Ischemic Heart Research Articles

Активація мітохондріальних механізмів кардіопротекції при ішемії-реперфузії ізольованого серця щурів з інсулінорезистентністю

Dysregulation of mitochondrial functions can significantly disrupt energy metabolism in the myocardium. However, mitochondrial mechanisms of cardioprotection and their disruption in metabolic disorders are still insufficiently studied. The aim of the our work was to characterize mitochondrial mechanisms of cardioprotection in ischemia-reperfusion of the rat heart under conditions of insulin resistance and hypoxic preconditioning. Adult male Wistar rats were induced to insulin resistance by consuming a high-fat diet with 58% fat for 14 days. Hypoxic preconditioning was reproduced by exposure to hypobaric hypoxia (360 Torr) in a pressure chamber for 3 hours. To assess the cardioprotective effects, 30-minute ischemia and 40-minute reperfusion of the isolated heart were simulated after 24 hours with isovolumic retrograde perfusion according to the Langendorff method. The size of the myocardial infarction, oxidative stress indicators and the level of expression of the mitochondrial protein PGC-1α were determined. Mitochondria were examined using electron microscopy. In the myocardium of insulin-resistant rats, there was a quantitative increase in all mitochondrial subpopulations, activation of their intracellular connections with other organelles, and an increase in the level of PGC-1α expression in the left ventricle. At the same time, activation of free radical processes in the myocardium was observed with an increase in the content of TBA-AP and activation of antioxidant mechanisms, in particular, the glutathione system. Hypoxic preconditioning increased the level of PGC-1α expression in the right ventricle, led to the activation of energy metabolism, increased mitochondrial dynamics with the elimination of damaged organelles by mitophagy and biogenesis of new mitochondria against the background of a decrease in mitochondrial dysfunction. After ischemia-reperfusion in the myocardium of insulin-resistant rats, limitations in mitochondrial damage and manifestations of their dysfunction were observed. Preconditioning contributed to a decrease in infarct size, enhanced the mitoprotective effect in the ischemic heart. Insulin resistance contributed to the intensification of PGC-1α-dependent mitochondrial mechanisms of protection against ischemic damage in the myocardium. Hypoxic preconditioning enhanced the myoprotective effect in insulin-resistant hearts compared with intact myocardium, leading to a reduction in myocardial infarct size during isolated heart ischemia-reperfusion, but the antioxidant effect was partially lost.

Comparing myocardial perfusion scan findings in patients with and without Covid-19

BackgroundCovid-19 is a pandemic viral disease that directly or indirectly affects multiple organ systems, including the cardiovascular system. SPECT GATED MPI is a non-invasive nuclear imaging modality used to assess myocardial perfusion and function. The aim of this study was to evaluate the effect of Covid-19 pandemic on myocardial perfusion imaging in ischemic heart disease.MethodsThis was a cross-sectional (descriptive-analytical) study of 750 patients requiring myocardial perfusion imaging (MPI) who were referred to the nuclear medicine center of Kowsar Hospital, a teaching hospital in Sanandaj, the center of Kurdistan Province in north-western Iran. Data collection was performed during the Covid-19 pandemic, between 6 April 2020 and 21 March 2021. Data analysis was performed in SPSS using independent samples t-test and chi-squared.ResultsA total of 750 patients, including 328 (43.7%) Covid-19 positive and 422 (56.3%) Covid-19 negative, were included in the analysis. Although Covid-19 infected obese patients had a significantly higher rate of abnormal MPI (P < 0.0001), no significant difference in abnormal MPI was observed between the two groups (p = 0.551).ConclusionThe lack of a significant difference in the incidence of abnormal MPI between the two groups suggests that there may be Covid-19 patients with potentially abnormal MPI who have gone undetected. In addition, Covid-19 patients with pleural chest pain, myalgia or dyspnea may have been misdiagnosed as having chest pain secondary to heart disease.

Loss of PKM2 dysregulates inflammatory signaling in the infarcted murine heart.

Inflammation and a metabolic shift from oxidative metabolism to glycolysis are common in the ischemic heart, the latter partly controlled by pyruvate kinase (muscle, PKM). We previously identified alternative splicing promoting the PKM2 isoform after myocardial infarction (MI). We examined the role of PKM2 physiological upregulation after MI, modeled by ligation of the left anterior descending coronary artery, using global PKM2 knockout (PKM2-/-) mice. Echocardiography showed similar cardiac function between PKM2-/- and control mice after MI. However, PKM2-/- infarcted hearts had increased abundances of transcripts associated with oxidative stress and immune responses. Immunohistochemistry revealed greater abundance of macrophages in PKM2-/- hearts prior to MI, with a small increase in CD86+ macrophages in PKM2-/- infarcted hearts. Elevated baseline plasma IL-6, IL-1β, and C-reactive protein, and cardiac IL-6, 3 days post-MI, were observed in PKM2-/- mice. Oxidative lipid products were also elevated in baseline PKM2-/- hearts, while antioxidant glutathione peroxidase 4 was reduced. Greater fibrosis was seen in PKM2-/- hearts 28 days after MI. These findings suggest Pkm2 ablation primes the heart for increased oxidative stress, inflammation, and fibrosis post-MI. The natural upregulation of PKM2 may mitigate fibrosis by reducing oxidative stress and inflammation, highlighting its protective role in the infarcted heart.

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.

Swimming induces physiological cardioprotection associated with pro-growth versus anti-inflammatory influences in extracardiac organs.

Physical activity improves myocardial structure, function, and resilience via complex, incompletely defined mechanisms. We explored the effects of 1- to 2-wk swim training on cardiac and systemic phenotype in young male C57Bl/6 mice. Two-week forced swimming (90 min twice daily) resulted in cardiac hypertrophy (22% increase in heart:body weight, P < 0.01), with improved inotropy (22% higher left ventricular +dP/dt, P < 0.01) and functional tolerance to ischemia-reperfusion (I-R) (40%-50% reductions in stunning and diastolic dysfunction, P < 0.01; without changes in cell death assessed from enzyme loss) in Langendorff perfused hearts. Initial Western immunoblot analysis indicated no shifts in cardiac expression of determinants of autophagy (LC3A/B), mitochondrial biogenesis/dynamics (PGC-1α, MFN-1, and OPA-1), or stress signaling (caveolin-3 and GSK-3β). Furthermore, no changes in cardiac cytokines (IL-1b, IL-6, IL-10, IL-12, GM-CSF, TNF-α, and IFN-γ) were detected in multiplex immunoassays. Exploratory profiling of RTK phosphorylation provided evidence for moderately increased activity of receptors involved in cardiac/coronary growth and protection (insulin, IGF-1, FGF R2, Tie-2, PDGFβ, and EphB4), together with a fall in M-CSF R and ephrin sub-type receptor phosphorylation. Swimming increased growth factor while reducing inflammatory mediators across extracardiac tissues [brain, pancreas, thymus, lymph nodes, and white adipose tissue (WAT)]. This included a pattern of increased LIF, VEGF, and pentraxin-2 versus reduced CXCL2/MIP-2a, chitinase 3-like 1, CCL6, MMP9, CD40/TNFRSF5, and IGFBP6 in multiple tissues, and a shift to a pro-browning profile in WAT. In summary, swimming produces integrated systemic benefits, improving cardiac growth, inotropy, and resilience in association with increased growth factor and reduced inflammatory and lipogenic mediators in multiple tissues.NEW & NOTEWORTHY Swimming may induce cardiac and systemic benefits distinct from other modes of physical activity. We show that 2-wk forced swim training increases cardiac growth, contractility, and functional resilience to ischemia in hearts of male mice. This is associated with increased growth factor levels and reduced inflammatory and lipogenic protein profiles in peripheral tissues.

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.

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

Ischemic heart disease (IHD) is a top non-infectious 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 ischemic heart disease have 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, 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 were summarized. This review is based on a literature survey of studies published between 2001 and 2024 using databases such as PubMed, Scopus, Web of Science, and relevant website like the World Health Organisation. The main goal of this literature survey is to create awareness that will help healthcare professionals save patients’ lives and aid researchers in developing new molecules to treat IHD.

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.

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 &lt;0.001), diabetes mellitus ( p &lt;0.001), chronic kidney disease ( p &lt;0.001), and prior CVD medications ( p &lt;0.001) were associated with cardiac hospitalisation. On multivariate analysis, prior history of heart failure ( p &lt;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.

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.