Topic: Congenital

Abstract

Challenges and Special Aspects of Pulmonary Hypertension in Middle- to Low-Income Regions: JACC State-of-the-Art Review.

Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

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

J Am Coll Cardiol: 18 May 2020; 75:2463-2477
Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,
J Am Coll Cardiol: 18 May 2020; 75:2463-2477 | PMID: 32408981
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Abstract

Characteristics of Adults With Congenital Heart Defects in the United States.

Gurvitz M, Dunn JE, Bhatt A, Book WM, ... Jenkins K, Riehle-Colarusso T
Background
In the United States, >1 million adults are living with congenital heart defects (CHDs), but gaps exist in understanding the health care needs of this growing population.
Objectives
This study assessed the demographics, comorbidities, and health care use of adults ages 20 to 64 years with CHDs.
Methods
Adults with International Classification of Disease-9th Revision-Clinical Modification CHD-coded health care encounters between January 1, 2008 (January 1, 2009 for Massachusetts) and December 31, 2010 were identified from multiple data sources at 3 U.S. sites: Emory University (EU) in Atlanta, Georgia (5 counties), Massachusetts Department of Public Health (statewide), and New York State Department of Health (11 counties). Demographics, insurance type, comorbidities, and encounter data were collected. CHDs were categorized as severe or not severe, excluding cases with isolated atrial septal defect and/or patent foramen ovale.
Results
CHD severity and comorbidities varied across sites, with up to 20% of adults having severe CHD and >50% having ≥1 additional cardiovascular comorbidity. Most adults had ≥1 outpatient encounters (80% EU, 90% Massachusetts, and 53% New York). Insurance type differed across sites, with Massachusetts having a large proportion of Medicaid (75%) and EU and New York having large proportions of private insurance (44% EU, 67% New York). Estimated proportions of adults with CHD-coded health care encounters varied greatly by location, with 1.2 (EU), 10 (Massachusetts), and 0.6 (New York) per 1,000 adults based on 2010 census data.
Conclusions
This was the first surveillance effort of adults with CHD-coded inpatient and outpatient health care encounters in 3 U.S. geographic locations using both administrative and clinical data sources. This information will provide a clearer understanding of health care use in this growing population.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 13 Jul 2020; 76:175-182
Gurvitz M, Dunn JE, Bhatt A, Book WM, ... Jenkins K, Riehle-Colarusso T
J Am Coll Cardiol: 13 Jul 2020; 76:175-182 | PMID: 32646567
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Abstract

Hydroxychloroquine to Prevent Recurrent Congenital Heart Block in Fetuses of Anti-SSA/Ro-Positive Mothers.

Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, ... Saxena A, Buyon JP
Background
Experimental and clinical evidence support the role of macrophage Toll-like receptor signaling in maternal anti-SSA/Ro-mediated congenital heart block (CHB).
Objectives
Hydroxychloroquine (HCQ), an orally administered Toll-like receptor antagonist widely used in lupus including during pregnancy, was evaluated for efficacy in reducing the historical 18% recurrence rate of CHB.
Methods
This multicenter, open-label, single-arm, 2-stage clinical trial was designed using Simon\'s optimal approach. Anti-SSA/Ro-positive mothers with a previous pregnancy complicated by CHB were recruited (n = 19 Stage 1; n = 35 Stage 2). Patients received 400 mg daily of HCQ prior to completion of gestational week 10, which was maintained through pregnancy. The primary outcome was 2° or 3° CHB any time during pregnancy, and secondary outcomes included isolated endocardial fibroelastosis, 1° CHB at birth and skin rash.
Results
By intention-to-treat (ITT) analysis, 4 of 54 evaluable pregnancies resulted in a primary outcome (7.4%; 90% confidence interval: 3.4% to 15.9%). Because 9 mothers took potentially confounding medications (fluorinated glucocorticoids and/or intravenous immunoglobulin) after enrollment but prior to a primary outcome, to evaluate HCQ alone, 9 additional mothers were recruited and followed the identical protocol. In the per-protocol analysis restricted to pregnancies exposed to HCQ alone, 4 of 54 (7.4%) fetuses developed a primary outcome as in the ITT. Secondary outcomes included mild endocardial fibroelastosis (n = 1) and cutaneous neonatal lupus (n = 4).
Conclusions
These prospective data support that HCQ significantly reduces the recurrence of CHB below the historical rate by >50%, suggesting that this drug should be prescribed for secondary prevention of fetal cardiac disease in anti-SSA/Ro-exposed pregnancies. (Preventive Approach to Congenital Heart Block With Hydroxychloroquine [PATCH]; NCT01379573).

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

J Am Coll Cardiol: 20 Jul 2020; 76:292-302
Izmirly P, Kim M, Friedman DM, Costedoat-Chalumeau N, ... Saxena A, Buyon JP
J Am Coll Cardiol: 20 Jul 2020; 76:292-302 | PMID: 32674792
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Abstract

Mouse models of neutropenia reveal progenitor-stage-specific defects.

Muench DE, Olsson A, Ferchen K, Pham G, ... Salomonis N, Grimes HL

Advances in genetics and sequencing have identified a plethora of disease-associated and disease-causing genetic alterations. To determine causality between genetics and disease, accurate models for molecular dissection are required; however, the rapid expansion of transcriptional populations identified through single-cell analyses presents a major challenge for accurate comparisons between mutant and wild-type cells. Here we generate mouse models of human severe congenital neutropenia (SCN) using patient-derived mutations in the GFI1 transcription factor. To determine the effects of SCN mutations, we generated single-cell references for granulopoietic genomic states with linked epitopes, aligned mutant cells to their wild-type equivalents and identified differentially expressed genes and epigenetic loci. We find that GFI1-target genes are altered sequentially, as cells go through successive states of differentiation. These insights facilitated the genetic rescue of granulocytic specification but not post-commitment defects in innate immune effector function, and underscore the importance of evaluating the effects of mutations and therapy within each relevant cell state.



Nature: 30 May 2020; 582:109-114
Muench DE, Olsson A, Ferchen K, Pham G, ... Salomonis N, Grimes HL
Nature: 30 May 2020; 582:109-114 | PMID: 32494068
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Abstract

Oral fluconazole use in the first trimester and risk of congenital malformations: population based cohort study.

Zhu Y, Bateman BT, Gray KJ, Hernandez-Diaz S, ... Straub L, Huybrechts KF
Objective
To examine the risk of congenital malformations associated with exposure to oral fluconazole at commonly used doses in the first trimester of pregnancy for the treatment of vulvovaginal candidiasis.
Design
Population based cohort study.
Setting
A cohort of pregnancies publicly insured in the United States, with data from the nationwide Medicaid Analytic eXtract 2000-14.
Participants
Pregnancies of women enrolled in Medicaid from three or more months before the last menstrual period to one month after delivery, and infants enrolled for three or more months after birth.
Interventions
Use of fluconazole and topical azoles was established by requiring one or more prescriptions during the first trimester of pregnancy.
Main outcome measures
Risk of musculoskeletal malformations, conotruncal malformations, and oral clefts (primary outcomes), associated with exposure to oral fluconazole, diagnosed during the first 90 days after delivery, were examined.
Results
The study cohort of 1 969 954 pregnancies included 37 650 (1.9%) pregnancies exposed to oral fluconazole and 82 090 (4.2%) pregnancies exposed to topical azoles during the first trimester. The risk of musculoskeletal malformations was 52.1 (95% confidence interval 44.8 to 59.3) per 10 000 pregnancies exposed to fluconazole versus 37.3 (33.1 to 41.4) per 10 000 pregnancies exposed to topical azoles. The risks of conotruncal malformations were 9.6 (6.4 to 12.7) versus 8.3 (6.3 to 10.3) per 10 000 pregnancies exposed to fluconazole and topical azoles, respectively; risks of oral clefts were 9.3 (6.2 to 12.4) versus 10.6 (8.4 to 12.8) per 10 000 pregnancies, respectively. The adjusted relative risk after fine stratification of the propensity score was 1.30 (1.09 to 1.56) for musculoskeletal malformations, 1.04 (0.70 to 1.55) for conotruncal malformations, and 0.91 (0.61 to 1.35) for oral clefts overall. Based on cumulative doses of fluconazole, the adjusted relative risks for musculoskeletal malformations, conotruncal malformations, and oral clefts overall were 1.29 (1.05 to 1.58), 1.12 (0.71 to 1.77), and 0.88 (0.55 to 1.40) for 150 mg of fluconazole; 1.24 (0.93 to 1.66), 0.61 (0.26 to 1.39), and 1.08 (0.58 to 2.04) for more than 150 mg up to 450 mg of fluconazole; and 1.98 (1.23 to 3.17), 2.30 (0.93 to 5.65), and 0.94 (0.23 to 3.82) for more than 450 mg of fluconazole, respectively.
Conclusions
Oral fluconazole use in the first trimester was not associated with oral clefts or conotruncal malformations, but an association with musculoskeletal malformations was found, corresponding to a small adjusted risk difference of about 12 incidents per 10 000 exposed pregnancies overall.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 19 May 2020; 369:m1494
Zhu Y, Bateman BT, Gray KJ, Hernandez-Diaz S, ... Straub L, Huybrechts KF
BMJ: 19 May 2020; 369:m1494 | PMID: 32434758
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Abstract

Gut Pathology and Its Rescue by ACE2 (Angiotensin-Converting Enzyme 2) in Hypoxia-Induced Pulmonary Hypertension.

Sharma RK, Oliveira AC, Yang T, Karas MM, ... Richards EM, Raizada MK

Therapeutic advances for pulmonary hypertension (PH) have been incremental because of the focus on the pulmonary vasculature in PH pathology. Here, we evaluate the concept that PH is, rather, a systemic disorder involving interplay among multiorgan systems, including brain, gut, and lungs. Therefore, the objective of this study was to evaluate the hypothesis that PH is associated with a dysfunctional brain-gut-lung axis and that global overexpression of ACE2 (angiotensin-converting enzyme 2) rebalances this axis and protects against PH. ACE2 knockin and wild-type (WT; C57BL/6) mice were subjected to chronic hypoxia (10% FIO2) or room air for 4 weeks. Cardiopulmonary hemodynamics, histology, immunohistochemistry, and fecal 16S rRNA microbial gene analyses were evaluated. Hypoxia significantly increased right ventricular systolic pressure, sympathetic activity as well as the number and activation of microglia in the paraventricular nucleus of the hypothalamus in WT mice. This was associated with a significant increase in muscularis layer thickening and decreases in both villi length and goblet cells and altered gut microbiota. Global overexpression of ACE2 prevented changes in hypoxia-induced pulmonary and gut pathophysiology and established distinct microbial communities from WT hypoxia mice. Furthermore, WT mice subjected to fecal matter transfer from ACE2 knockin mice were resistant to hypoxia-induced PH compared with their controls receiving WT fecal matter transfer. These observations demonstrate that ACE2 ameliorates these hypoxia-induced pathologies and attenuates PH. The data implicate dysfunctional brain-gut-lung communication in PH and provide novel avenues for therapeutic interventions.



Hypertension: 17 May 2020:HYPERTENSIONAHA12014931; epub ahead of print
Sharma RK, Oliveira AC, Yang T, Karas MM, ... Richards EM, Raizada MK
Hypertension: 17 May 2020:HYPERTENSIONAHA12014931; epub ahead of print | PMID: 32418496
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Abstract

Envelope protein ubiquitination drives entry and pathogenesis of Zika virus.

Giraldo MI, Xia H, Aguilera-Aguirre L, Hage A, ... Shi PY, Rajsbaum R

Zika virus (ZIKV) belongs to the family Flaviviridae, and is related to other viruses that cause human diseases. Unlike other flaviviruses, ZIKV infection can cause congenital neurological disorders and replicates efficiently in reproductive tissues. Here we show that the envelope protein (E) of ZIKV is polyubiquitinated by the E3 ubiquitin ligase TRIM7 through Lys63 (K63)-linked polyubiquitination. Accordingly, ZIKV replicates less efficiently in the brain and reproductive tissues of Trim7 mice. Ubiquitinated E is present on infectious virions of ZIKV when they are released from specific cell types, and enhances virus attachment and entry into cells. Specifically, K63-linked polyubiquitin chains directly interact with the TIM1 (also known as HAVCR1) receptor of host cells, which enhances virus entry in cells as well as in brain tissue in vivo. Recombinant ZIKV mutants that lack ubiquitination are attenuated in human cells and in wild-type mice, but not in live mosquitoes. Monoclonal antibodies against K63-linked polyubiquitin specifically neutralize ZIKV and reduce viraemia in mice. Our results demonstrate that the ubiquitination of ZIKV E is an important determinant of virus entry, tropism and pathogenesis.



Nature: 07 Jul 2020; epub ahead of print
Giraldo MI, Xia H, Aguilera-Aguirre L, Hage A, ... Shi PY, Rajsbaum R
Nature: 07 Jul 2020; epub ahead of print | PMID: 32641828
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Abstract

Identification of The Long Non-Coding RNA H19 as a New Biomarker and Therapeutic Target in Right Ventricular Failure in Pulmonary Arterial Hypertension.

Omura J, Habbout K, Shimauchi T, Wu WH, ... Boucherat O, Bonnet S

Right ventricular (RV) function is the major determinant for both functional capacity and survival in patients with pulmonary arterial hypertension (PAH). Despite the recognized clinical importance of preserving RV function, the subcellular mechanisms that govern the transition from a compensated to a decompensated state remain poorly understood and as a consequence there are no clinically established treatments for RV failure and a paucity of clinically useful biomarkers. Accumulating evidence indicates that long non-coding RNAs (lncRNAs) are powerful regulators of cardiac development and disease. Nonetheless, their implication in adverse RV remodeling in PAH is unknown.Expression of the lncRNA H19 was assessed by quantitative PCR in plasma and RV from patients categorized as control RV, compensated RV (cRV) or decompensated RV (dRV) based on clinical history and cardiac index. The impact of H19 suppression using GapmeR was explored in two rat models mimicking RV failure, namely the monocrotaline (MCT) and pulmonary artery banding (PAB). Echocardiographic, hemodynamic, histological and biochemical analyses were conducted.gain- and loss-of-function experiments were performed in rat cardiomyocytes.We demonstrated that H19 is up-regulated in dRV from PAH patients and correlates with RV hypertrophy and fibrosis. Similar findings were observed in MCT and PAB rats. We found that silencing H19 limits pathological RV hypertrophy, fibrosis and capillary rarefaction, thus preserving RV function in MCT and PAB rats without affecting pulmonary vascular remodeling. This cardioprotective effect was accompanied by E2F transcription factor 1-mediated up-regulation of enhancer of zeste homolog 2. , knockdown of H19 suppressed cardiomyocyte hypertrophy induced by phenylephrine, while its overexpression has the opposite effect. Finally, we demonstrated that circulating H19 levels in plasma discriminate PAH patients from controls, correlate with RV function and predict long-term survival in two independent idiopathic PAH cohorts. Moreover, H19 levels delineate subgroups of patients with differentiated prognosis when combined with the NT-proBNP levels or the risk score proposed by both REVEAL and the 2015 European pulmonary hypertension guidelines.Our findings identify H19 as a new therapeutic target to impede the development of maladaptive RV remodeling and a promising biomarker of PAH severity and prognosis.



Circulation: 22 Jul 2020; epub ahead of print
Omura J, Habbout K, Shimauchi T, Wu WH, ... Boucherat O, Bonnet S
Circulation: 22 Jul 2020; epub ahead of print | PMID: 32698630
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Abstract

Prenatal regenerative fetoscopic interventions for congenital anomalies.

Ruano R

Fetal intervention has progressed in the past two decades from experimental proof-of-concept to practice-adopted, life saving interventions in human fetuses with congenital anomalies. This progress is informed by advances in innovative research, prenatal diagnosis, and fetal surgical techniques. Invasive open hysterotomy, associated with notable maternal-fetal risks, is steadily replaced by less invasive fetoscopic alternatives. A better understanding of the natural history and pathophysiology of congenital diseases has advanced the prenatal regenerative paradigm. By altering the natural course of disease through regrowth or redevelopment of malformed fetal organs, prenatal regenerative medicine has transformed maternal-fetal care. This review discusses the uses of regenerative medicine in the prenatal diagnosis and management of three congenital diseases: congenital diaphragmatic hernia, lower urinary tract obstruction, and spina bifida.

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: 30 Jun 2020; 370:m1624
Ruano R
BMJ: 30 Jun 2020; 370:m1624 | PMID: 32611543
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Abstract

MDM2-Mediated Ubiquitination of ACE2 Contributes to the Development of Pulmonary Arterial Hypertension.

Shen H, Zhang J, Wang C, Jain PP, ... Yuan JX, Shyy JY

Angiotensin-converting enzyme 2 (ACE2) converts angiotensin II (Ang II), a potent vasoconstrictor, to Ang 1-7 and is also a membrane protein that enables COVID-19 infectivity. AMP-activated protein kinase (AMPK) phosphorylation of ACE2 enhances ACE2 stability. This mode of post-translational modification (PTM) of ACE2 in vascular endothelial cells (ECs) is causative of a pulmonary hypertension (PH)-protective phenotype. The oncoprotein murine double minute 2 (MDM2) is an E3 ligase that ubiquitinates its substrates to cause their degradation. In this study, we investigated whether MDM2 is involved in the PTM of ACE2 via its ubiquitination of ACE2, and whether an AMPK and MDM2 crosstalk regulates the pathogenesis of PH.Bioinformatic analyses were used to explore E3 ligase that ubiquitinates ACE2. Cultured endothelial cells, mouse models, and specimens from patients with idiopathic pulmonary arterial hypertension were used to investigate the crosstalk between AMPK and MDM2 in regulating ACE2 phosphorylation and ubiquitination in the context of PH.Levels of MDM2 were increased and those of ACE2 decreased in lung tissues or pulmonary arterial endothelial cells from patients with idiopathic pulmonary arterial hypertension and rodent models of experimental PH. MDM2 inhibition by JNJ-165 reversed the SU5416/hypoxia-induced PH in C57BL/6 mice. ACE2-S680L mice (dephosphorylation at S680) showed PH susceptibility, and ectopic expression of ACE2-S680L/K788R (deubiquitination at K788) reduced experimental PH. Moreover, ACE2-K788R overexpression in mice with endothelial cell-specific AMPKα2 knockout mitigated PH.Maladapted PTM (phosphorylation and ubiquitination) of ACE2 at Ser-680 and Lys-788 is involved in the pathogenesis of pulmonary arterial hypertension and experimental PH. Thus, a combined intervention of AMPK and MDM2 in the pulmonary endothelium might be therapeutically effective in PH treatment.



Circulation: 27 Jul 2020; epub ahead of print
Shen H, Zhang J, Wang C, Jain PP, ... Yuan JX, Shyy JY
Circulation: 27 Jul 2020; epub ahead of print | PMID: 32755395
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Abstract

Carbidopa for Afferent Baroreflex Failure in Familial Dysautonomia: A Double-Blind Randomized Crossover Clinical Trial.

Norcliffe-Kaufmann L, Palma JA, Martinez J, Kaufmann H

Afferent lesions of the arterial baroreflex occur in familial dysautonomia. This leads to excessive blood pressure variability with falls and frequent surges that damage the organs. These hypertensive surges are the result of excess peripheral catecholamine release and have no adequate treatment. Carbidopa is a selective DOPA-decarboxylase inhibitor that suppresses catecholamines production outside the brain. To learn whether carbidopa can inhibit catecholamine-induced hypertensive surges in patients with severe afferent baroreflex failure, we conducted a double-blind randomized crossover trial in which patients with familial dysautonomia received high dose carbidopa (600 mg/day), low-dose carbidopa (300 mg/day), or matching placebo in 3 4-week treatment periods. Among the 22 patients enrolled (13 females/8 males), the median age was 26 (range, 12-59 years). At enrollment, patients had hypertensive peaks to 164/116 (range, 144/92 to 213/150 mm Hg). Twenty-four hour urinary norepinephrine excretion, a marker of peripheral catecholamine release, was significantly suppressed on both high dose and low dose carbidopa, compared with placebo (=0.0075). The 2 co-primary end points of the trial were met. The SD of systolic BP variability was reduced at both carbidopa doses (low dose: 17±4; high dose: 18±5 mm Hg) compared with placebo (23±7 mm Hg; =0.0013), and there was a significant reduction in the systolic BP peaks on active treatment (=0.0015). High- and low-dose carbidopa were similarly effective and well tolerated. This study provides class Ib evidence that carbidopa can reduce blood pressure variability in patients with congenital afferent baroreflex failure. Similar beneficial effects are observed in patients with acquired baroreflex lesions.



Hypertension: 12 Jul 2020:HYPERTENSIONAHA12015267; epub ahead of print
Norcliffe-Kaufmann L, Palma JA, Martinez J, Kaufmann H
Hypertension: 12 Jul 2020:HYPERTENSIONAHA12015267; epub ahead of print | PMID: 32654554
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Abstract

Fontan-Associated Liver Disease: Screening, Management, and Transplant Considerations.

Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R

Surgical innovation and multidisciplinary management have allowed children born with univentricular physiology congenital heart disease to survive into adulthood. An estimated global population of 70 000 patients have undergone the Fontan procedure and are alive today, most of whom are <25 years of age. Several unexpected consequences of the Fontan circulation include Fontan-associated liver disease. Surveillance biopsies have demonstrated that virtually 100% of these patients develop clinically silent fibrosis by adolescence. As they mature, there are increasing reports of combined heart-liver transplantation resulting from advanced liver disease, including bridging fibrosis, cirrhosis, and hepatocellular carcinoma, in this population. In the absence of a transplantation option, these young patients face a poor quality of life and overall survival. Acknowledging that there are no consensus guidelines for diagnosing and monitoring Fontan-associated liver disease or when to consider heart transplantation versus combined heart-liver transplantation in these patients, a multidisciplinary working group reviewed the literature surrounding Fontan-associated liver disease, with a specific focus on considerations for transplantation.



Circulation: 10 Aug 2020; 142:591-604
Emamaullee J, Zaidi AN, Schiano T, Kahn J, ... Bucuvalas J, Fischer R
Circulation: 10 Aug 2020; 142:591-604 | PMID: 32776846
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Abstract

Oral 15-Hydroxyeicosatetraenoic Acid Induces Pulmonary Hypertension in Mice by Triggering T Cell-Dependent Endothelial Cell Apoptosis.

Ruffenach G, O\'Connor E, Vaillancourt M, Hong J, ... Reddy ST, Eghbali M

Pulmonary arterial hypertension (PAH) is a fatal disease characterized by increased mean pulmonary arterial pressure. Elevated plasma and lung concentrations of oxidized lipids, including 15-hydroxyeicosatetraenoic acid (15-HETE), have been demonstrated in patients with PAH and animal models. We previously demonstrated that feeding mice with 15-HETE is sufficient to induce pulmonary hypertension, but the mechanisms remain unknown. RNA sequencing data from the mouse lungs on 15-HETE diet revealed significant activation of pathways involved in both antigen processing and presentation and T cell-mediated cytotoxicity. Analysis of human microarray from patients with PAH also identified activation of identical pathways compared with controls. We show that in both 15-HETE-fed mice and patients with PAH, expression of the immunoproteasome subunit 5 is significantly increased, which was concomitant with an increase in the number of CD8/CD69 (cluster of differentiation 8 / cluster of differentiation 69) double-positive cells, as well as pulmonary arterial endothelial cell apoptosis in mice. Human pulmonary arterial endothelial cells cultured with 15-HETE were more prone to apoptosis when exposed to CD8 cells. Cultured intestinal epithelial cells secreted more oxidized lipids in response to 15-HETE, which is consistent with accumulation of circulating oxidized lipids in 15-HETE-fed mice. Administration of an apoA-I (apolipoprotein A-I) mimetic peptide, Tg6F (transgenic 6F), which is known to prevent accumulation of circulating oxidized lipids, not only inhibited pulmonary arterial endothelial cell apoptosis but also prevented and rescued 15-HETE-induced pulmonary hypertension in mice. In conclusion, our results suggest that (1) 15-HETE diet induces pulmonary hypertension by a mechanism that involves oxidized lipid-mediated T cell-dependent pulmonary arterial endothelial cell apoptosis and (2) Tg6F administration may be a novel therapy for treating PAH.



Hypertension: 26 Jul 2020:HYPERTENSIONAHA12014697; epub ahead of print
Ruffenach G, O'Connor E, Vaillancourt M, Hong J, ... Reddy ST, Eghbali M
Hypertension: 26 Jul 2020:HYPERTENSIONAHA12014697; epub ahead of print | PMID: 32713273
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Abstract

Adult congenital heart disease and the COVID-19 pandemic.

Radke RM, Frenzel T, Baumgartner H, Diller GP

Adults with congenital heart disease (ACHD) may be at high risk in the case of COVID-19. Due to the heterogeneity of ACHD and secondary complications, risk profiles are, however, not uniform. This document aims to give an overview of relevant data and outline our pragmatic approach to disease prevention and management. Based on anatomy and additional physiological factors including symptoms, exercise capacity, heart failure, pulmonary hypertension and cyanosis, we propose a pragmatic approach to categorising patients into low-risk, intermediate-risk and high-risk groups. We regard especially patients with complex cyanotic conditions, those with palliated univentricular hearts, heart failure, severe valvular disease or pulmonary hypertension as high-risk patients. To avoid infection, we recommend self-isolation and exemption from work for these cohorts. Infected ACHD patients with low or moderate risk and without signs of deterioration may be remotely followed and cared for at home while in self isolation. High-risk patients or those with signs of respiratory or cardiovascular impairment require admission ideally at a tertiary ACHD centre. Especially patients with complex, cyanotic disease, heart failure and arrhythmias require particular attention. Treatment in patients with cyanotic heart disease should be guided by the relative degree of desaturation compared with baseline and lactate levels rather than absolute oxygen saturation levels. Patients with right heart dilatation or dysfunction are potentially at increased risk of right heart failure as mechanical ventilation and acute respiratory distress syndrome can lead to increase in pulmonary arterial pressures.

© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 09 Jun 2020; epub ahead of print
Radke RM, Frenzel T, Baumgartner H, Diller GP
Heart: 09 Jun 2020; epub ahead of print | PMID: 32522822
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Abstract

Predicting sudden cardiac death in adults with congenital heart disease.

Oliver JM, Gallego P, Gonzalez AE, Avila P, ... Bermejo J,
Objectives
To develop, calibrate, test and validate a logistic regression model for accurate risk prediction of sudden cardiac death (SCD) and non-fatal sudden cardiac arrest (SCA) in adults with congenital heart disease (ACHD), based on baseline lesion-specific risk stratification and individual\'s characteristics, to guide primary prevention strategies.
Methods
We combined data from a single-centre cohort of 3311 consecutive ACHD patients (50% male) at 25-year follow-up with 71 events (53 SCD and 18 non-fatal SCA) and a multicentre case-control group with 207 cases (110 SCD and 97 non-fatal SCA) and 2287 consecutive controls (50% males). Cumulative incidences of events up to 20 years for specific lesions were determined in the prospective cohort. Risk model and its 5-year risk predictions were derived by logistic regression modelling, using separate development (18 centres: 144 cases and 1501 controls) and validation (two centres: 63 cases and 786 controls) datasets.
Results
According to the combined SCD/SCA cumulative 20 years incidence, a lesion-specific stratification into four clusters-very-low (<1%), low (1%-4%), moderate (4%-12%) and high (>12%)-was built. Multivariable predictors were lesion-specific cluster, young age, male sex, unexplained syncope, ischaemic heart disease, non-life threatening ventricular arrhythmias, QRS duration and ventricular systolic dysfunction or hypertrophy. The model very accurately discriminated (C-index 0.91; 95% CI 0.88 to 0.94) and calibrated (p=0.3 for observed vs expected proportions) in the validation dataset. Compared with current guidelines approach, sensitivity increases 29% with less than 1% change in specificity.
Conclusions
Predicting the risk of SCD/SCA in ACHD can be significantly improved using a baseline lesion-specific stratification and simple clinical variables.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Jun 2020; epub ahead of print
Oliver JM, Gallego P, Gonzalez AE, Avila P, ... Bermejo J,
Heart: 15 Jun 2020; epub ahead of print | PMID: 32546506
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Abstract

Long Range Endocrine Delivery of Circulating miR-210 to Endothelium Promotes Pulmonary Hypertension.

Zhao J, Florentin J, Tai YY, Torrino S, ... Dutta P, Chan SY

Unproven theories abound regarding the long-range uptake and endocrine activity of extracellular blood-borne microRNAs (miRNAs) into tissue. In pulmonary hypertension (PH), microRNA-210 (miR-210) in pulmonary endothelial cells promotes disease, but its activity as an extracellular molecule is incompletely defined.We investigated whether chronic and endogenous endocrine delivery of extracellular miR-210 to pulmonary vascular endothelial cells promotes PH.Usingreplete (WT) and knockout (KO) mice, we tracked blood-borne miR-210 using bone marrow transplantation (BMT) and parabiosis (conjoining of circulatory systems). With BMT, circulating miR-210 was derived predominantly from bone marrow. Via parabiosis during chronic hypoxia to induce miR-210 production and PH, miR-210 was undetectable in KO-KO mice pairs. However, in plasma and lung endothelium, but not smooth muscle or adventitia, miR-210 was observed in KO mice of WT-KO pairs. This was accompanied by down-regulation of miR-210 targets ISCU1/2 and COX10, indicating endothelial import of functional miR-210. Via hemodynamic and histologic indices, KO-KO pairs were protected from PH, while KO mice in WT-KO pairs developed PH. In particular, pulmonary vascular engraftment of miR-210-positive interstitial lung macrophages was observed in KO mice of WT-KO pairs. To address whether engrafted miR-210-positive myeloid or lymphoid cells contribute to paracrine miR-210 delivery, we studied miR-210 KO mice parabiosed with miR-210 WT; Cx3cr1 KO mice (deficient in myeloid recruitment) or miR-210 WT; Rag1 KO mice (deficient in lymphocytes). In both pairs, miR-210 KO mice still displayed miR-210 delivery and PH, thus demonstrating a pathogenic endocrine delivery of extracellular miR-210.Endogenous blood-borne transport of miR-210 into pulmonary vascular endothelial cells promotes PH, offering fundamental insight into the systemic physiology of miRNA activity. These results also describe a platform for RNA-mediated crosstalk in PH, providing an impetus for developing blood-based miR-210 technologies for diagnosis and therapy in this disease.



Circ Res: 03 Jun 2020; epub ahead of print
Zhao J, Florentin J, Tai YY, Torrino S, ... Dutta P, Chan SY
Circ Res: 03 Jun 2020; epub ahead of print | PMID: 32493166
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Abstract

The long and winding road of cardiomyocyte maturation.

Maroli G, Braun T

Knowledge about the molecular mechanisms regulating cardiomyocyte (CM) proliferation and differentiation has increased exponentially in recent years. Such insights together with the availability of more efficient protocols for generation of CMs from induced pluripotent stem cells (iPSCs) have raised expectations for new therapeutic strategies to treat congenital and non-congenital heart diseases. However, the poor regenerative potential of the postnatal heart and the incomplete maturation of iPSC-derived CMs represent important bottlenecks for such therapies in future years. CMs undergo dramatic changes at the doorstep between prenatal and postnatal life, including terminal cell cycle withdrawal, change in metabolism and further specialization of the cellular machinery required for high-performance contraction. Here, we review recent insights into pre- and early postnatal developmental processes that regulate CM maturation, laying specific focus on genetic and metabolic pathways that control transition of CM from the embryonic and perinatal to the fully mature adult CM state. We recapitulate the intrinsic features of CM maturation and highlight the importance of external factors such as energy substrate availability and endocrine regulation in shaping postnatal CM development. We also address recent approaches to enhance maturation of iPSC-derived CMs in vitro, and summarize new discoveries that might provide useful tools for translational research on repair of the injured human heart.

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

Cardiovasc Res: 07 Jun 2020; epub ahead of print
Maroli G, Braun T
Cardiovasc Res: 07 Jun 2020; epub ahead of print | PMID: 32514522
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Abstract

Prediction of adverse cardiac events in pregnant women with valvular rheumatic heart disease.

Baghel J, Keepanasseril A, Pillai AA, Mondal N, Jeganathan Y, Kundra P
Objective
To assess the incidence of adverse cardiac events in pregnant women with rheumatic valvular heart disease (RHD) and to derive a clinical risk scoring for predicting it.
Methods
This is an observational study involving pregnant women with RHD, attending a tertiary centre in south India. Data regarding obstetric history, medical history, maternal complications and perinatal outcome till discharge were collected. Eight-hundred and twenty pregnancies among 681 women were included in the analysis. Primary outcome was composite adverse cardiac event defined as occurrence of one or more of complications such as death, cardiac arrest, heart failure, cerebrovascular accident from thromboembolism and new-onset arrhythmias.
Results
Of the 681 women with RHD, 180 (26.3%) were diagnosed during pregnancy. Composite adverse cardiac outcome during pregnancy/post partum occurred in 122 (14.9%) pregnancies, with 12 of them succumbed to the disease. In multivariate analysis, prior adverse cardiac events (OR=8.35, 95% CI 3.54 to 19.71), cardiac medications at booking (OR=0.53, 95% CI 0.32 to 0.86), mitral stenosis (mild OR=2.48, 95% CI 1.08 to 5.69; moderate OR=2.23, 95% CI 1.19 to 4.18; severe OR=7.72,95% 4.05 to 12.89), valve replacement (OR=2.53, 95% CI 1.28 to 5.02) and pulmonary hypertension (OR=6.90, 3.81 to 12.46) were predictive of composite adverse cardiac events with a good discrimination (area under the curve=0.803) and acceptable calibration. A predictive score combining these factors is proposed for clinical utility.
Conclusion
Heart failure remains the most common adverse cardiac event during pregnancy or puerperium. Combining the lesion-specific characteristics and clinical information into a predictive score, which is simple and effective, could be used in routine clinical practice.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 28 Jun 2020; epub ahead of print
Baghel J, Keepanasseril A, Pillai AA, Mondal N, Jeganathan Y, Kundra P
Heart: 28 Jun 2020; epub ahead of print | PMID: 32601124
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Abstract

Pulmonary hypertension and right ventricular involvement in hospitalised patients with COVID-19.

Pagnesi M, Baldetti L, Beneduce A, Calvo F, ... Agricola E, Cappelletti AM
Objective
To assess the prevalence, characteristics and prognostic value of pulmonary hypertension (PH) and right ventricular dysfunction (RVD) in hospitalised, non-intensive care unit (ICU) patients with coronavirus disease 2019 (COVID-19).
Methods
This single-centre, observational, cross-sectional study included 211 patients with COVID-19 admitted to non-ICU departments who underwent a single transthoracic echocardiography (TTE). Patients with poor acoustic window (n=11) were excluded. Clinical, imaging, laboratory and TTE findings were compared in patients with versus without PH (estimated systolic pulmonary artery pressure >35 mm Hg) and with versus without RVD (tricuspid annular plane systolic excursion <17 mm or S wave <9.5 cm/s). The primary endpoint was in-hospital death or ICU admission.
Results
A total of 200 patients were included in the final analysis (median age 62 (IQR 52-74) years, 65.5% men). The prevalence of PH and RVD was 12.0% (24/200) and 14.5% (29/200), respectively. Patients with PH were older and had a higher burden of pre-existing cardiac comorbidities and signs of more severe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (radiological lung involvement, laboratory findings and oxygenation status) compared with those without PH. Conversely, patients with RVD had a higher burden of pre-existing cardiac comorbidities but no evidence of more severe SARS-CoV-2 infection compared with those without RVD. The presence of PH was associated with a higher rate of in-hospital death or ICU admission (41.7 vs 8.5%, p<0.001), while the presence of RVD was not (17.2 vs 11.7%, p=0.404).
Conclusions
Among hospitalised non-ICU patients with COVID-19, PH (and not RVD) was associated with signs of more severe COVID-19 and with worse in-hospital clinical outcome.
Trial registration number
NCT04318366.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 15 Jul 2020; epub ahead of print
Pagnesi M, Baldetti L, Beneduce A, Calvo F, ... Agricola E, Cappelletti AM
Heart: 15 Jul 2020; epub ahead of print | PMID: 32675217
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Abstract

High molecular weight kininogen contributes to early mortality and kidney dysfunction in a mouse model of sickle cell disease.

Sparkenbaugh EM, Kasztan M, Henderson MW, Ellsworth P, ... Pollock DM, Pawlinski R
Background
Sickle cell disease (SCD) is characterized by chronic hemolytic anemia, vaso-occlusive crises, chronic inflammation, and activation of coagulation. The clinical complications such as painful crisis, stroke, pulmonary hypertension, nephropathy and venous thromboembolism lead to cumulative organ damage and premature death. High molecular weight kininogen (HK) is a central cofactor for the kallikrein-kinin and intrinsic coagulation pathways, which contributes to both coagulation and inflammation.
Objective
We hypothesize that HK contributes to the hypercoagulable and pro-inflammatory state that causes end-organ damage and early mortality in sickle mice.
Methods
We evaluated the role of HK in the Townes mouse model of SCD.
Results/conclusions
We found elevated plasma levels of cleaved HK in sickle patients compared to healthy controls, suggesting ongoing HK activation in SCD. We used bone marrow transplantation to generate wild type and sickle cell mice on a HK-deficient background. We found that short-term HK deficiency attenuated thrombin generation and inflammation in sickle mice at steady state, which was independent of bradykinin signaling. Moreover, long-term HK deficiency attenuates kidney injury, reduces chronic inflammation, and ultimately improves of sickle mice.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 22 Jun 2020; epub ahead of print
Sparkenbaugh EM, Kasztan M, Henderson MW, Ellsworth P, ... Pollock DM, Pawlinski R
J Thromb Haemost: 22 Jun 2020; epub ahead of print | PMID: 32573897
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Abstract

Eisenmenger syndrome: diagnosis, prognosis and clinical management.

Arvanitaki A, Giannakoulas G, Baumgartner H, Lammers AE

Eisenmenger syndrome (ES) represents the most severe phenotype of pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) and occurs in patients with large unrepaired shunts. Despite early detection of CHD and major advances in paediatric cardiac surgery, ES is still prevalent and requires a multidisciplinary approach by adult CHD experts in tertiary centres. Central cyanosis is the primary clinical manifestation leading to secondary erythrocytosis and various multiorgan complications that increase morbidity and affect quality of life. Close follow-up is needed to early diagnose and timely manage these complications. The primary goal of care is to maintain patients\' fragile stability. Although the recent use of advanced PAH therapies has substantially improved functional capacity and increased life expectancy, long-term survival remains poor. Progressive heart failure, infectious diseases and sudden cardiac death comprise the main causes of death in patients with ES. Impaired exercise tolerance, decreased arterial oxygen saturation, iron deficiency, pre-tricuspid shunts, arrhythmias, increased brain natriuretic peptide, echocardiographic indices of right ventricular dysfunction and hospitalisation for heart failure predict mortality. Endothelin receptor antagonists are used as first-line treatment in symptomatic patients, while phosphodiesterase-5 inhibitors may be added. Due to the lack of evidence, current guidelines do not provide a clear therapeutic strategy regarding treatment escalation. Additional well-designed trials are required to assess the comparative efficacy of various PAH agents and the benefit of combination therapy. Finally, the development of a risk score is of utmost importance to guide clinical therapy.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 19 Jul 2020; epub ahead of print
Arvanitaki A, Giannakoulas G, Baumgartner H, Lammers AE
Heart: 19 Jul 2020; epub ahead of print | PMID: 32690623
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Abstract

Utility of 3D printed cardiac models in congenital heart disease: a scoping review.

Illmann CF, Ghadiry-Tavi R, Hosking M, Harris KC
Objective
Three-dimensional printing (3DP) is a novel technology with applications in healthcare, particularly for congenital heart disease (CHD). We sought to explore the spectrum of use of 3D printed CHD models (3D-CM) and identify knowledge gaps within the published body of literature to guide future research.
Methods
We conducted a scoping review targeting published literature on the use of 3D-CMs. The databases of MEDLINE, EMBASE and Web of Science were searched from their inception until 19 July 2019. Inclusion criteria were primary research; studies reporting use of 3D-CMs; and human subjects. Exclusion criteria were studies where 3D-CMs were generated for proof of concept but not used; and studies focused on bioprinting or computational 3D-CMs. Studies were assessed for inclusion and data were extracted from eligible articles in duplicate.
Results
The search returned 648 results. Following assessment, 79 articles were included in the final qualitative synthesis. The majority (66%) of studies are case reports or series. 15% reported use of a control group. Three main areas of utilisation are for (1) surgical and interventional cardiology procedural planning (n=62), (2) simulation (n=25), and (3) education for medical personnel or patients and their families (n=17). Multiple studies used 3D-CMs for more than one of these areas.
Conclusions
3DP for CHD is a new technology with an evolving literature base. Most of the published literature are experiential reports as opposed to manuscripts on scientifically robust studies. Our study has identified gaps in the literature and addressed priority areas for future research.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 28 Jul 2020; epub ahead of print
Illmann CF, Ghadiry-Tavi R, Hosking M, Harris KC
Heart: 28 Jul 2020; epub ahead of print | PMID: 32727918
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Abstract

The Year in Review in Cardiac Electrophysiology.

Kapa S, Chung MK, Gopinathannair R, Noseworthy PA, ... Wan E, Wang PJ

In the past year there have been numerous advances in our understanding of arrhythmia mechanisms, diagnosis, and new therapies. We have seen advances in basic cardiac electrophysiology with data suggesting that secretoneurin may be a biomarker for patients at risk of ventricular arrhythmias and we have learned of the potential role of a natriuretic peptide receptor-C in atrial fibrosis and the role of an atrial specific two-pore potassium channel TASK-1 as a therapeutic target for atrial fibrillation. We have seen studies demonstrating role of sensory neurons in sleep apnea-related atrial fibrillation and the association between bariatric surgery and atrial fibrillation ablation outcomes. Artificial intelligence applied to electrocardiography has yielded estimates of age, gender, and overall health. We have seen new tools for collection of patient-centered outcomes following catheter ablation. There have been significant advances in the ability to identify ventricular tachycardia termination sites through high-density mapping of deceleration zones. We have learned that right ventricular dysfunction may be a predictor of survival benefit after ICD implantation in non-ischemic cardiomyopathy patients. We have seen further insights into the role of His bundle pacing on improving outcomes. As our understanding of cardiac laminopathies advance, we may have new tools to predict arrhythmic event rates in gene carriers. Finally, we have seen numerous advances in the treatment of arrhythmias in patients with congenital heart disease.



Circ Arrhythm Electrophysiol: 17 May 2020; epub ahead of print
Kapa S, Chung MK, Gopinathannair R, Noseworthy PA, ... Wan E, Wang PJ
Circ Arrhythm Electrophysiol: 17 May 2020; epub ahead of print | PMID: 32423252
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Abstract

Performance and Interpretation of Invasive Hemodynamic Exercise Testing.

Jain CC, Borlaug BA

Exertional dyspnea is a common complaint for patients seen in pulmonary, cardiac and general medicine clinics, and elucidating the cause is often challenging, particularly when physical examination, echocardiography, radiography and pulmonary function test results are inconclusive. Invasive cardiopulmonary exercise testing (CPET) has emerged as the gold standard test to define causes of dyspnea and exertional limitation in this population. In this review, we describe the methods for performing and interpreting invasive CPET, with particular attention to the hemodynamic and blood sampling data as they apply to patients being evaluated for heart failure and pulmonary hypertension.

Copyright © 2020. Published by Elsevier Inc.

Chest: 27 May 2020; epub ahead of print
Jain CC, Borlaug BA
Chest: 27 May 2020; epub ahead of print | PMID: 32473950
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Abstract

Heart Failure with Preserved Ejection Fraction: Insights into Diagnosis and Pathophysiology.

Nagueh SF

Heart failure with preserved ejection fraction (HFpEF) accounts for at least half the cases of heart failure, currently diagnosed. There are several cardiac and non-cardiac manifestations of the syndrome. Structure and function abnormalities can include all four cardiac chambers. The left ventricle (LV) has abnormal systolic and diastolic functions which can be examined by invasive and noninvasive measurements. In addition, the left atrium (LA) enlarges with abnormal LA function, pulmonary hypertension occurs, and the right ventricle can develop hypertrophy, enlargement, and systolic dysfunction. There are a paucity of data on calcium handling in HFpEF patients. Growing literature supports the presence of abnormalities in titin and its phosphorylation, and increased interstitial fibrosis contributing to increased chamber stiffness. A systemic inflammatory state causing reduced myocardial c-GMP along with defects in the unfolded protein response have been recently reported. Diagnosis relies on signs and symptoms of heart failure, preserved EF, and detection of diastolic function abnormalities based on echocardiographic findings and abnormally elevated natriuretic peptide levels or invasive measurements of wedge pressure at rest or with exercise. There are currently two diagnostic algorithms: H2FPEF, and HFA-PEFF with limited data comparing their performance head to head in the same patient population. Despite the growing understanding of the syndrome\'s pathophysiology, there have been little success in developing specific treatment for patients with HFpEF.

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

Cardiovasc Res: 26 Jul 2020; epub ahead of print
Nagueh SF
Cardiovasc Res: 26 Jul 2020; epub ahead of print | PMID: 32717061
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Abstract

Additive Protective Effects of Sacubitril/Valsartan and Bosentan on Vascular Remodeling in Experimental Pulmonary Hypertension.

Chaumais MC, Djessas MRA, Thuillet R, Cumont A, ... Humbert M, Guignabert C
Aims
Although right ventricular (RV) function is an important determinant of morbidity and mortality in patients with pulmonary arterial hypertension (PAH), there is no treatment targeting directly the RV. We therefore evaluate the efficacy of sacubitril/valsartan (LCZ 696) as add-on therapy to bosentan in rats with severe pulmonary hypertension (PH).
Methods and results
Combination therapy of LCZ 696 and bosentan has additive vascular protective effects against the pulmonary vascular remodeling and PH in two preclinical models of severe PH. Compared with monotherapy, co-treatment of LCZ 696 (30 or 68mg/kg/day for 2 weeks, per os) and bosentan (100mg/kg/day for 2 weeks, per os) started 7-day after monocrotaline (MCT) injection substantially reduces pulmonary pressures, vascular remodeling and right ventricular hypertrophy and fibrosis in rats. Consistent with these observations, cotreatment of rats with established PH induced by sugen/hypoxia (SuHx) with LCZ 696 (30mg/kg/day for 3 weeks, per os) and bosentan (100mg/kg/day for 3 weeks, per os) started 5 weeks after sugen injection partially attenuate total pulmonary vascular resistance and cardiovascular structures. We also obtained evidence showing that LCZ 696 has anti-proliferative effect on cultured human pulmonary artery smooth muscle cells (PA-SMCs) derived from patients with idiopathic PAH, an effect that is more pronounced in presence of bosentan. Finally, we found that the plasma levels of ANP and cGMP are higher in rats co-treated with LCZ 696 (30mg/kg/day) and bosentan (100mg/kg/day) than in MCT and SuHx rats treated with vehicle.
Conclusion
Dual therapy with LCZ 696 plus bosentan proved significantly superior beneficial effect to LCZ 696 or bosentan alone on vascular remodeling and severity of experimental PH.
Translational perspective
Herein, we obtained several in vivo and in vitro evidence supporting that LCZ 696 could be used as an add-on therapy to bosentan to potentially prevent or even limit the remodeling of pulmonary blood vessels and to enhance cardiac function in patients with severe PH.

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

Cardiovasc Res: 10 Jul 2020; epub ahead of print
Chaumais MC, Djessas MRA, Thuillet R, Cumont A, ... Humbert M, Guignabert C
Cardiovasc Res: 10 Jul 2020; epub ahead of print | PMID: 32653925
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Abstract

Structure-function of platelet glycoprotein Ib-IX.

Quach ME, Li R

The glycoprotein (GP)Ib-IX receptor complex plays a critical role in platelet physiology and pathology. Its interaction with von Willebrand factor (VWF) on the subendothelial matrix instigates platelet arrest at the site of vascular injury, and is vital to primary hemostasis. Its reception to other ligands and counter-receptors in the blood stream also contribute to various processes of platelet biology that are still being discovered. While its basic composition and its link to congenital bleeding disorders were well documented and firmly established more than 25 years ago, recent years have witnessed critical advances in the organization, dynamics, activation, regulation and functions of the GPIb-IX complex. This review summarizes important findings and identifies questions that remain about this unique platelet mechanoreceptor complex.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 30 Jul 2020; epub ahead of print
Quach ME, Li R
J Thromb Haemost: 30 Jul 2020; epub ahead of print | PMID: 32735697
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Abstract

Periostin: A Potential Therapeutic Target For Pulmonary Arterial Hypertension?

Bian JS, Nie X, Shen C, Tan J, ... Ye S, Chen J

Periostin (POSTN) is an extracellular matrix protein involved in tissue remodeling in response to injury and a contributing factor in tumorigenesis, suggesting that POSTN plays a role in the pathogenesis of pulmonary hypertension (PH).We aimed to gain insight into the mechanistic contribution of POSTN in experimental mouse models of PH and correlate these findings with PH in humans.We utilized genetic epistasis approaches in human pulmonary artery endothelial cells (hPAECs), human pulmonary artery smooth muscle cells (PASMCs) and experimental mouse models of PH (Sugen 5416/hypoxia or chronic hypoxia) to discern the role of POSTN and its relationship to hypoxia inducible factor (HIF)-1 signaling. We found that POSTN expression was correlated with the extent of PH in mouse models and in humans. Decreasing POSTN improved hemodynamic and cardiac responses in PH mice, blunted the release of growth factors and HIF-1α and reversed the downregulated BMPR2 expression in hPAECs from PH patients, whereas increasing POSTIN had the opposite effects and induced a hyper-proliferative and pro-migratory phenotype in both hPAECs and hPASMCs. Overexpression of POSTN induced activation of HIFs and increased the production of ET-1 and VEGF in hPAECs. SiRNA-mediated knockdown of HIF-1α abolished the proangiogenic effect of POSTN. Blockade of TrkB attenuated the effect of POSTN on HIF-1α expression, while inhibition of HIF-1α reduced the expression of POSTN and TrkB. These results suggest that hPAECs produce POSTN via a HIF-1α-dependent mechanism.Our study reveals that POSTN expression is increased in human and animal models of PH and fosters PH development via a positive feedback loop between HIF-1α and POSTN during hypoxia. We propose that manipulating POSTIN expression may be an efficacious therapeutic target in the treatment of PH. Our results also suggest that POSTN may serve as a biomarker to estimate the severity of PH.



Circ Res: 04 Aug 2020; epub ahead of print
Bian JS, Nie X, Shen C, Tan J, ... Ye S, Chen J
Circ Res: 04 Aug 2020; epub ahead of print | PMID: 32752980
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Abstract

Phenotypes of Bronchopulmonary Dysplasia in Adults.

Cassady SJ, Lasso-Pirot A, Deepak J

Bronchopulmonary dysplasia (BPD), first described by Northway in 1967, is a process of neonatal lung injury that is most strongly associated with prematurity. The \"old\" form of the disease associated with the oxidative damage and volutrauma from perinatal mechanical ventilation has been increasingly supplanted by a \"new\" form resulting from interrupted growth of the lung at earlier stages of fetal development. Given the significant improvement in the survival of children with BPD since the 1980s, many more of these patients are living into adulthood and are being seen in adult pulmonary practices. In this review, we present three brief vignettes of patients from our practice to introduce three of the major patterns of disease seen in adult survivors of BPD, namely asthma-like disease, obstructive lung disease, and pulmonary hypertension. Additional factors shown to affect the lives of adult BPD survivors are also discussed. Finally, we discuss insights into the process of transitioning these complex patients from pediatric to adult pulmonary practices. As survivors of BPD enter adulthood and continue to require specialty pulmonary care, awareness of the disease\'s varied manifestations and responses to treatment will become increasingly important.

Copyright © 2020. Published by Elsevier Inc.

Chest: 27 May 2020; epub ahead of print
Cassady SJ, Lasso-Pirot A, Deepak J
Chest: 27 May 2020; epub ahead of print | PMID: 32473946
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Abstract

Mechanisms of exercise limitation and prevalence of pulmonary hypertension in pulmonary Langerhans cell histiocytosis.

Heiden GI, Sobral JB, Gonçalves Freitas CS, Pereira de Albuquerque AL, ... Souza R, Baldi BG
Background
Pulmonary Langerhans cell histiocytosis (PLCH) determines reduced exercise capacity. The speculated mechanisms of exercise impairment in PLCH are ventilatory and cardiocirculatory limitations, including pulmonary hypertension (PH).
Research question
What are the mechanisms of exercise limitation, the exercise capacity and the prevalence of dynamic hyperinflation (DH) and PH in PLCH?
Study design and methods
In a cross-sectional study, PLCH patients underwent an incremental treadmill cardiopulmonary exercise test with an evaluation of DH, pulmonary function tests, and transthoracic echocardiography. Those patients with lung diffusing capacity for carbon monoxide (DLCO) less than 40% predicted and/or transthoracic echocardiogram with tricuspid regurgitation velocity (TRV) greater than 2.5 m/s and/or with indirect PH signs underwent right heart catheterization.
Results
Thirty-five patients were included (68% women, 47 ± 11 years old). Ventilatory and cardiocirculatory limitations, impairment suggestive of PH, and impaired gas exchange occurred in 88%, 67%, 29%, and 88% of patients, respectively. The limitation was multifactorial in 71%, exercise capacity was reduced in 71%, and DH occurred in 68% of patients. Forced expiratory volume in the first second (FEV) and DLCO were 64 ± 22% predicted and 56 ± 21% predicted, respectively. Reduction in DLCO, an obstructive pattern, and air trapping occurred in 80%, 77%, and 37% of patients, respectively. FEV and DLCO were good predictors of exercise capacity. The prevalence of PH was 41%, predominantly with pre-capillary pattern, and mean pulmonary artery pressure correlated best with FEV and TRV.
Interpretation
PH is frequent and exercise impairment is common and multifactorial in PLCH. The most prevalent mechanisms include ventilatory, cardiocirculatory, and suggestive of PH limitations.

Copyright © 2020. Published by Elsevier Inc.

Chest: 28 Jun 2020; epub ahead of print
Heiden GI, Sobral JB, Gonçalves Freitas CS, Pereira de Albuquerque AL, ... Souza R, Baldi BG
Chest: 28 Jun 2020; epub ahead of print | PMID: 32615192
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Abstract

Genomic analyses implicate noncoding de novo variants in congenital heart disease.

Richter F, Morton SU, Kim SW, Kitaygorodsky A, ... Seidman CE, Gelb BD

A genetic etiology is identified for one-third of patients with congenital heart disease (CHD), with 8% of cases attributable to coding de novo variants (DNVs). To assess the contribution of noncoding DNVs to CHD, we compared genome sequences from 749 CHD probands and their parents with those from 1,611 unaffected trios. Neural network prediction of noncoding DNV transcriptional impact identified a burden of DNVs in individuals with CHD (n = 2,238 DNVs) compared to controls (n = 4,177; P = 8.7 × 10). Independent analyses of enhancers showed an excess of DNVs in associated genes (27 genes versus 3.7 expected, P = 1 × 10). We observed significant overlap between these transcription-based approaches (odds ratio (OR) = 2.5, 95% confidence interval (CI) 1.1-5.0, P = 5.4 × 10). CHD DNVs altered transcription levels in 5 of 31 enhancers assayed. Finally, we observed a DNV burden in RNA-binding-protein regulatory sites (OR = 1.13, 95% CI 1.1-1.2, P = 8.8 × 10). Our findings demonstrate an enrichment of potentially disruptive regulatory noncoding DNVs in a fraction of CHD at least as high as that observed for damaging coding DNVs.



Nat Genet: 28 Jun 2020; epub ahead of print
Richter F, Morton SU, Kim SW, Kitaygorodsky A, ... Seidman CE, Gelb BD
Nat Genet: 28 Jun 2020; epub ahead of print | PMID: 32601476
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Abstract

Long-Term Outcome after Ventricular Tachycardia Ablation in Non-Ischemic Cardiomyopathy: Late Potential Abolition and VT Noninducibility.

Okubo K, Gigli L, Trevisi N, Foppoli L, ... Mazzone P, Della Bella P

- In patients with an ischemic cardiomyopathy (ICM), the combination of late potential (LP) abolition and postprocedural ventricular tachycardia (VT) noninducibility is known to be the desirable endpoint for a successful long-term outcome after VT ablation. We investigated whether LP abolition and VT noninducibilty have a similar impact on the outcomes of patients with non-ICMs (NICM) undergoing VT ablation.- A total of 403 patients with NICMs (523 procedures) who underwent a VT ablation from 2010 to 2016 were included. The procedure endpoints were the LP abolition (if the LPs were absent, other ablation strategies were undertaken) and the VT noninducibilty.- The underlying structural heart disease consisted of dilated cardiomyopathy (DCM, 49%), arrhythmogenic right ventricular cardiomyopathy (ARVD, 17%), post-myocarditis (14%), valvular heart disease (8%), congenital heart disease (2%), hypertrophic cardiomyopathy (2%) and others (5%). The epicardial access was performed in 57% of the patients. At baseline, the LPs were present in 60% of the patients and a VT was either inducible or sustained/incessant in 85% of the cases. At the end of the procedure, the LP abolition was achieved in 79% of the cases and VT noninducibility in 80%. After a multivariable analysis, the combination of LP abolition and VT noninducibilty was independently associated with free survival from VT (hazard ratio (HR):0.45, 95% Confidence Interval (CI) [0.29-0.69], p= 0.0002) and cardiac death (HR: 0.38, 95%CI [0.18-0.74], p = 0.005). The benefit of the LP abolition on preventing the VT recurrence in ARVD and post-myocarditis patients appeared superior to that observed for those with DCM.- In patients with NICM undergoing VT ablation, the strategy of LP abolition and VT noninducibilty were associated with better outcomes in terms of long-term VT recurrences and cardiac survival.



Circ Arrhythm Electrophysiol: 11 Jul 2020; epub ahead of print
Okubo K, Gigli L, Trevisi N, Foppoli L, ... Mazzone P, Della Bella P
Circ Arrhythm Electrophysiol: 11 Jul 2020; epub ahead of print | PMID: 32657137
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Abstract

BMI is causally associated with pulmonary artery pressure but not hemodynamic evidence of pulmonary vascular remodeling.

Thayer TE, Levinson RT, Huang S, Assad T, ... Mosley JD, Brittain EL
Background
There is an unclear relationship of obesity to the pathogenesis and severity of pulmonary arterial hypertension (PAH) and pulmonary venous hypertension (PVH).
Research question
Is body mass index (BMI) casually associated with pulmonary artery pressure (PAP) and/or markers of pulmonary vascular remodeling?
Study design
Two-sample inverse-variance weighted Mendelian randomization Methods: We constructed two BMI genetic risk scores from GWAS summary data and deployed them in non-overlapping cohorts of subjects referred for right heart catheterization (RHC) or echocardiography. A highly polygenic BMI risk score (BMI_hpGRS) optimally powered to detect shared genetic architecture of obesity with other traits was tested for association with RHC parameters including markers of pulmonary vascular remodeling. A strict BMI genetic risk score (BMI_sGRS) composed of high-confidence genetic variants was used for Mendelian randomization analyses to assess if higher BMI causes higher PAP.
Results
Among all subjects, both directly measured BMI and BMI_hpGRS were positively associated with pulmonary arterial pressures but not markers of pulmonary vascular remodeling. Categorical analyses revealed BMI and BMI_hpGRS were associated with PVH but not PAH. Mendelian randomization of the BMI_sGRS supported that higher BMI is causal of higher systolic pulmonary artery pressure (sPAP). Sensitivity analyses showed sPAP∼BMI_sGRS relationship was preserved when either PAH or PVH individuals were excluded. In the echocardiographic cohort, BMI and BMI_hpGRS were positively associated with estimated PAP and markers of left heart remodeling.
Interpretation
BMI is a modifier of pulmonary hypertension severity in both PAH and PVH but is only involved in the pathogenesis of PVH.

Copyright © 2020. Published by Elsevier Inc.

Chest: 22 Jul 2020; epub ahead of print
Thayer TE, Levinson RT, Huang S, Assad T, ... Mosley JD, Brittain EL
Chest: 22 Jul 2020; epub ahead of print | PMID: 32712226
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Abstract

A 59-Year-Old Woman With Shortness of Breath and Chest Pain.

Duvvuri PD, Liu J, Bhardwaj C
Case presentation
A 59-year-old woman presented to the ED with syncope. She had progressive shortness of breath with minimal activity and precordial resting chest pain for 1 month prior to presentation. She had a medical history of heart failure with preserved ejection fraction, severe OSA well controlled with CPAP of 11 cm HO, and a history of DVT and pulmonary embolism, diagnosed 10 years ago for which she was maintained on warfarin. The patient also had chronic myeloid leukemia in the chronic phase; she had initially been treated with imatinib but was later switched to dasatinib about 4.5 years prior to presentation. The patient had achieved major molecular remission with dasatinib 140 mg daily. Her family history was noncontributory and specifically negative for pulmonary hypertension and heart failure. She had a history of smoking (50 pack years) but had quit 23 years ago.

Copyright © 2020 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.

Chest: 30 Jul 2020; 158:e65-e69
Duvvuri PD, Liu J, Bhardwaj C
Chest: 30 Jul 2020; 158:e65-e69 | PMID: 32768078
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Impact:
Abstract

Catheter Ablation of Intra-Atrial Reentrant/Focal Tachycardia in Adult Congenital Heart Disease: Value of Final Programmed Atrial Stimulation.

Waldmann V, Amet D, Zhao A, Ladouceur M, ... Iserin L, Marijon E
Background
While outcomes of intra-atrial reentrant/focal atrial tachycardia (IART/FAT) catheter ablation have considerably improved in adult congenital heart disease (ACHD), recurrences remain common with different circuits frequently encountered.
Objective
We aimed to assess the value of programmed atrial stimulation after successful clinical IART/FAT catheter ablation in ACHD patients.
Methods
Retrospective study including all ACHD patients undergoing IART/FAT catheter ablation in a tertiary center. After successful catheter ablation of the clinical arrhythmia, survival free from arrhythmia recurrence was analyzed according to whether all inducible IART/FAT were targeted.
Results
From 2004 to 2020, 238 IART/FAT catheter ablations were performed (mean age 44.1±15.0 years, 61.3% males). Acute procedural success of clinical arrhythmia was achieved in 208 (87.4%) procedures. Among 122 (58.7%) procedures with programmed atrial stimulation, at least one other IART/FAT was induced in 61 (50%) patients. All inducible IART/FAT were ablated in 54 (88.5%) patients, whereas 7 (11.5%) patients presented with at least one non-targeted inducible IART/FAT. Patients with non-targeted inducible IART/FAT had a higher risk of atrial arrhythmia episodes compared to inducible patients with ablation of all IART/FAT (HR = 5.7, 95% CI: 1.7-18.4, p=0.004), with 12-month atrial arrhythmias recurrence rates of 22.9% and 77.7%, respectively. Inducible patients with successful ablation of all IART/FAT had a similar risk of recurrence compared to non-inducible patients (HR = 0.6, 95% CI: 0.3-1.3, p=0.215).
Conclusions
Beyond clinical IART/FAT catheter ablation in ACHD patients, our findings suggest the interest of systematically targeting all remaining inducible arrhythmias, whether previously documented or not.

Copyright © 2020. Published by Elsevier Inc.

Heart Rhythm: 04 Jun 2020; epub ahead of print
Waldmann V, Amet D, Zhao A, Ladouceur M, ... Iserin L, Marijon E
Heart Rhythm: 04 Jun 2020; epub ahead of print | PMID: 32512179
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Abstract

Characteristics and Outcomes of Patients Undergoing Combined Organ Transplantation (from the United Network for Organ Sharing).

Briasoulis Α, Akintoye E, Kuno T, Alvarez P

Studies have shown that highly selected patients who underwent combined heart-kidney (HK) and heart-liver transplants (HLv) have short- and long-term outcomes comparable to those observed in primary heart transplantation (HT). Adults patients with stage D heart failure that underwent combined HK, HLv, and heart-lung (HL) were identified in the United Network for Organ Sharing registry from 1991 to 2016, with follow-up through March 2018. We conducted inverse probability of treatment weighting survival analysis of long-term survival stratified by type of combined organ transplant, accounting for donor, recipient, and operative characteristics. We identified 2,300 patients who underwent combined organ transplant (HK 1,257, HLv 212, HL 831). HL recipients were more likely white (77%), women (58%), with congenital heart disease (44.5%), and longer waiting list time (median 195 days). HK transplant increased significantly during the study period where as HL decreased significantly. Median survival was 12.2 years for HK (95% confidence intervals [CI] 10.8 to 12.8), 12 for HLv (95% CI 8.6 to 17.6) but significantly lower at 4.5 years for HL (95% CI 3.6 to 5.8). Combined HK and HLv transplantation rates are increasing and long-term survival is comparable to primary HT, unlike HL which is associated with decreasing trends and significantly lower survival.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 23 May 2020; epub ahead of print
Briasoulis Α, Akintoye E, Kuno T, Alvarez P
Am J Cardiol: 23 May 2020; epub ahead of print | PMID: 32540168
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Abstract

Towards Detection of Conduction Tissue During Cardiac Surgery: Light at the End of the Tunnel?

Sachse FB, Johnson J, Cottle B, Mondal A, Hitchcock R, Kaza AK

Postoperative conduction block requiring lifetime pacemaker placement continues to be a considerable source of morbidity for patients undergoing repair of congenital heart defects. Damage to the cardiac conduction system (CCS) during surgical procedures is thought to be a major cause of the conduction block. Intraoperative identification and avoidance of the CCS is thus a key strategy to improve surgical outcomes. In order to avoid conduction tissue damage and mitigate morbidity a number of approaches have been developed. Here, we review the historical and contemporary approaches for identification of conduction tissue during cardiac surgery. The established approach for intraoperative identification is based on anatomical landmarks established in extensive histological studies of the normal and diseased heart. We focus on landmarks to identify the sinus and atrioventricular nodes during cardiac surgery. We also review technologies explored for intraoperative tissue identification including electrical impedance measurements and electrocardiography. We describe new optical approaches, in particular, and optical spectroscopy and fiberoptic confocal microscopy (FCM), for identification of CCS regions and working myocardium during surgery. As a template for translation of future technology developments, we describe research and regulatory pathways to translate FCM for cardiac surgery. We suggest that along with more robust approaches to surgeon training including awareness of fundamental anatomical studies, optical approaches such as FCM show promise in aiding surgeons in repairs of heart defects. In particular, for complex defects, these approaches can complement landmark-based identification of conduction tissue and thus help to avoid injury to the CCS due to surgical procedures.

Copyright © 2020. Published by Elsevier Inc.

Heart Rhythm: 09 Jul 2020; epub ahead of print
Sachse FB, Johnson J, Cottle B, Mondal A, Hitchcock R, Kaza AK
Heart Rhythm: 09 Jul 2020; epub ahead of print | PMID: 32659372
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Abstract

Characteristics and Prognostic Associations of Echocardiographic Pulmonary Hypertension With Normal Left Ventricular Systolic Function in Patients ≥90 Years of Age.

Shimada S, Uno G, Omori T, Rader F, Siegel RJ, Shiota T

The high prevalence of pulmonary hypertension (PH) in elderly patients is well known. However, much remains unknown about those population. We sought to find the clinical characteristics of echocardiographic PH and the prognostic factors in patients ≥90 years of age. We retrospectively reviewed 310 patients ≥90 years of age (median age 92 years, 64% women) diagnosed as echocardiographic PH (peak systolic pulmonary arterial pressure ≥40 mm Hg) with normal left ventricular systolic function. We defined left heart disease (LHD) as significant left-sided valve diseases, left ventricular hypertrophy and left ventricular diastolic dysfunction by using echocardiography. The endpoint was all-cause death at 2,000 days after diagnosis. LHD was found in 92% of patients. During the median follow-up of 367 days (interquartile range, 39-1,028 days), 151 all-cause deaths (49%) occurred. Multivariable Cox regression analysis demonstrated that right ventricular fraction area change <35% (adjusted hazard ratio [HR]: 2.31; p <0.001), pericardial effusion (adjusted HR: 2.28; p <0.001), serum albumin <3.5 g/dL (adjusted HR: 1.76; p = 0.001), chronic obstructive pulmonary disease (adjusted HR: 1.93; p = 0.001) and New York Heart Association (NYHA) class ≥II (adjusted HR: 1.73; p = 0.004) were associated with mortality after adjusted for age. In conclusion, LHD was significantly associated with echocardiographic PH in most patients ≥90 years of age. Also, the co-morbid factors at diagnosis (right ventricular systolic dysfunction, pericardial effusion, hypoalbuminemia, chronic obstructive pulmonary disease, and NYHA class ≥II) were independently associated with mortality.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 25 May 2020; epub ahead of print
Shimada S, Uno G, Omori T, Rader F, Siegel RJ, Shiota T
Am J Cardiol: 25 May 2020; epub ahead of print | PMID: 32624190
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Abstract

New Comprehensive Reference Values for Arterial Vascular Parameters in Children.

Torigoe T, Dallaire F, Slorach C, Cardinal MP, ... Mertens L, Jaeggi E
Background
Noninvasive measurements of vascular parameters can be used for the detection and risk stratification of cardiovascular diseases. Most vascular parameters are influenced by age and body size, but pediatric reference values are scarce and limited to a few parameters. The aim of this study was to develop pediatric reference values and Z score equations for a comprehensive set of vascular parameters.
Methods
A total of 292 healthy subjects aged 0 to 18 years were prospectively recruited. Stiffness index β, pressure-strain elastic modulus, common carotid intima-media thickness, brachial flow-mediated dilation, radial augmentation index, central and right arm peripheral artery pulse-wave velocities, and pulse-wave velocity ratio were assessed. Normalization for age and anthropometric variables was performed using parametric multivariate regression modeling. Z scores were assessed for heteroscedasticity, residual association with age and body size, and distribution.
Results
Multivariate regression models with various combinations of height, weight, and age were used to obtain Z scores that were independent of age and body size. There was no residual association between Z scores and body size, age, or body mass index. There was no significant departure from the normal distribution.
Conclusions
The authors present reference values and Z score equations for a comprehensive set of vascular parameters during childhood. Further studies are necessary to assess their usefulness in detecting the vascular signs of subclinical atherosclerosis and chronic diseases, including congenital heart disease.

Copyright © 2020 American Society of Echocardiography. Published by Elsevier Inc. All rights reserved.

J Am Soc Echocardiogr: 18 May 2020; epub ahead of print
Torigoe T, Dallaire F, Slorach C, Cardinal MP, ... Mertens L, Jaeggi E
J Am Soc Echocardiogr: 18 May 2020; epub ahead of print | PMID: 32444330
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Abstract

Effect of Stiffened and Dilated Ascending Aorta on Aerobic Exercise Capacity in Repaired Patients With Complex Congenital Heart Disease.

Hayama Y, Ohuchi H, Negishi J, Iwasa T, ... Tsuda E, Kurosaki K

Several studies have reported aortic dilation and increased stiffness of the ascending aorta in patients after repair of congenital heart disease (CHD), which may be a predominant cardiovascular risk. However, the clinical significance has not been described in detail. In this retrospective study, 175 repaired patients with complex CHD achieving biventricular circulation and age-matched 39 control subjects were reviewed (median age: 14.9 and 15.7 years, respectively). We measured the diameters of the ascending aorta and descending aorta from catheterization angiograms to yield Z-scores and stiffness indexes (β) using diameter fluctuations corresponding to pulsatile pressures. Clinical profile, peak oxygen uptake during the cardiopulmonary exercise test, and incidence of unscheduled hospitalization during follow-up was also reviewed. Compared with controls, patients with complex CHD, except for those with aortic coarctation, exhibited significant dilation and increased stiffness of the aortic root and ascending aorta, but not of the descending aorta. In this CHD population (n = 147, including 112 conotruncal anomalies), exercise capacities correlated independently with the diameter Z-score and stiffness index of the ascending aorta along with the history of repetitive thoracotomies, reduced forced vital capacity, and right ventricular hypertension. During a follow-up period (median 15.6 years), either dilation (Z-score >3.5) or increased stiffness (β >6.0) of the ascending aorta stratified morbidity, but no synergistic impact was detected. In conclusion, in repaired patients with complex CHD, a stiffened and dilated ascending aorta was frequently found, exerting significant adverse impacts on diminished exercise capacity and morbidity.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 25 May 2020; epub ahead of print
Hayama Y, Ohuchi H, Negishi J, Iwasa T, ... Tsuda E, Kurosaki K
Am J Cardiol: 25 May 2020; epub ahead of print | PMID: 32593432
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Abstract

Thinking Inside the Box: Custom Pacemaker Improves Device Longevity in a Congenital Heart Patient.

Von Wald L, Brucker R, Salerno S, Ries A, Roukoz H

Patients with congenital heart disease have unique pacing challenges and often require epicardial systems. High pacing threshold is one of the major factors that decrease these systems\' durability. Sometimes surgical re-intervention or lead replacement is difficult or prohibitive in these patients due to repeated surgeries and extensive epicardial scar. We present a case report of a patient with Fontan physiology and chronically high epicardial lead pacing thresholds requiring frequent generator changes and a unique solution focusing on improving generator longevity. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 03 Jun 2020; epub ahead of print
Von Wald L, Brucker R, Salerno S, Ries A, Roukoz H
J Cardiovasc Electrophysiol: 03 Jun 2020; epub ahead of print | PMID: 32495370
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Abstract

Noggin regulates foregut progenitor cell programming and mis-expression leads to esophageal atresia.

Pinzon-Guzman C, Sangadala S, Riera KM, Popova EY, ... Boden SD, Goldenring JR

Esophageal atresia (EA/TEF) are common congenital abnormalities of the gastrointestinal tract. The etiology of EA/TEF is not well understood. We hypothesized that EA/TEF may be the direct consequence of abnormal expression of Noggin (NOG) signaling cascade. Here we showed that, in neonates with EA/TEF, NOG was missing from the atretic esophagus, resulting in immature esophagus that contains respiratory glands, and cilia. When using mouse esophageal organoid units (EOUs) or tracheal organoid units (TOU) as a model of foregut development in vitro, NOG determined the fate of foregut progenitors by allowing expression of esophageal epithelium proteins. When NOG was present in the culture of mTOU, it altered the cell morphology of the organoid unit epithelium, allowing expression of squamous cell proteins normally found in esophagus. On the other hand, when NOG was inhibited in mEOU, the organoid epithelium began to express respiratory markers mimicking the phenotype seen in pathology samples of human EA/TEF. Moreover, human EOU derived from EA/TEF patients were small, fibrotic and lack esophageal epithelium, but when NOG was added, the EOU grew larger, healthier and express esophageal proteins. These results indicate that Noggin is a critical regulator of cell fate decisions between esophageal and pulmonary morphogenesis.



J Clin Invest: 18 May 2020; epub ahead of print
Pinzon-Guzman C, Sangadala S, Riera KM, Popova EY, ... Boden SD, Goldenring JR
J Clin Invest: 18 May 2020; epub ahead of print | PMID: 32427591
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Impact:
Abstract

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients with Pulmonary Hypertension Associated with HFpEF.

Bashline MJ, Bachman TN, Helbling NL, Nouraie M, Gladwin MT, Simon MA
Background
The severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance (PVR), which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with HFpEF (PH-HFpEF), who were administered inhaled sodium nitrite to better understand the acute effects on afterload.
Methods and results
Fourteen patients with PH-HFpEF underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both pre and post-nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (Z, inversely related to proximal pulmonary artery compliance) and total work (W) performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output (W/CO). There was a mild reduction in pulmonary steady-state resistance (Z) after administration of inhaled sodium nitrite but this was not significant.
Conclusions
PVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance, via a reduction in Z, more so than pulmonary steady-state resistance. This was associated with improved RV efficiency and total work.

Copyright © 2020 Elsevier Ltd. All rights reserved.

J Card Fail: 20 May 2020; epub ahead of print
Bashline MJ, Bachman TN, Helbling NL, Nouraie M, Gladwin MT, Simon MA
J Card Fail: 20 May 2020; epub ahead of print | PMID: 32446946
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Impact:
Abstract

Left Atrial Diverticula: Innocent Bystanders or Wolves in Sheep\'s Clothing?

Veen D, Bruning TA, de Groot NMS
Introduction
The finding of left atria diverticula (LAD) on cardiac Computed Tomography (CT) images obtained from patients with atrial fibrillation (AF) referred for pulmonary vein isolation is not uncommon. Prior studies reporting on LAD do not always provide definitions of LAD resulting in confusion with other anatomical structures such as left atrial accessory appendages (LAAA) and atrial aneurysms. The aim of this review is to identify an accurate definition of LAD and to describe distinctive properties between LAD and other left atrial structures such as LAAA and aneurysms. Also, the relation between LAD and development of atrial tachyarrhythmias is discussed.
Methods
PubMed was searched for studies reporting on atrial aneurysms, left atrial diverticula, left atrial accessory appendages and atrial congenital aneurysms, resulting in 36 papers.
Results
LAD can be distinguished from LAAA by taking into account embryologic origins of the left atrium and their locations, resulting in the following definitions: 1) LAAA are contractile, trabeculated structures with circumscriptive ostia and narrow necks, originating from the primitive atria, 2) LAD are contractile, sac like structures with either smooth or trabeculated inner surfaces, circumscriptive ostia, narrow necks and variable morphologies, originating from the embryologic common pulmonary vein, that incorporates into the LA, 3) atrial aneurysms are non-contractile structures with wide necks and sac like bodies. There are no differences in prevalences of LAD between patients with sinus rhythm and AF.
Conclusion
The pathophysiology of LAD is not yet fully understood. It is unlikely, that LAD are related to the development of atrial tachycardia\'s and AF by either being a source of ectopic activity or being part of an arrhythmogenic substrate. No differences in LAD prevalences between patients with sinus rhythm and AF have been found. Thus, it is unlikely that LAD could potentially be wolves in sheep\'s clothing. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 22 May 2020; epub ahead of print
Veen D, Bruning TA, de Groot NMS
J Cardiovasc Electrophysiol: 22 May 2020; epub ahead of print | PMID: 32445428
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Impact:
Abstract

Patient care protocols and personal safety measures for health care professionals in cardiac catheterization rooms during the COVID-19 outbreak in the National Institute of Cardiology.

Eid-Lidt G, Farjat Pasos JI

The COVID-19 was first described in late 2019 that quickly became a pandemic affecting every health system as we know it. The high transmissibility among humans represents a well-known high burden of morbidity and mortality not only for cardiovascular patients but also for a higher risk between health care professionals that must deliver high-quality care to them in any scenario, and cardiac catheterization rooms are no exception. This creates a new dilemma, minimize exposure to patients and health care professionals to COVID-19 while maintaining high quality in cardiovascular therapeutics. In order to achieve this, several international recommendations on treatment algorithms modifications and in safety measures in the catheterization room have been published, always aiming to solve this dilemma in the best possible way. Hereby, we present a summary of the most recent treatment algorithms in the most important cardiovascular interventions (acute coronary syndromes, structural and congenital heart diseases) as well as specific safety measures with a step-by-step preparedness before and after any interventional procedure during COVID-19 outbreak. The objective of this document is to inform and to train health care professionals that works in cardiac catheterization rooms on the risks as well on the plan for containment, mitigation, and response to the global situation of COVID-19 infection in order to apply this in their own local work environments.

© 2020 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 31 May 2020; epub ahead of print
Eid-Lidt G, Farjat Pasos JI
Catheter Cardiovasc Interv: 31 May 2020; epub ahead of print | PMID: 32478472
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Abstract

Transbaffle/transconduit puncture using a simple CARTO-guided approach without echocardiography in patients with congenital heart disease.

Laredo M, Waldmann V, Soulat G, Amet D, ... Ladouceur M, Zhao A
Introduction
Catheter ablation (CA) of atrial tachyarrhythmias (ATs) in patients with complex congenital heart disease (CHD) often requires technically challenging transbaffle or transconduit puncture. The aim was to assess the feasibility and safety of transbaffle/transconduit puncture based on computed tomography (CT) 3D reconstruction merged with electro-anatomical mapping (EAM) without per-procedure echocardiographic guidance.
Methods and results
We included 18 consecutive CHD patients in two centers who had atrial-switch or Fontan surgery and underwent CA of AT by an antegrade approach requiring intracardiac puncture. Twelve patients with atrial-switch surgery and 6 patients with extracardiac Fontan surgery were referred for CA of atrial tachyarrhythmia. Cardiac CT with 3D reconstruction was performed before the procedure. The 3D volume of the systemic venous atrium or extracardiac conduit acquired by EAM was merged with the corresponding CT 3D reconstruction. The ablation catheter was positioned at the optimal puncture site. Under fluoroscopic guidance, the needle was positioned next to the ablation and the puncture was performed. Balloon expansion of the puncture site was performed in every case of transconduit puncture and in 2 (17%) cases of transbaffle puncture. Overall, 17 intra-atrial reentrant tachycarrythmias and 9 focal ATs were successfully ablated, with no acute complications. The median time to access the pulmonary atrium was 78.5 min (range 55-185) and total median fluoroscopy time was 23 min (range 7-53).
Conclusions
Transbaffle and transconduit punctures can be performed safely in CHD patients by using a simple technique relying on CT 3D reconstruction and EAM. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 25 May 2020; epub ahead of print
Laredo M, Waldmann V, Soulat G, Amet D, ... Ladouceur M, Zhao A
J Cardiovasc Electrophysiol: 25 May 2020; epub ahead of print | PMID: 32458508
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Abstract

Gadolinium contrast balloon pulmonary angioplasty for a patient with chronic thromboembolic pulmonary hypertension and severe iodine allergy.

Saito S, Ikeda N, Toi S, Nakamura M

Chronic thromboembolic pulmonary hypertension (CTEPH) is group 4 pulmonary hypertension caused by organized thrombi in the pulmonary arteries. Balloon pulmonary angioplasty (BPA) is an emerging treatment option for patients with inoperable CTEPH but needs contrast media. Therefore, management can be very difficult in patients who have severe iodine allergies. We present a case of a 61-year-old female with CTEPH. Right heart catheterization showed that the mean pulmonary arterial pressure (mPAP) was 47 mmHg. Her organized thrombi were not surgically accessible, so we performed BPA to improve her hemodynamic status. One session of BPA was performed, but the second session was halted because of iodine-induced anaphylactic shock. Despite the administration of pulmonary arterial hypertension-specific drugs for 3 months, the patient\'s mPAP was still 33 mmHg. CTEPH patients with mPAP ≥30 mmHg have a poor prognosis, so we decided to perform BPA using gadolinium contrast media. A total of six sessions of gadolinium contrast BPA (Gd-BPA) improved the patient\'s mPAP to the normal range. Gadolinium contrast media could also be used for visualizing pulmonary arteries during BPA. Our report is the first successful case of Gd-BPA, which improved the patient\'s hemodynamic status to the almost normal range. Gd-BPA may be an attractive treatment option for patients with inoperable CTEPH and severe iodine allergy.

© 2020 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 31 May 2020; epub ahead of print
Saito S, Ikeda N, Toi S, Nakamura M
Catheter Cardiovasc Interv: 31 May 2020; epub ahead of print | PMID: 32478464
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Impact:
Abstract

Hemodynamics in Adults With the Shone Complex.

Jain CC, Warnes CA, Egbe AC, Cetta F, ... Connolly HM, Miranda WR

Patients with Shone complex (SC) have multiple left-sided obstructive lesions and thus are at risk for left ventricular (LV) remodeling, LV diastolic dysfunction and pulmonary hypertension. Yet, to date, there has been no description of hemodynamics in adults with SC. Retrospective chart review of 25 patients with SC who underwent cardiac catheterization at Mayo Clinic, MN between 2002 and 2019 was performed. SC was defined as multiple left-sided obstructive lesions in the presence of an anatomically abnormal mitral valve. Median age was 32 years (22.5, 42) and 15 patients (60%) were female. The majority of patients (84%) had history of coarctation of the aorta, 10 (40%) had subaortic stenosis, 11 (44%) had prior aortic valve replacement, and 10 (40%) had prior mitral valve replacement. Structural disease at the time of catheterization which warranted intervention within the next year was present in 13 patients (52%). The mean LV end-diastolic pressure was 21.3 ± 9.0 mm Hg (>15 mm Hg in 71%), pulmonary artery peak systolic pressure was 55.4 ± 13.4 mm Hg, and the pulmonary artery mean pressure was 37.0 ± 9.4 mm Hg (>20 mm Hg in 96%). During a mean follow-up of 8.3 ± 4.4 years, there were 7 deaths (28%) and 3 additional patients (12%) underwent cardiac transplantation. In conclusion, adults with SC who underwent catheterization showed significant left-sided heart and pulmonary vascular remodeling. Elevated LV end-diastolic pressure and pulmonary artery pressures were highly prevalent. There were high mortality and cardiac transplant rates in our cohort.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 15 Jun 2020; epub ahead of print
Jain CC, Warnes CA, Egbe AC, Cetta F, ... Connolly HM, Miranda WR
Am J Cardiol: 15 Jun 2020; epub ahead of print | PMID: 32703525
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Impact:
Abstract

Impact of Combined Pre and Postcapillary Pulmonary Hypertension on Survival after Transcatheter Aortic Valve Implantation.

Sultan I, Fukui M, Bianco V, Brown JA, ... Gleason TG, Cavalcante JL

We aimed to evaluate the association between pulmonary hypertension (PH) hemodynamic classification and all-cause mortality in patients with symptomatic severe aortic stenosis (AS) undergoing transcatheter aortic valve implantation (TAVI). PH is common and associated with post-TAVI outcomes in patients with severe AS. Although PH in these patients is primarily driven by elevated left-sided pressures (postcapillary PH), some patients develop increased pulmonary vascular resistance (PVR) configuring the combined pre- and postcapillary PH (CpcPH). We analyzed severe AS patients with mean pulmonary artery pressure (mPAP) measured by right heart catheterization (RHC) before TAVI between 2011 and 2017. PH hemodynamic classification was defined as: No PH (mPAP < 25 mm Hg); precapillary PH (mPAP ≥ 25 mm Hg, pulmonary capillary wedge pressure (PCWP) ≤15 mm Hg); isolated postcapillary PH (IpcPH; mPAP ≥ 25 mm Hg, PCWP > 15 mm Hg, PVR ≤ 3 Wood units (WU); CpcPH (mPAP ≥ 25 mm Hg, PCWP > 15 mm Hg, PVR > 3 WU). Kaplan-Meier and Cox regression analyses were used to test the association of PH hemodynamic classification with post-TAVI all-cause mortality. We examined 561 patients (mean age 82 ± 8 years, 51% men, mean LVEF 54 ± 14%). The prevalence of no PH was 201 (36%); precapillary PH, 59 (10%); IpcPH, 189 (34%); and CpcPH, 112 (20%). During a median follow-up of 30 months, 240 all-cause deaths occurred. Patients with CpcPH had higher mortality than those with no-PH even after adjustment for baseline characteristics (Hazard ratio 1.56, 95% confidence interval 1.06 to 2.29, p = 0.025). There was no survival difference among patients with non-PH, precapillary PH and IpcPH. In conclusion, for patients with symptomatic severe AS treated with TAVI, CcpPH is independently associated with long-term all-cause mortality despite successful TAVI.

Copyright © 2020 Elsevier Inc. All rights reserved.

Am J Cardiol: 29 Jun 2020; epub ahead of print
Sultan I, Fukui M, Bianco V, Brown JA, ... Gleason TG, Cavalcante JL
Am J Cardiol: 29 Jun 2020; epub ahead of print | PMID: 32713655
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Impact:
Abstract

p38 mitogen-activated protein kinase regulates chamber specific perinatal growth in heart.

Yokota T, Li J, Huang J, Xiong Z, ... Minamisawa S, Wang Y

In mammalian heart, left ventricle (LV) rapidly becomes more dominant in size and function over right ventricle (RV) after birth. The molecular regulators responsible for this chamber specific differential growth are largely unknown. We found the cardiomyocytes in neonatal mouse RV had lower proliferation, more apoptosis and smaller sizes comparing to the LV. Such chamber specific growth pattern was associated with a selective activation of p38 MAPK activity in the RV and simultaneous inactivation in the LV. Cardiomyocyte-specific deletion of both mapk14 and mapk11 genes in mice results in loss of p38 MAP kinase expression and activity in the neonatal heart. Inactivation of p38 activity led to marked increase in myocytes proliferation and hypertrophy but diminished myocyte apoptosis, specifically in the RV. Consequently, the p38 inactivated hearts showed RV specific enlargement postnatally, progressing to pulmonary hypertension and right heart failure at adult stage. Chamber-specific p38 activity was associated with differential expression of dual-specific phosphatases (DUSPs) in neonatal hearts, including Dusp26. Unbiased transcriptome analysis revealed IRE1/XBP mediated gene regulation contributed to p38 MAPK dependent regulation of neonatal myocyte proliferation and binucleation. These findings establish an obligatory role of DUSP-p38-IRE1 signaling in myocytes for chamber specific growth in postnatal heart.



J Clin Invest: 22 Jun 2020; epub ahead of print
Yokota T, Li J, Huang J, Xiong Z, ... Minamisawa S, Wang Y
J Clin Invest: 22 Jun 2020; epub ahead of print | PMID: 32573492
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Abstract

Measurement, consequences and determinants of time to diagnosis in children with new-onset heart failure: A population-based retrospective study (DIACARD study).

Saïd B, David M, Nadir B, Laurianne LG, ... Alban-Elouen B, Elise L
Background
Time from first symptoms to diagnosis, called time to diagnosis, is related to prognosis in several diseases. The aim of this study was to assess time to diagnosis in children with new-onset heart failure (HF) and assess its consequences and determinants.
Methods
A retrospective population-based observational study was conducted between 2007 and 2016 in a French tertiary care center. We included all children under 16 years old with no known heart disease, and HF confirmed by echocardiography. With logistic regression used for outcomes and a Cox proportional-hazards model for determinants, analyses were stratified by HF etiology: congenital heart diseases (CHD) and cardiomyopathies/myocarditis (CM).
Results
A total of 117 children were included (median age [interquartile range (IQR)] 25 days (6-146), 50.4% were male, 60 had CHD and 57 had CM). Overall median (IQR) time to diagnosis was 3.3 days (1.0-21.2). The frequency of 1-year mortality was 17% and 1-year neuromotor sequel 18%. Death at 1 year was associated with low birth weight for all children (adjusted odds ratio 0.24, 95% confidence interval [CI] 0.08-0.68) and time to diagnosis below the median with CM (0.09, 0.01-0.87). Short time to diagnosis was associated with clinical severity on the first day of symptoms for all patients (adjusted hazard ratio 3.39, 95% CI 2.01-5.72), and young age with CM (0.09, 0.02-0.41).
Conclusions
In children with new-onset HF presenting in our region, median time to diagnosis was short. Long time to diagnosis was not associated with poor outcome.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 14 Jun 2020; epub ahead of print
Saïd B, David M, Nadir B, Laurianne LG, ... Alban-Elouen B, Elise L
Int J Cardiol: 14 Jun 2020; epub ahead of print | PMID: 32553597
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Abstract

Long-term changes of exercise hemodynamics and physical capacity in chronic thromboembolic pulmonary hypertension after pulmonary thromboendarterectomy.

Waziri F, Mellemkjær S, Clemmensen TS, Hjortdal VE, ... Nielsen SL, Poulsen SH
Background
A substantial number of chronic thromboembolic pulmonary hypertension (CTEPH) patients experience dyspnea on exertion and limited exercise capacity despite surgically successful pulmonary endarterectomy (PEA). We sought to prospectively evaluate resting and peak exercise hemodynamics before, 3 and 12 months after PEA in consecutive CTEPH-patients and correlate it to physical functional capacity.
Methods and results
Twenty consecutive CTEPH-patients were examined. Twelve months after PEA, 75% of patients with severely increased pre-PEA mean pulmonary arterial pressure (mPAP) at rest had normal or mildly increased mPAP. However, mPAP reduction was less pronounced during exercise where only 45% had normal or mildly increased mPAP at 12 months. Hemodynamic changes during exercise were tested using the pressure-flow relationship (i.e. mPAP/cardiac output (CO) slope). The average mPAP/CO slope was 7.5 ± 4.2 mm Hg/L/min preoperatively and 3.9 ± 3.0 mm Hg/L/min at 12 months (p < .005). CO reserve (CO increase from rest to peak exercise) was increased (5.7 ± 2.9 L/min) 12 months after PEA compared with pre-PEA (2.5 ± 1.8 L/min), p < .0001. However, 12 months after PEA, the CO reserve was only 49% of that of healthy controls, p < .0001. Changes in cardiac output (∆CO), calculated as the difference between CO before PEA and 12 months later, were significantly correlated with six-minute-walk-test and peak oxygen uptake (VO2), both at rest and peak exercise.
Conclusion
Invasive exercise hemodynamic examination in CTEPH-patients demonstrates that after otherwise successful PEA surgery, >50% of patients have a significant increase in exercise mPAP, and the CO reserve remains compromised 12 months after PEA. Improvement in physical capacity is correlated with ∆CO.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 31 May 2020; epub ahead of print
Waziri F, Mellemkjær S, Clemmensen TS, Hjortdal VE, ... Nielsen SL, Poulsen SH
Int J Cardiol: 31 May 2020; epub ahead of print | PMID: 32497568
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Abstract

Congenital heart disease with pulmonary artery hypertension in an Asian cohort-initial report from TACHYON (TAiwan congenital heart disease associated with pulmonarY arterial hypertension) registry.

Chiu SN, Weng KP, Lin MC, Wang JN, ... Wang JK,
Background
Prospective registry studies of congenital heart disease (CHD)-associated pulmonary artery hypertension (PAH) are rare. We established a multicenter registry of CHD-PAH: the TACHYON (TAiwan Congenital Heart disease associated with pulmonarY arterial hypertension) registry.
Methods
The prospective TACHYON registry was initiated in January 2016. Nine pediatric cardiology centers with 99 patients were included. Using this database, we evaluated clinical characteristics and outcomes.
Results
Twelve patients with incomplete data were excluded. For the remaining 87 patients, mean age of enrollment was 37.4(SD 18.2) years, and the male to female ratio was 60:27. PAH after defect closure accounted for 46 (52.9%) and Eisenmenger syndrome for 30 (34.5%) cases. Atrial septal defect was the most common (48.3%) disease, followed by ventricular septal defect. Mean pulmonary artery pressure was 56.7 (SD 19.4) mmHg. PAH-targeted therapy was used in 95.4% of patients. Sildenafil and bosentan were the most common drugs. After mean 23.9 months of follow-up, the 2-year Kaplan-Meier survival rate was 93.2%. According to univariate Cox regression analysis, significant risk factors included right heart failure signs, symptom progression, high-risk baseline N-terminal pro-brain natriuretic peptide (BNP)/BNP, high-risk baseline 6-min walking distance (6MWD), and high baseline hemoglobin/hematocrit level. Using the three noninvasive parameters (functional class, 6MWD, NT-pro BNP/BNP) proposed by the European Society of Cardiology, the total number of high-risk criteria predicted survival rate reliably.
Conclusions
Using the TACHYON registry is feasible, but the physicians\' adherences to guidelines are unsatisfactory. Midterm outcomes of PAH-target therapy are favorable and predictable using noninvasive parameters.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 05 Jun 2020; epub ahead of print
Chiu SN, Weng KP, Lin MC, Wang JN, ... Wang JK,
Int J Cardiol: 05 Jun 2020; epub ahead of print | PMID: 32522677
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Abstract

The tricuspid annular plane systolic excursion to systolic pulmonary artery pressure index: Association with all-cause mortality in patients with moderate or severe tricuspid regurgitation.

Saeed S, Smith J, Grigoryan K, Lysne V, Rajani R, Chambers JB
Background
In patients with significant tricuspid regurgitation (TR) the conventional markers for the assessment of right ventricular (RV) systolic function may be less accurate. Tricuspid annular plane systolic excursion (TAPSE) indexed to systolic pulmonary artery pressure (SPAP) (TAPSE/SPAP) may be prognostically useful in pulmonary hypertension and left ventricular dysfunction. Our aim was to explore its use in patients with moderate or severe TR.
Methods
A total of 209 patients (72 ± 14 years, 56% women) with moderate (n = 123) or severe (n = 86) TR (primary in 6% and secondary in 94%) were followed up for a median of 80 months (mean 70 ± 33 months). The clinical correlates of TAPSE/SPAP index and association with all-cause mortality were assessed.
Results
The TAPSE/SPAP index was inversely correlated with all-cause mortality with an optimal threshold of 0.49 mm/mmHg. A low index was found in 139 (68%) patients. In a multivariate Cox regression analysis adjusted for age, smoking, coronary artery disease, left ventricular ejection fraction, right atrium area and mitral valve replacement, low TAPSE/SPAP index was associated with significantly higher hazard ratio of all-cause mortality (HR: 2.07; 95% CI 1.32-3.27, p = .002). Age, coronary artery disease, left ventricular ejection fraction and right atrium area were other independent predictors of all-cause mortality.
Conclusion
The TAPSE/SPAP index, reflecting RV systolic function in the longitudinal axis corrected for force generating by the RV is a powerful predictor of all-cause mortality in patients with moderate or severe TR.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 04 Jun 2020; epub ahead of print
Saeed S, Smith J, Grigoryan K, Lysne V, Rajani R, Chambers JB
Int J Cardiol: 04 Jun 2020; epub ahead of print | PMID: 32512064
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Abstract

Risk of readmission after heart failure hospitalization in older adults with congenital heart disease.

Wang F, Sterling LH, Liu A, Brophy JM, Paradis G, Marelli A
Background
Hospital readmissions are common in adults with congenital heart disease (CHD) with heart failure (HF). We sought to examine the temporal risk of readmissions, the prompting diagnoses and their determinants within one-year after a first HF hospitalization in older CHD patients.
Method
We assembled a cohort from the Quebec CHD database of patients whose first-ever HFH occurred after age 40. Subjects were followed from the first HF discharge to the earliest of all-cause readmission, death, or one-year post-discharge. The Fine and Gray model was used to measure the weekly readmission risks. The one-year period was categorized into different stages based on readmission risks. A multinomial logistic regression model was adopted to identify the determinants of patients falling in different readmission stages.
Results
The one-year death-adjusted cumulative readmission risk was 48.8%. The absolute weekly risk of readmission was the highest at week 2, declined by 50% at week 8, and reached a plateau at week 27. Three phases-vigilance (1-8 weeks), transition (9-27 weeks), and plateau (28-52 weeks)-were identified, corresponding to high-risk, decreasing-risk, and stable-risk periods. Cardiovascular diseases accounted for 61.7%, 50.3%, and 43.2% of all readmissions during the three phases; systemic diseases accounted for 15.2%, 19.9%, and 31.2%. A history of past-12-month interventional procedures saw significantly decreased readmission risks. Longer hospital stays were associated with lower readmission risks at the vigilance phase only.
Conclusion
Policy makers and caregivers should account for the change in risk over time, and phase-tailored strategies should be planned to effectively reduce readmissions.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 19 Jun 2020; epub ahead of print
Wang F, Sterling LH, Liu A, Brophy JM, Paradis G, Marelli A
Int J Cardiol: 19 Jun 2020; epub ahead of print | PMID: 32574824
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Abstract

Triage and management of the ACHD patient with COVID-19: A single center approach.

Lastinger LT, Daniels CJ, Lee M, Sabanayagam A, Bradley EA

With the recent emergence of SARS-CoV-2 and COVID-19, healthcare facilities and personnel are expected to rapidly triage and care for even the most complex medical conditions. Adults with congenital heart disease (ACHD) represent an often-intimidating group of complex cardiovascular disorders. Given that general internists and general cardiologists will often be asked to evaluate this group during the pandemic, we propose here an abbreviated triage algorithm that will assist in identifying the patient\'s overarching ACHD phenotype and baseline cardiac status. The strategy outlined allows for rapid triage and groups various anatomic CHD variants into overarching phenotypes, permitting care teams to quickly review key points in the management of moderate to severely complex ACHD patients.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 17 Jun 2020; epub ahead of print
Lastinger LT, Daniels CJ, Lee M, Sabanayagam A, Bradley EA
Int J Cardiol: 17 Jun 2020; epub ahead of print | PMID: 32565296
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Abstract

Determinants and Impact of Heart Failure Readmission Following Transcatheter Aortic Valve Replacement.

Auffret V, Bakhti A, Leurent G, Bedossa M, ... Boulmier D, Le Breton H
Background
Heart failure (HF) readmission is common post-transcatheter aortic valve replacement (TAVR). Nonetheless, limited data are available regarding its predictors and clinical impact. This study evaluated the incidence, predictors, and impact of HF readmission within 1-year post-TAVR, and assessed the effects of the prescription of HF therapies at discharge on the risk of HF readmission and death.
Methods
Patients included in the TAVR registry of a single expert center from 2009 to 2017 were analyzed. Competing-risk and Cox regressions were performed to identify predictors of HF readmission and death.
Results
Among 750 patients, 102 (13.6%) were readmitted for HF within 1-year post-TAVR. Overall, 53 patients (7.1%) experienced late readmissions (>30 days post-TAVR), and 17 (2.3%) had multiple readmissions. In ≈30% of readmissions, no trigger could be identified. Predominant causes of readmissions were changes in medication/nonadherence and supraventricular arrhythmia. Independent predictors of HF readmission included diabetes mellitus, chronic lung disease, previous acute HF, grade III or IV aortic regurgitation, and pulmonary hypertension both at discharge from the index hospitalization but not HF therapies. Overall, HF readmission did not significantly impact all-cause mortality (hazard ratio [HR], 1.36 [95% CI, 0.99-1.85]). However, late (HR, 1.90 [95% CI, 1.30-2.78]) and multiple HF readmissions (HR, 2.10 [95% CI,1.17-3.76]) were significantly associated with all-cause mortality. Prescription of renin-angiotensin system inhibitors at discharge was associated with a lower rate of all-cause mortality, especially among patients receiving doses of 25% to <50% (HR, 0.67 [95% CI, 0.48-0.94]) and 75% to 100% (HR, 0.61 [95% CI, 0.37-0.98]) of the optimal daily dose.
Conclusions
HF readmission is common within 1-year of TAVR. Late and multiple HF readmissions associate with an increased risk of long-term all-cause mortality. Baseline comorbidities (diabetes, chronic lung disease, previous acute HF) and echocardiographic findings at discharge (grade III or IV aortic regurgitation, pulmonary hypertension) identified patients at high risk of HF readmission.



Circ Cardiovasc Interv: 29 Jun 2020; 13:e008959
Auffret V, Bakhti A, Leurent G, Bedossa M, ... Boulmier D, Le Breton H
Circ Cardiovasc Interv: 29 Jun 2020; 13:e008959 | PMID: 32600108
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Abstract

Implantable Cardioverter-Defibrillator Therapy to Reduce Sudden Cardiac Death in Adults with Congenital Heart Disease: A Registry Study.

Slater TA, Cupido B, Parry H, Drozd M, ... English KM, Sengupta A
Introduction
The Adult Congenital Heart Disease (ACHD) population is rapidly expanding. However, a significant proportion of these patients suffer sudden cardiac death. Recommending implantable cardioverter-defibrillator (ICD) insertion requires balancing need for appropriate therapy in malignant arrhythmia against the consequences of inappropriate therapy and procedural complications. Here we present long-term follow up data for ICD insertion in patients with ACHD from a large level 1 congenital cardiac centre.
Methods and results
All patients with ACHD undergoing ICD insertion over an 18 year period were identified. Data were extracted for baseline characteristics including demographics, initial diagnosis, ventricular function, relevant medication and indication for ICD insertion. Details regarding device insertion were gathered along with follow up data including appropriate and inappropriate therapy and complications. A total of 136 ICDs were implanted during this period: 79 for primary and 57 for secondary prevention. The most common congenital cardiac conditions in both groups were tetralogy of Fallot and transposition of the great arteries. Twenty-two individuals in the primary prevention group received appropriate anti-tachycardia pacing (ATP), 14 underwent appropriate cardioversion, 17 received inappropriate ATP and 15 received inappropriate cardioversion. In the secondary prevention group, 18 individuals received appropriate ATP, 8 underwent appropriate cardioversion, 8 received inappropriate ATP and 7 were inappropriately cardioverted. Our data demonstrate low complication rates, particularly with leads without advisories.
Conclusions
ICD insertion in the ACHD population involves careful balance of the risks and benefits. Our data show a significant proportion of patients receiving appropriate therapy indicating that ICDs were inserted appropriately. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 23 Jun 2020; epub ahead of print
Slater TA, Cupido B, Parry H, Drozd M, ... English KM, Sengupta A
J Cardiovasc Electrophysiol: 23 Jun 2020; epub ahead of print | PMID: 32583559
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Abstract

Outcomes and predictors of cardiac events in medically treated patients with atrial functional mitral regurgitation.

Kim K, Kitai T, Kaji S, Pak M, ... Kinoshita M, Furukawa Y
Background
Little is known about the outcomes and predictors of adverse cardiac events in medically treated patients with atrial functional mitral regurgitation (FMR).
Methods
We screened 1405 consecutive patients with grade ≥ 3+ mitral regurgitation (MR) detected by echocardiography. After excluding patients with previous or early (within 3 months from diagnosis) mitral valve surgery, congenital heart disease, hypertrophic cardiomyopathy, severe aortic valve disease, or unknown etiology, the study population consisted of 319 patients with primary MR, 395 patients with FMR with left ventricular (LV) dysfunction, and 184 patients with atrial FMR. Atrial FMR was defined as FMR in patients without LV wall motion abnormality or dilatation.
Results
The cumulative incidence of the composite of cardiac death and heart failure hospitalization at 3 years was 10.5% in primary MR, 37.5% in FMR with LV dysfunction, and 14.0% in atrial FMR (p < .001). In atrial FMR patients, LV end-diastolic volume index (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02-1.10), severe MR (grade 4+) (HR 2.73, 95% CI 1.21-6.12), being symptomatic (NYHA≥2) (HR 2.82, 95% CI 1.15-6.92), and having ≥1 comorbidities (HR 3.96, 95% CI 1.74-9.00) were independently associated with an increased risk for adverse cardiac events by a multivariable Cox regression analysis.
Conclusions
Outcomes of medically treated patients with atrial FMR were better than those of FMR with LV dysfunction, but worse than those of primary MR. In atrial FMR patients, LV dilatation, severe MR, being symptomatic, and the presence of comorbidities were independently associated with an increased risk for adverse cardiac events.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 27 Jun 2020; epub ahead of print
Kim K, Kitai T, Kaji S, Pak M, ... Kinoshita M, Furukawa Y
Int J Cardiol: 27 Jun 2020; epub ahead of print | PMID: 32610155
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Abstract

Young patients with heart failure - clinical characteristics and outcomes. Data from the Swedish Heart Failure, National Patient, Population and Cause of Death Registers.

Basic C, Rosengren A, Alehagen U, Dahlström U, ... Zverkova Sandström T, Schaufelberger M
Aims
The prevalence and hospitalizations of patients with heart failure (HF) aged <55 years have increased in Sweden during the last decades. We aimed to compare characteristics of younger and older patients with HF, and examine survival in patients <55 years compared with matched controls.
Methods and results
All patients >18 years in the Swedish Heart Failure Register from 2003 to 2014 were included. Data were merged with National Patient and Cause of Death Registers. Among 60,962 patients 3752 (6.2%) were <55 years, and were compared with. 7425 controls from the Population Register. Compared with patients ≥55 years, patients <55 years more frequently had registered diagnoses of obesity, dilated cardiomyopathy, congenital heart disease, and an ejection fraction (EF) <40% (9.8% vs. 4.7%, 27.2% vs 5.5%, 3.7% vs. 0.8%, 67.9% vs. 45.1%, all p<0.001). One-year all-cause mortality was 21.2%, 4.2%, and 0.3% in patients >55 years, patients <55 years, and controls <55 years (all p<0.001). Patients <55 years had a five times higher mortality risk compared with controls; hazard ratio (HR 5.48 (4.45- 6.74)); the highest HR was in patients 18-34 years (HR 38.3(8.70-169) (both p<0.001). At the age of 20 the estimated life-years lost was up to 36 years for 50% of patients, with declining estimates with increasing age.
Conclusion
Patients with HF <55 years had different comorbidities than patients ≥55 years. The highest mortality risk relative to that of controls was among the youngest patients.

This article is protected by copyright. All rights reserved.

Eur J Heart Fail: 01 Jul 2020; epub ahead of print
Basic C, Rosengren A, Alehagen U, Dahlström U, ... Zverkova Sandström T, Schaufelberger M
Eur J Heart Fail: 01 Jul 2020; epub ahead of print | PMID: 32613768
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Abstract

Determinants of Survival in Older Adults With Congenital Heart Disease Newly Hospitalized for Heart Failure.

Wang F, Liu A, Brophy JM, Cohen S, ... Paradis G, Marelli A
Background
Nearly 90% of patients with adult congenital heart disease (ACHD) die after the age of 40 years, and heart failure (HF) is the most common cause of death. We aimed to characterize the association between an incident HF hospitalization (HFH) and mortality and to identify the predictors of 1-year postdischarge mortality after incident and repeated HFHs, respectively.
Methods
Patients with ACHD aged ≥40 years between 2000 and 2010 were identified from the Québec CHD database. We conducted a propensity score-matched study to explore the association between an incident HFH and mortality. We performed Bayesian model averaging to identify the predictors of 1-year postdischarge mortality with a posterior probability ≥50% considered to be evidence of a significant association.
Results
The mortality hazard ratio was high at 6.01 (95% CI, 4.02-10.72) within 1-year postdischarge, decreasing significantly but entering an elevated equilibrium until year 4 with a continued 3-fold increase in death. Kidney dysfunction (hazard ratio, 2.28 [95% credible interval, 1.59-3.28], posterior probability, 100.0%) and a history of ≥2 HFHs in the past 12 months (hazard ratio, 1.77 [95% credible interval, 1.18-2.66], posterior probability: 82.2%) were the most robust predictors of 1-year mortality after incident and repeated HFHs, respectively.
Conclusions
In patients with ACHD aged ≥40 years, incident HFH was associated with high mortality risk at 1 year, declining but remaining elevated for 4 years. Kidney dysfunction was a potent predictor of 1-year mortality risk after incident HFHs. Repeated HFHs further increased mortality risk. These observations should inform early risk-tailored health services interventions for monitoring and prevention of HF and its associated complications in older patients with ACHD.



Circ Heart Fail: 15 Jul 2020:CIRCHEARTFAILURE119006490; epub ahead of print
Wang F, Liu A, Brophy JM, Cohen S, ... Paradis G, Marelli A
Circ Heart Fail: 15 Jul 2020:CIRCHEARTFAILURE119006490; epub ahead of print | PMID: 32673500
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Abstract

The molecular biology and immune control of chronic Toxoplasma gondii infection.

Zhao XY, Ewald SE

Toxoplasma gondii is an incredibly successful parasite owing in part to its ability to persist within cells for the life of the host. Remarkably, at least 350 host species of T. gondii have been described to date, and it is estimated that 30% of the global human population is chronically infected. The importance of T. gondii in human health was made clear with the first reports of congenital toxoplasmosis in the 1940s. However, the AIDS crisis in the 1980s revealed the prevalence of chronic infection, as patients presented with reactivated chronic toxoplasmosis, underscoring the importance of an intact immune system for parasite control. In the last 40 years, there has been tremendous progress toward understanding the biology of T. gondii infection using rodent models, human cell experimental systems, and clinical data. However, there are still major holes in our understanding of T. gondii biology, including the genes controlling parasite development, the mechanisms of cell-intrinsic immunity to T. gondii in the brain and muscle, and the long-term effects of infection on host homeostasis. The need to better understand the biology of chronic infection is underscored by the recent rise in ocular disease associated with emerging haplotypes of T. gondii and our lack of effective treatments to sterilize chronic infection. This Review discusses the cell types and molecular mediators, both host and parasite, that facilitate persistent T. gondii infection. We highlight the consequences of chronic infection for tissue-specific pathology and identify open questions in this area of host-Toxoplasma interactions.



J Clin Invest: 30 Jun 2020; 130:3370-3380
Zhao XY, Ewald SE
J Clin Invest: 30 Jun 2020; 130:3370-3380 | PMID: 32609097
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Abstract

National trends and inpatient outcomes of pulmonary arterial hypertension related hospitalizations - Analysis of the National Inpatient Sample Database.

Chaturvedi A, Kanwar M, Chandrika P, Thenappan T, Raina A, Benza RL
Background
Pulmonary arterial hypertension (PAH) is associated with a significant burden of morbidity and mortality. We examined national trends in PAH-related hospitalizations, associated inpatient mortality (IM), length of stay (LOS) and hospitalization charges from 2007 to 2016, as well as predictors of IM and LOS in this population.
Methods
We used the National Inpatient Sample to identify PAH admissions using International classification of diseases (ICD) codes 416.0 (ICD-9) and I27.0 (ICD-10). Records suggestive of secondary causes of pulmonary hypertension were excluded. 6162 (weighted) records with PAH as the primary diagnosis were analyzed.
Results
Mean age was 38.7 years, with the majority being females (78.8%). Overall IM was 6.03%, mean LOS 7.6 ± 0.5 days and mean charges $84,100 ± 6200. PAH-related hospitalizations (per million) (27 in 2007 vs. 28 in 2016, p = 0.19) and associated IM (4.5% in 2007 vs. 6.8% in 2016, p = 0.748) as well as LOS (5.9 days in 2007 vs 6.7 days in 2016, p = 0.304) remained unchanged over the decade. Charges increased by 2.4-fold ($43,800 in 2007 to $103,300 in 2016, p = 0.002). While right HF, fluid/electrolyte disorders, cardiac arrhythmia and neurological disorders were associated with increased IM, Hispanic race was found to have a survival benefit. Fluid/electrolyte disorders and coagulopathy were associated with increased LOS.
Conclusion
Despite significant advancements in PAH therapies over the duration of this study, the rate of PAH hospitalizations, and associated IM and LOS remain unchanged. The study identified the predictors of IM and prolonged LOS in PAH population which could be used for additional risk stratification of these patients.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 26 Jun 2020; epub ahead of print
Chaturvedi A, Kanwar M, Chandrika P, Thenappan T, Raina A, Benza RL
Int J Cardiol: 26 Jun 2020; epub ahead of print | PMID: 32603739
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Impact:
Abstract

Mutations in the iron-sulfur cluster biogenesis protein HSCB cause congenital sideroblastic anemia.

Crispin A, Guo C, Chen C, Campagna DR, ... Fleming MD, Ducamp S

The congenital sideroblastic anemias (CSAs) can be caused by primary defects in mitochondrial iron-sulfur cluster (Fe-S) biogenesis. HSCB (heat shock cognate B), which encodes a mitochondrial co-chaperone, also known as HSC20 (heat shock cognate protein 20), is the partner of mitochondrial heat shock protein A9 (HSPA9). Together with glutaredoxin 5 (GLRX5), HSCB and HSPA9 facilitate the transfer of nascent two-iron, two-sulfur ([2Fe-2S]) clusters to recipient mitochondrial proteins. Mutations in both HSPA9 and GLRX5 have previously been associated with CSA. Therefore, we hypothesized that mutations in HSCB could also cause CSA. We screened patients with genetically undefined CSA and identified a frameshift mutation and a rare promoter variant in HSCB in a female patient with non-syndromic CSA. We found that HSCB expression was decreased in patient-derived fibroblasts and K562 erythroleukemia cells engineered to have the patient-specific promoter variant. Furthermore, gene knockdown and deletion experiments performed in K562 cells, zebrafish, and mice demonstrate that loss of HSCB results in impaired Fe-S cluster biogenesis, a defect in red blood cell hemoglobinization, the development of siderocytes, and more broadly perturbs hematopoiesis in vivo. These results further affirm the involvement of Fe-S biogenesis in erythropoiesis and hematopoiesis and define HSCB as a CSA gene.



J Clin Invest: 06 Jul 2020; epub ahead of print
Crispin A, Guo C, Chen C, Campagna DR, ... Fleming MD, Ducamp S
J Clin Invest: 06 Jul 2020; epub ahead of print | PMID: 32634119
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Abstract

Pulmonary capillary wedge pressure (PCWP) as prognostic indicator in patients undergoing transcatheter valve repair (TTVR) of severe tricuspid regurgitation.

Kavsur R, Hupp H, Sugiura A, Öztürk C, ... Tiyerili V, Becher MU
Background
TTVR represents a minimal invasive alternative for patients with tricuspid regurgitation (TR). PCWP is a haemodynamic parameter indicating pulmonary hypertension due to left-sided heart failure.
Methods
We evaluated pulmonary capillary wedge pressure (PCWP) as prognostic outcome parameter in patients undergoing transcatheter tricuspid valve repair (TTVR). A total of 60 patients who underwent right heart catheterization prior to TTVR were included. Patient population was categorized into a low and high PCWP group according to the median PCWP of 16 mmHg.
Results
TTVR included transcatheter tricuspid annuloplasty (13 patients) and edge-to-edge repair [37 patients for isolated TR; 10 patients for combined TR and mitral regurgitation]. Kaplan-Meier analysis and log-rank test revealed reduced 6-months event-free survival for patients with high PCWP (>16 mmHg) in comparison to those with low PCWP (≤16 mmHg) (p = 0.009). High PCWP was associated with increased occurrence of the composite endpoint of death and cardiac readmission (HR 4.67, 1.32-16.55). Moreover, adjusted with other predictive variables within the univariate analysis (left ventricular ejection fraction, history of smoking, tricuspid annular plane systolic excursion), PCWP remained an endpoint predictor (HR 1.11, 1.003-1.24). Best predicting value was evaluated for the cut-off >16 mmHg (AUC 0.700, 0.552-0.848). Patients with a high PCWP tended to have less TR recurrence (p = 0,059) and lower NYHA class (p = 0.062) after one month of follow-up.
Conclusion
Here we demonstrate that PCWP is a predictive outcome parameter in TTVR patients. Patients with a PCWP ≤16 mmHg had a favourable outcome with lower mortality and morbidity gaining more benefit of TTVR.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 25 Jun 2020; epub ahead of print
Kavsur R, Hupp H, Sugiura A, Öztürk C, ... Tiyerili V, Becher MU
Int J Cardiol: 25 Jun 2020; epub ahead of print | PMID: 32598993
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Impact:
Abstract

Low bone mineral density in adults with complex congenital heart disease.

Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Aims
The majority of children with complex congenital heart disease (CHD) survive into adulthood due to advances in medical care. Adult patients with CHD have an increased incidence of diagnoses related to ageing such as heart failure, dementia, cancer and sarcopenia, despite a relatively low age. They also have a shorter life expectancy. It is unknown if their bone structures also show signs of premature ageing. We therefore investigated Bone Mineral Content (BMC) and bone mineral density (BMD) in an adult population with complex CHD.
Methods
The total body BMC and BMD was examined using dual energy X-ray absorptiometry (DXA) in 73 adults with complex CHD (mean age 35.8 ± 14.3, women n = 22) and 73 age and sex matched controls.
Results
The adults with complex CHD had lower total body BMC (2.6 ± 0.5 kg vs. 2.9 ± 0.5 kg, p < 0.001) and BMD (1.18 ± 0.12 g/cmvs. 1.26 ± 0.11 g/cm, p < 0.001) compared to controls. BMD was lower for patients with single ventricle physiology and for the other complex diagnoses, and it persisted after correction for most common risk factors for osteoporosis.
Conclusion
Adults with complex CHD have reduced total body BMC and BMD compared to healthy controls. These results are a sign of frailty that conforms with other previously reported signs of premature ageing. The risk of osteoporosis is low in our relatively young population, but it is assumed to increase with ageing. We recommend that clinicians pay close attention to risk factors for osteoporosis, and are generous in administering DXA-measurements in order to prevent future fractures among adults with complex CHD.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 03 Jul 2020; epub ahead of print
Sandberg C, Johansson K, Christersson C, Hlebowicz J, Thilén U, Johansson B
Int J Cardiol: 03 Jul 2020; epub ahead of print | PMID: 32634489
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Abstract

The long term results of the Ross procedure: The importance of candidate selection.

Pergola V, Di Salvo G, Fadel B, Galzerano D, ... Al-Ahmadi M, Al-Halees Z

The Ross procedure has been considered in children as an optimal surgical procedure due to potential growth of the aortic annulus, lack of anticoagulation requirement, very low morbidity rate and excellent survival. Five-hundred-thirty-six (366 male, mean age 29.4 ± 11.1 years) underwent Ross procedure between 1990 and 2016 and had complete clinical and echocardiographic follow-up. Mean follow-up was 16.3 ± 4.9 years. Patients were divided in 2 groups according to age at surgery. Group 1 consisted of 320 (60%) patients less than 18 years old (223 male, mean age at surgery of 9.5 ± 5.6 years). Group 2 consisted of 216 (40%) patients older than 18 years of age (143 male, mean age at surgery of 26.3 ± 8.2 years). One-hundred-thirty (24%) patients had a redo procedure or surgery. Freedom from all re-operation and or percutaneous reintervention on either the aortic and pulmonary valves was 99% after 1 year, 94% after 5 years, 89% after 10 years, 83% after 15 years and 78% after 20 years. Freedom from redo surgery for AV 99% after 1 year, 94% after 5 years, 90% after 10 years, 81% after 15 years and 80% after 20 years. Freedom from redo surgery for PV was 100% after 1 year, 95% after 5 years, 89% after 10 years, 78% after 15 years and 76% after 20 years. The ideal candidate for Ross operation is a patient with congenital aetiology and an aortic root diameter ≤ 15 mm/m. A pulmonary fresh preserved homograft seems to perform better on the long term.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 13 Jul 2020; epub ahead of print
Pergola V, Di Salvo G, Fadel B, Galzerano D, ... Al-Ahmadi M, Al-Halees Z
Int J Cardiol: 13 Jul 2020; epub ahead of print | PMID: 32679140
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Abstract

Maternal hypertension-related genotypes and congenital heart defects.

Lei Y, Ludorf KL, Yu X, Benjamin RH, ... Agopian AJ,
Background
Maternal hypertension has been associated with congenital heart defect occurrence in several studies. We assessed whether maternal genotypes associated with this condition were also associated with congenital heart defect occurrence.
Methods
We used data from the National Birth Defects Prevention Study to identify non-Hispanic white (NHW) and Hispanic women with (cases) and without (controls) a pregnancy in which a select simple, isolated heart defect was present between 1999-2011. We genotyped 29 hypertension-related single nucleotide polymorphisms (SNPs). We conducted logistic regression analyses separately by race/ethnicity to assess the relationship between the presence of any congenital heart defect and each SNP and an overall blood pressure genetic risk score (GRS). All analyses were then repeated to assess four separate congenital heart defect subtypes.
Results
Four hypertension-related variants were associated with congenital heart defects among NHW women (N=1,568 with affected pregnancies). For example, one intronic variant in ARHGAP2, rs633185, was associated with conotruncal defects (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1-1.6). Additionally, two variants were associated with congenital heart defects among Hispanic women (N=489 with affected pregnancies). The GRS had a significant association with septal defects (OR: 2.1, 95% CI: 1.2-3.5) among NHW women.
Conclusions
We replicated a previously reported association between rs633185 and conotruncal defects. Although additional hypertension-related SNPs were also associated with congenital heart defects, more work is needed to better understand the relationship between genetic risk for maternal hypertension and congenital heart defects occurrence.

© American Journal of Hypertension, Ltd 2020. All rights reserved. For Permissions, please email: [email protected]

Am J Hypertens: 24 Jul 2020; epub ahead of print
Lei Y, Ludorf KL, Yu X, Benjamin RH, ... Agopian AJ,
Am J Hypertens: 24 Jul 2020; epub ahead of print | PMID: 32710738
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Impact:
Abstract

Cardiac resynchronization therapy for the failing systemic right ventricle: A systematic review.

Kharbanda RK, Moore JP, Taverne YJHJ, Bramer WM, Bogers AJJC, de Groot NMS

Patients with a systemic right ventricle (SRV) are at high risk for development of heart failure early in life. An SRV is encountered in patients with congenitally corrected transposition of the great arteries (CCTGA) or dextro-transposition of the great arteries (DTGA) with previous atrial switch repair (Mustard or Senning procedure). Progressive heart failure is one of the leading cause of mortality in these patients. Therefore, cardiac resynchronization therapy (CRT) has gained increasing momentum for use in this challenging congenital heart disease (CHD) population. However, current guidelines differ in recommendations for CRT in patients with an SRV as evidence supporting CRT has thus far only been described in case reports and retrospectively in relatively small study populations. In fact, the European Society of Cardiology Guideline for the management of grown-up congenital heart disease consider CRT to be \'experimental\' in this population. This systematic review critically summarizes current literature on CRT in SRV patients and provides future perspectives for further research in this challenging and growing CHD population.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 05 Jul 2020; epub ahead of print
Kharbanda RK, Moore JP, Taverne YJHJ, Bramer WM, Bogers AJJC, de Groot NMS
Int J Cardiol: 05 Jul 2020; epub ahead of print | PMID: 32645324
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Impact:
Abstract

Left ventricular myocardial deformation as measure of hemodynamic burden in congenital valvular aortic stenosis.

Reddy SC, Zhang J, Jani V, Wolfe SB, ... Kutty S, Pignatelli RH
Background
Changes in 2D echocardiography (2DE) speckle tracking imaging (STI) derived left ventricular (LV) strain (S) and strain rate (SR) precedes diminution of LV ejection fraction (LVEF) in adult valvular aortic stenosis (AS). We prospectively examined whether 2DE-STI derived multidirectional LV S and SR correlate with AS severity in children using LV mass index (MI) as the principal outcome variable.
Methods
52 children (10.4 ± 7.3 years) with isolated congenital AS were included; 13 mild (2.5 m/s < V < 3.0 m/s), 25 moderate (3.0 m/s < V < 4.0 m/s), and 14 severe (V > 4.0 m/s). 2DE including Doppler and STI longitudinal strain (LS), strain rate (LSR), circumferential strain (CS), and strain rate (CSR) were measured. Univariate and multivariable linear regressions identified correlations between LVMI and strain indices.
Results
Three clinical and 2DE variables, and four strain indices were independently associated with LVMI. LVMI correlated positively with systolic blood pressure and aortic regurgitation, and negatively with LVEF. LVMI correlated positively with LSR (four-chamber) and CSR (basal), and negatively with segmental CS in the inferior (basal) and anteroseptal (distal) segments. LVMI showed significant inverse association with GLS (P = .05), GLSR (P < .001), CS (P < .005), CSR (P < .0001), RSR (P < .001), independent of AS severity.
Conclusions
Independent of clinical and 2DE findings including contemporaneous Doppler estimates of AS gradient, both longitudinal and circumferential strain indices correlate with LVMI as a measure of cumulative hemodynamic burden. This association implies subclinical LV dysfunction.

Copyright © 2020. Published by Elsevier B.V.

Int J Cardiol: 13 Jul 2020; epub ahead of print
Reddy SC, Zhang J, Jani V, Wolfe SB, ... Kutty S, Pignatelli RH
Int J Cardiol: 13 Jul 2020; epub ahead of print | PMID: 32679139
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Abstract

Inspiratory muscle dysfunction and restrictive lung function impairment in congenital heart disease: Association with immune inflammatory response and exercise intolerance.

Spiesshoefer J, Orwat S, Henke C, Kabitz HJ, ... Boentert M, Diller GP
Background
In adult patients with congenital heart disease (ACHD), both underlying disease and lung restriction contribute to exercise intolerance. In ACHD the yet incompletely understood mechanism underlying restricted ventilation may be inspiratory muscle weakness. Therefore, this study comprehensively evaluated inspiratory muscle function in ACHD and associations with systemic inflammation and the clinical severity of exercise intolerance.
Methods
30 ACHD patients (21 men, 35 ± 12 years) and 30 healthy controls matched for age, gender and body mass index underwent spirometry, measurement of mouth occlusion pressures, and diaphragm ultrasound. Six-minute walking distance (6MWD) and New York Heart Association functional class were used to quantify exercise intolerance. Interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-α) levels were measured using enzyme-linked immunosorbent assays.
Results
ACHD patients showed lower forced vital capacity (FVC), and maximum inspiratory (PImax) and expiratory (PEmax) pressures compared with controls (all p < 0.05). On ultrasound, ACHD patients showed a lower diaphragm thickening ratio (2.3 ± 0.5 vs. 2.8 ± 0.9, p < 0.01) and lower diaphragm excursion velocity during a voluntary sniff maneuver (5.7 ± 2.2 vs. 7.6 ± 2.0 cm/s, p < 0.01). Respiratory parameters, such as FVC (r = 0.53; p < 0.01) and PImax (r = 0.43; p = 0.02), correlated with 6MWD. Furthermore, amino terminal pro B-type natriuretic peptide levels were inversely correlated with FVC (r = -0.54; p < 0.01). Circulating pro-inflammatory cytokines were markedly increased, and IL-6 was correlated with 6MWD, dyspnea, and biomarkers of heart, lung and inspiratory muscle function (all p < 0.05).
Conclusions
Our findings show that diaphragm dysfunction is present in ACHD and relates to restrictive ventilation disorder and exercise intolerance, possibly mediated by increased IL-6 levels.

Copyright © 2020 Elsevier Ireland Ltd. All rights reserved.

Int J Cardiol: 03 Jul 2020; epub ahead of print
Spiesshoefer J, Orwat S, Henke C, Kabitz HJ, ... Boentert M, Diller GP
Int J Cardiol: 03 Jul 2020; epub ahead of print | PMID: 32634497
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Impact:
Abstract

4D flow cardiac magnetic resonance in children and adults with congenital heart disease: Clinical experience in a high volume center.

Isorni MA, Moisson L, Moussa NB, Monnot S, ... Kara M, Hascoet S
Background
Cardiac magnetic resonance (CMR) imaging with velocity encoding along all three directions of flow, known as 4DFlow CMR, provides both anatomical and functional information. Few data are available on the usefulness of 4DFlow CMR in everyday practice. Here, our objective was to investigate the usefulness of 4DFlow CMR for assessing congenital heart disease (CHD) in everyday practice.
Methods
From 2017 to 2019, consecutive patients who underwent 4DFlow CMR were included prospectively at a single high-volume centre. The parameters recommended by an expert\'s consensus statement for each diagnosis (congenital valvulopathy, septal defect, complex CHD, tetralogy of Fallot, aortic abnormalities) were assessed by two blinded experienced readers. 4DFlow CMRs that provided all recommended parameters were considered successful. Inter-observer and intra-observer agreement were investigated.
Results
We included 187 adults and 60 children covering broad ranges of weight (4.5-142 kg) and age (0.1-67 years). 4DFlow CMR was always the second-line imaging modality, after inconclusive echocardiography, and was successful in 231/247 (91%) patients, with no significant difference between children and adults (54/60, 90%; and 177/187, 95%; respectively; p = .13). Longer time using 4DFlow CMR at our centre was associated with success; in children, older age was also associated with exam success. There was an about 12-month learning curve in children. The success rate was lowest in neonates. Inter-observer and intra-observer agreement were substantial.
Conclusion
Our results suggest that 4DFlow CMR usually provides a comprehensive assessment of CHD in adults and children. A learning curve exists for children and the investigation remains challenging in neonates.

Copyright © 2020 Elsevier Ireland Ltd. All rights reserved.

Int J Cardiol: 22 Jul 2020; epub ahead of print
Isorni MA, Moisson L, Moussa NB, Monnot S, ... Kara M, Hascoet S
Int J Cardiol: 22 Jul 2020; epub ahead of print | PMID: 32712110
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Abstract

Extract-Stent-Replace for treatment of upper baffle stenosis with pacing leads after atrial switch procedures for transposition of the great arteries: An approach to avoid \"jailing\" the lead.

Merrill M, Krebsbach A, Przybylowicz R, Broberg CS, Burch G, Henrikson CA
Introduction
Venous stenosis is a late complication of the atrial switch (Mustard/Senning) procedure seen in patients with transposition of the great arteries (D-TGA). Many atrial switch patients require cardiac implantable electronic devices (CIEDs) which further increases the incidence of venous stenosis. Stenosis of the superior limb of the systemic venous pathway (SLSVP) in the presence of CIED leads presents a management challenge. We propose a method for navigating SLSVP stenosis in atrial switch patients with CIEDs.
Methods
The pulse generator and leads were removed using standard extraction techniques. Axillary access was retained via existing leads or new access was obtained. The interventional cardiology team, via groin access, performed stent-angioplasty of the stenotic SLSVP. After stent deployment, the axillary access wire was snared from below, guided through the stent, and pulled into a long groin sheath. A sheath was then advanced over the axillary wire and into the groin sheath creating a path for passage of leads through the stent. New leads were advanced through the axillary sheath into the heart. Leads were secured using standard techniques.
Results
All patients had a history of D-TGA and prior atrial switch procedures. In each case, there was stenosis of the SLSVP in the setting of a CIED lead. There were no immediate complications and there was no restenosis on follow-up.
Conclusion
Post-atrial switch patients with CIEDs can develop stenosis of the SLVSP. A collaboration between electrophysiology and interventional cardiology can allow for device extraction, stent-angioplasty and lead re-implantation to avoid \"jailing\" the leads. This article is protected by copyright. All rights reserved.

This article is protected by copyright. All rights reserved.

J Cardiovasc Electrophysiol: 08 Aug 2020; epub ahead of print
Merrill M, Krebsbach A, Przybylowicz R, Broberg CS, Burch G, Henrikson CA
J Cardiovasc Electrophysiol: 08 Aug 2020; epub ahead of print | PMID: 32776621
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Abstract

The complementary nature of multimodal imaging in the management of an anomalous aortic origin of the right coronary artery from the left coronary cusp.

Medepalli LC, Medepalli VM, Scully TA

Anomalous aortic origins of coronary arteries (AAOCA) are congenital abnormalities involving the origin and course of coronary arteries and present with diverse clinical manifestations in patients ranging from asymptomatic incidental findings to sudden cardiac death. The current case describes a patient with an anomalous right coronary artery with an anterior interarterial course originating from a separate ostium at the left coronary cusp. By utilizing complementary multimodality imaging techniques including fractional flow reserve (FFR), we obtained a comprehensive functional and anatomic assessment resulting in appropriate surgical therapy and a good clinical outcome.



J Nucl Cardiol: 11 Jun 2020; epub ahead of print
Medepalli LC, Medepalli VM, Scully TA
J Nucl Cardiol: 11 Jun 2020; epub ahead of print | PMID: 32533426
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Abstract

Clinical relevance of adding intravascular ultrasound to coronary angiography for the diagnosis of extrinsic left main coronary artery compression by a pulmonary artery aneurysm in pulmonary hypertension.

Velázquez Martín M, Montero Cabezas JM, Huertas S, Nuche J, ... Arribas F, Escribano Subias P
Objectives
We sought to assess the clinical value of adding intravascular ultrasound (IVUS) evaluation to coronary angiography (CA) to guide extrinsic left main coronary artery (LMCA) compression diagnosis and treatment in pulmonary hypertension (PH).
Background
LMCA compression due to a pulmonary artery aneurysm (PAA) is a severe complication of PH. Although guidelines encourage the use of IVUS for LMCA disease evaluation, it has hardly been used in this scenario.
Methods
We analyzed morbimortality of type 1 and 4 PH patients with clinically suspected LMCA compression by a PAA between 2010 and 2018 in a reference unit. LMCA compression was prospectively assessed with CA ± IVUS. Angiographic-LMCA compression was considered conclusive when LMCA stenosis>50% was present in four predetermined projections; inconclusive, when LMCA stenosis>50% was present in <4 projections and negative if no stenosis>50% was present. Patients with conclusive and inconclusive CA underwent IVUS. IVUS-LMCA compression was defined as systolic minimum lumen area < 6 mm .
Results
LMCA compression was suspected in 23/796 patients (3%). CA was conclusive for compression in 7(30.5%), inconclusive in 9(39%), and negative in 7(30.5%). IVUS confirmed LMCA compression in 6/7(86%) patients with conclusive CA and in 2/9(22%) with inconclusive CA. Patients fulfilling IVUS criteria for LMCA compression underwent stent implantation. At 20 months follow-up a composite end-point of death, stent restenosis/thrombosis, or lung transplant was reported in three patients (13%).
Conclusions
CA can misdiagnose LMCA extrinsic compression. IVUS discriminates better whether significant compression by a PAA exists or not, avoiding unnecessary LMCA stenting. Patients treated following this strategy show a low rate of major clinical events at 20 months follow-up.

© 2020 Wiley Periodicals LLC.

Catheter Cardiovasc Interv: 12 Aug 2020; epub ahead of print
Velázquez Martín M, Montero Cabezas JM, Huertas S, Nuche J, ... Arribas F, Escribano Subias P
Catheter Cardiovasc Interv: 12 Aug 2020; epub ahead of print | PMID: 32790221
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Impact:
Abstract

Prominent aortic radiotracer activity on equilibrium radionuclide ventriculography (ERNV) due to anterior transposition of aorta: A clue to diagnosing levo-transposition of great arteries (L-TGA) ?

Kavanal AJ, Singh H, Panda P, Vijay J, Parmar M, Mittal BR

Levo-transposition of great arteries (L-TGA) is a rare acyanotic congenital heart anomaly characterized by transposition of morphological left and right ventricles along with their corresponding atrio-ventricular valves in addition to transposition of primary arteries. Many cases of L-TGA are asymptomatic and are diagnosed accidently in adulthood during workup of other conditions. We hereby report a patient with incidentally diagnosed L-TGA who was subjected to Equilibrium Radionuclide Ventriculography (ERNV) for assessment of ventricular function. Planar ERNV images in best septal view showed prominent tracer activity in the anteriorly transposed aorta which can be a helpful clue to raise the suspicion of L-TGA in an asymptomatic adult undergoing ERNV.



J Nucl Cardiol: 16 Jun 2020; epub ahead of print
Kavanal AJ, Singh H, Panda P, Vijay J, Parmar M, Mittal BR
J Nucl Cardiol: 16 Jun 2020; epub ahead of print | PMID: 32557153
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Impact:
Abstract

In silico features of ADAMTS13 contributing to plasmatic ADAMTS13 levels in neonates with congenital heart disease.

Katneni UK, Holcomb DD, Hernandez NE, Hamasaki-Katagiri N, ... Ibla JC, Kimchi-Sarfaty C
Introduction
Risk factors contributing to heightened thrombosis in pediatric congenital heart disease (CHD) patients are not fully understood. Among the neonatal CHD population, those presenting with single ventricular physiology are at the highest risk for perioperative thrombosis. The von Willebrand factor and ADAMTS13 interactions have emerged as causative risk factors for pediatric stroke and could contribute to heightened thrombosis in CHD neonates.
Methods
This study investigates a cohort of children with single ventricle physiology and undergoing cardiac surgery, during which some patients developed thrombosis. In this cohort, we analyzed the relationship of several molecular features of ADAMTS13 with the plasma and activity levels in patients at risk of thrombosis. Additionally, in light of the natural antithrombotic activity of ADAMTS13, we have sequenced the ADAMTS13 gene for each patient and evaluated the role of genetic variants in determining the plasma ADAMTS13 levels using a series of in silico tools including Hidden Markov Models, EVmutation, and Rosetta.
Results
Lower ADAMTS13 levels were found in patients that developed thrombosis. A novel in silico analysis to assess haplotype effect of co-occurring variants identified alterations in relative surface area and solvation energy as important contributors. Our analysis suggested that beneficial or deleterious effect of a variant can be reasonably predicted by comprehensive analysis of in silico assessment and in vitro and/or in vivo data.
Conclusion
Findings from this study add to our understanding the role of genetic features of ADAMTS13 in patients at high risk of thrombosis related to an imbalanced relation between VWF and ADAMTS13.

Published by Elsevier Ltd.

Thromb Res: 31 May 2020; 193:66-76
Katneni UK, Holcomb DD, Hernandez NE, Hamasaki-Katagiri N, ... Ibla JC, Kimchi-Sarfaty C
Thromb Res: 31 May 2020; 193:66-76 | PMID: 32531546
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Impact:
Abstract

Increased levels of platelet-derived microparticles in pulmonary hypertension.

Ogawa A, Matsubara H
Introduction
Thrombosis and coagulation abnormalities are thought to be involved in disease progression of pulmonary hypertension. Platelet-derived microparticles (PDMP) are released from platelets following stimulation and have recently been demonstrated to play an important role in pathogenesis of various diseases. This study aimed to evaluate PDMP levels in patients with pulmonary hypertension.
Materials and methods
Our cross-sectional study enrolled a total of 113 participants including 73 patients with pulmonary hypertension and 40 participants to serve as a control group. PDMP levels were measured using a PDMP ELISA kit, which detects glycoproteins CD42a and CD42b. Clinical parameters, including exercise capacity and hemodynamic parameters, were collected, and the relationship to PDMP levels were evaluated.
Results
PDMP levels were significantly higher in patients than in participants in the control group (23.2 ± 39.4 U/mL and 7.8 ± 3.6 U/mL, respectively, P < 0.05). PDMP levels in patients with chronic thromboembolic pulmonary hypertension were correlated with right atrial pressure and cardiac index. PDMP levels were higher in male patients with idiopathic pulmonary arterial hypertension. Furthermore, patients administered a higher dose of epoprostenol had a tendency for lower PDMP levels.
Conclusions
The data suggest that PDMP levels are increased in patients with pulmonary hypertension. Further study is needed to understand the mechanism and impact of PDMP on disease progression.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Thromb Res: 11 Jul 2020; 195:120-124
Ogawa A, Matsubara H
Thromb Res: 11 Jul 2020; 195:120-124 | PMID: 32683150
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Impact:
Abstract

Prognostic Value of Cardiac Magnetic Resonance-Derived Right Ventricular Remodeling Parameters in Pulmonary Hypertension: A Systematic Review and Meta-Analysis.

Dong Y, Pan Z, Wang D, Lv J, ... Chen Md Y, Guo X

Background Cardiac right ventricular remodeling plays a substantial role in pathogenesis, progression, and prognosis of pulmonary hypertension. Cardiac magnetic resonance is considered an excellent tool for evaluation of right ventricle. However, value of right ventricular remodeling parameters derived from cardiac magnetic resonance in predicting adverse events is controversial. Methods The Pubmed (MEDLINE), Embase, Cochrane Library, Web of Science, China National Knowledge Infrastructure platform (CNKI), China Science and Technology Journal Database (VIP), and Wanfang databases were systematically searched until November 2019. Studies reporting hazard ratios (HRs) for all-cause death and composite end point of pulmonary hypertension were included. Univariate HRs were extracted from the included studies to calculate pooled HRs of each right ventricular remodeling parameter. Results Eight studies with 1120 patients examining all-cause death (female: 44%-92%, age: 40-67 years old, follow-up time: 27-48 months) and 10 studies with 604 patients examining composite end point (female: 60%-83%, age: 29-57 years old, follow-up time: 10-68 months) met the criteria. Right ventricular ejection fraction was the only parameter which could predict both all-cause death (pooled HR=0.95; =0.014) and composite end point (pooled HR=0.95; <0.001), although right ventricular end-diastolic volume index (pooled HR=1.01; <0.001), right ventricular end-systolic volume index (pooled HR=1.01, =0.045), and right ventricular mass index (pooled HR=1.03, =0.032) only predicted composite outcome. Similar results were observed when we conducted the meta-analysis among patients with World Health Organization type I of pulmonary hypertension. Conclusions Cardiac magnetic resonance-derived right ventricular remodeling parameters have independent prognostic value for all-cause death and composite end point of patients with pulmonary hypertension. Right ventricular ejection fraction was the strongest prognostic factor among all the right ventricular remodeling parameters. Right ventricular mass index, right ventricular end-diastolic volume index, and right ventricular end-systolic volume index also demonstrated prognostic value.



Circ Cardiovasc Imaging: 29 Jun 2020; 13:e010568
Dong Y, Pan Z, Wang D, Lv J, ... Chen Md Y, Guo X
Circ Cardiovasc Imaging: 29 Jun 2020; 13:e010568 | PMID: 32673506
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Impact:
Abstract

A perioperative bivalirudin anticoagulation protocol for neonates with congenital diaphragmatic hernia on extracorporeal membrane oxygenation.

Snyder CW, Goldenberg NA, Nguyen ATH, Smithers CJ, Kays DW
Introduction
There is little published data regarding bivalirudin anticoagulation for surgical neonates on extracorporeal membrane oxygenation (ECMO). This study described our perioperative anticoagulation protocol and evaluated the relationship of bivalirudin dose to activated partial thrombin time (aPTT) and thromboelastography reaction time (TEG-R) monitoring assays.
Materials and methods
Neonates with congenital diaphragmatic hernia (CDH) on ECMO and single-agent bivalirudin anticoagulation at our institution from 2016 to 2018 were included. Bivalirudin infusion rates, laboratory results, transfusions, and clinical events during the initial (cannulation to repair) and postoperative (up to 60 h post-repair) periods were recorded.
Results
Forty-two neonates met inclusion criteria. Bivalirudin was started at 0.16 mg/kg/h and titrated in 10-20% increments to target aPTT of 70-85 s and TEG-R of 9-12 min. All patients achieved target anticoagulation levels within the first 12 h on doses ranging from 0.12-0.36 mg/kg/h. Postoperatively, bivalirudin increased to median 0.16 (range 0.08-0.40), 0.22 (0.08-0.60), and 0.39 (0.08-0.80) mg/kg/h by 6, 24, and 60 h, respectively. On multivariable regression, no significant association of aPTT (p = 0.09) or TEG-R (p = 0.22) with bivalirudin dose was seen. Hemoglobin decrease ≥2 g/dL in 24 h occurred in 39%, but there were no reoperations, deaths, or circuit changes for thrombosis.
Conclusions
This standardized perioperative bivalirudin protocol achieved target anticoagulation level quickly. Postoperative bleeding was managed without significant morbidity. Consistent dose-response relationships between bivalirudin and aPTT or TEG-R were not seen, but gradually increasing doses were needed to maintain therapeutic anticoagulation.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Thromb Res: 24 Jul 2020; 193:198-203
Snyder CW, Goldenberg NA, Nguyen ATH, Smithers CJ, Kays DW
Thromb Res: 24 Jul 2020; 193:198-203 | PMID: 32763642
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Impact:
Abstract

Neuropsychological Status and Structural Brain Imaging in Adults With Simple Congenital Heart Defects Closed in Childhood.

Asschenfeldt B, Evald L, Heiberg J, Salvig C, ... Eskildsen SF, Hjortdal VE

Background Neurodevelopmental impairments are common in survivors of complex congenital heart defects (CHD). We report neuropsychological and brain imaging assessments in adults operated for isolated septal defects. Methods and Results Patients (mean age 25.6 yrs) who underwent childhood surgery for isolated atrial septal defect (n=34) or ventricular septal defect (n=32), and healthy matched peers (n=40), underwent a standard battery of neuropsychological tests and a 3.0T brain magnetic resonance imaging scan. Patient intelligence was affected with lower scores on Full-Scale intelligence quotient (<0.001), Verbal Comprehension (<0.001), Perceptual Reasoning (=0.007), and Working Memory (<0.001) compared with controls. Also, the CHD group had poorer visuospatial abilities (Immediate Recall, =0.033; Delayed Recall, =0.018), verbal memory (Trial 1, =0.015; Total Learning, <0.001; Delayed Recall, =0.007), executive function (Executive Composite Score, <0.001), and social recognition (Reading the Mind in the Eyes Test, =0.002) compared with controls. Self-reported levels of executive dysfunction, attention deficits and hyperactivity behavior, and social cognition dysfunction were higher in the CHD group compared with population means and controls. We found similar global and regional morphometric brain volumes and a similar frequency of brain magnetic resonance imaging abnormalities in the 2 groups. The CHD group had a high occurrence of psychiatric disease and a larger need for special teaching during school age. Conclusions Children operated for simple CHD demonstrate poorer neurodevelopmental outcomes in adulthood when compared with healthy controls and expected population means. REGISTRATION URL: https://www.clini​caltr​ials.gov. Unique identifier: NCT03871881.



J Am Heart Assoc: 18 May 2020:e015843; epub ahead of print
Asschenfeldt B, Evald L, Heiberg J, Salvig C, ... Eskildsen SF, Hjortdal VE
J Am Heart Assoc: 18 May 2020:e015843; epub ahead of print | PMID: 32427039
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Abstract

Pressure Overload Greatly Promotes Neonatal Right Ventricular Cardiomyocyte Proliferation: A New Model for the Study of Heart Regeneration.

Ye L, Wang S, Xiao Y, Jiang C, ... Xu Z, Hong H

Background Current mammalian models for heart regeneration research are limited to neonatal apex amputation and myocardial infarction, both of which are controversial. RNAseq has demonstrated a very limited set of differentially expressed genes between sham and operated hearts in myocardial infarction models. Here, we investigated in rats whether pressure overload in the right ventricle, a common phenomenon in children with congenital heart disease, could be used as a better animal model for heart regeneration studies when considering cardiomyocyte proliferation as the most important index. Methods and Results In the rat model, pressure overload was induced by pulmonary artery banding on postnatal day 1 and confirmed by echocardiography and hemodynamic measurements at postnatal day 7. RNA sequencing analyses of purified right ventricular cardiomyocytes at postnatal day 7 from pulmonary artery banding and sham-operated rats revealed that there were 5469 differentially expressed genes between these 2 groups. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analysis showed that these genes mainly mediated mitosis and cell division. Cell proliferation assays indicated a continuous overproliferation of cardiomyocytes in the right ventricle after pulmonary artery banding, in particular for the first 3 postnatal days. We also validated the model using samples from overloaded right ventricles of human patients. There was an approximately 2-fold increase of Ki67/pHH3/aurora B-positive cardiomyocytes in human-overloaded right ventricles compared with nonoverloaded right ventricles. Other features of this animal model included cardiomyocyte hypotrophy with no fibrosis. Conclusions Pressure overload profoundly promotes cardiomyocyte proliferation in the neonatal stage in both rats and human beings. This activates a regeneration-specific gene program and may offer an alternative animal model for heart regeneration research.



J Am Heart Assoc: 29 May 2020:e015574; epub ahead of print
Ye L, Wang S, Xiao Y, Jiang C, ... Xu Z, Hong H
J Am Heart Assoc: 29 May 2020:e015574; epub ahead of print | PMID: 32475201
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Abstract

Coronavirus Disease 2019 (COVID-19) Pandemic Implications in Pediatric and Adult Congenital Heart Disease.

Alsaied T, Aboulhosn JA, Cotts TB, Daniels CJ, ... Oster ME, Saidi A

The corona virus disease -2019 (COVID-19) is a recently described infectious disease caused by the severe acute respiratory syndrome corona virus 2 with significant cardiovascular implications. Given the increased risk for severe COVID-19 observed in adults with underlying cardiac involvement, there is concern that patients with pediatric and congenital heart disease (CHD) may likewise be at increased risk for severe infection. The cardiac manifestations of COVID-19 include myocarditis, arrhythmia and myocardial infarction. Importantly, the pandemic has stretched health care systems and many care team members are at risk for contracting and possibly transmitting the disease which may further impact the care of patients with cardiovascular disease. In this review, we describe the effects of COVID-19 in the pediatric and young adult population and review the cardiovascular involvement in COVID-19 focusing on implications for patients with congenital heart disease in particular.



J Am Heart Assoc: 21 May 2020:e017224; epub ahead of print
Alsaied T, Aboulhosn JA, Cotts TB, Daniels CJ, ... Oster ME, Saidi A
J Am Heart Assoc: 21 May 2020:e017224; epub ahead of print | PMID: 32441586
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Abstract

Clinical history and management of bicuspid aortic valve in children and adolescents.

Niaz T, Fernandes SM, Sanders SP, Michelena H, Hagler DJ

Bicuspid aortic valve (BAV) is one of the most common congenital heart defects in children, adolescents and adults. BAV can occur as an isolated lesion or in association with other congenital heart defects, such as coarctation of the aorta or genetic syndromes like Turner syndrome. Although the majority of long term complications associated with BAV manifest later in life, children and adolescents may present with early onset valvular dysfunction or dilation of the aorta. BAV is a heterogeneous disease with a wide array of presentations at various ages, depending on the degree of aortic valve dysfunction, aortic dilation and presence of associated lesions. Aortic valve stenosis and/or regurgitation are the primary indications for intervention in children and adolescents with BAV. Although a majority of young patients with BAV also have some aortic dilation, interventions on the aorta are very rare during this time frame. Children and adolescents with BAV benefit from comprehensive assessment of their risk profile to determine follow-up surveillance intervals, sports recommendations, and timing of surgical intervention. The morphologic phenotype of BAV is important to identify, as it may predict future complications and prognosis.

Copyright © 2020. Published by Elsevier Inc.

Prog Cardiovasc Dis: 31 May 2020; epub ahead of print
Niaz T, Fernandes SM, Sanders SP, Michelena H, Hagler DJ
Prog Cardiovasc Dis: 31 May 2020; epub ahead of print | PMID: 32497585
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Abstract

Clinical presentation and outcomes of adults with bicuspid aortic valves: 2020 update.

Yang LT, Tribouilloy C, Masri A, Bax JJ, ... Enriquez-Sarano M, Michelena HI

The congenital bicuspid aortic valve (BAV) is a heterogeneous condition that is better understood considering 3 types of valvulo-aortopathy presentations: A typical-presentation valvulo-aortopathy, a complex-presentation valvulo-aortopathy and an uncomplicated/undiagnosed-presentation. The burden of BAV-related complications has been elucidated in patients with the typical-presentation valvulo-aortopathy and is discussed in this review. These patients enjoy an overall normal expected long-term survival as long as complications are identified and treated in a timely manner. This notion and the fact that the most dreaded complications (infective endocarditis and aortic dissection) are infrequent, represent important reassuring points for the BAV patient. Common complications such as valve dysfunction and aorta dilatation must be the subject of focused research in prevention and treatment. Conversely, BAV patients with complex-presentation valvulo-artopathy, as well as typical valvulo-aortopathy BAV patients who are older, with advanced valvular dysfunction, and possible late-referral to specialized care, may incur a survival penalty as compared to the general population. An evidence-based discussion of these concepts is provided in this review.

Copyright © 2020. Published by Elsevier Inc.

Prog Cardiovasc Dis: 29 May 2020; epub ahead of print
Yang LT, Tribouilloy C, Masri A, Bax JJ, ... Enriquez-Sarano M, Michelena HI
Prog Cardiovasc Dis: 29 May 2020; epub ahead of print | PMID: 32485187
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Abstract

Adverse Pregnancy Conditions Among Privately Insured Women With and Without Congenital Heart Defects.

Downing KF, Tepper NK, Simeone RM, Ailes EC, ... Valente AM, Farr SL

Background In women with congenital heart defects (CHD), changes in blood volume, heart rate, respiration, and edema during pregnancy may lead to increased risk of adverse outcomes and conditions. The American Heart Association recommends providers of pregnant women with CHD assess cardiac health and discuss risks and benefits of cardiac-related medications. We described receipt of American Heart Association-recommended cardiac evaluations, filled potentially teratogenic or fetotoxic (Food and Drug Administration pregnancy category D/X) cardiac-related prescriptions, and adverse conditions among pregnant women with CHD compared with those without CHD. Methods and Results Using 2007 to 2014 US healthcare claims data, we ascertained a retrospective cohort of women with and without CHD aged 15 to 44 years with private insurance covering prescriptions during pregnancy. CHD was defined as ≥1 inpatient code or ≥2 outpatient CHD diagnosis codes >30 days apart documented outside of pregnancy and categorized as severe or nonsevere. Log-linear regression, accounting for multiple pregnancies per woman, generated adjusted prevalence ratios (aPRs) for associations between the presence/severity of CHD and stillbirth, preterm birth, and adverse conditions from the last menstrual period to 90 days postpartum. We identified 2056 women with CHD (2334 pregnancies) and 1 374 982 women without (1 524 077 pregnancies). During the last menstrual period to 90 days postpartum, 56% of women with CHD had comprehensive echocardiograms and, during pregnancy, 4% filled potentially teratogenic or fetotoxic cardiac-related prescriptions. Women with CHD, compared with those without, experienced more adverse conditions overall (aPR, 1.9 [95% CI, 1.7-2.1]) and, specifically, obstetric (aPR, 1.3 [95% CI, 1.2-1.4]) and cardiac conditions (aPR, 10.2 [95% CI, 9.1-11.4]), stillbirth (aPR, 1.6 [95% CI, 1.1-2.4]), and preterm delivery (aPR, 1.6 [95% CI, 1.4-1.8]). More women with severe CHD, compared with nonsevere, experienced adverse conditions overall (aPR, 1.5 [95% CI, 1.2-1.9]). Conclusions Women with CHD have elevated prevalence of adverse cardiac and obstetric conditions during pregnancy; 4 in 100 used potentially teratogenic or fetotoxic medications, and only half received an American Heart Association-recommended comprehensive echocardiogram.



Circ Cardiovasc Qual Outcomes: 07 Jun 2020:CIRCOUTCOMES119006311; epub ahead of print
Downing KF, Tepper NK, Simeone RM, Ailes EC, ... Valente AM, Farr SL
Circ Cardiovasc Qual Outcomes: 07 Jun 2020:CIRCOUTCOMES119006311; epub ahead of print | PMID: 32506927
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Abstract

Maternal Predictors of Disparate Outcomes in Children With Single Ventricle Congenital Heart Disease.

Asrani P, Pinto NM, Puchalski MD, Ou Z, ... Nance A, Miller TA

Background Significant variability in morbidity and mortality persists for children with functionally single ventricle congenital heart disease (SV-CHD) despite standardization in medical and surgical care. We hypothesized that maternal health factors may be associated with an increased risk of poor outcomes in children with SV-CHD. Methods and Results This retrospective, observational, cohort study included term maternal-infant pairs with a diagnosis of SV-CHD who underwent surgical palliation from 2006 to 2015 at Primary Children\'s Hospital. Pairs lacking maternal variables of interest or infant follow-up data were excluded. The association of maternal risk factors of abnormal pre-pregnancy body mass index, abnormal gestational weight gain (<7 or >20 kg), hypertensive disorders, and gestational diabetes mellitus with death/transplant and hemodynamics were analyzed using regression models. Of 190 infants, 135 (71%) maternal-infant dyads had complete data for inclusion. Death or transplant occurred in 48 infants (36%) during an average follow-up of 2.2 years (0.1-11.7 years). Abnormal gestational weight gain was associated with an increased risk of death and/or transplant in logistic regression (odds ratio, 3.22; 95% CI, 1.32-7.86; =0.01), but not Cox regression (hazard ratio, 1.9; 95% CI, 1.0-3.7; =0.055). Mean pulmonary artery pressures were higher in the setting of abnormal gestational weight gain (16.5±2.9 versus 14.7±3.0 mm Hg; <0.001), and abnormal pre-pregnancy body mass index (15.7±3.5 versus 14.2±2.1 mm Hg; <0.001) in the systemic right ventricle group. Conclusions Abnormal gestational weight gain (excessive or inadequate) is a novel risk factor for worse outcomes in SV-CHD. The fetoplacental environment may alter the trajectory of vascular development to impact outcomes in infants with SV-CHD.



J Am Heart Assoc: 08 Jun 2020:e014363; epub ahead of print
Asrani P, Pinto NM, Puchalski MD, Ou Z, ... Nance A, Miller TA
J Am Heart Assoc: 08 Jun 2020:e014363; epub ahead of print | PMID: 32515252
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Abstract

Embryonic development of bicuspid aortic valves.

Soto-Navarrete MT, López-Unzu MÁ, Durán AC, Fernández B

Bicuspid aortic valve (BAV) is the most common congenital cardiac malformation, frequently associated with aortopathies and valvulopathies. The congenital origin of BAV is suspected to impact the development of the disease in the adult life. During the last decade, a number of studies dealing with the embryonic development of congenital heart disease have significantly improved our knowledge on BAV etiology. They describe the developmental defects, at the molecular, cellular and morphological levels, leading to congenital cardiac malformations, including BAV, in animal models. These models consist of a spontaneous hamster and several mouse models with different genetic manipulations in genes belonging to a variety of pathways. In this review paper, we aim to gather information on the developmental defects leading to BAV formation in these animal models, in order to tentatively explain the morphogenetic origin of the spectrum of valve morphologies that characterizes human BAV. BAV may be the only defect resulting from gene manipulation in mice, but usually it appears as the less severe defect of a spectrum of malformations, most frequently affecting the cardiac outflow tract. The genes whose alterations cause BAV belong to different genetic pathways, but many of them are direct or indirectly associated with the NOTCH pathway. These molecular alterations affect three basic cellular mechanisms during heart development, i.e., endocardial-to-mesenchymal transformation, cardiac neural crest (CNC) cell behavior and valve cushion mesenchymal cell differentiation. The defective cellular functions affect three possible morphogenetic mechanisms, i.e., outflow tract endocardial cushion formation, outflow tract septation and valve cushion excavation. While endocardial cushion abnormalities usually lead to latero-lateral BAVs and septation defects to antero-posterior BAVs, alterations in cushion excavation may give rise to both BAV types. The severity of the original defect most probably determines the specific aortic valve phenotype, which includes commissural fusions and raphes. Based on current knowledge on the developmental mechanisms of the cardiac outflow tract, we propose a unified hypothesis of BAV formation, based on the inductive role of CNC cells in the three mechanisms of BAV development. Alterations of CNC cell behavior in three possible alternative key valvulogenic processes may lead to the whole spectrum of BAV.

Copyright © 2020. Published by Elsevier Inc.

Prog Cardiovasc Dis: 23 Jun 2020; epub ahead of print
Soto-Navarrete MT, López-Unzu MÁ, Durán AC, Fernández B
Prog Cardiovasc Dis: 23 Jun 2020; epub ahead of print | PMID: 32592706
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Abstract

Sex differences in bicuspid aortic valve disease.

Kong WKF, Bax JJ, Michelena HI, Delgado V

Bicuspid aortic valve (BAV), the most frequent congenital heart disease, is characterized by an uneven distribution between sexes. BAV is three to four times more frequent in men than in women which could be associated with a reduced dosage of X chromosome genes. In addition, BAV has a multifactorial inheritance, low penetrance and variable phenotypes that may lead to different form of valve degeneration and dysfunction over time as well as different incidence of aortic valve and vascular complications between men and women. Definition of the phenotype is the first step in the evaluation of patients with BAV. Among the various phenotypes, BAV with a fusion raphe between the left and the right coronary cusp is the most frequent phenotype observed in men and women. It has been hypothesized that the valve and vascular related complications vary according to the BAV phenotype and this could explain differences in the clinical outcomes of men versus women. However, the evidence on the distribution of the various BAV phenotypes between sexes in not consistent and while some series have described differences between male and female, others have not confirmed those findings. In terms of valvular complications, women present more frequently with aortic stenosis while aortic regurgitation is more frequently diagnosed in men. Furthermore, endocarditis is more frequently reported in men as compared to women. In terms of vascular complications, men show larger diameters of the various parts of the aortic root and ascending aorta and more frequently present complications in terms of aortic aneurysm and dissection as compared to women. Although there are no survival differences between men and women with BAV, compared to the general population some large series have shown that women have worse prognosis. The present review article summarizes the differences between men and women in terms of BAV phenotype, type and incidence of aortic valve and vascular complications that will determine the differences in clinical outcomes.

Copyright © 2020. Published by Elsevier Inc.

Prog Cardiovasc Dis: 25 Jun 2020; epub ahead of print
Kong WKF, Bax JJ, Michelena HI, Delgado V
Prog Cardiovasc Dis: 25 Jun 2020; epub ahead of print | PMID: 32599025
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Abstract

5-Year prognostic value of the right ventricular strain-area loop in patients with pulmonary hypertension.

Hulshof HG, van Dijk AP, Hopman MTE, Heesakkers H, ... Oxborough DL, Thijssen DHJ
Aims
Patients with pre-capillary pulmonary hypertension (PH) show poor survival, often related to right ventricular (RV) dysfunction. In this study, we assessed the 5-year prognostic value of a novel echocardiographic measure that examines RV function through the temporal relation between RV strain (ϵ) and area (i.e. RV ϵ-area loop) for all-cause mortality in PH patients.
Methods and results
Echocardiographic assessments were performed in 143 PH patients (confirmed by right heart catheterization). Transthoracic echocardiography was utilized to assess RV ϵ-area loop. Using receiver operating characteristic curve-derived cut-off values, we stratified patients in low- vs. high-risk groups for all-cause mortality. Kaplan-Meier survival curves and uni-/multivariable cox-regression models were used to assess RV ϵ-area loop\'s prognostic value (independent of established predictors: age, sex, N-terminal pro B-type natriuretic peptide, 6-min walking distance). During follow-up 45 (31%) patients died, who demonstrated lower systolic slope, peak ϵ, and late diastolic slope (all P < 0.05) at baseline. Univariate cox-regression analyses identified early systolic slope, systolic slope, peak ϵ, early diastolic uncoupling, and early/late diastolic slope to predict all-cause mortality (all P < 0.05), whilst peak ϵ possessed independent prognostic value (P < 0.05). High RV loop-score (i.e. based on number of abnormal characteristics) showed poorer survival compared to low RV loop-score (Kaplan-Meier: P < 0.01). RV loop-score improved risk stratification in high-risk patients when added to established predictors.
Conclusion
Our data demonstrate the potential for RV ϵ-area loops to independently predict all-cause mortality in patients with pre-capillary PH. The non-invasive nature and simplicity of measuring the RV ϵ-area loop, support the potential clinical relevance of (repeated) echocardiography assessment of PH patients.

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

Eur Heart J Cardiovasc Imaging: 05 Jul 2020; epub ahead of print
Hulshof HG, van Dijk AP, Hopman MTE, Heesakkers H, ... Oxborough DL, Thijssen DHJ
Eur Heart J Cardiovasc Imaging: 05 Jul 2020; epub ahead of print | PMID: 32632438
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