Evidence of pleiotropy by statins: Leukocyte Rho kinase (ROCK) activity and pretreated statin before percutaneous coronary interventions are clinical vascular outcome predictors

TY - JOUR

T1 - Evidence of pleiotropy by statins

T2 - Leukocyte Rho kinase (ROCK) activity and pretreated statin before percutaneous coronary interventions are clinical vascular outcome predictors

AU - Liu, Ping Yen

AU - Lee, Po Tseng

AU - Chang, Wei Ting

AU - Tai, Yun Ling

AU - Chao, Ting Hsing

AU - Lee, Cheng Han

AU - Li, Yi Heng

AU - Chen, Jyh Hong

AU - Tsai, Liang Miin

AU - Liao, James K.

N1 - Funding Information: Statin therapy prior to PCI is associated with overall improvement of cardiovascular outcome, mortality and peri-procedural myocardial injury after PCI in coronary artery disease (CAD) patients [1–3] . In one meta-analysis report [4] , statin pre-treated was better than nothing in the odds ratio of future coronary event outcomes. Interestingly, the level of low-density lipoprotein (LDL) cholesterol did not correlate with their outcome after PCI. This result probably implied that statin therapy has vascular protection beyond LDL lowering effect, but not for the whole group. However, it remained unknown what factors or conditions can be more beneficial from statin pretreatment during the PCI procedure. Mechanisms had been proposed as the inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) [5–7] and inflammation reaction including c reactive protein (CRP) [8] . These so-called “pleiotropic” or cholesterol-independent effects of statins have been associated with the mechanisms via improvement in flow-mediated vasodilation [9,10] , anti-inflammation [8,11] and also enhancement function of circulating vascular endothelial progenitor cells [12] . To test whether these important vascular biomarkers can predict those “high-risk” subgroup to be more beneficial to statin pretreatment strategy during PCI procedure, we conduct a clinical observational study based on the interplay of “pretreatment statin or not” and “the level of CRP or leukocyte ROCK activity” at baseline or after PCI, partially according our previous reports and methodologies [13–16] . We studied 138 patients who were documented as CAD with another 50 patients with normal coronary arteries who were compared as the control group. Patients' characteristics were presented in Table 1 . The prevalences of smoking behavior history, diabetes mellitus, hypertension, the levels of cholesterol as well as the baseline CRP and ROCK activity were all higher in the CAD group. There was no difference in the traditional cardiovascular risk factors, LDL-C levels and other inflammatory biomarkers when we divided the CAD group subjects into statin naïve or statin pretreated subgroups (Table S1). These data indicated that our study subgroups were well matched. The comparative procedural and angiographic characteristics of the subgroup defined by the pretreatment of statin or not were similar and presented in Table S1. The baseline ROCK activity did not correlate with baseline CRP levels (P = 0.33). Multiple logistic regression analysis with forward stepwise selection showed that in addition to hypertension (Odds ratio (OR) 3.2), smoking behavior (OR 2.3) and diabetes mellitus (OR 2.1), baseline higher levels of ROCK activity (> 0.38) remained an independent predictor for CAD diagnosis (OR 2.8) (all P value 0.38, n = 68) had 28 coronary events during the follow-up period, whereas patients with lower levels (≤ 0.38, n = 70) had only 21 events (40.2% vs. 30%, P = 0.03) ( Fig. 2 A). This indicates that baseline ROCK activity itself is an outcome predictor after PCI. As for ROCK activity after PCI, those patients with higher levels of leukocyte ROCK activity after PCI (> 0.9, n = 62) had 27 coronary events during the follow-up period, whereas patients with lower levels (≤ 0.9, n = 76) had only 22 events ( Fig. 2 B). In addition, statin pretreatment affected the prognosis after a 2-year follow-up. Those patients with statin pretreatment were observed to have less subsequent cardiovascular or coronary events during follow-up ( Fig. 2 C). These data support the hypothesis that statin pretreatment can not only lower the baseline ROCK activity, but also ameliorate the responsive increase of ROCK activity during PCI procedure. Multivariate forward stepwise Cox proportional hazard analysis showed that higher levels of baseline ROCK activity (> 0.38) or after PCI (> 0.9) and smoking were independent predictors of subsequent coronary events ( Table 2 ). Finally, the protective effect of pretreated statin was not associated with the type, duration or dosage of statin nor the stent type used (data not shown, all P > 0.05). Interestingly, the outcome after PCI was not related to their baseline LDL level. However, the improvement in subsequent coronary events in patients with statin pretreatment was observed more significantly among patients with higher leukocyte ROCK activity (> 0.9) after PCI. These results suggest that leukocyte ROCK activity after PCI predicts long-term outcome in patients especially among those without pre-treatment of statins. Our study was limited due to retrospective design, smaller size of population and lack of other associated inflammatory marker inputs. This research was supported in part by the Headquarters of University Advancement at the National Cheng Kung University, sponsored by the Ministry of Education and the National Science Council ( 95-2314-B-006-036-MY2 , 98-2314-B-006-047-MY3 and 101-2314-B-006-075-MY2 ), and the National Cheng Kung University Hospital, Tainan, Taiwan ( NCKUH-10204018 ) also the grant funded by the Ministry of Health and Welfare in Taiwan ( MOHW103-TDU-B-211-113002 ). Funding Information: Statin therapy prior to PCI is associated with overall improvement of cardiovascular outcome, mortality and peri-procedural myocardial injury after PCI in coronary artery disease (CAD) patients [1–3] . In one meta-analysis report [4] , statin pre-treated was better than nothing in the odds ratio of future coronary event outcomes. Interestingly, the level of low-density lipoprotein (LDL) cholesterol did not correlate with their outcome after PCI. This result probably implied that statin therapy has vascular protection beyond LDL lowering effect, but not for the whole group. However, it remained unknown what factors or conditions can be more beneficial from statin pretreatment during the PCI procedure. Mechanisms had been proposed as the inhibition of Rho-associated coiled-coil containing protein kinase (ROCK) [5–7] and inflammation reaction including c reactive protein (CRP) [8] . These so-called “pleiotropic” or cholesterol-independent effects of statins have been associated with the mechanisms via improvement in flow-mediated vasodilation [9,10] , anti-inflammation [8,11] and also enhancement function of circulating vascular endothelial progenitor cells [12] . To test whether these important vascular biomarkers can predict those “high-risk” subgroup to be more beneficial to statin pretreatment strategy during PCI procedure, we conduct a clinical observational study based on the interplay of “pretreatment statin or not” and “the level of CRP or leukocyte ROCK activity” at baseline or after PCI, partially according our previous reports and methodologies [13–16] . We studied 138 patients who were documented as CAD with another 50 patients with normal coronary arteries who were compared as the control group. Patients' characteristics were presented in Table 1 . The prevalences of smoking behavior history, diabetes mellitus, hypertension, the levels of cholesterol as well as the baseline CRP and ROCK activity were all higher in the CAD group. There was no difference in the traditional cardiovascular risk factors, LDL-C levels and other inflammatory biomarkers when we divided the CAD group subjects into statin naïve or statin pretreated subgroups ( Table S1 ). These data indicated that our study subgroups were well matched. The comparative procedural and angiographic characteristics of the subgroup defined by the pretreatment of statin or not were similar and presented in Table S1 . The baseline ROCK activity did not correlate with baseline CRP levels (P = 0.33). Multiple logistic regression analysis with forward stepwise selection showed that in addition to hypertension (Odds ratio (OR) 3.2), smoking behavior (OR 2.3) and diabetes mellitus (OR 2.1), baseline higher levels of ROCK activity (> 0.38) remained an independent predictor for CAD diagnosis (OR 2.8) (all P value 0.38, n = 68) had 28 coronary events during the follow-up period, whereas patients with lower levels (≤ 0.38, n = 70) had only 21 events (40.2% vs. 30%, P = 0.03) ( Fig. 2 A ). This indicates that baseline ROCK activity itself is an outcome predictor after PCI. As for ROCK activity after PCI, those patients with higher levels of leukocyte ROCK activity after PCI (> 0.9, n = 62) had 27 coronary events during the follow-up period, whereas patients with lower levels (≤ 0.9, n = 76) had only 22 events ( Fig. 2 B). In addition, statin pretreatment affected the prognosis after a 2-year follow-up. Those patients with statin pretreatment were observed to have less subsequent cardiovascular or coronary events during follow-up ( Fig. 2 C). These data support the hypothesis that statin pretreatment can not only lower the baseline ROCK activity, but also ameliorate the responsive increase of ROCK activity during PCI procedure. Multivariate forward stepwise Cox proportional hazard analysis showed that higher levels of baseline ROCK activity (> 0.38) or after PCI (> 0.9) and smoking were independent predictors of subsequent coronary events ( Table 2 ). Finally, the protective effect of pretreated statin was not associated with the type, duration or dosage of statin nor the stent type used (data not shown, all P > 0.05). Interestingly, the outcome after PCI was not related to their baseline LDL level. However, the improvement in subsequent coronary events in patients with statin pretreatment was observed more significantly among patients with higher leukocyte ROCK activity (> 0.9) after PCI. These results suggest that leukocyte ROCK activity after PCI predicts long-term outcome in patients especially among those without pre-treatment of statins. Our study was limited due to retrospective design, smaller size of population and lack of other associated inflammatory marker inputs. This research was supported in part by the Headquarters of University Advancement at the National Cheng Kung University, sponsored by the Ministry of Education and the National Science Council ( 95-2314-B-006-036-MY2 , 98-2314-B-006-047-MY3 and 101-2314-B-006-075-MY2 ), and the National Cheng Kung University Hospital, Tainan, Taiwan ( NCKUH-10204018 ).

PY - 2014/9

Y1 - 2014/9

UR - http://www.scopus.com/inward/record.url?scp=84906317827&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84906317827&partnerID=8YFLogxK

U2 - 10.1016/j.ijcard.2014.06.059

DO - 10.1016/j.ijcard.2014.06.059

M3 - Article

C2 - 25034804

AN - SCOPUS:84906317827

VL - 176

SP - 250

EP - 253

JO - International Journal of Cardiology

JF - International Journal of Cardiology

SN - 0167-5273

IS - 1

ER -