Abstract

Aims

To assess the short- and long-term effects of postconditioning (p-cond) on infarct size, extent of myocardial salvage, and left ventricular ejection fraction (LVEF) in a series of patients presenting with evolving ST-elevation myocardial infarction (STEMI). Previous studies have shown that p-cond during primary percutaneous coronary intervention (PCI) confers protection against ischaemia–reperfusion injury and thus might reduce myocardial infarct size.

Methods and results

Seventy-nine patients undergoing PCI for a first STEMI with TIMI grade flow 0–1 and no collaterals were randomized to p-cond (n= 39) or controls (n= 40). Postconditioning was performed by applying four consecutive cycles of 1 min balloon inflation, each followed by 1 min deflation. Infarct size, myocardial salvage, and LVEF were assessed by cardiac-MRI 1 week and 6 months after MI. Postconditioning was associated with lower myocardial salvage (4.1 ± 7.2 vs. 9.1 ± 5.8% in controls; P= 0.004) and lower myocardial salvage index (18.9 ± 27.4 vs. 30.9 ± 20.5% in controls; P= 0.038). No significant differences in infarct size and LVEF were found between the groups at 1 week and 6 months after MI.

Conclusion

This randomized study suggests that p-cond during primary PCI does not reduce infarct size or improve myocardial function recovery at both short- and long-term follow-up and might have a potential harmful effect.

See page 13 for the editorial comment on this article (doi:10.1093/eurheartj/ehr341)

Introduction

Reperfusion injury occurring after primary percutaneous coronary intervention (PCI) jeopardizes myocardial salvage and may increase infarct size.1 The occurrence of this procedure-related phenomenon in ∼30% of cases2 has been associated with higher mortality rates.2,3

Ischaemic preconditioning—an adaptive response triggered by transient ischaemia—has been shown to reduce myocardial injury caused by sudden reperfusion inherent to primary angioplasty.4,5 The inability to predict the onset of coronary artery occlusion limits the application of this therapeutic option in the setting of ST-elevation acute myocardial infarction (STEMI).

Postconditioning (p-cond), a sequence of ischaemia–reperfusion episodes induced by repeat cycles of balloon-catheter inflation and deflation immediately after reopening of the occluded vessel, has been proposed as a valid alternative to reduce infarct size. The first evidence of infarct size reduction associated with ischaemic p-cond was reported in a canine model.6 Two years later, Staat et al.7 performed the first clinical trial and reported p-cond benefits by showing a reduction in myocardial infarct size estimated by creatine kinase release. The effects of p-cond in STEMI patients have been assessed by using cardiac biomarkers,8–10 single-photon emission computed tomography (SPECT),10,11 echocardiography,10,11 and, more recently, by contrast-enhanced cardiac magnetic resonance (ce-CMR) imaging.12,13 Although most studies yielded positive results,5–10 the role of confounding factors, namely the presence of collaterals, multivessel coronary artery disease, or direct stenting usage, has not generally been taken into account. Moreover, the only two available studies that used ce-CMR to assess p-cond effects showed a modest12 or lack13 of infarct size reduction, with no impact on left ventricular ejection fraction (LVEF),12,13 and no data on long-term ce-CMR outcomes. The present investigation was therefore carried out to evaluate the short- and long-term effects of p-cond on infarct size, extent of myocardial salvage, and LVEF assessed by ce-CMR, in a series of patients presenting with evolving STEMI.

Methods

This was a prospective, single-centre, randomized, controlled, open study with blinded evaluation of outcomes. The study protocol was approved by the institution's Ethics Committee. All patients gave written informed consent.

Study population

Patients older than 18 years presenting within 12 h of a first STEMI and eligible for angioplasty were considered for the study. ST-elevation myocardial infarction was defined by the presence of prolonged chest pain (>30 min) and ST-segment elevation >1 mm in two or more adjacent leads. Exclusion criteria included: TIMI 2 or 3 flow in the infarct-related artery (IRA), previous myocardial infarction, the presence of other significant coronary lesions (≥70% by quantitative coronary angiography), the presence of collateral flow to the infarcted area as evidenced by a Rentrop score ≥1, cardiogenic shock, mechanical complications, any contraindication for ce-CMR, renal insufficiency (creatinine >1.5 mg/dL), and ongoing malignant process.

Experimental protocol

Unfractionated heparin was administered at a dose of 60 UI/kg, and a loading dose of clopidogrel (300 mg) was given at least 15 min before PCI. Glycoprotein IIb/IIIa receptor antagonists were routinely used, if there was no contraindication. Coronary angiography was performed by the percutaneous technique using the transradial or transfemoral approach. Coronary angiography allowed location of the culprit lesion and confirmation of no coronary blood flow distal to that lesion, either antegradely or from collaterals. Following angiographic data acquisition, patients were randomized, using a computerized 1:1 sequence, into the control or p-cond group. Allocation concealment was performed using opaque sealed envelopes. Direct stenting was strongly recommended whenever possible. Postconditioning sequence was performed by reinflating the same balloon (angioplasty balloon or stent balloon) at the site of the index lesion. Patients allocated to p-cond underwent four cycles of 60 s reperfusion followed by 60 s reocclusion, using reiterative low pressure (4–6 atmospheres) inflation and deflation, beginning 1min after reperfusion. Selection of this ischaemia–reperfusion sequence was based on the previous data.7 Controls did not undergo additional interventions. The use of intracoronary adenosine or nitroglycerin during PCI was left at operator discretion.

Outcomes analysis

Angiographic analysis

Angiographic assessment was performed independently by two experienced angiographers. It included TIMI flow grading,14 myocardial blush grade (MBG),15 Rentrop's score of collateral flow,16 and angiographic area at risk, depicted by the Bypass Angioplasty Revascularization Investigation (BARI) score as described previously.17

Electrocardiographic analysis

A standard 12-lead electrocardiographic (ECG) tracing was obtained at admission and 90 min after PCI. A cardiologist, blinded to the group assignment, measured the maximal ST-segment change 80 ms after the J-point. The ECG resolution was calculated as a percentage using the equation (initial sum of ST-segment elevation – post-PCI sum of ST-elevation/initial sum of ST-segment elevation).

Cardiac biomarkers

Plasma levels of troponin-I were measured using a fluorometric enzyme immunoassay analyzer (Tn I-Ultra, ADVIA Centaur CP). Creatine kinase, myocardial bound (CK-MB), and troponin-I were measured every 4 h for the first 24 h and then every 24 h for the first 3 days.

Echocardiographic analysis

Echocardiography was performed at baseline (between the third and the seventh day after PCI) and at 6 months, using Vivid 7 systems (GE-Vingmed, Milwaukee, WI, USA). The left ventricle was measured in the parasternal and apical views and ejection fraction was evaluated using the biplane Simpson's method by an expert cardiologist blinded to the group assignment.

Cardiac magnetic resonance evaluation

A standard ce-CMR study was performed during the first week after PCI and repeated at 6 months, using a 1.5 T clinical scanner (CV Signa, GE, Milwaukee, WI, USA) equipped with cardiac-dedicated software and a four-element cardiac phased-array surface coil. In addition to the standard two-, three-, and four-chamber views, a stack of sequential short-axis images every 10 mm with no gap was obtained from the LV base to the apex to achieve full LV coverage. All images were acquired during breath-holding and were electrocardiographically gated. Functional assessment of the LV was performed using a standard cine steady-state free precession sequence (FIESTA). A standard segmented inversion-recovery/fast gradient-echo pulse sequence was prescribed in identical positions 10–15 min after intravenous administration of gadodiamide (Omniscan, Amersham Health, Madrid, Spain) at a dose of 0.2 mmol/kg. The mean inversion time, adjusted to null normal myocardium, was 200–220 ms. Matrix size was set to 256 and the mean field of view was 360 mm, resulting in a typical voxel size of 1.4 by 1.4 by 10 mm. All CMR images were cropped, interpolated by a factor of 3, and anonymized for analysis by an independent, experienced cardiologist blinded to all clinical and angiographic data.

The presence of microvascular injury measured by the occurrence of microvascular obstruction was defined as any area of late hypoenhancement surrounded by hyperenhancement on ce-CMR images.

The infarcted myocardium, defined as areas of hyperenhancement with signal intensity 2 standard deviations (SDs) above that of the normal remote myocardium, was manually planimetered on short-axis contrast-enhanced images by an experienced observer as described previously.17 The total infarct area on sequential short-axis slices was divided by the total LV myocardial volume to calculate the infarct size as a percentage of the LV mass. The areas with microvascular obstruction were considered part of the infarct area. Infarct size by ce-CMR was subtracted from the estimated angiographic area at risk to compute myocardial salvage, expressed as percentage of LV mass. To account for differences in the anatomic area at risk, a myocardial salvage index (MSI) was computed as follows: MSI = (area at risk by angiography – infarct size by ce-CMR) × 100/area at risk by angiography, expressed as per cent of the area at risk.17

Using customized Image J (National Institutes of Health, Bethesda, MD, USA) tools, the endocardial and epicardial borders on sequential short-axis cine images were manually traced at end-systole and end-diastole to compute LV end-systolic and end-diastolic volumes as well as LV mass and LVEF.

Endpoints

The primary endpoints of the study were infarct size and degree of MSI measured with ce-CMR within the first week after primary PCI. The secondary endpoints included infarct size as assessed by ce-CMR at 6 months, LVEF at 1 week and 6 months as evaluated by ce-CMR and echocardiography, MBG after reperfusion, peak of cardiac biomarkers, ST-segment resolution at 90 min, and the presence of microvascular obstruction assessed by ce-CMR.

Sample size and statistical analysis

Calculation of sample size was performed according to the previous studies.7,10,18 Considering an expected reduction in 25% in infarct size, an average infarct size of 25% of the total LV mass, and an SD of 10%, we calculated a total sample size of 64 patients for α = 0.05 and β = 0.20, in a two-tailed test. To compensate for patient dropout, a total of 78 patients were planned to be recruited. The results are expressed as mean ± SD or median, depending on normal distribution as assessed by the Shapiro–Wilks test. Comparisons between groups were performed using unpaired t-test or Mann–Whitney U-test for continuous variables and χ2 or Fisher's exact test for categorical variables. To identify changes between study groups over the follow-up period, a repeated-measures ANOVA was used. To compare the relationship between the area at risk and the infarct size, a regression analysis was performed with treatment modality as a fixed factor. Results were considered statistically significant at a P-value of <0.05. A random sample of 30 baseline studies was selected to assess the intra- and interobserver variability in infarct size quantification. For this purpose, two distant measures were performed by the main observer and repeated by an additional operator. Similarly, the corresponding angiograms of the selected cases were re-evaluated by an experienced angiographer at the study completion to assess the intraobserver variability for the angiographic area-at-risk evaluation. The intraclass correlation coefficient and corresponding 95% confidence intervals were computed for all intra- and interobserver measurements. Statistical analyses were done using SPSS package v14.0 (Chicago, IL, USA).

Results

Study population and treatment assignment

From October 2006 to September 2009, 638 patients underwent primary or rescue PCI for evolving (<12 h) STEMI. Of these, 559 were not eligible due to the following: symptoms >12 h (2.5%), previous MI (10.1%), pre-PCI TIMI flow >1 (29.8%), non-culprit vessel disease (13.2%), cardiogenic shock (2.2%), Rentrop's collateral flow >1 (21.3%) and contraindication for ce-MRI or refused protocol (8.5%). In total, we included 79 (12.4%) patients (62 men and 17 women) aged 59.6 ± 11.7 years. After randomization, 39 patients were allocated to p-cond and the remaining 40 to the control group (Figure 1). There were no crossovers. The two study groups were well balanced in relation to baseline clinical characteristics (Table 1), as well as angiographic data (Table 2).

Table 1

Baseline characteristics of the study population

 Postconditioning (n= 39) Controls (n= 40) P-valuea 
Age (years) 59 ± 11.3 60 ± 12.2 0.68 
Gender (% males) 84 72 0.19 
Smokers (%) 51 62 0.31 
Hypertension (%) 49 50 0.91 
Dyslipidaemia (%) 44 35 0.43 
Diabetes (%) 23 17 0.53 
Peripheral artery disease (%) 2.8 0.31 
Body mass index (kg/m227.3 ± 4.1 28.0 ± 4.4 0.77 
Preinfarct angina pectoris (%) 13 12 0.72 

 
Treatment before admission (%) 
 ASA or clopidogrel 15 0.14 
 β-Blockers 26 26 
 Statins 20 18 0.77 
 ACE-inhibitors 13 21 0.36 
 Postconditioning (n= 39) Controls (n= 40) P-valuea 
Age (years) 59 ± 11.3 60 ± 12.2 0.68 
Gender (% males) 84 72 0.19 
Smokers (%) 51 62 0.31 
Hypertension (%) 49 50 0.91 
Dyslipidaemia (%) 44 35 0.43 
Diabetes (%) 23 17 0.53 
Peripheral artery disease (%) 2.8 0.31 
Body mass index (kg/m227.3 ± 4.1 28.0 ± 4.4 0.77 
Preinfarct angina pectoris (%) 13 12 0.72 

 
Treatment before admission (%) 
 ASA or clopidogrel 15 0.14 
 β-Blockers 26 26 
 Statins 20 18 0.77 
 ACE-inhibitors 13 21 0.36 

ASA, aspirin; ACE, angiotensin-converting enzyme.

aP-value assessed by χ2 (gender, smokers, hypertension, dyslipidaemia, and diabetes), Fisher's test (peripheral artery disease, preinfarct angina pectoris and treatment before admission), and t-test (age and body mass index).

Table 2

Clinical, electrocardiographic, angiographic, and intraprocedural treatment data

 Postconditioning (n= 39) Controls (n= 40) P-valuea 
Admission haemodynamics 
 Systolic blood pressure (mmHg) 135.7 ± 34.3 131.1 ± 26.9 0.51 
 Diastolic blood pressure (mmHg) 80.2 ± 23.2 79.8 ± 18.1 0.93 
 Heart rate (b.p.m.) 79 ± 18.8 69.2 ± 18.7 0.02 

 
Killip I at admission (%) 87 85 0.90 
Ischaemia time (min) 
Symptoms-to-balloon: mean/median (min) 326 ± 180/262 330 ± 211/235 0.91 
AMI location: anterior (%) 51 45 0.59 
Primary/rescue PCI (%) 92/8 88/12 0.48 

 
Admission ECG 
Mean ST-elevation (mm) 2.7 ± 1.3 2.44 ± 1  
Angiographic area at risk (% of the LV) 32.2 ± 11.5 31.1 ± 8.9 0.66 
Culprit artery (LAD/RCA) (%) 51/39 45/47 0.59 
Pre-PCI TIMI 0 (%) 100 93 0.08 
Direct stenting (%) 61 55 0.62 
Aspiration (%) 13 22 0.26 

 
Additional medical treatment (%) 
 Intracoronary nitroglycerin 92 85 0.30 
 Intracoronary adenosine 43 37 0.55 
 Postconditioning (n= 39) Controls (n= 40) P-valuea 
Admission haemodynamics 
 Systolic blood pressure (mmHg) 135.7 ± 34.3 131.1 ± 26.9 0.51 
 Diastolic blood pressure (mmHg) 80.2 ± 23.2 79.8 ± 18.1 0.93 
 Heart rate (b.p.m.) 79 ± 18.8 69.2 ± 18.7 0.02 

 
Killip I at admission (%) 87 85 0.90 
Ischaemia time (min) 
Symptoms-to-balloon: mean/median (min) 326 ± 180/262 330 ± 211/235 0.91 
AMI location: anterior (%) 51 45 0.59 
Primary/rescue PCI (%) 92/8 88/12 0.48 

 
Admission ECG 
Mean ST-elevation (mm) 2.7 ± 1.3 2.44 ± 1  
Angiographic area at risk (% of the LV) 32.2 ± 11.5 31.1 ± 8.9 0.66 
Culprit artery (LAD/RCA) (%) 51/39 45/47 0.59 
Pre-PCI TIMI 0 (%) 100 93 0.08 
Direct stenting (%) 61 55 0.62 
Aspiration (%) 13 22 0.26 

 
Additional medical treatment (%) 
 Intracoronary nitroglycerin 92 85 0.30 
 Intracoronary adenosine 43 37 0.55 

AMI, acute myocardial infarction; PCI, percutaneous coronary intervention; LV, left ventricle; LAD, left anterior descending artery; RCA, right coronary artery; TIMI, thrombolysis in myocardial infarction.

aP-value assessed by χ2 (Killip I at admission, AMI location, primary/rescue PCI, culprit artery, pre-PCI TIMI 0, direct stenting, aspiration, and additional medical treatment), t-test (admission haemodynamics and angiographic area at risk), and Mann–Whitney U-test ( ischaemia time).

Figure 1

Flow diagram. PCI, percutaneous coronary intervention; LVEF, left ventricular ejection fraction; ce-CMR, contrast-enhanced cardiac magnetic resonance; ICD, implantable cardiac defibrillator; AMI, acute myocardial infarction.

Figure 1

Flow diagram. PCI, percutaneous coronary intervention; LVEF, left ventricular ejection fraction; ce-CMR, contrast-enhanced cardiac magnetic resonance; ICD, implantable cardiac defibrillator; AMI, acute myocardial infarction.

Infarct size and myocardial salvage

The first ce-CMR was performed at 6.8 ± 3.3 days after MI. As shown in Figure 1, the baseline study could not be done in nine patients (imaging quality was poor in two obese patients and seven patients presented claustrophobia). In other four patients, the quality of the study was valid for LVEF and LV volume evaluation but not for infarct size measurements. Six-month ce-CMR was not possible in eight patients (two died, four needed an implantable cardiac defibrillator or pacemaker, and two refused follow-up).

No significant differences in infarct size were found between study groups (Table 3). In addition, the regression analysis in which the final infarct size was related to the area at risk did not show significant differences among groups (Figure 2).

Table 3

Reperfusion, myocardial salvage, infarct size, and left ventricle function outcomes

 Postconditioning (n= 39) Controls (n= 40) P-valueb 
Angiographic results 
 TIMI 3 post-PCI (%) 89 90 0.97 
 MBG ≤2 post-PCI (%) 56 48 0.63 

 
Cardiac biomarkers peak 
 CK (ng/mL) 3909 ± 485 3122 ± 379 0.20 
 CK-MB (ng/mL) 251 ± 28.9 195 ± 17.6 0.10 
 Troponin I (ng/mL) 299 ± 72 148 ± 23.8 0.05 
ECG resolution (%) 67 ± 4.2 64 ± 3.9 0.57 

 
Echocardiograpy (3–7 days) 
 LV end-diastolic diameter (mm) 54.4 ± 3.7 52.8 ± 4.4 0.11 
 LV end-systolic diameter (mm) 36.3 ± 4.8 36 ± 6.6 0.84 
 LV ejection fraction (%) 42.7 ± 9.8 43.7 ± 8.9 0.63 

 
ce-CMR (7 days)ª 
 LV end-diastolic volume (mL) 158.7 ± 35.7 152.5 ± 40.9 0.53 
 LV end-systolic volume (mL) 90 ± 34.8 82.7 ± 27.2 0.28 
 LV ejection fraction (%) 43.6 ± 13.1 46.7 ± 8.6 0.22 
 Angiographic area at risk (% LV mass) 32.2 ± 11.5 31.1 ± 8.9 0.66 
 Infarct size (% of LV mass) 27.5 ± 17.2 22.1 ± 10.2 0.11 
 Myocardial salvage (% LV mass) 4.1 ± 7.2 9.1 ± 5.8 0.004 
 Myocardial salvage index (% AAR) 18.9 ± 27.4 30.9 ± 20.5 0.038 
 Microvascular obstruction (%) 58 53 0.66 

 
Echocardiography (6 months) 
 LV end-diastolic diameter (mm) 55.6 ± 4 54.3 ± 4.2 0.11 
 LV end-systolic diameter (mm) 36.7 ± 4.8 35.4 ± 4.1 0.95 
 LV ejection fraction (%) 44.3 ± 10.4 47.5 ± 9.1 0.28 

 
ce-CMR (6 months)ª 
 LV end-diastolic volume (mm) 168.8 ± 42.9 174.4 ± 41.2 0.82 
 LV end-systolic volume (mm) 91.7 ± 40.3 88.3 ± 32.1 0.70 
 LV ejection fraction (%) 47.5 ± 12.8 50.3 ± 9.9 0.44 
 Infarct size (% of LV mass) 21.8 ± 13.2 18.7 ± 10.6 0.37 
 Postconditioning (n= 39) Controls (n= 40) P-valueb 
Angiographic results 
 TIMI 3 post-PCI (%) 89 90 0.97 
 MBG ≤2 post-PCI (%) 56 48 0.63 

 
Cardiac biomarkers peak 
 CK (ng/mL) 3909 ± 485 3122 ± 379 0.20 
 CK-MB (ng/mL) 251 ± 28.9 195 ± 17.6 0.10 
 Troponin I (ng/mL) 299 ± 72 148 ± 23.8 0.05 
ECG resolution (%) 67 ± 4.2 64 ± 3.9 0.57 

 
Echocardiograpy (3–7 days) 
 LV end-diastolic diameter (mm) 54.4 ± 3.7 52.8 ± 4.4 0.11 
 LV end-systolic diameter (mm) 36.3 ± 4.8 36 ± 6.6 0.84 
 LV ejection fraction (%) 42.7 ± 9.8 43.7 ± 8.9 0.63 

 
ce-CMR (7 days)ª 
 LV end-diastolic volume (mL) 158.7 ± 35.7 152.5 ± 40.9 0.53 
 LV end-systolic volume (mL) 90 ± 34.8 82.7 ± 27.2 0.28 
 LV ejection fraction (%) 43.6 ± 13.1 46.7 ± 8.6 0.22 
 Angiographic area at risk (% LV mass) 32.2 ± 11.5 31.1 ± 8.9 0.66 
 Infarct size (% of LV mass) 27.5 ± 17.2 22.1 ± 10.2 0.11 
 Myocardial salvage (% LV mass) 4.1 ± 7.2 9.1 ± 5.8 0.004 
 Myocardial salvage index (% AAR) 18.9 ± 27.4 30.9 ± 20.5 0.038 
 Microvascular obstruction (%) 58 53 0.66 

 
Echocardiography (6 months) 
 LV end-diastolic diameter (mm) 55.6 ± 4 54.3 ± 4.2 0.11 
 LV end-systolic diameter (mm) 36.7 ± 4.8 35.4 ± 4.1 0.95 
 LV ejection fraction (%) 44.3 ± 10.4 47.5 ± 9.1 0.28 

 
ce-CMR (6 months)ª 
 LV end-diastolic volume (mm) 168.8 ± 42.9 174.4 ± 41.2 0.82 
 LV end-systolic volume (mm) 91.7 ± 40.3 88.3 ± 32.1 0.70 
 LV ejection fraction (%) 47.5 ± 12.8 50.3 ± 9.9 0.44 
 Infarct size (% of LV mass) 21.8 ± 13.2 18.7 ± 10.6 0.37 

LV, left ventricle; MBG, myocardial blush grade; CK, creatinine kinase; PCI, percutaneous coronary intervention; AAR, area at risk; ce-CMR, contrast-enhanced cardiac magnetic resonance.

ªSample size force-CMR was 70 (36 controls and 34 p-cond) and 62 (31 controls and 31 p-cond) at 1 week and 6 months, respectively.

bP-value assessed by χ2 (angiographic results and microvascular obstruction), t-test (angiographic area at risk, ECG resolution, echocardiographic diameters, echocardiographic ejection fraction, ce-CMR volumes, CMR ejection fraction, and myocardial salvage), and Mann–Whitney U-test (cardiac biomarkers and CMR infarct size).

Figure 2

Infarct size vs. area at risk. Infarct size as a percentage of the total left ventricular mass was plotted against the myocardium area at risk depicted by the BARI score. The line for the postconditioning group does not differ significantly from the line for the controls (P= 0.129). In both groups, the infarct size correlates with the area-at-risk (r2 = 0.847 and 0.686, respectively). P-value assessed by regression analysis with treatment modality as a fixed factor. r2 obtained from two separate simple linear regression models.

Figure 2

Infarct size vs. area at risk. Infarct size as a percentage of the total left ventricular mass was plotted against the myocardium area at risk depicted by the BARI score. The line for the postconditioning group does not differ significantly from the line for the controls (P= 0.129). In both groups, the infarct size correlates with the area-at-risk (r2 = 0.847 and 0.686, respectively). P-value assessed by regression analysis with treatment modality as a fixed factor. r2 obtained from two separate simple linear regression models.

Left ventricular diameters and volumes as well as LVEF were similar in both groups at 1 week and 6 months as assessed by ce-CMR and echocardiography (Table 3). In contrast with p-cond, control patients presented a significant LVEF improvement between the first week and the sixth month after MI (46.71 ± 8.6% at 1 week vs. 50.32 ± 9.8% at 6 months; P= 0.01) (Figure 3). However, this difference became not significant when measuring the absolute change in LVEF (2.25 ± 6.1% in the p-cond group vs. 4.08 ± 8.3% in the control group; P= 0.35).

Figure 3

Left ventricular ejection fraction improvement (assessed in contrast-enhanced cardiac magnetic resonance). In contrast with postconditioning, patients allocated to the control group presented significant improvement of left ventricular ejection fraction between the first week and the sixth month after myocardial infarction. P-value assessed by repeated measures ANOVA. LVEF, left ventricular ejection fraction.

Figure 3

Left ventricular ejection fraction improvement (assessed in contrast-enhanced cardiac magnetic resonance). In contrast with postconditioning, patients allocated to the control group presented significant improvement of left ventricular ejection fraction between the first week and the sixth month after myocardial infarction. P-value assessed by repeated measures ANOVA. LVEF, left ventricular ejection fraction.

As shown in Figure 4, p-cond was associated with a lower myocardial salvage (4.1 ± 7.2 vs. 9.1 ± 5.8% in the control group; P= 0.004) and lower MSI (18.9 ± 27.4 vs. 30.9 ± 20.5% in the control group; P= 0.038). The results were homogeneous for all major studied subgroups: p-cond was also associated with a lower myocardial salvage after excluding patients with symptoms-to-balloon time >6 h, rescue PCI, and without direct stenting (Table 4). The group of patients with very short ischaemic times (symptoms-to-balloon time ≤3 h) also presented similar outcomes (Table 4).

Table 4

Contrast-enhanced cardiac magnetic resonance outcomes at 7 days in different subgroups of patients

 Postconditioning Controls P-value 
All patients 
 n 34 36  
 LV ejection fraction (%) 43.6 ± 13.1 46.7 ± 8.6 0.22 
 Angiographic area at risk (% of the LV) 32.2 ± 11.5 31.1 ± 8.9 0.66 
 Infarct size (% of LV mass) 27.5 ± 17.2 22.1 ± 10.2 0.11 
 Myocardial salvage (% LV mass) 4.1 ± 7.2 9.1 ± 5.8 0.004 
 Myocardial salvage index (% AAR) 18.9 ± 27.4 30.9 ± 20.5 0.038 

 
Patients with symptoms-to-balloon time ≤3 h 
n 10  
 LV ejection fraction (%) 44.2 ± 12.1 44.6 ± 12.5 0.94 
 Angiographic area at risk (% of the LV) 36 ± 9.1 33 ± 9.2 0.45 
 Infarct size (% of LV mass) 27.3 ± 17.9 23.1 ± 12.7 0.53 
 Myocardial salvage (% LV mass) 6.4 ± 3.9 10.6 ± 7.1 0.21 
 Myocardial salvage index (% AAR) 22.5 ± 17.2 35.8 ± 26.7 0.29 

 
Patients with symptoms-to-balloon time ≤6 h 
n 28 34  
 LV ejection fraction (%) 43.5 ± 13.8 47.1 ± 8.5 0.22 
 Angiographic area at risk (% of the LV) 33.6 ± 11.4 32 ± 8.3 0.58 
 Infarct size (% of LV mass) 27.2 ± 17.4 21.9 ± 10.5 0.15 
 Myocardial salvage (% LV mass) 4 ± 7.5 9 ± 5.9 0.006 
 Myocardial salvage index (% AAR) 19.2 ± 29 31.1 ± 21 0.07 

 
Patients with primary PCI 
n 30 31  
 LV ejection fraction (%) 43 ± 13.5 46.5 ± 9.2 0.24 
 Angiographic area at risk (% of the LV) 31.9 ± 11.6 30.9 ± 9.2 0.69 
 Infarct size (% of LV mass) 26.9 ± 16.5 21.1 ± 10.3 0.10 
 Myocardial salvage (% LV mass) 4.1 ± 6.8 9.7 ± 5.9 0.002 
 Myocardial salvage index (% AAR) 18.7 ± 27.0 33.3 ± 21.0 0.02 

 
Patients with direct stenting 
n 22 21  
 LV ejection fraction (%) 42.3 ± 14.9 47.2 ± 6.7 0.16 
 Angiographic area at risk (% of the LV) 34.3 ± 11.8 32.1 ± 8.2 0.44 
 Infarct size (% of LV mass) 30.9 ± 17 22.9 ± 9.7 0.07 
 Myocardial salvage (% LV mass) 3.3 ± 7.5 9.2 ± 6.4 0.01 
 Myocardial salvage index (% AAR) 14.0 ± 25.8 29.3 ± 20.9 0.04 

 
Patients with symptoms-to-balloon time ≤6 h, primary PCI and direct stenting 
n 19 17  
 LV ejection fraction (%) 40.9 ± 14.6 47.4 ± 7.5 0.11 
 Angiographic area at risk (% of the LV) 36 ± 10.3 31.9 ± 7.9 0.21 
 Infarct size (% of LV mass) 30.3 ± 15.3 20.9 ± 9.3 0.04 
 Myocardial salvage (% LV mass) 3.5 ± 6.8 10 ± 6.7 0.01 
 Myocardial salvage index (% AAR) 13.5 ± 23.7 32.5 ± 21.7 0.02 
 Postconditioning Controls P-value 
All patients 
 n 34 36  
 LV ejection fraction (%) 43.6 ± 13.1 46.7 ± 8.6 0.22 
 Angiographic area at risk (% of the LV) 32.2 ± 11.5 31.1 ± 8.9 0.66 
 Infarct size (% of LV mass) 27.5 ± 17.2 22.1 ± 10.2 0.11 
 Myocardial salvage (% LV mass) 4.1 ± 7.2 9.1 ± 5.8 0.004 
 Myocardial salvage index (% AAR) 18.9 ± 27.4 30.9 ± 20.5 0.038 

 
Patients with symptoms-to-balloon time ≤3 h 
n 10  
 LV ejection fraction (%) 44.2 ± 12.1 44.6 ± 12.5 0.94 
 Angiographic area at risk (% of the LV) 36 ± 9.1 33 ± 9.2 0.45 
 Infarct size (% of LV mass) 27.3 ± 17.9 23.1 ± 12.7 0.53 
 Myocardial salvage (% LV mass) 6.4 ± 3.9 10.6 ± 7.1 0.21 
 Myocardial salvage index (% AAR) 22.5 ± 17.2 35.8 ± 26.7 0.29 

 
Patients with symptoms-to-balloon time ≤6 h 
n 28 34  
 LV ejection fraction (%) 43.5 ± 13.8 47.1 ± 8.5 0.22 
 Angiographic area at risk (% of the LV) 33.6 ± 11.4 32 ± 8.3 0.58 
 Infarct size (% of LV mass) 27.2 ± 17.4 21.9 ± 10.5 0.15 
 Myocardial salvage (% LV mass) 4 ± 7.5 9 ± 5.9 0.006 
 Myocardial salvage index (% AAR) 19.2 ± 29 31.1 ± 21 0.07 

 
Patients with primary PCI 
n 30 31  
 LV ejection fraction (%) 43 ± 13.5 46.5 ± 9.2 0.24 
 Angiographic area at risk (% of the LV) 31.9 ± 11.6 30.9 ± 9.2 0.69 
 Infarct size (% of LV mass) 26.9 ± 16.5 21.1 ± 10.3 0.10 
 Myocardial salvage (% LV mass) 4.1 ± 6.8 9.7 ± 5.9 0.002 
 Myocardial salvage index (% AAR) 18.7 ± 27.0 33.3 ± 21.0 0.02 

 
Patients with direct stenting 
n 22 21  
 LV ejection fraction (%) 42.3 ± 14.9 47.2 ± 6.7 0.16 
 Angiographic area at risk (% of the LV) 34.3 ± 11.8 32.1 ± 8.2 0.44 
 Infarct size (% of LV mass) 30.9 ± 17 22.9 ± 9.7 0.07 
 Myocardial salvage (% LV mass) 3.3 ± 7.5 9.2 ± 6.4 0.01 
 Myocardial salvage index (% AAR) 14.0 ± 25.8 29.3 ± 20.9 0.04 

 
Patients with symptoms-to-balloon time ≤6 h, primary PCI and direct stenting 
n 19 17  
 LV ejection fraction (%) 40.9 ± 14.6 47.4 ± 7.5 0.11 
 Angiographic area at risk (% of the LV) 36 ± 10.3 31.9 ± 7.9 0.21 
 Infarct size (% of LV mass) 30.3 ± 15.3 20.9 ± 9.3 0.04 
 Myocardial salvage (% LV mass) 3.5 ± 6.8 10 ± 6.7 0.01 
 Myocardial salvage index (% AAR) 13.5 ± 23.7 32.5 ± 21.7 0.02 

PCI, percutaneous coronary intervention; LV, left ventricle; AAR, area at risk.

Figure 4

Myocardial salvage and myocardial salvage index. Patients assigned to postconditioning presented a lower myocardial salvage (left figure) and lower myocardial salvage index (right figure) compared with control subjects. P-value assessed by t-test.

Figure 4

Myocardial salvage and myocardial salvage index. Patients assigned to postconditioning presented a lower myocardial salvage (left figure) and lower myocardial salvage index (right figure) compared with control subjects. P-value assessed by t-test.

Other endpoints

Angiographic outcomes measured by TIMI and MBG post-angioplasty and ECG resolution at 90 min showed similar results in both groups. Troponin I peak release was higher in the p-cond group (299 ± 72 vs. 148 ± 23.8 ng/mL in controls; P= 0.05); no significant differences in CK and CK-MB peak were observed (Table 3).

Clinical outcomes

In the control group, there was one in-hospital death, secondary to progressive heart failure. One patient in the p-cond group died due to stent thrombosis 4 months after the index event. Three other patients (one control and two p-cond patients) were readmitted for heart failure within 6 months.

Infarct size and area-at-risk variability

The intra- and interobserver intraclass correlation coefficients for infarct size were 0.97 (0.95–0.99) and 0.95 (0.91–0.97), respectively. The intraobserver intraclass correlation coefficient for the angiographic area at risk was 0.98 (0.96–0.99) and 0.97 (0.95–0.98) between the two observers.

Discussion

This prospective, randomized, controlled trial using short- and long-term ce-MRI assessment failed to show cardioprotective effects of p-cond on infarct size and LVEF during primary PCI for STEMI. In addition, the results even suggest a potential harmful effect, given our observation of a significant reduction in myocardial salvage and MSI in the p-cond group.

Previous pilot studies have shown a 27–40% infarct size reduction with p-cond as assessed by CK release7,10,11 and myocardial scintigraphy.10,11 Lønborg et al.12 published the first clinical trial evaluating p-cond effects with a highly reproducible and accurate imaging technique like the ce-CMR. Although no difference in absolute infarct size was observed, patients with p-cond had a 18% relative reduction in infarct size, an effect two times lower than previously estimated.7,10,11 More recently, and in agreement with our results, Sörensson et al.13 did not observe differences in infarct size reduction using ce-CMR and suggested a possible valuable effect only in subjects with large areas at risk. However, the role of important confounding factors, namely the presence of collaterals, non-culprit vessel coronary artery disease, and direct stenting usage, was not generally taken into account, representing main limitations for both previous trials. The design of our study solved part of these limitations since all patients with Rentrop's collateral flow ≥1 or patent IRA (initial TIMI flow ≥2) were excluded. Using the same methodology of our study, a previous report found the presence of collaterals and initial TIMI flow to be major determinants of myocardial salvage.19 Exclusion of patients with residual flow in the area at risk may explain the large infarct sizes and the diminished amount of myocardial salvage when compared with other studies. In order to further decrease interference of confounding factors, we also excluded patients with significant non-culprit artery disease or previous MI, which could interfere with infarct size assessment. Patients with a symptom-to-balloon time between 6 and 12 h were not excluded, since p-cond has shown persistent protection even after delayed reperfusion20 and previous studies have reported similar ischaemic times.7,8,10,11 Nevertheless, after excluding from analysis patients with a symptom-to-balloon time >6 h, the results of the study did not change. Although the study was not powered for the subgroup analysis, we also observed that even in the subgroup of early comers (ischaemic times ≤3 h), there was no sign of benefit in infarct size or myocardial salvage with p-cond.

It is difficult to determine whether the present results are mainly due to study limitations or show the actual variability of p-cond effects. In agreement with our results, some studies performed in animals have failed to show infarct size reduction with p-cond21–24 even after short ischaemic times25,26 and following the same inflation–deflation protocol.27 Other sequences with longer9 or shorter12 inflation–deflation periods have been described in other clinical studies with positive results. Relevant co-morbidities, most notably ageing and diabetes, have also been reported as limiting factors for p-cond benefits in animal models.28,29 We used the same p-cond protocol applied by Staat et al. in the first p-cond clinical trial (four episodes of 1 min inflation and 1 min deflation). However, in contrast with their results, we did not observe any beneficial effect with p-cond. There are several factors to take into account when interpreting these opposing results. First, we did not exclude patients with ischaemic times >6 h. Second, distinct measures of infarct size were used in both studies, which precludes any direct comparison. Cardiac enzyme release into the blood stream can be affected by the perfusion status at the tissue level, especially when a distinct reperfusion strategy is being tested. Anatomical estimates of infarct size by SPECT or CMR are the preferred method when evaluating reperfusion strategies, since they are not affected by the perfusion status at the tissue level. Third, the percentage of patients who underwent direct stenting was vastly different between our study (58%) and the one performed by Staat et al. (100%). Direct stenting is one of the recommended strategies to reduce the embolic risk.30 Nevertheless, even with direct stenting, the risk of embolization after repeated balloon inflations remains unclear. Lønborg et al.12 stated that the absence of direct stenting could be one of the main reasons for their results. In our series, we did not find any differences between patients with or without direct stenting. Furthermore, the use of direct stenting in all STEMI patients with a TIMI 0 flow in the IRA is often not feasible because no distal anatomical reference could be inferred. Finally, although the other relevant demographic characteristics as well as the main determinants of infarct size like IRA or ischaemic time were similar to previous reports yielding positive results,7 the prevalence of diabetic patients in our study was higher than in those of Staat et al.,7 Thibault et al.,11 and Lønborg12 and this also might have contributed to explain our results.

The existence of a trend towards a higher degree of ST-segment elevation at admission in the p-cond group may be seen as a limitation, as it could be considered a surrogate of a larger infarct risk area. Nevertheless, we did not detect any difference in angiographic area at risk, STEMI location, or symptom-to-balloon time between groups. Our results cannot be explained neither by the lack of imaging technique accuracy. Contrast-enhanced cardiac magnetic resonance is considered the most accurate and reproducible imaging technique for infarct size evaluation.31,32 Furthermore, all other infarct size surrogate measurements presented consistent agreement with the ce-CMR results. No differences in ECG resolution, angiographic outcomes, or CK and CK-MB peak were observed, except for a higher troponin I peak in the p-cond group.

Long-term effects of p-cond were also analysed with ce-CMR and echocardiography after 6 months. Previous published data reported p-cond benefits with infarct size reduction assessed by SPECT at 6 months and LVEF improvement measured with echocardiography at 1 year.11 Our study, the first ever to employ ce-CMR in evaluating the long-term effects of p-cond, failed to demonstrate any significant long-term benefit. No differences in LVEF have also been reported in other studies.10,12,13

Postconditioning has also been linked to reduced microvascular dysfunction after STEMI. In the present study, no significant improvement in angiographic MBG and ce-CMR microvascular obstruction was observed in patients who underwent p-cond. The loss of p-cond benefit on microvascular function as a result of a higher rate of induced coronary embolization could be an explanation. Thrombectomy devices might represent a good alternative to reduce the incidence of distal embolization. In our series, the use of aspiration devices, although similar in both groups, was low (17%) because they may interfere with the p-cond protocol that should be implemented within 1min after coronary reperfusion. Conversely, starting with a p-cond sequence before thrombus aspiration would reduce thrombectomy benefits. Of note, the results of our study did not vary after excluding patients who underwent thrombectomy.

The use of pharmacological agents to emulate p-cond effects without requiring a mechanical intervention poses another alternative that would avoid the potential risk of embolization and allow a non-restricted aspiration sequence. Inhibition of a mitochondrial permeability-transition pore seems to be the main underlying mechanism for p-cond benefits.33 Cyclosporine, which also inhibits the opening of mitochondrial permeability-transition pores, has shown very promising results in a recent published clinical trial.34 Further studies will be required to know whether pharmacological strategies could have the same effect as mechanical p-cond.

Study limitations

There are several limitations to this study that need to be addressed. First, nine patients at baseline and eight patients at 6 months did not undergo ce-CMR for various reasons. Second, myocardium area at risk was calculated with an angiographic score (BARI score). Although, this method has been previously validated,17 scintigraphy is still considered the gold standard for measuring area at risk, although its application remains difficult, especially in an acute setting. Additionally, T2-weighted CMR to measure the area at risk is not an appropriate technique in this setting since any intervention aimed to reduce infarct size also reduces reperfusion oedema. Third, the use of intracoronary nitroglycerin or adenosine could modify reperfusion outcomes. However, both groups were very well balanced and this potential limitation reflects daily practice, where both drugs are commonly used during primary PCI. Finally, although this is the second largest cohort of patients studied to date, sample size is still relatively small.

Conclusion

In contrast with the previous work, our study suggests that p-cond during primary PCI fails to improve reperfusion and reduce MI size. In addition, p-cond could even have a potential harmful effect, given that lower myocardial salvage was observed. Future research will be necessary to determine whether our results show the actual variability of p-cond effects during STEMI.

Funding

This work was supported by the Spanish Society of Cardiology and the Hospital Clinic of Barcelona.

Conflict of interest: none declared.

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