Search

Cardiosphere-derived cells (CDCs) ameliorate skeletal and cardiac muscle deterioration in experimental models of Duchenne muscular dystrophy. The HOPE-2 trial examined the safety and efficacy of sequential intravenous infusions of human allogeneic CDCs in late-stage Duchenne muscular dystrophy.In this multicentre, randomised, double-blind, placebo-controlled, phase 2 trial, patients with Duchenne muscular dystrophy, aged 10 years or older with moderate upper limb impairment, were enrolled at seven centres in the USA. Patients were randomly assigned (1:1) using stratified permuted blocks to receive CAP-1002 (1·5 × 10Between March 1, 2018, and March 31, 2020, 26 male patients with Duchenne muscular dystrophy were enrolled, of whom eight were randomly assigned to the CAP-1002 group and 12 to the placebo group (six were not randomised due to screening failure). In patients who had a post-treatment PUL 1.2 assessment (eight in the CAP-1002 group and 11 in the placebo group), the mean 12-month change from baseline in mid-level elbow PUL1.2 favoured CAP-1002 over placebo (percentile difference 36·2, 95% CI 12·7-59·7; difference of 2·6 points; p=0·014). Infusion-related hypersensitivity reactions without long-term sequelae were observed in three patients, with one patient discontinuing therapy due to a severe allergic reaction. No other major adverse reactions were noted, and no deaths occurred.CAP-1002 cell therapy appears to be safe and effective in reducing deterioration of upper limb function in patients with late-stage Duchenne muscular dystrophy. Various measures of cardiac function and structure were also improved in the CAP-1002 group compared with the placebo group. Longer-term extension studies are needed to confirm the therapeutic durability and safety of CAP-1002 beyond 12 months for the treatment of skeletal myopathy and cardiomyopathy in Duchenne muscular dystrophy.Capricor Therapeutics.

Dystrophin deficiency results in cardiomyopathy and fibrosis with variable onset. Little is known about electrocardiographic abnormalities in Becker muscular dystrophy and their relationship to underlying cardiac pathology. We hypothesized QRS fragmentation is associated with myocardial fibrosis on cardiac magnetic resonance imaging in Becker muscular dystrophy patients. We retrospectively evaluated 44 patients, and extracted data from clinically obtained electrocardiogram and cardiac magnetic resonance. Ventricular function and presence or absence late gadolinium enhancement representing myocardial fibrosis were recorded from imaging. Nearly half (19/42, 45%) of patients interrogated had myocardial fibrosis on cardiac magnetic resonance. Total number of electrocardiogram leads with QRS fragmentation (median 1 vs 4, p 0.001) and either right or left axis deviation from median was significantly increased (13.6 vs. 44.8°, p 0.001) in patients with myocardial fibrosis. Decreased leftward voltage in V6 correlated to both increased fibrosis and decreased cardiac function (p 0.01). The positive likelihood ratio for underlying myocardial fibrosis in patients with two of the three findings on electrocardiogram was 8.47 (p 0.0001). QRS fragmentation and axis deviation on electrocardiography are strongly predictive of myocardial fibrosis in Becker muscular dystrophy and may inform the use of advanced imaging in evaluation of these patients.

BackgroundLeft ventricular hypertrophy (LVH) associated with hypertension (HTN) is a predictor of cardiovascular (CV) events in adulthood. LVH is defined using left ventricular mass indexed to height2.7(LVMI-ht2.7) with current guidelines using the adult cutoff of 51 g/ht2.7; however, the pediatric cutoff is lower. Adults with congenital heart disease (CHD) have higher rates of HTN compared to the general adult population. Data on the prevalence of elevated blood pressure (SBP) in youths with CHD is limited. The aim of our study was to determine the prevalence of elevated BP and LVH in adolescents with CHD.MethodsWe retrospectively analyzed echocardiograms from patients with CHD from 2012-2019. Patients with biventricular CHD aged 13-17 years with documented BP, height, weight, and measurement of LVMI-ht2.7were included. We defined LVH using the pediatric cutoff of LVMI-ht2.7≥ 38.6 g/ht2.7. Patients were grouped by BP category into normotensive (NT, SBP < 120 mm Hg), Elevated BP (E-BP, 120 ≤ SBP < 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP < 140 mm Hg), and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). Prevalence of LVH was reported in each group defined as LVMI-HT2.7≥ 38.6 g/ht2.7.Results855 patients were included. Mean (± standard deviation, SD) age was 15.5±1.5 years with 485/855 (56.7%) male, SBP 117±13.5 mmHg, and LVMI-ht2.734.2±10.5 g/ht2.7. 493/855 (57.7%) were in the NT group, 214/855 (25%) in E-BP, 99/855 (11.6%) in HTN-1, and 49/855 (5.7%) in HTN-2. Prevalence of LVH increased with higher SBP with 96/493 (19.5%) in NT, 80/214 (37.4%) in E-BP, 32/99 (32.3%) in HTN-1, and 20/49 (40.8%) in HTN-2. Of youths with LVH, 49/228 (21.5%) met adult criteria of ≥ 51 g/ht2.7. Age, male sex, and body mass index (BMI) percentile were significantly associated with increased LVMI-ht2.7.ConclusionsYouths with CHD have a high prevalence of elevated BP, HTN, and LVH. BMI is a significant risk factor for the development of LVH in this population. These findings support early screening for HTN in this group because youths with CHD have baseline increased CV risk that may be compounded by obesity and long-term HTN.Clinical PerspectiveWhat is new?The prevalence of abnormal blood pressure and LVH in adolescents with CHD is understudied and our data show that HTN and LVH are common in this population.One-fifth of adolescents with biventricular congenital heart disease and left ventricular hypertrophy met adult criteria for left ventricular hypertrophy.What are the clinical implications?Left ventricular hypertrophy secondary to hypertension is linked to adverse cardiac events in adulthood.Early screening and detection for abnormal blood pressure in the adolescent congenital heart disease population may lead to earlier initiation of lifestyle interventions or pharmacotherapy and mitigate long-term adverse clinical and financial outcomes in an already vulnerable population.

Evidence on the long-term efficacy of steroids in Duchenne muscular dystrophy (DMD) after loss of ambulation is limited.Characterize and compare disease progression by steroid treatment (prednisone, deflazacort, or no steroids) among non-ambulatory boys with DMD.Disease progression was measured by functional status (Performance of Upper Limb Module for DMD 1.2 [PUL] and Egen Klassifikation Scale Version 2 [EK] scale) and by cardiac and pulmonary function (left ventricular ejection fraction [LVEF], forced vital capacity [FVC] % -predicted, cough peak flow [CPF]). Longitudinal changes in outcomes, progression to key disease milestones, and dosing and body composition metrics were analyzed descriptively and in multivariate models.This longitudinal cohort study included 86 non-ambulatory patients with DMD (mean age 13.4 years; n = 40 [deflazacort], n = 29 [prednisone], n = 17 [no steroids]). Deflazacort use resulted in slower average declines in FVC % -predicted vs. no steroids (+3.73 percentage points/year, p 0.05). Both steroids were associated with significantly slower average declines in LVEF, improvement in CPF, and slower declines in total PUL score and EK total score vs. no steroids; deflazacort was associated with slower declines in total PUL score vs. prednisone (all p 0.05). Both steroids also preserved functional abilities considered especially important to quality of life, including the abilities to perform hand-to-mouth function and to turn in bed at night unaided (all p 0.05 vs. no steroids).Steroid use after loss of ambulation in DMD was associated with delayed progression of important pulmonary, cardiac, and upper extremity functional deficits, suggesting some benefits of deflazacort over prednisone.

In the field of congenital heart surgery, tissue-engineered vascular grafts (TEVGs) are a promising alternative to traditionally used synthetic grafts. Our group has pioneered the use of TEVGs as a conduit between the inferior vena cava and the pulmonary arteries in the Fontan operation. The natural history of graft remodeling and its effect on hemodynamic performance has not been well characterized. In this study, we provide a detailed analysis of the first U.S. clinical trial evaluating TEVGs in the treatment of congenital heart disease. We show two distinct phases of graft remodeling: an early phase distinguished by rapid changes in graft geometry and a second phase of sustained growth and decreased graft stiffness. Using clinically informed and patient-specific computational fluid dynamics (CFD) simulations, we demonstrate how changes to TEVG geometry, thickness, and stiffness affect patient hemodynamics. We show that metrics of patient hemodynamics remain within normal ranges despite clinically observed levels of graft narrowing. These insights strengthen the continued clinical evaluation of this technology while supporting recent indications that reversible graft narrowing can be well tolerated, thus suggesting caution before intervening clinically.

Children born with single ventricle physiology who undergo Fontan palliation face a diverse set of long-term complications. However, patient follow-up has in large part been limited to single institutional experiences without uniform application of diagnostic modalities to screen for relevant outcomes. Additionally, the use of different graft materials and variable surgical technique as part of the Fontan procedure has further complicated the evaluation of single ventricle patients. The purpose of this review is to define the changes in the Fontan pathway specific to the graft material used and its relationship to patient outcomes. As a means of introduction, we briefly review the historical evolution of the Fontan procedure with a focus on the intent behind design changes and incorporation of different biomaterials. We further delineate changes to the Fontan pathway which include the development of stenosis, differential growth, thrombosis, and calcification. Ultimately, the recognition of the changes noted within the Fontan pathway need to be assessed relative to their impact on patient hemodynamics, functional capacity, and Fontan-associated comorbidities.

Varied detection methods have resulted in conflicting reports on the prevalence of cardiac disease in Duchenne and Becker muscular dystrophy carriers (MDC).We performed a prospective cohort study of 77 genetically-confirmed MDC mothers, 22 non-carrier mothers, and 25 controls. All participants underwent Cardiopulmonary Exercise Testing (CPET) and Cardiac Magnetic Resonance imaging (CMR).25% of carriers had ventricular ectopy in recovery of exercise (RecVE) as compared to 1 non-carrier and no controls (p = .003). No difference in age or maximal oxygen consumption was noted. 11 carriers had abnormal (55%) left ventricular ejection fraction by CMR. Evidence of late gadolinium enhancement (LGE) was noted in 48% of MDC, 1 non-carrier patient and no control subjects (p .0001). Subset analysis of LGE+ and LGE- subjects revealed differences in age (44.1 v 38.6 yrs.; p = .005), presence of RecVE, (38.9% v 10.5%, p = .004), and high serum creatine kinase (CK) (289 U/l; 52.8% v 31.6%, p = .065).We describe the prevalence of disease using CPET and CMR in genetically-proven MDC. 49% of carriers had fibrosis, opposed to 5% of non-carriers, highlighting the importance of genetic testing in this population. Despite cardiomyopathy, functional assessment by treadmill was normal, illustrating the discrepancy in cardiac and skeletal muscle impacts. Age, RecVE and serum CK appear to have an important role in predicting cardiomyopathy. Serum CK levels suggest that a systemic higher global disease severity and not tissue heterogeneity may be the etiology for greater cardiac disease and relatively spared skeletal muscle disease in this population. Clinical Trial Registration https://clinicaltrials.gov/ct2/show/NCT02972580?term=mendellcond=Duchenne+Muscular+Dystrophyrank=5; ClinicalTrials.gov Identifier: NCT02972580.

Introduction: The Child Opportunity Index (COI) is a measure of neighborhood conditions encompassing educational, health, environmental, social, and economic components that affect child development. Worse COI has been associated with increased cardiometabolic risk in children. Hypertension (HTN) and obesity leads to left ventricular hypertrophy (LVH) and are risk factors for cardiac events in adulthood. However, the impact of COI on patients with congenital heart disease (CHD) has not been well described. Hypothesis: We hypothesized that CHD youths with lower COI would have higher rates of obesity and hypertension compared to higher COI patients. Methods: We retrospectively reviewed adolescent CHD patients with an echocardiogram between 2012-2019. Patients aged 13-17 years with blood pressure (BP), height, weight, and echo measurement for LVMi-HT 2.7 were included. Home location was geocoded and linked to public COI data. Patients were classified by COI into Very Low (VL), Low (L), Moderate (M), High (H), and Very High (VH) opportunity levels. Obesity was defined as body mass index (BMI) ≥ 95 th percentile. Blood pressure was defined as normotensive (NT, SBP < 120 mm Hg), elevated BP (E-BP, 120 ≤ SBP < 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP < 140 mm Hg), and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). Left ventricular hypertrophy (LVH) was defined as LVMi-HT 2.7 ≥ 38.6 g/ht 2.7 . Results: A total of 801 patients (mean age 15.5 ± 1.5 years, 57.43% male [460/801]) were included in this analysis. COI groups were VL 157/801 (19.6%), L 165/801 (20.6%), M 226/801 (28.2%), H 142/801 (17.7%), and VH 111/801 (13.9%). Overall, 117/801 (14.6%) patients were obese, 141/801 (17.6%) patients were hypertensive, and 209/801 (26.1%) patients had LVH. Obesity within COI groups was VL 34/157 (21.7%), L 26/165 (15.8%), M 30/226 (13.3%), H 20/142 (14.1%), and VH 7/111 (6.3%). HTN-1 or HTN-2 was seen in VL 25/157 (15.9%), L 36/165 (21.8%), M 41/226 (18.1%), H 23/142 (16.2%), VH 16/111 (14.4%). LVH was present in VL 50/157 (31.9%), L 47/165 (28.5%), M 63/226 (27.9%), H 26/142 (18.3%), and VH 23/111 (20.7%). Conclusions: Youths with CHD living in lower opportunity areas have a high proportion of obesity and hypertension. Furthermore, end-organ changes are seen with a high prevalence of LVH in lower opportunity CHD youths. In conclusion, these findings support the importance of considering social determinants of health like neighborhood opportunity in assessing cardiovascular risk in CHD youths.

Introduction: Left ventricular hypertrophy (LVH) is defined as LVM indexed to height 2.7 (LVMi-HT 2.7 ≥ 51 g/ht 2.7 in men, ≥ 47 g/ht 2.7 in women), and ≥ 38.6 g/ht 2.7 in the pediatric population. LVH associated with hypertension (HTN) is a predictor of adverse cardiovascular (CV) events in adulthood. Adults with congenital heart disease (CHD) have higher rates of HTN compared to the general adult population. Data on the prevalence of elevated systolic blood pressure (SBP) in youths with CHD is limited. The aim of our study was to determine the prevalence of elevated SBP and LVH in adolescents with CHD. Hypothesis: We hypothesized that youths with elevated SBP will have increased LVMi-HT 2.7 by echocardiography. Methods: We retrospectively analyzed echocardiograms with a diagnosis code of CHD from 2012 to 2019. We included patients aged 13-17 years with documented BP, height, weight, and echocardiography measurement for LVMi-HT 2.7 . Patients were grouped by BP category into normotensive (NT, SBP < 120 mm Hg), elevated BP (E-BP, 120 ≤ SBP < 130 mm Hg), Stage 1 HTN (HTN-1, 130 ≤ SBP < 140 mm Hg), and Stage 2 HTN (HTN-2, SBP ≥ 140 mm Hg). The prevalence of LVH was reported in each group defined as LVMi-HT 2.7 ≥ 38.6 g/ht 2.7 . Results: 855 patients were included with a mean age of 15.5±1.5 years with 485/855 (56.7%) male, SBP 117±13.5 mm Hg, and LVMi-HT 2.7 34.2±10.5 g/ht 2.7 . 493/855 (57.7%) were in the NT group, 214/855 (25%) in E-BP, 99/855 (11.6%) in HTN-1, and 49/855 (5.7%) in HTN-2. The prevalence of LVH increased with higher SBP with 96/493 (19.5%) in NT, 80/214 (37.4%) in E-BP, 32/99 (32.3%) in HTN-1, and 20/49 (40.8%) in HTN-2. Of the youths with LVH, 49/228 (21.5%) met adult criteria of ≥ 51 g/ht 2.7 . Conclusions: Youths with CHD have a high prevalence of elevated BP, HTN, and LVH. These findings support the importance of early detection and screening for high BP in this group because youths with CHD have baseline increased CV risk that may be compounded by HTN. Future studies will be needed to determine longitudinal changes and the influence of body mass index and sex on BP in this group.

Introduction: Duchenne muscular dystrophy (DMD) patients universally develop cardiomyopathy and considered a dilated cardiomyopathy. Cardiac magnetic resonance imaging (CMR) revealed LGE prior to ventricular dysfunction. Various novel trials including gene therapy are ongoing with growing interest on how it impacts the heart. There is paucity of CMR data at a given age. A major barrier is lack of age specific data. Hypothesis: We therefore, sought to determine the prevalence left ventricular (LV) dilation by endiastolic volume (LVEDV), ejection fraction (LVEF) and late gadolinium enhancement (LGE) status at a given age. Methods: Retrospective review of CMR studies in DMD. LV dilation is defined as LVEDVi z-score > 2, abnormal LVEF ( Results: 683 DMD patients were identified with average of 48.8±24 (range 19-94) patients per group divided into 14 age groups. Mean age was 12.3±4 (range 4-39 years). Table 1 summarizes the CMR data by age. LV dilation was uncommon even in older age patients (mean 1.9±2.6%, range 0-8.7%). LVEF is rarely abnormal before 10 years (50% after 11 (4.3% < 7 year group to > 80% by 18 years). Conclusions: This is the first and largest CMR natural history study by individual age showing low prevalence of LV dilation in DMD population. LVEF abnormality and LGE is uncommon before 10 years but increased with age. Future longitudinal assessment is ongoing to determine rate of change at a given age, quantifying LGE and myocardial strain for earlier cardiac disease assessment and modeling for disease progression at different age.

Introduction: Limb-Girdle Muscular Dystrophies (LGMD) are an inheritable group of genetic disorders primarily involving progressive weakening and atrophy of the pelvic or shoulder girdle musculature with potential cardiac dysfunction. Prior reports stratified frequency of cardiac disease based on genetic mutations. The general incidence of cardiac muscle involvement in LGMD is variable depending on genetic factors and carry important indications for clinical management. Cardiac magnetic resonance imaging (CMR) is increasingly used in dystrophinopathies and determining management. There is limited CMR data in adult LGMD patients and fewer reports in younger patients. Hypothesis: Therefore, we sought to determine the extent of cardiac involvement based on genetic risk of cardiomyopathy. Methods: This is a retrospective review of LGMD patients followed at our institution who underwent CMR assessment. Patients stratified into Group A (high incidence of cardiomyopathy; LGMDs 1B, 2E, 2F and 2I) and Group B (rare or no reported cardiomyopathy; LGMDs 1A, 1C, 2A, 2B, 2C, 2D, 2G, 2H, 2J) with CMR studies were assessed for presence of cardiac scar defined as late gadolinium enhancement (LGE) and LVEF for each subject. Results: 41 subjects were identified with average age of 21.3±11.5 years (range 6-50) with normal LVEF 58±12.1% and 12/41 (29.3%) with LGE with the youngest patient age 12.4 years. Group A included 14/41 (34%) and 27/41 (66%) were in Group B. Group A had higher incidence of LGE 6/14(42.9%) with preserved LVEF of 58.2±11% compared to Group B with 6/27 (22.2%) with no difference in LVEF of 55.7±16.4% (p = 0.5). When stratified by LGE status, the LGE-positive group was older at 26.4±11.9 years and had preserved LVEF of 61.9±11.1% versus LGE-negative group of 19.1±10.9 years (p = 0.03) with abnormal LVEF of 49.4±9.5% (p =0.0008). Conclusions: This is the largest study of CMR in LGMD patients, confirming presence of cardiac disease by LGE in the high risk group. Surprisingly, nearly 25% of the low risk mutations have evidence of LGE. Abnormal LGE predicted abnormalities in LVEF in both Group A and Group B. Management of LGMD patients should include CMR even in low risk population. Ongoing data collection may reveal disease cluster in previous low risk groups.

Introduction: After the initial surgical repair of tetralogy of Fallot (rTOF), right ventricular outflow tract dysfunction is common, with pulmonary stenosis (PS), regurgitation, or both. Obese adults with rTOF have worse biventricular systolic function, and greater post-operative pulmonary valve replacement morbidity than non-obese patients. Transcatheter PVR (TPVR) is used increasingly, though no studies have examined the impact of body mass index (BMI) on morbidity and hemodynamics in adults with rTOF and subsequent TPVR. Hypothesis: BMI affects outcomes of transcatheter PVR in adults with TOF. Methods: This was a 10 yr, single center, retrospective review of adults (>18 yo) with rTOF who underwent TPVR. The cohort was split into 2 groups based on BMI at time of TPVR. Group A (Grp A): normal and overweight (BMI Results: There were 81 adults, 42 (52%) normal, 18 (22%) overweight (Grp A) and 21 (26%) obese (Grp B). Mean follow up was 6.4 + 3.1 yrs. With most recent post-TPVR echocardiogram, there was no significant difference in LV or RV size and function across groups. Compared to Grp A, Grp B patients were more likely to develop any degree of PS (mild, moderate, or severe) following TPVR (69% vs 94%, respectively, p = 0.032). An ROC curve analysis demonstrated BMI ≥ 26.3 had a low sensitivity (45%), but good specificity (89%) for predicting PS post TPVR. There was no difference between groups requiring re- intervention for PVR. Conclusion: This is the first study to show greater BMI affects valve function in adults with rTOF following TPVR. BMI >26 was associated with a greater risk of PS in follow up echocardiograms after TPVR. Obesity is an epidemic in the US and patient prosthesis mismatch may be an issue when considering TPVR. Further studies are indicated to determine the long-term effects of BMI on TPVR and the need for re-intervention in adults with TOF.

Introduction: Cardiomyopathy (CM) is the leading cause of death in boys with Duchenne Muscular Dystrophy (DMD). Diastolic dysfunction precedes systolic dysfunction in DMD, but while CMR is used routinely to assess fibrosis and left ventricular ejection fraction (LVEF), CMR measures of DMD diastolic dysfunction have not been reported. Hypothesis: Boys with DMD have diastolic dysfunction based on CMR indices when compared with healthy controls. Methods: Prospectively enrolled DMD patients (n = 54) and healthy male controls (n = 40) underwent CMR. Standard volumes and function were calculated. LV filling curves were generated by contouring every phase in the short axis. Indices were compared between groups using a Wilcoxon rank sum and within DMD using a Spearman’s rho test. Results: There was no difference in LVEF between DMD and controls, though DMD patients had significantly smaller indexed left ventricular end diastolic volume (LVEDVi) (see data in Table 1). Peak ventricular filling rates (PFR) were significantly slower in DMD vs controls as were peak ventricular emptying rates (PER). Mean time to PFR (tPFR) and mean time to PER (tPER) were significantly shorter in DMD patients vs controls. In a subset analysis excluding patients with LVEF < 55%, observed differences in PFR, PER, tPFR and TPER remain statistically significant. In DMD patients, tPER correlates negatively with LVEF (rho = -0.57, p Conclusions: Despite having normal baseline systolic function, boys with DMD have significantly different CMR diastolic indices compared with controls. CMR diastolic indices may help detect subclinical dysfunction in DMD. Future analyses should evaluate for correlation between diastolic dysfunction and clinical outcomes.

Duchene muscular dystrophy (DMD) is a rare but devastating disease resulting in progressive loss of ambulation, respiratory failure, DMD-associated cardiomyopathy (DMD-CM), and premature death. The use of corticosteroids and supportive respiratory care has improved outcomes, such that DMD-CM is now the leading cause of death. Historically, most programs have focused on skeletal myopathy with less attention to the cardiac phenotype. This omission is rather astonishing since patients with DMD possess an absolute genetic risk of developing cardiomyopathy. Unfortunately, heart failure signs and symptoms are vague due to skeletal muscle myopathy leading to limited ambulation. Traditional assessment of cardiac symptoms by the New York Heart Association American College of Cardiology/American Heart Association Staging (ACC/AHA) classification is of limited utility, even in advanced stages. Echocardiographic assessment can detect cardiac dysfunction late in the disease course, but this has proven to be a poor surrogate marker of early cardiovascular disease and an inadequate predictor of DMD-CM. Indeed, one explanation for the paucity of cardiac therapeutic trials for DMD-CM has been the lack of a suitable end-point. Improved outcomes require a better proactive treatment strategy; however, the barrier to treatment is the lack of a sensitive and specific tool to assess the efficacy of treatment. The use of cardiac imaging has evolved from echocardiography to cardiac magnetic resonance imaging to assess cardiac performance. The purpose of this article is to review the role of cardiac imaging in characterizing the cardiac natural history of DMD-CM, highlighting the prognostic implications and an outlook on how this field might evolve in the future.

This early feasibility study was designed to obtain in vivo data to confirm assumptions on device loading conditions of the Medtronic Harmony transcatheter pulmonary valve (TPV). Secondary objectives included procedural feasibility, safety, and valve performance. The Harmony TPV was developed for nonsurgical pulmonary valve replacement in non-right ventricle-pulmonary artery conduit patients. The Native Outflow Tract TPV Research Clinical Study was the first study approved under the Food and Drug Administration Early Feasibility Study guidance. Enrollment required that patient anatomy be precisely matched to the single-size Harmony TPV implant, necessitating a rigorous selection process. The study was nonrandomized, prospective, and performed at 3 sites. All patients met standard indications for surgical pulmonary valve replacement. The goal of the screening committee was to match the candidate anatomy to predetermined engineering criteria thought to be predictive of secure Harmony TPV implantation for the single-size device under study. A majority of the screening committee was required to recommend a patient as eligible for implant. A total of 270 patients underwent prescreening cardiac magnetic resonance imaging, 66 were enrolled and received a computed tomography scan (24%), 21 met criteria for implant and were catheterized (8%), and 20 underwent implant. Nineteen of 20 met criteria for implant success. In conclusion, the Medtronic Harmony TPV represents an emerging therapeutic option for patients with complex postoperative right ventricular outflow tract failure. The initial clinical evaluation of this technology was unique, and the highly variable anatomy of this population required careful screening to ensure acceptable device fit.

Objectives This study sought to obtain in vivo data to confirm assumptions on device loading conditions and assess procedural feasibility, safety, and valve performance. Background The Harmony transcatheter pulmonary valve (Medtronic, Minneapolis, Minnesota) was designed for patients with severe pulmonary regurgitation who require pulmonary valve replacement. Methods Three sites participated in this first Food and Drug Administration–approved early feasibility study using an innovative device design to accommodate the complex anatomy of the right ventricular outflow tract. Potentially eligible patients underwent review by a screening committee to determine implant eligibility. Six-month outcomes are reported. Results Between May 2013 and May 2015, 66 subjects were enrolled, and 21 were approved for implant and underwent catheterization; 20 were implanted. Catheterized patients had a median age of 25 years, were predominantly diagnosed with tetralogy of Fallot (95%), had severe pulmonary regurgitation (95%), and had trivial or mild stenosis. The device was delivered in the desired location in 19 of 20 (95%) patients. Proximal migration occurred in 1 patient during delivery system removal. Two devices were surgically explanted. Premature ventricular contractions related to the procedure were reported in 3 patients; 2 were resolved without treatment. One patient had ventricular arrhythmias that required treatment and later were resolved. At 1 month, echocardiography revealed none or trivial pulmonary regurgitation in all and a mean right ventricular outflow tract gradient of 16 ± 8 mm Hg (range 6 to 31 mm Hg). Conclusions In this feasibility study of the Harmony transcatheter pulmonary valve device, there was high procedural success and safety, and favorable acute device performance.

Cardiac rhabdomyoma is the most prevalent cardiac tumors in the pediatric population, in close association with tuberous sclerosis complex. It is usually detected antenatally or postnatally by echocardiography. Clinical presentations depend greatly on the size and position of the tumor mass. Interestingly, rhabdomyoma has a propensity to regress spontaneously and is not usually operated upon, unless the patient becomes hemodynamically compromised. Herein, we report an unusual case of surgically treated cardiac rhabdomyoma in a baby boy presented at birth with a progressive enlarging intraventricular mass, complicated with left ventricular outflow tract obstruction 7 weeks later. Histopathological examination of the intracardiac mass revealed sheets of tumor cells with spider-like morphology (known as "spider cells"), confirmed the diagnosis of rhabdomyoma. Close disease monitoring of patient's hemodynamic status in a newly diagnosed cardiac rhabdomyoma is inevitable as the tumor, although rare, may progress.

We developed a tissue-engineered vascular graft (TEVG) for use in children and present results of a U.S. Food and Drug Administration (FDA)-approved clinical trial evaluating this graft in patients with single-ventricle cardiac anomalies. The TEVG was used as a Fontan conduit to connect the inferior vena cava and pulmonary artery, but a high incidence of graft narrowing manifested within the first 6 months, which was treated successfully with angioplasty. To elucidate mechanisms underlying this early stenosis, we used a data-informed, computational model to perform in silico parametric studies of TEVG development. The simulations predicted early stenosis as observed in our clinical trial but suggested further that such narrowing could reverse spontaneously through an inflammation-driven, mechano-mediated mechanism. We tested this unexpected, model-generated hypothesis by implanting TEVGs in an ovine inferior vena cava interposition graft model, which confirmed the prediction that TEVG stenosis resolved spontaneously and was typically well tolerated. These findings have important implications for our translational research because they suggest that angioplasty may be safely avoided in patients with asymptomatic early stenosis, although there will remain a need for appropriate medical monitoring. The simulations further predicted that the degree of reversible narrowing can be mitigated by altering the scaffold design to attenuate early inflammation and increase mechano-sensing by the synthetic cells, thus suggesting a new paradigm for optimizing next-generation TEVGs. We submit that there is considerable translational advantage to combined computational-experimental studies when designing cutting-edge technologies and their clinical management.

Patients with Duchenne muscular dystrophy suffer debilitating muscle destruction, resulting in loss of ambulation, diminished respiratory function, gastrointestinal disturbances and cardiomyopathy. Although it is the most common cause of death in these patients, cardiomyopathy is poorly understood in terms of distinct pathogenesis, natural history, and specific, effective therapeutic interventions. We review the state-of-the-art knowledge of Duchenne muscular dystrophy-associated cardiomyopathy including clinical evaluation, imaging, medical and perioperative management, and prospects for gene therapy. We also review cardiomyopathy in heterozygote carriers. By describing our current understanding and best practices, we hope to improve harmonization of care across institutions and identify collective knowledge gaps to guide future research efforts.

An ascending aortic aneurysm (AscAA) is a life-threatening disease whose molecular basis is poorly understood. Mutations in NOTCH1 have been linked to bicuspid aortic valve (BAV), which is associated with AscAA. Here, we describe a potentially novel role for Notch1 in AscAA. We found that Notch1 haploinsufficiency exacerbated the aneurysmal aortic root dilation seen in the Marfan syndrome mouse model and that heterozygous deletion of Notch1 in the second heart field (SHF) lineage recapitulated this exacerbated phenotype. Additionally, Notch1(+/-) mice in a predominantly 129S6 background develop aortic root dilation, indicating that loss of Notch1 is sufficient to cause AscAA. RNA sequencing analysis of the Notch1.129S6(+/-) aortic root demonstrated gene expression changes consistent with AscAA. These findings are the first to our knowledge to demonstrate an SHF lineage-specific role for Notch1 in AscAA and suggest that genes linked to the development of BAV may also contribute to the associated aortopathy.

BACKGROUND Improved neuromuscular and respiratory therapies have altered the natural history of Duchenne muscular dystrophy (DMD) such that the most common cause of mortality is progressive cardiomyopathy. Despite imaging evidence of progressive cardiomyopathy, troponin I (cTn) is not significantly elevated in asymptomatic DMD patients. RESULTS We describe eight boys with DMD evaluated for acute chest pain (ACP) and found to have acute cTn elevation with depressed left ventricular ejection fraction (LVEF). Of our eight patients, five presented with a primary complaint of ACP, while three presented with secondary myocardial injury in the context of systemic illness requiring hospitalization. Electrocardiograms showed diffuse ST changes and mean peak cTn level was 44±15.4 ng/mL (reference range

Graphical abstract, Highlights • Adult congenital patients with tetralogy of Fallot require life long follow-up. • Early left ventricular dysfunction in repaired tetralogy of Fallot warrants evaluation. • Multimodality imaging should be used when unusual echocardiography findings are present.

Systemic hypertension (HTN) is a major cause of morbidity in the general population and is an important risk factor for mortality. Pediatric cancer survivors with exposure to anthracycline chemotherapeutic agents (ACA) have an increased risk of cardiovascular disease compare to their peers. We

Adult literature has established a link between premature ventricular contraction (PVC) burden as low as 10% on 24 hour Holter monitor and cardiac dysfunction requiring monitoring and treatment to prevent cardiomyopathy. Frequent PVCs are common in the pediatric population. However, the impact of

Duchenne muscular dystrophy (DMD) is an X-linked results in dystrophin deficiency and universally develop cardiomyopathy and early mortality. Subepicardial myocardial fibrosis (MF) by late gadolinium enhancement (LGE) precedes decline in left ventricular ejection fraction (LVEF) by cardiac magnetic

Cardiac manifestations of Duchenne muscular dystrophy (DMD) include progressive cardiac dysfunction and an elevated resting heart rate (HR). We hypothesized this elevated HR reflects autonomic dysfunction that can be identified by heart rate variability (HRV) analyses which will be associated with myocardial fibrosis by cardiac magnetic resonance imaging (cMR). DMD patients (N = 74) and controls (N = 17) had time and frequency domain HRV analyses calculated via Holter monitoring. Cardiac magnetic resonance imaging was performed on DMD cases only. χ (2) test, T test, ANOVA, and logistic regression were used to perform comparisons between groups. A p value of0.05 was used for statistical significance. DMD cases had higher resting average HR than controls (99.4 ± 8.9, 85.4 + 6.2, p 0.001). Among HRV variables, decreases were seen in the following: standard deviation of R to R intervals, the percent RR intervals differing by50 ms from previous RR interval, the root-meansquare of successive differences of RR intervals, the standard deviation of the mean R to R segment (SDANN), low frequency, and high frequency domain, all p values 0.001. Maximum HR and SDANN most significantly associated with positive LGE on cMR (p = 0.008, p = 0.016). DMD cases on beta blocker had an average HR lower than those not on beta blocker (p = 0.009), but with no difference in HRV analysis. DMD patients have reduced HRV and therefore autonomic dysfunction prior to the onset of heart failure which is associated with myocardial fibrosis.

The aim of this study is to determine the contribution of strain ε cc in mid left ventricular (LV) segments to the reduction of composite LV circumferential ε cc in assess severity of duchenne muscular dystrophy (DMD) heart disease as assessed by cardiac magnetic resonance imaging (CMR). DMD patients and control subjects were stratified by age, LV ejection fraction, and late gadolinium enhancement (LGE) status. Tagged CMR images were analyzed for global ventricular function, LGE imaging, and composite and segmental ε cc. The relationship between changes in segmental ε cc changes and LGE across patient groups was assessed by a statistical step-down model. LV ε cc exhibited segmental heterogeneity; in control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. However, with increasing age and cardiac disease severity as demonstrated by decreased EF and development of myocardial strain the segmental differences diminished. In subjects with advanced heart disease as evidenced by reduced LV ejection fraction and presence of LGE, very little segmental heterogeneity was present. In control subjects and young DMD patients, ε cc was greatest in LV lateral free wall segments. Increased DMD heart disease severity was associated with reduced composite; ε cc diminished regional ε cc heterogeneity and positive LGE imaging. Taken together, these findings suggest that perturbation of segmental, heterogeneous ε cc is an early biomarker of disease severity in this cross-section of DMD patients.

Myocardial tagging using cardiovascular magnetic resonance (CMR) is the gold-standard for the assessment of myocardial mechanics. Feature-tracking cardiovascular magnetic resonance (FT-CMR) has been validated against myocardial tagging. We explore the potential of FT-CMR in the assessment of mechanical dyssynchrony, with reference to patients with cardiomyopathy and healthy controls.Healthy controls (n=55, age: 42.9 ± 13 yrs, LVEF: 70 ± 5%, QRS: 88 ± 9 ms) and patients with cardiomyopathy (n=108, age: 64.7 ± 12 yrs, LVEF: 29 ± 6%, QRS: 147 ± 29 ms) underwent FT-CMR for the assessment of the circumferential (CURE) and radial (RURE) uniformity ratio estimate based on myocardial strain (both CURE and RURE: 0 to 1; 1=perfect synchrony)CURE (0.79 ± 0.14 vs. 0.97 ± 0.02) and RURE (0.71 ± 0.14 vs. 0.91 ± 0.04) were lower in patients with cardiomyopathy than in healthy controls (both p0.0001). CURE (area under the receiver-operator characteristic curve [AUC]: 0.96), RURE (AUC: 0.96) and an average of these (CURE:RUREAVG, AUC: 0.98) had an excellent ability to discriminate between patients with cardiomyopathy and controls (sensitivity 90%; specificity 98% at a cut-off of 0.89). The time taken for semi-automatically tracking myocardial borders was 5.9 ± 1.4 min.Dyssynchrony measures derived from FT-CMR, such as CURE and RURE, provide almost absolute discrimination between patients with cardiomyopathy and healthy controls. The rapid acquisition of these measures, which does not require specialized CMR sequences, has potential for the assessment of mechanical dyssynchrony in clinical practice.

Left atrial (LA) size is a known predictor of adverse cardiovascular events. Echocardiography is the modality of choice for the evaluation of atrial size; however, cardiac magnetic resonance imaging (cMRI) remains the "gold standard." We sought to calculate atrial volumes using the area-length method by both echocardiography and cMRI and compare them with area-volume quantification by cMRI. Thiry-eight patients (mean age 20 ± 12 years, 71% male) who underwent cMRI and echocardiography between September 2010 and June 2012 were retrospectively identified. The time interval between the two studies was ≤ 6 months. LA volumes by echocardiogram were estimated using the area-length method: LA volume = (0.85 × area(4ch) × area(2ch))/(shortest atrial length). The atrial length and area were measured in standard apical two-chamber and four-chamber planes. Measured values were indexed to body surface area (BSA). CMRI measurements were obtained from prospectively gated steady-state free precession cine stack images obtained in a standard four-chamber plane. LA volumes were calculated using Simpson's method: LA volume = LA area × (slice thickness + gap) per slice. Slice thickness ranged from 5 to 7 mm with contiguous slices of 5 to 7 mm. The values were indexed to BSA. Statistics were summarized using measures of central tendency. LA volumes by echocardiography were significantly less than those by full-volume cMRI quantification. The mean LA volume by echocardiography and full-volume cMRI were 35 ± 14.5 and 42.4 ± 17.2, respectively (p = 0.05). The mean difference between LA volumes obtained by the two methods was 7.4 ± 10.6. LA volume measured by cMRI using the area-length method closely approximated full-volume assessment by cMRI with mean values of 42.9 ± 17.4 versus 42.4 ± 17.2, respectively (p = 0.91). There were no significant differences in the patient characteristics between the two study modalities. LA volumes as measured by echocardiography using the area-length method consistently underestimated the true volume when compared with cMRI. LA volumes measured using the area-length method by cMRI is an alternative technique for accurately quantifying chamber size and can be useful in decreasing scan time or when full-volume data sets are incomplete.

Advances in management of non-cardiac issues in Duchenne muscular dystrophy (DMD) have improved such that DMD-associated cardiac disease has become the leading cause of death for such patients. Cardiac dysfunction measured by standard transthoracic echocardiographic methods, e.g., fractional shortening (FS) and ejection fraction (EF), is rarely present during the first decade of life. The current study used transthoracic echocardiogram (TTE) to assess strain (e), an indicator of regional ventricular function, in young DMD patients. A retrospective review of the TTE database was performed. TTE results from DMD patients

This study sought to obtain in vivo data to confirm assumptions on device loading conditions and assess procedural feasibility, safety, and valve performance.The Harmony transcatheter pulmonary valve (Medtronic, Minneapolis, Minnesota) was designed for patients with severe pulmonary regurgitation who require pulmonary valve replacement.Three sites participated in this first Food and Drug Administration-approved early feasibility study using an innovative device design to accommodate the complex anatomy of the right ventricular outflow tract. Potentially eligible patients underwent review by a screening committee to determine implant eligibility. Six-month outcomes are reported.Between May 2013 and May 2015, 66 subjects were enrolled, and 21 were approved for implant and underwent catheterization; 20 were implanted. Catheterized patients had a median age of 25 years, were predominantly diagnosed with tetralogy of Fallot (95%), had severe pulmonary regurgitation (95%), and had trivial or mild stenosis. The device was delivered in the desired location in 19 of 20 (95%) patients. Proximal migration occurred in 1 patient during delivery system removal. Two devices were surgically explanted. Premature ventricular contractions related to the procedure were reported in 3 patients; 2 were resolved without treatment. One patient had ventricular arrhythmias that required treatment and later were resolved. At 1 month, echocardiography revealed none or trivial pulmonary regurgitation in all and a mean right ventricular outflow tract gradient of 16 ± 8 mm Hg (range 6 to 31 mm Hg).In this feasibility study of the Harmony transcatheter pulmonary valve device, there was high procedural success and safety, and favorable acute device performance.

Heart failure–induced cardiovascular morbidity and mortality constitute a major health problem worldwide and result from diverse pathogeneses, including coronary artery disease, nonischemic cardiomyopathies, and arrhythmias. Assessment of cardiovascular performance is important for early diagnosis and accurate management of patients at risk of heart failure. During the past decade, cardiovascular magnetic resonance myocardial feature tracking has emerged as a useful tool for the quantitative evaluation of cardiovascular function. The method allows quantification of biatrial and biventricular mechanics from measures of deformation: strain, torsion, and dyssynchrony. The purpose of this article is to review the basic principles, clinical applications, accuracy, and reproducibility of cardiovascular magnetic resonance myocardial feature tracking, highlighting the prognostic implications. It will also provide an outlook on how this field might evolve in the future.

This study evaluated efficacy and safety of growth hormone treatment in Duchenne muscular dystrophy boys with glucocorticoid-induced growth failure. We reviewed 39 consecutive boys (average age 11.5 years; 32 ambulatory) treated with growth hormone for 1 year during a four-year period. Boys were on long-term daily deflazacort or prednisone (mean duration 5 ± 2.2 years; dosing regimen prednisone 0.75 mg/kg/day equivalent). Primary outcomes were growth velocity and height-for-age z-scores (height SD) at 1 year. Height velocity increased from 1.3 ± 0.2 to 5.2 ± 0.4 cm/year on growth hormone (p

The present study evaluated progressive cardiac dysfunction using serial circumferential strain (epsilon(cc)) measurements in patients with Duchenne muscular dystrophy (DMD). DMD is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that serial epsilon(cc) changes could be detected in individual patients with DMD during a time when the left ventricular ejection fraction (EF) changes are insignificant. Cardiac magnetic resonance imaging data from patients with DMD were evaluated. The left ventricular EF was calculated from steady-state free precession cine images and the composite epsilon(cc) measurement from tagged cine images. The serial epsilon(cc) and EF values for each patient were analyzed using the Wilcoxon sign rank test. Data from 51 patients with DMD (2 studies per patient, mean age at the initial study 11.8 +/- 3.5 years, range 7.4 to 25.4) were analyzed, with a mean interval between cardiac magnetic resonance studies of 15.6 +/- 6.0 months (range 6.2 to 28.1). In the interval between studies, the epsilon(cc) had decreased in all patients with DMD. The average decrease was 1.8 +/- 1.3 (p0.001). However, the EF had decreased in 33 of the 51 patients and had increased in 18 of the 51 patients. On average, the EF decreased by 2.9 +/- 8.57% (p = NS). In conclusion, in patients with DMD, epsilon(cc) abnormalities indicate progression within a relatively short period when the EF changes were not significant. Serial epsilon(cc) measurements might provide reliable monitoring of the progression of DMD-associated cardiac dysfunction before overt heart failure develops, because it is more sensitive than the EF.

Objectives To compare a steady-state free precession cine sequence-based technique (feature tracking [FT]) to tagged harmonic phase (HARP) analysis for peak average circumferential myocardial strain (epsilon(cc)) analysis in a large and heterogeneous population of boys with Duchenne muscular dystrophy (DMD). Background Current epsilon(cc) assessment techniques require cardiac magnetic resonance-tagged imaging sequences, and their analysis is complex. The FT method can readily be performed on standard cine (steady-state free precession) sequences. Methods We compared mid-left ventricular whole-slice epsilon(cc) by the 2 techniques in 191 DMD patients grouped according to age and severity of cardiac dysfunction: group B: DMD patients 10 years and younger with normal ejection fraction (EF); group C: DMD patients older than 10 years with normal EF; group D: DMD patients older than 10 years with reduced EF but negative myocardial delayed enhancement (MDE); group E: DMD patients older than 10 years with reduced EF and positive MDE; and group A: 42 control subjects. Retrospective, offline analysis was performed on matched tagged and steady-state free precession slices. Results For the entire study population (N = 233), mean FT epsilon(cc) values (-13.3 +/- 3.8%) were highly correlated with HARP epsilon(cc) values (-13.6 +/- 3.4%), with a Pearson correlation coefficient of 0.899. The mean epsilon(cc) of DMD patients determined by HARP (-12.52 +/- 2.69%) and FT (-12.16 +/- 3.12%) was not significantly different (p = NS). Similarly, the mean epsilon(cc) of the control subjects by determined HARP (-18.85 +/- 1.86) and FT (-18.81 +/- 1.83) was not significantly different (p = NS). Excellent correlation between the 2 methods was found among subgroups A through E, except there was no significant difference in strain between groups B and C with FT analysis. Conclusions FT-based assessment of epsilon(cc) correlates highly with epsilon(cc) derived from tagged images in a large DMD patient population with a wide range of cardiac dysfunction and can be performed without additional imaging.

Objectives This study sought to evaluate the natural history of occult cardiac dysfunction in Duchenne muscular dystrophy (DMD). Background Duchenne muscular dystrophy is characterized by progressive cardiac dysfunction and myocardial fibrosis late in the disease process. We hypothesized that left ventricular myocardial peak circumferential strain (ecc) would decrease in DMD before global systolic functional abnormalities regardless of age or ventricular ejection fraction (EF). Methods We evaluated cardiac magnetic resonance image (MRI) data from 70 DMD patients and 16 aged-matched control subjects. Standard imaging data included steady-state free precession short-axis cine stack images, cine myocardial tagged images, and myocardial delayed enhancement (MDE) (an indicator of myocardial fibrosis) sequences. Analysis was performed with QMASS (Medis Medical Imaging Systems, Leiden, the Netherlands) and HARP (Diagnosoft, Palo Alto, California) software. The DMD patient data were subdivided by age ( 10 years), EF (>55% or Results The DMD patients with normal EF had reduced eccat an early age ( 10 years with normal EF had further decline in ecccompared with younger DMD patients (p Conclusions Myocardial strain abnormalities are prevalent in young DMD patients despite normal EF, and these strain values continue to decline with advancing age. Strain analysis in combination with standard MRI and MDE imaging provides a means to stratify DMD cardiomyopathy.

Previous studies have identified an increased incidence of bicuspid aortic valve (BAV) in patients with ventricular septal defect (VSD). Because endocardial cushion remodeling contributes to both the formation of semilunar valves and ventricular septation, we hypothesized that examination of humans with BAV and VSD would identify a specific VSD type. We evaluated VSD type in pediatric patients diagnosed with BAV and VSD (n=82) and compared findings to patients diagnosed with VSD and normal aortic valve morphology (n=429). VSD type was described as conoventricular, muscular, inlet or conoseptal using a clinical taxonomy. Based on the contribution of the outflow tract endocardial cushions to the membranous ventricular septum, we expected patients with BAV to have conoventricular VSD. In both patient groups, conoventricular VSD was most common; however, the prevalence was not significantly different when BAV patients were compared to those with normal aortic valve morphology (67% vs. 57%, p=0.11). The primary finding of this study is that despite a developmental link between semilunar valve formation and ventricular septation during cardiogenesis, there is no clear association between BAV and VSD type. This may be due to phenotypic and genetic heterogeneity of BAV and VSD, other modifying factors as manifested by differences in associated CVM, as well as limitations of the clinical taxonomy of VSD.