Clinical profile and outcomes of childhood dilated cardiomyopathy - A single-center three-decade experience.

Introduction and Aims: Dilated cardiomyopathy (DCM) is an important cause of heart failure (HF) among children. Research on pediatric DCM remains surprisingly scarce. The primary objective of the study was to evaluate the clinical profile and outcomes of pediatric DCM and the secondary objective was to study the predictors of outcome. Methods and Results: We enrolled all patients with cardiomyopathy who presented to us between 1990 and 2020 and were younger than 18 years. During the 30-year study period, we identified 233 cases of pediatric cardiomyopathy. One hundred and nineteen (51%) cases had DCM. This retrospective cohort was analyzed to study their outcome and the possible predictors of outcome. Nearly, 8% presented in the neonatal period, and 37% in infancy. The most common mode of presentation was dyspnea on exertion (71%). Ninety-three patients presented in heart failure (78%). The median left ventricular dimension z-score in diastole was 4.3 (range 2.5-9.06). The median left ventricle (LV) ejection fraction was 31%. Seventy-two percent of this cohort were on angiotensin-converting-enzyme inhibitors, 40% on aldosterone antagonists, and 47% on beta-blockers. One-third had syndromic, metabolic, genetic, or any secondary cause identified. Twenty-seven patients satisfied the three-tiered clinical classification for the diagnosis of probable acute myocarditis. Over a mean follow-up of 3.29 years, 27% were lost to follow-up. Among the remaining patients who were on follow-up (n = 86), 39 (45%) died, 31 (36%) recovered, and 16 (18%) had persistent LV dysfunction. Heart Failure was the most common cause of death. Eight patients in this cohort (4.2%) had thromboembolic phenomena. Nine had sustained ventricular arrhythmias and six had atrial/junctional arrhythmias. Among the various risk factors studied, only infantile onset had a significant relationship with death or ventricular arrhythmias (P value- 0.05). The 5-year survival rate of DCM patients was 59%. Conclusion: A reasonably good percentage of our population showed recovery of the left ventricular function (36%). Only infantile onset had a significant relationship with death or ventricular arrhythmias. The outcome in our DCM cohort is similar to other population cohorts.

Clinical profile and outcomes of pediatric hypertrophic cardiomyopathy in a South Indian tertiary care cardiac center: a three decade experience.

INTRODUCTION: Although much research has been done on adult hypertrophic cardiomyopathy, data on pediatric hypertrophic cardiomyopathy is still limited. METHODS AND RESULTS: The study enrolled all patients with cardiomyopathy who presented to us between 1990 to 2020 and were younger than 18 yrs. During the thirty-year study period, we identified 233 cases of pediatric cardiomyopathy. Sixty-three cases (27%) had hypertrophic cardiomyopathy. Out of the 63 HCM cases, 12% presented in the neonatal period and 37% presented in the first year of life. The median age of presentation was 7 yrs (Range 0.1-18 yrs). Sixteen patients had proven syndromic, metabolic, or genetic disease (25%). LV outflow obstruction was present in 30 patients (47%). Noonan syndrome was present in 9 of the 63 patients (14%). Dyspnea on exertion was the most common mode of presentation. Cardiac MRI was done in 28 patients, out of which 17 had late gadolinium enhancement (LGE). Mid myocardial enhancement was the most common pattern. Four patients had LGE of more than 15%. Over a mean follow-up period of 5.6 years (0.1-30 years), twenty-one were lost to follow-up (33%). Among the patients whose outcome was known, eleven died (26%), and thirty-one (73%) were alive. The 5-year survival rate of HCM patients was 82%, and the 10-year survival rate was 78%. Seven died of sudden cardiac death, three from heart failure, and one from ventricular arrhythmias. Sustained ventricular arrhythmias were seen in three patients and atrial arrhythmias in two. First-degree AV block was seen in 10 patients (15%) and bundle branch blocks (BBB) in five (8%). Eight patients required ICD or transplant (12.7%). Two patients underwent ICD for primary prevention, and one underwent PPI for distal AV conduction disease. Among the various clinical, echocardiographic, and radiological risk factors studied, only consanguinity showed a trend towards higher events of death or ventricular arrhythmias (P-value 0.08). CONCLUSION: More than one-third of our HCM cohort presented in infancy. LV outflow tract obstruction is common (47%). Mid myocardial enhancement was the most common pattern of late gadolinium enhancement. SCD was the most common cause of death. The outcome in our HCM cohort is good and similar to other population cohorts. Only Consanguinity showed a trend towards higher events of death or ventricular arrhythmias.

Safety of drug-eluting stents for stenting patent arterial duct in neonates.

OBJECTIVES: The primary objective was to evaluate the trend of blood sirolimus concentrations in neonates following ductal stenting. The long-term outcomes and incidence of infections were also evaluated. METHODS: Prospective open-label observational study in a tertiary referral centre over a 1-year period. Serum sirolimus levels were estimated at 1 hour and 24hrs post-stent insertion followed by 7 days in neonates who underwent ductal stenting. The trend in sirolimus levels, incidence of infections, complications and outcomes following ductal stenting were studied. RESULTS: Seven neonates with duct-dependent pulmonary circulation underwent ductal stenting at median age of 8.5 days and weight of 2.83kg. The average stent size was 3.5±0.4 mm, and average stent length was 16.3±5.1 mm. The mean sirolimus concentrations at 1 hour, 24 hours and 7 days were 41.3±6.9ng/ml, 15.4±7.1ng/ml and 3.1±0.85ng/ml respectively. Levels fell below therapeutic range for all patients by 7 days. Three patients had sepsis or necrotising enterocolitis, but responded well to antibiotics; 1 patient had aspiration related sudden death. There were no further events at a mean follow-up of 207 days, and 4 patients underwent elective surgery at 238 ± 81 days after ductal stenting. CONCLUSIONS: This study demonstrates applicability of drug-eluting stents for ductal stenting in newborns. Drug-eluting stents with abluminal drug delivery are associated with high sirolimus levels in initial hours but rapidly taper to negligible levels within a week of implantation. Neonates with high pre-procedure likelihood of infection developed sepsis but responded well to conservative management. The patency of drug-eluting ductal stents is preserved over long-term follow-up.

Normal pulmonary venous drainage in the setting of total anomalous pulmonary venous connection.

Total anomalous pulmonary venous connection (TAPVC) and anomalous pulmonary venous drainage are not synonymous. This has been described in the setting of right isomerism (bilateral right sidedness) where the pulmonary veins are connected anomalously but drain normally to the left-sided morphological right atrium. We describe another situation in right isomerism where normal pulmonary venous drainage is present in the setting of TAPVC.

Influence of age at surgery on left ventricular strain in patients with anomalous origin of left coronary artery from pulmonary artery.

OBJECTIVES: Myocardial strain abnormalities are described after surgical repair of anomalous left coronary artery from pulmonary artery (ALCAPA) even after recovery of ventricular function. The factors that predispose to the presence of these strain abnormalities in the presence of normal ventricular function are unknown. The aim of this study was to find out whether the age at repair influences the presence of global and regional strain abnormalities on follow-up. METHODS: Repaired ALCAPA patients from a single centre (n = 40) with good ventricular ejection fraction on follow-up were recruited. Baseline and follow-up data were collected from electronic records. Global and regional myocardial strain assessment was done by speckle tracking echocardiography prospectively. The association between age at repair and strain abnormalities on follow-up was analysed. RESULTS: The patients who presented earlier had significantly worse ventricular function pre-operatively compared to older patients (P < 0.0005). Global longitudinal strain was abnormal in 40% of patients with normal ventricular ejection fraction on follow-up. Presence of longitudinal strain abnormalities was more in patients who underwent repair at older age than in those who were repaired earlier (P < 0.0005). The probability of having normal longitudinal strain on follow-up was 81.6% if surgery was done before 7.8 months of age. If operated before 6 months, the odds of having normal myocardial strain was 11 times higher. Regional strain abnormalities of varying severity were present in all patients in the left and in some patients in the right coronary artery territories. CONCLUSIONS: Older age at ALCAPA repair is associated with increased incidence of myocardial strain abnormalities. Regional strain abnormalities were found in both left and right coronary artery territories.

Inhibition of pancreatic EZH2 restores progenitor insulin in T1D donor.

Type 1 diabetes (T1D) is an autoimmune disease that selectively destroys insulin-producing ß-cells in the pancreas. An unmet need in diabetes management, current therapy is focussed on transplantation. While the reprogramming of progenitor cells into functional insulin-producing ß-cells has also been proposed this remains controversial and poorly understood. The challenge is determining why default transcriptional suppression is refractory to exocrine reactivation. After the death of a 13-year-old girl with established insulin-dependent T1D, pancreatic cells were harvested in an effort to restore and understand exocrine competence. The pancreas showed classic silencing of ß-cell progenitor genes with barely detectable insulin (Ins) transcript. GSK126, a highly selective inhibitor of EZH2 methyltransferase activity influenced H3K27me3 chromatin content and transcriptional control resulting in the expression of core ß-cell markers and ductal progenitor genes. GSK126 also reinstated Ins gene expression despite absolute ß-cell destruction. These studies show the refractory nature of chromatin characterises exocrine suppression influencing ß-cell plasticity. Additional regeneration studies are warranted to determine if the approach of this n-of-1 study generalises to a broader T1D population.

Left ventricular-infundibular apical septal defect: a rare entity revisited.

Apical ventricular septal defects are a heterogeneous group of septal defects that need accurate anatomic characterisation for planning appropriate management. Left ventricular-infundibular apical septal defects are defects between the left ventricular septum and the infundibular apex of the right ventricle with distinctive morphological features. We describe two illustrative examples of this septal defect with focus on their therapeutic implications and long-term outcome.

Chylotamponade in Pediatric Primary Mediastinal Large B-Cell Lymphoma.

Chylotamponade involves rapid accumulation of chyle in the pericardium elevating the pericardial pressures above normal right heart filling pressures, and is extremely rare. A 12-y-old boy presented to the emergency with complaints of facial puffiness for 1 mo and breathing difficulty for 1 wk. The neck veins were distended, and the heart sounds were muffled. A chest CT demonstrated a large anterior mediastinal mass with pleural and pericardial effusions. Echocardiography confirmed cardiac tamponade. Pericardiocentesis revealed chylopericardium. He was placed on a chyle leak diet, and the drain was removed after 48 h. Biopsy of the mediastinal mass revealed a primary mediastinal B-cell lymphoma. He was successfully managed with chemotherapy. The index case demonstrates how prompt identification and management of chylotamponade and treatment of the underlying cause can lead to good clinical outcomes.

Percutaneous Closure of Giant Aortic Pseudoaneurysm in a Child.

Although percutaneous closure of aortic pseudoaneurysms have been described in adults with good results, there are no reports in children. This case demonstrates that in selected high-risk cases where the anatomy is suitable, percutaneous closure may be feasible and safe in children.

Hemianomalous pulmonary venous drainage and type IIb coronary sinus septal defect - Utility of subxiphoid and right parasternal views.

A 3-year-old boy presented with history of recurrent respiratory tract infections in infancy. Clinically he had hemodynamically significant pre-tricuspid left-to-right shunt and no pulmonary hypertension. Transthoracic echocardiography delineated anomalous drainage of the left sided pulmonary veins to a dilated coronary sinus opening into the right atrium. Closer evaluation from the subxiphoid and right parasternal views led to the diagnosis of an associated type IIb coronary sinus septal defect.

A Comparative Study of Invasive Modalities for Evaluation of Pulmonary Arteriovenous Fistula after Bidirectional Glenn Shunt.

Development of pulmonary AV fistula (PAVF) after bidirectional glenn shunt (BDG) results in significant cyanosis, impaired exercise performance, and increased morbidity and mortality. We attempted to detect and quantify PAVF in post-BDG patients by saline contrast transesophageal echocardiography (TEE) and compare with pulmonary angiography and pulmonary vein oximetry. This was a prospective study done between 2017 and 2018. Twenty-five children who underwent BDG and planned for cardiac catheterization prior to Fontan completion were included in the study. All patients underwent pulmonary angiography, oximetry, and saline contrast TEE at the time of cardiac catheterization. Twenty-two patients had undergone unilateral BDG surgery and three were palliated by bilateral BDG. The mean oxygen saturation was 80 ± 5.2%. Thirteen patients (52%) had preserved antegrade pulmonary blood flow. Eighteen patients (72%) had PAVF by angiography and oximetry, while 19 (76%) had PAVF identified by contrast echocardiography. There was moderate correlation between the degree of pulmonary venous desaturation and grading of PAVF by contrast echocardiography. PAVF was predominantly located in the lower zones of the lungs. Higher grades of PAVF were not seen in patients with preserved antegrade flow after BDG. Angiographically detected PAVF showed a steady increase with increasing delay to cardiac catheterization from BDG. Significant reduction in systemic saturation was limited to advanced grades of PAVF in patients after BDG. Saline contrast TEE, pulmonary venous oximetry, and pulmonary angiography equally identified PAVF in patients after BDG. Prognostic utility of the same needs to be assessed by long-term follow-up of these subjects.

Technical considerations of coarctation stenting in double-barreled aorta - A persistent fifth arch mimic.

The double-barreled aorta connecting the ascending aorta and descending aorta caudal to the normal fourth aortic arch has fascinated the interests of cardiac morphologists for over a century. This condition is commonly associated with coarctation. While the controversies surrounding the embryology of the double-barreled aorta have settled down, we present a case-based illustration of the technical aspects of coarctation stenting peculiar to this condition.

Valproic acid influences the expression of genes implicated with hyperglycaemia-induced complement and coagulation pathways.

Because the liver plays a major role in metabolic homeostasis and secretion of clotting factors and inflammatory innate immune proteins, there is interest in understanding the mechanisms of hepatic cell activation under hyperglycaemia and whether this can be attenuated pharmacologically. We have previously shown that hyperglycaemia stimulates major changes in chromatin organization and metabolism in hepatocytes, and that the histone deacetylase inhibitor valproic acid (VPA) is able to reverse some of these metabolic changes. In this study, we have used RNA-sequencing (RNA-seq) to investigate how VPA influences gene expression in hepatocytes. Interesting, we observed that VPA attenuates hyperglycaemia-induced activation of complement and coagulation cascade genes. We also observe that many of the gene activation events coincide with changes to histone acetylation at the promoter of these genes indicating that epigenetic regulation is involved in VPA action.

TRAK2, a novel regulator of ABCA1 expression, cholesterol efflux and HDL biogenesis.

Aims: The recent failures of HDL-raising therapies have underscored our incomplete understanding of HDL biology. Therefore there is an urgent need to comprehensively investigate HDL metabolism to enable the development of effective HDL-centric therapies. To identify novel regulators of HDL metabolism, we performed a joint analysis of human genetic, transcriptomic, and plasma HDL-cholesterol (HDL-C) concentration data and identified a novel association between trafficking protein, kinesin binding 2 (TRAK2) and HDL-C concentration. Here we characterize the molecular basis of the novel association between TRAK2 and HDL-cholesterol concentration. Methods and results: Analysis of lymphocyte transcriptomic data together with plasma HDL from the San Antonio Family Heart Study (n = 1240) revealed a significant negative correlation between TRAK2 mRNA levels and HDL-C concentration, HDL particle diameter and HDL subspecies heterogeneity. TRAK2 siRNA-mediated knockdown significantly increased cholesterol efflux to apolipoprotein A-I and isolated HDL from human macrophage (THP-1) and liver (HepG2) cells by increasing the mRNA and protein expression of the cholesterol transporter ATP-binding cassette, sub-family A member 1 (ABCA1). The effect of TRAK2 knockdown on cholesterol efflux was abolished in the absence of ABCA1, indicating that TRAK2 functions in an ABCA1-dependent efflux pathway. TRAK2 knockdown significantly increased liver X receptor (LXR) binding at the ABCA1 promoter, establishing TRAK2 as a regulator of LXR-mediated transcription of ABCA1. Conclusion: We show, for the first time, that TRAK2 is a novel regulator of LXR-mediated ABCA1 expression, cholesterol efflux, and HDL biogenesis. TRAK2 may therefore be an important target in the development of anti-atherosclerotic therapies.

Stenting and Reimplanting Disconnected Pulmonary Artery in Tetralogy of Fallot.

Tetralogy of Fallot with absent pulmonary valve syndrome (TOF/APV) is a rare congenital malformation. Although pulmonary artery (PA) anomalies have been observed in TOF, its association with disconnected PA is extremely rare. We report successful stenting of the disconnected left PA in a 3-year-old boy with TOF/APV followed by surgical reimplantation. The significance of this transcatheter intervention for guidance during surgery and the importance of visualizing a ductal stump on angiography as an indicator of disconnected PA are discussed.

Etiology matters - Genomic DNA Methylation Patterns in Three Rat Models of Acquired Epilepsy.

This study tested the hypothesis that acquired epileptogenesis is accompanied by DNA methylation changes independent of etiology. We investigated DNA methylation and gene expression in the hippocampal CA3/dentate gyrus fields at 3 months following epileptogenic injury in three experimental models of epilepsy: focal amygdala stimulation, systemic pilocarpine injection, or lateral fluid-percussion induced traumatic brain injury (TBI) in rats. In the models studies, DNA methylation and gene expression profiles distinguished controls from injured animals. We observed consistent increased methylation in gene bodies and hypomethylation at non-genic regions. We did not find a common methylation signature in all three different models and few regions common to any two models. Our data provide evidence that genome-wide alteration of DNA methylation signatures is a general pathomechanism associated with epileptogenesis and epilepsy in experimental animal models, but the broad pathophysiological differences between models (i.e. pilocarpine, amygdala stimulation, and post-TBI) are reflected in distinct etiology-dependent DNA methylation patterns.

Integration of Computed Tomography and Three-Dimensional Echocardiography for Hybrid Three-Dimensional Printing in Congenital Heart Disease.

Three-dimensional (3D) printing is an emerging technology aiding diagnostics, education, and interventional, and surgical planning in congenital heart disease (CHD). Three-dimensional printing has been derived from computed tomography, cardiac magnetic resonance, and 3D echocardiography. However, individually the imaging modalities may not provide adequate visualization of complex CHD. The integration of the strengths of two or more imaging modalities has the potential to enhance visualization of cardiac pathomorphology. We describe the feasibility of hybrid 3D printing from two imaging modalities in a patient with congenitally corrected transposition of the great arteries (L-TGA). Hybrid 3D printing may be useful as an additional tool for cardiologists and cardiothoracic surgeons in planning interventions in children and adults with CHD.

Hybrid 3D printing: a game-changer in personalized cardiac medicine?

Three-dimensional (3D) printing in congenital heart disease has the potential to increase procedural efficiency and patient safety by improving interventional and surgical planning and reducing radiation exposure. Cardiac magnetic resonance imaging and computed tomography are usually the source datasets to derive 3D printing. More recently, 3D echocardiography has been demonstrated to derive 3D-printed models. The integration of multiple imaging modalities for hybrid 3D printing has also been shown to create accurate printed heart models, which may prove to be beneficial for interventional cardiologists, cardiothoracic surgeons, and as an educational tool. Further advancements in the integration of different imaging modalities into a single platform for hybrid 3D printing and virtual 3D models will drive the future of personalized cardiac medicine.

Dynamic changes in the cardiac methylome during postnatal development.

Relatively little is known about the epigenetic control mechanisms that guide postnatal organ maturation. The goal of this study was to determine whether DNA methylation plays an important role in guiding transcriptional changes during the first 2 wk of mouse heart development, which is an important period for cardiomyocyte maturation, loss of proliferative capacity and loss of regenerative potential. Gene expression profiling (RNA-seq) and genome-wide sequencing of methylated DNA (MBD-seq) identified dynamic changes in the cardiac methylome during postnatal development [2545 differentially methylated regions (DMRs) from P1 to P14 in the mouse]. The vast majority (~80%) of DMRs were hypermethylated between P1 and P14, and these hypermethylated regions were associated with transcriptional shut down of important developmental signaling pathways, including Hedgehog, bone morphogenetic protein, TGF-ß, fibroblast growth factor, and Wnt/ß-catenin signaling. Postnatal inhibition of DNA methylation with 5-aza-2'-deoxycytidine induced a marked increase (~3-fold) in cardiomyocyte proliferation and ~50% reduction in the percentage of binucleated cardiomyocytes compared with saline-treated controls. This study provides novel evidence for widespread alterations in DNA methylation during postnatal heart maturation and suggests that cardiomyocyte cell cycle arrest during the neonatal period is subject to regulation by DNA methylation.