The outcome of genetic and non-genetic pediatric cardiomyopathies.

BACKGROUND: Pediatric cardiomyopathies (CMP) can be familial or idiopathic with increasing detection of genetic mutations. The study is a retrospective single-center review of cardiomyopathy patients from January 2011 to May 2020. Results of the genetic study, as well as the outcome, were reported. Patients were divided according to the type of CMP, age of presentation, and EF at presentation. Univariate and multivariate analysis and ROC and survival curves were done. RESULTS: We reported 229 patients under 14 years of age with a diagnosis of cardiomyopathy, most commonly DCM (160 patients (70%)) followed by HCM (26.2%). 52% presented at 6 months of age or less and 119 (52%) required ICU admission at presentation. The genetic and or metabolic disorder was confirmed in 21.4% of patients, most commonly VLCAD defect (16, 7%) and ELAC2 gene defect (10, 4.4%). During the disease course, 88 patients (38.4%) died (48 with DCM, 39 with HCM, and 1 with RCM). An EF of 20% or less at presentation and presentation at 6 months of age or less carries a risk for mortality in patients with DCM and HCM, respectively (RR 3.88 and 2.06 and OR of 11.09 and 4.35, respectively). Death was more common among HCM patients especially patients with positive genetic abnormality compared with patients with DCM. CONCLUSIONS: The mortality for CMP in children reaches up to 40%, (30% in DCM and 65% in HCM patients). Mortality was higher in those with HCM, DCM with EF of 20% or less, and HCM presented at 6 months of age or less. Whole-exome and/or whole-genome sequencing is advised for all patients of CMP and at-risk family members.

Variable phenotype of a null PPP1R13L allele in children with dilated cardiomyopathy.

Childhood-onset cardiomyopathy is a genetically heterogeneous group of conditions with several genes implicated. Recently, biallelic loss-of-function variants in PPP1R13L have been reported in association with a syndromic form of dilated cardiomyopathy (DCM). In addition, affected children manifest skin and hair abnormalities, cleft lip and palate (CLP), and eye findings. Here, we delineate the condition further by describing the phenotype associated with a homozygous frameshift variant (p.Arg330 ProfsTer76) in PPP1R13L detected in two sibships in a consanguineous family with six affected children. The index case had DCM and wooly hair, two of his siblings had DCM and CLP while three cousins had, in addition, glaucoma. Global developmental delay was observed in one child. All the children, except one, died during early childhood. Whole exome sequencing and whole genome sequencing did not reveal any other plausible variant. We provide further evidence that implicates PPP1R13L in a variable syndromic form of severe childhood-onset DCM and suggests expanding the spectrum of this condition to include glaucoma. Given the variability of the phenotype associated with PPP1R13-related DCM, a thorough evaluation of each case is highly recommended even in the presence of an apparently isolated DCM.

Postcardiotomy extracorporeal membrane oxygenation in patients with congenital heart disease; the effect of place of initiation.

BACKGROUND: Postcardiotomy extracorporeal membrane oxygenation (ECMO) in pediatric patients can be affected by the place of initiation, either in the operating room (OR) or the pediatric cardiac intensive care unit (PCICU). This study aimed to characterize and compare patients who had postcardiotomy ECMO initiation in the OR or PCICU and evaluate risk factors for hospital mortality. METHODS: This retrospective study included 103 patients who required postcardiotomy ECMO support after the repair of congenital cardiac lesions from 2010 to 2022. Patients were grouped according to the place of ECMO insertion into two groups. Group 1 (n = 69) had ECMO insertion in the OR, and Group 2 (n = 34) had ECMO insertion in the PCICU. RESULTS: Cardiac arrest occurred significantly more often in patients with ECMO insertion in the PCICU (21 (61.76%) vs. 13 (18.84%); p < 0.001). Pre-ECMO lactate levels, pH, VIS, base deficit, and PaO2 did not differ between the groups. Re-exploration for bleeding was significantly higher in Group 1 (32 (46.38%) vs. 8 (23.53%); p = 0.03). Cannula repositioning (4 (11.76%) v. 2 (2.90%); p = 0.09) and mechanical ventilation time were nonsignificantly higher in Group 2 (19.5 (10-31) vs. 11 (5-25) days; p = 0.07). No difference in mortality was found between groups (42 (60.87%) vs. 23 (67.65%), p = 0.50). By multivariable analysis, elevated lactate on ECMO and low pH before ECMO were associated with mortality. CONCLUSIONS: ECMO insertion in the OR has a comparable mortality rate to PCICU insertion. Pre-ECMO low pH and high lactate during ECMO could predict mortality.

Biallelic loss of LDB3 leads to a lethal pediatric dilated cardiomyopathy.

Autosomal dominant variants in LDB3 (also known as ZASP), encoding the PDZ-LIM domain-binding factor, have been linked to a late onset phenotype of cardiomyopathy and myofibrillar myopathy in humans. However, despite knockout mice displaying a much more severe phenotype with premature death, bi-allelic variants in LDB3 have not yet been reported. Here we identify biallelic loss-of-function variants in five unrelated cardiomyopathy families by next-generation sequencing. In the first family, we identified compound heterozygous LOF variants in LDB3 in a fetus with bilateral talipes and mild left cardiac ventricular enlargement. Ultra-structural examination revealed highly irregular Z-disc formation, and RNA analysis demonstrated little/no expression of LDB3 protein with a functional C-terminal LIM domain in muscle tissue from the affected fetus. In a second family, a homozygous LDB3 nonsense variant was identified in a young girl with severe early-onset dilated cardiomyopathy with left ventricular non-compaction; the same homozygous nonsense variant was identified in a third unrelated female infant with dilated cardiomyopathy. We further identified homozygous LDB3 frameshift variants in two unrelated probands diagnosed with cardiomegaly and severely reduced left ventricular ejection fraction. Our findings demonstrate that recessive LDB3 variants can lead to an early-onset severe human phenotype of cardiomyopathy and myopathy, reminiscent of the knockout mouse phenotype, and supporting a loss of function mechanism.

Retraction: Pulmonary Embolism in COVID-19 Patients: A Retrospective Case-Control Study.

[This retracts the article DOI: 10.7759/cureus.18887.].

Late Outcomes After Pulmonary Arterial Reconstruction in Patients With Arterial Tortuosity Syndrome.

BACKGROUND: Surgical pulmonary artery reconstruction in patients with arterial tortuosity syndrome has excellent outcomes. In this study, we report our late outcomes after more than a decade of experience with such complex interventions. METHODS: We conducted a retrospective review of 33 arterial tortuosity syndrome patients who underwent pulmonary artery reconstruction. The mean preoperative right ventricular to left ventricular pressure ratio was 1.19 ± 0.2. Our surgical approach included either a single-stage complete repair through a median sternotomy (17 patients) or a two-stage repair through sternotomy/left thoracotomy (16 patients), depending on the degree of distal involvement in the left pulmonary artery. RESULTS: Median age was 36 months. All patients had distal segmental peripheral pulmonary artery stenosis. Thirty patients (90.1%) were symptomatic before surgery. There was one hospital death due to viral pneumonia 78 days after the surgery (in-hospital mortality 3%). The mean right ventricular to left ventricular pressure ratio decreased to 0.31 ± 0.07 early postoperatively (P < 0.001), representing a 74% reduction compared with preoperative values. Follow-up was 100% complete for all hospital survivors (32 of 33) with a mean follow-up of 70.42 ± 43.32 months (range, 2 to 143). There was no late mortality or need for reintervention (surgical or catheter based) after hospital discharge. In late postoperative catheterization, the mean right ventricular to left ventricular pressure ratio was 0.27 ± 0.05 (P = .003 compared with early postoperative value). All patients were asymptomatic on their most recent follow-up. CONCLUSIONS: A strategy of complete surgical reconstruction of all stenotic pulmonary artery segments in patients with arterial tortuosity syndrome is recommended for sustainable successful outcomes more than a decade later.

Pulmonary Embolism in COVID-19 Patients: A Retrospective Case-Control Study.

BACKGROUND: Coagulopathy is a well-recognized complication in patients with coronavirus disease 2019 (COVID-19). Pulmonary embolism (PE) has substantial morbidity and mortality if the diagnosis is missed or the management is delayed. Computed tomography pulmonary angiography (CT-PA) is the imaging modality of choice for PE. Therefore, this study aimed to investigate the positive rate of CT-PA for PE among patients with COVID-19. METHODS: We conducted a retrospective study examining the diagnostic yield of CT-PA in patients with confirmed COVID-19 and compared it with that in patients without COVID-19. The study included all adult patients with confirmed COVID-19 who presented from June 2020 to June 2021. RESULTS: The study included 316 patients, including 158 patients with COVID-19, who underwent CT-PA for ruling out PE. Overall, 76 patients were found to have PE on the CT-PA scan, yielding a positive rate of 24.1%, with a significant difference between patients with COVID-19 (8.2%) and those without COVID-19 (39.9%). Further, 138 (87.3%) patients with COVID-19 had elevated D-dimer levels compared with 34 (21.5%) patients without COVID-19. A multivariable regression analysis model revealed that the smoking status (odds ratio [OR] = 1.94; 95% confidence interval [CI]: 1.4-3.8) and obesity (OR = 4.1; 95% CI: 1.5-8.9) were independent predictors of PE among patients with COVID-19. However, the elevated D-dimer level was not significantly associated with PE among patients with COVID-19 (OR = 0.7; 95% CI: 0.4-1.8). CONCLUSION: The study found that the positive rate of CT-PA for PE was lower among patients with PE indicating probable overutilization of investigation in these patients. Additionally, patients with COVID-19 had a higher proportion of elevated D-dimer levels that may be a contributor to the increased investigation for PE. Lastly, patients with COVID-19 who were current smokers had a higher tendency of having PE.

Categorized Genetic Analysis in Childhood-Onset Cardiomyopathy.

BACKGROUND: Childhood-onset cardiomyopathy is a heterogeneous group of conditions the cause of which is largely unknown. The influence of consanguinity on the genetics of cardiomyopathy has not been addressed at a large scale. METHODS: To unravel the genetic cause of childhood-onset cardiomyopathy in a consanguineous population, a categorized approach was adopted. Cases with childhood-onset cardiomyopathy were consecutively recruited. Based on the likelihood of founder mutation and on the clinical diagnosis, genetic test was categorized to either (1) targeted genetic test with targeted mutation test, single-gene test, or multigene panel for Noonan syndrome, or (2) untargeted genetic test with whole-exome sequencing or whole-genome sequencing. Several bioinformatics tools were used to filter the variants. RESULTS: Two-hundred five unrelated probands with various forms of cardiomyopathy were evaluated. The median age of presentation was 10 months. In 30.2% (n=62), targeted genetic test had a yield of 82.7% compared with 33.6% for whole-exome sequencing/whole-genome sequencing (n=143) giving an overall yield of 53.7%. Strikingly, 96.4% of the variants were homozygous, 9% of which were found in 4 dominant genes. Homozygous variants were also detected in 7 novel candidates (ACACB, AASDH, CASZ1, FLII, RHBDF1, RPL3L, ULK1). CONCLUSIONS: Our work demonstrates the impact of consanguinity on the genetics of childhood-onset cardiomyopathy, the value of adopting a categorized population-sensitive genetic approach, and the opportunity of uncovering novel genes. Our data suggest that if a founder mutation is not suspected, adopting whole-exome sequencing/whole-genome sequencing as a first-line test should be considered.

Intracardiac thrombus formation and thromboembolic events in children with cardiomyopathies: A single-center case series.

Intracardiac thrombosis and distant thromboembolic events are rare complications of patients diagnosed with any type of cardiomyopathies. The low prevalence of this entity makes it challenging and unfortunate for the patients and their families. This review aims to add to the current limited available data describing similar clinical entities.

Outcome of cardiac surgery in adults with congenital heart disease: A single center experience.

OBJECTIVES: Adult survivors with congenital heart diseases represent a large and growing population, yet the published data does not represent the magnitude of their needs specifically in the Middle East. We aimed to review our experience at King Faisal Heart Center, Riyadh, Saudi Arabia for the outcome of adult patients with congenital heart disease who underwent either primary or redo surgery. METHODS: A retrospective study at a tertiary care hospital. All patients who underwent surgery either as the first surgery or as a reoperation for congenital heart disease aged >16 years old at the time of cardiac surgery in the period between January 1, 2008 and January 1, 2013. We looked for incidence of postoperative bleeding, arrhythmias, acute kidney injury, neurological complications, duration of mechanical ventilation, hospital and intensive care unit (ICU) stay. Additionally, we assessed the mortality and 1- and 5-year survival. RESULTS: Ninety-eight patients were included in our study. Fifty-two (53%) were females and 46 (47%) were males, with a mean age of 26 ±â€¯8.4 years and a mean weight of 62 ±â€¯22.8 kg. Forty-nine patients (50%) required redo surgery. Ten patients (10%) suffered from postoperative bleeding. Eight patients (8%) had postoperative arrhythmias, of which two patients required permanent pacemaker insertion. Three patients (3%) had postoperative acute kidney injury and seven patients (7%) suffered from neurological complications. The mean duration of ventilation was 1.3 ±â€¯2 days, with a mean ICU and hospital stay of 3.7 ±â€¯3 days, and 10 ±â€¯7 days, respectively. The overall mortality rate in our series was 4% with a 1-5-year survival of 96%. CONCLUSION: Adult patients with congenital heart disease are prone to immediate postoperative multisystem complications, yet the majority of them are reversible. Their 1- and 5-year survival rate is excellent. Further follow up studies are required.

The Phenotype and Outcome of Infantile Cardiomyopathy Caused by a Homozygous ELAC2 Mutation.

OBJECTIVE: Cardiomyopathy (CMP) in children is a clinically and genetically heterogeneous group of disorders. Disease-associated mutations have been identified in more than 50 genes. Recently, mutations in the mitochondrial tRNA processing gene, ELAC2, were reported to be associated with the recessively inherited form of hypertrophic CMP (HCM). This study is aimed at describing the cardiac phenotype and outcome of ELAC2 mutation. METHODS: We performed whole exome sequencing followed by targeted mutation screening to identify the genetic etiology of severe infantile-onset CMP in 64 consanguineous Saudi families. RESULTS: A previously reported mutation (p.Phe154Leu) in ELAC2 gene was detected in 16 families. The index cases presented between 2 and 7 months of age with HCM in 13 infants and dilated CMP (DCM) in 3. Pericardial effusion was observed in 7 infants (44%). All infants died with a median age of death of 4 months. Almost 1/3 of them died during the initial presentation. CONCLUSION: Our study suggests screening the ELAC2 gene in severe infantile-onset HCM or DCM of unknown etiology, especially in the presence of pericardial effusion. Our work demonstrates a universally poor outcome of the (p.Phe154Leu) variant in ELAC2 gene; a correlation that helps in counseling parents and in planning appropriate medical intervention.

Octreotide use in post-cardiac surgery chylothorax: a 12-year perspective.

Background Chylothorax following cardiothoracic surgery is a rare condition in pediatric patients with significant morbidity and mortality. Pharmacological management with octreotide suggests possible efficacy; however, current evidence is inadequate. The objective of this study was to assess the safety and efficacy of octreotide as a therapeutic option in this clinical setting. Methods This was a 12-year single-center retrospective cohort study of all patients (birth to 18-years old) who received octreotide for management of post-cardiac surgery chylothorax between January 2003 to August 2015. The primary efficacy endpoint was resolution of chylothorax, categorized as complete (<2 mL·kg-1·day-1), partial (based on physician's judgement), or failed. The primary safety endpoint was any significant adverse drug reaction leading to discontinuation of octreotide therapy. Of the 46 patients identified as receiving octreotide for post-cardiac surgery chylothorax, 29 were included in efficacy and safety analyses. Results Resolution of chylothorax was achieved in 62% (complete in 28%, partial in 34%) of the total sample. The 38% who did not respond to octreotide therapy required thoracic duct ligation. The mean initial dose and duration of octreotide was 4 ± 3 µg·kg-1·h-1 and 10 ± 5 days, respectively. Besides minor side-effects including transient hyperglycemia (45%), abdominal distension (3%), and tachycardia (>150 beats·min-1; 10%), no patient developed a significant side-effect that required discontinuation of therapy. Conclusions Pharmacological management of post-cardiac surgery induced chylothorax with octreotide shows promising benefits with an acceptable safety profile.

Does single ventricle physiology affect survival of children requiring extracorporeal membrane oxygenation support following cardiac surgery?

BACKGROUND: Improved survival with postoperative extracorporeal membrane oxygenation (ECMO) has expanded its application to children with single ventricle (SV) anomalies. We examine current-era outcomes of postoperative ECMO with special focus on patients with SV. METHODS: Demographic, anatomic, surgical, and support details of 100 consecutive children requiring postoperative ECMO (2007-2012) were included into multivariable regression models to identify factors affecting survival. RESULTS: Median age was 73 days (4 days-16.2 years), 31 patients had SV physiology. The ECMO indication was failure to wean cardiopulmonary bypass (34%) and postoperative low cardiac output (66%) including 37% having extracorporeal cardiopulmonary resuscitation (ECPR). Median ECMO duration was four days (1-21). The ECMO decannulation and survival to hospital discharge were 62% and 37%. In SV group, decannulation and survival rates were 55% and 32%. The SV-ECMO outcomes were best in ECPR subgroup (54%), following shunt (57%) or Norwood (46%) and worst following Glenn, Fontan, or total anomalous pulmonary venous connection repair (0% survival). On multivariable analysis, factors affecting odds of survival were performing angiogram (odds ratio [OR]: 15.28, confidence interval [CI]: 2.34-99.89, P = .004), prolonged ECMO duration (OR: 0.64, CI: 0.47-0.88 per day, P = .005), leaving cannulation snares (OR: 28.41, CI: 2.65-304.70, P = .006), higher HCO3 (OR: 1.19, CI: 1.04-1.36, P = .01), renal failure requiring hemodialysis (OR: 0.21, CI: 0.06-0.76, P = .02), bleeding requiring re-exploration (OR: 0.21, CI: 0.06-0.75, P = .02), ECPR in patients with SV (OR: 11.84, CI: 1.11-126.07, P = .04), delayed lactate normalization (OR: 0.95, CI: 0.90-0.99 per hour, P = .02), and elevated liver enzymes (OR: 0.97, CI: 0.95-1.00 per 10 unit/L, P = .05). CONCLUSIONS: The ECMO is valuable in patients with SV however results depend on anatomy, procedure, and support indication. Persistent markers of poor perfusion, end-organ injury, and prolonged ECMO duration are associated with mortality. Those factors could be modified by early ECMO application before organ damage, meticulous homeostasis to ensure adequate perfusion, early diagnosis, and reoperation on residual lesions to expedite weaning.

Is the ross procedure a suitable choice for aortic valve replacement in children with rheumatic aortic valve disease?

BACKGROUND: Ross procedure is the aortic valve replacement of choice in children. Nonetheless, late autograft reoperation for dilatation and/or regurgitation is concerning. We examine whether Ross procedure is suitable in children with rheumatic fever. METHODS: Medical records of 104 children with rheumatic fever who underwent Ross procedure were reviewed (1991-2004). Competing risks methodology determined time-related prevalence and associated factors for two mutually exclusive end states: autograft reoperation and death prior to subsequent reoperation. RESULTS: Mean age was 13.8 ± 2.7, 83 (80%) were males. Hemodynamic dysfunction was primarily regurgitation (n = 92, 88%) and stenosis/mixed (n = 12, 12%). Competing risks analysis showed that in ten years after the Ross procedure, 1% of patients died, 32% underwent autograft reoperation, and 67% were alive and free from reoperation. Ten-year freedom from aortic regurgitation greater than or equal to moderate was 63%. Ten-year freedom from autograft reoperation was 65% for regurgitation versus 90% for stenosis/mixed disease. Risk factors for autograft reoperation were earlier surgery year (PE: 0.26 ± 0.06 per year; P < .001), additional surgery (PE: 0.82 ± 0.39, P = .04), no annular stabilization (PE: 1.21 ± 0.61, P = .05). Ten-year freedom from homograft replacement was 83%. Risk factors were fresh homografts (PE: 1.36 ± 0.71; P = .06) and aortic homografts (PE: 1.15 ± 0.59; P = .05). Ten-year freedom from any cardiac reoperation was 53%. Concomitant cardiac surgery was risk factor (PE: 1.37 ± 0.47; P = .004). CONCLUSIONS: Ross procedure in children with rheumatic fever is associated with excellent survival but results are plagued by aortic regurgitation and frequent autograft reoperation. Risk factors include preoperative regurgitation, concomitant surgery, dilated annulus, and earlier surgery era. Better patient selection in later era has mitigated autograft reoperation risk. Continued, improved candidate selection, along with modifications in autograft implantation and root/sinotubular stabilization techniques, may further decrease late autograft failure.