Impaired Cardiac Function Research Articles

Evaluation of cardiac function using echocardiography in childhood-onset systemic lupus erythematosus patients treated with hydroxychloroquine.

This study aimed to evaluate the effects of hydroxychloroquine on cardiac functions and left ventricular mass in patients with childhood-onset systemic lupus erythematosus (cSLE). Fifty patients with cSLE undergoing treatment with hydroxychloroquine underwent echocardiographic evaluation. All patients exhibited negative disease activity markers and were clinically in remission. The median duration of hydroxychloroquine exposure was 7.1 (5.2-9.5) years, with a median cumulative dose of 784.8 (509.5-3437.6) grams. No correlation was identified between the parameters of left ventricular ejection fraction, left ventricular mass index and geometry, and cumulative hydroxychloroquine dose (p = 0.245, p = 0.094, p = 0.146, respectively). Furthermore, no significant correlation was identified between the cumulative dose of hydroxychloroquine and diastolic cardiac parameters (all p > 0.05). A comparison of the patients who received a cumulative dose of hydroxychloroquine below the median dose (the low-dose group) with those who received a higher dose (the high-dose group) revealed no significant differences in the echocardiographic parameters (all p > 0.05). The findings of this study indicate that chronic hydroxychloroquine use in patients with cSLE does not result in adverse changes in left ventricular mass or impairment of cardiac functions. However, these patients should undergo regular evaluation to monitor for the potential development of cardiotoxicity.

Cardiometabolic Index is associated with heart failure: a cross-sectional study based on NHANES

IntroductionHeart failure is a complex syndrome characterized by impaired cardiac function. Despite improvements in treatment, the prevalence of heart failure continues to rise. The Cardiometabolic Index (CMI), a novel measure combining abdominal obesity and lipid levels, has emerged as a potential predictor of cardiac metabolic risk.MethodsWe analyzed data from the National Health and Nutrition Examination Survey (NHANES) involving 22,586 participants to investigate the association between CMI and heart failure. Multivariable logistic regression models and RCS analysis were used to explore the association between heart failure and CMI after adjusting for potential confounders. Subgroup analyses were performed among populations with different demographic and clinical characteristics.ResultsOur results revealed a significant positive correlation between CMI and heart failure, with odds ratios of 2.77 and 1.87 for the highest quartile after adjusting for confounders. Subgroup analyses indicated heightened risks among older adults and those with hypertension or diabetes. ROC curve analysis demonstrated that CMI offers good diagnostic value for heart failure, surpassing traditional measures like BMI.DiscussionOur findings suggest that CMI is a valuable tool for assessing the risk of heart failure, particularly in individuals with increased abdominal obesity or abnormal lipid profiles. This highlights the importance of addressing cardiac metabolic health in both prevention and treatment strategies for heart failure. Future research should focus on exploring causal relationships and refining predictive models that incorporate CMI to enhance early detection and intervention.

Aerobic Capacity of Adults With Fontan Palliation: Disease-Specific Reference Values and Relationship to Outcomes.

Patients with Fontan palliation have reduced aerobic capacity because of impaired cardiac, pulmonary, and skeletal muscle function. However, the assessment of aerobic capacity in this population still relies on comparisons with people without cardiovascular disease rather than comparison with the expected aerobic capacity of other Fontan patients. The purpose of this study was to determine the expected aerobic capacity of adults with Fontan palliation. Adults with Fontan palliation who underwent a cardiopulmonary exercise test at Mayo Clinic (2003-2023) were stratified into quartiles based on the predicted peak oxygen consumption (VO2). We assessed the correlates of predicted peak VO2 and the relationship between predicted peak VO2 quartiles and cardiovascular outcomes (death/transplant). Of 323 patients (age, 29±9 years; 177 [55%] men), the median peak VO2 was 19.1 (15.2-23.9) mL/kg per minute, and this corresponds to a predicted peak VO2 of 51% (range, 19-88; interquartile range, 41-62). After multivariable adjustments, the correlates of predicted peak VO2 were body mass index (β±SE, -2.61±0.95; 2.61% decrease in predicted peak VO2 per 5 kg/m2 increase in body mass index; P=0.009), systemic saturation (β±SE, 3.65±0.85; 3.65% increase in predicted peak VO2 per 5% increase in oxygen saturation; P<0.001), and Fontan pressure (β±SE, -1.24±0.22; 1.24% decrease in predicted peak VO2 per 1 mm Hg increase in Fontan pressures; P<0.001). There was a 47% increase in the risk for death/transplant from a higher predicted peak VO2 quartile to the next lower quartile (adjusted hazard ratio, 1.47 [95% CI, 1.09-2.05]; P=0.01). The results of the current study would help calibrate the interpretation of exercise test data in adults with Fontan palliation and improve risk stratification in this population. It also underscores the need to maintain normal Fontan hemodynamics and body weight, which are important determinants of aerobic capacity.

PACS2/CPT1A/DHODH signaling promotes cardiomyocyte ferroptosis in diabetic cardiomyopathy

ObjectivesThe pathophysiology of diabetic cardiomyopathy (DCM) is a phenomenon of great interest, but its clinical problems have not yet been effectively addressed. Recently, the mechanism of ferroptosis in the pathophysiology of various diseases, including DCM, has attracted widespread attention. Here, we explored the role of PACS2 in ferroptosis in DCM through its downregulation of PACS2 expression.Methods and resultsCardiomyocytes were treated with high glucose and palmitic acid (HGPA), and the detection of cardiomyocyte iron ions, lipid peroxides, and reactive oxygen species (ROS) revealed clear ferroptosis during these treatments. Silencing PACS2 downregulated CPT1A expression and upregulated DHODH expression significantly, reversing HGPA-induced ferroptosis. Further silencing of PACS2 with a CPT1A agonist exacerbated cardiomyocyte ferroptosis while promoting mitochondrial damage in cardiomyocytes. Using a mouse model of type 2 diabetes induced by streptozotocin (STZ) and a high-fat diet (HFD), we found that PACS2 deletion reversed these treatment-induced increases in cellular iron ions, impaired cardiac function, mitochondrial damage and ferroptosis in cardiac muscle tissues.ConclusionsThe PACS2/CPT1A/DHODH signalling pathway may be involved in ferroptosis in DCM by regulating cardiomyocyte mitochondrial function.

The effect of trimetazidine on cardiac haemodynamics and mitochondrial function in wild-type transthyretin amyloidosis.

Wild-type transthyretin cardiac amyloidosis (ATTRwt) is a cardiomyopathy causing myocardial hypoperfusion and impaired cardiac mitochondrial function. Trimetazidine is an antianginal agent used in patients with stable angina pectoris, which improves cardiac contractility and mitochondrial function. The aim of the study was to investigate the effect of trimetazidine on invasive haemodynamics and cardiac mitochondrial function in ATTRwt. In a randomized, double-blind, placebo-controlled, crossover trial, 22 patients with ATTRwt received 4weeks of trimetazidine and placebo in randomized order. After each treatment period followed examinations with endomyocardial biopsies taken for high-resolution respirometry and right heart catheterization at rest and during a cardiopulmonary exercise test. The primary endpoint was mean pulmonary artery wedge pressure (mPAWP) during peak exercise. The secondary endpoint was cardiac mitochondrial oxidative phosphorylation capacity. Exploratory endpoints were echocardiographic parameters, cardiac biomarker levels and quality of life. Trimetazidine did not significantly reduce mPAWP during peak exercise (31±12 vs. 31±13mmHg, P=0.61) or improve the cardiac mitochondrial oxidative phosphorylation capacity (73.4±7.7 vs. 75.3±7.7pmol O2/(mg*s), P=0.81) compared with placebo, nor did treatment with trimetazidine improve ejection fraction (P=0.93), global longitudinal strain (P=0.23), N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (P=0.92) or the patients' quality of life (P=0.98). In ATTRwt, treatment with trimetazidine did not improve mPAWP or cardiac mitochondrial oxidative phosphorylation capacity compared with placebo.

Exploring the mechanism of Ling-Gui-Zhu-Gan decoction in metabolic cardiomyopathy via inhibiting ferroptosis

ObjectiveThis study was to investigate the mechanism of Ling-Gui-Zhu-Gan decoction (LGZGD) in regulating lipid metabolism and thus inhibiting ferroptosis. MethodsUPLC for the determination of the main chemical composition of LGZGD. A HF-induced rat model of metabolic cardiomyopathy was established. Echocardiography was used to detect cardiac function. Serum lipid levels, myocardial injury markers, and lipid peroxidation levels were detected. Pathological changes were detected. Lipid deposition was assessed by oil red O, and the mitochondrial ultrastructure was observed by electron microscopy. Mechanistically, PLIN5, CD36, ATGL, GPX4, ACSL4, FPN1, DRP1, MFF, FIS1, and OPA1 expressions were examined. After PA-induced H9c2 cells established, apoptosis, myocardial injury markers, and lipid peroxidation levels were detected and lipid deposition levels were assessed. The expressions of PLIN5, CD36, ATGL, GPX4, ACSL4 and FPN1 were detected. H9c2 cardiomyocytes with transient knockdown of PLIN5 and overexpression of PLIN5 were constructed and treated with drug administration and modeling, and the apoptosis level was detected by flow cytometry, the levels of lipid peroxidation and ROS were detected by fluorescence, and the protein and gene expressions of ACSL4 and GPX4 were detected. Results The main active components of LGZGD were liquiritin, isoliquiritin, cinnamic acid, cinnamaldehyde, glycyrrhizic acid, and atractylenolide III. LGZGD significantly improved cardiac dysfunction, lowered lipid level and lipid deposition, reduced CK, NT-proBNP and MDA levels, restored SOD levels, and improved inflammatory cell infiltration as well as collagen fiber deposition. LGZGD decreased the expression of PLIN5, CD36, ACSL4, and increased the expression of ATGL, GPX4, and FPN1. LGZGD also decreased the gene expression of DRP1, MFF, FIS1, and increased OPA1 expression. LGZGD significantly ameliorated PA-induced apoptosis, decreased lipid deposition, lowered lipid peroxidation levels and CK level, decreased PLIN5, CD36, and ACSL4 expressions, and increased ATGL, GPX4, and FPN1 expressions. LGZGD reversed cardiomyocyte injury aggravated by transient knockdown of PLIN5, decreased apoptosis levels, lipid peroxidation levels, ROS levels, and ACSL4 expressions, and increased GPX4 expression. LGZGD enhanced cardiomyocyte protection after overexpression of PLIN5, reduced apoptosis levels, lipid peroxidation level and ROS level, decreased ACSL4 expression, and increased GPX4 expression. ConclusionPLIN5 interferes with lipid peroxidation, regulates mitochondrial function, and inhibits HF-induced ferroptosis in cardiomyocytes. LGZGD ameliorates impairment of cardiac structural function in model rats through PLIN5-mediated ferroptosis pathway, and has the effect of preventing metabolic cardiomyopathy.

Identification and validation of autophagy‑related genes in hypertrophic cardiomyopathy.

Hypertrophic cardiomyopathy (HCM) is an autosomal dominant cardiac disorder characterized by ventricular hypertrophy resulting from the disordered arrangement of myocardial cells, which leads to impaired cardiac function or death. Autophagy (AT) is a biochemical process through which lysosomes degrade and recycle damaged or discarded intracellular components to protect cells against external environmental conditions, such as hypoxia and oxidative stress. AT is closely related to HCM, and thus, serves an important role in myocardial hypertrophy. However, the precise mechanism underlying the regulation of AT in cardiac hypertrophy remains elusive. The present study aimed to examine the role and mechanisms of AT-related genes (ARGs) in HCM through bioinformatics analysis and experimental validation and to identify potential targeted drugs for HCM. In this study, cardiac samples were obtained from healthy individuals and patients with HCM from the GEO database, and screened for differentially expressed ARGs to further investigate their potential interactions and functional pathways. These genes were subjected to functional enrichment analysis to identify potential crosstalk and involved pathways. Based on a protein-protein interaction network, EIF4EBP1, MCL1, PIK3R1, CCND1 and PPARG were identified as potential biomarkers for the diagnosis and treatment of HCM. Furthermore, 10 components with therapeutic potential for HCM were predicted based on the aforementioned hub genes. The results of bioinformatics analysis were validated using H9c2 cells stimulated with angiotensin II, which represented an in vitro model of cardiac hypertrophy. Overall, the present study demonstrated that the expression levels of ARGs were substantially altered in HCM. Therefore, these genes may be used as diagnostic biomarkers and therapeutic targets for HCM.

New insights into FGF21 alleviates diabetic cardiomyopathy by suppressing ferroptosis: a commentary.

Diabetic cardiomyopathy (DCM) is a severe cardiovascular complication of diabetes characterized by myocardial hypertrophy, fibrosis, and impaired cardiac function. Fibroblast growth factor 21 (FGF21) has emerged as a promising therapeutic target due to its antifibrotic, antioxidant, and anti-inflammatory properties. Our commentary summarizes and affirms the recent study by Wang et al., which demonstrates the significant role of ferroptosis in DCM pathogenesis. FGF21 has shown promise as a therapeutic target for DCM, potentially inhibiting ferroptosis, mitigating oxidative damage, and protecting cardiomyocyte function. Mechanistically, the study identified ATF4 as an upstream regulator of FGF21 in DCM, revealing that FGF21 directly interacts with ferritin and extends its half-life, thus inhibiting ferroptosis in DCM. These findings provide a theoretical basis for understanding the pathogenesis and treatment of DCM. Our commentary suggests that future studies should explore the role of non-cardiomyocyte cell types in DCM, verify findings with clinical samples, and address comprehensive methods for ferroptosis detection. Additionally, we discuss the clinical application and future potential of FGF21-based therapies for DCM. Such efforts may contribute to advancing DCM diagnosis and treatment, fostering the development of innovative therapeutic strategies.

P-Wave Duration Is Associated With Aging Patterns in Structural Brain Networks.

Impaired cardiac function is associated with cognitive impairment and brain imaging features of aging. Cardiac arrhythmias, including atrial fibrillation, are implicated in clinical and subclinical brain injuries. Even in the absence of a clinical diagnosis, subclinical or prodromal substrates of arrhythmias, including an abnormally long or short P-wave duration (PWD), a measure associated with atrial abnormalities, have been associated with stroke and cognitive decline. However, the extent to which PWD has subclinical influences on overall aging patterns of the brain is not clearly understood. Here, using neuroimaging and ECG data from the UK Biobank, we use a novel regional "brain age" method to identify the brain aging networks associated with abnormal PWD. We find associations between short PWD and accelerated brain aging in the sensorimotor, frontoparietal, ventral attention, and dorsal attention networks, even in the absence of overt cardiac diseases. These findings contribute to our understanding of the relationship between PWD and structural brain aging. This work emphasizes the need for continued study designs that consider brain-based outcomes related to abnormally short PWD.

Gastrodin attenuates diabetic cardiomyopathy characterized by myocardial fibrosis by inhibiting the KLK8-PAR1 signaling axis

BackgroundDiabetic cardiomyopathy (DCM), characterized by myocardial fibrosis, is a major cause of mortality and morbidity in diabetic patients; the inhibition of cardiac fibrosis is a fundamental strategy for treating DCM. Gastrodin (GAS), a compound extracted from Gastrodia elata protects against DCM, but the molecular mechanism underlying its antifibrotic effect has not been elucidated.MethodsIn vivo, the effects of GAS were investigated using C57BL/6 mice with DCM, which was induced by administering a high-sugar, high-fat (HSF) diet and streptozotocin (STZ). We assessed the cardiac function in these mice and detected histopathological changes in their hearts and the degree of cardiac fibrosis. In vitro, neonatal rat cardiac fibroblasts (CFs) were transformed into myofibroblasts by exposing them to high glucose combined with high palmitic acid (HG-PA), and CFs were induced by pEX-1 (pGCMV/MCS/EGFP/Neo) plasmid-mediated overexpression of KLK8, which contains the rat KLK8 gene. The KLK8 siRNA was knocked down to study the effects of GAS on CF differentiation, collagen synthesis, and cell migration by specific mechanisms of action of GAS.ResultsGAS attenuated pathological changes in the hearts of DCM mice, rescued impaired cardiac function, and attenuated cardiac fibrosis. Additionally, the results of molecular docking analysis showed that GAS binds to kinin-releasing enzyme-related peptidase 8 (KLK8) to inhibit the increase in protease-activated receptor-1 (PAR-1), thus attenuating myocardial fibrosis. Specifically, GAS attenuated the transformation of neonatal rat CFs to myofibroblasts exposed to HG-PA. Overexpressing KLK8 promoted CF differentiation, collagen synthesis, and cell migration, and KLK8 siRNA attenuated HG-PA-induced CF differentiation, collagen synthesis, and cell migration. Further studies revealed that a PAR-1 antagonist, but not a PAR-2 antagonist, could attenuate CF differentiation, collagen synthesis, and cell migration. Additionally, GAS inhibited KLK8 upregulation and PAR1 activation, thus blocking the differentiation, collagen synthesis, and cell migration of HG-PA-exposed CFs and triggering TGF-β1/Smad3 signaling.ConclusionGAS alleviated pathological changes in the hearts of DCM model mice induced by an HSF diet combined with STZ. KLK8 mediated HG-PA-induced differentiation, collagen synthesis, and the migration of CFs. GAS attenuated the differentiation, collagen synthesis, and migration of CFs by inhibiting the KLK8-PAR1 signaling axis, a process in which TGF-β1 and Smad3 are involved.Graphical

Left atrial rupture during on-pump beating coronary artery bypass grafting

BackgroundOn-pump beating coronary artery bypass grafting (CABG) is a procedure that uses cardiopulmonary bypass to maintain circulation and it is a useful technique for CABG in patients with severely impaired cardiac function. Here, we report a case of left atrial rupture that occurred during CABG. Reports of left atrial injury are rare, and there have been no previous reports of such cases associated with on-pump beating CABG.Case presentationAn 80-year-old man with a history of myocardial infarction was admitted to another hospital for acute heart failure. Coronary angiography revealed triple-vessel disease, and echocardiography showed reduced left ventricular function and moderate mitral regurgitation. He was transferred to our hospital for coronary artery bypass grafting and the operation was scheduled. Surgery was started with the intention of off-pump CABG, but due to circulatory instability, the patient was converted to on-pump beating CABG. While the heart was being dislocated and anastomosis was being performed, sudden bleeding from the left atrium occurred. To achieve hemostasis, we needed to arrest the patient's heart. A 5-cm laceration along the posterior mitral annulus was found in the left atrium and repaired with a bovine pericardial patch. Mitral annuloplasty with a flexible ring was performed simultaneously. He recovered uneventfully.ConclusionsThe left atrial rupture during on-pump beating coronary artery bypass grafting is extremely rare. The wall of the atrium is thought to have been damaged by the stress applied during the displacement of the heart and the impact of the enlarged mitral regurgitant jet. Repair under cardiac arrest is necessary, and in some cases, mitral annuloplasty may be additionally required.

Abstract 4137935: Adipogenesis in Bone Marrow Niche under Cardiac Stress Worsens Cardiac Function

Background: We have recently reported that repetitive cardiac decompensation with multimorbidity often experienced by patients with heart failure (HF) is attributed to epigenetic modifications of hematopoietic stem cells (HSCs) in the bone marrow (BM). HF reprogrammed HSCs differentiation and altered tissue macrophage homeostasis. These findings demonstrate that the BM can carry an innate immune memory of cardiac stress that may exacerbate HF and predispose other organs to pathology. Aims: Because the stemness of HSCs is mainly regulated by mesenchymal stromal cells (MSCs) in the BM niche, we investigated phenotypic alterations of MSCs under cardiac stress. Methods&amp;Results: Transcriptome analysis of MSCs showed preferential differentiation toward adipocytes in murine pressure overload models. In vitro assays and histological BM sections also support this finding. Furthermore, single-cell RNA sequencing of MSCs demonstrated that the percentage of adipocyte-primed MSCs increased in proportion to the severity of cardiac dysfunction, and also correlated with the frequency of myeloid-lineage progenitor cells. To investigate the influence of adipo-lineage MSCs on HSCs, we conducted BM transplantation supplemented with MSCs from control or HF mice. Recipient mice transplanted with HF-MSCs showed significant increases in myeloid-biased multipotent progenitors in BM and myeloid cells in peripheral blood. Additionally, the number of proinflammatory cardiac macrophages was significantly increased in the HF-MSCs group, promoting cardiac fibrosis and dysfunction. Conclusions: Our results demonstrated that the BM niche could perceive cardiac stress in the form of adipocytic skewing of MSCs in the setting of HF, which changed the differentiation behavior in HSCs and ultimately led to further deterioration of cardiac function through the impaired differentiation of circulating monocytes into cardiac macrophages. Therefore, suppressing the adipocytic differentiation of MSCs could have a novel therapeutic potential to avoid repeated HF events.

Abstract 4136452: Acute Cardiac Function Change After Catheter Ablation of Ventricular Arrhythmias in Patients with Arrhythmogenic Right Ventricular Cardiomyopathy

Introduction: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a genetic disorder characterized by fibrofatty replacement of myocardial tissue, creating areas of electrical heterogeneity and increasing the risk of ventricular arrhythmias (VAs) and sudden cardiac death (SCD). Catheter ablation is commonly performed in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) for management of ventricular arrhythmias (VAs). Whether catheter ablation affects cardiac function post-procedurally is uncertain. Research Question: Does catheter ablation for ARVC result in acute change in cardiac function? Goals/Aims: To assess the impact of catheter ablation for VAs on cardiac function in the acute post-procedure setting. Methods: This retrospective study included patients with ARVC who underwent catheter ablation for VAs at Mayo Clinic. Cardiac function was assessed on pre- and post-procedure transthoracic echocardiograms (TTEs). Post-procedure TTEs were obtained within 4 weeks after the ablation procedure. Right ventricular (RV) enlargement and systolic dysfunction were evaluated as continuous variables (0=none, 1=mild, 2=mild-moderate, 3=moderate, 4=moderate-severe, 5=severe). Results: The study included 32 patients who underwent a total of 44 ablations. Mean age at the time of ablation was 49±16 years, and 24 (75%) were male. After a mean follow-up duration of 2.6±5.5 days, there was a significant worsening in mean RV dysfunction (1.6±1.5 to 2.0±1.4, P = 0.001). There were no significant changes in mean left ventricular ejection fraction (LVEF), left ventricular (LV) dimensions, and RV size. 6 (14%) patients had a &gt;5% decline in LVEF, and 14 (32%) patients had worsening RV function. Transient inotropic support was required in 4 (9%) patients. Conclusion(s): This study is the first to assess the acute impact of catheter ablation for VAs on cardiac function in ARVC patients. These results underscore the importance of careful post-procedure monitoring and planning of the ablation target in these patients to avoid excessive ablation and therefore impairment in cardiac function.

Abstract 4118360: Lipocalin10 is Critical for Macrophage Efferocytosis to Repair Myocardial Ischemia/Reperfusion Injury

Introduction: Efficient clearance of dead/dying cells by macrophages (MΦs) (termed efferocytosis) is critical for timely repairing the injured heart after ischemia/reperfusion (I/R). Prior work by us and others shows that Lipocalin 10 (Lcn10), a secreted protein of lipocalin family, can regulate MΦ polarization and is greatly downregulated in cardiac tissue of patients with heart failure. However, the potential role of Lcn10 in MΦ efferocytosis during cardiac I/R has never been investigated. Methods: Wild-type (WT) and Lcn10-knockout (KO) mice were subjected to 45 minutes of ischemia via the ligation of left anterior descending artery (LAD) followed by reperfusion. Cardiac function was measured by echocardiography. Flow cytometry was utilized to assess MΦ efferocytosis. Bone marrow-derived MΦs (BMDMs) were used to test efferocytosis in vitro and dissect mechanism. Dead cells were prepared by treating red-dye-labelled H9C2 cells with H 2 O 2 (1mM, 2h). Results: After co-culturing BMDMs with dead H9C2 cells for 2h, we observed a 25% reduction of efferocytosis in Lcn10-KO BMDMs, compared to WTs. Using Lcn10-KO mCherry mouse model (cardiomyocyte-specific overexpression of mCherry in Lcn10-KO background), we consistently found that cardiac MΦs in Lcn10-KO mice taken up fewer dead mCherry-myocytes at 4 days post-I/R surgery, leading to an increased accumulation of cardiac dead cells, higher serum levels of troponin I, greater myocardial fibrosis, and dramatically impaired cardiac function, compared to WT mCherry controls. In contrast, pre-treatment of BMDMs with recombinant Lcn10 protein (rLcn10) enhanced efferocytosis by 50%. Mechanistically, RNA-seq analysis revealed that many efferocytosis-related genes were dysregulated ( e.g., downregulation of Id 1, Id 3, Itga 8, Itga v, Cd 44, Cx3cr 1, Msr 1, and upregulation of Sirp α) in Lcn10-KO BMDMs, compared to WTs. Interestingly, most of these dysregulated genes are controlled by transcription factors Id1/3. Further studies showed that rLcn10 interacted with Cd44 and activated the expression of its downstream Id1/3, leading to enhanced MΦ efferocytosis. Importantly, rLcn10-mediated efferocytosis was greatly impaired by pre-treatment of MΦs with either anti-CD44 blocking antibody (KM201, 10µg/ml) or Id1/3 inhibitor (AGX51, 25µM). Conclusion: Our data indicate that Lcn10 is essential for MΦ efficient efferocytosis to repair I/R-induced cardiac damage though affecting the Cd44-Id1/3 signaling and its related MΦ surface receptors.

IL1RAP Blockade With a Monoclonal Antibody Reduces Cardiac Inflammation and Preserves Heart Function in Viral and Autoimmune Myocarditis.

Currently, there are no therapies targeting specific pathogenic pathways in myocarditis. IL (interleukin)-1 blockade has shown promise in preclinical studies and case reports. We hypothesized that blockade of IL1RAP (IL-1 receptor accessory protein), a shared subunit of the IL-1, IL-33, and IL-36 receptors, could be more efficient than IL-1 blockade alone. We induced coxsackievirus B3 (CVB3)-mediated or experimental autoimmune myocarditis (EAM) in BALB/c mice, followed by treatment with an Fc (fragment crystallizable)-modified mIgG2a mouse anti-mouse IL1RAP monoclonal antibody (mCAN10). Myocarditis severity and immune infiltration were assessed by histology and flow cytometry. Cardiac function was measured by echocardiography. We used spatial transcriptomics (Visium 10× Genomics) to compare the gene expression landscape in the hearts of mCAN10-treated versus control mice. IL1RAP blockade reduced CVB3 and EAM severity. In EAM, the treatment prevented deterioration of cardiac function, measured on day 42 post-disease induction (left ventricular ejection fraction: 56.5% versus 51.0% in isotype controls [P=0.002] and versus 51.4% in mice treated with anti-IL-1β antibodies alone [P=0.003]; n=10-11 mice per group). In the CVB3 model, mCAN10 did not impede viral clearance from the heart and significantly lowered the numbers of CD4+ (cluster of differentiation 4) T cells (P=0.025), inflammatory Ly6C+CCR2+ (lymphocyte antigen 6 complex, locus C/C-C motif chemokine receptor 2) monocytes (P=0.038), neutrophils (P=0.001) and eosinophils (P<0.001) infiltrating the myocardium. The spatial transcriptomic analysis revealed reduced canonical IL-1 signaling and chemokine expression in cardiac immune foci in CVB3-infected mice treated with IL1RAP blockade. Blocking IL1RAP reduces acute CVB3 myocarditis and EAM severity and preserves cardiac function in EAM. We conclude that IL1RAP blockade is a potential therapeutic strategy in viral and autoimmune myocarditis.

Chronic Constrictive Pericarditis in Northeast India: A 10-Year Single-Center Study of Demographic and Clinical Profiles.

Introduction Chronic constrictive pericarditis (CCP) is a progressive disease characterized by thickening and fibrosis of the pericardium, leading to restricted diastolic filling and impaired cardiac function. In Northeast India, limited healthcare infrastructure poses challenges in diagnosing and managing CCP, potentially worsening patient outcomes. Therefore, this study aims to assess the demographic and clinical profiles of patients with CCPin this regionover 10 years and compare our findings to the relevant but limited published literature in South Asia. Methods We retrospectively analyzed the medical records of 42 patients diagnosed with CCP referred to our department from 2011 to 2020. Demographic, clinical, and paraclinical data during hospitalization and follow-up were collected. All patients underwent clinical examination imaging studies, including high-resolution chest computed tomography and echocardiography. Symptomatic patients underwent open pericardiectomy, and postoperative histopathological examination was performed. Results Of the 42 patients, 34 (81%) were male and eight (19%) were female. A significant proportion of the patients were under the age of 20 years (n = 18, 42.9%), followed by the 21- to 40-year age group (n = 13, 31%). Eighteen patients (42.9%) were from Meghalaya, 12 (28.6%) were from Assam, and seven (16.7%) were from Nagaland. Twenty-two patients (52.4%) had a prior history of pulmonary or extrapulmonary tuberculosis (TB) and had received antitubercular therapy for at least six months. Dyspnea on exertion was the most common symptom among the patients: 12 (28.6%) of them were classified as New York Heart Association class IV, 20 (47.6%) as class III, and 10 (23.8%) as class II. Clinical examination revealed pedal edema in 36(85.7%), hepatomegaly in 22 (52.4%), ascites in 15 (35.7%), and pleural effusion in 13 (31%) patients. Echocardiography showed septal bounce in 26 (61.9%), pericardial calcification in 17 (40.5%), and hepatic vein flow reversal in 12 (28.6%) patients. All patients were on diuretics and digoxin before surgery. Postoperative biopsy confirmed TBas the etiology in 28 (66.7%) patients and nonspecific etiology in 14 (33.3%) of them. Conclusions CCP in Northeast India predominantly affects young males and is largely associated with TB. Despite efforts to control TB, it remains a major contributor to CCP in this region. Recognizing the clinical presentation and diagnostic profile is essential for improving management strategies and patient outcomes.

Disfunção Cardíaca Associada À Quimioterapia Em Paciente Pediátrico: Relato De Caso

Introduction: Due to advances in antineoplastic treatments, there has been a notable improvement in the outlook of cancer patients. However, it is crucial to highlight that the cardiotoxicity associated with these therapeutic approaches is recognized as one of the most significant adverse effects. This phenomenon is characterized by the ability of chemical agents or therapeutic procedures to induce damage to the heart muscle, resulting in compromised cardiac function. Objectives: To present a case report of a patient suffering from Non-Hodgkin's Lymphoma (NHL), with impaired cardiac function due to cardiotoxicity. Methods: This is a descriptive observational study, of the case report type, which describes the clinical manifestations and management of a patient with cardiac dysfunction associated with chemotherapy. The research data used were collected through medical records made available by the public health service reference in pediatric oncology in the city of João Pessoa-PB. Results: Report the case of an 18-year-old pediatric patient, diagnosed with non-Hodgkin's Lymphoma, presenting with underlying heart disease, who underwent chemotherapy treatment, developing cardiotoxicity that led to death. Conclusion: Therefore, it is essential that continuous monitoring is implemented throughout the entire cancer treatment. Additionally, it is necessary to ensure that patients have broad access to diagnostic tests and chemotherapy with a cardioprotective profile, aiming to minimize the risk of cardiotoxicity. These measures are essential to reduce the incidence of adverse effects on the myocardium and improve the safety and effectiveness of oncological treatment.

A comprehensive evaluation of available evidence of mavacamten in obstructive HCM: a meta-analysis of randomised controlled trials

Abstract Introduction Obstructive hypertrophic cardiomyopathy (HCM) poses a significant clinical challenge, characterized by left ventricular hypertrophy and impaired cardiac function. mavacamten, a novel medication targeting the sarcomere protein myosin, has emerged as a promising therapeutic option for patients with symptomatic obstructive HCM. Despite its potential efficacy, the comparative effectiveness and safety of Mavacamten remain uncertain, necessitating a comprehensive evaluation of available evidence. Purpose We aimed to give a comprehensive appraisal on mavacamten as a treatment option for patients with obstructive HCM informing clinical decision-making. Methods We systematically searched PubMed, Web of Science, Scopus, and Cochrane Central, and EMBASE from inception until February 2024. We included randomised controlled trials (RCTs) comparing mavacamten versus placebo in patients with obstructive HCM. The primary outcomes were improvement in NYHA class, Change from baseline in KCCQ-CSS, and the incidence of atrial fibrillation. All data were pooled as either Mean difference in the random effect model with the corresponding SD or pooled as RR and 95% CI for dichotomous data. Results Four randomised controlled trials involving 503 patients were included in the final analysis. the overall odds ratio demonstrated a substantial preference for Mavacamten in achieving more than a one-level improvement in NYHA functional class from baseline (OR: 3.83 (95% CI [2.54 to 5.77], P=0.0001). However, there was no significant difference in terms of KCCQ-CSS (MD= 1.06, 95% CI [ -0.03 to 2.15], P=0.06) or the incidence of atrial fibrillation (OR=1.27, 95% CI [0.51 to 3.14], P=0.60). Conclusion Mavacamten showed a significant improvement on NYHA functional class, with no observed significance in terms of reducing the incidence of AF, or improving the KCCQ-CSS score.KCCQ-CSSNYHA

ND15, subunit of the electron transport chain protein-complex I, age-dependently worsens cardiac performance in Drosophila melanogaster

Abstract Introduction In the natural aging process of the heart, aside others, mitochondrial dysfunction is an essential driver for the development of reduced cardiac performance. Previous analysis of protein expression levels in cardiomyocytes of aged mice and have found aberrancies in subunits of the mitochondrial Complexes I – IV of the electron transport chain. Especially, the complex I subunit ND15 was highly downregulated. To elucidate the functional effects of this gene on the cardiac performance, we generated cardiomyocyte specific ND15 knock-downs in Drosophila melanogaster. Methods We generated Drosophila with heart-specific (+/+; Hand4.2-GAL4/UAS-ND15; tdtK/+) (ND15-KD)knockdown of ND15 using the UAS/GAL4 system. The flies' cardiomyocytes endogenously express tdTomato, facilitating fluorescence-based live imaging of the heart by high-resolution video fluorescence microscopy. The recorded data was processed using a R-Script, resulting in Results We compared wild type (WT) flies to ND15-KD flies at age 3 weeks(young) and 7 weeks(old). Knockdown of ND15 resulted in impaired cardiac function. Most parameters deteriorated in aged flies in comparison to young flies. The heart frequency was significantly reduced (WT:6 beats/s – KD:4 beats/s – p&amp;lt;0.0001) in the 7 weeks old group, end-diastolic diameter of the heart tube increased significantly in 3 weeks old ND15KD flies compared to controls(WT:65µm – KD:74µm p&amp;lt;0,0001), resulting in a dilated heart tube Interestingly enough, this dilation in ND15-KD disappeared in 7 weeks old flies. The fractional shortening was significantly decreased in young(WT:33,5% - KD:30% p&amp;lt;0,01) and deteriorated in old flies (WT:35% - KD:22% p&amp;lt;0,0001), indicating a reduced contraction capability. For both 3 weeks and 7 weeks old groups, the heart-rate adjusted interbeat interval variance (WT:22% -KD: 40% p&amp;lt;0,0001) as well as the time of no cardiac action (WT: 22% - KD: 35% p&amp;lt;0,0001) increased and showed significant irregularities. The duration of systole and diastole combined also exhibited arrhythmic patterns (WT:15% - KD:20.5% p&amp;lt;0,0001). A general arrhythmia index (AI) increased significantly (WT: 0.25 – KD:0.5 p&amp;lt;0,0001) These arrhythmia parameters emphasize the arrhythmogenic potential of the ND15-knockdown. The relative relaxation capabilities drastically worsened with age, displaying a diastolic dysfunction in the 7 weeks old group. At half-time relaxation, the WT was at 60% relaxation, ND15KD at 46%). Conclusion This study demonstrates that heart-specific deletion of ND15 results in a marked impairment of systolic and diastolic cardiac function in Drosophila accompanied by pro-arrhythmogenic actions. We could identify ND15 as a new mitochondrial molecular target for the maintenance of regular cardiac function and rhythmicity, especially with increasing age. Further mechanistic studies and translation to mammalian organisms are ongoing.

The transcription factor foxo3 regulates cardiac remodeling after myocardial infarction

Abstract Background Myofibroblast and myeloid cell differentiation following acute myocardial infarction (MI) are important for myocardial fibrosis but also cause adverse remodeling leading to cardiac dysfunction and heart failure. The transcription factor forkhead box O 3 (Foxo3) inhibits hypertrophic cardiac remodeling. We hypothesized that Foxo3, a key regulator of cell differentiation and immunity might inhibit differentiation of fibroblasts and myoloid cells and therefore cardiac fibrosis after MI. Methods MI was induced in Foxo3-/- and wild-type mice by permanent LAD ligation. Cardiac function was determined by transthoracic echocardiography. Cell differentiation was investigated by single nucleus RNA-sequencing (snRNA-seq). Moreover, transdifferentiation assays ex vivo were performed. Results Foxo3-/- mice showed significantly improved survival post- MI (p&amp;lt;0.01) that was in part due to reduced cardiac ruptures (p&amp;lt;0.05). TTE showed reduced LV function, cardiac output, and global strain 4 days post-MI in both groups of animals. However, LV function was significantly attenuated in Foxo3-/- mice 14 d post-MI while diastolic parameters indicated enhanced wall stiffness. snRNA-seq on day 4 post-MI revealed significantly increased numbers of myofibroblasts (p&amp;lt;0.05) transdifferentiating from Progenitor-like state fibroblasts and epicardial derived fibroblasts in Foxo3-/- mice. Myofibroblasts upregulated genes important for extracellular matrix structure and cell migration. Moreover, an upregulation of pro-fibrotic genes was observed in other fibroblast clusters in Foxo3-/- mice and corroborated by significantly elevated collagen type 1 and 3 as well as periostin protein expression. Mechanistically, fibroblasts from Foxo3a-/- mice exhibited enhanced Smad3 dependent myofibroblast marker expression after TGF-ß stimulation. Cell chat analysis indicated enhanced number of interactions and interaction strength of myeloid cells with fibroblasts in Foxo3-/- animals. In line with these observations, differences in cardiac myeloid cell differentiation characterized by reduced center-log ratios of cardiac resident macrophages (Lyve1hiMHCIIlo and Lyve1loMHCIIhi) and increase in monocyte-derived macrophages (Ccr2hi MΦ and Trem2hi MΦ) on day 4 post-MI that was enhanced in Foxo3-/- mice were determined. Differential gene expression patterns on day 4 in pro-inflammatory macrophages (Ccr2hi MΦ) showed upregulation of genes in the interleukin-12 pathway while reparative macrophages (Trem2hi MΦ) revealed an increased expression of genes for extracellular matrix proteins and ECM-collagen interactions in Foxo3-/- mice. Conclusion Our data identify Foxo3 as a master regulator of cardiac remodeling inhibiting myofibroblast and myeloid cell differentiation after acute MI, and suggesting that deficiency of Foxo3 promotes early scar formation but also contributes to adverse matricellular remodeling resulting in impaired cardiac function and enhanced fibrosis.