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 Table of Contents  
ORIGINAL ARTICLE
Year : 2020  |  Volume : 4  |  Issue : 3  |  Page : 239-245

Brain natriuretic peptide in patients with acute ischemic stroke: Role of statins


Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriya University, Baghdad, Iraq

Date of Submission22-Mar-2020
Date of Acceptance02-May-2020
Date of Web Publication12-Sep-2020

Correspondence Address:
Prof. Hayder M Al-Kuraishy
Department of Pharmacology, Toxicology and Medicine, College of Medicine, Al-Mustansiriya University, P.O. Box: 14132, Baghdad
Iraq
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/bbrj.bbrj_44_20

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  Abstract 


Background: Acute ischemic stroke (AIS) is associated with disturbances in brain natriuretic peptide (BNP) serum levels. Therefore, the objective of this study is to illustrate the potential effects of atorvastatin and rosuvastatin on BNP in patients with AIS. Methods: A total of 88 patients with AIS with or without statins therapy compared with 22 healthy controls were recruited. The patients with AIS were divided into: Group A: Patients with AIS on statins therapy (atorvastatin or rosuvastatin), (n = 44) and Group B: Patients with AIS not were on statins therapy (n = 22). Body mass index, blood pressure profile, lipid profile, and serum levels of human BNP were measured. As well, stroke risk score (SRS) was assessed in all involved patients and healthy volunteers. Results: BNP serum level was higher in patients with AIS compared with healthy controls (P = 0.0006). It was higher in patients with AIS not were on statins therapy (29.96 ± 17.21 μg/dL) as compared with patients with AIS on statins therapy (21.66 ± 14.22 μg/dL), P < 0.001. However, BNP serum level was (20.33 ± 6.05 μg/dL) in AIS patients on atorvastatin and (21.51 ± 6.82 μg/dL) AIS patients on rosuvastatin, which was not significantly differed (P = 0.54). Moreover, BNP serum levels were correlated with SRS in patients with AIS on statins therapy (r = 0.42, P= 0.03), but it was highly correlated with SRS in patients with AIS not were on statins therapy (r = 0.89, P < 0.001). Conclusion: BNP serum level is elevated in patients with AIS and correlated significantly with SRS. Statins therapy mainly atorvastatin and rosuvastatin are effective anti-inflammatory agents in the management of AIS through the reduction of BNP serum levels. However, there is no significant difference between the two statins.

Keywords: acute ischemic stroke, atorvastatin, brain natriuretic peptide, cardiometabolic profile, inflammation, rosuvastatin, stroke risk score


How to cite this article:
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

How to cite this URL:
Al-Kuraishy HM, Al-Gareeb AI, Naji MT. Brain natriuretic peptide in patients with acute ischemic stroke: Role of statins. Biomed Biotechnol Res J [serial online] 2020 [cited 2020 Sep 25];4:239-45. Available from: http://www.bmbtrj.org/text.asp?2020/4/3/239/294856




  Introduction Top


Stroke was defined by the World Health Organization (WHO) as a “rapidly growing clinical disorder with a rapid onset of focal or global neurological deficit persisting for more than 24 h.” There are identifiable consequences for stroke, such as vascular ischemia and neurodegenerative diseases.[1]

Stroke, the second-leading cause of disability and death globally, is often leads to irreversible and devastating brain damage. The hazard of stroke is expanding exponentially from the age of 30 years, 95% of stroke occur at age 45 years and older, though, it can happen at any age including childhood.[2] Stroke is defined as “a medical emergency status due to reducing brain blood flow results in brain ischemia and cellular death.” Two divisions of stroke have been mostly identified (thrombotic strok 85% and hemorrhagic stroker 15%). Thrombotic strok (also known as ischemic stroke [IS]) is further divided into subcategories. Furthermore, stroke with unknown source is known as cryptogenic stroke.[3]

Cardioembolic stroke (CES) is a subcategory of IS, which is mainly caused by distant embolism that resulted from precardiac problems mainly atrial fibrillation (AF). CES results in more severe stroke outcomes than other IS categories.[4]

Acute IS (AIS) is defined as a quick incidence of neurological insufficiency resulting from brain ischemia. The mechanisms of AIS are thromboembolic, hemodynamic, atherothrombotic, and microangiopathic. AIS triggers blood–brain barrier (BBB) disruption through a complex cascade. Several phenomena are known to mediate BBB disruption, including oxidative stress, reactive gliosis, dysfunction of hemostatic system, and immunological response.[5]

The thought that stroke is a disorder solely of blood vessels has been expanded to include the effects of a detrimental interaction between neurons, matrix components, glia, and vascular cells, referred to as neurovascular unit.[6] So far, there are some inflammatory biomarkers that have been estimated for their association with AIS. Brain natriuretic peptide (BNP) is a peptide belonging to natriuretic peptides family. BNP is mainly produced by the myocytes of cardiac ventricles during the ventricular wall stretching due to volume expansion. BNP has a serious role in maintaining the homeostasis of kidney and heart with stabilizing endothelial functions. Moreover, BNP can reduce central of venous pressure, counteracts renin-angiotensin-aldosterone axis through induction of natriuresis, hence, reducing cardiac output and blood pressure. Furthermore, BNP activates lipolysis and adipocyte browning in addition to antifibrotic and antimitotic effects.[7] BNP was one of the highly studied biomarkers in the field of AIS. BNP can be used to predict the risk of cardiovascular events in AIS as high level of BNP is associated with CESs.[8]

The precise mechanism of increased BNP level during AIS is not clearly understood. Although elevated BNP may indicate underlying cardiac problems mainly AF. Moreover, BNP level is found to be related with stroke severity in AIS patients. Thus, measuring BNP level earlier in AIS might be beneficial to estimate risk, progression, severity, and outcomes of AIS.[9] Cerebral ischemia (regardless of cardiac problem) was found to induce BNP release from astrocytes and hypothalamus, thus, BNP can be a possible biomarker to evaluate the risk of AIS.[10]

Statins are a class of lipid-lowering drugs, act through the inhibition of 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase (HMG-CoA) which widely prescribed to treat dyslipidemia.[11] Atorvastatin and rosuvastatin are the most widely prescribed statins that are found to promote vasodilation, stabilize atheroma, enable angiogenesis, protect endothelium, inhibit inflammation, stabilize plaques, decrease vascular permeability, improve neuronal repair, and suppress oxidative stress, all of which are called as nonlipid-lowering pleiotropic properties (NLPPs). Most of NLPPs of statins are linked to statins' ability to interrupt mevalonate pathway. Thus, statins carry a protective role against AIS, which was assumed to be due to their NLPPs.[12]

The anti-inflammatory role of statins is due to the ability of statins to stop prenylation of GTPase proteins in mevalonate pathway, which is an important process needed for the regulation of serious pro-atherogenic and pro-inflammatory pathways.[13]

Therefore, the aim of the present study was to elucidate the potential effect of atorvastatin or rosuvastatin on BNP serum level in patients with AIS.


  Materials and Methods Top


Study design

This case–control study was done in the Department of Clinical Pharmacology, College of Medicine, AL-Mustansiriya University in cooperation with the Department of Neurology and Internal Medicine, Al-Yarmok Teaching hospital, Baghdad, Iraq, from October 2019 to January 2020. This study was approved by Scientific and Ethical Committee Editorial Board, College of Medicine, AL-Mustansiriya University according to the ethical No.45YU in 26-12-2019.

A total of 88 patients with AIS with mean aged of 67.81 ± 12.84 years of both genders, and those who fulfilled AIS criteria by WHO, including patients who were admitted to hospital with the signs of neuronal deficit within at least 2 days from ischemic attack and had a magnetic resonance imaging (MRI) or CT scan confirming their AIS. Included patients were either on atorvastatin or rosuvastatin, or statins free. Forty-four out of 66 patients were on statins therapy. The selected 66 patients were allocated into two groups, which were

  • Group A: Patients with AIS on statins therapy (atorvastatin or rosuvastatin), (n = 44)
  • Group B: Patients with AIS not were on statins therapy (n = 22).


Those patients were evaluated in comparison with healthy controls (n = 22), that were recruited from the medical staff subjects and patient relatives.

Inclusion criteria

Patients with AIS with or without of statins therapy were included in the study.

Exclusion criteria

Hemorrhagic stroke, brain tumor, chronic stroke, transient ischemic attack (TIA), diabetes mellitus, hypothyroidism, chronic infection, sepsis, heart failure, rheumatic and connective tissue diseases, psychiatric and mental disorders, chronic liver dysfunctions, and end-stage chronic kidney diseases. The exclusions depend on the detailed medical history, clinical examinations, routine investigations, and radiological investigations, including brain computed tomography scanning (CT scans) and MRI.

At first 131 patients were recruited, 65 of them were excluded due to hemorrhagic stroke (n = 12), TIA (n = 13), acute renal failure (n = 15), heart failure (n = 9), liver cirrhosis (n = 3), brain tumors (n = 3), and sepsis (n = 10). Therefore, only 66 patients were involved that subdivided according to the statins therapy into three groups, as illustrated in the consort flow chart [Figure 1].
Figure 1: Consort-flow diagram of the present study

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Anthropometric profiles

Height (Ht) in meter (m) and body weight (BW) in a kilogram (kg) were calculated by graduate tape and digital electronic balance, respectively, the body mass index (BMI) was calculated by specific equation, BMI = BW (kg)/Ht (m2).[14] Blood pressure profile, including systolic blood pressure (SBP) and diastolic blood pressure (DBP) were measured by automated digital sphygmomanometer, and then, pulse pressure (PP) and mean arterial pressure (MAP) were calculated by specific equations according to the previous study, PP = SBP-DBP, MAP = SBP + 2 (DBP)/3.[15]

Biochemical variables

Ten milliliters of venous blood samples was drained from all patients and healthy controls, which centrifuged at 3000/rpm for 5 mins, and stored at −20°Ċ till the time of analysis.

Lipid profile, including total cholesterol (TC), triglyceride (TG), and high-density lipoprotein (HDL), were measured by enzyme-linked immunosorbent assay (ELISA) kit method (cholesterol, TG, HDL Assay Kit, Abcam, ab65390, Chicago, USA). Low-density lipoprotein (LDL), very LDL, Atherogenic Index (AI), (AI = log (TG/HDL) and cardiac risk ratio (CRR), CRR = TC/HDL, non-HDL-cholesterol (HDL-c) = TC-HDL-c, and cardiovascular risk index (CVRI) = TG/HDL were measured according to be measured by specific equation according to a previous study.[16]

Serum levels of human BNP were measured by the ELISA kit method (BNP ELISA Assay Kit, YH Biological Laboratory, China).

Assessment of stroke risk score

Stroke risk score (SRS) was assessed in all involved patients and healthy volunteers depending on the age, lipid profile, blood pressure, and evidence of cardiometabolic disorders according to the American stroke Association.[17]

Statistical analysis

Data analysis was done using the Statistical Package for the Social Sciences (SPSS version 21.00, IBM Corp, Statistic for Window, Armonk, NY, USA). The results of the present study are presented as mean ± standard deviation. Un-paired student t-test was used to determine the significance of differences between two groups, whereas one-way ANOVA test was used to find out the significance of differences among different groups. Pearson correlation β was used to find the significant correlations with the other parameters of the present study. The level of significance was regarded when P < 0.05.


  Results Top


Demographic characteristic of the present study

In the present study, 75% of enrollments were patients with AIS compared to 25% healthy controls with a mean age of 67.81 ± 12.84 (years) and nearly equal male-female ratio (51.13%–48.86%). As well, 45.45% of patients with AIS were cigarette smokers. Regarding the clinical presentation of patients with AIS, the duration of AIS was short (days), and most of patients presented with motor deficits and paralysis (48.49%), coma (12.12%), sudden visual loss (10.60%), and other neurological dysfunction such as aphasia, dysphasia, dysphagia, delirium, and convulsion. Moreover, patients with AIS were associated with different cardiometabolic disorders, including hypertension (100%), dyslipidemia (98.48%), ischemic heart disease (27.27%), previous cerebrovascular accidents (CVAs) (33.34%), AF (6.06%), and other neurological disorders such as dementia (3.03%) and Parkinson disease (3.03%). Concerning the associated and current pharmacotherapy, 44 patients (66.67%) were on statins therapy compared with 22 patients (33.37%) not were on statins therapy, and according to the medical history of drug therapies, those patients as well received but in an intermittent manner of other medications such as antihypertensive and antiplatelet drugs [Table 1].
Table 1: Characteristics of the present study

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Cardiometabolic profile in with acute ischemic stroke

BMI was not differed significantly in patients with AIS compared to the controls (P = 0.34). SBP was higher in patients with AIS as compared to the controls (P = 0.0001); however, it was lower in patients with AIS on statins as compared with the patients with AIS not were on statins therapy (P = 0.03). While, DBP was not differed significantly in patients with AIS compared to the controls (P = 0.22). Both PP and MAP were higher in patients with AIS compared to the controls (P = 0.0001) and (P = 0.003), respectively. On the other hand, lipid profile (TC, TG, LDL, and non-HDL) was higher in patients with AIS compared to the controls (P = 0.0001), whereas HDL-c was lower in patients with AIS compared to the controls (P = 0.0001). Similarly, lipid profile ratio showed that LDL/HDL ratio, non-HDL-c, CRR, and CVRI were higher in patients with AIS compared to the controls (P = 0.0001), [Table 2].
Table 2: Cardio-metabolic profile in patients with acute ischemic stroke

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Differential effect of atorvastatin and rosuvastatin on the cardio-metabolic risk indices

There were insignificant differential effects of rosuvastatin or atorvastatin on the CRR, CVRI, and AI in patients with AIS. Furthermore, AI was (0.23 ± 0.02) in rosuvastatin as compared with atorvastatin (0.23 ± 0.01), (P = 0.25). CRR was higher in rosuvastatin (4.22 ± 1.42) as compared with atorvastatin (4.12 ± 1.33), (P = 0.09). As well, CVRI was higher in rosuvastatin (3.89 ± 1.22) as compared with atorvastatin (3.45 ± 1.20), (P = 0.06), [Figure 2].
Figure 2: Differential effect of atorvastatin and rosuvastatin on the cardio-metabolic risk indices. AIS (RS): Acute ischemic stroke on rosuvastatin, AIS (AS): Acute ischemic stroke on atorvastatin, AI: Atherogenic index, CRR: Cardiac risk ratio, CVRI: Cardiovascular risk index

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Brain natriuretic peptide serum level in patients with acute ischemic stroke

BNP serum level was higher in patients with AIS compared with healthy controls (P = 0.0006). It was higher in patients with AIS not were on statins therapy (29.96 ± 17.21 μg/dL) as compared with patients with AIS on statins therapy (21.66 ± 14.22 μg/dL), P < 0.001, [Figure 3]. However, BNP serum level was (20.33 ± 6.05 μg/dL) in AIS patients on atorvastatin and (21.51 ± 6.82 μg/dL) AIS patients on rosuvastatin, which was not significantly differed (P = 0.54), [Figure 4].
Figure 3: Brain natriuretic peptide serum levels in patients with acute ischemic stroke regarding statins therapy

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Figure 4: Differential effect of atorvastatin and rosuvastatin on brain natriuretic peptide serum level was in patients with acute ischemic stroke

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Stroke risk score in acute ischemic stroke patients

SRS was significantly greater in AIS patients as compared with controls (P < 0.0001). Moreover, SRS was (9.10 ± 3.22) in patients with AIS on statins therapy, (20.82 ± 7.87) in patients with AIS not on statins therapy, and (5.62 ± 2.75) in healthy controls [Figure 5]
Figure 5: Stroke risk score in patients with acute ischemic stroke regarding statins therapy. *P < 0.001 as compared with statins and control groups.#P < 0.05 as compared with control group

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As well, SRS was lower in AIS patients, were on atorvastatin therapy (7.60 ± 2.05) as compared with AIS patients, were on rosuvastatin therapy (9.11 ± 2.72), (P = 0.04), [Figure 6].
Figure 6: Stroke risk score in patients with acute ischemic stroke on atorvastatin or rosuvastatin therapy

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Moreover, BNP serum levels was correlated with SRS in patients with AIS on statins therapy (r = 0.42, P = 0.03), but it was highly correlated with SRS in patients with AIS not were on statins therapy (r = 0.89, P < 0.001), [Figure 7].
Figure 7: Correlation of stroke risk score and brain natriuretic peptide serum level in patients with acute ischemic stroke regarding statins therapy

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  Discussion Top


AIS is one of the most everyday leading causes of mortality and disability, predominantly in the developing countries. Following AIS, there is a subsequent neuroinflammation that exacerbates neuronal injury, resulting in cell death, but also plays an advantageous role, by promoting recovery.[18] Statins have interesting anti-inflammatory actions due to their influence on mevalonate pathway and isoprenoids depletion. The current study is designed to discover the differential anti-inflammatory effect of atorvastatin and rosuvastatin on BNP serum levels in patients with AIS.

In the present study, lipid profile (TC, TG, LDL, and non-HDL) was greater in AIS patients compared to the healthy controls; however, HDL-c was lower in AIS patients compared to the controls, which highly approves with most of previous cohort and epidemiological studies, which found an association between high cholesterol concentrations and increased risk of AIS. Moreover, an inverse association was shown between HDL-c levels and risk of AIS.[19] High level of LDL-c triggers endothelial dysfunction and atherosclerosis, whereas, high HDL-c levels provide a protection against the incidence of AIS.[20] Another study showed that TG level is significantly lower in AIS patients against controls, which might due to poor nutritional status of patients, regardless of the statins use.[21]

BNP serum level is assumed to be the most sensitive bio-marker indicating the presence of heart problem as compared to troponin. BNP is mostly secreted by myocardium during high intracardiac pressure.[22] Furthermore, BNP is thought to be upregulated after cerebral ischemia and secreted by astrocytes. Despite the ambiguous association between BNP and AIS, high BNP values were thought to result from cardioembolic etiology or heart failure. Rapid BNP measurement (during 24 h from ischemic onset) could be more accurate for the estimation of stroke mortality and severity.[12]

The present study observed interesting elevation in BNP serum concentrations in patients with AIS regardless the presence or absence of prior cardiac problems. Sayan et al. detect increases in BNP concentrations in patients with AIS, due to ischemic injury to the astrocyte.[23]

In the current study, high serum levels of BNP within 48 h from ischemic onset were significantly correlated with high SRS in AIS patients. Furthermore, most of BNP elevations were mainly in patients having a previous history of TIA or IS. Another study suggested that early and high levels of BNP following TIA are associated with increased risk of recurrence, particularly in the first few hours.[24] In the current study, the association between BNP levels, SRS, and previous history of TIA or IS, could be promising in expecting the prognosis, severity, and recurrence following AIS, regardless the source of AIS. On contrast, an inverse association between stroke outcomes and earlier BNP levels (within 24 h from ischemic onset) has been observed.[25] Moreover, there is an association between delayed elevations in BNP levels (during the subacute and chronic phase of AIS) and AF in cryptogenic stroke. Indeed, high serum concentrations of BNP in AIS patients indicated underlying cardiometabolic problem and associated with poor functional outcomes at 6 months after AIS.[26]

However, a recent study by Sakamoto et al. corroborate that initial high serum level of BNP in AIS patients with the coexistence AF is not link with underlying cardiac origin.[27]

SRS was significantly greater in AIS patients compared with controls (P < 0.0001), due to underlying cardiometabolic risk factors such as hypertension, old age, and smoking. Recently, revised Framingham SRS illustrates that the stroke risk is augmented in the presence of inflammatory reactions in addition to the basic risk factors.[28]

Moreover, the anti-inflammatory, anti-oxidant, and other pleiotropic properties of statins decrease the SRS; this might explain low SRS in patients with statins therapy.[29]

As well, SRS was lower in AIS patients, were on atorvastatin therapy (7.60 ± 2.05) as compared with AIS patients, were on rosuvastatin therapy (9.11 ± 2.72), (P = 0.04), which might be due to the higher neuroprotective effect of atorvastatin compared with rosuvastatin.[30] Furthermore, atorvastatin is more effective in the management of AIS as compared to other statins, due to potent antiinflammatory effect and activation of brain-derived neurotrophic factor.[31] Furthermore, high lipophilicity of atorvastatin enhances its penetration to CNS. On the other hand, rosuvastatin lower LDL-c and increase HDL-c more efficiently than atorvastatin, which thought to be the reason for hemorrhagic transformation triggered by rosuvastatin, but not by atorvastatin, after AIS.[32]

Due to the above-mentioned properties regarding atorvastatin, atorvastatin could be superior to rosuvastatin in AIS prevention and management. However, the effect of both atorvastatin, atorvastatin on BNP was not significantly differed, so further researches are needed to confirm that.

SRS showed significant and interesting correlation with BNP serum levels in AIS patients. However, BNP serum levels were not significantly differed regarding statins type in patients with AIS. According to another study, atorvastatin showed more significant reduction in BNP and lower all-causes mortality in patients with AIS due to neuroprotective effects and high lipophilicity.[33]

Last but not least, the association between BNP serum levels, SRS values, and previous history of TIA or AIS can be promising in considering BNP as novel biomarker in the diagnosis of AIS, and in estimating the severity of AIS, though further researches are needed to approve that.


  Conclusion Top


BNP serum level is elevated in patients with AIS and correlated significantly with SRS. Statins therapy mainly atorvastatin and rosuvastatin are effective antiinflammatory agents in the management of AIS through the reduction of BNP serum levels. However, there is no significant difference between the two statins.

Acknowledgment

The authors express deep thanks for all enrolled patients and volunteers.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

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