Myocardial Infarct Size Research Articles

Peoniflorin Preconditioning Protects Against Myocardial Ischemia/Reperfusion Injury Through Inhibiting Myocardial Apoptosis: RISK Pathway Involved.

Preconditioning with Peoniflorin, a component of traditional Chinese prescriptions, was proposed to be a potential strategy for cardioprotection against ischemia/reperfusion (I/R) injury. However, the cardioprotective effect of Peoniflorin preconditioning has not been thoroughly confirmed, and the underlying mechanism remains unclear. Here, we examined the cardioprotective effect and its mechanism of Peoniflorin preconditioning against myocardial I/R injury. Rats were subjected to 30min of transient ischemia followed by 2h of reperfusion with or without Peoniflorin (100mg/kg) prior to reperfusion. Peoniflorin preconditioning significantly limited myocardial infarct size and reperfusion arrhythmias, as well as obviously attenuated the histomorphological and micromorphological damages induced by I/R injury. The reduced myocardial injury was also associated with the anti-apoptotic effect of Peoniflorin, as evidence by decreased TUNEL-positive cells, upregulation of BCL-2 expression, and downregulation of Bax and caspase-3 expression. In an effort to evaluate the mechanism responsible for the observed cardioprotective and anti-apoptotic effect, Western blot of phosphorylated protein was performed after 20min of reperfusion. Results showed that Peoniflorin preconditioning activated both the Akt and ERK1/2 arm of the reperfusion injury salvage kinase (RISK) pathway. To further confirm this mechanism, the PI3K signaling inhibitor LY294002 and ERK1/2 signaling inhibitor PD98059 were administered in vivo. The cardioprotective and anti-apoptotic effects of Peoniflorin preconditioning were diminished but not abolished by pretreatment with LY294002 or PD98059. Taken together, these results indicate that Peoniflorin preconditioning protects the myocardial against I/R injury and inhibits myocardial apoptosis via the activation of the RISK pathway, highlighting the potential therapeutic effects of Peoniflorin on reducing myocardial I/R injury.

The circRNA CNEACR regulates necroptosis of cardiomyocytes through Foxa2 suppression.

Circular RNAs (circRNAs) are differentially expressed in various cardiovascular disease including myocardial ischemia-reperfusion (I/R) injury. However, their functional impact on cardiomyocyte cell death, in particular, in necrotic forms of death remains elusive. In this study, we found that the level of mmu_circ_000338, a cardiac- necroptosis-associated circRNA (CNEACR), was reduced in hypoxia-reoxygenation (H/R) exposed cardiomyocytes and I/R-injured mice hearts. The enforced expression of CNEACR attenuated the necrotic form of cardiomyocyte death caused by H/R and suppressed of myocardial necrosis in I/R injured mouse heart, which was accompanied by a marked reduction of myocardial infarction size and improved cardiac function. Mechanistically, CNEACR directly binds to histone deacetylase (HDAC7) in the cytoplasm and interferes its nuclear entry. This leads to attenuation of HDAC7-dependent suppression of forkhead box protein A2 (Foxa2) transcription, which can repress receptor-interacting protein kinase 3 (Ripk3) gene by binding to its promoter region. In addition, CNEACR-mediated upregulation of FOXA2 inhibited RIPK3-dependent necrotic/necroptotic death of cardiomyocytes. Our study reveals that circRNAs such as CNEACR can regulate the cardiomyocyte necroptosis associated activity of HDACs, promotes cell survival and improves cardiac function in I/R-injured heart. Hence, the CNEACR/HDAC7/Foxa2/ RIPK3 axis could be an efficient target for alleviating myocardial damage caused by necroptotic death in ischemia heart diseases.

Association of Circulating Ketone Bodies With Functional Outcomes After ST-Segment Elevation Myocardial Infarction

BackgroundCirculating ketone bodies (KBs) are increased in patients with heart failure (HF), corresponding with increased cardiac KB metabolism and HF severity. However, the role of circulating KBs in ischemia/reperfusion remains unknown. ObjectivesThis study sought to investigate longitudinal changes of KBs and their associations with functional outcomes in patients presenting with ST-segment elevation myocardial infarction (STEMI). MethodsKBs were measured in 369 participants from a randomized trial on early metformin therapy after STEMI. Nonfasting plasma concentrations of KBs (β-hydroxybutyrate, acetoacetate, and acetone) were measured by nuclear magnetic resonance spectroscopy at presentation, at 24 hours, and after 4 months. Myocardial infarct size and left ventricular ejection fraction (LVEF) were determined by cardiac magnetic resonance imaging at 4 months. Associations of circulating KBs with infarct size and LVEF were determined using multivariable linear regression analyses. ResultsCirculating KBs were high at presentation with STEMI (median total KBs: 520 μmol/L; interquartile range [IQR]: 315-997 μmol/L). At 24 hours after reperfusion, KBs were still high compared with levels at 4-month follow-up (206 μmol/L [IQR: 174-246] vs 166 μmol/L [IQR: 143-201], respectively; P < 0.001). Increased KB concentrations at 24 hours were independently associated with larger myocardial infarct size (total KBs, per 100 μmol/L: β = 1.56; 95% confidence interval: 0.29-2.83; P = 0.016) and lower LVEF (β = −1.78; 95% CI: (−3.17 to −0.39; P = 0.012). ConclusionsCirculating KBs are increased in patients presenting with STEMI. Higher KBs at 24 hours are associated with functional outcomes after STEMI, which suggests a potential role for ketone metabolism in response to myocardial ischemia. (Metabolic Modulation With Metformin to Reduce Heart Failure After Acute Myocardial Infarction: Glycometabolic Intervention as Adjunct to Primary Coronary Intervention in ST Elevation Myocardial Infarction (GIPS-III): a Randomized Controlled Trial; NCT01217307)

Dexmedetomidine Preconditioning Reduces Myocardial Ischemia-Reperfusion Injury in Rats by Inhibiting the PERK Pathway.

ResumoFundamento A cardiopatia isquêmica atraiu muito atenção devido às altas taxas de mortalidade, custos do tratamento e a crescente morbidade na população jovem. Estratégias de reperfusão reduziram a mortalidade. Porém, a reperfusão pode levar à morte do cardiomiócito e subsequente dano irreversível ao miocárdio. No momento, não há um tratamento eficiente e direcionado para a lesão de isquemia-reperfusão (I/R).Objetivos Avaliar se a dexmedetomidina (DEX) tem efeito protetivo na I/R do miocárdio e explorar os possíveis mecanismos por trás dela.Métodos Corações de ratos foram perfundidos com o sistema de perfusão de Langendorff e aleatoriamente distribuídos em cinco grupos: grupo controle, perfundido com solução de Krebs-Henseleit (K-H) por 205 minutos sem isquemia; e quatro grupos de teste que foram submetidos a 40 minutos de isquemia global e 120 minutos de reperfusão. O Grupo DEX, o grupo ioimbina (IO) e o grupo DEX + IO foram perfundidos com DEX (10 nM), IO (1 μM) ou a combinação de DEX e IO antes da reperfusão, respectivamente. A hemodinâmica cardíaca, o tamanho do infarto do miocárdio e a histologia do miocárdio foram avaliados. A expressão da proteína-78 regulada pela glicose (GRP78), a proteína quinase do retículo endoplasmático (PERK), a PERK fosforilada, o fator de iniciação eucariótico 2α (eIF2α), eIF2α fosforilado, o fator de transcrição 4 (TCF-4) e a proteína homóloga à proteína ligadora do acentuador CCAAT (CHOP) foram avaliados. P< 0,05 foi considerado para indicar a diferença estatisticamente significativa.Resultados O pré-condicionamento com DEX melhorou a função cardíaca nos corações com I/R, reduziu o infarto do miocárdio, a apoptose do miocárdio e a expressão de GRP78, p-PERK, eIF2α, p-eIF2α, TCF-4 e CHOP.Conclusões O pré-tratamento com DEX reduziu a lesão de I/R no miocárdio ao suprimir a apoptose, o que foi induzido pela via PERK.

Cardioprotective effect of fingolimod against calcium paradox-induced myocardial injury in the isolated rat heart.

Fingolimod (FTY720) inhibits Ca2+-permeable, Mg2+-sensitive channels called transient receptor potential melastatin 7 (TRPM7), but its effects on Ca2+ paradox (CP) - induced myocardial damage has not been evaluated. We studied the effect of FTY720 on CP-induced myocardial damage and used other TRPM7 channel inhibitors nordihydroguaiaretic acid (NDGA) and Mg2+ to test if any effect of FTY720 was via TRPM7 inhibition. Langendorff-perfused Wistar rat hearts were treated with FTY720 or NDGA and subjected to a CP protocol consisting of Ca2+ depletion followed by Ca2+ repletion. Hearts of rats pre-treated with MgSO4 were also subjected to CP. Hemodynamic parameters were measured using an intraventricular balloon, and myocardial infarct size was quantified using triphenyltetrazolium chloride stain. TRPM7 proteins in ventricular tissue were detected using immunoblot analysis. FTY720, but not NDGA, decreased CP-induced infarct size. Both FTY720 and NDGA minimized the CP-induced elevation of left ventricular end-diastolic pressure, but only FTY720 ultimately improved ventricular developed pressure. Mg2+ pre-treatment had no effect on CP-induced infarct size, nor hemodynamic parameters during CP, nor the level of TRPM7 protein expression in ventricular tissue. Overall, FTY720 attenuated CP-induced myocardial damage, with potential therapeutic implications on Ca2+-mediated cardiotoxicity; however, the cardioprotective mechanism of FTY720 seems to be unrelated to TRPM7 channel modulation.

Old Age and Myocardial Injury in ST-Segment Elevation Myocardial Infarction

BackgroundLittle is known about the causality and pathological mechanism underlying the association between old age and myocardial injury in patients with ST-segment elevation myocardial infarction (STEMI). We evaluated the association between old age and myocardial injury in STEMI patients undergoing primary percutaneous coronary intervention (PCI) using cardiovascular magnetic resonance imaging (CMR). MethodsA total of 279 patients with STEMI who underwent primary PCI and CMR were enrolled. Of these, 52 patients were over the age of 70 years (18.6%, Age ≥70 group) and 227 patients were under the age of 70 years (81.4%, Age <70 group) at STEMI occurrence. We compared myocardial infarct size on CMR according to age at STEMI occurrence and performed inverse probability of treatment weighting. ResultsOn CMR analysis, myocardial infarct size on CMR tended to be greater in the Age ≥70 group than in the Age <70 group (21.2 ± 10.2% versus 19.5 ± 11.1%; p = 0.072). After performing inverse probability of treatment weighting adjustment, myocardial infarct size was significantly greater in the Age ≥70 group compared with the Age <70 group (22.6 ± 10.4% versus 19.6 ± 11.1%; p = 0.001). Subgroup analysis of patients older than 70 years revealed no significant difference in myocardial infarct size according to sex (20.1 ± 11.5% in females versus 20.4 ± 9.9% in males; p = 0.901). ConclusionsDespite appropriate coronary revascularization, old age was associated with greater extent of myocardial injury in STEMI patients.

Cardio-protective effect of tetrahydrocurcumin, the primary hydrogenated metabolite of curcumin in vivo and in vitro: Induction of apoptosis and autophagy via PI3K/AKT/mTOR pathways

Tetrahydrocurcumin (THC) is an essential metabolite of curcumin, a major active component of the Curcuma species, which have been used traditionally for the treatment of cardiovascular diseases. The PI3K/AKT/mTOR signaling pathways serve a vital role during myocardial ischemia-reperfusion (MI/R) injury. The aim of the present study was to investigate the cardioprotective potential and mechanism of THC. In the in vivo study, an animal model of MI/R was induced by coronary occlusion. Results indicated that THC (50 mg/kg/day) protected the rat hearts from MI/R-induced heart failure by increasing ejection fraction (EF) and fractional shortening (FS) and decreasing left ventricular end systolic diameter (LVESD) and left ventricular end systolic volume (LVESV). THC also reduced myocardial infarct size and apoptosis. Furthermore, H9c2 cells were incubated with THC (20 μM) to explore its potential effect following exposure to hypoxia and reoxygenation (H/R). THC post-treatment significantly augmented cell viability and prevented lactate dehydrogenase (LDH) release after H/R exposure. THC effectively improved antioxidant activity by increasing SOD and CAT activities and decreasing MDA level. THC also enhanced mitochondrial membrane potential, inhibited apoptotic cell death, diminished the Bax/Bcl-2 ratio and cleaved caspase-3 level relative to the H/R model. In addition, THC effectively decreased Beclin1 expression and LC3 II/LC3 I ratio, but increased p62 expression, compared with the H/R model group, and decreased the formation of H/R-induced autophagosomes and autolysosomes. Furthermore, THC promoted the phosphorylation of PI3K/AKT/mTOR and induced the expression of hypoxia-inducible factor 1α (HIF-1α) after H/R. However, these effects on H9c2 cells were notably abolished by the PI3K inhibitor LY294002 and mTOR inhibitor rapamycin. In conclusion, THC effectively inhibited H/R-induced autophagy and apoptosis via, at least partially, activating the PI3K/AKT/mTOR pathways. THC might have the potential to be further developed into a potential candidate for the treatment of MI/R injury.

MiR-24 Alleviates MI/RI by Blocking the S100A8/TLR4/MyD88/NF-kB Pathway.

Although inflammation plays an important role in myocardial ischemia/reperfusion injury (MI/RI), an anti-inflammatory treatment with a single target has little clinical efficacy because of the multifactorial disorders involved in MI/RI. MicroRNAs (miR-24) can achieve multitarget regulation in several diseases, suggesting that this factor may have ideal effects on alleviation of MI/RI. In the present study, bioinformatics method was used to screen potential therapeutic targets of miR-24 associated with MI/RI. Three days before ischemia/reperfusion surgery, rats in the ischemia/reperfusion, miR-24, and adenovirus-negative control groups were injected with saline, miR-24, and adenovirus-negative control (0.1 mL of 5 × 109 PFU/mL), respectively. Myocardial enzymes, myocardial infarct size, cardiac function, and the possible molecular mechanism were subsequently analyzed. In contrast to the level of S100A8, the level of miR-24 in myocardial tissue was significantly reduced after 30 minutes of ischemia followed by reperfusion for 2 hours. Overexpression of miR-24 reduced the myocardial infarction area and improved the heart function of rats 3 days after MI/RI. Moreover, miR-24 inhibited infiltration of inflammatory cells in the peri-infarction area and decreased creatine kinase myocardial band and lactate dehydrogenase release. Interestingly, miR-24 upregulation reduced S100A8 expression, followed by inhibition of toll-like receptor 4/MyD-88/nuclear factor-k-gene binding signaling activation. In conclusion, miR-24 can alleviate MI/RI via inactivation of the S100A8/toll-like receptor 4/MyD-88/nuclear factor-k-gene binding signaling pathway.

CCN family member 1 (CCN1) is an early marker of infarct size and left ventricular dysfunction in STEMI patients

Background and aimsCCN family member 1 (CCN1) has recently been proposed as a novel biomarker of myocardial injury, improving prediction of 30-day and one-year mortality following acute coronary syndromes. Among ST-elevation myocardial infarction (STEMI) patients, we evaluated the utility of CCN1 measured immediately before primary percutaneous coronary intervention (PPCI) as a predictor of two earlier endpoints: final myocardial infarct size and post-infarction left ventricular ejection fraction (LVEF). Furthermore, we evaluated the impact of CCN1 on the discriminatory power of the CADILLAC score. MethodsSTEMI patients were obtained from the SPUM-ACS cohort. Serum CCN1 was measured prior to PPCI. Linear regression assessed the association between CCN1, peak creatinine kinase (CK), and post-infarction LVEF. Cox models assessed an association between CCN1 and 30-day all-cause mortality. ResultsCCN1 was measured in 989 patients with a median value of 706.2 ng/l (IQR 434.3–1319.6). A significant correlation between CCN1, myocardial infarct size (peak CK) and LVEF was observed in univariate and multivariate analysis (both p < 0.001). Even among patients with normal classical cardiac biomarker levels at the time of PPCI, CCN1 correlated significantly with final infarct size. CCN1 significantly improved prediction of 30-day all-cause mortality by the CADILLAC score (C-index 0.864, likelihood-ratio chi-square test statistic 6.331, p = 0.012; IDI 0.026, p= 0.050). ConclusionsCompared with classical cardiac biomarkers, CCN1 is potentially the earliest predictor of final myocardial infarct size and post-infarction LVEF. CCN1 improved the discriminatory capacity of the CADILLAC score suggesting a potential role in the very-early risk stratification of STEMI patients.

Rationale and Design of the Groningen Intervention Study for the Preservation of Cardiac Function with Sodium Thiosulfate after St-segment Elevation Myocardial Infarction (GIPS-IV) trial

Ischemia and subsequent reperfusion cause myocardial injury in patients presenting with ST-segment elevation myocardial infarction (STEMI). Hydrogen sulfide (H2S) reduces "ischemia-reperfusion injury" in various experimental animal models, but has not been evaluated in humans. This trial will examine the efficacy and safety of the H2S-donor sodium thiosulfate (STS) in patients presenting with a STEMI. The Groningen Intervention study for the Preservation of cardiac function with STS after STEMI (GIPS-IV) trial (NCT02899364) is a double-blind, randomized, placebo-controlled, multicenter trial, which will enroll 380 patients with a first STEMI. Patients receive STS 12.5 grams intravenously or matching placebo in addition to standard care immediately at arrival at the catheterization laboratory after providing consent. A second dose is administered 6 hours later at the coronary care unit. The primary endpoint is myocardial infarct size as quantified by cardiac magnetic resonance imaging 4 months after randomization. Secondary endpoints include the effect of STS on peak CK-MB during admission and left ventricular ejection fraction and NT-proBNP levels at 4 months follow-up. Patients will be followed-up for 2 years to assess clinical endpoints. The GIPS-IV trial is the first study to determine the effect of a H2S-donor on myocardial infarct size in patients presenting with STEMI.

Size of Acute Myocardial Infarction Correlates with Earlier Time of Initiation of Reperfusion Therapy with Cardiac Perfusion Scintigraphy: A National Single-Center Study

BackgroundThe aim of this study was to determine the correlation between the size of acute myocardial infarction (AMI) and the time of initiation of reperfusion therapy with cardiac perfusion scintigraphy.Material/MethodsOverall, 80 patients with acute ST elevation myocardial infarction (STEMI) were examined. All patients were treated with primary percutaneous coronary intervention (pPCI). Data on patient and system delay expressed in minutes were recorded and compared with recommended timelines. Cardiac scintigraphy was performed with 99m Tc-sestamibi single-photon emission computed tomography (SPECT). The median time of cardiac scintigraphy was 20 days. The correlation between the size of infarction and the time of initiation of reperfusion therapy was evaluated.ResultsThe mean age of patients was 60.5±11.5 years, and 72.5% were male. The average system delay was 348 min, and the average patient delay was 173 min. The mean total ischemic time was 800 min. There was a correlation between time delays of reperfusion therapy and infarct size. Patients with a shorter time delay to patent artery after FMC showed smaller infarct size when compared to the patients with longer delay times. Multiple linear regression analysis showed that FMC, being male, and smokers had statistical significance when predicting infarct size.ConclusionsThere is a correlation between the size of myocardial infarction and the time of initiation of reperfusion therapy determined by perfusion myocardial scintigraphy. The study showed that there are time delays in starting the treatment of AMI with pPCI when compared to the recommended time, which requires an action plan in the near future to ensure earlier treatment for our patients.

MicroRNA-24 protects against myocardial ischemia-reperfusion injury via the NF-κB/TNF-α pathway.

Acute myocardial infarction (AMI) is a form of cardiomyopathy in which a blocked coronary artery leads to an irreversible loss of cardiomyocytes due to inadequate blood and oxygen supply to the distal myocardium tissues, eventually leading to heart failure. Recently, studies have revealed that microRNA (miRNA/miR)-24 has diagnostic value in the pathogenesis of AMI by affecting multiple cell processes such as cell proliferation, differentiation and apoptosis. However, the specific mechanism of miR-24 in ischemia-reperfusion injury (IRI) after AMI remains to be fully elucidated. The present study aimed to investigate the effects and mechanisms of miR-24 in IRI. In vitro, the current study detected cellular apoptosis and apoptotic-related protein expression levels in the cardiomyocyte H9C2 cell line (negative control group, model group and miRNA group) via flow cytometry and western blot analysis. In the in vivo study, rats were randomly divided into sham, model and miRNA groups. The infarct area was observed using nitro blue tetrazolium staining, pathological changes of the myocardium were detected via hematoxylin and eosin staining and TUNEL staining was used to detect cardiomyocyte apoptosis. The expression levels of related proteins were evaluated via immunohistochemistry and western blot analysis. The in vitro and in vivo results demonstrated that miR-24 significantly inhibited cardiomyocyte apoptosis compared with the model group. Concurrently, the expression levels of proteins associated with the NF-κB/TNF-α pathway (NF-κB, caspase-3, Bax, Bcl-2, TNF-α, vascular cell adhesion molecule 1, intercellular adhesion molecule 1 and monocyte chemoattractant protein-1) in the miRNA group were significantly different from the model group (P<0.001). Compared with the model group, miR-24 significantly improved pathological damage and infarct size of rat myocardium. Overall, the present results suggested that miR-24 improves myocardial injury in rats by inhibiting the NF-κB/TNF-α pathway.

Upregulation of Small Ubiquitin-Like Modifier 2 and Protein SUMOylation as a Cardioprotective Mechanism Against Myocardial Ischemia-Reperfusion Injury

Background: Small ubiquitin-like modifier (SUMO) proteins modify proteins through SUMOylation as an essential protein post-translational modification (PTM) for regulating redox status, inflammation, and cardiac fibrosis in myocardial infarction. This study aimed to investigate whether natural product puerarin could alleviate myocardial ischemia/reperfusion injury (MI-RI) by targeting protein SUMOylation.Methods: Mouse MI-RI model was induced by ligating the left anterior descending (LAD) coronary artery and subsequently treated with puerarin at the dose of 100 mg/kg. Rat cardiomyocyte H9c2 cells were challenged by hypoxia/reoxygenation and treated with puerarin at concentrations of 10, 20, and 40 μM. The infarction area of mouse hearts was assessed by 2% TTC staining. Cell damage was analyzed for the release of lactate dehydrogenase (LDH) in serum and cell culture medium. Western blot technique was employed to detect the expression of SUMO2, phospho-ERK, pro-inflammatory biomarker COX2, fibrosis index galectin-3, apoptosis-related protein cleaved PARP-1. The activation of the estrogen receptor (ER) pathway was assayed by the dual-luciferase reporter system.Results: The present study validated that puerarin effectively reduced myocardial infarct size and LDH release in the mouse MI-RI model. In the cell culture system, puerarin effectively decreased the release of LDH and the protein level of COX2, galectin-3, and cleaved PARP-1. Mechanistic studies revealed that puerarin increased the expression of SUMO2, SUMOylation of proteins and the activation of ER/ERK pathway in cardiomyocytes. ER, ERK and SUMO2 inhibitors attenuated the cardioprotective effects of puerarin.Conclusion: Puerarin may alleviate myocardial injury by promoting protein SUMOylation through ER/ERK/SUMO2-dependent mechanism.

Diabetic Aldehyde Dehydrogenase 2 Mutant (ALDH2*2) Mice Are More Susceptible to Cardiac Ischemic-Reperfusion Injury Due to 4-Hydroxy-2-Nonenal Induced Coronary Endothelial Cell Damage.

BackgroundAldehyde dehydrogenase‐2 (ALDH2), a mitochondrial enzyme, detoxifies reactive aldehydes such as 4‐hydroxy‐2‐nonenal (4HNE). A highly prevalent E487K mutation in ALDH2 (ALDH2*2) in East Asian people with intrinsic low ALDH2 activity is implicated in diabetic complications. 4HNE‐induced cardiomyocyte dysfunction was studied in diabetic cardiac damage; however, coronary endothelial cell (CEC) injury in myocardial ischemia‐reperfusion injury (IRI) in diabetic mice has not been studied. Therefore, we hypothesize that the lack of ALDH2 activity exacerbates 4HNE‐induced CEC dysfunction which leads to cardiac damage in ALDH2*2 mutant diabetic mice subjected to myocardial IRI.Methods and ResultsThree weeks after diabetes mellitus (DM) induction, hearts were subjected to IRI either in vivo via left anterior descending artery occlusion and release or ex vivo IRI by using the Langendorff system. The cardiac performance was assessed by conscious echocardiography in mice or by inserting a balloon catheter in the left ventricle in the ex vivo model. Just 3 weeks of DM led to an increase in cardiac 4HNE protein adducts and, cardiac dysfunction, and a decrease in the number of CECs along with reduced myocardial ALDH2 activity in ALDH2*2 mutant diabetic mice compared with their wild‐type counterparts. Systemic pretreatment with Alda‐1 (10 mg/kg per day), an activator of both ALDH2 and ALDH2*2, led to a reduction in myocardial infarct size and dysfunction, and coronary perfusion pressure upon cardiac IRI by increasing CEC population and coronary arteriole opening.ConclusionsLow ALDH2 activity exacerbates 4HNE‐mediated CEC injury and thereby cardiac dysfunction in diabetic mouse hearts subjected to IRI, which can be reversed by ALDH2 activation.

The Synergistic Effects of Astragalus mongholicus and Salvia miltiorrhiza on Coronary Heart Disease Identified by Network Pharmacology and Experiment.

Background and PurposeTwo Chinese herbal medicines Huang Qi (HQ, Astragalus mongholicus) and Dan Shen (DS, Salvia miltiorrhiza) are often combined to treat coronary heart disease (CHD). The purpose of this study was to identify the underlying synergistic effects and mechanisms of HQ and DS against CHD.MethodsThe active components and targets of HQ and DS, CHD-related genes, and the biological progression were analysed by network pharmacology. The myocardial infarction (MI) rat model was established by ligating the left anterior descending coronary artery. Cardiac function was detected by ultrasonic electrocardiography. The MI size, fibrosis, cardiac hypertrophy, lipid metabolism, blood viscosity, and coagulation indexes were analysed by histological staining or chemical methods, respectively.ResultsA total of 170 shared and specific seed genes of HQ and DS against CHD were identified. The shared and specific biological processes of HQ and DS against CHD were obtained. The LVEF and LVFS values significantly increased, the myocardium infarct size and fibrosis significantly decreased, the values of lipid metabolism indexes and blood viscosity indexes significantly reduced in the HQ + DS treatment group vs HQ or DS single treatment (P < 0.05); the LVEDd, LVEDs, and the CSA values significantly reduced in HQ single and HQ + DS treatment groups vs MI group (P < 0.05); the coagulation index (APTT, PT, TT, and FIB) values decreased significantly in the DS single and HQ + DS treatment groups vs MI group (P < 0.05).ConclusionIn MI rats, HQ and DS exhibited synergistic effects on improving cardiac function, reducing MI size, fibrosis, regulating hyperlipidaemia, and maintaining circulatory system homeostasis; HQ had the specific advantage of alleviating cardiac remodelling; DS had the specific advantage of regulating hypercoagulability. This study revealed that HQ and DS not only exerted synergistic effects but also exhibited complementary effects on CHD.

Colchicine-Containing Nanoparticles Attenuates Acute Myocardial Infarction Injury by Inhibiting Inflammation.

Anti-inflammatory therapy is important for reducing myocardial injury after acute myocardial infarction (MI). New anti-inflammatory drugs and their mechanism are necessary to be explored to improve clinical efficacy. We aimed to improve the efficacy of colchicine on attenuating MI injury by nano-drug delivery systems and to investigate the mechanism of anti-inflammatory. A colchicine-containing delivery system based on calcium carbonate nanoparticles (ColCaNPs) was synthesized. The protection against MI by ColCaNPs was evaluated using an in vivo rat model established by ligating the left anterior descending coronary artery. Macrophage polarization and the levels of inflammatory cytokines were determined using immunohistochemistry, Western blot, and ELISA analysis. ColCaNP treatment showed about a 45% reduction in myocardial infarct size and attenuating myocardial fibrosis compared with groups without drug intervention after MI. Furthermore, ColCaNPs significantly decreased the levels of CRP, TNF-α, and IL-1β in serum and the expression of proinflammatory cytokine in myocardial tissues after MI (p &lt; 0.05). We also found that ColCaNPs notably restrained pyroptosis and inhibited inflammatory response by modulating on M1/M2 macrophage polarization and suppressing TLR4/NFκB/NLRP3 signal pathway. Colchicine-containing nanoparticles can protect against MI injury in a clinically relevant rat model by reducing inflammation. In addition, calcium carbonate nanoparticles can increase the cardioprotective effects of colchicine.

Near Complete Repair After Myocardial Infarction in Adult Mice by Altering the Inflammatory Response With Intramyocardial Injection of α-Gal Nanoparticles

Background: Neonatal mice, but not older mice, can regenerate their hearts after myocardial-infarction (MI), a process mediated by pro-reparative macrophages. α-Gal nanoparticles applied to skin wounds in adult-mice bind the anti-Gal antibody, activate the complement cascade and generate complement chemotactic peptides that recruit pro-reparative macrophages which are further activated by these nanoparticles. The recruited macrophages decrease wound healing time by ~50%, restore the normal skin structure and prevent fibrosis and scar formation in mice.Objectives: The objective of this study is to determine if α-gal nanoparticles injected into the reperfused myocardium after MI in adult-mice can induce myocardial repair that restores normal structure, similar to that observed in skin injuries.Methods and Results: MI was induced by occluding the mid-portion of the left anterior descending (LAD) coronary artery for 30 min. Immediately following reperfusion, each mouse received two 10 μl injections of 100 μg α-gal nanoparticles in saline into the LAD territory (n = 20), or saline for controls (n = 10). Myocardial infarct size was measured by planimetry following Trichrome staining and macrophage recruitment by hematoxylin-eosin staining. Left ventricular (LV) function was measured by echocardiography. Control mice displayed peak macrophage infiltration at 4-days, whereas treated mice had a delayed peak macrophage infiltration at 7-days. At 28-days, control mice demonstrated large transmural infarcts with extensive scar formation and poor contractile function. In contrast, mice treated with α-gal nanoparticles demonstrated after 28-days a marked reduction in infarct size (~10-fold smaller), restoration of normal myocardium structure and contractile function.Conclusions: Intramyocardial injection of α-gal nanoparticles post-MI in anti-Gal producing adult-mice results in near complete repair of the infarcted territory, with restoration of normal LV structure and contractile function. The mechanism responsible for this benefit likely involves alteration of the usual inflammatory response post-MI, as previously observed with regeneration of injured hearts in adult zebrafish, salamanders and neonatal mice.

New Interventional Therapies beyond Stenting to Treat ST-Segment Elevation Acute Myocardial Infarction.

Myocardial infarction remains the principal cause of death in Europe. In patients with ST-segment-elevation myocardial infarction (STEMI), a promptly revascularization with primary percutaneous intervention (PCI) has transformed prognosis in the last decades. However, despite increasing successful PCI procedures, mortality has remained unchanged in recent years. Also, due to an unsatisfactory reperfusion, some patients have significant myocardial damage and suffer left ventricular adverse remodeling with reduced function—all that resulting in the onset of heart failure with all its inherent clinical and socioeconomic burden. As a consequence of longer ischemic times, distal thrombotic embolization, ischemia-reperfusion injury and microvascular dysfunction, the resultant myocardial infarct size is the major prognostic determinant in STEMI patients. The improved understanding of all the pathophysiology underlying these events has derived to the development of several novel therapies aiming to reduce infarct size and to improve clinical outcomes in these patients. In this article, based on the mechanisms involved in myocardial infarction prognosis, we review the new interventional strategies beyond stenting that may solve the suboptimal results that STEMI patients still experience.

Azathioprine pretreatment ameliorates myocardial ischaemia reperfusion injury in diabetic rats by reducing oxidative stress, apoptosis, and inflammation.

This study was presented to observe the therapeutic effects of azathioprine (AZA) pretreatment on myocardial ischaemia reperfusion (I/R) damage in diabetic rats. All rats were randomly separated into control + sham operation; control +I/R; diabetes mellitus (DM) +I/R and DM +I/R + AZA groups. Diabetic rat models were established by intraperitoneally injecting 60 mg/kg streptozotocin (STZ). Diabetic rats were given 3 mg/kg AZA daily by gavage for 5 days. Then, myocardial I/R rat models were constructed. Myocardial infarction size and myocardial damage were respectively detected by TTC and H&E staining. Cardiac injury markers (CK‐MB and MPO) and oxidative stress factors (SOD and MDA) were measured via ELISA. The protein expression of apoptotic markers (Caspase8, Caspase3, BAX and Bcl2), inflammatory factors (TLR4 and TNF‐α) and AKT1/GSK3β in myocardial tissues was measured by western blot, immunohistochemistry or immunofluorescence. Data showed that AZA pretreatment could lessen myocardial infarction size and myocardial damage, and could down‐regulate serum CK‐MB, MPO, SOD and MDA levels in diabetic rats under I/R. Furthermore, AZA pretreatment decreased Caspase8, Caspase3, BAX, TLR4 and TNF‐α expression, and increased Bcl2 expression in myocardial tissues of diabetic rats following I/R. Also, AZA pretreatment lowered AKT1, p‐AKT1, GSK3β and p‐GSK3β expression in diabetic heart after I/R. This study found that AZA may reduce myocardial injury in diabetic rats following I/R via reducing oxidative stress, cardiomyocyte apoptosis, and inflammatory response, which could be related to AKT1/GSK3β pathway inactivation.

Advances in Ultrasound Therapeutics.

High mechanical index impulses from a diagnostic transducer are utilized in myocardial perfusion imaging, but can also be utilized therapeutically in three cardiovascular applications: (a) thrombus dissolution (sonothrombolysis), (b) improving microvascular flow in ischemic territories (sonoperfusion), and (c) targeted drug and nucleic acid delivery. The targeted therapeutic effect appears to be based on acoustic cavitation of the intravascular microbubbles which results in endothelial shear and pore formation, as well as mechanical destruction of thrombi. Within the last 5 years, clinical trials have been performed in acute myocardial infarction demonstrating successful reductions in myocardial infarct size with sonothrombolysis added to current guideline-based treatment. In patients with severe peripheral arterial disease, brief improvements in calf microvascular blood flow have been observed for 1 h after 10 min of sonoperfusion therapy. Targeted ultrasound therapies are developing for prevention of microvascular obstruction in acute coronary syndromes and peripheral vascular disease.