Cardioprotection and pharmacological therapies in acute myocardial infarction: Challenges in the current era

In patients with an acute ST-segment elevation myocardial infarction, timely myocardial reperfusion using primary percutaneous coronary intervention is the most effective therapy for limiting myocardial infarct size, preserving left-ventricular systolic function and reducing the onset of heart failure. Within minutes after the restoration of blood flow, however, reperfusion itself results in additional damage, also known as myocardial ischemia-reperfusion injury. An improved understanding of the pathophysiological mechanisms underlying reperfusion injury has resulted in the identification ofseveral promising pharmacological(cyclosporin-A, exenatide, glucose-insulin-potassium, atrial natriuretic peptide, adenosine, abciximab, erythropoietin, metoprolol and melatonin) therapeutic strategies for reducing the severity of myocardial reperfusion injury. Many of these agents have shown promise in initial proofof-principle clinical studies. In this article, we review the pathophysiology underlying myocardial reperfusion injury and highlight the potential pharmacological interventions which could be used in the future to prevent reperfusion injury and improve clinical outcomes in patients with coronary heart disease.

Late cardioprotection of exercise preconditioning against exhaustive exercise-induced myocardial injury by up-regulatation of connexin 43 expression in rat hearts

Objective: To investigate the expression of myocardium connexin 43(Cx43) in late exercise preconditioning(LEP) cardioprotection. Methods: Eight-week-old adult male Sprague Dawley rats were randomly assigned into four groups(n=8). Myocardial injury was judged in accordance with serum levels of c Tn and NT-pro BNP as well as hematoxylin basicfuchsin picric acid staining of myocardium. Cx43 m RNA was detected by in situ hybridization and qualified by real-time fluorescence quantitative PCR. Cx43 protein was localized by immunohistochemistry and its expression level was determined by western blotting. Results: The LEP obviously attenuated the myocardial ischemia/hypoxia injury caused by exhaustive exercise. There was no significant difference of Cx43 m RNA level between the four groups. Cx43 protein level was decreased significantly in group EE(P<0.05). However, LEP produced a significant increase in Cx43 protein level(P<0.05), and the decreased Cx43 protein level in exhaustive exercise was significantly up-regulated by LEP(P<0.05). Conclusions: LEP protects rat heart against exhaustive exercise-induced myocardial injury by up-regulating the expression of myocardial Cx43.

Effects of dexmedetomidine on cardioprotection and other postoperative complications in elderly patients after cardiac and non-cardiac surgerie

BACKGROUND After cardiac and non-cardiac surgeries,elderly patients have a high probability of developing cardiac complications and postoperative delirium.Although several clinical trials have investigated whether perioperative intravenous dexmedetomidine can protect the heart and reduce postoperative complications such as delirium in elderly patients,the obtained results have been inconsistent.We conducted a meta-analysis to investigate the effects of dexmedetomidine on cardioprotection and other postoperative complications in elderly patients undergoing cardiac or non-cardiac surgery.AIM To investigate the effects of dexmedetomidine on cardiac complications and delirium in elderly patients undergoing cardiac or non-cardiac surgery.METHODS The PubMed,Cochrane Library,web of science,and other sources were comprehensively searched for all randomized controlled trials published before May 2021 that investigated the efficacy of dexmedetomidine in the prevention of cardiac and postoperative delirium(POD).RESULTS In total,18 studies involving 1025 patients were included in the meta-analysis.Intravenous dexmedetomidine significantly reduced cardiac troponin I(cTnI)and the inflammatory factor tumor necrosis factor-α(TNF-α)was comparable to the control group.Dexmedetomidine also reduced the POD and mortality rates.However,patients in the dexmedetomidine group were more likely to have a decreased heart rate(within the normal range)and hypotension during dexmedetomidine administration than those in the control group.There was no difference in the occurrence of myocardial infarction,bradycardia,or stroke between the two groups.Dexmedetomidine significantly shortened the time to extubate;however,it did not shorten the length of stay in the intensive care unit.CONCLUSION The administration of dexmedetomidine during cardiac and non-cardiac surgeries can provide myocardial protection by inhibiting inflammation and cTnI,which may be beneficial for the rapid recovery of patients.Meanwhile,the administration of dexmedetomidine reduced the incidence of POD and decreased mortality(in-hospital).

Protein kinase A-mediated cardioprotection of Tongxinluo relates to the inhibition of myocardial inflammation, apoptosis, and edema in reperfused swine hearts

Background Our previous studies have demonstrated that Tongxinluo （TXL）, a traditional Chinese medicine, can protect hearts against no-reflow and reperfusion injury in a protein kinase A （PKA）-dependent manner. The present study was to investigate whether the PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis. Methods In a 90-minute ischemia and 3-hour reperfusion model, minipigs were randomly assigned to sham, control, TXL （0.05 g/kg, gavaged one hour prior to ischemia）, and TXL ＋ H-89 （a PKA inhibitor, intravenously and continuously infused at 1.0 μg/kg per minute） groups. Myocardial no-reflow, necrosis, edema, and apoptosis were determined by pathological and histological studies. Myocardial activity of PKA and myeloperoxidase was measured by colorimetric method. The expression of PKA, phosphorylated cAMP response element-binding protein （p-CREB） （Ser133）, tumor necrosis factor a （TNF-a）, P-selectin, apoptotic proteins, and aquaporins was detected by Western blotting analysis. Results TXL decreased the no-reflow area by 37.4% and reduced the infarct size by 27.0% （P〈0.05）. TXL pretreatment increased the PKA activity and the expression of Ser133 p-CREB in the reflow and no-reflow myocardium （P 〈0.05）. TXL inhibited the ischemia-reperfusion-induced elevation of myeloperoxidase activities and the expression of TNF-a and P-selectin, reduced myocardial edema in the left ventricle and the reflow and no-reflow areas and the expression of aquaporin-4, -8, and -9, and decreased myocytes apoptosis by regulation of apoptotic protein expression in the reflow and no-reflow myocardium. However, addition of the PKA inhibitor H-89 counteracted these beneficial effects of TXL. Conclusion PKA-mediated cardioprotection of TXL against no-reflow and reperfusion injury relates to the inhibition of myocardial inflammation, edema, and apoptosis in the reflow and no-reflow myocardium.

Association between delayed cardioprotection of aged rat myocytes and activation of mitogenactivated protein kinase

Objective To study the cardioprotective effects of hypoxic preconditioning (HPC) on aged rat ventricular myocytes and the cellular mechanism of protection Methods In the model of hypoxia/reoxygenation (H/R) of isolated ventricular myocytes of aged rat, the effects of HPC on aged rat ventricular myocytes against lethal H/R stimulated ischemia/reperfusion (I/R) injury 24 hours later and the changes of mitogen activated protein kinase (MAPK) system were observed in the present study Results HPC attenuated the lactate dehydrogenase (LDH) release and ATP depletion in myocytes and increased the viability of myocytes It was also found that MAPK and its down stream kinase—S6 kinase were also activated after HPC Conclusion There is delayed cardioprotection in cardiac myocytes of aged rat and the cellular mechanism underlying might involve the activation of MAPK system

Pim-1 Kinase Regulating Dynamics Related Protein 1 Mediates Sevoflurane Postconditioning-induced Cardioprotection

Background： It is well documented that sevoflurane postconditioning （SP） has a significant myocardial protection effect. However, the mechanisms underlying SP are still unclear. In the present study, we investigated the hypothesis that the Pim-1 kinase played a key role in SP-induced cardioprotection by regulating dynamics-related protein 1 （Drpl）. Methods： A Langendorff model was used in this study. Seventy-two rats were randomly assigned into six groups as follows： CON group, ischemia reperfusion （I/R） group, SP group, SP＋proto-oncogene serine/threonine-protein kinase 1 （Pim-1） inhibitor II group, SP＋dimethylsufoxide group, and Pim- 1 inhibitor II group （n = 12, each）. Hemodynamic parameters and infarct size were measured to reflect the extent of myocardial 1/R injury. The expressions ofPim-1, B-cell leukemia/lymphoma 2 （Bcl-2） and cytochrome C （Cyt C） in cytoplasm and mitochondria, the Drp 1 in mitochondria, and the total Drp I and p-Drp I^sor637 were measured by Western blotting. In addition, transmission electron microscope was used to observe mitochondrial morphology. The experiment began in October 2014 and continued until July 2016. Results： SP improved myocardial I/R injury-induced hemodynamic parametric changes, cardiac function, and preserved mitochondrial phenotype and decreased myocardial infarct size （24.49 ± 1.72% in Sev group compared with 41.98 ± 4.37% in I/R group; P 〈 0.05）. However, Pim-1 inhibitor II significantly （P 〈 0.05） abolished the protective effect of SP. Western blotting analysis demonstrated that, compared with I/R group, the expression of Pim-1 and Bcl-2 in cytoplasm and mitochondria as well as the total p-Drplset637 in Sev group （P 〈 0.05） were upregulated. Meanwhile, SP inhibited Drp 1 compartmentalization to the mitochondria followed by a reduction in the release ofCyt C. Pretreatment with Pim- 1 inhibitor II significantly （P 〈 0.05） abolished SP-induced Pim- 1/p-Drp 1^ser637 signaling activation. Conclusions： These findings suggested that SP could attenuate myocardial ischemia-reperfusion injury by increasing the expression of the Pim-1 kinase. Upregulation of Pim-1 might phosphorylate Drpl and prevent extensive mitochondrial fission through Drpl cytosolic sequestration.

Reducing the oxidative stress mediates the cardioprotection of bicyclol against ischemia-reperfusion injury in rats

Objective:To investigate the beneficial effect of bicyclol on rat hearts subjected to ischemia-reperfusion(IR) injuries and its possible mechanism.Methods:Male Sprague-Dawley rats were intragastrically administered with bicyclol(25,50 or 100 mg/(kg·d)) for 3 d.Myocardial IR was produced by occlusion of the coronary artery for 1 h and reperfusion for 3 h.Left ventricular hemodynamics was continuously monitored.At the end of reperfusion,myocardial infarct was measured by 2,3,5-triphenyltetrazolium chloride(TTC) staining,and serum lactate dehydrogenase(LDH) level and myocardial superoxide dismutase(SOD) activity were determined by spectrophotometry.Isolated ventricular myocytes from adult rats were exposed to 60 min anoxia and 30 min reoxygenation to simulate IR injuries.After reperfusion,cell viability was determined with trypan blue;reactive oxygen species(ROS) and mitochondrial membrane potential of the cardiomyocytes were measured with the fluorescent probe.The mitochondrial permeability transition pore(mPTP) opening induced by Ca2+(200 μmol/L) was measured with the absorbance at 520 nm in the isolated myocardial mitochondria.Results:Low dose of bicyclol(25 mg/(kg·d)) had no significant improving effect on all cardiac parameters,whereas pretreatment with high bicyclol markedly reduced the myocardial infarct and improved the left ventricular contractility in the myocardium exposed to IR(P<0.05).Medium dose of bicyclol(50 mg/(kg·d)) markedly improved the myocardial contractility,left ventricular myocyte viability,and SOD activity,as well decreased infarct size,serum LDH level,ROS production,and mitochondrial membrane potential in rat myocardium exposed to IR.The reduction of ventricular myocyte viability in IR group was inhibited by pretreatment with 50 and 100 mg/(kg·d) bicyclol(P<0.05 vs.IR),but not by 25 mg/(kg·d) bicyclol.The opening of mPTP evoked by Ca2+ was significantly inhibited by medium bicyclol.Conclusions:Bicyclol exerts cardioprotection against IR injury,at least,via reducing oxidative stress and its subsequent mPTP opening.

Activation of Akt and cardioprotection against reperfusion injury are maximal with only five minutes of sevoflurane postconditioning in isolated rat hearts

It had been proved that administration of sevoflurane for the first two minutes of reperfusion effectively protects the heart against reperfusion injury in rats in vivo.Our aim was to investigate the duration of effective sevoflurane administration and its underlying mechanism in isolated rat hearts exposed to global ischemia/reperfusion(I/R) injury.Adult male Sprague-Dawley rats were randomly divided into six groups(n=12):a sham-operation group,an I/R group,and four sevoflurane postconditioning groups(S2,S5,S10,and S15).In the S2,S5,S10,and S15 groups,the duration times of sevoflurane administration were 2,5,10,and 15 min after the onset of reperfusion,respectively.The isolated rat hearts were mounted on the Langendorff system,and after a period of equilibrium were subjected to 40 min global ischemia and 120 min reperfusion.Left ventricular(LV) hemodynamic parameters were monitored throughout each experiment and the data at 30 min of equilibrium and 30,60,90,and 120 min of reperfusion were analyzed.Myocardial infarct size at the end of reperfusion(n=7 in each group) and the expression of myocardial phosphorylated Akt(p-Akt) after 15-min reperfusion were determined in a duplicate set of six groups of rat hearts(n=5 in each group).Compared with the I/R group,the S5,S10,and S15 groups had significantly improved left ventricular end-diastolic pressure(LVEDP),left ventricular developed pressure(LVDP),and the maximal rate of rise or fall of the LV pressure(±dP/dtmax),and decreased myocardial infarct size(P<0.05),but not the S2 group.After 15 min of reperfusion,the expression of p-Akt was markedly up-regulated in the S5,S10,and S15 groups compared with that in the I/R group(P<0.05),but not in the S2 group.Sevoflurane postconditioning for 5 min was sufficient to activate Akt and exert maximal cardioprotection against I/R injury in isolated rat hearts.

Wnt/Glycogen Synthase Kinase 3β/β-catenin Signaling Activation Mediated Sevoflurane Preconditioning-induced Cardioprotection

Background： Sevoflurane preconditioning （SP） has been shown to invoke potent myocardial protection in animal studies and clinical trials. However, the mechanisms underlying SP are complex and not yet well understood. We investigated the hypothesis that the cardioprotection afforded by SP is mediated via the Writ/glycogen synthase kinase 3β（GSK3β）/β-catenin signaling pathway. Methods： Two models were established： A Langendorffperfused rat heart model and the H9C2 cell hypoxia/reoxygenation model. Both rats and H9C2 cells were randomly divided into 6 groups as follows： S group, ischemia-reperfusion （I/R） group, DMSO group, IWP group, SP group, and SP ＋ IWP group. Hemodynamic parameters, lactate dehydrogenase （LDH） activity in coronary effluent and cell culture supernatant, and the infarct size were measured to evaluate myocardial ischemia-reperfusion injuries. To determine the activity of Wnt/GSK3β/β-catenin signaling pathway, the expressions of Wnt3a, phospho-GSK3β, and β-catenin were measured by Western blotting. Results： SP improved cardiac function recovery, reduced infarct size （18 ±2% in the SP group compared with 35 ± 4% in the 1/R group; P 〈 0.05）, decreased LDH activity in coronary effluent, and culture supematant. IWP-2, an inhibitor of Wnt, abolished the cardioprotection by SR In addition, Western blotting analysis demonstrated that the expressions of Wnt3a, phospho-GSK3β, and β-catenin significantly （P 〈 0.05） increased in the I/R group, compared with the S group; and compared to I/R group, SP significantly （P 〈 0.05） increased Wnt3a, phospho-GSK3 β, and β-catenin expressions. Pretreatment with IWP-2 significantly （P 〈 0.05） abolished SP-induced Wnt/GSK3β/β-catenin signaling activation. Conclusions： The results showed for the first time that cardioprotection afforded by SP may be mediated partly via the Wnt/GSK3β/β-catenin signaling pathway.

Cardioprotection Afforded by Norepinephrine-mediated Postconditioning in Isolated Rat Hearts

Objectives Previous studies have demonstrated that endogenous norepinephrine （NE） plays an important role in the mediation of ischemic preconditioning. The present study is designed to determine whether NE is also involved in mediation of the protective effects of postconditioning. Methods The rat hearts were rapidly excised under anesthesia and attached to a Langendorff apparatus via the aorta for retrograde perfusion with Krebs-Henseleit buffer solution. All hearts were subjected to 30 min of left coronary artery occlusion followed by 60 min of reperfusion, except the control group. Animals were randomly divided into 5 groups as follows： （1） control group, the hearts were underwent same procedures without ischemic insult ; （2） ischemia reperfusion group, the left coronary artery was occluded for 30 rain and followed by 60 min of reperfusion ; （3） ischemic postconditioning （IPost） group, immediately at the onset of reperfusion, the heart was initiated with 1 min of full coronary flow, followed by 1 min of re-occlusion, repeated for a total of three cycles; （4） IPost plus prazosin group, the heart was perfused with prazosin for 10 min before ischemia; （5） IPost plus reserpine group, a single dose of reserpine was administered by i.m. injection, 24 hours before the experiment. Coronary flow was measured by timed collection of coronary effluent and sample of coronary effluent at 5 min of reperfusion were collected for the measurement of creatine kinase （CK）. Infarct size and risk area were determined at the end of experiments. Results 30 min of ischemia and followed by 60 rain of reperfusion caused a significant decrease in cardiac function and a significant increase in CK release and infarct size. Postconditioning with three cycles of 1-min ischemia and 1-min reperfusion markedly improved cardiac function and reduced CK release and infarct size. However, the cardioprotection afforded by postconditioning was abolished by prazosin （10^-6M） , a selective α adrenergic receptor antagonist, or by pretreatment with reserpine （0. 45 mg·kg^-1 ）, which significantly reduced NE level in both plasma and coronary effluent. Conclusions These results suggest that the protective effects of ischemic postconditioning are related to stimulation of endogenous NE release in rat hearts.

Beyond cardiomyocytes:Cellular diversity in the heart's response to exercise

Cardiomyocytes comprise~70%to 85%of the total volume of the adult mammalian heart but only about 25%to 35%of its total number of cells.Advances in single cell and single nuclei RNA sequencing have greatly facilitated investigation into and increased appreciation of the potential functions of non-cardiomyocytes in the heart.While much of this work has focused on the relationship between non-cardiomyocytes,disease,and the heart's response to pathological stress,it will also be important to understand the roles that these cells play in the healthy heart,cardiac homeostasis,and the response to physiological stress such as exercise.The present review summarizes recent research highlighting dynamic changes in non-cardiomyocytes in response to the physiological stress of exercise.Of particular interest are changes in fibrotic pathways,the cardiac vasculature,and immune or inflammatory cells.In many instances,limited data are available about how specific lineages change in response to exercise or whether the changes observed are functionally important,underscoring the need for further research.

Ischemia/reperfusion injury and cardioprotective mechanisms:Role of mitochondria and reactive oxygen species

Reperfusion therapy must be applied as soon as possible to attenuate the ischemic insult of acute myocardial infarction(AMI).However reperfusion is responsible for additional myocardial damage,which likely involves opening of the mitochondrial permeability transition pore(mPTP).In reperfusion injury,mitochondrial damage is a determining factor in causing loss of cardiomyocyte function and viability.Major mechanisms of mitochondrial dysfunction include the long lasting opening of mPTPs and the oxidative stress resulting from formation of reactive oxygen species(ROS).Several signaling cardioprotective pathways are activated by stimuli such as preconditioning and postconditioning,obtained with brief intermittent ischemia or with pharmacological agents.These pathways converge on a common target,the mitochondria,to preserve their function after ischemia/reperfusion.The present review discusses the role of mitochondria in cardioprotection,especially the involvement of adenosine triphosphate-dependent potassium channels,ROS signaling,and the mPTP.Ischemic postconditioning has emerged as a new way to target the mitochondria,and to drastically reduce lethal reperfusion injury.Several clinical studies using ischemic postconditioning during angioplasty now support its protective effects,and an interesting alternative is pharmacological postconditioning.In fact ischemic postconditioning and the mPTP desensitizer,cyclosporine A,have been shown to induce comparable protection in AMI patients.

Recent advances in the diagnosis and treatment of acute myocardial infarction

The Third Universal Definition of Myocardial Infarction(MI) requires cardiac myocyte necrosis with an increase and/or a decrease in a patient's plasma of cardiac troponin(cT n) with at least one cT n measurement greater than the 99 th percentile of the upper normal reference limit during:(1) symptoms of myocardialischemia;(2) new significant electrocardiogram(ECG) ST-segment/T-wave changes or left bundle branch block;(3) the development of pathological ECG Q waves;(4) new loss of viable myocardium or regional wall motion abnormality identified by an imaging procedure; or(5) identification of intracoronary thrombus by angiography or autopsy.Myocardial infarction,when diagnosed,is now classified into five types.Detection of a rise and a fall of troponin are essential to the diagnosis of acute MI.However,high sensitivity troponin assays can increase the sensitivity but decrease the specificity of MI diagnosis.The ECG remains a cornerstone in the diagnosis of MI and should be frequently repeated,especially if the initial ECG is not diagnostic of MI.There have been significant advances in adjunctive pharmacotherapy,procedural techniques and stent technology in the treatment of patients with MIs.The routine use of antiplatelet agents such as clopidogrel,prasugrel or ticagrelor,in addition to aspirin,reduces patient morbidity and mortality.Percutaneous coronary intervention(PCI) in a timely manner is the primary treatment of patients with acute ST segment elevation MI.Drug eluting coronary stents are safe and beneficial with primary coronary intervention.Treatment with direct thrombin inhibitors during PCI is non-inferior to unfractionated heparin and glycoprotein Ⅱb/Ⅲa receptor antagonists and is associated with a significant reduction in bleeding.The intra-coronary use of a glycoprotein Ⅱb/Ⅲa antagonist can reduce infarct size.Pre- and post-conditioning techniques can provide additional cardioprotection.However,the incidence and mortality due to MI continues to be high despite all these recent advances.The initial ten year experience with autologous human bone marrow mononuclear cells(BMCs) in patients with MI showed modest but significant increases in left ventricular(LV) ejection fraction,decreases in LV endsystolic volume and reductions in MI size.These studies established that the intramyocardial or intracoronary administration of stem cells is safe.However,many of these studies consisted of small numbers of patients who were not randomized to BMCs or placebo.The recent LateT ime,Time,and Swiss Multicenter Trials in patientswith MI did not demonstrate significant improvement in patient LV ejection fraction with BMCs in comparison with placebo.Possible explanations include the early use of PCI in these patients,heterogeneous BMC populations which died prematurely from patients with chronic ischemic disease,red blood cell contamination which decreases BMC renewal,and heparin which decreases BMC migration.In contrast,cardiac stem cells from the right atrial appendage and ventricular septum and apex in the SCIPIO and CADUCEUS Trials appear to reduce patient MI size and increase viable myocardium.Additional clinical studies with cardiac stem cells are in progress.

Protective effect of hyperoside on cardiac ischemia reperfusion injury through inhibition of ER stress and activation of Nrf2 signaling

Objective:To study the protective effect of hyperoside(Hyp) on cardiac ischemia reperfusion injury and its potential mechanism.Methods:Rats were divided into two groups for the evaluation,the Hyp(50 uM Hyp;n=8) and the control group(n=8).Rat hearts were isolated and perfused with Krebs-Henseleit buffer(KHB) for 30 min.After being inhibited with cardioplegic solution,they were stored for 4 h in B21 solution at 4℃.Afterwards,rat hearts were perfused with KHB again for 45 min.In this period.Hyp was added into solutions of cardioplegia for storage and KHB.Parameters of cardiac functions,including heart rate,the systolic pressure of the left ventricle,the end-diastolic pressure of the left ventricle,the developed pressure of the left ventricle,the left-ventricular systolic pressure and the peak rise rate of the pressure of the left ventricle were recorded.The levels of adenosine triphosphate(ATP),the content of malondialdehyde and apoptotic cells were determined to evaluate the protective effect of Hyp on hearts suffered from ischemia reperfusion injury.Moreover,cultured cardiac myocytes were subjected to the process simulating ischemia/reperfusion.What were analyzed included the endoplasmic reticulum(ER) stress hallmarks expressions,such as binding immunoglobulin protein and C/EBP homologous protein,using the western blot and real-time PCR.Besides,the NF-E2-related factor 2(Nrf2) expression was measured to explore the potential mechanism.Results:Compared with the control group,the Hyp group had better cardiac functional parameters and higher ATP levels;pretreatment of Hyp greatly relieved the apoptosis of myocyte,decreased oxidative stress as well as ER stress and activated the signaling pathway of anti-oxidative Nrf2 to a further extent.Conclusions:Hyp plays an important role in preserving cardiac function by improving ATP levels of tissue,easing oxidative injury of myocardium and reducing apoptosis following IRI dramatically,while the ER stress inhibition and the downstream Nrf2 signaling activation may contribute to the effects of protection.

The epigenetic landscape of exercise in cardiac health and disease

With the rising incidence of cardiovascular diseases,the concomitant mortality and morbidity impose huge burdens on quality of life and societal costs.It is generally accepted that physical inactivity is one of the major risk factors for cardiac disease and that exercise benefits the heart in both physiological and pathologic conditions.However,the molecular mechanisms governing the cardioprotective effects exerted by exercise remain incompletely understood.Most recently,an increasing number of studies indicate the involvement of epigenetic modifications in the promotion of cardiac health and prevention of cardiac disease.Exercise and other lifestyle factors extensively induce epigenetic modifications,including DNA/RNA methylation,histone post-translational modifications,and non-coding RNAs in multiple tissues,which may contribute to their positive effects in human health and diseases.In addition,several studies have shown that maternal or paternal exercise prevents age-associated or high-fat dietinduced metabolic dysfunction in the offspring,reinforcing the importance of epigenetics in mediating the beneficial effects of exercise.It has been shown that exercise can directly modify cardiac epigenetics to promote cardiac health and protect the heart against various pathological processes,or it can modify epigenetics in other tissues,which reduces the risk of cardiac disease and affords cardioprotection through exerkines.An in-depth understanding of the epigenetic landscape of cardioprotective response to exercise will provide new therapeutic targets for cardiac diseases.This review,therefore,aimed to acquaint the cardiac community with the rapidly advancing and evolving field of exercise and epigenetics.

Cardio- and hepato-protective potential of methanolic extract of Syzygium cumini(L.) Skeels seeds:A diabetic rat model study

Objective: To evaluate the effect of methanolic extract of Syzygium cumini(L.) Skeels(S. cumini) seeds on the major organs in an animal model of diabetes through biochemical and histopathological studies.Methods: The methanolic extracts of S. cumini seeds(100 and 200 mg/kg body weight) were administered to alloxan-induced diabetic rats daily, with fasting blood glucose levels being measured by glucometry at one-day interval for a duration of two weeks. Biochemical assays to evaluate changes in the functions of the heart, liver,pancreas and kidney were carried out. Histopathological changes in the diabetic rat organs(pancreas, liver, heart, kidney and spleen) were also observed after the 14 days of treatment with the extracts.Results: Oral administration of methanolic extracts of S. cumini seeds(100 and 200 mg/kg body weight), with gliclazide as a positive control(25 mg/kg), showed beneficial effects including lowering blood glucose levels(P < 0.001), improved heart and liver functions, and hyperlipidemia due to diabetes. At 200 mg/kg, the extracts reversed cardiac and liver damage caused by alloxan.Conclusions: In addition to the anti-hyperglycemic activity of methanolic extracts of S. cumini seeds, the extracts demonstrates potential to minimize cardiac and hepatic complications.

Cardioprotective activity of alcoholic extract of Tinospora cordifolia (Willd.) Miers in calcium chloride-induced cardiac arrhythmia in rats

The present study investigated the antiarrhythmic activity of alcoholic extract of Tinospora cordifolia （T. cordifolia） in CaCl2 induced arrhythmia. CaCl2 （25 mg/kg） was administered by intravenous infusion （iv） to produce arrhythmia in rats. The animals were then treated with T. cordifolia extract （150, 250, and 450 mg/kg） and verapamil （5 mg/kg,iv）. Lead II electrocardiogram was monitored. Plasma calcium, sodium and potassium levels were measured. In CaCl2 induced arrhythmia, heart rate was decreased by 41.10%, T. cordifolia at 150, 300, and 450 mg/kg decreased the heart rate by 26.30%, 29.16%, and 38.29%, respectively, and verapamil reduced the heart rate by 9.70% compared to the normal group. The PQRST waves were normalized and atrial and ventricular fibrillation was controlled in rats treated with verapamil and T. cordifolia. CaCl2 increased calcium and sodium levels and decreased potassium levels in blood. T. cordifolia dose-dependently decreased calcium and sodium levels and increased potassium levels. Hence, T. cordifolia can be used in antiarrhythmic clinical settings and beneficial in atrial and ventricular fibrillation and flutter and may be indicated in ventricular tachyarrhythmia.

Effect of Xuebijing injection on myocardium during cardiopulmonary bypass:A prospective,randomized,double blind trial

BACKGROUND Cardiopulmonary bypass(CPB)is an essential procedure for maintaining the blood supply to vital organs in patients undergoing cardiac surgery.However,perioperative cardiac injury related to CPB remains a severe complication in these patients.Cardiac protection is important for patients undergoing CPB.AIM To evaluate the potential cardioprotective efficacy of the Chinese medicine preparation Xuebijing injection(XBJ)in patients undergoing CPB.METHODS Sixty patients undergoing cardiac surgery with CPB were randomly allocated to the XBJ and control groups(saline).XBJ was administered intravenously three times:12 h prior to surgery,at the beginning of the surgery,and 12 h after the second injection.Cardiac function was evaluated by echocardiography 48 h after surgery.Circulating inflammation-and oxidative-stress-related markers were measured.Clinical outcomes related to intensive care unit(ICU)stay were recorded.RESULTS Compared to control treatment,XBJ was associated with improved PaO2/FiO2 and cardiac systolic function,but reduced troponin I and creatine kinase fraction after surgery(all P<0.05).The circulating concentrations of tumor necrosis factor-α,interleukin(IL)-1βand IL-8 in the XBJ group were significantly lower than those in the control group(all P<0.05),whereas the circulating concentration of IL-10 was significantly higher in the XBJ group(P<0.05).In addition,the lengths of ICU stay and hospitalization after surgery tended to be shorter in the XBJ group than in the control group,although the differences were not significant.CONCLUSION Perioperative administration of XBJ was associated with attenuated cardiac injury during CPB,likely via anti-inflammatory and antioxidative mechanisms.

Involvement of adenosine and standardization of aqueous extract of garlic(Allium sativum Linn.)on cardioprotective and cardiodepressant properties in ischemic preconditioning and myocardial ischemia-reperfusion induced cardiac injury

The present study investigated the effect of garlic （Allium sativum Linn.） aqueous extracts on ischemic pre- conditioning and ischemia-reperfusion induced cardiac injury, as well as adenosine involvement in ischemic pre- conditioning and garlic extract induced cardioprotection. A model of ischemia-reperfusion injury was established using Langendorff apparatus. Aqueous extract of garlic dose was standardized （0.5%, 0.4%, 0.3%, 0.2%, 0.1%, 0.07%, 0.05%, 0.03%, 0,01%）, and the 0.05% dose was found to be the most effective. Higher doses （more than 0.05%） were highly toxic, causing arrhythmia and cardiodepression, whereas the lower doses were ineffective. Garlic exaggerated the cardioprotective effect of ischemic preconditioning. The cardioprotective effect of ischemic preconditioning and garlic cardioprotection was significantly attenuated by theophylline （1,000 ~tmol/L） and 8-SPT （10 mg/kg, i.p.） and expressed by increased myocardial infarct size, increased LDH level, and reduced nitrite and adenosine levels. These findings suggest that adenosine is involved in the pharmacological and molecular mechanism of garlic induced cardioprotection and mediated by the modulation of nitric oxide.

Effects of Metallothionein on Isolated Rat Heart

To investigate the effects of metallothionein （MT） on isolated rat heart, 16 Wistar rats were randomly divided into 2 groups. In control group （group C）, distilled water was injected intraperitoneally and 24 h later isolated hearts were perfused with Langendorff and stored at 4℃ for 3 h with histidine-tryptophan-ketoglutarate （HTK） solutions, and then isolated hearts were perfused for 2 h by Langendorff. In experimental group （group E）, 3.6% ZnSO4 was injected intraperitoneally, 24 h later isolated hearts were perfused by Langendorff and stored at 4℃ for 3 h with HTK solutions, and then the isolated hearts were perfused for 2 h with Langendorff. MT content, the recovery of hemodynamics, myocardial water content （MWC）, lactate dehydrogenase （LDH） and creatine kinase （CK） leakage, adenosine triphosphate （ATP） and malondialdehyde （MDA） content, superoxide dismutase （SOD） activity, myocardial cell Ca^2＋ content, Ca^2＋-ATPase activity of mitochondria （[Ca^2＋-ATPase]m） and its Ca^2＋ content （[Ca^2＋]m）, synthesizing ATP activity of mitochondria （[ATP]m）, and the ultrastructure of cells were examined. There were a significant increase in group E in hemodynamic recovery, ATP content, SOD activity, [Ca^2＋-ATPase]m activity, [ATP]m activity, and substantial reduction in MWC, LDH and CK leakage, MDA content, myocardial cell Ca^2＋ content, [Ca^2＋]m content, and the ultrastructural injury were obviously milder than that of group C. This study demonstrated that MT has protective effects on isolated rat heart.