Objectives: To demonstrate the differential effect of atorvastatin and rosuvastatin on the Intercellular adhesive molecule 1(ICAM-1) in acute ischaemic stroke (AIS) patients.
Methods: The case-control study was done in the Department of Clinical Pharmacology and Therapeutic, Mustansiriyah University, Baghdad, from May to July, 2020 and involved sixty-six patients with AIS compared with twenty-two healthy controls. They were divided into four groups; Group I: Patients with AIS on atorvastatin therapy (n=22). Group II: Patients with AIS on rosuvastatin therapy (n=22), Group III: Patients with AIS not on statin therapy (n=22), Group IV: Healthy controls (n=22). Anthropometric, lipid, and pressure profiles were evaluated. As well, ICAM-1 serum level was estimated in different treatment groups. SPSS version 20.00 was used for data analysis.
Results ICAM-1 levels were increased in patients with AIS compared to the controls. ICAM-1 serum levels were higher in patients with AIS not on statins therapy compared to the controls (P=0.0001), and it was lower in patients with AIS on statins therapy (77.41±16.46) as compared with patients with AIS not on statin therapy (118.71±10.38), (P=0.001). Besides, there was differential effect of statin therapy on the ICAM-1 serum level, which was higher in patients with AIS on rosuvastatin (72.93±9.03) as compared with patients with AIS on atorvastatin (70.61±10.94), (P=0.44). Stroke risk score (SRS) was lower in patients with AIS on atorvastatin therapy (7.60±2.05) as compared with patients with AIS on rosuvastatin therapy (9.11±2.72), (P=0.04).
Conclusion: ICAM-1 is regarded as a surrogate biomarker of AIS in patients with underlying poor cardio-metabolic profile. Both atorvastatin and rosuvastatin are effective in attenuation of AIS measured by lowering of ICAM-1 serum levels.
Keywords: Acute ischemic stroke, Atorvastatin, Rosuvastatin, Intercellular adhesive molecule 1. (JPMA 71: S-11 [Suppl. 8]; 2021)
Acute ischaemic stroke (AIS) is a prompt inception of focal neurological deficit for more than 24 hours. AIS represent 70-80% of total stroke caused by different cardio-metabolic risk factors including; hypertension, dyslipidaemia, coagulation disorders, vasculitis and atrial fibrillation.2
Different studies identified that hypo-perfused and electrically nonfunctional part of the brain termed ischaemic penumbra in AIS is converted to irreversibly injured tissue over time (known as ischaemic core), but at a rate differs considerably between individuals.3 However, with a fast reperfusion, this penumbral region can be salvaged and can recover completely. This landmark finding formed the rational for the reperfusion therapies that have transformed outcomes for patients with ischaemic stroke since the first positive trial of stroke thrombolysis.4
Although different mechanisms are involved in AIS pathogenesis, increasing evidence shows that ischaemic injury and inflammation are the central mechanisms in the pathogenesis and progression of AIS. AIS triggers ischaemic cascades, which ultimately results in vascular injury, damage of blood brain barrier (BBB), brain oedema, and permanent cerebral injury.5
It has been reported that different biomarkers such as brain natriuretic peptide may reflect underlying cardio-metabolic derangements in patients with AIS.6
Intercellular adhesive molecule 1(ICAM-1), also recognized as cluster of differentiation 54 (CD54), is a trans-membrane glycoprotein belonging to immunoglobulin super-family of adhesive molecules, which is important in cell-cell interactions of immunological response.7 ICAM-1 over-expression is linked with different disorders including; chronic metabolic diseases, inflammatory illnesses, and malignancies. ICAM-1 triggers BBB disruption during AIS via the recruitment of leukocytes toward CNS.8
Statins inhibit de novo cholesterol biosynthesis through inhibiting the activity of hydroxyl-methyl-glutaryl-coenzyme-A (HMG-Co-A) reductase, a rate limiting enzyme in cholesterol biosynthesis.9 The interruption of mevalonate pathway by statins is with the pleiotropic effects of statins. In addition, administration of statins during AIS may avert stroke sequence and relapse.10
Therefore, the aim of the current study was to demonstrate the differential effect of atorvastatin and rosuvastatin on ICAM-1 in patients with AIS
Patients and Methods
This case-control study was completed in the Department of Clinical Pharmacology and therapeutic, College of Medicine, AL-Mustansiriyah University, in collaboration with the Al-Yarmouk Teaching Hospital, Baghdad-Iraq from May to July, 2020. This study was permitted by Scientific Committee and Institutional Review Board, College of Medicine, AL-Mustansiriyah University.
A total of 88 participants (66 patients with AIS and 22 healthy controls) were involved in this study. The sample size was calculated according to the population size regarding 95% confidence interval and 5% marginal error.
The selected 66 patients and healthy controls were divided into the following groups;
Group I: Patients with AIS on atorvastatin therapy (n=22). Group II: Patients with AIS on rosuvastatin therapy (n=22), Group III: Patients with AIS not on statin therapy (n=22), Group IV: Healthy controls (n=22).
Informed verbal consent was obtained from all recruited patients and healthy controls before starting of the study.
Inclusion criteria: Patients age > 45 years, with neurological symptoms of AIS within 48 hours and positive findings confirmed by computed tomography (CT) scan and magnetic resonance imaging (MRI).
Exclusion criteria: All patients with renal failure, heart failure, liver failure, thyroid disease, malignancy, head trauma, cerebral haemorrhage, pregnancy and lactation, psychiatric and mental disorders were excluded.
Anthropometric profiles: Body mass index (BMI) was calculated by explicit equation; BMI= BW (kg) /Ht (m2). Blood pressure profile, including; systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by automated digital sphygmomanometer. Besides, mean arterial pressure (MAP) and pulse pressure (PP) were estimated by specific equations.11
Biochemical variables: Five milliliters of blood samples were obtained from patients and healthy controls after an overnight fasting (8-12 hours). The blood samples were centrifuged at 3000/ rpm and kept at (-20 C°) for later analysis. Lipid profile including; triglyceride (TG), total cholesterol (TC), and high-density lipoprotein (HDL), were measured by ELISA kit methods (Abbott, A.S.A) in ARCHITECT C 4000). Though, low density lipoprotein (LDL) and very low-density lipoprotein (VLDL) were measured by specific equations; LDL=TC-HDL-(TG/5), VLDL= TGs/5. Furthermore, Atherogenic Index (AI) =log (TG/HDL), cardiovascular risk index (CVRI) = TG/HDL and cardiac risk ratio (CRR) =TC/HDL were also assessed.12
ICAM-1 serum level was measured by utilizing an ELISA kit (MyoBio source, U.S.A.) on the basis of sandwich method.
Evaluation of stroke risk score: Stroke risk score (SRS) was evaluated according to the underlying cardio-metabolic risk factors according to Kate et al. method.13
Data of the present study was analyzed by using SPSS version 20 and presented as means and standard deviations. Un-paired student t test was applied to detect the significance of differences between two groups. Besides, one-way analysis of variance (ANOVA) and post-hoc test were applied to detect significance of differences among different treated groups. Level of significance was regarded when P value less than 0.05.
Demographic characteristic: In the present study 66(75%) of contributors were patients with AIS compared to 22(25%) healthy controls with a mean age of 67.81±12.84 years and approximately equal male-female ratio (51.13-48.86%). In addition, 30(45.45%) of patients were cigarette smokers. The duration of AIS was short (days), and most of the patients presented with motor deficits and paralysis 32(48.49%). Besides, AIS patients had different cardio-metabolic disorders including; hypertension, dyslipidaemia, ischaemic heart disease, previous cerebrovascular accidents, and other neurological disorders. Regarding the associated and current pharmacotherapy,44(66.67%) patients were on statins therapy compared with 22(33.37%) patients not on statins therapy (Table-1).
Cardio-metabolic profile in AIS patients: BMI was similar between AIS patients and controls (P=0.34). SBP was greater in AIS patients compared to the controls (P=0.0001), though, it was lower in patients with AIS on statins as compared with the patients with AIS not were on statins therapy (P=0.03). DBP did not significantly differ in patients with AIS compared to the controls (P=0.22). Both PP and MAP were increased in AIS patients compared to the controls (P=0.0001) and (P=0.003) respectively. Further, lipid profiles were higher in AIS patients compared to the control (P=0.0001), while HDL-c was lower in patients with AIS compared to the controls (P=0.0001) (Table-2).
ICAM-1 serum levels: Serum levels of the ICAM-1 were significantly elevated in AIS patients compared to the controls. ICAM-1 serum levels were higher in patients with AIS and not on statins therapy compared to the controls (P=0.0001), alsoICAM-1 serum levels were lower in patients with AIS on statins therapy (77.41±16.46) as compared to patients with AIS not on statins therapy (118.71±10.38), (P=0.001) (Figure-1).
Differential effect of statins therapy on ICAM-1 serum levels of AIS patients: In the current study, there was differential effect of statins therapy on the ICAM-1 serum level which was non-significantly higher in patients with AIS on rosuvastatin (72.93±9.03) as compared with patients with AIS on atorvastatin (70.61±10.94), (P=0.44) (Figure-2).
Stroke risk score in patients with AIS: Stroke risk score (SRS) was advanced in AIS patients compared with the controls (P<0.0001). SRS was lower (9.10±3.22) in patients with AIS on statins therapy (20.82±7.87) compared with patients with AIS not were on statins therapy (Figure-3).
In addition, SRS was lower in patients with AIS on atorvastatin therapy (7.60±2.05) as compared with patients with AIS on rosuvastatin therapy (9.11±2.72), (P=0.04) (Figure-4).
AIS is one of the most important causes of mortality and disability in the developing countries. Of note, AIS is a dynamic process of several reactions, such as immunological response, oxidative stress, reactive gliosis, and dysfunction of homeostatic system.14
Studies suggest that inflammation has a role in the pathogenesis of AIS. Neuro-inflammation exacerbates the injury by inducing cell death, which also plays an advantageous role in promoting of cells recovery.15
ICAM-1 is a cell-bounded glycoprotein that participates in inflammation through interacting with lymphocytes, since it is expressed in astrocytes, endothelial cells, and microglia. As well, ICAM-1 affects BBB integrity and might be a useful biomarker for post-stroke inflammation.16
In the present study, ICAM-1 serum level was higher in AIS patients compared with controls. Since there is a noteworthy association between ICAM-1 and AIS, and mounting evidence suggests a possible association between ICAM-1serum level and severity of AIS as it linked with ischaemia-associated BBB injury.17
Kurkowska et al., proposed that ICAM-1 may act as an early biomarker for endothelial disruption in the acute phase of AIS.18
In the present study, ICAM-1 level was reduced in statins-On AIS patients compared to statins-Off AIS patients. However, there was no significant association between statins and ICAM-1serum levels in patients undergoing percutaneous cardiac intervention.19
Kurkowska et al showed a decrement in ICAM-1 serum level following using of statins due to attenuation of ICAM-1-induced endothelial disruption.20
Petit et al suggested that statins may inhibit ICAM-1 through preventing ICAM-1 from interacting with lymphocyte function-associated antigen-1 (LFA-1), thus limiting the exacerbation of inflammatory reaction.21
In the present study, ICAM-1 was non-significantly reduced in AIS patients on atorvastatin therapy compared to AIS patients on rosuvastatin therapy. Bubnova et al., illustrated an insignificant difference between the effect of atorvastatin or rosuvastatin in ameliorating AIS-associated inflammation and disruption of BBB.22
Similarly, rosuvastatin inhibits appearance of adhesion molecules (ICAM-1and VCAM-1) production through inhibition of p38-mitogen activated protein kinase (MAPK) pathway in AIS.23
Therefore, both atorvastatin and rosuvastatin improve endothelial inflammatory changes through modulation of inflammatory adhesion molecules in patients with AIS.
However, SRS was more linked with ICAM-1 in AIS patients not on statin therapy. This correlation gives a clue about the association between stroke risk and inflammatory/pro-inflammatory axis. It has been reported that poor cardio-metabolic risk factors are associated with chronic inflammatory reaction, which in turn increase the risk of AIS.24On the other hand, statins therapy reduces dyslipidaemia and systemic hypertension, thereby reducing neuronal damage in patients with AIS.25 Thus, SRS in the present study was less correlated with the studied biomarkers in AIS patients on statins therapy.
The present study had several limitations including; small sample size and pro-inflammatory cytokines like tumour necrosis factor alpha (TNF-a), which affects both cardio-metabolic profile and AIS was not measured. However, the present study provided evidence in association between AIS patients and ICAM-1 serum level. Enormous prospective and clinical trial studies are warranted in this regard to confirm the association between AIS and ICAM-1 serum level.
ICAM-1 is regarded as a surrogate biomarker of AIS in patients with underlying poor cardio-metabolic profile. Both atorvastatin and rosuvastatin are effective in attenuation of AIS measured by lowering of ICAM-1 serum levels.
Acknowledgment: To the all members in College of Medicine, Al-Mustansiyriah University.
Conflict of Interest: None.
Source of Support: None.
1. Al-Kuraishy HM, Al-Gareeb AI, Naji MT, Al-Mamorry F. Role of vinpocetine in ischemic stroke and poststroke outcomes: A critical review. Brain Circ 2020;6:1-10. doi: 10.4103/bc.bc_46_19.
2. Al-Kuraishy HM, Al-Gareeb AI, Alblihed M, Cruz-Martins N, Batiha GE. COVID-19 and Risk of Acute Ischemic Stroke and Acute Lung Injury in Patients With Type II Diabetes Mellitus: The Anti-inflammatory Role of Metformin. Front Med 2021;8:e644295. doi: 10.3389/fmed.2021.644295.
3. Al-kuraishy HM, Al-Gareeb AI. Vinpocetine and Ischemic Stroke. In: Sanchetee P, eds. Ischemic Stroke. London, UK: IntechOpen, 2021; pp 103. DOI: 10.5772/intechopen.90551
4. Hussien NR, Al-Naimi MS, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Sulfonylurea and neuroprotection: The bright side of the moon. J Adv Pharm Technol Res 2018;9:120-3. doi: 10.4103/japtr.JAPTR_317_18.
5. Alkuraishy HM, Al-Gareeb AI, Waheed HJ. Lipoprotein-Associated Phospholipase A2 is Linked with Poor Cardio-Metabolic Profile in Patients with Ischemic Stroke: A Study of Effects of Statins. J Neurosci Rural Pract 2018;9:496-503. doi: 10.4103/jnrp.jnrp_97_18.
6. Al-Kuraishy HM, Al-Gareeb AI, Naji MT. Brain natriuretic peptide in patients with acute ischemic stroke: Role of statins. Biomed Biotechnol Res J 2020;4:239-45. DOI: 10.4103/bbrj.bbrj_44_20
7. Gao H, Zhang X. Associations of intercellular adhesion molecule-1 rs5498 polymorphism with ischemic stroke: A meta-analysis. Mol Genet Genomic Med 2019;7:e643. doi: 10.1002/mgg3.643.
8. Wu BN, Wu J, Hao DL, Mao LL, Zhang J, Huang TT. High serum sICAM-1 is correlated with cerebral microbleeds and hemorrhagic transformation in ischemic stroke patients. Br J Neurosurg 2018;32:631-6. doi: 10.1080/02688697.2018.1518515.
9. Al-Kuraishy HM, Al-Gareeb AI, Al-Buhadily AK. Rosuvastatin as forthcoming antibiotic or as adjuvant additive agent: In vitro novel antibacterial study. J Lab Physicians 2018;10:271-5. doi: 10.4103/JLP.JLP_170_17.
10. Al-Kuraishy HM, Al-Gareeb AI. Acylation-stimulating protein is a surrogate biomarker for acute myocardial infarction: Role of statins. J Lab Physicians 2017;9:163-9. doi: 10.4103/0974-2727.208263.
11. Hayder M, Al-Kuraishy, Miqat T, Hamada, Abdilkarim Y, Al-Samerraie. Effects of metformin on omentin levels in a newly diagnosed type II diabetes mellitus: Randomized, placebo controlled study. Mustansiriya Med J 2016;15:49-55.
12. Al-Nami MS, Al-Kuraishy HM, Al-Gareeb AI, Al-Mamoori F. Metabolic profile and prolactin serum levels in men with type 2 diabetes mellitus: Old-new rubric. Int J Crit Illn Inj Sci 2019;9:120-6. doi: 10.4103/IJCIIS.IJCIIS_40_19.
13. Al-Naimi MS, Hussien NR, Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Levothyroxine improves Paraoxonase (PON-1) serum levels in patients with primary hypothyroidism: Case-control study. J Adv Pharm Technol Res 2018;9:113-8. doi: 10.4103/japtr.JAPTR_298_18.
14. Kamel H, Healey JS. Cardioembolic Stroke. Circ Res 2017;120:514-26. doi: 10.1161/CIRCRESAHA.116.308407.
15. Lambertsen KL, Finsen B, Clausen BH. Post-stroke inflammation-target or tool for therapy? Acta Neuropathol 2019;137:693-714. doi: 10.1007/s00401-018-1930-z.
16. Enzmann GU, Pavlidou S, Vaas M, Klohs J, Engelhardt B. ICAM- 1null C57BL/6 Mice Are Not Protected from Experimental Ischemic Stroke. Transl Stroke Res 2018;9:608-21. doi: J Pak Med Assoc (Suppl. 8) 15th Annual Conference of the College of Medicine, Mustansiriyah University, Baghdad S-15 10.1007/s12975-018-0612-4.
17. Nepal G, Yadav JK, Kong Y. Association between K469E polymorphism of ICAM-1 gene and susceptibility of ischemic stroke: An updated meta-analysis. Mol Genet Genomic Med 2019;7:e00784. doi: 10.1002/mgg3.784.
18. Kurkowska-Jastrzebska I, Karlinski MA, B?azejewska-Hyzorek B, Sarzynska-Dlugosz I, Filipiak KJ, Czlonkowska A. Carotid intima media thickness and blood biomarkers of atherosclerosis in patients after stroke or myocardial infarction. Croat Med J 2016;57:548-57. doi: 10.3325/cmj.2016.57.548.
19. Al-kuraishy HM, Al-Gareeb AI, Al-Maiahy TJ. Erectile dysfunction and statins: The assorted view of preponderance. Asian Pac J Reprod 2020;9:55-63. DOI: 10.4103/2305-0500.281074
20. Schultz NEØ, Hasseldam H, Rasmussen RS, Vindegaard N, McWilliam O, Iversen HK, et al. Statin treatment before stroke reduces pro-inflammatory cytokine levels after stroke. Neurol Res 2019;41:289-97. doi: 10.1080/01616412.2018.1558000.
21. Petit C, Batool F, Bugueno IM, Schwinté P, Benkirane-Jessel N, Huck O. Contribution of Statins towards Periodontal Treatment: A Review. Mediators Inflamm 2019;2019:e6367402. doi: 10.1155/2019/6367402.
22. Bubnova M, Aronov D, Persiyanova-Dubrova A. Effects of rosuvastatin and atorvastatin on blood pressure, cerebral blood flow, endothelial function, angiotensin ii in patients with ischemic stroke-complicated hypertension. J Hypertens 2019;37:e277. doi: 10.1097/01.hjh.0000573532.28026.dc
23. Al-Kuraishy HM, Al-Gareeb AI. Effects of rosuvastatin on metabolic profile: Versatility of dose-dependent effect. J Adv Pharm Technol Res 2019;10:33-8. doi: 10.4103/japtr.JAPTR_330_18.
24. Rasheed HA, Al-Kuraishy HM, Al-Gareeb AI. Rosuvastatin Attenuates acute nephrotoxicity through modulation of oxidative stress in Sprague Dawley rats. J Pak Med Assoc 2019;69(Suppl 3):s98-102.
25. Al-Kuraishy HM, Al-Gareeb AI, Hussien NR, Al-Naimi MS, Rasheed HA. Statins an oft-prescribed drug is implicated in peripheral neuropathy: The time to know more. J Pak Med Assoc 2019;69(Suppl 3):s108-12.