Publications by authors named "Sushma Reddy"

66 Publications

Transcriptomic and Functional Analyses of Mitochondrial Dysfunction in Pressure Overload-Induced Right Ventricular Failure.

J Am Heart Assoc 2021 Feb 30;10(4):e017835. Epub 2021 Jan 30.

Department of Pediatrics (Cardiology) Stanford University Palo Alto CA.

Background In complex congenital heart disease patients such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload, leading to RV hypertrophy and eventually RV failure. The mechanisms that promote the transition from stable RV hypertrophy to RV failure are unknown. We evaluated the role of mitochondrial bioenergetics in the development of RV failure. Methods and Results We created a murine model of RV pressure overload by pulmonary artery banding and compared with sham-operated controls. Gene expression by RNA-sequencing, oxidative stress, mitochondrial respiration, dynamics, and structure were assessed in pressure overload-induced RV failure. RV failure was characterized by decreased expression of electron transport chain genes and mitochondrial antioxidant genes (aldehyde dehydrogenase 2 and superoxide dismutase 2) and increased expression of oxidant stress markers (heme oxygenase, 4-hydroxynonenal). The activities of all electron transport chain complexes decreased with RV hypertrophy and further with RV failure (oxidative phosphorylation: sham 552.3±43.07 versus RV hypertrophy 334.3±30.65 versus RV failure 165.4±36.72 pmol/(s×mL), <0.0001). Mitochondrial fission protein DRP1 (dynamin 1-like) trended toward an increase, while MFF (mitochondrial fission factor) decreased and fusion protein OPA1 (mitochondrial dynamin like GTPase) decreased. In contrast, transcription of electron transport chain genes increased in the left ventricle of RV failure. Conclusions Pressure overload-induced RV failure is characterized by decreased transcription and activity of electron transport chain complexes and increased oxidative stress which are associated with decreased energy generation. An improved understanding of the complex processes of energy generation could aid in developing novel therapies to mitigate mitochondrial dysfunction and delay the onset of RV failure.
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http://dx.doi.org/10.1161/JAHA.120.017835DOI Listing
February 2021

Morphometric and genetic evidence for four species of gentoo penguin.

Ecol Evol 2020 Dec 5;10(24):13836-13846. Epub 2020 Nov 5.

Department of Biology & Biochemistry Milner Centre for Evolution University of Bath Bath UK.

Gentoo penguins () are found across the Southern Ocean with a circumpolar distribution and notable genetic and morphological variation across their geographic range. Whether this geographic variation represents species-level diversity has yet to be investigated in an integrative taxonomic framework. Here, we show that four distinct populations of gentoo penguins (Iles Kerguelen, Falkland Islands, South Georgia, and South Shetlands/Western Antarctic Peninsula) are genetically and morphologically distinct from one another. We present here a revised taxonomic treatment including formal nomenclatural changes. We suggest the designation of four species of gentoo penguin: in the Falkland Islands, in the South Shetland Islands/Western Antarctic Peninsula, in Iles Kerguelen, and a new gentoo species described herein, in South Georgia. These findings of cryptic diversity add to many other such findings across the avian tree of life in recent years. Our results further highlight the importance of reassessing species boundaries as methodological advances are made, particularly for taxa of conservation concern. We recommend reassessment by the IUCN of each species, particularly and , which both show evidence of decline.
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http://dx.doi.org/10.1002/ece3.6973DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7771148PMC
December 2020

Diagnosis and treatment of right ventricular dysfunction in congenital heart disease.

Cardiovasc Diagn Ther 2020 Oct;10(5):1625-1645

Congenital and Structural Cardiology, University Hospitals Leuven, Leuven, Belgium.

Right ventricular (RV) function is important for clinical status and outcomes in children and adults with congenital heart disease (CHD). In the normal RV, longitudinal systolic function is the major contributor to global RV systolic function. A variety of factors contribute to RV failure including increased pressure- or volume-loading, electromechanical dyssynchrony, increased myocardial fibrosis, abnormal coronary perfusion, restricted filling capacity and adverse interactions between left ventricle (LV) and RV. We discuss the different imaging techniques both at rest and during exercise to define and detect RV failure. We identify the most important biomarkers for risk stratification in RV dysfunction, including abnormal NYHA class, decreased exercise capacity, low blood pressure, and increased levels of NTproBNP, troponin T, galectin-3 and growth differentiation factor 15. In adults with CHD (ACHD), fragmented QRS is independently associated with heart failure (HF) symptoms and impaired ventricular function. Furthermore, we discuss the different HF therapies in CHD but given the broad clinical spectrum of CHD, it is important to treat RV failure in a disease-specific manner and based on the specific alterations in hemodynamics. Here, we discuss how to detect and treat RV dysfunction in CHD in order to prevent or postpone RV failure.
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http://dx.doi.org/10.21037/cdt-20-370DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7666946PMC
October 2020

Circulating whole genome miRNA expression corresponds to progressive right ventricle enlargement and systolic dysfunction in adults with tetralogy of Fallot.

PLoS One 2020 11;15(11):e0241476. Epub 2020 Nov 11.

Division of Cardiology, Department of Pediatrics, Stanford University, Stanford, California, United States of America.

Introduction: The adult congenital heart disease population with repaired tetralogy of Fallot (TOF) is subject to chronic volume and pressure loading leading to a 40% probability of right ventricular (RV) failure by the 3rd decade of life. We sought to identify a non-invasive signature of adverse RV remodeling using peripheral blood microRNA (miRNA) profiling to better understand the mechanisms of RV failure.

Methods: Demographic, clinical data, and blood samples were collected from adults with repaired TOF (N = 20). RNA was isolated from the buffy coat of peripheral blood and whole genome miRNA expression was profiled using Agilent's global miRNA microarray platform. Fold change, pathway analysis, and unbiased hierarchical clustering of miRNA expression was performed and correlated to RV size and function assessed by echocardiography performed at or near the time of blood collection.

Results: MiRNA expression was profiled in the following groups: 1. normal RV size (N = 4), 2. mild/moderate RV enlargement (N = 11) and 3. severe RV enlargement (N = 5). 267 miRNAs were downregulated, and 66 were upregulated across the three groups (fold change >2.0, FDR corrected p<0.05) as RV enlargement increased and systolic function decreased. qPCR validation of a subset of these miRNAs identified increasing expression of miRNA 28-3p, 433-3p, and 371b-3p to be associated with increasing RV size and decreasing RV systolic function. Unbiased hierarchical clustering of all patients based on miRNA expression demonstrates three distinct patient clusters that largely coincide with progressive RV enlargement. Pathway analysis of dysregulated miRNAs demonstrates up and downregulation of cell cycle pathways, extracellular matrix proteins and fatty acid synthesis. HIF 1α signaling was downregulated while p53 signaling was predicted to be upregulated.

Conclusion: Adults with TOF have a distinct miRNA profile with progressive RV enlargement and dysfunction implicating cell cycle dysregulation and upregulation in extracellular matrix and fatty acid metabolism. These data suggest peripheral blood miRNA can provide insight into the mechanisms of RV failure and can potentially be used for monitoring disease progression and to develop RV specific therapeutics to prevent RV failure in TOF.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241476PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7657553PMC
December 2020

Noncanonical WNT Activation in Human Right Ventricular Heart Failure.

Front Cardiovasc Med 2020 7;7:582407. Epub 2020 Oct 7.

Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.

No medical therapies exist to treat right ventricular (RV) remodeling and RV failure (RVF), in large part because molecular pathways that are specifically activated in pathologic human RV remodeling remain poorly defined. Murine models have suggested involvement of Wnt signaling, but this has not been well-defined in human RVF. Using a candidate gene approach, we sought to identify genes specifically expressed in human pathologic RV remodeling by assessing the expression of 28 WNT-related genes in the RVs of three groups: explanted nonfailing donors (NF, = 29), explanted dilated and ischemic cardiomyopathy, obtained at the time of cardiac transplantation, either with preserved RV function (pRV, = 78) or with RVF ( = 35). We identified the noncanonical WNT receptor ROR2 as transcriptionally strongly upregulated in RVF compared to pRV and NF (Benjamini-Hochberg adjusted < 0.05). ROR2 protein expression correlated linearly to mRNA expression ( = 0.41, = 8.1 × 10) among all RVs, and to higher right atrial to pulmonary capillary wedge ratio in RVF ( = 0.40 = 3.0 × 10). Utilizing Masson's trichrome and ROR2 immunohistochemistry, we identified preferential ROR2 protein expression in fibrotic regions by both cardiomyocytes and noncardiomyocytes. We compared RVF with high and low ROR2 expression, and found that high ROR2 expression was associated with increased expression of the WNT5A/ROR2/Ca responsive protease calpain-μ, cleavage of its target FLNA, and FLNA phosphorylation, another marker of activation downstream of ROR2. ROR2 protein expression as a continuous variable, correlated strongly to expression of calpain-μ ( = 0.25), total FLNA ( = 0.67), calpain cleaved FLNA ( = 0.32) and FLNA phosphorylation ( = 0.62, < 0.05 for all). We demonstrate robust reactivation of a fetal WNT gene program, specifically its noncanonical arm, in human RVF characterized by activation of ROR2/calpain mediated cytoskeleton protein cleavage.
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http://dx.doi.org/10.3389/fcvm.2020.582407DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7575695PMC
October 2020

4HNE Impairs Myocardial Bioenergetics in Congenital Heart Disease-Induced Right Ventricular Failure.

Circulation 2020 Oct 18;142(17):1667-1683. Epub 2020 Aug 18.

Department of Pediatrics (Cardiology) (HT.V.H., N.S., S.L.P., S. Ranjbarvairi, D-Q.H., M.Z., G.F., D.B., S. Reddy), Stanford University, Palo Alto, CA.

Background: In patients with complex congenital heart disease, such as those with tetralogy of Fallot, the right ventricle (RV) is subject to pressure overload stress, leading to RV hypertrophy and eventually RV failure. The role of lipid peroxidation, a potent form of oxidative stress, in mediating RV hypertrophy and failure in congenital heart disease is unknown.

Methods: Lipid peroxidation and mitochondrial function and structure were assessed in right ventricle (RV) myocardium collected from patients with RV hypertrophy with normal RV systolic function (RV fractional area change, 47.3±3.8%) and in patients with RV failure showing decreased RV systolic function (RV fractional area change, 26.6±3.1%). The mechanism of the effect of lipid peroxidation, mediated by 4-hydroxynonenal ([4HNE] a byproduct of lipid peroxidation) on mitochondrial function and structure was assessed in HL1 murine cardiomyocytes and human induced pluripotent stem cell-derived cardiomyocytes.

Results: RV failure was characterized by an increase in 4HNE adduction of metabolic and mitochondrial proteins (16 of 27 identified proteins), in particular electron transport chain proteins. Sarcomeric (myosin) and cytoskeletal proteins (desmin, tubulin) also underwent 4HNE adduction. RV failure showed lower oxidative phosphorylation (moderate RV hypertrophy, 287.6±19.75 versus RV failure, 137.8±11.57 pmol/[sec×mL]; =0.0004), and mitochondrial structural damage. Using a cell model, we show that 4HNE decreases cell number and oxidative phosphorylation (control, 388.1±23.54 versus 4HNE, 143.7±11.64 pmol/[sec×mL]; <0.0001). Carvedilol, a known antioxidant did not decrease 4HNE adduction of metabolic and mitochondrial proteins and did not improve oxidative phosphorylation.

Conclusions: Metabolic, mitochondrial, sarcomeric, and cytoskeletal proteins are susceptible to 4HNE-adduction in patients with RV failure. 4HNE decreases mitochondrial oxygen consumption by inhibiting electron transport chain complexes. Carvedilol did not improve the 4HNE-mediated decrease in oxygen consumption. Strategies to decrease lipid peroxidation could improve mitochondrial energy generation and cardiomyocyte survival and improve RV failure in patients with congenital heart disease.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.120.045470DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7606813PMC
October 2020

Evolution: Brainier Birds.

Curr Biol 2020 Jul;30(13):R778-R780

Bell Museum of Natural History and Department of Fisheries, Wildlife, Conservation Biology, University of Minnesota, Twin Cities, 35A Skok Hall, 2003 Upper Buford Circle, Saint Paul, MN 55108, USA. Electronic address:

A groundbreaking study of brain evolution across birds and dinosaurs reveals potential drivers of increased brain size including biogeography and ecology. The most dramatic change occurred in the Neoaves after the Cretaceous-Paleogene extinction rather than earlier in bird evolution.
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http://dx.doi.org/10.1016/j.cub.2020.05.025DOI Listing
July 2020

Proceedings From the 2019 Stanford Single Ventricle Scientific Summit: Advancing Science for Single Ventricle Patients: From Discovery to Clinical Applications.

J Am Heart Assoc 2020 04 19;9(7):e015871. Epub 2020 Mar 19.

Department of Pediatrics (Cardiology) Stanford University Palo Alto CA.

Abstracts Because of remarkable advances in survival over the past 40 years, the worldwide population of individuals with single ventricle heart disease living with Fontan circulation has grown to ≈70 000, with nearly half aged >18 years. Survival to at least 30 years of age is now achievable for 75% of Fontan patients. On the other hand, single ventricle patients account for the largest group of the 6000 to 8000 children hospitalized with circulation failure, with or without heart failure annually in the United States, with the highest in-hospital mortality. Because there is little understanding of the underlying mechanisms of heart failure, arrhythmias, pulmonary and lymphatic vascular abnormalities, and other morbidities, there are no specific treatments to maintain long-term myocardial performance or to optimize overall patient outcomes.
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http://dx.doi.org/10.1161/JAHA.119.015871DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428620PMC
April 2020

Delineating the molecular and histological events that govern right ventricular recovery using a novel mouse model of pulmonary artery de-banding.

Cardiovasc Res 2020 Aug;116(10):1700-1709

Division of Pulmonary and Critical Care Medicine, Department of Medicine, Stanford University, 300 Pasteur Drive, Grand Bld Rm S126B, Stanford, CA 94305, USA.

Aims: The temporal sequence of events underlying functional right ventricular (RV) recovery after improvement of pulmonary hypertension-associated pressure overload is unknown. We sought to establish a novel mouse model of gradual RV recovery from pressure overload and use it to delineate RV reverse-remodelling events.

Methods And Results: Surgical pulmonary artery banding (PAB) around a 26-G needle induced RV dysfunction with increased RV pressures, reduced exercise capacity and caused liver congestion, hypertrophic, fibrotic, and vascular myocardial remodelling within 5 weeks of chronic RV pressure overload in mice. Gradual reduction of the afterload burden through PA band absorption (de-PAB)-after RV dysfunction and structural remodelling were established-initiated recovery of RV function (cardiac output and exercise capacity) along with rapid normalization in RV hypertrophy (RV/left ventricular + S and cardiomyocyte area) and RV pressures (right ventricular systolic pressure). RV fibrotic (collagen, elastic fibres, and vimentin+ fibroblasts) and vascular (capillary density) remodelling were equally reversible; however, reversal occurred at a later timepoint after de-PAB, when RV function was already completely restored. Microarray gene expression (ClariomS, Thermo Fisher Scientific, Waltham, MA, USA) along with gene ontology analyses in RV tissues revealed growth factors, immune modulators, and apoptosis mediators as major cellular components underlying functional RV recovery.

Conclusion: We established a novel gradual de-PAB mouse model and used it to demonstrate that established pulmonary hypertension-associated RV dysfunction is fully reversible. Mechanistically, we link functional RV improvement to hypertrophic normalization that precedes fibrotic and vascular reverse-remodelling events.
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http://dx.doi.org/10.1093/cvr/cvz310DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7643543PMC
August 2020

Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society: Part 2.

Pediatr Crit Care Med 2019 11;20(11):1034-1039

Department of Pediatrics, INOVA Fairfax Hospital, Falls Church, VA.

Objectives: To make recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support including future research directions.

Data Sources: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts.

Study Selection: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support.

Data Extraction/data Synthesis: This white paper focuses on clinical understanding and limitations of current strategies to monitor anticoagulation. For each test of anticoagulation, limitations of current knowledge are addressed and future research directions suggested.

Conclusions: No consensus on best practice for anticoagulation monitoring exists. Structured scientific evaluation to answer questions regarding anticoagulation monitoring and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patient receiving extracorporeal life support to a registry.
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http://dx.doi.org/10.1097/PCC.0000000000002104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433702PMC
November 2019

Right ventricular failure in congenital heart disease.

Curr Opin Pediatr 2019 10;31(5):604-610

Department of Pediatrics (Cardiology), Stanford University, Stanford, California, USA.

Purpose Of Review: We aim to review select literature pertaining to congenital heart disease (CHD)-induced right ventricular (RV) function and failure.

Recent Findings: We review recent findings pertaining to children and adults with repaired tetralogy of Fallot (rTOF), systemic RV and hypoplastic left heart syndrome (HLHS). We emphasize pathophysiological mechanisms contributing to RV dysfunction in these conditions, the risk factors for adverse outcomes and the continuing challenges in treating these patients. We discuss how recent pathology findings, as well as developments in imaging and computer modeling have broadened our understanding of the pathophysiology of these conditions. We further review developments in the molecular and cellular basis of RV failure; and in particular, the RV molecular response to stress in repaired tetralogy of Fallot (rTOF). We highlight some of the genetic complexities in HLHS and how these may influence the long-term outcomes in these patients.

Summary: Recent literature has led to new understandings in the pathology, pathophysiology, risk factors for adverse outcomes, molecular and genetic basis for RV dysfunction and failure in CHD. Although these findings provide new therapeutic targets, the treatment of RV failure at this time remains limited.
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http://dx.doi.org/10.1097/MOP.0000000000000804DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433701PMC
October 2019

Bleeding and Thrombosis With Pediatric Extracorporeal Life Support: A Roadmap for Management, Research, and the Future From the Pediatric Cardiac Intensive Care Society: Part 1.

Pediatr Crit Care Med 2019 11;20(11):1027-1033

Department of Pediatrics, INOVA Fairfax Hospital, Falls Church, VA.

Objectives: To make practical and evidence-based recommendations on improving understanding of bleeding and thrombosis with pediatric extracorporeal life support and to make recommendations for research directions.

Data Sources: Evaluation of literature and consensus conferences of pediatric critical care and extracorporeal life support experts.

Study Selection: A team of 10 experts with pediatric cardiac and extracorporeal membrane oxygenation experience and expertise met through the Pediatric Cardiac Intensive Care Society to review current knowledge and make recommendations for future research to establish "best practice" for anticoagulation management related to extracorporeal life support.

Data Extraction/synthesis: The first of a two-part white article focuses on clinical understanding and limitations of medications in use for anticoagulation, including novel medications. For each medication, limitations of current knowledge are addressed and research recommendations are suggested to allow for more definitive clinical guidelines in the future.

Conclusions: No consensus on best practice for anticoagulation exists. Structured scientific evaluation to answer questions regarding anticoagulant medication and bleeding and thrombotic events should occur in multicenter studies using standardized approaches and well-defined endpoints. Outcomes related to need for component change, blood product administration, healthcare outcome, and economic assessment should be incorporated into studies. All centers should report data on patients receiving extracorporeal life support to a registry. The Extracorporeal Life Support Organization registry, designed primarily for quality improvement purposes, remains the primary and most successful data repository to date.
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http://dx.doi.org/10.1097/PCC.0000000000002054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7552911PMC
November 2019

Phylogeography of the Rufous Vanga and the role of bioclimatic transition zones in promoting speciation within Madagascar.

Mol Phylogenet Evol 2019 10 14;139:106535. Epub 2019 Jun 14.

Department of Biology, Loyola University Chicago, 1032 W. Sheridan Road, Chicago, IL 60660, USA; Bell Museum of Natural History and Department of Fisheries, Wildlife, and Conservation Biology, University of Minnesota, St. Paul, MN 55108, USA.

Madagascar is known as a biodiversity hotspot, providing an ideal natural laboratory for investigating the processes of avian diversification. Yet, the phylogeography of Madagascar's avifauna is still largely unexamined. In this study, we evaluated phylogeographic patterns and species limits within the Rufous Vanga, Schetba rufa, a monotypic genus of forest-dwelling birds endemic to the island. Using an integrative taxonomic approach, we synthesized data from over 4000 ultra-conserved element (UCE) loci, mitochondrial DNA, multivariate morphometrics, and ecological niche modeling to uncover two reciprocally monophyletic, geographically circumscribed, and morphologically distinct clades of Schetba. The two lineages are restricted to eastern and western Madagascar, respectively, with distributions broadly consistent with previously described subspecies. Based on their genetic and morphological distinctiveness, the two subspecies merit recognition as separate species. The bioclimatic transition between the humid east and dry west of Madagascar likely promoted population subdivision and drove speciation in Schetba during the Pleistocene. Our study is the first evidence that an East-West bioclimatic transition zone played a role in the speciation of birds within Madagascar.
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http://dx.doi.org/10.1016/j.ympev.2019.106535DOI Listing
October 2019

Loss of Endothelium-Derived Wnt5a Is Associated With Reduced Pericyte Recruitment and Small Vessel Loss in Pulmonary Arterial Hypertension.

Circulation 2019 04;139(14):1710-1724

Division of Pulmonary and Critical Care Medicine (K.Y., E.A.S., M.E.O., A.N., V.A.d.J.P.), Stanford University, Palo Alto, CA.

Background: Pulmonary arterial hypertension (PAH) is a life-threatening disorder of the pulmonary circulation associated with loss and impaired regeneration of microvessels. Reduced pericyte coverage of pulmonary microvessels is a pathological feature of PAH and is caused partly by the inability of pericytes to respond to signaling cues from neighboring pulmonary microvascular endothelial cells (PMVECs). We have shown that activation of the Wnt/planar cell polarity pathway is required for pericyte recruitment, but whether production and release of specific Wnt ligands by PMVECs are responsible for Wnt/planar cell polarity activation in pericytes is unknown.

Methods: Isolation of pericytes and PMVECs from healthy donor and PAH lungs was carried out with 3G5 or CD31 antibody-conjugated magnetic beads. Wnt expression profile of PMVECs was documented via quantitative polymerase chain reaction with a Wnt primer library. Exosome purification from PMVEC media was carried out with the ExoTIC device. Hemodynamic profile, right ventricular function, and pulmonary vascular morphometry were obtained in a conditional endothelium-specific Wnt5a knockout ( Wnt5a) mouse model under normoxia, chronic hypoxia, and hypoxia recovery.

Results: Quantification of Wnt ligand expression in healthy PMVECs cocultured with pericytes demonstrated a 35-fold increase in Wnt5a, a known Wnt/planar cell polarity ligand. This Wnt5a spike was not seen in PAH PMVECs, which correlated with an inability to recruit pericytes in Matrigel coculture assays. Exosomes purified from media demonstrated an increase in Wnt5a content when healthy PMVECs were cocultured with pericytes, a finding that was not observed in exosomes of PAH PMVECs. Furthermore, the addition of either recombinant Wnt5a or purified healthy PMVEC exosomes increased pericyte recruitment to PAH PMVECs in coculture studies. Although no differences were noted in normoxia and chronic hypoxia, Wnt5a mice demonstrated persistent pulmonary hypertension and right ventricular failure 4 weeks after recovery from chronic hypoxia, which correlated with significant reduction, muscularization, and decreased pericyte coverage of microvessels.

Conclusions: We identify Wnt5a as a key mediator for the establishment of pulmonary endothelium-pericyte interactions, and its loss could contribute to PAH by reducing the viability of newly formed vessels. We speculate that therapies that mimic or restore Wnt5a production could help prevent loss of small vessels in PAH.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037642DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443444PMC
April 2019

A process for academic societies to develop scientific statements and white papers: experience of the Pediatric Cardiac Intensive Care Society.

Cardiol Young 2019 Feb 4;29(2):174-177. Epub 2018 Dec 4.

Department of Pediatrics, Director Adult and Pediatric ECMO, INOVA Fairfax Medical Center, Falls Church, USA.

There are substantial knowledge gaps, practice variation, and paucity of controlled trials owing to the relatively small number of patients with critical heart disease. The Pediatric Cardiac Intensive Care Society has recognised this knowledge gap as an area needing a more comprehensive and evidence-based approach to the management of the critically ill child with heart disease. To address this, the Pediatric Cardiac Intensive Care Society created a scientific statements and white papers committee. Scientific statements and white papers will present the current state-of-the-art in areas where controversy exists, providing clinicians with guidance in diagnostic and therapeutic strategies, particularly where evidence-based data are lacking. This paper provides a template for other societies and organisations faced with the task of developing scientific statements and white papers. We describe the methods used to perform a systematic literature search and evidence rating that will be used by all scientific statements and white papers emerging from the Pediatric Cardiac Intensive Care Society. The Pediatric Cardiac Intensive Care Society aims to revolutionise the care of children with heart disease by shifting our efforts from individual institution-based practices to national standardised protocols and to lay the ground work for multicentre high-impact research directions.
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http://dx.doi.org/10.1017/S1047951118002019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7433703PMC
February 2019

Hidden diversity of forest birds in Madagascar revealed using integrative taxonomy.

Mol Phylogenet Evol 2018 07 21;124:16-26. Epub 2018 Feb 21.

Department of Biology, Loyola University Chicago, 1032 W. Sheridan Road, Chicago, IL 60660, USA.

Madagascar is renowned as a global biodiversity hotspot with high levels of microendemism. However, there are few molecular phylogenetic studies of Malagasy birds, particularly for forest-dwelling species, signifying a substantial gap in current measures of species diversity in the absence of genetic data. We evaluated species limits and explored patterns of diversification within the genus Newtonia (Family Vangidae), a group of forest-dwelling songbirds endemic to Madagascar. Our modern systematics approach combined genomic, morphometric, and ecological niche data to analyze the evolutionary history of the group. Our integrative analysis uncovered hidden species-level diversity within N. amphichroa, with two deeply divergent and morphologically distinct lineages isolated in different regions of humid forest. We describe the southern lineage as a new species. Conversely, N. brunneicauda, which we initially hypothesized may harbor cryptic diversity owing to its large distribution spanning a range of habitats, was found to have no distinct lineages and shared haplotypes across much of its distribution. The contrasting diversification patterns between Newtonia lineages may be the result of their elevational tolerances. Newtonia brunneicauda has a broad habitat tolerance and elevational range that appears to have facilitated population expansion and gene flow across the island, limiting opportunities for diversification. On the other hand, N. amphichroa is found predominantly in mid-elevation and montane humid forests, a restriction that appears to have promoted speciation associated with climatic fluctuations during the Pleistocene. Our findings indicate that species diversity of Malagasy forest-dwelling birds may be greater than currently recognized, suggesting an urgent need for further studies to quantify biodiversity in Madagascar's rapidly disappearing native forests.
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http://dx.doi.org/10.1016/j.ympev.2018.02.017DOI Listing
July 2018

The critically endangered forest owlet Heteroglaux blewitti is nested within the currently recognized Athene clade: A century-old debate addressed.

PLoS One 2018 5;13(2):e0192359. Epub 2018 Feb 5.

Indian Institute of Science Education and Research, Tirupati, Andhra Pradesh, India.

Range-restricted species generally have specific niche requirements and may often have unique evolutionary histories. Unfortunately, many of these species severely lack basic research, resulting in poor conservation strategies. The phylogenetic relationship of the Critically Endangered Forest Owlet Heteroglaux blewitti has been the subject of a century-old debate. The current classifications based on non-phylogenetic comparisons of morphology place the small owls of Asia into three genera, namely, Athene, Glaucidium, and Heteroglaux. Based on morphological and anatomical data, H. blewitti has been alternatively hypothesized to belong within Athene, Glaucidium, or its own monotypic genus Heteroglaux. To test these competing hypotheses, we sequenced six loci (~4300 bp data) and performed phylogenetic analyses of owlets. Mitochondrial and nuclear trees were not congruent in their placement of H. blewitti. However, both mitochondrial and nuclear combined datasets showed strong statistical support with high maximum likelihood bootstrap (>/ = 90) and Bayesian posterior probability values (>/ = 0.98) for H. blewitti being nested in the currently recognized Athene group, but not sister to Indian A. brama. The divergence of H. blewitti from its sister taxa was between 4.3 and 5.7 Ma coinciding with a period of drastic climatic changes in the Indian subcontinent. This study presented the first genetic analysis of H. blewitti, a Critically Endangered species, and addressed the long debate on the relationships of the Athene-Heteroglaux-Glaucidium complex. We recommend further studies with more data and complete taxon sampling to understand the biogeography of Indian Athene species.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0192359PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5798823PMC
April 2018

Colonization and diversification of the white-browed shortwing (Aves: Muscicapidae: Brachypteryx montana) in the Philippines.

Mol Phylogenet Evol 2018 04 2;121:121-131. Epub 2018 Jan 2.

Biology Department, Loyola University Chicago, 1050 W. Sheridan Road, Chicago, IL 60660, USA. Electronic address:

Molecular phylogenetic approaches have greatly improved our knowledge of the pattern and process of biological diversification across the globe; however, many regions remain poorly documented, even for well-studied vertebrate taxa. The Philippine archipelago, one of the least-studied 'biodiversity hotspots', is an ideal natural laboratory for investigating the factors driving diversification in an insular and geologically dynamic setting. We investigated the history and geography of diversification of the Philippine populations of a widespread montane bird, the White-browed Shortwing (Brachypteryx montana). Leveraging dense archipelago-wide sampling, we generated a multi-locus genetic dataset (one nuclear and two mtDNA markers), which we analyzed using phylogenetic, population genetic, and coalescent-based methods. Our results demonstrate that Philippine shortwings (1) likely colonized the Philippines from the Sunda Shelf to Mindanao in the late Miocene or Pliocene, (2) diversified across inter-island barriers into three divergent lineages during the Pliocene and early Pleistocene, (3) have not diversified within the largest island, Luzon, contrary to patterns observed in other montane taxa, and (4) colonized Palawan from the oceanic Philippines rather than from Borneo, challenging the assumption of Palawan functioning exclusively as a biogeographic extension of the Sunda Shelf. Additionally, our finding that divergent (c. 4.0 mya) lineages are coexisting in secondary sympatry on Mindanao without apparent gene flow suggests that the speciation process is likely complete for these shortwing lineages. Overall, these investigations provide insight into how topography and island boundaries influence diversification within remote oceanic archipelagos and echo the results of many other studies in demonstrating that taxonomic diversity continues to be underestimated in the Philippines.
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http://dx.doi.org/10.1016/j.ympev.2017.12.025DOI Listing
April 2018

Physiological Mitochondrial Fragmentation Is a Normal Cardiac Adaptation to Increased Energy Demand.

Circ Res 2018 01 12;122(2):282-295. Epub 2017 Dec 12.

From the Department of Pediatrics (Cardiology) (M.C., G.F., K.N., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.) and Cardiovascular Research Institute (M.C., G.F., M.Z., K.K., G.J., D.-Q.H., S.R., E.S., D.B.), Stanford University, CA; and Molecular Cardiology Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (A.S., R.A.G.).

Rationale: Mitochondria play a dual role in the heart, responsible for meeting energetic demands and regulating cell death. Paradigms have held that mitochondrial fission and fragmentation are the result of pathological stresses, such as ischemia, are an indicator of poor mitochondrial health, and lead to mitophagy and cell death. However, recent studies demonstrate that inhibiting fission also results in decreased mitochondrial function and cardiac impairment, suggesting that fission is important for maintaining cardiac and mitochondrial bioenergetic homeostasis.

Objective: The purpose of this study is to determine whether mitochondrial fission and fragmentation can be an adaptive mechanism used by the heart to augment mitochondrial and cardiac function during a normal physiological stress, such as exercise.

Methods And Results: We demonstrate a novel role for cardiac mitochondrial fission as a normal adaptation to increased energetic demand. During submaximal exercise, physiological mitochondrial fragmentation results in enhanced, rather than impaired, mitochondrial function and is mediated, in part, by β1-adrenergic receptor signaling. Similar to pathological fragmentation, physiological fragmentation is induced by activation of dynamin-related protein 1; however, unlike pathological fragmentation, membrane potential is maintained and regulators of mitophagy are downregulated. Inhibition of fission with P110, Mdivi-1 (mitochondrial division inhibitor), or in mice with cardiac-specific dynamin-related protein 1 ablation significantly decreases exercise capacity.

Conclusions: These findings demonstrate the requirement for physiological mitochondrial fragmentation to meet the energetic demands of exercise, as well as providing additional support for the evolving conceptual framework, where mitochondrial fission and fragmentation play a role in the balance between mitochondrial maintenance of normal physiology and response to disease.
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http://dx.doi.org/10.1161/CIRCRESAHA.117.310725DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5775047PMC
January 2018

Non-sister Sri Lankan white-eyes (genus Zosterops) are a result of independent colonizations.

PLoS One 2017 9;12(8):e0181441. Epub 2017 Aug 9.

Avian Evolution Node, Department of Zoology and Environment Sciences, Faculty of Science, University of Colombo, Colombo, Sri Lanka.

Co-occurrence of closely related taxa on islands could be attributed to sympatric speciation or multiple colonization. Sympatric speciation is considered to be rare in small islands, however multiple colonizations are known to be common in both oceanic and continental islands. In this study we investigated the phylogenetic relatedness and means of origin of the two sympatrically co-occurring Zosterops white-eyes, the endemic Zosterops ceylonensis and its widespread regional congener Z. palpebrosus, in the island of Sri Lanka. Sri Lanka is a continental island in the Indian continental shelf of the Northern Indian Ocean. Our multivariate morphometric analyses confirmed the phenotypic distinctness of the two species. Maximum Likelihood and Bayesian phylogenetic analyses with ~2000bp from two mitochondrial (ND2 and ND3) and one nuclear (TGF) gene indicated that they are phylogenetically distinct, and not sister to each other. The two subspecies of the peninsula India; Z. p. egregius of Sri Lanka and India and Z. p. nilgiriensis of Western Ghats (India) clustered within the Z. palpebrosus clade having a common ancestor. In contrast, the divergence of the endemic Z. ceylonensis appears to be much deeper and is basal to the other Zosterops white-eyes. Therefore we conclude that the two Zosterops species originated in the island through independent colonizations from different ancestral lineages, and not through island speciation or multiple colonization from the same continental ancestral population. Despite high endemism, Sri Lankan biodiversity is long considered to be a subset of southern India. This study on a speciose group with high dispersal ability and rapid diversification rate provide evidence for the contribution of multiple colonizations in shaping Sri Lanka's biodiversity. It also highlights the complex biogeographic patterns of the South Asian region, reflected even in highly vagile groups such as birds.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0181441PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5549887PMC
October 2017

miR-21 is associated with fibrosis and right ventricular failure.

JCI Insight 2017 May 4;2(9). Epub 2017 May 4.

Department of Pediatrics, Division of Cardiology, Stanford University, Stanford, California, USA.

Combined pulmonary insufficiency (PI) and stenosis (PS) is a common long-term sequela after repair of many forms of congenital heart disease, causing progressive right ventricular (RV) dilation and failure. Little is known of the mechanisms underlying this combination of preload and afterload stressors. We developed a murine model of PI and PS (PI+PS) to identify clinically relevant pathways and biomarkers of disease progression. Diastolic dysfunction was induced (restrictive RV filling, elevated RV end-diastolic pressures) at 1 month after generation of PI+PS and progressed to systolic dysfunction (decreased RV shortening) by 3 months. RV fibrosis progressed from 1 month (4.4% ± 0.4%) to 3 months (9.2% ± 1%), along with TGF-β signaling and tissue expression of profibrotic miR-21. Although plasma miR-21 was upregulated with diastolic dysfunction, it was downregulated with the onset of systolic dysfunction), correlating with RV fibrosis. Plasma miR-21 in children with PI+PS followed a similar pattern. A model of combined RV volume and pressure overload recapitulates the evolution of RV failure unique to patients with prior RV outflow tract surgery. This progression was characterized by enhanced TGF-β and miR-21 signaling. miR-21 may serve as a plasma biomarker of RV failure, with decreased expression heralding the need for valve replacement.
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http://dx.doi.org/10.1172/jci.insight.91625DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5414555PMC
May 2017

Why Do Phylogenomic Data Sets Yield Conflicting Trees? Data Type Influences the Avian Tree of Life more than Taxon Sampling.

Syst Biol 2017 Sep;66(5):857-879

Department of Biology, University of Florida, Gainesville, FL 32607, USA.

Phylogenomics, the use of large-scale data matrices in phylogenetic analyses, has been viewed as the ultimate solution to the problem of resolving difficult nodes in the tree of life. However, it has become clear that analyses of these large genomic data sets can also result in conflicting estimates of phylogeny. Here, we use the early divergences in Neoaves, the largest clade of extant birds, as a "model system" to understand the basis for incongruence among phylogenomic trees. We were motivated by the observation that trees from two recent avian phylogenomic studies exhibit conflicts. Those studies used different strategies: 1) collecting many characters [$\sim$ 42 mega base pairs (Mbp) of sequence data] from 48 birds, sometimes including only one taxon for each major clade; and 2) collecting fewer characters ($\sim$ 0.4 Mbp) from 198 birds, selected to subdivide long branches. However, the studies also used different data types: the taxon-poor data matrix comprised 68% non-coding sequences whereas coding exons dominated the taxon-rich data matrix. This difference raises the question of whether the primary reason for incongruence is the number of sites, the number of taxa, or the data type. To test among these alternative hypotheses we assembled a novel, large-scale data matrix comprising 90% non-coding sequences from 235 bird species. Although increased taxon sampling appeared to have a positive impact on phylogenetic analyses the most important variable was data type. Indeed, by analyzing different subsets of the taxa in our data matrix we found that increased taxon sampling actually resulted in increased congruence with the tree from the previous taxon-poor study (which had a majority of non-coding data) instead of the taxon-rich study (which largely used coding data). We suggest that the observed differences in the estimates of topology for these studies reflect data-type effects due to violations of the models used in phylogenetic analyses, some of which may be difficult to detect. If incongruence among trees estimated using phylogenomic methods largely reflects problems with model fit developing more "biologically-realistic" models is likely to be critical for efforts to reconstruct the tree of life. [Birds; coding exons; GTR model; model fit; Neoaves; non-coding DNA; phylogenomics; taxon sampling.].
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http://dx.doi.org/10.1093/sysbio/syx041DOI Listing
September 2017

Two new genera of songbirds represent endemic radiations from the Shola Sky Islands of the Western Ghats, India.

BMC Evol Biol 2017 01 23;17(1):31. Epub 2017 Jan 23.

National Centre for Biological Sciences, TIFR, Bellary Road, Bangalore, 560065, India.

Background: A long-standing view of Indian biodiversity is that while rich in species, there are few endemics or in-situ radiations within the subcontinent. One exception is the Western Ghats biodiversity hotspot, an isolated mountain range with many endemic species. Understanding the origins of the montane-restricted species is crucial to illuminate both taxonomic and environmental history.

Results: With evidence from genetic, morphometric, song, and plumage data, we show that two songbird lineages endemic to the Western Ghats montane forest each have diversified into multiple distinct species. Historically labeled as single species of widespread Asian genera, these two lineages are highly divergent and do not group with the taxa in which they were previously classified but rather are distinct early divergences in larger Asian clades of flycatchers and babblers. Here we designated two new genera, the Western Ghats shortwings as Sholicola and the laughingthrushes as Montecincla, and evaluated species-limits to reflect distinct units by revising six previously named taxa and describing one novel species. Divergence dating showed that both these montane groups split from their Himalayan relatives during the Miocene, which is coincident with a shift towards arid conditions that fragmented the previously contiguous humid forest across peninsular India and isolated these lineages in the Western Ghats. Furthermore, these two genera showed congruent patterns of diversification across the Western Ghats Sky Islands, coincident with other climatic changes.

Conclusion: Our study reveals the existence of two independent endemic radiations in the high montane Western Ghats or Shola Sky Islands with coincident divergence times, highlighting the role of climate in the diversification of these ancient lineages. The endemic and highly divergent nature of these previously unrecognized species underscores the dearth of knowledge about the biogeography of the Asian tropics, even for comparatively well-known groups such as birds. The substantial increase in the diversity of this region underscores the need for more rigorous systematic analysis to inform biodiversity studies and conservation efforts.
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http://dx.doi.org/10.1186/s12862-017-0882-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5259981PMC
January 2017

Institution of Veno-arterial Extracorporeal Membrane Oxygenation Does Not Lead to Increased Wall Stress in Patients with Impaired Myocardial Function.

Pediatr Cardiol 2017 Mar 22;38(3):539-546. Epub 2016 Dec 22.

Division of Pediatric Cardiology, Department of Pediatrics, Lucile Packard Children's Hospital at Stanford, Stanford University School of Medicine, 750 Welch Road, Suite # 325, Palo Alto, CA, 94304, USA.

The effect of veno-arterial extracorporeal membrane oxygenation (VA ECMO) on wall stress in patients with cardiomyopathy, myocarditis, or other cardiac conditions is unknown. We set out to determine the circumferential and meridional wall stress (WS) in patients with systemic left ventricles before and during VA ECMO. We established a cohort of patients with impaired myocardial function who underwent VA ECMO therapy from January 2000 to November 2013. Demographic and clinical data were collected and inotropic score calculated. Measurements were taken on echocardiograms prior to the initiation of VA ECMO and while on full-flow VA ECMO, in order to derive wall stress (circumferential and meridional), VCFc, ejection fraction, and fractional shortening. A post hoc sub-analysis was conducted, separating those with pulmonary hypertension (PH) and those with impaired systemic output. Thirty-three patients met inclusion criteria. The patients' median age was 0.06 years (range 0-18.7). Eleven (33%) patients constituted the organ failure group (Gr2), while the remaining 22 (66%) patients survived to discharge (Gr1). WS and all other echocardiographic measures were not different when comparing patients before and during VA ECMO. Ejection and shortening fraction, WS, and VCFc were not statistically different comparing the survival and organ failure groups. The patients' position on the VCFc-WS curve did not change after the initiation of VA ECMO. Those with PH had decreased WS as well as increased EF after ECMO initiation, while those with impaired systemic output showed no difference in those parameters with initiation of ECMO. The external workload on the myocardium as indicated by WS is unchanged by the institution of VA ECMO support. Furthermore, echocardiographic measures of cardiac function do not reflect the changes in ventricular performance inherent to VA ECMO support. These findings are informative for the interpretation of echocardiograms in the setting of VA ECMO. ECMO may improve ventricular mechanics in those with PH as the primary diagnosis.
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http://dx.doi.org/10.1007/s00246-016-1546-9DOI Listing
March 2017

Label-free Quantification of Proteins in Single Embryonic Cells with Neural Fate in the Cleavage-Stage Frog (Xenopus laevis) Embryo using Capillary Electrophoresis Electrospray Ionization High-Resolution Mass Spectrometry (CE-ESI-HRMS).

Mol Cell Proteomics 2016 08 17;15(8):2756-68. Epub 2016 Jun 17.

From the ‡Department of Chemistry and

Quantification of protein expression in single cells promises to advance a systems-level understanding of normal development. Using a bottom-up proteomic workflow and multiplexing quantification by tandem mass tags, we recently demonstrated relative quantification between single embryonic cells (blastomeres) in the frog (Xenopus laevis) embryo. In this study, we minimize derivatization steps to enhance analytical sensitivity and use label-free quantification (LFQ) for single Xenopus cells. The technology builds on a custom-designed capillary electrophoresis microflow-electrospray ionization high-resolution mass spectrometry platform and LFQ by MaxLFQ (MaxQuant). By judiciously tailoring performance to peptide separation, ionization, and data-dependent acquisition, we demonstrate an ∼75-amol (∼11 nm) lower limit of detection and quantification for proteins in complex cell digests. The platform enabled the identification of 438 nonredundant protein groups by measuring 16 ng of protein digest, or <0.2% of the total protein contained in a blastomere in the 16-cell embryo. LFQ intensity was validated as a quantitative proxy for protein abundance. Correlation analysis was performed to compare protein quantities between the embryo and n = 3 different single D11 blastomeres, which are fated to develop into the nervous system. A total of 335 nonredundant protein groups were quantified in union between the single D11 cells spanning a 4 log-order concentration range. LFQ and correlation analysis detected expected proteomic differences between the whole embryo and blastomeres, and also found translational differences between individual D11 cells. LFQ on single cells raises exciting possibilities to study gene expression in other cells and models to help better understand cell processes on a systems biology level.
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http://dx.doi.org/10.1074/mcp.M115.057760DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4974349PMC
August 2016

Compassionate deactivation of ventricular assist devices in pediatric patients.

J Heart Lung Transplant 2016 05 31;35(5):564-7. Epub 2016 Mar 31.

Department of Pediatrics (Cardiology), Stanford University Medical Center, Palo Alto, California, USA.

Despite greatly improved survival in pediatric patients with end-stage heart failure through the use of ventricular assist devices (VADs), heart failure ultimately remains a life-threatening disease with a significant symptom burden. With increased demand for donor organs, liberalizing the boundaries of case complexity, and the introduction of destination therapy in children, more children can be expected to die while on mechanical support. Despite this trend, guidelines on the ethical and pragmatic issues of compassionate deactivation of VAD support in children are strikingly absent. As VAD support for pediatric patients increases in frequency, the pediatric heart failure and palliative care communities must work toward establishing guidelines to clarify the complex issues surrounding compassionate deactivation. Patient, family and clinician attitudes must be ascertained and education regarding the psychological, legal and ethical issues should be provided. Furthermore, pediatric-specific planning documents for use before VAD implantation as well as deactivation checklists should be developed to assist with decision-making at critical points during the illness trajectory. Herein we review the relevant literature regarding compassionate deactivation with a specific focus on issues related to children.
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http://dx.doi.org/10.1016/j.healun.2016.03.020DOI Listing
May 2016

De Novo and Rare Variants at Multiple Loci Support the Oligogenic Origins of Atrioventricular Septal Heart Defects.

PLoS Genet 2016 Apr 8;12(4):e1005963. Epub 2016 Apr 8.

Cardiovascular Institute, Stanford University School of Medicine, Stanford University, Stanford, California, United States of America.

Congenital heart disease (CHD) has a complex genetic etiology, and recent studies suggest that high penetrance de novo mutations may account for only a small fraction of disease. In a multi-institutional cohort surveyed by exome sequencing, combining analysis of 987 individuals (discovery cohort of 59 affected trios and 59 control trios, and a replication cohort of 100 affected singletons and 533 unaffected singletons) we observe variation at novel and known loci related to a specific cardiac malformation the atrioventricular septal defect (AVSD). In a primary analysis, by combining developmental coexpression networks with inheritance modeling, we identify a de novo mutation in the DNA binding domain of NR1D2 (p.R175W). We show that p.R175W changes the transcriptional activity of Nr1d2 using an in vitro transactivation model in HUVEC cells. Finally, we demonstrate previously unrecognized cardiovascular malformations in the Nr1d2tm1-Dgen knockout mouse. In secondary analyses we map genetic variation to protein-interaction networks suggesting a role for two collagen genes in AVSD, which we corroborate by burden testing in a second replication cohort of 100 AVSDs and 533 controls (p = 8.37e-08). Finally, we apply a rare-disease inheritance model to identify variation in genes previously associated with CHD (ZFPM2, NSD1, NOTCH1, VCAN, and MYH6), cardiac malformations in mouse models (ADAM17, CHRD, IFT140, PTPRJ, RYR1 and ATE1), and hypomorphic alleles of genes causing syndromic CHD (EHMT1, SRCAP, BBS2, NOTCH2, and KMT2D) in 14 of 59 trios, greatly exceeding variation in control trios without CHD (p = 9.60e-06). In total, 32% of trios carried at least one putatively disease-associated variant across 19 loci,suggesting that inherited and de novo variation across a heterogeneous group of loci may contribute to disease risk.
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http://dx.doi.org/10.1371/journal.pgen.1005963DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825975PMC
April 2016