Improvement In Cardiac Function Research Articles

Abstract 16755: Changes in Mid-Regional Pro-Adrenomedullin During Treatment With Sacubitril/Valsartan

Background: Adrenomedullin is a vasodilatory peptide with a role in microcirculatory and endothelial homeostasis. Adrenomedullin is a substrate for neprilysin and may therefore play a role in beneficial effects of sacubitril/valsartan (Sac/Val) treatment. Methods: Mid-regional pro-peptide of adrenomedullin (MR-proADM) was measured in 156 patients with heart failure with reduced ejection fraction (HFrEF) treated with Sac/Val and 264 patients with HF with preserved EF (HFpEF) randomized to treatment with Sac/Val or valsartan. Echocardiography and Kansas City Cardiomyopathy Questionnaire results were collected at baseline and after 6 and 12 months in the HFrEF cohort. Results: Median (Q1-Q3) baseline MR-proADM concentrations were 0.80 (0.59-0.99) nMol/L in HFrEF and 0.88 (0.68-1.20) nMoL/L in HFpEF. After 12 weeks of treatment with Sac/Val, MR-proADM increased by median 49% in HFrEF and 60% in HFpEF, while there were no significant changes in valsartan-treated patients (median 2%). Greater increases in MR-proADM were associated with higher Sac/Val doses. Changes in MR-proADM correlated weakly with changes in N-terminal pro-B-type natriuretic peptide, cardiac troponin T and urinary cyclic guanosine monophosphate. Increases in MR-proADM were associated with decreases in blood pressure, but not significantly associated with changes in echocardiographic parameters or health status ( Figure ). Conclusions: MR-proADM concentrations rise substantially following treatment with Sac/Val, in contrast to no change from valsartan. Change in MR-proADM from neprilysin inhibition did not correlate with improvements in cardiac structure and function or health status. More data are needed regarding the role of adrenomedullin and its related peptides in the treatment of HF.

Abstract 17394: Minimally Invasive Delivery of Synthetic Cardiac Stromal Cells Improves Heart Repair in Pigs

Introduction: Myocardial infarction (MI) is the primary manifestation of cardiovascular events. Synthetic cardiac stromal cells (synCSCs) were shown to promote cardiac repair after MI. Minimally invasive delivery of synCSCs embedded in hyaluronic acid (HA) hydrogel via intrapericardial cavity (iPC) injections in a porcine model may provide a unique dataset for cardiac regeneration therapeutics. Hypothesis: Minimally invasive delivery of synCSCs via iPC injection will improve pig cardiac function and cardiomyocyte (CM) proliferation. Methods: A pig MI model was created using coronary balloon occlusion, and Yorkshire male pigs underwent video-assisted thoracoscopic surgery for iPC injections. Cardiac function studies were conducted using MRI to measure left ventricle ejection fraction (LVEF) and the infarct area. Histology and immunohistochemistry (IHC) analyses were performed to investigate CM proliferation. Single nucleus RNA-sequencing (snRNA-sq) analysis was performed to identify key gene features and phenotype changes that may be affected by the synCSC treatment. Results: The iPC injection of synCSCs embedded in HA hydrogel improves cardiac function, enhances cardiomyocyte proliferation, and induces phenotype alteration in the pig MI model. MRI analysis depicts significantly attenuated infarct size and improved LVEF at Day 28 in the synCSC group. Histology shows reduced fibrotic percentage and improved infarct wall thickness. IHC analysis shows a significant increase in cardiomyocyte proliferation. SnRNA-seq elucidates immature cardiomyocytes with higher proliferation gene features. Conclusion: The results show significant improvements in pig cardiac function and CM proliferation. Interestingly, immature cardiomyocytes of a different phenotype emerged in the therapeutic group. These findings provide an unprecedented dataset to facilitate the clinical translation of cardiac tissue regeneration therapeutics.

Abstract 13754: Bone Marrow Mesenchymal Stem Cell Derived Extracellular Vesicles Alleviate Fibrosis by Reducing Energy Production of Cardiac Fibroblast via Glutamate Metabolism Regulation

Background: Extracellular vesicles derived from bone marrow mesenchymal stem cells (MSC-EVs) have been validated for certain therapeutic effects on cardiac diseases, however, the underlying mechanism and precise bioactive components towards myocardial fibrosis remain unknown. Aim: The current research endeavors to investigate the utilization of MSC-EVs in pressure overload induced fibrosis and unravel the mechanisms of MSC-EVs mediated fibrosis regulation. Methods and Results: Compare to the control group, mice underwent intramyocardial injection of MSC-EVs showed remarkable improvement of cardiac function, as well as cardiac fibrosis post transverse aortic constriction (TAC) surgery. Seahorse XFe Extracellular Flux Analyzer unveiled decreased ATP production in fibroblasts after MSC-EVs administration in vitro . Targeted metabolomics and KEGG pathway analysis revealed glutamate metabolism as the predominantly metabolism process that regulated by MSC-EVs in cardiac fibroblasts. Meanwhile, cell metabolism assays indicated dysregulated α-ketoglutaric level in MSC-EVs treated fibroblasts, which directly lead to an activation of AMPK. Further screening identified glutamic pyruvate transaminase (GPT2) ,which catalyzes glutamic acid to α-ketoglutaric, to be pivotally suppressed by MSC-EVs treatment. Moreover, miR-30c-5p in MSC-EVs was uncovered to inhibit GPT2 expression. In the in vivo TAC model, MSC-EVs pretreated with the miR-30c-5p oligonucleotide did not recapitulated the same results as MSC-EVs do, while MSC-EVs with miR-30c-5p overexpression exerted better therapeutic effect than MSC-EVs alone. Conclusions: MSC-EVs ameliorate cardiac fibrosis via reducing the synthesis of ATP from cardiac fibroblast, which in turn improve cardiac function in mice under pressure overload condition. This effect is mediated by miR-30c-5p in MSC-EVs through the inhibition of GPT2 expression and subsequent AMPK activation in cardiac fibroblasts.

Stem Cell-Based Therapy and Cell-Free Therapy as an Alternative Approach for Cardiac Regeneration.

The World Health Organization reports that cardiovascular diseases (CVDs) represent 32% of all global deaths. The ineffectiveness of conventional therapies in CVDs encourages the development of novel, minimally invasive therapeutic strategies for the healing and regeneration of damaged tissue. The self-renewal capacity, multilineage differentiation, lack of immunogenicity, and immunosuppressive properties of mesenchymal stem cells (MSCs) make them a promising option for CVDs. However, growing evidence suggests that myocardial regeneration occurs through paracrine factors and extracellular vesicle (EV) secretion, rather than through differentiation into cardiomyocytes. Research shows that stem cells secrete or surface-shed into their culture media various cytokines, chemokines, growth factors, anti-inflammatory factors, and EVs, which constitute an MSC-conditioned medium (MSC-CM) or the secretome. The use of MSC-CM enhances cardiac repair through resident heart cell differentiation, proliferation, scar mass reduction, a decrease in infarct wall thickness, and cardiac function improvement comparable to MSCs without their side effects. This review highlights the limitations and benefits of therapies based on stem cells and their secretome as an innovative treatment of CVDs.

Xinyang tablet ameliorates sepsis-induced myocardial dysfunction by regulating Beclin-1 to mediate macrophage autophagy and M2 polarization through LncSICRNT1 targeting E3 ubiquitin ligase TRAF6

ObjectiveXinyang Tablet (XYT) has emerged as a potential intervention to counter sepsis-induced myocardial dysfunction (SMID) by influencing macrophage autophagy and M2 polarization. This study aimed to unravel the underlying mechanism of XYT in sepsis-induced myocardial dysfunction (SIMD).MethodsA microarray analysis was employed to explore sepsis-related changes, and bioinformatics analysis was used to predict lncRNAs binding to tumor necrosis factor receptor-associated factor 6 (TRAF6). This studio utilized SIMD mouse models induced by lipopolysaccharide (LPS) injection, followed by treatments involving varied doses of XYT, digoxin (positive control), or si-LncSICRNT1. After seven days, evaluations encompassing mouse hair/mental state/diet/weight were measured, and cardiac function via echocardiography were conducted. Myocardial tissue changes were observed using hematoxylin–eosin staining. Additionally, bone marrow-derived macrophages (BMDMs) subjected to LPS for M1 polarization were treated with oe-LncSICRNT1, si-TRAF6 and their negative control, XYT, or autophagy inhibitor 3-Methyladenine (3-MA) (positive control). RT-qPCR and Western blot analyses were employed to assess LncSICRNT1, TRAF6, Beclin-1, LC3II/LC3I, and p62 levels. Immunohistochemistry and flow cytometry were used for M1/M2 polarization markers, while enzyme-linked immunosorbent assay (ELISA) gauged inflammatory factor levels. Interaction between TRAF6 and LncSICRNT1 was probed using RNA pull-down and RNA immunoprecipitation (RIP) assays.ResultsChip analysis obtained 1463 differentially expressed lncRNAs, including LINC01550 (LncSICRNT1). Further prediction indicated that LncSICRNT1 was highly likely to directly bind to TRAF6. XYT treatment in LPS-induced SIMD mice led to notable enhancements in sleep/hair/diet/activity, increased weight/left ventricular end-diastolic diameter (LVEDd)/LV ejection fraction (LVEF)/LV fraction shortening (LVFS). These improvements were associated with elevated LncSICRNT1 expression and decreased TRAF6 protein levels, culminating in reduced myocardial inflammatory responses and improved cardiac function. Notably, XYT was found to suppress macrophage M1 polarization, while enhancing M2 polarization, ultimately benefitting cardiac function via LncSICRNT1 modulation. Furthermore, the study revealed LncSICRNT1 modulated Beclin-1 ubiquitination and restrained macrophage autophagy by targeting TRAF6 expression.ConclusionThe study highlights XYT’s potential to ameliorate LPS-induced SIMD by elevating LncSICRNT1 expression, influencing TRAF6 expression, and regulating Beclin-1 ubiquitination. These actions collectively inhibit macrophage autophagy and foster M1/M2 polarization, contributing to cardiac function improvement.

Benefit of Catheter Ablation for Atrial Fibrillation in Heart Failure Patients with Different Etiologies.

(1) Background: A plethora of studies have elucidated the safety and efficacy of catheter ablation (CA) for patients afflicted with atrial fibrillation (AF) and concomitant reduction in left ventricular ejection fraction (LVEF). Nevertheless, the literature on the benefits of CA in the specific etiological context of heart failure (HF) remains limited. This study delineates a comparative assessment of outcomes for patients with AF and reduced LVEF across the primary etiologies. (2) Methods: Our inquiry encompassed 216 patients diagnosed with congestive heart failure and an LVEF of less than 50 percent who were referred to our institution for circumferential pulmonary vein isolation (CPVI) between the years 2016 and 2020. The selection criteria included a detailed medical history while excluding those suffering from valvular disease, congenital heart disease, and hypertrophic cardiomyopathy. In an effort to scrutinize varying etiologies, patients were stratified into three categories: dilated cardiomyopathy (DCM, n = 56, 30.6%), ischemic cardiomyopathy (ICM, n = 68, 37.2%), and tachycardia-induced cardiomyopathy (TIC, n = 59, 32.2%). (3) Results: Following an average (±SD) duration of 36 ± 3 months, the prevalence of sinus rhythm was 52.1% in the DCM group, 50.0% in the ICM group, and 68.14% in the TIC group (p = 0.014). This study revealed a significant disparity between the DCM and TIC groups (p = 0.021) and the ICM and TIC groups (p = 0.007), yet no significant distinction was discerned between the TIC and ICM groups (p = 0.769). Importantly, there were no significant variations in the application of antiarrhythmic drugs or recurrence of procedures among the three groups. The mortality rates were 14.29% for the DCM group and 14.71% for the ICM group, which were higher than the 3.39% observed in the TIC group (DCM vs. TIC p = 0.035 (HR = 4.50 (95%CI 1.38-14.67)), ICM vs. TIC p = 0.021 (HR = 5.00 (95%CI 1.61-15.50))). A noteworthy enhancement in heart function was evidenced in the TIC group in comparison to the DCM and ICM groups, including a higher LVEF (p < 0.001), diminution of LV end-diastolic diameter (p < 0.001), and an enhanced New York Heart Association classification (p = 0.005). Hospitalization rates for heart failure were discernibly lower in TIC patients (0.98 (0,2) times) relative to those with DCM (1.74 (0,3) times, p < 0.01) and TIC (1.78 (0,4) times, p < 0.001). Patients with paroxysmal atrial fibrillation and brief episodes were found to achieve superior clinical outcomes through a catheter ablation strategy. (4) Conclusion: Patients diagnosed with TIC demonstrated a more pronounced benefit from catheter ablation compared to those with DCM and ICM. This encompassed an augmented improvement in cardiac function, an enhanced maintenance of sinus rhythm, and a reduced mortality rate.

Exploring the efficacy of Shexiang Tongxin extract pills in severe heart failure

The clinical efficacy of Shexiang Tongxin pills (STP) on cardiac function, inflammation, and prognosis was investigated in patients with severe heart failure. A total of 140 patients with severe heart failure, diagnosed and treated at the Shaoxing Central Hospital and its affiliates, were divided into control and experimental groups. Patients in the control group received conventional treatment, while those in the experimental group were given STP plus conventional treatment. The cardiac functions, levels of inflammatory factors, and outcomes of 6-minute walk distance (6MWD) were assessed and compared after 12 weeks of intervention. Besides, the rehospitalization and mortality proportions were also determined during a 1-year follow-up. In addition, oxygen-glucose deprivation and reperfusion (OGD/R) were conducted to mimic the injury of H9c2 cells in heart failure; cell survival, cytotoxicity, apoptosis, and inflammatory factors were also evaluated. Post-intervention, patients in the experiment group demonstrated greater improvement in cardiac functions, especially regarding left ventricular end-diastolic diameter and N-terminal pro-B-type natriuretic peptide, which were significantly decreased, while left ventricular ejection fraction was significantly increased (P &lt; 0.05). Further, the levels of inflammatory factors, including tumor necrosis factor-α, hypersensitive C-reactive-protein, and interleukin 6, were significantly lower (P &lt; 0.05), and a superior 6MWD outcome was observed in patients from the experimental group, compared to the control group (P &lt; 0.05). After 1-year follow-up, both rehospitalization rate and mortality were significantly decreased in the experimental group, compared to the control group (rehospitalization, 38.57% vs. 55.71%, and mortality, 12.86% vs. 27.14%, respectively; P &lt; 0.05). Furthermore, STP increased cell survival and reduced cell apoptosis, cytotoxicity, and inflammatory response in cardiomyocytes induced by OGD/R. Shexiang Tongxin pill demonstrated significant and promising clinical effects in treating severe heart failure by ameliorating cardiac functions, reducing inflammatory factor levels, and improving patients’ prognosis. In addition, STP ameliorated cellular damage and inflammation at cellular level. Thus, STP demonstrated important clinical values.

Preoperative sST2 levels relate to myocardial remodeling and cardiac function improvement after cardiac valve surgery.

We aim to investigate the correlation between preoperative soluble suppression of tumourigenicity 2 (sST2) and postoperative myocardial remodelling and cardiac function in patients with valvular heart disease. This retrospective study included patients who underwent heart valve surgery at the General Hospital of Northern Theatre Command from July 2019 to June 2020. Preoperative, early postoperative, and 1-month postoperative cardiac ultrasound data were collected. Multivariable linear regression was used to analyse the factors associated with preoperative sST2 and postoperative cardiac function parameters. A receiver operator characteristic curve analysis was used to analyse the predictive value of sST2 for left ventricular ejection fraction (LVEF) reduction at 1month after surgery. This study included 156 patients. Left ventricular end-systolic volume (b=0.125, P=0.004), atrial fibrillation (b=7.933, P=0.003), and coronary artery disease (b=5.826, P=0.043) were correlated with the preoperative sST2 levels. Preoperative sST2 was independently associated with early postoperative left ventricular end-systolic volume (b=-0.136, P=0.035), left ventricular end-diastolic volume (b=-0.225, P=0.036), and LVEF (b=0.056, P=0.008). At 1month after surgery, LVEF (r=-0.234, P=0.023) and reduction in LVEF (r=-0.316, P=0.002) were negatively correlated with preoperative sST2. The area under the receiver operator characteristic curve of preoperative sST2 in predicting LVEF reduction at 1month was 0.646, with a sensitivity of 0.357 and a specificity of 0.918. Preoperative sST2 levels are related to early postoperative myocardial remodelling and have a predictive value for the improvement of cardiac function 1month after surgery.

FRI245 Non-classic CAH Presenting As Bilateral Adrenal Incidentalomas

Abstract Disclosure: Y.A. Chin: None. T. Puar: None. T. King: None. Introduction: Congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency is an autosomal recessive disorder. Non-classic CAH usually presents in late childhood or asymptomatic may remain undiagnosed. Adrenal incidentalomas have been reported as a presentation of CAH. Clinical Case: A 56-year-old man presented with a 4-day history of epigastric pain associated with chest discomfort and diaphoresis. There was no postural giddiness, vomiting, paroxysm or constitutional symptoms. He was a smoker, his parents were non-consanguineous and he had fathered 2 children. He was tachycardic at 114 bpm, but normotensive (129/89 mmHg) with no postural hypotension and no abnormal pigmentation. He had evidence of heart failure with bibasal crepitations and pedal oedema. Secondary sexual characteristics were normal and testicular volume was 15 mls bilaterally with no palpable mass. CT abdomen showed grossly enlarged bilateral adrenal glands with heterogenous nodular appearance with several focal hypodense cystic components, with absolute washout &amp;lt;60%. Biochemistry was consistent with primary adrenal insufficiency (PAI); 8am serum cortisol 188 nmol/L, with peak cortisol post 250mcg synacthen of 195 nmol/L. Serum ACTH was elevated at 254.6 ng/L, aldosterone and renin were normal and 24hr urinary normetanephrine was mildly elevated at 1982 nmol/d (NR 600-1900 nmol/d). Echocardiography revealed severe global hypokinesia (EF 20%) but myocardial perfusion imaging was negative for ischemia. In view of suspicion for tuberculosis, malignancy or infiltrative disease, CT guided adrenal biopsy was performed. Histology showed hyperplastic adrenal cortex with lipofuscin pigments, focal lymphohistiocytic infiltrates. No lymphoplasmacytic infiltrate with IgG 4 plasma cells, granuloma, malignant cells or amyloid deposits were seen. Serum 17-OHP level later came back elevated at 39.7 nmol/L (NR 1.8-10.4 nmol/L). DNA sequencing of CYP21 revealed compound heterozygous mutations in c.292+1G&amp;gt;A and c.518T&amp;gt;A, both of which have been reported to be causative of CAH. He was transitioned from stress dose to physiological glucocorticoid replacement and ACTH normalised on subsequent outpatient visits. Follow up imaging after 6 months and 2 1/2 years revealed no change in size or morphology of the adrenal glands. Follow up echocardiography showed no improvement in ejection fraction despite intensive heart failure treatment. Conclusion: Nodular adrenal hyperplasia is well described among CAH individuals, especially in those with inadequate glucocorticoid replacement and chronically elevated ACTH levels. There was no change in size of the adrenal lesions despite adequate glucocorticoid replacement. Improvement of cardiac function with glucocorticoid replacement has been reported in paediatric patients with CAH, but our case did not show any improvement on serial echocardiography. Presentation: Friday, June 16, 2023

Acute Coronary Syndrome Induced by Carbon Monoxide Intoxication: A Case Report

Carbon monoxide (CO) intoxication is the most frequent etiology of toxicological morbidity and mortality in the world. If the neurological manifestations are in the foreground, then cardiovascular signs of myocardial damage by necrosis are possible, which can result in angina, an acute coronary syndrome followed by myocardial stupor, collapse or even cardiac arrest.&#x0D; We report a case of CO intoxication inducing an acute coronary syndrome without ST elevation in an elderly diabetic patient with no coronary artery disease history.&#x0D; Diagnosis: This patient presented a CO intoxication after an accidental exposure; the electrocardiogram showed a depressed ST segment of the inferior and apico-lateral leads; cardiac enzyme troponins gradually increased. Echocardiography showed a preserved systolic function with a disorder of the heart wall motions. Coronary angiography revealed significant lesions of the proximal left anterior descending artery (LAD) and the first marginal evoking a diagnosis of acute coronary syndrome induced by CO intoxication.&#x0D; Interventions: His management consisted of the administration of hyperbaric oxygen therapy, a platelet aggregation inhibitor (aspirin plus clopidogrel), an anticoagulant (low molecular weight heparin) and myocardial support (Bisoprolol). Coronary angiography and the placement of two active stents were performed after 24hrs onset diagnosis.&#x0D; Results: The patient had a good clinical outcome under hyperbaric oxygen therapy, complete revascularization of the angiographic lesions which showed improvement in cardiac function and a slight improvement of heart wall motion on echocardiography performed on the 5th day. After 6 days, the patient had recovered well and was discharged from the hospital without chest discomfort, dizziness or headache.&#x0D; Lecture: This case suggests that the symptoms of carbon monoxide intoxication are complex and diverse. This can manifest as a primary hypoxic symptom or cause an exacerbation of underlying diseases due to hypoxia. Therefore, patients with carbon monoxide intoxication should actively seek a comprehensive cardiac examination to ensure early diagnosis. Whenever necessary, coronary angiography and stent implantation should be performed to improve the patient's chances of survival.

MiR-182/183-Rasa1 axis induced macrophage polarization and redox regulation promotes repair after ischemic cardiac injury

Few therapies have produced significant improvement in cardiac structure and function after ischemic cardiac injury (ICI). Our possible explanation is activation of local inflammatory responses negatively impact the cardiac repair process following ischemic injury. Factors that can alter immune response, including significantly altered cytokine levels in plasma and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI is a valid strategy for reducing infarct size and damage after myocardial injury.Our previous studies showed that cortical bone stem cells (CBSCs) possess reparative effects after ICI. In our current study, we have identified that the beneficial effects of CBSCs appear to be mediated by miRNA in their extracellular vesicles (CBSC-EV). Our studies showed that CBSC-EV treated animals demonstrated reduced scar size, attenuated structural remodeling, and improved cardiac function versus saline treated animals. These effects were linked to the alteration of immune response, with significantly altered cytokine levels in plasma, and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI. Our detailed in vitro studies demonstrated that CBSC-EV are enriched in miR-182/183 that mediates the pro-reparative polarization and metabolic reprogramming in macrophages, including enhanced OXPHOS rate and reduced ROS, via Ras p21 protein activator 1 (RASA1) axis under Lipopolysaccharides (LPS) stimulation. In summary, CBSC-EV deliver unique molecular cargoes, such as enriched miR-182/183, that modulate the immune response after ICI by regulating macrophage polarization and metabolic reprogramming to enhance repair.

CFLIPL alleviates myocardial ischemia-reperfusion injury by regulating pyroptosis.

Alleviating myocardial ischemia-reperfusion injury (MIRI) plays a critical role in the prognosis and improvement of cardiac function following acute myocardial infarction. Pyroptosis is a newly identified form of cell death that has been implicated in the regulation of MIRI. In our study, H9c2 cells and SD rats were transfected using a recombinant adenovirus vector carrying cFLIPL , and the transfection was conducted for 3 days. Subsequently, H9c2 cells were subjected to 4 h of hypoxia followed by 12 h of reoxygenation to simulate an in vitro ischemia-reperfusion model. SD rats underwent 30 min of ischemia followed by 2 h of reperfusion to establish an MIRI model. Our findings revealed a notable decrease in cFLIPL expression in response to ischemia/reperfusion (I/R) and hypoxia/reoxygenation (H/R) injuries. Overexpression of cFLIPL can inhibit pyroptosis, reducing myocardial infarction area in vivo, and enhancing H9c2 cell viability in vitro. I/R and H/R injuries induced the upregulation of ASC, cleaved Caspase 1, NLRP3, GSDMD-N, IL-1β, and IL-18 proteins, promoting cell apoptosis. Our research indicates that cFLIPL may suppress pyroptosis by strategically binding with Caspase 1, inhibiting the release of inflammatory cytokines and preventing cell membrane rupture. Therefore, cFLIPL could potentially serve as a promising target for alleviating MIRI by suppressing the pyroptotic pathway.

Stem cell antigen-1+cell-derived fibroblasts are crucial for cardiac fibrosis during heart failure.

Mesenchymal stem cells (MSCs) present in the heart cannot differentiate into cardiomyocytes, but may play a role in pathological conditions. Therefore, the aim of this study was to scrutinise the role and mechanism of MSC differentiation in vivo during heart failure. We performed single-cell RNA sequencing of total non-cardiomyocytes from murine and adult human hearts. By analysing the transcriptomes of single cells, we illustrated the dynamics of the cell landscape during the progression of heart hypertrophy, including those of stem cell antigen-1 (Sca1)+ stem/progenitor cells and fibroblasts. By combining genetic lineage tracing and bone marrow transplantation models, we demonstrated that non-bone marrow-derived Sca1+ cells give rise to fibroblasts. Interestingly, partial depletion of Sca1+ cells alleviated the severity of myocardial fibrosis and led to a significant improvement in cardiac function in Sca1-CreERT2;Rosa26-eGFP-DTA mice. Similar non-cardiomyocyte cell composition and heterogeneity were observed in human patients with heart failure. Mechanistically, our study revealed that Sca1+ cells can transform into fibroblasts and affect the severity of fibrosis through the Wnt4-Pdgfra pathway. Our study describes the cellular landscape of hypertrophic hearts and reveals that fibroblasts derived from Sca1+ cells with a non-bone marrow source largely account for cardiac fibrosis. These findings provide novel insights into the pathogenesis of cardiac fibrosis and have potential therapeutic implications for heart failure. Non-bone marrow-derived Sca1+ cells differentiate into fibroblasts involved in cardiac fibrosis via Wnt4-PDGFRα pathway.

Safety confirmation of induced pluripotent stem cell-derived cardiomyocyte patch transplantation for ischemic cardiomyopathy: first three case reports.

With the expected increase in patients with heart failure and ischemic 15 cardiomyopathy, the development of myocardial regenerative medicine using cell transplantation as a novel treatment method is progressing. This first-in-human clinical trial aimed to confirm the safety of cardiomyocyte patch transplantation derived from allogeneic induced pluripotent stem (iPS) cells based on the results of several preclinical studies. The inclusion criteria were left ventricular ejection fraction of 35% or less; heart failure symptoms of New York Heart Association class III or higher despite existing therapies such as revascularization; and a 1-year observation period that included a 3-month immunosuppressive drug administration period after transplantation of iPS cell-derived cardiomyocyte patches to evaluate adverse events, cardiac function, myocardial blood flow, heart failure symptoms, and immune response. In the first three cases of this trial, no transplanted cell-related adverse events were observed during the 1-year observation period, and improvement in heart failure symptoms was observed. In addition, improvements in left ventricular contractility and myocardial blood flow were observed in two of the three patients. Regarding immune response, an increase in transplant cell-specific antibody titer was observed in all three patients after immunosuppressive drug administration. In one patient with poor improvement in cardiac function and myocardial blood flow, an increase in antibody titer against HLA-DQ was observed even before cell transplantation. Our case findings demonstrate that the transplantation of iPS cell-derived cardiomyocyte patches for ischemic cardiomyopathy can be safely performed; however, further investigation of the therapeutic effect and its relationship with an immune response is needed by accumulating the number of patients through continued clinical trials.

Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway

High-intensity interval training (HIIT) has been found to be more effective in relieving heart failure (HF) symptoms, than moderate-intensity continuous aerobic training (MICT). Additionally, higher meteorin-like protein (Metrnl) levels are seen after HIIT versus MICT. We investigated whether Metrnl contributed to post-HF cardiac functional improvements, and the signaling pathways involved. 50 HF patients underwent MICT, and another 50, HIIT, which was followed by cardiac function and serum Metrnl measurements. Metrnl was also measured in both blood and skeletal muscle samples of mice with transverse aortic constriction-induced HF after undergoing HIIT. Afterward, shRNA-containing adenovectors were injected into mice, yielding five groups: control, HF, HF + HIIT + scrambled shRNA, HF + HIIT + shMetrnl, and HF + Metrnl (HF + exogenous Metrnl). Mass spectrometry identified specific signaling pathways associated with increased Metrnl, which was confirmed with biochemical analyses. Glucose metabolism and mitochondrial functioning were evaluated in cardiomyocytes from the five groups. Both HF patients and mice had higher circulating Metrnl levels post-HIIT. Metrnl activated AMPK in cardiomyocytes, subsequently increasing histone deacetylase 4 (HDAC4) phosphorylation, leading to its cytosolic sequestration and inactivation via binding with chaperone protein 14-3-3. HDAC4 inactivation removed its repression on glucose transporter type 4, which, along with increased mitochondrial complex I-V expression, yielded improved aerobic glucose respiration and alleviation of mitochondrial dysfunction. All these changes ultimately result in improved post-HF cardiac functioning. HIIT increased skeletal muscle Metrnl production, which then operated on HF hearts to alleviate their functional defects, via increasing aerobic glucose metabolism through AMPK-HDAC4 signaling.

Effective myocardial infarction treatment by targeted accumulation of Sulforaphane using porous magnetic silica nanoparticles

Myocardial infarction (MI) is a common cardiovascular pathology that induces extensive sterile inflammation during its early stages, posing a severe threat to human health. Effectively modulating cardiac inflammation may improve post-MI outcomes. Unfortunately, owing to the side effects of therapeutic drugs and cardiac coronary artery occlusion, current MI drugs are sub-optimal for the clinical management of ischemic myocardia. Sulforaphane (SFN) has been adopted for MI treatment due to its myocardial protective effects and low toxicity. However, the targeted accumulation of SFN in infarcted areas remains challenging. Herein, porous magnetic silica nanoparticles (PMSNs) were synthesized and loaded with SFN to improve the specificity of targeted SFN delivery to infarcted areas in mouse models of MI. PMSNs loaded with SFN (PMSNs + SFN) decreased the levels of pro-inflammatory cytokines, thus leading to the improvement of cardiac function and cell survival without adverse effects. To further explore SFN’s mechanisms of action in MI, a cellular (in vitro) model was established via oxygen and glucose deprivation (OGD). HSF1 and Nrf2 knockdown resulted in a decrease of SFN-induced HSP70 expression in OGD cells. Moreover, as a result of HSP70 knockdown, the pro-survival and anti-inflammatory effects of SFN were blocked in OGD cells. The level of pro-inflammatory cytokines decreased upon HSP70 overexpression, and cell survival rate increased under OGD conditions. In summary, the results confirm that PMSNs are capable of transporting SFN to infarcted areas in the myocardium, where the drug exerts cardioprotective effects against myocardial injury by up-regulating HSP70 through Nrf2/HSF1.

Irisin deficiency exacerbates diet-induced insulin resistance and cardiac dysfunction in type II diabetes in mice.

Irisin is involved in the regulation of a variety of physiological conditions, metabolism, and survival. We and others have demonstrated that irisin contributes critically to modulation of insulin resistance and the improvement of cardiac function. However, whether the deletion of irisin will regulate cardiac function and insulin sensitivity in type II diabetes remains unclear. We utilized the CRISPR/Cas-9 genome-editing system to delete irisin globally in mice and high-fat diet (HFD)-induced type II diabetes model. We found that irisin deficiency did not result in developmental abnormality during the adult stage, which illustrates normal cardiac function and insulin sensitivity assessed by glucose tolerance test in the absence of stress. The ultrastructural analysis of the transmission electronic microscope (TEM) indicated that deletion of irisin did not change the morphology of mitochondria in myocardium. Gene expression profiling showed that several key signaling pathways related to integrin signaling, extracellular matrix, and insulin-like growth factors signaling were coordinately downregulated by deletion of irisin. However, when mice were fed a high-fat diet and chow food for 16 wk, ablation of irisin in mice exposed to HFD resulted in much more severe insulin resistance, metabolic derangements, profound cardiac dysfunction, and hypertrophic response and remodeling as compared with wild-type control mice. Taken together, our results indicate that the loss of irisin exacerbates insulin resistance, metabolic disorders, and cardiac dysfunction in response to HFD and promotes myocardial remodeling and hypertrophic response. This evidence reveals the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.NEW & NOTEWORTHY By utilizing the CRISPR/Cas-9 genome-editing system and high-fat diet (HFD)-induced type II diabetes model, our results provide direct evidence showing that the loss of irisin exacerbates cardiac dysfunction and insulin resistance while promoting myocardial remodeling and a hypertrophic response in HFD-induced diabetes. This study provides new insight into understanding the molecular evidence and the critical role of irisin in modulating insulin resistance and cardiac function in type II diabetes.

β1 Adrenergic Receptor Autoantibodies and IgG Subclasses: Current Status and Unsolved Issues.

A wide range of anti-myocardial autoantibodies have been reported since the 1970s. Among them, autoantibodies against the β1-adrenergic receptor (β1AR-AAb) have been the most thoroughly investigated, especially in dilated cardiomyopathy (DCM). Β1AR-Aabs have agonist effects inducing desensitization of β1AR, cardiomyocyte apoptosis, and sustained calcium influx which lead to cardiac dysfunction and arrhythmias. Β1AR-Aab has been reported to be detected in approximately 40% of patients with DCM, and the presence of the antibody has been associated with worse clinical outcomes. The removal of anti-myocardial autoantibodies including β1AR-AAb by immunoadsorption is beneficial for the improvement of cardiac function for DCM patients. However, several studies have suggested that its efficacy depended on the removal of AAbs belonging to the IgG3 subclass, not total IgG. IgG subclasses differ in the structure of the Fc region, suggesting that the mechanism of action of β1AR-AAb differs depending on the IgG subclasses. Our previous clinical research demonstrated that the patients with β1AR-AAb better responded to β-blocker therapy, but the following studies found that its response also differed among IgG subclasses. Further studies are needed to elucidate the possible pathogenic role of IgG subclasses of β1AR-AAbs in DCM, and the broad spectrum of cardiovascular diseases including HF with preserved ejection fraction.

Aloe-Emodin Derivative, an Anthraquinone Compound, Attenuates Pyroptosis by Targeting NLRP3 Inflammasome in Diabetic Cardiomyopathy.

Diabetic cardiomyopathy (DCM) is widely recognized as a major contributing factor to the development of heart failure in patients with diabetes. Previous studies have demonstrated the potential benefits of traditional herbal medicine for alleviating the symptoms of cardiomyopathy. We have chemically designed and synthesized a novel compound called aloe-emodin derivative (AED), which belongs to the aloe-emodin (AE) family of compounds. AED was formed by covalent binding of monomethyl succinate to the anthraquinone mother nucleus of AE using chemical synthesis techniques. The purpose of this study was to investigate the effects and mechanisms of AED in treating DCM. We induced type 2 diabetes in Sprague-Dawley (SD) rats by administering a high-fat diet and streptozotocin (STZ) injections. The rats were randomly divided into six groups: control, DCM, AED low concentration (50 mg/kg/day), AED high concentration (100 mg/kg/day), AE (100 mg/kg/day), and positive control (glyburide, 2 mg/kg/day) groups. There were eight rats in each group. The rats that attained fasting blood glucose of ˃16.7 mmol/L were considered successful models. We observed significant improvements in cardiac function in the DCM rats with both AED and AE following four weeks of intragastric treatment. However, AED had a more pronounced therapeutic effect on DCM compared to AE. AED exhibited an inhibitory effect on the inflammatory response in the hearts of DCM rats and high-glucose-treated H9C2 cells by suppressing the pyroptosis pathway mediated by the nucleotide-binding oligomerization domain (NOD)-like receptor pyrin domain 3 (NLRP3) inflammasome. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis of differentially expressed genes showed a significant enrichment in the NOD-like receptor signaling pathway compared to the high-glucose group. Furthermore, overexpression of NLRP3 effectively reversed the anti-pyroptosis effects of AED in high-glucose-treated H9C2 cells. This study is the first to demonstrate that AED possesses the ability to inhibit myocardial pyroptosis in DCM. Targeting the pyroptosis pathway mediated by the NLRP3 inflammasome could provide a promising therapeutic strategy to enhance our understanding and treatment of DCM.

When infection strikes the heart: identifying and treating non-rheumatic streptococcal myocarditis in a young man with chest pain and concurrent streptococcal pharyngitis

Pharyngitis and tonsillitis are common reasons for seeking medical care. While mostly viral, Streptococcus pyogenescauses 5-20% of adult cases. Non-rheumatic streptococcal myocarditis is a distinct form of myocarditis associated with streptococcal infection and has clinical features resembling acute coronary syndrome. It mainly affects young men and can lead to significant complications, including sudden cardiac death. We present a case of a young man with non-rheumatic streptococcal myocarditis that developed three days after streptococcal pharyngitis. This is the first documented case in which a treatment approach using a combination of benzathine phenoxymethylpenicillin, perindopril, and bisoprolol, followed by extended therapy with extencillin, resulted in a rapid improvement in the patient's cardiac function and general health. The insights gained from this case offer valuable guidance for managing similar conditions in the future.