Circulating mir-483-5p as a novel diagnostic biomarker for acute coronary syndrome and its predictive value for the clinical outcome after PCI.

BACKGROUND: MicroRNA (miRNA) plays a critical function in the progression of acute coronary syndrome (ACS) and is associated with major adverse cardiovascular events (MACEs) after undergoing percutaneous coronary intervention (PCI). This research was designed to probe the diagnostic accuracy of miR-483-5p in patients with ACS and its predictive value of MACEs. METHODS: 118 patients with ACS (40 with unstable angina pectoris [UAP] and 78 with acute myocardial infarction [AMI]) and 75 healthy controls were enrolled. Serum miR-483-5p was detected in the subjects by reverse transcription-quantitative real-time PCR (RT-qPCR). ROC curve and logistic regression models were employed to estimate the diagnosis. Patients were monitored for 6 months after PCI to document the occurrence of MACEs. Kaplan-Meier survival was conducted to explore the predictive significance of miR-483-5p for the MACEs. RESULTS: Serum miR-483-5p levels were higher in ACS patients and associated with SYNTAX score and Gensini score. miR-483-5p was effective in identifying ACS patients from healthy individuals (AUC = 0.919) and AMI patients from ACS patients (AUC = 0.867), demonstrating a high diagnostic value, proven by logistic regression (OR = 9.664, 95%CI = 4.462-20.928, P < 0.001). The prevalence of MACEs during follow-up were 24.58%, and a higher prevalence of MACEs were observed in patients with elevated miR-483-5p (P = 0.01). miR-483-5p was also an effective predictor of MACE occurrence (HR = 5.955, 95%CI = 1.928-18.389, P = 0.002). CONCLUSION: Expression of serum miR-483-5p can be utilized as a non-invasive marker for diagnosing ACS and predicting the onset of MACE after PCI.

A novel use of small ballons to reduce the risk of subintimal hematoma formation during recanalization of chronic total occlusion: two case reports.

BACKGROUND: Subintimal hematoma remains a major challenge associated with unnecessary technical complexity, failure of the antegrade approach or imperfection of revascularization in percutaneous coronary intervention (PCI) for chronic total occlusion (CTO). Some techniques and devices release the hematoma after its formation. Here, we describe a novel use of small ballons to prevent the hematoma formation during antegrade approach in two cases. CASE PRESENTATION: We report two cases of CTO-PCI in which balloon occlusion was successfully applied to prevent haematoma formation. The first case, a 72-year-old female with diabetes, was hospitalized because of unstable angina. Angiography showed right coronary artery (RCA) CTO, which initiated from the proximal part to the trifurcation at the distal part of the RCA. Considering the high likelihood and serious consequences of subintimal haematoma, a small balloon is employed to prevent subintimal hematoma formation. A balloon and microcatheter or double-lumen microcatheter are placed in the proximal coronary CTO lesion; then the balloon was dilated beside the catheter, most of the antegrade blood flow was sealed which reduced the likelihood of haematoma formation. The procedure was successfully completed without subintimal hematoma formation. The second case a 62-year-old male with unstable angina, was hospitalized for PCI. Angiography showed left anterior descending coronary artery CTO. Similar to case 1, we also used a small balloon to prevent hematoma formation. Both patients underwent PCI, which employed a small balloon to prevent hematoma formation and both procedures were successful without complications. CONCLUSION: In patients who underwent CTO-PCI, balloon occlusion offers an alternative for reducing the incidence of subintimal haematomas.

Atherogenic L5 LDL induces cardiomyocyte apoptosis and inhibits KATP channels through CaMKII activation.

BACKGROUND: Cardiac Ca2+/calmodulin-dependent protein kinase II (CaMKII) activation plays a critical role in cardiomyocyte (CM) apoptosis and arrhythmia. Functional ATP-sensitive potassium (KATP) channels are essential for cardiac protection during ischemia. In cultured CMs, L5 low-density lipoprotein (LDL) induces apoptosis and QTc prolongation. L5 is a highly electronegative and atherogenic aberrant form of LDL, and its levels are significantly higher in patients with cardiovascular-related diseases. Here, the role of L5 in cardiac injury was studied by evaluating the effects of L5 on CaMKII activity and KATP channel physiology in CMs. METHODS: Cultured neonatal rat CMs (NRCMs) were treated with a moderate concentration (ie, 7.5 µg/mL) of L5 or L1 (the least electronegative LDL subfraction). NRCMs were examined for apoptosis and viability, CaMKII activity, and the expression of phosphorylated CaMKIIδ and NOX2/gp91phox. The function of KATP and action potentials (APs) was analyzed by using the patch-clamp technique. RESULTS: In NRCMs, L5 but not L1 significantly induced cell apoptosis and reduced cell viability. Furthermore, L5 decreased Kir6.2 expression by more than 50%. Patch-clamp analysis showed that L5 reduced the KATP current (IKATP) density induced by pinacidil, a KATP opener. The partial recovery of the inward potassium current during pinacidil washout was susceptible to subsequent inhibition by the IKATP blocker glibenclamide. Suppression of IKATP by L5 significantly prolonged the AP duration. L5 also significantly increased the activity of CaMKII, the phosphorylation of CaMKIIδ, and the expression of NOX2/gp91phox. L5-induced apoptosis was prevented by the addition of the CaMKII inhibitor KN93 and the reactive oxygen species scavenger Mn (III)TBAP. CONCLUSIONS: L5 but not L1 induces CM damage through the activation of the CaMKII pathway and increases arrhythmogenicity in CMs by modulating the AP duration. These results help to explain the harmful effects of L5 in cardiovascular-related disease.

Apolipoprotein-J blocks increased cell injury elicited by ox-LDL via inhibiting ROS-CaMKII pathway.

BACKGROUND: Oxidized low-density lipoprotein (ox-LDL) is crucial in cardiac injury. Apolipoprotein-J (ApoJ) contributes to antiapoptotic effects in the heart. We aimed to evaluate the protective effects of ApoJ against ox-LDL cytotoxicity in Neonatal rat ventricular cells (NRVCs). METHODS AND RESULTS: NRVCs were damaged by exposure to ox-LDL, as shown by increased caspase-3/7 activity, enhanced caspase-3 expression, and decreased cell viability. ApoJ overexpression, using an adenovirus vector, significantly reduced ox-LDL-induced cell injury. ApoJ also prevented ox-LDL from augmenting reactive oxygen species (ROS) production, as demonstrated by elevated Nox2/gp91phox and P47 expression. Furthermore, ApoJ overexpression reduced CaMKIIδ expression elicited by ox-LDL in cultured NRVCs. Upregulating CaMKIIδ activity, mediated by ox-LDL, was significantly inhibited by ApoJ overexpression. A CaMKIIδ inhibitor, KN93, prevented ApoJ's protective effect against ox-LDL cytotoxicity. A ROS scavenger, Mn (III)meso-tetrakis (4-benzoic acid) porphyrin (Mn (III)TBAP), also attenuated CaMKIIδ's increased expression and activity, induced by ox-LDL, and showed similar results to ApoJ by attenuating ox-LDL-induced cell damage, as ApoJ did. CONCLUSIONS: ApoJ confers cytoprotection to NRVCs against ox-LDL cytotoxicity through the ROS-CaMKII pathways.

Involvement of MicroRNA-133a in the Protective Effect of Hydrogen Sulfide against Ischemia/Reperfusion-Induced Endoplasmic Reticulum Stress and Cardiomyocyte Apoptosis.

AIM: Myocardial ischemia/reperfusion (I/R) injury is a severe trauma that cells undergo and is associated with cardiomyocyte apoptosis. Recently, miRNAs have been demonstrated to play an important role in cardiovascular biology and disease. However, whether the miR-133a and ER stress play a role in hydrogen sulfide (H2S) protection of cardiomyocytes against I/R-induced apoptosis remains unclear. METHODS: The neonatal cardiomyocytes were prepared to be treated with H2S or transfected with miR-133a activator or miR-133a inhibitor, either separately or in combination. Non-treated cardiomyocytes served as control. The ER stress biomarker GRP78, CHOP, and eIF2α expression levels were measured by Western blot. Cell apoptosis was assessed by flow cytometry after staining with the Annexin V- FITC. Proliferation was monitored by BrdU labeling, while cell migration and invasion were determined by Transwell assays. RESULTS: Pre-treatment of H2S and overexpression of miR-133a reversed I/R-induced ER stress and cardiomyocyte apoptosis in vitro and in vivo. The proliferation, migration, and invasion of cardiomyocytes were significantly increased by co-treatment with H2S and overexpression of miR-133a. CONCLUSION: These findings suggest the protective effect of miR-133a against I/R-induced ER stress and cardiomyocyte apoptosis and its enhancement of cell motility. Thus, cardioprotection by miR-133a overexpression provides a novel therapeutic approach to the treatment of ischemic heart diseases.

Atorvastatin blocks increased l-type Ca2+ current and cell injury elicited by angiotensin II via inhibiting oxide stress.

Thel-type Ca(2+)current (ICa,l) plays a crucial role in shaping action potential and is involved in cardiac arrhythmia. Statins have been demonstrated to contribute to anti-apoptotic and anti-arrhythmic effects in the heart. Here, we examined whether atorvastatin regulates theICa,land cell injury induced by angiotensin II (AngII) as well as the putative intracellular cascade responsible for the effects. Cultured neonatal rat ventricular myocytes were incubated with AngII for 24 h, and then cell injury and expression levels of Nox2/gp91(phox), p47(phox) ,and Cav1.2 were analyzed. In addition,ICa,lwas recorded using the whole-cell patch-clamp technique, and mechanisms of atorvastatin actions were also investigated. It was found that the number of apoptotic cardiomyocytes was increased and cell viability was significantly decreased after AngII administration. AngII also augmented the expressions of Nox2/gp91(phox)and p47(phox)compared with control cardiomyocytes. Exposure to AngII evokedICa,lin a voltage-dependent manner without affecting theI-Vrelationship. In addition, AngII enhanced membrane Cav1.2 expression. These effects were abolished in the presence of the reactive oxygen species (ROS) scavenger, manganese (III)-tetrakis 4-benzoic acid porphyrin [Mn(III)TBAP], or the 3-hydroxy-3-methylglutaryl-CoA reductase inhibitor, atorvastatin. These results suggested that atorvastatin mediates cardioprotection against arrhythmias and cell injury by controlling the AngII-ROS cascade.

Apolipoprotein-J prevents angiotensin II-induced apoptosis in neonatal rat ventricular cells.

BACKGROUND: Up-regulation of angiotensin II (AngII) occurs in cardiac diseases, such as congestive heart failure, cardiac hypertrophy, myocardial ischemia and atrial fibrillation, which represent major health problems. Evidence from in vivo studies suggests that the level of Apolipoprotein-J (ApoJ) is also elevated but plays a protective role in cardiovascular disease. This study aimed to evaluate the protective effects of ApoJ against cytotoxicity of AngII in neonatal rat ventricular cells (NRVCs). METHODS AND RESULTS: In culture, NRVCs were damaged by exposure to AngII, and ApoJ overexpression using an adenovirus vector significantly reduced the AngII-induced cell injury. ApoJ also prevented AngII from augmenting Nox2/gp91(phox) expression. The reactive oxygen species (ROS) scavenger, Mn(III)TBAP, showed similar results of attenuating AngII-induced cell damage. Furthermore, ApoJ overexpression increased phosphorylation of Akt, and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 diminished the antioxidant effects of ApoJ, and prevented the protective effect of ApoJ against the cytotoxicity of AngII. Moreover, upregulation of nuclear factor κB (NF-κB) p65 expression and phosphorylation of p38 mitogen-activated protein kinase (MAPK) mediated by AngII in cultured NRVCs were significantly inhibited by overexpression of ApoJ. The p38 MAPK inhibitor SB203580 and the NF-κB inhibitor PDTC protected NRVCs from injury caused by AngII. CONCLUSIONS: ApoJ serves as a cytoprotective protein in NRVCs against cytotoxicity of AngII through the PI3K-Akt-ROS and MAPK/ NF-κB pathways.

The Different Therapeutic Effects of Traditional Chinese Medicine Shensong Yangxin Capsule and Salubrinal in High-intensity Exercise-induced Heart Failure in Rats with Acute Myocardial Infarction.

BACKGROUND: Currently, endoplasmic reticulum stress is studied utilizing a dephosphorylation inhibitor (Sal). The traditional Chinese patent medicine and simple formulation Shensong Yangxin Capsule is a commonly used medication for the treatment of arrhythmia. However, the efficacy and underlying mechanism of the capsule in treating post-ischemic heart failure in myocardial tissue have not yet been investigated. OBJECTIVE: The therapeutic effects and the underlying mechanism of the Shensong Yangxin Capsule (SSYX) and the dephosphorylation inhibitor Salubrinal (Sal) on heart failure (HF) induced by high-intensity exercise in rats with acute myocardial infarction (AMI) were investigated. METHODS: Male infants of 8 weeks Spragge-Dawley (SD) rats were randomly assigned to one of four groups: sham surgery group, AMI+placebo group, AMI+Shensong Yangxin Capsule group (AMI+SSYX), and AMI+Sal administration group. Rats' myocardial infarction was induced by left coronary artery ligation. Rats were subjected to a 3-week high-intensity exercise program to simulate heart failure after 7 days of postoperative rest. After the fourth postoperative week, echocardiography was applied to determine the left ventricular ejection fraction (LVEF), left ventricular fractional shortening (LVFS), and left ventricular systolic volume (LVESV) in each group. HE and TUNEL labeling were employed to examine the morphology of cardiac cells and measure the percentage of apoptosis in each group; Western blotting was applied to detect the cardiomyocyte apoptosis-related proteins p-JNK, p-P38, and NOX2, while ELISA was used to detect glutathione(GSH), malondialdehyde (MDA), and superoxide dismutase (SOD) in serum. RESULTS: Following a 4-week drug intervention:(1)LVFS and LVEF in the AMI+placebo group were statistically significantly reduced, while LVESV were significantly higher, compared to those in the sham surgery group (P<0.05); The AMI+SSYX group performed statistically significantly better than the AMI+placebo group(P<0.05). (2) The myocardial cells in the AMI+placebo group exhibited significant swelling and inflammatory cell infiltration; the myocardial cells in the AMI+SSYX group and AMI+Sal group displayed mild swelling and minimal inflammatory cell infiltration; the AMI+SSYX group's myocardial cell morphology was superior to that of the AMI+Sal group; (3) The apoptosis rate of the AMI+placebo group was around 95%, greater than that of the sham surgery group (2.55%). The apoptosis rate of the AMI+SSYX group is approximately 21%, while the apoptosis rate of the AMI+Sal group is about 43%. (4) In the AMI+placebo group, p-JNK, p-P38, and NOX2 protein expression dramatically increased compared to the sham surgery group. The expression of p-P38, NOX2, and p-JNK/t-JNK was considerably reduced in the AMI+Shensong group and AMI+Sal group, compared to the AMI+placebo group. (P<0.01)The AMI+SSYX group's result is superior to that of the AMI+Sal group. (5) Compared to the sham surgery group, the serum levels of SOD and GSH were significantly lower, and MDA was significantly higher in the AMI+placebo group. Compared to the AMI+placebo group, the serum levels of SOD and GSH were significantly higher, and MDA was significantly lower in the AMI+SSYX group and the AMI+Sal group. (P<0.05) Conclusion: In rats with acute myocardial infarction in high-intensity exercise-induced heart failure, Shensong Yangxin Capsule dramatically reduces myocardial cell death and cardiac dysfunction. SSYX has a shorter course of treatment and a better therapeutic effect than Sal.

Cardiac-derived adiponectin induced by long-term insulin treatment ameliorates myocardial ischemia/reperfusion injury in type 1 diabetic mice via AMPK signaling.

Type 1 diabetes (T1DM) portends poor prognosis concerning ischemic heart disease. Adiponectin (APN), an adipocytokine possessing insulin sensitizing and metabolic regulatory effects, has been recognized as a potent cardioprotective molecule. However, the relationship between APN and T1DM remains controversial and the role of cardiac-derived APN in T1DM is unclear. This study is aimed to investigate the dynamic change of both plasma and cardiac-derived APN expressions in T1DM, and the particular role of cardiac-derived APN in T1DM against myocardial ischemia/reperfusion (MI/R) injury. T1DM was established via intraperitoneal injection of streptozocin and followed by twice-daily subcutaneous injection of insulin or vehicle for 14 days. Non-diabetic mice of wild type and APN knockout were subjected to insulin or vehicle injection. MI/R was induced in Langendorff-perfused hearts. Compared to non-diabetic mice, plasma APN levels of diabetic mice significantly increased at 7 days, and slightly decreased at 14 days, while cardiac-derived APN levels gradually decreased over time. The MI/R injury measured as infarct size and cardiomyocyte apoptosis nearly doubled in diabetic mice. 14 days of insulin treatment increased both plasma and cardiac-derived APN levels in diabetic mice and attenuated myocardial injury via increasing AMPK phosphorylation in T1DM, which was partly reversed by Compound C (an AMPK inhibitor). Moreover, APN deficiency aggravated MI/R injury and partly abolished the protective effect of insulin treatment against MI/R injury, which was associated with decreased AMPK phosphorylation. The results suggest that cardiac-derived APN stimulated by long-term insulin treatment in T1DM exerts cardioprotection against MI/R injury via myocardial AMPK activation.

Preparation and performance of latanoprost-loaded hydrogels as a lacrimal suppository for the treatment of glaucoma.

Glaucoma is the leading cause of irreversible blindness, and its treatment is attracting widespread attention. Drug-loaded lacrimal suppositories can effectively treat xerophthalmia, but there is little research on the treatment of glaucoma with drug-loaded lacrimal suppositories. This article explored and expanded the non-pharmacological model of lacrimal suppository therapy for glaucoma by using a combination of lacrimal suppository and medication. The drug-loaded lacrimal suppository was rationally designed through the conjugation of gelatin with polyamide (PAM) via the formation of amide linkages, followed by Schiff base reaction grafting with latanoprost. In vitro drug release studies showed that latanoprost released from drug-loaded lacrimal embolus had sustained-release properties with a release time of 33 days and a drug release volume of 82.6%. The biological evaluation of drug-loaded lacrimal thrombus was carried out by IOP test, retinal potential test, and retinal H&E staining. The results showed that the IOP decreased to 27.125 ± 1.1254 mmHg, and the a and b waves of retinal potential increased to 4.39 ± 0.16 µV and 67.9 ± 2.17 µV, respectively. It indicated that latanoprost lacrimal suppository has a good therapeutic effect on glaucoma.

Impact of a medical supply bulk-buy program on treatment of patients with coronary artery disease in China: A single-center study.

BACKGROUND: The Chinese government recently introduced a program to buy medical supplies in bulk to reduce the patient cost burden. For patients undergoing percutaneous coronary intervention (PCI), little is known about the effect on outcomes of this bulk-buy program. AIMS: This study investigated whether the bulk-buy program to decrease the price of stents used in PCI affected clinical decision-making and outcomes. METHODS: This single-center study enrolled patients undergoing PCI from January 2020-December 2021. Prices decreased for stents on January 1, 2021, and balloons on March 1, 2021. Patients were grouped by surgical year as either before (2020) or after (2021) policy implementation. All clinical data were collected. To examine whether clinical decision-making for PCI was affected by the bulk-buy program, procedure appropriateness was analyzed using the 2017 appropriate use criteria (AUC). To assess outcomes, the rates of major adverse cardiac and cerebrovascular events (MACCE) and complications were compared between groups. RESULTS: Study participants were 601 patients in 2020 (before bulk buying) and 699 patients in 2021 (after bulk buying). Results of analysis by AUC for procedure appropriateness were 74.5% appropriate, 21.6% may be appropriate, and 3.8% rarely appropriate in 2020, with no differences for patients who underwent PCI in 2021. Between-group comparisons showed MACCE rates of 0.5% in 2020 and 0.6% in 2021, whereas complication rates were 5.5% and 5.7%, respectively. No statistically significant differences were found between groups (p > 0.05). CONCLUSION: The bulk-buy program did not impact physician clinical decision-making or surgical outcomes for patients undergoing PCI.

The alternative crosstalk between RAGE and nitrative thioredoxin inactivation during diabetic myocardial ischemia-reperfusion injury.

The receptor for advanced glycation end products (RAGE) and thioredoxin (Trx) play opposing roles in diabetic myocardial ischemia-reperfusion (MI/R) injury. We recently demonstrated nitrative modification of Trx leads to its inactivation and loss of cardioprotection. The present study is to determine the relationship between augmented RAGE expression and diminished Trx activity pertaining to exacerbated MI/R injury in the diabetic heart. The diabetic state was induced in mice by multiple intraperitoneal low-dose streptozotocin injections. RAGE small-interfering RNA (siRNA) or soluble RAGE (sRAGE, a RAGE decoy) was via intramyocardial and intraperitoneal injection before MI/R, respectively. Mice were subjected to 30 min of myocardial infarction followed by 3 or 24 h of reperfusion. At 10 min before reperfusion, diabetic mice were randomized to receive EUK134 (peroxynitrite scavenger), recombinant hTrx-1, nitrated Trx-1, apocynin (a NADPH oxidase inhibitor), or 1400W [an inducible nitric oxide synthase (iNOS) inhibitor] administration. The diabetic heart manifested increased RAGE expression and N(ε)-(carboxymethyl)lysine (CML, major advanced glycation end product subtype) content, reduced Trx-1 activity, and increased Trx nitration after MI/R. RAGE siRNA or administration of sRAGE in diabetic mice decreased MI/R-induced iNOS and gp91(phox) expression, reduced Trx nitration, preserved Trx activity, and decreased infarct size. Apocynin or 1400W significantly decreased nitrotyrosine production and restored Trx activity. Conversely, administration of either EUK134 or reduced hTrx, but not nitrated hTrx, attenuated MI/R-induced superoxide production, RAGE expression, and CML content and decreased cardiomyocyte apoptosis in diabetic mice. Collectively, we demonstrate that RAGE modulates the MI/R injury in a Trx nitrative inactivation fashion. Conversely, nitrative modification of Trx blocked its inhibitory effect upon RAGE expression in the diabetic heart. This is the first direct evidence demonstrating the alternative cross talk between RAGE overexpression and nitrative Trx inactivation, suggesting that interventions interfering with their interaction may be novel means of mitigating diabetic MI/R injury.

Case report: What course to follow when left bundle branch pacing encounters acute myocardial infarction?

Compared with traditional right ventricular apical pacing, His-bundle pacing (HBP) provides more physiologic pacing by activating the normal conduction system. However, HBP has some limitations including higher pacing thresholds. In addition, disease in the distal His-Purkinje system may prevent the correction of abnormal conduction. Left bundle branch pacing (LBBP) may overcome these disadvantages by providing lower pacing thresholds and relatively narrow QRS duration that improve cardiac function. Here, we describe a rare case of a transient loss of ventricular capture due to acute anterior wall myocardial infarction in an LBB-paced patient. With the improvement of the ischemia, the function of the pacemaker partly recovered. We review the adaptations, advantages, and limitations, and long-term safety of LBBP.

Dynamic alteration of adiponectin/adiponectin receptor expression and its impact on myocardial ischemia/reperfusion in type 1 diabetic mice.

The present study determined the dynamic change of adiponectin (APN, a cardioprotective adipokine), its receptor expression, and their impact upon myocardial ischemia/reperfusion (MI/R) injury during type 1 diabetes mellitus (T1DM) progression, and involved underlying mechanisms. Diabetic state was induced in mice via multiple intraperitoneal injections of low-dose streptozotocin. The dynamic change of plasma APN concentration and cardiac APN receptor-1 and -2 (AdipoR1/2) expression were assessed immediately after diabetes onset (0 wk) and 1, 3, 5, and 7 wk thereafter. Indicators of MI/R injury (infarct size, apoptosis, and LDH release) were determined at 0, 1, and 7 wk of DM duration. The effect of APN on MI/R injury was determined in mice subjected to different diabetic durations. Plasma APN levels (total and HMW form) increased, whereas cardiac AdipoR1 expression decreased early after T1DM onset. With T1DM progression, APN levels were reduced and cardiac AdipoR1 expression increased. MI/R injury was exacerbated with T1DM progression in a time-dependent manner. Administration of globular APN (gAD) failed to attenuate MI/R injury in 1-wk T1DM mice, while an AMP-activated protein kinase (AMPK) activator (AICAR) reduced MI/R injury. However, administration of gAD (and AICAR) reduced infarct size and cardiomyocyte apoptosis in 7-wk T1DM mice. In conclusion, our results demonstrate a dynamic dysfunction of APN/AdipoR1 during T1DM progression. Reduced cardiac AdipoR1 expression and APN concentration may be responsible for increased I/R injury susceptibility at early and late T1DM stages, respectively. Interventions bolstering AdipoR1 expression during early T1DM stages and APN supplementation during advanced T1DM stages may potentially reduce the myocardial ischemic injury in diabetic patients.

Downregulation of adiponectin induced by tumor necrosis factor α is involved in the aggravation of posttraumatic myocardial ischemia/reperfusion injury.

OBJECTIVE: Recent clinical observations have indicated that nonlethal mechanical trauma significantly increases myocardial infarction risk even in the presence of completely normal coronary arteries. We investigated the molecular mechanisms responsible for exacerbation of ischemic myocardial injury after nonlethal mechanical trauma with a special focus on the role of tumor necrosis factor α and its potential downstream effector adiponectin, a novel adipokine with anti-inflammatory and cardioprotective properties. DESIGN: Laboratory study. SETTING: University research unit. SUBJECTS: Male adult adiponectin knockout mice and wild-type mice. INTERVENTIONS: The animals were subjected to nonlethal mechanical trauma using the Noble-Collip drum (40 rpm ± 5 mins) followed by myocardial ischemia/reperfusion injury 7 days posttrauma. We also investigated the effects of neutralizing tumor necrosis factor α with etanercept and exogenous adiponectin supplementation on ischemic myocardial injury after trauma. MEASUREMENTS AND MAIN RESULTS: Trauma significantly sensitized myocardium to ischemia/reperfusion injury as evidenced by increased apoptosis, enlarged infarct size, and decreased cardiac function. Plasma adiponectin concentrations were reduced after traumatic injury (the nadir occurring 3 days posttrauma), an effect abrogated by etanercept-mediated tumor necrosis factor α blockade. The downregulation of adiponectin was accompanied by increased myocardial superoxide and nitric oxide generation and peroxynitrite formation. Both etanercept and exogenous adiponectin supplementation (on day 3 posttrauma or 10 mins before reperfusion on day 7 posttrauma) markedly inhibited oxidative/nitrative stress and ischemia/reperfusion injury in posttraumatic ischemic/reperfused hearts of wild-type mice, whereas only adiponectin supplementation (but not tumor necrosis factor α inhibition) substantially attenuated posttraumatic ischemia/reperfusion injury in adiponectin knockout mice. CONCLUSIONS: Tumor necrosis factor α-induced downregulation of adiponectin and the resultant enhanced oxidative/nitrative stress are involved in exacerbated posttraumatic ischemic myocardial injury. Therapeutic approaches blocking tumor necrosis factor α production or restoring adiponectin might have prophylactic value against secondary myocardial ischemic injury after a primary nonlethal mechanical trauma.

A novel real-time intravascular ultrasound double-lumen microcatheter for recanalization of chronic total occlusion: a case report.

BACKGROUND: Chronic total occlusion revascularization remains a challenging problem because of its complexity. We present a case of a patient with chronic total occlusion who was successfully revascularized with the use of a new device called a real-time intravascular ultrasound double-lumen microcatheter. CASE PRESENTATION: A 58-year-old East Asians woman presented to our hospital with a complaint of recurrent chest pain of 5 months' duration. Angiography revealed chronic total occlusion of the right coronary artery from the right coronary artery ostium to the ostia of the posterolateral and posterior descending branches. A guidewire was passed to the distal right coronary artery but went into the false lumens at the posterior descending and posterolateral ostia after use of the antegrade and retrograde approaches. Hence, we used the new device to pass through the subintimal right coronary artery space with reentry into the true lumen before the posterior descending and posterolateral ostia. A stent was successfully deployed at the posterior descending and posterolateral ostia, and the final result was excellent. CONCLUSIONS: This device was useful for finding the entry point and for reentry into the true lumen of a chronic total occlusion. It may be a valuable tool for recanalization of complex chronic total occlusion lesions.

Exhaustive exercise decreases L-type calcium current by activating endoplasmic reticulum stress.

BACKGROUND: This study investigated effects of exhaustive exercise on L-type calcium current (ICa,L) and the putative intracellular cascade responsible for the effects. METHODS: Rats were randomly divided into three treatment groups: sedentary (without exercise), exercised to exhaustion and salubrinal injection before each exhaustive exercise period. Exercise group rats were forced to swim until exhaustion each time for 9 days with 5% body weight attached to the head. Salubrinal (1 mg/kg) or an equivalent volume of placebo solution (dimethyl sulfoxide) was injected via the intraperitoneal route daily for the first 3 days, followed by subcutaneous injections of salubrinal (0.5 mg/kg) or placebo solution daily for 9 days (starting 30 min before exercise). After a 1-day recovery period, whole-cell patch clamping was used to investigate the L-type Ca2+ current (ICa,L), with sedentary control rats. Additionally, endoplasmic reticulum (ER) chaperone protein levels were analyzed. RESULTS: Exhaustive exercise triggered ER stress, demonstrated by elevated expression of ER stress markers: phospho-eIF2α, CCAT/enhancer-binding homologous protein (CHOP) and caspase-12. Compared to controls, ICa,L was inhibited by exhaustive exercise, which was blocked by salubrinal, a selective eIF2α dephosphorylation inhibitor used to inhibit ER stress. These results suggest that ER stress participates in regulation of ICa,L. However, exhaustive exercise did not change the voltage dependence of steady-state activation and inactivation of ICaL, and salubrinal infusion caused no difference in voltage dependence of steady-state activation and inactivation of ICa,L. CONCLUSIONS: Exhaustive exercise activates ER stress, thus inhibiting ICaL, which may change the action potential duration and contribute to proarrhythmia.

Advanced glycation end products accelerate ischemia/reperfusion injury through receptor of advanced end product/nitrative thioredoxin inactivation in cardiac microvascular endothelial cells.

The advanced glycation end products (AGEs) are associated with increased cardiac endothelial injury. However, no causative link has been established between increased AGEs and enhanced endothelial injury after ischemia/reperfusion. More importantly, the molecular mechanisms by which AGEs may increase endothelial injury remain unknown. Adult rat cardiac microvascular endothelial cells (CMECs) were isolated and incubated with AGE-modified bovine serum albumin (BSA) or BSA. After AGE-BSA or BSA preculture, CMECs were subjected to simulated ischemia (SI)/reperfusion (R). AGE-BSA increased SI/R injury as evidenced by enhanced lactate dehydrogenase release and caspase-3 activity. Moreover, AGE-BSA significantly increased SI/R-induced oxidative/nitrative stress in CMECs (as measured by increased inducible nitric oxide synthase expression, total nitric oxide production, superoxide generation, and peroxynitrite formation) and increased SI/R-induced nitrative inactivation of thioredoxin-1 (Trx-1), an essential cytoprotective molecule. Supplementation of EUK134 (peroxynitrite decomposition catalyst), human Trx-1, or soluble receptor of advanced end product (sRAGE) (a RAGE decoy) in AGE-BSA precultured cells attenuated SI/R-induced oxidative/nitrative stress, reduced SI/R-induced Trx-1 nitration, preserved Trx-1 activity, and reduced SI/R injury. Our results demonstrated that AGEs may increase SI/R-induced endothelial injury by increasing oxidative/nitrative injury and subsequent nitrative inactivation of Trx-1. Interventions blocking RAGE signaling or restoring Trx activity may be novel therapies to mitigate endothelial ischemia/reperfusion injury in the diabetic population.