Recovery Of Cardiac Function Research Articles

CircBCL2L13 attenuates cardiomyocyte oxidative stress and apoptosis in cardiac ischemia‒reperfusion injury via miR-1246/PEG3 signaling.

Ischemia‒reperfusion (I/R) is a common complication in the clinical treatment of acute myocardial infarction (MI), in which cardiomyocytes play a pivotal role in the recovery of cardiac function after reperfusion injury. The expression of numerous circular ribonucleic acids (circRNAs) is disrupted in I/R-induced cardiac damage, but the potential role of circRNAs in I/R damage has not been fully elucidated. The purpose of the present study was to clarify the biological action and molecular mechanism of circRNA 002166 (also termed circCL2L13) in postmyocardial I/R. Oxygen-glucose deprivation/reoxygenation (OGD/R) in an in vivo model was performed to simulate I/R damage. real-time polymerase chain reaction analysis was also conducted to evaluate the relationships of the SOD1, SOD2, NRF2, HO1 and GPX4 indicators with oxidative stress injury. TUNEL immunofluorescence was used to evaluate the degree of cardiomyocyte apoptosis in the different treatment groups. The circBCL2L13 level was markedly upregulated in myocardial tissues from a mouse I/R model. Overexpression of circBCL2L13 markedly attenuated the expression of oxidative stress-related genes and apoptosis in OGD/R-induced cardiomyocytes. A mechanistic study revealed that circBCL2L13 functions as a ceRNA for miR-1246 and modulates paternally expressed gene 3 (PEG3). Eventually, circBCL2L13 was proven to regulate PEG3 by targeting miR-1246, thereby protecting against OGD/R-induced cardiomyocyte oxidative damage and apoptosis. In conclusion, our study confirmed that the circBCL2L13/miR-1246/PEG3 axis suppressed the progression of OGD/R injury in cardiomyocytes, which might lead to new therapeutic strategies for cardiac I/R injury.

Abnormal conduction-induced cardiomyopathy: a poorly explored entity.

A dyssynchronous biventricular activation, which can be determined by left bundle branch block, chronic right ventricular pacing, frequent premature ventricular complexes, or pre-excitation, can cause a global abnormal contractility, thus leading to systolic dysfunction and left ventricular remodelling in a unique nosological entities: abnormal conduction-induced cardiomyopathies. In this clinical scenario, the mainstay therapy is eliminating or improving LV dyssynchrony, removing the trigger. This usually ensures the improvement and even recovery of cardiac geometry and left ventricular function, especially in the absence of genetic background. A multidisciplinary approach, integrating advanced multimodal imaging, is essential for the systematic aetiological definition and the subsequent evaluation and aetiology-guided therapies of patients and their families. This review aims to describe mechanisms, prevalence, risk factors, and diagnostic and therapeutic approach to the various abnormal conduction-induced cardiomyopathies, starting from reasonable certainties and then analysing the grey areas requiring further studies.

Extracorporeal membrane oxygenation (ECMO) during aplasia: A bridge towards myopericarditis recovery after autologous hematopoietic stem cell transplant for systemic sclerosis and recent Coronarovirus disease (COVID-19) vaccination

Systemic sclerosis (SSc) is a rare autoimmune disease (AD), characterised by early diffuse vasculopathy, activation of the immune response and progressive skin and internal organ fibrosis. In severe progressive diffuse SSc (dSSc), autologous hematopoietic stem cell transplantation (aHSCT) improves survival, despite its own risk of complications and transplant related mortality (TRM).We present herein the case of a dSSc patient undergoing aHSCT with low dose cyclophosphamide conditioning and sudden acute myopericarditis and cardiogenic shock, four weeks after a second mRNA SARS-CoV-2 vaccine (Pfizer) injection. Four days of extracorporeal membrane oxygenation (ECMO) support during the aplasia period, allowed to observe full cardiac function recovery and progressive SSc rehabilitation with sustained disease response at 30 months follow-up. This report illustrates, for the first time to our knowledge, that ECMO can be indicated despite aplasia during aHSCT and successfully used as a bridge towards heart function recovery in highly selected and fragile AD patients. We review the factors that may contribute to endothelial and myocardial stunning and acute reversible cardiac failure in SSc and aggravate intrinsic endothelial injury during the aHSCT procedure. These classically include: cyclophosphamide drug toxicity, viral infections and autoimmune activation with disease flair per se. In the COVID-19 pandemic times, acute myocarditis due to recent viral infection or mRNA vaccine per se, must also be considered.

MiR-522-3p Attenuates Cardiac Recovery by Targeting FOXP1 to Suppress Angiogenesis.

Angiogenesis is crucial for blood supply reconstitution after myocardial infarction in patients with acute coronary syndrome (ACS). MicroRNAs are recognized as important epigenetic regulators of endothelial angiogenesis. The purpose of this study is to determine the roles of miR-522-3p in angiogenesis after myocardial infarction. The expression levels of miR-522-3p in rats' plasma and in the upper part of the ligation of the heart tissues at 28 days after myocardial infarction were significantly higher than those of the sham group. miR-522-3p mimics inhibited cell proliferations, migrations, and tube formations under hypoxic conditions in HUVECs (human umbilical vein endothelial cells), whereas miR-522-3p inhibitors did the opposite. Furthermore, studies have indicated that the inhibition of miR-522-3p by antagomir infusion promoted angiogenesis and accelerated the recovery of cardiac functions in rats with myocardial infarction.Data analysis and experimental results revealed that FOXP1 (Forkhead-box protein P1) was the target gene of miR-522-3p. Our study explored the mechanism of cardiac angiogenesis after myocardial infarction and provided a potential therapeutic approach for the treatment of ischemic heart disease in the future.

Subcutaneous anakinra in the management of refractory MIS-C in France.

Multisystemic inflammatory syndrome in children (MIS-C) is a therapeutic emergency and can lead to myocardial dysfunction (17%-75%) and heart failure (52%-53%). Intravenous immunoglobulins (IVIG) and corticosteroids (CST) have been validated for the management of this condition. Recent reports suggest that an interleukin-1(IL-1) receptor antagonist, namely anakinra, may be a valuable add-on to the 2019 novel coronavirus disease (COVID-19) treatment for refractory patients. The purpose of this study was to describe the clinico-biological characteristics of patients treated with anakinra as well as the efficacy and safety of subcutaneous anakinra therapy in this condition. The prospective multicentre study of children hospitalized for MIS-C between March 2020 and September 2022, including 23 international paediatric centres, followed for a mean duration of 3.072 ± 3.508 months. The patient data were extracted from the Juvenile Inflammatory Rheumatism (JIR) cohort. The clinico-pathological characteristics, cardiac ultrasound data, and adverse events were reported in patients receiving anakinra. Of the 470 children admitted with MIS-C, 18 French patients (50% girls) with a mean age of 10.06 ± 3.9 years were treated with subcutaneous anakinra. Anakinra was used in two situations, macrophage activation syndrome (MAS) (4 patients) and heart failure (14 patients) with a median left ventricular ejection fraction (LVEF) of 39.5% (30%-45%). The average dose of anakinra received was 2.53 ± 1.3 mg/kg/day for a median duration of 3 days. Prior to introduction, 78% (n = 14/18) of the patients had received CST and 56% (n = 10/18) had received IVIG. Only two patients received IVIG alone and six received CST alone plus anakinra. In 10% of cases, IVIG was poorly tolerated from a cardiovascular point of view and was discontinued. Transient elevations in serum transaminases were noted in four patients on anakinra without the need for treatment or dose modification. In all patients, rapid (48 h) improvement in myocardial function was observed (LVEF > 55%) with a concomitant significant decrease in myocardial enzymes (p < 0.05). All patients survived with complete recovery of cardiac function without sequelae. Subcutaneous anakinra appears to be a safe and effective treatment for the management of heart failure or MAS in MIS-C patients. The value of IVIG in these two situations remains to be reviewed.

Preserving flow, saving lives: Successful treatment of aortic valve failure in acute myocardial infarction without flow down-regulation using ECMO - a case report and mini review.

Direct percutaneous coronary intervention (PPCI) has significantly reduced cardiac mortality in patients with acute myocardial infarction (AMI), but the mortality rate remains high for those who develop cardiogenic shock (CS), reaching 40% to 50%. Veno-arterial extracorporeal membrane oxygenation (V-A ECMO) provides robust hemodynamic support and oxygen delivery for AMI patients with refractory CS, ensuring adequate organ perfusion and oxygen supply. However, there is currently no standardized optimal Mean Arterial Pressure (MAP) range during V-A ECMO support. Achieving the proper MAP is crucial for adequate myocardial perfusion, cardiac function recovery, successful weaning off of V-A ECMO, and improving long-term outcomes. In this case study, we successfully treated a 55-year-old man with AMI and refractory cardiogenic shock using V-A ECMO. By adjusting ECMO blood flow and employing hemodynamic strategies, including vasoactive drugs, we optimized the MAP, leading to improved cardiac function and successful weaning off of V-A ECMO. This presents a potential opportunity for MAP optimization under ECMO support in patients with acute myocardial infarction and cardiogenic shock.

Nicorandil-Pretreated Mesenchymal Stem Cell-Derived Exosomes Facilitate Cardiac Repair After Myocardial Infarction via Promoting Macrophage M2 Polarization by Targeting miR-125a-5p/TRAF6/IRF5 Signaling Pathway.

Exosomes derived from bone marrow mesenchymal stem cells (MSC-exo) have been considered as a promising cell-free therapeutic strategy for ischemic heart disease. Cardioprotective drug pretreatment could be an effective approach to improve the efficacy of MSC-exo. Nicorandil has long been used in clinical practice for cardioprotection. This study aimed to investigate whether the effects of exosomes derived from nicorandil pretreated MSC (MSCNIC-exo) could be enhanced in facilitating cardiac repair after acute myocardial infarction (AMI). MSCNIC-exo and MSC-exo were collected and injected into the border zone of infarcted hearts 30 minutes after coronary ligation in rats. Macrophage polarization was detected 3 days post-infarction, cardiac function as well as histological pathology were measured on the 28th day after AMI. Macrophages were separated from the bone marrow of rats for in vitro model. Exosomal miRNA sequencing was conducted to identify differentially expressed miRNAs between MSCNIC-exo and MSC-exo. MiRNA mimics and inhibitors were transfected to MSCs or macrophages to explore the specific mechanism. Compared to MSC-exo, MSCNIC-exo showed superior therapeutic effects on cardiac functional and structural recovery after AMI and markedly elevated the ratio of CD68+ CD206+/ CD68+cells in infarcted hearts 3 days post-infarction. The notable ability of MSCNIC-exo to promote macrophage M2 polarization was also confirmed in vitro. Exosomal miRNA sequencing and both in vivo and in vitro experiments identified and verified that miR-125a-5p was an effector of the roles of MSCNIC-exo in vivo and in vitro. Furthermore, we found miR-125a-5p promoted macrophage M2 polarization by inhibiting TRAF6/IRF5 signaling pathway. This study suggested that MSCNIC-exo could markedly facilitate cardiac repair post-infarction by promoting macrophage M2 polarization by upregulating miR-125a-5p targeting TRAF6/IRF5 signaling pathway, which has great potential for clinical translation.

Coenzyme Q10 mitigates macrophage mediated inflammation in heart following myocardial infarction via the NLRP3/IL1β pathway

BackgroundThe protective effect of Coenzyme Q10 (CoQ10) on the cardiovascular system has been reported, however, whether it can promote early recovery of cardiac function and alleviate cardiac remodeling after myocardial infarction (MI) remains to be elucidated. Whether CoQ10 may regulate the macrophage-mediated pro-inflammatory response after MI and its potential mechanism are worth further exploration.MethodsTo determine the baseline plasma levels of CoQ10 by LC-MS/MS, healthy controls and MI patients (n = 11 each) with age- and gender-matched were randomly enrolled. Additional MI patients were consecutively enrolled and randomized into the blank control (n = 59) or CoQ10 group (n = 61). Follow-ups were performed at 1- and 3-month to assess cardiac function after percutaneous coronary intervention (PCI). In the animal study, mice were orally administered CoQ10/vehicle daily and were subjected to left anterior descending coronary artery (LAD) ligation or sham operation. Echocardiography and serum BNP measured by ELISA were analyzed to evaluate cardiac function. Masson staining and WGA staining were performed to analyze the myocardial fibrosis and cardiomyocyte hypertrophy, respectively. Immunofluorescence staining was performed to assess the infiltration of IL1β/ROS-positive macrophages into the ischemic myocardium. Flow cytometry was employed to analyze the recruitment of myeloid immune cells to the ischemic myocardium post-MI. The expression of inflammatory indicators was assessed through RNA-seq, qPCR, and western blotting (WB).ResultsCompared to controls, MI patients showed a plasma deficiency of CoQ10 (0.76 ± 0.31 vs. 0.46 ± 0.10 µg/ml). CoQ10 supplementation significantly promoted the recovery of cardiac function in MI patients at 1 and 3 months after PCI. In mice study, compared to vehicle-treated MI mice, CoQ10-treated MI mice showed a favorable trend in survival rate (42.85% vs. 61.90%), as well as significantly alleviated cardiac dysfunction, myocardial fibrosis, and cardiac hypertrophy. Notably, CoQ10 administration significantly suppressed the recruitment of pro-inflammatory CCR2+ macrophages into infarct myocardium and their mediated inflammatory response, partially by attenuating the activation of the NLR family pyrin domain containing 3 (NLRP3)/Interleukin-1 beta (IL1β) signaling pathway.ConclusionsThese findings suggest that CoQ10 can significantly promote early recovery of cardiac function after MI. CoQ10 may function by inhibiting the recruitment of CCR2+ macrophages and suppressing the activation of the NLRP3/IL1β pathway in macrophages.Trial registrationDate of registration 09/04/2021 (number: ChiCTR2100045256).

IL-13 promotes functional recovery after myocardial infarction via direct signaling to macrophages.

There is great interest in identifying signaling pathways that promote cardiac repair after myocardial infarction (MI). Prior studies suggest a beneficial role for IL-13 signaling in neonatal heart regeneration; however, the cell types mediating cardiac regeneration and the extent of IL-13 signaling in the adult heart after injury are unknown. We identified an abundant source of IL-13 and the related cytokine, IL-4, in neonatal cardiac type 2 innate lymphoid cells, but this phenomenon declined precipitously in adult hearts. Moreover, IL-13 receptor deletion in macrophages impaired cardiac function and resulted in larger scars early after neonatal MI. By using a combination of recombinant IL-13 administration and cell-specific IL-13 receptor genetic deletion models, we found that IL-13 signaling specifically to macrophages mediated cardiac functional recovery after MI in adult mice. Single transcriptomics revealed a subpopulation of cardiac macrophages in response to IL-13 administration. These IL-13-induced macrophages were highly efferocytotic and were identified by high IL-1R2 expression. Collectively, we elucidated a strongly proreparative role for IL-13 signaling directly to macrophages following cardiac injury. While this pathway is active in proregenerative neonatal stages, reactivation of macrophage IL-13 signaling is required to promote cardiac functional recovery in adults.

Effect of cardiac rehabilitation care after coronary intervention on cardiac function recovery and negative mood in patients with myocardial infarction.

Cardiovascular disease, particularly myocardial infarction (MI) profound impact on patients' quality of life and places a substantial burden on the healthcare and economy systems. Developments in medical technology have led to the emergence of coronary intervention as an essential method for treating MI. To assess the effects of cardiac rehabilitation care on cardiac function recovery and negative emotions in MI after coronary intervention. This study included a total of 180 patients with MI during the period from June 2022 to July 2023. Selected patients were divided into two groups: An observation group, which receiving cardiac rehabilitation care; a control group, which receiving conventional care. By comparing multiple observation indicators such as cardiac function indicators, blood pressure, exercise tolerance, occurrence of adverse cardiac events, and negative emotion scores between the two groups of patients. All the data were analyzed and compared between two groups. There were 44 males and 46 females in the observation group with an average age of 36.26 ± 9.88 yr; there were 43 males and 47 females in the control group, with an average age of 40.87 ± 10.5 yr. After receiving the appropriate postoperative nursing measures, the results of the observation group showed significant improvement in several indicators compared with the control group. Indicators of cardiac function, such as left ventricular end-diastolic internal diameter and left ventricular ejection fraction were significantly better in the observation group than in the control group (P < 0.05). Exercise endurance assessment showed that the 6-minute walking test distance was significantly increased in the patients of the observation group (P < 0.01). In addition, the incidence of adverse cardiac events was significantly lower in the observation group, and negative mood scores were significantly reduced (P < 0.05). Cardiac rehabilitation care after coronary intervention has a significant positive impact on functional recovery. This emphasizes the importance of cardiac rehabilitation care to improve patient recovery.

Translating thyroid hormone into clinical practice: lessons learned from the post-hoc analysis on data available from the ThyRepair study.

Thyroid hormone (TH) appears to have a reparative action on the postinfarcted myocardium. This novel action was recently tested in a pilot, randomized, double-blind, placebo-controlled trial (ThyRepair). The present study performed a post-hoc analysis of data from the ThyRepair study to provide further insights into the novel actions of TH on the human postischemic myocardium. Data from 41 patients participating in the ThyRepair study (n = 20 placebo and n = 21 LT3) were included in the analysis. LT3 treatment started after stenting and continued intravenously for 48h. All patients had cardiac magnetic resonance (CMR) at hospital discharge; left ventricular (LV) ejection fraction (LVEF%), LV end-diastolic volume index (LVEDVi; mL/m2), LV end-systolic volume index (LVESVi; mL/m2), infarct volume (IV), left ventricular mass index (LVMi) as edema index, and microvascular obstruction (MVO) were assessed. Patients were divided into two groups based on the median value of the IV: patients with IV ≤ 20% of the LV (group A) and patients with IV > 20% (group B). CMR measurements at discharge are expressed as mean ± SD. In group A, the placebo and T3-treated groups had similar LVEF% (56.8 ± 10.2 vs. 52.2 ± 10.5), LVEDVi (90.9 ± 19.8 vs. 92.8 ± 14.5), and LVESVi (40.8 ± 18.2 vs. 44.9 ± 14.1) at discharge. In group B, LVEDVi and LVESVi were 112 ± 23.8 and 68.3 ± 21.5 for placebo vs. 91.8 ± 18.6 and 49.0 ± 14.0 for the T3-treated group, respectively, p < 0.05. LVEF% was significantly increased in the T3-treated group vs. placebo, 47.3 ± 6.5 vs. 39.9 ± 8.7, p < 0.05. In group B, CMR LVMi was lower in T3-treated patients vs. placebo but did not reach statistical significance (p = 0.1). MVO was 1.95 ± 2.2 in placebo vs. 0.84 ± 0.9 in the LT3-treated group, p = 0.15. The present study suggests that acute LT3 treatment may exert more favorable effects on the recovery of cardiac function in patients with large infarct size. Furthermore, it signals a potential effect of LT3 on myocardial edema and microvascular obstruction. These novel findings merit further investigation in large trials.

Magnesium Ion-Doped Mesoporous Bioactive Glasses Loaded with Gallic Acid Against Myocardial Ischemia/Reperfusion Injury by Affecting the Biological Functions of Multiple Cells.

Excessive generation of reactive oxygen species (ROS) following myocardial ischemia-reperfusion (I/R) can result in additional death of myocardial cells. The rapid clearance of ROS after reperfusion injury and intervention during subsequent cardiac repair stages are crucial for the ultimate recovery of cardiac function. Magnesium-doped mesoporous bioactive glasses were prepared and loaded with the antioxidant drug gallic acid into MgNPs by sol-gel method. The antioxidant effects of MgNPs/GA were tested for their pro-angiogenic and anti-inflammatory effects based on the release characteristics of GA and Mg2+ from MgNPs/GA. Later, we confirmed in our in vivo tests through immunofluorescence staining of tissue sections at various time points that MgNPs/GA exhibited initial antioxidant effects and had both pro-angiogenic and anti-inflammatory effects during the cardiac repair phase. Finally, we evaluated the cardiac function in mice treated with MgNPs/GA. We provide evidence that GA released by MgNPs/GA can effectively eliminate ROS in the early stage, decreasing myocardial cell apoptosis. During the subsequent cardiac repair phase, the gradual release of Mg2+ from MgNPs/GA stimulated angiogenesis and promoted M2 macrophage polarization, thereby reducing the release of inflammatory factors. MgNPs/GA acting on multiple cell types is an integrated solution for comprehensive attenuation of myocardial ischaemia-reperfusion injury and cardiac function protection.

Combined ROS Sensitive PEG-PPS-PEG with Peptide Agonist for Effective Target Therapy in Mouse Model.

Growth hormone-releasing hormone (GHRH) agonist, a 29-amino acid peptide, shows significant potential in treating myocardial infarction (MI) by aiding the repair of injured heart tissue. The challenge lies in the effective on-site delivery of GHRH agonist. This study explores the use of a targetable delivery system employing ROS-responsive PEG-PPS-PEG polymers to encapsulate and deliver GHRH agonist MR409 for enhanced therapeutic efficacy. We synthesized a self-assembling poly (ethylene glycol)-poly (propylene sulfide)-poly (ethylene glycol) polymer (PEG-PPS-PEG) amphiphilic polymer responsive to reactive oxygen species (ROS). The hydrophilic peptide GHRH agonist MR409 was encapsulated within these polymers to form nano PEG-PPS-PEG@MR409 vesicles (NPs). Cardiomyocyte apoptosis was induced under hypoxia and serum-free culture condition for 24 hours, and their production of ROS was detected by fluorescence dye staining. The cellular uptake of PEG-PPS-PEG@MR409 NPs was observed using fluorescence-labeled MR409. Targeting ability and therapeutic efficacy were evaluated using a mouse MI model. PEG-PPS-PEG@MR409 NPs were efficiently internalized by cardiomyocytes, reducing ROS levels and apoptosis. These NPs exhibited superior targeting to the infarcted heart compared to naked MR409 peptide. With a reduced injection frequency (once every three days), PEG-PPS-PEG@MR409 NPs significantly promoted cardiac function recovery post-MI, matching the efficacy of daily MR409 injections. ROS-responsive PEG-PPS-PEG polymers provide a novel and effective platform for the targeted delivery of GHRH agonist peptides, improving cardiac function and offering a new approach for peptide therapy in MI treatment.

Development of a thick and functional human adipose-derived stem cell tissue sheet for myocardial infarction repair in rat hearts

BackgroundHeart failure (HF) is a major cause of death worldwide. The most effective treatment for HF is heart transplantation, but its use is limited by the scarcity of donor hearts. Recently, stem cell-based therapy has emerged as a promising approach for treating myocardial infarction. Our research group has been investigating the use of human induced pluripotent stem cell-derived cardiomyocyte patches as a potential therapeutic candidate. We have successfully conducted eight cases of clinical trials and demonstrated the safety and effectiveness of this approach. However, further advancements are necessary to overcome immune rejection and enhance therapeutic efficacy. In this study, we propose a novel and efficient technique for constructing mesenchymal stem cell (MSC) tissue sheets, which can be transplanted effectively for treating myocardial infarction repair.MethodsWe applied a one-step method to construct the human adipose-derived mesenchymal stem cell (hADSC) tissue sheet on a poly(lactic-co-glycolic acid) fiber scaffold. Histology, immunofluorescence, and paracrine profile assessment were used to determine the organization and function of the hADSC tissue sheet. Echocardiography and pathological analyses of heart sections were performed to evaluate cardiac function, fibrosis area, angiogenesis, and left ventricular remodeling.ResultsIn vitro, the hADSC tissue sheet showed great organization, abundant ECM expression, and increased paracrine secretion than single cells. In vivo, the hADSC tissue sheet group demonstrated improved cardiac functional recovery, less ventricular remodeling, decreased fibrosis, and enhanced angiogenesis than the MI group.ConclusionsWe developed thick and functional hADSC tissue sheets via the one-step strategy. The hADSC tissue sheet showed excellent performance in treating myocardial infarction in the rat model.Graphical

Therapeutic efficacy of AAV-mediated restoration of PKP2 in arrhythmogenic cardiomyopathy

Arrhythmogenic cardiomyopathy is a severe cardiac disorder characterized by lethal arrhythmias and sudden cardiac death, with currently no effective treatment. Plakophilin 2 (PKP2) is the most frequently affected gene. Here we show that adeno-associated virus (AAV)-mediated delivery of PKP2 in PKP2c.2013delC/WT induced pluripotent stem cell-derived cardiomyocytes restored not only cardiac PKP2 levels but also the levels of other junctional proteins, found to be decreased in response to the mutation. PKP2 restoration improved sodium conduction, indicating rescue of the arrhythmic substrate in PKP2 mutant induced pluripotent stem cell-derived cardiomyocytes. Additionally, it enhanced contractile function and normalized contraction kinetics in PKP2 mutant engineered human myocardium. Recovery of desmosomal integrity and cardiac function was corroborated in vivo, by treating heterozygous Pkp2c.1755delA knock-in mice. Long-term treatment with AAV9–PKP2 prevented cardiac dysfunction in 12-month-old Pkp2c.1755delA/WT mice, without affecting wild-type mice. These findings encourage clinical exploration of PKP2 gene therapy for patients with PKP2 haploinsufficiency.

SerpinA3 Promotes Myocardial Infarction in Rat and Cell-based Models.

This study aimed to examine the role and molecular mechanism of the nuclear factor κB (NFκB)/serine protease inhibitor A3 (SerpinA3) interaction in myocardial ischemia-reperfusion (IR) injury. First, a rat model for myocardial ischemia-reperfusion injury was established, using 2,3,5-triphenyltetrazolium chloride to measure the size of the myocardial infarction. Pathological variations in myocardial tissue were detected using hematoxylin-eosin staining. Flow cytometry and terminal deoxynucleotidyl transferase biotin-dUTP nick end labeling (TUNEL) staining were used to measure cell death in the rat model. The SerpinA3 mRNA and protein expressions in the myocardium of IR-model rats were remarkably higher than those in the control group. Furthermore, the oxidative, inflammatory, and apoptotic activities of the myocardial tissue of SerpinA3-knockdown (KD) rats were significantly improved compared to those in the WT group. SerpinA3-KD also contributed to the recovery of cardiac function in IR-model rats. Additionally, silencing of SerpinA3 inhibited p65 phosphorylation in myocardial tissues and reduced H2O2-induced inflammation, oxidative stress, and apoptosis in myocardial cells. The expression of SerpinA3 increased in myocardial tissue after IR stimulation. Knockdown of SerpinA3 can deactivate NF-κB and reduce inflammation, oxidative stress, and apoptosis in vivo and in vitro, thereby lessening myocardial injury caused by IR. In conclusion, SerpinA3 promotes myocardial infarction in rat and cell-based models by activating NF-κB. However, the mechanism by which increased Serpina3 expression causes downstream NF-κB activation to mediate the proposed, pathological effects in myocardial IR injury remain untested and worthy of future investigations.

Predictive values of stress hyperglycaemia and glycosylated haemoglobin on admission for long-term recovery of cardiac function in patients with acute myocardial infarction after primary percutaneous coronary intervention.

We aimed to explore the predictive values of stress hyperglycaemia (SHG) and glycosylated haemoglobin (HbA1c) levels on admission for long-term recovery of cardiac function in patients with acute myocardial infarction (AMI) after primary percutaneous coronary intervention (PPCI). A total of 210 AMI patients were randomly selected. The levels of SHG and HbA1c were measured on admission, and all patients were treated with PPCI and followed up for one year. According to the recovery status of cardiac function during follow up, the patients were divided into a good recovery group and a poor recovery group. At one year after treatment, there were statistically significant differences in the levels of SHG (6.75 ± 0.69 vs 7.81 ± 0.92 mmol/l) and HbA1c (5.13 ± 0.25 vs 5.91 ± 0.39%) between the good and poor recovery groups (p < 0.05). The levels of SHG and HbA1c were associated with long-term recovery of cardiac function (p < 0.05). The receiver operating characteristic curves were plotted, and the area under the curves of SHG and HbA1c for predicting the long-term recovery of cardiac function were > 0.70. The levels of SHG and HbA1c were closely associated with longterm recovery of cardiac function after PPCI in AMI patients, displaying high predictive values.

Inflammation in endomyocardial biopsies correlates with improved cardiac recovery and correlates inversely with mortality in patients with non-ischemic heart failure with reduced ejection fraction

Abstract Background Heart failure (HF) is a major cause of morbidity, mortality and healthcare costs worldwide. Although the overall mortality is high, individual outcomes show a large variability, reflecting our incomplete comprehension of the complex pathophysiology. Effective treatment requires rapid therapy initiation addressing the specific etiology. Purpose As reliable predictors of the outcome of HF remain ambiguous, we retrospectively analyzed patients with non-ischemic HF with reduced ejection fraction (HFrEF) to identify prognostic factors of myocardial recovery and mortality. Methods We included N = 305 consecutive patients from our MyBiopsy-HF study (DRKS #00022178)) who presented with non-ischemic, non-valvular HFrEF (Left ventricular ejection fraction LVEF ≤40%) as quantified by echocardiography and received a comprehensive medical workup including endomyocardial biopsy (EMB) at the time of initial diagnosis and follow-up echocardiography at 6 months. We defined HF with improved LVEF (HFimpEF) as LVEF&amp;gt;40% and ≥10% increase from initial LVEF. Myocardial inflammation was classified according to the current recommendations by the Dallas criteria or immunohistologic criteria (≥14 leucocytes/mm² with the presence of CD3 positive T-lymphocytes ≥7 cells/mm²). Viral persistence was quantified by qPCR from the EMB tissue. We obtained patients’ mortality data from the Rhineland-Palatinate mortality register. Results The presence of myocardial inflammation in the EMB at the time of initial diagnosis was a significant predictor of increased transition to HFimpEF (83 of 143 patients, 58,0% with inflammation vs 63 of 151 patients, 41,7% without inflammation, odds ratio (OR) 1,93, confidence interval (CI) = 1,20-3,09, p-value 0,006). Viral persistence did not differ significantly between groups. Also, female patients (55 of 91 patients, 60,4%) were more likely to transition to HFimpEF compared to male patients (94 of 214 patients, 43,9%, OR 2,27, 95% CI = 1,35-3,85, p-value 0,002). Transition to HFimpEF was associated with better survival: After five years, 71 of the 78 patients with HFimpEF were alive (91,0%) as compared to 68 of the 88 patients (77,3%) with persistent HFrEF (OR 2,58, CI = 1,08-6,20, p-value 0,03). Transition of HFimpEF was the lone age-adjusted significant predictor of five-year survival. All other factors (presentation with dyspnea, angina pectoris, palpitations, history of hypertension, diabetes, or hyperlipidemia, initial LVEF, heart failure medication and immunosupressive treatment) were not found to be of significance. Conclusion Presence of myocardial inflammation and female sex are predictors of increased recovery of cardiac systolic function as measured by LVEF in patients with HFrEF. Recovery of cardiac systolic function in turn predicts five-year survival. These findings may help to stratify HF therapy and indicate that further studies are needed to foster our understanding of the phenomenon of myocardial inflammation.

Nicotinamide riboside cardioprotection is mediated through glycolysis activation

Abstract Purpose Low NAD+ levels are observed in pathologies such as ageing, diabetes, heart failure and ischemia-reperfusion (IR) injury. Nicotinamide riboside (NR) has emerged as promising therapeutic NAD+ precursor [1,2]. NR was recently reported to protect against in vivo cardiac IR injury [3], but underlying mechanisms of protection were unexplored. Here we used the isolated mouse heart allowing metabolic control to examine NR’s metabolic mechanisms of cardiac protection. Methods Isolated C57BL/6N hearts were Langendorff-perfused with 5.5 mM glucose and 0.2 mM fatty acids (FA), and subjected to 35 min global ischemia and 90 min reperfusion. NR (50 mg/L) or vehicle were administered for 25 min before ischemia, and during the first 25 min of reperfusion. Cardiac functional recovery and cell death parameters (lactate dehydrogenase (LDH) release, % infarct size) were determined. To examine NR’s effects on cardiac metabolism, hearts were perfused with 5.5 mM 13C-glucose and 0.2 mM FA and analyzed by metabolomics and fluxomics using LC-MS techniques before ischemia. The dependency of NR’s protection on glycolysis was tested in hearts perfused with glucose replaced by pyruvate and lactate ("no glycolysis" hearts). Finally, NR’s protection and effects on cardiac metabolism were also examined in "high glycolysis" hearts, by adding insulin to the perfusate. Results NR reduced infarct size, LDH release and improved cardiac functional recovery for glucose/FA perfused hearts, demonstrating NR’s cardioprotection. In these glucose/FA hearts, metabolomics analysis showed NR increased NAD+, glycolytic intermediate phosphoenolpyruvate (PEP), Krebs cycle intermediate succinate and pentose phosphate pathway (PPP) intermediates ribose-5P (R5P) and sedoheptulose-7P (S7P) (Fig. 1). Fluxomics analysis demonstrated that NR’s protection was associated with activated glycolysis, without changes in tricarboxylic acid (TCA) cycle or PPP activities. No 13C-labeling of S7P was observed (Fig. 1). NR protection was lost in the "no glycolysis" hearts. In the "high glycolysis" hearts, NR was unable to protect the heart and increase glycolysis and reduced anaerobic glycolysis and ATP with increases in AMP, indicative of NR-induced energetic stress (Fig. 2). Remarkably, in these insulin perfused hearts, NR still increased PPP intermediates, with high 13C-labeling of S7P (Fig. 2). Conclusions NR’s protection against IR injury is only present in hearts with low glycolysis, associated with activation of pre-ischemic glycolysis. When activation of glycolysis was prevented, through either examining "no glycolysis" hearts or "high glycolysis" hearts, NR protection was abolished. NR treatment increased pre-ischemic PPP intermediates in either low or high glycolysis hearts, whereby insulin was necessary to incorporate 13C-glucose into S7P. The data suggest that NR’s acute cardioprotective effects are mediated through the activation of glycolysis.NR effects in low-glycolysis heartsNR effects in high-glycolysis hearts

Circulating SerpinA3 as a novel indicator of cardiovascular dysfunction after anthracycline chemotherapy

Abstract Background Close monitoring of development of cardiovascular toxicity during anthracycline (AC) chemotherapy is crucial for early diagnosis and guidance of therapy. SerpinA3, a serine protease inhibitor, was recently described as prognostic marker for heart failure and elevated plasma levels are associated with increased mortality. The effect of AC on SERPINA3 levels in a cancer population has not been studied yet Purpose To investigate whether SERPINA3 plasma levels could serve as a marker for cancer therapy-related cardiac dysfunction and whether its levels are influenced by AC chemotherapy Methods Adult cancer patients requiring AC chemotherapy were enrolled between January 2020 and June 2022. Patients with a history of heart failure or prior cardiotoxicity were excluded. Measurement of cTnI and NT-proBNP and echocardiography (LVEF and GLS) were performed at four timepoints: before the start of AC (V1), directly after completion of chemotherapy (V2), 3 months thereafter (V3) and 1 year after V2 (V4). CTRCD was diagnosed according to the recent ESC guidelines. Results Fifty-one patients fulfilled inclusion criteria and agreed to participate in the study. Patients were on average 54 years old and the majority were female (80.4%). After anthracyclines, 38 patients developed asymptomatic CTRCD, graded as mild in 29 patients and moderate (LVEF 40-49%) in patients. SerpinA3 plasma levels at V3 were significantly higher in patients with moderate CTRCD (247.7; [196.4-428.9]) compared to patients with no CTRCD (142.7; [126.5-170.2]; p=0.004). In patients developing moderate CTRCD, a significant increase in SerpinA3 from baseline to V2 ( 209.0 [162.025-2.7]; 313.3 [212.6- 387.1, p=0.028) and remained elevated till V3 (247.7 [196.4-428.9], p=0.038). In patients with no CTRCD SerpinA3 showed an opposite trend with no significant difference at V2 compared to V1 (190.1 [165.2-230.5] vs 196.3 [170.8-297.1]; p= 0.972), but a subsequent significant decline from V2 to V3 (142.7 [126.5-170.2]; p=0.003). In patients with mild CTRCD a similar, but non-significant trend as in no CTRCD patients was seen(211.4 [167.8-302.6] vs 218.3 [171.9-277.7]; p=0.346 vs 167.5 [140.5-286.8]; p=0.122). These findings were confirmed by the absolute change in SerpinA3 from baseline to V4 which differed significantly in moderate CTRCD (+51.3; [7.1-176.4]) compared to both patients with no CTRCD (-47.5;[ -78.0- -35.4]; p=0.019) and patients with mild CTRCD (-52.0;[ -78.6- 32.8]; p=0.043). In patients with moderate CTRCD SerpinA3 values at V4 remained significantly elevated in patients without full cardiac recovery 1 year after the end of chemotherapy (4/5 patients; p=0.050). Conclusion SerpinA3 is increased after anthracycline chemotherapy in patients with moderate CTRCD. A lasting increase of serpinA3 was observed in in patients who did not show a complete recovery of cardiac function, potentially indicative of a worse cardiac prognosis.Figure 1Figure 2