Metabolic remodeling and calcium handling abnormality in induced pluripotent stem cell-derived cardiomyocytes in dilated phase of hypertrophic cardiomyopathy with MYBPC3 frameshift mutation.

Hypertrophic cardiomyopathy (HCM) is an inherited disorder characterized by left ventricular hypertrophy and diastolic dysfunction, and increases the risk of arrhythmias and heart failure. Some patients with HCM develop a dilated phase of hypertrophic cardiomyopathy (D-HCM) and have poor prognosis; however, its pathogenesis is unclear and few pathological models exist. This study established disease-specific human induced pluripotent stem cells (iPSCs) from a patient with D-HCM harboring a mutation in MYBPC3 (c.1377delC), a common causative gene of HCM, and investigated the associated pathophysiological mechanisms using disease-specific iPSC-derived cardiomyocytes (iPSC-CMs). We confirmed the expression of pluripotent markers and the ability to differentiate into three germ layers in D-HCM patient-derived iPSCs (D-HCM iPSCs). D-HCM iPSC-CMs exhibited disrupted myocardial sarcomere structures and an increased number of damaged mitochondria. Ca2+ imaging showed increased abnormal Ca2+ signaling and prolonged decay time in D-HCM iPSC-CMs. Cell metabolic analysis revealed increased basal respiration, maximal respiration, and spare-respiratory capacity in D-HCM iPSC-CMs. RNA sequencing also showed an increased expression of mitochondrial electron transport system-related genes. D-HCM iPSC-CMs showed abnormal Ca2+ handling and hypermetabolic state, similar to that previously reported for HCM patient-derived iPSC-CMs. Although further studies are required, this is expected to be a useful pathological model for D-HCM.

An Improved Archimedes Optimization-aided Multi-scale Deep Learning Segmentation with dilated ensemble CNN classification for detecting lung cancer using CT images.

Early detection of lung cancer is necessary to prevent deaths caused by lung cancer. But, the identification of cancer in lungs using Computed Tomography (CT) scan based on some deep learning algorithms does not provide accurate results. A novel adaptive deep learning is developed with heuristic improvement. The proposed framework constitutes three sections as (a) Image acquisition, (b) Segmentation of Lung nodule, and (c) Classifying lung cancer. The raw CT images are congregated through standard data sources. It is then followed by nodule segmentation process, which is conducted by Adaptive Multi-Scale Dilated Trans-Unet3+. For increasing the segmentation accuracy, the parameters in this model is optimized by proposing Modified Transfer Operator-based Archimedes Optimization (MTO-AO). At the end, the segmented images are subjected to classification procedure, namely, Advanced Dilated Ensemble Convolutional Neural Networks (ADECNN), in which it is constructed with Inception, ResNet and MobileNet, where the hyper parameters is tuned by MTO-AO. From the three networks, the final result is estimated by high ranking-based classification. Hence, the performance is investigated using multiple measures and compared among different approaches. Thus, the findings of model demonstrate to prove the system's efficiency of detecting cancer and help the patient to get the appropriate treatment.

Ethanol Ablation of Refractory Premature Ventricular Complex Originating from a Left Ventricular Summit Communicating Vein after Radiofrequency Catheter Ablation Failed in a Dilated Cardiomyopathy Patient.

During follow-up of a 60-year-old patient with dilated cardiomyopathy, a Holter electrocardiogram revealed monomorphic premature ventricular complexes (PVCs) accounting for 21-30% of total beats. Oral beta-blockers led to no improvement in PVC burden. The first radiofrequency catheter ablation attempt identified the PVC arising from the left ventricle summit communicating vein (CV) but failed to eliminate the PVC's origin. The second ablation attempt with selective infusions of 100% ethanol into the summit CV resulted in immediate termination of PVCs. The post-ablation course was uneventful. Echocardiography showed an improved ejection fraction, and a repeated Holter electrocardiogram showed no recurrence of PVCs during follow-up. Ethics The RCVEA procedures were approved by the Takagi Hospital Ethical Committee and were performed under an institutional review board-approved protocol. (Kouhou-kai Ethical Committee, ID: KR168) Fundings This work was supported by the Takagi Hospital Cardiology Research Grant. The authors declare no competing interests. Acknowledgements: We thank the patient, the patient's family, and the medical staff of Takagi Hospital for their valuable cooperation and kind support. Consent Written informed consent was obtained from the patient for the publication of this case report and accompanying images.

Quantifying dilated perivascular spaces in children with sickle cell disease.

Sickle cell disease (SCD)-related neurological effects are particularly devastating. Dilated perivascular spaces (dPVS) are a well-described component of cerebral small vessel disease in older adults without SCD. However, the burden and association of dPVS with neurological complications in children with SCD have not been described. In this study, we used the international consensus criteria to quantify dPVS in the centrum semiovale and basal ganglia in T2-weighted magnetic resonance images (MRI) of children with SCD who were randomized as part of the Silent Cerebral Infarct Transfusion (SIT) trial. We examined the relationship between global and/or regional dPVS burden and presence or area of silent cerebral infarctions, hematological measures, demographic variables, and full-scale intelligence quotient (FSIQ) scores. The study included 156 SIT trial participants who had pre-randomization and study exit MRI. Their median age was 9.6 (5-15) years, 39% were female, and 94 (60%) participants had a high dPVS burden. Participants randomized to the blood transfusion arm and who had a high dPVS burden at baseline had a moderate decline in dPVS score over 36 months compared to no change in the observation group. On multivariable logistic regression, intelligence quotient was not associated with dPVS burden. Children with SCD included in the SIT trial have a high burden of dPVS compared to children without SCD. However, dPVS do not appear to have the same pathophysiology of silent cerebral infarcts. Further study is needed to determine both their etiology and clinical relevance.

Serum microRNA-125b-5p expression in patients with dilated cardiomyopathy combined with heart failure and its effect on myocardial fibrosis.

OBJECTIVE: This paper was performed to decipher the serum microRNA (miR)-125b-5p expression in patients with dilated cardiomyopathy (DCM) combined with heart failure (HF) and its effect on myocardial fibrosis. METHODS: Serum miR-125b-5p expression, LVEDD, LVESD, LVEF, LVFS, and NT-proBNP levels were evaluated in clinical samples. A rat DCM model was established by continuous intraperitoneal injection of adriamycin and treated with miR-125b-5p agomir and its negative control. Cardiac function, serum TNF-α, hs-CRP, and NT-proBNP levels, pathological changes in myocardial tissues, cardiomyocyte apoptosis, and the expression levels of miR-125b-5p and fibrosis-related factors were detected in rats. RESULTS: In comparison to the control group, the case group had higher levels of LVEDD, LVESD, and NT-pro-BNP, and lower levels of LVEF, LVFS, and miR-125b-5p expression levels. Overexpression of miR-125b-5p effectively led to the improvement of cardiomyocyte hypertrophy and collagen arrangement disorder in DCM rats, the reduction of blue-stained collagen fibers in the interstitial myocardium, the reduction of the levels of TNF-α, hs-CRP, and NT-proBNP and the expression levels of TGF-1ß, Collagen I, and α-SMA, and the reduction of the number of apoptosis in cardiomyocytes. CONCLUSION: Overexpression of miR-125b-5p is effective in ameliorating myocardial fibrosis.

Increased expression of human endogenous retrovirus K in endomyocardial biopsies from patients with cardiomyopathy - a transcriptomics meta-analysis.

Most studied, investigating transcriptional changes in myocardial biopsies focus on human genes. However, the presence and potential consequence of persistent expression of viral genes within the myocardium is unclear. The aim of the study was to analyze viral gene expression in RNAseq data from endomyocardial biopsies. The NCBI Bioproject library was screened for published projects that included bulk RNA sequencing data from endomyocardial biopsies from both healthy and diseased patients with a sample size greater than 20. Diseased patients with hypertrophic, dilated, and ischemic cardiomyopathies were included. A total of 507 patients with 507 samples from 6 bioprojects were included and mapped to the human genome (hg38). Unmappable sequences were extracted and mapped to an artificial 'super-virus' genome comprising 12,182 curated viral reference genomes. Subsequently, the sequences were reiteratively permutated and mapped again to account for randomness. In total, sequences from 68 distinct viruses were found, all of which were potentially human pathogenic. No increase in cardiotropic viruses was found in patients with dilated cardiomyopathy. However, the expression levels of the particle forming human endogenous retrovirus K were significantly increased (q < 0.0003, ANOVA). Higher expression levels were associated with increased expression in mitochondrial pathways such as oxidative phosphorylation (p < 0.0001). In Conclusion, expression of human endogenous retrovirus K is significantly increased in patients with dilated cardiomyopathy, which in turn was associated with transcriptional alterations in major cellular pathways.

Identification of senescence related hub genes and potential therapeutic compounds for dilated cardiomyopathy via comprehensive transcriptome analysis.

BACKGROUND: Dilated cardiomyopathy (DCM) is a common cause of heart failure. However, the role of cellular senescence in DCM has not been fully elucidated. Here, we aimed to investigate senescence in DCM, identify senescence related characteristic genes, and explore the potential small molecule compounds for DCM treatment. METHODS: DCM-associated datasets and senescence-related genes were respectively obtained from Gene Expression Omnibus (GEO) database and CellAge database. The characteristic genes were identified through methods including weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO), and random forest. The expression of characteristic genes was verified in the mouse DCM model. Moreover, the CIBERSORT algorithm was applied to analyze immune characteristics of DCM. Finally, several therapeutic compounds were predicted by CMap analysis, and the potential mechanism of chlorogenic acid (CGA) was investigated by molecular docking and molecular dynamics simulation. RESULTS: Three DCM- and senescence-related characteristic genes (MME, GNMT and PLA2G2A) were ultimately identified through comprehensive transcriptome analysis, and were experimentally verified in the doxorubicin induced mouse DCM. Meanwhile, the established diagnostic model, derived from dataset analysis, showed ideal diagnostic performance for DCM. Immune cell infiltration analysis suggested dysregulation of inflammation in DCM, and the characteristic genes were significantly associated with invasive immune cells. Finally, based on the specific gene expression profile of DCM, several potential therapeutic compounds were predicted through CMap analysis. In addition, molecular docking and molecular dynamics simulations suggested that CGA could bind to the active pocket of MME protein. CONCLUSION: Our study presents three characteristic genes (MME, PLA2G2A, and GNMT) and a novel senescence-based diagnostic nomogram, and discusses potential therapeutic compounds, providing new insights into the diagnosis and treatment of DCM.

Pathological mutations in the phospholamban cytoplasmic region affect its topology and dynamics modulating the extent of SERCA inhibition.

Phospholamban (PLN) is a 52 amino acid regulin that allosterically modulates the activity of the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA) in the heart muscle. In its unphosphorylated form, PLN binds SERCA within its transmembrane (TM) domains, approximately 20 Å away from the Ca2+ binding site, reducing SERCA's apparent Ca2+ affinity (pKCa) and decreasing cardiac contractility. During the enzymatic cycle, the inhibitory TM domain of PLN remains anchored to SERCA, whereas its cytoplasmic region transiently binds the ATPase's headpiece. Phosphorylation of PLN at Ser16 by protein kinase A increases the affinity of its cytoplasmic domain to SERCA, weakening the TM interactions with the ATPase, reversing its inhibitory function, and augmenting muscle contractility. How the structural changes caused by pathological mutations in the PLN cytoplasmic region are transmitted to its inhibitory TM domain is still unclear. Using solid-state NMR spectroscopy and activity assays, we analyzed the structural and functional effects of a series of mutations and their phosphorylated forms located in the PLN cytoplasmic region and linked to dilated cardiomyopathy. We found that these missense mutations affect the overall topology and dynamics of PLN and ultimately modulate its inhibitory potency. Also, the changes in the TM tilt angle and cytoplasmic dynamics of PLN caused by these mutations correlate well with the extent of SERCA inhibition. Our study unveils new molecular determinants for designing variants of PLN that outcompete endogenous PLN to regulate SERCA in a tunable manner.

Personalized care in dilated cardiomyopathy: Rationale and study design of the activeDCM trial.

BACKGROUND: Dilated cardiomyopathy (DCM) is a leading cause of heart failure, particularly in younger individuals. Low physical strength is a global risk factor for cardiovascular mortality, and physical activity and a healthy lifestyle have been shown to improve outcomes in patients with heart failure. However, inappropriate exercise may increase the risk of arrhythmias in certain individuals with DCM. The determinants for predicting individual risks in this setting are poorly understood, and clinicians are hesitant to recommend sports for cardiomyopathy patients. The activeDCM trial aims to assess the safety and efficacy of a personalized exercise and activity programme for individuals with DCM. STUDY DESIGN: The activeDCM trial is a prospective, randomized, interventional trial with a 12 month follow-up. Three hundred patients, aged 18-75 years with DCM, left ventricular ejection fraction (LVEF) ≤ 50% and New York Heart Association (NYHA) classes I-III, will be enrolled. The intervention includes a personalized exercise and activity programme. The primary outcome is the increase in peak oxygen uptake (VO2max, mL/kg/min) from baseline to 12 months. Secondary endpoints include adherence to personalized activity programmes, freedom from clinically relevant arrhythmia, unplanned hospitalization for heart failure and changes in NYHA class, quality of life scores, 6 min walk distance, muscular strength, N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hsTnT) levels and cardiac function. Advanced research questions include high-density phenome and omics analysis combined with digital biomarkers derived from Apple Watch devices. DISCUSSION: The activeDCM trial will provide valuable insights into the safety and efficacy of personalized exercise training in DCM patients, inform clinical practice and contribute to the development of heart failure management programmes. The study will generate data on the impact of exercise on various aspects of cardiovascular disease, including genetic, metabolic, phenotypic and longitudinal aspects, facilitating the development of future digital tools and strategies, including the incorporation of smart wearable devices.

Integrated Bioinformatics Analysis Reveals the Aberrantly Methylated Differentially Expressed Genes in Dilated Cardiomyopathy.

Dilated cardiomyopathy (DCM) causes heart failure and sudden death. Epigenetics is crucial in cardiomyopathy susceptibility and progression; however, the relationship between epigenetics, particularly DNA methylation, and DCM remains unknown. Therefore, this study identified aberrantly methylated differentially expressed genes (DEGs) associated with DCM using bioinformatics analysis and characterized their clinical utility in DCM. DNA methylation expression profiles and transcriptome data from public datasets of human DCM and healthy control cardiac tissues were obtained from the Gene Expression Omnibus public datasets. Then an epigenome-wide association study was performed. DEGs were identified in both DCM and healthy control cardiac tissues. In total, 3,353 cytosine-guanine dinucleotide sites annotated to 2,818 mRNAs were identified, and 479 DCM-related genes were identified. Subsequently, core genes were screened using logistic, least absolute shrinkage and selection operator, random forest, and support vector machine analyses. The overlapping of these genes resulted in DEGs with abnormal methylation patterns. Cross-tabulation analysis identified 8 DEGs with abnormal methylation. Real-time quantitative polymerase chain reaction confirmed the expression of aberrantly methylated DEGs in mice. In DCM murine cardiac tissues, the expressions of SLC16A9, SNCA, PDE5A, FNDC1, and HTRA1 were higher compared to normal murine cardiac tissues. Moreover, logistic regression model associated with aberrantly methylated DEGs was developed to evaluate the diagnostic value, and the area under the receiver operating characteristic curve was 0.949, indicating that the diagnostic model could reliably distinguish DCM from non-DCM samples. In summary, our study identified 5 DEGs through integrated bioinformatic analysis and in vivo experiments, which could serve as potential targets for further comprehensive investigation.

Echocardiographic Documentation of Dilated Cardiomyopathy Development in Dogs Naturally Infected with Trypanosoma cruzi.

We aimed to characterize the echocardiographic alterations in dogs from an endemic region that were naturally infected with T. cruzi. Dogs (n = 130) seropositive for antibodies against T. cruzi and/or with acute parasitemia were enrolled in the study. Indicators of changes in the structure and systolic and diastolic functions of the left ventricle (LV) and blood flow patterns were evaluated by echocardiography. The frequency and extent of alterations in these indicators were associated with the severity of the disease. Briefly, 15 (11.54%) dogs were diagnosed with dilated cardiomyopathy (DCM), and 115 (88.46%) dogs were diagnosed as being without DCM. Infected dogs with DCM exhibited structural features of LV dysfunction, e.g., a significant (p < 0.05) increase in the LV internal diameter at systole and diastole (LVID-s, LVID-d) and a decline in the LV posterior wall (LVPW-d) thickness at diastole. Despite an increase in stroke volume and cardiac output indicating contraction force, DCM resulted in a decreased ejection fraction, affecting systolic function. Dogs that were diagnosed as DCM-negative but were positive for T. cruzi by PCR exhibited a high frequency of an increase in the thickness of the interventricular septum in systole (IVS-s) and the LV posterior wall in diastole (LVPW-d), a decline in the LV inner diameter (LVID-d, LVID-s), and fractional shortening (FS). The thinning of the LVPW at systole was the most defining feature observed in chronically infected dogs. In summary, this is the first study reporting the echocardiographic changes occurring in dogs naturally infected with T. cruzi and developing DCM. Our data suggest that changes in LVID are a major indicator of risk of cardiac involvement, and the observation of changes in the IVS, LVPW, and FS have predictive value in determining the risk of DCM development in infected dogs.

Echocardiography-Derived Hemodynamic Forces Are Associated with Clinical Outcomes in Patients with Non-Ischemic Dilated Cardiomyopathy.

Introduction: Non-ischemic dilated cardiomyopathy (NIDCM) is characterized by a reduced left ventricular (LV) ejection fraction (LVEF, <50%) and a high risk for heart failure (HF) and death. Echocardiography-derived hemodynamic forces (HDFs) may provide important information on LV mechanics, but their prognostic value is unknown. Aim: To explore the features of echocardiography-derived HDFs in NIDCM and their association with clinical endpoints. Methods: Asymptomatic, non-hospitalized NIDCM patients free from coronary artery disease and moderate or severe valvular heart disease were included in this single-center observational retrospective longitudinal study. Those with atrial fibrillation and a follow-up <12 months were excluded. Major adverse cardiovascular events (MACE) were defined as a composite of all-cause death, HF hospitalization, and ambulatory intravenous diuretics administration. LV HDFs were analyzed with a prototype software. Apex-base (HDFs-ab), lateral-septal (HDFs-ls), and HDFs-angle were computed. Results: Ninety-seven patients were included, sixty-seven (69%) were males, mean age was 62 ± 14 years, and mean LVEF was 39.2 ± 8.6%. During a median follow-up of 4.2 (3.1-5.1) years, 19 (20%) patients experienced MACE. These patients had a higher HDFs-angle (71.0 (67.0-75.0) vs. 68.0 (63.0-71.0)°, p = 0.005), lower HDFs-ls (1.36 (1.01-1.85) vs. 1.66 ([1.28-2.04])%, p = 0.015), but similar HDFs-ab (5.02 (4.39-6.34) vs. 5.66 (4.53-6.78)%, p = 0.375) compared to those without MACE. in a Cox regression analysis, HDFs-angle (HR 1.16 (95%-CI 1.04-1.30), p = 0.007) was associated with MACE, while other conventional echocardiography parameters, including LVEF and LV longitudinal strain, were not. Conclusions: HDFs-angle is associated with clinical endpoints in NIDCM. A higher HDFs-angle may be a marker of impaired myocardial performance in patients with reduced LVEF.

The Application of Mesenchymal Stem Cells in Different Cardiovascular Disorders: Ways of Administration, and the Effectors.

The heart is an organ with a low ability to renew and repair itself. MSCs have cell surface markers such as CD45-, CD34-, CD31-, CD4+, CD11a+, CD11b+, CD15+, CD18+, CD25+, CD49d+, CD50+, CD105+, CD73+, CD90+, CD9+, CD10+, CD106+, CD109+, CD127+, CD120a+, CD120b+, CD124+, CD126+, CD140a+, CD140b+, adherent properties and the ability to differentiate into cells such as adipocytes, osteoblasts and chondrocytes. Autogenic, allogeneic, normal, pretreated and genetically modified MSCs and secretomes are used in preclinical and clinical studies. MSCs and their secretomes (the total released molecules) generally have cardioprotective effects. Studies on cardiovascular diseases using MSCs and their secretomes include myocardial infraction/ischemia, fibrosis, hypertrophy, dilated cardiomyopathy and atherosclerosis. Stem cells or their secretomes used for this purpose are administered to the heart via intracoronary (Antegrade intracoronary and retrograde coronary venous injection), intramyocardial (Transendocardial and epicardial injection) and intravenous routes. The protective effects of MSCs and their secretomes on the heart are generally attributed to their differentiation into cardiomyocytes and endothelial cells, their immunomodulatory properties, paracrine effects, increasing blood vessel density, cardiac remodeling, and ejection fraction and decreasing apoptosis, the size of the wound, end-diastolic volume, end-systolic volume, ventricular myo-mass, fibrosis, matrix metalloproteins, and oxidative stress. The present review aims to assist researchers and physicians in selecting the appropriate cell type, secretomes, and technique to increase the chance of success in designing therapeutic strategies against cardiovascular diseases.

A Unique Case of Goodpasture's Syndrome-Induced Cardiorenal Syndrome.

Goodpasture's syndrome (GPS) is a rare small vessel vasculitis characterized by circulating antibodies directed against the glomerular and alveolar basement membrane leading to renal and pulmonary manifestations. Here, we discuss a unique case of a 30-year-old Caucasian male smoker initially presenting with hemoptysis and anemia who was found to have biopsy-proven GPS with elevated anti-glomerular basement membrane (anti-GBM) antibodies. Unfortunately, the patient failed four months of standard treatment for GPS leading to end-stage renal disease (ESRD), while uniquely developing cardiorenal syndrome (CRS) with non-ischemic cardiomyopathy resulting in systolic and diastolic heart failure (HF). Despite aggressive medical management and hemodialysis, the patient's cardiac function continued to decline and the decision was made to insert an automatic implantable cardioverter defibrillator (AICD). To our knowledge, this is the first reported case of an anti-GBM-positive GPS patient who developed dilated cardiomyopathy. The importance of this report is to illustrate the rarity of developing CRS with non-ischemic cardiomyopathy and congestive heart failure from GPS and highlight the difficulty of determining management changes beyond guideline-directed medical therapy (GDMT) in GPS to slow the progression of worsening cardiac function.

Relationship between obesity and hypertrophic or dilated cardiomyopathy: The role of sex.

Evidence suggests an association between obesity and the risk for cardiomyopathy development; however, robust evidence is still lacking. In this study we sought to explore the relationship of obesity with hypertrophic cardiomyopathy (HCM) and dilated cardiomyopathy (DCM) and possible interactions with sex using large-scale epidemiological real-world data. We analysed data from the Nationwide Inpatient Sample of US hospitalisations for the years 2015-2019. There were a total of 46 934 admissions with diagnosis of HCM and 170 924 with DCM. There was a significant interaction between cardiomyopathies' diagnosis with sex and age subgroups; the rates of both DCM and HCM increased with age (p < .001 for both); DCM diagnosis was significantly higher in males compared with females (0.85% vs. 0.35%, p < .001). After adjustment for age, sex, race and presence of arterial hypertension there was a significant stepwise positive association between obesity and the population rates of both cardiomyopathy subtypes. For hospitalised patients with a body mass index (BMI) ≥30 kg/m2 there was an odds ratio (OR) of 1.68 (95% CI: 1.55-1.81, p < .001) for HCM and OR = 1.82 (95% CI: 1.79-1.84, p < .001) for DCM. More importantly, the positive relationship between a cardiomyopathy diagnosis (HCM or DCM) with increasing BMI was driven by the male sex (p < .001 for both) and it was non-significant in females. The findings from this nationwide observational analysis support a sexual dimorphism in the relationship between obesity and HCM or DCM, which should be further investigated.

A novel optimization-assisted multi-scale and dilated adaptive hybrid deep learning network with feature fusion for event detection from social media.

Social media networks become an active communication medium for connecting people and delivering new messages. Social media can perform as the primary channel, where the globalized events or instances can be explored. Earlier models are facing the pitfall of noticing the temporal and spatial resolution for enhancing the efficacy. Therefore, in this proposed model, a new event detection approach from social media data is presented. Firstly, the essential data is collected and undergone for pre-processing stage. Further, the Bidirectional Encoder Representations from Transformers (BERT) and Term Frequency Inverse Document Frequency (TF-IDF) are employed for extracting features. Subsequently, the two resultant features are given to the multi-scale and dilated layer present in the detection network of GRU and Res-Bi-LSTM, named as Multi-scale and Dilated Adaptive Hybrid Deep Learning (MDA-HDL) for event detection. Moreover, the MDA-HDL network's parameters are tuned by Improved Gannet Optimization Algorithm (IGOA) to enhance the performance. Finally, the execution of the system is done over the Python platform, where the system is validated and compared with baseline methodologies. The accuracy findings of model acquire as 94.96 for dataset 1 and 96.42 for dataset 2. Hence, the recommended model outperforms with the superior results while detecting the social events.

REALM-DCM: A Phase 3, Multinational, Randomized, Placebo-Controlled Trial of ARRY-371797 in Patients With Symptomatic LMNA-Related Dilated Cardiomyopathy.

BACKGROUND: LMNA (lamin A/C)-related dilated cardiomyopathy is a rare genetic cause of heart failure. In a phase 2 trial and long-term extension, the selective p38α MAPK (mitogen-activated protein kinase) inhibitor, ARRY-371797 (PF-07265803), was associated with an improved 6-minute walk test at 12 weeks, which was preserved over 144 weeks. METHODS: REALM-DCM (NCT03439514) was a phase 3, randomized, double-blind, placebo-controlled trial in patients with symptomatic LMNA-related dilated cardiomyopathy. Patients with confirmed LMNA variants, New York Heart Association class II/III symptoms, left ventricular ejection fraction ≤50%, implanted cardioverter-defibrillator, and reduced 6-minute walk test distance were randomized to ARRY-371797 400 mg twice daily or placebo. The primary outcome was a change from baseline at week 24 in the 6-minute walk test distance using stratified Hodges-Lehmann estimation and the van Elteren test. Secondary outcomes using similar methodology included change from baseline at week 24 in the Kansas City Cardiomyopathy Questionnaire-physical limitation and total symptom scores, and NT-proBNP (N-terminal pro-B-type natriuretic peptide) concentration. Time to a composite outcome of worsening heart failure or all-cause mortality and overall survival were evaluated using Kaplan-Meier and Cox proportional hazards analyses. RESULTS: REALM-DCM was terminated after a planned interim analysis suggested futility. Between April 2018 and October 2022, 77 patients (aged 23-72 years) received ARRY-371797 (n=40) or placebo (n=37). No significant differences (P>0.05) between groups were observed in the change from baseline at week 24 for all outcomes: 6-minute walk test distance (median difference, 4.9 m [95% CI, -24.2 to 34.1]; P=0.82); Kansas City Cardiomyopathy Questionnaire-physical limitation score (2.4 [95% CI, -6.4 to 11.2]; P=0.54); Kansas City Cardiomyopathy Questionnaire-total symptom score (5.3 [95% CI, -4.3 to 14.9]; P=0.48); and NT-proBNP concentration (-339.4 pg/mL [95% CI, -1131.6 to 452.7]; P=0.17). The composite outcome of worsening heart failure or all-cause mortality (hazard ratio, 0.43 [95% CI, 0.11-1.74]; P=0.23) and overall survival (hazard ratio, 1.19 [95% CI, 0.23-6.02]; P=0.84) were similar between groups. No new safety findings were observed. CONCLUSIONS: Findings from REALM-DCM demonstrated futility without safety concerns. An unmet treatment need remains among patients with LMNA-related dilated cardiomyopathy. REGISTRATION: URL: https://classic.clinicaltrials.gov; Unique Identifiers: NCT03439514, NCT02057341, and NCT02351856.

Relation between cardiac magnetic resonance-assessed interstitial fibrosis and diastolic dysfunction in heart failure due to dilated cardiomyopathy.

Background: Dilated cardiomyopathy (DCM) is distinguished by left ventricle (LV) dilation accompanied by systolic dysfunction. However, some studies suggested also a high prevalence of LV diastolic dysfunction (LVDD), similar to a general cohort of heart failure (HF) with reduced ejection fraction (LVEF). The bulk of evidence, mostly arising from basic studies, suggests a causative link between cardiac fibrosis (CF) and LVDD. However, still, there remains a scarcity of data on LVDD and CF. Therefore, the aim of the study was to investigate the association between CF and LVDD in DCM patients. Methods: The study population was composed of 102 DCM patients. Replacement CF was evaluated qualitatively (late gadolinium enhancement - LGE) and quantitively (LGE extent); interstitial cardiac fibrosis was assessed via extracellular volume (ECV). Based on echocardiography patients were divided into normal and elevated left atrial pressure (nLAP, eLAP) groups. Results: 42 % of patients had eLAP. They displayed higher troponin and NT-proBNP. Both groups did not differ in terms of LGE presence and extent; however, eLAP patients had larger ECV: 30.1 ± 5.6 % vs. 27.8 ± 3.9 %, p = 0.03. Moreover, ECV itself was found to be an independent predictor of LVDD (OR = 0.901; 95 %CI 0.810-0.999; p = 0.047; normalised for LVEF and RVOT diameter). Conclusions: More than two-in-five DCM patients had at least moderate LVDD. The mere presence or extent of replacement cardiac fibrosis is similar in patients with nLAP and eLAP. On the other hand, interstitial cardiac fibrosis is more pronounced in those with a higher grade of LVDD. ECV was found to be an independent predictor of LVDD in DCM.

Pediatric dilated cardiomyopathy: a review of current clinical approaches and pathogenesis.

Pediatric dilated cardiomyopathy (DCM) is a rare, yet life-threatening cardiovascular condition characterized by systolic dysfunction with biventricular dilatation and reduced myocardial contractility. Therapeutic options are limited with nearly 40% of children undergoing heart transplant or death within 2 years of diagnosis. Pediatric patients are currently diagnosed based on correlating the clinical picture with echocardiographic findings. Patient age, etiology of disease, and parameters of cardiac function significantly impact prognosis. Treatments for pediatric DCM aim to ameliorate symptoms, reduce progression of disease, and prevent life-threatening arrhythmias. Many therapeutic agents with known efficacy in adults lack the same evidence in children. Unlike adult DCM, the pathogenesis of pediatric DCM is not well understood as approximately two thirds of cases are classified as idiopathic disease. Children experience unique gene expression changes and molecular pathway activation in response to DCM. Studies have pointed to a significant genetic component in pediatric DCM, with variants in genes related to sarcomere and cytoskeleton structure implicated. In this regard, pediatric DCM can be considered pediatric manifestations of inherited cardiomyopathy syndromes. Yet exciting recent studies in infantile DCM suggest that this subset has a distinct etiology involving defective postnatal cardiac maturation, such as the failure of programmed centrosome breakdown in cardiomyocytes. Improved knowledge of pathogenesis is central to developing child-specific treatment approaches. This review aims to discuss the established biological pathogenesis of pediatric DCM, current clinical guidelines, and promising therapeutic avenues, highlighting differences from adult disease. The overarching goal is to unravel the complexities surrounding this condition to facilitate the advancement of novel therapeutic interventions and improve prognosis and overall quality of life for pediatric patients affected by DCM.