- Email: [email protected]
Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial infarction
Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial infarction☆,☆☆ Yaniv Levi a,b, Ayyaz Sultan a,b, Mistre Alemayehu b, Sabrina Wall b, Shahar Lavi a,b,⁎ a b
Western University, N6A 5A5 London, ON, Canada London Health Sciences Centre, N6A 5A5 London, ON, Canada
a r t i c l e
i n f o
Article history: Received 27 April 2016 Received in revised form 25 August 2016 Accepted 31 August 2016 Available online xxxx Keywords: Angiography Acute MI No-reflow
a b s t r a c t 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. © 2016 Elsevier Inc. All rights reserved.
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) [1,2]. However, a subset of these patients demonstrate angiographic characteristics of delayed flow in the IRA despite its patency [3]. This decoupling of successful coronary reperfusion and micro vascular reperfusion is recognized as Slow-Flow or No-Flow phenomenon [4,5]. Slow flow occurs in 8%–11.5% of PPCI [6,7] and in up to 2% in patients undergoing elective percutaneous coronary intervention (PCI) [6]. The mechanism of slow flow is likely multifactorial and involves distal embolization of plaque and thrombus [8,9], platelets activation [9], localized inflammation [9,10], coronary micro vascular
spasm and reperfusion injury [11]. 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) [12,13] In patients with stable coronary artery disease, coronary and peripheral endothelial dysfunction (ED) identifies subjects at high risk for cardio-vascular events [14,15]. Microvascular coronary endothelial dysfunction is characterized by abnormal coronary flow [16]. 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 ☆ Presented in part at Cardiovascular Research Technologies 2015 and presented as an abstract: J Am Coll Cardiol Intv. 2015;8(2_S):S10-S10 ☆☆ Conflicts of Interest: None ⁎ Corresponding author at: London Health Sciences Centre, Western University, 339 Windermere Rd, London, Ontario N6A 5A5. Tel.: +1 519 663 3611; fax: +1 519 663 3117. E-mail address: [email protected] (S. Lavi).
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
http://dx.doi.org/10.1016/j.carrev.2016.08.013 1553-8389/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
2
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
approved the study. All patients, including patients in the comparison group, provided written informed consent prior to enrollment.
Table 1 Baseline characteristics and associated medical conditions. Characteristic
No reflow (n = 19)
Normal flow (n = 30)
p Value
Age (years) Male (%) Hypertension (%) Diabetes (%) Smoking (%) Previous CHF (%) Previous CVA (%) Previous PVD (%) LDL (mmol/l) HDL (mmol/l) Anterior MI (%) Symptoms to balloon time (min)
62 ± 12 18 (95) 10 (53) 1 (5) 4 (21) 1 (5.2) 0 0 2.33 ± 0.99 1.13 ± 0.09 11 (58) 215.6 ± 27.3
59 ± 10 24 (80) 17 (57) 3 (10) 17 (57) 0 0 2 (6.6) 2.93 ± 0.80 1.08 ± 0.05 9 (30) 180.9 ± 24.8
0.47 0.15 0.78 0.78 0.01 0.39 1 0.51 0.02 0.05 0.07 0.037
Medication at time of endothelial function study beta Blocker ACEI Statins
18 (94) 17 (89) 17 (89)
28 (93) 26 (86) 29 (97)
1 1 0.55
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 b20% 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 [17]. 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 [18]. 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.
CHF, chronic heart failure; CVA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease; LDL, low density lipoprotein; HDL, high density lipoprotein; MI, myocardial infarction; ACEI, angiotensin converting enzyme inhibitor.
statistical significance was defined as p b 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 reflow 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 Table 2 Procedural and laboratory findings.
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
Initial TIMI flow 0–1 (%) Final TIMI flow 3 (%) Blush Score 0–1 (%) Thrombectomy (%) Total ST resolution (%) LVEF (%) CK pick (u/l) RHI
No reflow (n = 19)
Normal flow (n = 30)
p Value
16 (84.2) 10 (53) 12 (63) 12 (63) 48 ± 7 39 ± 10 2831 ± 631 1.91 ± 0.3
22 (73) 30 (100) 5 (16) 7 (23) 81 ± 6 47 ± 10 2242 ± 464 2.09 ± 0.11
0.49 0.01 b0.01 0.65 b0.01 0.01 0.45 0.24
TIMI, Thrombolysis in Myocardial Infarction; LVEF, left ventricle ejection fraction; CK, creatine kinase; RHI, Reactive Hyperemia Index.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
Fig. 1. Reactive hyperemia index (RHI) according to presence or absence of no-reflow during PPCI.
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. 4. Discussion The results of this study suggest that systemic ED is not associated with the occurrence of the no-reflow phenomenon during PPCI. The mechanism of no reflow is complex and likely multifactorial. It is plausible that coronary vascular function plays a role in this process. However, this is difficult to assess during STEMI. It is well established that systemic ED correlates with coronary ED [19]. Therefore, we chose to assess systemic endothelial function as a surrogate of pre-existing systemic and coronary ED. We have previously shown that elective PCI induces an acute inflammatory response, without affecting systemic endothelial function [20]. As the effect of STEMI is more robust compared to that of elective PCI, the test was performed 48–72 h post PPCI. The absence of correlation between systemic endothelial function and no-reflow in our study, suggest that pre-existing systemic or coronary ED has no role in the mechanism of no-reflow during STEMI. Our findings do not rule out the possibility that local and transient ED at the time of STEMI contribute to this process. The absence of association between peripheral ED and no reflow extend prior observations suggesting that no-reflow is a local rather than systemic process. Local intra coronary administration of verapamil or adenosine dilates the microcirculation and improves coronary flow in patients presenting with ACS [21]. Local administration of the nitric oxide donor nitroprusside to patients with impaired flow following intervention also improves coronary flow [22]. Although a few studies showed association between baseline Creactive protein level and inflammation to no reflow, findings that suggest that no –reflow is associated with a systemic process, the association between baseline inflammation and development of no reflow remains controversial [23,24]. Further, there is no clear association between inflammation and ED [20]. In our study, patients with no-reflow had a longer delay from symptom onset to PCI, a known factor that may increase the risk of no-reflow. As the mechanism for no-reflow is multifactorial, the effect of delay to Table 3 Multivariate regression for endothelial function (RHI).
Age No Flow Blush Score LVEF Total ST resolution. (%) Post Procedure TIMI Flow
B
t
p Value
Confidence interval
-0.14 0.54 0.039 2.208 0.001 0.054
-1.79 0.251 0.475 3.021 0.335 0.251
0.09 0.8 0.64 b0.01 0.33 0.8
-0.03 to 0.002 -0.38 to 0.487 -0.129 to 0.207 0.726–3.690 -0.004 to 0.006 -0.581 to 0.492
RHI, Reactive Hyperemia Index; B, unstandardized coefficients; t, t statistics; LVEF, left ventricle ejection fraction; TIMI, thrombolysis in myocardial infarction.
3
therapy and other contributing factors may mask a potential mild effect of ED on coronary flow. We found a lower prevalence of smokers among the no-reflow group compared to the control group. Smoking has been previously characterized by epicardial coronary ED but preserved microvascular coronary function in patients without obstructive coronary artery disease [16]. The negative association between smoking and no reflow may have important clinical implications. Although smoking can lead to clot formation [25], the potential lower risk of no reflow among smokers may partially explain the smoking paradox and the lower mortality rate of smokers after acute myocardial infarction (AMI) [26–29]. As the patients were selected into the study according to presence of no reflow or not, it is possible that there is a selection bias in which patients in the no reflow group were less likely to be smokers but have other contributing risks. Interestingly, contrary to other reports [23,30], the LDL levels were lower in patients with no re-flow. The mechanism is unclear and may be a chance finding. 4.1. Limitations The sample size is small and therefore possibly missed a minor association between no reflow and ED. The endothelial function assessment was performed 48–72 h following PPCI. We chose this time frame to minimize potential acute effect of STEMI on endothelial function, while not delaying the test to a time when new medications may affect ED [31,32]. However the results may not represent endothelial function prior to STEMI. The method we chose for assessment of endothelial function assessed mainly microvascular dysfunction. We have not assessed other functions of the endothelium. However, this method was preferred in this setting, being non-invasive, and correlate well with coronary microvascular ED [19]. 5. Conclusion In conclusion, systemic peripheral endothelial function does not differ between STEMI patients with and without no reflow during primary PCI. Acknowledgements This work was supported by The Program of Experimental Medicine in the Department of Medicine, Western University. References [1] Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–42. [2] Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20. [3] Sorajja P, Gersh BJ, Costantini C, McLaughlin MG, Zimetbaum P, Cox DA, et al. Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous coronary intervention in acute myocardial infarction. Eur Heart J 2005;26:667–74. [4] Yip HK, Chen MC, Chang HW, Hang CL, Hsieh YK, Fang CY, et al. Angiographic morphologic features of infarct-related arteries and timely reperfusion in acute myocardial infarction: predictors of slow-flow and no-reflow phenomenon. Chest 2002; 122:1322–32. [5] Rezkalla SH, Kloner RA. Coronary no-reflow phenomenon: from the experimental laboratory to the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2008;72:950–7. [6] Piana RN, Paik GY, Moscucci M, Cohen DJ, Gibson CM, Kugelmass AD, et al. Incidence and treatment of 'no-reflow' after percutaneous coronary intervention. Circulation 1994;89:2514–8. [7] Resnic FS, Wainstein M, Lee MK, Behrendt D, Wainstein RV, Ohno-Machado L, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J 2003;145:42–6. [8] Heusch G, Schulz R, Haude M, Erbel R. Coronary microembolization. J Mol Cell Cardiol 2004;37:23–31. [9] Skyschally A, Leineweber K, Gres P, Haude M, Erbel R, Heusch G. Coronary microembolization. Basic Res Cardiol 2006;101:373–82.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
4
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
[10] Furuichi K, Wada T, Iwata Y, Kokubo S, Hara A, Yamahana J, et al. Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia–reperfusion injury. Crit Care Med 2006;34:2447–55. [11] Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol 2000;190:255–66. [12] Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998;105:32S–9S. [13] Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992;267:14519–22. [14] Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106: 653–8. [15] Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–8. [16] Lavi S, Prasad A, Yang EH, Mathew V, Simari RD, Rihal CS, et al. Smoking is associated with epicardial coronary endothelial dysfunction and elevated white blood cell count in patients with chest pain and early coronary artery disease. Circulation 2007;115:2621–7. [17] Lavi S, Bainbridge D, D'Alfonso S, Diamantouros P, Syed J, Jablonsky G, et al. Sevoflurane in acute myocardial infarction: a pilot randomized study. Am Heart J 2014;168:776–83. [18] Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31:1142–8. [19] Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004;44:2137–41. [20] Lavi S, Thorpe K, Luca MC, Liuni A, Floras J, Horlick EM, et al. Inhibition of sPLA2 and endothelial function: a substudy of the SPIDER-PCI trial. Can J Cardiol 2012;28: 215–21.
[21] Vijayalakshmi K, Whittaker VJ, Kunadian B, Graham J, Wright RA, Hall JA, et al. Prospective, randomised, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes. Heart 2006;92:1278–84. [22] Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol 2001;37:1335–43. [23] Ndrepepa G, Tiroch K, Keta D, Fusaro M, Seyfarth M, Pache J, et al. Predictive factors and impact of no reflow after primary percutaneous coronary intervention in patients with acute myocardial infarction. Circ Cardiovasc Interv 2010;3:27–33. [24] Niccoli G, Lanza GA, Spaziani C, Altamura L, Romagnoli E, Leone AM, et al. Baseline systemic inflammatory status and no-reflow phenomenon after percutaneous coronary angioplasty for acute myocardial infarction. Int J Cardiol 2007;117:306–11. [25] Barua RS, Ambrose JA. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler Thromb Vasc Biol 2013;33:1460–7. [26] Andrikopoulos GK, Richter DJ, Dilaveris PE, Pipilis A, Zaharoulis A, Gialafos JE, et al. In-hospital mortality of habitual cigarette smokers after acute myocardial infarction; the "smoker's paradox" in a countrywide study. Eur Heart J 2001;22:776–84. [27] Gourlay SG, Rundle AC, Barron HV. Smoking and mortality following acute myocardial infarction: results from the National Registry of myocardial infarction 2 (NRMI 2. Nicotine Tob Res 2002;4:101–7. [28] Kelly TL, Gilpin E, Ahnve S, Henning H, Ross Jr J. Smoking status at the time of acute myocardial infarction and subsequent prognosis. Am Heart J 1985;110:535–41. [29] Molstad P. First myocardial infarction in smokers. Eur Heart J 1991;12:753–9. [30] Dong-bao L, Qi H, Zhi L, Shan W, Wei-ying J. Predictors and long-term prognosis of angiographic slow/no-reflow phenomenon during emergency percutaneous coronary intervention for ST-elevated acute myocardial infarction. Clin Cardiol 2010;33:E7–12. [31] Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs 2002;62:265–84. [32] John S, Schneider MP, Delles C, Jacobi J, Schmieder RE. Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients. Am Heart J 2005;149:473.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
Contents lists available at ScienceDirect
Cardiovascular Revascularization Medicine
Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial infarction☆,☆☆ Yaniv Levi a,b, Ayyaz Sultan a,b, Mistre Alemayehu b, Sabrina Wall b, Shahar Lavi a,b,⁎ a b
Western University, N6A 5A5 London, ON, Canada London Health Sciences Centre, N6A 5A5 London, ON, Canada
a r t i c l e
i n f o
Article history: Received 27 April 2016 Received in revised form 25 August 2016 Accepted 31 August 2016 Available online xxxx Keywords: Angiography Acute MI No-reflow
a b s t r a c t 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. © 2016 Elsevier Inc. All rights reserved.
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) [1,2]. However, a subset of these patients demonstrate angiographic characteristics of delayed flow in the IRA despite its patency [3]. This decoupling of successful coronary reperfusion and micro vascular reperfusion is recognized as Slow-Flow or No-Flow phenomenon [4,5]. Slow flow occurs in 8%–11.5% of PPCI [6,7] and in up to 2% in patients undergoing elective percutaneous coronary intervention (PCI) [6]. The mechanism of slow flow is likely multifactorial and involves distal embolization of plaque and thrombus [8,9], platelets activation [9], localized inflammation [9,10], coronary micro vascular
spasm and reperfusion injury [11]. 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) [12,13] In patients with stable coronary artery disease, coronary and peripheral endothelial dysfunction (ED) identifies subjects at high risk for cardio-vascular events [14,15]. Microvascular coronary endothelial dysfunction is characterized by abnormal coronary flow [16]. 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 ☆ Presented in part at Cardiovascular Research Technologies 2015 and presented as an abstract: J Am Coll Cardiol Intv. 2015;8(2_S):S10-S10 ☆☆ Conflicts of Interest: None ⁎ Corresponding author at: London Health Sciences Centre, Western University, 339 Windermere Rd, London, Ontario N6A 5A5. Tel.: +1 519 663 3611; fax: +1 519 663 3117. E-mail address: [email protected] (S. Lavi).
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
http://dx.doi.org/10.1016/j.carrev.2016.08.013 1553-8389/© 2016 Elsevier Inc. All rights reserved.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
2
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
approved the study. All patients, including patients in the comparison group, provided written informed consent prior to enrollment.
Table 1 Baseline characteristics and associated medical conditions. Characteristic
No reflow (n = 19)
Normal flow (n = 30)
p Value
Age (years) Male (%) Hypertension (%) Diabetes (%) Smoking (%) Previous CHF (%) Previous CVA (%) Previous PVD (%) LDL (mmol/l) HDL (mmol/l) Anterior MI (%) Symptoms to balloon time (min)
62 ± 12 18 (95) 10 (53) 1 (5) 4 (21) 1 (5.2) 0 0 2.33 ± 0.99 1.13 ± 0.09 11 (58) 215.6 ± 27.3
59 ± 10 24 (80) 17 (57) 3 (10) 17 (57) 0 0 2 (6.6) 2.93 ± 0.80 1.08 ± 0.05 9 (30) 180.9 ± 24.8
0.47 0.15 0.78 0.78 0.01 0.39 1 0.51 0.02 0.05 0.07 0.037
Medication at time of endothelial function study beta Blocker ACEI Statins
18 (94) 17 (89) 17 (89)
28 (93) 26 (86) 29 (97)
1 1 0.55
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 b20% 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 [17]. 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 [18]. 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.
CHF, chronic heart failure; CVA, cerebrovascular accident/transient ischemic attack; PVD, peripheral vascular disease; LDL, low density lipoprotein; HDL, high density lipoprotein; MI, myocardial infarction; ACEI, angiotensin converting enzyme inhibitor.
statistical significance was defined as p b 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 reflow 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 Table 2 Procedural and laboratory findings.
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
Initial TIMI flow 0–1 (%) Final TIMI flow 3 (%) Blush Score 0–1 (%) Thrombectomy (%) Total ST resolution (%) LVEF (%) CK pick (u/l) RHI
No reflow (n = 19)
Normal flow (n = 30)
p Value
16 (84.2) 10 (53) 12 (63) 12 (63) 48 ± 7 39 ± 10 2831 ± 631 1.91 ± 0.3
22 (73) 30 (100) 5 (16) 7 (23) 81 ± 6 47 ± 10 2242 ± 464 2.09 ± 0.11
0.49 0.01 b0.01 0.65 b0.01 0.01 0.45 0.24
TIMI, Thrombolysis in Myocardial Infarction; LVEF, left ventricle ejection fraction; CK, creatine kinase; RHI, Reactive Hyperemia Index.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
Fig. 1. Reactive hyperemia index (RHI) according to presence or absence of no-reflow during PPCI.
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. 4. Discussion The results of this study suggest that systemic ED is not associated with the occurrence of the no-reflow phenomenon during PPCI. The mechanism of no reflow is complex and likely multifactorial. It is plausible that coronary vascular function plays a role in this process. However, this is difficult to assess during STEMI. It is well established that systemic ED correlates with coronary ED [19]. Therefore, we chose to assess systemic endothelial function as a surrogate of pre-existing systemic and coronary ED. We have previously shown that elective PCI induces an acute inflammatory response, without affecting systemic endothelial function [20]. As the effect of STEMI is more robust compared to that of elective PCI, the test was performed 48–72 h post PPCI. The absence of correlation between systemic endothelial function and no-reflow in our study, suggest that pre-existing systemic or coronary ED has no role in the mechanism of no-reflow during STEMI. Our findings do not rule out the possibility that local and transient ED at the time of STEMI contribute to this process. The absence of association between peripheral ED and no reflow extend prior observations suggesting that no-reflow is a local rather than systemic process. Local intra coronary administration of verapamil or adenosine dilates the microcirculation and improves coronary flow in patients presenting with ACS [21]. Local administration of the nitric oxide donor nitroprusside to patients with impaired flow following intervention also improves coronary flow [22]. Although a few studies showed association between baseline Creactive protein level and inflammation to no reflow, findings that suggest that no –reflow is associated with a systemic process, the association between baseline inflammation and development of no reflow remains controversial [23,24]. Further, there is no clear association between inflammation and ED [20]. In our study, patients with no-reflow had a longer delay from symptom onset to PCI, a known factor that may increase the risk of no-reflow. As the mechanism for no-reflow is multifactorial, the effect of delay to Table 3 Multivariate regression for endothelial function (RHI).
Age No Flow Blush Score LVEF Total ST resolution. (%) Post Procedure TIMI Flow
B
t
p Value
Confidence interval
-0.14 0.54 0.039 2.208 0.001 0.054
-1.79 0.251 0.475 3.021 0.335 0.251
0.09 0.8 0.64 b0.01 0.33 0.8
-0.03 to 0.002 -0.38 to 0.487 -0.129 to 0.207 0.726–3.690 -0.004 to 0.006 -0.581 to 0.492
RHI, Reactive Hyperemia Index; B, unstandardized coefficients; t, t statistics; LVEF, left ventricle ejection fraction; TIMI, thrombolysis in myocardial infarction.
3
therapy and other contributing factors may mask a potential mild effect of ED on coronary flow. We found a lower prevalence of smokers among the no-reflow group compared to the control group. Smoking has been previously characterized by epicardial coronary ED but preserved microvascular coronary function in patients without obstructive coronary artery disease [16]. The negative association between smoking and no reflow may have important clinical implications. Although smoking can lead to clot formation [25], the potential lower risk of no reflow among smokers may partially explain the smoking paradox and the lower mortality rate of smokers after acute myocardial infarction (AMI) [26–29]. As the patients were selected into the study according to presence of no reflow or not, it is possible that there is a selection bias in which patients in the no reflow group were less likely to be smokers but have other contributing risks. Interestingly, contrary to other reports [23,30], the LDL levels were lower in patients with no re-flow. The mechanism is unclear and may be a chance finding. 4.1. Limitations The sample size is small and therefore possibly missed a minor association between no reflow and ED. The endothelial function assessment was performed 48–72 h following PPCI. We chose this time frame to minimize potential acute effect of STEMI on endothelial function, while not delaying the test to a time when new medications may affect ED [31,32]. However the results may not represent endothelial function prior to STEMI. The method we chose for assessment of endothelial function assessed mainly microvascular dysfunction. We have not assessed other functions of the endothelium. However, this method was preferred in this setting, being non-invasive, and correlate well with coronary microvascular ED [19]. 5. Conclusion In conclusion, systemic peripheral endothelial function does not differ between STEMI patients with and without no reflow during primary PCI. Acknowledgements This work was supported by The Program of Experimental Medicine in the Department of Medicine, Western University. References [1] Andersen HR, Nielsen TT, Rasmussen K, Thuesen L, Kelbaek H, Thayssen P, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med 2003;349:733–42. [2] Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet 2003;361:13–20. [3] Sorajja P, Gersh BJ, Costantini C, McLaughlin MG, Zimetbaum P, Cox DA, et al. Combined prognostic utility of ST-segment recovery and myocardial blush after primary percutaneous coronary intervention in acute myocardial infarction. Eur Heart J 2005;26:667–74. [4] Yip HK, Chen MC, Chang HW, Hang CL, Hsieh YK, Fang CY, et al. Angiographic morphologic features of infarct-related arteries and timely reperfusion in acute myocardial infarction: predictors of slow-flow and no-reflow phenomenon. Chest 2002; 122:1322–32. [5] Rezkalla SH, Kloner RA. Coronary no-reflow phenomenon: from the experimental laboratory to the cardiac catheterization laboratory. Catheter Cardiovasc Interv 2008;72:950–7. [6] Piana RN, Paik GY, Moscucci M, Cohen DJ, Gibson CM, Kugelmass AD, et al. Incidence and treatment of 'no-reflow' after percutaneous coronary intervention. Circulation 1994;89:2514–8. [7] Resnic FS, Wainstein M, Lee MK, Behrendt D, Wainstein RV, Ohno-Machado L, et al. No-reflow is an independent predictor of death and myocardial infarction after percutaneous coronary intervention. Am Heart J 2003;145:42–6. [8] Heusch G, Schulz R, Haude M, Erbel R. Coronary microembolization. J Mol Cell Cardiol 2004;37:23–31. [9] Skyschally A, Leineweber K, Gres P, Haude M, Erbel R, Heusch G. Coronary microembolization. Basic Res Cardiol 2006;101:373–82.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013
4
Y. Levi et al. / Cardiovascular Revascularization Medicine xxx (2016) xxx–xxx
[10] Furuichi K, Wada T, Iwata Y, Kokubo S, Hara A, Yamahana J, et al. Interleukin-1-dependent sequential chemokine expression and inflammatory cell infiltration in ischemia–reperfusion injury. Crit Care Med 2006;34:2447–55. [11] Carden DL, Granger DN. Pathophysiology of ischaemia-reperfusion injury. J Pathol 2000;190:255–66. [12] Quyyumi AA. Endothelial function in health and disease: new insights into the genesis of cardiovascular disease. Am J Med 1998;105:32S–9S. [13] Janssens SP, Shimouchi A, Quertermous T, Bloch DB, Bloch KD. Cloning and expression of a cDNA encoding human endothelium-derived relaxing factor/nitric oxide synthase. J Biol Chem 1992;267:14519–22. [14] Halcox JP, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw MA, et al. Prognostic value of coronary vascular endothelial dysfunction. Circulation 2002;106: 653–8. [15] Heitzer T, Schlinzig T, Krohn K, Meinertz T, Munzel T. Endothelial dysfunction, oxidative stress, and risk of cardiovascular events in patients with coronary artery disease. Circulation 2001;104:2673–8. [16] Lavi S, Prasad A, Yang EH, Mathew V, Simari RD, Rihal CS, et al. Smoking is associated with epicardial coronary endothelial dysfunction and elevated white blood cell count in patients with chest pain and early coronary artery disease. Circulation 2007;115:2621–7. [17] Lavi S, Bainbridge D, D'Alfonso S, Diamantouros P, Syed J, Jablonsky G, et al. Sevoflurane in acute myocardial infarction: a pilot randomized study. Am Heart J 2014;168:776–83. [18] Rubinshtein R, Kuvin JT, Soffler M, Lennon RJ, Lavi S, Nelson RE, et al. Assessment of endothelial function by non-invasive peripheral arterial tonometry predicts late cardiovascular adverse events. Eur Heart J 2010;31:1142–8. [19] Bonetti PO, Pumper GM, Higano ST, Holmes Jr DR, Kuvin JT, Lerman A. Noninvasive identification of patients with early coronary atherosclerosis by assessment of digital reactive hyperemia. J Am Coll Cardiol 2004;44:2137–41. [20] Lavi S, Thorpe K, Luca MC, Liuni A, Floras J, Horlick EM, et al. Inhibition of sPLA2 and endothelial function: a substudy of the SPIDER-PCI trial. Can J Cardiol 2012;28: 215–21.
[21] Vijayalakshmi K, Whittaker VJ, Kunadian B, Graham J, Wright RA, Hall JA, et al. Prospective, randomised, controlled trial to study the effect of intracoronary injection of verapamil and adenosine on coronary blood flow during percutaneous coronary intervention in patients with acute coronary syndromes. Heart 2006;92:1278–84. [22] Hillegass WB, Dean NA, Liao L, Rhinehart RG, Myers PR. Treatment of no-reflow and impaired flow with the nitric oxide donor nitroprusside following percutaneous coronary interventions: initial human clinical experience. J Am Coll Cardiol 2001;37:1335–43. [23] Ndrepepa G, Tiroch K, Keta D, Fusaro M, Seyfarth M, Pache J, et al. Predictive factors and impact of no reflow after primary percutaneous coronary intervention in patients with acute myocardial infarction. Circ Cardiovasc Interv 2010;3:27–33. [24] Niccoli G, Lanza GA, Spaziani C, Altamura L, Romagnoli E, Leone AM, et al. Baseline systemic inflammatory status and no-reflow phenomenon after percutaneous coronary angioplasty for acute myocardial infarction. Int J Cardiol 2007;117:306–11. [25] Barua RS, Ambrose JA. Mechanisms of coronary thrombosis in cigarette smoke exposure. Arterioscler Thromb Vasc Biol 2013;33:1460–7. [26] Andrikopoulos GK, Richter DJ, Dilaveris PE, Pipilis A, Zaharoulis A, Gialafos JE, et al. In-hospital mortality of habitual cigarette smokers after acute myocardial infarction; the "smoker's paradox" in a countrywide study. Eur Heart J 2001;22:776–84. [27] Gourlay SG, Rundle AC, Barron HV. Smoking and mortality following acute myocardial infarction: results from the National Registry of myocardial infarction 2 (NRMI 2. Nicotine Tob Res 2002;4:101–7. [28] Kelly TL, Gilpin E, Ahnve S, Henning H, Ross Jr J. Smoking status at the time of acute myocardial infarction and subsequent prognosis. Am Heart J 1985;110:535–41. [29] Molstad P. First myocardial infarction in smokers. Eur Heart J 1991;12:753–9. [30] Dong-bao L, Qi H, Zhi L, Shan W, Wei-ying J. Predictors and long-term prognosis of angiographic slow/no-reflow phenomenon during emergency percutaneous coronary intervention for ST-elevated acute myocardial infarction. Clin Cardiol 2010;33:E7–12. [31] Taddei S, Virdis A, Ghiadoni L, Sudano I, Salvetti A. Effects of antihypertensive drugs on endothelial dysfunction: clinical implications. Drugs 2002;62:265–84. [32] John S, Schneider MP, Delles C, Jacobi J, Schmieder RE. Lipid-independent effects of statins on endothelial function and bioavailability of nitric oxide in hypercholesterolemic patients. Am Heart J 2005;149:473.
Please cite this article as: Levi Y, et al, Association of endothelial dysfunction and no-reflow during primary percutaneous coronary intervention for ST-elevation myocardial..., Cardiovasc Revasc Med (2016), http://dx.doi.org/10.1016/j.carrev.2016.08.013