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Andrew Paul Landstrom

Associate Professor of Pediatrics
Pediatrics, Cardiology

Selected Publications


Risk Factors and Outcomes Associated with Gaps in Care in Children with Congenital Heart Disease.

Conference Pediatr Cardiol · June 2024 Adults with congenital heart disease (CHD) benefit from cardiology follow-up at recommended intervals of ≤ 2 years. However, benefit for children is less clear given limited studies and unclear current guidelines. We hypothesize there are identifiable risk ... Full text Link to item Cite

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.

Journal Article JACC Heart Fail · May 2024 BACKGROUND: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general populati ... Full text Link to item Cite

Obesity Predisposes Anthracycline-Treated Survivors of Childhood and Adolescent Cancers to Subclinical Cardiac Dysfunction.

Journal Article Pediatr Cardiol · March 8, 2024 Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of ... Full text Link to item Cite

Underrepresentation of Diverse Ancestries Drives Uncertainty in Genetic Variants Found in Cardiomyopathy-Associated Genes.

Journal Article JACC Adv · February 2024 BACKGROUND: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important f ... Full text Link to item Cite

Cardiovascular Disease in Childhood, Adolescent, and Young Adult Cancer Survivors: The Impact of Family History of Premature Heart Disease.

Journal Article J Adolesc Young Adult Oncol · January 23, 2024 Purpose: Childhood, adolescent, and young adult (CAYA) cancer survivors (age 0-39 years at diagnosis) are at increased risk of cardiovascular disease (CVD). Family history of early heart disease increases the risk of CVD in the general population; however, ... Full text Link to item Cite

LMNA Cardiomyopathy: Important Considerations for the Heart Failure Clinician.

Journal Article J Card Fail · December 2023 BACKGROUND: A diagnosis of Lamin proteins A and C cardiomyopathy (LMNA-CM) not only impacts disease prognosis, but also leads to specific guideline-recommended treatment options for these patients. This etiology is fundamentally different from other geneti ... Full text Link to item Cite

Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade.

Journal Article JACC Basic Transl Sci · December 2023 Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)-mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a ... Full text Link to item Cite

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

Journal Article Circ Heart Fail · December 2023 BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human c ... Full text Link to item Cite

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Journal Article Genome Med · October 23, 2023 BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited card ... Full text Link to item Cite

Cardiovascular Risk Factor Disparities in Adult Survivors of Childhood Cancer Compared With the General Population.

Journal Article JACC CardioOncol · August 2023 BACKGROUND: It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population. OBJECTIVES: We sought to determine if disparities in CVRFs by race/ethnicity are ... Full text Link to item Cite

PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

Journal Article Circ Genom Precis Med · August 2023 BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients wit ... Full text Link to item Cite

DiscoVari: A Web-Based Precision Medicine Tool for Predicting Variant Pathogenicity in Cardiomyopathy- and Channelopathy-Associated Genes.

Journal Article Circ Genom Precis Med · August 2023 BACKGROUND: With genetic testing advancements, the burden of incidentally identified cardiac disease-associated gene variants is rising. These variants may carry a risk of sudden cardiac death, highlighting the need for accurate diagnostic interpretation. ... Full text Link to item Cite

Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.

Journal Article Curr Cardiol Rep · May 2023 PURPOSE OF REVIEW: Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of th ... Full text Link to item Cite

Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Journal Article Circ Genom Precis Med · April 2023 Rapid advances in genetic technologies have led to expanding use of diagnostic, research, and direct-to-consumer exome and genome sequencing. Incidentally identified variants from this sequencing represent a significant and growing challenge to interpret a ... Full text Link to item Cite

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Journal Article Mol Genet Metab · March 2023 Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads t ... Full text Link to item Cite

Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.

Journal Article Circ Arrhythm Electrophysiol · February 2023 BACKGROUND: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca2+) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca2+ clock is critical to understanding nodal a ... Full text Link to item Cite

One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.

Journal Article Trends Cardiovasc Med · January 2023 Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspon ... Full text Link to item Cite

Risk Factors and Outcomes Associated with Gaps in Care in Children with Congenital Heart Disease.

Conference Pediatr Cardiol · June 2024 Adults with congenital heart disease (CHD) benefit from cardiology follow-up at recommended intervals of ≤ 2 years. However, benefit for children is less clear given limited studies and unclear current guidelines. We hypothesize there are identifiable risk ... Full text Link to item Cite

Predicted Deleterious Variants in Cardiomyopathy Genes Prognosticate Mortality and Composite Outcomes in the UK Biobank.

Journal Article JACC Heart Fail · May 2024 BACKGROUND: Inherited cardiomyopathies present with broad variation of phenotype. Data are limited regarding genetic screening strategies and outcomes associated with predicted deleterious variants in cardiomyopathy-associated genes in the general populati ... Full text Link to item Cite

Obesity Predisposes Anthracycline-Treated Survivors of Childhood and Adolescent Cancers to Subclinical Cardiac Dysfunction.

Journal Article Pediatr Cardiol · March 8, 2024 Anthracyclines are effective chemotherapeutics used in approximately 60% of pediatric cancer cases but have a well-documented risk of cardiotoxicity. Existing cardiotoxicity risk calculators do not include cardiovascular risk factors present at the time of ... Full text Link to item Cite

Underrepresentation of Diverse Ancestries Drives Uncertainty in Genetic Variants Found in Cardiomyopathy-Associated Genes.

Journal Article JACC Adv · February 2024 BACKGROUND: Thousands of genetic variants have been identified in cardiomyopathy-associated genes. Diagnostic genetic testing is key for evaluation of individuals with suspected cardiomyopathy. While accurate variant pathogenicity assignment is important f ... Full text Link to item Cite

Cardiovascular Disease in Childhood, Adolescent, and Young Adult Cancer Survivors: The Impact of Family History of Premature Heart Disease.

Journal Article J Adolesc Young Adult Oncol · January 23, 2024 Purpose: Childhood, adolescent, and young adult (CAYA) cancer survivors (age 0-39 years at diagnosis) are at increased risk of cardiovascular disease (CVD). Family history of early heart disease increases the risk of CVD in the general population; however, ... Full text Link to item Cite

LMNA Cardiomyopathy: Important Considerations for the Heart Failure Clinician.

Journal Article J Card Fail · December 2023 BACKGROUND: A diagnosis of Lamin proteins A and C cardiomyopathy (LMNA-CM) not only impacts disease prognosis, but also leads to specific guideline-recommended treatment options for these patients. This etiology is fundamentally different from other geneti ... Full text Link to item Cite

Junctional Ectopic Tachycardia Caused by Junctophilin-2 Expression Silencing Is Selectively Sensitive to Ryanodine Receptor Blockade.

Journal Article JACC Basic Transl Sci · December 2023 Junctional ectopic tachycardia (JET) is a potentially fatal cardiac arrhythmia. Hcn4:shJph2 mice serve as a model of nodal arrhythmias driven by ryanodine type 2 receptor (RyR2)-mediated Ca2+ leak. EL20 is a small molecule that blocks RyR2 Ca2+ leak. In a ... Full text Link to item Cite

Nonsense Variant PRDM16-Q187X Causes Impaired Myocardial Development and TGF-β Signaling Resulting in Noncompaction Cardiomyopathy in Humans and Mice.

Journal Article Circ Heart Fail · December 2023 BACKGROUND: PRDM16 plays a role in myocardial development through TGF-β (transforming growth factor-beta) signaling. Recent evidence suggests that loss of PRDM16 expression is associated with cardiomyopathy development in mice, although its role in human c ... Full text Link to item Cite

Beyond gene-disease validity: capturing structured data on inheritance, allelic requirement, disease-relevant variant classes, and disease mechanism for inherited cardiac conditions.

Journal Article Genome Med · October 23, 2023 BACKGROUND: As the availability of genomic testing grows, variant interpretation will increasingly be performed by genomic generalists, rather than domain-specific experts. Demand is rising for laboratories to accurately classify variants in inherited card ... Full text Link to item Cite

Cardiovascular Risk Factor Disparities in Adult Survivors of Childhood Cancer Compared With the General Population.

Journal Article JACC CardioOncol · August 2023 BACKGROUND: It is unknown whether a history of childhood cancer modifies the established disparities in cardiovascular risk factors (CVRFs) observed in the general population. OBJECTIVES: We sought to determine if disparities in CVRFs by race/ethnicity are ... Full text Link to item Cite

PRDM16 Deletion Is Associated With Sex-dependent Cardiomyopathy and Cardiac Mortality: A Translational, Multi-Institutional Cohort Study.

Journal Article Circ Genom Precis Med · August 2023 BACKGROUND: 1p36 deletion syndrome can predispose to pediatric-onset cardiomyopathy. Deletion breakpoints are variable and may delete the transcription factor PRDM16. Early studies suggest that deletion of PRDM16 may underlie cardiomyopathy in patients wit ... Full text Link to item Cite

DiscoVari: A Web-Based Precision Medicine Tool for Predicting Variant Pathogenicity in Cardiomyopathy- and Channelopathy-Associated Genes.

Journal Article Circ Genom Precis Med · August 2023 BACKGROUND: With genetic testing advancements, the burden of incidentally identified cardiac disease-associated gene variants is rising. These variants may carry a risk of sudden cardiac death, highlighting the need for accurate diagnostic interpretation. ... Full text Link to item Cite

Induced Pluripotent Stem Cell-Based Modeling of Single-Ventricle Congenital Heart Diseases.

Journal Article Curr Cardiol Rep · May 2023 PURPOSE OF REVIEW: Congenital heart disease includes a wide variety of structural cardiac defects, the most severe of which are single ventricle defects (SVD). These patients suffer from significant morbidity and mortality; however, our understanding of th ... Full text Link to item Cite

Interpreting Incidentally Identified Variants in Genes Associated With Heritable Cardiovascular Disease: A Scientific Statement From the American Heart Association.

Journal Article Circ Genom Precis Med · April 2023 Rapid advances in genetic technologies have led to expanding use of diagnostic, research, and direct-to-consumer exome and genome sequencing. Incidentally identified variants from this sequencing represent a significant and growing challenge to interpret a ... Full text Link to item Cite

Diagnosis and management of glycogen storage disease type IV, including adult polyglucosan body disease: A clinical practice resource.

Journal Article Mol Genet Metab · March 2023 Glycogen storage disease type IV (GSD IV) is an ultra-rare autosomal recessive disorder caused by pathogenic variants in GBE1 which results in reduced or deficient glycogen branching enzyme activity. Consequently, glycogen synthesis is impaired and leads t ... Full text Link to item Cite

Reduction in Junctophilin 2 Expression in Cardiac Nodal Tissue Results in Intracellular Calcium-Driven Increase in Nodal Cell Automaticity.

Journal Article Circ Arrhythm Electrophysiol · February 2023 BACKGROUND: Spontaneously depolarizing nodal cells comprise the pacemaker of the heart. Intracellular calcium (Ca2+) plays a critical role in mediating nodal cell automaticity and understanding this so-called Ca2+ clock is critical to understanding nodal a ... Full text Link to item Cite

One gene, two modes of inheritance, four diseases: A systematic review of the cardiac manifestation of pathogenic variants in JPH2-encoded junctophilin-2.

Journal Article Trends Cardiovasc Med · January 2023 Rare variants in JPH2 have been associated with a range of cardiac disease, including hypertrophic cardiomyopathy (HCM), dilated cardiomyopathy (DCM), arrhythmias, and sudden cardiac death (SCD); however, our understanding of how variants in JPH2 correspon ... Full text Link to item Cite

Addressing the challenges of polygenic scores in human genetic research.

Journal Article Am J Hum Genet · December 1, 2022 The genotyping of millions of human samples has made it possible to evaluate variants across the human genome for their possible association with risks for numerous diseases and other traits by using genome-wide association studies (GWASs). The association ... Full text Link to item Cite

Rapid Whole Genome Sequencing in Critically Ill Neonates Enables Precision Medicine Pipeline.

Journal Article J Pers Med · November 18, 2022 Rapid genome sequencing in critically ill infants is increasingly identified as a crucial test for providing targeted and informed patient care. We report the outcomes of a pilot study wherein eight critically ill neonates received rapid whole genome seque ... Full text Link to item Cite

Determining the Likelihood of Disease Pathogenicity Among Incidentally Identified Genetic Variants in Rare Dilated Cardiomyopathy-Associated Genes.

Journal Article J Am Heart Assoc · October 4, 2022 Background As utilization of clinical exome sequencing (ES) has expanded, criteria for evaluating the diagnostic weight of incidentally identified variants are critical to guide clinicians and researchers. This is particularly important in genes associated ... Full text Link to item Cite

From diagnostic testing to precision medicine: the evolving role of genomics in cardiac channelopathies and cardiomyopathies in children.

Journal Article Curr Opin Genet Dev · October 2022 Pediatric sudden cardiac death (SCD) is the sudden unexpected death of a child or adolescent due to a presumed cardiac etiology. Heritable causes of pediatric SCD are predominantly cardiomyopathies and cardiac ion channelopathies. This review illustrates r ... Full text Link to item Cite

Addressing underrepresentation in genomics research through community engagement.

Journal Article Am J Hum Genet · September 1, 2022 The vision of the American Society of Human Genetics (ASHG) is that people everywhere will realize the benefits of human genetics and genomics. Implicit in that vision is the importance of ensuring that the benefits of human genetics and genomics research ... Full text Link to item Cite

Anesthetic Implications in Alternating Hemiplegia of Childhood: A Case Report.

Journal Article AANA J · August 2022 The following case report describes a 13-year-old child with alternating hemiplegia of childhood (AHC) who underwent magnetic resonance imaging MRI with general anesthesia and experienced a hemiplegic spell, seizure, apnea, and sudden cardiac arrest with s ... Link to item Cite

Frequency, Penetrance, and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants.

Journal Article Circulation · July 12, 2022 BACKGROUND: There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene variants in a general adul ... Full text Link to item Cite

Pathogenicity Assignment of Variants in Genes Associated With Cardiac Channelopathies Evolve Toward Diagnostic Uncertainty.

Journal Article Circ Genom Precis Med · June 2022 BACKGROUND: Accurately determining variant pathogenicity is critical in the diagnosis of cardiac channelopathies; however, it remains unknown how variant pathogenicity status changes over time. Our aim is to use a comprehensive analysis of ClinVar to under ... Full text Link to item Cite

BRG1 is a biomarker of hypertrophic cardiomyopathy in human heart specimens.

Journal Article Sci Rep · May 17, 2022 Hypertrophic cardiomyopathy (HCM) is a genetic disease of the sarcomere that causes otherwise unexplained cardiac hypertrophy and is associated with sudden death. While previous studies showed the role of the epigenetic modifier Brg1 in mouse models of HCM ... Full text Link to item Cite

Molecular characterization and investigation of the role of genetic variation in phenotypic variability and response to treatment in a large pediatric Marfan syndrome cohort.

Journal Article Genet Med · May 2022 PURPOSE: In a large cohort of 373 pediatric patients with Marfan syndrome (MFS) with a severe cardiovascular phenotype, we explored the proportion of patients with MFS with a pathogenic FBN1 variant and analyzed whether the type/location of FBN1 variants w ... Full text Link to item Cite

Characterization of sedation and anesthesia complications in patients with alternating hemiplegia of childhood.

Journal Article Eur J Paediatr Neurol · May 2022 BACKGROUND: Alternating hemiplegia of childhood (AHC) pathophysiology suggests predisposition to sedation and anesthesia complications. GOALS: Hypotheses: 1) AHC patients experience high rates of sedation-anesthesia complications. 2) ATP1A3 mutation genoty ... Full text Link to item Cite

Signal-to-Noise Analysis Can Inform the Likelihood That Incidentally Identified Variants in Sarcomeric Genes Are Associated with Pediatric Cardiomyopathy.

Journal Article J Pers Med · April 30, 2022 Background: Hypertrophic cardiomyopathy (HCM) is the most common heritable cardiomyopathy and can predispose individuals to sudden death. Most pediatric HCM patients host a known pathogenic variant in a sarcomeric gene. With the increase in exome sequencin ... Full text Link to item Cite

Relation of Norwood Shunt Type and Frequency of Arrhythmias at 6 Years (from the Single Ventricle Reconstruction Trial).

Journal Article Am J Cardiol · April 15, 2022 The Norwood procedure with a right ventricular to pulmonary artery shunt (RVPAS) decreases early mortality, but requires a ventriculotomy, possibly increasing risk of ventricular arrhythmias (VAs) compared with the modified Blalock-Taussig shunt (MBTS). Th ... Full text Link to item Cite

GENESIS: Gene-Specific Machine Learning Models for Variants of Uncertain Significance Found in Catecholaminergic Polymorphic Ventricular Tachycardia and Long QT Syndrome-Associated Genes.

Journal Article Circ Arrhythm Electrophysiol · April 2022 BACKGROUND: Cardiac channelopathies such as catecholaminergic polymorphic tachycardia and long QT syndrome predispose patients to fatal arrhythmias and sudden cardiac death. As genetic testing has become common in clinical practice, variants of uncertain s ... Full text Link to item Cite

Early clinical phenotype of late onset Pompe disease: Lessons learned from newborn screening.

Journal Article Mol Genet Metab · March 2022 PURPOSE: Thoroughly phenotype children with late-onset Pompe disease (LOPD) diagnosed via newborn screening (NBS) to provide guidance for long-term follow up. METHODS: Twenty infants ages 6-21 months with LOPD diagnosed by NBS underwent systematic clinical ... Full text Open Access Link to item Cite

Engineered bacterial voltage-gated sodium channel platform for cardiac gene therapy.

Journal Article Nat Commun · February 2, 2022 Therapies for cardiac arrhythmias could greatly benefit from approaches to enhance electrical excitability and action potential conduction in the heart by stably overexpressing mammalian voltage-gated sodium channels. However, the large size of these chann ... Full text Link to item Cite

Inflammation and Immune Response in Arrhythmogenic Cardiomyopathy: State-of-the-Art Review.

Journal Article Circulation · November 16, 2021 Arrhythmogenic cardiomyopathy (ACM) is a primary disease of the myocardium, predominantly caused by genetic defects in proteins of the cardiac intercalated disc, particularly, desmosomes. Transmission is mostly autosomal dominant with incomplete penetrance ... Full text Link to item Cite

Leveraging Clinical Informatics Tools to Extract Cumulative Anthracycline Exposure, Measure Cardiovascular Outcomes, and Assess Guideline Adherence for Children With Cancer.

Journal Article JCO Clin Cancer Inform · October 2021 PURPOSE: Cardiovascular disease is a significant cause of late morbidity and mortality in survivors of childhood cancer. Clinical informatics tools could enhance provider adherence to echocardiogram guidelines for early detection of late-onset cardiomyopat ... Full text Link to item Cite

Genetic Testing for Heritable Cardiovascular Diseases in Pediatric Patients: A Scientific Statement From the American Heart Association.

Journal Article Circ Genom Precis Med · October 2021 Genetic diseases that affect the cardiovascular system are relatively common and include cardiac channelopathies, cardiomyopathies, aortopathies, hypercholesterolemias, and structural diseases of the heart and great vessels. The rapidly expanding availabil ... Full text Link to item Cite

ATP1A3-Encoded Sodium-Potassium ATPase Subunit Alpha 3 D801N Variant Is Associated With Shortened QT Interval and Predisposition to Ventricular Fibrillation Preceded by Bradycardia.

Journal Article J Am Heart Assoc · September 7, 2021 Background Pathogenic variation in the ATP1A3-encoded sodium-potassium ATPase, ATP1A3, is responsible for alternating hemiplegia of childhood (AHC). Although these patients experience a high rate of sudden unexpected death in epilepsy, the pathophysiologic ... Full text Open Access Link to item Cite

The clinical utility of pediatric cardiomyopathy genetic testing: From diagnosis to a precision medicine-based approach to care.

Journal Article Prog Pediatr Cardiol · September 2021 BACKGROUND: Pediatric-onset cardiomyopathies are rare yet cause significant morbidity and mortality in affected children. Genetic testing has a major role in the clinical evaluation of pediatric-onset cardiomyopathies, and identification of a variant in an ... Full text Open Access Link to item Cite

Differential inflammatory responses of the native left and right ventricle associated with donor heart preservation.

Journal Article Physiol Rep · September 2021 BACKGROUND: Dysfunction and inflammation of hearts subjected to cold ischemic preservation may differ between left and right ventricles, suggesting distinct strategies for amelioration. METHODS AND RESULTS: Explanted murine hearts subjected to cold ischemi ... Full text Link to item Cite

The genetic underpinnings of anthracycline-induced cardiomyopathy predisposition.

Journal Article Clin Genet · August 2021 Anthracyclines, chemotherapeutic agents that have contributed to significant improvements in cancer survival, also carry risk of both acute and chronic cardiotoxicity. This has led to significantly elevated risks of cardiac morbidity and mortality among ca ... Full text Link to item Cite

Interpretation of Incidental Genetic Findings Localizing to Genes Associated With Cardiac Channelopathies and Cardiomyopathies.

Journal Article Circ Genom Precis Med · August 2021 Recent advances in next-genetic sequencing technology have facilitated an expansion in the use of exome and genome sequencing in the research and clinical settings. While this has aided in the genetic diagnosis of individuals with atypical clinical present ... Full text Link to item Cite

Efficacy of RyR2 inhibitor EL20 in induced pluripotent stem cell-derived cardiomyocytes from a patient with catecholaminergic polymorphic ventricular tachycardia.

Journal Article J Cell Mol Med · June 10, 2021 Catecholaminergic polymorphic ventricular tachycardia (CPVT) is an inherited cardiac arrhythmia syndrome that often leads to sudden cardiac death. The most common form of CPVT is caused by autosomal-dominant variants in the cardiac ryanodine receptor type- ... Full text Open Access Link to item Cite

A comprehensive guide to genetic variants and post-translational modifications of cardiac troponin C.

Journal Article J Muscle Res Cell Motil · June 2021 Familial cardiomyopathy is an inherited disease that affects the structure and function of heart muscle and has an extreme range of phenotypes. Among the millions of affected individuals, patients with hypertrophic (HCM), dilated (DCM), or left ventricular ... Full text Open Access Link to item Cite

Disparities in cardiovascular risk factors by race/ethnicity among adult survivors of childhood cancer: A report from the Childhood Cancer Survivorship Study (CCSS).

Conference Journal of Clinical Oncology · May 20, 2021 10017 Background: Racial, ethnic, and socioeconomic disparities are documented in outcomes for childhood cancer survivors. Understanding whether childhood cancer modifies established disparities in cardiovascular risk factors (CV ... Full text Cite

Essential roles of the dystrophin-glycoprotein complex in different cardiac pathologies.

Journal Article Adv Med Sci · March 2021 The dystrophin-glycoprotein complex (DGC), situated at the sarcolemma dynamically remodels during cardiac disease. This review examines DGC remodeling as a common denominator in diseases affecting heart function and health. Dystrophin and the DGC serve as ... Full text Open Access Link to item Cite

TBX5-encoded T-box transcription factor 5 variant T223M is associated with long QT syndrome and pediatric sudden cardiac death.

Journal Article Am J Med Genet A · March 2021 Long QT syndrome (LQTS) is a genetic disease resulting in a prolonged QT interval on a resting electrocardiogram, predisposing affected individuals to polymorphic ventricular tachycardia and sudden death. Although a number of genes have been implicated in ... Full text Open Access Link to item Cite

Amino Acid-Level Signal-to-Noise Analysis Aids in Pathogenicity Prediction of Incidentally Identified TTN-Encoded Titin Truncating Variants.

Journal Article Circ Genom Precis Med · February 2021 BACKGROUND: TTN, the largest gene in the human body, encodes TTN (titin), a protein that plays key structural, developmental, and regulatory roles in skeletal and cardiac muscle. Variants in TTN, particularly truncating variants (TTNtvs), have been implica ... Full text Open Access Link to item Cite

Genetic Etiology of Left-Sided Obstructive Heart Lesions: A Story in Development.

Journal Article J Am Heart Assoc · January 19, 2021 Congenital heart disease is the most common congenital defect observed in newborns. Within the spectrum of congenital heart disease are left-sided obstructive lesions (LSOLs), which include hypoplastic left heart syndrome, aortic stenosis, bicuspid aortic ... Full text Open Access Link to item Cite

BRG1 IS A BIOMARKER OF HYPERTROPHIC CARDIOMYOPATHY IN HUMAN HEART SPECIMENS

Conference JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY · 2021 Cite

The Frequency, Penetrance and Variable Expressivity of Dilated Cardiomyopathy-Associated Putative Pathogenic Gene Variants in UK Biobank Participants

Journal Article · 2021 ABSTRACTBackground There is a paucity of data regarding the phenotype of dilated cardiomyopathy (DCM) gene variants in the general population. We aimed to determine the frequency and penetrance of DCM-associated putative pathogenic gene ... Full text Cite

Risk Factors for Sudden Infant Death in North Carolina.

Journal Article Front Pediatr · 2021 Background: Sudden infant death syndrome (SIDS) is the sudden, unexplained death of infants <1 year old. SIDS remains a leading cause of death in US infants. We aim to identify associations between SIDS and race/ethnicity, birth weight/gestational age, and ... Full text Open Access Link to item Cite

Genotype Predicts Outcomes in Fetuses and Neonates With Severe Congenital Long QT Syndrome.

Journal Article JACC Clin Electrophysiol · November 2020 OBJECTIVES: This study sought to determine the relationship between long QT syndrome (LQTS) subtype (LTQ1, LTQ2, LTQ3) and postnatal cardiac events (CEs). BACKGROUND: LQTS presenting with 2:1 atrioventricular block or torsades de pointes in the fetus and/o ... Full text Open Access Link to item Cite

Genetic Testing for Inherited Cardiovascular Diseases: A Scientific Statement From the American Heart Association.

Journal Article Circ Genom Precis Med · August 2020 Advances in human genetics are improving the understanding of a variety of inherited cardiovascular diseases, including cardiomyopathies, arrhythmic disorders, vascular disorders, and lipid disorders such as familial hypercholesterolemia. However, not all ... Full text Open Access Link to item Cite

Meta-analysis of cardiomyopathy-associated variants in troponin genes identifies loci and intragenic hot spots that are associated with worse clinical outcomes.

Journal Article J Mol Cell Cardiol · May 2020 INTRODUCTION: Troponin (TNN)-encoded cardiac troponins (Tn) are critical for sensing calcium and triggering myofilament contraction. TNN variants are associated with development of cardiomyopathy; however, recent advances in genetic analysis have identifie ... Full text Open Access Link to item Cite

Cardiac dysregulation following intrahippocampal kainate-induced status epilepticus.

Journal Article Sci Rep · March 4, 2020 Status epilepticus (SE) is a prevalent disorder associated with significant morbidity, including the development of epilepsy and mortality. Cardiac arrhythmias (i.e. inappropriate sinus tachycardia and bradycardia, asystole, and atrioventricular blocks) ar ... Full text Open Access Link to item Cite

Variant R94C in TNNT2-Encoded Troponin T Predisposes to Pediatric Restrictive Cardiomyopathy and Sudden Death Through Impaired Thin Filament Relaxation Resulting in Myocardial Diastolic Dysfunction.

Journal Article J Am Heart Assoc · March 3, 2020 Background Pediatric-onset restrictive cardiomyopathy (RCM) is associated with high mortality, but underlying mechanisms of disease are under investigated. RCM-associated diastolic dysfunction secondary to variants in TNNT2-encoded cardiac troponin T (TNNT ... Full text Open Access Link to item Cite

An International Multicenter Evaluation of Type 5 Long QT Syndrome: A Low Penetrant Primary Arrhythmic Condition.

Journal Article Circulation · February 11, 2020 BACKGROUND: Insight into type 5 long QT syndrome (LQT5) has been limited to case reports and small family series. Improved understanding of the clinical phenotype and genetic features associated with rare KCNE1 variants implicated in LQT5 was sought throug ... Full text Open Access Link to item Cite

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

Journal Article J Card Fail · December 2019 BACKGROUND: Wolff-Parkinson-White (WPW) has been associated with left ventricular noncompaction (LVNC) in children. Little is known about the prevalence of this association, clinical outcomes, and treatment options. METHODS: Retrospective review of subject ... Full text Open Access Link to item Cite

Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.

Journal Article Sci Rep · June 21, 2019 Junctophilin-2 (JPH2) is a part of the junctional membrane complex that facilitates calcium-handling in the cardiomyocyte. Previously, missense variants in JPH2 have been linked to hypertrophic cardiomyopathy; however, pathogenic "loss of function" (LOF) v ... Full text Open Access Link to item Cite

Incidentally identified genetic variants in arrhythmogenic right ventricular cardiomyopathy-associated genes among children undergoing exome sequencing reflect healthy population variation.

Journal Article Mol Genet Genomic Med · June 2019 BACKGROUND: With expanding use of clinical whole exome sequencing (WES), genetic variants of uncertain significance are increasingly identified. As pathologic mutations in genes associated with arrhythmogenic right ventricular cardiomyopathy (ARVC) carry a ... Full text Open Access Link to item Cite

Determining the Likelihood of Variant Pathogenicity Using Amino Acid-level Signal-to-Noise Analysis of Genetic Variation.

Journal Article J Vis Exp · January 16, 2019 Advancements in the cost and speed of next generation genetic sequencing have generated an explosion of clinical whole exome and whole genome testing. While this has led to increased identification of likely pathogenic mutations associated with genetic syn ... Full text Open Access Link to item Cite

A 14-year-old in heart failure with multiple cardiomyopathy variants illustrates a role for signal-to-noise analysis in gene test re-interpretation.

Journal Article Clin Case Rep · January 2019 Variants of unknown significance in cardiomyopathic disease should be analyzed systematically based on the prevalence of the variant in the population compared to prevalence of disease, evidence that other variants in the gene are pathologic, consistency o ... Full text Open Access Link to item Cite

Early experience with intravenous sotalol in children with and without congenital heart disease.

Journal Article Heart Rhythm · December 2018 BACKGROUND: Arrhythmias are common in the pediatric population. In patients unable to take oral medications or in need of acute therapy, options of intravenous (IV) antiarrhythmic medications are limited. Recently IV sotalol has become readily available, b ... Full text Open Access Link to item Cite

Copy Number Variants of Undetermined Significance Are Not Associated with Worse Clinical Outcomes in Hypoplastic Left Heart Syndrome.

Journal Article J Pediatr · November 2018 OBJECTIVE: To determine the prevalence, spectrum, and prognostic significance of copy number variants of undetermined significance (cnVUS) seen on chromosomal microarray (CMA) in neonates with hypoplastic left heart syndrome (HLHS). STUDY DESIGN: Neonates ... Full text Open Access Link to item Cite

Amino acid-level signal-to-noise analysis of incidentally identified variants in genes associated with long QT syndrome during pediatric whole exome sequencing reflects background genetic noise.

Journal Article Heart Rhythm · July 2018 BACKGROUND: Due to rapid expansion of clinical genetic testing, an increasing number of genetic variants of undetermined significance and unclear diagnostic value are being identified in children. Variants found in genes associated with heritable channelop ... Full text Open Access Link to item Cite

Corrigendum.

Journal Article Am J Physiol Heart Circ Physiol · May 1, 2018 Full text Link to item Cite

Hypertension Susceptibility Loci are Associated with Anthracycline-related Cardiotoxicity in Long-term Childhood Cancer Survivors.

Journal Article Sci Rep · August 29, 2017 Anthracycline-based chemotherapy is associated with dose-dependent, irreversible damage to the heart. Childhood cancer survivors with hypertension after anthracycline exposure are at increased risk of cardiotoxicity, leading to the hypothesis that genetic ... Full text Open Access Link to item Cite

Calcium Signaling and Cardiac Arrhythmias.

Journal Article Circ Res · June 9, 2017 There has been a significant progress in our understanding of the molecular mechanisms by which calcium (Ca2+) ions mediate various types of cardiac arrhythmias. A growing list of inherited gene defects can cause potentially lethal cardiac arrhythmia syndr ... Full text Open Access Link to item Cite

Interpreting Incidentally Identified Variants in Genes Associated With Catecholaminergic Polymorphic Ventricular Tachycardia in a Large Cohort of Clinical Whole-Exome Genetic Test Referrals.

Journal Article Circ Arrhythm Electrophysiol · April 2017 BACKGROUND: The rapid expansion of genetic testing has led to increased utilization of clinical whole-exome sequencing (WES). Clinicians and genetic researchers are being faced with assessing risk of disease vulnerability from incidentally identified genet ... Full text Open Access Link to item Cite

Novel junctophilin-2 mutation A405S is associated with basal septal hypertrophy and diastolic dysfunction.

Journal Article JACC Basic Transl Sci · February 2017 BACKGROUND: Hypertrophic cardiomyopathy (HCM), defined as asymmetric left ventricular hypertrophy, is a leading cause of cardiac death in the young. Perturbations in calcium (Ca2+) handling proteins have been implicated in the pathogenesis of HCM. JPH2-enc ... Full text Open Access Link to item Cite

Hypertrophic Cardiomyopathy Cardiac Troponin C Mutations Differentially Affect Slow Skeletal and Cardiac Muscle Regulation.

Journal Article Front Physiol · 2017 Mutations in TNNC1-the gene encoding cardiac troponin C (cTnC)-that have been associated with hypertrophic cardiomyopathy (HCM) and cardiac dysfunction may also affect Ca2+-regulation and function of slow skeletal muscle since the same gene is expressed in ... Full text Open Access Link to item Cite

Novel long QT syndrome-associated missense mutation, L762F, in CACNA1C-encoded L-type calcium channel imparts a slower inactivation tau and increased sustained and window current.

Journal Article Int J Cardiol · October 1, 2016 BACKGROUND: Mutations in the CACNA1C-encoded L-type calcium channel have been associated with Timothy syndrome (TS) with severe QT prolongation, syndactyly, facial dysmorphisms, developmental delay, and sudden death. Recently, patients hosting CACNA1C muta ... Full text Open Access Link to item Cite

Reduced junctional Na+/Ca2+-exchanger activity contributes to sarcoplasmic reticulum Ca2+ leak in junctophilin-2-deficient mice.

Journal Article Am J Physiol Heart Circ Physiol · November 1, 2014 Expression silencing of junctophilin-2 (JPH2) in mouse heart leads to ryanodine receptor type 2 (RyR2)-mediated sarcoplasmic reticulum (SR) Ca(2+) leak and rapid development of heart failure. The mechanism and physiological significance of JPH2 in regulati ... Full text Open Access Link to item Cite

Emerging roles of junctophilin-2 in the heart and implications for cardiac diseases.

Journal Article Cardiovasc Res · July 15, 2014 Cardiomyocytes rely on a highly specialized subcellular architecture to maintain normal cardiac function. In a little over a decade, junctophilin-2 (JPH2) has become recognized as a cardiac structural protein critical in forming junctional membrane complex ... Full text Open Access Link to item Cite

The junctophilin family of proteins: from bench to bedside.

Journal Article Trends Mol Med · June 2014 Excitable tissues rely on junctional membrane complexes to couple cell surface signals to intracellular channels. The junctophilins have emerged as a family of proteins critical in coordinating the maturation and maintenance of this cellular ultrastructure ... Full text Open Access Link to item Cite

Distinguishing hypertrophic cardiomyopathy-associated mutations from background genetic noise.

Journal Article J Cardiovasc Transl Res · April 2014 Despite the significant progress that has been made in identifying disease-associated mutations, the utility of the hypertrophic cardiomyopathy (HCM) genetic test is limited by a lack of understanding of the background genetic variation inherent to these s ... Full text Open Access Link to item Cite

Mutation E169K in junctophilin-2 causes atrial fibrillation due to impaired RyR2 stabilization.

Journal Article J Am Coll Cardiol · November 19, 2013 OBJECTIVES: This study sought to study the role of junctophilin-2 (JPH2) in atrial fibrillation (AF). BACKGROUND: JPH2 is believed to have an important role in sarcoplasmic reticulum (SR) Ca(2+) handling and modulation of ryanodine receptor Ca(2+) channels ... Full text Open Access Link to item Cite

Junctophilin-2 is necessary for T-tubule maturation during mouse heart development.

Journal Article Cardiovasc Res · October 1, 2013 AIMS: Transverse tubules (TTs) provide the basic subcellular structures that facilitate excitation-contraction (EC) coupling, the essential process that underlies normal cardiac contractility. Previous studies have shown that TTs develop within the first f ... Full text Open Access Link to item Cite

A mutation in TNNC1-encoded cardiac troponin C, TNNC1-A31S, predisposes to hypertrophic cardiomyopathy and ventricular fibrillation.

Journal Article J Biol Chem · September 14, 2012 Defined as clinically unexplained hypertrophy of the left ventricle, hypertrophic cardiomyopathy (HCM) is traditionally understood as a disease of the cardiac sarcomere. Mutations in TNNC1-encoded cardiac troponin C (cTnC) are a relatively rare cause of HC ... Full text Open Access Link to item Cite

Beyond the cardiac myofilament: hypertrophic cardiomyopathy- associated mutations in genes that encode calcium-handling proteins.

Journal Article Curr Mol Med · June 2012 Traditionally regarded as a genetic disease of the cardiac sarcomere, hypertrophic cardiomyopathy (HCM) is the most common inherited cardiovascular disease and a significant cause of sudden cardiac death. While the most common etiologies of this phenotypic ... Full text Open Access Link to item Cite

The Achilles' heel of cardiovascular genetic testing: distinguishing pathogenic mutations from background genetic noise.

Journal Article Clin Pharmacol Ther · October 2011 Although the etiologies of sudden cardiac death (SCD) are diverse, genetic mutations associated with cardiomyopathic and channelopathic diseases are major causes, and clinically available genetic tests offer the potential to identify at-risk family members ... Full text Open Access Link to item Cite

Distinguishing arrhythmogenic right ventricular cardiomyopathy/dysplasia-associated mutations from background genetic noise.

Journal Article J Am Coll Cardiol · June 7, 2011 OBJECTIVES: The aims of this study were to determine the spectrum and prevalence of "background genetic noise" in the arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC) genetic test and to determine genetic associations that can guide the int ... Full text Open Access Link to item Cite

Dysferlin, annexin A1, and mitsugumin 53 are upregulated in muscular dystrophy and localize to longitudinal tubules of the T-system with stretch.

Journal Article J Neuropathol Exp Neurol · April 2011 Mutations in dysferlin cause an inherited muscular dystrophy because of defective membrane repair. Three interacting partners of dysferlin are also implicated in membrane resealing: caveolin-3 (in limb girdle muscular dystrophy type 1C), annexin A1, and th ... Full text Open Access Link to item Cite

Disrupted junctional membrane complexes and hyperactive ryanodine receptors after acute junctophilin knockdown in mice.

Journal Article Circulation · March 8, 2011 BACKGROUND: Excitation-contraction coupling in striated muscle requires proper communication of plasmalemmal voltage-activated Ca2+ channels and Ca2+ release channels on sarcoplasmic reticulum within junctional membrane complexes. Although previous studies ... Full text Open Access Link to item Cite

Junctophilin-2 expression silencing causes cardiocyte hypertrophy and abnormal intracellular calcium-handling.

Journal Article Circ Heart Fail · March 2011 BACKGROUND: Junctophilin-2 (JPH2), a protein expressed in the junctional membrane complex, is necessary for proper intracellular calcium (Ca(2+)) signaling in cardiac myocytes. Downregulation of JPH2 expression in a model of cardiac hypertrophy was recentl ... Full text Open Access Link to item Cite

PLN-encoded phospholamban mutation in a large cohort of hypertrophic cardiomyopathy cases: summary of the literature and implications for genetic testing.

Journal Article Am Heart J · January 2011 BACKGROUND: hypertrophic cardiomyopathy (HCM) is a major cause of sudden death in young athletes and one of the most common inherited cardiovascular diseases, affecting 1 in 500 individuals. Often viewed as a disease of the cardiac sarcomere, mutations in ... Full text Open Access Link to item Cite

Role of genetic testing for sudden death predisposing heart conditions in athletes

Journal Article Sports Cardiology Essentials: Evaluation, Management and Case Studies · 2011 Open Access Cite

Mutation type is not clinically useful in predicting prognosis in hypertrophic cardiomyopathy.

Journal Article Circulation · December 7, 2010 Hypertrophic cardiomyopathy (HCM), or clinically unexplained hypertrophy of the heart, is a common genetic cardiovascular disorder marked by genetic and phenotypic heterogeneity. As the genetic mutations underlying the pathogenesis of this disease have bee ... Full text Open Access Link to item Cite

Molecular evolution of the junctophilin gene family.

Journal Article Physiol Genomics · May 13, 2009 Junctophilins (JPHs) are members of a junctional membrane complex protein family important for the physical approximation of plasmalemmal and sarcoplasmic/endoplasmic reticulum membranes. As such, JPHs facilitate signal transduction in excitable cells betw ... Full text Link to item Cite

Molecular and functional characterization of novel hypertrophic cardiomyopathy susceptibility mutations in TNNC1-encoded troponin C.

Journal Article J Mol Cell Cardiol · August 2008 Hypertrophic Cardiomyopathy (HCM) is a common primary cardiac disorder defined by a hypertrophied left ventricle, is one of the main causes of sudden death in young athletes, and has been associated with mutations in most sarcomeric proteins (tropomyosin, ... Full text Link to item Cite

Philadelphia chromosome mosaicism at diagnosis in chronic myeloid leukemia: clinical correlates and effect on imatinib mesylate treatment outcome.

Journal Article Leuk Lymphoma · November 2007 In chemotherapy-treated patients with chronic myeloid leukemia (CML), the karyotypic detection of Philadelphia chromosome (Ph)-negative metaphases at diagnosis (i.e. Ph mosaicism) is not considered significant as a prognostic factor for survival. In the cu ... Full text Link to item Cite

Gain-of-function RAF1 mutations cause Noonan and LEOPARD syndromes with hypertrophic cardiomyopathy.

Journal Article Nat Genet · August 2007 Noonan and LEOPARD syndromes are developmental disorders with overlapping features, including cardiac abnormalities, short stature and facial dysmorphia. Increased RAS signaling owing to PTPN11, SOS1 and KRAS mutations causes approximately 60% of Noonan sy ... Full text Link to item Cite

Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans.

Journal Article J Mol Cell Cardiol · June 2007 Junctophilin-2 (JPH2) is a cardiac specific member of the junctophilins, a newly characterized family of junctional membrane complex proteins important in physically approximating the plasmalemmal L-type calcium channel and the sarcoplasmic reticulum ryano ... Full text Link to item Cite

Utility of peripheral blood dual color, double fusion fluorescent in situ hybridization for BCR/ABL fusion to assess cytogenetic remission status in chronic myeloid leukemia.

Journal Article Leuk Lymphoma · October 2006 The molecular signature of BCR-ABL fusion in chronic myeloid leukemia (CML) provides a unique tool for diagnosis and monitoring of tumor burden during therapy. The gold standard in this regard is conventional bone marrow cytogenetics. Peripheral blood fluo ... Full text Link to item Cite

Fluorescent in situ hybridization in the diagnosis, prognosis, and treatment monitoring of chronic myeloid leukemia.

Journal Article Leuk Lymphoma · March 2006 The unique molecular characteristic of chronic myeloid leukemia (CML), the disease-causing ABL (9q34) to BCR (22q11) translocation, has provided an invaluable tool for disease diagnosis and monitoring of treatment response. The traditional standard in this ... Full text Link to item Cite