534310 research-article2014

VMJ0010.1177/1358863X14534310Vascular MedicineDwyer et al.

Original Article

Ischemic postconditioning does not improve peripheral endothelial function in ST-segment elevation myocardial infarction patients

Vascular Medicine 2014, Vol. 19(3) 160­–166 © The Author(s) 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/1358863X14534310 vmj.sagepub.com

Nathan B Dwyer, Darlene Hilland, Mouhieddin Traboulsi and Todd J Anderson

Abstract The purpose of this study was to determine whether ischemic postconditioning (IPC) could improve peripheral endothelial function in patients with acute ST-segment elevation myocardial infarction (STEMI) undergoing primary percutaneous coronary intervention (PCI). Of 102 patients randomly assigned to an IPC or standard protocol to study infarct size utilizing cardiovascular magnetic resonance imaging, 84 patients had peripheral endothelial function assessed with brachial ultrasound measures and peripheral arterial tonometry (PAT) during reactive hyperemia 3 days after PCI. Overall IPC was not associated with a smaller infarct size compared to controls, though there was a trend towards greater myocardial salvage with IPC. Patients randomized to IPC (n=43; age 56 ± 11 years; 85% male) and standard protocol (n=41; age 56 ± 10 years; 88% male) underwent endothelial function assessment. Flow mediated vasodilatation was not significantly greater in the IPC group than in the standard group (7.4 ± 4.9% versus 6.6 ± 4.0% respectively, p=0.40) nor was peak hyperemic velocity-time integral (78 ± 26 cm versus 71 ± 30 cm respectively, p=0.28). Similarly, the PAT hyperemic ratio was not significantly greater in the IPC group than in the standard group (2.0 ± 0.9 versus 1.8 ± 0.6 respectively, p=0.14). In conclusion, IPC did not improve early peripheral endothelial function in patients with STEMI undergoing primary PCI. Keywords endothelial function, flow mediated vasodilatation, peripheral arterial tonometry, postconditioning, reperfusion injury

Introduction The endothelium plays a vital role in the regulation of vascular tone and protection from atherosclerosis.1 The acute increases in oxidative stress and pro-inflammatory markers following myocardial infarction have been shown to have detrimental effects on peripheral endothelial function.2–4 Coronary endothelial dysfunction is related to peripheral vasodilatory dysfunction, allowing peripheral endothelial function to be a surrogate measure of coronary endothelial function.5,6 Ischemic postconditioning (IPC), a sequence of brief repeated episodes of ischemia-reperfusion applied before allowing permanent reperfusion, has demonstrated marked cardioprotective effects in animal models of myocardial ischemia.7 It is recognized that IPC improves the coronary endothelial dysfunction that accompanies reperfusion injury in animals.8,9 However, there are only a limited number of studies that have evaluated the effect of IPC on measures of vascular function in humans. We have previously published data on the influence of IPC on myocardial salvage and infarct size in patients undergoing primary percutaneous coronary intervention (PCI) for

STEMI10 and hypothesized that those patients undergoing IPC would have improved endothelial function assessed utilizing the well established non-invasive tools of brachial artery ultrasound11 and finger arterial pulse wave amplitude.12

Methods This study was performed according to the Declaration of Helsinki and Canadian Guidelines of Good Clinical Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, Alberta, Canada Corresponding author: Dr. Nathan Dwyer Department of Cardiac Sciences and Libin Cardiovascular Institute of Alberta University of Calgary 1403-29th Street NW Calgary, T2N 2T9, Alberta Canada Email: [email protected]

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Dwyer et al. Practice. The Conjoint Ethics Committee of the University of Calgary approved the protocol (E20039). The study was registered with the Clinical Trials Protocol registration system (clinicaltrials.gov – NCT00334373). All patients gave written informed consent before enrolment.

Study design and post conditioning protocol Patients ≥ 18 years of age presenting within 6 hours of the onset of chest pain with ST-segment elevation undergoing primary PCI were considered for inclusion. Details of the inclusion and exclusion criteria have been published previously.10 This was conducted as a single centre, prospective, randomized trial with blinded evaluation of all endpoints. All patients received standard doses of antiplatelet and anticoagulation agents. After establishing reflow with guidewire passage or balloon inflation patients were randomized to standard PCI alone or IPC protocol utilizing a computerized 1:1 randomization 4 block sequence placed in a numbered sealed envelope. IPC was performed by 4 cycles of 30-second low pressure balloon inflations (4-6 atm) within the previously occluded segment each separated by 30 seconds of reflow. PCI was then performed according to the preferences of experienced operators.

Brachial artery ultrasound measurements Endothelial function was assessed 3 days following primary PCI after all vasoactive medicines were stopped for 24 hours. Subjects underwent assessment of brachial artery flow-mediated vasodilation as previously published by our group.13–15 Studies were performed in a quiet clinical laboratory with the temperature maintained at 21-23 °C. Subjects rested for at least 10 minutes before the first scan and remained supine throughout the study. Baseline longitudinal 2-dimensional images of the right brachial artery were acquired with a 7.5 MHz linear phase-arrayed ultrasound transducer attached to a Hewlett-Packard 5500 ultrasound machine. Pulse-wave Doppler was used to record brachial artery velocity. A blood pressure cuff was placed on the right lower arm with a 5-minute occlusion time. On cuff release, hyperemic velocity was recorded for 30 seconds, and 2-dimensional imaging was resumed for up to 2 minutes after cuff release. Analysis of the brachial artery images was performed in our core laboratory using automated edge detection software (DEA, Montreal PQ). During the procedure, 2 images were digitized during baseline from 5 seconds to 60 seconds. During reactive hyperemia, 2 arterial diameters were sampled starting 60 seconds after cuff release, and repeated every 10 seconds, ending at the 90 second mark, for a total of 8 images. Any poor quality images were discarded. The maximum dilation occurring between 60 and 90 seconds was determined. Flow-mediated vasodilatation (FMD) was calculated from the diameters as (reactive hyperemia – baseline)/baseline × 100%. The intra- and inter-observer variability in our laboratory is 1% for the measurement of baseline brachial artery diameter. Brachial artery flow was calculated as the product of velocity and cross-sectional arterial area.

Hyperemic velocity was determined as the peak velocitytime integral (VTI) of the first complete velocity envelope obtained after cuff release. Higher values represent better microvascular dilation. The co-efficient of variation for intra-observer variability for the measurement of VTI is 2%. Flow velocity (V) was converted to local shear stress (SS) using the following equation: SS = 8 × μ × V/D, where D is brachial artery diameter and μ was viscosity of blood, which was assumed to be 0.035 dyne.s.cm-2. The hyperemic ratio was determined for volumetric flow, VTI and SS compared to the respective baseline values.

Pulse wave amplitude measurements Finger pulse wave amplitude (PWA) was recorded with peripheral arterial tonometry (PAT) using a plethysmographic device (Itamar-Medical Inc., Caesaria, Israel).12 PAT testing was performed simultaneously with brachial ultrasound measures. One PAT finger probe was placed on the right index finger that would undergo hyperemia testing. Another probe was placed on the contralateral index finger. The PAT hyperemia ratio was defined as the ratio of the average PWA during the 1-minute period beginning 1-minute after reactive hyperemia compared with the average PWA during a 3.5-minute pre-occlusion baseline period. The PWA signal was fed to a personal computer, band-filtered (0.3 to 30 Hz), amplified, displayed, and analyzed with automated software that generates a PAT ratio and normalizes to the control arm to compensate for potential systemic changes.

Statistical analysis Continuous variables were reported as mean ± SD. Categorical data were reported as frequencies and percentages. Differences between groups were assessed by the chisquare test for categorical variables and by the non-paired Student’s t test for continuous data with normal distribution. Otherwise, the non-parametric Wilcoxon rank-sum test was used. All analysis was conducted using SPSS for Macintosh, version 19.0 (SPSS, Inc., Chicago, Illinois). A two-tailed p value of less than 0.05 was considered statistically significant.

Results Study population Of the 102 patients randomized in our original myocardial IPC study, 84 patients consented to participate in the endothelial function sub-study with 43 patients in the IPC group (age 56 ± 11 years, 85% male) and 41 patients in the standard group (age 56 ± 10 years, 88% male). The two groups were well balanced with regard to baseline demographic and angiographic characteristics (Table 1). A high proportion of patients had dyslipidemia, systemic hypertension, and were active smokers, but were balanced across both groups (Table 1). There was very high utilization of standard medical therapy prescribed post myocardial infarction (Table 2).

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Table 1.  Baseline characteristics.  

Standard (n = 41)

Postconditioning (n = 43)

P 

Age (yrs) Male Ethnicity   Caucasian   Middle Eastern   Asian Body Mass Index (kg.m-2) Diabetes Mellitus Hypertension Dyslipidemia Current Smoker Family History History Stroke Serum Creatinine (μ.L-1) Random Glucose (mmol.L-1) Total Cholesterol (mmol.L-1) LDL (mmol.L-1) HDL (mmol.L-1) Triglycerides (mmol.L-1) Multivessel Disease   1   2   3 LAD Culprit LVEF (%)

56 ± 10 36 (88)

56 ± 11 37 (86)

0.91 0.81

32 (78)   4 (10)   5 (12) 28 ± 5   3 (7) 14 (34) 13 (32) 17 (42) 17 (42)   1 (2) 87 ± 18 8.2 ± 4.0 4.6 ± 0.9 2.9 ± 0.6 1.1 ± 0.2 1.7 ± 1.0

36 (84)   4 (9)   3 (7) 29 ± 6   4 (9) 17 (40) 15 (35) 18 (42) 15 (35)   0 (0) 85 ± 18 7.5 ± 1.5 4.7 ± 0.9 3.0 ± 0.9 1.0 ± 0.3 1.6 ± 1.0

23 (56) 12 (29)   6 (15) 20 (49) 51 ± 10

30 (70)   5 (12)   8 (18) 21 (49) 56 ± 10

0.71     0.42 0.33 0.54 0.95 0.59 0.46 0.34 0.62 0.24 0.54 0.50 0.70 0.59   0.13     1.0 0.07

Values are mean ± SD or n (%). HDL, high density lipoprotein; LAD, left anterior descending; LDL, low density lipoprotein; LVEF, left ventricular ejection fraction.

Table 2.  Medical therapy utilized.                    

Aspirin Clopidogrel Beta Blocker ACE Inhibitor ARB Statin Warfarin CCB Nitrates

Standard (n = 41)

Postconditioning (n = 43)

P 

41 (100) 40 (98) 37 (90) 40 (98) 0 (0) 40 (98) 9 (22) 0 (0) 19 (46)

43 (100) 42 (98) 41 (95) 41 (95) 1 (2) 41 (95) 8 (19) 0 (0) 20 (47)

1.00 0.97 0.43 1.00 1.00 1.00 0.79 1.00 0.99

Values are n (%). ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; CCB, calcium channel blocker.

Endothelial function assessments Endothelial function assessment was performed 3.5 ± 1.3 days after PCI in the IPC group and 3.3 ± 1.1 days after PCI in the standard group (p = 0.40). The baseline and hyperemic brachial ultrasound measures are shown in Table 3. Resting brachial artery diameter was marginally but significantly smaller in the IPC group than the standard group (4.4 ± 0.8 mm versus 4.8 ± 0.6 mm respectively, p=0.02) and there was a trend towards lower resting brachial flow in the

IPC group (145 ± 53 ml.min-1 versus 183 ± 113 ml.min-1 respectively, p=0.06). The mean flow-mediated dilatation (FMD) in the IPC group was 7.4 ± 4.9 % as compared with 6.6 ± 4.0 % in the standard group, for a difference of 0.8% (95% confidence interval [CI], -1.1 to 2.8%, p = 0.40) (Figure 1). There was no difference in the absolute brachial artery diameter change with hyperemia between the IPC group (0.30 ± 0.18 mm) and standard groups (0.29 ± 0.18 mm), for a mean difference of 0.01 mm (95% CI, -0.07 to 0.08 mm, p=0.88). On multivariate regression analysis there was no significant interaction between the FMD response to IPC and age, gender, diabetes, hypertension, dyslipidemia, smoking, or family history of premature coronary artery disease. There was no difference in peak hyperemic VTI between the IPC and standard groups (77.7 ± 26.2 cm versus 70.9 ± 30.2 cm respectively, p=0.28) (Figure 2). Similarly, the hyperemic flow ratio, shear stress ratio, and VTI ratio were not greater in the IPC group than in the standard group (Table 2). Furthermore, the hyperemic PAT ratio was not statistically greater in the IPC group than in the standard group (2.0 ± 0.9 versus 1.8 ± 0.6 respectively, p=0.14) (Figure 1).

Discussion The present study demonstrates that myocardial IPC does not acutely improve peripheral endothelial function in

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Dwyer et al. Table 3.  Peripheral endothelial function parameters post PCI.   Rest   Systolic BP (mm Hg)   Diastolic BP (mm Hg)   Heart Rate (min-1)   Brachial Diameter (mm)   Flow (ml.min-1)   Shear Stress (dyne.cm-2)   VTI (cm) Hyperemia   Systolic BP (mm Hg)   Diastolic BP (mm Hg)   Heart Rate (min-1)   Brachial Diameter (mm)   Flow (ml.min-1)   Shear Stress (dyne.cm-2)   VTI (cm) FMD (%) Flow Ratio Shear Stress Ratio VTI Ratio PAT Ratio

Standard (n = 41)

Postconditioning (n = 43)

110 ± 10 70 ± 7 67 ± 12 4.8 ± 0.6 182 ± 113 10.0 ± 4.9 15.6 ± 8.2

112 ± 14 70 ± 10 63 ± 10 4.4 ± 0.8 145 ± 53 11.5 ± 7.9 15.9 ± 6.7

105 ± 10 68 ± 8 66 ± 13 5.1 ± 0.6 900 ± 366 45.0 ± 17.5 70.9 ± 30.2 6.6 ± 4.0 5.6 ± 2.1 5.0 ± 1.9 5.0 ± 1.9 1.8 ± 0.6

105 ± 16 67 ± 10 63 ± 10 4.7 ± 0.7 821 ± 285 54.9 ± 27.8 77.7 ± 26.2 7.4 ± 4.9 6.1 ± 2.3 5.3 ± 1.9 5.3 ± 1.8 2.0 ± 0.9

P    0.48 0.87 0.13 0.02 0.06 0.30 0.87   0.79 0.71 0.21 0.02 0.28 0.06 0.28 0.40 0.31 0.47 0.52 0.14

Values are mean ± SD or n (%). BP, blood pressure; FMD, flow mediated dilatation; PAT, peripheral arterial tonometry; PCI, percutaneous coronary intervention;VTI, velocity-time integral.

Figure 1.  Average flow mediated dilatation and PAT ratio for the postconditioned and standard groups.

FMD, flow mediated vasodilatation; PAT, peripheral arterial tonometry. Error bars are 95% confidence intervals.

patients undergoing PCI for STEMI. Several studies have explored the influence of IPC on endothelial function in human models of forearm ischemia-reperfusion (IR) injury with mixed results.16–18 In 11 healthy volunteers brachial FMD was measured before and after IR (20 minutes of arm ischemia followed by 20 minutes of reperfusion).16 IR caused endothelial dysfunction (FMD 9.1 ± 1.2% pre-IR, 3.6 ± 0.7% post-IR, p < 0.001), which was prevented by three 10-second cycles (FMD 9.9 ± 1.7% pre-IR, 8.3 ±

Figure 2.  Average hyperemic velocity time integral (VTI) for the postconditioned and standard groups. Error bars are 95% confidence intervals.

1.4% post-IR, p = NS) or three 30-second cycles of postconditioning (FMD 10.8 ± 1.7% pre-IR, 9.5 ± 1.5% postIR, p = NS). No protection was observed when the 10-second post-conditioning stimulus was delayed for 1 minute after the onset of reperfusion. These findings were confirmed in 9 healthy volunteers.17 However, in a small cross-over study of 10 healthy male volunteers post-conditioning did not limit the impaired FMD of the radial artery induced by 15 minutes of forearm ischemia.18 The post-conditioning protocol used was 3 cycles of 10 seconds of reperfusion separated by 20 seconds of brachial re-occlusion.

164 Only one previous study has specifically explored the influence of myocardial IPC on endothelial function in STEMI patients.19 In this single-center randomized study of 92 Chinese patients, the depressed brachial FMD was improved in those who had undergone coronary IPC. The IPC protocol was three cycles of 30-second reperfusion followed by 30-seconds of re-occlusion and FMD was assessed 1 day after PCI. The FMD in the standard, IPC, and healthy control group was 4.3 ± 3.7%, 9.8 ± 5.5% and 14.5 ± 3.4% respectively, p

Ischemic postconditioning does not improve peripheral endothelial function in ST-segment elevation myocardial infarction patients.

The purpose of this study was to determine whether ischemic postconditioning (IPC) could improve peripheral endothelial function in patients with acut...
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