Myocardial Infarction Remodeling Research Articles

Shock wave-pretreated ADMSCs of cell-sheet scaffold (CSS) patched on left ventricular wall (LVW) inhibited LVW remodeling in mini-pig MI ---role CSS on counteracting Laplace's Law of LVW stress: Experimental study.

We investigated whether shock wave (SW)-pretreated autologous adipocyte-derived mesenchymal stem cells (ADMSCs) seeded in the cell-sheet scaffold (CSS) could inhibit left ventricular (LV) remodeling and improve LV ejection fraction (LVEF) in old myocardial infarction (MI). Mini-pigs (n=20) were divided into group 1 (sham-operated control), group 2 (old MI), group 3 (old MI + autologous ADMSCs/1.0×107 in CSS on LV myocardium), and group 4 [old MI + SW (0.12mJ/mm2 for total 140 shots)-pretreated ADMSCs in CSS on LV myocardium]. Treatments started on day 28 after MI induction. In vivo and in vitro studies were conducted. Cell viability/relative mitochondria DNA expression/mitochondrial cytochrome C/adenosine triphosphate concentration in ADMCSs and protein expressions of angiogenesis factors (vascular endothelial growth factor [VEGF]/stromal cell-derived factor-1 [SDF-1])/mitochondrial respiratory chain complexes I-IV/oxygen consumption rate were higher in group 4 than in group 3 (P<0.001). By day 180, LVEF and small vessel numbers in the peri-infarct or infarct area were highest in group 1, lowest in group 2, and significantly lower in group 3 than in group 4. In contrast, the LV dimension was opposite to the pattern of change in LVEF in all groups (P<0.0001). The basal/middle/apical infarct and fibrotic areas were inversely related to LVEF in all groups (all P<0.0001). Protein levels of angiogenetic markers (SDF-1α/C-X-C chemokine receptor type 4/VEGF/angiopoietin-1) were significantly and persistently increased from groups 1 to 4. In contrast, protein levels of endothelial-cell markers (von Willebrand factor or endothelial nitric oxide synthase) showed an identical pattern to LVEF in all groups (all P<0.0001). SW pretreatment of ADMSCs seeded in CSS offered significant benefits in preserving LV performance and ameliorating LV remodeling in mini-pigs with old MI.

Long-term transcranial ultrasound stimulation regulates neuroinflammation to ameliorate post–myocardial infarction cardiac arrhythmia and remodeling

BackgroundSympathetic overactivation and neuroinflammation in the paraventricular nucleus (PVN) are crucial factors in post–myocardial infarction (MI) cardiac remodeling and ventricular arrhythmias (VAs). Prior study has indicated that low-intensity focused ultrasound stimulation could attenuate sympathetic neuroinflammation within the PVN to prevent the occurrence of VAs in an acute MI model. Meanwhile, the cGAS-STING pathway has shown potential to ameliorate the neuroinflammatory response. However, the effect and mechanisms of long-term transcranial ultrasound stimulation (LTUS) for modulating neuroinflammation in the chronic stage of MI remain unclear. ObjectiveThis study aimed to ascertain whether LTUS could mitigate post-MI neuroinflammation and improve cardiac arrhythmia and remodeling through the cGAS-STING pathway. MethodsThirty-six SD rats were equally randomized to the sham group (pseudo-MI modeling), chronic MI group (MI modeling), and LTUS group (MI modeling and long-term ultrasound stimulation). Transcranial ultrasound stimulation (15 min/d) was conducted on the PVN for 4 consecutive weeks. After 4-week intervention, echocardiography, electrophysiologic experiments, and histopathologic staining were performed to assess the role of LTUS on post-MI neuroinflammation and cardiac remodeling. ResultsThe results indicated that LTUS significantly facilitated microglial M1 to M2 polarization through the cGAS-STING signaling pathway within the PVN. Furthermore, LTUS inhibited MI-induced sympathetic neuroinflammation, thereby improving cardiac dysfunction, ameliorating cardiac remodeling, and reducing VA inducibility. ConclusionLong-term ultrasound stimulation of the PVN was found to alleviate post-MI neuroinflammation and to improve cardiac remodeling, which might inspire novel insights and clinical strategies for noninvasive neuromodulation and the treatment of post-MI VAs.

Mineralocorticoid Receptor Blocker Prevents Mineralocorticoid Receptor-Mediated Inflammation by Modulating Transcriptional Activity of Mineralocorticoid Receptor-p65-Signal Transducer and Activator of Transcription 3 Complex.

Mineralocorticoid receptor (MR) induces cardiac inflammation cooperatively with nuclear factor-κB and signal transducer and activator of transcription 3 (STAT3); MR blockers exert anti-inflammatory effects. However, the underlying mechanism remains unclear. We investigated the anti-inflammatory effect of esaxerenone, a novel MR blocker, in experimental myocardial infarction (MI) and its underlying mechanisms. Male C57BL/6J mice subjected to ligation of the left anterior descending artery were randomly assigned to either the vehicle or esaxerenone group. Esaxerenone was provided with a regular chow diet. The mice were euthanizedat either 4 or 15 days after MI. Cardiac function, fibrosis, and inflammation were evaluated. Esaxerenone significantly improved cardiac function and attenuated cardiac fibrosis at 15 days after MI independently of its antihypertensive effect. Inflammatory cell infiltration, inflammatory-related gene expression, and elevated serum interleukin-6 levels at 4 days after MI were significantly attenuated by esaxerenone. Invitro experiments using mouse macrophage-like cell line RAW264.7 cells demonstrated that esaxerenone- and spironolactone-attenuated lipopolysaccharide-induced interleukin-6 expression without altering the posttranslational modification and nuclear translocation of p65 and STAT3. Immunoprecipitation assays revealed that MR interacted with both p65 and STAT3 and enhanced the p65-STAT3 interaction, leading to a subsequent increase in interleukin-6 promoter activity, which was reversed by esaxerenone. Esaxerenone ameliorated postinfarct remodeling in experimental MI through its anti-inflammatory properties exerted by modulating the transcriptional activity of the MR-p65-STAT3 complex. These results suggest that the MR-p65-STAT3 complex can be a novel therapeutic target for treating MI.

The role of inflammatory response in the development of atherosclerosis, myocardial infarction, and remodeling

Inflammation is an intrinsic part of the body’s immune response, significantly influencing a myriad of physiological and pathological processes. There is now clinical and experimental evidence suggesting that inflammation accelerates atherosclerosis and its associated complications. The presence of macrophages, T and B cells inside the atherosclerotic plaque fueled this concept and steered subsequent research endeavors toward understanding the pathophysiology of atherosclerosis including plaque formation and destabilization leading to plaque rupture resulting in myocardial injury and remodeling. Understanding the mechanism behind atherosclerosis will aid in developing appropriate treatment interventions. Shifting research and drug development from a singular focus on cholesterol-lowering agents to include adjunctive anti-inflammatory therapies is crucial. Targeting a root cause, i.e., inflammation, will help decrease the incidence and progression of atherosclerosis and improve patient outcomes. In this review, we aim to discuss the current understanding of the intricate role of inflammation in the pathogenesis of atherosclerosis, myocardial infarction, and cardiac remodeling. This synthesis will encompass an exploration of the various inflammatory cells involved, the intricate network of chemokines orchestrating inflammatory responses, and the pathways that underpin these cardiovascular conditions. Furthermore, we will explore promising diagnostic and therapeutic strategies aimed at addressing inflammation in cardiovascular diseases. These include interventions such as colchicine, monoclonal antibodies, and nanoparticles designed to deliver and accumulate drugs at the molecular level within cells.

Abstract Tu048: Viscoelastic remodeling of the left ventricular myocardium in myocardial infarction

Introduction. Myocardial infarction (MI) leads to cardiac myocyte death and the formation of a fibrotic scar in the left ventricular myocardium (LV). LV free wall (LVFW) remodeling in MI is known to significantly alter the biomechanical response of the LV and, in turn, LV function. While changes in the elastic behavior of the LVFW in MI have been reported, changes in the viscoelastic behavior of the LVFW remain understudied. Our objective in this study was to determine the changes in the stress relaxation behavior of the LVFW in MI. Methods. MI was induced in rats via the ligation of the LAD artery, and hearts were harvested for three groups: sham, 2-week (2wk), and 4wk post-MI (n=3 for each group). Prior to sacrifice, echocardiography was performed to estimate ejection fraction (EF). LVFW specimens were harvested and subjected to viscoelastic stress relaxation tests. The specimens were stretched to 15% along the circumferential and longitudinal directions and allowed to relax. The stress was normalized against the peak (initial) stress for each specimen for proper comparison across the groups. Results. The EF at 2wk and 4wk specimens was reduced compared to the sham specimens (Fig. 1A). The 4wk post-MI specimens showed slower stress relaxation compared to that in the sham and 2wk specimens in both directions (Figs. 1B, C). Considering a 2-minute stress relaxation span, the normalized stress in the 4wk specimens was significantly higher than the sham specimens in both directions (Fig. 1D). Conclusions. Our results suggest that the viscoelastic relaxation rate of the LVFW diminishes at late MI timepoints. A larger and more mature scar in the LVFW is expected to contribute to slower relaxation at late MI. Future studies can determine the effect of LVFW viscoelastic remodeling on LV diastolic dysfunction and impaired relaxation in MI.

Modeling acute myocardial infarction and cardiac fibrosis using human induced pluripotent stem cell-derived multi-cellular heart organoids.

Heart disease involves irreversible myocardial injury that leads to high morbidity and mortality rates. Numerous cell-based cardiac in vitro models have been proposed as complementary approaches to non-clinical animal research. However, most of these approaches struggle to accurately replicate adult human heart conditions, such as myocardial infarction and ventricular remodeling pathology. The intricate interplay between various cell types within the adult heart, including cardiomyocytes, fibroblasts, and endothelial cells, contributes to the complexity of most heart diseases. Consequently, the mechanisms behind heart disease induction cannot be attributed to a single-cell type. Thus, the use of multi-cellular models becomes essential for creating clinically relevant in vitro cell models. This study focuses on generating self-organizing heart organoids (HOs) using human-induced pluripotent stem cells (hiPSCs). These organoids consist of cardiomyocytes, fibroblasts, and endothelial cells, mimicking the cellular composition of the human heart. The multi-cellular composition of HOs was confirmed through various techniques, including immunohistochemistry, flow cytometry, q-PCR, and single-cell RNA sequencing. Subsequently, HOs were subjected to hypoxia-induced ischemia and ischemia-reperfusion (IR) injuries within controlled culture conditions. The resulting phenotypes resembled those of acute myocardial infarction (AMI), characterized by cardiac cell death, biomarker secretion, functional deficits, alterations in calcium ion handling, and changes in beating properties. Additionally, the HOs subjected to IR efficiently exhibited cardiac fibrosis, displaying collagen deposition, disrupted calcium ion handling, and electrophysiological anomalies that emulate heart disease. These findings hold significant implications for the advancement of in vivo-like 3D heart and disease modeling. These disease models present a promising alternative to animal experimentation for studying cardiac diseases, and they also serve as a platform for drug screening to identify potential therapeutic targets.

Peptides Are Cardioprotective Drugs of the Future: The Receptor and Signaling Mechanisms of the Cardioprotective Effect of Glucagon-like Peptide-1 Receptor Agonists.

The high mortality rate among patients with acute myocardial infarction (AMI) is one of the main problems of modern cardiology. It is quite obvious that there is an urgent need to create more effective drugs for the treatment of AMI than those currently used in the clinic. Such drugs could be enzyme-resistant peptide analogs of glucagon-like peptide-1 (GLP-1). GLP-1 receptor (GLP1R) agonists can prevent ischemia/reperfusion (I/R) cardiac injury. In addition, chronic administration of GLP1R agonists can alleviate the development of adverse cardiac remodeling in myocardial infarction, hypertension, and diabetes mellitus. GLP1R agonists can protect the heart against oxidative stress and reduce proinflammatory cytokine (IL-1β, TNF-α, IL-6, and MCP-1) expression in the myocardium. GLP1R stimulation inhibits apoptosis, necroptosis, pyroptosis, and ferroptosis of cardiomyocytes. The activation of the GLP1R augments autophagy and mitophagy in the myocardium. GLP1R agonists downregulate reactive species generation through the activation of Epac and the GLP1R/PI3K/Akt/survivin pathway. The GLP1R, kinases (PKCε, PKA, Akt, AMPK, PI3K, ERK1/2, mTOR, GSK-3β, PKG, MEK1/2, and MKK3), enzymes (HO-1 and eNOS), transcription factors (STAT3, CREB, Nrf2, and FoxO3), KATP channel opening, and MPT pore closing are involved in the cardioprotective effect of GLP1R agonists.

Effects of the Low-Dose Colchicine Regimen on Left Ventricular Adverse Remodeling and Systolic Function in Acute Myocardial Infarction Patients with Anterior ST-Segment Elevation Undergoing Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial

Background: Inflammation in reperfusion injury results in adverse ventricular remodeling and reduced systolic function. The anti-inflammatory effects of colchicine have shown beneficial effects in cardiovascular disease. Objective: To determine the effects of low-dose colchicine on left ventricular (LV) adverse remodeling and systolic function in acute myocardial infarction with anterior ST-segment elevation (anterior STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). Material and Methods: This prospective, randomized, double-blinded study randomly assigned anterior STEMI patients who underwent PPCI to receive either low-dose colchicine (1mg loading dose followed by 0.5mg daily) or a matching placebo for 30 days in addition to standard therapy. Outcomes included adverse LV remodeling and systolic function, determined by transthoracic echocardiography (TTE) in the first and third month. Result: Enrollment comprised 196 patients, with 92 patients in the colchicine group and 104 patients in the placebo group. Adverse LV remodeling and a decrease in systolic function were observed in both groups. No significant differences in LV remodeling were observed between the colchicine and placebo groups, as indicated by the change in LV end-systolic volume index (LVESVI) at the first month (16.5% vs. 18.25% [p=0.091]) and third month (19.5% vs. 21.5% [p=0.124]). Similar results were found in LV systolic function between the colchicine and placebo groups, with a reduction in LV ejection fraction (LVEF) observed in the first month (6.3% vs. 8.95% [p=0.083]) and third month (9.5% vs. 11.5% [p=0.163]). Diarrhea was the only reported side effect, occurring in 6.5% of patients in the colchicine group. Conclusion: Low-dose colchicine administration in anterior STEMI patients undergoing PPCI did not reduce LV adverse remodeling or systolic function. Keyword: Adverse Remodeling, Colchicine, Reperfusion Injury, STEMI, Systolic Function.

Efficacy and safety of CDR132L in patients with reduced left ventricular ejection fraction after myocardial infarction: Rationale and design of the HF-REVERT trial.

Inhibition of microRNA (miR)-132 effectively prevents and reverses adverse cardiac remodelling, making it an attractive heart failure (HF) target. CDR132L, a synthetic antisense oligonucleotide selectively blocking pathologically elevated miR-132, demonstrated beneficial effects on left ventricular (LV) structure and function in relevant preclinical models, and was safe and well tolerated in a Phase 1b study in stable chronic HF patients. Patients with acute myocardial infarction (MI) and subsequent LV dysfunction and remodelling have limited therapeutic options, and may profit from early CDR132L treatment. The HF-REVERT (Phase 2, multicenter, randomized, parallel, 3-arm, placebo-controlled Study to Assess Efficacy and Safety of CDR132L in Patients with Reduced Left Ventricular Ejection Fraction after Myocardial Infarction) evaluates the efficacy and safety of CDR132L in HF patients post-acute MI (n = 280), comparing the effect of 5 and 10 mg/kg CDR132L, administered as three single intravenous doses 28 days apart, in addition to standard of care. Key inclusion criteria are the diagnosis of acute MI, the development of systolic dysfunction (LV ejection fraction ≤45%) and elevated N-terminal pro-B-type natriuretic peptide. The study consists of a 6-month double-blinded treatment period with the primary endpoint LV end-systolic volume index and relevant secondary endpoints, followed by a 6-month open-label observation period. The HF-REVERT trial may underpin the concept of miR-132 inhibition to prevent or reverse cardiac remodelling in post-MI HF. The results will inform the design of subsequent outcome trials to test CDR132L in HF.

Dapagliflozin protects against chronic heart failure in mice by inhibiting macrophage-mediated inflammation, independent of SGLT2

The specific mechanism of sodium-glucose cotransporter 2 (SGLT2) inhibitor in heart failure (HF) needs to be elucidated. In this study, we use SGLT2-global-knockout (KO) mice to assess the mechanism of SGLT2 inhibitor on HF. Dapagliflozin ameliorates both myocardial infarction (MI)- and transverse aortic constriction (TAC)-induced HF. Global SGLT2 deficiency does not exert protection against adverse remodeling in both MI- and TAC-induced HF models. Dapagliflozin blurs MI- and TAC-induced HF phenotypes in SGLT2-KO mice. Dapagliflozin causes major changes in cardiac fibrosis and inflammation. Based on single-cell RNA sequencing, dapagliflozin causes significant differences in the gene expression profile of macrophages and fibroblasts. Moreover, dapagliflozin directly inhibits macrophage inflammation, thereby suppressing cardiac fibroblasts activation. The cardio-protection of dapagliflozin is blurred in mice treated with a C-C chemokine receptor type 2 antagonist. Taken together, the protective effects of dapagliflozin against HF are independent of SGLT2, and macrophage inhibition is the main target of dapagliflozin against HF.

In-Hospital and readmission outcomes of patients with myeloproliferative neoplasms and heart failure: Insights from the National Readmissions Database

BackgroundMyeloproliferative neoplasms (MPNs) are chronic leukemias associated with increased risk of cardiovascular (CV) events. Prior studies suggest patients with MPN are at increased risk of HF. Additionally, pre-clinical murine models harboring the JAK2 mutation, the most common driver mutation in MPNs, have shown accelerated adverse cardiac remodeling in myocardial infarction and pressure overload HF models. However, clinical outcomes, including in-hospital and readmission outcomes, of patients with MPN admitted for HF have not been well characterized. MethodsPatients hospitalized for HF with and without MPN were identified using the 2017 and 2018 National Readmission Database. Propensity score matching (PSM) was performed to match 1 MPN with 10 non-MPN controls. Outcomes were in-hospital death, 90-day CV-related, HF-related, and all-cause readmissions. Logistic regression and Cox proportional hazards regression models were used to estimate risk of in-hospital death and 90-day readmission outcomes, respectively. ResultsAfter PSM, 4,626 patients with MPN were matched with 46,260 without. Patients with MPN were associated with increased risk of in-hospital death (OR 1.17, 95% CI 1.00 – 1.35), 90-day CV-related (HR 1.10, 95% CI 1.02 – 1.18) and all-cause (HR 1.24, 95% CI 1.17 – 1.31) but not HF-related (HR 1.05, 95% CI 0.97 – 1.14) readmissions. ConclusionAmong patients hospitalized for HF, MPN was associated with increased risk of in-hospital death, and 90-day CV-related readmissions (driven primarily by thrombotic readmissions). Further investigation is needed in order to improve outcomes in patients with MPN and HF.

Endothelial cells adopt a pro-reparative immune responsive signature during cardiac injury.

Modulation of the heart's immune microenvironment is crucial for recovery after ischemic events such as myocardial infarction (MI). Endothelial cells (ECs) can have immune regulatory functions; however, interactions between ECs and the immune environment in the heart after MI remain poorly understood. We identified an EC-specific IFN responsive and immune regulatory gene signature in adult and pediatric heart failure (HF) tissues. Single-cell transcriptomic analysis of murine hearts subjected to MI uncovered an EC population (IFN-ECs) with immunologic gene signatures similar to those in human HF. IFN-ECs were enriched in regenerative-stage mouse hearts and expressed genes encoding immune responsive transcription factors (Irf7, Batf2, and Stat1). Single-cell chromatin accessibility studies revealed an enrichment of these TF motifs at IFN-EC signature genes. Expression of immune regulatory ligand genes by IFN-ECs suggests bidirectional signaling between IFN-ECs and macrophages in regenerative-stage hearts. Our data suggest that ECs may adopt immune regulatory signatures after cardiac injury to accompany the reparative response. The presence of these signatures in human HF and murine MI models suggests a potential role for EC-mediated immune regulation in responding to stress induced by acute injury in MI and chronic adverse remodeling in HF.

Granzyme B PET imaging inflammation and remodeling in myocardial infarction.

This study aimed to evaluate whether granzyme B (GzmB)-targeted positron emission tomography (PET) imaging agent (68Ga-grazytracer) can characterize cardiac inflammation and remodeling in myocardial infarction (MI). Rats with MI were subjected to GzmB-targeted PET/CT on post-operative days 1, 3, 6, 14, and 28. Autoradiography, Masson staining, immunohistochemistry, and ELISA were performed to verify the inflammatory response and remodeling after MI in vitro. Rats were treated with GzmB inhibitor Z-IETD-FMK to improve cardiac remodeling. Cardiac function tests were performed by echocardiography at 6weeks after MI. The highest uptake of 68Ga-grazytracer was observed on day 3 after MI compared with the values obtained on the other days (0.294 ± 0.03% ID/g at 3days vs. 0.122 ± 0.01% ID/g in the sham group, P < 0.001). Immunohistochemistry showed significantly high expression of GzmB and CD8, in line with the PET/CT imaging results. Autoradiography revealed 68Ga-grazytracer accumulation in the infarcted myocardium. The 68Ga-grazytracer uptake of treated rats was significantly reduced compared with that in the MI groups (0.184 ± 0.03%ID/g vs. 0.286 ± 0.03%ID/g; P < 0.001). Echocardiography showed that the left ventricular ejection fraction was lower in the MI groups than in the ischemia reperfusion group. GzmB inhibitor treatment was shown to be effective in improving cardiac function without significantly shortening infarct size. This study demonstrated the potential of 68Ga-grazytracer imaging to delineate adverse inflammatory responses and pathological cardiac remodeling, which can help predict heart function. PET/CT imaging-guided therapy may reduce myocardial injury and improve heart function in MI.

Cis-trans isomerization of peptoid residues in the collagen triple-helix

Cis-peptide bonds are rare in proteins, and building blocks less favorable to the trans-conformer have been considered destabilizing. Although proline tolerates the cis-conformer modestly among all amino acids, for collagen, the most prevalent proline-abundant protein, all peptide bonds must be trans to form its hallmark triple-helix structure. Here, using host-guest collagen mimetic peptides (CMPs), we discover that surprisingly, even the cis-enforcing peptoid residues (N-substituted glycines) form stable triple-helices. Our interrogations establish that these peptoid residues entropically stabilize the triple-helix by pre-organizing individual peptides into a polyproline-II helix. Moreover, noting that the cis-demanding peptoid residues drastically reduce the folding rate, we design a CMP whose triple-helix formation can be controlled by peptoid cis-trans isomerization, enabling direct targeting of fibrotic remodeling in myocardial infarction in vivo. These findings elucidate the principles of peptoid cis-trans isomerization in protein folding and showcase the exploitation of cis-amide-favoring residues in building programmable and functional peptidomimetics.

Cardiac reprogramming reduces inflammatory macrophages and improves cardiac function in chronic myocardial infarction

Cardiomyocytes (CMs) have little regenerative capacity. After myocardial infarction (MI), scar formation and myocardial remodeling proceed in the infarct and non-infarct areas, respectively, leading to heart failure (HF). Prolonged activation of cardiac fibroblasts (CFs) and inflammatory cells may contribute to this process; however, therapies targeting these cell types remain lacking. Cardiac reprogramming converts CFs into induced CMs, reduces fibrosis, and improves cardiac function in chronic MI through the overexpression of Mef2c/Gata4/Tbx5/Hand2 (MGTH). However, whether cardiac reprogramming reduces inflammation in infarcted hearts remains unclear. Moreover, the mechanism through which MGTH overexpression in CFs affects inflammatory cells remains unknown. Here, we showed that inflammation persists in the myocardium until three months after MI, which can be reversed with cardiac reprogramming. Single-cell RNA sequencing demonstrated that CFs expressed pro-inflammatory genes and exhibited strong intercellular communication with inflammatory cells, including macrophages, in chronic MI. Cardiac reprogramming suppressed the inflammatory profiles of CFs and reduced the relative ratios and pro-inflammatory signatures of cardiac macrophages. Moreover, fluorescence-activated cell sorting analysis (FACS) revealed that cardiac reprogramming reduced the number of chemokine receptor type 2 (CCR2)-positive inflammatory macrophages in the non-infarct areas in chronic MI, thereby restoring myocardial remodeling. Thus, cardiac reprogramming reduced the number of inflammatory macrophages to exacerbate cardiac function after MI.

Remodeling in early myocardial infarction: alteration of extracellular matrix; Collagen-1, Collagen-3, α-SMA, and α-Actinin in Porcine heart model

Link of Video Abstract: https://youtu.be/lThOW40upEc Background: Myocardial infarction (MI) leads to remodeling due to altered cardiac structure and function. The study of MI histopathology in humans or large animals mimicking the human heart is limited. Using the porcine heart model, our study investigated the composition of myocardial extracellular matrix (ECM) in collagen-1, collagen-3, α-smooth muscle actin (α-SMA), and α-actinin before and after myocardial infarction. Methods: This study used two groups of domestic pigs: the Infarct group (n=4) and the Sham group (n=4). MI was induced by permanent ligation of the proximal branch of the posterior left ventricular artery. Cardiac enzymes, electrocardiography, and echocardiography data were collected before and after ligation. Cardiac tissue was harvested from the infarcted area after 60 minutes of ligation and stained with hematoxylin-eosin and Movat's Pentachrome. Collagen-1, collagen-3, and α-SMA were identified with immunohistochemical labeling, and the labeled area was measured using ImageJ. Meanwhile, α-actinin was visualized using immunofluorescence. Results: Expression of collagen-1, collagen-3, and α-SMA in the infarct group were significantly decreased after 60 minutes of infarction compared with those in the sham group (p&lt;0.01). The α-actinin was fragmented and diminished in the infarct group. Conclusion: Myocardial remodeling was detected 60 minutes after infarction with mild alteration in myocardial histoarchitecture and significant deterioration of ECM composition of collagen-1, collagen-3, α-SMA, and fragmented α-actinin fibers in the porcine heart model.

BAK contributes critically to necrosis and infarct generation during reperfused myocardial infarction

At least seven cell death programs are activated during myocardial infarction (MI), but which are most important in causing heart damage is not understood. Two of these programs are mitochondrial-dependent necrosis and apoptosis. The canonical function of the pro-cell death BCL-2 family proteins BAX and BAK is to mediate permeabilization of the outer mitochondrial membrane during apoptosis allowing apoptogen release. BAX has also been shown to sensitize cells to mitochondrial-dependent necrosis, although the underlying mechanisms remain ill-defined. Genetic deletion of Bax or both Bax and Bak in mice reduces infarct size following reperfused myocardial infarction (MI/R), but the contribution of BAK itself to cardiomyocyte apoptosis and necrosis and infarction has not been investigated. In this study, we use Bak-deficient mice and isolated adult cardiomyocytes to delineate the role of BAK in the pathogenesis of infarct generation and post-infarct remodeling during MI/R and non-reperfused MI. Generalized homozygous deletion of Bak reduced infarct size ∼50% in MI/R in vivo, which was attributable primarily to decreases in necrosis. Protection from necrosis was also observed in BAK-deficient isolated cardiomyocytes suggesting that the cardioprotection from BAK loss in vivo is at least partially cardiomyocyte-autonomous. Interestingly, heterozygous Bak deletion, in which the heart still retains ∼28% of wild type BAK levels, reduced infarct size to a similar extent as complete BAK absence. In contrast to MI/R, homozygous Bak deletion did not attenuate acute infarct size or long-term scar size, post-infarct remodeling, cardiac dysfunction, or mortality in non-reperfused MI. We conclude that BAK contributes significantly to cardiomyocyte necrosis and infarct generation during MI/R, while its absence does not appear to impact the pathogenesis of non-reperfused MI. These observations suggest BAK may be a therapeutic target for MI/R and that even partial pharmacological antagonism may provide benefit.

Ligustrazine and liguzinediol protect against doxorubicin-induced cardiomyocytes injury by inhibiting mitochondrial apoptosis and autophagy.

Preventing or treating heart failure (HF) by blocking cardiomyocyte apoptosis is an effective strategy that improves survival and reduces ventricular remodelling and dysfunction in the chronic stage. Autophagy is a mechanism that degrades intracellular components and compensates for energy deficiency, which is commonly observed in cardiomyocytes of failed hearts. Cardiomyocytes activated by doxorubicin (DOX) exhibit strong autophagy. This study aims to investigate the potential protective effect of ligustrazine and its derivative liguzinediol on regulating DOX-induced cardiomyocyte apoptosis and explore the use of the embryonic rat heart-derived myoblast cell line H9C2 for identifying novel treatments for HF. The results indicated that it has been demonstrated to reverse myocardial infarction remodelling in failed hearts by promoting autophagy in salvaged cardiomyocytes and anti-apoptosis of cardiomyocytes in granulation tissue. Our study suggests that ligustrazine and liguzinediol can be a promising agents and autophagy is potential pathway in the management of HF.

LncRNA-encoded peptides: unveiling their significance in cardiovascular physiology and pathology - current research insights.

Long non-coding RNAs (lncRNAs), which are RNA transcripts exceeding 200 nucleotides, were believed to lack any protein-coding capacity. But advancements in -omics technology have revealed that some lncRNAs have small open reading frames (sORFs) that can be translated by ribosomes to encode peptides, some of which have important biological functions. These encoded peptides subserve important biological functions by interacting with their targets to modulate transcriptional or signaling axes, thereby enhancing or suppressing CVD occurrence and progression. In this review, we summarize what is known about the research strategy of lncRNA-encoded peptides, mainly comprising predictive websites/tools and experimental methods that have been widely used for prediction, identification, and validation. More importantly, we have compiled a list of lncRNA- encoded peptides, with a focus on those that play significant roles in cardiovascular physiology and pathology, including RNO-sORF6/RNO-sORF7/RNO-sORF8, DOWRF, and NLN etc. Additionally, we have outlined the functions and mechanisms of these peptides in cardiovascular physiology and pathology, such as cardiomyocyte hypertrophy, myocardial contraction, myocardial infarction and vascular remodeling. Finally, an overview of the existing challenges and potential future developments in the realm of lncRNA-encoded peptides was provided, with consideration given to prospective avenues for further research. Given that many lncRNA encoded peptides have not been functionally annotated yet, their application in CVD diagnosis and treatment still requires further research.

Cardiac magnetic resonance for the early prediction of reverse left ventricular remodeling in patients with ST-segment elevation myocardial infarction.

To evaluate the changes in cardiac magnetic resonance (CMR) characteristics and investigate the predictors of reverse left ventricular remodeling (r-LVR) in ST-segment elevation myocardial infarction (STEMI) patients. Eighty-six STEMI patients (median 56 years) were retrospectively studied. The patients were divided into r-LVR and without r-LVR groups. CMR analysis included LV volume, infarct characteristics, and global and regional myocardial function. The strain and displacement were assessed by CMR-feature tracking. The predictors of r-LVR were analyzed by the logistic regression method. There were 37 patients in the r-LVR group and 49 patients in the without r-LVR group. At initial CMR, there was no difference in LV volume and global cardiac function between the two groups. However, the infarct zone radial and longitudinal displacements were higher in the r-LVR group (p< 0.05, respectively). At the second CMR, the r-LVR group showed higher LVEF, lower LV volume, and total enhanced mass (all p< 0.05). The infarct zone radial and circumferential strains and radial displacement were higher in the r-LVR group (all p< 0.05). The r-LVR group had better recovery of myocardial injury and function. Of note, microvascular obstruction (MVO) mass (odds ratio: 0.779 (0.613-0.989), p= 0.041) and infarct zone peak longitudinal displacement (PLD) (odds ratio: 1.448 (1.044-2.008), p= 0.026) were independent predictors of r-LVR. At initial CMR, there were no differences in global cardiac function between the two groups, but infarct zone displacements were higher in the r-LVR group. The r-LVR group had better recovery of cardiac function. In addition, MVO mass and infarct zone PLD were independent predictors of r-LVR. Our study assessed changes in cardiac structure, function, and tissue characteristics after STEMI by CMR, investigated the best predictors of r-LVR in STEMI patients, and laid the foundation for the development of new parameter-guided treatment strategies for STEMI patients. • At initial CMR, the reverse left ventricular remodeling (r-LVR) group had less myocardial damage and higher infarct zone displacement, but there were no differences in global function between the two groups. • Both groups showed recovery of myocardial injury and cardiac function over time, but the r-LVR group had less enhanced mass and better cardiac function compared to the without r-LVR group at the second CMR. • Microvascular obstruction mass and infarct zone peak longitudinal displacement by cardiac magnetic resonance feature-tracking were significant predictors of r-LVR in STEMI patients.