Daily remote ischaemic conditioning following acute myocardial infarction: a randomised controlled trial.
ABSTRACT: BACKGROUND:Remote ischaemic conditioning (rIC) is a cardioprotective tool which has shown promise in preclinical and clinical trials in the context of acute ischaemia. Repeated rIC post myocardial infarction may provide additional benefits which have not previously been tested clinically. METHODS:The trial assessed the role of daily rIC in enhancing left ventricular ejection fraction (LVEF) recovery in patients with impaired LVEF (<45%) after ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (P-PCI). Patients were recruited from four UK hospitals and randomised to receive either 4 weeks of daily rIC or sham conditioning using the autoRIC Device (CellAegis) starting on day 3 post P-PCI. The primary endpoint was the improvement in LVEF over 4 months assessed by cardiac MRI (CMR). Seventy-three patients (38 cases, 35 controls) completed the study. RESULTS:The treatment and control groups were well matched at baseline including for mean LVEF (42.8% vs 44.3% respectively, p=0.952). There was no difference in the improvement in LVEF over 4 months between the treatment and control groups (4.8%±7.8% vs 4.6%±5.9% respectively, p=0.924). No differences were seen in the secondary outcome measures including changes in infarct size and left ventricular end-diastolic and systolic volumes, major adverse cardiac and cerebral event, mean Kansas City Cardiomyopathy Questionnaire score and change in N-terminal pro-brain natriuretic peptide levels. CONCLUSIONS:Daily rIC starting on day 3 and continued for 4 weeks following successful P-PCI for STEMI did not improve LVEF as assessed by CMR after 4 months when compared with a matched control group. TRIAL REGISTRATION NUMBER:NCT0166461.
Project description:Remote ischemic conditioning (RIC) applied during or after ST-segment elevation myocardial infarction (STEMI) is currently the most promising adjuvant therapy to reduce reperfusion injury. Recent animal studies showed that RIC may help the myocardium recover if applied daily during the month after STEMI. The Comprehensive Remote Ischemic Conditioning in Myocardial Infarction (CORIC-MI) trial is a single-center randomized controlled study in which 200 patients undergoing primary percutaneous coronary intervention (PPCI) for anterior STEMI will be randomized in a 1:1 ratio into comprehensive RIC (CORIC) or no intervention (control) groups. CORIC consists of per-RIC (5 cycles of 5-minute ischemia and 5-minute reperfusion of the lower limb immediately after randomization and before reperfusion), post-RIC (5 cycles of 5-minute ischemia and 5-minute reperfusion of the lower limb immediately post-PPCI), and delayed RIC (5 cycles of 5-minute ischemia and 5-minute reperfusion of the lower limb once daily on 2-28 days). Primary endpoint is left ventricular ejection fraction assessed by cardiac magnetic resonance imaging at 30 days. Major secondary endpoints include infarct size and left ventricular volume assessed by cardiac magnetic resonance imaging at 30 days, left ventricular ejection fraction assessed by echocardiography, and major adverse cardiovascular events up to 12 months. This report presents the baseline characteristics of 93 patients (CORIC group, n = 49; control group, n = 44) enrolled into the study as of March 31, 2018. The CORIC-MI trial aims to test the hypothesis that CORIC will improve cardiac function and remodeling in patients with anterior STEMI undergoing PPCI.
Project description:ST-elevation myocardial infarction (STEMI) accounts for nearly one third of acute coronary syndromes. Despite improved STEMI patient care, mortality remains high, contributing significantly to the ischemic heart disease burden. This may partly be related to ischemia-reperfusion injury (IRI). Remote ischemic conditioning (RIC), through short cycles of ischemia-reperfusion applied to a limb, has been shown to reduce IRI in various clinical settings. Our primary hypothesis is that RIC will reduce adverse events related to STEMI when applied as adjunctive therapy to primary percutaneous coronary intervention (PCI)."Remote ischemic conditioning in ST-elevation myocardial infarction as adjuvant to primary angioplasty" (RIC-STEMI) is an ongoing prospective, single-center, open-label, randomized controlled trial to assess whether RIC as an adjunctive therapy during primary PCI in patients presenting with STEMI can improve clinical outcomes. After enrollment, participants are randomized according to a computer-generated randomization schedule, in a ratio of 1:1 to RIC or no intervention, in blocks of four individuals. RIC is begun at least 10 min before the estimated time of the first balloon inflation and its duration is 30 min. Ischemia is induced by three cycles of inflation of a blood pressure cuff placed on the left lower limb to 200 mmHg and then deflation to 0 mmHg for another 5 min. Primary endpoint is a combined endpoint of death from cardiac cause or hospitalization for heart failure (HF) on follow-up (including device implantation: implantable cardioverter defibrillator, cardiac resynchronization and left ventricular assist device). Secondary endpoints are myocardial infarction (MI) size (estimated by the 48 h area under the curve of serum troponin I levels), development of Q-wave MI, left ventricular function (assessed by echocardiography within the first 3 days after admission), contrast-induced nephropathy, in-hospital mortality, all-cause mortality and, finally, major adverse cardiovascular events. Patients will have a minimum follow-up period of 12 months. From 11 March 2013 to 31 December 2014, 324 patients have been enrolled and randomized. We expect to complete enrollment of the 494 patients deemed necessary within 3 years.ClinicalTrials.gov identifier: NCT02313961; registered on 8 December 2014.
Project description:OBJECTIVES:Global left ventricular (LV) function is routinely used to assess cardiac function; however, myocardial strain is able to identify more subtle dysfunction. We aimed to determine the recovery and prognostic value of featuring tracking (FT) cardiovascular magnetic resonance (CMR) strain in ST-segment elevation myocardial infarction (STEMI) patients with a concurrent chronic total occlusion (CTO). METHODS:In the randomized EXPLORE trial, there was no significant difference in global LV function after percutaneous coronary intervention (PCI) of the CTO, compared with no-CTO PCI, post-STEMI. In the current study, we included 200 of the 302 EXPLORE patients with a baseline CMR, of which 180 also had 4-month follow-up (serial) CMR. Global longitudinal strain (GLS) was calculated from 3 long-axis views. Global circumferential strain (GCS) and segmental strain were calculated from 3 short-axis views (basal, mid, and apical). RESULTS:Global strain significantly improved at 4 months (GLS ? -?1.8?±?4.3%, p?<?0.001; GCS ? -?1.7?±?4.7%, p?<?0.001); however, there was no treatment effect of CTO-PCI on strain recovery. GLS was a significant predictor for 4 months of LV ejection fraction (p?=?0.006), incremental to other CMR parameters including infarct size. For mortality, infarct size remained the strongest predictor. On regional level, segmental strain independently predicted recovery in the dysfunctional segments (p?<?0.001). CONCLUSIONS:Global and segmental myocardial strains significantly improved over time, with no effect of CTO-PCI. Global strain was associated with outcome and segmental strain was an independent predictor for regional LV recovery in the dysfunctional CTO territory. Further research is needed to determine the additional prognostic value of strain beyond routine CMR parameters. KEY POINTS:• In STEMI patients with a concurrent CTO, strain significantly improves over time, regardless of CTO-PCI. • Global strain is an independent predictor for functional recovery, incremental to infarct size, LVEF, and clinical parameters. • Segmental strain was able to predict the recovery of wall thickening, incremental to transmural extent of infarction.
Project description:BACKGROUND:Elevated levels of osteoprotegerin (OPG) have been associated with adverse outcomes in ST-elevation myocardial infarction (STEMI). However, the role of OPG in myocardial injury and adverse remodeling in STEMI patients remains unclear. The aims of this observational cohort study were to evaluate: 1) the temporal profile of OPG during STEMI, 2) possible associations between OPG measured acutely and after 4 months, with infarct size, adverse left ventricular (LV) remodeling, microvascular obstruction (MVO) and myocardial salvage and 3) the effect of heparin administration on OPG levels. METHODS:Blood samples were drawn repeatedly from 272 STEMI patients treated with primary percutaneous coronary intervention (PCI). Cardiac magnetic resonance imaging (CMR) was performed in the acute phase and after 4 months. The effect of heparin administration on OPG levels was studied in 20 patients referred to elective coronary angiography. RESULTS:OPG levels measured acutely were significantly higher than Day 1 and during follow-up. OPG levels were correlated with age. No association was found between early OPG levels and CMR measurements at 4 months. Patients with >median OPG levels measured at Day 1 had larger final infarct size, lower LV ejection fraction (LVEF) at 4 months and higher frequency of MVO. There were no associations between OPG and change in end-diastolic volume or myocardial salvage. OPG remained associated with infarct size and LVEF after adjustment for relevant covariates, except peak troponin T and CRP. A 77% increase in OPG levels following heparin administration was found in patients undergoing elective coronary angiography. CONCLUSIONS:OPG was found to be associated with myocardial injury, but not with LV remodeling or myocardial salvage. The use of OPG as a biomarker in STEMI patients seems to be limited by a strong association with age, confounding effect of heparin administration, and little additive value to established biomarkers.
Project description:Reliable noninvasive prognostic biomarkers for left ventricular (LV) remodeling in ST-segment elevation myocardial infarction (STEMI) are needed. This study aimed to evaluate a panel of circulating microRNAs (miRNAs) as biomarkers of LV remodeling using cardiovascular magnetic resonance (CMR). We prospectively evaluated patients with a first STEMI treated with primary percutaneous coronary intervention who underwent CMR imaging at 1 week and 6 months after STEMI (n?=?70). miRNAs were measured using PCR-based technologies in plasma samples collected at admission. The associations between miRNAs and LV diastolic and systolic volumes, and ejection fraction at 6-months were estimated in adjusted models. Median age was 60 years, 71.4% were male. miR-1254 was significantly associated in univariate analyses. Patients in the highest tertile of miR-1254 exhibited lower values of LVEDVI and LVESVI and higher values of LVEF at 1 week. After comprehensive multivariate adjustment including clinical, CMR variables, hs-troponin-T and NT-proBNP, miRNA-1254 was associated with decreasing LVESVI (P?=?0.006), and borderline negative associated with LVEDVI (P?=?0.063) at 6-months. miR-1254 also exhibited a significant positive association with increasing LVEF during follow-up (P?<?0.001). Plasma miRNA-1254 predicted changes in LV volumes and LVEF at 6 months after STEMI. The value of miR-1254 to inform tailored treatment selection and monitor ongoing efficacy deserves further investigation.
Project description:Telomere length has been associated with coronary artery disease and heart failure. We studied whether leukocyte telomere length is associated with left ventricular ejection fraction (LVEF) after ST-elevation myocardial infarction (STEMI).Leukocyte telomere length (LTL) was determined using the monochrome multiplex quantitative PCR method in 353 patients participating in the glycometabolic intervention as adjunct to primary percutaneous coronary intervention in STEMI III trial. LVEF was assessed by magnetic resonance imaging. The mean age of patients was 58.9 ± 11.6 years, 75 % were male. In age- and gender-adjusted models, LTL at baseline was significantly associated with age (beta ± standard error; -0.33 ± 0.01; P < 0.01), gender (0.15 ± 0.03; P < 0.01), TIMI flow pre-PCI (0.05 ± 0.03; P < 0.01), TIMI flow post-PCI (0.03 ± 0.04; P < 0.01), myocardial blush grade (-0.05 ± 0.07; P < 0.01), serum glucose levels (-0.11 ± 0.01; P = 0.03), and total leukocyte count (-0.11 ± 0.01; P = 0.04). At 4 months after STEMI, LVEF was well preserved (54.1 ± 8.4 %) and was not associated with baseline LTL (P = 0.95). Baseline LTL was associated with n-terminal pro-brain natriuretic peptide (NT-proBNP) at 4 months (-0.14 ± 0.01; P = 0.02), albeit not independent for age and gender.Our study does not support a role for LTL as a causal factor related to left ventricular ejection fraction after STEMI.
Project description:There exists controversy on whether and for how long anticoagulation is necessary after primary percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI).We aimed to study the impact of prolonged (>24?h) or brief (<24?h) postprocedural anticoagulation on infarct size assessed by cardiac magnetic resonance (CMR) after 30 days as well as on left ventricular ejection fraction (LVEF) and left ventricular (LV) remodeling evaluated by 2D-echocardiography after 9 months from the INNOVATION trial (Clinical Trial Registration: NCT02324348).Of the 114 patients (mean age: 59.5 years) enrolled, 76 (66.7%) received prolonged anticoagulation therapy (median duration: 72.6?h) and 38 (33.3%) patients received brief anticoagulation therapy (median duration: 5?h) after primary PCI. There was no significant difference in infarct size (mean size: 15.6% after prolonged anticoagulation versus 19.8% after brief anticoagulation, P = .100) and the incidence of microvascular obstruction (50.7% versus 52.9%, P?=?.830) between the groups. Even after adjusting, prolonged anticoagulation therapy could not reduce larger infarct (defined as >75 percentile of infarct size; 19.7% versus 35.3%; adjusted odd ratio [OR]: 0.435; 95% confidence interval [CI]: 0.120-1.57; P?=?.204). Similar results were observed in subanalyses of major high-risk subgroups. Moreover, follow-up LVEF <35% (3.2% versus 7.4%; adjusted OR: 0.383; 95% CI: 0.051-2.884; P?=?.352) and LV remodeling (defined as >20% increase in LV end-diastolic volume; 37.1% versus 18.5%; adjusted OR: 2.249; 95% CI: 0.593-8.535; P?=?.234) were similar between groups.These data suggest that prolonged postprocedural anticoagulation may not provide much benefit after successful primary PCI in patients with STEMI. However, further studies are needed.
Project description:(1) Background: Extracellular vesicles (EVs) have been recognized as a cellular communication tool with cardioprotective properties; however, it is unknown whether cardioprotection by remote ischemic conditioning (RIC) involves EVs. (2) Methods: We randomized patients with ST-elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI) to additionally receive a protocol of RIC or a sham-intervention. Blood was taken before and immediately, 24 h, four days and one month after PCI. Additionally, we investigated EVs from healthy volunteers undergoing RIC. EVs were characterized by a high-sensitive flow cytometer (Beckman Coulter Cytoflex S, Krefeld, Germany). (3) Results: We analyzed 32 patients (16 RIC, 16 control) and five healthy volunteers. We investigated platelet-, endothelial-, leukocyte-, monocyte- and granulocyte-derived EVs and their pro-thrombotic sub-populations expressing superficial phosphatidylserine (PS+). We did not observe a significant effect of RIC on the numbers of circulating EVs, although granulocyte-derived EVs were significantly higher in the RIC group. In line, RIC had not impact on EVs in healthy volunteers. Additionally, we observed changes of PS+/PEV, EEVs and PS+/CD15+ EVs irrespective of RIC with time following STEMI. 4) Conclusion: We provide further insights into the course of different circulating EVs during the acute and sub-acute phases of STEMI. With respect to the investigated EV populations, RIC seems to have no effect, with only minor differences found for granulocyte EVs.
Project description:This study aimed to evaluate the incremental prognostic value of infarct size, microvascular obstruction (MO), myocardial salvage index (MSI), and left ventricular ejection fraction (LV-EFCMR) assessed by cardiac magnetic resonance imaging (CMR) in comparison to traditional outcome markers in patients with ST-elevation myocardial infarction (STEMI) reperfused by primary percutaneous intervention (PCI).STEMI patients reperfused by primary PCI (n=278) within 12 hours after symptom onset underwent CMR three days after the index event (interquartile range [IQR] two to four). Infarct size and MO were measured 15 minutes after gadolinium injection. T2-weighted and contrast-enhanced CMR were used to calculate MSI. In addition, traditional outcome markers such as ST-segment resolution, pre- and post-PCI Thrombolysis In Myocardial Infarction (TIMI)-flow, maximum level of creatine kinase-MB, TIMI-risk score, and left ventricular ejection fraction assessed by echocardiography were determined in all patients. Clinical follow-up was conducted after 19 months (IQR 10 to 27). The primary endpoint was defined as a composite of death, myocardial reinfarction, and congestive heart failure (MACE).In multivariable Cox regression analysis, adjusting for all traditional outcome parameters significantly associated with the primary endpoint in univariable analysis, MSI was identified as an independent predictor for the occurrence of MACE (Hazard ratio 0.94, 95% CI 0.92 to 0.96, P<0.001). Further, C-statistics comparing a model including only traditional outcome markers to a model including CMR parameters on top of traditional outcome markers revealed an incremental prognostic value of CMR parameters (0.74 versus 0.94, P<0.001).CMR parameters such as infarct size, MO, MSI, and LV-EFCMR add incremental prognostic value above traditional outcome markers alone in acute reperfused STEMI.Clinicaltrials.gov NCT00463749, Clinicaltrials.gov NCT00359918.
Project description:Background:The relevance of neutrophil extracellular traps (NETs) in acute ST-elevation myocardial infarction (STEMI) is unclear. We explored the temporal profile of circulating NET markers and their associations to myocardial injury and function and to adverse clinical events in STEMI patients. Methods and Results:In 259 patients, blood samples were drawn before and after PCI, on day 1, and after 4 months. Double-stranded deoxyribonucleic acid (dsDNA) and myeloperoxidase-DNA (MPO-DNA) were measured in serum by a nucleic acid stain and ELISA. Cardiac magnetic resonance imaging assessed microvascular obstruction (MVO), area at risk, infarct size, myocardial salvage index, left ventricular ejection fraction (LVEF), and change in indexed left ventricular end-diastolic volume (LVEDVi). Clinical events were registered after 12 months. dsDNA and MPO-DNA levels were highest before PCI, with reduced levels thereafter (all p ? 0.02). Patients with high vs. low day 1 dsDNA levels (>median; 366?ng/ml) more frequently had MVO, larger area at risk, larger infarct size acutely and after 4 months, and lower myocardial salvage index (all p < 0.03). Moreover, they had lower LVEF acutely and after 4 months, and larger change in LVEDVi (all p ? 0.014). High day 1 dsDNA levels also associated with risk of having a large infarct size (>75th percentile) and low LVEF (?49%) after 4 months when adjusted for gender, time from symptoms to PCI, and infarct localization (OR 2.3 and 3.0, both p < 0.021), and patients with high day 1 dsDNA levels were more likely to experience an adverse clinical event, also when adjusting for peak troponin T (hazard ratio 5.1, p = 0.012). No such observations were encountered for MPO-DNA. Conclusions:High day 1 dsDNA levels after STEMI were associated with myocardial infarct size, adverse left ventricular remodeling, and clinical outcome. Although the origin of dsDNA could be discussed, these observations indicate a potential role for dsDNA in acute myocardial ischemia. This trial is registered with S-08421d, 2008/10614 (Regional Committee for Medical Research Ethics in South-East Norway (2008)).