Ischemic Dilated Cardiomyopathy Research Articles

Descriptive Study of Patients with Heart Failure in Nangarhar University Teaching Hospital

Failure of the heart to meet the metabolic demands of the body bears numerous complications subsequently leading to death. The overall aim of the study was to find out heart failure prevalence in patients visiting Nangarhar University Teaching Hospital and further elaborate it. It was a descriptive retrospective study including both male and female patients aging 18 years and more during six months at Nangarhar University Teaching Hospital located at Nangarhar province of Afghanistan. Out of 13077 patients, only 367 (2.8%) patients of whom 207 (56.6%) and 159 (43.4%) were females had heart failure. Heart failure cases increased with advancing age as there were 8.2% cases in age group 20-39 years, 11.5% cases in 40-49 years, 26.2% cases in 50-59 years, and 54.5% cases in patients with age of 60 years and over. In fact, 335 (91.1%) patients had exertional dyspnea, 102 (27.8%) patients had orthopnea, 23 (6.3%) patients had pulmonary edema. Most abundant physical signs were neck vein distention (56.6%), lower limb edema (52.4%), and pulmonary rales (31.1%), followed by gallop rhythm (12.5%) and hepatomegaly (5.1%). In addition, 42.8% patients had mildly reduced ejection fraction while 29.8% patients had moderately reduced ejection fraction and 16.4% had severely reduced ejection fraction. Moreover, 28.7% patient had regional wall motion abnormality on echocardiography while 15.8% patients had dilated cardiomyopathy, 13.9% patients had valvular heart disease, and 10.6% patients had pulmonary arterial hypertension. Heart failure was a common disease in Nangarhar University Teaching Hospital; more specifically in females and patients with advanced age. In fact, echocardiographic findings revealed ischemic heart disease, dilated cardiomyopathy, and valvular heart disease as the leading associated factors. Measures should be taken to reduce risk factors and raise social awareness about heart failure in order to reduce its prevalence and subsequent morbidity, mortality, and expenditure.

Unraveling the Etiology of Dilated Cardiomyopathy through Differential miRNA–mRNA Interactome

Dilated cardiomyopathy (DCM) encompasses various acquired or genetic diseases sharing a common phenotype. The understanding of pathogenetic mechanisms and the determination of the functional effects of each etiology may allow for tailoring different therapeutic strategies. MicroRNAs (miRNAs) have emerged as key regulators in cardiovascular diseases, including DCM. However, their specific roles in different DCM etiologies remain elusive. Here, we applied mRNA-seq and miRNA-seq to identify the gene and miRNA signature from myocardial biopsies from four patients with DCM caused by volume overload (VCM) and four with ischemic DCM (ICM). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis were used for differentially expressed genes (DEGs). The miRNA–mRNA interactions were identified by Pearson correlation analysis and miRNA target-prediction programs. mRNA-seq and miRNA-seq were validated by qRT-PCR and miRNA–mRNA interactions were validated by luciferase assays. We found 112 mRNAs and five miRNAs dysregulated in VCM vs. ICM. DEGs were positively enriched for pathways related to the extracellular matrix (ECM), mitochondrial respiration, cardiac muscle contraction, and fatty acid metabolism in VCM vs. ICM and negatively enriched for immune-response-related pathways, JAK-STAT, and NF-kappa B signaling. We identified four pairs of negatively correlated miRNA–mRNA: miR-218-5p-DDX6, miR-218-5p-TTC39C, miR-218-5p-SEMA4A, and miR-494-3p-SGMS2. Our study revealed novel miRNA–mRNA interaction networks and signaling pathways for VCM and ICM, providing novel insights into the development of these DCM etiologies.

Prognostic Utility of Left Atrial Strain From MRI Feature Tracking in Ischemic and Nonischemic Dilated Cardiomyopathy: A Multicenter Study.

BACKGROUND. MRI-based prognostic evaluation in patients with dilated cardiomyopathy (DCM) has historically used markers of late gadolinium enhancement (LGE) and feature tracking (FT)-derived left ventricular global longitudinal strain (LVGLS). Early data indicate that FT-derived left atrial strain (LAS) parameters, including reservoir, conduit, and booster, may also have prognostic roles in such patients. OBJECTIVE. The purpose of our study was to evaluate the prognostic utility of LAS parameters, derived from MRI FT, in patients with ischemic or nonischemic DCM, including in comparison with the traditional parameters of LGE and LVGLS. METHODS. This retrospective study included 811 patients with ischemic or nonischemic DCM (median age, 60 years; 640 men, 171 women) who underwent cardiac MRI at any of five centers. FT-derived LAS parameters and LVGLS were measured using two- and four-chamber cine images. LGE percentage was quantified. Patients were assessed for a composite outcome of all-cause mortality or heart failure hospitalization. Multivariable Cox regression analyses including demographic characteristics, cardiovascular risk factors, medications used, and a wide range of cardiac MRI parameters were performed. Kaplan-Meier analyses with log-rank tests were also performed. RESULTS. A total of 419 patients experienced the composite outcome. Patients who did, versus those who did not, experience the composite outcome had larger LVGLS (-6.7% vs -8.3%, respectively; p < .001) as well as a smaller LAS reservoir (13.3% vs 19.3%, p < .001), LAS conduit (4.7% vs 8.0%, p < .001), and LAS booster (8.1% vs 10.3%, p < .001) but no significant difference in LGE (10.1% vs 11.3%, p = .51). In multivariable Cox regression analyses, significant independent predictors of the composite outcome included LAS reservoir (HR = 0.96, p < .001) and LAS conduit (HR = 0.91, p < .001). LAS booster and LGE were not significant independent predictors in the models. LVGLS was a significant independent predictor only in a model that initially included LAS booster but not the other LAS parameters. In Kaplan-Meier analysis, all three LAS parameters were significantly associated with the composite outcome (p < .001). CONCLUSION. In this multicenter study, LAS reservoir and LAS conduit were significant independent prognostic markers in patients with ischemic or nonischemic DCM, showing greater prognostic utility than the currently applied markers of LVGLS and LGE. CLINICAL IMPACT. FT-derived LAS analysis provides incremental prognostic information in patients with DCM.

Efficacy of Isosorbide dinitrate and Hydralazine combination in non ischemic dilated cardiomyopathy in a tribal based population at a tertiary care hospital

Non ischemic dilated cardiomyopathy is an important cause of heart failure and cardiovascular mortality. Numerous pharmacologic therapies have been applied from the ancient era for treatment. Some of them have shown improve morbidity. From various literatures it was concluded that combination therapy with H-ISDN in addition to conventional medicines are very effective in black population group. In our study we have tried to establish the efficacy of fixed dose drug combination (Hydralazine + Isosorbide dinitrate) to alleviation of heart failure symptoms and mortality benefit if any. : Patient in NYHA 3 or ambulatory class 4 were included in study. Total two hundred populations were included in the prospective study. One hundred patients were treated by conventional optimum medications for heart failure including ACE inhibitors, ARBs. One hundred patients were given ISDN+Hydralazine (fixed dose) in addition to conventional medicines.: Mean age of study and controlled group was 62.5 years and 61.4 years respectively. Base line mean ejection fraction in control group was 33% and study group was 33%. After a mean one and half year follow up 61% of patient population achieved NYHA 2 in case group and 53% in control group. We assess the NT pro BNP level in both group of population at baseline and every six month interval. There is significant reduction in BNP level in study patients. 72% achieved below baseline cut off value for the age in control. In control population 51% achieved the estimated BNP value cut off for age. : Significant scope remains to improve the outcome for these patients through research related to use of H-ISDN in heart failure patients.

Intestinal microbiota and metabolome perturbations in ischemic and idiopathic dilated cardiomyopathy

BackgroundVarious clinical similarities are present in ischemic (ICM) and idiopathic dilated cardiomyopathy (IDCM), leading to ambiguity on some occasions. Previous studies have reported that intestinal microbiota appeared dysbiosis in ICM, whether implicating in the IDCM remains unclear. The aim of this study was to assess the alterations in intestinal microbiota and fecal metabolites in ICM and IDCM.MethodsICM (n = 20), IDCM (n = 22), and healthy controls (HC, n = 20) were enrolled in this study. Stool samples were collected for 16S rRNA gene sequencing and gas chromatography-mass spectrometry (GC–MS) analysis.ResultsBoth ICM and IDCM exhibited reduced alpha diversity and altered microbial community structure compared to HC. At the genus level, nine taxa including Blautia, [Ruminococcus]_torques_group, Christensenellaceae_R-7_group, UCG-002, Corynebacterium, Oceanobacillus, Gracilibacillus, Klebsiella and Citrobacter was specific to ICM, whereas one taxa Alistipes uniquely altered in IDCM. Likewise, these changes were accompanied by significant metabolic differences. Further differential analysis displayed that 18 and 14 specific metabolites uniquely changed in ICM and IDCM, respectively. The heatmap was generated to display the association between genera and metabolites. Receiver operating characteristic curve (ROC) analysis confirmed the predictive value of the distinct microbial-metabolite features in disease status. The results showed that microbial (area under curve, AUC = 0.95) and metabolic signatures (AUC = 0.84) were effective in discriminating ICM from HC. Based on the specific microbial and metabolic features, the patients with IDCM could be separated from HC with an AUC of 0.80 and 0.87, respectively. Furthermore, the gut microbial genus (AUC = 0.88) and metabolite model (AUC = 0.89) were comparable in predicting IDCM from ICM. Especially, the combination of fecal microbial-metabolic features improved the ability to differentiate IDCM from ICM with an AUC of 0.96.ConclusionOur findings highlighted the alterations of gut microbiota and metabolites in different types of cardiomyopathies, providing insights into the pathophysiological mechanisms of myocardial diseases. Moreover, multi-omics analysis of fecal samples holds promise as a non-invasive tool for distinguishing disease status.Graphical

Key Cell Types and Biomarkers in Heart Failure Identified through Analysis of Single-Cell and Bulk RNA Sequencing Data.

Heart failure (HF) is a complex clinical syndrome resulting from various cardiac diseases and a significant medical issue worldwide. Although the role of inflammation in HF pathogenesis is well-known, the specific cell types and regulatory molecules involved remain poorly understood. Here, we identified key cell types and novel biomarkers via an analysis of single-cell and bulk RNA sequencing data obtained from patients with two major HF types of ischemic cardiomyopathy and dilated cardiomyopathy. Myeloid cells were identified as the primary cell population involved in HF through cellular fraction and gene set enrichment analysis. Additionally, differential analysis of myeloid cells revealed crosstalk between cellular communication and cytokine-regulated immune responses in HF, with the MIF pathway emerging as a crucial immune regulatory pathway. The CD74/CXCR4 receptor complex in myeloid cell subgroup Mφ2 was significantly upregulated, potentially acting as a crucial regulator in HF. Upon receiving the MIF signal molecule, the CD74/CXCR4 receptor can activate NF-κB signaling to produce chemokines and thereby enhance the inflammatory response. CD74 and CXCR4 may serve as biomarkers and treatment targets for HF.

Extracellular vesicles (EVs): A promising therapeutic tool in the heart tissue regeneration.

Mesenchymal stem cells (MSCs) treatment has been widely explored as a therapy for myocardial infarction, peripheral ischemic vascular diseases, dilated cardiomyopathy, and pulmonary hypertension. Latest in vitro studies suggest that MSCs can differentiate into contractile cardiomyocytes. One of the best-characterized MSCs products are MSCs-derived extracellular vesicles (EVs). EVs are crucial paracrine effectors of MSCs. Based on previous works, paracrine effects of MSCs play a primary role in the regenerative ability. Hence, in the current paper, we focused our attention on an alternative approach, exploiting products derived from human dental pulp stem cells (hDPSCs) rather than MSCs themselves, which may denote a cost-effective and safer approach. The focus has been on EVs and the bioactive molecules they contain to evaluate their ability to influence the differentiation process toward cardiomyogenic lineage. The expression of GATA4, ACTC1, CX43, and Nkx2.5 was evaluated using Immunofluorescence, real time-PCR, and Western blotting analyses. Furthermore, the expression profiling analysis of the microRNA hsa-miR-200c-3p, targeting the GATA4 gene, was studied. The hsa-miR-200c-3p was found significantly down-regulated in both c-hDPSCs + EVs-hDPSCs and c-hDPSCs + EVs-HL-1 compared to untreated c-hDPSCs underlying a possible epigenetic mechanism behind the prevalent up-regulation of its targeted GATA4 gene. The aim of the present work was to develop an in vitro model of hDPSCs able to differentiate into cardiomyocytes in order to investigate the role of EVs derived from hDPSCs and derived from HL-1 cardiomyocyte cell line in modulating the differentiation process toward cardiomyogenic lineage.

Parameters of the mitral apparatus in patients with ischemic and nonischemic dilated cardiomyopathy.

The mitral valve apparatus is a complex structure consisting of several coordinating components: the annulus, two leaflets, the chordae tendineae, and the papillary muscles. Due to the intricate interplay between the mitral valve and the left ventricle, a disease of the latter may influence the normal function of the former. As a consequence, valve insufficiency may arise despite the absence of organic valve disease. This is designated as functional or secondary mitral regurgitation, and it arises from a series of distortions to the valve components. This narrative review describes the normal anatomy and the pathophysiology behind the mitral valve changes in ischemic and non-ischemic dilated cardiomyopathies. It also explains the value of a complete multiparametric assessment of this structure. Not only must an assessment include quantitative measures of regurgitation, but also various anatomical parameters from the mitral apparatus and left ventricle, since they carry prognostic value and are predictors of mitral valve repair success and durability.

Synchrotron-based X-ray phase contrast imaging of transmural cardiac tissue in patients treated for advanced heart failure

Abstract Background Cardiac imaging is essential for identifying structural changes in advanced heart failure (HF) and understanding underlying pathophysiology. Synchrotron radiation-based X-ray phase contrast imaging (X-PCI) is a non-destructive imaging modality that can provide high resolution three-dimensional (3D) visualisation of cardiac tissue on the microstructural level. Thus far, such analyses including the quantification of myocyte aggregates ranging from the epicardium to the endocardium, have been confined to animal models and human fetal tissue. We aimed to explore the feasibility of using X-PCI to quantify and compare structural organisation and orientation of myocyte aggregates in the myocardium across different advanced HF aetiologies. Methods and design Four adult patients were included - two receiving a left ventricular assist device (LVAD), and two undergoing heart transplantation (HTx). Aetiology of advanced HF in both the LVAD and HTx group was ischaemic heart disease and dilated cardiomyopathy (DCM), respectively. Transmural tissue samples were obtained by left ventricular apical coring (LVAD) and from the explanted hearts (HTx). The tissue specimens were imaged by X-PCI at the TOMCAT beamline using an effective pixel size of 5.8 µm. Orientation of aggregates of cardiomyocytes was assessed using a structure tensor-based method and morphological parameters were derived - the helical angle (HA), or the angle between the circumferential left ventricular plane and myocyte aggregates, and fractional anisotropy (FA), the degree of anisotropy or disorganisation of the local myocardium. Results The general patient characteristics are shown in Table 1. X-PCI enabled 3D visualisation of transmural myocardial tissue samples showing differences in organisation of myocardial structure in different HF aetiologies (Figure 1). The epicardial adipose layer was thicker in DCM, paired with a thinner epicardial myocyte layer (yellow arrows). Furthermore, the epi-to-endocardial HA transition was clearly visualized in ICM (double arrows), whereas there was clear disruption of the HA gradient in DCM samples – a finding further quantified via FA (green arrows). Conclusion X-PCI allows non-destructive advanced imaging of ex-vivo tissue. By harnessing the power of digital 3D imaging on a cellular level, it provides a novel insight to differential information on tissue organisation in different aetiologies of advanced heart failure.Table 1Figure 1

Abstract 18729: cBIN1 Gene Therapy Improves Recovery of Peri-Infarction Muscle in a Canine Model of Chronic Ischemic Heart Failure

BACKGROUND: Heart failure (HF) due to ischemic dilated cardiomyopathy (IDCM) is a major cause of morbidity and mortality. In failing hearts, loss of T-tubule microdomains is central to impaired calcium transients and loss of cardiac function. Cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein that organizes T-tubule microdomains, is transcriptionally reduced in failing hearts. Hypothesis: cBIN1 gene therapy will improve cardiac function in ischemic cardiomyopathy. AIM: Evaluate the effectiveness of catheter-based delivery of cBIN1 gene therapy in preserving bipolar voltage (an assay of muscle health) and LVEF in a canine model of IDCM. Methods: Nine healthy adult mongrel dogs (30±3 kg) underwent LAD ligation, developing IDCM and HFrEF (LVEF &lt; 40% and NT-proBNP &gt;900 pmol/L) over 3-4 months. Animals received a single treatment at 20 sites by intramyocardial injection of either AAV9-GFP (control, n=3) or AAV9-cBIN1 (n=6) using a MyoStar catheter-mediated subendocardial injection. Low voltage LV regions were quantified as percent of total endocardial area with bipolar voltage &lt;1.5 mV on the day of the treatment (pre-therapy) and the terminal study (5-10 weeks post-therapy). Results: In control-treated dogs, low voltage areas did not change significantly (19.5±3.4 vs. 28.7±9.8%, p=0.143, Figure A ), whereas in the cBIN1-treated cohort, the low voltage areas surrounding infarction zones decreased significantly (18.9±10.9 vs. 13.4±9.1%, p=0.038, Figure B ). Control therapy was associated with an additional 9.2% loss LV myocardium, whereas cBIN1 therapy caused a 6.5% recovery of myocardium (p=0.024, Figure C ). Post-therapy week 5, LVEF decreased in control animals (36±2 vs. 29±3%, p&lt;0.001) yet improved in the cBIN1-treated animals (37±2 vs. 41±3%, P=0.003). CONCLUSION: Intramyocardial injection of cBIN1 gene therapy can halt and reverse expansion of peri-infarction low voltage areas and improve LVEF in a preclinical IDCM model of chronic HF.

Abstract 15640: Long Term Event-Free Survival in Patients With Ischemic and Non-Ischemic Cardiomyopathy up to Thirteen Years Following Cell-Based Therapy: Results From the Hyperion Observational Cohort

Introduction: The long-term clinical outcomes of cell-based therapies to treat ischemic (ICM) and non-ischemic dilated cardiomyopathy (NIDCM) are unknown. We therefore prospectively followed patients (pts) with ICM/NICDM treated by targeted transcatheter endocardial mesenchymal stromal cell (MSC) injections (TESI). Methods: Of the 155 pts enrolled in prior MSC TESI studies, 111 were eligible to be contacted. Of these, 47 (42%) agreed to participate and have periodic follow-up assessments (Cardiac MRI/CT, 6MWT, labs, PE, EKG, and MLHFq) for up to 13 years following their index procedure. Time-to-event information was captured from all 155 former participants. Endpoints included event-free survival, changes in left ventricular ejection fraction (EF), and ventricular remodeling. Clinical endpoint events were defined as the composite of: Death (all-cause mortality), Left Ventricular Assist Device (LVAD) placement, or Heart Transplant. Descriptive statistics were used to classify the sample, and Kaplan-Meier survival analysis was generated to examine time-to-event trends. Results: There were 134 men and 21 women, mean age 60.0±11.0 years, including 121 (78%) with ICM, and 34 (22%) with NIDCM. In pts with ICM, mean EF at baseline was 31 %±10.8% and after 1 year was 32.6%±11.8% (P=0.08). In pts with NIDCM baseline EF was 27%±10% and increased to 34%±13% after 1 year (P=0.002). Overall, 40% of pts had a decrease in LVEF, 26% had &lt;5% increase, 34% had a ≥5% increase, and 17% had a ≥10% increase in LVEF after 1 year. Increases of ≥5% LVEF post-therapy were associated with longer event-free survival in NIDCM (OR: 2.57; 95% CI: 0.6, 11.1) but not ICM (OR: 1.25; 95% CI: 0.4, 3.6). Conversely, reductions in LVEDV were associated with longer event-free survival in ICM (OR: 7.23; 95% CI: 1.9, 27.1) but not NIDCM (OR: 1.88; 95% CI: 0.4, 10.0). Conclusion: In this long-term observational cohort analysis, improvement of EF and/or reduction in LVEDV was associated with survival benefits among pts with NIDCM and ICM respectively. Future studies are needed with placebo controls to determine which pts are most likely to respond to MSC therapy. Clinical Trial Registration: URL: http://www.clinicaltrials.gov.; Unique ID: NCT03071835.

Safety and outcomes analysis: transcatheter implantation of autologous angiogenic cell precursors for the treatment of cardiomyopathy

BackgroundStem cell transplantation is an emerging therapy for severe cardiomyopathy, proffering stem cell recruitment, anti-apoptosis, and proangiogenic capabilities. Angiogenic cell precursors (ACP-01) are autologous, lineage-specific, cells derived from a multipotent progenitor cell population, with strong potential to effectively engraft, form blood vessels, and support tissue survival and regeneration.MethodsThis IRB approved outcome analysis reports upon 74 consecutive patients who failed medical management for severe cardiomyopathy, and were selected to undergo transcatheter intramyocardial or intracoronary implantation of ACP-01. Serious adverse events (SAEs) were reported. Cell analysis was conducted for each treatment. The left ventricular ejection fraction (LVEF) was measured by multi-gated acquisition scan (MUGA) or echocardiogram at 4 months ± 1.9 months and 12 months ± 5.5 months. Patients reported quality of life statements at 6 months (± 5.6 months).ResultsFifty-four of 74 patients met requirements for inclusion (48 males and five females; age 68.1 ± 11.3 years). The mean treatment cell number of 57 × 106 ACP-01 included 7.7 × 106 CD34 + and 21 × 106 CD31 + cells with 97.6% viability. SAEs included one death (previously unrecognized silent MI), ventricular tachycardia (n = 2) requiring cardioversion, and respiratory infection (n = 2). LVEF in the ischemic subgroup (n = 41) improved by 4.7% ± 9.7 from pre-procedure to the first follow-up (4 months ± 1.9 months) (p < 0.004) and by 7.2% ± 10.9 at final follow-up (n = 25) at average 12 months (p < 0.004). The non-ischemic dilated cardiomyopathy subgroup (n = 8) improved by 7.5% ± 6.0 at the first follow-up (p < 0.017) and by 12.2% ± 6.4 at final follow-up (p < 0.003, n = 6). Overall improvement in LVEF from pre-procedure to post-procedure was significant (Fisher’s exact test p < 0.004). LVEF improvement was most marked in the patients with the most severe cardiomyopathy (LVEF < 20%) improving from a mean 14.6% ± 3.4% pre-procedurally to 28.4% ± 8% at final follow-up. Quality of life statements reflected improvement in 33/50 (66%), no change in 14/50 (28%), and worse in 3/50 (6%).ConclusionTranscatheter implantation of ACP-01 for cardiomyopathy is safe and improves LVEF in the setting of ischemic and non-ischemic cardiomyopathy. The results warrant further investigation in a prospective, blinded, and controlled clinical study.Trial Registration: IRB from Genetic Alliance #APC01-001, approval date July 25, 2022.Condensed Cardiomyopathy is common and associated with high mortality. Stem cell transplantation is an emerging therapy. Angiogenic cell precursors (ACP-01) are lineage-specific endothelial progenitors, with strong potential for migration, engraftment, angiogenesis, and support of tissue survival and regeneration. A retrospective outcomes analysis of 53 patients with ischemic and non-ischemic dilated cardiomyopathy undergoing transcatheter implantation of ACP-01 demonstrated improvements in the left ventricular ejection fraction of 7.2% ± 10.9 (p < 0.004) and 12.2% ± 6.4, respectively, at 12 months (± 5) follow-up. Quality of life statements reflected improvement in 33/50 (66%) patients.

Left ventricle mechanical dispersion is a new universal marker of malignant ventricular tachyarrhythmias in patients with structural heart disease

Aim. To evaluate the possibility to use parameters of global, segmental longitudinal left ventricle (LV) strain and LV mechanical dispersion (MD) as new possible markers of malignant ventricular tachyarrhythmias (MVT) in patients with structural heart disease and reduced and intermediate LV ejection fraction (EF).Methods. The study included 113 patients (105 male, age 66 [59;73] year) with ischemic (n=89) or non-ischemic (n=24) dilated cardiomyopathy and LVEF&lt;50%, implanted cardioverter-defibrillators, cardiac resynchronization therapy devices-defibrillators, pacemakers or documented MVT. All patients underwent transthoracic echocardiography with an assessment of speckle-tracking echocardiography parameters (global and segmental longitudinal LV strain, LV MD). Comparative univariate and ROC-analyses were performed between patients with and without MVT separately for patients with LVEF &lt;35% (n=60) and LVEF 36-50% (n=53) LVEF.Results. The group of patients with LVEF ≤35% with MVT (n=30) was characterized by lower values of longitudinal strain of the basal segment of the LV septum wall (-5[-6,5;-0,5] vs -6,8[-11;-4.4], р=0,01, respectively) and the middle segment of the LV inferior wall (-3[-6;2] vs -6[-9;-1,5], р=0,04, respectively). The group of patients with LVEF 36-50% with MVT (n=33) was distinguished by a large value of LV end-diastolic volume (166,5[146,3;193] vs 156[133,8;165,5], р=0,04, respectively). The greater values of LV MD were noted in both groups of patients with MVT. The optimal cut-off value of LV MD was 120 ms (area under the ROC curve 0.817, sensitivity-73,3%, specificity-80%) for patients with LVEF≤35%, and 90 ms (area under the ROC curve 0.761, sensitivity-72.7%, specificity-75%) for patients with LVEF 36-50%.Conclusion. Speckle-tracking echocardiography parameters may serve as additional markers of increased risk of MVT in patients with structural heart disease and impaired LVEF. Only LV MD is useful for risk stratification of MVT in patients with either reduced or intermediate LVEF.

Integrative Proteomic Analysis Reveals the Cytoskeleton Regulation and Mitophagy Difference Between Ischemic Cardiomyopathy and Dilated Cardiomyopathy

Ischemic cardiomyopathy (ICM) and dilated cardiomyopathy (DCM) are the two primary etiologies of end-stage heart failure. However, there remains a dearth of comprehensive understanding the global perspective and the dynamics of the proteome and phosphoproteome in ICM and DCM, which hinders the profound comprehension of pivotal biological characteristics as well as differences in signal transduction activation mechanisms between these two major types of heart failure. We conducted high-throughput quantification proteomics and phosphoproteomics analysis of clinical heart tissues with ICM or DCM, which provided us the system-wide molecular insights into pathogenesis of clinical heart failure in both ICM and DCM. Both protein and phosphorylation expression levels exhibit distinct separation between heart failure and normal control heart tissues, highlighting the prominent characteristics of ICM and DCM. By integrating with omics results, Western blots, phosphosite-specific mutation, chemical intervention, and immunofluorescence validation, we found a significant activation of the PRKACA–GSK3β signaling pathway in ICM. This signaling pathway influenced remolding of the microtubule network and regulated the critical actin filaments in cardiac construction. Additionally, DCM exhibited significantly elevated mitochondria energy supply injury compared to ICM, which induced the ROCK1–vimentin signaling pathway activation and promoted mitophagy. Our study not only delineated the major distinguishing features between ICM and DCM but also revealed the crucial discrepancy in the mechanisms between ICM and DCM. This study facilitates a more profound comprehension of pathophysiologic heterogeneity between ICM and DCM and provides a novel perspective to assist in the discovery of potential therapeutic targets for different types of heart failure.

Expression of m6A Regulator Genes can Facilitate the Diagnosis of Chronic Heart Failure.

RNA N6-methyladenosine (m6A) is the most common type of modification in eukaryotic mRNA. The relationship between m6A modification and disease has been studied extensively, but there have been few studies on chronic heart failure (CHF). This study investigated a possible role for m6A in the diagnosis of CHF. Seven candidate m6A regulators (writers: WTAP and ZC3H13; readers: YTHDF3, FMR1, IGFBP1, and ELAVL1; eraser: FTO) were identified using a random forest (RF) model and the GSE5406 dataset from the Gene Expression Omnibus database. A nomogram model was developed to predict the risk of CHF, while consensus clustering methodology assigned CHF samples into two m6A patterns (cluster A and cluster B) according to the 7 candidate m6A regulators. Principal component analysis was used to calculate an m6A score for each sample and to quantify m6A patterns. Decision curve analysis and the nomogram model were used to obtain predictions that may be of clinical use. Patients in cluster B had higher m6A scores than patients in cluster A. Cluster B patients also had higher expression levels (ELs) of IL-4, IL-5, IL-10 and IL-13 than patients in cluster A, whereas cluster A patients had a higher EL for IL-33. The m6A cluster B pattern likely represents the ischemic heart failure (HF) disease group. m6A regulators are important in the pathogenesis of CHF associated with ischemic and idiopathic dilated cardiomyopathy, and may prove useful for the diagnosis and treatment of CHF.

Right ventricular systolic function and mechanical dyssynchrony in ischemic or non-ischemic dilated cardiomyopathy: A speckle-tracking study.

This study assessed RV dyssynchrony (irrespective to QRS duration) and RV systolic function in non-ischemic dilated cardiomyopathy (NIDCM) versus ischemic dilated cardiomyopathy (IDCM) patients by using different echo-Doppler modalities. Eighty-five cases (48 patients with DCM [whether ischemic or non-ischemic] and 37 age-matched healthy controls) were studied. Conventional echo-Doppler study, tissue Doppler (TDI), and speckle tracking (STE) were carried out to measure LV and RV systolic function. Time-to-peak negative longitudinal strain at the four RV sites were assessed by TDI derived strain and 2D speckle tracking. Patients with DCM (whether ischemic or non-ischemic) had significantly lower fractional area change, RV tricuspid annular systolic velocity (p<.001 for both), tricuspid annular plane systolic excursion (p=.01), RV-GLS whether TDI or 2D derived (p<.001). Twenty-nine patients (60%) showed right intraventricular delay (RV4SD>60ms). The RV-dyssynchrony index was negatively correlated to %FAC (r=-.362, p=.01), RV Sm (r=-.312, p=.04), and 2D-RV GLS (r=-.305, p=.05). Insignificant higher RV-dysynchrony index was detected in NIDCM compared to IDCM group; however, the basal septal segment was significantly delayed in dilated group. More impaired RV systolic function was detected in ischemic group. 2D STE and TDI showed a significant correlation in the assessment of the right-intraventricular delay (p=.001). Right-intraventricular dyssynchrony are detectable in patients with dilated cardiomyopathy (whether ischemic or non-ischemic) with a higher statistically insignificant value in non-ischemic group by using tissue Doppler imaging and 2D speckle tracking. More impairment of the RV systolic function was noticed in the ischemic group. Impaired RV systolic function was associated with right intraventricular delay.

Cardiac Magnetic Resonance Imaging-Derived Left Atrial Characteristics in Relation to Atrial Fibrillation Detection in Patients With an Implantable Cardioverter-Defibrillator.

Background Among patients with an implantable cardioverter-defibrillator, a high prevalence of atrial fibrillation (AF) is present. Identification of AF predictors in this patient group is of clinical importance to initiate appropriate preventive therapeutic measures to reduce the risk of AF-related complications. This study assesses whether cardiac magnetic resonance imaging-derived atrial characteristics are associated with AF development in patients with a dual-chamber implantable cardioverter-defibrillator or cardiac resynchronization therapy defibrillator, as detected by the cardiac implantable electronic device. Methods and Results This single-center retrospective study included 233 patients without documented AF history at the moment of device implantation (dual-chamber implantable cardioverter-defibrillator [63.5%] or cardiac resynchronization therapy defibrillator [36.5%]). All patients underwent cardiac magnetic resonance imaging before device implantation. Cardiac magnetic resonance-derived features of left atrial (LA) remodeling were evaluated in all patients. Detection of AF episodes was based on cardiac implantable electronic device interrogation. During a median follow-up of 6.1 years, a newly diagnosed AF episode was detected in 88 of the 233 (37.8%) patients with an ICD. In these patients, increased LA volumes and impaired LA function (LA emptying fraction and LA strain) were found as compared with patients without AF during follow-up. However, a significant association was only found in patients with dilated cardiomyopathy and not in patients with ischemic cardiomyopathy. Conclusions LA remodeling characteristics were associated with development of AF in patients with dilated cardiomyopathy but not patients with ischemic cardiomyopathy, suggesting different mechanisms of AF development in ischemic cardiomyopathy and dilated cardiomyopathy. Assessment of LA remodeling before device implantation might identify high-risk patients for AF.

A unified framework for multi-lead ECG characterization using Laplacian Eigenmaps

Background. The analysis of multi-lead electrocardiographic (ECG) signals requires integrating the information derived from each lead to reach clinically relevant conclusions. This analysis could benefit from data-driven methods compacting the information in those leads into lower-dimensional representations (i.e. 2 or 3 dimensions instead of 12). Objective. We propose Laplacian Eigenmaps (LE) to create a unified framework where ECGs from different subjects can be compared and their abnormalities are enhanced. Approach. We conceive a normal reference ECG space based on LE, calculated using signals of healthy subjects in sinus rhythm. Signals from new subjects can be mapped onto this reference space creating a loop per heartbeat that captures ECG abnormalities. A set of parameters, based on distance metrics and on the shape of loops, are proposed to quantify the differences between subjects. Main results. This methodology was applied to find structural and arrhythmogenic changes in the ECG. The LE framework consistently captured the characteristics of healthy ECGs, confirming that normal signals behaved similarly in the LE space. Significant differences between normal signals, and those from patients with ischemic heart disease or dilated cardiomyopathy were detected. In contrast, LE biomarkers did not identify differences between patients with cardiomyopathy and a history of ventricular arrhythmia and their matched controls. Significance. This LE unified framework offers a new representation of multi-lead signals, reducing dimensionality while enhancing imperceptible abnormalities and enabling the comparison of signals of different subjects.

Rejuvenating a failing heart: A Case report

Heart Failure (HF) is a complicated, fatal medical condition that poses a severe threat to human life. It is a complex ailment that can lead to death and is associated with high healthcare costs, significant morbidity and mortality rates, and a reduction in functional capacity and quality of life. Recent data analysis reveals that approximately 64million people worldwide are affected by HF.1 Patients with HFrEF can benefit from cardiac contractility modulation (CCM), a revolutionary device-based treatment. In patients with HFrEF, CCM treatment has been associated with an improvement in exercise tolerance, an improvement in quality of life, a decrease in HF hospitalizations, and a reversal remodeling of the left ventricle. In this instance, we describe the therapeutic benefit of CCM in an elderly individual with advanced HFrEF triggered by ischemic dilated cardiomyopathy who frequently required hospitalization for heart failure-related issues and had a low quality of life despite receiving the best possible guideline-directed medical therapy (GDMT).

P19 INCIDENTAL DIAGNOSIS OF MASSIVE MOBILE LEFT VENTRICLE THROMBI FOLLOWING COVID–19 INFECTION IN A HEART FAILURE PATIENT

Abstract Background Intracardiac thrombus can be a complication of ischemic heart disease and cardiomyopathies. The advancements in imaging modalities have increased the capacity to diagnose this condition helping to reduce the associated complications (i.e. embolization). Previous reports suggest a possible link between intracardiac thrombosis and COVID–19 infection, especially in patients with severe “endotheliitis”, pneumonia, or myocarditis. COVID–19 effects on the cardiovascular system are partly evaluated. Venous and arterial thrombosis is commonly associated with COVID–19 but detection of intracardiac thrombus has not been frequently reported. Case Description: A 71–year–old woman, known to have a non–ischemic dilated cardiomyopathy with reduced ejection fraction (EF) and a previous transcatheter edge–to–edge mitral valve repair (MitraClip), was admitted after a routine echocardiogram showing new onset multiple, highly mobile, left ventricle (LV) masses. The patient, fully vaccinated against Sars–Cov–2, experienced a paucisymptomatic COVID–19 infection 1 month before, followed by a full recovery. A transthoracic echocardiogram performed 3 months showed no LV masses. On admission she was completely asymptomatic with no clinical signs of heart failure or systemic embolization. A multimodality imaging evaluation (contrast echocardiography, cardiac computed tomography, cardiac magnetic resonance) confirmed a severe dilation of the LV with severe EF reduction, and 3 mobile LV masses. The largest mass was adhered to the middle portion of the anterolateral wall (maximum diameter 49x15 mm). A diagnostic endomyocardial biopsy and cardiac surgery were excluded due to prohibitive embolic/procedural risk and an anticoagulant treatment with warfarin was started with a progressive reduction of the masses’ dimension at transthoracic echocardiography. Thus, a diagnosis of exclusion of LV thrombosis was made. After 2–week a complete resolution of the masses was documented with no clinical or embolic events. Conclusion The pro–thrombotic nature of COVID–19 infection is well known. This case demonstrates how vulnerable patients, i.e. those with heart failure, may experience thrombotic complications following non–severe COVID–19 infection and despite having completed the vaccine course. Although currently unconfirmed by dedicated clinical trials, more assiduous echocardiographic monitoring and/or the use of anticoagulant therapies could yield a benefit in selected patients.