Topic: Congenital

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

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

Echocardiographic Features of Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction.

Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
Background
The PARAGON-HF (Prospective Comparison of ARNI With ARB Global Outcomes in HF With Preserved Ejection Fraction) trial tested the efficacy of sacubitril-valsartan in patients with heart failure with preserved ejection fraction (HFpEF). Existing data on cardiac structure and function in patients with HFpEF suggest significant heterogeneity.
Objectives
The aim of this study was to characterize cardiac structure and function, quantify their associations with clinical outcomes, and contextualize these findings with other HFpEF studies.
Methods
Echocardiography was performed in 1,097 of 4,822 PARAGON-HF patients within 6 months of enrollment. Associations with incident first heart failure hospitalization or cardiovascular death were assessed using Cox proportional hazards models adjusted for age, sex, region of enrollment, randomized treatment, N-terminal pro-brain natriuretic peptide, and clinical risk factors.
Results
Average age was 74 ± 8 years, 53% of patients were women, median N-terminal pro-brain natriuretic peptide level was 918 pg/ml (interquartile range: 485 to 1,578 pg/ml), 94% had hypertension, and 35% had atrial fibrillation. The mean left ventricular (LV) ejection fraction was 58.6 ± 9.8%, prevalence of LV hypertrophy was 21%, prevalence of left atrial enlargement was 83%, prevalence of elevated E/e\' ratio was 53%, and prevalence of pulmonary hypertension was 31%. Heart failure hospitalization or cardiovascular death occurred in 288 patients at 2.8-year median follow-up. In fully adjusted models, higher LV mass index (hazard ratio [HR]: 1.05 per 10 g/m; 95% confidence interval [CI]: 1.00 to 1.10; p = 0.03), E/e\' ratio (HR: 1.04 per unit; 95% CI: 1.02 to 1.06; p < 0.001), pulmonary artery systolic pressure (HR: 1.51 per 10 mm Hg; 95% CI: 1.29 to 1.76; p < 0.001), and right ventricular end-diastolic area (HR: 1.04 per cm; 95% CI: 1.01 to 1.07; p = 0.003) were each associated with this composite, while LV ejection fraction and left atrial size were not (p > 0.05 for all). Appreciable differences were observed in cardiac structure compared with other HFpEF clinical trials, despite similar E/e\' ratio, pulmonary artery systolic pressure, and event rates.
Conclusions
Diastolic dysfunction, left atrial enlargement, and pulmonary hypertension were common in PARAGON-HF. LV hypertrophy, elevated left- and right-sided pressures, and right ventricular enlargement were independently predictive of incident heart failure hospitalization or cardiovascular death. Echocardiographic differences among HFpEF trials despite similar clinical event rates highlight the heterogeneity of this syndrome. (Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction [PARAGON-HF]; NCT01920711).

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

J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873
Shah AM, Cikes M, Prasad N, Li G, ... Solomon SD,
J Am Coll Cardiol: 09 Dec 2019; 74:2858-2873 | PMID: 31806129
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Abstract

Improved Outcomes of Heart Transplantation in Adults With Congenital Heart Disease Receiving Regionalized Care.

Nguyen VP, Dolgner SJ, Dardas TF, Verrier ED, McMullan DM, Krieger EV
Background
The number of adult congenital heart disease (CHD) patients undergoing heart transplantation is increasing rapidly. CHD patients have higher surgical risk at transplantation. High-volume adult CHD transplant centers may have better transplant outcomes.
Objectives
This study aimed to evaluate the effect of center CHD transplant volume and expertise on transplant outcomes in CHD patients.
Methods
The authors studied heart transplantations in CHD patients age ≥18 years using the United Network of Organ Sharing (UNOS) database for the primary outcomes of waitlist mortality and post-transplant outcomes at 30 days and 1 year. Transplant centers were assessed by status as the highest CHD transplant volume center in a UNOS region versus all others, presence of Adult Congenital Heart Association accreditation, and adult versus pediatric hospital designation.
Results
Between January of 2000 and June of 2018, 1,746 adult CHD patients were listed for transplant; 1,006 (57.6%) of these underwent heart transplantation. After adjusting for age, sex, listing status, and inotrope requirement, waitlist mortality risk was lower at Adult Congenital Heart Association accredited centers (hazard ratio: 0.730; p = 0.020). Post-transplant 30-day mortality was lower at the highest volume CHD transplant center in each UNOS region (hazard ratio: 0.706; p = 0.014).
Conclusions
Designated expertise in CHD care is associated with improved waitlist outcomes for CHD patients listed for transplantation. Post-transplant survival was improved at the highest volume regional center. These findings suggest a possible advantage of regionalization of CHD transplantation.

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

J Am Coll Cardiol: 09 Dec 2019; 74:2908-2918
Nguyen VP, Dolgner SJ, Dardas TF, Verrier ED, McMullan DM, Krieger EV
J Am Coll Cardiol: 09 Dec 2019; 74:2908-2918 | PMID: 31806135
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Abstract

Adverse Events, Radiation Exposure, and Reinterventions Following Transcatheter Pulmonary Valve Replacement.

Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
Background
Transcatheter pulmonary valve replacement (TPVR) is associated with a risk of procedural serious adverse events (SAE) and exposure to ionizing radiation.
Objectives
The purpose of this study was to define the risk of, and associations with, SAE and high-dose radiation exposure using large-scale registry data.
Methods
The analysis of the multicenter C3PO-QI registry was limited to patients who underwent TPVR from January 1, 2014, to December 31, 2016. SAE were defined as the occurrence of ≥1 moderate, major, or catastrophic events. Radiation dose was reported as dose area product adjusted for weight. Associations with outcome measures were explored in univariate and multivariable analyses.
Results
A total of 530 patients (59% male) underwent TPVR at a median age of 18.3 years (interquartile range [IQR]: 12.9 to 27.3 years) and weight of 58 kg (IQR: 43 to 77 kg) at 14 centers. Implant substrate included homograft (41%), bioprosthesis (30%), native right ventricular outflow tract (RVOT) (27%) and other (2%). TPVR indications were pulmonary insufficiency (28%), stenosis (23%), and mixed (49%). AE and SAE occurred in 26% and 13% of cases, respectively, including 1 mortality. SAE were more frequent in homograft conduit than other RVOT substrates, although SAE type and severity differed between implant substrates. Median radiation dose was 198 μGy·m/kg (IQR: 94 to 350 μGy·m/kg). Higher radiation dose was associated with older age, greater RVOT obstruction, and concomitant interventions (p < 0.001). During a median follow-up duration of 1 year, 13.3% underwent catheterization, surgery, or both, unrelated to infection. Younger age, smaller size, and hemodynamic and anatomic factors indicative of greater RVOT obstruction were associated with TPV reintervention.
Conclusions
The incidence of SAE during TPVR in the C3PO-QI registry is high, but mortality is uncommon. Radiation dose is greater than for other congenital interventions and is associated with patient and procedural factors. Reintervention is common during early follow-up.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:363-376
Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
J Am Coll Cardiol: 03 Feb 2020; 75:363-376 | PMID: 32000947
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Abstract

Exercise Pulmonary Hypertension Predicts Clinical Outcomes in Patients With Dyspnea on Effort.

Ho JE, Zern EK, Lau ES, Wooster L, ... Malhotra R, Lewis GD
Background
Abnormal pulmonary arterial pressure (PAP) responses to exercise have been described in select individuals; however, clinical and prognostic implications of exercise pulmonary hypertension (exPH) among broader samples remains unclear.
Objectives
This study sought to investigate the association of exPH with clinical determinants and outcomes.
Methods
The authors studied individuals with chronic exertional dyspnea and preserved ejection fraction who underwent cardiopulmonary exercise testing with invasive hemodynamic monitoring. Exercise pulmonary hypertension was ascertained using minute-by-minute PAP and cardiac output (CO) measurements to calculate a PAP/CO slope, and exPH defined as a PAP/CO slope >3 mm Hg/l/min. The primary outcome was cardiovascular (CV) hospitalization or all-cause mortality.
Results
Among 714 individuals (age 57 years, 59% women), 296 (41%) had abnormal PAP/CO slopes. Over a mean follow-up of 3.7 ± 2.9 years, there were 208 CV or death events. Individuals with abnormal PAP/CO slope had a 2-fold increased hazard of future CV or death event (multivariable-adjusted hazard ratio: 2.03; 95% confidence interval: 1.48 to 2.78; p < 0.001). The association of abnormal PAP/CO slope with outcomes remained significant after excluding rest PH (n = 146, hazard ratio: 1.75; 95% confidence interval: 1.21 to 2.54; p = 0.003). Both pre- and post-capillary contributions to exPH independently predicted adverse events (p < 0.001 for both).
Conclusions
Exercise pulmonary hypertension is independently associated with CV event-free survival among individuals undergoing evaluation of chronic dyspnea. These findings suggest incremental value of exercise hemodynamic assessment to resting measurements alone in characterizing the burden of PH in individuals with dyspnea. Whether PH and PH subtypes unmasked by exercise can be used to guide targeted therapeutic interventions requires further investigation.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 06 Jan 2020; 75:17-26
Ho JE, Zern EK, Lau ES, Wooster L, ... Malhotra R, Lewis GD
J Am Coll Cardiol: 06 Jan 2020; 75:17-26 | PMID: 31918830
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Abstract

Structural basis of DNA targeting by a transposon-encoded CRISPR-Cas system.

Halpin-Healy TS, Klompe SE, Sternberg SH, Fernández IS

Bacteria use adaptive immune systems encoded by CRISPR and Cas genes to maintain genomic integrity when challenged by pathogens and mobile genetic elements. Type I CRISPR-Cas systems typically target foreign DNA for degradation via joint action of the ribonucleoprotein complex Cascade and the helicase-nuclease Cas3, but nuclease-deficient type I systems lacking Cas3 have been repurposed for RNA-guided transposition by bacterial Tn7-like transposons. How CRISPR- and transposon-associated machineries collaborate during DNA targeting and insertion remains unknown. Here we describe structures of a TniQ-Cascade complex encoded by the Vibrio cholerae Tn6677 transposon using cryo-electron microscopy, revealing the mechanistic basis of this functional coupling. The cryo-electron microscopy maps enabled de novo modelling and refinement of the transposition protein TniQ, which binds to the Cascade complex as a dimer in a head-to-tail configuration, at the interface formed by Cas6 and Cas7 near the 3\' end of the CRISPR RNA (crRNA). The natural Cas8-Cas5 fusion protein binds the 5\' crRNA handle and contacts the TniQ dimer via a flexible insertion domain. A target DNA-bound structure reveals critical interactions necessary for protospacer-adjacent motif recognition and R-loop formation. This work lays the foundation for a structural understanding of how DNA targeting by TniQ-Cascade leads to downstream recruitment of additional transposase proteins, and will guide protein engineering efforts to leverage this system for programmable DNA insertions in genome-engineering applications.



Nature: 17 Dec 2019; epub ahead of print
Halpin-Healy TS, Klompe SE, Sternberg SH, Fernández IS
Nature: 17 Dec 2019; epub ahead of print | PMID: 31853065
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Abstract

Aetiology and outcomes of severe right ventricular dysfunction.

Padang R, Chandrashekar N, Indrabhinduwat M, Scott CG, ... Pellikka PA, Kane GC
Aims
Right ventricular dysfunction (RVD) is an important determinant of functional status and survival in various diseases states. Data are sparse on the epidemiology and outcome of patients with severe RVD. This study examined the characteristics, aetiology, and survival of patients with severe RVD.
Methods and results
Retrospective study of consecutive patients with severe RVD diagnosed by transthoracic echocardiography (TTE) between 2011 and 2015 in a single tertiary referral institution. Patients with prior cardiac surgery, mechanical assist devices, and congenital heart disease were excluded. Primary endpoint was all-cause mortality. In 64 728 patients undergoing TTE, the prevalence of ≥mild RVD was 21%. This study focused on the cohort of 1299 (4%) patients with severe RVD; age 64 ± 16 years; 61% male. The most common causes of severe RVD were left-sided heart diseases (46%), pulmonary thromboembolic disease (18%), chronic lung disease/hypoxia (CLD; 17%), and pulmonary arterial hypertension (PAH; 11%). After 2 ± 2 years of follow-up, 701 deaths occurred, 66% within the first year of diagnosis. The overall probability of survival at 1- and 5 years for the entire cohort were 61% [95% confidence interval (CI) 58-64%] and 35% (95% CI 31-38%), respectively. In left-sided heart diseases, 1- and 5-year survival rates were 61% (95% CI 57-65%) and 33% (95% CI 28-37%), respectively; vs. 76% (95% CI 68-82%) and 50% (95% CI 40-59%) in PAH, vs. 71% (95% CI 64-76%) and 49% (95% CI 41-58%) in thromboembolic diseases, vs. 42% (95% CI 35-49%) and 8% (95% CI 4-15%) in CLD (log-rank P < 0.0001). Presence of ≥moderate tricuspid regurgitation portended worse survival in severe RVD.
Conclusion
One-year mortality of patients with severe RVD was high (∼40%) and dependent on the aetiology of RVD. Left-sided heart diseases is the most common cause of severe RVD but prognosis was worst in CLD.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 10 Feb 2020; epub ahead of print
Padang R, Chandrashekar N, Indrabhinduwat M, Scott CG, ... Pellikka PA, Kane GC
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047900
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Abstract

Microvascular Disease in Chronic Thromboembolic Pulmonary Hypertension: Hemodynamic Phenotyping and Histomorphometric Assessment.

Gerges C, Gerges M, Friewald R, Fesler P, ... Klepetko W, Lang IM

Pulmonary endarterectomy (PEA) is the gold standard treatment for patients with operable chronic thromboembolic pulmonary hypertension (CTEPH). However, persistent pulmonary hypertension (PH) after PEA remains a major determinant of poor prognosis. A concomitant small-vessel arteriopathy in addition to major pulmonary artery obstruction has been suggested to play an important role in the development of persistent PH and survival after PEA. One of the greatest unmet needs in the current preoperative evaluation is to assess the presence and severity of small-vessel arteriopathy. Using the pulmonary artery occlusion technique, we sought to assess the presence and degree of smallvessel disease in CTEPH patients undergoing PEA in order to predict postoperative outcome before surgery.Based on pulmonary artery occlusion waveforms yielding an estimate of the effective capillary pressure (P), we partitioned pulmonary vascular resistance in larger arterial (R, upstream resistance) and small arterial plus venous components (R, downstream resistance) in 90 patients prior to PEA. For validation, lung wedge biopsies were taken from non-obstructed and obstructed lung territories during PEA in 49 cases. Biopsy sites were chosen according to the pulmonary angiogram still frames that were mounted in the operating room. All vessels per specimen were measured, in each patient. Percent media (%MT) (arteries) and intima thickness (%IT) (arteries, veins, and indeterminate vessels) were calculated relative to external vessel diameter.Decreased R was an independent predictor of persistent PH (OR per 10%: 0.40 [0.23-0.69]; p=0.001) and survival (HR per 10%: 0.03 [0.00-0.33]; p=0.004). Arterial %MT and %IT of non-obstructed lung territories and venous %IT of obstructed lung territories were significantly increased in patients with persistent PH and non-survivors. R correlated inversely with %MT (r=-0.72, p<0.001) and %IT (r=-0.62, p<0.001) of arteries from nonobstructed lung territories and with %IT (r=-0.44, p=0.024) of veins from obstructed lung territories. Receiver operating characteristic analysis disclosed that R <66% predicted persistent PH after PEA, while R <60% identified patients with poor prognosis after PEA.Pulmonary artery occlusion waveform analysis with estimation of R seems to be a valuable technique for assessing the degree of small-vessel disease and postoperative outcome after PEA in CTEPH.



Circulation: 02 Jan 2020; epub ahead of print
Gerges C, Gerges M, Friewald R, Fesler P, ... Klepetko W, Lang IM
Circulation: 02 Jan 2020; epub ahead of print | PMID: 31896275
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Abstract

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Background
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
Methods
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year\'s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year\'s edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association\'s 2020 Impact Goals.
Results
Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
Conclusions
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.



Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print
Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print | PMID: 31992061
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Abstract

Pan-cancer analysis of whole genomes.



Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale. Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter; identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation; analyses timings and patterns of tumour evolution; describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity; and evaluates a range of more-specialized features of cancer genomes.



Nature: 30 Jan 2020; 578:82-93
Nature: 30 Jan 2020; 578:82-93 | PMID: 32025007
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Abstract

Women\'s Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Background
Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials.
Methods
We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation).
Results
We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (=0.007) and heart failure (=0.01) trials compared with previous periods.
Conclusions
Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.



Circulation: 17 Feb 2020; 141:540-548
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Circulation: 17 Feb 2020; 141:540-548 | PMID: 32065763
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Abstract

Improving National Outcomes in Congenital Heart Surgery: The Time Has Come for Regionalization of Care.

Backer CL, Pasquali SK, Dearani JA

Recently there have been several high-profile articles in the national media reporting on US congenital heart surgery programs, which have led in part to closure or curtailing of surgical services of at least 5 programs. These articles stemmed from concerns raised by families and practitioners regarding program outcomes and lack of transparency, which led to news media investigations and reported findings of mortality and complication rates that exceeded national norms. These cases highlight what has been well-documented for many years, the wide variability in care delivery, practices, and outcomes across US centers performing congenital heart surgery (1).



Circulation: 11 Feb 2020; epub ahead of print
Backer CL, Pasquali SK, Dearani JA
Circulation: 11 Feb 2020; epub ahead of print | PMID: 32078377
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Abstract

Circ- Serves as an Sponge to Regulate Myo10 (Myosin 10) and Promote Pulmonary Artery Smooth Muscle Proliferation.

Zhang J, Li Y, Qi J, Yu X, ... Wu B, Zhu D

Pulmonary artery smooth muscle cell proliferation is the pathological basis of pulmonary vascular remodeling in hypoxic pulmonary hypertension. Recent studies suggest that circular RNA (circRNA) can regulate various biological processes, including cell proliferation. Therefore, it is possible that circRNA may have important roles in pulmonary artery smooth muscle cell proliferation in hypoxic pulmonary hypertension. In the present study, we aimed to identify functional circRNAs and clarify their roles and mechanisms in pulmonary artery smooth muscle cell proliferation in pulmonary hypertension. RNA sequencing identified 67 circRNAs that were differentially expressed in hypoxic lung tissues of mice. Screening by bioinformatics and quantitative polymerase chain reaction revealed significant elevation of a circRNA derived from alternative splicing of thegene (designated circ-). Notably, this circRNA absorbed . We further identified Myo10 (myosin 10) as a target protein of .bound to the 3\'-untranslated region of Myo10 mRNA, thereby attenuating the translation of Myo10. Using loss-of-function and gain-of-function approaches, we found that circ- regulated cell proliferation by regulating the cell cycle. Additionally, we verified the functions ofand Myo10 in hypoxic pulmonary artery smooth muscle. Our results suggested that the circ-//Myo10 signal transduction axis modulated the proliferation of pulmonary artery smooth muscle cells at the molecular level, thus establishing potential targets for the early diagnosis and treatment of pulmonary hypertension.



Hypertension: 02 Feb 2020:HYPERTENSIONAHA11913715; epub ahead of print
Zhang J, Li Y, Qi J, Yu X, ... Wu B, Zhu D
Hypertension: 02 Feb 2020:HYPERTENSIONAHA11913715; epub ahead of print | PMID: 32008463
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Abstract

Sickle cell disease: at the crossroads of pulmonary hypertension and diastolic heart failure.

Wood K, Gladwin M, Straub A

Sickle cell disease (SCD) is caused by a single point mutation in the gene that codes for beta globin synthesis, causing haemoglobin polymerisation, red blood cell stiffening and haemolysis under low oxygen and pH conditions. Downstream effects include widespread vasculopathy due to recurring vaso-occlusive events and haemolytic anaemia, affecting all organ systems. Cardiopulmonary complications are the leading cause of death in patients with SCD, primarily resulting from diastolic heart failure (HF) and/or pulmonary hypertension (PH). HF in SCD often features biventricular cardiac hypertrophy and left ventricular (LV) diastolic dysfunction. Among HF cases in the general population, approximately half occur with preserved ejection fraction (HFpEF). The insidious evolution of HFpEF differs from the relatively acute evolution of HF with reduced ejection fraction. The PH of SCD has diverse origins, which can be pulmonary arterial (precapillary), pulmonary venous (postcapillary) or pulmonary thromboembolic. It is also appreciated that patients with SCD can develop both precapillary and postcapillary PH, with elevations in LV diastolic pressures, as well as elevations in transpulmonary pressure gradient and pulmonary vascular resistance. Regardless of the cause of PH in SCD, its presence significantly reduces functional capacity and increases mortality. PH that occurs in the presence of HFpEF is usually of postcapillary origin. This review aims to assemble what has been learnt from clinical and animal studies about the manifestation of PH-HFpEF in SCD, specifically the contributions of LV diastolic dysfunction and myocardial fibrosis, in an attempt to gain an understanding of its evolution.

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

Heart: 09 Dec 2019; epub ahead of print
Wood K, Gladwin M, Straub A
Heart: 09 Dec 2019; epub ahead of print | PMID: 31822569
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Abstract

Three-dimensional and four-dimensional flow assessment in congenital heart disease.

Warmerdam E, Krings GJ, Leiner T, Grotenhuis HB

Congenital heart disease (CHD) is the most common form of congenital defects, with an incidence of 8 per 1000 births. Due to major advances in diagnostics, perioperative care and surgical techniques, the survival rate of patients with CHD has improved dramatically. Conversely, although 70%-95% of infants with CHD survive into adulthood, the rate of long-term morbidity, which often requires (repeat) intervention, has increased. Recently, the role of altered haemodynamics in cardiac development and CHD has become a subject of interest. Patients with CHD often have abnormal blood flow patterns, either due to the primary cardiac defect or as a consequence of the surgical intervention(s). Research suggests that these abnormal blood flow patterns may contribute to diminished cardiac and vascular function. Serial assessment of haemodynamic parameters in patients with CHD may allow for improved understanding of the often complex haemodynamics in these patients and thereby potentially guide the timing and nature of interventions with the aim of preventing progression of cardiovascular deterioration. In this article we will discuss two novel non-invasive four-dimensional (4D) techniques to evaluate cardiovascular haemodynamics: 4D-flow cardiac magnetic resonance and computational fluid dynamics. This review focuses on the additional value of these two modalities in the evaluation of patients with CHD with abnormal flow patterns, who could benefit from advanced haemodynamic evaluation: patients with coarctation of the aorta, bicuspid aortic valve, tetralogy of Fallot and patients after Fontan palliation.

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

Heart: 18 Dec 2019; epub ahead of print
Warmerdam E, Krings GJ, Leiner T, Grotenhuis HB
Heart: 18 Dec 2019; epub ahead of print | PMID: 31857355
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Abstract

Current state of home-based exercise interventions in patients with congenital heart disease: a systematic review.

Meyer M, Brudy L, García-Cuenllas L, Hager A, ... Oberhoffer R, Müller J

Home-based exercise training is a promising alternative to conventional supervised training for patients with congenital heart disease (CHD). Even though the beneficial effect of exercise interventions is well established in patients with CHD, knowledge concerning variety and utility of existing programmes is still lacking. Therefore, the aim of this review is to give an overview about existing home-based exercise interventions in patients with CHD. A systematic search was performed in PubMed, Cochrane, Scopus and PEDro (2008-2018) for relevant clinical trials that provided any kind of home-based exercise with patients with CHD. All articles were identified and assessed by two independent reviewers. Seven articles with 346 paediatric CHD (18 months to 16 years) and five articles with 200 adults with CHD (21-41 years) were included. Most studies performed a supervised home-based exercise intervention with children and adolescents exercising at least three times per week with duration of 45 min for 12 weeks. Reported outcome measurements were health-related quality of life and physical activity, but mostly exercise capacity measured as peak oxygen uptake that improved in four studies (1.2%, 7%, 7.7%, 15%; p<0.05), walking distance in two (3.5%, 19.5%, p<0.05,) or walking time (2 min, p=0.003) in one. The dropout rates were high (15%), and compliance to the training programme was not reported in the majority of the studies (58%). Home-based exercise interventions are safe, feasible and a useful alternative to supervised cardiac rehabilitation for all age groups of patients with CHD. Nevertheless, training compliance represents a major challenge.

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

Heart: 04 Dec 2019; epub ahead of print
Meyer M, Brudy L, García-Cuenllas L, Hager A, ... Oberhoffer R, Müller J
Heart: 04 Dec 2019; epub ahead of print | PMID: 31806699
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Abstract

Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study.

Huybrechts KF, Bateman BT, Pawar A, Bessette LG, ... Upadhyaya HP, Hernandez-Diaz S
Objective
To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine.
Design
Cohort study nested in the Medicaid Analytic eXtract for 2004-13.
Setting
Publicly insured pregnancies in the United States.
Participants
Pregnant women 18 to 55 years of age and their liveborn infants.
Interventions
Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy.
Main outcome measures
Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage.
Results
Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses.
Conclusions
On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient.
Trial registration
EUPAS 15946.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 18 Feb 2020; 368:m237
Huybrechts KF, Bateman BT, Pawar A, Bessette LG, ... Upadhyaya HP, Hernandez-Diaz S
BMJ: 18 Feb 2020; 368:m237 | PMID: 32075794
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Abstract

Fibrinogen concentrate for treatment of bleeding and surgical prophylaxis in congenital fibrinogen deficiency patients.

Lissitchkov T, Madan B, Djambas Khayat C, Zozulya N, ... Knaub S, Peyvandi F
Background
Congenital fibrinogen deficiency is an ultra-rare disorder where patients can experience severe and/or frequent bleeding episodes (BEs). Here, we present the largest prospective study to date on the treatment of this disorder.
Methods
Hemostatic efficacy of human fibrinogen concentrate (HFC; FIBRYGA , Octapharma AG) for treatment of bleeding or surgical prophylaxis was assessed by investigators and adjudicated by an independent data monitoring and endpoint adjudication committee (IDMEAC) according to a 4-point scale, using objective criteria. Thromboelastometry maximum clot firmness (MCF) was also determined.
Results
Twenty-five afibrinogenemia patients were treated with HFC: 24 for on-demand treatment of 89 BEs, and nine as prophylaxis for 12 surgeries. For BEs, treatment success (rating of excellent or good) evaluated by investigators was 96.6% (90% confidence interval [CI], 0.92-0.99; two missing ratings, classified as failures) and by the IDMEAC was 98.9% (90% CI, 0.95-0.999). Mean ± standard deviation (SD) increase in MCF was 5.8±2.5 mm one hour after the first HFC infusion (mean ± SD dose, 61.88±11.73 mg/kg). For the 12 surgeries (median [range] HFC dose/surgery, 85.80 mg/kg [34.09-225.36]), intraoperative and postoperative treatment success were both rated 100% (90% CI, 0.82-1.00) by investigators and the IDMEAC. Three adverse events were possibly treatment-related, including a moderate case of thrombosis. There were no deaths, no severe allergic or hypersensitivity reactions and no clinical evidence of neutralizing anti-fibrinogen antibodies.
Conclusions
HFC was efficacious for on-demand treatment of bleeding and as surgical prophylaxis, with a favorable safety profile, in patients with congenital afibrinogenemia.

© 2019 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 28 Dec 2019; epub ahead of print
Lissitchkov T, Madan B, Djambas Khayat C, Zozulya N, ... Knaub S, Peyvandi F
J Thromb Haemost: 28 Dec 2019; epub ahead of print | PMID: 31885190
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Abstract

An anti-factor IXa/factor X bispecific antibody, emicizumab, improves ex vivo coagulant potentials in plasma from patients with acquired hemophilia A.

Takeyama M, Nogami K, Matsumoto T, Noguchi-Sasaki M, Kitazawa T, Shima M

Acquired hemophilia A (AHA) is caused by autoantibodies against factor (F)VIII, and is characterized by severe, spontaneous bleeding, which can be life-threatening. Emicizumab, an anti-FIXa/FX bispecific antibody, significantly reduces bleeding events in congenital HA with and without inhibitors. The known pathophysiological mechanisms and current preclinical data in HA suggest that emicizumab could provide effective treatment for AHA, but the coagulation activities of emicizumab in these patients remain unknown.
Aim
To evaluate the coagulant effects of emicizumab in plasma from AHA patients.
Methods and results
Tissue factor-triggered thrombin generation assays using normal plasma preincubated with anti-FVIII monoclonal antibodies recognizing different epitopes demonstrated that 20 µg/mL emicizumab recovered the depressed peak levels of thrombin generation to 46-72%. Further studies were devised, therefore, to simulate the clinical course in AHA patients, including during the acute phase for severe bleeding requiring FVIII-bypassing therapy, and during the sub-acute/chronic phase with less bleeding. Various concentrations of emicizumab were utilized to represent the potential changes in plasma levels based on the half-life of the antibody (~30 days). The ex vivo addition of emicizumab to plasma samples from AHA patients (n=16) increased peak thrombin in all cases, irrespective of the inhibitor epitope specificity. Thrombin generation at 20 and 100 µg/mL emicizumab was restored to (median) 43.9% and 92.2%, respectively. Differences were evident in some cases, however, and recovery rates appeared likely to be greater in patients with type 2 inhibitor than those with type 1.
Conclusion
Emicizumab improved ex-vivo coagulation potential in plasma from AHA patients.

© 2020 International Society on Thrombosis and Haemostasis.

J Thromb Haemost: 25 Jan 2020; epub ahead of print
Takeyama M, Nogami K, Matsumoto T, Noguchi-Sasaki M, Kitazawa T, Shima M
J Thromb Haemost: 25 Jan 2020; epub ahead of print | PMID: 31984625
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Abstract

PBI-4050 reduces pulmonary hypertension, lung fibrosis, and right ventricular dysfunction in heart failure.

Nguyen QT, Nsaibia MJ, Sirois MG, Calderone A, ... Laurin P, Dupuis J
Aims
Heart failure with reduced ejection fraction (HFrEF) causes lung remodelling with myofibroblasts proliferation and fibrosis leading to a restrictive lung syndrome with pulmonary hypertension (PH) and right ventricular (RV) dysfunction. PBI-4050 is a first-in-class anti-fibrotic, anti-inflammatory, and anti-proliferative compound. The present study evaluated the therapeutic impact of PBI-4050 on PH in an HFrEF model.
Methods and results
HFrEF was induced after myocardial infarction (MI) in rats. Two weeks later, sham-operated and MI groups received PBI-4050 (200 mg/kg/day by gavage) or saline for 3 weeks. Animals were analysed according to infarct size as large (≥30% left ventricle) or medium MI (<30%). Large MI caused PH and RV hypertrophy (RVH) with a restrictive lung syndrome. PBI-4050 did not adversely affect left ventricular (LV) function but markedly reduced PH and RVH and improved RV dysfunction. PBI-4050 reduced lung remodelling and improved respiratory compliance with decreased lung fibrosis, alveolar wall cellular proliferation and α-smooth muscle actin expression. The increased expression of endothelin-1 (ET-1), transforming growth factor beta (TGF-β), interleukin-6 (IL-6) and of tissue inhibitor of metalloprotease-1 in the lungs from HFrEF were reduced with PBI-4050 therapy. Activation of isolated human lung fibroblasts (HLFs) to a myofibroblastic pro-fibrogenic phenotype was markedly reduced by PBI-4050. The fatty acid receptor GPR84 was increased in HFrEF lungs and in activated HLFs, and reduced by PBI-4050. GPR84 agonists activated fibrogenesis in HLFs and finally, PBI-4050 reduced ERK1/2 phosphorylation.
Conclusions
PBI-4050 reduces PH and RVH in HFrEF by decreasing lung fibrosis and remodelling. This novel agent decreases the associated restrictive lung syndrome and recovers RV function. A contributing mechanism involves reducing the activation of lung fibroblasts by IL-6, TGF-β, and ET-1 by antagonism of GPR84 and reduced ERK1/2 phosphorylation. PBI-4050 is a novel promising therapy for targeting lung remodelling in group II PH.

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

Cardiovasc Res: 31 Dec 2019; 116:171-182
Nguyen QT, Nsaibia MJ, Sirois MG, Calderone A, ... Laurin P, Dupuis J
Cardiovasc Res: 31 Dec 2019; 116:171-182 | PMID: 30753422
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Abstract

Perforation of a Stenotic Congenitally Bicuspid Aortic Valve Cusp by Heavy Calcium in the Other Cusp.

Roberts WC, Roberts CS, Kale I

On occasion in patients with stenotic congenitally bicuspid aortic valves (BAVs), the quantity of calcium in one of the cusps is considerably greater than in the other cusp. We examined operatively excised stenotic congenitally BAVs in 630 patients having isolated aortic valve replacement (No other cardiac valve was replaced, and none had had infective endocarditis.) Of the 630 valves, 3 contained a perforation in the mildly calcified cusp due to a large calcific \"spur\" extending across the orifice from a heavily calcified cusp. In conclusion, heavy calcific deposits in 1 of 2 BAVs may extend across the orifice causing a perforation in the noncalcified portion of the opposing cusp.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 14 Jan 2020; 125:299-301
Roberts WC, Roberts CS, Kale I
Am J Cardiol: 14 Jan 2020; 125:299-301 | PMID: 31847960
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Abstract

Exome-Based Case-Control Analysis Highlights the Pathogenic Role of Ciliary Genes in Transposition of the Great Arteries.

Liu X, Chen W, Li W, Priest JR, ... Hu S, Zhou Z

Transposition of the great arteries (TGA) is one of the most severe types of congenital heart diseases (CHD). Understanding the clinical characteristics and pathogenesis of TGA is therefore urgently needed for patient management of this severe disease. However, the clinical characteristics and genetic etiology underlying TGA remain largely unexplored.We sought to systematically examine the clinical characteristics and genetic etiology for isolated nonsyndromic TGA.We recruited 249 TGA patients (66 family trios) and performed whole-exome sequencing. The incidence of patent ductus arteriosus in dextro-TGA (52.7%) and dextrocardia/mesocardia in congenitally corrected TGA (32.8%) were significantly higher than that in other subtypes. A high prevalence of bicuspid pulmonic valve (9.6%) was observed in TGA patients. Similar results were observed in a replication group of TGA (n=132). Through a series of bioinformatics filtering steps, we obtained 82 candidate genes harboring potentially damaging de novo, loss of function, compound heterozygous or X-linked recessive variants. Established CHD-causing genes, such as FOXH1, were found among the list of candidate genes. A total of 19 ciliary genes harboring rare potentially damaging variants were also found; for example, DYNC2LI1 with a de novo putatively damaging variant. The enrichment of ciliary genes supports the roles of cilia in the pathogenesis of TGA. In total, 33% of the TGA probands had more than one candidate gene hit by putatively deleterious variants, suggesting that a portion of the TGA cases were probably affected by oligogenic or polygenic inheritance.The findings of clinical characteristic analyses have important implications for TGA patient stratification. The results of genetic analyses highlight the pathogenic role of ciliary genes and a complex genetic architecture underlying TGA.



Circ Res: 10 Feb 2020; epub ahead of print
Liu X, Chen W, Li W, Priest JR, ... Hu S, Zhou Z
Circ Res: 10 Feb 2020; epub ahead of print | PMID: 32078439
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Abstract

Impact of preoperative right heart chambers measurement in the evaluation of pulmonary hypertension after aortic valve replacement.

Cladellas M, Garcia-Ribas C, Ble M, Gómez M, ... Vila J, Martí-Almor J
Background
Severe pulmonary hypertension (PH) in patients with aortic stenosis is related to poor prognosis after aortic valve replacement (AVR). Current European PH guidelines recommend adding two different echocardiographic signs to tricuspid regurgitation velocity (TRV) in PH estimation, classifying its probability as \"low\" (TRV≤2.8m/s), \"intermediate\" (TRV 2.9-3.4m/s) and \"high\" (TRV>3.4m/s). Right ventricle (RV) is an important determinant of prognosis in PH. Our aim was to analyze the value of right atrial area>18cm and RV/left ventricle ratio>1 in the long-term prognosis after AVR, mainly in the \"intermediate\" group.
Methods
We included 429 consecutive patients (mean age 73±8 years, 55% males) with median follow-up of 4.25 years (completed in 98%). Patients were divided into \"low\" (n=247), \"intermediate\" (n=117) and \"high\" groups (n=65). The \"intermediate\" group was divided into 2 subgroups: \"subgroup 2a\" (n=27, TRV non-measurable or ≤2.8m/s and two signs present) and \"subgroup 2b\" (n=90, TRV 2.9-3.4m/s and none or only one sign present).
Results
Overall mortality rates during follow-up of the \"low\", \"intermediate\" and \"high\" were 24%, 32% and 42%, respectively. \"High\" PH probability was an independent predictor of all-cause mortality (HR 1.82; 95% CI:1.11-3.00), but the \"intermediate\" group did not reach significance after multivariate analysis (HR 1.40; 95% CI: 0.91-2.16). When the \"intermediate\" group was divided into subgroups, \"subgroup 2a\" mortality rate (56%) was higher than that of both \"subgroup 2b\" (24%, p=0.002) and the \"low\" group (24%, p<0.001). After multivariate analysis, \"subgroup 2a\" showed a significantly higher mortality (HR 2.13; 95% CI: 1.11-4.10) in contrast to \"subgroup 2b\" (HR 1.24, 95% CI: 0.75-2.05), both compared to the low group.
Conclusions
Incorporating right cavities measures to the PH probability model in the assessment of long-term prognosis after AVR, allows better risk discrimination, especially in the \"intermediate\" group.

Copyright © 2020. Published by Elsevier Inc.

Chest: 16 Jan 2020; epub ahead of print
Cladellas M, Garcia-Ribas C, Ble M, Gómez M, ... Vila J, Martí-Almor J
Chest: 16 Jan 2020; epub ahead of print | PMID: 31958443
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Abstract

Noninvasive prognostic biomarkers for left heart failure as predictors of survival in pulmonary arterial hypertension.

Simpson CE, Damico RL, Hassoun PM, Martin LJ, ... Nichols WC, Everett AD
Background
Three biomarkers, soluble suppression of tumorigenicity 2 (ST2), galectin 3 (Gal3), and the N-terminal brain natriuretic peptide prohormone (NT-proBNP) are approved for noninvasive risk assessment in left heart failure, and small observational studies have shown their prognostic utility in heterogeneous pulmonary hypertension cohorts. We examined associations between these biomarkers and disease severity and survival in a large cohort of patients with Group I pulmonary arterial hypertension (PAH). We hypothesized that additive use of biomarkers in combination would improve the prognostic value of survival models.
Methods
Biomarker measurements and clinical data were obtained from 2,017 adults with Group I PAH. Associations between biomarker levels and clinical variables, including survival times, were examined with multivariable regression models. Likelihood ratio tests and Akaike Information Criteria were used to compare survival models.
Results
Higher ST2 and NT-proBNP were associated with higher pulmonary pressures and vascular resistance and lower 6 minute walk distance. Higher ST2 and NT-proBNP levels were associated with increased risk of death (hazard ratios 2.79, 95% CI 2.21-3.53, p<0.001 and 1.84, 95% CI 1.62-2.10, p<0.001 respectively). The addition of ST2 to survival models comprised of other predictors of survival, including NT-proBNP, significantly improved model fit and predictive capacity.
Conclusions
ST2 and NT-proBNP are strong, noninvasive prognostic biomarkers in PAH. Despite its prognostic value in left heart failure, Gal3 was not predictive in PAH. Adding ST2 to survival models significantly improves model predictive capacity. Future studies are needed to develop multimarker assays that improve noninvasive risk stratification in PAH.

Copyright © 2020. Published by Elsevier Inc.

Chest: 23 Jan 2020; epub ahead of print
Simpson CE, Damico RL, Hassoun PM, Martin LJ, ... Nichols WC, Everett AD
Chest: 23 Jan 2020; epub ahead of print | PMID: 31987881
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Abstract

Potent Zika and dengue cross-neutralizing antibodies induced by Zika vaccination in a dengue-experienced donor.

Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, ... Joyce MG, Krebs SJ

Zika virus (ZIKV) has caused significant disease, with widespread cases of neurological pathology and congenital neurologic defects. Rapid vaccine development has led to a number of candidates capable of eliciting potent ZIKV-neutralizing antibodies (reviewed in refs. ). Despite advances in vaccine development, it remains unclear how ZIKV vaccination affects immune responses in humans with prior flavivirus immunity. Here we show that a single-dose immunization of ZIKV purified inactivated vaccine (ZPIV) in a dengue virus (DENV)-experienced human elicited potent cross-neutralizing antibodies to both ZIKV and DENV. Using a unique ZIKV virion-based sorting strategy, we isolated and characterized multiple antibodies, including one termed MZ4, which targets a novel site of vulnerability centered on the Envelope (E) domain I/III linker region and protects mice from viremia and viral dissemination following ZIKV or DENV-2 challenge. These data demonstrate that Zika vaccination in a DENV-experienced individual can boost pre-existing flavivirus immunity and elicit protective responses against both ZIKV and DENV. ZPIV vaccination in Puerto Rican individuals with prior flavivirus experience yielded similar cross-neutralizing potency after a single vaccination, highlighting the potential benefit of ZIKV vaccination in flavivirus-endemic areas.



Nat Med: 02 Feb 2020; epub ahead of print
Dussupt V, Sankhala RS, Gromowski GD, Donofrio G, ... Joyce MG, Krebs SJ
Nat Med: 02 Feb 2020; epub ahead of print | PMID: 32015557
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Abstract

Genetics and other omics in pediatric pulmonary arterial hypertension.

Welch CL, Chung WK

Pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Clinical management of children with PAH is particularly challenging due to increased complexity of disease etiology and clinical presentation, as well as the lack of data from pediatric-specific clinical trials. In children, PAH often develops in association with congenital heart disease (APAH-CHD) and other developmental disorders. Emerging data from genetic studies of pediatric-onset PAH indicate that the genetic basis is different than that of adults. There is a greater genetic burden in children, with rare genetic factors contributing to at least 35% of pediatric-onset idiopathic PAH (IPAH) compared to ∼11% of adult-onset IPAH. De novo variants are the most frequent monogenetic cause of PAH in children, likely contributing to ∼15% of all cases. Rare deleterious variants in bone morphogenetic protein receptor 2 (BMPR2) contribute to pediatric-onset IPAH and familial PAH with similar frequency as adult-onset disease but rarely explain APAH cases. Rare deleterious variants in developmental genes - including T-box 4 containing protein (TBX4), SRY-related HMG box transcription factor (SOX17), and other genes requiring confirmation in larger cohorts - are emerging as important contributors to pediatric-onset disease. Since each causal gene contributes to only small numbers of cases, large cohorts of pediatric-onset PAH are needed to further identify the unique etiological differences of PAH in children. We propose a genetics-first approach followed by focused phenotyping of pediatric patients grouped by genetic diagnosis to define endophenotypes that can be used to improve risk stratification and treatment.

Copyright © 2020. Published by Elsevier Inc.

Chest: 28 Jan 2020; epub ahead of print
Welch CL, Chung WK
Chest: 28 Jan 2020; epub ahead of print | PMID: 32006592
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Abstract

Rationale and design of the optical coherence tomography observation of pulmonary ultra-structural changes in heart failure (OCTOPUS-CHF) study.

Ortiz-Bautista C, Gutiérrez-Ibañes E, García-Cosío MD, Calviño-Santos R, ... Martínez-Solano J, Martínez-Sellés M
Background
The assessment of vascular remodeling using optical coherence tomography (OCT) has been previously described in some types of pulmonary hypertension. However, evidence about its feasibility and clinical utility for evaluation of pulmonary arterial vasculopathy in advanced heart failure (HF) is scarce. Optical Coherence Tomography Observation of Pulmonary Ultra-Structural Changes in Heart Failure (OCTOPUS-CHF) study is designed to study the correlation between OCT-morphometric parameters and hemodynamic data measured or derived from right heart catheterization (RHC).
Methods
OCTOPUS-CHF is an observational, prospective, multicentre study aiming to recruit 100 patients with advanced HF referred for heart transplantation (HTx) evaluation. As part of such evaluation, all patients will undergo RHC in order to rule out severe pulmonary hypertension. After RHC, a Dragonfly™ OPTIS™ imaging catheter will be used to perform OCT evaluation of a right-lower-lobe pulmonary artery with a luminal diameter ≤ 5 mm. The primary objective is to study the correlation of OCT parameters with hemodynamic RHC data. The secondary objective is to determine if OCT parameters improve prognostic stratification.
Conclusions
The OCTOPUS-CHF study will investigate the feasibility and clinical utility of pulmonary arterial vasculopathy evaluation with OCT in advanced HF patients and its correlation with hemodynamic RHC data. The ability of OCT-morphometric parameters to improve prognostic stratification will also be tested.

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

Int J Cardiol: 14 Jan 2020; 299:296-300
Ortiz-Bautista C, Gutiérrez-Ibañes E, García-Cosío MD, Calviño-Santos R, ... Martínez-Solano J, Martínez-Sellés M
Int J Cardiol: 14 Jan 2020; 299:296-300 | PMID: 31278027
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Abstract

Pan-cancer analysis of whole genomes identifies driver rearrangements promoted by LINE-1 retrotransposition.

Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, ... Tubio JMC,

About half of all cancers have somatic integrations of retrotransposons. Here, to characterize their role in oncogenesis, we analyzed the patterns and mechanisms of somatic retrotransposition in 2,954 cancer genomes from 38 histological cancer subtypes within the framework of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project. We identified 19,166 somatically acquired retrotransposition events, which affected 35% of samples and spanned a range of event types. Long interspersed nuclear element (LINE-1; L1 hereafter) insertions emerged as the first most frequent type of somatic structural variation in esophageal adenocarcinoma, and the second most frequent in head-and-neck and colorectal cancers. Aberrant L1 integrations can delete megabase-scale regions of a chromosome, which sometimes leads to the removal of tumor-suppressor genes, and can induce complex translocations and large-scale duplications. Somatic retrotranspositions can also initiate breakage-fusion-bridge cycles, leading to high-level amplification of oncogenes. These observations illuminate a relevant role of L1 retrotransposition in remodeling the cancer genome, with potential implications for the development of human tumors.



Nat Genet: 04 Feb 2020; epub ahead of print
Rodriguez-Martin B, Alvarez EG, Baez-Ortega A, Zamora J, ... Tubio JMC,
Nat Genet: 04 Feb 2020; epub ahead of print | PMID: 32024998
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Abstract

Vitamin C Deficiency-Induced Pulmonary Arterial Hypertension.

Gayen SK, Abdelrahman AA, Preston IR, Petit RD, Hill NS

We report a case of a man in his 60s who developed pulmonary arterial hypertension (PAH) in association with profound vitamin C deficiency. Decreased availability of endothelial nitric oxide and activation of the hypoxia-inducible family of transcription factors, both consequences of vitamin C deficiency, are believed to be mechanisms contributing to the pathogenesis of the pulmonary hypertension. The PAH resolved following vitamin C supplementation. The current case highlights the importance of testing for vitamin C deficiency in patients with PAH in the proper clinical setting.

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

Chest: 30 Jan 2020; 157:e21-e23
Gayen SK, Abdelrahman AA, Preston IR, Petit RD, Hill NS
Chest: 30 Jan 2020; 157:e21-e23 | PMID: 32033656
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Impact:
Abstract

Non-vitamin K antagonist oral anticoagulants (NOACs) for thromboembolic prevention, are they safe in congenital heart disease? Results of a worldwide study.

Yang H, Bouma BJ, Dimopoulos K, Khairy P, ... Aboulhosn J, Mulder BJM
Background
Current guidelines consider vitamin K antagonists (VKA) the oral anticoagulant agents of choice in adults with atrial arrhythmias (AA) and moderate or complex forms of congenital heart disease, significant valvular lesions, or bioprosthetic valves, pending safety data on non-VKA oral anticoagulants (NOACs). Therefore, the international NOTE registry was initiated to assess safety, change in adherence and quality of life (QoL) associated with NOACs in adults with congenital heart disease (ACHD).
Methods
An international multicenter prospective study of NOACs in ACHD was established. Follow-up occurred at 6 months and yearly thereafter. Primary endpoints were thromboembolism and major bleeding. Secondary endpoints included minor bleeding, change in therapy adherence (≥80% medication refill rate, ≥6 out of 8 on Morisky-8 questionnaire) and QoL (SF-36 questionnaire).
Results
In total, 530 ACHD patients (mean age 47 SD 15 years; 55% male) with predominantly moderate or complex defects (85%), significant valvular lesions (46%) and/or bioprosthetic valves (11%) using NOACs (rivaroxaban 43%; apixaban 39%; dabigatran 12%; edoxaban 7%) were enrolled. The most common indication was AA (91%). Over a median follow-up of 1.0 [IQR 0.0-2.0] year, thromboembolic event rate was 1.0% [95%CI 0.4-2.0] (n = 6) per year, with 1.1% [95%CI 0.5-2.2] (n = 7) annualized rate of major bleeding and 6.3% [95%CI 4.5-8.5] (n = 37) annualized rate of minor bleeding. Adherence was sufficient during 2 years follow-up in 80-93% of patients. At 1-year follow-up, among the subset of previous VKA-users who completed the survey (n = 33), QoL improved in 6 out of 8 domains (p ≪ 0.05).
Conclusions
Initial results from our worldwide prospective study suggest that NOACs are safe and may be effective for thromboembolic prevention in adults with heterogeneous forms of congenital heart disease.

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

Int J Cardiol: 14 Jan 2020; 299:123-130
Yang H, Bouma BJ, Dimopoulos K, Khairy P, ... Aboulhosn J, Mulder BJM
Int J Cardiol: 14 Jan 2020; 299:123-130 | PMID: 31307847
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Impact:
Abstract

Protective role of endothelial progenitor cells stimulated by riociguat in chronic thromboembolic pulmonary hypertension.

Yamamoto K, Nishimura R, Kato F, Naito A, ... Tanabe N, Tatsumi K
Background
Pulmonary endothelial damage has a negative impact on the maintenance of normal pulmonary vascular function. Such damage results in delayed thrombus dissolution and vascular remodeling in chronic thromboembolic pulmonary hypertension (CTEPH). Although endothelial progenitor cells (EPCs) may be incorporated into neovasculature during vascular repair, their function in CTEPH remains unclarified, especially under the augmentation of soluble guanylate cyclase (sGC) activity.
Methods and results
We evaluated the effect of EPCs on endothelial function and compared the effect of riociguat, a sGC stimulator, on the number and function of circulating EPCs in two groups of CTEPH patients. The two groups consisted 16 CTEPH patients who were treatment naïve (Naïve group), and 14 CTEPH patients who were being treated with riociguat, a sGC stimulator (Riociguat group). The number of circulating EPCs in the Riociguat group was significantly higher than that in the Naïve group. Gene expression levels associated with angiogenesis were significantly higher in EPCs of the Riociguat group. EPC-stimulated tube formation and migration of human pulmonary microvascular endothelial cell (hPMVEC) in the Riociguat group exceeded that in the Naïve group. The angiogenic ability of hPMVECs stimulated by EPCs in the Riociguat group was enhanced compared to that of the sGC stimulator, BAY 41-2272.
Conclusion
These findings indicate that riociguat may induce EPCs to play a protective role via modulation of endothelial functions associated with CTEPH.
Translation aspect of the work
Endothelial dysfunction exacerbates CTEPH. Riociguat enhanced the protective role of EPCs via neovascularization, which prevented vascular remodeling and alleviated CTEPH.

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

Int J Cardiol: 14 Jan 2020; 299:263-270
Yamamoto K, Nishimura R, Kato F, Naito A, ... Tanabe N, Tatsumi K
Int J Cardiol: 14 Jan 2020; 299:263-270 | PMID: 31337550
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Impact:
Abstract

Myocardial blood flow and cardiac sympathetic innervation in young adults late after arterial switch operation for transposition of the great arteries.

Possner M, Buechel RR, Vontobel J, Mikulicic F, ... Greutmann M, Kaufmann PA
Background
The arterial switch operation (ASO) for repair of transposition of the great arteries (TGA) requires transection of the great arterial trunks and re-implantation of the coronary arteries into the neoaortic root resulting in cardiac sympathetic denervation which may affect myocardial blood flow (MBF) regulation. The aims of the present study were to evaluate sympathetic (re-)innervation in young adults after ASO and its impact on MBF.
Methods
Twelve patients (age 22.5 ± 2.6 years) after ASO for TGA in the neonatal period and ten healthy controls (age 22.0 ± 1.7 years) were included. Positron emission tomography (PET) was used for measuring cardiac sympathetic innervation with [C]meta-hydroxyephedrine (mHED) and MBF with [O]HO PET at rest, during adenosine stimulation, and during sympathetic stimulation with cold pressor test. Cold pressor-induced MBF response capacity was calculated as maximal global MBF over peak rate-pressure product multiplied by 10\'000.
Results
Global [C]mHED uptake was significantly lower in patients compared to controls (7.0 ± 2.3 versus 11.8 ± 2.1%/min, p < 0.001). Global MBF was lower in patients compared to controls at rest and during adenosine-induced hyperemia (0.66 ± 0.08 versus 0.82 ± 0.15 ml/min/g, p = 0.005; 2.23 ± 1.19 versus 3.36 ± 1.04 ml/min/g, p = 0.030, respectively). Interestingly, MBF during cold pressor test did not differ between patients and controls (0.99 ± 0.20 versus 1.07 ± 0.16 ml/min/g, p = 0.330). However, cold pressor-induced MBF response capacity was significantly lower for patients as compared to controls (1.09 ± 0.35 versus 1.44 ± 0.39 ml/g/10,000 mmHg, p = 0.040).
Conclusions
With only partial sympathetic re-innervation of the coronary arteries, maximal dilator capacity of the coronary microvasculature and cold pressor-induced MBF response capacity remain substantially impaired in young adults after ASO compared to healthy controls.

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

Int J Cardiol: 14 Jan 2020; 299:110-115
Possner M, Buechel RR, Vontobel J, Mikulicic F, ... Greutmann M, Kaufmann PA
Int J Cardiol: 14 Jan 2020; 299:110-115 | PMID: 31337551
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Impact:
Abstract

A single-centre, placebo-controlled, double-blind randomised cross-over study of nebulised iloprost in patients with Eisenmenger syndrome: A pilot study.

Nashat H, Kempny A, Harries C, Dormand N, ... Dimopoulos K, Wort SJ
Background
Pulmonary arterial hypertension (PAH), is a rare and progressive disease with a high morbidity and mortality. Prostanoid pulmonary vasodilators are the most effective treatment for idiopathic and connective tissue associated PAH. Nonetheless, data examining their safety and efficacy in patients with Eisenmenger syndrome the most severe form of PAH, that is, related to cyanotic congenital heart disease (CHD-PAH) remains limited.
Aim
To evaluate safety and the clinical efficacy of nebulised iloprost in patients with Eisenmenger syndrome who are on maximum background oral PAH therapy.
Methods
This pilot study was a randomised, double-blind, placebo-controlled, cross-over study. Patients were randomised to receive nebulised placebo or iloprost for 12 weeks and were then crossed over, with a 7-14-day washout. The primary endpoint was a change in 6-minute walk distance (6MWD).
Results
Sixteen patients (11 females, aged 47.3 ± 9.8 year) were recruited, twelve completed the study. All were in WHO-FC III, with a resting oxygen saturation of 84 [81-87] % and a median 6MWD of 290 [260-300] m. There was no significant difference in the primary endpoint between nebulised iloprost (0[-4-9]m) and placebo (10 [-15-51]m), p = 0.58. There were no safety concerns with nebulised iloprost.
Conclusions
Our pilot study provides preliminary evidence that the addition of nebulised iloprost to maximum oral PAH therapy did not improve the primary endpoint of 6MWD. Nebulised iloprost was well tolerated with no significant safety concerns in CHD-PAH.

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

Int J Cardiol: 14 Jan 2020; 299:131-135
Nashat H, Kempny A, Harries C, Dormand N, ... Dimopoulos K, Wort SJ
Int J Cardiol: 14 Jan 2020; 299:131-135 | PMID: 31371115
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Impact:
Abstract

Assessing Pregnancy, Gestational Complications, and Co-morbidities in Women With Congenital Heart Defects (Data from ICD-9-CM Codes in 3 US Surveillance Sites).

Raskind-Hood C, Saraf A, Riehle-Colarusso T, Glidewell J, ... Rodriguez Iii FH, Book WM

Improved treatment of congenital heart defects (CHDs) has resulted in women with CHDs living to childbearing age. However, no US population-based systems exist to estimate pregnancy frequency or complications among women with CHDs. Cases were identified in multiple data sources from 3 surveillance sites: Emory University (EU) whose catchment area included 5 metropolitan Atlanta counties; Massachusetts Department of Public Health (MA) whose catchment area was statewide; and New York State Department of Health (NY) whose catchment area included 11 counties. Cases were categorized into one of 5 mutually exclusive CHD severity groups collapsed to severe versus not severe; specific ICD-9-CM codes were used to capture pregnancy, gestational complications, and nongestational co-morbidities in women, age 11 to 50 years, with a CHD-related ICD-9-CM code. Pregnancy, CHD severity, demographics, gestational complications, co-morbidities, and insurance status were evaluated. ICD-9-CM codes identified 26,655 women with CHDs, of whom 5,672 (21.3%, range: 12.8% in NY to 22.5% in MA) had codes indicating a pregnancy. Over 3 years, age-adjusted proportion pregnancy rates among women with severe CHDs ranged from 10.0% to 24.6%, and 14.2% to 21.7% for women with nonsevere CHDs. Pregnant women with CHDs of any severity, compared with nonpregnant women with CHDs, reported more noncardiovascular co-morbidities. Insurance type varied by site and pregnancy status. These US population-based, multisite estimates of pregnancy among women with CHD indicate a substantial number of women with CHDs may be experiencing pregnancy and complications. In conclusion, given the growing adult population with CHDs, reproductive health of women with CHD is an important public health issue.

Copyright © 2019 Elsevier Inc. All rights reserved.

Am J Cardiol: 08 Dec 2019; epub ahead of print
Raskind-Hood C, Saraf A, Riehle-Colarusso T, Glidewell J, ... Rodriguez Iii FH, Book WM
Am J Cardiol: 08 Dec 2019; epub ahead of print | PMID: 31902476
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Impact:
Abstract

Echocardiographic evaluation of left ventricular filling pressure in patients with heart failure with preserved ejection fraction: usefulness of inferior vena cava measurements and 2016 EACVI/ASE recommendations.

Berthelot E, Jourdain P, Bailly MT, Bouchachi A, ... Chemla D, Assayag P

Context;: The left ventricular filling pressure (LVFP) is correlated to right atrial pressure (RAP) in heart failure.  We compared diagnostic value of the inferior vena cava (IVC) measurements to the one of the 2016 echocardiographic recommendations to estimate LVFP in patients with suspected heart failure with preserved ejection fraction (HFpEF). METHODS;: Invasive hemodynamics and echocardiography were obtained within 48h in 132 consecutive patients with left ventricular ejection fraction (LVEF)≥50%, and suspected pulmonary hypertension. Increased LVFP was defined by a pulmonary artery wedge pressure (PAWP)>15mmHg. RESULTS;: In 83 sinus rhythm patients, a score of the 2016 recommendations ≥ 2 (E/e\' ratio >14 and/or tricuspid regurgitation velocity>2.8m/s and/or indexed left atrial volume>34ml/m²) had a PPV of 63% for PAWP>15mmHg, whereas a dilated IVC (>2.1 cm) and/or non-collapsible (≤50%) had a PPV of 83%. The net reclassification improvement was 0.44 (p<0.05). In atrial fibrillation (AF), a dilated and/or non-collapsible IVC had an 86% PPV for PAWP>15mmHg. The correlation between RAP and PAWP was 0.60, with 75.7% concordance (100/132) between dichotomized pressures (both RAP>8 mmHg and PAWP>15mmHg and vice-versa). CONCLUSION;: The IVC size and collapsibility is valuable to identify HFpEF patients with high LVFP in both sinus rhythm and AF.

Copyright © 2020. Published by Elsevier Inc.

J Card Fail: 29 Jan 2020; epub ahead of print
Berthelot E, Jourdain P, Bailly MT, Bouchachi A, ... Chemla D, Assayag P
J Card Fail: 29 Jan 2020; epub ahead of print | PMID: 32007555
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Impact:
Abstract

Implantable Cardioverter-Defibrillators and Patient-Reported Outcomes in Adults with Congenital Heart Disease: an International Study.

Lévesque V, Laplante L, Shohoudi A, Apers S, ... Khairy P,
Background
Implantable cardioverter-defibrillators (ICDs) are increasingly used to prevent sudden deaths in the growing population of adults with congenital heart disease (CHD). Yet, little is known about their impact on patient-reported outcomes (PROs).
Objective
We assessed and compared PROs in adults with CHD with and without ICDs.
Methods
A propensity-based matching weight analysis was conducted to evaluate PROs in an international cross-sectional study of adults with CHD from 15 countries across 5 continents.
Results
A total of 3,188 patients were included: 107 with ICDs and 3,081 weight-matched controls without ICDs. ICD recipients averaged 40.1±12.4 years of age, with >95% having moderate or complex CHD. Defibrillators were implanted for primary and secondary prevention in 38.3% and 61.7%, respectively. Perceived health status, psychological distress, sense of coherence, and health behaviours did not differ significantly in patients with and without ICDs. However, ICD recipients had a more threatening view of their illness (relative % difference 8.56, P=0.011). Those with secondary compared to primary prevention indications had a significantly lower quality of life score (linear analogue scale 72.0±23.1 versus 79.2±13.0, P=0.047). Marked geographic variations were observed. Overall sense of well-being, assessed by a summary score that combines various PROs, was significantly lower in ICD recipients (versus controls) from Switzerland, Argentina, Taiwan, and USA.
Conclusions
In an international cohort of adults with CHD, ICDs were associated with a more threatening illness perception, with a lower quality of life in those with secondary compared to primary prevention indications. However, marked geographic variability in PROs was observed.

Copyright © 2019. Published by Elsevier Inc.

Heart Rhythm: 28 Nov 2019; epub ahead of print
Lévesque V, Laplante L, Shohoudi A, Apers S, ... Khairy P,
Heart Rhythm: 28 Nov 2019; epub ahead of print | PMID: 31790832
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Impact:
Abstract

mAdverse Event Rate during Inpatient Sotalol Initiation for the Management of Supraventricular and Ventricular Tachycardia in the Pediatric and Young Adult Population.

Chandler SF, Chu E, Whitehill RD, Bevilacqua LM, ... Walsh EP, Mah DY
Background
Sotalol is an important antiarrhythmic in the pediatric population. Given the risk for proarrhythmia, sotalol is initiated in inpatient settings, with adult studies as recent as 2015 supporting this practice.
Objective
To determine the frequency of adverse events (AE) during sotalol initiation for the management of atrial, supraventricular or ventricular arrhythmias in pediatric patients.
Methods
A retrospective cohort analysis of pediatric patients <21 years of age initiated on oral sotalol for SVT or VT at Boston Children\'s Hospital from January 1, 2007-July 1, 2016 was performed. The primary endpoint was an adverse event (AE) defined as significant bradycardia, new or increased ventricular arrhythmias, conduction block or corrected QT interval (QTc) prolongation resulting in dose reduction or cessation.
Results
There were 190 patients who met inclusion criteria, with 110 patients (58%) < 6 months old. 115 patients (60%) had congenital heart disease (CHD). Arrhythmias for which sotalol was started included AV-reciprocating tachycardia/AV nodal reciprocating tachycardia 105 patients (55%), atrial flutter 31 patients (16%), ectopic atrial tachycardia 26 patients (14%), VT 21 patients (11%), and atrial fibrillation 7 patients (4%). The median pre-sotalol QTc was 438 milliseconds (msec) (range 348-530msec). Five patients (3%) had AEs (ages 0.1-18 yrs) including bradycardia <40 beats per minute (bpm) (n=2) and <100bpm (n=1) and QTc prolongation (n=2). All 5 patients with AEs had repaired CHD.
Conclusion
The incidence of AE in pediatric patients initiating sotalol for AT, SVT or VT is low (3%) with no deaths or malignant rhythms reported in this series.

Copyright © 2020. Published by Elsevier Inc.

Heart Rhythm: 30 Jan 2020; epub ahead of print
Chandler SF, Chu E, Whitehill RD, Bevilacqua LM, ... Walsh EP, Mah DY
Heart Rhythm: 30 Jan 2020; epub ahead of print | PMID: 32014568
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Impact:
Abstract

Rationale and design of CH STRONG: Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG.

Farr SL, Klewer SE, Nembhard WN, Alter C, ... Riser AP, Oster ME

Studies of outcomes among adults with congenital heart defects (CHDs) have focused on those receiving cardiac care, limiting generalizability. The Congenital Heart Survey To Recognize Outcomes, Needs, and well-beinG (CH STRONG) will assess comorbidities, health care utilization, quality of life, and social and educational outcomes from a US population-based sample of young adults living with CHD.
Methods
Individuals with CHD born between 1980 and 1997 were identified using active, population-based birth defects surveillance systems from 3 US locations (Arkansas [AR]; Arizona [AZ]; and Atlanta, Georgia [GA]) linked to death records. Individuals with current contact information responded to mailed survey materials during 2016 to 2019. Respondents and nonrespondents were compared using χ tests.
Results
Sites obtained contact information for 74.6% of the 9,312 eligible individuals alive at recruitment. Of those, 1,656 returned surveys, either online (18.1%) or via paper (81.9%), for a response rate of 23.9% (AR: 18.3%; AZ: 30.7%; Atlanta, GA: 28.0%; P value < .01). For 20.0% of respondents, a proxy completed the survey, with 63.9% reporting that the individual with CHD was mentally unable. Among respondents and nonrespondents, respectively, sex (female: 54.0% and 47.3%), maternal race/ethnicity (non-Hispanic white: 74.3% and 63.0%), CHD severity (severe: 33.8% and 27.9%), and noncardiac congenital anomalies (34.8% and 38.9%) differed significantly (P value < .01); birth year (1991-1997: 56.0% and 57.5%) and presence of Down syndrome (9.2% and 8.9%) did not differ.
Conclusions
CH STRONG will provide the first multisite, population-based findings on long-term outcomes among the growing population of US adults with CHD.

Published by Elsevier Inc.

Am Heart J: 08 Jan 2020; 221:106-113
Farr SL, Klewer SE, Nembhard WN, Alter C, ... Riser AP, Oster ME
Am Heart J: 08 Jan 2020; 221:106-113 | PMID: 31986287
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Impact:
Abstract

Contraceptive methods of privately insured US women with congenital heart defects.

Anderson KN, Tepper NK, Downing K, Ailes EC, Abarbanell G, Farr SL
Background
The American Heart Association recommends women with congenital heart defects (CHD) receive contraceptive counseling early in their reproductive years, but little is known about contraceptive method use among women with CHD. We describe recent female sterilization and reversible prescription contraceptive method use by presence of CHD and CHD severity in 2014.
Methods
Using IBM MarketScan Commercial Databases, we included women aged 15 to 44 years with prescription drug coverage in 2014 who were enrolled ≥11 months annually in employer-sponsored health plans between 2011 and 2014. CHD, CHD severity, contraceptive methods, and obstetrics-gynecology and cardiology provider encounters were identified using billing codes. We used log-binomial regression to calculate adjusted prevalence ratios (aPRs) and 95% confidence intervals (CIs) to compare contraceptive method use overall and by effectiveness tier by CHD presence and, for women with CHD, severity.
Results
Recent sterilization or current reversible prescription contraceptive method use varied slightly among women with (39.2%) and without (37.3%) CHD, aPR = 1.04, 95% CI [1.01-1.07]. Women with CHD were more likely to use any Tier I method (12.9%) than women without CHD (9.3%), aPR = 1.41, 95% CI [1.33-1.50]. Women with severe, compared to non-severe, CHD were less likely to use any method, aPR = 0.85, 95% CI [0.78-0.92], or Tier I method, aPR = 0.84, 95% CI [0.70-0.99]. Approximately 60% of women with obstetrics-gynecology and <40% with cardiology encounters used any included method.
Conclusions
There may be missed opportunities for providers to improve uptake of safe, effective contraceptive methods for women with CHD who wish to avoid pregnancy.

Published by Elsevier Inc.

Am Heart J: 20 Jan 2020; 222:38-45
Anderson KN, Tepper NK, Downing K, Ailes EC, Abarbanell G, Farr SL
Am Heart J: 20 Jan 2020; 222:38-45 | PMID: 32014720
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Impact:
Abstract

Nationwide Frequency, Sequential Trends, and Impact of Co-morbid Mental Health Disorders on Hospitalizations, Outcomes, and Healthcare Resource Utilization in Adult Congenital Heart Disease.

Desai R, Patel K, Dave H, Shah K, ... Khanna A, Kumar G

Despite the growing prevalence of adult congenital heart disease (ACHD), data on trends in prevalence of mental health disorders (MHD) among patients with ACHD remain limited. The National Inpatient Sample (2007 to 2014) was queried to identify the frequency and trends of MHD among ACHD hospitalizations (stratification by age, sex, and race); demographics and co-morbidities for ACHD cohorts, with (MHD+) versus without MHD (MHD-); the rate and trends of all-cause in-hospital mortality, disposition, mean length of stay, and hospitalization charges among both cohorts. A total of 11,709 (13.8%, mean age: 49.1 years, 56.0% females, 78.7% white) out of 85,029 ACHD patient encounters had a coexistent MHD (anxiety, depression, mood disorder, or psychosis). ACHD-MHD+ cohort was more often admitted nonelectively (38.1% vs 32.8%, p <0.001) and had a higher frequency of cardiac/extra-cardiac co-morbidities. The trends in prevalence of coexistent MHD increased from 10.3% to 17.5% (70% relative increase) from 2007 to 2014 with a consistently higher prevalence among females (from 13% to 20.3%) compared to males (from 7.6% to 15.5%) (p <0.001). The hospitalization trends with MHD increased in whites (12.1% to 19.8%) and Hispanics (5.9% to 12.7%). All-cause mortality was lower (0.7% vs 1.1%, p = 0.002) in ACHD-MHD+; however, mean length of stay (∼5.7 vs 4.9 days, p <0.001) was higher without significant difference in charges ($97,710 vs $96,058, p = 0.137). ACHD-MHD+ cohort was less often discharged routinely (declining trend) and more frequently transferred to other facilities and required home healthcare (rising trends). In conclusion, this study reveals increasing trends of MHD, healthcare resource utilization and a higher frequency of co-morbidities in patients with ACHD.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 29 Jan 2020; epub ahead of print
Desai R, Patel K, Dave H, Shah K, ... Khanna A, Kumar G
Am J Cardiol: 29 Jan 2020; epub ahead of print | PMID: 32085866
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Impact:
Abstract

Long-term outcomes of percutaneous closure of coronary artery fistulae in the adult: A single-center experience.

Shah AH, Osten M, Benson L, Alnasser S, ... Meier L, Horlick E

Coronary artery fistulae (CAF) are rare congenital cardiac abnormalities. With increasing age, patients with moderate to large fistulae are likely to become symptomatic and encounter complications. Percutaneous closure has been accepted as a safe and effective alternative to surgery; however, information regarding long-term outcomes in adult patients after transcatheter closure is limited.
Methods
We describe our 20-year experience with percutaneous closure of CAF in adult patients, focusing on long-term outcomes.
Results
From 1995 to 2015, 25 adult patients underwent 33 transcatheter interventions to close 26 CAF at our institution. Mean age was 51.4 ± 16.8 years, and 14 (56%) were female. All the patients were symptomatic with dyspnea (21/25, 84%) being the most common complaint followed by chest pain (17/25, 68%), palpitations (9/25, 36%), and heart failure (2/25, 8%). Two patients presented with acute coronary syndrome, whereas 10/25 (40%) also had inducible ischemia on stress test. These CAFs were classified as medium (12, 46.2%), large (5, 19.2%), and giant (9, 34.6%). Immediately postprocedure complete occlusion was achieved in 21 (21/26, 81%), and residual trace leak was observed in three fistulae, whereas we could not deliver coils/device in two cases. Periprocedural complications occurred in the form of coronary dissection (n = 1), myocardial infarction (n = 2), coil embolization (n = 1), transient ST elevation (n = 1); the majority of complications were observed in the early years of our experience. Patients reported marked improvement in symptoms after the intervention. During a mean follow-up of 76 ± 69 (5-214 months) (n = 22), 15 patients were investigated by either conventional (n = 6) or CT angiography (n = 8) or both (n = 1) that demonstrated thrombotic occlusion of a proximal coronary artery where a distal fistula was treated. Another patient was noted to have thrombus proximal to a vascular plug in a distal giant fistula. Three patients were lost to follow-up. None of the investigated patients had recanalization of their fistula. We did not observe remodeling of the native coronary artery that was feeding the fistula, even after successful complete closure.
Conclusion
Percutaneous device closure of CAF is a feasible and effective therapeutic intervention in adult patients; however, patients with distal fistulas represent a significant challenge and the outcomes of these procedures are in question. All patients should have long-term angiographic follow-up.

© 2019 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 25 Dec 2019; epub ahead of print
Shah AH, Osten M, Benson L, Alnasser S, ... Meier L, Horlick E
Catheter Cardiovasc Interv: 25 Dec 2019; epub ahead of print | PMID: 31876376
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Impact:
Abstract

Hybrid trans-apical atrioventricular valve-in-valve implantation in Fontan circulation.

Butera G, Lucchese G, Austin C, Frigiola A

Trans-apical approach has been proved successful in failing surgical bio-prosthesis in both mitral and aortic position in adult patients. Recently, valve-in-valve treatments have been applied even in patients with complex congenital heart disease. Here, we report the case of a 32 years old lady with left atrial isomerism, complete AV septal defect, interrupted inferior vena cava with azygos continuation who underwent Kawashima procedure with atrial Fontan. Severe systemic atrioventricular valve regurgitation necessitated a 33 mm Perimount valve implantation and conversion to lateral tunnel Fontan. After only 4 years there was severe valve stenosis and the patient underwent successful trans-apical transcatheter implantation of a 29 mm Sapien valve.

© 2020 Wiley Periodicals, Inc.

Catheter Cardiovasc Interv: 07 Jan 2020; epub ahead of print
Butera G, Lucchese G, Austin C, Frigiola A
Catheter Cardiovasc Interv: 07 Jan 2020; epub ahead of print | PMID: 31912986
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Impact:
Abstract

Parameters of Right Ventricular Function Reveal Ventricular-Vascular Mismatch as Determined by Right Ventricular Stroke Work versus Pulmonary Vascular Resistance in Children with Pulmonary Hypertension.

Di Maria MV, Campbell KR, Burkett DA, Younoszai AK, ... Hunter KS, Friedberg MK
Background
Right ventricular (RV) failure, a determinant of outcomes in pulmonary hypertension (PH), occurs when the right ventricle cannot compensate for increased afterload. The authors showed that RV stroke work (RVSW) can be estimated in children with PH as the product of stroke volume and RV pressure and is related to adverse outcomes. The aim of this study was to test the hypothesis that ventricular-vascular (VV) mismatch (high afterload and low RVSW) is associated with echocardiographic measures of RV performance and adverse outcomes.
Methods
Invasive hemodynamic data and concurrent echocardiograms were reviewed. Fifty subjects with PH were included. Four groups were created by dividing the patients using median RVSW and median pulmonary vascular resistance. For each group, tricuspid annular plane systolic excursion, fractional area change, myocardial performance index, and anterior RV wall thickness were determined. Both major (i.e., death) and minor (i.e., worsening World Health Organization class) clinical outcomes were tabulated. Groups were compared using the Kruskal-Wallis or Fisher exact test.
Results
Patients in the high pulmonary vascular resistance/low RVSW cohort (VV mismatch) had the worst RV dysfunction: median tricuspid annular plane systolic excursion, 0.8 cm (interquartile range, 0.7-0.8 cm; P = .0002); median fractional area change, 0.29% (interquartile range, 0.27%-0.30%; P = .004); median myocardial performance index, 0.622 (interquartile range, 0.548-0.789; P = .0004). This group had the highest incidence of adverse outcomes: major events in 40%, minor events in 80%, and syncope in 60%.
Conclusion
VV mismatch in pediatric PH can be assessed using RVSW and pulmonary vascular resistance and is associated with RV performance and adverse events. RVSW increases in compensated high-afterload states and falls as the right ventricle fails to meet increased load; thus, VV matching status may be a sensitive predictor of outcomes in pediatric PH.

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

J Am Soc Echocardiogr: 09 Dec 2019; epub ahead of print
Di Maria MV, Campbell KR, Burkett DA, Younoszai AK, ... Hunter KS, Friedberg MK
J Am Soc Echocardiogr: 09 Dec 2019; epub ahead of print | PMID: 31836268
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Impact:
Abstract

Disrupted ER membrane protein complex-mediated topogenesis drives congenital neural crest defects.

Marquez J, Criscione J, Charney RM, Prasad MS, ... García-Castro MI, Khokha MK

Multipass membrane proteins have a myriad of functions, including transduction of cell-cell signals, ion transport, and photoreception. Insertion of these proteins into the membrane depends on the endoplasmic reticulum (ER) membrane protein complex (EMC). Recently, birth defects have been observed in patients with variants in the gene encoding a member of this complex, EMC1. Patient phenotypes include congenital heart disease, craniofacial malformations, and neurodevelopmental disease. However, a molecular connection between EMC1 and these birth defects is lacking. Using Xenopus, we identified defects in neural crest cells (NCCs) upon emc1 depletion. We then used unbiased proteomics and discovered a critical role for emc1 in WNT signaling. Consistent with this, readouts of WNT signaling and Frizzled (Fzd) levels were reduced in emc1-depleted embryos, while NCC defects could be rescued with β-catenin. Interestingly, other transmembrane proteins were mislocalized upon emc1 depletion, providing insight into additional patient phenotypes. To translate our findings back to humans, we found that EMC1 was necessary for human NCC development in vitro. Finally, we tested patient variants in our Xenopus model and found the majority to be loss-of-function alleles. Our findings define molecular mechanisms whereby EMC1 dysfunction causes disease phenotypes through dysfunctional multipass membrane protein topogenesis.



J Clin Invest: 05 Jan 2020; epub ahead of print
Marquez J, Criscione J, Charney RM, Prasad MS, ... García-Castro MI, Khokha MK
J Clin Invest: 05 Jan 2020; epub ahead of print | PMID: 31904590
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Impact:
Abstract

Congenital pituitary hypoplasia model demonstrates hypothalamic OTX2 regulation of pituitary progenitor cells.

Matsumoto R, Suga H, Aoi T, Bando H, ... Ogawa W, Takahashi Y

Pituitary develops from oral ectoderm in contact with adjacent ventral hypothalamus. Impairment in this process results in congenital pituitary hypoplasia (CPH); however, there have been no human disease models for CPH thus far, prohibiting the elucidation of the underlying mechanisms. In this study, we established a disease model of CPH using patient-derived induced pluripotent stem cells (iPSCs) and 3D organoid technique, in which oral ectoderm and hypothalamus develop simultaneously. Interestingly, patient iPSCs with a heterozygous mutation in the orthodenticle homeobox 2 (OTX2) gene showed increased apoptosis in the pituitary progenitor cells, and the differentiation into pituitary hormone-producing cells was severely impaired. As an underlying mechanism, OTX2 in hypothalamus, not in oral ectoderm, was essential for progenitor cell maintenance by regulating LHX3 expression in oral ectoderm via FGF10 expression in the hypothalamus. Convincingly, the phenotype was reversed by the correction of the mutation, and the haploinsufficiency of OTX2 in control iPSCs revealed a similar phenotype, demonstrating that this mutation was responsible. Thus, we established an iPSC-based congenital pituitary disease model, which recapitulated interaction between hypothalamus and oral ectoderm and demonstrated the essential role of hypothalamic OTX2.



J Clin Invest: 16 Dec 2019; epub ahead of print
Matsumoto R, Suga H, Aoi T, Bando H, ... Ogawa W, Takahashi Y
J Clin Invest: 16 Dec 2019; epub ahead of print | PMID: 31845906
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Impact:
Abstract

XMEN: welcome to the glycosphere.

Freeze HH

XMEN (X-linked immunodeficiency with magnesium defect, EBV infection, and neoplasia) is a complex primary immunological deficiency caused by mutations in MAGT1, a putative magnesium transporter. In this issue of the JCI, Ravell et al. greatly expand the clinical picture. The authors investigated patients\' mutations and symptoms and reported distinguishing immunophenotypes. They also showed that MAGT1 is required for N-glycosylation of key T cell and NK cell receptors that can account for some of the clinical features. Notably, transfection of the affected lymphocytes with MAGT1 mRNA restored both N-glycosylation and receptor function. Now we can add XMEN to the ever-growing family of congenital disorders of glycosylation (CDG).



J Clin Invest: 08 Dec 2019; epub ahead of print
Freeze HH
J Clin Invest: 08 Dec 2019; epub ahead of print | PMID: 31815737
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Impact:
Abstract

Clinical Utility of Echocardiography in Former Preterm Infants with Bronchopulmonary Dysplasia.

Nawaytou H, Steurer MA, Zhao Y, Guslits E, ... Fineman JR, Keller RL
Background
The clinical utility of echocardiography for the diagnosis of pulmonary vascular disease (PVD) in former preterm infants with bronchopulmonary dysplasia (BPD) is not established. Elevated pulmonary vascular resistance (PVR) rather than pulmonary artery pressure (PAP) is the hallmark of PVD. We evaluated the utility of echocardiography in infants with BPD in diagnosing pulmonary hypertension and PVD (PVR >3 Wood units × m) assessed by cardiac catheterization.
Methods
A retrospective single center study of 29 infants born ≤29 weeks of gestational age with BPD who underwent cardiac catheterization and echocardiography was performed. PVD was considered present by echocardiography if the tricuspid valve regurgitation jet peak velocity was >2.9 m/sec, post-tricuspid valve shunt systolic flow velocity estimated a right ventricular systolic pressure >35 mm Hg, or systolic septal flattening was present. The utility (accuracy, sensitivity, and positive predictive value [PPV]) of echocardiography in the diagnosis of PVD was tested. Subgroup analysis in patients without post-tricuspid valve shunts was performed. Echocardiographic estimations of right ventricular pressure, dimensions, function, and pulmonary flow measurements were evaluated for correlation with PVR.
Results
The duration between echocardiography and cardiac catheterization was a median of 1 day (interquartile range, 1-4 days). Accuracy, sensitivity, and PPV of echocardiography in diagnosing PVD were 72%, 90.5%, and 76%, respectively. Accuracy, sensitivity, and PPV increased to 93%, 91.7%, and 100%, respectively, when infants with post-tricuspid valve shunts were excluded. Echocardiography had poor accuracy in estimating the degree of PAP elevation by cardiac catheterization. In infants without post-tricuspid valve shunts, there was moderate to good correlation between indexed PVR and right ventricular myocardial performance index (rho = 0.89, P = .005), systolic to diastolic time index (0.84, P < .001), right to left ventricular diameter ratio at end systole (0.66, P = .003), and pulmonary artery acceleration time (0.48, P = .05).
Conclusions
Echocardiography performs well in screening for PVD in infants with BPD and may be diagnostic in the absence of a post-tricuspid valve shunt. However, cardiac catheterization is needed to assess the degree of PAP elevation and PVR. The diagnostic utility of echocardiographic measurements that correlate with PVR should be evaluated prospectively in this patient population.

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

J Am Soc Echocardiogr: 12 Jan 2020; epub ahead of print
Nawaytou H, Steurer MA, Zhao Y, Guslits E, ... Fineman JR, Keller RL
J Am Soc Echocardiogr: 12 Jan 2020; epub ahead of print | PMID: 31948712
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Impact:
Abstract

Outpatient volumes and medical staffing resources as predictors for continuity of follow-up care during transfer of adolescents with congenital heart disease.

Skogby S, Moons P, Johansson B, Sunnegårdh J, ... Goossens E, Bratt EL
Background
Providing continuous follow-up care to patients with congenital heart disease (CHD) remains a challenge in many settings. Previous studies highlight that patients with CHD experience discontinuation of follow-up care, but mainly describe a single-centre perspective, neglecting inter-institutional variations. Hospital-related factors above and beyond patient-related factors are believed to affect continuity of care. The present multicentre study therefore investigated (i) proportion of \"no follow-up care\"; (ii) transfer destinations after leaving paediatric cardiology; (iii) variation in proportions of no follow-up between centres; (iv) the association between no follow-up and outpatient volumes, and (v) its relationship with staffing resources at outpatient clinics.
Methods
An observational, multicentre study was conducted in seven university hospitals. In total, 654 adolescents with CHD, born between 1991 and 1993, with paediatric outpatient visit at age 14-18 years were included. Transfer status was determined 5 years after the intended transfer to adult care (23y), based on medical files, self-reports and registries.
Results
Overall, 89.7% of patients were receiving adult follow-up care after transfer; 6.6% had no follow-up; and 3.7% were untraceable. Among patients in follow-up care, only one remained in paediatric care and the majority received specialist adult CHD care. Significant variability in proportions of no follow-up were identified across centres. Higher outpatient volumes at paediatric outpatient clinics were associated with better continued follow-up care after transfer (OR = 1.061; 95% CI = 1.001 - 1.124). Medical staffing resources were not found predictive.
Conclusion
Our findings support the theory of hospital-related factors influencing continuity of care, above and beyond patient-related characteristics.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 16 Jan 2020; epub ahead of print
Skogby S, Moons P, Johansson B, Sunnegårdh J, ... Goossens E, Bratt EL
Int J Cardiol: 16 Jan 2020; epub ahead of print | PMID: 31959410
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Impact:
Abstract

Pulmonary hypertension after shunt closure in patients with simple congenital heart defects.

Lammers AE, Bauer LJ, Diller GP, Helm PC, ... Baumgartner H,
Background
Patients with simple shunt lesions, such as atrial septal defect (ASD), ventricular septal defect (VSD) and persistent arterial duct (PDA) remain at risk of developing pulmonary hypertension (PH) even after correction of their cardiac defect. We aimed to assess the contemporary prevalence of PH in a well characterized nationwide group of patients based on the German National Register for Congenital Heart Defects.
Methods and results
We included all patients >16 years of age with an isolated diagnosis of ASD, VSD or PDA. Only patients with previous surgical or interventional closure of the defect were included. Patients with genetic syndromes were excluded. Out of 49,597 CHD patients in the register we identified 825 patients with closed, isolated simple defects (52% ASD, 41% VSD, 7% PDA). Of these, 25 (3%) developed PH after a median follow-up of 16 years from defect closure. The risk of PH increased significantly with age at follow-up (p < 0.0001) and age at repair (p < 0.0001) on logistic regression analysis Patients with PH were significantly more likely to be symptomatic (59% vs. 9% in NYHA class ≥2, p < 0.0001) and had significantly higher mortality (hazard ratio 13.4, p < 0.0001) compared to the remaining patients.
Conclusions
Based on data from the German National Register CHD Register we report a PH prevalence of 3.0% in patients with corrected, simple lesions. Patients with PH were more symptomatic and had significantly increased mortality risk. Life-long surveillance and low threshold for workup is recommended to ascertain diagnosis of PH, which has important prognostic and clinical implications.

Copyright © 2018. Published by Elsevier B.V.

Int J Cardiol: 01 Jan 2020; epub ahead of print
Lammers AE, Bauer LJ, Diller GP, Helm PC, ... Baumgartner H,
Int J Cardiol: 01 Jan 2020; epub ahead of print | PMID: 31926641
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Impact:
Abstract

Early detection of ventricular arrhythmias in adults with congenital heart disease using an insertable cardiac monitor (EDVA-CHD study).

Sakhi R, Kauling RM, Theuns DA, Szili-Torok T, ... Roos-Hesselink JW, Yap SC
Background
Sudden cardiac death (SCD) due to ventricular arrhythmias (VA) is an important mode of death in adults with congenital heart disease (CHD). Risk stratification is difficult in this heterogeneous population. Insertable cardiac monitors (ICM) may be useful for risk stratification. The purpose of the present study was to evaluate the use of ICM for the detection of VA in adults with CHD.
Methods
In this prospective single-center observational study we included consecutive adults with CHD deemed at risk of VA who received an ICM between March 2013 and February 2019. The decision to implant an ICM was made in a Heart Team consisting of a cardiac electrophysiologist and a cardiologist specialized in CHD.
Results
A total of 30 patients (mean age, 38 ± 15 years; 50% male) received an ICM. During a median follow-up of 16 months, 8 patients (27%) had documented nonsustained VA. Of these 8 patients, 3 (10%) received a prophylactic ICD. Furthermore, ICM-detected arrhythmias were present in 22 patients (73%) leading to a change in clinical management in 16 patients (53%). Besides the patients receiving an ICD, 10 patients (33%) had a change in their antiarrhythmic drugs, 6 patients (20%) underwent an electrophysiology study, and 1 patient (3%) received a pacemaker.
Conclusions
The detection of VA by the ICM contributed to the clinical decision to implant a prophylactic ICD. Furthermore, ICM-detected arrhythmias led to important changes in the clinical management. Therefore, long-term arrhythmia monitoring by an ICM seems valuable for risk stratification in adults with CHD.

Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.

Int J Cardiol: 03 Feb 2020; epub ahead of print
Sakhi R, Kauling RM, Theuns DA, Szili-Torok T, ... Roos-Hesselink JW, Yap SC
Int J Cardiol: 03 Feb 2020; epub ahead of print | PMID: 32057477
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Impact:
Abstract

Biomarker profile in stable Fontan patients.

Saraf A, De Staercke C, Everitt I, Haouzi A, ... Quyyumi A, Book W
Background
As the population of adults with congenital heart disease (CHD) grows, cardiologists continue to encounter patients with complex anatomies that challenge the standard treatment of care. Single ventricle Fontan palliated patients are the most complex within CHD, with a high morbidity and mortality burden. Factors driving this early demise are largely unknown.
Methods and results
We analyzed biomarker expression in 44 stable Fontan outpatients (29.2 ± 10.7 years, 68.2% female) seen in the outpatient Emory Adult Congenital Heart Center and compared them to 32 age, gender and race matched controls. In comparison to controls, Fontan patients had elevated levels of multiple cytokines within the inflammatory pathway including Tumor Necrosis Factor-α (TNF-α) (p < 0.001), Interleukin-6 (IL-6) (p < 0.011), Growth Derived Factor-15 (GDF-15) (p < 0.0001), β2-macroglobulin, (p = 0.0006), stem cell mobilization: Stromal Derived Factor-1∝ (SDF-1α) (p = 0.006), extracellular matrix turnover: Collagen IV (p < 0.0001), neurohormonal activation: Renin (p < 0.0001), renal dysfunction: Cystatin C (p < 0.0001) and Urokinase Receptor (uPAR) (p = 0.022), cardiac injury: Troponin-I (p < 0.0004) and metabolism: Adiponectin (p = 0.0037). Within 1 year of enrollment 50% of Fontan patients had hospitalizations, arrhythmias or worsening hepatic function. GDF-15 was significantly increased in Fontan patients with clinical events (p < 0.0001). In addition, GDF-15 moderately correlated with longer duration of Fontan (r = 0.55, p = 0.01) and was elevated in atriopulmonary (AP) Fontan circulation. Finally, in a multivariate model, VEGF-D and Collagen IV levels were found to be associated with a change in MELDXI, a marker of liver dysfunction.
Conclusion
Multiple clinical and molecular biomarkers are upregulated in Fontan patients, suggesting a state of chronic systemic dysregulation.

Copyright © 2020 Elsevier B.V. All rights reserved.

Int J Cardiol: 08 Jan 2020; epub ahead of print
Saraf A, De Staercke C, Everitt I, Haouzi A, ... Quyyumi A, Book W
Int J Cardiol: 08 Jan 2020; epub ahead of print | PMID: 31959411
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Impact:
Abstract

Incidence of Type 1 diabetes mellitus and effect on mortality in young patients with congenital heart defect - A nationwide cohort study.

Björk A, Mandalenakis Z, Giang KW, Rosengren A, Eriksson P, Dellborg M
Background
1% of all live born children are born with a congenital heart defect (CHD) and currently 95% reach adulthood. Type 1 diabetes mellitus (T1DM) is an autoimmune disease that can develop due to i.e. heredity, exposure to infections and stress-strain. The incidence of T1DM in patients with CHD is unknown and we analysed the risk of developing T1DM for patients with CHD, and how this influences mortality.
Methods
By combining registries, the incidence of T1DM and the mortality was analysed in patients with CHD by birth cohort (1970-1993, 1970-1984 and 1984-1993) matched with population-based controls matched for sex, county and year of birth without CHD and followed from birth until a maximum of 42 years.
Results
221 patients with T1DM among 21,982 patients with CHD and 1553 patients with T1DM among 219,816 matched controls were identified. The hazard ratio (HR) for developing T1DM was 1.50 (95%, CI 1.31-1.73) in patients with CHD compared to the controls and the first birth cohort (1970-1984) had the highest risk for T1DM, HR 1.87 (95%, CI 1.56-2.24). After onset, mortality risk was 4.21 times higher (95%, CI 2.40-7.37) in patients with CHD and T1DM compared to controls with T1DM.
Conclusion
From a nationwide cohort of patients with CHD and controls, the incidence of developing T1DM was 50% higher in patients with CHD, showing a significant increase in risk among birth cohort 1970-1984. The combination of CHD and T1DM was associated with a 4-fold increase in mortality compared to controls with only T1DM.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 09 Jan 2020; epub ahead of print
Björk A, Mandalenakis Z, Giang KW, Rosengren A, Eriksson P, Dellborg M
Int J Cardiol: 09 Jan 2020; epub ahead of print | PMID: 32001038
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Impact:
Abstract

Comprehensive Diagnostic Evaluation of Cardiovascular Physiology in Patients With Pulmonary Vascular Disease: Insights From the PVDOMICS Program.

Tang WHW, Wilcox JD, Jacob MS, Rosenzweig EB, ... Leopold JA, Rischard FP
Background
Invasive hemodynamic evaluation through right heart catheterization plays an essential role in the diagnosis, categorization, and risk stratification of patients with pulmonary hypertension.
Methods
Subjects enrolled in the PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) program undergo an extensive invasive hemodynamic evaluation that includes repeated measurements at rest and during several provocative physiological challenges. It is a National Institutes of Health/National Heart, Lung, and Blood Institute initiative to reclassify pulmonary hypertension groups based on clustered phenotypic and phenomic characteristics. At a subset of centers, participants also undergo an invasive cardiopulmonary exercise test to assess changes in hemodynamics and gas exchange during exercise.
Conclusions
When coupled with other physiological testing and blood -omic analyses involved in the PVDOMICS study, the comprehensive right heart catheterization protocol described here holds promise to clarify the diagnosis and clustering of pulmonary hypertension patients into cohorts beyond the traditional 5 World Symposium on Pulmonary Hypertension groups. This article will describe the methods applied for invasive hemodynamic characterization in the PVDOMICS program. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02980887.



Circ Heart Fail: 28 Feb 2020; 13:e006363
Tang WHW, Wilcox JD, Jacob MS, Rosenzweig EB, ... Leopold JA, Rischard FP
Circ Heart Fail: 28 Feb 2020; 13:e006363 | PMID: 32088984
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Impact:
Abstract

\"The post-pulmonary syndrome - results of echocardiographic driven follow up after acute pulmonary embolism\".

Dzikowska-Diduch O, Kostrubiec M, Kurnicka K, Lichodziejewska B, ... Gołębiowski M, Pruszczyk P
Introduction
The concept of post Pulmonary Embolism syndrome includes various combinations of functional, haemodynamic or imaging abnormalities in patients after pulmonary embolism (PE). Although residual obstruction of pulmonary vascular bed is suggested to be a major cause of post Pulmonary Embolism syndrome (post-PE syndrome) other cardiopulmonary abnormalities can be responsible for functional impairment. Therefore, we analyzed the frequency of post-PE syndrome and its potential causes.
Material and methods
We report data of consecutive 845 PE survivors (468 F, aged 62 ± 18 yrs) who were anticoagulated, and followed for at least 6 months. All symptomatic subjects at follow up underwent diagnostic workup.
Results
35% (290/845) of PE survivors recovered functionally, while 65% patients reported a decreased exercise tolerance compatible with post-PE syndrome. One hundred and five symptomatic cases were lost to follow up. After diagnostic workup, chronic thromboembolic pulmonary hypertension (CTEPH) was diagnosed in 38 of 450 (8.4%) symptomatic subjects and chronic thromboembolic pulmonary disease (CTED) was diagnosed in 15/450 (3.3%) of them. Chronic heart failure with reduced ejection fraction (EF) was found in 6.9% (31/450) of patients and 154 patients (34.2%) had leftsided diastolic dysfunction. Valve heart disease was detected in 6.2% (28/450), atrial fibrillation in 31/450 (6.9%), Other causes of reduced exercise tolerance include coronary artery disease in 31/450 (6.9%), pulmonary disease 42/450 (9.3%), morbid obesity 15/450 (3.3%), neoplasms 15/450 (3.3%), psychiatric disorders 1%, rheumatoid disease 1%, anemia 1%.
Conclusions
Approximately 65% of PE survivors report functional impairment, despite at least 6 months of anticoagulation. Persistent pulmonary artery thromboemboli resulting in CTEPH or CTED were detected in 7.2% of PE survivors and 11.8% of symptomatic patients. Leftsided diastolic dysfunction was the most prevalent echocardiographic abnormality, and remained the most common cause of functional limitation affected 34.2% of symptomatic cases.

Copyright © 2019. Published by Elsevier Ltd.

Thromb Res: 11 Dec 2019; 186:30-35
Dzikowska-Diduch O, Kostrubiec M, Kurnicka K, Lichodziejewska B, ... Gołębiowski M, Pruszczyk P
Thromb Res: 11 Dec 2019; 186:30-35 | PMID: 31862573
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Impact:
Abstract

The year 2018 in the European Heart Journal-Cardiovascular Imaging: Part II.

Cosyns B, Haugaa KH, Gerber BL, Gimelli A, ... Maurer G, Edvardsen T

European Heart Journal - Cardiovascular Imaging was launched in 2012 as a multimodality cardiovascular imaging journal. It has gained an impressive impact factor during its first 5 years and is now established as one of the top cardiovascular journals and has become the most important cardiovascular imaging journal in Europe. The most important studies from 2018 will be highlighted in two reports. Part I of the review has focused on studies about myocardial function and risk prediction, myocardial ischaemia, and emerging techniques in cardiovascular imaging, while Part II will focus on cardiomyopathies, congenital heart diseases, valvular heart diseases, and heart failure.

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

Eur Heart J Cardiovasc Imaging: 30 Nov 2019; 20:1337-1344
Cosyns B, Haugaa KH, Gerber BL, Gimelli A, ... Maurer G, Edvardsen T
Eur Heart J Cardiovasc Imaging: 30 Nov 2019; 20:1337-1344 | PMID: 31750534
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Impact:
Abstract

Strain-oriented strategy for guiding cardioprotection initiation of breast cancer patients experiencing cardiac dysfunction.

Santoro C, Esposito R, Lembo M, Sorrentino R, ... Arpino G, Galderisi M
Aims
This study assessed the impact of the strain-guided therapeutic approach on cancer therapy-related cardiac dysfunction (CTRCD) and rate of cancer therapy (CT) interruption in breast cancer.
Methods and results
We enrolled 116 consecutive female patients with HER2-positive breast cancer undergoing a standard protocol by EC (epirubicine + cyclophosphamide) followed by paclitaxel + trastuzumab (TRZ). Coronary artery, valvular and congenital heart disease, heart failure, primary cardiomyopathies, permanent or persistent atrial fibrillation, and inadequate echo-imaging were exclusion criteria. Patients underwent an echo-Doppler exam with determination of ejection fraction (EF) and global longitudinal strain (GLS) at baseline and every 3 months during CT. All patients developing subclinical (GLS drop >15%) or overt CTRCD (EF reduction <50%) initiated cardiac treatment (ramipril+ carvedilol). In the 99.1% (115/116) of patients successfully completing CT, GLS and EF were significantly reduced and E/e\' ratio increased at therapy completion. Combined subclinical and overt CTRCD was diagnosed in 27 patients (23.3%), 8 at the end of EC and 19 during TRZ courses. Of these, 4 (3.4%) developed subsequent overt CTRCD and interrupted CT. By cardiac treatment, complete EF recovery was observed in two of these patients and partial recovery in one. These patients with EF recovery re-started and successfully completed CT. The remaining patient, not showing EF increase, permanently stopped CT. The other 23 patients with subclinical CTRCD continued and completed CT.
Conclusion
These findings highlight the usefulness of \'strain oriented\' approach in reducing the rate of overt CTRCD and CT interruption by a timely cardioprotective treatment initiation.

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

Eur Heart J Cardiovasc Imaging: 30 Nov 2019; 20:1345-1352
Santoro C, Esposito R, Lembo M, Sorrentino R, ... Arpino G, Galderisi M
Eur Heart J Cardiovasc Imaging: 30 Nov 2019; 20:1345-1352 | PMID: 31326981
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Impact:
Abstract

Magnetic resonance hyperpolarization imaging detects early myocardial dysfunction in a porcine model of right ventricular heart failure.

Agger P, Hyldebrandt JA, Hansen ESS, Omann C, ... Nielsen PM, Laustsen C
Aims
Early detection of heart failure is important for timely treatment. During the development of heart failure, adaptive intracellular metabolic processes that evolve prior to macro-anatomic remodelling, could provide an early signal of impending failure. We hypothesized that metabolic imaging with hyperpolarized magnetic resonance would detect the early development of heart failure before conventional echocardiography could reveal cardiac dysfunction.
Methods and results
Five 8.5 kg piglets were subjected to pulmonary banding and subsequently examined by [1-13C]pyruvate hyperpolarization, conventional magnetic resonance imaging, echocardiography, and blood testing, every 4 weeks for 16 weeks. They were compared with a weight matched, healthy control group. Conductance catheter examination at the end of the study showed impaired right ventricular systolic function along with compromised left ventricular diastolic function. After 16 weeks, we saw a significant decrease in the conversion ratio of pyruvate/bicarbonate in the left ventricle from 0.13 (0.04) in controls to 0.07 (0.02) in animals with pulmonary banding, along with a significant increase in the lactate/bicarbonate ratio to 3.47 (1.57) compared with 1.34 (0.81) in controls. N-terminal pro-hormone of brain natriuretic peptide was increased by more than 300%, while cardiac index was reduced to 2.8 (0.95) L/min/m2 compared with 3.9 (0.95) in controls. Echocardiography revealed no changes.
Conclusion
Hyperpolarization detected a shift towards anaerobic metabolism in early stages of right ventricular dysfunction, as evident by an increased lactate/bicarbonate ratio. Dysfunction was confirmed with conductance catheter assessment, but could not be detected by echocardiography. Hyperpolarization has a promising future in clinical assessment of heart failure in both acquired and congenital heart disease.

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

Eur Heart J Cardiovasc Imaging: 31 Dec 2019; 21:93-101
Agger P, Hyldebrandt JA, Hansen ESS, Omann C, ... Nielsen PM, Laustsen C
Eur Heart J Cardiovasc Imaging: 31 Dec 2019; 21:93-101 | PMID: 31329841
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Impact:
Abstract

Pulmonary hypertension detection by computed tomography pulmonary transit time in heart failure with reduced ejection fraction.

Colin GC, Pouleur AC, Gerber BL, Poncelet PA, ... Gevenois PA, Ghaye B
Aims
To evaluate the relationships between pulmonary transit time (PTT), cardiac function, and pulmonary haemodynamics in patients with heart failure with reduced ejection fraction (HFrEF) and to explore how PTT performs in detecting pulmonary hypertension (PH).
Methods and results
In this prospective study, 57 patients with advanced HFrEF [49 men, 51 years ± 8, mean left ventricular (LV) ejection fraction 26% ± 8] underwent echocardiography, right heart catheterization, and cardiac computed tomography (CT). PTT was measured as the time interval between peaks of attenuation in right ventricle (RV) and LV and was compared between patients with or without PH and 15 controls. PTT was significantly longer in HFrEF patients with PH (21 s) than in those without PH (11 s) and controls (8 s) (P < 0.001) but not between patients without PH and controls (P = 0.109). PTT was positively correlated with pulmonary artery wedge pressure (PAWP) (r = 0.74), mean pulmonary artery pressure (r = 0.68), N-terminal pro-B-type natriuretic peptide (r = 0.60), mitral (r = 0.54), and tricuspid (r = 0.37) regurgitation grades, as well as with LV, RV, and left atrial volumes (r from 0.39 to 0.64) (P < 0.01). PTT was negatively correlated with cardiac index (r = -0.63) as well as with LV (r = -0.66) and RV (r = -0.74) ejection fractions. PAWP, cardiac index, mitral regurgitation grade, and RV end-diastolic volume were all independent predictors of PTT. PTT value ≥14 s best-detected PH with 91% sensitivity and 88% specificity (area under the receiver operating characteristic curve: 0.95).
Conclusion
In patients with HFrEF, PTT correlates with cardiac function and pulmonary haemodynamics, is determined by four independent parameters, and performs well in detecting PH.

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

Eur Heart J Cardiovasc Imaging: 05 Dec 2019; epub ahead of print
Colin GC, Pouleur AC, Gerber BL, Poncelet PA, ... Gevenois PA, Ghaye B
Eur Heart J Cardiovasc Imaging: 05 Dec 2019; epub ahead of print | PMID: 31808507
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Impact:
Abstract

Involvement of Low-Density Lipoprotein Receptor in the Pathogenesis of Pulmonary Hypertension.

Umar S, Ruffenach G, Moazeni S, Vaillancourt M, ... Reddy ST, Eghbali M

Background Recently, we and others have reported a causal role for oxidized lipids in the pathogenesis of pulmonary hypertension (PH). However, the role of low-density lipoprotein receptor (LDL-R) in PH is not known. Methods and Results We examined the role of LDL-R in the development of PH and determined the efficacy of high-density lipoprotein mimetic peptide 4F in mitigating PH. Explanted human lungs and plasma from patients with PH and control subjects were analyzed for gene expression, histological characteristics, and lipoprotein oxidation. Male LDL-R null (LDL-R knockout) mice (12-15 months old) were fed chow, Western diet (WD), WD with 4F, and WD with scramble peptide for 12 weeks. Serial echocardiography, cardiac catheterization, oxidized LDL assay, real-time quantitative reverse transcription-polymerase chain reaction, and histological analysis were performed. The effect of LDL-R knockdown and oxidized LDL on human pulmonary artery smooth muscle cell proliferation was assessed in vitro. LDL-R and CD36 expression levels were significantly downregulated in the lungs of patients with PH. Patients with PH also had increased lung lipid deposits, oxidized LDL, E06 immunoreactivity, and plasma oxidized LDL/LDL ratio. LDL-R knockout mice on WD developed PH, right ventricular hypertrophy, right ventricular dysfunction, pulmonary vascular remodeling, fibrosis, and lipid deposition in lungs, aortic atherosclerosis, and left ventricular dysfunction, which were prevented by 4F. Interestingly, PH in WD group preceded left ventricular dysfunction. Oxidized LDL or LDL-R knockdown significantly increased proliferation of human pulmonary artery smooth muscle cells in vitro. Conclusions Human PH is associated with decreased LDL-R in lungs and increased oxidized LDL in lungs and plasma. WD-fed LDL-R knockout mice develop PH and right ventricular dysfunction, implicating a role for LDL-R and oxidized lipids in PH.



J Am Heart Assoc: 20 Jan 2020; 9:e012063
Umar S, Ruffenach G, Moazeni S, Vaillancourt M, ... Reddy ST, Eghbali M
J Am Heart Assoc: 20 Jan 2020; 9:e012063 | PMID: 31914876
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Abstract

Systematic Review of Genotype-Phenotype Correlations in Noncompaction Cardiomyopathy.

van Waning JI, Moesker J, Heijsman D, Boersma E, Majoor-Krakauer D

Background A genetic cause can be identified in 30% of noncompaction cardiomyopathy patients (NCCM) with clinical features ranging from asymptomatic cardiomyopathy to heart failure with major adverse cardiac events (MACE). Methods and Results To investigate genotype-phenotype correlations, the genotypes and clinical features of genetic NCCM patients were collected from the literature. We compared age at diagnosis, cardiac features and risk for MACE according to mode of inheritance and molecular effects for defects in the most common sarcomere genes and NCCM subtypes. Geno- and phenotypes of 561 NCCM patients from 172 studies showed increased risk in children for congenital heart defects (<0.001) and MACE (<0.001). In adult NCCM patients the main causes were single missense mutations in sarcomere genes. Children more frequently had an X-linked or mitochondrial inherited defect (=0.001) or chromosomal anomalies (<0.001).was involved in 48% of the sarcomere gene mutations.andmutations had lower risk for MACE thanand(=0.001). The NCCM/dilated cardiomyopathy cardiac phenotype was the most frequent subtype (56%; =0.022) and was associated with an increased risk for MACE and high risk for left ventricular systolic dysfunction (<0.001). In multivariate binary logistic regression analysis ,arrhythmia -, non-sarcomere non-arrhythmia cardiomyopathy-and X-linked genes were genetic predictors for MACE. Conclusions Sarcomere gene mutations were the most common cause in adult patients with lower risk of MACE. Children had multi-systemic disorders with severe outcome, suggesting that the diagnostic and clinical approaches should be adjusted to age at presentation. The observed genotype-phenotype correlations endorsed that DNA diagnostics for NCCM is important for clinical management and counseling of patients.



J Am Heart Assoc: 02 Dec 2019; 8:e012993
van Waning JI, Moesker J, Heijsman D, Boersma E, Majoor-Krakauer D
J Am Heart Assoc: 02 Dec 2019; 8:e012993 | PMID: 31771441
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Abstract

Endpoints for tricuspid regurgitation trans-catheter therapy trials.

Hahn RT, Ben-Yehuda O, Leon MB

Tricuspid regurgitation (TR), particularly functional or secondary TR, is increasingly recognized in clinical practice and when at least moderate in severity is associated with significant increase in mortality. In recent years multiple new trans-catheter devices have been developed to treat tricuspid regurgitation and are now undergoing clinical trial evaluations. The choice of appropriate endpoints in TR trials is particularly challenging as the disease is complex, often co-exists with left heart disease and pulmonary hypertension, and has not been extensively studied. Endpoints utilized in left heart disease trials have been applied with success to TR trials, and innovative trial designs will allow the initiation of pivotal randomized trials. Ultimately the development of TR specific endpoints may provide for more specific and robust assessment of these novel therapies.

Copyright © 2019. Published by Elsevier Inc.

Prog Cardiovasc Dis: 01 Dec 2019; epub ahead of print
Hahn RT, Ben-Yehuda O, Leon MB
Prog Cardiovasc Dis: 01 Dec 2019; epub ahead of print | PMID: 31805295
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Abstract

High density mapping and catheter ablation of atrial tachycardias in adults with congenital heart disease.

Krause U, Müller MJ, Stellmacher C, Backhoff D, Schneider H, Paul T
Aims
We used a new grid-style multi-electrode mapping catheter (Advisor™ HD Grid, Abbott) and investigated its use for high density mapping of atrial tachycardias in adult patients with congenital heart disease.
Patients and methods
All patients with congenital heart disease who had mapping of atrial tachycardias using the new grid-style catheter between March 2018 and April 2019 were included.
Results
A total of 24 adult patients had high density mapping of atrial tachycardias using the grid-style multi-electrode catheter. Mean procedure duration was 207 ± 72 min., mean fluoroscopy time was 7.1 ± 7.9 min. In patients with right atrial substrates, fluoroscopy time was shorter compared to biatrial or left atrial substrates (0.9 ± 2.2 min for right atrial substrates, n = 19 vs. 6.3 ± 8.3 min for left atrial substrates, n = 2 and 7.5 ± 4.3 min for biatrial substrates, n = 3, p = 0.01). A mean number of 14.814 ± 10.140 endocardial points were collected and 2.319 ± 1244 points were finally used to characterize the tachycardia. Procedural success was achieved in 21/24 (88%) subjects and partial success in 2/24 (8%) patients. Recurrence rate was low (12.5%). In one patient, radiofrequency ablation within the cavotricuspid isthmus resulted in occlusion of a branch of the right coronary artery. No complications related to the use of the mapping catheter itself occurred.
Conclusion
High density mapping of AT using the grid-style catheter showed promising results with respect to procedural and midterm outcome and fluoroscopy time. Using the grid-style catheter might offer advantages compared to other multi-electrode catheters used for high density mapping of AT in patients with CHD.



Clin Res Cardiol: 01 Jan 2020; epub ahead of print
Krause U, Müller MJ, Stellmacher C, Backhoff D, Schneider H, Paul T
Clin Res Cardiol: 01 Jan 2020; epub ahead of print | PMID: 31897601
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Abstract

Atrial fibrillation ablation in adults with congenital heart disease on uninterrupted oral anticoagulation is safe and efficient.

Kottmaier M, Baur A, Lund S, Bourier F, ... Deisenhofer I, Hessling G
Background
The prevalence of atrial fibrillation (AF) is significantly higher in adults with congenital heart disease (ACHD) compared to patients without congenital heart disease (CHD). As AF in ACHD patients might have significant hemodynamic consequences, rhythm control is particularly desirable but rarely achieved by antiarrhythmic drugs. The aim of this study was to investigate safety and long-term outcome of AF ablation in ACHD patients.
Methods
All ACHD patients (n = 46) that underwent AF ablation at our centre from 2013 to 2017 were included in the study. CHD was classified as simple (46%), moderate (41%) or complex (13%). The majority of patients (61%) suffered from persistent AF (paroxysmal AF 39%). Persistent AF was present in 57% of patients with simple, in 58% of patients with moderate and 83% of patients with complex CHD. All patients underwent radiofrequency (RF) ablation on uninterrupted oral anticoagulation. Pulmonary vein isolation (PVI) was performed in patients with paroxysmal AF, whereas patients with persistent AF underwent PVI and ablation of complex fractionated atrial electrograms (CFAE).
Results
No major complications occurred. Single-procedure success after 18 months off antiarrhythmic drugs was 61% for paroxysmal AF and 29% for persistent AF (p = 0.003). Multiple procedures (mean 2.1 ± 1.4) increased long-term success to 82% for paroxysmal AF and 48% for persistent AF (p = 0.05). Long-term ablation success was 64% for simple, 62% for moderate and 50% for complex CHD patients.
Conclusions
AF ablation in ACHD patients is feasible and safe regardless of CHD complexity. Success rates in patients with paroxysmal AF are high and comparable to patients without CHD. In ACHD patients with persistent AF, success rates of ablation are markedly reduced which might be due to a different and/or more extensive (bi-)atrial substrate. In the cohort of complex ACHD patients with persistent AF as the dominant AF type, long-term success of AF ablation is limited.



Clin Res Cardiol: 31 Dec 2019; epub ahead of print
Kottmaier M, Baur A, Lund S, Bourier F, ... Deisenhofer I, Hessling G
Clin Res Cardiol: 31 Dec 2019; epub ahead of print | PMID: 31894385
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Abstract

Advanced Heart Failure in Adults With Congenital Heart Disease.

Menachem JN, Schlendorf KH, Mazurek JA, Bichell DP, ... Book W, Lindenfeld J

As a result of improvements in care for patients with congenital heart disease (CHD), >90% of children born with CHD are expected to survive to adulthood. For those adults, heart failure (HF) is the leading cause of death. Advances in recognition of, and treatments for, these patients continue to improve. Specifically, adults with CHD are candidates for both heart transplantation and mechanical circulatory support. However, challenges remain that require investigation to improve outcomes.

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

JACC Heart Fail: 02 Dec 2019; epub ahead of print
Menachem JN, Schlendorf KH, Mazurek JA, Bichell DP, ... Book W, Lindenfeld J
JACC Heart Fail: 02 Dec 2019; epub ahead of print | PMID: 31838031
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Abstract

Imaging Risk in Multisystem Inflammatory Diseases.

Ikonomidis I, Makavos G, Katsimbri P, Boumpas DT, Parissis J, Iliodromitis E

Rheumatic diseases are immune-mediated inflammatory multisystem diseases with frequent cardiovascular manifestations including perimyocarditis, valvular disease, coronary artery disease, heart failure with or without preserved ejection fraction, pulmonary hypertension, aneurysms, and thrombosis. Echocardiography, carotid ultrasonography, cardiac computed tomography, cardiac magnetic resonance imaging, and positron emission tomography are valid diagnostic tools for the detection of the cardiovascular complications of the multisystem diseases that frequently determine prognosis. Furthermore, the findings of these methods may offer additive risk stratification in asymptomatic patients over the conventional risk scores used to assess cardiovascular risk in the primary prevention setting. Finally, the imaging methods offer a unique opportunity to monitor the effects of treatment on atherosclerotic lesions, coronary microcirculatory dysfunction, myocardial inflammation and fibrosis. However, studies are needed to investigate whether improvement of imaging markers by treatment or selection of treatment according to its effects on surrogate imaging markers is linked to improved prognosis.

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

JACC Cardiovasc Imaging: 29 Nov 2019; 12:2517-2537
Ikonomidis I, Makavos G, Katsimbri P, Boumpas DT, Parissis J, Iliodromitis E
JACC Cardiovasc Imaging: 29 Nov 2019; 12:2517-2537 | PMID: 30878436
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Abstract

Is Carotid Intima-Media Thickness Increased in Adults With Congenital Heart Disease?

Reiner B, Oberhoffer R, Häcker AL, Ewert P, Müller J

Background Because of the increasing numbers of congenital patients surviving into adulthood, early diagnosis and prevention of acquired cardiovascular disease is reasonable. The aim of this study was to detect diagnostic subgroups of adults with congenital heart disease (ACHD) that have increased carotid intima-media thickness (cIMT), a subclinical marker of cardiovascular damage. Methods and Results This study enrolled 831 ACHD patients (392 women, aged 38.8±11.7 years) from May 2015 to February 2019 at their regular outpatient visit. Far wall cIMT was measured using a semiautomatic ultrasound system at 4 angles. Age, sex, height, weight, blood pressure, smoking status, and antihypertensive medication were registered and entered in a multiple linear regression model to compare diagnostic subgroups to 191 healthy controls (111 women, aged 36.7±13.5 years). There were no significant differences in cIMT of ACHD (0.538±0.086 mm) compared with healthy controls (0.541±0.083 mm; =0.649) after adjusting for the aforementioned covariates. Only patients with coarctation of the aorta showed significantly higher cIMT values (0.592±0.075 mm; <0.001) compared with healthy controls. In addition, ACHD patients who were men (=0.032), older (<0.001), and were prescribed antihypertensive medications (=0.003) were all found to have thicker cIMT values. Conclusions Overall, we determined that within the ACHD cohort, only those patients with a history of coarctation have higher cIMT values. To better determine the mechanism of abnormal vasculature, further basic research is needed.



J Am Heart Assoc: 03 Feb 2020; 9:e013536
Reiner B, Oberhoffer R, Häcker AL, Ewert P, Müller J
J Am Heart Assoc: 03 Feb 2020; 9:e013536 | PMID: 31983324
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Abstract

A machine learning cardiac magnetic resonance approach to extract disease features and automate pulmonary arterial hypertension diagnosis.

Swift AJ, Lu H, Uthoff J, Garg P, ... Wild JM, Kiely DG
Aims
Pulmonary arterial hypertension (PAH) is a progressive condition with high mortality. Quantitative cardiovascular magnetic resonance (CMR) imaging metrics in PAH target individual cardiac structures and have diagnostic and prognostic utility but are challenging to acquire. The primary aim of this study was to develop and test a tensor-based machine learning approach to holistically identify diagnostic features in PAH using CMR, and secondarily, visualize and interpret key discriminative features associated with PAH.
Methods and results
Consecutive treatment naive patients with PAH or no evidence of pulmonary hypertension (PH), undergoing CMR and right heart catheterization within 48 h, were identified from the ASPIRE registry. A tensor-based machine learning approach, multilinear subspace learning, was developed and the diagnostic accuracy of this approach was compared with standard CMR measurements. Two hundred and twenty patients were identified: 150 with PAH and 70 with no PH. The diagnostic accuracy of the approach was high as assessed by area under the curve at receiver operating characteristic analysis (P < 0.001): 0.92 for PAH, slightly higher than standard CMR metrics. Moreover, establishing the diagnosis using the approach was less time-consuming, being achieved within 10 s. Learnt features were visualized in feature maps with correspondence to cardiac phases, confirming known and also identifying potentially new diagnostic features in PAH.
Conclusion
A tensor-based machine learning approach has been developed and applied to CMR. High diagnostic accuracy has been shown for PAH diagnosis and new learnt features were visualized with diagnostic potential.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J Cardiovasc Imaging: 29 Jan 2020; epub ahead of print
Swift AJ, Lu H, Uthoff J, Garg P, ... Wild JM, Kiely DG
Eur Heart J Cardiovasc Imaging: 29 Jan 2020; epub ahead of print | PMID: 31998956
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Abstract

Prediction of Pulmonary to Systemic Flow Ratio in Patients With Congenital Heart Disease Using Deep Learning-Based Analysis of Chest Radiographs.

Toba S, Mitani Y, Yodoya N, Ohashi H, ... Shimpo H, Takao M
Importance
Chest radiography is a useful noninvasive modality to evaluate pulmonary blood flow status in patients with congenital heart disease. However, the predictive value of chest radiography is limited by the subjective and qualitive nature of the interpretation. Recently, deep learning has been used to analyze various images, but it has not been applied to analyzing chest radiographs in such patients.
Objective
To develop and validate a quantitative method to predict the pulmonary to systemic flow ratio from chest radiographs using deep learning.
Design, setting, and participants
This retrospective observational study included 1031 cardiac catheterizations performed for 657 patients from January 1, 2005, to April 30, 2019, at a tertiary center. Catheterizations without the Fick-derived pulmonary to systemic flow ratio or chest radiography performed within 1 month before catheterization were excluded. Seventy-eight patients (100 catheterizations) were randomly assigned for evaluation. A deep learning model that predicts the pulmonary to systemic flow ratio from chest radiographs was developed using the method of transfer learning.
Main outcomes and measures
Whether the model can predict the pulmonary to systemic flow ratio from chest radiographs was evaluated using the intraclass correlation coefficient and Bland-Altman analysis. The diagnostic concordance rate was compared with 3 certified pediatric cardiologists. The diagnostic performance for a high pulmonary to systemic flow ratio of 2.0 or more was evaluated using cross tabulation and a receiver operating characteristic curve.
Results
The study included 1031 catheterizations in 657 patients (522 males [51%]; median age, 3.4 years [interquartile range, 1.2-8.6 years]), in whom the mean (SD) Fick-derived pulmonary to systemic flow ratio was 1.43 (0.95). Diagnosis included congenital heart disease in 1008 catheterizations (98%). The intraclass correlation coefficient for the Fick-derived and deep learning-derived pulmonary to systemic flow ratio was 0.68, the log-transformed bias was 0.02, and the log-transformed precision was 0.12. The diagnostic concordance rate of the deep learning model was significantly higher than that of the experts (correctly classified 64 of 100 vs 49 of 100 chest radiographs; P = .02 [McNemar test]). For detecting a high pulmonary to systemic flow ratio, the sensitivity of the deep learning model was 0.47, the specificity was 0.95, and the area under the receiver operating curve was 0.88.
Conclusions and relevance
The present investigation demonstrated that deep learning-based analysis of chest radiographs predicted the pulmonary to systemic flow ratio in patients with congenital heart disease. These findings suggest that the deep learning-based approach may confer an objective and quantitative evaluation of chest radiographs in the congenital heart disease clinic.



JAMA Cardiol: 21 Jan 2020; epub ahead of print
Toba S, Mitani Y, Yodoya N, Ohashi H, ... Shimpo H, Takao M
JAMA Cardiol: 21 Jan 2020; epub ahead of print | PMID: 31968049
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Abstract

Predictive factors of death associated with infective endocarditis in adult patients with congenital heart disease.

Ly R, Compain F, Gaye B, Pontnau F, ... Lebeaux D, Ladouceur M
Aims
Infective endocarditis is a severe infection which can occur in adult patients with congenital heart disease. We aimed to determine outcomes and risk factors of death in adult congenital heart disease and to investigate differences with infective endocarditis in non-congenital heart disease.
Methods and results
Between March 2000 and June 2018, 671 consecutive episodes of infective endocarditis in adult patients were retrospectively recorded. Cases were classified according to the modified Duke classification. All adult congenital heart disease cases were managed by infectious disease specialists and adult congenital heart disease cardiologists. During this period, 142 infective endocarditis episodes (21%) occurred in adult congenital heart disease patients with simple (46.5%), moderate (21.1%), or complex (32.4%) congenital heart disease. In-hospital mortality was 12.7%. The strongest predictive factors of in-hospital death in multivariate analysis were complexity of congenital heart disease (odds ratio (OR) 8.02, 95% confidence interval (CI) 1.53-42.07), age (OR 1.05, 95% CI 1.00-1.19) and white blood cell count 12 g/L or greater (OR 8.72, 95% CI 2.42-31.43). Patients with congenital heart disease were significantly younger (median age 36 vs. 67 years, <0.001), had undergone more redo cardiac surgeries (35.7% vs. 11.3%, <0.01) and presented with more right-sided infective endocarditis (39.4% vs. 7.9%, <0.01) than patients without congenital heart disease. Congenital heart disease was associated with two-fold lower in-hospital mortality rates (OR 0.37, 95% CI 0.19-0.74), independently of age, gender, obesity, renal function and side of infective endocarditis.
Conclusion
Although mortality associated with infective endocarditis is lower in adult patients with congenital heart disease than patients without congenital heart disease, infective endocarditis mortality is particularly high in patients with complex congenital heart disease. Education and prevention about the risk of infective endocarditis is essential, especially in this group.



Eur Heart J Acute Cardiovasc Care: 27 Jan 2020:2048872620901394; epub ahead of print
Ly R, Compain F, Gaye B, Pontnau F, ... Lebeaux D, Ladouceur M
Eur Heart J Acute Cardiovasc Care: 27 Jan 2020:2048872620901394; epub ahead of print | PMID: 31990202
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Abstract

Pulmonary vascular imaging characteristics after pulmonary endarterectomy for chronic thromboembolic pulmonary hypertension.

Braams NJ, Ruigrok D, Schokker MGM, Padervinskiene L, ... Bogaard HJ, Meijboom LJ
Background
Between 16% and 51% of patients with chronic thromboembolic pulmonary hypertension will have residual pulmonary hypertension (PH) after pulmonary endarterectomy (PEA). Whether residual PH is related to remaining (sub-)segmental macrovascular lesions or to microvascular disease is unknown. New imaging techniques can provide detailed information about (sub-)segmental pulmonary arteries and parenchymal perfusion. The aim of this study was to describe the prevalence after PEA of remaining (sub-)segmental vascular lesions on electrocardiogram-gated computed tomography pulmonary angiography (CTPA) and parenchymal hypoperfusion on magnetic resonance imaging (MRI) and to relate these imaging abnormalities to the presence or absence of residual PH after PEA.
Methods
In a prospective cohort of patients with operable chronic thromboembolic pulmonary hypertension, hemodynamics, CTPA, and lung perfusion MRI were performed before and 6 months after PEA. The percentage of (sub-)segmental vascular lesions was calculated on CTPA and parenchymal hypoperfusion on lung perfusion MRI.
Results
PEA led to significant improvements in hemodynamics and a reduction of imaging abnormalities. Residual PH was present in 45% of patients after PEA, whereas remaining (sub-)segmental vascular lesions and parenchymal hypoperfusion were present in 20% and 21% of the pulmonary vasculature, respectively. Patients with and without residual PH after PEA had similar percentages of remaining (sub-)segmental vascular lesions (25% ± 14% vs 17% ± 15%; p = 0.16) and similar degrees of parenchymal hypoperfusion (20% ± 7% vs 19% ± 6%; p = 0.63).
Conclusions
After successful PEA, advanced imaging shows that around 20% of the pulmonary vasculature remains abnormal, independent of the presence of residual PH. This may suggest that microvascular disease, rather than residual macrovascular lesions, plays a prominent role in residual PH after PEA.

Copyright © 2019 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 04 Dec 2019; epub ahead of print
Braams NJ, Ruigrok D, Schokker MGM, Padervinskiene L, ... Bogaard HJ, Meijboom LJ
J Heart Lung Transplant: 04 Dec 2019; epub ahead of print | PMID: 31866175
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Abstract

Survival after delivery room cardiopulmonary resuscitation: A national registry study.

Foglia EE, Jensen EA, Wyckoff MH, Sawyer T, ... Ratcliffe SJ,
Aims
Survival after delivery room cardiopulmonary resuscitation (DR-CPR) is not well characterized in full-term infants, and survival outcomes after DR-CPR have not been defined across the spectrum of gestation. The study objectives were to define gestational age (GA) specific survival following DR-CPR and to assess the association between GA and DR-CPR characteristics and survival outcomes.
Methods
Retrospective cohort study of prospectively collected data in the American Heart Association Get With the Guidelines-Resuscitation registry. Newborn infants without congenital abnormalities who received greater than 1 minute of chest compressions for DR-CPR were included. GA was stratified by categorical subgroups: ≥36 weeks; 33-35 weeks; 29-32 weeks; 25-28 weeks; 22-24 weeks. The primary outcome was survival to hospital discharge; the secondary outcome was return of circulation (ROC).
Results
Among 1,022 infants who received DR-CPR, 83% experienced ROC and 64% survived to hospital discharge. GA-stratified hospital survival rates were 83% (> = 36 weeks), 66% (33-35 weeks), 60% (29-32 weeks), 52% (25-28 weeks), and 25% (22-24 weeks). Compared with GA > = 36 weeks, lower GA was independently associated with decreasing odds of survival (33-35 weeks: adjusted Odds Ratio [aOR] 0.46, 95% Confidence Interval [CI] 0.26-0.81; 29-32 weeks: aOR 0.40, 95% CI 0.23-0.69; 25-28 weeks: aOR 0.21, 95% CI 0.11-0.41; 22-24 weeks: aOR 0.06, 95% CI 0.03-0.10).
Conclusions
In this national registry of infants who received delivery room cardiopulmonary resuscitation (DR-CPR), 83% survived the event and two-thirds survived to hospital discharge. These results contribute to defining survival outcomes following DR-CPR across the continuum of gestation.

Copyright © 2020. Published by Elsevier B.V.

Resuscitation: 22 Jan 2020; epub ahead of print
Foglia EE, Jensen EA, Wyckoff MH, Sawyer T, ... Ratcliffe SJ,
Resuscitation: 22 Jan 2020; epub ahead of print | PMID: 31982507
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Impact:
Abstract

Development and validation of a procedure-specific assessment tool for hands-on surgical training in congenital heart surgery.

Hussein N, Lim A, Honjo O, Haller C, ... Van Arsdell G, Yoo SJ
Background
Hands-on surgical simulation has been sought to address training limitations within congenital heart surgery (CHS). However, there is a need for objective assessment methods to measure surgeons\' performance to justify its global adoption. This study aimed to validate a procedure-specific assessment tool for the simulation of the arterial switch operation on 3D-printed models and to evaluate the consistency of scoring among evaluators with different levels of experience in CHS.
Methods
Five \"expert\" and 5 \"junior\" surgeons performed the arterial switch procedure on 3D-printed models with transposition of the great arteries during 2 hands-on surgical training courses. Their performance was retrospectively assessed by 9 evaluators with varying experience in CHS (staff surgeons, resident surgeons, and non-MD raters). Assessments were done using 2 assessment tools: the Hands-On Surgical Training-Congenital Heart Surgery (HOST-CHS) assessment tool and the global rating scale (GRS).
Results
The HOST-CHS tool showed a higher interrater and intrarater reliability compared with the GRS. Total scores for expert surgeons were highly consistent across all evaluators. Non-MD raters\' total scores for junior surgeons were slightly higher than those of residents and staff evaluators. All grades of evaluator were able to discriminate between junior and expert surgeons.
Conclusions
This study demonstrates the development and validation of an objective, procedure-specific assessment tool for the arterial switch operation with consistency among evaluators with different experience. There is now a platform for quantifying and accurately evaluating performance, which will be highly beneficial in training and developing the next generation of congenital heart surgeons.

Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

J Thorac Cardiovasc Surg: 23 Dec 2019; epub ahead of print
Hussein N, Lim A, Honjo O, Haller C, ... Van Arsdell G, Yoo SJ
J Thorac Cardiovasc Surg: 23 Dec 2019; epub ahead of print | PMID: 31973896
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Abstract

Combined Tricuspid and Mitral Versus Isolated Mitral Valve Repair for Severe Mitral and Tricuspid Regurgitation: An Analysis From the TriValve and TRAMI Registries.

Mehr M, Karam N, Taramasso M, Ouarrak T, ... Hausleiter J,
Objectives
The aim of this study was to retrospectively compare the characteristics, procedural courses, and outcomes of patients presenting with concomitant mitral regurgitation (MR) and tricuspid regurgitation (TR) in the TriValve (Transcatheter Tricuspid Valve Therapies) and TRAMI (Transcatheter Mitral Valve Interventions) registries.
Background
Transcatheter mitral edge-to-edge valve repair (TMVR) has been shown to be successful in patients with severe MR. Lately, edge-to-edge repair has also emerged as a possible treatment for severe TR in patients at high risk for cardiac surgery. In patients with both severe MR and TR, the yield of concomitant transcatheter mitral and tricuspid valve repair (TMTVR) for patients at high surgical risk is unknown.
Methods
The characteristics, procedural data, and 1-year outcomes of all patients in the international multicenter TriValve registry and the German multicenter TRAMI registry, who presented with both severe MR and TR, were retrospectively compared. Patients in TRAMI (n = 106) underwent isolated TMVR, while those in TriValve (n = 122) additionally underwent concurrent TMTVR in compassionate and/or off-label use.
Results
All 228 patients (mean age 77 ± 8 years, 44.3% women) presented with significant dyspnea at baseline (New York Heart Association functional class III or IV in 93.9%), without any differences in the rates of pulmonary hypertension and chronic pulmonary disease. The proportion of patients with left ventricular ejection fraction <30% was higher in the TMVR group (34.9% vs. 18.0%; p < 0.001), while patients in the TMTVR group had lower glomerular filtration rates. At discharge, MR was comparably reduced in both groups. At 1 year, overall all-cause mortality was 34.0% in the TMVR group and 16.4% in the TMTVR group (p = 0.035, Cox regression). On multivariate analysis, TMTVR was associated with a 2-fold lower mortality rate (hazard ratio: 0.52; p = 0.02). The rate of patients in New York Heart Association functional class ≤II at 1 year did not differ (69.4% vs. 67.0%; p = 0.54).
Conclusions
Concurrent TMTVR was associated with a higher 1-year survival rate compared with isolated TMVR in patients with both MR and TR. Further randomized trials are needed to confirm these results.

Copyright © 2020. Published by Elsevier Inc.

JACC Cardiovasc Interv: 09 Jan 2020; epub ahead of print
Mehr M, Karam N, Taramasso M, Ouarrak T, ... Hausleiter J,
JACC Cardiovasc Interv: 09 Jan 2020; epub ahead of print | PMID: 31954679
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Impact:
Abstract

Circulating NEDD9 is increased in pulmonary arterial hypertension: A multicenter, retrospective analysis.

Samokhin AO, Hsu S, Yu PB, Waxman AB, ... Leary PJ, Maron BA
Background
Pulmonary arterial hypertension (PAH) is a highly morbid disease characterized by elevated pulmonary vascular resistance (PVR) and pathogenic right ventricular remodeling. Endothelial expression of the prometastatic protein NEDD9 is increased in fibrotic PAH arterioles, and NEDD9 inhibition decreases PVR in experimental PAH. We hypothesized that circulating NEDD9 is increased in PAH and informs the clinical profile of patients.
Methods
Clinical data and plasma samples were analyzed retrospectively for 242 patients from 5 referral centers (2010-2017): PAH (n = 139; female 82%, 58 [48-67] years), non-PAH pulmonary hypertension (PH) (n = 54; female 56%, 63.4 ± 12.2 years), and dyspnea non-PH controls (n = 36; female 75%, 54.2 ± 14.0 years).
Results
Compared with controls, NEDD9 was increased in PAH by 1.82-fold (p < 0.0001). Elevated NEDD9 correlated with PVR in idiopathic PAH (ρ = 0.42, p < 0.0001, n = 54), connective tissue disease (CTD)-PAH (ρ = 0.53, p < 0.0001, n = 53), and congenital heart disease-PAH (ρ = 0.68, p < 0.0001, n = 10). In CTD-PAH, NEDD9 correlated with 6-minute walk distance (ρ = -0.35, p = 0.028, n = 39). In contrast to the PAH biomarker N-terminal pro-brain natriuretic peptide (n = 38), NEDD9 correlated inversely with exercise pulmonary artery wedge pressure and more strongly with right ventricular ejection fraction (ρ = -0.41, p = 0.006, n = 45) in a mixed population. The adjusted hazard ratio for lung transplant-free survival was 1.12 (95% confidence interval [CI], 1.02-1.22, p = 0.01) and 1.75 (95% CI, 1.12-2.73, p = 0.01) per 1 ng/ml and 5 ng/ml increase in plasma NEDD9, respectively, by Cox proportional hazard model.
Conclusions
In PAH, plasma NEDD9 is increased and associates with key prognostic variables. Prospective studies that include hard end points are warranted to validate NEDD9 as a novel PAH biomarker.

Published by Elsevier Inc.

J Heart Lung Transplant: 30 Dec 2019; epub ahead of print
Samokhin AO, Hsu S, Yu PB, Waxman AB, ... Leary PJ, Maron BA
J Heart Lung Transplant: 30 Dec 2019; epub ahead of print | PMID: 31952977
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Impact:
Abstract

Quantitative assessment of technical performance during hands-on surgical training of the arterial switch operation using 3-dimensional printed heart models.

Hussein N, Honjo O, Haller C, Coles JG, ... Van Arsdell G, Yoo SJ
Objective
Data supporting the use of hands-on simulation in congenital heart surgery are promising but primarily qualitative. This study aimed to demonstrate if there was an objective improvement in time and technical performance of the arterial switch procedure on 3-dimensional printed heart models by surgeons using a validated assessment method.
Methods
A total of 30 surgeons of varying experience performed the arterial switch procedure twice on 3-dimensional printed models with transposition of the great arteries during the Hands-on Surgical Training courses. Surgeons\' performances were recorded and retrospectively assessed for both time and performance using the Hands-on Surgical Training-Congenital Heart Surgery tool, a validated procedure-specific assessment tool for the arterial switch.
Results
A total of 60 videos were scored. Eighty percent of surgeons (24/30) had improved from their first attempt. The mean total score of the first attempt performance compared with the second was 103 and 120, respectively, with a mean difference in score of 17 (95% confidence interval, 10-24). All surgeons were statistically significantly quicker in their second attempt. The mean time for the first attempt compared with the second was 1 hour, 28 minutes, 4 seconds and 1 hour, 5 minutes, and 45 seconds, respectively, with a mean difference of 0 hours, 22 minutes, 19 seconds (95% confidence interval, 0 hours, 15 minutes, 22 seconds to 0 hours, 25 minutes, 34 seconds).
Conclusions
This is the first study to demonstrate an objective improvement in time and technical performance of the arterial switch procedure on 3-dimensional printed heart models. This supports the evidence that simulation in the form of deliberate practice with constructive, objective feedback is fundamental in the training of future congenital heart surgeons. These simulations and assessments should be incorporated to create structured, standardized training curricula within congenital heart surgery.

Crown Copyright © 2019. Published by Elsevier Inc. All rights reserved.

J Thorac Cardiovasc Surg: 19 Dec 2019; epub ahead of print
Hussein N, Honjo O, Haller C, Coles JG, ... Van Arsdell G, Yoo SJ
J Thorac Cardiovasc Surg: 19 Dec 2019; epub ahead of print | PMID: 31983523
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Impact:
Abstract

In Vitro and In Vivo Preclinical Testing of Pericyte-Engineered Grafts for the Correction of Congenital Heart Defects.

Alvino VV, Kilcooley M, Thomas AC, Carrabba M, ... Caputo M, Madeddu P

Background We have previously reported the possibility of using pericytes from leftovers of palliative surgery of congenital heart disease to engineer clinically certified prosthetic grafts. Methods and Results Here, we assessed the feasibility of using prosthetic conduits engineered with neonatal swine pericytes to reconstruct the pulmonary artery of 9-week-old piglets. Human and swine cardiac pericytes were similar regarding anatomical localization in the heart and antigenic profile following isolation and culture expansion. Like human pericytes, the swine surrogates form clones after single-cell sorting, secrete angiogenic factors, and extracellular matrix proteins and support endothelial cell migration and network formation in vitro. Swine pericytes seeded or unseeded (control) CorMatrix conduits were cultured under static conditions for 5 days, then they were shaped into conduits and incubated in a flow bioreactor for 1 or 2 weeks. Immunohistological studies showed the viability and integration of pericytes in the outer layer of the conduit. Mechanical tests documented a reduction in stiffness and an increase in strain at maximum load in seeded conduits in comparison with unseeded conduits. Control and pericyte-engineered conduits were then used to replace the left pulmonary artery of piglets. After 4 months, anatomical and functional integration of the grafts was confirmed using Doppler echography, cardiac magnetic resonance imaging, and histology. Conclusions These findings demonstrate the feasibility of using neonatal cardiac pericytes for reconstruction of small-size branch pulmonary arteries in a large animal model.



J Am Heart Assoc: 17 Feb 2020; 9:e014214
Alvino VV, Kilcooley M, Thomas AC, Carrabba M, ... Caputo M, Madeddu P
J Am Heart Assoc: 17 Feb 2020; 9:e014214 | PMID: 32067581
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Abstract

Nucleophosmin contributes to vascular inflammation and endothelial dysfunction in atherosclerosis progression.

Rao C, Liu B, Huang D, Chen R, ... Li F, Dong N
Objective
It is unclear whether nucleophosmin (NPM) participates in cardiovascular disease. The present study aimed to investigate the role and underlying mechanisms of NPM in atherosclerosis.
Methods
Levels and location of NPM in human carotid atherosclerotic plaques and healthy controls were detected by real-time polymerase chain reaction, immunoblots, and immunofluorescence. Atherosclerotic prone ApoE mice were fed with a Western diet for 16 weeks as an in vivo model. Human primary umbilical vein endothelial cells (HUVECs) were cultured as an in vitro model.
Results
Compared with controls, we found that NPM levels in human carotid atherosclerotic plaques were more than twice as high as in normal arteries, which mainly localized in endothelial cells. In vivo, adenovirus-containing NPM small hairpin RNA attenuated atherosclerotic lesion and promoted plaque stabilization in ApoE mice fed a Western diet by reducing vascular inflammation, maintaining endothelial function, and decreasing macrophage infiltration. Furthermore, NPM knockdown decreased nuclear factor-κB (NF-κB) p65 phosphorylation. In cultured HUVECs, palmitic acid increased the protein levels of NPM and induced the expression of inflammatory cytokines and monocyte adhesion, whereas NPM knockdown attenuated this effect. In HUVECs, NPM protein physically interacted with NF-κB p65 subunit and promoted its nuclear transposition. NPM also increased the transcriptional activity of NF-κB p65 promoter and enhance its binding to target genes, including interleukin-1β, interleukin-6, intercellular adhesion molecule-1, and E-selectin.
Conclusions
These data provide novel evidence that NPM promotes atherosclerosis by inducing vascular inflammation and endothelial dysfunction through the NF-κB signaling pathway and suggest that NPM may be a promising target for atherosclerosis prevention and treatment.

Copyright © 2020. Published by Elsevier Inc.

J Thorac Cardiovasc Surg: 24 Dec 2019; epub ahead of print
Rao C, Liu B, Huang D, Chen R, ... Li F, Dong N
J Thorac Cardiovasc Surg: 24 Dec 2019; epub ahead of print | PMID: 32007256
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Abstract

Ambrisentan in portopulmonary hypertension: A multicenter, open-label trial.

Preston IR, Burger CD, Bartolome S, Safdar Z, ... Gomberg-Maitland M, Hill NS
Background
Ambrisentan has shown effectiveness in the treatment of Group 1 pulmonary arterial hypertension (PAH). Although portopulmonary hypertension (PoPH) is a subset of Group 1 PAH, few clinical trials have been testing PAH therapies in patients with PoPH. The objective of this study is to evaluate the efficacy and safety of ambrisentan in PoPH.
Methods
This study is a prospective, multicenter, open-label trial in which treatment-naive patients with PoPH with Child-Pugh class A/B were administered with ambrisentan for 24 weeks, followed by a long-term extension (24-28 weeks). The primary end-points were change in pulmonary vascular resistance (PVR) and 6-minutes walk distance (6MWD) at 24 weeks, whereas secondary end-points included safety, World Health Organization (WHO) functional class (FC) and echocardiographic assessments.
Results
Of the 31 patients, 23 finished 24 weeks of ambrisentan therapy and 19 finished the extension. PVR decreased significantly (mean ± SD) (7.1 ± 5 vs 3.8 ± 1.8 Wood units, p < 0.001), whereas 6MWD remained unchanged (314 ± 94 vs 336 ± 108 m). Other hemodynamic parameters such as right atrial pressure (13 ± 8 vs 9 ± 4 mm Hg, p < 0.05), mean pulmonary arterial pressure (46 ± 13 vs. 38 ± 8 mm Hg, p < 0.01), cardiac index (2.6 ± 0.6 vs. 3.5 ± 0.7 liter/min/m, p < 0.001) showed improvement, whereas pulmonary capillary wedge pressure remained unchanged. Of the 22 patients with WHO FC assessments at baseline and 24 weeks, WHO FC improved significantly (p = 0.005). Most frequent drug-related adverse events were edema (38.7%) and headache (22.5%). One episode of leg edema resulted into the permanent discontinuation of ambrisentan.
Conclusions
Ambrisentan monotherapy in PoPH improves hemodynamics and FC at 24 weeks; however, it did not show any improvement in 6MWD. These preliminary outcomes should be interpreted with caution (Clinicaltrials.Gov:NCT01224210).

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 20 Jan 2020; epub ahead of print
Preston IR, Burger CD, Bartolome S, Safdar Z, ... Gomberg-Maitland M, Hill NS
J Heart Lung Transplant: 20 Jan 2020; epub ahead of print | PMID: 32008947
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Impact:
Abstract

Preoperative C-reactive protein predicts early postoperative outcomes after pulmonary endarterectomy in patients with chronic thromboembolic pulmonary hypertension.

Arthur Ataam J, Amsallem M, Guihaire J, Haddad F, ... Mercier O, Fadel E
Objective
To determine whether preoperative systemic inflammation (defined by C-reactive protein [CRP] levels ≥10 mg/L) is associated with worse functional and hemodynamic status and poor early outcomes postendarterectomy in patients with chronic thromboembolic pulmonary hypertension (CTEPH).
Methods
This study included 159 patients who underwent pulmonary endarterectomy from 2009 to 2013 (derivation cohort) and 238 patients from 2015 to 2016 (validation cohort) with CRP data from the national CTEPH registry. The correlations between proinflammatory markers (CRP, interleukins 1 and 6, fibrinogen, and leukocytes) and hemodynamics were assessed in the derivation cohort. Pre-, perioperative characteristics, and 30-day outcomes (ie, death or lung transplant or extracorporeal membrane oxygenation need or inotropic or vasopressor need ≥3 days) of patients with CRP levels ≥ or <10 mg/L were compared.
Results
Median age of the derivation cohort was 63 [52-73] years with 48% female, 80% in New York Heart Association class III/IV. The validation cohort had similar demographics and disease severity. Patients with CRP ≥10 mg/L had greater resistance levels and lower cardiac index than those with CRP <10 mg/L in both cohorts. The primary endpoint was reached in 38% (derivation) and 42% (validation) of patients. In multivariable logistic regression analysis, CRP ≥10 mg/L was associated with the primary endpoint in both the derivation cohort (odd ratio, 2.49 [1.11-5.61], independently of New York Heart class class IV and aortic clamping duration) and the validation cohort (odd ratio, 1.89 [1.09-3.61], independently of age and aortic clamping duration).
Conclusions
Preoperative CRP ≥10 mg/L is independently associated with adverse early outcomes postendarterectomy.

Copyright © 2020 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

J Thorac Cardiovasc Surg: 02 Jan 2020; epub ahead of print
Arthur Ataam J, Amsallem M, Guihaire J, Haddad F, ... Mercier O, Fadel E
J Thorac Cardiovasc Surg: 02 Jan 2020; epub ahead of print | PMID: 32007254
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Abstract

Long-term durability of bioprosthetic valves in pulmonary position: Pericardial versus porcine valves.

Kwak JG, Bang JH, Cho S, Kim ER, ... Lee CH, Kim WH
Objectives
The long-term durability of the 2 most commonly used types of bioprosthetic valves in the pulmonic position, the porcine and pericardial valves, is unclear. We compared the long-term durability of the pericardial (Carpentier-Edwards PERIMOUNT [CE]) and porcine (Hancock II) valves in the pulmonic position in patients with congenital cardiac anomalies.
Methods
We retrospectively reviewed the medical records of 258 cases (248 patients) of pulmonary valve implantation or replacement using CE (129 cases, group CE) or porcine (129 cases, group H) valves from 2 institutions between 2001 and 2009.
Results
The patients\' age at pulmonary valve implantation was 14.9 ± 8.7 years. No significant differences in perioperative characteristics were observed between groups CE and H. Follow-up data were complete in 219 cases (84.9%) and the median follow-up duration was 10.5 (interquartile range, 8.4∼13.0) years. Ten mortalities (3.9%) occurred. Sixty-four patients underwent reoperation for pulmonary valve replacement due to prosthetic valve failure; 10 of these 64 patients underwent reoperation during the study period. Patients in group CE were significantly more likely to undergo reoperation (hazard ratio, 2.17; confidence interval, 1.26-3.72; P = .005) than patients in group H. Patients in group CE showed had a greater prosthetic valve dysfunction (moderate-to-severe pulmonary regurgitation or pulmonary stenosis with ≥3.5 m/s peak velocity through the prosthetic pulmonary valve) rate (hazard ratio, 1.83; confidence interval, 1.07-3.14; P = .027) than patients in group H.
Conclusions
Compared with the pericardial valve, the porcine valve had long-term advantages in terms of reduced reoperation rate and prosthetic valve dysfunction in the pulmonic position in patients with congenital cardiac anomalies.

Copyright © 2019 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.

J Thorac Cardiovasc Surg: 02 Jan 2020; epub ahead of print
Kwak JG, Bang JH, Cho S, Kim ER, ... Lee CH, Kim WH
J Thorac Cardiovasc Surg: 02 Jan 2020; epub ahead of print | PMID: 32014323
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Impact:
Abstract

Effects of Exercise Training in Postoperative Patients With Congenital Heart Disease: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Xu C, Su X, Ma S, Shu Y, ... Hu Y, Mo X

Background The purpose of this meta-analysis is to assess the effects of exercise training on quality of life, specific biomarkers, exercise capacity, and vascular function in congenital heart disease (CHD) subjects after surgery. Methods and Results We searched the Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE from the date of the inception of the database through April 2019. Altogether, 1161 records were identified in the literature search. Studies evaluating outcomes before and after exercise training among postoperative patients with congenital heart disease were included. The assessed outcomes were exercise capacity, vascular function, serum NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels and quality of life. We analyzed heterogeneity by using the I statistic and evaluated the evidence quality according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) guidelines. Nine randomized controlled trials were included. The evidence indicated that exercise interventions increased the one of the quality of life questionnaire score (mean difference=3.19 [95% CI, 0.23, 6.16]; =0.03; I=39%) from the score before the interventions. However, no alterations in exercise capacity, vascular function, NT-proBNP or quality of life were observed after exercise training. The results of the subgroup analysis showed that NT-proBNP levels were lower in the group with exercise training than in the group without exercise training over the same duration of follow-up. The evidence quality was generally assessed to be low. Conclusions In conclusion, there is insufficient evidence to suggest that physical exercise improves long-term follow-up outcomes of congenital heart disease, although it has some minor effects on quality of life.



J Am Heart Assoc: 02 Mar 2020; 9:e013516
Xu C, Su X, Ma S, Shu Y, ... Hu Y, Mo X
J Am Heart Assoc: 02 Mar 2020; 9:e013516 | PMID: 32070206
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Impact:
Abstract

Impact of race on survival in pulmonary arterial hypertension: Results from the REVEAL registry.

Medrek S, Sahay S, Zhao C, Selej M, Frost A
Background
Prior research has suggested that the prevalence and outcomes of pulmonary arterial hypertension (PAH) may vary by race or ethnicity. However, these studies have been limited by small sample size or methodological techniques relying on epidemiologic data. The purpose of this study is to evaluate the relationship between race/ethnicity and survival in a large U.S.-based prospective multicenter registry.
Methods
Patients in the Registry to Evaluate Early and Long-term PAH Disease Management (REVEAL), a 5-year observational study of Group 1 PAH, were categorized by race/ethnicity. Baseline hemodynamic characteristics, clinical characteristics, and medication use was described. The relationship between race/ethnicity and outcome was evaluated by Kaplan-Meier and Cox proportional hazards modeling techniques. Left-truncation analysis, which adjusted for time from diagnosis to study enrollment, was used to minimize the effect of survivor bias.
Results
This analysis included 3,046 patients; 2,202 identified as white, 393 as black, 263 as Hispanic, 100 as Asian or Pacific Islander, and 88 as other. Unadjusted Kaplan-Meier survival analysis indicated that white patients had the lowest survival rates. After adjusting for variables of prognostic impact, race/ethnicity was no longer significantly associated with survival. Other results showed that black patients were more likely to have connective tissue disease-associated PAH, Hispanic patients were more likely to have portopulmonary hypertension, and Asian patients were more likely to have congenital heart disease-associated PAH.
Conclusions
Analysis of the REVEAL registry did not find race/ethnicity to be a significant predictor of mortality. This is the largest analysis to date evaluating the role of race/ethnicity on outcomes in PAH.

Published by Elsevier Inc.

J Heart Lung Transplant: 23 Jan 2020; epub ahead of print
Medrek S, Sahay S, Zhao C, Selej M, Frost A
J Heart Lung Transplant: 23 Jan 2020; epub ahead of print | PMID: 32067864
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Impact:
Abstract

Clinical implications of idiopathic pulmonary arterial hypertension phenotypes defined by cluster analysis.

Badagliacca R, Rischard F, Papa S, Kubba S, ... Fedele F, Vizza CD
Background
Despite advances in drug development, life expectancy in idiopathic pulmonary arterial hypertension (IPAH) remains unacceptable. Contemporary IPAH characterization is based on criteria that may not adequately capture disease heterogeneity and may be proposed as a possible explanation for why patient outcome is still unfavorable. The aim of this study was to apply cluster analysis to improve phenotyping of patients with IPAH and analyze long-term clinical outcome of derived clusters.
Methods
Patients with IPAH from 2 referral centers (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Patients were classified according to cluster analysis and followed for clinical worsening occurrence.
Results
The cluster analysis identified 4 IPAH phenotypes. Cluster 1 was characterized by young patients, mild pulmonary hypertension (PH), mild right ventricular (RV) dilation and high oxygen (O) pulse; Cluster 2 by severe PH and RV dilation and high O pulse; and Cluster 3 by male patients, severe PH and RV dilation, and low O pulse. Cluster 4 patients were older and overweight, with mild PH and RV dilation and low O pulse. After a mean follow-up of 995 ± 623 days, 123 (48.8%) patients had clinical worsening. Cluster 1 patients presented the best prognosis, whereas Cluster 3 had the highest rates of clinical worsening. Compared with Cluster 1, risk of clinical worsening ranged from 4.12 (confidence interval [CI] 1.43-11.92; p = 0.009) for Cluster 4 to 7.38 (CI 2.80-19.40) for Cluster 2 and 13.8 (CI 5.60-34.0; p = 0.0001) for Cluster 3.
Conclusions
Cluster analysis of clinical variables identified 4 distinct phenotypes of IPAH. Our findings underscore the high degree of disease heterogeneity that exists within patients with IPAH and the need for advanced clinical testing to define phenotypes to improve treatment strategy decision-making. CONDENSED ABSTRACT Idiopathic pulmonary arterial hypertension (IPAH) characterization is based on criteria that may not adequately capture disease heterogeneity. The aim of this study was to apply cluster analysis to improve phenotyping of IPAH. Patients with IPAH (n = 252) were evaluated with clinical, hemodynamic, and echocardiographic assessment and cardiopulmonary exercise test. Within the umbrella category of IPAH, it was the combination of mean pulmonary arterial pressure, right ventricular size, and oxygen pulse that further stratified patients into novel IPAH phenotypes that significantly associate with clinical worsening. These findings underscore the need for novel multidimensional IPAH phenotyping for improved patient care and trial quality.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 20 Jan 2020; epub ahead of print
Badagliacca R, Rischard F, Papa S, Kubba S, ... Fedele F, Vizza CD
J Heart Lung Transplant: 20 Jan 2020; epub ahead of print | PMID: 32061507
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Impact:
Abstract

Obesity Is Associated With Pulmonary Hypertension and Modifies Outcomes.

Frank RC, Min J, Abdelghany M, Paniagua S, ... Pomerantsev E, Ho JE

Background Experimental studies support a link between obesity and pulmonary hypertension (PH), yet clinical studies have been limited. This study sought to determine the association of obesity and pulmonary hemodynamic measures and mortality in PH. Methods and Results We examined patients undergoing right-sided heart catherization (2005-2016) in a hospital-based cohort. Multivariable regression models tested associations of body mass index and pulmonary vascular hemodynamics, with PH defined as mean pulmonary artery pressure >20 mm Hg, and further subclassified into precapillary, postcapillary, and mixed PH. Multivariable Cox models were used to examine the effect of PH and obesity on mortality. Among 8940 patients (mean age, 62 years; 40% women), 52% of nonobese and 69% of obese individuals had evidence of PH. Higher body mass index was independently associated with greater odds of overall PH (odds ratio, 1.34; 95% CI, 1.29-1.40; <0.001 per 5-unit increase in body mass index) as well as each PH subtype (<0.001 for all). Patients with PH had greater risk of mortality compared with individuals without PH regardless of subgroup (<0.001 for all). We found that obesity was associated with 23% lower hazard of mortality among patients with PH (hazard ratio, 0.77; 95% CI, 0.69-0.85; <0.001). The effect of obesity was greatest among those with precapillary PH (hazard ratio, 0.57; 95% CI, 0.46-0.70; <0.001), where obesity modified the effect of PH on mortality ( for interaction=0.02). Conclusions Obesity is independently associated with PH. PH is associated with greater mortality; this is modified by obesity such that obese patients with precapillary PH have lower mortality compared with nonobese counterparts. Further studies are needed to elucidate mechanisms underlying obesity-related PH.



J Am Heart Assoc: 02 Mar 2020; 9:e014195
Frank RC, Min J, Abdelghany M, Paniagua S, ... Pomerantsev E, Ho JE
J Am Heart Assoc: 02 Mar 2020; 9:e014195 | PMID: 32079475
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Impact:
Abstract

Neonatal Outcomes in Very Preterm Infants With Severe Congenital Heart Defects: An International Cohort Study.

Norman M, Håkansson S, Kusuda S, Vento M, ... Shah PS,

Background Very preterm infants are at high risk of death or severe morbidity. The objective was to determine the significance of severe congenital heart defects (CHDs) for these risks. Methods and Results This cohort study included infants from 10 countries born from 2007-2015 at 24 to 31 weeks\' gestation with birth weights <1500 g. Severe CHDs were defined by() and() codes and categorized as those compromising systemic output, causing sustained cyanosis, or resulting in congestive heart failure. The primary outcome was in-hospital mortality. Secondary outcomes were neonatal brain injury, necrotizing enterocolitis, bronchopulmonary dysplasia, and retinopathy of prematurity. Adjusted and propensity score-matched odds ratios (ORs) were calculated. Analyses were stratified by type of CHD, gestational age, and network. A total of 609 (0.77%) infants had severe CHD and 76 371 without any malformation served as controls. The mean gestational age and birth weight were 27.8 weeks and 1018 g, respectively. The mortality rate was 18.6% in infants with CHD and 8.9% in controls (propensity score-matched OR, 2.30; 95% CI, 1.61-3.27). Severe CHD was not associated with neonatal brain injury, necrotizing enterocolitis, or retinopathy of prematurity, whereas the OR for bronchopulmonary dysplasia increased. Mortality was higher in all types, with the highest propensity score-matched OR (4.96; 95% CI, 2.11-11.7) for CHD causing congestive heart failure. While mortality did not differ between groups at <27 weeks\' gestational age, adjusted OR for mortality in infants with CHD increased to 10.9 (95% CI, 5.76-20.70) at 31 weeks\' gestational age. Rates of CHD and mortality differed significantly between networks. Conclusions Severe CHD is associated with significantly increased mortality in very preterm infants.



J Am Heart Assoc: 02 Mar 2020; 9:e015369
Norman M, Håkansson S, Kusuda S, Vento M, ... Shah PS,
J Am Heart Assoc: 02 Mar 2020; 9:e015369 | PMID: 32079479
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Impact:
Abstract

Predicted heart mass-based size matching among recipients with moderate pulmonary hypertension: Outcomes and sex effect.

Shah M, Saeed O, Shin J, Murthy S, ... Jorde UP, Patel SR
Background
There is a lack of evidence to guide appropriate donor sizing in recipients with moderate pulmonary hypertension (pHTN) awaiting heart transplantation (HTx). It is common practice to oversize donor hearts for such recipients to prevent post-operative right ventricular failure. Therefore, our objective was to determine if oversizing in pre-transplant moderate pHTN provides a survival advantage.
Methods
The United Network for Organ Sharing database was analyzed to include HTx recipients from 1994 to 2016. Recipients were considered as having moderate pHTN if the pulmonary vascular resistance (PVR) was 2.5 to 5 Wood units (WU) or transpulmonary gradient (TPG) was 10 to 18 mm Hg. Heart size mismatch was determined using the predicted heart mass equations. A size mismatch of ≥15% in either direction was considered undersized or oversized, respectively. Ninety-day and 1-year survival were analyzed based on size matching via univariate and Cox regression analysis. Propensity matching was performed to specifically evaluate the effect of donor sex among male transplant recipients.
Results
Among 29,441 HTx recipients, 10,666 had moderate pHTN by PVR criteria and 12,624 HTx patients had moderate pHTN according to TPG criteria. Among patients with a PVR of 2.5 to 5 WU, oversizing was not associated with lower mortality compared with matched hearts at 90 days (7.6% vs 7.4%; p = 0.75) and 1 year (12.1% vs 11.3%; p = 0.26). Conversely, undersizing the donor was associated with a higher 90-day (10.6% vs 7.6% vs 7.4%; p < 0.01) and 1-year (15.3% vs 12.1% vs 11.3%; p < 0.01) mortality than recipients receiving oversized or matched hearts, respectively. On Cox regression analysis, there was no benefit with oversizing at 90 days (hazard ratio [HR] 0.88; p = 0.23) and 1 year (HR 0.99; p = 0.90), whereas undersizing was associated with higher 90-day (HR 1.32; p = 0.02) and 1-year mortality (HR 1.23; p = 0.03) compared to size-matched controls. Among patients with moderate pHTN based on TPG of 10 to 18 mm Hg, neither undersizing nor oversizing was predictive of mortality at 90 days and 1 year according to Cox regression analysis. Propensity matching revealed that female-to-male transplantation had similar 1-year mortality to male-to-male transplantation, and there was no advantage to oversizing female donors for male recipients.
Conclusions
In this registry-based analysis, there was no benefit to oversizing donors for cardiac transplant recipients with moderate pHTN. Elimination of this restriction could increase the donor pool and reduce wait times for such recipients.

Copyright © 2020 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.

J Heart Lung Transplant: 30 Jan 2020; epub ahead of print
Shah M, Saeed O, Shin J, Murthy S, ... Jorde UP, Patel SR
J Heart Lung Transplant: 30 Jan 2020; epub ahead of print | PMID: 32085934
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Impact:
Abstract

Newly Developed Adult Congenital Heart Disease Anatomic and Physiological Classification: First Predictive Validity Evaluation.

Ombelet F, Goossens E, Van De Bruaene A, Budts W, Moons P

Background Risk stratification for adults with congenital heart disease is usually based on the anatomic complexity of the patients\' defect. The 2018 American Heart Association/American College of Cardiology guidelines for the management of adults with congenital heart disease proposed a new classification scheme, combining anatomic complexity and current physiological stage of the patient. We aimed to investigate the capacity of the Adult Congenital Heart Disease Anatomic and Physiological classification to predict 15-year mortality. Methods and Results Data on 5 classification systems were collected for 629 patients at the outpatient clinic for a previous study. After 15 years, data on mortality were obtained through medical record review. For this assessment, we additionally collected information on physiological state to determine the Adult Congenital Heart Disease Anatomic and Physiological classification. Harrell\'s concordance statistics index, obtained through a univariate Cox proportional hazards regression, was 0.71 (95% CI, 0.63-0.78) for the Adult Congenital Heart Disease Anatomic and Physiological classification. Harrell\'s concordance statistics index of the congenital heart disease anatomic component only was 0.67 (95% CI, 0.60-0.74). The highest Harrell\'s concordance statistics index was obtained for the anatomic complexity in combination with the Congenital Heart Disease Functional Index (0.79; 95% CI, 0.73-0.84). Conclusions This first investigation of the Adult Congenital Heart Disease Anatomic and Physiological classification system provides empirical support for adding the physiological component to the anatomic complexity in the prediction of 15-year cardiac mortality.



J Am Heart Assoc: 02 Mar 2020; 9:e014988
Ombelet F, Goossens E, Van De Bruaene A, Budts W, Moons P
J Am Heart Assoc: 02 Mar 2020; 9:e014988 | PMID: 32089057
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Impact:
Abstract

Standardized cardiovascular magnetic resonance imaging (CMR) protocols: 2020 update.

Kramer CM, Barkhausen J, Bucciarelli-Ducci C, Flamm SD, Kim RJ, Nagel E

This document is an update to the 2013 publication of the Society for Cardiovascular Magnetic Resonance (SCMR) Board of Trustees Task Force on Standardized Protocols. Concurrent with this publication, 3 additional task forces will publish documents that should be referred to in conjunction with the present document. The first is a document on the Clinical Indications for CMR, an update of the 2004 document. The second task force will be updating the document on Reporting published by that SCMR Task Force in 2010. The 3rd task force will be updating the 2013 document on Post-Processing. All protocols relative to congenital heart disease are covered in a separate document.The section on general principles and techniques has been expanded as more of the techniques common to CMR have been standardized. A section on imaging in patients with devices has been added as this is increasingly seen in day-to-day clinical practice. The authors hope that this document continues to standardize and simplify the patient-based approach to clinical CMR. It will be updated at regular intervals as the field of CMR advances.



J Cardiovasc Magn Reson: 23 Feb 2020; 22:17
Kramer CM, Barkhausen J, Bucciarelli-Ducci C, Flamm SD, Kim RJ, Nagel E
J Cardiovasc Magn Reson: 23 Feb 2020; 22:17 | PMID: 32089132
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Impact:

This program is still in alpha version.