Shanmuganathan Limalanathan

Effect of Ischemic Postconditioning on Infarct Size in Patients With ST-Elevation Myocardial Infarction Treated by Primary PCI Results of the POSTEMI (POstconditioning in ST-Elevation Myocardial Infarction) Randomized Trial

Background Reduction of infarct size by ischemic postconditioning (IPost) has been reported in smaller proof‐of‐concept clinical studies, but has not been confirmed in other smaller studies. The principle needs to be evaluated in larger groups of ST‐elevation myocardial infarction (STEMI) patients before being implemented in clinical practice. This study assessed the effect of ischemic postcoditioning (IPost) on infarct size in patients with STEMI treated by primary percutaneous coronary intervention (PCI). Methods and Results Patients with first‐time STEMI, <6 hours from symptom onset, referred to primary PCI were randomized to IPost or control groups. IPost was administered by 4 cycles of 1‐minute reocclusion and 1‐minute reperfusion, starting 1 minute after opening, followed by stenting. In the control group, stenting was performed immediately after reperfusion. The primary endpoint was infarct size measured by cardiac magnetic resonance after 4 months. A total of 272 patients were randomized. Infarct size (percent of left ventricular mass) after 4 months (median values and interquartile range) was 14.4% (7.7, 24.6) and 13.5% (8.1, 19.3) in the control group and IPost group, respectively (P=0.18). No significant impact of IPost was found when controlling for baseline risk factors of infarct size in a multivariate linear regression model (P=0.16). The effects of IPost on secondary endpoints, including markers of necrosis, myocardial salvage, and ejection fraction, as well as adverse cardiac events during follow‐up, were consistently neutral. Conclusions In contrast to several smaller trials reported previously, we found no significant effects of IPost on infarct size or secondary study outcomes. Clinical Trial Registration URL: http://www.clinicaltrials.gov Unique identifier: NCT.No.PO1506.

Rationale and Design of the POSTEMI (Postconditioning in ST-Elevation Myocardial Infarction) Study

Rapid reperfusion of the infarct-related coronary artery is essential in the treatment of acute ST-elevation myocardial infarction (STEMI). Paradoxically, restoration of the blood flow to the ischemic area may result in further injury to the myocardium. This phenomenon is described as ‘ischemia/reperfusion injury’ and the pathophysiological mechanisms are not fully elucidated. A cardioprotective effect of ischemic postconditioning (short repetitive cycles of reperfusion and re-occlusion) has been demonstrated in experimental studies and in pilot studies on patients with acute STEMI treated with primary percutaneous coronary intervention. We present the study design of the Postconditioning in ST-Elevation Myocardial Infarction (POSTEMI) study, which is a prospective, randomized, open-label clinical trial with blinded endpoint evaluation designed to evaluate the effect of postconditioning on final infarct size. Patients with acute STEMI with symptoms of less than 6 h and proximal or mid-coronary artery occlusion will be included. The primary endpoint is infarct size, assessed by cardiac MRI after 4 months. The secondary endpoints are to evaluate the effect of postconditioning on TIMI myocardial perfusion grade, resolution of ST-segment elevation, release of markers of ischemia, left ventricular function and final infarct size related to the area at risk. A total of 260 patients will be included in the study.

Postconditioning in ST-elevation myocardial infarction: a systematic review, critical appraisal, and meta-analysis of randomized clinical trials

Objective We aimed to summarize the evidence from randomized clinical trials studies examining the efficacy of ischemic postconditioning (IPost) in ST-elevation myocardial infarction. Design The study was a systematic review and critical appraisal, with meta-analysis of randomized clinical trials. Materials and methods We searched the literature. A total of 21 randomized clinical trials were identified. Both fixed effect and random effects models were used to synthesize the results of individual studies. Heterogeneity between studies was examined by subgroup and random effects meta-regression analyses, considering ptient-related and study-level variables. Publication bias, or “small-study effect”, was evaluated. Results Substantial heterogeneity was present. The random effects model pooled estimate for the outcome infarct size assessed by cardiac magnetic resonance was estimated by the standardized mean difference (SMD) =−0.06, 95% confidence interval (CI): −0.34 to 0.21, ie, no effect of IPost. For the end point infarct size, estimated by biomarkers of myocardial necrosis, an overall pooled effect was SMD =−0.58, 95% CI: −0.96 to −0.19. This effect disappeared in powered and nonbiased studies (SMD =0.03, 95% CI: −0.48 to 0.55). Finally, for the outcome left ventricular ejection fraction, SMD =0.47 95% CI: 0.20 to 0.74. Unfortunately, selection bias (small-study effect) was present. For this outcome, the meta-regression showed that both presence of hypertension and the inclusion of nonbiased studies explained 28.3% of the heterogeneity among the studies. Simulation by the “trim and fill” method, which controlled for selection bias using random effects model, diluted the effect (SMD =0.17 95% CI: −0.13 to 0.48). No effects by IPost on ST-segment resolution or on the majority of adverse clinical events were observed during follow up, except the incidence of congestive heart failure was found. Conclusion Evidence from this study suggests no cardioprotection from IPost, on surrogate and the majority of clinical end points. A possible beneficial effect on the incidence of congestive heart failure needs to be replicated by a large clinical trial.

Myocardial salvage is reduced in primary PCI-treated STEMI patients with microvascular obstruction, demonstrated by early and late CMR.

Objectives This study evaluates the association between microvascular obstruction and myocardial salvage, determined by cardiac magnetic resonance performed both in the acute stage of myocardial infarction and after 4 months. Methods In patients with acute ST-elevation myocardial infarction treated by primary percutaneous coronary intervention, myocardial salvage, infarct size, left ventricular volumes, and ejection fraction were assessed by early (1–4 days) and follow-up (4 months) cardiac magnetic resonance. These variables were related to the presence or absence of microvascular obstruction at early investigation. Myocardial salvage was determined by: (1) myocardium at risk and infarct size measured in the acute stage and (2) myocardium at risk, measured acutely, and infarct size measured after 4 months. Multivariate analyses were performed, adjusting for clinical confounders at baseline. Results Microvascular obstruction was present in 49 of 94 included patients, (52%). Myocardial salvage was significantly reduced in patients with microvascular obstruction, compared to those without: 23% vs. 38%, measured acutely, and 39.8% vs. 65.4%, after 4 months (p<0.001). The presence of microvascular obstruction was significantly and independently associated with large infarct size, lower left ventricular ejection fraction, and larger left ventricular end-systolic volume. Conclusion The presence of microvascular obstruction demonstrated by cardiac magnetic resonance early after infarction was associated with impaired myocardial salvage. This association was more marked when based on measurement of infarct size after 4 months compared to assessment in the acute stage.

Osteoprotegerin levels in ST-elevation myocardial infarction: Temporal profile and association with myocardial injury and left ventricular function

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.

Influence of ischemic postconditioning on myocardial dysfunction measured by speckle tracking echocardiography in patients with ST-elevation myocardial infarction

a Department of Cardiology, Unit of Epidemiology and Biostatistics, Oslo University Hospital Ullevål, Oslo, Norway b Department of Radiology, Unit of Epidemiology and Biostatistics, Oslo University Hospital Ullevål, Oslo, Norway c Center for Clinical Research, Unit of Epidemiology and Biostatistics, Oslo University Hospital Ullevål, Oslo, Norway d Center for Heart Failure Research, Oslo, Norway e Section for Interventional Cardiology, Oslo, Norway f Faculty of Medicine, University of Oslo, Oslo, Norway

Soluble IL-1 receptor 2 is associated with left ventricular remodelling in patients with ST-elevation myocardial infarction

BACKGROUND The inflammatory response following myocardial infarction (MI) is prerequisite for proper healing of infarcted tissue, but can also have detrimental effects on cardiac function. Interleukin (IL)-1α and IL-1β are potent inflammatory mediators and their bioactivity is tightly regulated by IL-1 receptor antagonist (IL-1ra) and soluble (s) IL-1 receptors (R). We aimed to examine whether levels of soluble regulators of IL-1 signalling are changed during ST-elevation MI (STEMI) and their associations with parameters of cardiac injury and ventricular remodelling. METHODS Plasma levels of IL-1Ra, sIL-1R1, sIL-1R2 and sIL-1R accessory protein (sIL-1RAcP) were measured by immunoassays in repeated samples from patients with STEMI (n = 255) and compared to healthy controls (n = 65). RESULTS IL-1Ra, sIL-1R1 and sIL-1R2 levels were all significantly elevated after STEMI, while levels of sIL-1RAcP were lower compared to controls. sIL-1R2 levels (at different time points) correlated positively with C-reactive protein, myocardial infarct size and change in indexed left ventricular end-diastolic and end-systolic volume (LVEDVi and LVESVi) measured by cardiac MR acutely and after 4 months, and negatively with LV ejection fraction. Patients with >median levels of sIL-1R2 in the acute phase were more likely to have increased change in LVEDVi and LVESVi. Importantly, sIL-1R2 remained significantly associated with change in LVEDVi and LVESVi also after adjustment for clinical covariates. CONCLUSION Levels of sIL-1R2 are independently associated with parameters of LV adverse remodelling following STEMI.

Evaluation of circulating levels of CCN2/connective tissue growth factor in patients with ST-elevation myocardial infarction

CCN2/Connective tissue growth factor seems to be involved in development of cardiac hypertrophy and fibrosis, but a possible cardioprotective role in left ventricular (LV) remodelling following myocardial infarction has also been suggested. The main objectives of the study were therefore to investigate whether circulating CCN2 levels were associated with infarct size, LV function, adverse remodelling or clinical outcome in two cohorts of patients with ST-elevation myocardial infarction (STEMI). CCN2 was measured in 988 patients 18 hours after PCI and clinical events were recorded after 55 months in the BAMI cohort. In the POSTEMI trial, serial measurements of CCN2 were performed in 258 STEMI patients during index hospitalisation and cardiac magnetic resonance imaging was performed in the acute phase and after 4 months. Clinical events were also recorded. There were no significant associations between levels of CCN2 and infarct size, LV ejection fraction, changes in LV end-diastolic or end-systolic volume, myocardial salvage or microvascular obstruction. There were no significant associations between CCN2 levels and clinical events including mortality, in either of the study cohorts. In conclusion, circulating levels of CCN2 measured in the acute phase of STEMI were not associated with final infarct size, left ventricular function or new clinical events.

What Is the Optimal Cardioprotective Treatment of Reperfusion Injury

ceptions, the effect has generally been neutral [2] . Postconditioning, a nonpharmacological intervention applied at the time of reperfusion, consisting of intermittent reperfusion and occlusion of the infarct-related artery in several cycles, was shown by Zhao et al. [3] to reduce infarct size in an animal model. Evidence suggests that this approach targets several mediators of lethal I/R injury [2] . In smaller proof-of-concept studies in STEMI patients treated by primary percutaneous coronary intervention, an effect of postconditioning on infarct size was demonstrated [4–6] . More recently, however, neutral or possibly adverse effects of postconditioning have been reported [7–9] . Thus, at present, it is uncertain whether postconditioning of STEMI patients undergoing primary percutaneous coronary intervention can be recommended. We have recently completed the enrolment of patients in the POSTEMI trial [10] , to date the largest randomized trial on postconditioning with final infarct size as primary endpoint, and the results will be available later this year. In this issue of Cardiology, Koyama et al. [11] propose an altered postconditioning protocol using a modified reperfusionocclusion algorithm with gradually increasing reperfusion duration from 10 to 60 s over 7 cycles, combined with intracoronary injection of lactated Ringer’s solution. The rationale for this approach is In spite of improved treatment and follow-up strategies of acute ST-elevation myocardial infarction (STEMI), the incidence of both death and heart failure after STEMI is still high. Reperfusion of the infarct-related artery, preferably by primary percutaneous coronary intervention if it can be undertaken within guideline-recommended time frames, should be performed as early as possible [1] . However, reperfusion of the infarct-related artery may paradoxically result in further injury of the ischemic myocardium by mechanisms collectively called ischemia-reperfusion (I/R) injury. Experimental data indicate that I/R injury may account for up to 50% of the final myocardial infarct size [2] . The pathophysiology of I/R injury is not fully understood, but oxidative stress, intracellular calcium overload, intracellular acidosis, inflammation, and metabolic disturbances seem to contribute. Part of the I/R injury is mediated by opening of the mitochondrial permeability transition pore of the inner mitochondrial membrane, resulting in cell death [2] . Numerous experimental studies in animal models have shown that interventions applied at the time of reperfusion can reduce infarct size. In these models, an effect of many different pharmacological principles targeting mediators of I/R injury has been demonstrated. When applied in clinical studies, however, with a few possible exReceived: March 28, 2013 Accepted: March 28, 2013 Published online: May 24, 2013