Hugh D. Allen

A randomized, double-blind trial of lisinopril and losartan for the treatment of cardiomyopathy in duchenne muscular dystrophy.

Objectives: This study sought to compare the effectiveness and safety of an angiotensin converting enzyme inhibitor (ACE-I) (lisinopril) vs. an angiotensin receptor blocker (ARB) (losartan) for the treatment of cardiomyopathy (CM) in boys with Duchenne muscular dystrophy (DMD). Background: Development of CM is universal in boys with DMD. ACE-I and ARB have both been suggested as effective treatment options. ARBs have been associated with skeletal muscle regeneration in a mouse model of DMD. The question of which, if either, is more effective for CM treatment in DMD remains. The purpose of this multicenter double-blind prospective study was to compare efficacy and safety of lisinopril versus losartan in the treatment of newly diagnosed CM in boys with DMD. Methods: Echocardiographic technician inter- and intraobserver variability were tested on 2 separate days on 2 different boys with DMD CM. Results were compared with paired t-testing. Twenty-two boys with newly diagnosed DMD CM (echocardiographic ejection fraction (EF) 10% EF drop. Three boys in the aCE-I group had 3 visits, due to study funding termination. Two were withdrawn because of low EF. All their data are included in the analysis for as long as they remained in the study. Mean EF’s were similar at baseline (47.5%- ACE-I, 48.4%- ARB). After 1 year each group significantly improved to 54.6% and 55.2% respectively (p=.02). There was no difference between the 2 treatment groups at 1 year. Conclusions: Inter-observer and intra-observer reliability studies showed no differences between echocardiographers on serial examinations. EF improved equally in the two groups. There is no therapeutic difference in EF improvement between lisinopril and losartan over the one-year duration for treatment of boys with DMD-related CM. Trial Registration: ClinicalTrials.gov NCT01982695

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.

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 mutations with only long QT syndrome (LQTS) have been described. We sought to identify novel variants in CACNA1C associated with either TS or LQTS, and to determine the impact of the mutation on channel function. METHODS/RESULTS Two probands were identified with mutations in CACNA1C, one with a TS-associated mutation, G406R, and a second with genotype-negative LQTS. Illumina HiSeq 2000 whole exome sequencing on the genotype-negative LQTS proband revealed a novel variant, CACNA1C-L762F, that co-segregated within a multi-generational family. The missense mutation localized to the DII/DIII intracellular interlinker segment of the channel in a highly conserved region in close proximity to the 6th transmembrane segment of domain II (DIIS6). Whole cell patch clamp of heterologously expressed CACNA1C-L762F in TSA201 cells demonstrated slower inactivation tau and increased sustained and window current. Comprehensive review and topological mapping of all described CACNA1C mutations revealed TS-specific hotspots localizing to the cytoplasmic aspect of 6th transmembrane segment of respective domains. Probands hosting TS mutations were associated with elevated QTc, higher prevalence of 2:1 AV block, and a younger age at presentation compared to LQTS. CONCLUSIONS The CACNA1C-L762F mutation is associated with development of LQTS through slower channel inactivation and increased sustained and window current. TS-associated mutations localize to specific areas of CACNA1C and are associated with a younger age at presentation, higher QTc, and 2:1 AV block than isolated LQTS-associated mutations.

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

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 genetic variants which is typified by variants found in genes associated with sudden death-predisposing catecholaminergic polymorphic ventricular tachycardia (CPVT). We sought to determine whether incidentally identified variants in genes associated with CPVT from WES clinical testing represent disease-associated biomarkers. Methods and Results— CPVT-associated genes RYR2 and CASQ2 variants were identified in one of the world’s largest collections of clinical WES referral tests (N=6517, Baylor Miraca Genetics Laboratories) and compared with a control cohort of ostensibly healthy individuals (N=60 706) and a case cohort of CPVT cases (N=155). Within the WES cohort, the rate of rare variants in CPVT-associated genes was 8.8% compared with 6.0% among controls and 60.0% among cases. There was a predominance of variants of undetermined significance (97.7%). After protein topology mapping, WES variants colocalized more frequently to residues with variants found in controls compared with cases. Retrospective clinical evaluation of individuals referred to our institution with WES-positive variants demonstrated no evidence of clinical CPVT in individuals with a low pretest clinical suspicion for CPVT. Conclusions— The prevalence of incidentally identified CPVT-associated variants is ≈9% among WES tests. Variants of undetermined significances in CPVT-associated genes in WES genetic testing, in the absence of clinical suspicion for CPVT, are unlikely to represent markers of CPVT pathogenicity.

Visual Diagnosis: Chest Pain in a Boy With Duchenne Muscular Dystrophy and Cardiomyopathy

1. Philip T. Thrush, MD* 2. Kevin M. Flanigan, MD†,‡§ 3. Jerry R. Mendell, MD†,‡§ 4. Subha V. Raman, MD|| 5. Curt J. Daniels, MD*,|| 6. Hugh D. Allen, MD¶ 1. *Department of Pediatrics, The Ohio State University, The Heart Center, Nationwide Childrens Hospital, Columbus, OH. 2. †The Center for Gene Therapy, Research Institute, Nationwide Children’s Hospital, Columbus, OH. 3. ‡Muscular Dystrophy Cooperative Research Center, Nationwide Childrens Hospital, Columbus, OH. 4. §Departments of Pediatrics and Neurology, The Ohio State University, Nationwide Childrens Hospital, Columbus, OH. 5. ||Division of Cardiovascular Medicine, The Ohio State University, Columbus, OH. 6. ¶Associate Editor. Department of Pediatrics, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX. * Abbreviations: DMD: : Duchenne muscular dystrophy EF: : ejection fraction ECG: : electrocardiography CMRI: : cardiac magnetic resonance imaging LGE: : late gadolinium enhancement A 17-year-old boy with Duchenne muscular dystrophy (DMD) due to a deletion of exons 18 to 37 in the DMD gene was diagnosed in our clinic as having cardiomyopathy at age 12 years. His current medications include deflazacort (30 mg/d), lisinopril (10 mg once daily for cardiomyopathy), and metoprolol succinate (50 mg twice daily for disordered automaticity). His cardiac function had been stable, with ejection fractions (EFs) ranging from 47% to 55%. After 1 day of headache and emesis, he presents to a local emergency department with acute onset of chest pain and shortness of breath. Electrocardiography (ECG) reveals ST-segment elevation in the inferolateral leads and ST-segment depression in the midprecordial leads, which prompts further testing (Figure 1). His initial troponin I level is elevated. He is transferred to a tertiary care facility for further evaluation. At the time of admission, his chest pain is substantially improved without intervention, but his troponin I level is now 40.27 ng/mL (40.27 μg/L) (reference range, <0.04 ng/mL [<0.04 μg/L]). Further laboratory evaluation reveals a white blood cell count of 12,900 /μL, 72% neutrophils, 20% lymphocytes, a C-reactive protein level of 299.8 mg/L (2855.3 nmol/L) (reference range, <12.0 mg/L [114.3 nmol/L]), and a lactate level of 7.2 mg/dL (0.8 mmol/L) (reference range, 4.5-19.8 mg/dL [0.5-2.2 mmol/L]). Cardiac magnetic resonance imaging (CMRI) with late gadolinium enhancement (LGE) reveals extensive left ventricular lateral wall epicardial enhancement (Figure 2A) and an EF of 50%. Quantitative T2 mapping reveals an increased T2 signal (80 milliseconds compared with 48 milliseconds in the unaffected interventricular septum) in the same region consistent with acute inflammation and injury …

Visual Diagnosis: A 7-year-old Boy with Dyspnea and an Unusual Chest Radiograph

1. Katherine B. Salciccioli, MD* 2. Athar M. Qureshi, MD*,† 3. Hugh D. Allen, MD*,† 1. *Department of Cardiology, Texas Children’s Hospital, Houston, TX 2. †Baylor College of Medicine, Houston, TX A 7-year-old boy presents to his pediatrician with gradually worsening shortness of breath and exercise intolerance over months to years. He was admitted for right-sided pneumonia twice during childhood with seemingly complete recovery each time, but otherwise he has been generally healthy and developmentally appropriate. Current medications include albuterol inhalers taken as needed since early childhood for wheezing during viral illnesses. With the recent worsening of his symptoms, albuterol is again tried without any improvement in his symptoms. He does not have fever, cough, nasal congestion, chest pain, palpitations, vomiting, diarrhea, or weight changes. On physical examination, the patient has normal vital signs. He is small for his age but is following his growth curve appropriately with height in the 15th percentile and weight in the 11th percentile. He has normal findings on head and neck examination. His cardiac examination is notable for a fixed split S2 with no murmurs, rubs, or gallops. He has diminished breath sounds on the right with a soft, intermittent expiratory wheeze and a clear left lung. He has no abdominal organomegaly. Pulses are 2+ and symmetric in all extremities. In addition to his physical examination findings, a chest radiograph (Fig 1) is interpreted as showing dextrocardia, so the patient is referred to the cardiology clinic where echocardiography reveals the diagnosis. Figure 1. Chest radiograph interpreted as dextrocardia, prominent right-sided pulmonary vasculature, and hyperinflation of the left lung. In the cardiology clinic, echocardiography shows the heart located in the right chest, with the cardiac apex pointing leftward, partial anomalous venous return to the inferior vena cava (IVC) (Video 1), and mild right heart dilation (Video 2 …

Visual Diagnosis: Visual Impairment, Polydactyly, and Obesity: Red Flags in a Child

1. Hitesh Agrawal, MD* 2. Gunjan Dokania, MD† 3. Hugh D. Allen, MD* 1. *Lille Frank Abercrombie Section of Pediatric Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX 2. †Hope Clinic, Asian American Health Coalition of the Greater Houston Area, Houston, TX A 6-year-old boy who recently emigrated from Afghanistan presents for a routine health supervision visit. His parents are concerned about his progressive poor night vision, and he has polydactyly in the right hand. Speech and motor development are delayed. He started walking and talking late, at approximately 2 years of age according to his parents. He was born at full term via normal vaginal delivery and had an unremarkable hospital course. He had extra digits on the bilateral upper and lower extremities consisting of 6 and 7 digits, respectively. All the extra digits were surgically removed at 1 year of age, except the sixth digit in the right hand (Fig 1A), which was left on the parents’ request. There are healed surgical scars secondary to the removal of extra digits from the left upper extremity and both lower extremities (Fig 1B). He has short stature (height for age is at the third percentile) and truncal obesity (body mass …

Congenital Heart Disease

1. Kriti Puri, MD* 2. Hugh D. Allen, MD* 3. Athar M. Qureshi, MD*,† 1. *Department of Pediatrics, 2. †CE Mullins Cardiac Catheterization Laboratories, The Lillie Frank Abercombie Section of Cardiology, Texas Children’s Hospital, Baylor College of Medicine, Houston, TX * Abbreviations: ASD: : atrial septal defect AVSD: : atrioventricular septal defect CHD: : congenital heart disease CHF: : congestive heart failure CoA: : coarctation of the aorta EKG: : electrocardiogram HLHS: : hypoplastic left heart syndrome IAA: : interrupted aortic arch IVC: : inferior vena cava LV: : left ventricle mBTT: : modified Blalock-Taussig-Thomas PAPVD: : partial anomalous pulmonary venous drainage PDA: : patent ductus arteriosus RV: : right ventricle SBE: : subacute bacterial endocarditis TAPVD: : total anomalous pulmonary venous drainage VSD: : ventricular septal defect Congenital heart disease (CHD) is present in about 9 of every 1,000 live-born children. (1)(2)(3)(4)(5) Children with CHD are surviving longer, and better understanding of the long-term complications of CHD is continuously emerging. Hence, it is important to be comfortable with the primary care requirements for these children, including physical manifestations prior to surgery and interventional cardiac catheterizations, as well as those concerning for potential need for reintervention, the latest recommendations for endocarditis prophylaxis, respiratory precautions and immunization considerations, and close monitoring of development and behavior. In this article, we will discuss the common types of cyanotic (“blue”) and acyanotic (“pink”) CHD and the role of the primary care physician in the health care of these children before and after surgery and interventional cardiac catheterizations. After completing this article, readers should be able to: 1. Describe newborn pulse oximetry screening for congenital heart disease (CHD) and clinical features of CHD during the newborn period. 2. Describe the clinical presentations and briefly outline management strategies of infants and children with different types of CHD. 3. Discuss single-ventricle palliation by using hypoplastic left heart syndrome as the model lesion. 4. Describe the evaluation and primary care management factors (including endocarditis prophylaxis, immunizations, and exercise restriction) in children with different types of CHD. Newborns with critical congenital heart disease (CHD) may present with symptoms of cyanosis, congestive heart failure (CHF), poor pedal pulses, or a failed newborn CHD pulse oximetry screen prior to discharge. CHD lesions that are dependent on a patent ductus arteriosus (PDA) to support flow either to the systemic circulation or to the pulmonary circulation …