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Background: Exploratory studies have shown that remote ischemic conditioning (RIC) has the potential to lower blood pressure (BP). We investigated whether chronic RIC reduces BP for hypertension. Methods: This is a multicenter, randomized, double-blind, parallel-controlled trial. Patients with an office BP of 130/80 to 160/100 mm Hg and a 24-hour average BP ≥125/75 mm Hg not on antihypertensive medications were recruited. After a 1-week compliance screening phase, they were randomly assigned in a 1:1 ratio to receive RIC or sham RIC twice daily for 4 weeks. The primary efficacy outcome was the change in 24-hour average systolic BP from baseline to 4 weeks. Safety events were assessed over the study period. Results: Ninety-five participants were randomly allocated to the RIC (n=49) and sham RIC (n=46) groups. In the intention-to-treat analysis, the reduction in 24-hour average systolic BP was greater in the RIC group than the sham RIC group (−4.6±9.5 versus −0.9±6.8 mm Hg; baseline-adjusted between-group mean difference: −3.6 mm Hg [95% CI, −6.9 to −0.3 mm Hg]; adjusted P =0.035). The per-protocol analysis showed that 24-hour average systolic BP reduced −5.9±8.6 mm Hg in the RIC group and −0.7±6.7 mm Hg in the sham RIC group (baseline-adjusted between-group mean difference: −5.2 mm Hg [95% CI, −8.5 to −1.9 mm Hg]; adjusted P =0.002). No major adverse events were reported in both groups. Conclusions: RIC is safe in patients with mild hypertension and may lower BP in the absence of antihypertensive medications. However, the effects of RIC on clinical outcomes in these patients require further investigation. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04915313. [ABSTRACT FROM AUTHOR]

For patients presenting with an acute ST-segment-elevation myocardial infarction, the most effective therapy for reducing myocardial infarct size and preserving left ventricular systolic function is primary percutaneous coronary intervention (PPCI). However, mortality and morbidity remain significant. This is partly attributed to the development of microvascular obstruction, which occurs in around 50% of ST-segment-elevation myocardial infarction patients post-PPCI, and it is associated with adverse left ventricular remodeling and worse clinical outcomes. Although microvascular obstruction can be detected by cardiac imaging techniques several hours post-PPCI, it may be too late to intervene at that time. Therefore, being able to predict the development of microvascular obstruction at the time of PPCI may identify high-risk patients who might benefit from further adjuvant intracoronary therapies, such as thrombolysis, vasodilators, glycoprotein IIb/IIIa inhibitors, and anti-inflammatory agents that may reduce microvascular obstruction. Recent studies have shown that invasive coronary physiology measurements performed during PPCI can be used to assess the coronary microcirculation. In this article, we provide an overview of the various invasive methods currently available to assess the coronary microcirculation in the setting of ST-segment-elevation myocardial infarction, and how they could potentially be used in the future for tailoring therapies to those most at risk. [ABSTRACT FROM AUTHOR]

Background--The presence of intramyocardial hemorrhage (IMH) in ST-segment-elevation myocardial infarction patients reperfused by primary percutaneous coronary intervention has been associated with residual myocardial iron at followup, and its impact on adverse left ventricular (LV) remodeling is incompletely understood and is investigated here. Methods and Results--Forty-eight ST-segment-elevation myocardial infarction patients underwent cardiovascular magnetic resonance at 4«2 days post primary percutaneous coronary intervention, of whom 40 had a follow-up scan at 5«2 months. Native T1, T2, and T2* maps were acquired. Eight out of 40 (20%) patients developed adverse LV remodeling. A subset of 28 patients had matching T2* maps, of which 15/28 patients (54%) had IMH. Eighteen of 28 (64%) patients had microvascular obstruction on the acute scan, of whom 15/18 (83%) patients had microvascular obstruction with IMH. On the follow-up scan, 13/15 patients (87%) had evidence of residual iron within the infarct zone. Patients with residual iron had higher T2 in the infarct zone surrounding the residual iron when compared with those without. In patients with adverse LV remodeling, T2 in the infarct zone surrounding the residual iron was also higher than in those without (60 [54-64] ms versus 53 [51-56] ms; P=0.025). Acute myocardial infarct size, extent of microvascular obstruction, and IMH correlated with the change in LV end-diastolic volume (Pearson’s rho of 0.64, 0.59, and 0.66, respectively; P=0.18 and 0.62, respectively, for correlation coefficient comparison) and performed equally well on receiver operating characteristic curve for predicting adverse LV remodeling (area under the curve: 0.99, 0.94, and 0.95, respectively; P=0.19 for receiver operating characteristic curve comparison). Conclusions--The majority of ST-segment-elevation myocardial infarction patients with IMH had residual myocardial iron at follow-up. This was associated with persistently elevated T2 values in the surrounding infarct tissue and adverse LV remodeling. IMH and residual myocardial iron may be potential therapeutic targets for preventing adverse LV remodeling in reperfused ST-segment-elevation myocardial infarction patients. [ABSTRACT FROM AUTHOR]

Background: Reports from animal studies indicate that volatile anaesthetics protect the myocardium against the effects of acute ischaemia-reperfusion injury by reducing infarct size. This cardioprotective effect in the clinical setting of coronary artery bypass graft (CABG) surgery, where the heart is subjected to global ischaemia-reperfusion injury, remains controversial.Objective: The objective was to demonstrate that clinical studies investigating the cardioprotective effect of volatile anaesthetics on cardiac troponins in CABG are no longer warranted. We also investigated the effect of volatile anaesthetics on cardiac enzymes in off-pump cardiac surgery.Design: Systematic review of randomised clinical trials, meta-analyses and trial sequential analysis (TSA).Data Sources: Trials between January 1985 and March 2015 were obtained from electronic databases (Medline, Excerpta Medica Database (EMBASE), Cochrane Controlled Trial Register, abstracts from major anaesthesiology and cardiology journals and reference lists of relevant randomised trials and review articles.Eligibility Criteria: Relevant randomised clinical trials were included. We investigated the effect of volatile anaesthetics in both off-pump and on-pump CABG surgery with respect to troponin release [peak postoperative cardiac troponin I (cTnI) and cardiac troponin T (cTnT), cTnI/cTnT] and performed two separate meta-analyses. TSA was used to overcome the weakness of a type-1 error associated with repeated meta-analyses.Results: From 30 studies, 2578 patients were pooled for the meta-analysis. The outcome significantly favours the use of peroperative volatile over non-volatile anaesthetics during on-pump CABG surgery with regard to peak postoperative cTnI (0.995 mg l; standard mean difference, 95% confidence interval, -1.316 to -0.673; P < 0.001). Meta-analysis of 11 off-pump studies showed no difference in peak postoperative cTnI (0.385 mg l; standard mean difference, 95% confidence interval, -0.857 to 0.087; P = 0.11). TSA indicated that the required information size for on-pump surgery was 1072 patients, and for off-pump surgery it was 1442; this latter figure has not yet been reached.Conclusion: Studies investigating the cardioprotective effect of volatile anaesthetics on cardiac troponins in on-pump CABG surgery are no longer warranted. This is not yet the case for off-pump surgery. [ABSTRACT FROM AUTHOR]

Background-Hybrid positron emission tomography and magnetic resonance allows the advantages of magnetic resonance in tissue characterizing the myocardium to be combined with the unique metabolic insights of positron emission tomography. We hypothesized that the area of reduced myocardial glucose uptake would closely match the area at risk delineated by T2 mapping in ST-segment-elevation myocardial infarction patients. Methods and Results-Hybrid positron emission tomography and magnetic resonance using 18F-fluorodeoxyglucose (FDG) for glucose uptake was performed in 21 ST-segment-elevation myocardial infarction patients at a median of 5 days. Follow-up scans were performed in a subset of patients 12 months later. The area of reduced FDG uptake was significantly larger than the infarct size quantified by late gadolinium enhancement (37.2±11.6% versus 22.3±11.7%; P<0.001) and closely matched the area at risk by T2 mapping (37.2±11.6% versus 36.3±12.2%; P=0.10, R=0.98, bias 0.9±4.4%). On the follow-up scans, the area of reduced FDG uptake was significantly smaller in size when compared with the acute scans (19.5 [6.3%-31.8%] versus 44.0 [21.3%-55.3%]; P=0.002) and closely correlated with the areas of late gadolinium enhancement (R 0.98) with a small bias of 2.0±5.6%. An FDG uptake of ≥45% on the acute scans could predict viable myocardium on the follow-up scan. Both transmural extent of late gadolinium enhancement and FDG uptake on the acute scan performed equally well to predict segmental wall motion recovery. Conclusions-Hybrid positron emission tomography and magnetic resonance in the reperfused ST-segment-elevation myocardial infarction patients showed reduced myocardial glucose uptake within the area at risk and closely matched the area at risk delineated by T2 mapping. FDG uptake, as well as transmural extent of late gadolinium enhancement, acutely can identify viable myocardial segments. [ABSTRACT FROM AUTHOR]

The article states the need for novel cardioprotective therapies to reduce myocardial infarct (MI) size and preserve left ventricular (LV) systolic function to prevent heart failure and improve clinical outcomes after primary percutaneous coronary intervention (PPCI). Topics discussed include the reasons for the failure to translate cardioprotection for patient benefit and a study on the MI-limiting effects of combining N-acetylcysteine and nitroglycerin.

A letter to the editor is presented in response to the article "Air Versus Oxygen in ST-Segment-Elevation Myocardial Infarction" by Bulluck and Hausenloy in the 2015 issue.

Background: Cardiocerebral infarction (CCI), which is concomitant with acute myocardial infarction (AMI) and acute ischemic stroke (AIS), is a rare but severe presentation. However, there are few data on CCI, and the treatment options are uncertain. We investigated the characteristics and outcomes of CCI compared with AMI or AIS alone., Methods: We performed a retrospective cohort study of 120 531 patients with AMI and AIS from the national stroke and AMI registries in Singapore. Patients were categorized into AMI only, AIS only, synchronous CCI (same-day), and metachronous CCI (within 1 week). The primary outcome was all-cause mortality, and the secondary outcome was cardiovascular mortality. The mortality risks were compared using Cox regression. Multivariable models were adjusted for baseline demographics, clinical variables, and treatment for AMI or AIS., Results: Of 127 919 patients identified, 120 531 (94.2%) were included; 74 219 (61.6%) patients had AMI only, 44 721 (37.1%) had AIS only, 625 (0.5%) had synchronous CCI, and 966 (0.8%) had metachronous CCI. The mean age was 67.7 (SD, 14.0) years. Synchronous and metachronous CCI had a higher risk of 30-day mortality (synchronous: adjusted HR [aHR], 2.41 [95% CI, 1.77-3.28]; metachronous: aHR, 2.80 [95% CI, 2.11-3.73]) than AMI only and AIS only (synchronous: aHR, 2.90 [95% CI, 1.87-4.51]; metachronous: aHR, 4.36 [95% CI, 3.03-6.27]). The risk of cardiovascular mortality was higher in synchronous and metachronous CCI than AMI (synchronous: aHR, 3.03 [95% CI, 2.15-4.28]; metachronous: aHR, 3.41 [95% CI, 2.50-4.65]) or AIS only (synchronous: aHR, 2.58 [95% CI, 1.52-4.36]; metachronous: aHR, 4.52 [95% CI, 2.95-6.92]). In synchronous CCI, AMI was less likely to be managed with PCI and secondary prevention medications ( P <0.001) compared with AMI only., Conclusions: Synchronous CCI occurred in 1 in 200 cases of AIS and AMI. Synchronous and metachronous CCI had higher mortality than AMI or AIS alone.

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., Competing Interests: L.T. is on the Astra Zeneca international advisory board of management of adverse events with the new antibody drug conjugate T-DXd in Asian patients with metastatic breast cancer, Roche Singapore immunotherapy in early stage NSCLC patient journey advisory board. L.T. has received a Philips speaker honorarium in kind and a Siemens Healthineers speaker honorarium. Y.K.K. has received research funding from Amgen, Astra Zeneca, Abbott Vascular, Bayer, Boston Scientific, Shockwave Medical, and Novartis (via institution); consulting fees from Abbott Vascular, Medtronic, Novartis, and Peijia Medical; and speaker fees from Shockwave Medical, Abbott Vascular, Boston Scientific, Medtronic, Alvimedica, Biotronik, Orbus Neich, Amgen, Novartis, Astra Zeneca, Microport, Terumo, and Omnicare. Y.K.K. is also cofounder and owns equity in Trisail, for which OrbusNeich is an investor. D.J.H. has received consultant fees from Faraday Pharmaceuticals Inc and Boehringer Ingelheim International GmbH, honoraria from Servier, and research funding from Astra Zeneca and Merck Sharp & Dohme Corp. C.Y.C. has received speaker fees from Novartis and consultancy fees from Boston Scientific and Philips. The other authors report no conflicts.

Time-critical acute ischemic conditions such as ST-elevation myocardial infarction and acute ischemic stroke are staples in Emergency Medicine practice. While timely reperfusion therapy is a priority, the resultant acute ischemia/reperfusion injury contributes to significant mortality and morbidity. Among therapeutics targeting ischemia/reperfusion injury (IRI), remote ischemic conditioning (RIC) has emerged as the most promising.RIC, which consists of repetitive inflation and deflation of a pneumatic cuff on a limb, was first demonstrated to have protective effect on IRI through various neural and humoral mechanisms. Its attractiveness stems from its simplicity, low-cost, safety, and efficacy, while at the same time it does not impede reperfusion treatment. There is now good evidence for RIC as an effective adjunct to reperfusion in ST-elevation myocardial infarction patients for improving clinical outcomes. For other applications such as acute ischemic stroke, subarachnoid hemorrhage, traumatic brain injury, cardiac arrest, and spinal injury, there is varying level of evidence.This review aims to describe the RIC phenomenon, briefly recount its historical development, and appraise the experimental and clinical evidence for RIC in selected emergency conditions. Finally, it describes the practical issues with RIC clinical application and research in Emergency Medicine.

Background: Whether alterations in mitochondrial morphology affect the susceptibility of the heart to ischemia/reperfusion injury is unknown. We hypothesized that modulating mitochondrial morphology protects the heart against ischemia/reperfusion injury., Methods and Results: In response to ischemia, mitochondria in HL-1 cells (a cardiac-derived cell line) undergo fragmentation, a process that is dependent on the mitochondrial fission protein dynamin-related protein 1 (Drp1). Transfection of HL-1 cells with the mitochondrial fusion proteins mitofusin 1 or 2 or with Drp1(K38A), a dominant-negative mutant form of Drp1, increased the percentage of cells containing elongated mitochondria (65+/-4%, 69+/-5%, and 63+/-6%, respectively, versus 46+/-6% in control: n=80 cells per group; P<0.05), decreased mitochondrial permeability transition pore sensitivity (by 2.4+/-0.5-, 2.3+/-0.7-, and 2.4+/-0.3-fold, respectively; n=80 cells per group; P<0.05), and reduced cell death after simulated ischemia/reperfusion injury (11.6+/-3.9%, 16.2+/-3.9%, and 12.1+/-2.9%, respectively, versus 41.8+/-4.1% in control: n=320 cells per group; P<0.05). Treatment of HL-1 cells with mitochondrial division inhibitor-1, a pharmacological inhibitor of Drp1, replicated these beneficial effects. Interestingly, elongated interfibrillar mitochondria were identified in the adult rodent heart with confocal and electron microscopy, and in vivo treatment with mitochondrial division inhibitor-1 increased the percentage of elongated mitochondria from 3.6+/-0.5% to 14.5+/-2.8% (P=0.023). Finally, treatment of adult murine cardiomyocytes with mitochondrial division inhibitor-1 reduced cell death and inhibited mitochondrial permeability transition pore opening after simulated ischemia/reperfusion injury, and in vivo treatment with mitochondrial division inhibitor-1 reduced myocardial infarct size in mice subject to coronary artery occlusion and reperfusion (21.0+/-2.2% with mitochondrial division inhibitor-1 versus 48.0+/-4.5% in control; n=6 animals per group; P<0.05)., Conclusions: Inhibiting mitochondrial fission protects the heart against ischemia/reperfusion injury, suggesting a novel pharmacological strategy for cardioprotection.