Ischemic Postconditioning After Routine Thrombus Aspiration During Primary Percutaneous Coronary Intervention: Rationale and Design of the POstconditioning Rotterdam Trial.

BACKGROUND: Whether ischemic postconditioning (IPOC) immediately after routine thrombus aspiration (TA) reduces infarct size (IS) in patients with ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PPCI) has not been established. STUDY DESIGN: The POstconditioning Rotterdam Trial (PORT) is a dual-center, prospective, open-label, randomized trial with blinded endpoint evaluation enrolling 72 subjects with first-time STEMI, and an occluded infarct-related artery (IRA) without collaterals undergoing PPCI. Subjects are randomized 1:1 to a strategy of IPOC immediately after TA followed by stenting of the IRA or to conventional percutaneous coronary intervention (PCI), including TA followed by stenting of the IRA (controls). Cardiac magnetic resonance imaging (MRI) is performed at 3-5 days after STEMI and at 3 months. The primary endpoint is IS at 3 months measured by delayed enhancement MRI. Other secondary endpoints include MRI-derived microvascular obstruction (MVO), left ventricular ejection fraction, myocardial salvage index, enzymatic IS, ST-segment resolution, myocardial blush grade, microcirculatory resistance, inflammation markers, and clinical events through 3-month follow-up. CONCLUSIONS: PORT is testing the hypothesis that adding IPOC (against lethal reperfusion injury) to TA (against distal embolization and MVO) is cardioprotective and reduces ultimate IS in STEMI patients undergoing PPCI (Dutch Trial Register identifier: NTR4040). © 2015 Wiley Periodicals, Inc.

Vagal nerve stimulation started just prior to reperfusion limits infarct size and no-reflow.

Vagal nerve stimulation (VNS) started prior to, or during, ischemia has been shown to reduce infarct size. Here, we investigated the effect of VNS when started just prior to, and continued during early, reperfusion on infarct size and no-reflow and studied the underlying mechanisms. For this purpose, swine (13 VNS, 10 sham) underwent 45 min mid-LAD occlusion followed by 120 min of reperfusion. VNS was started 5 min prior to reperfusion and continued until 15 min of reperfusion. Area at risk, area of no-reflow (% of infarct area) and infarct size (% of area at risk), circulating cytokines, and regional myocardial leukocyte influx were assessed after 120 min of reperfusion. VNS significantly reduced infarct size from 67 ± 2 % in sham to 54 ± 5 % and area of no-reflow from 54 ± 6 % in sham to 32 ± 6 %. These effects were accompanied by reductions in neutrophil (~40 %) and macrophage (~60 %) infiltration in the infarct area (all p < 0.05), whereas systemic circulating plasma levels of TNFα and IL6 were not affected. The degree of cardioprotection could not be explained by the VNS-induced bradycardia or the VNS-induced decrease in the double product of heart rate and left ventricular systolic pressure. In the presence of NO-synthase inhibitor LNNA, VNS no longer attenuated infarct size and area of no-reflow, which was paralleled by similarly unaffected regional leukocyte infiltration. In conclusion, VNS is a promising novel adjunctive therapy that limits reperfusion injury in a large animal model of acute myocardial infarction.

Impact of multiple balloon inflations during primary percutaneous coronary intervention on infarct size and long-term clinical outcomes in ST-segment elevation myocardial infarction: real-world postconditioning.

Interrupting myocardial reperfusion with intermittent episodes of ischemia (i.e., postconditioning) during primary percutaneous coronary intervention (PPCI) has been suggested to protect myocardium in ST-segment elevation myocardial infarction (STEMI). Nevertheless, trials provide inconsistent results and any advantage in long-term outcomes remains elusive. Using a retrospective study design, we evaluated the impact of balloon inflations during PPCI on enzymatic infarct size (IS) and long-term outcomes. We included 634 first-time STEMI patients undergoing PPCI with an occluded infarct-related artery and adequate reperfusion thereafter and divided these into: patients receiving 1-3 inflations in the infarct-related artery [considered minimum for patency/stent placement (controls); n = 398] versus ≥4 [average cycles in clinical protocols (postconditioning analogue); n = 236]. IS, assessed by peak creatine kinase, was lower in the postconditioning analogue group compared with controls [median (interquartile range) 1,287 (770-2,498) vs. 1,626 (811-3,057) UI/L; p = 0.02], corresponding to a 21 % IS reduction. This effect may be more pronounced in women, patients without diabetes/hypercholesterolemia, patients presenting within 3-6 h or with first balloon re-occlusion ≤1 min. No differences were observed in 4-year mortality or MACCE between groups. Four or more inflations during PPCI reduced enzymatic IS in STEMI patients under well-defined conditions, but did not translate into improved long-term outcomes in the present study. Large-scale randomized trials following strict postconditioning protocols are needed to clarify this effect.

Remote ischemic conditioning in percutaneous coronary intervention and coronary artery bypass grafting.

BACKGROUND: Although remote ischemic conditioning (RIC) by transient limb ischemia in percutaneous coronary intervention (PCI) and coronary artery bypass grafting (CABG) has shown favorable effects on myocardial (ischemia-reperfusion) injury, recent trials provide inconsistent results. The aim of the present study was to assess the effect of RIC in PCI or CABG. METHODS AND RESULTS: Medline/Embase/conference reports were searched for randomized RIC trials and were included if they reported on biomarkers of myocardial injury (CK-MB/troponin T/I), after which, standardized mean differences (SMDs) were calculated (Hedges g statistic). Meta-analysis of 4 studies on PCI, involving 557 patients, indicated reduced biomarkers for myocardial injury with RIC compared to control (random effects model: SMD, -0.21; 95% confidence interval [CI]: -0.66 to 0.24). Analysis of primary PCI studies, involving 314 patients, indicated a highly significant positive effect of RIC on myocardial injury (SMD, -0.55; 95% CI: -0.77 to -0.32). The 13 CABG studies taken together, involving 891 patients, indicated a significant effect of RIC on myocardial injury (SMD, -0.34; 95% CI: -0.59 to -0.08). The statistical tests indicated moderate to high heterogeneity across the studies (Q-statistic: PCI, P=0.0006, I(2)=83%; CABG, P<0.0001, I(2)=69%). CONCLUSIONS: In patients undergoing PCI or CABG, RIC with transient episodes of limb ischemia is associated with lower biomarkers of myocardial injury compared to control, but this effect failed to reach statistical significance in the overall PCI analysis.

A tool for predicting the outcome of reperfusion in ST-elevation myocardial infarction using age, thrombotic burden and index of microcirculatory resistance (ATI score).

AIMS: Restoration of effective myocardial reperfusion by primary percutaneous coronary intervention (PPCI) in patients with ST-elevation myocardial infarction is difficult to predict. A method to assess the likelihood of a suboptimal response to conventional pharmacomechanical therapies could be beneficial. We aimed to derive and validate a scoring system that can be used acutely at the time of coronary reopening to predict the likelihood of downstream microvascular impairment in patients with STEMI. METHODS AND RESULTS: A score estimating the risk of post-procedural microvascular injury defined by an index of microcirculatory resistance (IMR) >40 was initially derived in a cohort of 85 STEMI patients (derivation cohort). This score was then tested and validated in three further cohorts of patients (retrospective [30 patients], prospective [42 patients] and external [29 patients]). The ATI score (age [>50=1]; pre-stenting IMR [>40 and <100=1; ≥100=2]; thrombus score [4=1; 5=3]) was highly predictive of a post-stenting IMR >40 in all four cohorts (AUC: 0.87; p<0.001-derivation cohort, 0.84; p=0.002-retrospective cohort, 0.92; p<0.001-prospective cohort and 0.81; p=0.006-external cohort). In the whole population, an ATI score ≥4 presented a 95.1% risk of final IMR >40, while no cases of final IMR >40 occurred in the presence of an ATI score <2. CONCLUSIONS: The ATI score appears to be a promising tool capable of identifying patients during PPCI who are at the highest risk of coronary microvascular impairment following revascularisation. This procedural risk stratification has a number of potential research and clinical applications and warrants further investigation.

STENTYS Self-Apposing sirolimus-eluting stent in ST-segment elevation myocardial infarction: results from the randomised APPOSITION IV trial.

AIMS: We sought to investigate the impact of the self-apposing, sirolimus-eluting STENTYS stent on midterm and long-term stent apposition and strut coverage compared with a zotarolimus-eluting balloon-expandable stent in ST-segment elevation myocardial infarction (STEMI) patients undergoing primary percutaneous coronary intervention (PPCI). METHODS AND RESULTS: In the APPOSITION IV trial, 152 STEMI patients were randomised (3:2) to the self-apposing, sirolimus-eluting STENTYS stent or a commercially available zotarolimus-eluting balloon-expandable stent at 12 sites in five countries with angiographic follow-up and optical coherence tomography at four or nine months. At four months, a lower percentage of malapposed stent struts was observed in the STENTYS group (N=21; Nstruts=501) compared with controls (N=26; Nstruts=326; 0.07% vs. 1.16%; p=0.002) with significantly more covered struts, using a 20 µm cut-off (94.32% vs. 89.09%; p=0.003). At nine months, the primary endpoint (percentage malapposed stent struts) was similar in both groups (STENTYS, N=40; Nstruts=566; control, N=21; Nstruts=292), showing complete apposition (p=0.55) and near total (>96%) coverage (p=0.58). CONCLUSIONS: In STEMI patients undergoing PPCI, the self-apposing, sirolimus-eluting STENTYS stent was equivalent to a conventional drug-eluting balloon-expandable stent with respect to late stent strut apposition and coverage at nine months. However, stent strut apposition and coverage at four months were significantly better in the STENTYS group.

Alternative stents in ST-segment elevation myocardial infarction: improving the efficacy of primary percutaneous coronary intervention.

Despite the efficacy of primary percutaneous coronary intervention in achieving epicardial reperfusion in ST-segment elevation myocardial infarction, it is often limited by impaired microvascular perfusion attributable to distal embolization of plaque and thrombus, and stent malappostion due to vessel constriction and thrombus apposition, attenuating the full benefits of myocardial reperfusion and resulting in unfavorable clinical outcomes. In the long run implantation of permanent metallic implants have negative effect the biological behavior of the target vessel with a continuous low device failure over the years. Recently, however, efforts have been realized to tackle these shortcomings and optimize mechanical reperfusion by improvements to stent design, as substantiated by the self-expanding stent, the mesh-covered stent and the bioresorbable vascular scaffold. In this article, we provide an overview of the role of these novel, innovatively designed, alternative devices in patients undergoing primary percutaneous coronary intervention for ST-segment elevation myocardial infarction.

Limitation of Infarct Size and No-Reflow by Intracoronary Adenosine Depends Critically on Dose and Duration.

OBJECTIVES: In the absence of effective clinical pharmacotherapy for prevention of reperfusion-mediated injury, this study re-evaluated the effects of intracoronary adenosine on infarct size and no-reflow in a porcine model of acute myocardial infarction using clinical bolus and experimental high-dose infusion regimens. BACKGROUND: Despite the clear cardioprotective effects of adenosine, when administered prior to ischemia, studies on cardioprotection by adenosine when administered at reperfusion have yielded contradictory results in both pre-clinical and clinical settings. METHODS: Swine (54 ± 1 kg) were subjected to a 45-min mid-left anterior descending artery occlusion followed by 2 h of reperfusion. In protocol A, an intracoronary bolus of 3 mg adenosine injected over 1 min (n = 5) or saline (n = 10) was administered at reperfusion. In protocol B, an intracoronary infusion of 50 µg/kg/min adenosine (n = 15) or saline (n = 21) was administered starting 5 min prior to reperfusion and continued throughout the 2-h reperfusion period. RESULTS: In protocol A, area-at-risk, infarct size, and no-reflow were similar between groups. In protocol B, risk zones were similar, but administration of adenosine resulted in significant reductions in infarct size from 59 ± 3% of the area-at-risk in control swine to 46 ± 4% (p = 0.02), and no-reflow from 49 ± 6% of the infarct area to 26 ± 6% (p = 0.03). CONCLUSIONS: During reperfusion, intracoronary adenosine can limit infarct size and no-reflow in a porcine model of acute myocardial infarction. However, protection was only observed when adenosine was administered via prolonged high-dose infusion, and not via short-acting bolus injection. These findings warrant reconsideration of adenosine as an adjuvant therapy during early reperfusion.

Percutaneous coronary interventions during ST-segment elevation myocardial infarction: current status and future perspectives.

The present article focuses on recent innovations and possible future perspectives in the reperfusion treatment of ST-segment elevation myocardial infarction (STEMI). Among these, the shift from the femoral to the radial vascular access, the recent availability of bioresorbable coronary scaffolds, other innovative forms of stent specifically designed for STEMI patients, the use of cardioprotective strategies, as well as the possibility of including autologous bone marrow stem cell transplantation as part of the treatment of patients with STEMI are described and commented on as a glance into the future.

The emerging application of remote ischemic conditioning in the clinical arena.

Remote ischemic conditioning (RIC) is an intervention, in which intermittent episodes of ischemia and reperfusion in an organ or tissue distant from the target organ requiring protection, provide armour against lethal ischemia-reperfusion injury. Although the exact mechanisms underlying the protection mediated through RIC have not been clearly established, the release of humoral factors and the activation of neural pathways have been implicated. There is now clinical evidence suggesting that this form of protection can be induced by a simple, noninvasive, and cost-effective procedure such as inflation and deflation of a blood pressure cuff and that this intervention provides increased organ protection in a variety of clinical scenarios, for example, in myocardial infarction. Here we provide an overview of the history and evolution of RIC, the potential mechanisms underlying its protective effects, and published randomized clinical trials in cardiovascular procedures.