Myocardial Preconditioning Research Articles

Dihydrotanshinone I preconditions myocardium against ischemic injury via PKM2 glutathionylation sensitive to ROS

Ischemic preconditioning (IPC) is a potential intervention known to protect the heart against ischemia/reperfusion injury, but its role in the no-reflow phenomenon that follows reperfusion is unclear. Dihydrotanshinone I (DT) is a natural compound and this study illustrates its role in cardiac ischemic injury from the aspect of IPC. Pretreatment with DT induced modest ROS production and protected cardiomyocytes against oxygen and glucose deprivation (OGD), but the protection was prevented by a ROS scavenger. In addition, DT administration protected the heart against isoprenaline challenge. Mechanistically, PKM2 reacted to transient ROS via oxidization at Cys423/Cys424, leading to glutathionylation and nuclear translocation in dimer form. In the nucleus, PKM2 served as a co-factor to promote HIF-1α-dependent gene induction, contributing to adaptive responses. In mice subjected to permanent coronary ligation, cardiac-specific knockdown of Pkm2 blocked DT-mediated preconditioning protection, which was rescued by overexpression of wild-type Pkm2, rather than Cys423/424-mutated Pkm2. In conclusion, PKM2 is sensitive to oxidation, and subsequent glutathionylation promotes its nuclear translocation. Although IPC has been viewed as a protective means against reperfusion injury, our study reveals its potential role in protection of the heart from no-reflow ischemia.

A CASE OF VENTRICULAR SEPTAL RUPTURE AFTER ACUTE MYOCARDIAL INFARCTION

When ventricular septal rupture (VSR) complicates acute myocardial infarction the mortality is usually high. Reperfusion therapy has reduced its incidence. However if VSR has developed then rapid diagnosis, aggressive medical management, and surgical intervention are required to optimize recovery and survival. In the era before reperfusion therapy, septal rupture complicated 1 to 3 percent of acute myocardial infarctions. Among the 41,021 patients in the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial, ventricular septal rupture was suspected in 140 patients (0.34 percent) and confirmed by a retrospective review in 84 (0.2 percent). Thus, reperfusion therapy has decreased the incidence of septal rupture. Septal rupture occurs more frequently with anterior wall acute myocardial infarction than other types of acute myocardial infarction. Risk factors for septal rupture included hypertension, advanced age (60 to 69 years), female sex and the absence of a history of angina or myocardial infarction. Angina or previous infarction may lead to myocardial preconditioning as well as to the development of coronary collaterals, both of which reduce the likelihood of septal rupture. In patients undergoing thrombolysis advanced age, female sex, and the absence of smoking are often associated with an increased risk of septal rupture, whereas the absence of antecedent angina has not been associated with an increased risk. In the GUSTO-I trial, there was a nonlinear relation between the systolic and diastolic blood pressures at enrolment and septal rupture, since hypertension and extensive myocardial infarction and right ventricular infarction are also risk factors for septal rupture

Volatile anesthetic preconditioning modulates oxidative stress and nitric oxide in patients undergoing coronary artery bypass grafting.

Background:Myocardial preconditioning using volatile anesthetics such as isoflurane and sevoflurane have beneficial effects in decreasing morbidity in cardiac surgical patients. Studies in animal models have indicated that reactive oxygen and nitrogen species probably play a role in mediating these effects. However, data from human studies are scarce and the differential effect of sevoflurane vs. isoflurane on reactive oxygen species (ROS) and reactive nitrogen species (RNS) has not been studied extensively.Materials and Methods:Randomized clinical control trial comparing preconditioning effects of volatile agents isoflurane and sevoflurane when administered during coronary artery bypass surgeries on cardiopulmonary bypass (CPB). Serum samples were collected at 3 time points before induction, after cross clamp release and one hour after separation from CPB. Levels of oxidative stress markers and nitric oxide were analyzed in these samples.Results:Hemodynamic indices, cardio-pulmonary bypass duration, and ICU stay were similar between the groups. CKMB values 12 hours post-op were decreased in majority of patients in the sevoflurane group compared to isoflurane. Serum malondialdehyde and nitrate levels were lower with sevoflurane (P < 0.05) when compared to the isoflurane group, but no significant differences in protein carbonyl content or protein thiol content were evident between the 2 groups. Sevoflurane also prevented the decrease in total thiols during later stages of surgery.Conclusions:Volatile anesthetics, isoflurane and sevoflurane modulate oxidative and nitrosative stress during CABG. Between the two pre-conditioning agents, isoflurane seems to provide better protection during the pre-bypass period, while sevoflurane provides protection during both pre- as well as post-bypass period.

Remote and Anesthetic-Induced Myocardial Preconditioning Is Preserved in Atherosclerotic LDL Receptor-/- Mice In Vivo

Introduction In the animal model, preconditioning is a powerful weapon against ischemic damage. The reason why the human heart cannot be protected from ischemic damage by preconditioning remains unclear. There are assumptions that the lack of preconditioning in humans is caused by concomitant diseases such as dyslipoproteinemia and arteriosclerosis. This study investigates whether dyslipoproteinemia and the resulting arteriosclerosis can be a cause of a reduced precondition effect of heart in mice. Methods LDL receptor-deficient mice were fed a long-term (14-16 weeks) high-fat atherogenic diet to induce arteriosclerosis. Arteriosclerosis was identified by histological examination and vessel contraction tests. LDLR-/- and wild-type mice were randomly assigned to anesthetic-induced, remote ischemic, or no preconditioning. All mice were subjected to 45 minutes of coronary artery occlusion and 180 minutes of reperfusion. The area at risk and infarct size were determined by Evans Blue and triphenyltetrazolium chloride staining. Results Histopathological examination showed atherosclerosis in high-fat atherogenic fed LDLR-/- mice, and the vessel relaxation capacity was significantly reduced compared to wild-type mice. In the wild type, as expected, infarct size was significantly reduced by preconditioning compared to the control. In LDLR-/- mice, infarct size was significantly reduced by preconditioning compared to the control. Surprisingly, the LDLR-/- control group also had a significantly reduced infarct size compared to the wild-type control group. Conclusion We were able to demonstrate that a high-fat diet morphologically and functionally triggered atherosclerosis in LDLR-/- mice. Interestingly, LDLR-/- mice with an atherogenic diet had smaller infarct sizes compared to wild-type mice. Moreover, preconditioning additionally reduced myocardial infarct size in LDLR-/- mice. A long-term high-fat atherogenic diet and preconditioning seem to result in additive cardioprotection in LDLR-/- mice.

Trehalose preconditioning for transient global myocardial ischemia in rats

Autophagy is an intracellular pathway that degrades unnecessary proteins and organelles and provides energy substrates during cellular ischemic conditions. Although pharmacological myocardial preconditioning with an autophagy inducer has been reported to protect cells against ischemic reperfusion (I/R), the effects of preconditioning using naturally occurring substances are still unknown. We aimed to examine whether autophagic preconditioning with trehalose improves cardiac function after myocardial stunning by global ischemia in rats. Rat hearts were perfused by oxygenized Krebs Henseleit (KH) solution in Langendorff system. Ten rats were randomized into the following two groups according to the perfusates during the preconditioning: control (KH solution only, n = 5) and trehalose (KH + 2% trehalose, n = 5). After the 35-min preconditioning period and subsequent 20 min of global ischemia, the hearts were reperfused for 60 min. Cardiac function was assessed during the reperfusion. To evaluate autophagy, myocardial protein expression of microtubule-associated protein light chain 3 (LC3) II was evaluated by western blotting. During I/R, a systolic functional parameter, maximum dP/dt was significantly higher; meanwhile, coronary flow tended to be higher in the trehalose group than in the control group. Myocardial LC3-II expression after preconditioning was higher in the trehalose group than in the control group and decreased to the control level after I/R. In conclusion, in a rat model of global myocardial ischemia, trehalose preconditioning improved cardiac function during I/R. Further studies would be needed to identify the mechanism and effects of trehalose preconditioning.

Estimation of the Predictive Factors of Myocardial Ischemic Preconditioning in Elective Surgical Patients

Knowledge of the physiological response to aggression produced by surgical trauma provides effective treatment capacity...

Myocardial Preconditioning by Intracoronary Adenosine before Elective Percutaneous Coronary Intervention (short term outcome)

Background and Purpose: Pre- and post-conditioning by transient episodes of ischemia render the myocardium more resistant to subsequent ischemia, a phenomenon known as ischemic pre-conditioning. This effect is thought to be partly mediated by endogenous adenosine. The aim of the study was to investigate the efficacy and safety of intracoronary adenosine on myocardial perfusion in patients schedule for elective percutaneous coronary intervention. Methods: A prospective observational comparative study of 120 patients with coronary artery disease scheduled for elective percutaneous coronary intervention. Patients were randomly to receive intracoronary adenosine (n = 60 ) or placebo (n= 60), both groups were compared regarding clinical risk factors electrocardiographic, echocardiographic, cardiac troponin ,C-reactive protein, angiographic variables and major adverse cardiac events. Results: Among clinical risk factors, smoking and obesity were significantly higher in placebo group. ECG data, echocardiographic data, Troponin data and myonecrosis were not statistically significant different between both groups before and after percutaneous coronary intervention, but high sensitive C-reactive protein was statistically significantly higher post percutaneous coronary intervention in placebo group. There was no statistically significant difference between both groups regarding percutaneous coronary intervention results, periprocedural complications and short term clinical outcome. Conclusion: Myocardial preconditioning by intracoronary adenosine in patients schedule for elective percutaneous coronary intervention is safe but did not provide any benefit in terms of decreasing periprocedural myonecrosis or improving short term clinical outcome. The elevation of high sensitive C-reactive protein is determined by more vessels manipulation by more pre dilation , post dilatation and more number of stents.

Prevention of doxorubicin-induced Cardiotoxicity by pharmacological non-hypoxic myocardial preconditioning based on Docosahexaenoic Acid (DHA) and carvedilol direct antioxidant effects: study protocol for a pilot, randomized, double-blind, controlled trial (CarDHA trial)

BackgroundAnthracycline-induced cardiotoxicity (AIC), a condition associated with multiple mechanisms of damage, including oxidative stress, has been associated with poor clinical outcomes. Carvedilol, a β-blocker with unique antioxidant properties, emerged as a strategy to prevent AIC, but recent trials question its effectiveness. Some evidence suggests that the antioxidant, not the β-blocker effect, could prevent related cardiotoxicity. However, carvedilol’s antioxidant effects are probably not enough to prevent cardiotoxicity manifestations in certain cases. We hypothesize that breast cancer patients taking carvedilol as well as a non-hypoxic myocardial preconditioning based on docosahexaenoic acid (DHA), an enhancer of cardiac endogenous antioxidant capacity, will develop less subclinical cardiotoxicity manifestations than patients randomized to double placebo.Methods/designWe designed a pilot, randomized controlled, two-arm clinical trial with 32 patients to evaluate the effects of non-hypoxic cardiac preconditioning (DHA) plus carvedilol on subclinical cardiotoxicity in breast cancer patients undergoing anthracycline treatment. The trial includes four co-primary endpoints: changes in left ventricular ejection fraction (LVEF) determined by cardiac magnetic resonance (CMR); changes in global longitudinal strain (GLS) determined by two-dimensional echocardiography (ECHO); elevation in serum biomarkers (hs-cTnT and NT-ProBNP); and one electrocardiographic variable (QTc interval). Secondary endpoints include other imaging, biomarkers and the occurrence of major adverse cardiac events during follow-up. The enrollment and follow-up for clinical outcomes is ongoing.DiscussionWe expect a group of anthracycline-treated breast cancer patients exposed to carvedilol and non-hypoxic myocardial preconditioning with DHA to show less subclinical cardiotoxicity manifestations than a comparable group exposed to placebo.Trial registrationISRCTN registry, ID: ISRCTN69560410. Registered on 8 June 2016.

Sevoflurane but not Propofol Induces Immunomodulatory Effects in Patients Undergoing Aortic Valve Replacement and Cardiopulmonary Bypass

Volatile anaesthetics, most of all sevoflurane, have been described as providers of myocardial preconditioning, but few articles are focused on immunomodulatory effects of these agents. We aimed to study the effects of different anaesthetic procotols with sevoflurane and propofol on immunomodulation in patients undergoing cardiopulmonary bypass (CBP).

Comparative effects of calcium and potassium channel modulators on ischemia/reperfusion injury in the isolated rat heart.

The aim of this study was to examine and compare the effects of the acute administration of verapamil or amlodipine as representatives of the calcium channel blockers or nicorandil as a representative of the mitochondrial ATP-dependent potassium (KATP) channel opener to cardiac contractility, coronary flow, and oxidative stress markers on ischemia/reperfusion injury in the isolated rat heart. The hearts of adult male Wistar albino rats (n = 60 total, 12 per group) were divided into five groups, two controls (preconditioning with Krebs-Henseleit solution) and three experimental depending on acute administrated pharmacological agents (0,63µmol/L of verapamil, 0,1µmol/L of amlodipine, and 200µmol/L of nicorandil). After stabilization and 5min of preconditioning in experimental groups, hearts from I/R control and all experimental groups underwent global ischemia (20min) and reperfusion (30min). Hearts from sham group were continuously followed for 50min, after stabilization period. Cardiodynamic parameters and coronary flow were recorded at the end of stabilization (S), at the last minute of pharmacological preconditioning (P) and at intervals of 5min after global ischemia, during reperfusion, or in case of sham group during 20-50min after stabilization. At the same intervals, we collected coronary venous effluent from which we spectrophotometrically measured the parameters of oxidative stress: the index of lipid peroxidation, superoxide anion radical, hydrogen peroxide, and nitrite. In summary, our findings clearly indicate that the blocking of the calcium channel or the activation of KATP may mediate the protective effect of myocardial preconditioning. The ex vivo results showed that all examined drugs after ischemia and reperfusion have beneficial cardioprotective properties associated with lower values of major pro-oxidative molecules. Obtained effects seem to be the most convincible in case of nicorandil.

Role of Calcium Channel Blockers in Myocardial Preconditioning

Abstract Coronary heart disease is the leading cause of mortality and morbidity worldwide. The effects of coronary heart disease are usually attributable to the detrimental effects of acute myocardial ischaemia-reperfusion injury. Newer strategies such as ischaemic or pharmacological preconditioning have been shown to condition the myocardium to ischaemia-reperfusion injury and thus reduce the final infarct size. This review investigates the role of calcium channel blockers in myocardial preconditioning. Additionally, special attention is given to nicorandil whose mechanism of action may be associated with the cardioprotective effects of preconditioning. There are still many uncertainties in understanding the role of these agents in preconditioning, but future research in this direction will certainly help reduce coronary heart disease.

Cardioprotection with halogenated gases: how does it occur?

Numerous studies have studied the effect of halogenated agents on the myocardium, highlighting the beneficial cardiac effect of the pharmacological mechanism (preconditioning and postconditioning) when employed before and after ischemia in patients with ischemic heart disease. Anesthetic preconditioning is related to the dose-dependent signal, while the degree of protection is related to the concentration of the administered drug and the duration of the administration itself. Triggers for postconditioning and preconditioning might have numerous pathways in common; mitochondrial protection and a decrease in inflammatory mediators could be the major biochemical elements. Several pathways have been identified, including attenuation of NFκB activation and reduced expression of TNFα, IL-1, intracellular adhesion molecules, eNOS, the hypercontraction reduction that follows reperfusion, and antiapoptotic activating kinases (Akt, ERK1/2). It appears that the preconditioning and postconditioning triggers have numerous similar paths. The key biochemical elements are protection of the mitochondria and reduction in inflammatory mediators, both of which are developed in various ways. We have studied this issue, and have published several articles on cardioprotection with halogenated gases. Our results confirm greater cardioprotection through myocardial preconditioning in patients anesthetized with sevoflurane compared with propofol, with decreasing levels of troponin and N-terminal brain natriuretic peptide prohormone. The difference between our studies and previous studies lies in the use of sedation with sevoflurane in the postoperative period. The results could be related to a prolonged effect, in addition to preconditioning and postconditioning, which could enhance the cardioprotective effect of sevoflurane in the postoperative period. With this review, we aim to clarify the importance of various mechanisms involved in preconditioning and postconditioning with halogenated gases, as supported by our studies.

The Inhibitory Effect of Telmisartan on the Metabolism of Arachidonic Acid by CYP2C9 and CYP2C8: An in Vitro Study.

Epoxyeicosatorienoic acids (EETs) are generated from arachidonic acid (AA) by CYPs. EETs comprise four regioisomers (14,15-, 11,12-, 8,9-, and 5,6-EET). EETs show potent physiological effects, including vasodilation, anti-inflammation, myocardial preconditioning, and anti-platelet aggregation effects. We recently demonstrated that telmisartan, one of angiotensin II receptor blockers, inhibits AA metabolism by CYP enzymes, including CYP2C8, CYP2C9, and CYP2J2. We conducted studies of AA metabolism using recombinant CYP enzymes to estimate the inhibition constant and the type of inhibition by telmisartan of CYP2C9 and CYP2C8. The contribution ratio (CR) of each CYP enzyme was investigated using human liver microsomes. Dixon and Lineweaver-Burk plots indicated that telmisartan is a mixed inhibitor of both CYP2C9 and CYP2C8; telmisartan did not show a time-dependent inhibition toward these CYP enzymes. Based on the CRs, both CYP2C9 and CYP2C8 are the key enzymes in the metabolism of AA in the human liver. Uptake of telmisartan in the liver by organic anion transporting polypeptide (OATP) 1B3 and the non-linear metabolism in gastrointestinal tract augment the potential of the drug to inhibit the CYP enzymes in the liver.

Morphine-Induced Preconditioning: Involvement of Protein Kinase A and Mitochondrial Permeability Transition Pore.

BackgroundMorphine induces myocardial preconditioning (M-PC) via activation of mitochondrial large conductance Ca2+-sensitive potassium (mKCa) channels. An upstream regulator of mKCa channels is protein kinase A (PKA). Furthermore, mKCa channel activation regulates mitochondrial bioenergetics and thereby prevents opening of the mitochondrial permeability transition pore (mPTP). Here, we investigated in the rat heart in vivo whether 1) M-PC is mediated by activation of PKA, and 2) pharmacological opening of the mPTP abolishes the cardioprotective effect of M-PC and 3) M-PC is critically dependent on STAT3 activation, which is located upstream of mPTP within the signalling pathway.MethodsMale Wistar rats were randomised to six groups (each n = 6). All animals underwent 25 minutes of regional myocardial ischemia and 120 minutes of reperfusion. Control animals (Con) were not further treated. Morphine preconditioning was initiated by intravenous administration of 0.3 mg/kg morphine (M-PC). The PKA blocker H-89 (10 μg/kg) was investigated with and without morphine (H-89+M-PC, H-89). We determined the effect of mPTP opening with atractyloside (5 mg/kg) with and without morphine (Atr+M-PC, Atr). Furthermore, the effect of morphine on PKA activity was tested in isolated adult rat cardiomyocytes. In further experiments in isolated hearts we tested the protective properties of morphine in the presence of STAT3 inhibition, and whether pharmacological prevention of the mPTP-opening by cyclosporine A (CsA) is cardioprotective in the presence of STAT3 inhibition.ResultsMorphine reduced infarct size from 64±5% to 39±9% (P<0.05 vs. Con). H-89 completely blocked preconditioning by morphine (64±9%; P<0.05 vs. M-PC), but H-89 itself had not effect on infarct size (61±10%; P>0.05 vs. Con). Also, atractyloside abolished infarct size reduction of morphine completely (65±9%; P<0.05 vs. M-PC) but had no influence on infarct size itself (64±5%; P>0.05 vs. Con). In isolated hearts STAT3 inhibitor Stattic completely abolished morphine-induced preconditioning. Administration of Stattic and mPTP inhibitor cyclosporine A reduced infarct size to 31±6% (Stat+CsA, P<0.05 vs. Con). Cyclosporine A alone reduced infarct size to 26±7% (CsA P<0.05 vs. Con). In cardiomyocytes, PKA activity was increased by morphine.ConclusionOur data suggest that morphine-induced cardioprotection is mediated by STAT3-activation and inhibition of mPTP, with STA3 located upstream of mPTP. There is some evidence that protein kinase A is involved within the signalling pathway.

Phosphodiesterase inhibitor KMUP-3 displays cardioprotection via protein kinase G and increases cardiac output via G-protein-coupled receptor agonist activity and Ca2+ sensitization

KMUP-3 (7-{2-[4-(4-nitrobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) displays cardioprotection and increases cardiac output, and is suggested to increase cardiac performance and improve myocardial infarction. To determine whether KMUP-3 improves outcomes in hypoperfused myocardium by inducing Ca2+ sensitization to oppose protein kinase (PK)G-mediated Ca2+ blockade, we measured left ventricular systolic blood pressure, maximal rates of pressure development, mean arterial pressure and heart rate in rats, and measured contractility and expression of PKs/RhoA/Rho kinase (ROCK)II in beating guinea pig left atria. Hemodynamic changes induced by KMUP-3 (0.5–3.0 mg/kg, intravenously) were inhibited by Y27632 [(R)-(+)-trans-4-1-aminoethyl)-N-(4-Pyridyl) cyclohexane carboxamide] and ketanserin (1 mg/kg, intravenously). In electrically stimulated left guinea pig atria, positive inotropy induced by KMUP-3 (0.1–100μM) was inhibited by the endothelial NO synthase (eNOS) inhibitors N-nitro-l-arginine methyl ester (L-NAME) and 7-nitroindazole, cyclic AMP antagonist SQ22536 [9-(terahydro-2-furanyl)-9H-purin-6-amine], soluble guanylyl cyclase (sGC) antagonist ODQ (1H-[1,2,4] oxadiazolo[4,3-a] quinoxalin-1-one), RhoA inhibitor C3 exoenzyme, β-blocker propranolol, 5-hydroxytryptamine 2A antagonist ketanserin, ROCK inhibitor Y27632 and KMUP-1 (7-{2-[4-(2-chlorobenzene) piperazinyl]ethyl}-1, 3-dimethylxanthine) at 10μM. Western blotting assays indicated that KMUP-3 (0.1–10μM) increased PKA, RhoA/ROCKII, and PKC translocation and CIP-17 (an endogenous 17-kDa inhibitory protein) activation. In spontaneous right atria, KMUP-3 induced negative chronotropy that was blunted by 7-nitroindazole and atropine. In neonatal myocytes, L-NAME inhibited KMUP-3-induced eNOS phosphorylation and RhoA/ROCK activation. In H9c2 cells, Y-27632 (50μM) and PKG antagonist KT5823 [2,3,9,10,11,12-hexahydro-10R- methoxy-2,9-dimethyl-1-oxo-9S,12R-epoxy-1H-diindolo(1,2,3-fg:3′,2′,1′-kl) pyrrolo(3,4-i)(1,6)benzodiazocine-10-carboxylic acid, methyl ester] (3μM) reversed KMUP-3 (1–100μM)-induced Ca2+-entry blockade. GPCR agonist activity of KMUP-3 appeared opposed to KMUP-1, and increased cardiac output via Ca2+ sensitization, and displayed cardioprotection via cyclic GMP/PKG-mediated myocardial preconditioning in animal studies.

Preconditioning offers cardioprotection in hyperlipidemic rat hearts: possible role of Dopamine (D2) signaling.

BackgroundIschemic preconditioning (IPC) induced cardioprotection has been reported to be blunted in hyperlipidemic subjects. Dopamine, via its D2 receptor signaling, appears to mimic the signaling cascade involved in myocardial preconditioning and is also involved in the inhibition of hyperlipidemia induced mediators. The present study was designed to investigate the possible involvement of D2 receptors in IPC and to see whether dopamine preconditioning can offer cardioprotection in hyperlipidemic rat hearts.MethodsWistar albino rats were divided into 8 groups and fed on normal or high fat diet for 4 weeks. Hyperlipidemia was confirmed after 4 weeks by serum lipid estimations. Isolated perfused hearts were subjected to ischemic preconditioning or dopamine induced pharmacological preconditioning followed by 30-min ischemic insult and 60-min reperfusion. Clozapine was administered as D2 antagonist. Coronary perfusate (basal and post-ischemic) was collected for the estimations of LDH (Lactate dehydrogenase) and CKMB (Creatine kinase MB). Hearts were then removed and frozen for infarct size measurement.ResultsA significant increase body weight, serum lipids except HDL was noted in high fat diet fed rats, as compared to normal rats. The level of LDH, CKMB in coronary effluent and infarct size were found to be decreased in preconditioned normal hearts, as compared to hearts treated with ischemia reperfusion. This effect was found to be blunted in hyperlipidemic animals. Dopamine (10 μM) alone and in combination with ischemic preconditioning significantly reduced the levels of LDH, CKMB and infarct size in hyperlipidemic hearts, as compared to preconditioned and non-preconditioned hyperlipidemic hearts. This effect was abolished significantly by Clozapine (D2 antagonist).ConclusionThe present study reveals possible involvement of D2 receptors in ischemic preconditioning and suggests that dopamine preconditioning may offer significant cardioprotection in hyperlipidemic rat hearts.

Abstract 256: Renal Denervation Preconditions the Myocardium by Promoting Nitric Oxide Signaling and Attenuating Oxidative Stress in Spontaneously Hypertensive Rats

Background: Recent clinical studies suggest that renal denervation (RDN) not only decreases blood pressure (BP) and sympathetic nerve activity, but may also exert additional systemic cardioprotective actions. We investigated whether RDN preconditions the heart against subsequent myocardial ischemia/reperfusion (MI/R) injury in spontaneously hypertensive rats (SHR). Materials and Methods: SHR (20w old) received either bilateral radiofrequency (RF) RDN or sham RDN (Biosense Webster Stockert 70 RF generator). After 4w of BP recording, Plasma and left ventricle (LV) tissue were collected for measurement of nitric oxide (NO) metabolites, nitrite (NO2-, ion chromatography) and S-Nitrosothiol (RSNO). RT PCR was used to examine transcriptional changes. Colorimetric assays were used to quantify malondialdehyde (MDA) and carbonyl content. In additional studies, 4w after RDN (n = 8) or Sham (n = 9) treatment, SHR were subjected to 30m of left coronary artery ischemia followed by 24h reperfusion and myocardial infarct/area-at-risk (AAR) was determined. Results: 4w after treatment, mean BP was significantly decreased in RDN compared to Sham SHR (157±2 vs 142±2 mmHg, p &lt; 0.05). Plasma NO2- levels were elevated 4w following RDN (p &lt; 0.01). Cardiac NO2- levels increased from 2.6 to 3.2 nmol/mg (p &lt; 0.05) and RSNO levels increased from 0.5 to 1.1 nmol/mg (p &lt; 0.05) following RDN. Moreover, myocardial oxidative stress was markedly attenuated as measured by carbonyl content (p &lt; 0.05) and MDA levels (p &lt; 0.01). Greater transcription of antioxidants, SOD1 (p &lt; 0.05) and GPX-1 (p &lt; 0.05) were also observed in the RDN treated group. SHR receiving RDN therapy exhibited a trend in infarct size reduction (42% per AAR reduction, p = 0.09) compared to sham following MI/R. We observed 2-fold greater survival in the RDN treated group (88%, 7 of 8) compared to sham (44%, 4 of 9) following MI/R. Conclusions: RDN produced a sustained elevation in NO bioavailability and signaling in the heart and blood. Additionally, RDN attenuated myocardial oxidative stress and augmented the antioxidant defense system in SHR. Although further studies are warranted, preliminary results indicate that these mechanisms may promote myocardial preconditioning and improve survival in the setting of MI/R injury.

Association of Plasma Nucleotide levels with severity of Coronary Arterial lesion and left ventricular systolic Function in Acute Myocardial infarction

Background: Purinergic receptors can be divided into adenosine (P1) and adenosine 5’-triphosphate (ATP) (P2) receptors, which play crucial roles in regulating vessel tone, arthrosclerosis, myocardial preconditioning and heart function. However, the relationship of plasma nucleotides with coronary artery disease (CAD) and heart function have not been reported. Methods and results: Total 97 patients undergoing coronary angiogram had been tested for the plasma nucleotides, including ATP, uridine 5’-triphosphate (UTP) and adenosine monophosphate (AMP), and their association with CAD and heart function. They were divided into ST-elevation myocardial infarction (STEMI, n=33) group, unstable angina (UA, n=33) group and control (normal angiography, n=31) group. The UTP (1263.23 ± 137.76 vs. 635.61 ± 124.82 nmol/L, P Conclusion: Plasma nucleotides levels have significant association with the myocardial damage, severity of coronary arterial lesion and left ventricular systolic function in acute myocardial infarction. Key words: Coronary artery disease, Left ventricular systolic function, Purinergic receptor, ST-elevation myocardial infarction, Unstable angina.

Interleukin-6 mediates exercise preconditioning against myocardial ischemia reperfusion injury.

Interleukin-6 (IL-6) is a pleiotropic cytokine that protects against cardiac ischemia-reperfusion (I/R) injury following pharmacological and ischemic preconditioning (IPC), but the affiliated role in exercise preconditioning is unknown. Our study purpose was to characterize exercise-induced IL-6 cardiac signaling (aim 1) and evaluate myocardial preconditioning (aim 2). In aim 1, C57 and IL-6(-/-) mice underwent 3 days of treadmill exercise for 60 min/day at 18 m/min. Serum, gastrocnemius, and heart were collected preexercise, immediately postxercise, and 30 and 60 min following the final exercise session and analyzed for indexes of IL-6 signaling. For aim 2, a separate cohort of exercise-preconditioned (C57 EX and IL-6(-/-) EX) and sedentary (C57 SED and IL-6(-/-) SED) mice received surgical I/R injury (30 min I, 120 min R) or a time-matched sham operation. Ischemic and perfused tissues were examined for necrosis, apoptosis, and autophagy. In aim 1, serum IL-6 and IL-6 receptor (IL-6R), gastrocnemius, and myocardial IL-6R were increased following exercise in C57 mice only. Phosphorylated (p) signal transducer and activator of transcription 3 was increased in gastrocnemius and heart in C57 and IL-6(-/-) mice postexercise, whereas myocardial iNOS and cyclooxygenase-2 were unchanged in the exercised myocardium. Exercise protected C57 EX mice against I/R-induced arrhythmias and necrosis, whereas arrhythmia score and infarct outcomes were higher in C57 SED, IL-6(-/-) SED, and IL-6(-/-) EX mice compared with SH. C57 EX mice expressed increased p-p44/42 MAPK (Thr(202)/Tyr(204)) and p-p38 MAPK (Thr(180)/Tyr(182)) compared with IL-6(-/-) EX mice, suggesting pathway involvement in exercise preconditioning. Findings indicate exercise exerts cardioprotection via IL-6 and strongly implicates protective signaling originating from the exercised skeletal muscle.

Peri-operative anaesthetic myocardial preconditioning and protection - cellular mechanisms and clinical relevance in cardiac anaesthesia.

Preconditioning has been shown to reduce myocardial damage caused by ischaemia–reperfusion injury peri-operatively. Volatile anaesthetic agents have the potential to provide myocardial protection by anaesthetic preconditioning and, in addition, they also mediate renal and cerebral protection. A number of proof-of-concept trials have confirmed that the experimental evidence can be translated into clinical practice with regard to postoperative markers of myocardial injury; however, this effect has not been ubiquitous. The clinical trials published to date have also been too small to investigate clinical outcome and mortality. Data from recent meta-analyses in cardiac anaesthesia are also not conclusive regarding intra-operative volatile anaesthesia. These inconclusive clinical results have led to great variability currently in the type of anaesthetic agent used during cardiac surgery. This review summarises experimentally proposed mechanisms of anaesthetic preconditioning, and assesses randomised controlled clinical trials in cardiac anaesthesia that have been aimed at translating experimental results into the clinical setting.