Limit Infarct Size Research Articles

Endothelial dysfunction in acute coronary syndrome: a complex association with cardiovascular risk factors, sleep quality and cardiorespiratory capacity

Abstract Introduction It is widely acknowledged that normal endothelial function plays a pivotal role in conferring cardioprotective effects against ischemia-reperfusion injury following acute myocardial infarction (AMI) treated by a primary percutaneous coronary intervention (PCI), thereby limiting infarct size (1). However, endothelial dysfunction (ED) has been extensively documented in patients with cardiovascular (CV) risk factors (2). This study proposes a novel perspective, positing that ED could be intricately linked not only with traditional CV risk factors, but also it can be associated with poor sleep quality. Consequently, this interplay might significantly contribute to the attenuation of exercise capacity. Objective The aim of this study was to assess endothelial function following AMI treated with a PCI and investigate the link between endothelial function, CV risk factors, sleep quality and exercise capacity. Furthermore, the study aimed to determine if endothelial function could serve as a predictive factor for future major adverse acute cardiac events (MAACE) following AMI. Materials and methods Sixty-three patients with AMI (56.21 ± 7.6 years) volunteered to participate in this study, . Endothelial function was assessed using the Endothelium Quality Index (EQI) . Sleep quality was evaluated using both actigraphy and the PSQI (Pittsburgh Sleep Quality Index) questionnaire. Exercise capacity was quantified through the 6-minute walking test (6mwt). Results ED was evident, as indicated by an EQI of 1.4 ± 0.7. Furthermore, ED was notably influenced by CV risk factors such as low physical activity level, age, and smoking. A significant correlation was found between EQI and both sleep efficiency (r = 0.340; p = 0.006) and PSQI score (r = -0.533; p < 0.001). Additionally, a strong association was observed between endothelial function and the results of the 6mwt (r = 0.291; p = 0.021). Furthermore, during a follow up period ( near 4 months) following PCI, MAACE were observed in patients with severe ED only. Conclusion In summary, findings of this study may emphasize the importance of enhancing sleep quality and advocating for an active lifestyle as modifiable elements to enhance endothelial function, which can be regarded as a prognostic tool subsequent to AMI, ultimately contributing to improved clinical outcomes. Moreover, this study concluded that AMI patients with severe endothelial dysfunction were more likely to develop MAACE.Endothelial Dysfunction after AMIED following AMI : Causes and effect

Hypothermia for Cardioprotection in Acute Coronary Syndrome Patients: From Bench to Bedside.

Early revascularization for patients with acute myocardial infarction (AMI) is of outmost importance in limiting infarct size and associated complications, as well as for improving long-term survival and outcomes. However, reperfusion itself may further damage the myocardium and increase the infarct size, a condition commonly recognized as myocardial reperfusion injury. Several strategies have been developed for limiting the associated with reperfusion myocardial damage, including hypothermia. Hypothermia has been shown to limit the degree of infarct size increase, when started before reperfusion, in several animal models. Systemic hypothermia, however, failed to show any benefit, due to adverse events and potentially insufficient myocardial cooling. Recently, the novel technique of intracoronary selective hypothermia is being tested, with preclinical and clinical results being of particular interest. Therefore, in this review, we will describe the pathophysiology of myocardial reperfusion injury and the cardioprotective mechanics of hypothermia, report the animal and clinical evidence in both systemic and selective hypothermia and discuss the potential future directions and clinical perspectives in the context of cardioprotection for myocardial reperfusion injury.

Management of Myocardial Infarction: Emerging Paradigms for the Future.

Despite significant advancements in managing acute ST-segment elevation myocardial infarctions, the prevalence of heart failure has not decreased. Emerging paradigms with a focus on reducing infarct size show promising evidence in the improvement of the incidence of heart failure after experiencing acute coronary syndromes. Limiting infarct size has been the focus of multiple clinical trials over the past decades and has led to left ventricular (LV) unloading as a potential mechanism. Contemporary use of microaxial flow devices for LV unloading has suggested improvement in mortality in acute myocardial infarction complicated by cardiogenic shock. This review focuses on clinical data demonstrating evidence of infarct size reduction and highlights ongoing clinical trials that provide a new therapeutic approach to the management of acute myocardial infarction.

Cardioprotective potential of oleuropein, hydroxytyrosol, oleocanthal and their combination: Unravelling complementary effects on acute myocardial infarction and metabolic syndrome

Clinical studies have previously established the role of olive products in cardiovascular disease (CVD) prevention, whilst the identification of the responsible constituents for the beneficial effects is still pending. We sought to assess and compare the cardioprotective potential of oleuropein (OL), hydroxytyrosol (HT), oleocanthal (OC) and oleanolic Acid (OA), regarding Ischemia/Reperfusion Injury (IRI) and CVD risk factors alleviation. The scope of the study was to design a potent and safe combinatorial therapy for high-cardiovascular-risk patients on a bench-to-bedside approach. We evaluated the IRI-limiting potential of 6-weeks treatment with OL, HT, OC or OA at nutritional doses, in healthy and metabolic syndrome (MS)-burdened mice. Three combinatorial regimens were designed and the mixture with preponderant benefits (OL-HT-OC, Combo 2), including infarct sparing and antiglycemic potency, compared to the isolated compounds, was further investigated for its anti-atherosclerotic effects. In vivo experiments revealed that the combination regimen of Combo 2 presented the most favorable effects in limiting infarct size and hyperglycemia, which was selected to be further investigated in the clinical setting in Chronic Coronary Artery Syndrome (CCAS) patients. Cardiac function, inflammation markers and oxidative stress were assessed at baseline and after 4 weeks of treatment with the OL-HT-OC supplement in the clinical study. We found that OL, OC and OA significantly reduced infarct size in vivo compared to Controls. OL exhibited antihyperglycemic properties and OA attenuated hypercholesterolemia. OL-HT-OA, OL-HT-OC and OL-HT-OC-OA combination regimens were cardioprotective, whereas only OL-HT-OC mitigated hyperglycemia. Combo 2 cardioprotection was attributed to apoptosis suppression, enhanced antioxidant effects and upregulation of antioxidant enzymes. Additionally, it reduced atherosclerotic plaque extent in vivo. OL-HT-OC supplement ameliorated cardiac, vascular and endothelial function in the small-scale clinical study. Conclusively, OL-HT-OC combination therapy exerts potent cardioprotective, antihyperglycemic and anti-atherosclerotic properties in vivo, with remarkable and clinically translatable cardiovascular benefits in high-risk patients.

Effect of Intramyocardial Administration of Baculovirus Encoding the Transcription Factor Tbx20 in Sheep With Experimental Acute Myocardial Infarction.

Gene therapy has been proposed as a strategy to induce cardiac regeneration following acute myocardial infarction (AMI). Given that Tbx20, a transcription factor of the T-box subfamily, stimulates cell proliferation and angiogenesis, we designed a baculovirus overexpressing Tbx20 (Bv-Tbx20) and evaluated its effects in cultured cardiomyocytes and in an ovine model of AMI. Cell proliferation and angiogenesis were measured in cardiomyocytes transduced with Bv-Tbx20 or Bv-Null (control). Subsequently, in sheep with AMI, Bv-Tbx20 or Bv-Null was injected in the infarct border. Cardiomyocyte cell cycle activity, angioarteriogenesis, left ventricular function, and infarct size were assessed. Cardiomyocytes transduced with BvTbx20 increased cell proliferation, cell cycle regulatory and angiogenic gene expression, and tubulogenesis. At 7 days posttreatment, sheep treated with Bv-Tbx20 showed increased Tbx20, promitotic and angiogenic gene expression, decreased levels of P21, increased Ki67- (17.09±5.73 versus 7.77±7.24 cardiomyocytes/mm2, P<0.05) and PHH3 (phospho-histone H3)-labeled cardiomyocytes (10.10±3.51 versus 5.23±2.87 cardiomyocytes/mm2, P<0.05), and increased capillary (2302.68±353.58 versus 1694.52±211.36 capillaries/mm2, P<0.001) and arteriolar (146.95±53.14 versus 84.06±16.84 arterioles/mm2, P<0.05) densities. At 30 days, Bv-Tbx20 decreased infarct size (9.89±1.92% versus 12.62±1.33%, P<0.05) and slightly improved left ventricular function. Baculoviral gene transfer-mediated Tbx20 overexpression exerted angiogenic and cardiomyogenic effects invitro. In sheep with AMI, Bv-Tbx20 induced angioarteriogenesis, cardiomyocyte cell cycle activity, infarct size limitation, and a slight recovery of left ventricular function, suggesting that Bv-Tbx20 gene therapy may contribute to cardiac regeneration following AMI.

Pharmacological inhibition of RUNX1 reduces infarct size after acute myocardial infarction in rats and underlying mechanism revealed by proteomics implicates repressed cathepsin levels

Myocardial infarction (MI) results in prolonged ischemia and the subsequent cell death leads to heart failure which is linked to increased deaths or hospitalizations. New therapeutic targets are urgently needed to prevent cell death and reduce infarct size among patients with MI. Runt-related transcription factor-1 (RUNX1) is a master-regulator transcription factor intensively studied in the hematopoietic field. Recent evidence showed that RUNX1 has a critical role in cardiomyocytes post-MI. The increased RUNX1 expression in the border zone of the infarct heart contributes to decreased cardiac contractile function and can be therapeutically targeted to protect against adverse cardiac remodelling. This study sought to investigate whether pharmacological inhibition of RUNX1 function has an impact on infarct size following MI. In this work we demonstrate that inhibiting RUNX1 with a small molecule inhibitor (Ro5-3335) reduces infarct size in an in vivo rat model of acute MI. Proteomics study using data-independent acquisition method identified increased cathepsin levels in the border zone myocardium following MI, whereas heart samples treated by RUNX1 inhibitor present decreased cathepsin levels. Cathepsins are lysosomal proteases which have been shown to orchestrate multiple cell death pathways. Our data illustrate that inhibition of RUNX1 leads to reduced infarct size which is associated with the suppression of cathepsin expression. This study demonstrates that pharmacologically antagonizing RUNX1 reduces infarct size in a rat model of acute MI and unveils a link between RUNX1 and cathepsin-mediated cell death, suggesting that RUNX1 is a novel therapeutic target that could be exploited clinically to limit infarct size after an acute MI.

Protective Effects of Trans-Chalcone on Myocardial Ischemia and Reperfusion Challenge through Targeting Phosphoinositide 3-kinase/Akt-inflammosome Interaction.

Ischemia-reperfusion (IR) injury remains a pivotal contributor to myocardial damage following acute coronary events and revascularization procedures. Phosphoinositide 3-kinase (PI3K), a key mediator of cell survival signaling, plays a central role in regulating inflammatory responses and cell death mechanisms. Trans-chalcone (Tch), a natural compound known for its anti-inflammatory activities, has shown promise in various disease models. The aim of the current study was to investigate the potential protective effects of Tch against myocardial injury induced by ischemia and reperfusion challenges by targeting the PI3K-inflammasome interaction. Experimental models utilizing male rats subjected to an in vivo model of IR injury and myocardial infarction were employed. Administration of Tch (100 μg/kg, intraperitoneally) significantly reduced myocardial injury, as indicated by limited infarct size and decreased levels of the myocardial enzyme troponin. Mechanistically, Tch upregulated PI3K expression, thereby inhibiting the activity of the NOD-like receptor protein 3 inflammasome followed by the activation of pro-inflammatory cytokines interleukin-1β (IL-1β) and IL-18. Moreover, it mitigated oxidative stress and suppressed vascular-intercellular adhesion molecules, contributing to its cardioprotective effects. The PI3K/Akt pathway inhibitor LY294002 considerably attenuated the beneficial effects of Tch. These findings highlight the therapeutic potential of Tch in ameliorating myocardial injury associated with IR insults through its modulation of the PI3K/Akt-inflammasome axis. The multifaceted mechanisms underlying its protective effects signify Tch as a promising candidate for further exploration in developing targeted therapies aimed at mitigating ischemic heart injury and improving clinical outcomes in cardiovascular diseases characterized by IR injury.

Aloperine Alleviates Myocardial Injury Induced by Myocardial Ischemia and Reperfusion by Activating the ERK1/2/β-catenin Signaling Pathway.

Myocardial ischemia/reperfusion (I/R) injury can cause severe cardiac damage. Aloperine is a quinolizidine alkaloid found in the leaves and seeds of Sophora alopecuroides L. It has been recognized that aloperine has organ-protective properties; however, its role in cardioprotection is poorly characterized. This study aimed to evaluate the cardioprotective effects of aloperine against myocardial I/R injury in vivo. Adult male Sprague‒Dawley rats were randomly divided into sham-operated, control, and aloperine groups. All rats except for the sham-operated rats were subjected to 45min of myocardial ischemia (by left anterior descending ligation) followed by 3h of reperfusion. Aloperine (10mg/kg) was given intravenously at the onset of reperfusion. The cardioprotective effects of aloperine were evaluated by determining infarct size, hemodynamics, histological changes, cardiac biomarkers, and cardiac apoptosis. Aloperine limited infarct size; improved hemodynamics; attenuated myocardial I/R-induced histological deterioration; decreased serum LDH, CK-MB, and α-HBDH levels; and inhibited apoptosis after myocardial I/R injury. Moreover, aloperine stimulated the phosphorylation of ventricular ERK1/2, which is a major module of MAPK signaling pathways. Furthermore, aloperine increased the ventricular expression levels of β-catenin. Pharmacological inhibition of ERK1/2 diminished aloperine-induced cardioprotection and blocked ERK1/2/β-catenin signaling. These data support the cardioprotective effect of aloperine against myocardial I/R injury, which is mediated, at least in part, by the ERK1/2/β-catenin signaling pathway.

Exploring the therapeutic potential of Sirt6-enriched adipose stem cell-derived exosomes in myocardial ischemia–reperfusion injury: unfolding new epigenetic frontiers

BackgroundThe management of myocardial ischemia–reperfusion injury (MIRI) presents continuous therapeutic challenges. NAD-dependent deacetylase Sirtuin 6 (Sirt6) plays distinct roles in various disease contexts and is hence investigated for potential therapeutic applications for MIRI. This study aimed to examine the impact of Sirt6-overexpressing exosomes derived from adipose stem cells (S-ASC-Exo) on MIRI, focusing on their influence on AIM2-pyroptosis and mitophagy processes. The sirtuin family of proteins, particularly Sirtuin 6 (Sirt6), play a pivotal role in these processes. This study aimed to explore the potential therapeutic effects of Sirt6-enriched exosomes derived from adipose stem cells (S-ASC-Exo) on regulating MIRI.ResultsBioinformatic analysis revealed a significant downregulation of Sirt6 in MIRI subjected to control group, causing a consequential increase in mitophagy and pyroptosis regulator expressions. Therefore, our study revealed that Sirt6-enriched exosomes influenced the progression of MIRI through the regulation of target proteins AIM2 and GSDMD, associated with pyroptosis, and p62 and Beclin-1, related to mitophagy. The introduction of S-ASC-Exo inhibited AIM2-pyroptosis while enhancing mitophagy. Consequently, this led to a significant reduction of GSDMD cleavage and pyroptosis in endothelial cells, catalyzing a deceleration in the progression of atherosclerosis. Extensive in vivo and in vitro assays were performed to validate the expressions of these specific genes and proteins, which affirmed the dynamic modulation by Sirt6-enriched exosomes. Furthermore, treatment with S-ASC-Exo drastically ameliorated cardiac functions and limited infarct size, underlining their cardioprotective attributes.ConclusionsOur study underscores the potential therapeutic role of Sirt6-enriched exosomes in managing MIRI. We demonstrated their profound cardioprotective effect, evident in the enhanced cardiac function and attenuated tissue damage, through the strategic modulation of AIM2-pyroptosis and mitophagy. Given the intricate interplay between Sirt6 and the aforementioned processes, a comprehensive understanding of these pathways is essential to fully exploit the therapeutic potential of Sirt6. Altogether, our findings indicate the promise of Sirt6-enriched exosomes as a novel therapeutic strategy in treating ischemia–reperfusion injuries and cardiovascular diseases at large. Future research needs to underscore optimizing the balance of mitophagy during myocardial ischemia to avoid potential loss of normal myocytes.

Guanxin V alleviates ventricular remodeling after acute myocardial infarction with circadian disruption by regulating mitochondrial dynamics.

Circadian disruption has been a common issue due to modern lifestyles. Ventricular remodeling (VR) is a pivotal progressive pathologic change after acute myocardial infarction (AMI) andcircadian disruption may have anegative influence on VR according to thelatest research. Whether or notGuanxin V (GXV) has a positive effect on VR after AMI with circadian disruption drew our interest. Rats were randomly divided into asham group, anAMI group, anAMI with circadian disruption group, and anAMI with circadian disruption treated with the GXV group according to a random number table. RNA sequencing (RNA-Seq) was utilized to confirm the different expressed genes regulated by circadian disruption. Cardiac function, inflammation factors, pathological evaluation, and mitochondrial dynamics after the intervention were conducted to reveal the mechanism by which GXV regulated VR after AMI with circadian disruption. RNA-Seq demonstrated that NF-κB was up-regulated by circadian disruption in rats with AMI. Functional and pathological evaluation indicated that compared with the AMI group, circadian disruption was associcataed withdeteriorated cardiac function, expanded infarcted size, and exacerbated fibrosis and cardiomyocyte apoptosis. Further investigation demonstrated that mitochondrial dynamics imbalance was induced by circadian disruption. GXV intervention reversed the inflammatory status including down-regulation of NF-κB. Reserved cardiac function, limited infarct size, and ameliorated fibrosis and apoptosis were also observed in the GXV treated group. GXV maintained mitochondrial fission/fusion imbalance through suppressed expression of mitochondrial fission-associated proteins. The study findings suggestthat identified mitochondrial dysfunctions may underlie the link between circadian disruption and VR. GXV may exert cardioprotection after AMI with circadian disruption through regulating mitochondrial dynamics.

Selective cardiac myosin inhibitors protect the heart following ischemia-reperfusion injury

Abstract Background/Introduction Following an acute myocardial infarction, reperfusion of an occluded coronary artery is often accompanied by cardiomyocyte injury, leading to a worse long-term prognosis. Cardiomyocyte hypercontracture in the first few minutes of post-ischemic reperfusion (IR) is a critical determinant of reperfusion-induced cell death. Inhibition of hypercontracture is highly cardioprotective, but the therapies available are non-specific and unsuitable for clinical translation. Recently, cardiac myosin-targeted inhibitors (CMIs) of contraction, Mavacamten and Aficamten, have been developed to treat patients with hypertrophic cardiomyopathy. These CMIs are well tolerated and safe in clinical trials, however they have not been investigated in the setting of IR injury. Purpose To investigate whether these CMIs could be repurposed to reduce reperfusion-induced hypercontracture following IR, which in turn would limit infarct size. Methods Male Sprague Dawley rats underwent in-vivo myocardial infarction with 30 min ischemia followed by 120 min reperfusion. 15 min prior to reperfusion, Mavacamten or vehicle (10 % DMSO with 90 % corn oil) were administered intraperitoneally. In addition, in vitro experiments using primary adult rat cardiomyocytes (ARVC) were undertaken to confirm the ability of both CMIs to inhibit hypercontracture. Isolated ARVC were pre-treated with either Mavacamten or Aficamten for 30 min before incubating with carbonyl cyanide m-chlorophenylhydrazone (cCCP) to induce cell contracture. Results Mavacamten (2mg/kg) vs control significantly reduced regional infarct size (38.4 ± 4.6 % vs 60.3 ± 5 %, p &amp;lt; 0.05, n= 7-8). Notably, treatment with both Mavacamten (10mM) and Aficamten (1mM) were also inhibited the ability of cCCP to induce ARVC contracture in vitro, with significant reduction in cell contracture (59.7 ± 10.1 % and 49.8 ± 18.5 %, respectively vs control, 99.1 ± 0.6 %, p &amp;lt; 0.05, n= 7). Conclusion These findings provide additional information for further studies into the potential of these CMIs to reduce reperfusion-induced hypercontracture clinically.

Arg389Gly beta-1-adrenergic receptor polymorphism determines neutrophil-stunning-associated cardioprotection by metoprolol

Abstract Background Cardioprotective strategies to limit infarct size (IS) have become crucial. The damaged inflicted on the myocardium is the result of the processes of Ischemia and Reperfusion (I/R). In the clinical trial METOCARD-CNIC, it was shown that the intravenous (i.v.) pre-reperfusion administration of the β1-selective antagonist metoprolol reduces IS and improves long-term cardiac function in patients after acute myocardial infarction (1). However, the small sample size precludes a definite conclusion. Despite not having demonstrated a solid clinical benefit in terms of hard endpoints reduction, the clinical guidelines for the management of ST-Elevation Myocardial Infarction (STEMI) recommend the early administration of i.v. β-blockers in patients undergoing Primary Coronary Intervention. Additionally, our group has recently described that the beneficial effect of metoprolol against myocardial I/R injury is due to neutrophil stunning (2), which represents a one-of-a-kind property not shared by other i.v. β-blockers, such as atenolol or propranolol (3). Purpose Since β1-adrenergic receptor (ADRB1) is one of major targets of pharmacological therapy, great efforts are now underway to account for the relevance of the polymorphic variation. Here we explore whether the cardioprotection exerted by metoprolol is dependent on genetic polymorphisms in human ADRB1. Methods Patients included in the METOCARD-CNIC trial were grouped into the different variants for the ADRB1, rs1801252 and rs1801253 (SerGly49 and Arg389Gly, respectively), which might affect their response to the beta-1 modulation exerted by metoprolol on neutrophils and thus its cardioprotective effect. Additionally, the polymorphic-dependent effect of metoprolol on neutrophil migration was evaluated in healthy volunteers, whose neutrophils were exposed across the transwell filter to the CXCL1 in the presence or absence of metoprolol. Drug-receptor interaction properties were evaluated in silico. Results We found that Arg389Gly polymorphism of the human ADRB1 impacts the cardioprotective effect of metoprolol in STEMI patients. Therefore, Arg389 homozygosity was associated with lower infarcts (Figure 1) and better long-term left ventricle ejection fraction when metoprolol was intravenously administered prior reperfusion. Moreover, the disrupting effect of metoprolol on neutrophil migration was only observed in Arg389 homozygote volunteers (Figure 2). These differences were attributed to alterations in the drug-receptor complex stability when Gly residues are present in position 389 of the ADRB1. Conclusions From our perspective, these results are the first showing a polymorphic implication in drug response against myocardial I/R injury. All the data presented refine cardiovascular pharmacotherapy, and have major implications for the prospective clinical trial design aiming at positioning metoprolol as the beta-blocker of choice to reduce hard endpoints in STEMI patients.CardioprotectionNeutrophil migration

Myocardial infarction elevates endoplasmic reticulum stress and protein aggregation in heart as well as brain

Cardiovascular diseases, including myocardial infarction (MI), constitute the leading cause of morbidity and mortality worldwide. Protein-aggregate deposition is a hallmark of aging and neurodegeneration. Our previous study reported that aggregation is strikingly elevated in hearts of hypertensive and aged mice; however, no prior study has addressed MI effects on aggregation in heart or brain. Here, we present novel data on heart and brain aggregation in mice following experimental MI, induced by left coronary artery (LCA) ligation. Infarcted and peri-infarcted heart tissue, and whole cerebra, were isolated from mice at sacrifice, 7 days following LCA ligation. Sham-MI mice (identical surgery without ligation) served as controls. We purified detergent-insoluble aggregates from these tissues, and quantified key protein constituents by high-resolution mass spectrometry (LC–MS/MS). Infarct heart tissue had 2.5- to 10-fold more aggregates than non-infarct or sham-MI heart tissue (each P = 0.001). Protein constituents from MI cerebral aggregates overlapped substantially with those from human Alzheimer’s disease brain. Prior injection of mice with mesenchymal stem cell (MSC) exosomes, shown to limit infarct size after LCA ligation, reduced cardiac aggregation ~ 60%, and attenuated markers of endoplasmic reticulum (ER) stress in heart and brain (GRP78, ATF6, P-PERK) by 50–75%. MI also elevated aggregate constituents enriched in Alzheimer’s disease (AD) aggregates, such as proteasomal subunits, heat-shock proteins, complement C3, clusterin/ApoJ, and other apolipoproteins. These data provide novel evidence that aggregation is elevated in mouse hearts and brains after myocardial ischemia, leading to cognitive impairment resembling AD, but can be attenuated by exosomes or drug (CDN1163) interventions that oppose ER stress.

Inflammation in Myocardial Ischemia/Reperfusion Injury: Underlying Mechanisms and Therapeutic Potential.

Acute myocardial infarction (MI) occurs when blood flow to the myocardium is restricted, leading to cardiac damage and massive loss of viable cardiomyocytes. Timely restoration of coronary flow is considered the gold standard treatment for MI patients and limits infarct size; however, this intervention, known as reperfusion, initiates a complex pathological process that somewhat paradoxically also contributes to cardiac injury. Despite being a sterile environment, ischemia/reperfusion (I/R) injury triggers inflammation, which contributes to infarct expansion and subsequent cardiac remodeling and wound healing. The immune response is comprised of subsets of both myeloid and lymphoid-derived cells that act in concert to modulate the pathogenesis and resolution of I/R injury. Multiple mechanisms, including altered metabolic status, regulate immune cell activation and function in the setting of acute MI, yet our understanding remains incomplete. While numerous studies demonstrated cardiac benefit following strategies that target inflammation in preclinical models, therapeutic attempts to mitigate I/R injury in patients were less successful. Therefore, further investigation leveraging emerging technologies is needed to better characterize this intricate inflammatory response and elucidate its influence on cardiac injury and the progression to heart failure.

The role and mechanisms of microvascular damage in the ischemic myocardium.

Following myocardial ischemic injury, the most effective clinical intervention is timely restoration of blood perfusion to ischemic but viable myocardium to reduce irreversible myocardial necrosis, limit infarct size, and prevent cardiac insufficiency. However, reperfusion itself may exacerbate cell death and myocardial injury, a process commonly referred to as ischemia/reperfusion (I/R) injury, which primarily involves cardiomyocytes and cardiac microvascular endothelial cells (CMECs) and is characterized by myocardial stunning, microvascular damage (MVD), reperfusion arrhythmia, and lethal reperfusion injury. MVD caused by I/R has been a neglected problem compared to myocardial injury. Clinically, the incidence of microvascular angina and/or no-reflow due to ineffective coronary perfusion accounts for 5-50% in patients after acute revascularization. MVD limiting drug diffusion into injured myocardium, is strongly associated with the development of heart failure. CMECs account for > 60% of the cardiac cellular components, and their role in myocardial I/R injury cannot be ignored. There are many studies on microvascular obstruction, but few studies on microvascular leakage, which may be mainly due to the lack of corresponding detection methods. In this review, we summarize the clinical manifestations, related mechanisms of MVD during myocardial I/R, laboratory and clinical examination means, as well as the research progress on potential therapies for MVD in recent years. Better understanding the characteristics and risk factors of MVD in patients after hemodynamic reconstruction is of great significance for managing MVD, preventing heart failure and improving patient prognosis.

Impact of quercetin in patients with myocardial infarction. A multicenter, randomized, and open-label pilot study

ObjectiveMyocardial infarction (MI) is one of the leading causes of death in the world. Early myocardial reperfusion improves acute MI survival. Bioflavonoid quercetin is known to have antioxidant, anti-inflammatory, and anti-proliferative properties. The presented pilot study aims to investigate the cardioprotective effect of quercetin on infarct size limiting in patients with ST-segment elevation myocardial infarction (STEMI). MethodsPatients (n = 143) with first anterior STEMI within 6 hours from symptoms onset were included in this open-label multicenter pilot study. Patients were randomized either into quercetin group (n = 70) in addition to standard treatment or recommended therapy alone group (control group, n = 73). Quercetin infusions were initiated before reperfusion and repeated during the next 5 days. The infarct size assessed using creatine kinase-myocardial band area under curve (CK-MB AUC) was the primary study outcome. ResultsThe study arms did not differ in demographics, time to admission, and main clinical data. The median early CK-MB AUC was significantly lower in quercetin group than in controls (8036 ± 7594 vs 11219 ± 8146 U × 1 h/L, p = 0.015). Intravenous quercetin administration was associated with less reperfusion-induced intramyocardial hemorrhage by Cardiac Magnetic Resonance on Day 3 (11.1% of patients in quercetin group vs 53.3% of patients in control group, p < 0.024). There were no significant differences in left ventricle ejection fraction and LV remodeling indicators. ConclusionOur pilot study is the first to demonstrate novel insight into ischemia/reperfusion damage in STEMI patients. The addition of quercetin to standard STEMI therapy limits infarct size and prevents intramyocardial hemorrhage after the first anterior STEMI. Further research will be necessary to both validate and expand upon these findings.

Abstract P2115: (2R,6R)-Hydroxynorketamine Prevents Myocardial Ischemia Reperfusion Injury By Regulating Immune And Inflammatory Response

Background: The ketamine metabolite 2R,6R-hydroxynorketamine (HNK) has recently attracted increasing attention by its potential as a novel fast-acting antidepressant candidate to treat depression. HNK has anti-inflammatory properties which contribute to its protective effects against ischemia and reperfusion (I/R) injury. However, whether HNK produces beneficial effects on myocardial I/R injury has not been elucidated yet. Here we tested the hypothesis that HNK might protects the heart from myocardial I/R injury by limiting myocardial inflammation. Methods and Results: Twelve male C57BL/6J mice (8-10 weeks old, 20-25 g) were used to produce acute myocardial I/R (30 min/24 h) by micro-surgery. Mice were divided into four groups: Sham, HNK+Sham, I/R, HNK+I/R. A single-dose of HNK (30 mg/kg) was intraperitoneally injected one hour before the I/R. Echocardiographic imaging and TTC staining showed that HKN administration before myocardial I/R increased fraction shortening by 26.5% and limited infarct size by 40% compared to I/R alone. Proteomics analysis showed HNK caused 81 proteins down-regulated and 18 proteins up-regulated in the left ventricle after I/R (HNK+I/R vs . I/R). The gene name of the top 5 down-regulated proteins are Ighg2b, Igkv17-121, Igkc, Igtp and Cd68. The go enrichment analysis showed that HNK in the I/R group could modulate immune response via downregulating signal transducer and activation of transcription 1 and 2 (STAT1 and STAT2) and type 1 interferon pathway. The KEGG enrichment analysis showed that HNK affected antigen processing and presentation via down-regulating beta-2-microglobulin, TAPBP and TAP1/2. Cytokine analysis showed that HNK attenuated the increased tissue levels of TNF-alpha, IL-1 beta, CTnI and BNP induced by I/R. HNK also significantly decreased I/R induced-neutrophil infiltration, apoptosis and oxidative stress in the myocardium as detected by Ly6G staining, tunel staining and DHE probe staining. Conclusion: We demonstrated for the first time the administration of HNK regulates immune response through STAT1 and STAT2 and type 1 interferon pathway in the heart, leading to the cardioprotection against I/R injury. The use of HNK may become an immunomodulatory therapy for the ischemic heart disease.

Declining risk of heart failure hospitalization following first acute myocardial infarction in Scotland between 1991-2016.

Mortality from acute myocardial infarction (AMI) has declined, increasing the pool of survivors at risk of later development of heart failure (HF). However, coronary reperfusion limits infarct size and secondary prevention therapies have improved. In light of these competing influences, we examined long-term trends in the risk of HF hospitalization (HFH) following a first AMI occurring in Scotland over 25 years. All patients in Scotland discharged alive after a first AMI between 1991 and 2015 were followed until a first HFH or death until the end of 2016 (minimum follow-up 1 year, maximum 26 years). A total of 175 672 people with no prior history of HF were discharged alive after a first AMI during the period of study. A total of 21 445 (12.2%) patients had a first HFH during a median follow-up of 6.7 years. Incidence of HFH (per 1000 person-years) at 1 year following discharge from a first AMI decreased from 59.3 (95% confidence interval [CI] 54.2-64.7) in 1991 to 31.3 (95% CI 27.3-35.8) in 2015, with consistent trends seen for HF occurring within 5 and 10 years. Accounting for the competing risk of death, the adjusted risk of HFH at 1 year after discharge decreased by 53% (95% CI 45-60%), with similar decreases at 5 and 10 years. The incidence of HFH following AMI in Scotland has decreased since 1991. These trends suggest that better treatment of AMI and secondary prevention are having an impact on the risk of HF at a population level.

Infarct Size With Incremental Global Myocardial Ischemia Times: Cyclosporine A in Donation After Circulatory Death Rat Hearts

We quantified the myocardial infarct size with varying global ischemia durations and studied the benefits of Cyclosporine A (CyA) in reducing cardiac injury in ex vivo and transplanted rat hearts. Infarct size was measured after 15, 20, 25, 30, and 35 minutes of in vivo global ischemia (n=34) and compared with control beating-heart donor (CBD) hearts (n=10). For heart function assessment, donation after circulatory death (DCD) rat hearts (n=20) were procured after 25 minutes of in vivo ischemia and reanimated ex vivo for 90 minutes. Half of the DCD hearts received CyA (0.5 mM) at reanimation. The CBD hearts (n=10) served as controls. A separate group of CBD and DCD (with or without CyA treatment) hearts underwent heterotopic heart transplantation; heart function was measured at 48 hours. Infarct size was 25% with 25 minutes of ischemia and increased significantly with 30 and 35 minutes to 32% and 41%, respectively. CyA treatment decreased infarct size in DCD hearts (15% vs 25%). Heart function in the transplanted DCD hearts was significantly better with CyA treatment and was comparable to CBD hearts. CyA administered at reperfusion limited infarct size in DCD hearts and improved their function in transplanted hearts.

Down-regulation of Hrd1 protects against myocardial ischemia-reperfusion injury by regulating PPARα to prevent oxidative stress, endoplasmic reticulum stress, and cellular apoptosis

The E3 ubiquitin ligase HMG-CoA reductase degradation protein 1 (Hrd1) is a key enzyme for ER-associated degradation of misfolded proteins. Its role in ischemic heart disease has not been fully elucidated. Here, we investigated its effect on oxidative status and cell survival in cardiac ischemia-reperfusion injury (MIRI). We found that virus-induced down-regulation of Hrd1 expression limited infarct size, decreased creatinine kinase (CK) and lactate dehydrogenase (LDH), and preserved cardiac function in mice subjected to left anterior descending coronary artery ligation and reperfusion. Silencing of the Hrd1 gene also prevented the ischemia/reperfusion (I/R)-induced (i) increase in dihydroethidium (DHE) intensity, mitochondrial production of reactive oxygen species (ROS), malondialdehyde (MDA), and nitric oxide (NO), (ii) decrease in total antioxidant capacity (T-AOC) and glutathione (GSH), (iii) disruption of mitochondrial membrane potential, and (iv) increase in the expression of glucose-regulated protein 78 (GRP78) and C/EBP homologous protein (CHOP) in ischemic heart tissue. In addition, down-regulation of Hrd1 expression prevented the abnormally increased caspase-3/caspase-9/Bax expression and decreased Bcl-2 expression in ischemic heart tissue of I/R mice. Further analysis showed that the I/R stimulus reduced peroxisome proliferation activated receptor α (PPARα) expression in ischemic heart tissue, which was partially prevented by down-regulation of Hrd1. Pharmacological inhibition of PPARα was able to abolish the preventive effect of down-regulation of Hrd1 on oxidative stress, endoplasmic reticulum stress, and cellular apoptosis in ischemic heart tissue. These data suggest that down-regulation of Hrd1 protects the heart from I/R-induced damage by suppressing oxidative stress and cellular apoptosis likely through PPARα.