Post-myocardial Infarction Research Articles

Low dose threshold for measuring cardiac functional metrics using four-dimensional CT with deep learning.

Four-dimensional CT is increasingly used for functional cardiac imaging, including prognosis for conditions such as heart failure and post myocardial infarction. However, radiation dose from an acquisition spanning the full cardiac cycle remains a concern. This work investigates the possibility of dose reduction in 4DCT using deep learning (DL)-based segmentation techniques as an objective observer. A 3D residual U-Net was developed for segmentation of left ventricle (LV) myocardium and blood pool. Two networks were trained: Standard DL (trained with only standard-dose [SD] data) and Noise-Robust DL (additionally trained with low-dose data). The primary goal of the proposed DL methods is to serve as an unbiased and consistent observer for functional analysis performance. Functional cardiac metrics including ejection fraction (EF), global longitudinal strain (GLS), circumferential strain (CS), and wall thickness (WT), were measured for an external test set of 250 Cardiac CT volumes reconstructed at five different dose levels. Functional metrics obtained from DL segmentations of standard dose images matched well with those from expert manual analysis. Utilizing Standard-DL, absolute difference between DL-derived metrics obtained with standard dose data and 100mA (corresponding to ∼76±13% dose reduction) data was less than 0.8±1.0% for EF, GLS, and CS, and 5.6±6.7% for Average WT. Performance variation of Noise-Robust DL remained acceptable at even 50mA. We demonstrate that on average radiation dose can be reduced by a factor of 5 while introducing minimal changes to global functional metrics (especially EF, GLS, and CS). The robustness to reduced image quality can be further boosted by using emulated low-dose data in the DL training set.

Comparison of Body Quality Composition, Including Phase Angle, in PostMyocardial Infarction Patients Qualified for Rehabilitation under the MC-AMI Program and Patients with Angina Pectoris

Background: In some diseases, such as heart failure, there is talk of an obesity paradox, as lower mortality is observed in patients with higher BMI. Both obesity and frailty syndrome are risk factors for adverse prognosis and treatment, including high mortality. Body composition analysis with electrical bioimpedance (BIA) appears to be a good method for assessing changes in patients after various cardiovascular incidents, as well as for primary prevention of cardiovascular disease. Aim of the study: The aim of this study is to evaluate the qualitative composition of the body (including but not limited to phase angle (PhA), visceral fat, and lean body mass) using BIA in post-MI patients qualified for rehabilitation under the Managed Care after Acute Myocardial Infarction (MC-AMI) program. The control group consisted of patients with suspected ischemic heart disease with symptoms of angina but without myocardial infarction. Methods: The project was conducted as a retrospective analysis of prospectively collected data from 148 patients. The final study included 94 patients after revascularization for myocardial infarction and 54 patients with stable angina admitted electively to the Cardiology Department for coronary angiography. Results: The group of patients after myocardial infarction had statistically significantly higher values of total cholesterol, LDL, and triglycerides. The group of women after myocardial infarction had lower values for fat-free tissue mass and muscle mass in the trunk and limbs. No significant differences in PhA values were observed between the two groups. Conclusions: Learning more about the role of electrical bioimpedance brings much hope as a non-invasive method that can be used as a predictive marker of health change in cardiology.

Functions of TAM Receptors and Ligands Protein S and Gas6 in Atherosclerosis and Cardiovascular Disease

Atherosclerosis and cardiovascular disease are associated with high morbidity and mortality in industrialized nations. The Tyro3, Axl, and Mer (TAM) family of receptor tyrosine kinases is involved in the amplification or resolution of atherosclerosis pathology and other cardiovascular pathology. The ligands of these receptors, Protein S (PS) and growth arrest specific protein 6 (Gas6), are essential for TAM receptor functions in the amplification and resolution of atherosclerosis. The Axl-Gas6 interaction has various effects on cardiovascular disease. Mer and PS dampen inflammation, thereby protecting against atherosclerosis progression. Tyro3, the least studied TAM receptor in cardiovascular disease, appears to protect against fibrosis in post-myocardial infarction injury. Ultimately, PS, Gas6, and TAM receptors present an exciting avenue of potential therapeutic targets against inflammation associated with atherosclerosis and cardiovascular disease.

SIRT1-dependent regulation of mitochondrial metabolism participates in miR-30a-5p-mediated cardiac remodeling post-myocardial infarction

Myocardial infarction-triggered myocardial remodeling is fatal for therapies. The miR-30 family is an essential component of several physiological and pathological processes. Previous studies have proved that the miR-30 family may contribute to regulating myocardial infarction. This study aimed to demonstrate that the combination of miR-30a-5p and mitochondrial metabolism recapitulates the critical features for remodeling post-myocardial infarction. Using gain- and loss-of-function of miR-30a-5p in mice, we found miR-30a-5p is highly expressed in the heart and is reduced in infarcted hearts. Further evidence showed that miR-30a-5p acts as a protective molecule to maintain myocardial remodeling, fibrosis, and mitochondrial structure. Mitochondrial function, ATP production, and mitochondrial respiratory chain proteins were positively regulated by miR-30a-5p. Mechanistically, alterations in these properties depend on SIRT1, which modulates miR-30a-5p-regulated mitochondrial metabolism. Remarkably, reactivation of SIRT1 prevented miR-30a-5p deficiency-aggravated myocardial infarction-induced myocardial remodeling. These data identified miR-30a-5p as a critical modulator of mitochondrial function in cardiomyocytes and revealed that the miR-30a-5p-SIRT1-mitochondria network is essential for myocardial infarction-induced cardiac remodeling.

Mechanisms and Implications of Electrical Heterogeneity in Cardiac Function in Ischemic Heart Disease.

A healthy heart shows intrinsic electrical heterogeneities that play a significant role in cardiac activation and repolarization. However, cardiac diseases may perturb the baseline electrical properties of the healthy cardiac tissue, leading to increased arrhythmic risk and compromised cardiac functions. Moreover, biological variability among patients produces a wide range of clinical symptoms, which complicates the treatment and diagnosis of cardiac diseases. Ischemic heart disease is usually caused by a partial or complete blockage of a coronary artery. The onset of the disease begins with myocardial ischemia, which can develop into myocardial infarction if it persists for an extended period. The progressive regional tissue remodeling leads to increased electrical heterogeneities, with adverse consequences on arrhythmic risk, cardiac mechanics, and mortality. This review aims to summarize the key role of electrical heterogeneities in the heart on cardiac function and diseases. Ischemic heart disease has been chosen as an example to show how adverse electrical remodeling at different stages may lead to variable manifestations in patients. For this, we have reviewed the dynamic electrophysiological and structural remodeling from the onset of acute myocardial ischemia and reperfusion to acute and chronic stages post-myocardial infarction. The arrhythmic mechanisms, patient phenotypes, risk stratification at different stages, and patient management strategies are also discussed. Finally, we provide a brief review on how computational approaches incorporate human electrophysiological heterogeneity to facilitate basic and translational research.

An Immunoregulatory and Metabolism-Improving Injectable Hydrogel for Cardiac Repair After Myocardial Infarction

Abstract The hypoxia microenvironment post myocardial infarction (MI) critically disturbs cellular metabolism and inflammation response, leading to scarce bioenergy supplying, prolonged inflammatory phase and high risk of cardiac fibrosis during cardiac restoration. Herein, an injectable hydrogel is prepared by Schiff-base reaction between fructose-1,6-bisphosphate (FBP)-grafted carboxymethyl chitosan (CF) and oxidized dextran (OD), following by loading fucoidan-coated baicalin (BA)-encapsulated zein nanoparticles (BFZ NPs), in which immunoregulatory and metabolism improving functions are integrally included. The grafted FBP serves to enhance glycolysis and provide more bioenergy for cardiomyocytes survival under hypoxia microenvironment, and elevating cellular antioxidant capacity via pentose phosphate pathway. OD with intrinsic anti-inflammatory effect can induce M2 polarization of macrophages to accelerate inflammatory elimination. While facing the possibility of endothelial-to-mesenchymal transition (EndoMT) caused by excessive expressed TGF-β1 secreted from M2 macrophages, BFZ NPs can target endothelia cells and intracellularly release BA to regulate the level of fatty acid oxidation, resulting in retained endothelial features and decreased risk of cardiac fibrosis. After being injecting the hydrogel into rats’ infarcted cardiac, the 28 day-post surgical outcomes demonstrate its benign effects on restoring cardiac functions and attenuating adverse left ventricular remodeling. This study shows a promising measure for MI treatment with immunoregulating and metabolism regulation comprehensively.

Abstract 4136204: Clearing Senescent Cells Improves Mouse Survival Rate Post Myocardial Infarction through Alteration of Cardiomyocyte and Immune Cell Subpopulations

Introduction: Cellular senescence often involves a p16-pathway, and p16 overexpression is a hallmark of senescent cells. The role of cellular senescence in myocardial infarction (MI) and any mediating mechanisms remain unclear. Aims: To investigate the effect of p16 + cell clearance on survival post MI and elucidate underlying mechanisms. Methods: We utilized INK-ATTAC transgenic mice, in which p16 + cells undergo targeted apoptosis upon exposure to AP20187 (AP). Sham and MI mice were treated with AP or vehicle (V) twice-weekly for one month, starting 3-4 hours post-MI. Survival rate improvement post MI in the AP group (Fig A, P<0.001) prompted us to evaluate effects of senescent cell clearance at the cardiac cellular level and its involvement in MI-associated pathways at 3 days post-MI. The infarct and peri-infarct areas were collected and snap-frozen. Nuclei were extracted with modified gentleMACS methods; libraries were constructed using 10X Genomics. Standard software (CellRanger, Seurat) were employed for single-nuclei-RNA-seq data analysis. Results: Cardiomyocytes (CMs) showed 5 distinct subsets. CM subclusters 1 and 2 showed enrichments of genes characteristic of infarct boarder zones, while most sham CMs were found in subcluster 0, reflecting healthy-CMs. AP-treated mice exhibited a higher proportion of healthy CMs (Fig B). Differentially expressed genes (DEGs) between V and AP group were enriched in the healthy CMs, suggesting that clearance of p16 + cells improves the status of CMs post MI (Fig C). Immune-cell profiling showed that by far the largest number of DEG for AP vs vehicle were expressed in the (arginase-1) Arg1 macrophage subgroup (Fig D). The percentage of Arg1 macrophages decreased in the AP group (FDR=0.059) (Fig E). We noted significant enrichment in the hypoxia and cardiac rupture pathways in Arg1 macrophages (Fig F), correlating with the high death rate from myocardial rupture in V-mice. Conclusion: These results suggest a significant role of p16 + senescent cells in post-MI mortality, potentially through effects on cardiomyocytes and a specific macrophage subpopulation, Arg1 macrophages.

Abstract 4134837: Checkpoint Kinase 1 Attenuates Myocardial Ischemia-Reperfusion Injury Through Maintaining SIRT1-Dependent Mitochondrial Homeostasis

Background: Mitochondrial dysfunction is linked to myocardial ischemia-reperfusion (I/R) injury. Checkpoint kinase 1 (CHK1) could facilitate cardiomyocyte proliferation and cardiac repair post myocardial infarction, however, its role on mitochondrial function in I/R injury remains unknown. Research Questions: The purpose of this study is to explore the potential effects and mechanisms of CHK1 on mitochondrial homeostasis during myocardial I/R injury. Methods: To investigate the role of CHK1 on mitochondrial function following I/R injury, cardiomyocyte-specific knockout/knock-in mouse models were generated. Mass spectrometry-proteomics analysis and protein co-immunoprecipitation assays were conducted to dissect the molecular mechanism of CHK1. The interaction between CHK1 and SIRT1 was explored using truncated plasmids. Results: CHK1 was downregulated in myocardium post I/R and neonatal mouse cardiomyocytes (NMCMs) post oxygen-glucose deprivation/re-oxygenation (OGD/R). In vivo , CHK1 overexpression protected against myocardial I/R injury, while heterogenous CHK1 knockout exacerbated cardiomyopathy. In vitro , CHK1 inhibited OGD/R-induced cardiomyocyte apoptosis and bolstered cardiomyocyte survival. Mechanistically, CHK1 attenuated oxidative stress and preserved mitochondrial metabolism in cardiomyocytes under I/R. Moreover, disrupted mitochondrial homeostasis in I/R myocardium was restored by CHK1 through the promotion of mitochondrial biogenesis and mitophagy. Through mass spectrometry analysis following co-immunoprecipitation, SIRT1 was identified as a direct target of CHK1. The 266-390 domain of CHK1 interacted with the 160-583 domain of SIRT1. Importantly, CHK1 phosphorylated SIRT1 at Thr530 residue, thereby inhibiting SMURF2-mediated degradation of SIRT1. CHK1 Δ390 amino acids (aa) mutant functioned similarly to full-length CHK1 in scavenging ROS and maintaining mitochondrial dynamics. Consistently, cardiac-specific SIRT1 knockdown partially attenuated the protective role of CHK1 in I/R injury. Conclusions: Our findings revealed that CHK1 mitigates I/R injury and restores mitochondrial dynamics in cardiomyocytes through a SIRT1-dependent mechanism.

Abstract 4138662: Mineralocorticoid receptor antagonist in patients with acute myocardial infarction: An updated systematic review and meta-analysis of randomized trials

Background: While mineralocorticoid antagonists (MRA) reduce mortality in patients developing heart failure post myocardial infarction (MI), it is unclear whether they are beneficial in an unselected post-MI population. Aims: Using a systematic review and meta-analysis, we aim to determine the effect of MRA treatment versus no MRA treatment on all-cause mortality in unselected post-MI patients from randomized data, simultaneously with the presentation of the largest randomized controlled trial on the topic, the CLEAR SYNERGY trial. Methods/Approach: We completed a systematic review of all randomized controlled trials comparing MRA treatment to no MRA treatment in post-MI patients. We will perform our primary analysis using fixed effects with the Peto odds ratio method and use random effects as a sensitivity analysis. The primary outcome will be all-cause mortality, and secondary outcomes will include cardiovascular mortality, new or worsening heart failure, recurrent myocardial infarction and stroke. Results/Data: Our systematic review of Pubmed, Embase, and CENTRAL from inception until April 30, 2024, yielded 456 records. A total of 11,199 participants from 11 randomized clinical trials will be included in addition to the late-breaking CLEAR SYNERGY trial. The CLEAR SYNERGY trial is a 2 x 2 factorial randomized controlled trial of low-dose colchicine 0.5mg daily versus placebo and spironolactone 25mg daily versus placebo in 7,062 post-MI patients who were within 72h of the index percutaneous coronary intervention. The results of the spironolactone factorial will be presented in the fall of 2024 with an expected median follow-up of 3.5 years. As the investigators of the CLEAR SYNERGY trial, we will combine our data with the other 11 trials for a total of 12 trials and 18,261 participants. Conclusions: CLEAR SYNERGY is the largest randomized controlled trial with the longest follow-up of spironolactone in the post-MI population. Our meta-analysis will provide updated effect estimates of post-MI MRA treatment, leveraging the late-breaking CLEAR SYNERGY data to reflect the totality of the evidence.

Abstract 4136969: Empagliflozin's Role in Post-Myocardial Infarction Management: Insights from a Meta-Analysis

Background: Empagliflozin, a Sodium Glucose Cotransporter 2 (SGLT2) Inhibitor, is used to treat type 2 diabetes mellitus and heart failure. Its safety and efficacy in patients with Myocardial Infarction (MI) have been studied recently. Research Questions/Hypothesis: What is the role of Empagliflozin in post-myocardial infarction management by preventing cardiovascular deaths, reducing hospitalization due to heart failure, and minimizing adverse events? Goals/Aims: Role of Empagliflozin in post-myocardial infarction management by preventing cardiovascular deaths, reducing hospitalization due to heart failure, and minimizing adverse events Methods: A literature search was done on PubMed, Medline, Web of Science, Scopus, and Cochrane Central Register of Controlled Trials from inception until May 2024. All Randomized Control Trials (RCT) reporting the safety and efficacy of Empagliflozin in MI management were selected. Outcomes were pooled as Mean Difference (MD) or Risk Ratio (RR) with 95% Confidence Intervals (CI) in this meta-analysis using Revman 5.4. Results: Data from ten RCTs, with a combined sample size of 10,560 patients was pooled, and showed that Empagliflozin is superior to placebo in terms of Cardiovascular death (RR=0.75, 95% CI [0.64, 0.88],p < 0.0004) and hospitalization due to heart failure (RR=0.70, 95% CI [0.59, 0.82], p < 0.0001). However, the results were non-significant for both groups in terms of adverse events (RR=1.00, 95% CI [0.96, 1.03], p < 0.78). Conclusion: Empagliflozin significantly lowers the risk of cardiovascular events in patients with MI who are at a high risk of death due to cardiovascular causes.

Abstract 4139191: ETX-258 - A GalOmic™ siRNA for the Treatment of Heart Failure Following Myocardial Infarction

Introduction: Heart failure with reduced ejection fraction (HFrEF) remains a significant clinical challenge, evidenced by high hospitalization rates and five-year mortality. Current treatments are limited by side effects, poor patient compliance, and the necessity for gradual drug titration. These challenges highlight the need for new therapies that are both safe and effective in targeting the structural remodeling pivotal to disease progression post-myocardial infarction (MI). e-therapeutics (ETX) uniquely combines computation and RNAi to discover life-transforming medicines. ETX’s RNAi platform, GalOmic™, enables generation of specific, potent, and long-acting siRNA therapies that effectively silence novel gene targets in hepatocytes. This highly specific mechanism of action limits unwanted side effects, positioning it as a promising approach to HFrEF treatment. Methods: Potent siRNAs against a hepatic target with cardioprotective potential were designed in silico. Candidate siRNAs were screened in vitro in HEK293 cells and in vivo in C57BL/6J mice to select the lead GalOmic™ siRNA, ETX-258. MI was induced by ligation of the left anterior descending artery in C57BL/6J mice after which ETX-258 was injected subcutaneously weekly for 6 weeks. Eplerenone, a mineralocorticoid receptor antagonist which is part of the current treatment regimen for HFrEF, was used as a comparator. Cardiac function was assessed by echocardiography at 2-, 4- and 6-weeks post-MI. Cardiac damage and structural remodeling were evaluated using circulating biomarkers of cardiac function and histological assessment. Results: ETX-258 was selected as a highly active siRNA for the treatment of heart failure with a long duration of action. Post-MI treatment with ETX-258 significantly improved key echocardiographic parameters of cardiac function, including ejection fraction and total cardiac output, achieving results comparable to eplerenone. Additionally, both structural cardiac parameters and markers of damage and remodeling showed significant improvements, reaching similar levels in both ETX-258 and eplerenone-treated mice. Conclusions: High unmet need remains for HFrEF patients despite existing therapies. These results highlight the potential of ETX-258 to improve cardiac function and pathogenic structural remodeling post-MI. This, paired with the long duration of action and favorable safety profile of GalOmic™ siRNAs, makes ETX-258 a promising candidate for further clinical development.

Abstract 4140122: Bioengineered Self-Adhering Electrospun Nanoscaffolds to Deliver Mitochondrial Antioxidant, JP4-039

Introduction: Treatment of pathologic remodeling and subsequent decline in cardiac function post-myocardial infarction (MI) remains limited. Our lab has previously demonstrated that the targeted mitochondrial antioxidant, JP4-039 (JP4), can abrogate post-MI remodeling and decline in cardiac function, and that JP4 released from electrospun nanoscaffolds improved proliferation and migration of coronary vascular endothelial cells in vitro . The aims of this study were to develop a suture-free, bioadhesive electrospun nanoscaffold that will adhere post-MI cardiac tissue and reliably release JP4 in a localized manner. Hypothesis: Plasma treatment of JP4-loaded biocompatible electrospun nanoscaffold will adhere to cardiac tissue and deliver active moiety of JP4. Methods: A 2% poly(l-lactide-co-glycolide) (PGLA) was electrospun with and without 1% JP4. Nanoscaffolds then underwent plasma treatment for one minute followed by a force adhesion assay. SEM imaging and electron paramagnetic resonance ( EPR ) assays before and after plasma treatment of both control and JP4-loaded patches were performed to examine patch consistency and ensure the release of the unaltered, active structure of JP4. Results: JP4 loading and plasma treatment did not affect fiber dimeter of the scaffolds (p > 0.5 for all; Fig. 1B). JP4-loaded patches demonstrated similar release pattern of the antioxidant’s nitroxide moiety by displaying a characteristic triple peak both before and after plasma treatment as determined by EPR (Fig. 1C). Plasma-treated patches demonstrated significant increase in force adhesion compared to non-treated patches in both the control and JP4-loaded scaffolds (p < 0.0001) (Fig. 1A.). No significant difference in force adhesion was observed between the plasma treated control and JP4 loaded patch (p > 0.05) as determined by ANOVA (Fig. 1A). There was no significant difference in force adhesion between one minute and two minutes of plasma treatment (p > 0.05; Fig. 1A lower panel). Conclusion: The findings demonstrate that plasma-treated biocompatible JP4-loaded patches may reliably adhere to cardiac tissue and release the bioactive component of the mitochondrial antioxidant, JP4.

Percutaneous Closure of Postmyocardial Infarction Ventricular Septal Rupture – A Single Center Experience from the Eastern Part of India

Abstract Background: Postinfarction ventricular septal rupture (VSR) is a rare but lethal mechanical complication of an acute myocardial infarction (AMI). It results in 90%–95% mortality within 2 months of diagnosis without any kind of intervention. Given high surgical mortality, transcatheter closure has emerged as a potential strategy and as an alternative to high-risk surgical closure. Indian data on percutaneous device closure of post-AMI VSR are limited; hence, we report our resource-limited single-center experience with different kinds of occluder devices for closure of post-AMI VSR. Methods and Results: In this single-center, retrospective cohort study, patients who underwent transcatheter closure of postmyocardial infarction (MI) VSR between 2018 and 2024 at Health World Hospitals in Durgapur, West Bengal, were included. The primary outcome was a mortality rate of 30 days. The study population was eleven primary cases of post-MI VSR. The mean age of the population was 61 years. The majority of the patients had anterior wall MI (54.5%), and the remaining had inferior wall MI. Different kinds of devices (Amplatzer atrial septal occlude, post-MI VSD device, and Konar-Multifunctional Occluder) were used to close VSR. Successful closure was performed in 9 patients (81%) with minimal residual shunt in 2 patients. Of 9 cases, 3 patients expired; one was lost to follow-up, and the rest are doing well at 30-day follow-up. Conclusion: Transcatheter closure of PMI VSRs can be performed with different kinds of devices with high technical success, relatively low procedural complication rates, and a good 30-day survival even in a setup outside the metropolis with limited availability of devices, as an alternative to very high-risk surgical closure.

New left ventricular thrombus and embolic events in left ventricular dysfunction postmyocardial infarction

Background: We aimed to assess the incidence and evolution of new left ventricular thrombus (LVT), and the incidence of manifest systemic embolism, in patients with severe left ventricular (LV) systolic dysfunction postacute anterior myocardial infarction (MI) who had been discharged on dual antiplatelet therapy. Methods: We prospectively included consecutive patients with postacute anterior MI and LV ejection fraction (LVEF) ≤35% or apical aneurysms or large infarctions with LVEF ≤40%. Transthoracic echocardiography (TTE) confirmed no LVT before hospital discharge, and a second TTE was performed at 30 days and a third one at 3 months. All TTE studies were prespecified to assess LVT, and the patients were screened for the development of clinically manifest systemic embolisms. Results: Two hundred and two consecutive patients (males 93%; mean age 55.2±6.4 years; mean LVEF 29.5±5.0%) were included. At 30 days (interquartile range: 2837 days), a new LVT was detected in 12 (5.9%) patients. Oral anticoagulant was added to all patients with LVT, and aspirin was continued in 5 (42.7%) patients for a month. The 3month TTE showed favorable evolution of LV size, LVEF and apical wall motion score index compared to the baseline. At 3 months, the LVT disappeared in 7 (58.3%) patients and 5 patients still had a mural LVT of smaller size, and none got new LVT. Among the group without LVT, one patient had a stroke, and another had a myocardial infarction and died. Conclusions: In contemporary practice, and using routine TTE, the incidence of new LVT in patients with severe LV dysfunction postacute anterior MI is low. They have a favorable LVT evolution with minor risk for clinically manifest systemic embolism.

Vitamin D status, physical activity and long-term mortality risk after myocardial infarction: a prospective analysis in the Alpha Omega Cohort.

In post-myocardial infarction (MI) patients, we examined independent and combined associations of vitamin D status and physical activity (PA) with long-term mortality, including effect modification by health determinants. We conducted a prospective analysis of 4,837 MI patients from the Alpha Omega Cohort. Baseline blood samples (2002-2006) were assessed for plasma 25-hydroxyvitamin D (25[OH]D) levels using LC-MS/MS. PA was assessed using a validated questionnaire. Patients were followed for mortality through December 2022. HRs for CVD and all-cause mortality were obtained across sex-specific tertiles of 25(OH)D and four categories of PA using Cox models, adjusted for sociodemographic and lifestyle factors. Potential effect modification by health determinants was examined through stratification. Patients were 69±5.6 years old, 78% was male, 21% had diabetes, and 10% used vitamin D-containing supplements. Over 14.4 years, 3,206 deaths occurred, including 1,244 from CVD. Median 25(OH)D was 21.1 ng/mL and 44% was vitamin D deficient (<20 ng/mL). Higher 25(OH)D levels were associated with lower CVD (HR:0.63, 95%CI:0.54,0.74) and all-cause mortality (HR:0.68, 95%CI:0.62,0.75). For PA levels (high vs. light), HRs were 0.72 (95%CI:0.61,0.85) for CVD mortality and 0.83 (95%CI:0.75,0.92) for all-cause mortality. Patients with low 25(OH)D and no PA had a threefold higher mortality risk than those with high 25(OH)D levels and high PA. The associations were not significantly modified by sex, comorbidities and other health determinants. Vitamin D status and PA were inversely and independently associated with long-term risk of CVD and all-cause mortality after MI, regardless of other health determinants.

Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction.

Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart's inability to regenerate after injury effectively. In adult mammals, the adverse cardiac remodelling, which compensates for the loss of cardiac cells, impairs cardiac function due to the non-contractile nature of fibrotic tissue. Moreover, the neovascularisation after MI is inadequate to restore blood flow to the infarcted myocardium. This review aims to synthesise the most recent insights into the molecular and cellular players involved in endogenous myocardial and vascular regeneration, facilitating the identification of mechanisms that could be targeted to trigger cardiac regeneration, reduce fibrosis, and improve functional recovery post-MI. Reprogramming adult cardiomyocytes to regain their proliferative potential, along with the modulation of target cells responsible for neovascularisation, represents promising therapeutic strategies. An updated overview of endogenous mechanisms that regulate both myocardial and coronary vasculature regeneration-including stem and progenitor cells, growth factors, cell cycle regulators, and key signalling pathways-could help identify new critical intervention points for therapeutic applications.

Reversing metabolic reprogramming by CPT1 inhibition with etomoxir promotes cardiomyocyte proliferation and heart regeneration via DUSP1 ADP-ribosylation-mediated p38 MAPK phosphorylation

The neonatal mammalian heart has a remarkable regenerative capacity, while the adult heart has difficulty to regenerate. A metabolic reprogramming from glycolysis to fatty acid oxidation occurs along with the loss of cardiomyocyte proliferative capacity shortly after birth. In this study, we sought to determine if and how metabolic reprogramming regulates cardiomyocyte proliferation. Reversing metabolic reprogramming by carnitine palmitoyltransferase 1 (CPT1) inhibition, using cardiac-specific Cpt1a and Cpt1b knockout mice promoted cardiomyocyte proliferation and improved cardiac function post-myocardial infarction. The inhibition of CPT1 is of pharmacological significance because those protective effects were replicated by etomoxir, a CPT1 inhibitor. CPT1 inhibition, by decreasing poly(ADP-ribose) polymerase 1 expression, reduced ADP-ribosylation of dual-specificity phosphatase 1 in cardiomyocytes, leading to decreased p38 MAPK phosphorylation, and stimulation of cardiomyocyte proliferation. Our present study indicates that reversing metabolic reprogramming is an effective strategy to stimulate adult cardiomyocyte proliferation. CPT1 is a potential therapeutic target for promoting heart regeneration and myocardial infarction treatment.

Sodium-glucose cotransporter 2 inhibitors in cardiocerebrovascular disease

Cardiovascular disease is a leading cause of global mortality, necessitating effective strategies for prevention and treatment. The cardiovascular disease continuum concept highlights the progression from risk factors such as hypertension and diabetes mellitus to advanced stages, including heart failure (HF) and death. Sodium-glucose cotransporter 2 (SGLT2) inhibitors, initially developed to manage diabetes, have emerged as effective therapies across all stages of the cardiovascular disease continuum. Numerous cardiovascular outcome trials demonstrate that SGLT2 inhibitors significantly reduce major adverse cardiovascular events and hospitalizations for HF in patients with and without established atherosclerotic cardiovascular disease. Notably, SGLT2 inhibitors have shown remarkable benefits in reducing HF risk, even in patients without diabetes, including those with HF and preserved ejection fraction. Furthermore, recent studies in post–myocardial infarction patients suggest potential benefits in reducing hospitalizations for HF. Despite their widespread use, the precise mechanisms by which SGLT2 inhibitors confer cardiovascular protection remain unclear, suggesting the need for further investigation. In conclusion, SGLT2 inhibitors have revolutionized cardiovascular disease management, offering significant therapeutic potential across a broad spectrum of patients, and are expected to play an increasingly prominent role in both the prevention and treatment of cardiovascular disease.

The prognostic impact of therapeutic hypothermia after a sudden cardiac arrest in the course of myocardial infarction.

Mild therapeutic hypothermia (MTH) is one of the treatment methods recommended in post-sudden cardiac arrest (SCA) patients who remain unconscious after cardiopulmonary resuscitation. The present study aimed at assessing the prognostic impact of intravascular MTH on invasively treated patients with an acute myocardial infarction complicated by SCA. The presented data were collected via a single-center retrospective analysis of the hospitalization and follow-up of 54 patients with post-myocardial infarction complicated by SCA. The patients were treated in the years 2014-2020 and the average follow-up period was 1141 ± 163 days. The population was divided into two groups: 28 patients treated with MTH (a therapeutic hypothermia [TH] group) and 26 patients treated without MTH (a non-TH group). The results indicate a trend toward improved in-hospital prognosis in the TH group, but the differences did not reach statistical significance: TH 25.0% vs. non-TH 34.5%, p = 0.554. An additional analysis of younger patients (under 60 years of age) revealed no significant differences between the TH and non-TH subgroups concerning in-hospital survival (in-hospital mortality rate: TH 6.7% vs. non-TH 30.0%, p = 0.267). Still, TH patients aged < 60 achieved a significantly better rate of follow-up survival (p = 0.041). The older (≥ 60) patient group showed no in-hospital mortality rate differences (TH 46.2% vs. non-TH 37.5%, p = 0.638). However, in-hospital bleeding frequency was significantly higher in patients aged ≥ 60 from the hypothermia group (TH 50.0% vs. non-TH 6.7%, p = 0.011). Intravascular MTH may improve the follow-up prognosis in patients aged < 60 with SCA in the early phase of myocardial infarction.

Cardioprotective effects of novel antioxidants post-myocardial infarction: An integrative review of preclinical and clinical data

Myocardial infarction (MI), is still a major public health problem, and oxidative stress contributes to the degree of myocardial damage after MI. Oxygen-derived free radicals (ODFR) worsen myocardial injury and result in chronic heart failure in many patients. These harms have led to interest in antioxidant treatment to reduce these adverse effects; new antioxidants with the potential for cardioprotection are the subject of significant interest. This review summarizes basic and clinical research comparing the effectiveness of newly synthesized antioxidants in attenuating oxidative stress and enhancing recovery after myocardial infarction. The review synthesizes evidence of a reduction in infarct size, enhancement of cardiac function, and repression of apoptosis in myocardial cells by the use of antioxidants from animal models. Melatonin, N-acetylcysteine, edaravone, and coenzyme Q10 demonstrated a wide range of preclinical positive effects by acting as ROS free radicals scavengers, modulating mitochondria dysfunction, and reducing inflammation. These findings are extrapolated from humans, although advances in antioxidant therapy are beginning to be viewed in initial clinical trials. From human data, although clinical trials are scarce, the evidence of new antioxidants can improve point and long-term outcomes in patients undergoing MI, help to increase the contractility of the injured myocardium, and decrease the mortality level. However, some issues are still there, such as high inter- and intra-individual variability in patient response and dosing schedule, as well as adverse effects such as pro-oxidant activity at high Oral administered doses of melatonin. The limitations of the current research discussed in this review include the general lack of large-scale, well-controlled clinical trials and the need for long-term follow-up studies. This review also proposed future research directions for improving antioxidant applications in post-MI management.