Effect of Cangrelor on Infarct Size in ST-Segment-Elevation Myocardial Infarction Treated by Primary Percutaneous Coronary Intervention: A Randomized Controlled Trial (The PITRI Trial).

BACKGROUND: The administration of intravenous cangrelor at reperfusion achieves faster onset of platelet P2Y12 inhibition than oral ticagrelor and has been shown to reduce myocardial infarction (MI) size in the preclinical setting. We hypothesized that the administration of cangrelor at reperfusion will reduce MI size and prevent microvascular obstruction in patients with ST-segment-elevation MI undergoing primary percutaneous coronary intervention. METHODS: This was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial conducted between November 2017 to November 2021 in 6 cardiac centers in Singapore. Patients were randomized to receive either cangrelor or placebo initiated before the primary percutaneous coronary intervention procedure on top of oral ticagrelor. The key exclusion criteria included presenting <6 hours of symptom onset; previous MI and stroke or transient ischemic attack; on concomitant oral anticoagulants; and a contraindication for cardiovascular magnetic resonance. The primary efficacy end point was acute MI size by cardiovascular magnetic resonance within the first week expressed as percentage of the left ventricle mass (%LVmass). Microvascular obstruction was identified as areas of dark core of hypoenhancement within areas of late gadolinium enhancement. The primary safety end point was Bleeding Academic Research Consortium-defined major bleeding in the first 48 hours. Continuous variables were compared by Mann-Whitney U test (reported as median [first quartile-third quartile]), and categorical variables were compared by Fisher exact test. A 2-sided P<0.05 was considered statistically significant. RESULTS: Of 209 recruited patients, 164 patients (78%) completed the acute cardiovascular magnetic resonance scan. There were no significant differences in acute MI size (placebo, 14.9% [7.3-22.6] %LVmass versus cangrelor, 16.3 [9.9-24.4] %LVmass; P=0.40) or the incidence (placebo, 48% versus cangrelor, 47%; P=0.99) and extent of microvascular obstruction (placebo, 1.63 [0.60-4.65] %LVmass versus cangrelor, 1.18 [0.53-3.37] %LVmass; P=0.46) between placebo and cangrelor despite a 2-fold decrease in platelet reactivity with cangrelor. There were no Bleeding Academic Research Consortium-defined major bleeding events in either group in the first 48 hours. CONCLUSIONS: Cangrelor administered at the time of primary percutaneous coronary intervention did not reduce acute MI size or prevent microvascular obstruction in patients with ST-segment-elevation MI given oral ticagrelor despite a significant reduction of platelet reactivity during the percutaneous coronary intervention procedure. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03102723.

Myocardial infarct size for predicting improvements in cardiac function in patients with ischemic cardiomyopathy following coronary artery bypass grafting.

Background: This study used late gadolinium enhancement-cardiac magnetic resonance (LGE-CMR) to assess myocardial infarct size, with the data being employed to predict whether patients with ischemic cardiomyopathy (ICM) would experience improvements in left ventricular function at 6 months following coronary artery bypass grafting (CABG). Methods: The data of patients with ICM with left ventricular ejection fraction (LVEF) ≤40% who underwent CABG were retrospectively analyzed. All patients underwent preoperative LGE-CMR imaging. Echocardiography results from 6 months post-CABG were used to assess improvements in LVEF, with improvement being defined as ΔLVEF ≥5%. The value of myocardial infarction segments and infarct size as predictors of improved cardiac function following CABG was analyzed. Results: Of the included patients, 66.7% (52/78) exhibited improved cardiac function at 6 months post-CABG. LGE-CMR imaging data revealed that compared to improved group, the improved group had significantly more myocardial infarct segments [improved group: median 1.0, interquartile range (IQR) 0-3; nonimproved group: median 4.0, IQR 3.0-6.0; P<0.001] and significantly greater myocardial infarct size (improved group: 22.4%±8.2%; nonimproved group: 34.7%±5.9%; P<0.001). The area under the receive operating characteristic curve values for myocardial infarct size in predicting cardiac function improvement were significantly higher than those of myocardial infarct segments (0.88 vs. 0.81; P=0.041). The respective sensitivity and specificity values for using a myocardial infarct size cutoff of 26.4% in differentiating between these 2 patient groups were 92.3% and 71.2%, respectively. According to logistic regression analysis, myocardial infarct size was an independent predictor of nonimprovement in cardiac function [odds ratio (OR) =1.244; 95% confidence interval (CI): 1.114-1.389; P<0.001]. A median 1.6-year follow-up interval (range, 0.5-4.1 years) revealed that the incidences of major adverse cerebrovascular events and cardiovascular events were significantly higher in the nonimproved group (5.8% vs. 26.9%; P<0.001), with these individuals having a higher New York Heart Association grading than patients with improved cardiac function (P=0.019). Conclusions: Myocardial infarct size can be measured to reliably predict improvements in cardiac function in patients with ICM following CABG. These results can guide clinicians in their efforts to identify those patients most likely to achieve positive outcomes following CABG.

Interaction of exercise training with taurine attenuates infarct size and cardiac dysfunction via Akt-Foxo3a-Caspase-8 signaling pathway.

This research aimed to investigate the synergistic protective effect of exercise training and taurine on Akt-Foxo3a-Caspase-8 signaling related to infarct size and cardiac dysfunction. Therefore, 25 male Wistar rats with MI were divided into five groups: sham (Sh), control-MI(C-MI), exercise training-MI(Exe-MI), taurine supplementation-MI(Supp-MI), and exercise training + taurine-MI(Exe + Supp-MI). The taurine groups were given a 200 mg/kg/day dose of taurine by drinking water. Exercise training was conducted for 8 weeks (5 days/week), each session alternated 2 min with 25-30% VO2peak and 4 min with 55-60% VO2peak for 10 alternations. Then, the left ventricle tissue samples were taken from all groups. Exercise training and taurine activated Akt and decreased Foxo3a. Expression of the caspase-8 gene was increased in cardiac necrosis after MI, While, after 12 weeks of intervention decreased. Results exhibited that exercise training combined with taurine has a greater effect than either alone on activating the Akt-Foxo3a-caspase signaling pathway (P < 0.001). MI-induced myocardial injury leads to increase collagen deposition (P < 0.001) and infarct size and results in cardiac dysfunction via reduced stroke volume, ejection fraction, and fractional shortening (P < 0.001). Exercise training and taurine improved cardiac functional parameters (SV, EF, FS) and infarct size (P < 0.001) after 8 weeks of intervention in rats with MI. Also, the interaction of exercise training and taurine has a greater effect than alone on these variables. Interaction of exercise training with taurine supplementation induces a general amelioration of the cardiac histopathological profiles and improves cardiac remodeling via activating Akt-Foxo3a-Caspase-8 signaling with protective effects against MI.

Differences in left ventricular myocardial function and infarct size in female patients with ST elevation myocardial infarction and spontaneous coronary artery dissection.

Introduction: Differences in pathophysiology, clinical presentation, and natural course of ST-elevation myocardial infarction in female patients due to either spontaneous dissection (SCAD-STEMI) or atherothrombotic occlusion (type 1 STEMI) have been discussed. Current knowledge on differences in left ventricular myocardial function and infarct size is limited. The aim of this study was to assess baseline clinical characteristics, imaging findings, and therapeutic approach and to compare differences in echocardiographic findings at baseline and 3-month follow-up in patients with SCAD-STEMI and type 1 STEMI. Methods: This was a prospective multicenter study of 32 female patients (18-55 years of age) presenting with either SCAD-STEMI due to left anterior descending coronary artery (LAD) dissection or type 1 STEMI due to atherothrombotic LAD occlusion. Results: The two groups were similar in age, risk factors, comorbidities, and complications. SCAD-STEMI patients more often had Thrombolysis in Myocardial Infarction 3 flow, while type 1 STEMI patients were more often treated with percutaneous coronary intervention and dual antiplatelet therapy. Baseline mean left ventricular (LV) ejection fraction (LVEF) was similar in the two groups (48.0% vs. 48.6%, p = 0.881), but there was a significant difference at the 3-month follow-up, driven by an improvement in LVEF in SCAD-STEMI compared to type 1 STEMI patients (Δ LVEF 10.1 ± 5.3% vs. 1.8 ± 5.1%, p = 0.002). LV global longitudinal strain was slightly improved in both groups at follow-up; however, the improvement was not significantly different between groups (-4.6 ± 2.9% vs. -2.0 ± 2.8%, p = 0.055). Conclusions: The results suggest that female patients with SCAD-STEMI are more likely to experience improvement in LV systolic function than type 1 STEMI patients.

Serum uric acid in patients with ST-segment elevation myocardial infarction: An innocent bystander or leading actor?

Elevated serum uric acid (SUA) levels have been associated with several cardiovascular risk factors and the progression of coronary artery disease. In the setting of acute myocardial infarction, increasing evidence suggests that high SUA levels could be related to adverse outcomes. Interestingly elevated SUA levels have been linked to endothelial dysfunction, inflammation and oxidative stress. The aim of this review is to discuss the potential negative effects of SUA in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention, analyzing the possible underlying pathophysiological mechanisms.

Relationship Between Exposure to Sulphur Dioxide Air Pollution, White Cell Inflammatory Biomarkers and Enzymatic Infarct Size in Patients With ST-segment Elevation Acute Coronary Syndromes.

Aims: To analyse the relationship among air pollutants, markers of inflammation and infarct size in patients with acute coronary syndrome (ACS). Methods: This was a prospective analysis of consecutive patients admitted to hospital because of ACS. Cardiac biomarkers were drawn. The daily mean values of the air pollutants from the day before until 7 days before admission were analysed. The study population was stratified according to infarct size, based on median peak troponin value. Results: Patients were divided into two groups of 108 subjects each, according to median peak troponin value. Patients with extensive MIs had a higher neutrophil:lymphocyte ratio and leukocyte and neutrophil counts than patients with smaller MIs. In addition, they were exposed to higher concentrations of sulphur dioxide (9.7 ± 4.1 versus 8.4 ± 3.1 µg/m3; p=0.009) and lower concentrations of ozone (33.8 ± 13.7 versus 38.6 ± 14.5 µg/m3; p=0.014). Multivariate analysis showed that sulphur dioxide levels (OR 1.12; 95% CI [1.031-1.21]; p=0.007) and neutrophil/lymphocyte ratio (OR 1.08; 95% CI [1.011-1.17]; p=0.024) were independent predictors of infarct size. Conclusion: Patients with extensive MIs had higher white cell inflammatory levels and had been exposed to higher sulphur dioxide concentrations in the ambient air.

Effect of remote ischaemic conditioning on infarct size and remodelling in ST-segment elevation myocardial infarction patients: the CONDI-2/ERIC-PPCI CMR substudy.

The effect of limb remote ischaemic conditioning (RIC) on myocardial infarct (MI) size and left ventricular ejection fraction (LVEF) was investigated in a pre-planned cardiovascular magnetic resonance (CMR) substudy of the CONDI-2/ERIC-PPCI trial. This single-blind multi-centre trial (7 sites in UK and Denmark) included 169 ST-segment elevation myocardial infarction (STEMI) patients who were already randomised to either control (n = 89) or limb RIC (n = 80) (4 × 5 min cycles of arm cuff inflations/deflations) prior to primary percutaneous coronary intervention. CMR was performed acutely and at 6 months. The primary endpoint was MI size on the 6 month CMR scan, expressed as median and interquartile range. In 110 patients with 6-month CMR data, limb RIC did not reduce MI size [RIC: 13.0 (5.1-17.1)% of LV mass; control: 11.1 (7.0-17.8)% of LV mass, P = 0.39], or LVEF, when compared to control. In 162 patients with acute CMR data, limb RIC had no effect on acute MI size, microvascular obstruction and LVEF when compared to control. In a subgroup of anterior STEMI patients, RIC was associated with lower incidence of microvascular obstruction and higher LVEF on the acute scan when compared with control, but this was not associated with an improvement in LVEF at 6 months. In summary, in this pre-planned CMR substudy of the CONDI-2/ERIC-PPCI trial, there was no evidence that limb RIC reduced MI size or improved LVEF at 6 months by CMR, findings which are consistent with the neutral effects of limb RIC on clinical outcomes reported in the main CONDI-2/ERIC-PPCI trial.

Modification of ischemia/reperfusion induced infarct size by ischemic preconditioning in hypertrophied hearts.

This study examined the effects of ischemic preconditioning (IP) on the ischemia/reperfusion (I/R) induced injury in normal and hypertrophied hearts. Cardiac hypertrophy in rabbits was induced by L-thyroxine (0.5 mg/kg/day for 16 days). Hearts with or without IP (3 cycles of 5 min ischemia and 10 min reperfusion) were subjected to I/R (60 min ischemia followed by 60 min reperfusion). IP reduced the I/R-induced infarct size from 68% to 24% and 57% to 33% in the normal and hypertrophied hearts, respectively. Leakage of creatine phosphokinase in the perfusate from the hypertrophied hearts due to I/R was markedly less than that form the normal hearts; IP prevented these changes. Although IP augmented the increase in phosphorylated p38-mitogen-activated protein kinase (p38-MAPK) content due to I/R, this effect was less in the hypertrophied than in the normal heart. These results suggest that reduced cardioprotection by IP of the I/R-induced injury in hypertrophied hearts may be due to reduced activation of p38-MAPK in comparison with normal hearts.

Update on Cardioprotective Strategies for STEMI: Focus on Supersaturated Oxygen Delivery.

Despite the fact that door-to-balloon times have been greatly reduced, the rates of death and the incidence of heart failure in patients with ST-segment elevation myocardial infarction (MI) have plateaued. There is still an unmet need to further reduce MI size in the reperfusion era. Most adjunctive therapies to enhance myocardial salvage have failed, but some have shown promise. Currently, the only adjunctive therapy in a pivotal trial that has demonstrated reductions in infarct size is localized delivery of supersaturated oxygen (SSO2) therapy. This review provides background on prior infarct size reduction efforts. The authors describe the preclinical data that shows the effectiveness of SSO2 in reducing MI size, improving regional myocardial blood flow and cardiac function, and reducing adverse left ventricular remodeling-presumably by reducing patchy areas of residual ischemia within the reperfused risk zone. Potential mechanisms by which SSO2 is beneficial are described, including the delivery of high levels of dissolved oxygen through plasma to ischemic, but viable, vascular and myocardial cells, thus allowing their survival and function. The authors then describe the SSO2 clinical trials, demonstrating that in patients with anterior ST-segment elevation MI, SSO2 therapy safely and effectively reduces infarct size, improves cardiac function, and reduces adverse left ventricular remodeling.

Effects of nicorandil on myocardial infarct size in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention: study design and protocol for the randomized controlled trial.

Previous studies have shown that nicorandil has a protective effect on cardiomyocytes. However, there is no study to investigate whether perioperative intravenous nicorandil can further reduce the myocardial infarct size in patients with ST-segment elevation myocardial infarction (STEMI) compared to the current standard of percutaneous coronary intervention (PCI) regimen. The CHANGE (China-Admini stration of Nicorandil Group) study is a multicenter, prospective, randomized, double-blind and parallel-controlled clinical study of STEMI patients undergoing primary PCI in China, aiming to evaluate the efficacy and safety of intravenous nicorandil in ameliorating the myocar dial infarct size in STEMI patients undergoing primary PCI and provide evidence-based support for myocardial protection strategies of STEMI patients.

SGLT2 inhibitors reduce infarct size in reperfused ischemic heart and improve cardiac function during ischemic episodes in preclinical models.

The sodium-glucose cotransporter 2 (SGLT2) inhibitors are a new class of effective drugs managing patients, who suffer from type 2 diabetes (T2D): Landmark clinical trials including EMPA-REG, CANVAS and Declare-TIMI have demonstrated that SGLT2 inhibitors reduce cardiovascular mortality and re-hospitalization for heart failure (HF) in patients with T2D. It is well established that there is a strong independent relationship among infarct size measured within 1 month after reperfusion and all-cause death and hospitalization for HF: The fact that cardiovascular mortality was significantly reduced with the SGLT2 inhibitors, fuels the assumption that this class of therapies may attenuate myocardial infarct size. Experimental evidence demonstrates that SGLT2 inhibitors exert cardioprotective effects in animal models of acute myocardial infarction through improved function during the ischemic episode, reduction of infarct size and a subsequent attenuation of heart failure development. The aim of the present review is to outline the current state of preclinical research in terms of myocardial ischemia/reperfusion injury (I/R) and infarct size for clinically available SGLT2 inhibitors and summarize some of the proposed mechanisms of action (lowering intracellular Na+ and Ca2+, NHE inhibition, STAT3 and AMPK activation, CamKII inhibition, reduced inflammation and oxidative stress) that may contribute to the unexpected beneficial cardiovascular effects of this class of compounds.

Remote Ischemic Conditioning in Acute Myocardial Infarction and Shock States.

Remote ischemic conditioning is the phenomenon whereby brief, nonlethal episodes of ischemia in one organ (such as a limb) protect a remote organ from ischemic necrosis induced by a longer duration of severe ischemia followed by reperfusion. This phenomenon has been reproduced by dozens of experimental laboratories and was shown to reduce the size of myocardial infarction in many but not all clinical studies. In one recent large clinical trial, remote ischemic conditioning induced by repetitive blood pressure cuff inflations on the arm did not reduce infarct size or improve clinical outcomes. This negative result may have been related in part to the overall success of early reperfusion and current adjunctive therapies, such as antiplatelet therapy, antiremodeling therapies, and low-risk patients, that may make it difficult to show any advantage of newer adjunctive therapies on top of existing therapies. One relevant area in which current outcomes are not as positive as in the treatment of heart attack is the treatment of shock, where mortality rates remain high. Recent experimental studies show that remote ischemic conditioning may improve survival and organ function in shock states, especially hemorrhagic shock and septic shock. In this study, we review the preclinical studies that have explored the potential benefit of this therapy for shock states and describe an ongoing clinical study.

Prognostic Impact of Ischemic Mitral Regurgitation Severity and Myocardial Infarct Quantification by Cardiovascular Magnetic Resonance.

OBJECTIVES: This study sought to evaluate the role of cardiac magnetic resonance (CMR) for the quantification of ischemic mitral regurgitation (IMR) and myocardial infarct size (MIS) in patients with ischemic cardiomyopathy (ICM). This study also sought to explore the interaction between IMR severity and MIS and its association with outcomes in patients with ICM. BACKGROUND: IMR occurs secondary to a disease of the left ventricle and is associated with poor outcomes. The role of CMR for the evaluation and risk stratification of patients with ICM and IMR remains uncertain. METHODS: Consecutive patients with ICM who underwent baseline CMR were included. MIS was quantified on late gadolinium enhancement imaging as the proportion of left ventricular mass. IMR was quantified with CMR by calculating the mitral regurgitant fraction (MRFraction). Cox proportional hazards models were built to assess the association of IMR and MIS quantification with the combined endpoint of all-cause death or heart transplant. RESULTS: We evaluated 578 patients (mean age: 62 ± 11 years, 76% males). The mean left ventricular ejection fraction was 25 ± 11%, with an MIS of 24 ± 16% and MRFraction of 18 ± 17%. Over a median follow-up time of 4.9 years, 198 (34%) patients experienced death or cardiac transplant. On multivariable analysis, after comprehensive medical risk score, subsequent revascularization, implantable cardioverter-defibrillator insertion, and surgical mitral valve intervention were controlled for, the interaction of IMR severity and MIS emerged as a powerful predictor of adverse outcomes (p = 0.008). For patients with significant IMR (MRFraction: ≥35%), the hazard ratio comparing moderate MIS (15% to 29%) versus small MIS (<15%) was 1.51 (0.57 to 3.98), and the hazard ratio comparing large MIS (≥30%) versus small MIS was 5.41 (2.34 to 12.7). CONCLUSIONS: Risk associated with IMR is more comprehensively described as an interaction between IMR severity and MIS. Further studies in patients IMR using comprehensive CMR evaluation are needed to verify whether this approach can improve patient selection and procedural outcomes to address IMR.

Plasma LDL-Cholesterol Level at Admission is Independently Associated with Infarct Size in Patients with ST-Segment Elevation Myocardial Infarction Treated with Primary Percutaneous Coronary Intervention.

INTRODUCTION: Hypercholesterolemia is a well-known risk factor for developing atherosclerosis and subsequently for the risk of a myocardial infarction (MI). Moreover, it might also be related to the extent of damaged myocardium in the event of a MI. The aim of this study was to evaluate the association of baseline low density lipoprotein-cholesterol (LDL-c) level with infarct size in patients with ST-segment elevation myocardial infarction (STEMI) after primary percutaneously coronary intervention (pPCI). METHODS: Baseline blood samples were obtained from all patients admitted between 2004 and 2014 with STEMI who underwent pPCI. Patients were excluded in case of out of hospital cardiac arrest, treatment delay of at least 10 h or no complete reperfusion after pPCI in the culprit vessel. Peak creatine kinase (CK) level was used for infarct size estimation, defined as the maximal value during admission. RESULTS: A total of 2248 patients were included in this study (mean age 61.8 ± 12.2 years; 25.0% female). Mean LDL-c level was 3.6 ± 1.1 mmol/L and median peak CK level was 1275 U/L (IQR 564-2590 U/L). Baseline LDL-c level [ß = 0.041; (95% CI 0.019-0.062); p < 0.001] was independently associated with peak CK level. Furthermore, left anterior descending artery as culprit vessel, initial TIMI 0-1 flow in the culprit vessel, male gender, and treatment delay were also correlated with high peak CK level (p < 0.05). Prior aspirin therapy was associated with lower peak CK level [ß = - 0.073 (95% CI - 0.146 to 0.000), p = 0.050]. CONCLUSION: This study demonstrates that besides the more established predictors of infarct size, elevated LDL-c is associated with augmented infarct size in patients with STEMI treated with pPCI.

Platelet inhibition to target reperfusion injury trial: Rationale and study design.

BACKGROUND: In ST-segment elevation myocardial infarction (STEMI) patients treated with primary percutaneous coronary intervention (PPCI), current oral P2Y12 platelet inhibitors do not provide maximal platelet inhibition at the time of reperfusion. Furthermore, administration of cangrelor prior to reperfusion has been shown in pre-clinical studies to reduce myocardial infarct (MI) size. Therefore, we hypothesize that cangrelor administered prior to reperfusion in STEMI patients will reduce the incidence of microvascular obstruction (MVO) and limit MI size in STEMI patients treated with PPCI. METHODS: The platelet inhibition to target reperfusion injury (PITRI) trial, is a phase 2A, multi-center, double-blinded, randomized controlled trial, in which 210 STEMI patients will be randomized to receive either an intravenous (IV) bolus of cangrelor (30 µg/kg) followed by a 120-minute infusion (4 µg/kg/min) or matching saline placebo, initiated prior to reperfusion (NCT03102723). RESULTS: The study started in October 2017 and the anticipated end date would be July 2020. The primary end-point will be MI size quantified by cardiovascular magnetic resonance (CMR) on day 3 post-PPCI. Secondary endpoints will include markers of reperfusion, incidence of MVO, MI size, and adverse left ventricular remodeling at 6 months, and major adverse cardiac and cerebrovascular events. SUMMARY: The aim of the PITRI trial is to assess whether cangrelor administered prior to reperfusion would reduce acute MI size and MVO, as assessed by CMR.

Impact of Chronic Antiplatelet Therapy on Infarct Size and Bleeding in Patients With Acute Myocardial Infarction.

BACKGROUND: Patients hospitalized with acute myocardial infarction (AMI) are often on prior single antiplatelet therapy (SAPT) or a dual antiplatelet therapy (DAPT). Whether chronic SAPT or DAPT is beneficial or associated with an increased risk in AMI is still controversial. METHODS AND RESULTS: We prospectively enrolled 1718 consecutive patients with AMI (798 ST-segment elevation myocardial infarction and 920 non-ST-segment elevation myocardial infarction) who were divided according to their chronic APT (no APT, SAPT, or DAPT). The study primary end point was the infarct size, as estimated by troponin I peak. Incidence of major bleeding was also evaluated. Five hundred thirty-six (31%) patients were on chronic SAPT and 215 (13%) on DAPT. A graded increase in Global Registry of Acute Coronary Events (GRACE) and Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA guidelines (CRUSADE) risk scores was found going from patients without APT to those with DAPT, while a progressive smaller troponin I peak was observed with the increasing number of chronic antiplatelet agents (11.2 [interquartile range: 2-45] ng/mL, 6.6 [1-33] ng/mL, and 4.1 [1-24] ng/mL; P < .001 for trend). This result was maintained after adjustment for baseline ischemic risk profile (GRACE score) and other major confounders ( P < .001). The incidence of bleeding was higher in patients on chronic APT than in those without APT (5.2% vs 2.4%; P = .002). However, when the bleeding risk was adjusted for the CRUSADE risk score, chronic SAPT (odds ratio [OR]: 1.40, 95% confidence interval [CI]: 0.77-2.53) and DAPT (OR: 0.70, 95% CI: 0.29-1.70) were not associated with an increased bleeding risk. CONCLUSION: In patients with AMI, chronic APT is associated with higher baseline ischemic and bleeding risks. Despite this and unexpectedly, they have a smaller infarct size and similar adjusted bleeding risk.

Circadian dependence of manual thrombus aspiration benefit in patients with ST-segment elevation myocardial infarction undergoing primary percutaneous coronary intervention.

BACKGROUND: The clinical benefit of manual thrombus aspiration (TA) during primary percutaneous coronary intervention (PPCI) in patients with ST-segment elevation myocardial infarction (STEMI) remains uncertain. This study assessed the impact of circadian rhythms on the effectiveness of manual TA. METHODS AND RESULTS: We conducted an observational study of patients enrolled in the Acute Myocardial Infarction in Switzerland Plus registry. STEMI patients undergoing PPCI with (TA group) or without (PCI-alone group) manual TA were divided based on time-of-day symptom onset: group 1 (00:00-05:59), group 2 (06:00-11:59), group 3 (12:00-17:59) and group 4 (18:00-23:59). The primary endpoint was circadian variation of myocardial infarction (MI) size. The secondary endpoint was in-hospital all-cause mortality. Between 2009 and 2014, 3648 patients underwent PPCI (TA, 49%). After propensity-score matching, 2860 patients were included. Minimal myocardial Injury was observed in groups 2 and 3 (peak creatine kinase level group 1, 2723 ± 148 U/l; group 2, 2493 ± 105 U/l; group 3, 2550 ± 106 U/l; group 4, 2952 ± 144 U/l; p = 0.044) in the TA group, whereas no time-of-day dependence was found in PCI-alone group. After periodic sinusoidal regression analysis, a circadian relationship between time-of-day symptom onset and MI size was demonstrated in the TA group (p < 0.001). In-hospital all-cause mortality was 3.4% in the TA group and 4.3% in the PCI-alone group (p = 0.20). CONCLUSIONS: In this large registry of STEMI patients, manual TA did not reduce in-hospital all-cause mortality. Nonetheless, there was a circadian dependence of TA effectiveness with greatest myocardial salvage for patients with symptom onset between 06:00 and 17:59.

What is the best ST-segment recovery parameter to predict clinical outcome and myocardial infarct size? Amplitude, speed, and completeness of ST-segment recovery after primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

AIMS: ST-segment recovery (STR) is a strong mechanistic correlate of infarct size (IS) and outcome in ST-segment elevation myocardial infarction (STEMI). Characterizing measures of speed, amplitude, and completeness of STR may extend the use of this noninvasive biomarker. METHODS AND RESULTS: Core laboratory continuous 24-h 12-lead Holter ECG monitoring, IS by single-photon emission computed tomography (SPECT), and 30-day mortality of 2 clinical trials of primary percutaneous coronary intervention in STEMI were combined. Multiple ST measures (STR at last contrast injection (LC) measured from peak value; 30, 60, 90, 120, and 240min, residual deviation; time to steady ST recovery; and the 3-h area under the time trend curve [ST-AUC] from LC) were univariably correlated with IS and predictive of mortality. After multivariable adjustment for ST-parameters and GRACE risk factors, STR at 240min remained an additive predictor of mortality. Early STR, residual deviation, and ST-AUC remained associated with IS. CONCLUSIONS: Multiple parameters that quantify the speed, amplitude, and completeness of STR predict mortality and correlate with IS.

Saffron (Crocus sativus) intake provides nutritional preconditioning against myocardial ischemia-reperfusion injury in Wild Type and ApoE(-/-) mice: Involvement of Nrf2 activation.

BACKGROUND AND AIMS: Saffron is an antioxidant herbal derivative; however, its efficacy as a nutritional cardioprotective agent has not been fully elucidated. We investigated the cardioprotective properties of a standardized saffron aqueous extract (SFE) against ischemia/reperfusion (I/R) injury in Wild-Type (WT) and ApoE(-/-) mice and the underlying molecular mechanisms. METHODS AND RESULTS: WT and ApoE(-/-) mice were subjected to 30 min I and 2 h R, with the following per os interventions for 4 weeks: 1) WT Control Group, receiving Water for Injection (WFI); 2) WT Crocus Group, receiving SFE at a dose of 60 mg/kg/day; 3) WT Crocus + Wort group, receiving SFE as described above and wortmannin at a dose of 60 µg/kg bolus 15 min before R; 4) ApoE(-/-) Control Group, receiving WFI; 5) ApoE(-/-) Crocus Group, receiving SFE at a dose of 60 mg/kg/day and 6) ApoE(-/-) Crocus + Wort: receiving SFE as described above and wortmannin at a dose of 60 µg/kg bolus, 15 min before R. Ischemic area/area at risk (I/R%) ratio was measured. Blood samples and ischemic myocardial tissue were collected at the 10th min of reperfusion for assessment of troponin I, malondialdehyde (MDA), nitrotyrosine (NT), p-eNOS, eNOS, p-Akt, Akt, p-p42/p-p44, p-GSK3ß, GSK3ß, IL-6, Nrf2, HO-1 and MnSOD expression. The effect of SFE on Nrf2 expression was also evaluated in vitro. SFE reduced infarct size in WT (16.15 ± 3.7% vs 41.57 ± 2.48%, ***p < 0.001) and in ApoE(-/-) mice (16.14 ± 1.47% vs 45.57 ± 1.73%, ***p < 0.001). The administration of wortmannin resulted in partial inhibition of the infarct size limitation efficacy of SFE (in both WT and Apo-E(-/-) mice). Mice receiving SFE showed increased levels of eNOS, p-Akt, p-ERK1/2, p-44/p-42 and p-GSK3ß-Ser9 and reduced expression of IL-6 and iNOS; furthermore, SFE reduced the levels of MDA and NT. SFE induced Nrf2 expression and its downstream targets, HO-1 and MnSOD in the myocardium of the treated animals, and induced Nrf2 expression in vitro in a dose-dependent manner. CONCLUSIONS: SFE limits myocardial infarction in Wild-Type and ApoE(-/-) mice in a multifaceted manner including activation of Akt/eNOS/ERK1/2/GSK3-ß and through Nrf2 pathway, bestowing antioxidant protection against I/R.

Quantification of both the area-at-risk and acute myocardial infarct size in ST-segment elevation myocardial infarction using T1-mapping.

BACKGROUND: A comprehensive cardiovascular magnetic resonance (CMR) in reperfused ST-segment myocardial infarction (STEMI) patients can be challenging to perform and can be time-consuming. We aimed to investigate whether native T1-mapping can accurately delineate the edema-based area-at-risk (AAR) and post-contrast T1-mapping and synthetic late gadolinium (LGE) images can quantify MI size at 1.5 T. Conventional LGE imaging and T2-mapping could then be omitted, thereby shortening the scan duration. METHODS: Twenty-eight STEMI patients underwent a CMR scan at 1.5 T, 3 ± 1 days following primary percutaneous coronary intervention. The AAR was quantified using both native T1 and T2-mapping. MI size was quantified using conventional LGE, post-contrast T1-mapping and synthetic magnitude-reconstructed inversion recovery (MagIR) LGE and synthetic phase-sensitive inversion recovery (PSIR) LGE, derived from the post-contrast T1 maps. RESULTS: Native T1-mapping performed as well as T2-mapping in delineating the AAR (41.6 ± 11.9% of the left ventricle [% LV] versus 41.7 ± 12.2% LV, P = 0.72; R2 0.97; ICC 0.986 (0.969-0.993); bias -0.1 ± 4.2% LV). There were excellent correlation and inter-method agreement with no bias, between MI size by conventional LGE, synthetic MagIR LGE (bias 0.2 ± 2.2%LV, P = 0.35), synthetic PSIR LGE (bias 0.4 ± 2.2% LV, P = 0.060) and post-contrast T1-mapping (bias 0.3 ± 1.8% LV, P = 0.10). The mean scan duration was 58 ± 4 min. Not performing T2 mapping (6 ± 1 min) and conventional LGE (10 ± 1 min) would shorten the CMR study by 15-20 min. CONCLUSIONS: T1-mapping can accurately quantify both the edema-based AAR (using native T1 maps) and acute MI size (using post-contrast T1 maps) in STEMI patients without major cardiovascular risk factors. This approach would shorten the duration of a comprehensive CMR study without significantly compromising on data acquisition and would obviate the need to perform T2 maps and LGE imaging.