified within our centre between 2005 and 2018. SD ratios were adjusted for heart rate at diagnosis and follow up.
Results
In 98 patients at diagnosis, the mean SD ratio was 1.03 ± 0.37 decreasing to 0.85 ± 0.25, p < 0.001 at follow-up echocardiogram performed at a median interval of 9.0 months. The SD ratio at diagnosis correlated weakly with RV basal diameter (r = 0.24, p = 0.04) and 6MWD (r = 0.23, p = 0.04). At follow up, the mean SD ratio was lower in those receiving combination vs monotherapy pulmonary vasodilator treatment (71 ± 25 vs 92 ± 22% baseline respectively, p < 0.001). After a median follow-up of 4.8 years, 3 patients were transplanted and 23 patients died. The SD ratio at diagnosis and follow up predicted an increased risk of death/transplantation (HR 2.41 (1.09-5.29), p = 0.03; HR 5.02 (1.27-19.77), p = 0.02 respectively), retaining its predictive value at diagnosis in bivariate models with 6MWD (HR 2.18 (1.06-4.08)), WHO Functional Class (HR 2.33 (1.04-5.21)) and TAPSE (HR 2.36 (1.07-5.19)), all p < 0.05.
Conclusions
The SD ratio carries prognostic value at diagnosis and follow up in IPAH. Its further evaluation alongside current PAH risk stratification parameters should be considered.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Oct 2019; 293:218-222
McCabe C, Vranesic II, Verdes MC, Kempny A, ... Wort SJ, Li W
Int J Cardiol: 14 Oct 2019; 293:218-222 | PMID: 31126734
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Abstract

Prevalence and Anatomic Characteristics of Single Coronary Artery Diagnosed by Computed Tomography Angiography.

Michalowska AM, Tyczynski P, Pregowski J, Skowronski J, ... Witkowski A, Michalowska I

Single coronary artery (SCA) is a rare congenital anomaly. We assessed the prevalence and anatomic characteristics of SCA diagnosed with coronary computed tomography angiography and compared the dimensions of the proximal SCA trunk with a reference group of 199 subjects with normal coronary arteries. We screened 30,230 patients who underwent coronary computed tomography angiography from 2008 to 2018 to identify 17 with SCA (age 55 ± 19.0 years, 8 men [47%]). The prevalence of SCA was 0.056%. SCA originated from the right sinus of Valsalva in 11 patients (65%) and from the left sinus of Valsalva in 6 subjects. According to Lipton\'s classification, the 17 SCAs were L1 (n = 5, 29%), L2-A (n = 1, 6%), R2-A (n = 2, 12%), R2-B (n = 6, 35%), R2-P (n = 2, 12%), and R3 (n = 1, 6%). (Lipton\'s classification consists of 3 groups and the division is based on the site of origin of SCA [\"R\" - right, \"L\" - left sinus of Valsalva] and its anatomical course relating to the ascending aorta and pulmonary trunk [\"A\" - anterior to the pulmonary trunk, \"B\" - between the aorta and pulmonary trunk, \"P\" - posterior to the aorta].) As compared with the reference group, SCA patients had shorter proximal trunks (5.0 ± 3.6 mm vs 8.6 ± 4.8 mm, p = 0.0012). The lumen area (LA) and lumen diameter of the proximal trunk in patients with SCA were larger than the LA and lumen diameter of the left main coronary artery from the reference group (49.5 ± 18.0 mm2 vs 21.3 ± 6.5 mm2, p <0.0001, and 7.8 ± 1.6 mm vs 5.1 ± 0.75 mm, p <0.0001, respectively). Moreover, the LA of the proximal SCA trunk was larger than the sum of respective measurement performed in left main coronary artery and proximal right coronary artery segments in the control group (49.5 ± 18.0 mm2 vs 34.0 ± 7.9mm2, p = 0.0001). In conclusion, the incidence of SCA is very low; but this condition is associated with significant enlargement of the proximal vessel segment.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Sep 2019; 124:939-946
Michalowska AM, Tyczynski P, Pregowski J, Skowronski J, ... Witkowski A, Michalowska I
Am J Cardiol: 14 Sep 2019; 124:939-946 | PMID: 31350001
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Abstract

Factors Associated With Increased Exercise in Adults With Congenital Heart Disease.

Connor B, Osborne W, Peir G, Smith M, John A

Despite the known benefits of regular exercise, the majority of adults with congenital heart disease (CHD) fail to meet recommended standards for physical activity. We aimed to evaluate the factors associated with exercise frequency in adults with CHD, which remain largely unknown. From September 2015 to December 2016, 446 adults with CHD completed clinical questionnaires regarding exercise frequency. Questionnaires also measured related demographic and psychosocial variables. Retrospective chart review was utilized to determine cardiac function and cardiopulmonary exercise capacity. Exercise frequency was classified as none (33%), low (<3×/month, 2%), occasional (<2×/week, 8%), or frequent (≥2×/week, 57%). Frequent exercisers were more highly educated (odds ratio [OR] 1.65, 95% confidence interval [CI] 1.06 to 2.57), reported improved sleep quality, with decreased nocturnal awakenings and sleep latency (OR 0.52, 95% CI 0.32 to 0.83), and had a lower prevalence of depression (OR 0.30, 95% CI 0.12 to 0.75). There was no significant association between exercise frequency and disease complexity or cardiac function. Of the original cohort, 74 patients completed exercise testing within 1 year of their visit. Frequent exercisers (n = 46) had better indicators of cardiovascular capacity, including higher peak maximal oxygen consumption [VO] (28.8 ± 8.5 vs 24.6 ± 8.4, p = 0.04). After controlling for exercise frequency, higher educational attainment independently predicted an improved exercise capacity (peak [VO]: OR = 1.09, 95% CI 1.01 to 1.18). In conclusion, frequent exercise in adults with CHD is associated with improved cardiopulmonary exercise capacity and psychosocial functioning, irrespective of underlying cardiac disease complexity and severity. Increased physical activity levels and improved exercise capacity were observed in more highly educated patients, highlighting the potential importance of socioeconomic influences on physical and mental functioning.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Sep 2019; 124:947-951
Connor B, Osborne W, Peir G, Smith M, John A
Am J Cardiol: 14 Sep 2019; 124:947-951 | PMID: 31327487
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Abstract

Doppler-Derived Renal Venous Stasis Index in the Prognosis of Right Heart Failure.

Husain-Syed F, Birk HW, Ronco C, Schörmann T, ... Gall H, Ghofrani HA

Background Persistent congestion with deteriorating renal function is an important cause of adverse outcomes in heart failure. We aimed to characterize new approaches to evaluate renal congestion using Doppler ultrasonography. Methods and Results We enrolled 205 patients with suspected or prediagnosed pulmonary hypertension (PH) undergoing right heart catheterization. Patients underwent renal Doppler ultrasonography and assessment of invasive cardiopulmonary hemodynamics, echocardiography, renal function, intra-abdominal pressure, and neurohormones and hydration status. Four spectral Doppler intrarenal venous flow patterns and a novel renal venous stasis index (RVSI) were defined. We evaluated PH-related morbidity using the Cox proportional hazards model for the composite end point of PH progression (hospitalization for worsening PH, lung transplantation, or PH-specific therapy escalation) and all-cause mortality for 1-year after discharge. The prognostic utility of RVSI and intrarenal venous flow patterns was compared using receiver operating characteristic curves. RVSI increased in a graded fashion across increasing severity of intrarenal venous flow patterns (<0.0001) and was significantly associated with right heart and renal function, intra-abdominal pressure, and neurohormonal and hydration status. During follow-up, the morbidity/mortality end point occurred in 91 patients and was independently predicted by RVSI (RVSI in the third tertile versus referent: hazard ratio: 4.72 [95% CI, 2.10-10.59; <0.0001]). Receiver operating characteristic curves suggested superiority of RVSI to individual intrarenal venous flow patterns in predicting outcome (areas under the curve: 0.789 and 0.761, respectively; =0.038). Conclusions We propose RVSI as a conceptually new and integrative Doppler index of renal congestion. RVSI provides additional prognostic information to stratify PH for the propensity to develop right heart failure. Clinical Trial registration URL: https://www.clinicaltrials.gov/. Unique identifier: NCT03039959.



J Am Heart Assoc: 04 Nov 2019; 8:e013584
Husain-Syed F, Birk HW, Ronco C, Schörmann T, ... Gall H, Ghofrani HA
J Am Heart Assoc: 04 Nov 2019; 8:e013584 | PMID: 31630601
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Abstract

Long-Term Survival of Patients With Coarctation Repaired During Infancy (from the Pediatric Cardiac Care Consortium).

Oster ME, McCracken C, Kiener A, Aylward B, ... Hunting J, Kochilas LK

Patients who undergo coarctation repair during infancy have excellent early survival but long-term survival is unknown. We aimed to describe the long-term survival of patients with coarctation repaired during infancy and determine predictors of mortality. We performed a retrospective cohort study using data from the Pediatric Cardiac Care Consortium for patients with coarctation who underwent surgical repair before 12 months of age between 1982 and 2003. Long-term transplant-free survival was obtained by linkage with the National Death Index and the Organ Sharing Procurement Network. Kaplan Meier survival plots were constructed, and univariate and multivariable analyses were performed to determine predictors of mortality. We identified 2,424 coarctation patients who met inclusion criteria. At 20 years postoperatively, 94.5% of all patients and 95.8% of those discharged after initial operation remained alive, respectively. Significant multivariable predictors of mortality included surgical weight <2.5 kg (hazard ratio [HR] 3.70, 95% confidence interval [CI] 2.19 to 6.24), presence of a genetic syndrome (HR 2.40, 95% CI 1.13 to 5.10), and repair before 1990 (HR 1.91, 95% CI 1.09 to 3.34). None of the other factors examined including age at repair, gender, coarctation type, or surgical approach were found to be statistically significant. Over half of the deaths were due to the underlying congenital heart disease or other cardiovascular etiology. Overall long-term survival of patients who undergo coarctation repair during infancy is excellent. However, patients do experience small continued survival attrition throughout early adulthood. Ongoing monitoring of this cohort is necessary to assess late mortality risk.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 31 Aug 2019; 124:795-802
Oster ME, McCracken C, Kiener A, Aylward B, ... Hunting J, Kochilas LK
Am J Cardiol: 31 Aug 2019; 124:795-802 | PMID: 31272703
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Abstract

Failure to Rescue as an Outcome Metric for Pediatric and Congenital Cardiac Catheterization Laboratory Programs: Analysis of Data From the IMPACT Registry.

O\'Byrne ML, Kennedy KF, Jayaram N, Bergersen LJ, ... Rome JJ, Glatz AC

Background Risk-adjusted adverse event (AE) rates have been used to measure the quality of pediatric and congenital cardiac catheterization laboratories. In other settings, failure to rescue (FTR) has demonstrated utility as a quality metric. Methods and Results A multicenter retrospective cohort study was performed using data from the IMPACT (Improving Adult and Congenital Treatment) Registry between January 2010 and December 2016. A modified FTR metric was developed for pediatric and congenital cardiac catheterization laboratories and then compared with pooled AEs. The associations between patient- and hospital-level factors and outcomes were evaluated using hierarchical logistic regression models. Hospital risk standardized ratios were then calculated. Rankings of risk standardized ratios for each outcome were compared to determine whether AEs and FTR identified the same high- and low-performing centers. During the study period, 77 580 catheterizations were performed at 91 hospitals. Higher annual hospital catheterization volume was associated with lower odds of FTR (odds ratio: 0.68 per 300 cases; =0.0003). No association was seen between catheterization volume and odds of AEs. Odds of AEs were instead associated with patient- and procedure-level factors. There was no correlation between risk standardized ratio ranks for FTR and pooled AEs (=0.46). Hospital ranks by catheterization volume and FTR were associated (=-0.28, =0.01) with the largest volume hospitals having the lowest risk of FTR. Conclusions In contrast to AEs, FTR was not strongly associated with patient- and procedure-level factors and was significantly associated with pediatric and congenital cardiac catheterization laboratory volume. Hospital rankings based on FTR and AEs were not significantly correlated. We conclude that FTR is a complementary measure of catheterization laboratory quality and should be included in future research and quality-improvement projects.



J Am Heart Assoc: 04 Nov 2019; 8:e013151
O'Byrne ML, Kennedy KF, Jayaram N, Bergersen LJ, ... Rome JJ, Glatz AC
J Am Heart Assoc: 04 Nov 2019; 8:e013151 | PMID: 31619106
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Abstract

Radiofrequency ablation of the cavotricuspid isthmus for management of atrial flutter in patients with congenital heart disease after tricuspid valve surgery: A single-center experience.

Kella DK, Yasin OZ, Isath AM, McLeod CJ, ... Asirvatham SJ, Wackel PL
Background
Typical atrial flutter involving the cavotricuspid isthmus (CTI) is the most common reentrant arrhythmia in congenital heart disease and ablation is effective in its management. However, congenital heart disease patients often require surgical interventions on their tricuspid valve that utilize prosthetic material, making CTI ablation technically challenging.
Objective
To describe the techniques and outcomes of CTI ablation in the presence of prior tricuspid valve repair or replacement.
Methods
We included all patients who had undergone tricuspid valve repair utilizing an annuloplasty ring or tricuspid valve replacement who underwent CTI ablation for treatment of atrial arrhythmias between 2005 and 2017. Acute procedural success was defined as demonstration of bidirectional conduction block across the CTI. Long-term success was defined as lack of arrhythmia recurrence on monitoring or related symptoms.
Results
Sixteen patients met the inclusion criteria. Twelve (75%) patients had Ebstein\'s anomaly, 14 (88%) patients had a prosthetic tricuspid valve, and 2 (12%) patients had annuloplasty ring. Acute success was achieved in all cases, with no complications. Radiofrequency ablation was required on the ventricular side in 9 (56%) patients. In 1 case, ablation in the small cardiac vein was required. All patients remained free from atrial flutter during 18 months follow-up (range, 1-101 months).
Conclusion
Our study demonstrates the safety and efficacy of catheter ablation of the CTI in the presence of a tricuspid annuloplasty ring or a prosthetic tricuspid valve. This may require ablation from the ventricular side of the valve to target atrial tissue rendered inaccessible as a result of tricuspid valve surgery.

Copyright © 2019 Heart Rhythm Society. Published by Elsevier Inc. All rights reserved.

Heart Rhythm: 30 Oct 2019; 16:1621-1628
Kella DK, Yasin OZ, Isath AM, McLeod CJ, ... Asirvatham SJ, Wackel PL
Heart Rhythm: 30 Oct 2019; 16:1621-1628 | PMID: 31048063
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Abstract

Circulating Plasma Metabolomic Profiles Differentiate Rodent Models of Pulmonary Hypertension and Idiopathic Pulmonary Arterial Hypertension Patients.

Zhao JH, He YY, Guo SS, Yan Y, ... Jing ZC, Han ZY
Background
Pulmonary arterial hypertension (PAH) is a severe progressive disease with systemic metabolic dysregulation. Monocrotaline (MCT)-induced and hypoxia-induced pulmonary hypertension (PH) rodent models are the most widely used preclinical models, however, whether or not these preclinical models recapitulate metabolomic profiles of PAH patients remain unclear.
Methods
In this study, a targeted metabolomics panel of 126 small molecule metabolites was conducted. We applied it to the plasma of the 2 preclinical rodent models of PH and 30 idiopathic pulmonary arterial hypertension (IPAH) patients as well as 30 healthy controls to comparatively assess the metabolomic profiles of PAH patients and rodent models.
Results
Significantly different metabolomics profiling and pathways were shown among the 2 classical rodent models and IPAH patients. Pathway analysis demonstrated that methionine metabolism and urea cycle metabolism were the most significant pathway involved in the pathogenesis of hypoxia-induced PH model and MCT-induced model, respectively, and both of them were also observed in the dysregulated pathways in IPAH patients.
Conclusions
These 2 models may develop PAH through different metabolomic pathways and each of the 2 classical PH model resembles IPAH patients in certain aspects.

© American Journal of Hypertension, Ltd 2019. All rights reserved. For Permissions, please email: [email protected]

Am J Hypertens: 15 Oct 2019; 32:1109-1117
Zhao JH, He YY, Guo SS, Yan Y, ... Jing ZC, Han ZY
Am J Hypertens: 15 Oct 2019; 32:1109-1117 | PMID: 31350549
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Impact:
Abstract

Comparison of In-Hospital Outcomes When Repair of Tetralogy of Fallot Is in the Neonatal Period Versus in the Post-Neonatal Period.

Ghimire LV, Chou FS, Devoe C, Moon-Grady A

Tetralogy of Fallot (TOF) is the most common form of cyanotic congenital heart disease (CHD) and optimal timing for total repair of TOF is controversial. We hypothesize that TOF repair in the neonatal period is associated with worse outcomes compared with those who undergo repair later in infancy. We analyzed data using the Kids\' Inpatient Database (KID) from 2003 to 2012. We used multivariable logistic regression analyses to compare the in-hospital outcomes between those who underwent total repair of TOF during the neonatal period vs the postneonatal period. There were 6,856 cases of TOF and 7.83% (n = 537) of those underwent repair during the neonatal period. The average mortality in all TOF repair was 2.1% (n = 147). In multiple regression model, compared with repair in postneonatal period, neonatal repair was associated with increased mortality, with adjusted odds ratio of 2.2 (95% confidence interval [CI]: 1.1 to 4.3, p = 0.023). Regarding complications, the neonatal group was associated with higher risk of acute renal failure (8.9% vs 2.3%, p <0.001), need for cardiac catheterization (18.6% vs 8.3%, p <0.001), and ECMO use (4.4% vs1.6%, p <0.001). There was no difference in the rates of arrhythmia, respiratory failure, pulmonary hypertension, or sudden cardiac arrest. Children who underwent repair in the neonatal period had longer hospital stay compared with the postneonatal group (45.5 days [95% CI: 39.3 to 51.7] vs 12.6 days [95% CI: 11.7 to 13.4], p <0.001). Hospital charges were higher for children who underwent repair in the neonatal period compared with those in the postneonatal period. In conclusion, TOF repair in the neonatal period is associated with higher rates of mortality, more postoperative complications, longer hospital stays, and higher hospitalization cost.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 10 Oct 2019; epub ahead of print
Ghimire LV, Chou FS, Devoe C, Moon-Grady A
Am J Cardiol: 10 Oct 2019; epub ahead of print | PMID: 31703806
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Abstract

Application of transcatheter valves for aortic valve replacement in pediatric patients: A case series.

Sinha S, Khan A, Qureshi AM, Suh W, ... Fernando A, Levi D
Objectives
To describe our initial experience with pediatric transcatheter aortic valve replacement.
Background
Transcatheter aortic valve replacement (TAVR) has been approved and used to treat calcific aortic stenosis in adult patients. Select pediatric patients with congenital heart disease (CHD) who are poor candidates for conventional surgical aortic valve replacement can benefit from TAVR.
Methods
A retrospective review was performed to identify and describe pediatric patients with CHD who underwent transcatheter or hybrid aortic valve replacement using a Melody Valve (Medtronic, Minneapolis, MN), or Sapien S3/XT valve (Edwards Life sciences LLC, Irvine, CA). Patients in whom transcatheter valves were implanted on cardiopulmonary bypass were included. Imaging data, procedural elements, and clinical follow-up data were collected to evaluate acute and short-term results.
Results
A total of eight pediatric patients underwent treatment of aortic valvular disease using balloon expandable valves and delivery systems. Two patients had Melody valve implantation and six received a Sapien valve (one XT/five S3). In one patient, a Melody valve was placed surgically, failed, and was replaced with a Sapien valve 2 years later. Two patients were treated using a standard transfemoral route, four had the valve delivered on cardiopulmonary bypass via a median sternotomy, one was placed with a transapical approach, and one via a carotid cut down. Patients were followed for an average 16 months (range 1-208 weeks). There were no early or late deaths in this cohort. There were no embolic events, and all valves worked well in the immediate postoperative period. Both Melody implants developed moderate to severe regurgitation at 2 years and 4 years, respectively, and both required replacement at that time. One Sapien 3 valve developed a paravalvular leak that required reintervention within 6 months of implantation.
Conclusions
Transcatheter valves offer a reasonable alternative to traditional surgical aortic valve replacement in certain pediatric patients who are suboptimal surgical candidates. Hybrid approaches and valve delivery on cardiopulmonary bypass has been used in smaller patients. Long-term performance of these valves in young patients has not been studied.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 13 Oct 2019; epub ahead of print
Sinha S, Khan A, Qureshi AM, Suh W, ... Fernando A, Levi D
Catheter Cardiovasc Interv: 13 Oct 2019; epub ahead of print | PMID: 31609055
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Abstract

Comparison of Transcatheter Pulmonic Valve Implantation With Surgical Pulmonic Valve Replacement in Adults (from the National Inpatient Survey Dataset).

Chatterjee A, Bhatia N, Torres MG, Cribbs MG, Mauchley DC, Law MA

There are no large reports of comparative outcomes of transcatheter pulmonic valve implantation (TPVI) and surgical pulmonic valve replacement (SPVR). Prospective studies are unlikely to be feasible in the future also. Thus, we utilized a large adult inpatient database to compare the two with respect to temporal trends, in hospital outcomes and costs. Data from the National Inpatient Sample database from 2003 to 2014 was analyzed to extract patients who underwent TPVI and SPVR using unique ICD 9-CM codes. In-hospital outcomes and charges were then analyzed. All charges were converted to 2018 dollars and a loss of wages analysis was performed using the Bureau of Labor Statistics published median weekly wages. A total of 8,449 and 555 SPVR and TPVI discharges were identified. 5.8% SPVR procedures were done in rural setting versus 1.8% of TPVI. Complications including in-hospital mortality (2.3 vs 0.9%; p = 0.02) were higher in SPVR group. Length of stay was significantly shorter for the TPVI group (1 vs 5 days; p <0.001), which also contributed to lower loss of wages ($1028.57 vs $6042.86; p <0.001) with similar hospital charges. In conclusion, volumes of both TPVI and SPVR are increasing across adult hospitals in the United States, reflecting an overall increase in the adult congenital heart disease population. TPVI offers improved short-term outcomes and decreased loss of wages through shorter recovery time in this real-world database analysis.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 10 Oct 2019; epub ahead of print
Chatterjee A, Bhatia N, Torres MG, Cribbs MG, Mauchley DC, Law MA
Am J Cardiol: 10 Oct 2019; epub ahead of print | PMID: 31711632
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Abstract

Management of Adults With Normally Functioning Congenitally Bicuspid Aortic Valves and Dilated Ascending Aortas.

Roberts WC, Siddiquiz S, Rafael-Yarihuaman AE, Roberts CS

We describe herein a 65-year-old woman who underwent resection of a dilated (5.1 cm) ascending aorta associated with a normally functioning congenitally bicuspid aortic valve. The patient provided the framework to discuss proper management-operative versus nonoperative-of the dilated ascending aorta associated with a normally functioning bicuspid aortic valve. Unfortunately, there is inadequate data to provide an unequivocal answer to this dilemma. Operative intervention requires that the short-term risk of the prophylactic procedure be considerably lower than the long-term risk of aortic dissection/rupture without operative intervention. Because there is no proof that operative intervention provides less morbidity and lower mortality, nonoperative management at this time seems to be the better approach.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 25 Sep 2019; epub ahead of print
Roberts WC, Siddiquiz S, Rafael-Yarihuaman AE, Roberts CS
Am J Cardiol: 25 Sep 2019; epub ahead of print | PMID: 31718787
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Abstract

Implantable pulmonary artery pressure monitoring device in patients with palliated congenital heart disease: Technical considerations and procedural outcomes.

Salavitabar A, Bradley EA, Chisolm JL, Hickey J, ... Daniels CJ, Berman DP
Objective
We describe the technical considerations of transcatheter implantation of the CardioMEMS™ HF System (Abbott, Abbott Park, IL) in adult patients with complex palliated congenital heart disease (CHD) and advanced heart failure (HF).
Background
Ambulatory pulmonary artery (PA) pressure monitoring with implantable hemodynamic monitors (IHMs) has been shown to reduce HF-related hospital admissions in non-CHD populations. HF is a common late cardiovascular complication in adult CHD necessitating better understanding of IHM application in this population.
Methods
We analyzed adults with complex CHD and advanced HF who were referred for CardioMEMS™ device implantation (2015-2018). Feasibility of device implantation, defined by successful device implantation and calibration, and procedural outcomes were evaluated.
Results
CardioMEMS™ was successfully implanted in all 14 adults (35.5 ± 9.2 years old, 72 ± 12 kg) with complex CHD (single ventricle/Fontan, n = 8 [57%]; d-transposition of the great arteries/atrial switch, n = 6 [43%]). The device was delivered via femoral venous access in 13 (93%) patients and implanted in the left PA in 12 (86%). A long sheath was used in 8 (57%) patients, including 5/6 with an atrial switch operation. There was one device migration that did not require retrieval.
Conclusions
Transcatheter implantation of an IHM is feasible in select complex adult CHD patients with advanced HF. Further studies evaluating integration of ambulatory hemodynamics and the impact on clinical care are needed. This technology has the potential to improve medical management of advanced HF in patients with Fontan and atrial switch physiologies and provide new insights into their ambulatory hemodynamics.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 13 Oct 2019; epub ahead of print
Salavitabar A, Bradley EA, Chisolm JL, Hickey J, ... Daniels CJ, Berman DP
Catheter Cardiovasc Interv: 13 Oct 2019; epub ahead of print | PMID: 31609082
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Abstract

Acute pulmonary embolism unmasking underlying chronic thromboembolic pulmonary hypertension and iliac vein compression syndrome.

Brener MI, Green P, Parikh SA, Sethi SS

We describe the case of a 72-year-old gentleman who was referred to our institution for management of cardiogenic shock from a massive pulmonary embolism. Right heart catheterization revealed a low cardiac index and markedly elevated pulmonary pressures, suggested long-standing venous thromboembolic (VTE) disease that evolved into chronic thromboembolic pulmonary hypertension (CTEPH). The patient was cannulated to veno-arterial extra-corporeal membrane oxygenation and eventually treated with pulmonary embolectomy and thromboendarterectomy. Subsequently discovered inferior vena cava clot and left iliac deep vein thrombosis were treated with suction and mechanical thrombectomy. Intravascular ultrasound of the left lower extremity venous system identified iliac vein compression syndrome (IVCS) as the culprit of the patient\'s VTE and CTEPH. A left iliac stent was placed and the patient was discharged on Warfarin for anticoagulation. The case illustrates the rapidly expanding armamentarium for VTE treatment and proposes IVCS as a new, potentially underrecognized risk factor for CTEPH.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 07 Oct 2019; epub ahead of print
Brener MI, Green P, Parikh SA, Sethi SS
Catheter Cardiovasc Interv: 07 Oct 2019; epub ahead of print | PMID: 31595624
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Abstract

Congenital and Structural Heart Disease Interventions Using Echocardiography-Fluoroscopy Fusion Imaging.

Jone PN, Haak A, Ross M, Wiktor DM, ... Salcedo EE, Carroll JD

With the increasing frequency of catheter-based interventions in congenital heart disease and structural heart disease, the use of fusion imaging has become a major enhancement for understanding complex anatomy and facilitating key steps in interventional procedures. Because transesophageal echocardiography and fluoroscopy are displayed in different visual perspectives, the interventional cardiologist must mentally reregister the images from the two modalities during the procedure. Echocardiography-fluoroscopy fusion (EFF) imaging displays the x-ray and ultrasound overlay images in the same visual perspective. This new technology allows for enhanced team communication, improved visual guidance, and more efficient navigation. The purpose of this review is to describe the EFF imaging technology, current uses of EFF imaging in congenital and structural heart disease, and future directions that will enhance this unique imaging technology to guide interventional procedures.

Published by Elsevier Inc.

J Am Soc Echocardiogr: 05 Oct 2019; epub ahead of print
Jone PN, Haak A, Ross M, Wiktor DM, ... Salcedo EE, Carroll JD
J Am Soc Echocardiogr: 05 Oct 2019; epub ahead of print | PMID: 31597599
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Abstract

Incremental Utility of Right Ventricular Dysfunction in Patients With Myeloproliferative Neoplasm-Associated Pulmonary Hypertension.

Kim J, Krichevsky S, Xie L, Palumbo MC, ... Scandura JM, Weinsaft JW
Background
Myeloproliferative neoplasm (MPN) has been associated with pulmonary hypertension (PH) on the basis of small observational studies, but the mechanism and clinical significance of PH in MPN are not well established. The aims of this study were to expand understanding of PH in a well-characterized MPN cohort via study of PH-related symptoms, mortality risk, and cardiac remodeling sequalae of PH using quantitative echocardiographic methods.
Methods
The population comprised a retrospective cohort of patients with MPN who underwent transthoracic echocardiography: Doppler-derived pulmonary arterial systolic pressure applied established cutoffs for PH (≥35 mm Hg) and advanced PH (≥50 mm Hg); right ventricular (RV) performance was assessed via conventional indices (tricuspid annular plane systolic excursion [TAPSE], S\') and global longitudinal strain. Symptoms and mortality were discerned via standardized review.
Results
Three hundred one patients were studied; 56% had echocardiography-demonstrated PH (20% advanced) paralleling a high prevalence (67%) among patients with invasively quantified PASP. PH was associated with adverse left ventricular (LV) remodeling indices, including increased myocardial mass and diastolic dysfunction (P ≤ .001 for all): LV mass and filling pressure (P < .01) were associated with PH independent of LV ejection fraction. RV dysfunction by strain and TAPSE and S\' increased in relation to PH (P ≤ .001) and was about threefold greater among patients with advanced PH compared with those without PH. Patients with RV dysfunction were more likely to report dyspnea, as were those with advanced PH (P < .05). During median follow-up of 2.2 years, all-cause mortality was 27%. PH grade (hazard ratio, 1.9; 95% CI, 1.1-3.0; P = .012) and TAPSE- and S\'-demonstrated RV dysfunction (hazard ratio, 3.3; 95% CI, 1.3-8.2; P = .01) were independently associated with mortality; substitution of global longitudinal strain for TAPSE and S\' yielded similar associations of RV dysfunction with death (hazard ratio, 3.2; 95% CI, 1.5-6.7; P = .003) independent of PH.
Conclusions
PH is highly prevalent in patients with MPN and is linked to LV diastolic dysfunction; echocardiography-quantified RV dysfunction augments risk for mortality independent of PH.

Copyright © 2019 American Society of Echocardiography. All rights reserved.

J Am Soc Echocardiogr: 02 Oct 2019; epub ahead of print
Kim J, Krichevsky S, Xie L, Palumbo MC, ... Scandura JM, Weinsaft JW
J Am Soc Echocardiogr: 02 Oct 2019; epub ahead of print | PMID: 31587969
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Abstract

Lack of Increased Cardiovascular Risk due to Functional Tricuspid Regurgitation in Patients with Left-Sided Heart Disease.

Mutlak D, Khoury E, Lessick J, Kehat I, Agmon Y, Aronson D
Background
Significant tricuspid regurgitation (TR) is associated with higher risk for adverse cardiovascular outcomes. Left-sided heart disease (LHD) is a potentially important confounder of this association because it is strongly linked to both TR and clinical outcome.
Methods
We studied 5,886 patients who were followed for a period of 10 years after the index echocardiographic examination. The relationship between TR severity and the end point of admission for heart failure or cardiovascular mortality was analyzed using competing risk analysis, Cox model, and propensity score matching.
Results
Higher TR grade was associated with markers of LHD including left ventricular systolic dysfunction, valvular heart disease ≥ moderate, left atrial enlargement, and pulmonary hypertension (all P < .001). There was a significant interaction between TR and the presence of LHD with regard to the end point of heart failure in the competing risks model (P = .01) and the combined end point of heart failure and cardiovascular mortality (P = .02). In both models, moderate/severe TR was associated with higher risk for heart failure (hazard ratio [HR] = 3.10; 95% CI, 1.41-6.84; P = .005) and the combined end point of heart failure or cardiovascular mortality (HR = 2.75; 95% CI, 1.33-5.63, P = .006) only in patients without LHD. Propensity score matching yielded 350 patient pairs, of which 88% had LHD. The HR for heart failure or cardiovascular mortality at 10 years was 0.78 (95% CI, 0.56-1.08; P = .14) in the moderate/severe TR group as compared with the trivial/mild TR.
Conclusions
Moderate or severe functional TR portends an increased risk for heart failure and cardiovascular mortality only when isolated, without concomitant LHD.

Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 13 Oct 2019; epub ahead of print
Mutlak D, Khoury E, Lessick J, Kehat I, Agmon Y, Aronson D
J Am Soc Echocardiogr: 13 Oct 2019; epub ahead of print | PMID: 31624025
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Abstract

The entirely subcutaneous ICDTM system in patients with congenital heart disease: experience from a large single-centre analysis.

Willy K, Reinke F, Bögeholz N, Köbe J, Eckardt L, Frommeyer G
Aims
The subcutaneous implantable cardioverter-defibrillator (S-ICDTM) is an important advance in device therapy for the prevention of sudden cardiac death (SCD). Although current guidelines recommend S-ICDTM use, long-term data are still limited, especially in subgroups such as adult patients with congenital heart diseases. This cohort is of high interest because of the difficult anatomic conditions in these patients.
Methods and results
All S-ICDTM patients with an underlying congenital heart disease (CHD) resulting in an indication for ICD implantation (n = 20 patients) in our large-scaled single-centre S-ICDTM registry (n = 249 patients) were included in this study. Baseline characteristics, appropriate and inappropriate shocks, and complications were documented in a mean follow-up of 36 months. Primary prevention of SCD was the indication for implantation of an S-ICDTM in six patients (30%). Of all 20 patients with an overall mean age of 40.5 ± 11.5 years, 12 were male (60%). The mean left ventricular ejection fraction was 46.5 ± 11.3%. Nine episodes of ventricular tachycardia (two monomorphic and seven polymorphic) were adequately terminated in three patients (15%). In two patients, T-Wave-Oversensing resulting in an inappropriate shock was observed, which could be managed by changing the sensing vector or activation of the SMART PASSTM filter. There were no S-ICDTM system-related infections. In one patient, surgical revision was necessary due to a persistent haematoma.
Conclusion
The S-ICDTM seems to be a valuable option for the prevention of SCD in patients with various CHDs and complex anatomical anomalies. The S-ICDTM is safe and works effectively, also in these complex patients. Inadequate shock delivery was rare and could be managed by reprogramming.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Europace: 30 Sep 2019; 21:1537-1542
Willy K, Reinke F, Bögeholz N, Köbe J, Eckardt L, Frommeyer G
Europace: 30 Sep 2019; 21:1537-1542 | PMID: 31302706
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Abstract

Association of Wolff-Parkinson-White with Left Ventricular Noncompaction Cardiomyopathy in Children.

Howard TS, Valdes SO, Hope KD, Morris SA, ... Wang Y, Kim JJ
Background
Wolff-Parkinson-White (WPW) has been associated with left ventricular noncompaction (LVNC) in children. Little is known about the prevalence of this association, clinical outcomes, and treatment options.
Methods
Retrospective review of subjects with LVNC. LVNC was defined by established criteria; those with congenital heart disease were excluded. Electrocardiograms were reviewed for presence of preexcitation. Outcomes were compared between those with isolated LVNC and those with WPW and LVNC.
Results
A total of 348 patients with LVNC were identified. Thirty-eight (11%) were found to have WPW pattern on ECG, and 84% of those with WPW and LVNC had cardiac dysfunction. In Kaplan Meier analysis, there was significantly lower freedom from significant dysfunction (ejection fraction ≤40%) among those with WPW and LVNC (p<0.001). Further analysis showed a higher risk of developing significant dysfunction in patients with WPW and LVNC vs. LVNC alone (HR 4.64, (2.79, 9.90). Twelve patients underwent an ablation procedure with an acute success rate of 83%. Four patients with cardiac dysfunction were successfully ablated, 3 having improvement in function.
Conclusion
WPW is common among children with LVNC and is associated with cardiac dysfunction. Ablation therapy can be safely and effectively performed and may result in improvement in function.

Copyright © 2019 Elsevier Ltd. All rights reserved.

J Card Fail: 14 Oct 2019; epub ahead of print
Howard TS, Valdes SO, Hope KD, Morris SA, ... Wang Y, Kim JJ
J Card Fail: 14 Oct 2019; epub ahead of print | PMID: 31626950
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Abstract

Left bundle branch pacing, the only feasible physiological pacing modality for a patient with complete atrioventricular septal defect after surgical correction.

Hu Y, Gu M, Hua W, Li H, ... Liu X, Zhang S

Complete atrioventricular septal defect (AVSD) is an uncommon congenital heart disease accounting for about 3% of cardiac malformations, mainly caused by the disorders in the development of endocardial cushions of the ventricular inflow tract. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 30 Oct 2019; epub ahead of print
Hu Y, Gu M, Hua W, Li H, ... Liu X, Zhang S
J Cardiovasc Electrophysiol: 30 Oct 2019; epub ahead of print | PMID: 31670426
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Abstract

An unbiased approach de-livers unexpected insight into torsin biology.

Prophet SM, Schlieker C

Mutations affecting the integrity of the essential torsin ATPase/cofactor system have been identified in a steadily increasing number of congenital disorders. Since most of these mutations affect brain function, much of the research has focused on deciphering disease etiology in the brain. However, torsin is expressed in a wide variety of nonneural tissues and is strictly conserved across species, including the lowest metazoans, suggesting that it plays roles extending beyond neurons. In this issue of the JCI, Shin et al. explored torsin function in the mammalian liver. The group reports major defects in hepatic lipid metabolism when the torsin system is compromised in mice. Remarkably, conditional deletion of either torsinA or its cofactor, lamina-associated polypeptide 1 (LAP1), resulted in fatty liver disease and steatohepatitis, likely from a secretion defect of VLDLs. This study considerably expands our understanding of torsin biology, while providing defined opportunities for future investigations of torsin function and dysfunction in human pathologies.



J Clin Invest: 06 Oct 2019; epub ahead of print
Prophet SM, Schlieker C
J Clin Invest: 06 Oct 2019; epub ahead of print | PMID: 31589164
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Abstract

Efficacy of catheter ablation for atrial fibrillation in patients with congenital heart disease.

Guarguagli S, Kempny A, Cazzoli I, Barracano R, ... Dimopoulos K, Ernst S
Aims
Advances in surgical techniques allow an increasing number of children with congenital heart disease (CHD) to reach adulthood. As patients grow older, atrial fibrillation (AF) is evolving into a major clinical concern and can be difficult to manage medically. Primary AF catheter ablation may, therefore, have a role in this setting but few reports have evaluated its efficacy in CHD patients.
Methods and results
We retrospectively reviewed 58 consecutive patients [median age 51, interquartile range (IQR) 44-63 years, 57% male] with AF (45% paroxysmal) who underwent 122 ablation procedures in our tertiary centre in the last decade. The majority had CHD of moderate or severe complexity (57%, Bethesda Class 2 or 3) with a dilated left atrium (LA) (81%) and/or right atrium (86%). At 1-year from the first ablation, 32.8% of patients remained in sinus rhythm. Multiple procedures were required in 35 (60%) patients. Freedom from AF at 1-year after the 2nd and 3rd ablation was 40.9% and 36.5%, respectively. Multivariable predictors of AF recurrence were underlying anatomic complexity [hazard ratio (HR) in Bethesda 3 1.98, P = 0.006], type of AF (HR for persistent 1.87, P = 0.004), and indexed LA dimensions (HR for cm2/m2 1.06, P = 0.03).
Conclusion
While ablation may be a valid option for the treatment of AF in CHD patients, multiple procedures are likely to be required. Early referral and careful patient selection are essential to optimize the results of AF ablation, achieving a low rate of recurrence. Further studies are needed to validate our prognostic model and guide clinical practice.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Europace: 31 Aug 2019; 21:1334-1344
Guarguagli S, Kempny A, Cazzoli I, Barracano R, ... Dimopoulos K, Ernst S
Europace: 31 Aug 2019; 21:1334-1344 | PMID: 31168581
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Impact:
Abstract

Effects of combined angiotensin II receptor antagonism and neprilysin inhibition in experimental pulmonary hypertension and right ventricular failure.

Andersen S, Axelsen JB, Ringgaard S, Nyengaard JR, ... Nielsen-Kudsk JE, Andersen A
Background
Combined angiotensin II receptor antagonism and neprilysin inhibition by LCZ696 reduces morbidity and mortality in heart failure patients and works by reducing RAAS activity and increasing cGMP levels. This study aims to evaluate the effects of LCZ696 in rats with pulmonary hypertension and right ventricular (RV) failure.
Methods
Pulmonary hypertension was induced in rats (n = 34) by combined exposure to the vascular endothelial growth factor-receptor antagonist SU5416 and hypoxia (SuHx). To distinguish pulmonary vascular from cardiac effects, isolated RV failure was induced by pulmonary trunk banding (PTB) in another group of rats (n = 40). In both models, the development of RV dysfunction was verified before randomization to treatment with LCZ696 (60 mg/kg/day) or vehicle for five weeks.
Results
In the SuHx rats, LCZ696 treatment reduced the increase in RV pressure and the development of RV hypertrophy and RV dilatation compared with vehicle treatment. LCZ696 also reduced wall thickness of the smaller pulmonary arteries. In the PTB rats, LCZ696 treatment did not have any effects on RV hypertrophy or function.
Conclusions
Combined angiotensin II receptor antagonism and neprilysin inhibition reduced RV systolic pressure, hypertrophy, and dilatation in rats with pulmonary hypertension. These effects seem secondary to pulmonary vascular changes, including reduced pulmonary vascular remodeling, as similar effects were not seen in rats with isolated RV failure. LCZ696 may have a therapeutic potential in the treatment of pulmonary hypertension.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 14 Oct 2019; 293:203-210
Andersen S, Axelsen JB, Ringgaard S, Nyengaard JR, ... Nielsen-Kudsk JE, Andersen A
Int J Cardiol: 14 Oct 2019; 293:203-210 | PMID: 31307846
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Abstract

Transcatheter treatment of acquired coronary sinus ostium atresia in a child with complex congenital heart disease.

Kops SA, Pangburn S, Barber BJ, Seckeler MD

Congenital coronary sinus ostium atresia is a rare condition that is typically considered benign, as long as there is adequate drainage via another route. However, in children with single ventricle congenital heart disease, adequate drainage may not be assured after complex surgical interventions, putting them at risk for myocardial injury. We present a patient with complex single ventricle congenital heart disease who developed acquired coronary sinus ostium atresia after surgical intervention that was treated by a transcatheter approach to prevent the sequelae of coronary sinus hypertension.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 04 Sep 2019; epub ahead of print
Kops SA, Pangburn S, Barber BJ, Seckeler MD
Catheter Cardiovasc Interv: 04 Sep 2019; epub ahead of print | PMID: 31486566
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Abstract

Pulmonary Vascular Resistance Is Associated With Brachial-Ankle Pulse-Wave Velocity and Adverse Clinical Outcomes in Patients With Heart Failure With Preserved Ejection Fraction.

Nakamura T, Uematsu M, Deyama J, Watanabe Y, ... Obata JE, Kugiyama K
Background
The precise mechanisms underlying the high prevalence of pulmonary hypertension (PH) with increased pulmonary vascular resistance (PVR) in heart failure with preserved ejection fraction (HFpEF) remain largely unknown. Measurements of brachial-ankle pulse wave velocity (baPWV) have been shown to be useful for risk assessment in HF patients. Thus, this study sought to define the association of PVR with baPWV and clinical outcomes in HFpEF.
Methods and results
Patients with HFpEF (n = 198) had measurements of baPWV and PVR by right heart catheterization, and were prospectively followed-up for <96 months or until the occurrence of a composite of all-cause death, hospitalization with worsening HF, and nonfatal acute coronary syndrome.
Results
Multivariate logistic analysis showed that baPWV was independently associated with PH with increased PVR (P < .001). During the follow-up period, 46 clinical events occurred. Multivariate Cox proportional hazards analysis showed that PH with increased PVR was a significant predictor of adverse outcomes after adjustment for conventional risk factors (HR 1.96, 95% CI 1.03-3.76, P = .04).
Conclusions
PH with increased PVR was associated with increased baPWV and adverse clinical outcomes in HFpEF. Thus, increased arterial stiffness may contribute to increased risk predictability of PVR for patients with HFpEF.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 30 Aug 2019; 25:725-732
Nakamura T, Uematsu M, Deyama J, Watanabe Y, ... Obata JE, Kugiyama K
J Card Fail: 30 Aug 2019; 25:725-732 | PMID: 30825643
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Impact:
Abstract

Association Between Right Ventricular Contractile Function and Cardiac Events in Isolated Postcapillary and Combined Pre- and Postcapillary Pulmonary Hypertension.

Kusunose K, Yamada N, Yamada H, Nishio S, ... Wakatsuki T, Sata M
Background
Recent studies have shown that patients with combined pre- and postcapillary pulmonary hypertension (CpcPH) had worse outcomes than those with isolated postcapillary pulmonary hypertension (IpcPH). However, the prognostic factors including right ventricular (RV) function have not been well documented. The aim of this study was to assess the differentiation of PH phenotypes, using echocardiography, and the association between RV longitudinal strain and cardiac events.
Methods and results
We prospectively recruited consecutive patients who had undergone right heart catheterization. The primary endpoint was cardiovascular death or readmission due to heart failure. We included 137 patients with Group 2 PH. A RV longitudinal strain of 17% was sensitive (85%) and specific (70%) to determine the CpcPH. During a median period of 31 months, 43 patients experienced the primary endpoint during follow-up. In a multivariate analysis, RV longitudinal strain was associated with the primary endpoint in both CpcPH and IpcPH (HR: 0.84, P = 0.003; HR: 0.86, P = 0.001).
Conclusions
Lower RV longitudinal strain was independently associated with worse outcomes in CpcPH and IpcPH. RV longitudinal strain may play a prognostic role in PH phenotypes.

Copyright © 2019 Elsevier Inc. All rights reserved.

J Card Fail: 01 Sep 2019; epub ahead of print
Kusunose K, Yamada N, Yamada H, Nishio S, ... Wakatsuki T, Sata M
J Card Fail: 01 Sep 2019; epub ahead of print | PMID: 31487533
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Abstract

Reproducibility and Intervendor Agreement of Left Ventricular Global Systolic Strain in Children Using a Layer-Specific Analysis.

Ramlogan S, Aly D, France R, Schmidt S, ... Goudar SP, Forsha D
Background
Speckle-tracking strain analysis provides additive data to the assessment of pediatric and congenital heart disease; however, the variety of strain analysis software platforms by different vendors and the lack of data on intervendor strain agreement in children have limited its utility. The purpose of this study is to evaluate the intervendor agreement of strain on two commonly used analysis platforms in pediatrics by layer of myocardium and data compression.
Methods
This prospective study analyzed two-dimensional speckle-tracking strain on two software platforms in 53 children with normal cardiac segmental anatomy and varying function. Three standard apical views and one parasternal short-axis view were exported at their acquired frame rates to workstations with GE EchoPAC and TomTec software and then also to TomTec at compressed frame rates. Both software platforms had been updated with European Association of Cardiovascular Imaging/American Society of Echocardiography Task Force recommendations for left ventricular (LV) global strain. Intravendor and intervendor agreement between layer-specific comparisons were assessed using Bland-Altman analysis (limits of agreement and bias) and intraclass correlation coefficients.
Results
This study included subjects with normal LV function (n = 38) and cardiomyopathy (n = 15) with an age range of 1 month to 18 years. Intertechnique agreement by default vendor myocardial layer (GE mid-TomTec endocardial layer) was robust for both global longitudinal (GLS) and circumferential strain (GCS; higher for GLS than GCS). Intravendor (inter- and interreader) agreement was slightly higher than intervendor. Only small differences in intraclass correlation coefficients were present between various myocardial layers and acquired versus compressed TomTec data with narrow limits of agreement and small bias except in certain subgroup comparisons.
Conclusions
Comparison of LV GLS and GCS between two commonly used software platforms after European Association of Cardiovascular Imaging/American Society of Echocardiography Industry Task Force recommendations demonstrated good to excellent agreement in pediatrics, regardless of the layer of analysis or the image format, although some degree of variability remains between vendor platforms. Overall, GLS agreement was more robust than GCS, and this difference is exaggerated in specific subanalyses. These data suggest that comparisons of strain values obtained on these two vendors will be reasonable, but caution should be used when the indication is the detection of small differences between serial echocardiograms.

Copyright © 2019 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 22 Oct 2019; epub ahead of print
Ramlogan S, Aly D, France R, Schmidt S, ... Goudar SP, Forsha D
J Am Soc Echocardiogr: 22 Oct 2019; epub ahead of print | PMID: 31668503
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Abstract

Long-term results of atrial maze surgery in patients with congenital heart disease.

Gonzalez Corcia MC, Walsh EP, Emani S
Aims
Recurrent atrial tachycardia is common after repair of many types of congenital heart disease, and surgical ablation with a maze procedure represents a potential treatment strategy. The objective of this study is to report a single-centre 19 years\' experience with maze surgery in congenital heart patients.
Methods and results
Patients undergoing maze procedure concomitantly with cardiac surgical procedures were retrospectively analysed. The maze procedure was classified as therapeutic if the patient demonstrated preoperative atrial arrhythmias, or as prophylactic if done because the patient was considered high risk for post-operative arrhythmias. Acute outcomes and longer-term freedom from atrial arrhythmias were analysed. Maze surgery was performed in 166 patients: 137 in the therapeutic group, and 29 in the prophylactic group. The most common congenital heart lesion was single ventricle for the therapeutic group (27%) and Ebstein\'s anomaly for the prophylactic group (76%). Surgery consisted of a right atrial maze in 63%, left atrial maze in 4%, and bilateral maze in 33%. There were no direct complications or mortality related to the maze procedure itself. For the therapeutic group, freedom from arrhythmias was 82% and 67% at 1 and 5 years post-maze. Younger age at the time of surgery correlated with a lower long-term recurrence risk.
Conclusion
Maze procedure at the time of an elective anatomic surgery is reasonably effective to prevent and treat atrial arrhythmias in patients with congenital heart disease at short- and mid-term, with low morbidity and mortality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: [email protected]

Europace: 31 Aug 2019; 21:1345-1352
Gonzalez Corcia MC, Walsh EP, Emani S
Europace: 31 Aug 2019; 21:1345-1352 | PMID: 31004150
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Abstract

The additive value of echocardiographic pulmonary to left atrial global strain ratio in the diagnosis of pulmonary hypertension.

Venkateshvaran A, Manouras A, Kjellström B, Lund LH
Background
The distinction between pre-capillary and post-capillary pulmonary hypertension (PH) is central to accurate diagnosis and appropriate therapy. We aimed to investigate the ability of the novel echocardiographic pulmonary to left atrial global strain ratio (ePLAGS) to distinguish pre-capillary from post-capillary PH and compare its discriminatory strength with the echocardiographic pulmonary to left atrial ratio (ePLAR).
Methods
Consecutive subjects with unexplained dyspnea or heart failure underwent echocardiography immediately followed by right heart catheterization. Subjects who did not satisfy the ESC/ERS criteria for PH, in atrial fibrillation or under pacemaker therapy, or with significant concomitant valvular disease were excluded. ePLAGS was calculated as peak tricuspid regurgitation velocity divided by left atrial global reservoir strain.
Results
One hundred and thirty PH subjects, as defined by right heart catheterization, were included in the analysis (pre-capillary: n = 64, post-capillary: n = 66). ePLAGS was lower in pre-capillary compared with post-capillary PH (0.19 ± 0.14 vs. 0.45 ± 0.58 m/s/%; p = 0.02) and significantly different between combined post- and pre-capillary PH (Cpc-PH) and isolated post-capillary PH (Ipc-PH) (0.62 ± 0.85 vs. 0.32 ± 0.19 m/s/%; p = 0.04). ePLAR was higher in pre-capillary as compared with post-capillary PH (0.37 ± 0.16 vs. 0.20 ± 0.08; p < 0.001) but did not differ between Ipc-PH and Cpc-PH. ePLAGS demonstrated stronger discriminating power than ePLAR to distinguish pre-capillary from post-capillary PH (AUC = 0.80 vs. 0.70). In the setting of post capillary PH, ePLAGS showed reasonable ability to distinguish Ipc-PH from Cpc-PH (AUC = 0.65). ePLAR, however, did not differentiate these two groups (AUC = 0.49; p > 0.05).
Conclusions
ePLAGS accurately differentiates pre-capillary from post-capillary PH and demonstrates higher diagnostic ability than ePLAR.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Sep 2019; 292:205-210
Venkateshvaran A, Manouras A, Kjellström B, Lund LH
Int J Cardiol: 30 Sep 2019; 292:205-210 | PMID: 31176524
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Abstract

First paediatric cohort for the evaluation of inflammation in endomyocardial biopsies derived from congenital heart surgery.

Degener F, Salameh A, Manuylova T, Pickardt T, ... Schubert S, Klingel K
Background
Endomyocardial biopsies (EMB) are the gold standard for the diagnosis of myocarditis in children and adults. The existing WHO/ISFC criteria for lymphocytic cell infiltrates by are based on the myocardium of adults. The aim of this study was to present a paediatric control cohort for the evaluation of inflammation in EMB of children.
Methods
In this study endomyocardial tissue from 62 children under 4 years of age was investigated, being collected during a planned open heart surgery with routine resection from ventricular site. Patients had no history of infection or myocardial inflammation. The heart tissue was formalin fixed and embedded in paraffin. Four μm thick tissue sections were stained with haematoxylin and eosin, Masson\'s trichrome, and Giemsa. Immunohistochemical stainings included quantitative evaluation of CD3 T cells, CD20 B cells, CD68 macrophages and MHCII expression.
Results
The myocardium was obtained in 96.8% (n = 60) of the cases from the right and in 3.2% (n = 2) from the left ventricle. The median age (interquartile range) at biopsy was 0.5 years (0.3-0.9), 66.1% male. Within this cohort, a median of 2.5/mm (1.0-4.0) CD3 T cells, 0.5/mm (0.0-0.6) CD20 B cells and 4.0/mm (2.5-6.0) CD68 macrophages were detected. The MHC II grade was 0 in 71.0% (n = 44) and 1 in 29.0% (n = 18).
Conclusion
This is the first paediatric control cohort being relevant for the correct interpretation of inflammatory heart diseases in EMB. The lymphocytic cell numbers in children needing congenital heart surgery without myocardial inflammation are below the existing values in adults.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 04 Oct 2019; epub ahead of print
Degener F, Salameh A, Manuylova T, Pickardt T, ... Schubert S, Klingel K
Int J Cardiol: 04 Oct 2019; epub ahead of print | PMID: 31611088
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Abstract

Factors associated with exercise capacity in patients with a systemic right ventricle.

Gavotto A, Abassi H, Rola M, Serrand C, ... Bredy C, Amedro P
Background
Systemic right ventricle (RV) is a rare and complex congenital heart disease (CHD). Patients with a systemic RV present with a significant decrease of their exercise capacity. We aimed at identifying clinical and paraclinical factors associated with maximum oxygen uptake (VO2) in adults with a systemic RV.
Methods
This multicentre cross-sectional study was performed in 2017 in three French tertiary care CHD centres. Adult patients with a D-transposition of the great artery (d-TGA) or a congenitally corrected TGA (cc-TGA) were included. Demographic, clinical, laboratory and imaging data were collected. Univariate and multivariate analyses were performed to identify predictors of impaired VO2, as measured by cardiopulmonary exercise test (CPET).
Results
A total of 111 patients were included in the study (85% d-TGA, median age 37.2 ± 8.2 years). Most patients presented with impaired physical capacity (mean VO2 of 23.3 ± 6.9 ml/kg/min, representing 68.4 ± 16.6% of predicted values) and ventilatory anaerobic threshold (VAT) impaired (mean VAT of 32.7 ± 10.9% of the predicted values). In univariate analysis, VO2 correlated with professional status, NYHA functional class, BNP level, the type of systemic RV, decreased RV function values in cardiac imaging, the severity of tricuspid regurgitation, the presence of a pacemaker or an implantable defibrillator, the VAT, the maximum load, and the maximal heart rate during exercise. In multivariate analysis, the VO2 remained associated with the NYHA functional class. The final multivariate model explained 49% of the variability of VO2.
Conclusion
NYHA functional class and RV function are predictors of impaired exercise capacity in adult patients with systemic RV.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Sep 2019; 292:230-235
Gavotto A, Abassi H, Rola M, Serrand C, ... Bredy C, Amedro P
Int J Cardiol: 30 Sep 2019; 292:230-235 | PMID: 31256996
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Abstract

Neonates and infants requiring life-long cardiac pacing: How reliable are epicardial leads through childhood?

Stanner C, Horndasch M, Vitanova K, Strbad M, ... Lange R, Cleuziou J
Background
In the literature, data is lacking on mid-term results of epicardial pacemaker implantation in neonates and infants. Our aim was to evaluate the mid-term results of epicardial pacemakers implanted in infants under 1 year of age.
Methods and results
We conducted a retrospective review of patients who underwent pacemaker implantation between 2000 and 2017. Pacemaker and lead parameters were reviewed at discharge, 2, 4 and more than 5 years after implantation. A total of 71 patients aged 4 ± 3 months and weighing 4 ± 2 kg were included in the study. Indications for pacemaker implantation were: acquired AV-block (n = 44), congenital AV block (n = 22), sick sinus syndrome (n = 4) and AV block type Mobitz II (n = 1). Median follow-up time was 5 years (range: 1 month-17 years). At 5 years of follow-up, atrial lead energy threshold for pacing decreased significantly (0.72 ± 0.71 μJ to 0.45 ± 0.35 μJ; P < 0.001) but was stable for ventricular leads (0.57 μJ [0.05; 39.47] to 0.64 μJ [0.13; 9.45], P = 0.97). Atrial lead impedance increased significantly (569 ± 137 Ω to 603 ± 134 Ω, P < 0.001), whereas ventricular lead impedance decreased (603 ± 202 Ω to 490 ± 150 Ω, P < 0.001) after 5 years. Repeat operations were required for generator change (n = 55), lead exchange (n = 17) and infection (n = 1). At 2, 5 and 10 years, atrial lead survival was 96%, 91% and 76% and ventricular lead survival was 94%, 82% and 75%, respectively (P = 0.45).
Conclusion
Stable pacing thresholds after 5 years indicated that epicardial pacemakers are safe for infants under 1 year of age until at least school enrolment age. However, due to stimulation at higher heart rates in infancy, battery depletion is a frequent occurrence.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 08 Oct 2019; epub ahead of print
Stanner C, Horndasch M, Vitanova K, Strbad M, ... Lange R, Cleuziou J
Int J Cardiol: 08 Oct 2019; epub ahead of print | PMID: 31630820
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Abstract

Staffing, activities, and infrastructure in 96 specialised adult congenital heart disease clinics in Europe.

Thomet C, Moons P, Budts W, De Backer J, ... Schwerzmann M,
Background
Clinical guidelines emphasise the need for specialised adult congenital heart disease (ACHD) programmes. In 2014, the working group on Grown-up Congenital Heart Disease of the European Society of Cardiology (ESC) published recommendations on the organisation of specialised care for ACHD. To appraise the extent to which these recommendations were being implemented throughout Europe, we assessed the number of patients in active follow-up and available staff resources in European ACHD programmes.
Methods
We conducted a descriptive, cross-sectional, paper-based survey of specialised ACHD centres in Europe in late 2017 concerning their centre status in 2016. Data from 96 ACHD centres were analysed. We categorised ACHD programmes into seven different centre types based on their staff resources and composition of interdisciplinary teams.
Results
Only four centres fulfilled all medical and non-medical staffing requirements of the ESC recommendations. Although 60% of the centres offered all forms of medical care, they had incomplete non-medical resources (i.e., specialised nurses, social workers, or psychologists). The participating centres had 226,506 ACHD patients in active follow-up, with a median of 1500 patients per centre (IQR: 800-3400). Six per cent of the patients were followed up in a centre that lacked a CHD surgeon or congenital interventional cardiologist.
Conclusions
A minority of European ACHD centres have the full recommended staff resources available. This suggests that as of 2016 either ACHD care in Europe was still not optimally organised, or that the latest ESC recommendations were not fully implemented in clinical practice.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 30 Sep 2019; 292:100-105
Thomet C, Moons P, Budts W, De Backer J, ... Schwerzmann M,
Int J Cardiol: 30 Sep 2019; 292:100-105 | PMID: 31085084
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Abstract

Catheter ablation for patients with end-stage complex congenital heart disease or cardiomyopathy considered for transplantation: Trials and tribulations.

Cazzoli I, Gunturiz-Beltran C, Guarguagli S, Alonso-Gonzalez R, ... Gatzoulis MA, Ernst S
Introduction
Arrhythmia contributes significantly to morbidity and mortality of patients with congenital heart disease (CHD) or cardiomyopathy (CMP). It also has the potential to worsen symptoms and is particularly detrimental to patients with advanced heart failure awaiting cardiac transplantation. We report our experience using catheter ablation to treat recurrent arrhythmia in patients with CHD or CMP considered for transplantation.
Methods
Five consecutive patients (3 female, mean age 47.8 ± 12.8 years) with complex CHD or CMP (tricuspid atresia, mitral atresia, double inlet left ventricle, arrhythmogenic right ventricular cardiomyopathy, left ventricular non-compaction) presented with either atrial (n = 3) or ventricular (n = 2) arrhythmias. All ablations were guided by three-dimensional (3D) electro-anatomical mapping, plus remote magnetic navigation in 3 patients.
Results
Patients underwent a median of 2 ablation procedures for a total number of 26 tachycardias. None of the 5 patients experienced further arrhythmia at a median of 939 days (range 4-1375) from their last ablation. During a median follow up of 31 months (range 1-70), three patients underwent successful transplantation at 1375, 1062 and 321 days following their last ablation. One patient with a Fontan circulation died from hepatic cancer and one from end-stage heart failure despite urgent transplant listing.
Conclusions
Catheter ablation is feasible in complex cardiac patients considered for heart transplantation and should be offered for rhythm management and patient optimization until a suitable donor is found.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 09 Sep 2019; epub ahead of print
Cazzoli I, Gunturiz-Beltran C, Guarguagli S, Alonso-Gonzalez R, ... Gatzoulis MA, Ernst S
Int J Cardiol: 09 Sep 2019; epub ahead of print | PMID: 31604655
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Impact:
Abstract

Loss-of-function variants in myocardin cause congenital megabladder in humans and mice.

Houweling AC, Beaman GM, Postma AV, Gainous TB, ... Woolf AS, Creemers EE

Myocardin (MYOCD) is the founding member of a class of transcriptional co-activators that bind serum response factor to activate gene expression programs critical in smooth muscle (SM) and cardiac muscle development. Insights into the molecular functions of MYOCD have been obtained from cell culture studies and, to date, knowledge about in vivo roles of MYOCD comes exclusively from experimental animals. Here, we defined an often lethal congenital human disease associated with inheritance of pathogenic MYOCD variants. This disease manifested as a massively dilated urinary bladder, or megabladder, with disrupted SM in its wall. We provided evidence that monoallelic loss-of-function variants in MYOCD caused congenital megabladder in males only, whereas biallelic variants were associated with disease in both sexes, with a phenotype additionally involving the cardiovascular system. These results were supported by co-segregation of MYOCD variants with the phenotype in four unrelated families, by in vitro transactivation studies where pathogenic variants resulted in abrogated SM gene expression, and finding megabladder in two distinct mouse models with reduced Myocd activity. In conclusion, we have demonstrated that variants in MYOCD result in human disease, and the collective findings highlight a vital role for MYOCD in mammalian organogenesis.



J Clin Invest: 11 Sep 2019; epub ahead of print
Houweling AC, Beaman GM, Postma AV, Gainous TB, ... Woolf AS, Creemers EE
J Clin Invest: 11 Sep 2019; epub ahead of print | PMID: 31513549
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Impact:
Abstract

Prioritising transplantation for adult congenital heart disease, UK national data.

Burch M, Taylor A, Mehew J, Dominguez T, ... Venkateswaran R, Banner N
Objective
There are no multi-centre data on the outcomes of transplant for adult congenital heart disease (ACHD) outside of North America. The literature has identified a number of concerns for this population such as increased wait-list and early post-operative mortality. We investigated outcomes in a national cohort to see if these problems are replicated outside of America.
Methods
Adults (aged ≥16 years) undergoing primary heart transplantation 1995-2014 were identified in the UK Registry and registration, operative and post-transplantation related clinical factors were compared to non ACHD recipients.
Results
Of 3026 adults who underwent primary heart transplantation, 134 (4.4%) had ACHD (median age 30 years; 40.3% female). For the ACHD patients listed as urgent status, the time to transplant was not significantly different to non ACHD patients and ACHD were not more likely to die or be removed from the wait list. Despite ACHD recipients having longer hospital stays (27 vs. 22 days; p = 0.003) and worse 90-day survival (79.5% vs. 86.6%; p = 0.02), long-term post-transplantation survival was not significantly different. Creatinine clearance was significantly better in ACHD patients at follow-up. In the last 10 years of our study period, all single ventricle transplants have been restricted to experienced ACHD teams, one year survival for Fontan patients was 89.5%.
Conclusions
The use of urgent listing appears to have benefited the ACHD group by allowing equal access to transplantation, and recent concentration of expertise for single ventricle transplants has been associated with excellent early survival.

Copyright © 2019. Published by Elsevier B.V.

Int J Cardiol: 05 Sep 2019; epub ahead of print
Burch M, Taylor A, Mehew J, Dominguez T, ... Venkateswaran R, Banner N
Int J Cardiol: 05 Sep 2019; epub ahead of print | PMID: 31604656
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Impact:
Abstract

Mortality and morbidity of major congenital heart disease related to general prenatal screening for malformations.

Lytzen R, Vejlstrup N, Bjerre J, Petersen OB, ... Jørgensen FS, Søndergaard L
Background
Major congenital heart diseases (CHD) often demand intervention in the neonatal period. Prenatal diagnosis may improve mortality by eliminating the diagnostic delay; however, there is controversy concerning its true effect. We aimed to evaluate the effect of general prenatal screening on prognosis by comparing a period without general prenatal screening to a period with general prenatal screening.
Methods
We conducted a nationwide retrospective study including live born children and terminated fetuses diagnosed with major CHD. Prenatal screening was recommended only in high risk pregnancies between 1996 and 2004, whereas general prenatal screening was recommended between 2005 and 2013. We assessed the influence of general prenatal screening on all-cause mortality, cardiac death, preoperative and postoperative 30-day mortality and complication rate.
Results
1-year mortality decreased over both periods, but the decrease was greater in the screening period (Odds ratio 0.92 (CI 0.83-1.00), p = 0.047). Prenatal detection of major CHD was associated with cardiac death in the period without general screening (Hazard Ratio 2.40 (CI 1.72-3.33), p < 0.001), whereas there was no significant association once general screening was implemented. Similarly, the association between prenatal diagnosis and pre- and postoperative mortality found in the period without general screening was insignificant after the implementation of general screening.
Conclusion
Mortality in major CHD decreased throughout the study, especially in the period with general prenatal screening. However, comparing a prenatally diagnosed group with a postnatally diagnosed group is vulnerable to selection bias and proper interpretation is difficult.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Aug 2019; 290:93-99
Lytzen R, Vejlstrup N, Bjerre J, Petersen OB, ... Jørgensen FS, Søndergaard L
Int J Cardiol: 31 Aug 2019; 290:93-99 | PMID: 31130278
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Impact:
Abstract

Does gender affect the prognosis and risk of complications in patients with congenital heart disease in the modern era?

D\'Alto M, Budts W, Diller GP, Mulder B, ... Gatzoulis MA, Dimopoulos K

Gender differences in the outcome of acquired cardiovascular disease are well known, but available literature on the influence of gender in congenital heart disease (CHD) is limited. Registries have provided valuable, albeit at times conflicting data. Higher mortality rates have been reported in older males with CHD, while sudden cardiac death is more prevalent in young males. However, mortality around surgery for CHD is higher in girls compared to boys, likely due to smaller body size. Women are at higher risk of developing pulmonary arterial hypertension, but at lower risk of adverse aortic outcomes, even though they are less likely to receive aortic surgery. Finally, women have a lower risk of presenting with infective endocarditis compared to men. The underlying reasons for gender differences in CHD can be attributed to genetic, hormonal, behavioural and other causes. The aim of the present paper is to provide an overview of available evidence on gender differences in CHD and their impact on outcome.

Copyright © 2019 Elsevier B.V. All rights reserved.

Int J Cardiol: 31 Aug 2019; 290:156-161
D'Alto M, Budts W, Diller GP, Mulder B, ... Gatzoulis MA, Dimopoulos K
Int J Cardiol: 31 Aug 2019; 290:156-161 | PMID: 31085083
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Impact:
Older ...

This program is still in alpha version.