Type Of Cardiomyopathy Research Articles

Abstract 4134590: Procedural Related Major Adverse Events of Cardiac Catheterization in Pediatric Patients with Cardiomyopathy: Insights from IMPACT Registry

Background: Despite the role of cardiac catheterization for hemodynamic assessment and endomyocardial biopsy (EMB) in children with cardiomyopathy, data on procedure-related major adverse events (MAE) in this population is lacking. We aim to describe the rate of MAE in children with cardiomyopathy undergoing cardiac catheterization. Our secondary objective is to compare the rate of MAE among patient subsets within this population. Hypothesis: We hypothesize that the rate of MAE will vary among cardiomyopathy types and that EMB will be associated with an increased rate of MAE. Methods: We included patients with cardiomyopathy from the National Cardiovascular Data Registry Improving Pediatric and Adult Congenital Treatment (IMPACT) who were 18 years or younger and had cardiac catheterization from April 2016 to June 2023. We collected demographic, pre-procedural, procedural, and outcome-related variables. We performed univariate and multivariate analyses to identify variables independently associated with MAE. Results: A total of 15,656 procedures were evaluated, with a median age of 11 years; 50.3% were females. Dilated cardiomyopathy (DCM) was the most prevalent cardiomyopathy in 68%, followed by restrictive cardiomyopathy (RCM) in 14% and hypertrophic cardiomyopathy (HCM) in 9%. MAE was present in 1.6%. The most common MAE was arrhythmia, representing 46% of MAE, followed by cardiac arrest and bleeding each 20%. EMB was associated with a lower rate of MAE in univariate analysis p<0.001. The association between a lower rate of MAE and EMB persisted in the multivariate model when those with heart transplant who had EMB were compared to those without heart transplant who did not have EMB p=0.001. The multivariate analysis also revealed that age less than a year, HCM compared to DCM, history of heart failure, pre-procedural inotropic support, and non-elective procedure were associated with increased rate of MAE. The overall mortality rate was 1.66%. The leading cause of mortality was heart failure in 51% of deceased patients. MAE was associated with an increased mortality rate of 11% p<0.001. Conclusion: Cardiac catheterization is a safe procedure in pediatric patients with cardiomyopathy, with an overall MAE rate of 1.6%. Age of less than a year, HCM, history of heart failure, and prior inotropic support are associated with an increased rate of MAE. EMB was not associated with a higher rate of MAE. MAE occurrence is associated with a sevenfold increase in mortality rate.

“Red Flags”: Case Report of Cardiac Amyloidosis with Significant Coronary Artery Disease

BACKGROUND: Cardiac Amyloidosis is a disorder of protein misfolding and metabolism in which insoluble fibrils are deposited in the myocardial extracellular matrix causing organ dysfunction and eventually death. It can exhibit cardiac signs and symptoms, or it can be identified through screening in patients who exhibit extracardiac symptoms of amyloidosis. As there were no clear clinical signs of cardiac amyloidosis and a biopsy is required to show amyloid deposition, the condition has been historically challenging to diagnose. Thus, a high index of suspicion based on the clinical presentation and the outcomes of the preliminary testing arecrucial to determine the approach to diagnosis. CASE SUMMARY: We outline a case of 75-year-old Filipino male who was admitted due to progressive exertional dyspnea. Cardiac Amyloidosis was considered due to evaluation findings of heart failure with preserved ejection fraction with restrictive type of cardiomyopathy. This was subsequently confirmed through extracardiac fat pad biopsy, echocardiographic strain analysis and Technetium (99mTc) Pyrophosphate (PYP) single photon emission computed tomography scan (SPECT). CONCLUSION: This case report discussed the red flags of clinical manifestations of cardiac amyloidosis and highlighted the use of non-invasive diagnostic modalities to diagnose the disease. Cardiac amyloidosis remains a rare entity and with emerging therapies that have the potential to improve patient outcomes, early diagnosis is really important. Having high index of suspicion based on signs and symptoms can lead to early detection and an increased number of patients being referred for treatment.

Genetic Association of the Ins/Del Variant of ACE and Risk of Cardiomyopathy: A Case-Control Study and Updated Meta-Analysis.

Cardiomyopathy, is a complex condition influenced by multiple genes and environmental factors. It has been suspected that cardiomyopathy is affected by the ACE gene's I/D polymorphism. Our study aimed to evaluate the association between this polymorphism and cardiomyopathy risk in the Jammu population of North India, alongside a meta-analysis to determine the specific risks associated with different types of cardiomyopathy. In the case-control study, we opted for a convenient sampling technique to gather patients from hospitals. Meanwhile, for the meta-analysis registered under PROSPERO with CRD42024519763, and in line with PRISMA guidelines, we accessed online databases and applied predefined inclusion criteria. Data extraction and quality assessment were performed using the Newcastle-Ottawa scale. Statistical analysis included genotypic frequencies, Hardy-Weinberg equilibrium testing, logistic regression models, and assessments for heterogeneity and publication bias. The case-control study revealed a significant association between the ACE I/D risk variant and cardiomyopathy risk in the Jammu population (OR: 1.30, CI [1.04-1.63], p-value=0.021). Furthermore, a total of 34 studies were fund-eligible for the meta-analysis and demonstrated a significant association between the risk variant and both dilated (OR: 1.25, CI [1.03-1.50], p-value=0.022) and hypertrophic (OR: 1.31, CI [1.0876-1.5776], p-value = 0.004446) cardiomyopathy. Our study found a significant association between the I/D polymorphism and cardiomyopathy risk in the Jammu population. Further, the meta-analysis strengthens the findings by consistently linking the ACE I/D polymorphism to both dilated and hypertrophic cardiomyopathy. These results underscore the importance of genetic factors in cardiomyopathy risk assessment and further research is needed to understand the underlying mechanisms and potential therapeutic implications.

Determination of Genotype and Phenotypes in Pediatric Patients With Biventricular Noncompaction.

Left ventricular noncompaction (LVNC) is a hereditary type of cardiomyopathy characterized by prominent trabeculations. Detailed characteristics of biventricular noncompaction (BiVNC) remain unknown. This study aimed to elucidate the clinical characteristics and genetic landscape of BiVNC. We recruited children with left ventricular noncompaction from Japanese multi-institutional centers from 2013 to 2021. Left ventricular noncompaction was classified as BiVNC, congenital heart disease, arrhythmia, dilated cardiomyopathy, or normal function. In these patients, cardiomyopathy-associated genes were screened. A total of 234 patients (127 male; mean age, 4 months [range, 0-6.6 years]) were enrolled in this study, of whom 25 had BiVNC; 55, normal function; 84, dilated cardiomyopathy; 38, congenital heart disease; and 32, arrhythmia. BiVNC was diagnosed during the perinatal period in 10 patients, in whom the prevalence was higher than that in other patients. A total of 14 patients in the group with BiVNC had congenital heart disease, but not necessarily right heart lesions. Left ventricular dyskinesis was frequently observed in the lateral wall (24%) and apex (28%). Eleven pathogenic variants were found in 11 patients with BiVNC (44.0%). The group with BiVNC had a higher ratio of mitochondrial and developmental gene variants than the other groups. Among all groups, the group with BiVNC had the worst survival rate (P=0.0009). Pediatric patients with BiVNC had a high rate of ventricular dyskinesis and poor outcome. A comprehensive and careful screening for disease-causing genes and phenotype may help identify specific patients with left ventricular noncompaction and mortality-related cardiac phenotypes.

Alcohol Septal Ablation in Hypertrophic Obstructive Cardiomyopathy: A Patient with a High LVOT Gradient

Background: Hypertrophic obstructive cardiomyopathy is a type of cardiomyopathy. The presence of a pressure gradient between the mid ventricle and LVOT on the hemodynamic evaluation revealed by echocardiography serves as the basis for the diagnosis. Objective: To Perform Alcohol Septal Ablation in patient with Hypertrophic Cardiomyopathy Method: Under both Echocardiography and Fluoroscopy first septal branch of LAD is identified and alcohol is injected to cause necrosis of the selected myocardial tissue to reduce the outflow gradient. Result: A reduction of the outflow gradient measured after the procedure indicates that it wassuccessful. J Inv Clin Cardiol 2023; 5(2): 56-59

Reinterpretation of genetic testing for Cardiomyopathies: Less is more

Abstract Background In the last years, the concept of reinterpretation of genetic testing has been considered as part of the diagnostic workflow. However, this process requires time, expert curators and new pieces of evidence to evaluate, as functional studies, segregation and allele frequency data. Last year, the European Society of Cardiology (ESC) published new guidelines for the management of cardiomyopathies. This document includes a precise list of genes associated with the different types of Cardiomyopathies and their level of contribution, according to ClinGen evaluation: definitive/strong, moderate, limited, and refuted/disputed. This document poses a real support in the reinterpretation of tests that report variants in genes not clearly correlated with these phenotypes. Purpose To evaluate the impact of the new ESC indications regarding genetic testing, we reconsidered all genetic results performed in our Clinic in patients with confirmed or suspicious Cardiomyopathy. Methods From 2017 to 2023 we analyzed 296 probands eligible for Cardiomyopathy genetic testing, in particular: 105 patients were tested for Arrhythmogenic Cardiomyopathy (ACM), 113 for Hypertrophic Cardiomyopathy (HCM) and 78 for Dilated Cardiomyopathy (DCM), using a custom sequencing panel including 44 genes (11 genes for ACM, 34 for DCM and 29 for HCM). Results Comparison analysis with the genes reported from the ESC guidelines, considering only the definitive, moderate, and strong genes, showed that 24 genes are not more associated with the phenotype and then not clinically actionable. In this scenario, we reconsidered 12 variants (8%), previously classified as VUS, changing the referral status of 8 patients, from uncertain to negative. Conclusions These results highlight the importance of variant reinterpretation as a fundamental step of genetic testing, posing the importance of the selection of the genes to analyze, in order to improve the management of the patients.

How different types of cardiomyopathy with hypertrophic phenotype affect left atrial remodeling and function

Abstract Background Left atrial (LA) dysfunction is a common feature in hypertrophic cardiomyopathies. How the underlying etiology and pathophysiology of different cardiomyopathies affects LA remodeling and function remains unexplored. Purpose The aim of our study is to investigate the influence of various cardiomyopathies with hypertrophic phenotype on LA remodeling and function. Methods Patients with left ventricular (LV) hypertrophic phenotype who underwent cardiac magnetic resonance (CMR) were included. A group of patients with a normal CMR was included as a control group. CMR acquisitions used for clinical indication of heart failure diagnosis and etiology were retrospectively analyzed to obtain LA reservoir, conduit, and booster strain, left atrioventricular coupling index (LACI) and LA sphericity. Differences between groups were assessed. To investigate the independent clinical associates of LA reservoir, conduit and booster strain, multivariable linear regression analyses were performed. Results A total of 375 individuals were analyzed including 321 patients diagnosed with LV hypertrophy and 54 patients with a normal CMR. Of the 321 patients with LV hypertrophy, 148 were diagnosed with hypertrophic cardiomyopathy (HCM), 35 with cardiac amyloidosis (CA), 41 with hypertensive cardiomyopathy (HTN) and 97 with severe asymptomatic aortic stenosis (AS). CMR LA characteristic and strain analysis results are summarized in Figure 1. The indexed LA end-systolic volume (iLAVmax), indexed LA end-diastolic volume (iLAVmin) and LA sphericity were larger in patients with CA when compared to other groups (all p<0.05). CA patients displayed more left atrioventricular uncoupling (lower LACI) when compared to individuals with HCM, HTN, AS, and controls (all p<0.001), while no significant differences were observed across other groups. CA patients exhibited lower LA reservoir and booster strains compared to the other groups (all p<0.05), whereas no significant differences were observed across other hypertrophic phenotype diseases. Age, iLAVMax and LACI were independently associated with all the three LA strain components (Figure 2, all p<0.05). Conclusions LA remodeling and function are affected differently across the various etiologies of LV hypertrophy. CA patients exhibit more pronounced atrial involvement, whereas those with HCM, asymptomatic AS, and HTN display similar patterns of atrial dysfunction and remodeling. Additionally, CMR-derived iLAVmax and LACI are independently correlated with LA function.

Pregnancy and inherited cardiomyopathies: insights from specialized care

Abstract Background Pregnancy and postpartum represent periods of increased risk of cardiovascular complications. Management of women with modified World Health Organization (mWHO) class II–III, III, and IV during pregnancy and around delivery should be conducted at an expert centre by a multidisciplinary team. Purpose Our objective was to analyze the impact of pregnancy on cardiomyopathy outcomes in a centre specialized in inherited cardiovascular conditions in the United Kingdom. Methods All women with cardiomyopathy referred due to pregnancy to our centre between 2016 and 2023 were retrospectively analyzed. Demographic, clinical, obstetric, genetic, electrocardiographic, and multimodal imaging variables were collected. Results Between 2016 and 2023, follow-up and delivery planning were initiated for 86 pregnancies in women with cardiomyopathies referred to our centre, resulting in 81 live births and 5 miscarriages, all in the first trimester. Among the full-term pregnancies, 17 (21%) were in patients in mWHO class I or II, 22 (27.2%) in II-III, 34 (42%) in III, and 8 (9.8%) in IV. The distribution of cardiomyopathy types among different mWHO classification is represented in Table 1. Women in mWHO class ≥ II-III had more pregnancy-related events than patients in mWHO I or II [28 (34.6%) vs 1 (1.2%); p = 0.004]. The most common complication in the first group was supraventricular tachycardia in 11 pregnancies (13.6%), followed by gestational diabetes in 9 (11.1%), left ventricular ejection fraction impairment in 4 (4.9%), preeclampsia in 3 (3.7%), and 1 (1.2%) ventricular tachycardia. One patient in the second group developed gestational diabetes. The distribution of the type of delivery among different mWHO classification is represented in Table 2. Only one patient with hypertrophic cardiomyopathy in mWHO II-III who underwent a caesarean section presented a post-delivery complication related to retroperitoneal haematoma, with no statistical significative differences between the groups (p = 0.604). 100% of the patients survived pregnancy and postpartum period. Conclusions Pregnant women with cardiomyopathy face an increased risk of adverse events. Despite the presence of cardiovascular and obstetric complications, careful monitoring at a specialized centre leads to favourable outcomes particularly concerning mortality rates for both the mother and fetus. This highlights the importance of a comprehensive risk assessment and meticulous pregnancy and delivery planning to ensure optimal maternal and fetal health.Table 1.Cardiomyopathy and mWHOTable 2.Type of delivery and mWHO

Novel <i>FLNC</i> Gene Variant Associated with Hypertrophic Cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, affecting approximately 1 in 500 people. It is the most common genetic cardiomyopathy inherited as a Mendelian trait in approximately 50% of patients, mainly due to pathogenic variants in genes encoding sarcomeric proteins. Mutations in the sarcomeric protein filamin C (<em>FLNC</em>) gene, with a cytogenetic localization on 7q32.1, have been linked to hypertrophic cardiomyopathy, as they have been determined to increase the risk of ventricular arrhythmia and sudden death. We present the case of a patient with HCM recognized by magnetic resonance imaging and echocardiography with a family history of cardiopathies. The molecular study in this patient was performed by next-generation sequencing on the Illumina MiniSeq instrument, comparing the results with international databases. In genetic studies, a novel mutation in the protein <em>FLNC</em> was detected. It is heterozygous, missence type. It is a variant where Cytosine is changed by timina at position 6305 of the <em>FLNC</em> gene. This produces the change of the amino acid proline by leucine at position 2102 of the Filamin C protein. The rare variant is located in Ig-like domain 19 within the ROD2 domain. This variant report suggests that there may indeed be a direct relationship between <em>FLNC</em> variants, mainly the ROD2 domain, and HCM. We think this new result should be considered for future genetic counseling of families affected by this type of cardiomyopathy.

SnRNA-seq reveals differential functional transcriptional pathway alterations in three mutant types of dilated cardiomyopathy

Dilated cardiomyopathy (DCM) is a leading cause of heart failure, characterized by ventricular dilation, thinning of the ventricular walls, and systolic dysfunction in either the left or both ventricles, often accompanied by fibrosis. Human cardiac tissue is composed of various cell types, including cardiomyocytes (CMs), fibroblasts (FBs), endothelial cells (ECs), macrophages, lymphocytes and so on. In DCM patients, these cells frequently undergo functional and phenotypic changes, contributing to contractile dysfunction, inflammation, fibrosis, and cell death, thereby increasing the risk of heart failure. This study focuses on DCM patients with mutations (LMNA, RBM20, and TTN) and analyzes functional changes in subpopulations of four cardiac cell types. The study involves functional annotation of subpopulations within each cell type and explores the association between gene mutations and specific functions and pathways. Additionally, the SCENIC method is employed of a particular cell subpopulation with significant functional importance, aiming to identify key transcriptional regulators in specific cell states. By analyzing the expression levels of ligand-receptor pairs in vCM4, vFB2, EC5.0, T cells, and NK cells across the DCM mutant genotypes, we predicted their signaling pathways and communications. This research provides insights into the molecular mechanisms of DCM and potential therapeutic targets.

Analysis of ACADVL gene variant in a Chinese pedigree affected with Very-long-chain acl-CoA dehydrogenase deficiency

To carry out genetic testing on a child diagnosed with Very-long-chain acyl-CoA dehydrogenase deficiency (VLADD) in order to provide a basis for genetic counseling and prenatal diagnosis for his family. Whole exome sequencing was performed for the proband. Candidate variant sites in the ACADVL gene were verified by Sanger sequencing, and their pathogenicity was predicted based on the guidelines from the American College of Medical Genetics and Genomics (ACMG). Prenatal diagnosis was performed on the fetus upon subsequent pregnancy. This study was approved by the Luoyang Maternal and Child Health Care Hospital (Ethics No. ). The proband was found to harbor compound heterozygous variants of the ACADVL gene, namely c.1532G>A and 1827+2_1827+12del, which were inherited from his mother and father, and classified as likely pathogenic and pathogenic, respectively. By combining the clinical manifestations of the proband and the results of blood tandem mass spectrometry and genetic testing, the child was ultimately diagnosed as cardiomyopathy type VLADD. Prenatal diagnosis showed that the fetus has carried the same compound heterozygous variants, and the couple had opted to terminate the pregnancy. The c.1532G>A/1827+2_1827+12del compound heterozygous variants of the ACADVL gene probably underlay the pathogenesis of VLADD in this pedigree. The discovery of the 1827+2_1827+12del variant has enriched the mutational spectrum of the ACADVL gene.

Revolutionizing Cardiac Care: The Role of Gene Therapy in Treating Cardiomyopathy

Gene therapy presents a method for addressing types of cardiomyopathies that play a substantial role in heart failure. This innovative approach, leveraging technologies such as clustered regularly interspaced short palindromic repeats/Cas9 for modifying genomes, holds promise for lasting treatments or potential cures that go beyond therapies. It is essential to grasp the workings of gene therapy, including gene silencing, clustered regularly interspaced short palindromic repeats genome editing, and enhancing sarcomere function to effectively apply it to treating cardiomyopathy. Examining current trials will shed light on the advancements and accomplishments in this field while also addressing the obstacles, uncertainties, and opportunities ahead. Delving into the possibilities of gene therapy involves exploring targets and inventive delivery methods that underscore the evolving landscape of research in this domain hinting at a future brimming with opportunities to transform care. The progress made in using gene therapy to treat cardiomyopathies represents the progress of medicine in driving forward scientific innovation to provide more precise and enduring solutions for patients. Continuously refining gene therapy techniques and deepening our knowledge of genetics are factors that will shape the future direction of cardiac care. The potential of gene therapy does not just benefit individuals with cardiomyopathy but also represents a move toward effective treatments for various genetic conditions. This signifies a step in the pursuit of holistic healthcare solutions.

Cardiomyopathy-Associated Chronic HeartFailure in Infants Aged

There have been few large-scale studies on the outcomes of cardiomyopathy-associated heart failure (HF) in infants aged <1 year. This study aimed to assess longitudinal echocardiographic outcomes of infants with HF secondary to cardiomyopathy who survived for >1 year. A prospective observational study following 327 infant patients up to 5 years in 2 large pediatric heart centers in Northern China between January 2010 and December 2018. A total of 236 (72.2%) patients had reduced left ventricular ejection fraction (LVEF) (HF with reduced ejection fraction group; LVEF <40%), 91 (27.8%) patients had midrange LVEF (HF with midrange ejection fraction group; LVEF ≥40% but <55%). LVEF improved significantly within the first year and remained stable in years 2 through 5 for both groups. The HF with midrange ejection fraction group had a higher rate of LVEF normalization (hazard ratio, 1.65; P<0.001). Baseline LVEF ≥40%, baseline left ventricular end-diastolic diameter Z score <7.8, the absence of left bundle-branch block, and the absence of β-blocker use were 4 independent favorable predictors for future LVEF normalization. A total of 62.4% of enrolled patients were diagnosed with left ventricular noncompaction. No significant difference in LVEF normalization was found among the different types of cardiomyopathy studied. A significant number of infants with cardiomyopathy who survived >1 year were found to improve with medical therapies during the first year of diagnosis. Poorer outcomes were associated with decreased LVEF and increased heart size at diagnosis baseline, the presence of left bundle-branch block and use of β blockers. The Northern Chinese pediatric population may have a high proportion of left ventricular noncompaction.

Current Strategies for Atrial Fibrillation Prevention and Management: Taming the Commonest Cardiac Arrhythmia.

Atrial fibrillation (AF) is the commonest cardiac arrhythmia, constituting a major cause of morbidity and mortality, with an age-dependent incidence and prevalence ranging from 1-2% in the general population to ~10% in persons aged >60 years. The global prevalence of AF is rapidly increasing, mostly due to the aging population. If not properly and timely managed, this arrhythmia adversely affects left ventricular function, increases the risk of stroke five-fold, impairs quality of life, and shortens longevity. There is a genetic, hence non-modifiable, predisposition to the arrhythmia, while several life-style and cardiometabolic inciting factors, such as hypertension, heart failure, coronary disease, metabolic syndrome, alcohol use, and thyroid disorders, can be addressed, attesting to the importance of a holistic approach to its management. Thromboembolism is a serious consequence of AF, which could lead to a disabling stroke or have a lethal outcome. The risk of a thromboembolic complication can be estimated as based on a scoring system that takes into consideration the patient's age, previous thromboembolic events, and clinical comorbidities. In addition, rapid AF could affect cardiac performance, leading to an elusive type of arrhythmia-induced cardiomyopathy and heart failure with grave consequences if undetected and untreated. Furthermore, AF may cause silent brain infarcts and/or its hemodynamic perturbations can account for a type of dementia that needs to be taken into account, emphasizing the need for AF screening and prevention strategies. All these issues are herein detailed, the causes of the arrhythmia are tabulated, and an algorithm illustrates our current approach to its management.

Anti-ageing interventions for the treatment of cardiovascular disease.

As the global demographic landscape continues to shift towards an aged population, so does the medical and socioeconomic burden of cardiovascular diseases. Indeed, ageing is one of, if not the, key risk factor for the development of cardiovascular diseases. However, there are currently no approved cardiovascular therapeutics that primarily target the molecular and cellular mechanisms underlying the ageing process itself. In this review, we present the potential of emerging anti-ageing strategies, including epigenetic rejuvenation, metabolic reprogramming, autophagy activation, as well as senolytic and anti-inflammatory therapies, in delaying or reversing the development of age-related cardiovascular disorders, while considering potential sex differences. In doing so, we implicate cellular ageing processes in the pathogenesis of several prevalent cardiovascular diseases, such as atherosclerosis, hypertension, various types of cardiomyopathies (including its hypertrophic, ischemic, dilated, diabetic, and arrhythmogenic forms) and heart failure, particularly that with preserved ejection fraction. Finally, we outline future challenges and steps needed for the implementation of these novel anti-ageing strategies in the clinical setting, with the aim of challenging the long-held notion of ageing as a 'nonmodifiable' risk factor for cardiovascular diseases.

Abstract Tu062: FLNC Deficiency Triggers Unfolded Protein Response and Leads to Dilated Cardiomyopathy

Background: The FLNC gene encodes filamin C, which is highly expressed in cardiomyocytes. Dysfunction of filamin C, due to different types of FLNC mutations, has been reported to be associated with various types of cardiomyopathy. Truncating mutations in FLNC often result in insufficient expression of filamin C, resulting in dilated cardiomyopathy (DCM). However, the specific processes via which the deficiency of filamin C causes DCM remain incompletely comprehended. Aims: To investigate the pathogenic mechanisms of DCM caused by the deficiency of filamin C in cardiomyocytes using a mouse model with cardiac-specific knockout of Flnc and to explore potential therapeutic approaches. Methods and Results: We used tamoxifen to induce cardiac-specific Flnc gene knockout in cardiomyocytes and found that mice with cardiac-specific Flnc knockout exhibited left ventricular dilation, heart failure, increased heart weight, cardiomyocyte enlargement and fibrosis, suggesting that Flnc deficiency in cardiomyocytes causes DCM. Transcriptional profiling of primary cardiomyocytes isolated on the seventh day after tamoxifen injections showed the activation of ER stress and the unfolded protein response (UPR) upon Flnc deletion. Then we measured the expression levels of proteins in UPR pathway in cardiac tissue and found that PDI and pIRE1a proteins were significantly upregulated, while there were no changes in the other two branches of UPR, including the PERK and ATF6 branches. Intraperitoneal injection of a PDI inhibitor E64FC26 significantly improved heart function and reduced fibrosis in cardiac-specific Flnc deletion mice. Conclusion: Cardiac-specific knockout of Flnc leads to DCM in mice, during which the UPR pathway is activated. Treatment with the PDI inhibitor E64FC26 improves the heart function and the fibrosis in Flnc -deficient DCM mice, offering novel perspectives on the pathological mechanisms of DCM and providing new insights into therapeutic strategies in treating DCM caused by FLNC dysfunction.

Abstract Or125: Numb Family Proteins regulate left ventricular compaction by modulating autophagic process

Background: Left ventricular noncompaction (LVNC) is a type of cardiomyopathy, which patients manifest clinical features of heart failure, arrhythmias, thrombotic events, and sudden death. We previously found that the ablation of Numb(Nb) , and its homologue Numbl(Nl) at early stage, causes LVNC defects resulting in embryonic lethality. In this study, we found that mice with Nb and Nl deletion at later stage survive to adulthood and develop toLVNC cardiomyopathy. Method: We applied aMHC-Cre to delete and generate Nb and Nl double knockout (ADKO); examine the structure and functions of the ADKO hearts via echocardiography (ECHO); determine the heart arrhythmia via telemetry; determine the Nb subcellular localization via a Nb overexpression line (R26-Flag:mCherry:Numb); and determine the mechanistic function of NFPs in autophagy via autophagic reporter, electron microscopy, and molecular and biochemical assays. Results: The cTnT-Cre mediated Nb and Nl deletion causes LVNC and embryonic lethality, while the ADKO can survive to adulthood and died between eight- and twelve-month-old. The ADKO hearts display LVNC by two months of age, a reduced systolic function by four months old, and left ventricular remodeling and dilatation starting at six months old. ADKO hearts manifest major clinical features of LVNC, including arrhythmias and thrombosis. ADKO hearts exhibit significant accumulation of damaged mitochondria, autophagosomes and autophagolysosomes compared to controls. Biochemical analyses reveal elevated levels of p62 and a higher ratio of LC3II/LC3I in ADKO hearts. NFP null cells and ADKO hearts exhibit abnormal autophagic flux, characterized by arrested at autophagolysosome, increased expression of Lamp1 and Lamp2, but reduced levels of cathepsin D. Mass spectrometry analyses reveal Numb's interaction with proteins involved in endocytosis and autophagy. Consistently, Numb localizes to autophagosomes and autophagolysosomes. Conclusion: NFPs regulate left ventricular compaction at both embryonic and postnatal stages, suggesting that LVNC can be both congenital and acquired. As LVNC mice progress, they develop dilated cardiomyopathy (DCM) at later stage, suggesting that LVNC can occur independently at early stage, and is associated with DCM at later stage. Deletion of NFPs in cardiomyocytes disrupts endocytosis and autophagic flux. Our studies suggest that NFPs mediated endocytosis and autophagy are essential for left ventricular compaction.

Proteome-wide Characterization and Pathophysiology Correlation in Non-ischemic Cardiomyopathies.

Although the clinical consequences of advanced heart failure (HF) may be similar across different etiologies of cardiomyopathies, their proteomic expression may show substantial differences in relation to underlying pathophysiology. We aimed to identify myocardial tissue-based proteomic characteristics and the underlying molecular pathophysiology in non-ischemic cardiomyopathy with different etiologies. Comparative extensive proteomic analysis of the myocardium was performed in nine patients with biopsy-proven non-ischemic cardiomyopathies (3 dilated cardiomyopathy [DCM], 2 hypertrophic cardiomyopathy [HCM], and 4 myocarditis) as well as five controls using tandem mass tags combined with liquid chromatography-mass spectrometry. Differential protein expression analysis, Gene Ontology (GO) analysis, and Ingenuity Pathway Analysis (IPA) were performed to identify proteomic differences and molecular mechanisms in each cardiomyopathy type compared to the control. Proteomic characteristics were further evaluated in accordance with clinical and pathological findings. The principal component analysis score plot showed that the controls, DCM, and HCM clustered well. However, myocarditis samples exhibited scattered distribution. IPA revealed the downregulation of oxidative phosphorylation and upregulation of the sirtuin signaling pathway in both DCM and HCM. Various inflammatory pathways were upregulated in myocarditis with the downregulation of Rho GDP dissociation inhibitors. The molecular pathophysiology identified by extensive proteomic analysis represented the clinical and pathological properties of each cardiomyopathy with abundant proteomes. Different etiologies of non-ischemic cardiomyopathies in advanced HF exhibit distinct proteomic expression despite shared pathologic findings. The benefit of tailored management strategies considering the different proteomic expressions in non-ischemic advanced HF requires further investigation.

The Long-Term Survival of LVAD Patients-A TriNetX Database Analysis.

Background: Donor shortage limits the utilization of heart transplantation, making it available for only a fraction of the patients on the transplant waiting list. Therefore, continuous-flow left ventricular assist devices (CF-LVADs) have evolved as a standard of care for end-stage heart failure. It is imperative therefore to investigate long-term survival in this population. Methods: This study assesses the impact of demographics, infections, comorbidities, types of cardiomyopathies, arrhythmias, and end-organ dysfunction on the long-term survival of LVAD recipients. The TriNetX database comprises de-identified patient information across healthcare organizations. The log-rank test assessed post-implant survival effects, while Cox regression was used in the univariate analysis to obtain the Hazard Ratio (HR). All analyses were conducted using the Python programming language and the lifelines library. Results: This study identified CMV, hepatitis A exposure, atrial fibrillation, paroxysmal ventricular tachycardia, ischemic cardiomyopathy, renal dysfunction, diabetes, COPD, mitral valve disease, and essential hypertension as risk factors that impact long-term survival. Interestingly, hypokalemia seems to have a protective effect and gender does not affect survival significantly. Conclusions: This is the first report of a detailed long-term survival assessment of the LVAD population using a decoded database.

Heart Size Difference Drives Sex-Specific Response to Cardiac Resynchronization Therapy: A Post Hoc Analysis of the MORE-MPP CRT Trial.

Studies have reported that female sex predicts superior cardiac resynchronization therapy (CRT) response. One theory is that this association is related to smaller female heart size, thus increased relative dyssynchrony at a given QRS duration (QRSd). Our objective was to investigate the mechanisms of sex-specific CRT response relating to heart size, relative dyssynchrony, cardiomyopathy type, QRS morphology, and other patient characteristics. This is a post hoc analysis of the MORE-CRT MPP (More Response on Cardiac Resynchronization Therapy with Multipoint Pacing)trial (n=3739, 28% women), with a subgroup analysis of patients with nonischemic cardiomyopathy and left bundle-branch block (n=1308, 41% women) to control for confounding characteristics. A multivariable analysis examined predictors of response to 6 months of conventional CRT, including sex and relative dyssynchrony, measured by QRSd/left ventricular end-diastolic volume (LVEDV). Women had a higher CRT response rate than men (70.1% versus 56.8%, P<0.0001). In subgroup analysis, regression analysis of the nonischemic cardiomyopathy left bundle-branch block subgroup identified QRSd/LVEDV, but not sex, as a modifier of CRT response (P<0.0039). QRSd/LVEDV was significantly higher in women (0.919) versus men (0.708, P<0.001). CRT response was 78% for female patients with QRSd/LVEDV greater than the median value, compared with 68% with QRSd/LVEDV less than the median value (P=0.012). The association between CRT response and QRSd/LVEDV was strongest at QRSd <150 ms. In the nonischemic cardiomyopathy left bundle-branch block population, increased relative dyssynchrony in women, who have smaller heart sizes than their male counterparts, is a driver of sex-specific CRT response, particularly at QRSd <150 ms. Women may benefit from CRT at a QRSd <130 ms, opening the debate on whether sex-specific QRSd cutoffs or QRS/LVEDV measurement should be incorporated into clinical guidelines.