Ischemic Cardiomyopathy Research Articles

Assessing the Role of Primary Heart Failure Etiology on Cardiac Transplant Outcomes.

There are diverse indications for heart transplantation (HTx), often categorized into ischemic (ICM) and nonischemic (NICM) cardiomyopathy. Although there is extensive research comparing the outcomes for these disease processes following certain therapeutic interventions, there are limited data on how recipient etiology impacts post-HTx survival. Our investigation seeks to identify this relationship. We conducted a retrospective analysis using adult HTx patients from the United Network for Organ Sharing database between 2000 and 2021. Patients with a combined heart-lung transplant or previous HTx were excluded. ICM included coronary artery disease (CAD) and ischemic dilated cardiomyopathy. NICM included nonischemic dilated (NIDCM), hypertrophic (HCM), and restrictive (RCM) cardiomyopathy. Overall survival was analyzed using Kaplan-Meier curves, log-rank tests, and multivariable Cox regression models. A total of 42268 patients were included in our study. Recipients with ICM were older and more likely to be males, obese, diabetics, and smokers. We found that patients with ICM had an increased incidence of transplant CAD (OR=1.23, p<0.001) and risk of mortality (hazard ratio [HR]=1.22, p<0.001) compared to NICM. When NICM was expanded, RCM had a similar hazard risk compared to ICM (HR=1.03, p=0.650), whereas both NIDCM (HR=0.81, p<0.001) and HCM (HR=0.70, p<0.001) had improved survival. Our study provides evidence to suggest that ICM has decreased survival when compared to NICM. When NICM was expanded, RCM was found to have an increased mortality risk similar to ICM, whereas NIDCM and HCM both had superior outcomes. The clinical implication of this investigation will allow clinicians to better understand the prognosis of certain patient groups.

Age-Related Outcomes in Heart Failure with Mildly Reduced Ejection Fraction.

Objective: This study investigates age-related differences and outcomes in patients hospitalized with heart failure with a mildly reduced ejection fraction (HFmrEF). Background: The characterization of patients with HFmrEF and the prognostic value of age has rarely been investigated. Methods: Patients with HFmrEF were retrospectively included at one institution between 2016 and 2022. The distribution of HF aetiology and prognostic outcomes were investigated comparing patients with ≤40, >40 to ≤60, >60 to ≤80, and >80 years of age. The primary endpoint was long-term all-cause mortality. Kaplan-Meier and multivariable Cox proportional regression analyses were applied for statistics. Results: For the present study, 2184 patients with HFmrEF with a median age of 76 years were included. Non-ischemic cardiomyopathy was the most common HF aetiology in patients <40 years of age, whereas patients with 60-80 years of age (60.2%) and >80 years of age (58.2%) had the higher rates of ischemic cardiomyopathies. The risk of long-term all-cause mortality at 30 months was highest in patients with >80 years of age (HR = 2.167; 95% CI 1.928-2.436; p = 0.001), even after multivariable adjustment. Furthermore, patients with >80 years of age had the highest risk of HF-related rehospitalization (HR = 1.529; 95% CI 1.293-1.807; p = 0.001). Conclusions: Ischemic cardiomyopathy represents the most common cause of HF in elderly patients with HFmrEF, whereas younger patients were more likely to suffer from non-ischemic HF aetiologies. Increasing age was an independent predictor of long-term all-cause mortality in patients hospitalized with HFmrEF.

Stereotactic Ablative Radiotherapy for Early-stage Lung Cancer in Patients With Left Ventricular Assist Device: A Case Series.

Radiotherapy-induced malfunction of pacemakers and cardiac defibrillators has been reported, and corresponding guidelines have been developed in various countries. Although several studies have reported the effects of radiotherapy in patients with implantable left ventricular assist device (LVAD), its safety remains unclear. Herein, we report three cases of stereotactic ablative radiotherapy (SABR) using CyberKnife for early-stage lung cancer in patients with implantable LVAD. Three patients in their 50s or 60s, including two women and one man, who had LVADs due to dilated or ischemic cardiomyopathy and performance status of 0 or 1, were diagnosed with stage IA2 lung cancer (cT1bN0M0) by imaging only. All three patients were deemed inoperable due to cardiac comorbidity and underwent SABR at the Osaka University Hospital. The total radiation dose was 42-52 Gy, administered in four fractions. All treatment plans were designed to keep the LVAD dose below 2 Gy. In all patients, SABR was completed without acute adverse events or LVAD malfunction. During the follow-up period of 3-29 months, no disease progression or chronic adverse events were observed in any of the patients. This case series indicated that SABR using CyberKnife is a safe treatment option for early-stage lung cancer in patients with LVAD by reducing the dose to the LVAD.

Spatially clustered type I interferon responses at injury borderzones

Sterile inflammation after myocardial infarction is classically credited to myeloid cells interacting with dead cell debris in the infarct zone1,2. Here we show that cardiomyocytes are the dominant initiators of a previously undescribed type I interferon response in the infarct borderzone. Using spatial transcriptomics analysis in mice and humans, we find that myocardial infarction induces colonies of interferon-induced cells (IFNICs) expressing interferon-stimulated genes decorating the borderzone, where cardiomyocytes experience mechanical stress, nuclear rupture and escape of chromosomal DNA. Cardiomyocyte-selective deletion of Irf3 abrogated IFNIC colonies, whereas mice lacking Irf3 in fibroblasts, macrophages, neutrophils or endothelial cells, Ccr2-deficient mice or plasmacytoid-dendritic-cell-depleted mice did not. Interferons blunted the protective matricellular programs and contractile function of borderzone fibroblasts, and increased vulnerability to pathological remodelling. In mice that died after myocardial infarction, IFNIC colonies were immediately adjacent to sites of ventricular rupture, while mice lacking IFNICs were protected from rupture and exhibited improved survival3. Together, these results reveal a pathological borderzone niche characterized by a cardiomyocyte-initiated innate immune response. We suggest that selective inhibition of IRF3 activation in non-immune cells could limit ischaemic cardiomyopathy while avoiding broad immunosuppression.

Ventricular tachycardia ablation with pentaspline pulsed field technology in two patients with ischemic cardiomyopathy.

Due to its unique features, pulsed field ablation (PFA) could potentially overcome some limitations of current radiofrequency (RF) ventricular tachycardia (VT) ablation. However, data on the use of PFA in this setting are currently scarce. Two patients with ischemic cardiomyopathy and previously failed RF VT ablations were treated with PFA. A total of 18 bipolar applications (case1) and seven bipolar applications (case2) were delivered to the infero-lateral and infero-septal areas (case1) and to the apical lateral left ventricular (LV) wall (case2), placing the catheter adjacent to the LVwall in the flower configuration. A rapid cessation of VT and restoration of sinus rhythm were observed during PFA delivery in both cases. Further applications were delivered to achieve complete elimination of late potentials. In case 1, during the in-hospital stay, ECG monitoring did not show VT recurrences. Six-month follow-up was uneventful, with no VT recurrences at ICD interrogation. In case 2, due to postdischarge VT recurrences, a second RF procedure was scheduled 1 month later. The voltage map performed in sinus rhythm showed a low-voltage zone located at the anterolateral wall, near the previous ablation site. Numerous late potentials were recorded. At the 6-month follow-up, no further VT recurrences were documented after RF redo ablation. While the speed of application and potential transmural effect can facilitate the ablation of large diseased endocardial areas, early loss of contact due to difficult pentaspline catheter manipulation in the LV could lead to insufficient contact force and, consequently, inadequate energy penetration.

Myocardial scar area predicts major adverse cardiovascular events after coronary artery bypass grafting in patients with ischemic cardiomyopathy

Objective: To investigate the value of myocardium scar area in predicting adverse cardiovascular events (MACEs) after coronary artery bypass grafting (CABG) in patients with ischemic cardiomyopathy (ICM). Methods: The first part of this study was a retrospective study. Patients diagnosed with ICM and undergoing CABG surgery at Beijing Anzhen Hospital, Capital Medical University from January 2017 to December 2022 were enrolled as the discovery cohort. All patients underwent cardiac magnetic resonance-late gadolinium enhancement (CMR-LGE) before surgery. According to the occurrence of postoperative MACEs, the patients were divided into MACEs group and MACEs-free group. Preoperative clinical and imaging data, intraoperative and postoperative data were collected and compared between the two groups. The primary endpoint was postoperative MACEs. Univariate and multifactor regression analyses were used to analyze the risk factors for MACEs. Receiver operating characteristic (ROC) curves were constructed to evaluate the predictive efficacy and optimal cut-off value of myocardial scar area for endpoint events. The second part of this study was a prospective study. Patients with ICM who received CABG at Beijing Anzhen Hospital, Capital Medical University from January 2023 to June 2023 were enrolled as a validation cohort, and were divided into MACEs group and MACEs-free group according to whether MACEs occurred after surgery. Preoperative clinical and imaging data, intraoperative and postoperative data were collected and compared between the two groups. Verify the reliability of the cut-off value obtained by ROC curve in the validation cohort. Results: A total of 120 patients with ICM (30 patients in MACEs group and 90 patients in MACEs-free group), aged (61.6±8.7) years, including 93 males, were included in the discovery cohort. A total of 22 ICM patients (5 patients in MACEs group and 17 patients in MACEs-free group), aged (59.5±8.2) years, including 18 males, were included in the validation cohort. Multivariate Cox regression showed that myocardial scar area (HR=1.258, 95%CI 1.096-1.444, P=0.001) was an independent risk factor for the primary endpoint event. The area under ROC curve of myocardial scar area for predicting postoperative MACEs was 0.90 (95%CI 0.83-0.95), and myocardial scar area≥36.0% was the optimal cut-off value for predicting postoperative MACEs, and its sensitivity, specificity and accuracy were 96.7%, 72.2% and 78.3%, respectively. In the validation cohort, the sensitivity, specificity and accuracy of myocardial scar area in predicting postoperative MACEs in patients with ICM after CABG were 80.0%, 82.4% and 81.8%, respectively. Conclusion: Myocardial scar area is an independent risk factor for MACEs after CABG in patients with ICM, and myocardial scar area≥36.0% is the optimal cut-off value for predicting MACEs after CABG. Myocardial scar area can help to identify patients at high risk of surgery and provide a basis for risk stratification of patients.

Prognostic value of electroanatomic-guided endomyocardial biopsy in patients with myocarditis, arrhythmogenic cardiomyopathy and non dilated left ventricular cardiomyopathy

A wide variety of non-invasive and invasive techniques for SCD risk stratification in non ischemic cardiomyopathy (NICM) have been proposed, including left ventricular (LV) ejection fraction, QRS duration, late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and invasive electrophysiologic study with or without three-dimensional electroanatomic mapping (3D-EAM), to identify and characterize the arrhythmogenic substrate. There is still no clear consensus on the risk stratification in this clinical setting.The aim of our study is to characterize the 3D-EAM substrate in patients with the same clinical presentation of unexplained complex VAs and NICM using CMR, three-dimensional electranatomic mapping (3D-EAM) in association with endomyocardial biopsy (EMB) and genetic screening, as a more precise and early diagnostic assessment may provide important subsequent prognostic impact. The study was designed as a prospective multi-center observational evaluation and the patient follow-up was scheduled at 6 months interval. We enrolled 125 patients distinct into four different group by complete diagnostic work-up: myocarditis, non-dilated left ventricular cardiomyopathy, arrhythmogenic cardiomyopathy and control group. The four groups were compared in terms of clinical, imaging and 3D-EAM data. At multivariate analysis sustained VT/VF on admission [HR: 3.64 (1.79–7.4), p < 0.001], total bipolar scar area of left and right ventricle detected by 3D-EAM [HR: 2.24 (1.13–4.49), p = 0.02], histological diagnosis of myocarditis by 3D-EAM guided endomyocardial biopsy (EBM) [HR: 2.79 (1.04–7.44), p = 0.01] were independent predictors of complex VAs or death at follow-up. 3D-EAM guided EMB represent not only a valid diagnostic tool to identify the arrhythmogenic substrate in patients with NICM and ventricular arrhythmic phenotype but also an important predictor of complex Vas at long term follow-up.

Robotic mitral surgery: recent advances and outcomes.

This review explores recent advancements in robotic cardiac surgery, specifically focusing on its application in diverse mitral valve surgeries. The aim is to provide an overview of current clinical practices and supporting evidence in this evolving field. A literature review indicates a 30% surge in robotic mitral valve repair from 2015 to 2021, paralleled by a decline in sternotomy-based repair per the STS database. Robotic mitral valve repair consistently shows effective and safe outcomes, with comparable mortality but lower morbidity risks than sternotomy and thoracotomy. The robotic approach exhibits lower conversion to valve replacement, shorter ICU stays, and reduced 30-day readmissions. For experienced programs, robotic techniques prove versatile in various pathologies, including rheumatic heart valve disease, infective endocarditis, ischemic cardiomyopathy, and mitral annular calcification necessitating valve replacement. Literature supports their selective use in high-risk scenarios, including redo surgeries and elderly patients. Recent evidence supports the growing use of robotic approaches in mitral valve surgery, highlighting their efficacy with comparable mortality rates but lower morbidity risks. Robotic techniques consistently yield positive outcomes across various pathologies and patient profiles, signaling a potential paradigm shift in mitral valve interventions.

Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischemic cardiomyopathy.

The development of cell therapy as a widely-available clinical option for ischemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery. Pigs with chronic ischemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigor guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of LV function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and hemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of left ventricular (LV) function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits. To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically-relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischemic cardiomyopathy.

Characterization of a novel mitophagy-related 5-genes signature for diagnosis of acute myocardial infarction

Myocardial infarction (MI) and the ensuing heart failure (HF) remain the main cause of morbidity and mortality worldwide. One of the strategies to combat MI and HF lies in the ability to accurately predict the onset of these disorders. Alterations in mitochondrial homeostasis have been reported to be involved in the pathogenesis of various cardiovascular diseases (CVDs). In this regard, perturbations to mitochondrial dynamics leading to impaired clearance of dysfunctional mitochondria have been previously established to be a crucial trigger for MI/HF.In this study, we found that MI patients could be classified into three clusters based on the expression levels of mitophagy-related genes and consensus clustering. We identified a mitophagy-related diagnostic 5-genes signature for MI using support vector machines-Recursive Feature Elimination (SVM-RFE) and random forest, with the area under the ROC curve (AUC) value of the predictive model at 0.813. Additionally, the single-cell transcriptome and pseudo-time analyses showed that the mitoscore was significantly upregulated in macrophages, endothelial cells, pericytes, fibroblasts and monocytes in patients with ischemic cardiomyopathy, while sequestosome 1 (SQSTM1) exhibited remarkable increase in the infarcted (ICM) and non-infarcted (ICMN) myocardium samples dissected from the left ventricle compared with control samples. Lastly, through analysis of peripheral blood from MI patients, we found that the expression of SQSTM1 is positively correlated with troponin-T (P < 0.0001, R = 0.4195, R2 = 0.1759). Therefore, this study provides the rationale for a cell-specific mitophagy-related gene signature as an additional supporting diagnostic for CVDs.

Chronic systolic heart failure: association of remodeling of the right heart and renal dysfunction with cardiac arrhythmias

Introduction. Ischemic (ICMP) and dilated cardiomyopathy (DCMP) are the leading causes of chronic heart failure (CHF) with the most frequent indication for heart transplantation. The similarity of these diseases consists in the widespread and high mortality rate due to pathological remodeling of both the left and right chambers of the heart, which is accompanied by the progression of CHF, increasing the risk of sudden cardiac death.The purpose of the study. To study the relationship of systolic function of the left ventricle (LV) with remodeling of the right heart, renal dysfunction and their relationship with cardiac arrhythmia.Materials and methods. The study included 72 patients with CHF with reduced ejection fraction (CHFrEF), who were being treated at the N. V. Sklifosovsky Scientific Research Institute of EM in connection with worsening CHF. Group I consisted of 48 patients with DCMP; group II – 24 patients with ICMP.Results. LV ejection fraction (LV EF) in patients of both groups was &lt;30 %, but it was significantly lower in group I (p=0.001). The EF of the right ventricle (RV) in group I was low and amounted to 24.6 [19.5; 28.5]%. In group I, the volume of the right atrium (PP) and the size of the pancreas correlated with LV EF (r= –0.489, p=0.015 and r= –0.410, p=0.005, respectively); each subsequent increase in the volume of right atrium (RA) by 1 ml increased the likelihood of atrial fibrillation (AF) by 1.018 times (OR: 1.018, 95 % CI: 1.0042–1.033, p=0.011). The estimated glomerular filtration rate (eGFR) &lt;60 ml/min/1.73 m2 increased the chances of ventricular tachycardia (VT) by 9.5 times (OR: 9.5, 95 % CI: 2.32–38.87, p=0.002). Each subsequent decrease in eGFR by 1 ml/min/1.73 m2 increased the chances of developing VT by 1.03 times (OR: 0.967, 95 % CI: 0.937–0.988, p=0.036)].Conclusions. In patients with CHFrEF, regardless of the etiology, a decrease in LV EF leads to structural and functional changes in the right parts of the heart. In individuals with DCMP, an increase in RA volume by 1 ml increases the likelihood of AF by 1.018 times; a decrease in eGFR by 1 ml/min/1.73 m2 increases the chances of developing VT by 1.03 times.

Emerging Trends and Innovations in the Treatment and Diagnosis of Atherosclerosis and Cardiovascular Disease: A Comprehensive Review towards Healthier Aging.

Cardiovascular diseases (CVDs) are classed as diseases of aging, which are associated with an increased prevalence of atherosclerotic lesion formation caused by such diseases and is considered as one of the leading causes of death globally, representing a severe health crisis affecting the heart and blood vessels. Atherosclerosis is described as a chronic condition that can lead to myocardial infarction, ischemic cardiomyopathy, stroke, and peripheral arterial disease and to date, most pharmacological therapies mainly aim to control risk factors in patients with cardiovascular disease. Advances in transformative therapies and imaging diagnostics agents could shape the clinical applications of such approaches, including nanomedicine, biomaterials, immunotherapy, cell therapy, and gene therapy, which are emerging and likely to significantly impact CVD management in the coming decade. This review summarizes the current anti-atherosclerotic therapies' major milestones, strengths, and limitations. It provides an overview of the recent discoveries and emerging technologies in nanomedicine, cell therapy, and gene and immune therapeutics that can revolutionize CVD clinical practice by steering it toward precision medicine. CVD-related clinical trials and promising pre-clinical strategies that would significantly impact patients with CVD are discussed. Here, we review these recent advances, highlighting key clinical opportunities in the rapidly emerging field of CVD medicine.

Abstract Tu113: Metabolomic Profile of Human End-Stage Ischemic Cardiomyopathy Reveals Few Differences from Non-Ischemic Cardiomyopathy

Background: The heart is highly metabolic, relying on a range of fuels to sustain its high generation of ATP. The primary source of energy in the human heart is fatty acids, but fatty acid oxidation is reduced in failing hearts, contributing to a decrease in ATP production. Previously, we provided a comprehensive metabolic profile of human non-ischemic cardiomyopathy (NICM) hearts, including maintained ATP levels despite decreased energy charge (EC), lower acylcarnitines, acyl CoAs, and free fatty acids, suggesting a defect in fatty acid import. Research Questions: The pathogenesis of ischemic cardiomyopathy (ICM) is dramatically different from that of NICM, raising the question of whether metabolic defects differ between these two conditions. Aims: Our current study was therefore aimed at elucidating the metabolomic profile of end-stage ICM compared to that of NICM. Methods: Whole human hearts were obtained either from patients with end-stage heart failure (NICM or ICM) undergoing cardiac transplantation or from brain-dead organ donors. Hearts were arrested in situ and kept in ice-cold cardioplegia solution at all times. Transmural tissue samples were obtained from left ventricular free wall, snap frozen, and extracted metabolites were quantified by liquid chromatography coupled with mass spectrometer. Results: The comparison of metabolomics data from non-failing (NF) control heart samples and NICM samples were consistent with our previous study, with marked decrease in acylcarnitines and increase in lysophosphatidylcholine. On the other hand, the metabolomics profiles of ICM and NICM samples were remarkably similar. Phenylacetylglutamine and trimethylamine N-oxide, both related to atherosclerotic disease risk, were statistically significantly higher in ICM samples compared to NICM samples. Conclusion(s): The human cardiac metabolome of end-stage ICM is nearly identical to that of NICM, despite dramatically different pathogeneses, suggesting that end-stage heart failure constitutes a final common pathway. It would be of great interest to evaluate metabolomic profiles of the diseases differ at earlier timepoints.

Abstract We055: Role of Classical Dendritic Cells in the Sterile Inflammatory Response Following Myocardial Infarction

Myocardial infarction and the subsequent development of chronic ischemic cardiomyopathy is the most common cause of congestive heart failure. Infarction is associated with an intense sterile inflammatory response which can lead to adverse remodeling over the long term. Dendritic cells (DCs) are antigen presenting cells that function as a bridge between innate and adaptive immunity. Precursor DCs give rise to several distinct classical DC (cDC) subsets that mediate a variety of functions. The cDC1 subset is essential for cross-presentation of antigens to CD8 + T cells, while the cDC2 lineage is a potent inducer of CD4 + T cell proliferation. The aim of the study was to characterize the profile of the cDC populations present during the various stages of the development of chronic ischemic cardiomyopathy. We hypothesized that cDCs are essential mediators of chronic LV remodeling in the period following ischemic myocardial injury. We sought to determine which specific cDC subtype (cDC1 vs cDC2) forms the predominant population in the heart and secondary lymphoid tissues following ischemic injury. Adult male C57BL/6 (WT) mice underwent non-perfused myocardial infarction by ligating the left anterior descending artery (LAD) to induce sterile injury, with sham operated mice used as controls. Left ventricular (LV) remodeling was assessed by echocardiography at 1 w and 8 w following surgery. Alterations in cDC1 (CD45+CD11c+CD103-XCR1-) and cDC2 (CD45+CD11c+CD103+XCR1+) profile were examined by flow cytometry. When compared with the sham operated mice, mice with ischemic cardiomyopathy following LAD ligation exhibited the following features. There is an initial influx of cDC2 into the myocardium 1 w after MI (mean of 3.0% vs 0.26% of CD45 + leukocytes, p=0.02). This is followed by a subsequent influx of cDC1 into the myocardium 4 weeks after MI (mean of 1.98% vs 0.16% of CD45 + leukocytes, p=0.001). This influx of cDC into the heart is accompanied by an egress of cDC from the spleen (mean of 0.37% vs 0.76% of CD45 + leukocytes, P=0.001) at 4 weeks following MI. In conclusion, the findings of our study suggest that there is an initial influx of cDC2 followed by a more sustained influx of cDC1 into the myocardium in the weeks following an infarct. Antigen presentation by cDC likely plays a critical role in driving the inflammatory response and inducing chronic LV remodeling in the period following MI.

Abstract Mo054: Long Noncoding RNA LINC00667 Downregulation Leads to SCN5A Alternative Splicing and Arrhythmogenesis

Background: The voltage-gated sodium channel SCN5A, which encodes the Nav1.5 protein, is integral to the propagation of electrical signals in cardiac tissue. SCN5A expression is diminished in cardiomyopathy, significantly increasing the susceptibility to arrhythmias. This reduction in channel activity can be attributed to decreased mRNA stability coupled with aberrant mRNA splicing. The underlying mechanisms driving the dysregulation of mRNA splicing under pathophysiological conditions remain poorly understood. Objective: This study explores the role of long noncoding RNA LINC00667 in the abnormal alternative splicing of SCN5A mRNA. Methods: LINC00667 expression was analyzed using public databases, human heart tissue, iPSC-derived cardiomyocytes (iPSCMs), and cell lines. The impact of SCN5A on action potentials and sodium currents was studied in iPSCMs. LINC00667 and SCN5A expressions were measured using qRT-PCR, while Nav1.5 protein levels were assessed through Western blot. Alternative splicing of SCN5A mRNA was examined using PCR with exon-specific primers. Gene ontology and in silico analysis identified RNA binding proteins (RBPs) potentially interacting with LINC00667. RNA immunoprecipitation (RIP) assays confirmed direct binding with key splice factors. Group differences were assessed using 2-tailed Student’s t-tests, with P &lt; 0.05 indicating significance. Results: LINC00667, found at chromosome 18p11.31, is expressed in the human heart and associated cells, including cardiomyocytes. Its levels are inversely related to arrhythmic risk, decreasing in heart failure and ischemic cardiomyopathy as well as under hypoxic conditions. Gene ontology linked RBPs to SCN5A mRNA splicing, with RBM25, RBM5, and TIA1 identified as LINC00667 interactors. LINC00667 reduction affected regions of SCN5A mRNA encompassing Exons 6, 24, and 28, which could potentially be linked to decreased function/expression or increased unfolded protein response (UPR). Abnormal RNA splicing decreased SCN5A-encoded sodium current, reduced action potential upstroke velocity, and shortened AP duration without altering resting membrane potential. Conclusion: Decreased LINC00667 releases splicing factors that result in abnormal SCN5A mRNA splicing and reduced sodium current. Since LINC00667 is reduced in cardiomyopathy, overexpression may be antiarrhythmic by preventing sodium channel downregulation.

Abstract Tu075: Cardiac macrophages expressing CD206 and IL-4Ra are required for adverse LV remodeling in HF

Cardiac macrophages significantly expand in chronic heart failure (HF). We tested the hypothesis that CD206 + macrophages expressing interleukin (IL)-4Ra in the failing heart are key drivers of left ventricular (LV) remodeling and ischemic cardiomyopathy. Cardiac macrophages were profiled using flow cytometry in adult male C57BL/6 (WT) mice following non-reperfused myocardial infarction (MI) to induce HF or sham operation. CD206 + macrophages progressively expanded in post-MI hearts during the progression of LV remodeling and comprised ~85% of macrophages at 8 w. These macrophages were exclusively proliferative and predominantly C-C motif chemokine receptor (CCR2) – and major histocompatibility complex (MHC)II hi in failing hearts, with the majority (92%) of CD206 + CCR2 – macrophages expressing LYVE-1, an embryonically-derived resident macrophage marker. Nearly half of cardiac CD206 + macrophages expressed IL-4Ra; the abundance of CD206 + IL-4Ra + directly correlated with LV dysfunction and fibrosis. Intramyocardial adoptive transfer of IL-4-polarized bone marrow derived CD206 + macrophages induced progressive LV dilation, dysfunction and fibrosis over 4 w in naïve recipient mice. To evaluate the role of CD206 + IL-4Ra + macrophages in LV remodeling, we used male and female LysM CreERT2 ;IL-4Ra F/F mice that allow for inducible myeloid-specific IL-4Ra gene deletion. Administration of tamoxifen from at 4 to 10 w post-MI (in established HF), effectively deleted IL-4Ra in cardiac macrophages and significantly reduced CD206 + macrophage abundance and proliferation in the remodeling heart. Myeloid-specific IL-4Ra deletion further prevented LV remodeling progression, improved fibrosis and neovascularization, and alleviated LV systolic dysfunction, while suppressing expansion of cardiac immune cells and blood Ly6C high monocytosis. We conclude that an expanded and proliferative population of CD206 + IL-4Ra + macrophages primarily derived from resident macrophages are key mediators of pathological LV remodeling and fibrosis. Inhibition of CD206 + macrophage IL-4Ra signaling may be a fruitful therapeutic approach to alleviate disease progression in HF.

Out of hospital cardiac arrest - new insights and a call for a worldwide registry and guidelines

IntroductionOut of hospital cardiac arrest (OHCA) is a major public health problem with substantial mortality rates worldwide. Genetic diseases and primary electrical disorders are the most common etiologies at younger ages, while ischemic heart disease and cardiomyopathies are common causes at older ages. Despite improvement in prevention and treatment in recent years, OHCA is still a major cause of cardiovascular death.MethodWe report prospective data regarding etiology, characteristics, clinical course, and outcomes of patients with OHCA who were admitted to a tertiary care center intensive cardiac care unit (ICCU) between 2020–2023.ResultsA total of 92 patients admitted after OHCA were included in the cohort. Mean age was 63.8 ± 13.8 years and 75 (82%) were males. The most common etiology of OHCA was acute coronary syndrome (ACS) in 54 (59%) patients, of whom 46 (85%) patients had ST elevation myocardial infarction and 8 (15%) had non-ST elevation myocardial infarction. During hospitalization, 42 (46%) patients underwent targeted temperature management and 13 (14%) received mechanical circulatory support. Interestingly, 77 (84%) patients underwent coronary angiography, while only 51 (55%) received percutaneous coronary intervention (PCI). Neurologic status was favorable in 49 (53%) patients with Cerebral Performance Category score of 1–2. Overall, mortality rates were relatively low, with 15 (16%) in-hospital deaths and 24 (26%) deaths at 30-day follow-up.ConclusionAlthough ACS was the most common etiology for OHCA, only 55% of patients underwent PCI. Most OHCA patients admitted to the ICCU survived hospitalization and were discharged. Increased awareness, public education, worldwide registries, and specific evidence-based guidelines for the treatment of OHCA patients may lead to improved outcomes for these patients who often carry poor prognoses.

Abstract We105: cBIN1 Gene Therapy Improves Left Ventricular Filling Pressure in a Canine Model of Ischemic Dilated Cardiomyopathy

Introduction: In heart failure patients, increased left ventricular end diastolic pressure (LVEDP) is pathognomonic of myocardial dysfunction. Previously, we presented that gene therapy with exogeneous cardiac bridging integrator 1 (cBIN1), a membrane scaffolding protein that organizes T-tubule microdomains and is decreased in failing hearts, recovers systolic function in a canine model of chronic ischemic dilated cardiomyopathy (IDCM). The effect of catheter-based delivery of cBIN1 gene therapy on increased LVEDP is unclear. Hypothesis: We tested the hypothesis that cBIN1 gene therapy improves LVEDP in a canine model of IDCM. Methods: Twelve healthy dogs (30±2 kg) underwent left anterior descending artery ligation and developed IDCM with LVEF &lt;40% and NT-proBNP &gt;900 pmol/L over 3–4 months. Animals received a single application at 20 subendocardial LV sites of either AAV9-GFP (control, n=6) or AAV9-cBIN1 (n=6) using a MyoStar catheter-based injection. Pressure-volume loops were acquired in vivo, including measurement of LVEDP, end-systolic pressure-volume relation (ESPVR), isovolumic relaxation time (IVRT) and isovolumetric contraction time (IVCT). Measurements were performed on the day prior to administering the therapy ( pre-therapy ) and 5–8 weeks post-intramyocardial injection ( post-therapy ). For statistics, student t-test was used, and p&lt;0.05 refers as significant. Results are reported as mean±SD. Results: In AAV9-GFP control-treated dogs, compared with pre-therapy, post-therapy LVEDP elevated significantly (13±1 vs. 17±1 mmHg, p=0.002, Figure A ), whereas in the cBIN1-treated cohort, elevated LVEDP improved significantly (13±4 vs. 11±3 mmHg, p=0.042). With control therapy, ESPVR exhibited a significant decrease in contractility (1.40±0.44 vs. 1.81±0.49 mmHg/mL, p=0.001, Figure B ), whereas cBIN1 therapy caused a substantial improvement in ESPVR (1.54±0.71 vs. 1.34±0.43 mmHg/mL, p=0.022, Figure B ). At the post-therapy time-point, compared with control therapy, cBIN1 therapy improved IVRT (96±10 vs. 72±8 ms, p&lt;0.001, Figure C ) and IVCT (49±4 vs. 40±3 ms, p=0.009, Figure D ). Conclusion: cBIN1 gene therapy reduces elevated LV filling pressure and improves overall hemodynamics in a canine model of chronic IDCM.

Proteomic Characterisation of Heart Failure Reveals a Unique Molecular Phenotype for Hypertrophic Cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is a disease, which is difficult to diagnose at an early stage and for which there is a pressing need for more effective treatment options. The purpose of this study was to compare the molecular profile of HCM to that of ischaemic cardiomyopathy (ISCM) and dilated cardiomyopathy (DCM) for identification of protein and pathway targets that could support the development of better diagnostic and treatment options for HCM. A high-throughput mass spectrometry workflow was applied to achieve deep quantitative coverage of left ventricular tissue from HCM, DCM, ISCM and non-heart-failure control patients. HCM had a diverse proteomic profile compared to that of DCM and ISCM. Differentially expressed proteins unique to HCM were identified based on an observed fold change of ≥1.5 or ≤0.67 and q-value ≤ 0.05. Candidate proteins of interest were found to be significantly associated with clinical features of HCM. The significant association between these proteins and HCM was validated in an independent dataset. This represents one of the largest and deepest proteomic datasets for myocardial tissue reported to date. The dataset highlights the diverse proteomic profile of HCM, relative to other cardiomyopathies, and reveals disease-relevant pathways and promising biomarker candidates that are uniquely associated with HCM.

A Systematic Review and Meta-Analysis of Catheter Ablation Versus Anti-arrhythmic Drugs for Treatment of Ventricular Arrhythmia.

Catheter ablation (CA) and anti-arrhythmic drugs (AADs) minimize implanted cardioverter-defibrillator (ICD) shocks in individuals with ischemic cardiomyopathy and an ICD, while the best strategy is still unknown. CA has been proposed as a potentially effective means of reducing the occurrence of ICD events in a number of studies; however, there were insufficient relevant dates from randomized controlled trials. A meta-analysis and systematic review of randomized controlled trials were carried out to evaluate the efficacy of CA for the prevention of VA in patients with ischemic heart disease. Cardiovascular mortality, an unscheduled hospitalization due to increasing heart failure, appropriate ICD shock, or serious treatment-related consequences comprised the composite primary outcome. AADs were examined in six trials (n = 1564; follow-up = 15 ± 8 months), while CA was evaluated in four trials (n = 682; follow-up = 12 ± 6 months). Both CA (odds ratio (OR) 0.65, 95% confidence interval (CI) 0.47-0.82, p = 0.001) and AADs (OR 0.76, 95% CI 0.32-0.84, p = 0.034) significantly reduced the number of suitable ICD interventions, with no discernible difference between the two treatment approaches. AADs were observed to reduce incorrect ICD interventions (OR 0.38, p = 0.001), but CA did not. During follow-up, there was no correlation seen between reduced mortality and either CA or AAD. When compared to AAD, CA decreased the composite endpoint of cardiovascular death, adequate ICD shock, heart failure-related hospitalization, or severe treatment-related consequences in ICD patients with ischemic cardiomyopathy and symptomatic VT.