Cardiomyopathy, an uncommon phenotype of congenital disorders of glycosylation: Recommendations for baseline screening and follow-up evaluation.

INTRODUCTION: Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to multi-systemic manifestations. These disorders are categorized into various groups depending on which part of the glycosylation process is impaired. The cardiac manifestations in CDG can significantly differ, not only across different types but also among individuals with the same genetic cause of CDG. Cardiomyopathy is an important phenotype in CDG. The clinical manifestations and progression of cardiomyopathy in CDG patients have not been well characterized. This study aims to delineate common patterns of cardiomyopathy across a range of genetic causes of CDG and to propose baseline screening and follow-up evaluation for this patient population. METHODS: Patients with molecular confirmation of CDG who were enrolled in the prospective or memorial arms of the Frontiers in Congenital Disorders of Glycosylation Consortium (FCDGC) natural history study were ascertained for the presence of cardiomyopathy based on a retrospective review of their medical records. All patients were evaluated by clinical geneticists who are members of FCDGC at their respective academic centers. Patients were screened for cardiomyopathy, and detailed data were retrospectively collected. We analyzed their clinical and molecular history, imaging characteristics of cardiac involvement, type of cardiomyopathy, age at initial presentation of cardiomyopathy, additional cardiac features, the treatments administered, and their clinical outcomes. RESULTS: Of the 305 patients with molecularly confirmed CDG participating in the FCDGC natural history study as of June 2023, 17 individuals, nine females and eight males, were identified with concurrent diagnoses of cardiomyopathy. Most of these patients were diagnosed with PMM2-CDG (n = 10). However, cardiomyopathy was also observed in other diagnoses, including PGM1-CDG (n = 3), ALG3-CDG (n = 1), DPM1-CDG (n = 1), DPAGT1-CDG (n = 1), and SSR4-CDG (n = 1). All PMM2-CDG patients were reported to have hypertrophic cardiomyopathy. Dilated cardiomyopathy was observed in three patients, two with PGM1-CDG and one with ALG3-CDG; left ventricular non-compaction cardiomyopathy was diagnosed in two patients, one with PGM1-CDG and one with DPAGT1-CDG; two patients, one with DPM1-CDG and one with SSR4-CDG, were diagnosed with non-ischemic cardiomyopathy. The estimated median age of diagnosis for cardiomyopathy was 5 months (range: prenatal-27 years). Cardiac improvement was observed in three patients with PMM2-CDG. Five patients showed a progressive course of cardiomyopathy, while the condition remained unchanged in eight individuals. Six patients demonstrated pericardial effusion, with three patients exhibiting cardiac tamponade. One patient with SSR4-CDG has been recently diagnosed with cardiomyopathy; thus, the progression of the disease is yet to be determined. One patient with PGM1-CDG underwent cardiac transplantation. Seven patients were deceased, including five with PMM2-CDG, one with DPAGT1-CDG, and one with ALG3-CDG. Two patients died of cardiac tamponade from pericardial effusion; for the remaining patients, cardiomyopathy was not necessarily the primary cause of death. CONCLUSIONS: In this retrospective study, cardiomyopathy was identified in ∼6% of patients with CDG. Notably, the majority, including all those with PMM2-CDG, exhibited hypertrophic cardiomyopathy. Some cases did not show progression, yet pericardial effusions were commonly observed, especially in PMM2-CDG patients, occasionally escalating to life-threatening cardiac tamponade. It is recommended that clinicians managing CDG patients, particularly those with PMM2-CDG and PGM1-CDG, be vigilant of the cardiomyopathy risk and risk for potentially life-threatening pericardial effusions. Cardiac surveillance, including an echocardiogram and EKG, should be conducted at the time of diagnosis, annually throughout the first 5 years, followed by check-ups every 2-3 years if no concerns arise until adulthood. Subsequently, routine cardiac examinations every five years are advisable. Additionally, patients with diagnosed cardiomyopathy should receive ongoing cardiac care to ensure the effective management and monitoring of their condition. A prospective study will be required to determine the true prevalence of cardiomyopathy in CDG.

Two-hit mouse model of heart failure with preserved ejection fraction combining diet-induced obesity and renin-mediated hypertension.

Heart failure with preserved ejection fraction (HFpEF) is increasingly common but its pathogenesis is poorly understood. The ability to assess genetic and pharmacologic interventions is hampered by the lack of robust preclinical mouse models of HFpEF. We have developed a novel "2-hit" model, which combines obesity and insulin resistance with chronic pressure overload to recapitulate clinical features of HFpEF. C57BL6/NJ mice fed a high fat diet for >10 weeks were administered an AAV8-driven vector resulting in constitutive overexpression of mouse Renin1d . Control mice, HFD only, Renin only and HFD-Renin (aka "HFpEF") littermates underwent a battery of cardiac and extracardiac phenotyping. HFD-Renin mice demonstrated obesity and insulin resistance, a 2-3-fold increase in circulating renin levels that resulted in 30-40% increase in left ventricular hypertrophy, preserved systolic function, and diastolic dysfunction indicated by altered E/e', IVRT, and strain measurements; increased left atrial mass; elevated natriuretic peptides; and exercise intolerance. Transcriptomic and metabolomic profiling of HFD-Renin myocardium demonstrated upregulation of pro-fibrotic pathways and downregulation of metabolic pathways, in particular branched chain amino acid catabolism, similar to findings in human HFpEF. Treatment of these mice with the sodium-glucose cotransporter 2 inhibitor empagliflozin, an effective but incompletely understood HFpEF therapy, improved exercise tolerance, left heart enlargement, and insulin homeostasis. The HFD-Renin mouse model recapitulates key features of human HFpEF and will enable studies dissecting the contribution of individual pathogenic drivers to this complex syndrome. Addition of HFD-Renin mice to the preclinical HFpEF model platform allows for orthogonal studies to increase validity in assessment of interventions. NEW & NOTEWORTHY: Heart failure with preserved ejection fraction (HFpEF) is a complex disease to study due to limited preclinical models. We rigorously characterize a new two-hit HFpEF mouse model, which allows for dissecting individual contributions and synergy of major pathogenic drivers, hypertension and diet-induced obesity. The results are consistent and reproducible in two independent laboratories. This high-fidelity pre-clinical model increases the available, orthogonal models needed to improve our understanding of the causes and assessment treatments for HFpEF.

Hybrid stage 1 palliation with simultaneous off-pump ventricular assist device placement in neonates with high-risk single ventricle anatomy: Initial experience.

Background: Infants with single ventricle heart disease and severe atrioventricular valve regurgitation have poor outcomes following conventional staged palliation. As such, ventricular assist device (VAD) placement along with hybrid stage 1 palliation has been proposed as a bridge to heart transplant. We present a novel surgical technique for VAD implantation concurrent with hybrid stage 1 that avoids cardiopulmonary bypass. Methods: We performed a retrospective review of our institutional experience with this novel surgical technique. Results: Three patients (weight, 2.7-3.5 kg; age, 3 to 5 days) underwent hybrid stage 1 with VAD placement, consisting of bilateral 3.5-mm expandable polytetrafluoroethylene (PTFE) pulmonary artery bands, a ductal stent, a 6-mm Berlin Heart outflow cannula onto the main pulmonary trunk with a 10-mm graft, a 6-mm Berlin Heart outflow cannula onto the right atrium, and a 10-mL Berlin Heart pump. In patients with severe aortic arch hypoplasia or coarctation, a 4-mm PTFE graft was sewn from the VAD outflow graft to the innominate artery to protect coronary and cerebral perfusion. Procedures were performed off bypass with minimal blood product use. Patients were extubated on postoperative days 2, 2, and 5. There were no procedural complications. All patients were transferred out of the intensive care unit and demonstrated appropriate weight gain. Anticoagulation strategy was bivalirudin and antiplatelet therapy. The patients underwent transplantation after 149 days, 157 days, and 288 days of support. Conclusions: Off-pump single ventricle VAD placement is technically feasible and can be done at the time of hybrid stage 1 palliation with minimal operative morbidity as a bridge to transplant.

Sodium-glucose co-transporter 2 Inhibitors Act Independently of SGLT2 to Confer Benefit for Heart Failure with Reduced Ejection Fraction in Mice.

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) are novel, potent heart failure medications with an unknown mechanism of action. We sought to determine if the beneficial actions of SGLT2i in heart failure were on- or off-target, and related to metabolic reprogramming, including increased lipolysis and ketogenesis. The phenotype of mice treated with empagliflozin and genetically engineered mice constitutively lacking SGLT2 mirrored metabolic changes seen in human clinical trials (including reduced blood glucose, increased ketogenesis, and profound glucosuria). In a mouse heart failure model, SGLT2i treatment, but not generalized SGLT2 knockout, resulted in improved systolic function and reduced pathologic cardiac remodeling. SGLT2i treatment of the SGLT2 knockout mice sustained the cardiac benefits, demonstrating an off-target role for these drugs. This benefit is independent of metabolic changes, including ketosis. The mechanism of action and target of SGLT2i in HF remain elusive.

Post-Shock Asystole in Patients Dying Out of Hospital While Wearing a Cardioverter Defibrillator.

BACKGROUND: The wearable cardioverter-defibrillator (WCD) prevents sudden cardiac death due to ventricular tachycardia (VT) or ventricular fibrillation (VF) but does not pace for post-shock asystole (PS-A) or bradycardia (PS-B;<50 beats/ min). OBJECTIVES: The purpose of this study was to assess PS-A and PS-B in patients dying out of hospital (OOH) while wearing a WCD. METHODS: The database of the U.S. Food and Drug Administration Manufacturers and User Facility Device Experience (MAUDE) was queried for manufacturers' reports of OOH deaths while patients were wearing a WCD. Excluded were patients who did not receive a shock or were initially shocked for asystole or during resuscitation. RESULTS: From January 2017 to March 2022, 313 patients received an initial WCD shock for VF (n = 150), VT (n = 90), and non-VF/VT rhythms (n = 73). PS-A occurred in 204 patients (65.2%), and PS-B occurred in 111 (35.5%); 85 (41.7%) PS-A patients also had PS-B. Most PS-A patients (n = 185; 90.7%) had an initial shocked rhythm of VF or VT, but 19 patients (9.3%) were initially inappropriately shocked for atrial fibrillation/supraventricular tachycardia (n = 7) and idioventricular (n = 8) or sinus (n = 4) rhythm. PS-A occurred after the first WCD shock in 118 (63.8%) and after the first, second, or third shocks in 159 patients (85.9%). Seven patients had post-shock heart block. Eight patients had permanent pacemakers; 1 became nonfunctional after 1 shock, and 7 showed noncapture and/or asystole after 1 to 4 shocks. CONCLUSIONS: Post-shock asystole appears to be common in patients who die OOH after being shocked by a WCD for VF or VT. PS-A also occurs after inappropriate WCD shocks for non-VF/VT rhythms. Implanted pacemakers may not prevent PS-A after a WCD shock. WCD backup pacing should be explored.

Causes and clinical consequences of inappropriate shocks experienced by patients wearing a cardioverter-defibrillator.

BACKGROUND: The LifeVest® wearable cardioverter-defibrillator (WCD) prevents sudden cardiac death in at-risk patients who are not candidates for an implantable defibrillator. The safety and efficacy of the WCD may be impacted by inappropriate shocks (IAS). OBJECTIVE: The purpose of this study was to assess the causes and clinical consequences of WCD IAS in survivors of IAS events. METHODS: The Food and Drug Administration's Manufacturers and User Facility Device Experience database was searched for IAS adverse events (AE) that were reported during 2021 and 2022. RESULTS: A total of 2568 IAS-AE were found (average number of IAS per event: 1.5 ± 1.9; range 1-48). IAS were caused by tachycardias (1255 [48.9%]), motion artifacts (840 [32.7%]), and oversensing (OS) of low-level electrical signals (473 [18.4%]) (P <.001). Tachycardias included atrial fibrillation (AF) (828 [32.2%]), supraventricular tachycardia (SVT) (333 [13.0%]), and nonsustained ventricular tachycardia/fibrillation (NSVT/VF) (87 [3.4%]). Activities responsible for motion-induced IAS included riding a motorcycle, lawnmower, or tractor (n = 128). In 19 patients, IAS induced sustained ventricular tachycardia or ventricular fibrillation that subsequently were terminated by appropriate WCD shocks. Thirty patients fell and suffered physical injuries. Conscious patients (n = 1905) did not use the response buttons to abort shocks (47.9%) or used them improperly (20.2%). IAS resulted in 1190 emergency room visits or hospitalizations, and 17.3% of patients (421/2440) discontinued the WCD after experiencing IAS, especially multiple IAS. CONCLUSIONS: The LifeVest WCD may deliver IAS caused by AF, SVT, NSVT/VF, motion artifacts, and oversensing of electrical signals. These shocks may be arrhythmogenic, result in injuries, precipitate WCD discontinuation, and consume medical resources. Improved WCD sensing, rhythm discrimination, and methods to abort IAS are needed.

Adherence With Lipid Screening Guidelines in Children With Acquired and Congenital Heart Disease: An Observational Study Using Data From The MarketScan Commercial and Medicaid Databases.

Background Universal lipid screening in children provides an opportunity to mitigate the lifetime risk of atherosclerosis, particularly in children with chronic conditions that are predisposed to early atherosclerosis. In response, national guidelines recommend additional early screening in a subset of cardiac conditions. The penetration of such guidelines has not been evaluated. Methods and Results We performed a retrospective study of a geographically representative sample of US children using the MarketScan Commercial and Medicaid claims databases. The study population was children with cardiac disease between ages 2 and 18 years and ≥3 years of continuous coverage from January 1, 2013, to June 30, 2018, divided into 4 major strata of heart disease. We assessed the likelihood of screening between these classifications and compared with healthy children and calculated multivariate models to identify patient factors associated with screening likelihood. Of the eligible 8.4 million children, 155 000 children had heart disease, of which 1.8% (31 216) had high-risk conditions. Only 17.5% of healthy children underwent lipid screening. High-risk children were more likely to be screened (odds ratio [OR], 2.1; 95% CI, 2.09-2.19; P<0.001) than standard-risk children, but that likelihood varied depending on strata of cardiac disease (22%-77%). Timing of screening also varied, with most occurring between ages 9 and 11 years. Among cardiac conditions, heart transplantation (OR, 16.8; 95% CI, 14.4-19.7) and cardiomyopathy (OR, 2.9; 95% CI, 2.8-3.1) were associated with the highest likelihood of screening. Conclusions Children with cardiac disease are more likely to undergo recommended lipid screening than healthy children, but at lower rates and later ages than recommended, highlighting the importance of quality improvement and advocacy for this vulnerable population.

MLIP causes recessive myopathy with rhabdomyolysis, myalgia and baseline elevated serum creatine kinase.

Striated muscle needs to maintain cellular homeostasis in adaptation to increases in physiological and metabolic demands. Failure to do so can result in rhabdomyolysis. The identification of novel genetic conditions associated with rhabdomyolysis helps to shed light on hitherto unrecognized homeostatic mechanisms. Here we report seven individuals in six families from different ethnic backgrounds with biallelic variants in MLIP, which encodes the muscular lamin A/C-interacting protein, MLIP. Patients presented with a consistent phenotype characterized by mild muscle weakness, exercise-induced muscle pain, variable susceptibility to episodes of rhabdomyolysis, and persistent basal elevated serum creatine kinase levels. The biallelic truncating variants were predicted to result in disruption of the nuclear localizing signal of MLIP. Additionally, reduced overall RNA expression levels of the predominant MLIP isoform were observed in patients' skeletal muscle. Collectively, our data increase the understanding of the genetic landscape of rhabdomyolysis to now include MLIP as a novel disease gene in humans and solidifies MLIP's role in normal and diseased skeletal muscle homeostasis.

Variants in NAA15 cause pediatric hypertrophic cardiomyopathy.

The NatA N-acetyltransferase complex is important for cotranslational protein modification and regulation of multiple cellular processes. The NatA complex includes the core components of NAA10, the catalytic subunit, and NAA15, the auxiliary component. Both NAA10 and NAA15 have been associated with neurodevelopmental disorders with overlapping clinical features, including variable intellectual disability, dysmorphic facial features, and, less commonly, congenital anomalies such as cleft lip or palate. Cardiac arrhythmias, including long QT syndrome, ventricular tachycardia, and ventricular fibrillation were among the first reported cardiac manifestations in patients with NAA10-related syndrome. Recently, three individuals with NAA10-related syndrome have been reported to also have hypertrophic cardiomyopathy (HCM). The general and cardiac phenotypes of NAA15-related syndrome are not as well described as NAA10-related syndrome. Congenital heart disease, including ventricular septal defects, and arrhythmias, such as ectopic atrial tachycardia, have been reported in a small proportion of patients with NAA15-related syndrome. Given the relationship between NAA10 and NAA15, we propose that HCM is also likely to occur in NAA15-related disorder. We present two patients with pediatric HCM found to have NAA15-related disorder via exome sequencing, providing the first evidence that variants in NAA15 can cause HCM.

Adherence with lipid screening guidelines in standard- and high-risk children and adolescents.

Because atherosclerosis begins in childhood, universal lipid screening is recommended with special attention to conditions predisposing to early atherosclerosis. Data about real-world penetration of these guidelines is not available. METHODS: Retrospective cohort study using MarketScan® commercial and Medicaid insurance claims databases, a geographically representative sample of U.S. children. Subjects who passed through the 9- to 11-year window and had continuous insurance coverage between 1/1/2013 and 12/31/2016 were studied. Multivariable models were calculated, evaluating the association between other patient factors and the likelihood of screening. The primary hypothesis was that screening rates would be low, but that high-risk conditions would be associated with a higher likelihood of screening. RESULTS: In total, 572,522 children (51% male, 33% black, 11% Hispanic, 51% Medicaid) were studied. The prevalence of high-risk conditions was 2.2%. In unadjusted and adjusted analyses, these subjects were more likely to be screened than standard-risk subjects (47% vs. 20%, OR: 3.7, 95% CI 3.5-3.8, P < .001). Within this group, the diagnosis-specific likelihood of screening varied (26-69%). Endocrinopathies (OR 5.4, 95% CI 5.2-5.7), solid organ transplants (OR 5.0, 95% CI 3.8-6.6), and metabolic disease (OR 3.9, 95% CI 3.1-5.0, all P < .001) were associated with the highest likelihood of undergoing screening. CONCLUSIONS: Despite national recommendations, lipid screening was performed in a minority of children. Though subjects with high-risk conditions had a higher likelihood of screening, rates remained low. This study highlights the need for research and advocacy regarding obstacles to lipid screening of children in the United States.

Cytomegalovirus Enterocolitis secondary to experimental COVID-19 therapy.

The novel coronavirus-2019 (COVID-19) has caused a global pandemic of historical proportions, infecting millions of people worldwide. Due to its high mortality rate and a paucity of clinical data, experimental therapies have been utilized with uncertain success and, unfortunately, poor outcomes. We describe a gentleman who was treated with experimental therapies and subsequently developed cytomegalovirus colitis and hypovolemic shock. Additionally, this case validates colonoscopy as a mode to rule out concurrent infectious etiologies causing diarrhea in COVID-19-positive patients.

Clinical utility of exome sequencing in infantile heart failure.

PURPOSE: Pediatric cardiomyopathy is rare, has a broad differential diagnosis, results in high morbidity and mortality, and has suboptimal diagnostic yield using next-generation sequencing panels. Exome sequencing has reported diagnostic yields ranging from 30% to 57% for neonates in intensive care units. We aimed to characterize the clinical utility of exome sequencing in infantile heart failure. METHODS: Infants diagnosed with acute heart failure prior to 1 year old over a period of 34 months at a large tertiary children's hospital were recruited. Demographic and diagnostic information was obtained from medical records. Fifteen eligible patients were enrolled. RESULTS: Dilated cardiomyopathy was the predominant cardiac diagnosis, seen in 60% of patients. A molecular diagnosis was identified in 66.7% of patients (10/15). Of those diagnoses, 70% would not have been detected using multigene next-generation sequencing panels focused on cardiomyopathy or arrhythmia disease genes. Genetic testing changed medical decision-making in 53% of all cases and 80% of positive cases, and was especially beneficial when testing was expedited. CONCLUSION: Given the broad differential diagnosis and critical status of infants with heart failure, rapid exome sequencing provides timely diagnoses, changes medical management, and should be the first-tier molecular test.

Disruption of cardiac thin filament assembly arising from a mutation in LMOD2: A novel mechanism of neonatal dilated cardiomyopathy.

Neonatal heart failure is a rare, poorly-understood presentation of familial dilated cardiomyopathy (DCM). Exome sequencing in a neonate with severe DCM revealed a homozygous nonsense variant in leiomodin 2 (LMOD2, p.Trp398*). Leiomodins (Lmods) are actin-binding proteins that regulate actin filament assembly. While disease-causing mutations in smooth (LMOD1) and skeletal (LMOD3) muscle isoforms have been described, the cardiac (LMOD2) isoform has not been previously associated with human disease. Like our patient, Lmod2-null mice have severe early-onset DCM and die before weaning. The infant's explanted heart showed extraordinarily short thin filaments with isolated cardiomyocytes displaying a large reduction in maximum calcium-activated force production. The lack of extracardiac symptoms in Lmod2-null mice, and remarkable morphological and functional similarities between the patient and mouse model informed the decision to pursue cardiac transplantation in the patient. To our knowledge, this is the first report of aberrant cardiac thin filament assembly associated with human cardiomyopathy.

Isolated Single Right Coronary Artery in a Pediatric Patient.

Anatomic single coronary arteries are quite rare but can be a potential cause of sudden cardiac death. We present the first case of a pediatric patient with an anatomic single right coronary artery (Lipton type R1 or Shirani-Roberts type IIA), of a type which has been associated with adult-onset ischemic cardiac disease. We review the evaluation and management of this young patient.