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Journal of Anaesthesiology, Clinical... 2024
PubMed: 38919428
DOI: 10.4103/joacp.joacp_287_22 -
Molecular Genetics and Metabolism Jun 2024Congenital disorders of glycosylation (CDG) are a continuously expanding group of monogenic disorders that disrupt glycoprotein and glycolipid biosynthesis, leading to...
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.
PubMed: 38917675
DOI: 10.1016/j.ymgme.2024.108513 -
Cureus May 2024Peripherally inserted central catheter (PICC) placement under real-time ultrasound guidance has emerged as a favorable procedure in children as a method to efficiently...
Peripherally inserted central catheter (PICC) placement under real-time ultrasound guidance has emerged as a favorable procedure in children as a method to efficiently obtain central access. Nevertheless, small infants with hemodynamic instability are at high risk of complications and extra precautions are necessary. We present a case of an inadvertent arterial placement of a PICC in a two-month-old infant with dilated cardiomyopathy and decompensated heart failure. Differentiation of arteries and veins under ultrasonographic evaluation may sometimes be difficult when the applied tourniquet pressure exceeds the patient's arterial blood pressure. In particular, arterial flow can be easily compromised by applying tourniquet pressure in small children with low blood pressure. A thorough understanding of the upper extremity vascular anatomy, basic scanning techniques, and meticulous preparation especially in small infants with hemodynamic instability are essential for maintaining the safety and efficacy of this procedure.
PubMed: 38916025
DOI: 10.7759/cureus.61053 -
BioRxiv : the Preprint Server For... Jun 2024related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking...
related dilated cardiomyopathy ( -DCM) is one of the most severe forms of DCM. The incomplete understanding of the molecular disease mechanisms results in lacking treatment options, leading to high mortality amongst patients. Here, using an inducible, cardiomyocyte-specific lamin A/C depletion mouse model, we conducted a comprehensive transcriptomic study, combining both bulk and single nucleus RNA sequencing, and spanning -DCM disease progression, to identify potential disease drivers. Our refined analysis pipeline identified 496 genes already misregulated early in disease. The expression of these genes was largely driven by disease specific cardiomyocyte sub-populations and involved biological processes mediating cellular response to DNA damage, cytosolic pattern recognition, and innate immunity. Indeed, DNA damage in -DCM hearts was significantly increased early in disease and correlated with reduced cardiomyocyte lamin A levels. Activation of cytosolic pattern recognition in cardiomyocytes was independent of cGAS, which is rarely expressed in cardiomyocytes, but likely occurred downstream of other pattern recognition sensors such as IFI16. Altered gene expression in cardiac fibroblasts and immune cell infiltration further contributed to tissue-wide changes in gene expression. Our transcriptomic analysis further predicted significant alterations in cell-cell communication between cardiomyocytes, fibroblasts, and immune cells, mediated through early changes in the extracellular matrix (ECM) in the -DCM hearts. Taken together, our work suggests a model in which nuclear damage in cardiomyocytes leads to activation of DNA damage responses, cytosolic pattern recognition pathway, and other signaling pathways that activate inflammation, immune cell recruitment, and transcriptional changes in cardiac fibroblasts, which collectively drive -DCM pathogenesis.
PubMed: 38915720
DOI: 10.1101/2024.06.11.598511 -
BioRxiv : the Preprint Server For... Jun 2024-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure...
-Related Dilated Cardiomyopathy: Single-Cell Transcriptomics during Patient-derived iPSC Differentiation Support Cell type and Lineage-specific Dysregulation of Gene Expression and Development for Cardiomyocytes and Epicardium-Derived Cells with Lamin A/C Haploinsufficiency.
-Related Dilated Cardiomyopathy (DCM) is an autosomal-dominant genetic condition with cardiomyocyte and conduction system dysfunction often resulting in heart failure or sudden death. The condition is caused by mutation in the Lamin A/C ( ) gene encoding Type-A nuclear lamin proteins involved in nuclear integrity, epigenetic regulation of gene expression, and differentiation. Molecular mechanisms of disease are not completely understood, and there are no definitive treatments to reverse progression or prevent mortality. We investigated possible mechanisms of -Related DCM using induced pluripotent stem cells derived from a family with a heterozygous splice-site mutation. We differentiated one mutant iPSC line derived from an affected female (Patient) and two non-mutant iPSC lines derived from her unaffected sister (Control) and conducted single-cell RNA sequencing for 12 samples (4 Patient and 8 Control) across seven time points: Day 0, 2, 4, 9, 16, 19, and 30. Our bioinformatics workflow identified 125,554 cells in raw data and 110,521 (88%) high-quality cells in sequentially processed data. Unsupervised clustering, cell annotation, and trajectory inference found complex heterogeneity: ten main cell types; many possible subtypes; and lineage bifurcation for Cardiac Progenitors to Cardiomyocytes (CM) and Epicardium-Derived Cells (EPDC). Data integration and comparative analyses of Patient and Control cells found cell type and lineage differentially expressed genes (DEG) with enrichment to support pathway dysregulation. Top DEG and enriched pathways included: 10 genes and RNA polymerase II transcription in Pluripotent cells (PP); and TGF Beta/BMP signaling, sarcomere gene subsets and cardiogenesis, and EMT in CM; and epigenetic regulation and and mTORC1 signaling in EPDC. Top DEG also included: and other X-linked genes, six imprinted genes: , , , , , , and enriched gene sets in metabolism, proliferation, and homeostasis. We confirmed Lamin A/C haploinsufficiency by allelic expression and Western blot. Our complex Patient-derived iPSC model for Lamin A/C haploinsufficiency in PP, CM, and EPDC provided support for dysregulation of genes and pathways, many previously associated with Lamin A/C defects, such as epigenetic gene expression, signaling, and differentiation. Our findings support disruption of epigenomic developmental programs as proposed in other disease models. We recognized other factors influencing epigenetics and differentiation; thus, our approach needs improvement to further investigate this mechanism in an iPSC-derived model.
PubMed: 38915555
DOI: 10.1101/2024.06.12.598335 -
European Journal of Cardio-thoracic... Jun 2024Paediatric heart transplantation in children who fail multistage palliation for hypoplastic left heart syndrome is associated with challenges related to immune,...
OBJECTIVES
Paediatric heart transplantation in children who fail multistage palliation for hypoplastic left heart syndrome is associated with challenges related to immune, clinical, or anatomic risk factors. We review current outcomes and risk factors for survival following heart transplantation in this challenging patient population.
METHODS
The United Network for Organ Sharing transplantation database was merged with Paediatric Health Information System database to identify children who received heart transplantation following prior palliation for hypoplastic left heart syndrome. Multivariable Cox analysis of outcomes and factors affecting survival was performed.
RESULTS
Our cohort included 849 children between 2009-21. Median age was 1044 days (interquartile range 108-3535) and median weight was 13 kg (interquartile range 7-26). Overall survival at 10 years following heart transplantation was 71%, with the majority of death being peri-operative. On multivariable analysis, risk factors for survival included black race (HR = 1.630, p = 0.0253), blood type other than B (HR = 2.564, p = 0.0052), and male donor gender (HR = 1.367, p = 0.0483). Recipient age, the use of ventricular assist device or extracorporeal membrane oxygenation were not significantly associated with survival. 24 patients underwent retransplantation and 10-year freedom from retransplantation was 98%. Rejection prior to hospital discharge and within one year from transplantation was 20% and 24%, respectively, with infants having lower rejection rates.
CONCLUSIONS
Compared to existing literature, the number of children with prior hypoplastic left heart syndrome palliation who receive heart transplantation has increased in the current era. Survival following transplantation in this patient population is acceptable. The majority of death is perioperative. Efforts to properly support these patients prior to transplantation might decrease early mortality and improve overall survival.
PubMed: 38913846
DOI: 10.1093/ejcts/ezae255 -
Frontiers in Medicine 2024Systemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high...
BACKGROUND
Systemic lupus erythematosus (SLE) is frequently accompanied by various complications, with cardiovascular diseases being particularly concerning due to their high mortality rate. Although there is clinical evidence suggesting a potential correlation between SLE and heart failure (HF), the underlying shared mechanism is not fully understood. Therefore, it is imperative to explore the potential mechanisms and shared therapeutic targets between SLE and HF.
METHODS
The SLE and HF datasets were downloaded from the NCBI Gene Expression Omnibus database. Differentially expressed genes (DEGs) in both SLE and HF were performed using "limma" R package. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genes (KEGG) analyses were conducted to analyze the enriched functions and pathways of DEGs in both SLE and HF datasets. Protein-Protein Interaction network (PPI) and the molecular complex detection (MCODE) plugins in the Cytoscape software were performed to identify the shared hub genes between SLE and HF datasets. R package "limma" was utilized to validate the expression of hub genes based on SLE (GSE122459) and HF (GSE196656) datasets. CIBERSORT algorithm was utilized to analyze the immune cell infiltration of SLE and HF samples based on SLE (GSE112087) and HF (GSE116250) datasets. A weighted gene co-expression network analysis (WGCNA) network was established to further validate the hub genes based on HF dataset (GSE116250). Molecular biology techniques were conducted to validate the hub genes.
RESULTS
999 shared DGEs were identified between SLE and HF datasets, which were mainly enriched in pathways related to Th17 cell differentiation. 5 shared hub genes among the common DGEs between SLE and HF datasets were screened and validated, including HSP90AB1, NEDD8, RPLP0, UBB, and UBC. Additionally, 5 hub genes were identified in the central part of the MEbrown module, showing the strongest correlation with dilated cardiomyopathy. HSP90AB1 and UBC were upregulated in failing hearts compared to non-failing hearts, while UBB, NEDD8, and RPLP0 did not show significant changes.
CONCLUSION
HSP90AB1 and UBC are closely related to the co-pathogenesis of SLE and HF mediated by immune cell infiltration. They serve as promising molecular markers and potential therapeutic targets for the treatment of SLE combined with HF.
PubMed: 38912340
DOI: 10.3389/fmed.2024.1402010 -
Circulation. Heart Failure Jun 2024The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type...
BACKGROUND
The mechanism of cardiac reverse remodeling (CRR) mediated by the left ventricular assist device remains unclear. This study aims to identify the specific cell type responsible for CRR and develop the therapeutic target that promotes CRR.
METHODS
The nuclei were extracted from the left ventricular tissue of 4 normal controls, 4 CRR patients, and 4 no cardiac reverse remodeling patients and then subjected to single-nucleus RNA sequencing for identifying key cell types responsible for CRR. Gene overexpression in transverse aortic constriction and dilated cardiomyopathy heart failure mouse model (C57BL/6J background) and pathological staining were performed to validate the results of single-nucleus RNA sequencing.
RESULTS
Ten cell types were identified among 126 156 nuclei. Cardiomyocytes in CRR patients expressed higher levels of than the other 2 groups. The macrophages in CRR patients expressed more anti-inflammatory genes and functioned in angiogenesis. Endothelial cells that elevated in no cardiac reverse remodeling patients were involved in the inflammatory response. Echocardiography showed that overexpressing through cardiomyocyte-specific adeno-associated virus 9 demonstrated an ability to improve heart function and morphology. Pathological staining showed that overexpressing could reduce fibrosis and cardiomyocyte size in the heart failure mouse model.
CONCLUSIONS
The present results of single-nucleus RNA sequencing and heart failure mouse model indicated that could mediate CRR and supported the development of therapeutics for overexpressing in promoting CRR.
PubMed: 38910562
DOI: 10.1161/CIRCHEARTFAILURE.123.011504 -
Circulation Journal : Official Journal... Jun 2024The incidence and prognostic predictors of heart failure (HF) without left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM), particularly...
BACKGROUND
The incidence and prognostic predictors of heart failure (HF) without left ventricular systolic dysfunction (LVSD) in hypertrophic cardiomyopathy (HCM), particularly their differences in terms of developing LVSD (progression to end-stage) or sudden cardiac death (SCD), are not fully elucidated.Methods and Results: This study included 330 consecutive HCM patients with left ventricular ejection fraction (LVEF) ≥50%. HF hospitalization without LVSD and development of LVSD were evaluated as main outcomes. During a median follow-up of 7.3 years, the incidence of HF hospitalization without LVSD was 18.8%, which was higher than the incidence of developing LVSD (10.9%) or SCD (8.8%). Among patients who developed LVSD, only 19.4% experienced HF hospitalization without LVSD before developing LVSD. Multivariable analysis showed that predictors for HF hospitalization without LVSD (higher age, atrial fibrillation, history of HF hospitalization, and higher B-type natriuretic peptide concentrations) were different from those of developing LVSD (male sex, lower LVEF, lower left ventricular outflow tract gradient, and higher tricuspid regurgitation pressure gradient). Known risk factors for SCD did not predict either HF without LVSD or developing LVSD.
CONCLUSIONS
In HCM with LVEF ≥50%, HF hospitalization without LVSD was more frequently observed than development of LVSD or SCD during mid-term follow-up. The overlap between HF without LVSD and developing LVSD was small (19.4%), and these 2 HF events had different predictors.
PubMed: 38910134
DOI: 10.1253/circj.CJ-24-0049 -
Heart Rhythm Jun 2024Studies evaluating the systematic use of cardiac computer tomography (CCT) for the pre-procedural assessment of myocardial fibrosis are limited and their implementation...
BACKGROUND
Studies evaluating the systematic use of cardiac computer tomography (CCT) for the pre-procedural assessment of myocardial fibrosis are limited and their implementation in the electrophysiology workflow has not been extensively described.
OBJECTIVE
To explore the degree of concordance between cardiac fibrosis evaluated by CCT compared to electroanatomical mapping (EAM) in patients undergoing endo-epicardial ventricular tachycardia (VT) ablation.
METHODS
From November-2017 to December-2021, patients undergoing endo-epicardial VT catheter ablation (CA) with CCT as the only source of pre-procedural scar assessment were prospectively enrolled. After image integration, myocardial fibrosis detected with CCT was compared with low voltage areas identified by endo-epicardial EAM. Post-procedural VT recurrences of this approach were evaluated after at least one-year follow-up.
RESULTS
35 patients (mean age 60.7±13.2 years, 94.2% males) were enrolled. The most common underlying arrhythmic substrate was dilated cardiomyopathy (48.6%). CCT was employed for contraindications to cardiac magnetic resonance, as unstable VTs (31.4%) or non-conditional ICDs (28.8%), but also for patients' and operators' preferences (14.3%-25.7%). Myocardial fibrosis was correctly identified by CCT and EAM, with strong agreement between these two techniques, both overall (Cohen's Kappa for agreement=0.933) and in per-segment analysis (K ranging from 0.796 to 1.0). Ischemic patients showed the best correlation (K=1.000) while myocarditis showed the worst (K=0.750). After a median follow-up of 14 [12-24] months, 1-year freedom from recurrences was achieved in 74.3% patients; overall freedom from recurrences was 60.0%.
CONCLUSIONS
A CCT-based pre-procedural assessment pre-VT ablation is feasible, showing high diagnostic concordance with EAM in detecting myocardial fibrosis.
PubMed: 38908459
DOI: 10.1016/j.hrthm.2024.06.025