Abstract
Background
Coronary no-reflow during primary percutaneous coronary intervention (PPCI) is a predictor of poorer cardiovascular outcome. Both endothelial dysfunction and no-reflow involves abnormal vascular function and hemostasis. Our aim was to assess the association between endothelial dysfunction and no reflow during primary PCI.
Methods
Thirty consecutive patients with ST elevation myocardial infarction (STEMI) and normal flow during primary PCI were compared to 19 consecutive patients who had no reflow. All subjects underwent assessment of peripheral endothelial function by reactive hyperemia index (RHI) 48–72 h post PCI using the EndoPAT device.
Results
Age, sex and hypertension were similar in both groups. Smokers were less likely to have no-reflow. Post PPCI there was less ST segment resolution in the no-reflow group (48% ± 7 vs. 81% ± 6; p = 0.001). Patients who had no reflow had subsequently lower ejection fraction (39% ± 10 vs. 47% ± 10; p = 0.015). There was no difference in vascular function (RHI), between the no-reflow and normal flow groups (1.91 ± 0.3 vs. 2.09 ± 0.11; p = 0.24).
Conclusions
Systemic peripheral endothelial function does not differ between STEMI patients with and without no reflow during primary PCI.
Highlights
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This study assessed the association between endothelial dysfunction and no reflow.
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Thirty consecutive patients with ST elevation myocardial infarction (STEMI) and normal flow were compared to 19 consecutive patients who had no reflow.
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Peripheral endothelial function was assessed by reactive hyperemia index (RHI) 48–72 h post procedure.
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Peripheral endothelial function does not differ between STEMI patients with and without no reflow during primary PCI.
1
Introduction
Primary percutaneous coronary intervention (PPCI) is established as the preferred reperfusion therapy for acute ST-elevation myocardial infarction (STEMI) and usually results in restoration of patency of the infarct related artery (IRA) . However, a subset of these patients demonstrate angiographic characteristics of delayed flow in the IRA despite its patency . This decoupling of successful coronary reperfusion and micro vascular reperfusion is recognized as Slow-Flow or No-Flow phenomenon . Slow flow occurs in 8%–11.5% of PPCI and in up to 2% in patients undergoing elective percutaneous coronary intervention (PCI) . The mechanism of slow flow is likely multifactorial and involves distal embolization of plaque and thrombus , platelets activation , localized inflammation , coronary micro vascular spasm and reperfusion injury . These factors may cause micro vascular endothelial dysfunction at the infarcted territory.
The endothelium plays a pivotal role as a regulator of micro vascular tone and local hemostasis. It reacts to various physical stimuli by micro vascular dilatation, primarily controlled by localized release of endothelial nitric oxide (eNO) In patients with stable coronary artery disease, coronary and peripheral endothelial dysfunction (ED) identifies subjects at high risk for cardio-vascular events . Microvascular coronary endothelial dysfunction is characterized by abnormal coronary flow . It is unknown if patients with systemic microvascular ED are more prone to have no-reflow in the coronary arteries when presenting with STEMI. The aim of this study was to evaluate systemic (peripheral) microvascular ED and its association to the occurrence of slow flow/no reflow, in patients who underwent PPCI for acute STEMI.
2
Methods
This was a prospective observational study performed at London Health Sciences Centre, London, Ontario, Canada, that examined the relationship between slow flow during primary PCI and microvascular endothelial dysfunction. The Research Ethics Board of Western University approved the study. All patients, including patients in the comparison group, provided written informed consent prior to enrollment.
2.1
Study population and inclusion/exclusion criteria
The enrollment period was between August 2011 and November 2014. All patients who presented during the enrolment period with STEMI and who had no reflow during primary PCI were eligible to participate. The comparison group was composed of consecutive patients with STEMI and normal flow who presented between August 2011 and January 2012. Patients had to receive a stent in order to be included in the study. Patients with a history of coronary artery bypass grafting were excluded. All patients who met the inclusion/exclusion criteria were approached to participate and were enrolled. The informed consent was obtained following the procedure for the purpose of data collection and endothelial function assessment.
The diagnosis of acute STEMI was based on symptoms lasting for more than 30 min and ST elevation of at least 2 mm in two contiguous peripheral or precordial leads. Index diagnostic coronary angiography was performed via the femoral or radial approach. Primary PCI of the IRA was performed using a conventional technique. Thrombolysis in myocardial infarction (TIMI) flow grade 3 for the treated coronary vessel with a residual stenosis <20% was considered successful PCI. No reflow was defined as TIMI flow grade 0–2 following stent implantation and in the absence of visible coronary dissection or a reduction of TIMI flow following establishment of TIMI 3 flow. Patients with transient no-reflow that had TIMI 3 at the end of the procedure were included in the no-reflow group. Choice of conventional anticoagulation and drug treatment was at the discretion of operating physician.
The study protocol was reviewed and approved by Western University Research Ethics Board. Informed consent to participate in this study was obtained from all patients.
A 12-lead ECG was recorded before and at completion of the procedure. The total number of leads with ST-elevation, maximum ST elevation and the sum of ST-segment elevation from the leads representative of the infarct area was measured before and after the procedure. Resolution of maximum and total ST elevation following primary PCI was calculated as a percentage of the value obtained from the baseline ECG. Greater than 70% reduction was considered ST resolution .
Patients underwent assessment of endothelial function after 48–72 h post PCI. Endothelial function was assessed using the EndoPAT2000 (EndoPAT) device (Itamar Medical Inc., Caesarea, Israel), a validated FDA approved device for non-invasive assessment of endothelial function . The test protocol consisted of a 5-min baseline measurement of the peripheral arterial tonometry (PAT) tracing in both arms, after which a blood pressure cuff placed on the test arm was inflated to 60 mmHg above baseline systolic blood pressure, and at least 200 mmHg for 5 min. After 5 min, the cuff was deflated, and the PAT tracing was recorded for a further 5 min. The degree of endothelial function was assessed by Reactive Hyperemia Index (RHI) which is the ratio of the PAT signal after cuff release, compared to baseline, calculated through a computer algorithm automatically normalizing for baseline signal, and indexed to the contralateral arm.
2.2
Statistical analysis
Results are presented according to the occurrence or not of no reflow during PPCI. Continuous variables are summarized by mean and standard deviation, and counts/percentages (categorical variables). Comparisons between continuous variables were performed using the Student t test. Categorical variables were compared with the Fisher’s exact test. Multivariable linear regression models were used to calculate the correlation of no reflow to endothelial function (RHI). Age, no reflow, and variables found to show association with no reflow in the single predictor models were included. p-Values are two-tailed and statistical significance was defined as p < 0.05. Analyses were performed using the SPSS 20.0 for windows (SPSS Inc., Chicago, Illinois, USA).
Sample size- There was no data available for sample size calculation. Since slow flow is not a frequent event, all patients who had slow flow/no-reflow during the study period were included. Due to the fact that data was collected prospectively, with a need to perform endothelial function assessment at a specific time point, and in order to minimize bias, the comparison group was composed of consecutive patients. We initially collected data on 30 patients with normal flow. Since we did not match this number in the no-reflow group, all patients were included.
2
Methods
This was a prospective observational study performed at London Health Sciences Centre, London, Ontario, Canada, that examined the relationship between slow flow during primary PCI and microvascular endothelial dysfunction. The Research Ethics Board of Western University approved the study. All patients, including patients in the comparison group, provided written informed consent prior to enrollment.
2.1
Study population and inclusion/exclusion criteria
The enrollment period was between August 2011 and November 2014. All patients who presented during the enrolment period with STEMI and who had no reflow during primary PCI were eligible to participate. The comparison group was composed of consecutive patients with STEMI and normal flow who presented between August 2011 and January 2012. Patients had to receive a stent in order to be included in the study. Patients with a history of coronary artery bypass grafting were excluded. All patients who met the inclusion/exclusion criteria were approached to participate and were enrolled. The informed consent was obtained following the procedure for the purpose of data collection and endothelial function assessment.
The diagnosis of acute STEMI was based on symptoms lasting for more than 30 min and ST elevation of at least 2 mm in two contiguous peripheral or precordial leads. Index diagnostic coronary angiography was performed via the femoral or radial approach. Primary PCI of the IRA was performed using a conventional technique. Thrombolysis in myocardial infarction (TIMI) flow grade 3 for the treated coronary vessel with a residual stenosis <20% was considered successful PCI. No reflow was defined as TIMI flow grade 0–2 following stent implantation and in the absence of visible coronary dissection or a reduction of TIMI flow following establishment of TIMI 3 flow. Patients with transient no-reflow that had TIMI 3 at the end of the procedure were included in the no-reflow group. Choice of conventional anticoagulation and drug treatment was at the discretion of operating physician.
The study protocol was reviewed and approved by Western University Research Ethics Board. Informed consent to participate in this study was obtained from all patients.
A 12-lead ECG was recorded before and at completion of the procedure. The total number of leads with ST-elevation, maximum ST elevation and the sum of ST-segment elevation from the leads representative of the infarct area was measured before and after the procedure. Resolution of maximum and total ST elevation following primary PCI was calculated as a percentage of the value obtained from the baseline ECG. Greater than 70% reduction was considered ST resolution .
Patients underwent assessment of endothelial function after 48–72 h post PCI. Endothelial function was assessed using the EndoPAT2000 (EndoPAT) device (Itamar Medical Inc., Caesarea, Israel), a validated FDA approved device for non-invasive assessment of endothelial function . The test protocol consisted of a 5-min baseline measurement of the peripheral arterial tonometry (PAT) tracing in both arms, after which a blood pressure cuff placed on the test arm was inflated to 60 mmHg above baseline systolic blood pressure, and at least 200 mmHg for 5 min. After 5 min, the cuff was deflated, and the PAT tracing was recorded for a further 5 min. The degree of endothelial function was assessed by Reactive Hyperemia Index (RHI) which is the ratio of the PAT signal after cuff release, compared to baseline, calculated through a computer algorithm automatically normalizing for baseline signal, and indexed to the contralateral arm.
2.2
Statistical analysis
Results are presented according to the occurrence or not of no reflow during PPCI. Continuous variables are summarized by mean and standard deviation, and counts/percentages (categorical variables). Comparisons between continuous variables were performed using the Student t test. Categorical variables were compared with the Fisher’s exact test. Multivariable linear regression models were used to calculate the correlation of no reflow to endothelial function (RHI). Age, no reflow, and variables found to show association with no reflow in the single predictor models were included. p-Values are two-tailed and statistical significance was defined as p < 0.05. Analyses were performed using the SPSS 20.0 for windows (SPSS Inc., Chicago, Illinois, USA).
Sample size- There was no data available for sample size calculation. Since slow flow is not a frequent event, all patients who had slow flow/no-reflow during the study period were included. Due to the fact that data was collected prospectively, with a need to perform endothelial function assessment at a specific time point, and in order to minimize bias, the comparison group was composed of consecutive patients. We initially collected data on 30 patients with normal flow. Since we did not match this number in the no-reflow group, all patients were included.
3
Results
Nineteen consecutive patients with STEMI who had no reflow during primary PCI, were compared to thirty patients with STEMI and normal flow. Baseline characteristics are shown in Table 1 . The prevalence of smoking was lower in the no-reflow group. Patients with no re-flow had lower low density lipoproteins (LDL) and higher high density lipoproteins (HDL) levels. The time from symptom onset to PPCI and first device was longer in patients with no-reflow. Procedural and laboratory findings are presented in Table 2 . There was no difference between the groups in initial TIMI flow, but patients who experienced no reflow during the procedure had less TIMI grade III flow at the end of the procedure. Patients who had no reflow at any time during the procedure (the no reflow group) had significantly lower blush score and less ST segment elevation resolution at end of PCI and had lower left ventricle ejection fraction (LVEF). There was no significant difference in post PPCI peripheral endothelial function, between the two groups as presented in Table 2 and Fig. 1 . There was no correlation between endothelial function and the degree of ST resolution. No reflow had no correlation to RHI following adjustment in the multivariable model, as presented in Table 3 .
