Evaluation and Management of Chronic Heart Failure in Children and Adolescents With Congenital Heart Disease: A Scientific Statement From the American Heart Association.

With continued medical and surgical advancements, most children and adolescents with congenital heart disease are expected to survive to adulthood. Chronic heart failure is increasingly being recognized as a major contributor to ongoing morbidity and mortality in this population as it ages, and treatment strategies to prevent and treat heart failure in the pediatric population are needed. In addition to primary myocardial dysfunction, anatomical and pathophysiological abnormalities specific to various congenital heart disease lesions contribute to the development of heart failure and affect potential strategies commonly used to treat adult patients with heart failure. This scientific statement highlights the significant knowledge gaps in understanding the epidemiology, pathophysiology, staging, and outcomes of chronic heart failure in children and adolescents with congenital heart disease not amenable to catheter-based or surgical interventions. Efforts to harmonize the definitions, staging, follow-up, and approach to heart failure in children with congenital heart disease are critical to enable the conduct of rigorous scientific studies to advance our understanding of the actual burden of heart failure in this population and to allow the development of evidence-based heart failure therapies that can improve outcomes for this high-risk cohort.

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

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 with 1p36 deletion; however, the prognostic impact of PRDM16 loss is unknown. METHODS: This retrospective cohort included subjects with 1p36 deletion syndrome from 4 hospitals. Prevalence of cardiomyopathy and freedom from death, cardiac transplantation, or ventricular assist device were analyzed. A systematic review cohort was derived for further analysis. A cardiac-specific Prdm16 knockout mouse (Prdm16 conditional knockout) was generated. Echocardiography was performed at 4 and 6 to 7 months. Histology staining and qPCR were performed at 7 months to assess fibrosis. RESULTS: The retrospective cohort included 71 patients. Among individuals with PRDM16 deleted, 34.5% developed cardiomyopathy versus 7.7% of individuals with PRDM16 not deleted (P=0.1). In the combined retrospective and systematic review cohort (n=134), PRDM16 deletion-associated cardiomyopathy risk was recapitulated and significant (29.1% versus 10.8%, P=0.03). PRDM16 deletion was associated with increased risk of death, cardiac transplant, or ventricular assist device (P=0.04). Among those PRDM16 deleted, 34.5% of females developed cardiomyopathy versus 16.7% of their male counterparts (P=0.2). We find sex-specific differences in the incidence and the severity of contractile dysfunction and fibrosis in female Prdm16 conditional knockout mice. Further, female Prdm16 conditional knockout mice demonstrate significantly elevated risk of mortality (P=0.0003). CONCLUSIONS: PRDM16 deletion is associated with a significantly increased risk of cardiomyopathy and cardiac mortality. Prdm16 conditional knockout mice develop cardiomyopathy in a sex-biased way. Patients with PRDM16 deletion should be assessed for cardiac disease.

Longitudinal effect of disease-modifying therapy on left ventricular diastolic function in children with sickle cell anemia.

Cardiac abnormalities seen in sickle cell anemia (SCA) include diastolic dysfunction, which has been shown to be associated with high morbidity and early mortality. The effect of disease-modifying therapies (DMT) on diastolic dysfunction is poorly understood. We prospectively evaluated the effects of hydroxyurea and monthly erythrocyte transfusions on diastolic function parameters over 2 years. A total of 204 subjects with HbSS or HbSß0-thalassemia (mean age 11 ± 3.7 years), unselected for disease severity, had diastolic function assessed with surveillance echocardiograms twice, 2 years apart. During this 2-year observation period, 112 participants received DMTs (hydroxyurea, n = 72, monthly erythrocyte transfusions, n = 40), 34 initiated hydroxyurea, and 58 did not receive any DMT. The entire cohort showed an increase in left atrial volume index (LAVi) of 3.40 ± 10.86 mL/m2, p = .001 over 2 years. This increase in LAVi was independently associated with anemia, high baseline E/e' or LV dilation. Individuals not exposed to DMT were younger (mean age 8.8 ± 2.9 years), but at baseline their prevalence of abnormal diastolic parameters was similar to that of the DMT-exposed participants who were older (mean age 12 ± 3.8 years). Participants on DMTs saw no improvement in diastolic function over the study period. In fact, participants on hydroxyurea saw a possible worsening in diastolic parameters (14% increase in LAVi and ~5% decrease in septal e') but also a ~9% decrease in fetal hemoglobin (HbF) levels. Further studies are needed to evaluate if exposure to DMT for a longer duration or achieving higher HbF might be beneficial in alleviating diastolic dysfunction.

Biomarker sST2 in Adults with Transposition of the Great Arteries Palliated by Mustard Procedure: A Five-Year Follow-up.

The Mustard procedure was an early cardiac surgery for transposition of the great arteries (TGA). Despite being successful, it has been associated with long-term arrhythmias and heart failure. A key factor complicating management in adults with congenital heart disease (CHD) is the deficiency of biomarkers predicting outcome. Soluble suppression of tumorogenicity-2 (sST2) is secreted by cardiomyocytes in response to mechanical strain and fibrosis. We hypothesized that adults with a Mustard procedure would have higher levels of sST2 than healthy individuals, and this would correlate with clinical outcome. We performed a single-center study in patients managed during childhood with a Mustard procedure versus age-matched controls. Clinical and demographic data were collected and biomarkers (sST2, cTnI, BNP, lipid panel, insulin, and glucose) were obtained. There were 18 patients (12 male) in the Mustard cohort and 18 patients (6 male) in the control group (22-49 years, mean of 35.8 vs. mean 32.6 years, respectively, p = ns). Nine Mustard subjects were NYHA class II, and 9 subjects were class III. The control group was asymptomatic. sST2 in the Mustard group was elevated in 56% vs. 17% in controls (p = 0.035). Of the Mustard subjects with elevated sST2, 60% had elevated cTnI and BNP, and 90% had low HDL. Over five years, the Mustard patients with elevated sST2 values had greater medication use, arrhythmias, hospitalizations, and ablation/pacer implantations than Mustard subjects with normal sST2. Mustard subjects with elevated sST2 had other biomarker abnormalities and clinically worse outcomes. Thus, sST2 may add a predictive value to cardiac-related morbidity and mortality.

Exploring the Regulation and Function of Rpl3l in the Development of Early-Onset Dilated Cardiomyopathy and Congestive Heart Failure Using Systems Genetics Approach.

BACKGROUND: Cardiomyopathies, diseases affecting the myocardium, are common causes of congestive heart failure (CHF) and sudden cardiac death. Recently, biallelic variants in ribosomal protein L3-like (RPL3L) have been reported to be associated with severe neonatal dilated cardiomyopathy (DCM) and CHF. This study employs a systems genetics approach to gain understanding of the regulatory mechanisms underlying the role of RPL3L in DCM. METHODS: Genetic correlation, expression quantitative trait loci (eQTL) mapping, differential expression analysis and comparative functional analysis were performed using cardiac gene expression data from the patients and murine genetic reference populations (GRPs) of BXD mice (recombinant inbred strains from a cross of C57BL/6J and DBA/2J mice). Additionally, immune infiltration analysis was performed to understand the relationship between DCM, immune cells and RPL3L expression. RESULTS: Systems genetics analysis identified high expression of Rpl3l mRNA, which ranged from 11.31 to 12.16 across murine GRPs of BXD mice, with an ~1.8-fold difference. Pathways such as "diabetic cardiomyopathy", "focal adhesion", "oxidative phosphorylation" and "DCM" were significantly associated with Rpl3l. eQTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l. The mRNA expression of Rpl3l, Myl4 and Sdha was significantly correlated with multiple echocardiography traits in BXD mice. Immune infiltration analysis revealed a significant association of RPL3L and SDHA with seven immune cells (CD4, CD8-naive T cell, CD8 T cell, macrophages, cytotoxic T cell, gamma delta T cell and exhausted T cell) that were also differentially infiltrated between heart samples obtained from DCM patients and normal individuals. CONCLUSIONS: RPL3L is highly expressed in the heart tissue of humans and mice. Expression of Rpl3l and its upstream regulators, Myl4 and Sdha, correlate with multiple cardiac function traits in murine GRPs of BXD mice, while RPL3L and SDHA correlate with immune cell infiltration in DCM patient hearts, suggesting important roles for RPL3L in DCM and CHF pathogenesis via immune inflammation, necessitating experimental validations of Myl4 and Sdha in Rpl3l regulation.

Bridging the gap to advance the care of individuals with cancer: collaboration and partnership in the Cardiology Oncology Innovation Network (COIN).

Cardiovascular diseases and cancer continue to be the two leading causes of death in the United States. While innovations in artificial intelligence, digital health, and telemedicine may revolutionize cardio-oncology clinical practice, barriers to widespread adoption continue to exist. The most effective way to advance these technologies is through a broad range of stakeholders sharing a common vision. Additionally, as we enter the digital era in healthcare, we must help lead this charge for the benefit of our cardiology and oncology patients. Bolstering collaborations in cardiology and oncology is key, in partnership with technology firms, industry, academia, and private practice, with an emphasis on various forms of innovation. The ultimate goal is to connect our patients and their health to informatics-based opportunities to advance cardiovascular disease prevention in cancer patients. We have established the Cardiology Oncology Innovation Network in accordance with this vision, to develop new care delivery options through the use of innovative technological strategies. Our tripartite mission - innovation, collaboration, and education - aims to increase access to and expertise in digital transformation to prevent cardiovascular diseases in cancer patients. Here we describe network initiatives, early accomplishments, and future milestones.

Current Practices in Treating Cardiomyopathy and Heart Failure in Duchenne Muscular Dystrophy (DMD): Understanding Care Practices in Order to Optimize DMD Heart Failure Through ACTION.

Cardiac disease has emerged as a leading cause of mortality in Duchenne muscular dystrophy in the current era. This survey sought to identify the diagnostic and therapeutic approach to DMD among pediatric cardiologists in Advanced Cardiac Therapies Improving Outcomes Network. Pediatric cardiology providers within ACTION (a multi-center pediatric heart failure learning network) were surveyed regarding their approaches to cardiac care in DMD. Thirty-one providers from 23 centers responded. Cardiac MRI and Holter monitoring are routinely obtained, but the frequency of use and indications for ordering these tests varied widely. Angiotensin converting enzyme inhibitor and aldosterone antagonist are generally initiated prior to onset of systolic dysfunction, while the indications for initiating beta-blocker therapy vary more widely. Seventeen (55%) providers report their center has placed an implantable cardioverter defibrillator in at least 1 DMD patient, while 11 providers (35%) would not place an ICD for primary prevention in a DMD patient. Twenty-three providers (74%) would consider placement of a ventricular assist device (VAD) as destination therapy (n = 23, 74%) and three providers (10%) would consider a VAD only as bridge to transplant. Five providers (16%) would not consider VAD at their institution. Cardiac diagnostic and therapeutic approaches vary among ACTION centers, with notable variation present regarding the use of advanced therapies (ICD and VAD). The network is currently working to harmonize medical practices and optimize clinical care in an era of rapidly evolving outcomes and cardiac/skeletal muscle therapies.

Connected Health Innovation Research Program (C.H.I.R.P.): A bridge for digital health and wellness in cardiology and oncology.

Study objective: Cancer and heart disease are leading causes of mortality, and cardio-oncology is emerging as a new field addressing the cardiovascular toxicities related to cancer and cancer therapy. Interdisciplinary research platforms that incorporate digital health to optimize cardiovascular health and wellness in cancer survivors are therefore needed as we advance in the digital era. Our goal was to develop the Connected Health Innovation Research Program (C.H.I.R.P.) to serve as a foundation for future integration and assessments of adoption and clinical efficacy of digital health tools for cardiovascular health and wellness in the general population and in oncology patients. Design/setting/participants: Partner companies were identified through the American Medical Association innovation platform, as well as LinkedIn and direct contact by our team. Company leaders met with our team to discuss features of their technology or software. Non-disclosure agreements were signed and data were discussed and obtained for descriptive or statistical analysis. Results: A suite of companies with technologies focused on wellness, biometrics tracking, audio companions, oxygen saturation, weight trends, sleep patterns, heart rate variability, electrocardiogram patterns, blood pressure patterns, real-time metabolism tracking, instructional video modules, or integration of these technologies into electronic health records was collated. We formed an interdisciplinary research team and established an academia-industry collaborative foundation for connecting patients with wellness digital health technologies. Conclusions: A suite of software and device technologies accessible to the cardiology and oncology population has been established and will facilitate retrospective, prospective, and case research studies assessing adoption and clinical efficacy of digital health tools in cardiology/oncology.

Pediatric Cardio-Oncology Medicine: A New Approach in Cardiovascular Care.

Survival for pediatric patients diagnosed with cancer has improved significantly. This achievement has been made possible due to new treatment modalities and the incorporation of a systematic multidisciplinary approach for supportive care. Understanding the distinctive cardiovascular characteristics of children undergoing cancer therapies has set the underpinnings to provide comprehensive care before, during, and after the management of cancer. Nonetheless, we acknowledge the challenge to understand the rapid expansion of oncology disciplines. The limited guidelines in pediatric cardio-oncology have motivated us to develop risk-stratification systems to institute surveillance and therapeutic support for this patient population. Here, we describe a collaborative approach to provide wide-ranging cardiovascular care to children and young adults with oncology diseases. Promoting collaboration in pediatric cardio-oncology medicine will ultimately provide excellent quality of care for future generations of patients.

Cardiac remodeling after anthracycline and radiotherapy exposure in adult survivors of childhood cancer: A report from the St Jude Lifetime Cohort Study.

BACKGROUND: Limited data exist regarding left ventricular remodeling patterns observed in adult survivors of childhood cancer after therapy. METHODS: Among 1190 adult survivors diagnosed with childhood cancer (median age at diagnosis, 9 years [interquartile range (IQR), 3.8-14.4 years]; age at evaluation, 35.6 years [IQR, 29.5-42.8 years]), treatment exposures included anthracyclines (n = 346), chest radiotherapy (n = 174), both (n = 245), or neither (n = 425). Prospective echocardiographic assessment compared survivors with 449 noncancer controls classified according to left ventricle geometric patterns. Associations between left ventricle geometric patterns and decreased exercise tolerance were assessed. RESULTS: Overall, 28.2% of survivors (95% confidence interval [CI], 25.6%-30.8%) exhibited concentric remodeling, 2.4% (95% CI, 1.6%-3.5%) exhibited eccentric hypertrophy, and 1.1% (95% CI, 0.6%-1.9%) exhibited concentric hypertrophy. A greater proportion of survivors who received only chest radiotherapy (41%) had concentric remodeling compared with those who received only anthracyclines (24%), both (27%), or neither (27%; all P < .001), and all were greater than the proportions in noncancer controls (18%; all P < .05). Concentric remodeling was associated with radiation exposure, but not with anthracycline exposure, in multivariable models. Survivors who had concentric remodeling were more likely to have a maximal oxygen uptake peak <85% compared with those who had normal geometry (81.0% vs 66.3%; odds ratio, 1.75; 95% CI, 1.15-2.68). CONCLUSIONS: Chest radiation therapy, but not anthracycline therapy, increased the risk for concentric remodeling in survivors of childhood cancer. The presence of concentric remodeling was associated with increased exercise intolerance.

Association of persistent tachycardia with early myocardial dysfunction in children undergoing allogeneic hematopoietic cell transplantation.

Cancer survivors who have undergone hematopoietic cell transplantation (HCT) are at risk for myocardial dysfunction. Children who receive allogenic HCT encounter systemic inflammation resulting in tachycardia and hypertension. The effect of these abnormalities on myocardial function is not known. The aim of this study was to determine whether cardiac dysfunction early after HCT can be predicted by tachycardia or hypertension, within a retrospective single-center sample of pediatric HCT recipients. Early tachycardia or hypertension was defined as a majority of values taken from infusion date to 90 days post-infusion being abnormal. Ejection fraction <53% determined systolic dysfunction. A composite score of accepted pediatric diastolic abnormalities determined diastolic dysfunction. Among 80 subjects (median age 8 years), early tachycardia, systolic dysfunction, and diastolic dysfunction were present in 64%, 25%, and 48% of the sample, respectively. In multivariable models, early tachycardia was an independent predictor of early systolic dysfunction (OR = 12.6 [1.4-112.8], p = 0.024) and diastolic dysfunction (OR = 3.9 [1.3-11.5], p = 0.013). Tachycardia and cardiac dysfunction are common and associated with one another in the early period after pediatric HCT. Future studies may elucidate the role of tachycardia and myocardial dysfunction early after HCT as important predictors of future cardiovascular dysfunction.

Clinical Insights Into Heritable Cardiomyopathies.

Cardiomyopathies (CMs) encompass a heterogeneous group of structural and functional abnormalities of the myocardium. The phenotypic characteristics of these myocardial diseases range from silent to symptomatic heart failure, to sudden cardiac death due to malignant tachycardias. These diseases represent a leading cause of cardiovascular morbidity, cardiac transplantation, and death. Since the discovery of the first locus associated with hypertrophic cardiomyopathy 30 years ago, multiple loci and molecular mechanisms have been associated with these cardiomyopathy phenotypes. Conversely, the disparity between the ever-growing landscape of cardiovascular genetics and the lack of awareness in this field noticeably demonstrates the necessity to update training curricula and educational pathways. This review summarizes the current understanding of heritable CMs, including the most common pathogenic gene variants associated with the morpho-functional types of cardiomyopathies: dilated, hypertrophic, arrhythmogenic, non-compaction, and restrictive. Increased understanding of the genetic/phenotypic associations of these heritable diseases would facilitate risk stratification to leveraging appropriate surveillance and management, and it would additionally provide identification of family members at risk of avoidable cardiovascular morbidity and mortality.

Echocardiographic myocardial strain analysis describes subclinical cardiac dysfunction after craniospinal irradiation in pediatric and young adult patients with central nervous system tumors.

BACKGROUND: Craniospinal irradiation (CSI) is part of the treatment of central nervous system (CNS) tumors and is associated with cardiovascular disease in adults. Global myocardial strain analysis including longitudinal peak systolic strain (GLS), circumferential peak systolic strain (GCS), and radial peak systolic strain (GRS) can reveal subclinical cardiac dysfunction. METHODS: Retrospective, single-center study in patients managed with CSI vs. age-matched controls. Clinical data and echocardiography, including myocardial strain analysis, were collected at early (< 12 months) and late (≥ 12 months) time points after completion of CSI. RESULTS: Echocardiograms were available at 20 early and 34 late time points. Patients at the late time point were older (21.7 ± 10.4 vs. 13.3 ± 9.6 years) and further out from CSI (13.1 ± 8.8 vs. 0.2 ± 0.3 years). Standard echocardiographic parameters were normal for both groups. For early, CSI vs. control: GLS was - 16.8 ± 3.6% vs. -21.3 ± 4.0% (p = 0.0002), GCS was - 22.5 ± 5.2% vs. -21.3 ± 3.4% (p = 0.28), and GRS was 21.8 ± 11.0% vs. 26.9 ± 7.7% (p = 0.07). For late, CSI vs. control: GLS was - 16.2 ± 5.4% vs. -21.6 ± 3.7% (p < 0.0001), GCS was - 20.9 ± 6.8% vs. -21.9 ± 3.5% (p = 0.42), and GRS was 22.5 ± 10.0% vs. 27.3 ± 8.3% (p = 0.03). Radiation type (proton vs. photon), and radiation dose (< 30 Gy vs. ≥ 30 Gy) did not impact any parameter, although numbers were small. CONCLUSIONS: Subclinical cardiac systolic dysfunction by GLS is present both early and late after CSI. These results argue for future studies to determine baseline cardiovascular status and the need for early initiation of longitudinal follow-up post CSI.

Novel use of cangrelor in pediatrics: A pilot cohort study demonstrating use in ventricular assist devices.

Thromboembolic events and bleeding are major sources of morbidity among pediatric patients supported on a ventricular assist device (VAD). Pharmacokinetics and pharmacodynamics of enteral antiplatelet agents are affected and variable due to erratic enteral absorption in end-stage heart failure and VAD circulation. Additionally, 20%-40% of the population are poor metabolizers of clopidogrel, a prodrug, making cangrelor an alternative when antiplatelet therapy is crucial. Cangrelor has been used effectively and safely for short durations in adults during percutaneous coronary interventions, but the use of cangrelor is still under investigation in pediatrics. This case series utilized cangrelor, a novel short-acting, reversible, intravenous P2Y12 platelet inhibitor in managing pediatric patients supported with a VAD. We performed a retrospective, single-center review of patients admitted to a tertiary medical center with end-stage heart failure requiring mechanical circulatory support and concomitant cangrelor administration between January 2019 and March 2020. Platelet function testing, cangrelor dose, bleeding complications, thromboembolic events, and frequency of circuit interventions during the use of cangrelor were recorded. Optimal platelet reactivity, defined as P2Y12 < 180 platelet reaction units (PRU), was measured with serial point-of-care testing (VerifyNow). Seven patients, median age of 4.9 years, met the above criteria. Three patients had a diagnosis of complex congenital heart disease. Four patients had dilated or restrictive cardiomyopathy. All patients were on continuous flow VADs. The median VAD duration was 84.5 days (IQR 61.5-103). The median duration on cangrelor was 43 days (IQR 8-70). The median cangrelor dose to reach the therapeutic threshold was 0.75 µg/kg/min with the mean P2Y12 , while on cangrelor of 164.75 PRU. Bleeding complications included mild gastrointestinal bleeding and hematuria. There was one patient with pump thrombosis requiring intervention. There were no cerebrovascular events while on cangrelor. We report the first successful long-term use of cangrelor in pediatric patients. The reversibility and short half-life of cangrelor make it a feasible antiplatelet agent in selected patients. This data supports the use of cangrelor in children as a viable antiplatelet option; with minimal bleeding complications and no cerebrovascular events demonstrated in this cohort.

Profound Iron Deficiency Anemia and Irreversible Dilated Cardiomyopathy in a Child.

Iron deficiency anemia has been associated with a secondary and potentially reversible cardiomyopathy. The pathophysiologic paradigm has been that the hematologic disease begets cardiac dysfunction. There may be, however, a point at which myocardial injury is irreversible in susceptible individuals. We present the case of a 4-year-old, developmentally normal, child who presented with iron deficiency anemia and a dilated cardiomyopathy with congestive heart failure. Despite appropriate correction of the anemia, the patient developed decompensated heart failure requiring milrinone therapy and eventual heart transplantation. This report will alert clinicians to the potential for irreversible adverse cardiac remodeling and the importance of close pediatric cardiology consultation and serial assessment in order to implement appropriate heart failure therapy.

Identifiable Risk Factors and Miscalculations During Listing for Pediatric Heart Transplantation.

The objective of this study is to describe identifiable risk factors, complications, and pitfalls while listing pediatric patients for heart transplantation, which is the standard of care for end-stage heart disease in children. Since the introduction of cyclosporine in the 1980s, the management in pediatric heart transplantation has shown consistent improvement, mainly because of technological advances and the integration of multidisciplinary teams in the field. However, the complexity of this patient population makes medical providers vulnerable to complications as a result of undesirable mistakes. Transplant survival is impacted negatively when mistakes from health-care providers compound the high-risk status of the patient. The identification of multiple risk factors and undesirable miscalculations may help transplant teams make decisions before allocating organs, intervene or minimize morbidity, and provide the best quality of life to recipients.

Noncompaction cardiomyopathy and heterotaxy syndrome.

Left ventricular noncompaction cardiomyopathy (LVNC) is characterized by compact and trabecular layers of the left ventricular myocardium. This cardiomyopathy may occur with congenital heart disease (CHD). Single cases document co-occurrence of LVNC and heterotaxy, but no data exist regarding the prevalence of this association. This study sought to determine whether a non-random association of LVNC and heterotaxy exists by evaluating the prevalence of LVNC in patients with heterotaxy. In a retrospective review of the Indiana Network for Patient Care, we identified 172 patients with heterotaxy (69 male, 103 female). Echocardiography and cardiac magnetic resonance imaging results were independently reviewed by two cardiologists to ensure reproducibility of LVNC. A total of 13/172 (7.5%) patients met imaging criteria for LVNC. The CHD identified in this subgroup included atrioventricular septal defects [11], dextrocardia [10], systemic and pulmonary venous return abnormalities [7], and transposition of the great arteries [5]. From this subgroup, 61% (n = 8) of the patients developed arrhythmias; and 61% (n = 8) required medical management for chronic heart failure. This study indicates that LVNC has increased prevalence among patients with heterotaxy when compared to the general population (0.014-1.3%) suggesting possible common genetic mechanisms. Interestingly, mice with a loss of function of Scrib or Vangl2 genes showed abnormal compaction of the ventricles, anomalies in cardiac looping, and septation defects in previous studies. Recognition of the association between LVNC and heterotaxy is important for various reasons. First, the increased risk of arrhythmias demonstrated in our population. Secondly, theoretical risk of thromboembolic events remains in any LVNC population. Finally, many patients with heterotaxy undergo cardiac surgery (corrective and palliative) and when this is associated with LVNC, patients should be presumed to incur a higher peri-operative morbidity based on previous studies. Further research will continue to determine long-term and to corroborate genetic pathways.

Loss of Function Mutations in NNT Are Associated With Left Ventricular Noncompaction.

BACKGROUND: Left ventricular noncompaction (LVNC) is an autosomal-dominant, genetically heterogeneous cardiomyopathy with variable severity, which may co-occur with cardiac hypertrophy. METHODS AND RESULTS: Here, we generated whole exome sequence data from multiple members from 5 families with LVNC. In 4 of 5 families, the candidate causative mutation segregates with disease in known LVNC genes MYH7 and TPM1. Subsequent sequencing of MYH7 in a larger LVNC cohort identified 7 novel likely disease causing variants. In the fifth family, we identified a frameshift mutation in NNT, a nuclear-encoded mitochondrial protein, not implicated previously in human cardiomyopathies. Resequencing of NNT in additional LVNC families identified a second likely pathogenic missense allele. Suppression of nnt in zebrafish caused early ventricular malformation and contractility defects, probably driven by altered cardiomyocyte proliferation. In vivo complementation studies showed that mutant human NNT failed to rescue nnt morpholino-induced heart dysfunction, indicating a probable haploinsufficiency mechanism. CONCLUSIONS: Together, our data expand the genetic spectrum of LVNC and demonstrate how the intersection of whole exome sequence with in vivo functional studies can accelerate the identification of genes that drive human genetic disorders.

Novel cardiovascular findings in association with a POMT2 mutation: three siblings with α-dystroglycanopathy.

Dystroglycanopathies are a genetically heterogeneous subset of congenital muscular dystrophies that exhibit autosomal recessive inheritance and are characterized by abnormal glycosylation of α-dystroglycan. In particular, POMT2 (protein O-mannosyltransferase-2) mutations have been identified in congenital muscular dystrophy patients with a wide range of clinical involvement, ranging from the severe muscle-eye-brain disease and Walker-Warburg syndrome to limb girdle muscular dystrophy without structural brain or ocular involvement. Cardiovascular disease is thought to be uncommon in congenital muscular dystrophy, with rare reports of cardiac involvement. We describe three brothers aged 21, 19, and 17 years with an apparently homozygous POMT2 mutation who all presented with congenital muscular dystrophy, intellectual disabilities, and distinct cardiac abnormalities. All three brothers were homozygous for a p.Tyr666Cys missense mutation in exon 19 of the POMT2 gene. On screening echocardiograms, all siblings demonstrated significant dilatation of the aortic root and depressed left ventricular systolic function and/or left ventricular wall motion abnormalities. Our report is the first to document an association between POMT2 mutations and aortopathy with concomitant depressed left ventricular systolic function. On the basis of our findings, we suggest patients with POMT2 gene mutations be screened not only for myocardial dysfunction but also for aortopathy. In addition, given the potential for progression of myocardial dysfunction and/or aortic dilatation, longitudinal surveillance imaging is recommended both for patients with disease as well as those that have normal baseline imaging.