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Table of Contents    
ORIGINAL ARTICLE
Year : 2021  |  Volume : 69  |  Issue : 6  |  Page : 1637-1644

Statins Therapy Improves Acute Ischemic Stroke in Patients with Cardio-metabolic Disorders Measured by Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): New Focal Point


Department of Clinical Pharmacology and Therapeutic, Medical FacultyCollege of Medicine, Al-Mustansiriyah University, Baghdad, Iraq

Date of Submission27-Apr-2018
Date of Decision23-Jul-2020
Date of Acceptance06-Aug-2020
Date of Web Publication23-Dec-2021

Correspondence Address:
Dr. Hayder M Al-kuraishy
Department of Clinical Pharmacology and Therapeutic, Medical FacultyCollege of Medicine, Al-Mustansiriyah University, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.333482

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 » Abstract 


Background: Acute ischemic stroke (AIS) leads to neuronal and endothelial damage that activate the release of proinflammatory mediators such as lipoprotein-associated phospholipase A2 (Lp-PLA2), which lead to the development of brain edema injury. Most of statins produce differential effects on Lp-PLA2 activity and mass with a comparable reduction in low-density lipoprotein (LDL) serum levels.
Aims: The aim of this study is to evaluate the differential effect of different statins on the mass of level of Lp-PLA2 in patients with AIS.
Methods: A total of 69 patients with AIS aged 40–70 years compared with matched 39 healthy controls were involved in this case-control study. The AIS patients were divided according to the statins therapy into 39 patients on statins therapy (statins on), and 30 patients were not on the statins therapy (statins off). Anthropometric variables including weight, height, body mass index (BMI), and blood pressure profile were estimated. Besides, biochemical variables including lipid profile[total cholesterol (TC), triglyceride (TG), LDL, very low-density lipoprotein (VLDL), high-density lipoprotein (HDL)], Lp-PLA2 mass levels, high-sensitive C-reactive protein (Hs-CRP) were estimated.
Results: Patients with AIS had high Lp-PLA2 mass levels (P < 0.01) that positively correlated with high Hs-CRP, blood pressure, BMI, TC, TG, VLDL, LDL, and negatively correlated with HDL as compared with healthy controls. As well, statins on patients had lower Lp-PLA2 mass levels (9.82 ± 3.19 IU/mL) compared with statins off patients (16.55 ± 4.72 IU/mL), (P = 0.0001). Regarding the gender differences in the Lp-PLA2 mass level, it was higher in men patients with AIS compared with comparable females (P = 0.03).
Conclusions: Lp-PLA2 mass level was higher in patients with AIS and linked with underlying poor cardio-metabolic disorders. Therefore, the Lp-PLA2 mass level is observed to be a surrogate biomarker of AIS mainly in patients with poor cardio-metabolic disorders. Statin therapy improves the Lp-PLA2 mass level and the poor cardio-metabolic profile in patients with AIS.


Keywords: Acute ischemic stroke, cerebral stroke, Lp-PLA2 serum levels, statins
Key Message: Acute ischemic stroke (AIS) leads to neuronal and endothelial damage that activate the release of proinflammatory mediators such as lipoprotein-associated phospholipase A2 (Lp-PLA2). Statin therapy improves the Lp-PLA2 mass level and the poor cardio-metabolic profile in patients with AIS.


How to cite this article:
Al-kuraishy HM, Hussien NR, Al-naimi MS, Al-Gareeb AI, Lugnier C. Statins Therapy Improves Acute Ischemic Stroke in Patients with Cardio-metabolic Disorders Measured by Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): New Focal Point. Neurol India 2021;69:1637-44

How to cite this URL:
Al-kuraishy HM, Hussien NR, Al-naimi MS, Al-Gareeb AI, Lugnier C. Statins Therapy Improves Acute Ischemic Stroke in Patients with Cardio-metabolic Disorders Measured by Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): New Focal Point. Neurol India [serial online] 2021 [cited 2022 Jan 19];69:1637-44. Available from: https://www.neurologyindia.com/text.asp?2021/69/6/1637/333482




Acute ischemic stroke (AIS) is a medical emergency status due to reduction ofcerebral blood flow results in brain ischemia and cellular death. Stroke leads to focal neurological dysfunction depending on the affected area that presented as motor and/or sensory deficits. If these deficits last less than 24h is called transient ischemic attack (TIA) or mini-stroke, but if lasting more than 24h is called complete stroke.[1],[2] The most important risk factorsofAIS are hypertension, obesity, dyslipidemia, smoking, and diabetes mellitus.[3]

AIS leads to brain tissue hypoxemia, which activates neuronal anaerobic metabolism that provokes lactic acid production causing secondary ischemic area called ischemic penumbra. During AIS, the neuronal energy and adenosine triphosphateare declined leading to neuronal cell membrane damage and interruption of ion pumping.[4] In AIS, neuronal and endothelial damage provoke the release of proinflammatory mediators, which leadto the development of brain edema and further brain injury.[5] Consequently, AIS triggers cascade of pathological episodes including neuronal excitability, intracellular calcium overload, ion homeostasis disturbances, lipid peroxidation, and free radical productions.[6] These events are time-dependent manner as neuronal excitability occur within minutes, whereas inflammatory changes happen within hours after AIS. These sequential events might explain the differences in the levels of inflammatory biomarkers following AIS.[7] Inflammation plays a critical role in the pathophysiology of AIS since neuronal damage provokes the release of inflammatory-related molecules that activate the immune system. These inflammatory mediators could escape into cerebrospinal fluid and bloodstream; thus, these mediators could be simply being detectable following AIS.[8]

Lipoprotein-associated phospholipaseA2(Lp-PLA2) is a phospholipase A2 enzyme produced by inflammatory cells, encoded by the PLA2G7gene; which is 45-kDa of 441 amino acids. Lp-PLA2 is mainly attached with low-density lipoprotein (LDL) and high density lipoprotein (HDL) in about 80 and 20%, respectively.[9] Besides, Lp-PLA2 is also produced from cells at atherosclerotic plaque, thus the high Lp-PLA2 serum level is linked with atherosclerosis, acute coronary syndrome, and AIS.[10] Into the bargain, Ashrafi-Asgarabad and Safiri show that high Lp-PLA2 serum levels are associated with twofold increase in the risk of AIS and poor outcomes; thus, Lp-PLA2 appears as an admirable predictor of AIS.[11]

Statinsis 3-hydroxy-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors, inhibit denovo cholesterol biosynthesis and LDL levels as well as triglyceride (TG). Statins is effective for the prevention of ischemic heart disease and AIS through LDL-dependent and LDL-independent effects.[12] Similarly, most of statins produced differential effects on Lp-PLA2 activity and mass with an equivalent reduction in LDL serum levels. However, pravastatins may increase the Lp-PLA2activity and reduces Lp-PLA2 mass.[13]

Hence, the aim of the present study was to explore the effect of statins on the Lp-PLA2 mass serum levels in patients with AIS regarding the gender difference and the underlying cardio-metabolic profile.


 » Methods Top


Study design and patients population

Inthis case-control study, a total number of 69 patient aged 40–70 years with AIS were recruited from stroke unite compared with 39 matched healthy controls. All AIS patients were diagnosed by a neurologist and they set aside under supervision. Full medical history and detailed current and previous pharmacotherapy were taken from each patient.

The recruited patients and healthy controls were divided into three groups; Group I: 39 patients (20 males + 19 females) previously and currently on statins therapy allocated as statins users (Statins ON). Group II: 30 patients (16 males + 14 females) not were on statins therapy allocated as non-statins users (Statins OFF), and Group III: 39 healthy controls (20 males + 19 females).

All of the recruited patients were selected according to the guidelines and diagnostic criteria of American Academy of Neurology.[14] Besides, the study procedures were done in concord to the Declaration of Helsinki. Moreover, all of the recruited patients and healthy controls gave an informed verbal permission for their contribution in this study. The study was approved by the Ethical Committee and Clinical Research Editorial Board, College of Medicine, Al-Mustansiriyiah University, Baghdad, Iraq, from June to September 2018 under ethical approval number 22H/3 in 2018. In this study, any patients aged 40–70 years with AIS on or off statins therapy were included in this study. However, the duration of statins therapy should be >3 months to be included. However, any patients with hemorrhagic stroke, diabetes mellitus, thyroid disorders, valvular heart diseases, acute and chronic liver diseases, acute and chronic kidney disorders, rheumatic and connective tissues diseases, sepsis, acute and chronic infections, complicated stroke, psychiatric and mental disorders, and interrupted statins therapy were excluded. The inclusion and exclusion criteria were depended on the full medical history, general and neurological examinations complete blood picture, renal and liver investigations as well as random blood sugar and glycated hemoglobin.

Measurement of anthropometric variables

Body weight, height, and body mass index (BMI) were recorded, BMI = Weight (kg)/Height (cm)2. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) were recorded by at supine position from the left arm by automated digital sphygmomanometer (OMRON Upper Arm Type Sphygmomanometer HEM-1021, Japan Domestic genuine product). Pulse pressure (PP) = SBP-DBP, mean arterial pressure .[15]

Measurement of biochemical variables

Ten milliliters of venous blood sample were drown from antecubital area from each patient at morning after an overnight fasting, 5mL was kept into plain tubes for routine investigations, and 5mL was putted into a EDTA tube for the assessment of the inflammatory biomarkers.

Measurement of lipid profile and fasting blood glucose

Lipid profile including total cholesterol (TC), TG, and HDL were measured by specific ELISA kits methods. Very low-density lipoprotein (VLDL) = TG/5, LDL was calculated according to the Friedewald formula.[16] Atherogenic index (AI) = log (TG/HDL), Atherogenic coefficient (AC) = TC-HDL/HDL, cardiac risk ratio (CRR) = TC/HDL.[17] Fasting glucose in mg/dL was measured by a glucometer, while HbA1c was measured by glycated haemoglobin A1C (ELISA Kit, MB845, BioVision, China).

Measurement of inflammatory markers

The blood samples were centrifuged for 10 min, and the separated sera were used for the evaluation of Lp-PLA2 serum concentration, which was the mass of level of Lp-PLA2 by the specific ELISA kit method in IU/mL (SEA867Hu, Double-antibody Sandwich, Wuhan USCN Business Co. Ltd, China). While high-sensitive CRP serum levels were assessed by the specific ELISA kit method in mg/dL (Cat.No.ABIN1115432, Wuhan USCN Business Co. Ltd, China).

Evaluation of stroke risk score (SRS)

SRS was evaluated according to the underlying cardio-metabolic risk factors according to the Kate et al. method.[18]

Statistical analysis

Data analysis was prepared using SPSS (IBM, Statics for Window, Version 20.00; Armonk, NY, USA: IBM Corp.). Results are presented as mean ± SD, percentage, and number. Unpaired Student'st-test was used for the determination of the significant difference between two different groups, while the two-wayANOVAtest was used for assessing the differences among different groups. Pearson correlation was used for estimating the correlation ofLp-PLA2serum concentration with other study parameters. The differences were significant when the P -value was less than 0.05.


 » Results Top


In the present study, a total number of 120 recruited patients with AIS and healthy controls were initially involved in this study. Twelve (10%) patients were excluded due to hemorrhagic stroke, TIA, acute renal failure, and heart failure. Therefore, only 108 subjects (90%) were involved, and 69 (63.88%) were AIS patients compared with 39 (36.11%) of healthy controls. Besides, 39 (36.11%) of AIS patients were on statins therapy (statins ON) compared to 30 (27.77%) not were on statins therapy (statins OFF). All AIS patients and healthy controls were subjected to anthropometric and biochemical measurements, and all continued the study procedures without any discontinue, consort-flow diagram [Figure 1].
Figure 1: Consort-flow diagram HS: hemorrhagic stroke, TIA: transient ischemic Attack, ARF: acute renal failure, HF: heart failure

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Characteristics of the present study

In a total number of 108 recruited subjects, 63.88% of them were patients with AIS and 36.11% were healthy subjects that were regarded as controls. Regarding the gender and race in the present study, 48.14 and 51.85% were females and males, respectively, with a high percentage of white race 91.5% compared to the black race 8.5%. The patients with AIS had positive family history in about 57.62% compared to 42.37% with a negative family history. In the present study, the AIS patients currently on statins therapy were 56.52% compared to 43.47% of AIS patients not were on statins therapy. The duration of statins therapy was 3.12 ± 1.05 years. Furthermore, various associated diseases were recorded in AIS patients, including hypertension (74.57%), dyslipidemia (67.79%), ischemic heart diseases (18.64%), and asthma (3.38%) as shown in the characteristics of the present study [Table 1].
Table 1: Characteristics of the present study

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Ischemic stroke etiologies of the patient population

Findings of the present study showed that systemic hypertension, dyslipidemia, smoking, obesity, and other idiopathic risk factors were the chief etiopathological factors contribute into the incidence of AIS [Table 2].
Table 2: The Etiopathological risk factors of acute ischemic stroke (AIS)

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Potential effects of statins therapy on the cardio-metabolic profile in patients with AIS

Regarding the cardio-metabolic profile, statins ON patients showed a better cardio-metabolic profile than statins OFF regarding atherogenic index, atherogenic coefficient, CRR, and hsCRP P > 0.05 compared to the controls; other parameters were significantly differed P < 0.01. Statins therapy illustrated an improvement in lipid profile, atherogenic index, atherogenic coefficient, CRR, and SRS compared to statins OFF P < 0.01. There were insignificant differences between statins ON and statins OFF regarding BMI and blood pressure profile [Table 3]. As well, statins ON patients had lower Lp-PLA2 mass levels (9.82 ± 3.19 IU/mL) compared with statins off patients (16.55 ± 4.72 IU/mL) and healthy controls (3.39 ± 1.98) (P = 0.0001), [Figure 2]. Lp-PLA2 mass levels were positively correlated with BMI, blood pressure changes, TC, TG, VLDL, AC, CCR, SR %, and HsCRP, but they were negatively correlated with HDL serum levels in statins user stroke patients. On the other hand, nonstatins user showed high hsCRP, which illustrated high correlation with Lp-PLA2 mass P < 0.01 compared to P < 0.05 in statins user [Table 4]. Moreover, the differential effects of statins on the Lp-PLA2 mass levels were 9.8 ± 2.5 in atorvastatin, 8.95 ± 2.6 in rosuvastatin, 10.11 ± 2.1 in simvastatin, and 12.9 ± 3.1 in fluvastatin-treated patients; thus, rosuvastatin produced the powerful reduction effect on Lp-PLA2 mass levels compared to other types of statins but not to the significant level P > 0.05 [Figure 3].
Figure 2: Lipoprotein-associated phospholipase A2 (Lp-PLA2) in patients with acute ischemic stroke regarding the effect of statins therapy compared with healthy controls .*P < 0.05 as compared with statins ON patients. #P < 0.01 as compared with controls. ^P < 0.05 as compared with controls

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Figure 3: Differential effect of statins therapy on Lp-PLA2 mass levels in patients with acute ischemic stroke

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Table 3: Effect of statins therapy on the cardio-metabolic profile in patients with acute ischemic stroke

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Table 4: Correlation of Lp-PLA2 with cardio-metabolic profile in patients with acute ischemic stroke

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Gender differences in the Lp-PLA2 mass levels in patients with AIS

In addition, there was specific gender effect on the Lp-PLA2 mass levels in patients with AIS. Male patient observed high Lp-PLA2 mass levels compared to female patients in both statins ON and statins OFF, but the differences were nonsignificant P > 0.05 [Figure 4].
Figure 4: Gender differences in Lp-PLA2 mass levels in patients with acute ischemic stroke

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 » Discussion Top


It has been reported that inflammation plays an imperative role in the progress of AIS by unknown mechanisms, as AIS may probably affects the balance between the inflammatory and pro-inflammatory response.[7] For that reasons, the inhibition of inflammatory reactions might lessen and recover the neurological functions. Into the bargain, the inhibition of systemic inflammations may affect the subsequent outcomes and may perhaps deteriorate the cerebral repair and functional recovery following AIS.[19] However, LDL-associated Lp-PLA2 is linked with the atherogenic potential, whereas HDL-associated Lp-PLA2 at low levels plays a critical role in antiatherogenic effects.[20]

In the current study, AIS patients were linked with a poor cardio-metabolic profile as consistent with Lee et al. study that illustrated both obesity and overweight are associated with a high risk of AIS.[21] However, a protective role of obesity and overweight on stroke outcome including functional recovery and reducing of mortality rate was reported by Doehner et al.[22]

In the existing study, most of AIS patients were hypertensive with poor management and therapeutic control, since both acute and chronic systemic hypertensions are regarded as important risk factors in the development of AIS.[23] Besides, Zhaoet al.demonstrate the strong relationship between dyslipidemia and AIS as in the present study.[24]

Countless observational studies point up the associations between lipid biomarkers mainly TC, LDL, and low HDL with the frequency of AIS due to dyslipidemia-induced atherogenic and prothrombotic changes as well as of the abnormality in the fibrinolytic cascades.[25]

Albeit a good knowledge, our results also revealed elevation in high-sensitive CRP levels in patients with AIS as high hsCRP serum level is linked with risk of AIS and regarded as a predictor factor for the incidence and recurrence of AIS as well as prediction of postAIS complications.[26]

Entertainingly, the Lp-PLA2 mass serum level in the present study was higher in AIS patients compared to the controls as established by recent Tian et al., a study that showed the association between high, Lp-PLA2 mass serum levels but not Lp-PLA2 activity with the riskof AIS.[27] This is the chief reason for the selection of Lp-PLA2 mass serum levels but not Lp-PLA2 activity in the present study to assess the potential inflammatory role of the Lp-PLA2 mass serum level in AIS as it shows less time-dependent biological variability compared to the Lp-PLA2 activity.[28] Furthermore, the Lp-PLA2 activity level is related to TIA and complicated vascular events, while the Lp-PLA2 mass level is more specific and accurate than the Lp-PLA2 activity in the association with stroke risk.[29]

The present study documented that AIS patient had elevated levels of Lp-PLA2 mass as there is a significant association between high Lp-PLA2 mass levels and AIS.[30] Asciutto et al. reported a higher expression of Lp-PLA2 in AIS patients. Therefore, a higher Lp-PLA2 mass levelis linkedwith the development and progression of atherosclerotic changes AIS.[31] Garg et al. revealed a significant difference in the Lp-PLA2 mass level in relation to the ethnicity,[32] but in this study, ethnic difference was simply affect our results since 91.5% of our patients were white race compared to 8.5% of the black race.

Regarding the effect of statins therapy on the Lp-PLA2 mass level in AIS patients, our findings showed that statins therapy led to a significant reduction of Lp-PLA2 mass levels in AIS patients due to the noteworthy effect of statins therapy on the reduction of Lp-PLA2 mass levels in patients with progressive atherosclerosis.[33] Albert et al. reported the potential effect of statins therapy on the reduction of Lp-PLA2 mass levels in atherosclerotic patients.[34] In the present study, estimation of Lp-PLA2 mass levels in AIS patients was during the acute phase of AIS since acute phase leads to more elevation in Lp-PLA2 mass levels compared with the chronic phase in AIS.[35]

What is more, different statins in the present study including simvastatin, fluvastatin, lovastatin, and atorvastatin-reduced Lp-PLA2 mass serum levels in correspond with the reduction of LDL-c serum levels, but pravastatin might increase the serum levels of Lp-PLA2 mass.[36] In addition, Ishida and Cucchiara reported the potential effect of rosuvastatin in the reduction of Lp-PLA2 mass serum levels due to the reduction of total LDL or due to the special reductive effect on the Lp-PLA2 mass serum levels.[37] As well, simvastatin reduce LDL-associated Lp-PLA2 through the reduction of LDL and increase the clearance of LDL-associated enzyme.[38] These findings are consistent with the findings of the present study that illustrated the potent effect of rosuvastatin compared to the lowest effect of simvastatin, which might be due to the half-life of different statins.[39] Besides, rosuvastatin improves endothelial function and inflammatory biomarkers and vaspin serum levels in obese patients[40], which might explain it ameliorative effect on Lp-PLA2 mass serum levels in patients with ischemic stroke.

Regarding the gender differences in Lp-PLA2 mass serum levels, the male AIS patients showed a higher level compared to the female in both statin ON and statins OFF as revealed by different studies[41]; in contrast, a recent Yu et al. study disclosed high inflammatory biomarkers in women compared to male following cardiovascular ischemic disorders.[41]


 » Conclusions Top


The Lp-PLA2 mass level was higher in male patients with AIS and linked with underlying poor cardio-metabolic disorders. Therefore, the Lp-PLA2 mass level is observed to be a surrogate biomarker of AIS mainly in patients with poor cardio-metabolic disorders. Statins therapy improves the Lp-PLA2 mass level and the poor cardio-metabolic profile in patients with AIS.

Acknowledgement

The authors kindly acknowledge Professor Sadiq M. Al-Hamashhead of Al-Mustansiriyiah University for his great support in this study.

Financial support and sponsorship

Nil.

Conflict of interest

Nil.



 
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    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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