Ischemic Heart Research Articles

Impact of Smokeless Oral Nicotine Products on Cardiovascular Disease: Implications for Policy, Prevention, and Treatment: A Policy Statement From the American Heart Association.

Smokeless oral nicotine products are addictive, and their use has potential adverse effects on some but not all biomarkers of cardiovascular risk. The use of some types of these products, for instance, is associated with an increased mortality risk in those with ischemic heart or cerebrovascular disease. Similarly, smokeless tobacco has the potential to increase the risk of oral cancer, but the risks depend on the chemical composition of the product. The market of smokeless oral nicotine products has transformed since the last American Heart Association smokeless tobacco policy statement. Several varieties of tobacco-free oral nicotine products-including oral nicotine pouches; nontherapeutic nicotine gums, lozenges, and tablets; and nicotine gummies-have rapidly proliferated. The sales of oral nicotine pouches, in particular, have increased substantially; however, no data are available on their cardiovascular or health risks. In addition, synthetic (compared with tobacco-derived) nicotine has been used in some brands of oral nicotine products, but its cardiovascular and health effects have been inadequately studied. Robust public policy levers are identified to support ending addiction to all commercial tobacco products. Critical components and policy initiatives include clinicians emphasizing the prevention of tobacco product initiation and supporting cessation with established pharmacological and behavioral tobacco dependence treatment therapies as primary goals for achieving an end to commercial tobacco and nicotine addiction.

Multimodal Data-Driven Prognostic Model for Predicting Long-Term Prognosis in Patients With Ischemic Cardiomyopathy and Heart Failure With Preserved Ejection Fraction After Coronary Artery Bypass Grafting: A Multicenter Cohort Study.

Limited data from the literature are available to assess the efficacy of coronary artery bypass grafting in patients with ischemic cardiomyopathy and heart failure with preserved ejection fraction. Therefore, our objective was to use machine learning techniques integrating clinical features, biomarker data, and echocardiography data to enhance comprehension and risk stratification in patients diagnosed with ischemic cardiomyopathy and heart failure with preserved ejection fraction who have undergone coronary artery bypass grafting surgery. For this study, 294 patients with ischemic cardiomyopathy and heart failure with preserved ejection fraction who underwent coronary artery bypass grafting surgery were assigned to the development cohort (n=176) and the independent validation cohort (n=118). A total of 52 clinical variables were extracted for each patient. The principal clinical end point was the incidence of major adverse cardiovascular events, encompassing cardiac mortality, acute myocardial infarction, acute heart failure, and graft failure. From least absolute shrinkage and selection operator regression, 4 predictors were selected for the final prediction nomogram: diabetes, hypertension, the systemic immune-inflammation index, and NT-proBNP (N-terminal pro-B-type natriuretic peptide). The prediction nomogram achieved satisfactory prediction performance in both the development cohort (C index, 0.768 [95% CI, 0.701-0.835]) and independent validation cohort (C index, 0.633 [95% CI, 0.521-0.745]). Adequate calibration was noted for the likelihood of major adverse cardiovascular events in both the development and independent validation cohorts. Decision curve analysis confirmed the clinical usefulness of the established prediction nomogram. A clinically feasible prognostic model, based on preoperative multimodal data, was developed for risk stratification of patients with ischemic heart and heart failure with preserved ejection fraction who receive coronary artery bypass grafting surgery. https://www.chictr.org.cn; Unique identifier: ChiCTR2300074439.

VDAC1-NF-κB/p65-mediated S100A16 contributes to myocardial ischemia/reperfusion injury by regulating oxidative stress and inflammatory response via Calmodulin/CaMKK2/AMPK pathway

Myocardial injury triggers intense inflammatory reactions and oxidative stress responses. S100 calcium-binding protein A16 (S100A16), a multi-functional calcium (Ca2+)-binding protein, participates in inflammatory responses and contributes to ischemia/reperfusion (I/R) injury. Nevertheless, the precise mechanism by which S100A16 operates in myocardial I/R injury remains uncertain. Cardiac I/R injury was produced by ligation/release of the left anterior descending artery, and mouse cardiac cells were subjected to hypoxia/reoxygenation (H/R) to determine the biological effects in vitro. We demonstrated that S100A16 was upregulated in the ischemic hearts and cardiac cells after I/R and H/R injury. Adenovirus-mediated S100A16 inhibition led to a considerable improvement in cardiac function with a reduced infarct size, accompanied by a reduction in cardiomyocyte apoptosis. Similar effects of S100A16 inhibition on inflammation and reactive oxygen species (ROS) production were observed in cultured cardiomyocytes. Importantly, we showed that I/R and H/R treatment upregulated the expression of voltage-dependent anion channel 1 (VDAC1), which subsequently activated NF-κB/p65 to facilitate the binding of NF-κB/p65 to the S100A16 promoter, thereby activating the transcription and expression of S100A16. Mechanically, S100A16 responded to increasing Ca2+ and interacted with calmodulin (CaM) to regulate the activation of calcium/calmodulin-dependent protein kinase 2 (CAMKK2)/AMPK pathway. In conclusion, VDAC1 sustained the NF-κB p65 pathway activation to elicit increased S100A16 expression, contributing to myocardial damage and heart failure post-I/R via the CaM/CaMKK2/AMPK pathway. This study revealed a crucial role of the VDAC1-S100A16 axis in the process of myocardial I/R injury, providing novel molecular targets for the treatment of cardiac conditions associated with I/R injury.

Hypertensive pregnancy disorder, an under-recognized women specific risk factor for heart failure?

During pregnancy, the maternal cardiovascular (CV) system undergoes major haemodynamic alterations ensuring adequate placental perfusion and a healthy pregnancy course. Hypertensive disorders of pregnancy (HDP) occur in almost 10% of gestations and preeclampsia, a more severe form, in 3-4%. Women with HDP demonstrated impaired myocardial function, biventricular chamber dysfunction and adverse biventricular remodelling. Shortly after delivery, women who experienced HDP express increased risk of classic CV risk factors such as hypertension, renal disease, abnormal lipid profile, and diabetes. Within the first two decades following a HDP, women experience increased rates of heart failure, chronic hypertension, ischaemic heart and cerebral disease. The mechanism underlying the relationship between HDP in younger women and CV disease later in life could be explained by sharing pre-pregnancy CV risk factors or due to a direct impact of HDP on the maternal CV system conferring a state of increased susceptibility to future metabolic or haemodynamic insults. Racial disparities in CV risk and social determinants of health also play an important role in their remote CV risk. Although there is general agreement that women who suffered from HDP should undertake early CV screening to allow appropriate prevention and timely treatment, a screening and intervention protocol has not been standardized due to limited available evidence. In this review, we discuss why women with hypertensive pregnancy may be disproportionately affected by heart failure with preserved ejection fraction and how cardiac remodelling during or after pregnancy may influence its development.

M6A-modified circCacna1c regulates necroptosis and ischemic myocardial injury by inhibiting Hnrnpf entry into the nucleus

BackgroundCircular RNAs (circRNAs) are differentially expressed in various cardiovascular diseases, including myocardial infarction (MI) injury. However, their functional role in necroptosis-induced loss of cardiomyocytes remains unclear. We identified a cardiac necroptosis-associated circRNA transcribed from the Cacna1c gene (circCacna1c) to investigate the involvement of circRNAs in cardiomyocyte necroptosis.MethodsTo investigate the role of circCacna1c during oxidative stress, H9c2 cells and neonatal rat cardiomyocytes were treated with hydrogen peroxide (H2O2) to induce reactive oxygen species (ROS)-induced cardiomyocyte death. The N6-methyladenosine (m6A) modification level of circCacna1c was determined by methylated RNA immunoprecipitation quantitative polymerase chain reaction (MeRIP–qPCR) analysis. Additionally, an RNA pull-down assay was performed to identify interacting proteins of circCacna1c in cardiomyocytes, and the regulatory role of circCacna1c in target protein expression was tested using a western blotting assay. Furthermore, the MI mouse model was constructed to analyze the effect of circCacna1c on heart function and cardiomyocyte necroptosis.ResultsThe expression of circCacna1c was found to be reduced in cardiomyocytes exposed to oxidative stress and in mouse hearts injured by MI. Overexpression of circCacna1c inhibited necroptosis of cardiomyocytes induced by hydrogen peroxide and MI injury, resulting in a significant reduction in myocardial infarction size and improved cardiac function. Mechanistically, circCacna1c directly interacts with heterogeneous nuclear ribonucleoprotein F (Hnrnpf) in the cytoplasm, preventing its nuclear translocation and leading to reduced Hnrnpf levels within the nucleus. This subsequently suppresses Hnrnpf-dependent receptor-interacting protein kinase 1 (RIPK1) expression. Furthermore, fat mass and obesity-associated protein (FTO) mediates demethylation of m6A modification on circCacna1c during necrosis and facilitates degradation of circCacna1c.ConclusionOur study demonstrates that circCacna1c can improve cardiac function following MI-induced heart injury by inhibiting the Hnrnpf/RIPK1-mediated cardiomyocyte necroptosis. Therefore, the FTO/circCacna1c/Hnrnpf/RIPK1 axis holds great potential as an effective target for attenuating cardiac injury caused by necroptosis in ischemic heart disease.Graphical

Abstract 4135265: When the Beat Drops: A Pilot Project for a Case-Based Resident’s Guide to Cardiovascular Care

Residents care for patients with a vast array of cardiovascular (CV) diagnoses in settings ranging from primary care clinic to the cardiac intensive care unit. However, the resources available are mainly intended for advanced cardiology trainees. We created a resident-driven, case-based reference for residents to serve as a companion to traditional CV medicine educational resources. Methods: We surveyed residents, fellows, and cardiology attendings to identify topics within CV care for which residents are responsible. We recruited residents from multiple ACGME-accredited Internal Medicine residency programs to write a chapter on each identified topic that would be published on a central website. The chapters included a topic overview with key learning points, a case presentation, review questions, attending pearls, and high-yield articles for further reading. Chapters were reviewed for accuracy and completeness by cardiology fellows, pharmacologists, and attendings. The chapters were sent out to residents weekly via email and through social media platforms. Website analytics were used to track usage and monitor engagement. Each chapter concluded with a brief survey regarding learning gains, comprehension, and if the reader would recommend the resources to others. Results: A total of 52 cases were submitted by resident contributors from four residency programs. Topics included management of arrhythmias, structural heart disease, ischemia, cardiogenic shock, and post-procedure complications. Within the first two months of publication, the website was being accessed throughout 30+ states and 6 countries with more than 2,500 views and 1,500 unique visitors. Topics with high traffic included chapters regarding arrhythmias and post-procedural complications. The website was viewed throughout the entire day with no specific time pattern; however, there were significantly more views on days when each chapter was released via email and social media. Preliminary survey results show that residents and other trainees find this resource useful, and many want to get involved and help create more content. Conclusion: Our resident-created and cardiologist reviewed website is a unique resource created for residents caring for patients with CV disease. Using email and social media marketing has allowed this resource to be widely accessible to a large global audience. Survey feedback suggests the importance of this resource and need for continued CV resources for trainees.

Abstract 4117414: Risk Factors Associated with Cardiac Hospital Admissions in Cancer Patients Treated with Immune Checkpoint Inhibitors

Background: Immune checkpoint inhibitors (ICIs) are highly effective anti-cancer treatments for several cancers. However, treatment with ICIs is associated with metabolic perturbations, accelerated atherosclerosis, and increased risks of adverse cardiovascular events. In this study, we aimed to determine risk factors associated with cardiac hospital admissions in patients treated with ICIs for their cancer. Methods: Retrospective data was collected for all patients treated with ICIs between 1 January 2010 and 1 January 2020 through the Hunter New England Local Health District (HNELHD), Australia. Patient medical history and demographics were collected through electronic medical records. Outcome data was obtained from the HNELHD Institutional Cardiac and Stroke Outcomes Unit database. Cardiac admission was defined as cardiac disease based on hospital administration ICD-10 codes. Binary logistic regression was used for multivariate analysis and performed through SPSS version 28. Results: A total of 1,080 patients were included in the final analysis. Mean age of patients was 66.9 ± 11.7 years, with the majority male sex ( n =685; 63.4%). Primary cancer diagnosis of patients treated with ICIs included melanoma ( n =417; 38.7%), and cancer of the lung ( n =327; 30.3%). Nivolumab monotherapy was the most used first-line ICI treatment ( n =475; 44.0%) followed by pembrolizumab monotherapy ( n =428; 39.6%). A total of 266 (24.6%) patients had at least one cardiac hospital admission. On univariate analysis, pre-existing cardiovascular disease (CVD) ( p <0.001), diabetes mellitus ( p <0.001), chronic kidney disease ( p <0.001), and prior CVD medications ( p <0.001) were associated with cardiac hospitalisation. On multivariate analysis, prior history of heart failure ( p <0.001), hypertension ( p =0.003), ischaemia, and peripheral vascular disease ( p =0.049) were independently associated with an increased risk of cardiac hospital admission. Conclusions: In cancer patients treated with ICIs, pre-existing CVD risk factors increases the risk of cardiac-associated hospitalisations. Adequate CVD risk modification and monitoring during treatment with ICIs may be necessary to reduce cardiac hospitalisations.

An interpretable electrocardiogram-based model for predicting arrhythmia and ischemia in cardiovascular disease

IntroductionCardiovascular disease (CVD) is a leading cause of death and disability globally, with ischemia and arrhythmias being critical contributors. Ischemia, due to reduced myocardial blood flow, can lead to sudden cardiac death, while arrhythmias, marked by abnormal heart rhythms, are common in the elderly. Electrocardiography (ECG) is essential for the diagnosis of these conditions. This study aims to develop a clinically interpretable diagnostic framework for ischemia and arrhythmias using key ECG fiducial features. MethodsTo develop a robust ECG-based model for predicting cardiovascular diseases, we integrated data from three well-established ECG datasets: MIT-BIH Arrhythmia, European ST-T, and Fantasia. This aggregated dataset was employed to train multiple machine learning (ML) models aimed at automatically classifying heart conditions, including arrhythmia, ischemia, and healthy states. We designed a predictive framework utilizing boosting ML algorithms, enhanced by explainable artificial intelligence (XAI) techniques, to ensure high predictive performance in model interpretation. ResultsThe histogram gradient boosting classifier demonstrated superior classification performance, achieving an overall accuracy of 90 % in predicting heart disease based on ECG fiducial features. The model achieved area under the curve (AUC) scores of 0.99, 0.99, and 0.89 for the healthy, ischemic, and arrhythmic classes, respectively. XAI methods revealed that ECG fiducial features, such as the P-H, R-H, RR interval, QRS duration, QT interval, and ST segment, were significant diagnostic indicators for heart disease. ConclusionsThis study uses machine learning and XAI models to classify arrhythmia and ischemia from ECG data, enhancing interpretability clinical diagnostics for prevention and intervention to reduce disabilities.

Characterization of the cardiac Osr1+ cells in normal and ischemic hearts

Characterization of the cardiac Osr1+ cells in normal and ischemic hearts

Ischemic Rescue Potential of Conditioned Medium Derived from Skeletal Muscle Cells-Seeded Electrospun Fiber-Coated Human Amniotic Membrane Scaffolds.

Revascularization procedures such as percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) are crucial to restore blood flow to the heart and are used in the treatment of myocardial infarction (MI). However, these techniques are known to cause myocardial reperfusion injury in the ischemic heart. The present study aims to mimic ischemia-reperfusion injury in vitro on primary human cardiomyocytes (HCMs) and use the established injury model to study the rescue mechanism of skeletal muscle cell (SkM)-seeded electrospun fiber-coated human amniotic membrane scaffold (EF-HAM) on injured cardiomyocytes through paracrine secretion. An in vitro ischemia-reperfusion injury model was established by exposing the HCM to 5 h of hypoxia, followed by a 6 h reoxygenation period. Six different conditioned media (CM) including three derived from SkM-seeded EF-HAMs were introduced to the injured cells to investigate the cardioprotective effect of the CM. Cell survival analysis, caspase-3 and XIAP expression profiling, mitochondrial membrane potential analysis, and measurement of reactive oxygen species (ROS) were conducted to evaluate the outcomes of the study. The results revealed a significant increase in the viability of HCM exposed to H/R injury by 77.2% (p < 0.01), 111.8% (p < 0.001), 68.7% (p < 0.05), and 69.5% (p < 0.05) when supplemented with HAM CM, EF-HAM 3 min CM, EF-HAM 5 min CM, and EF-HAM 7 min CM, respectively. Furthermore, CM derived from SkM-seeded EF-HAM scaffolds positively impacted hypoxia-/reoxygenation-induced changes in caspase-3 expression, mitochondrial membrane potential, and reactive oxygen species generation, but not in XIAP expression. These findings suggest that EF-HAM composite scaffolds can exert antiapoptotic and cardioregenerative effects on primary human cardiomyocytes through the paracrine mechanism.

Empagliflozin treatment pre- and post- acute myocardial infarction reduces no-reflow, inflammatory cell infiltration and infarct size while preserving cardiac function.

Abstract Background and aims Empagliflozin (EMPA) and other members of the family of sodium glucose co-transporter 2 inhibitors have demonstrated clinical benefit in terms of survival and rehospitalizations in heart failure. However, their effect on acute myocardial infarction (AMI) is still under investigation. Microvascular injury (MVI) and no-reflow are major determinants of myocardial infarct size (IS) and prognosis. We investigated EMPA’s cardioprotective potential in AMI in terms of no-reflow, MVI and IS emphasizing on a translational regimen with EMPA treatment after AMI. Methods In a first series of experiments, C57Bl6 male mice (n=10 per group) were randomized into 1) Sham, 2) Control-AMI and 3) EMPA-Pre-AMI (10mg/kg/day orally for 6 weeks) groups. Mice underwent 30 min ischemia (I) and 2h reperfusion (R) or sham operation. Cell sorting and 3’ mRNA sequencing were applied to identify the cell types that are transcriptionally affected by EMPA pretreatment in mice with AMI. In a second series of experiments, the protocol was repeated, and an additional group was added, EMPA-Post-AMI (n=8-11 mice per group) in which oral treatment was performed 1h after R. Assessment of no-reflow via thioflavin S staining and electron microscopy was performed at 48 h. The infiltration of inflammatory cells in the ischemic heart was examined via flow cytometry. IS and myocardial function were determined by cardiac magnetic resonance (CMR). Type-2 diabetes mellitus patients received insulin (n=18) or EMPA (n=24) within 2 months post-AMI. Endothelial glycocalyx and endothelial-related circulating markers were examined at 4 months and 12 months post-AMI. Results EMPA pretreatment reversed AMI-induced alterations in cardiac endothelial cells’ (ECs) transcriptome. As such, it promoted the expression of survival genes, reduced gene expression related to adhesion molecules and ECs matrix degradation. Conversely, EMPA pretreatment exerted minimal effects on cardiomyocyte and fibroblast transcriptome. In support of the effect of EMPA on ECs, EMPA-Pre-AMI and EMPA-Post-AMI groups significantly reduced no-reflow and MVI as indicated by electron microscopy and histology at 48h of R. Moreover, both EMPA treatment pre-AMI and post-AMI reduced the infiltration of inflammatory monocytes and neutrophils in the infarcted myocardium suggesting enhanced vascular integrity. Both EMPA-Pre-AMI and EMPA-Post-AMI reduced IS and preserved cardiac function defined by CMR. Patients receiving EMPA presented with improved endothelial glycocalyx thickness, % global longitudinal strain and preserved pulse wave velocity. Conclusions EMPA treatment either before or after AMI protects against MVI, reduces no-reflow and IS and preserves cardiac function. Our data support the use of EMPA after recanalization in patients with AMI to confer improvement of cardiovascular function.

The management of high flow arteriovenous fistula and possible solutions.

The development of a high flow rate arteriovenous fistula (AVF) can expose the patient to development of heart failure due to increased cardiac preload and pulmonary hypertension. AVF flow measurement (Qa) is considered a screening tool for AVF surveillance, aiming to evaluate the access dysfunction and prevent complications, like a non-maturation, suspected stenosis, high-flow AVF, and distal ischemia. In the upper arm AVF, a high Qa may develops, which can expose the patient to the risk of high-output heart failure and ischemia. Although, the exact threshold to define high-flow access is not universally accepted, AVF with a Qa of 1-1.5 L/min or cardio-pulmonary recirculation (Qa/CO) >20% are considered at risk. In our work we describe the treatment performed in three patients with high flow AVF treated with DRIL technique with interposition of a Prosthetic Patch, revascularization procedures such as distal inflow revision or RUDI and with innovative technique a "tench snout," removal the previous anastomosis and reconstruction of the integrity of the radial artery at the terminal in pre and post anastomosis. A PTFE prosthetic segment measuring 5 cm in length and 5 mm in diameter was interposed, terminally anastomosed with the efferent cephalic vein and terminally lateral with the radial artery, reducing the anastomosis to approximately 4 mm. All treated patients showed a clear improvement in the clinical picture in particularly heart failure. The calculation of the post-intervention flow rate approximately 1500 mL/min. The patient on hemodialysis with arteriovenous fistula must be constantly monitored with clinical examination, monitoring during the hemodialysis session and color Doppler ultrasound of the AVF with calculation of the flow rate. The surgical technique used for flow reduction is chosen on the surgical experience of each operator with the main objective of preserving the autologous AVF.

Ischemia Heart Disease: Current Diagnosis, Treatment Methods, and Genetic Research.

Ischemia heart disease is a top non-communicable disease that causes more deaths worldwide and it increases progressively over the years. It becomes a burden to low and middle-income countries. The management and treatment of ischemia heart disease become more challenging due to improper lifestyle, adverse effects of currently available drugs, limited access to various diagnostic methods, genetic variations, and lack of knowledge among healthcare professionals. In this comprehensive survey, we summarized the different kinds of diagnostic approaches and modes of therapy, current research, molecular and genetic basis, future directions like integrative therapy and precision medicine, and global health initiatives related to IHD to create awareness that will help healthcare professionals to save the life of patients and researchers to develop a new molecule to treat ischemia heart disease.

Phosphodiesterase 5 and its inhibitors with ischemic heart disease: a Mendelian randomization analysis and a real-world study.

Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits. This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data. In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers. MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A=1.22,95% CI=1.06-1.40; ORPDE8A=1.26,95% CI=1.07-1.49) and MI (ORPDE5A=1.27,95% CI=1.09-1.48; ORPDE8A=1.24,95% CI=1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR=1.17,95% CI=1.05-1.32) and MI (OR=1.15,95% CI=1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR=0.70,95% CI=0.66-0.73) and MI (adjusted HR=0.79,95% CI=0.73-0.84). This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.

Sodium-Glucose Cotransporter 2 (SGLT2) Inhibitors: Guardians against Mitochondrial Dysfunction and Endoplasmic Reticulum Stress in Heart Diseases.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors are an innovative class of antidiabetic drugs that provide cardiovascular benefits to both diabetic and nondiabetic patients, surpassing those of other antidiabetic drugs. Although the roles of mitochondria and endoplasmic reticulum (ER) in cardiovascular research are increasingly recognized as promising therapeutic targets, the exact molecular mechanisms by which SGLT2 inhibitors influence mitochondrial and ER homeostasis in the heart remain incompletely elucidated. This review comprehensively summarizes and discusses the impacts of SGLT2 inhibitors on mitochondrial dysfunction and ER stress in heart diseases including heart failure, ischemic heart disease/myocardial infarction, and arrhythmia from preclinical and clinical studies. Based on the existing evidence, the effects of SGLT2 inhibitors may potentially involve the restoration of mitochondrial biogenesis and alleviation of ER stress. Such consequences are achieved by enhancing adenosine triphosphate (ATP) production, preserving mitochondrial membrane potential, improving the activity of electron transport chain complexes, maintaining mitochondrial dynamics, mitigating oxidative stress and apoptosis, influencing cellular calcium and sodium handling, and targeting the unfolded protein response (UPR) through three signaling pathways including inositol requiring enzyme 1α (IRE1α), protein kinase R like endoplasmic reticulum kinase (PERK), and activating transcription factor 6 (ATF6). Therefore, SGLT2 inhibitors have emerged as a promising target for treating heart diseases due to their potential to improve mitochondrial functions and ER stress.

AAV9-mediated CIRP gene transfer protects against cardiac dysfunction and remodelling in a rat model of myocardial infarction.

Cold-inducible RNA-binding protein (CIRP) is a stress-response protein that has been shown to protect cardiomyocytes under a variety of stress conditions from apoptosis. Our recent study showed that the expression of CIRP protein in the heart was downregulated in patients with heart failure and an animal model of ischaemia heart failure, but its role in heart failure is still unknown. The present study aimed at evaluating the potential role of CIRP on the heart in an animal model of myocardial infarction (MI). MI model of rats was induced by the ligation of the left coronary artery. CIRP overexpression was mediated by direct intracardiac injection of adeno-associated virus serotype 9 (AAV9) vectors carrying a CIRP coding sequence with a cardiac-specific promoter before the induction of the MI model. The effects of CIRP elevation on MI-induced heart were analysed through echocardiographic, pathological and molecular analysis. Our results showed that the intracardiac injection of AAV9 successfully mediated CIRP upregulation in cardiomyocytes. Upregulation of cardiac CIRP prevented MI-induced cardiac dysfunction and adverse remodelling, coupled with the reduced inflammatory response in the heart. Collectively, these results demonstrated the beneficial role of intracellular CIRP on the heart and suggest that CIRP may be a therapeutic target in ischaemic heart disease.

Comorbidity and Disease Activity in Multiple Sclerosis

Multiple studies suggest that comorbidity worsens clinically relevant outcomes in multiple sclerosis (MS), including the severity of disability at diagnosis and rate of disability worsening after diagnosis. However, less is known regarding the association of comorbidity with measures of disease activity, such as relapse rate and magnetic resonance imaging lesion accrual, which are relevant to clinicians and clinical trialists. To evaluate the association of comorbidities with disease activity in clinical trials of disease-modifying therapies (DMTs) in populations with MS. A 2-stage meta-analytic approach was used in this cohort study of individual participant data from phase 3 clinical trials of MS DMTs that had 2 years of follow-up and were conducted from November 2001 to March 2018. Data were analyzed from February 2023 to June 2024. Comorbidity burden and individual comorbidities present at trial enrollment, including hypertension; hyperlipidemia; functional cardiovascular disease, ischemic heart, cerebrovascular, and peripheral vascular disease; diabetes; autoimmune thyroid and miscellaneous autoimmune conditions; migraine; lung and skin conditions; depression; anxiety; and other psychiatric disorders. The main outcome was evidence of disease activity (EDA) over 2 years of follow-up, defined as confirmed relapse activity, disability worsening, or any new lesions on magnetic resonance imaging. A total of 16 794 participants with MS were included from 17 clinical trials (67.2% female). Over the 2-year follow-up, 61.0% (95% CI, 56.2%-66.3%; I2 = 97.9%) of the pooled trials had EDA. After adjusting for multiple factors, the presence of 3 or more comorbidities was associated with an increased hazard of EDA (adjusted hazard ratio [AHR], 1.14; 95% CI, 1.02-1.28) compared with no comorbidity. Presence of 2 or more cardiometabolic conditions was also associated with an increased hazard of EDA (AHR, 1.21; 95% CI, 1.08-1.37) compared with no cardiometabolic comorbidity. Presence of 1 psychiatric disorder was associated with an increased hazard of EDA (AHR, 1.07; 95% CI, 1.02-1.14). In this study, a higher burden of comorbidity was associated with worse clinical outcomes in people with MS, although comorbidity could potentially be a partial mediator of other negative prognostic factors. Our findings suggest a substantial adverse association of the comorbidities investigated with MS disease activity and that prevention and management of comorbidities should be a pressing concern in clinical practice.

A composite patch loaded with 2-Deoxy Glucose facilitates cardiac recovery after myocardial infarction via attenuating local inflammatory response

Local inflammatory microenvironment in the early stage of myocardial infarction (MI) severely impaired cardiac recovery post-MI. Macrophages play a pivotal role in this process. A classical glycolytic inhibitor, 2-Deoxy-Glucose (2-DG), has been found to regulate the excessive pro-inflammatory macrophage polarization in the infarcted myocardium. This study investigated the effect of 2-DG-loaded chitosan/gelatin composite patch on the infarct microenvironment post-MI and its impact on cardiac repair. The results showed that the 2-DG patch significantly inhibited the expression of inflammatory cytokines, alleviated reactive oxygen species (ROS) accumulation, repressed the proinflammatory polarization of macrophages, attenuated local inflammatory microenvironment in the ischemic hearts, as well as improved cardiac function, reduced scar size, and promoted angiogenesis post-MI. In terms of mechanism, 2-DG exerts anti-inflammatory effects through inhibiting the NF-κB signaling pathway and reducing the assembly and activation of the NLRP3 inflammasome. These findings suggest that 2-DG composite patch may represent a promising therapeutic strategy for cardiac repair after MI.

The effect and safety of acupuncture as adjunctive therapy for STEMI patients after PCI: study protocol of a randomized controlled trial

BackgroundST-elevation myocardial infarction (STEMI) is a common acute ischemia heart disease that causes serious damage to human health worldwide. Even though morbidity and mortality have significantly decreased by percutaneous coronary intervention (PCI), an additional cardiac protection strategy is still required. Acupuncture therapy has presented a dominant cardiac protection in many studies lately. Thus, we aim to evaluate the effect and safety of acupuncture as an adjunctive therapy in STEMI patients after PCI through a randomized controlled trial.Methods/DesignThis study describes a protocol of multicenter, double-blinded, parallel-controlled, randomized controlled trial. Ninety-six patients with STEMI aged 18–85 years who undergoing PCI will be recruited from the Affiliated Hospital of Chengdu University of Traditional Chinese Medicine, The Affiliated Third Hospital of Chengdu Traditional Chinese Medicine University/Chengdu Pidu District Hospital of Traditional Chinese Medicine, and Zhaotong Municipal Hospital of Traditional Chinese Medicine. Participants will be randomly assigned (1:1 ratio) to the verum acupuncture plus basic therapy (i.e., treatment) group or the sham acupuncture plus basic therapy (i.e., control) group. These participants will be treated for 5 days and then will be followed up for 24 weeks. Any adverse events will be recorded throughout the study to evaluate safety.DiscussionThe present study aims to investigate the effect and safety of acupuncture for patients with STEMI after PCI and set up standardized treatment programs for acupuncture of these patients.Trial registrationThis study was registered in the Chinese Clinical Trial Registry (Registration ID: [ChiCTR2400081117]), on February 22, 2024.

Intramyocardial Sprouting Tip Cells Specify Coronary Arterialization.

The elaborate patterning of coronary arteries critically supports the high metabolic activity of the beating heart. How coronary endothelial cells coordinate hierarchical vascular remodeling and achieve arteriovenous specification remains largely unknown. Understanding the molecular and cellular cues that pattern coronary arteries is crucial to develop innovative therapeutic strategies that restore functional perfusion within the ischemic heart. Single-cell transcriptomics and histological validation were used to delineate heterogeneous transcriptional states of the developing and mature coronary endothelium with a focus on sprouting endothelium and arterial cell specification. Genetic lineage tracing and high-resolution 3-dimensional imaging were used to characterize the origin and mechanisms of coronary angiogenic sprouting, as well as to fate-map selective endothelial lineages. Integration of single-cell transcriptomic data from ischemic adult mouse hearts and human embryonic data served to assess the conservation of transcriptional states across development, disease, and species. We discover that coronary arteries originate from cells that have previously transitioned through a specific tip cell phenotype. We identify nonoverlapping intramyocardial and subepicardial tip cell populations with differential gene expression profiles and regulatory pathways. Esm1-lineage tracing confirmed that intramyocardial tip cells selectively contribute to coronary arteries and endocardial tunnels, but not veins. Notably, prearterial cells are detected from development stages to adulthood, increasingly in response to ischemic injury, and in human embryos, suggesting that tip cell-to-artery specification is a conserved mechanism. A tip cell-to-artery specification mechanism drives arterialization of the intramyocardial plexus and endocardial tunnels throughout life and is reactivated upon ischemic injury. Differential sprouting programs govern the formation and specification of the venous and arterial coronary plexus.