Cell Biochem Biophys (2014) 70:437–442 DOI 10.1007/s12013-014-9936-1
ORIGINAL PAPER
Late Remote Ischemic Preconditioning Provides Benefit to Patients Undergoing Elective Percutaneous Coronary Intervention Zhi Liu • Yan-Ling Wang • Dong Xu • Qi Hua • Yan-Yan Chu • Xun-Ming Ji
Published online: 12 July 2014 Ó Springer Science+Business Media New York 2014
Abstract To assess whether late remote ischemic preconditioning (L-RIPC) is effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention (PCI). L-RIPC is exerted by newly synthesized cardioprotective proteins. The cardioprotective effects of L-RIPC are more durable. 200 consecutive patients undergoing elective PCI were randomized to receive L-RIPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion) or control (an uninflated cuff around the arm) at 18 h before PCI. Creatine phosphokinase (CK), its cardiac isoenzyme (CK-MB), troponin I (TNI), and high-sensitivity C-reactive protein (hs-CRP) levels were measured at 24 h after PCI. Adverse events’ rates at 6 months were assessed. Compared with the control group, patients in L-RIPC group were observed with significantly lower incidences in Chest pain score [1 and ECG ST deviation [1 mm (P \ 0.05). The median TNI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.009 vs. 0.036 ng/mL, 123 vs. 186 IU/L, 15 vs. 27 IU/L; P \ 0.05). There was no statistical difference in hs-CRP between two groups. At 6 months, the adverse events’ rate was lower in the L-RIPC
The authors Zhi Liu and Yan-Ling Wang have contributed equally to this work and should be considered co-first authors. Z. Liu Y.-L. Wang D. Xu Q. Hua Y.-Y. Chu Department of Cardiology, Xuanwu Hospital, Capital Medical University, Beijing, China X.-M. Ji (&) Department of Intervention, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xicheng District, Beijing 100053, China e-mail: [email protected]
group (P = 0.036). L-RIPC is effective in myocardial protection in patients undergoing elective PCI and reduces adverse events’ rate at 6 months. Keywords Late remote ischemic preconditioning Ischemic heart disease Elective percutaneous coronary intervention Troponin I
Introduction Brief episodes of nonlethal ischemia and reperfusion applied to the organ or tissue distal to the heart before a prolonged ischemia–reperfusion injury is known as remote ischemic preconditioning (RIPC) [1–3], which has been shown to protect myocardium against ischemia–reperfusion injury and reduce the cardiac troponin I (cTnI) release in patients undergoing PCI [4, 5]. The cardioprotective effects of remote ischemic preconditioning disappear 2–3 h after the onset of the preconditioning insult, but reappear 18 h later and lasting up to 3 days [6]. This phenomenon is recognized as ‘‘late/delayed’’ ischemic preconditioning. A major difference in the cardioprotective mechanisms of early and late preconditioning is that early ischemic preconditioning results in the modification or turnover/translocation of existing molecules, whereas late ischemic preconditioning is exerted by newly synthesized cardioprotective proteins [7]. They transcribe the de novo synthesized proteins involved in late ischemic preconditioning, including manganese superoxide dismutase, heat stress proteins, and inducible nitric oxide synthase [8]. The cardioprotective effects of late ischemic preconditioning is more durable [9]. However, the late-phase effects of RIPC (L-RIPC) have not yet been studied in patients undergoing PCI. Therefore, we aimed to assess whether L-RIPC is
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effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention.
Cell Biochem Biophys (2014) 70:437–442
Thereafter, all patients underwent PCI by an interventionist blinded to the study allocation. Percutaneous Coronary Intervention
Materials and Methods Patients 232 consecutive patients referred for elective percutaneous coronary intervention, who were admitted to our institute, were enrolled from January 2010 to July 2011. The study protocol was approved by the ethics committee of our institution, and written informed consent was obtained from all participating subjects. Exclusion criteria were (1) emergency PCI, (2) elevation of cTnI before PCI, (3) nicorandil or glibenclamide use (preconditioning-mimetic and preconditioning blocking medication, respectively), (4) severe comorbidity (estimated life expectancy \6 months), and (5) recent systemic infection. A total of 200 consenting patients were randomized to receive either control treatment (102 patients) or the L-RIPC (98 patients). No changes were made to the clinical care of the patients enrolled in this study. Clinical Data Collection A special questionnaire was used to collect information on lifestyle, environmental factors, and medical history of the study population. Patients who reported smoking at least one cigarette per day for at least 1 year were defined as current smokers. Diabetes mellitus was defined as a previous diagnosis, use of diet or antidiabetic medicines, or fasting venous blood glucose level C126 mg/dL on two occasions in previously untreated patients. Patients who received medications for hypertension or those with seated systolic blood pressure C140 mmHg and/or diastolic blood pressure C90 mmHg on at least three separate clinic visits were also identified. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Left ventricular ejection fractions (LVEF) were measured with Doppler echocardiography at enrolment. Protocols for Late Remote Ischemic Preconditioning L-RIPC was applied at 18–24 h before starting the PCI. L-RIPC consisted of three five-minute cycles of upper limb ischaemia and three five-minute pauses using a blood pressure cuff inflated to 200 mmHg. Control patients had a similar cuff placed around the upper arm, but it was not inflated. Cuff-to-balloon time was the time between the last blood pressure cuff deflation and stent balloon inflation.
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PCI was performed via a radial arterial approach with 5F guiding catheters. All patients received aspirin 300 mg and clopidogrel 300 mg at least 6 h before PCI and were anticoagulated with a heparin bolus (70–100 U/kg) after arterial sheath insertion to achieve an activated clotting time [250 s. Glycoprotein IIb/IIIa antagonists were not administered. Ultravist (Omnipaque) (GE HealthCare, Shanghai, China) was used as the contrast agent in all cases. Lesion complexity was classified into Types A, B, and C according to the American Heart Association/ American College of Cardiology grading system. Coronary stents were implanted in all patients of both groups after balloon pre-dilatation of the target lesion according to the decision of the operators. Total time of ischemia was calculated as the time of duration of coronary balloon occlusion. All patients received aspirin 100 mg and clopidogrel 75 mg everyday for 1 year after drug-eluting stent implantation, in accordance with local practice. All other medication was given at the discretion of the attending physician, and the PCI strategy was at the discretion of the treating interventional cardiologist according to conventional practice. Chest pain severity during PCI was graded on a scale of 0 for no pain to ten for the most severe discomfort ever experienced. Angiographic success was defined as a residual stenosis of\15 % by visual angiographic assessment. Blood Sampling and Laboratory Measurements Venous blood samples for measurements were obtained at enrolment and 24 h after PCI. Creatine phosphokinase (CK), its cardiac isoenzyme (CK-MB), troponin I (TNI), and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Blood samples were collected in serum separation tubes. Serum hs-CRP, CK, and CK-MB concentrations were determined by our biochemistry department using standard methods. hs-CRP concentrations between 0 and 3 mg/L and CK concentrations between 24 and 195 IU/L were considered to be within the reference range. The reference range of CK-MB was 0–25 IU/L. TNI levels were measured with the immuno-analyzer, using a two-site fluorometric enzyme immunoassay (Mitsubishi Kagaku Latron, Inc, Japan). Values are expressed as nanograms per milliliter. The 99th percentile of the cTnI level in a reference population (upper reference limit) of healthy volunteers was below the lower limit of detection of 0.02 ng/mL. The variation coefficient, a measure of precision within the analytical range, is \10 %.
Cell Biochem Biophys (2014) 70:437–442 Table 1 Preprocedure demographic and clinical data of patients randomized to L-RIPC and control subjects
Variable
439
Control (n = 102)
L-RIPC (n = 98)
P
Demographics Age (years)
56.32 ± 14.30
59.86 ± 16.16
0.102
Male n (%)
62 (60.8)
47 (48.0)
0.069
37 (36.3)
35 (35.7)
0.934
Risk factors Diabetes mellitus N (%) Hypertension n (%)
63 (61.8)
62 (63.3)
0.827
Current smokers n (%)
74 (72.5)
71 (72.4)
0.987
BMI (kg/m2)
25.85 ± 5.58
25.79 ± 5.02
0.937
61.23 ± 10.14
61.79 ± 9.60
0.689
Clinical details LVEF (%) BMI body mass index, LVEF left ventricular ejection fraction, NYHA New York Heart Association, Scr serum creatinine, hs-CRP highsensitivity C-reactive protein, CK creatine phosphokinase, CK-MB cardiac isoenzyme of creatine phosphokinase, TnI troponin-I, ACEI angiotensinconverting enzyme inhibitor, ARB angiotensin II receptor blocker
NYHA class III/IV, n (%)
7 (6.9)
6 (6.1)
0.832
CCS grade III/IV, n (%)
26 (25.5)
28 (28.6)
0.624
Scr (lmol/L)
69.59 ± 16.17
67.03 ± 17.96
0.291
hs-CRP (mg/L)
1.41 (5.48)
1.37 (5.54)
0.830
CK (IU/L) CK-MB (IU/L)
77 (157) 10 (17)
78 (160) 11 (17)
0.531 0.709
TNI (ng/mL)
0.012 (0.016)
0.011 (0.017)
0.912
Statins
97 (95.1)
94 (95.9)
0.780
Beta-blockers
82 (80.4)
80 (81.6)
0.823
ACEI/ARB
94 (92.2)
87 (88.8)
0.415
Medications n (%)
Study Endpoints
Results
All patients were followed up for up to 6 months after discharge using a standardized protocol that included outpatient visits, telephone contacts, and the recording of recurrent cardiac events. The endpoints of adverse events, including cardiac death, hospital admissions with unstable angina/acute coronary syndrome, MI, heart failure, and stroke/transient ischemic attack, were recorded. The medical notes were then reviewed to confirm the details and the cause of death. The investigators who evaluated outcomes were blinded to treatment assignment.
Study Population
Statistical Analysis Continuous variables were summarized as mean ± standard deviation (SD) or median (quartiles) and compared by use of Student’s t test or a Mann–Whitney–Wilcoxon test when appropriate. Categorical data were expressed as numbers (percentages) and compared by a Chi square test. The Kaplan–Meier method was used for cumulative eventfree survival analysis, and the log-rank test for assessing the statistical differences between the curves. A value of P \ 0.05 was considered significant. All calculations were performed using SPSS statistical software for Windows (version 12.0).
Table 1 shows the demographics of the groups. There were no important differences between the groups. There were no significant differences between groups in baseline levels of hs-CRP, CK, CK-MB, and TNI. PCI Procedure There were no major procedure-related complications in either group (death or urgent revascularization within the first 24 h). Angiographic and periprocedure parameters were similar in both groups (Table 2). Compared with the control group, patients in L-RIPC group were observed with significantly lower incidences in Chest pain score [1 (P = 0.001) and ECG ST deviation [1 mm (P = 0.002). Biochemistry Concentrations at 24 h After PCI After PCI, the median TnI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.009 vs. 0.036 ng/mL, 123 vs. 186 IU/L, 15 vs. 27 IU/L; P \ 0.05). To ensure that our findings did not arise from side branch jailing in procedure, we repeated to compare the median
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Cell Biochem Biophys (2014) 70:437–442
Table 2 Angiographic and periprocedure data of patients randomized to L-RIPC and control subjects
Variable
Control (n = 102)
L-RIPC (n = 98)
P
Cuff-to-balloon time (h)
18.82 ± 0.90
18.84 ± 0.83
0.877 0.981
Target vessel n (%) LCX
5 (4.9)
6 (6.1)
LAD
25 (24.5)
24 (24.5)
RCA
16 (15.7)
16 (16.3)
Combined/other
56 (54.9)
52 (53.1)
A
17 (16.7)
15 (15.3)
B
45 (44.1)
46 (46.9)
C
40 (39.2)
37 (37.8)
Total time of ischemia (s)
49.25 ± 7.59
48.37 ± 8.23
Lesion type (AHA/ACC) 0.917
0.428
Clinical state during stent implantation
LCX left circumflex artery, LAD left anterior descending artery, RCA right coronary artery, SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate, TIMI thrombolysis in myocardial infarction
SBP (mmHg)
125.17 ± 15.27
126.03 ± 15.17
0.690
DBP (mmHg)
73.51 ± 8.36
73.89 ± 8.73
0.754
HR (bpm) Chest pain score [1 n (%)
69.06 ± 10.71 78(76.5)
69.02 ± 10.54 56(57.1)
0.979 0.004
ECG ST deviation [1 mm n (%)
36(35.3)
17(17.3)
0.004
Stent width (mm)
3.12 ± 0.31
3.07 ± 0.32
0.232
Total number of stents
2.39 ± 0.87
2.37 ± 0.80
0.834
Jailed side branch (TIMI 0/1)
8 (7.8)
6 (6.1)
0.634
Table 3 TnI, CK, CK-MB, and hs-CRP concentrations at 24 h after PCI Variable
Control (n = 102)
L-RIPC (n = 98)
TnI (ng/mL)
0.036 (1.029)
0.009 (0.329)
0.002
186 (405)
123 (286)
0.001
CK (IU/L) CK-MB (IU/L)
27 (50)
15 (34)
hs-CRP (mg/L)
1.37 (5.54)
1.38 (5.54)
P
\0.001 0.927
TnI troponin-I, CK creatine phosphokinase, CK-MB cardiac isoenzyme of creatine phosphokinase, hs-CRP high-sensitivity C-reactive protein
TnI, CK, and CK-MB concentrations excluding these patients between control group(94 patients) and L-RIPC group(92 patients). We also found that the median TnI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.008 vs. 0.04 ng/mL, 126 vs. 191 IU/L, 16 vs. 28 IU/L; P \ 0.05). There was no statistical difference in hs-CRP between two groups (Table 3). Follow-up Information at 6 months Follow-up information was available for 199 patients (99.5 %) from the 200 patients at 6 months. There were 16 adverse events (8.0 %) at 6 months after PCI. In those patients who received remote ischemic preconditioning before elective PCI, the adverse events’ rate at 6 months was lower (four hospital admissions with an acute coronary
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syndrome vs. 12 events in the control group: eight acute coronary syndromes, one acute left ventricular failure, two transient ischemic attacks, and one death). Kaplan–Meier curves were derived for the entire cohort of patients with complete data. Kaplan–Meier plots demonstrated a significant increase in adverse events’ rate in control group (v2 = 4.374, P = 0.036 by log-rank test) (Fig. 1).
Discussion In this clinical study, we demonstrate that L-RIPC induced by applying brief ischemia and reperfusion to the forearm with a blood pressure cuff at 18 h before PCI can reduce cardiac injury. This increased protection was shown by a significant reduction in serum troponin I release at 24 h after PCI. The use of L-RIPC before PCI appears to confer improved clinical outcome at 6 months. Remote ischemic preconditioning has a biphasic pattern of myocardial protection. An early classic phase is believed to act within a few minutes to 2 h after the preconditioning stimulus and is mediated through opening of mitochondrial ATP-sensitive potassium channels [10–12]. A late second window of protection occurs at 18–72 h and probably is the result of modified gene expression that suppresses the proinflammatory response to the ischemia/reperfusion injury [13, 14]. Several studies in adult patients have shown that transient upper- or lower-limb ischemia has the potential to attenuate myocardial injury, indicated by
Cell Biochem Biophys (2014) 70:437–442
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numbers of patients in most trials. In our larger randomized controlled study, those patients who received remote ischemic preconditioning at 18 h before elective PCI, the adverse events’ rate at 6 months was lower. The mechanism for this effect is unknown and is not associated with a change in plasma CRP concentration. Preconditioning has a beneficial platelet inhibitory and anti-thrombotic effect, which might stabilize vulnerable plaques, improve endothelial function, and reduce inflammation [22]. Furthermore, the effector signal-mediating myocardial protection after limb ischemia through remote ischemic preconditioning is not defined and appears to depend on both humoral and neuronal integrity [23].
Limitations Fig. 1 Kaplan–Meier graph of the adverse events’ rate at 6 months
troponin release, in a number of clinical situations, including coronary artery surgery and noncardiac surgery [15, 16]. Wagner and colleagues shown for the first time that late remote ischemic preconditioning induced by applying brief ischaemia and reperfusion 18 h before CABG can reduce injury above the myocardial protection provided by coldcrystalloid cardioplegia [17]. In our study, angiographic and periprocedure parameters were similar in both groups. We found that RIPC applied at 18 h before PCI reduced cTnI, CK, and CK-MB release at 24 h after PCI. Excluding patients with side branch jailing in procedure, we also found the same trend. Compared with the control group, L-RIPC appeared to increase the tolerance of the myocardium to ischemia. Chest discomfort and ECG ST-segment deviation during first coronary balloon occlusion were both significantly improved after L-RIPC. These results were similar to the CRISP Stent study (a prospective, randomized control trial). In the study, Hoole and colleagues demonstrated that remote ischemic preconditioning, applied to a broad case mix &1 h before PCI, attenuates PCI-related troponin release in patients undergoing elective PCI [18]. Although the magnetic resonance studies suggest that myocardial injury sustained during PCI is the result of more distal and peri-stent microcirculatory obstruction and/ or side-branch occlusion, myocyte damage and troponin release also may be associated with a form of ischemia/ reperfusion injury during stent deployment [19, 20]. Brevoord et al. [21] reported that there was no evidence that remote preconditioning reduced mortality or major adverse cardiac events, despite a reduction in biomarker release. However, that was only a Meta analysis, in the context of the current state of this field with only small
There are certain limitations in our study. First, the cTnI concentration was measured only once at 24 h after PCI, although it is generally accepted that the maximum concentration occurs between 12 and 24 h after myocyte necrosis. Second, this study is applied in a single center, the effectiveness make it attractive for testing in large-scale clinical trials.
Conclusions In conclusion, late remote ischemic preconditioning increases the tolerance of the myocardium to ischemia and reduces the prevalence of cTnI release after elective PCI. The observed cardio-protection reduces adverse events’ rate at 6 months after PCI. The effectiveness of remote ischemic preconditioning could have implications. Moreover, the intervention’s simplicity, low cost, and effectiveness make it attractive for testing in large-scale clinical trials.
Conflict of interest
None of authors have a conflict of interest.
Disclosure The contents are solely the responsibility of the authors and do not represent the official view of any organization.
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442 3. Bøtker, H. E., Kharbanda, R., Schmidt, M. R., et al. (2010). Remote ischaemic conditioning before hospital admission, as a complement to angioplasty, and effect on myocardial salvage in patients with acute myocardial infarction: A randomised trial. Lancet, 375, 727–734. 4. Nageh, T., Sherwood, R. A., Harris, B. M., et al. (2005). Prognostic role of cardiac troponin I after percutaneous coronary intervention in stable coronary disease. Heart, 91, 1181–1185. 5. Hausenloy, D. J., Mwamure, P. K., Venugopal, V., et al. (2007). Effect of remote ischaemic preconditioning on myocardial injury in patients undergoing coronary artery bypass graft surgery: A randomised controlled trial. Lancet, 370, 575–579. 6. Schmidt, M. R., Sloth, A. D., Johnsen, J., et al. (2012). Remote ischemic conditioning: The cardiologist’s perspective. Journal of Cardiovascular Medicine (Hagerstown), 13, 667–674. 7. Qiao, S., Xie, H., Wang, C., et al. (2012). Delayed anesthetic preconditioning protects against myocardial infarction via activation of nuclear factor-jB and upregulation of autophagy. Journal of Anesthesia, 27, 251–260. 8. Kocsis, G. F., Sa´rko¨zy, M., Bencsik, P., et al. (2012). Preconditioning protects the heart in a prolonged uremic condition. American Journal of Physiology Heart and Circulatory Physiology, 303, H1229–H1236. 9. Ahmed, L. A., Salem, H. A., Mawsouf, M. N., et al. (2012). Cardioprotective effects of ozone oxidative preconditioning in an in vivo model of ischemia/reperfusion injury in rats. Scandinavian Journal of Clinical and Laboratory Investigation, 72, 345–354. 10. Minamino, T. (2012). Cardioprotection from ischemia/reperfusion injury: basic and translational research. Circulation Journal, 76, 1074–1082. 11. Millar, P. J., & McGowan, C. L. (2012). Serial remote ischemic preconditioning and rhythmic isometric exercise training: A hypothesis. Medical Hypotheses, 78, 822–823. 12. Loukogeorgakis, S. P., Williams, R., Panagiotidou, A. T., et al. (2007). Transient limb ischemia induces remote preconditioning and remote postconditioning in humans by a K(ATP)-channel dependent mechanism. Circulation, 116, 1386–1395. 13. Duan, X., Ji, B., Wang, X., et al. (2012). Expression of microRNA-1 and microRNA-21 in different protocols of ischemic conditioning in an isolated rat heart model. Cardiology, 122, 36–43.
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Cell Biochem Biophys (2014) 70:437–442 14. Dow, J., Bhandari, A., Simkhovich, B. Z., et al. (2012). The effect of acute versus delayed remote ischemic preconditioning on reperfusion induced ventricular arrhythmias. Journal of Cardiovascular Electrophysiology, 23, 1374–1383. 15. Meybohm, P., Zacharowski, K., Cremer, J., RIP Heart-Study Investigator Group, et al. (2012). Remote ischaemic preconditioning for heart surgery. The study design for a multi-center randomized double-blinded controlled clinical trial—The RIPHeart-Study. European Heart Journal, 33, 1423–1426. 16. Pilcher, J. M., Young, P., Weatherall, M., et al. (2012). A systematic review and meta-analysis of the cardioprotective effects of remote ischaemic preconditioning in open cardiac surgery. Journal of the Royal Society of Medicine, 105, 436–445. 17. Wagner, R., Piler, P., Bedanova, H., et al. (2010). Myocardial injury is decreased by late remote ischaemic preconditioning and aggravated by tramadol in patients undergoing cardiac surgery: A randomised controlled trial. Interactive Cardio Vascular and Thoracic Surgery, 11, 758–762. 18. Hoole, S. P., Heck, P. M., Sharples, L., et al. (2009). Cardiac remote ischemic preconditioning in coronary stenting (CRISP stent) study: A prospective, randomized control trial. Circulation, 119, 820–827. 19. Porto, I., Selvanayagam, J. B., Van Gaal, W. J., et al. (2006). Plaque volume and occurrence and location of periprocedural myocardial necrosis after percutaneous coronary intervention: insights from delayed-enhancement magnetic resonanceimaging, thrombolysis in myocardial infarction myocardial perfusion grade analysis, and intravascular ultrasound. Circulation, 114, 662–669. 20. Ramirez-Moreno, A., Cardenal, R., Pera, C., et al. (2004). Predictors and prognostic value of myocardial injury following stent implantation. International Journal of Cardiology, 97, 193–198. 21. Brevoord, D., Kranke, P., Kuijpers, M., et al. (2012). Remote ischemic conditioning to protect against ischemia-reperfusion injury: A systematic review and meta-analysis. PLoS ONE, 7, e42179. 22. Dm, R., Ve, H., Ge, T., et al. (2012). Remote ischemic preconditioning reduces thrombus formation in the rat. The Journal of Thrombosis and Haemostasis, 10, 1538–7836. 23. Hepponstall, M., Ignjatovic, V., Binos, S., et al. (2012). Remote ischemic preconditioning (RIPC) Modifies plasma proteome in humans. PLoS ONE, 7, e48284.
ORIGINAL PAPER
Late Remote Ischemic Preconditioning Provides Benefit to Patients Undergoing Elective Percutaneous Coronary Intervention Zhi Liu • Yan-Ling Wang • Dong Xu • Qi Hua • Yan-Yan Chu • Xun-Ming Ji
Published online: 12 July 2014 Ó Springer Science+Business Media New York 2014
Abstract To assess whether late remote ischemic preconditioning (L-RIPC) is effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention (PCI). L-RIPC is exerted by newly synthesized cardioprotective proteins. The cardioprotective effects of L-RIPC are more durable. 200 consecutive patients undergoing elective PCI were randomized to receive L-RIPC (induced by three 5-minute inflations of a blood pressure cuff to 200 mmHg around the upper arm, followed by 5-min intervals of reperfusion) or control (an uninflated cuff around the arm) at 18 h before PCI. Creatine phosphokinase (CK), its cardiac isoenzyme (CK-MB), troponin I (TNI), and high-sensitivity C-reactive protein (hs-CRP) levels were measured at 24 h after PCI. Adverse events’ rates at 6 months were assessed. Compared with the control group, patients in L-RIPC group were observed with significantly lower incidences in Chest pain score [1 and ECG ST deviation [1 mm (P \ 0.05). The median TNI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.009 vs. 0.036 ng/mL, 123 vs. 186 IU/L, 15 vs. 27 IU/L; P \ 0.05). There was no statistical difference in hs-CRP between two groups. At 6 months, the adverse events’ rate was lower in the L-RIPC
The authors Zhi Liu and Yan-Ling Wang have contributed equally to this work and should be considered co-first authors. Z. Liu Y.-L. Wang D. Xu Q. Hua Y.-Y. Chu Department of Cardiology, Xuanwu Hospital, Capital Medical University, Beijing, China X.-M. Ji (&) Department of Intervention, Xuanwu Hospital, Capital Medical University, 45 Changchun Street, Xicheng District, Beijing 100053, China e-mail: [email protected]
group (P = 0.036). L-RIPC is effective in myocardial protection in patients undergoing elective PCI and reduces adverse events’ rate at 6 months. Keywords Late remote ischemic preconditioning Ischemic heart disease Elective percutaneous coronary intervention Troponin I
Introduction Brief episodes of nonlethal ischemia and reperfusion applied to the organ or tissue distal to the heart before a prolonged ischemia–reperfusion injury is known as remote ischemic preconditioning (RIPC) [1–3], which has been shown to protect myocardium against ischemia–reperfusion injury and reduce the cardiac troponin I (cTnI) release in patients undergoing PCI [4, 5]. The cardioprotective effects of remote ischemic preconditioning disappear 2–3 h after the onset of the preconditioning insult, but reappear 18 h later and lasting up to 3 days [6]. This phenomenon is recognized as ‘‘late/delayed’’ ischemic preconditioning. A major difference in the cardioprotective mechanisms of early and late preconditioning is that early ischemic preconditioning results in the modification or turnover/translocation of existing molecules, whereas late ischemic preconditioning is exerted by newly synthesized cardioprotective proteins [7]. They transcribe the de novo synthesized proteins involved in late ischemic preconditioning, including manganese superoxide dismutase, heat stress proteins, and inducible nitric oxide synthase [8]. The cardioprotective effects of late ischemic preconditioning is more durable [9]. However, the late-phase effects of RIPC (L-RIPC) have not yet been studied in patients undergoing PCI. Therefore, we aimed to assess whether L-RIPC is
123
438
effective in myocardial protection in patients with ischemic heart disease undergoing elective percutaneous coronary intervention.
Cell Biochem Biophys (2014) 70:437–442
Thereafter, all patients underwent PCI by an interventionist blinded to the study allocation. Percutaneous Coronary Intervention
Materials and Methods Patients 232 consecutive patients referred for elective percutaneous coronary intervention, who were admitted to our institute, were enrolled from January 2010 to July 2011. The study protocol was approved by the ethics committee of our institution, and written informed consent was obtained from all participating subjects. Exclusion criteria were (1) emergency PCI, (2) elevation of cTnI before PCI, (3) nicorandil or glibenclamide use (preconditioning-mimetic and preconditioning blocking medication, respectively), (4) severe comorbidity (estimated life expectancy \6 months), and (5) recent systemic infection. A total of 200 consenting patients were randomized to receive either control treatment (102 patients) or the L-RIPC (98 patients). No changes were made to the clinical care of the patients enrolled in this study. Clinical Data Collection A special questionnaire was used to collect information on lifestyle, environmental factors, and medical history of the study population. Patients who reported smoking at least one cigarette per day for at least 1 year were defined as current smokers. Diabetes mellitus was defined as a previous diagnosis, use of diet or antidiabetic medicines, or fasting venous blood glucose level C126 mg/dL on two occasions in previously untreated patients. Patients who received medications for hypertension or those with seated systolic blood pressure C140 mmHg and/or diastolic blood pressure C90 mmHg on at least three separate clinic visits were also identified. Body mass index (BMI) was calculated as the weight in kilograms divided by the square of the height in meters. Left ventricular ejection fractions (LVEF) were measured with Doppler echocardiography at enrolment. Protocols for Late Remote Ischemic Preconditioning L-RIPC was applied at 18–24 h before starting the PCI. L-RIPC consisted of three five-minute cycles of upper limb ischaemia and three five-minute pauses using a blood pressure cuff inflated to 200 mmHg. Control patients had a similar cuff placed around the upper arm, but it was not inflated. Cuff-to-balloon time was the time between the last blood pressure cuff deflation and stent balloon inflation.
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PCI was performed via a radial arterial approach with 5F guiding catheters. All patients received aspirin 300 mg and clopidogrel 300 mg at least 6 h before PCI and were anticoagulated with a heparin bolus (70–100 U/kg) after arterial sheath insertion to achieve an activated clotting time [250 s. Glycoprotein IIb/IIIa antagonists were not administered. Ultravist (Omnipaque) (GE HealthCare, Shanghai, China) was used as the contrast agent in all cases. Lesion complexity was classified into Types A, B, and C according to the American Heart Association/ American College of Cardiology grading system. Coronary stents were implanted in all patients of both groups after balloon pre-dilatation of the target lesion according to the decision of the operators. Total time of ischemia was calculated as the time of duration of coronary balloon occlusion. All patients received aspirin 100 mg and clopidogrel 75 mg everyday for 1 year after drug-eluting stent implantation, in accordance with local practice. All other medication was given at the discretion of the attending physician, and the PCI strategy was at the discretion of the treating interventional cardiologist according to conventional practice. Chest pain severity during PCI was graded on a scale of 0 for no pain to ten for the most severe discomfort ever experienced. Angiographic success was defined as a residual stenosis of\15 % by visual angiographic assessment. Blood Sampling and Laboratory Measurements Venous blood samples for measurements were obtained at enrolment and 24 h after PCI. Creatine phosphokinase (CK), its cardiac isoenzyme (CK-MB), troponin I (TNI), and high-sensitivity C-reactive protein (hs-CRP) levels were measured. Blood samples were collected in serum separation tubes. Serum hs-CRP, CK, and CK-MB concentrations were determined by our biochemistry department using standard methods. hs-CRP concentrations between 0 and 3 mg/L and CK concentrations between 24 and 195 IU/L were considered to be within the reference range. The reference range of CK-MB was 0–25 IU/L. TNI levels were measured with the immuno-analyzer, using a two-site fluorometric enzyme immunoassay (Mitsubishi Kagaku Latron, Inc, Japan). Values are expressed as nanograms per milliliter. The 99th percentile of the cTnI level in a reference population (upper reference limit) of healthy volunteers was below the lower limit of detection of 0.02 ng/mL. The variation coefficient, a measure of precision within the analytical range, is \10 %.
Cell Biochem Biophys (2014) 70:437–442 Table 1 Preprocedure demographic and clinical data of patients randomized to L-RIPC and control subjects
Variable
439
Control (n = 102)
L-RIPC (n = 98)
P
Demographics Age (years)
56.32 ± 14.30
59.86 ± 16.16
0.102
Male n (%)
62 (60.8)
47 (48.0)
0.069
37 (36.3)
35 (35.7)
0.934
Risk factors Diabetes mellitus N (%) Hypertension n (%)
63 (61.8)
62 (63.3)
0.827
Current smokers n (%)
74 (72.5)
71 (72.4)
0.987
BMI (kg/m2)
25.85 ± 5.58
25.79 ± 5.02
0.937
61.23 ± 10.14
61.79 ± 9.60
0.689
Clinical details LVEF (%) BMI body mass index, LVEF left ventricular ejection fraction, NYHA New York Heart Association, Scr serum creatinine, hs-CRP highsensitivity C-reactive protein, CK creatine phosphokinase, CK-MB cardiac isoenzyme of creatine phosphokinase, TnI troponin-I, ACEI angiotensinconverting enzyme inhibitor, ARB angiotensin II receptor blocker
NYHA class III/IV, n (%)
7 (6.9)
6 (6.1)
0.832
CCS grade III/IV, n (%)
26 (25.5)
28 (28.6)
0.624
Scr (lmol/L)
69.59 ± 16.17
67.03 ± 17.96
0.291
hs-CRP (mg/L)
1.41 (5.48)
1.37 (5.54)
0.830
CK (IU/L) CK-MB (IU/L)
77 (157) 10 (17)
78 (160) 11 (17)
0.531 0.709
TNI (ng/mL)
0.012 (0.016)
0.011 (0.017)
0.912
Statins
97 (95.1)
94 (95.9)
0.780
Beta-blockers
82 (80.4)
80 (81.6)
0.823
ACEI/ARB
94 (92.2)
87 (88.8)
0.415
Medications n (%)
Study Endpoints
Results
All patients were followed up for up to 6 months after discharge using a standardized protocol that included outpatient visits, telephone contacts, and the recording of recurrent cardiac events. The endpoints of adverse events, including cardiac death, hospital admissions with unstable angina/acute coronary syndrome, MI, heart failure, and stroke/transient ischemic attack, were recorded. The medical notes were then reviewed to confirm the details and the cause of death. The investigators who evaluated outcomes were blinded to treatment assignment.
Study Population
Statistical Analysis Continuous variables were summarized as mean ± standard deviation (SD) or median (quartiles) and compared by use of Student’s t test or a Mann–Whitney–Wilcoxon test when appropriate. Categorical data were expressed as numbers (percentages) and compared by a Chi square test. The Kaplan–Meier method was used for cumulative eventfree survival analysis, and the log-rank test for assessing the statistical differences between the curves. A value of P \ 0.05 was considered significant. All calculations were performed using SPSS statistical software for Windows (version 12.0).
Table 1 shows the demographics of the groups. There were no important differences between the groups. There were no significant differences between groups in baseline levels of hs-CRP, CK, CK-MB, and TNI. PCI Procedure There were no major procedure-related complications in either group (death or urgent revascularization within the first 24 h). Angiographic and periprocedure parameters were similar in both groups (Table 2). Compared with the control group, patients in L-RIPC group were observed with significantly lower incidences in Chest pain score [1 (P = 0.001) and ECG ST deviation [1 mm (P = 0.002). Biochemistry Concentrations at 24 h After PCI After PCI, the median TnI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.009 vs. 0.036 ng/mL, 123 vs. 186 IU/L, 15 vs. 27 IU/L; P \ 0.05). To ensure that our findings did not arise from side branch jailing in procedure, we repeated to compare the median
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440
Cell Biochem Biophys (2014) 70:437–442
Table 2 Angiographic and periprocedure data of patients randomized to L-RIPC and control subjects
Variable
Control (n = 102)
L-RIPC (n = 98)
P
Cuff-to-balloon time (h)
18.82 ± 0.90
18.84 ± 0.83
0.877 0.981
Target vessel n (%) LCX
5 (4.9)
6 (6.1)
LAD
25 (24.5)
24 (24.5)
RCA
16 (15.7)
16 (16.3)
Combined/other
56 (54.9)
52 (53.1)
A
17 (16.7)
15 (15.3)
B
45 (44.1)
46 (46.9)
C
40 (39.2)
37 (37.8)
Total time of ischemia (s)
49.25 ± 7.59
48.37 ± 8.23
Lesion type (AHA/ACC) 0.917
0.428
Clinical state during stent implantation
LCX left circumflex artery, LAD left anterior descending artery, RCA right coronary artery, SBP systolic blood pressure, DBP diastolic blood pressure, HR heart rate, TIMI thrombolysis in myocardial infarction
SBP (mmHg)
125.17 ± 15.27
126.03 ± 15.17
0.690
DBP (mmHg)
73.51 ± 8.36
73.89 ± 8.73
0.754
HR (bpm) Chest pain score [1 n (%)
69.06 ± 10.71 78(76.5)
69.02 ± 10.54 56(57.1)
0.979 0.004
ECG ST deviation [1 mm n (%)
36(35.3)
17(17.3)
0.004
Stent width (mm)
3.12 ± 0.31
3.07 ± 0.32
0.232
Total number of stents
2.39 ± 0.87
2.37 ± 0.80
0.834
Jailed side branch (TIMI 0/1)
8 (7.8)
6 (6.1)
0.634
Table 3 TnI, CK, CK-MB, and hs-CRP concentrations at 24 h after PCI Variable
Control (n = 102)
L-RIPC (n = 98)
TnI (ng/mL)
0.036 (1.029)
0.009 (0.329)
0.002
186 (405)
123 (286)
0.001
CK (IU/L) CK-MB (IU/L)
27 (50)
15 (34)
hs-CRP (mg/L)
1.37 (5.54)
1.38 (5.54)
P
\0.001 0.927
TnI troponin-I, CK creatine phosphokinase, CK-MB cardiac isoenzyme of creatine phosphokinase, hs-CRP high-sensitivity C-reactive protein
TnI, CK, and CK-MB concentrations excluding these patients between control group(94 patients) and L-RIPC group(92 patients). We also found that the median TnI, CK, and CK-MB concentrations at 24 h were lower in the L-RIPC group (0.008 vs. 0.04 ng/mL, 126 vs. 191 IU/L, 16 vs. 28 IU/L; P \ 0.05). There was no statistical difference in hs-CRP between two groups (Table 3). Follow-up Information at 6 months Follow-up information was available for 199 patients (99.5 %) from the 200 patients at 6 months. There were 16 adverse events (8.0 %) at 6 months after PCI. In those patients who received remote ischemic preconditioning before elective PCI, the adverse events’ rate at 6 months was lower (four hospital admissions with an acute coronary
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syndrome vs. 12 events in the control group: eight acute coronary syndromes, one acute left ventricular failure, two transient ischemic attacks, and one death). Kaplan–Meier curves were derived for the entire cohort of patients with complete data. Kaplan–Meier plots demonstrated a significant increase in adverse events’ rate in control group (v2 = 4.374, P = 0.036 by log-rank test) (Fig. 1).
Discussion In this clinical study, we demonstrate that L-RIPC induced by applying brief ischemia and reperfusion to the forearm with a blood pressure cuff at 18 h before PCI can reduce cardiac injury. This increased protection was shown by a significant reduction in serum troponin I release at 24 h after PCI. The use of L-RIPC before PCI appears to confer improved clinical outcome at 6 months. Remote ischemic preconditioning has a biphasic pattern of myocardial protection. An early classic phase is believed to act within a few minutes to 2 h after the preconditioning stimulus and is mediated through opening of mitochondrial ATP-sensitive potassium channels [10–12]. A late second window of protection occurs at 18–72 h and probably is the result of modified gene expression that suppresses the proinflammatory response to the ischemia/reperfusion injury [13, 14]. Several studies in adult patients have shown that transient upper- or lower-limb ischemia has the potential to attenuate myocardial injury, indicated by
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numbers of patients in most trials. In our larger randomized controlled study, those patients who received remote ischemic preconditioning at 18 h before elective PCI, the adverse events’ rate at 6 months was lower. The mechanism for this effect is unknown and is not associated with a change in plasma CRP concentration. Preconditioning has a beneficial platelet inhibitory and anti-thrombotic effect, which might stabilize vulnerable plaques, improve endothelial function, and reduce inflammation [22]. Furthermore, the effector signal-mediating myocardial protection after limb ischemia through remote ischemic preconditioning is not defined and appears to depend on both humoral and neuronal integrity [23].
Limitations Fig. 1 Kaplan–Meier graph of the adverse events’ rate at 6 months
troponin release, in a number of clinical situations, including coronary artery surgery and noncardiac surgery [15, 16]. Wagner and colleagues shown for the first time that late remote ischemic preconditioning induced by applying brief ischaemia and reperfusion 18 h before CABG can reduce injury above the myocardial protection provided by coldcrystalloid cardioplegia [17]. In our study, angiographic and periprocedure parameters were similar in both groups. We found that RIPC applied at 18 h before PCI reduced cTnI, CK, and CK-MB release at 24 h after PCI. Excluding patients with side branch jailing in procedure, we also found the same trend. Compared with the control group, L-RIPC appeared to increase the tolerance of the myocardium to ischemia. Chest discomfort and ECG ST-segment deviation during first coronary balloon occlusion were both significantly improved after L-RIPC. These results were similar to the CRISP Stent study (a prospective, randomized control trial). In the study, Hoole and colleagues demonstrated that remote ischemic preconditioning, applied to a broad case mix &1 h before PCI, attenuates PCI-related troponin release in patients undergoing elective PCI [18]. Although the magnetic resonance studies suggest that myocardial injury sustained during PCI is the result of more distal and peri-stent microcirculatory obstruction and/ or side-branch occlusion, myocyte damage and troponin release also may be associated with a form of ischemia/ reperfusion injury during stent deployment [19, 20]. Brevoord et al. [21] reported that there was no evidence that remote preconditioning reduced mortality or major adverse cardiac events, despite a reduction in biomarker release. However, that was only a Meta analysis, in the context of the current state of this field with only small
There are certain limitations in our study. First, the cTnI concentration was measured only once at 24 h after PCI, although it is generally accepted that the maximum concentration occurs between 12 and 24 h after myocyte necrosis. Second, this study is applied in a single center, the effectiveness make it attractive for testing in large-scale clinical trials.
Conclusions In conclusion, late remote ischemic preconditioning increases the tolerance of the myocardium to ischemia and reduces the prevalence of cTnI release after elective PCI. The observed cardio-protection reduces adverse events’ rate at 6 months after PCI. The effectiveness of remote ischemic preconditioning could have implications. Moreover, the intervention’s simplicity, low cost, and effectiveness make it attractive for testing in large-scale clinical trials.
Conflict of interest
None of authors have a conflict of interest.
Disclosure The contents are solely the responsibility of the authors and do not represent the official view of any organization.
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