The Role of Lipoprotein (a) in Intracranial Atherosclerotic Disease: A Hospital
Based Cross Sectional Study from India

The Role of Lipoprotein (a) in Intracranial Atherosclerotic Disease: A Hospital Based Cross Sectional Study from India

Dnyaneshwar Asole^*, PP Ashok and Mahendra Thakre

Department of Neurology, Hinduja National Hospital & research centre, Mahim, Mumbai

*Corresponding Author:: Dnyaneshwar Asole
Department of Neurology, Hinduja National Hospital & research centre, Mahim,
Mumbai,
Tel: 8879875830;
E-mail: dcastle1980@gmail.com

Received: February 18, 2022, Manuscript No. IPSRT-22-11887; Editor assigned: February 21, 2022, PreQC No. IPSRT-22-11887 (PQ); Reviewed: March 07, 2022, QC No. IPSRT-22-11887; Revised: March 11, 2022, Manuscript No. IPSRT-22-11887 (R); Published: March 18, 2022, Invoice No. IPSRT-22-11887

Citation: Asole D, Ashok PP, Thakre M (2022) The Role of Lipoprotein (a) in Intracranial Atherosclerotic Disease: a Hospital Based Cross Sectional Study from India. Stroke Res Ther Vol:6 No:2

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Abstract

The atherosclerotic plaque develops due to the accumulation of lipids, inflammatory cells, smooth muscle cells, and extracellular matrix in the sub-endothelial space over time. Atherosclerotic plaques are mainly found at arterial bifurcations, branch points and vessel curvatures, whereas straight non branching arterial segments are generally spared. Stroke is a major cause of mortality and morbidity worldwide, with ischemic stroke being the predominant type (approximately 80%) found in stroke patients. With the current ageing population, the number of people suffering from stroke will inevitably escalate leading to increasing demand for more effective prevention, diagnosis and treatment strategies.

Keywords

Atherosclerotic Plaque; Preventive Treatments; Accumulation

Introduction

As one of the most common causes of ischemic stroke worldwide [1], Intracranial Atherosclerosis (ICAS) accounts for about 30-50% of ischemic stroke or transient ischemic attacks in Asia, 15-29% in Africa, and 5-10% in Europe or North America [2]. Exploring the distribution of risk factors among these subtypes is essential for understanding potential pathogenic mechanisms of stroke and targeting preventive treatments. This will also influence choices for management.

In this regard, lipoprotein (a) [Lp (a)] is a Low-Density Lipid (LDL)-particle which is composed of apolipoprotein B-100 to which apolipoprotein (a) is covalently bound. Recently, Lp(a) has been recognized as a potentially important risk factor for atherosclerotic disease.

To the best of our knowledge, there is no study from India which has compared Lp (a) levels between ECAS and ICAS patients. This led us to undertake the present study to find out whether raised Lp(a) is linked to increased incidence of intracranial atherosclerosis in Indians [3,4].

Methodology

Study design

The present cross-sectional study was conducted by the Department of Neurology, PD Hinduja National Hospital & Medical Research Centre, Mumbai in which patients with a diagnosis of ischemic stroke were included from January 2016 till December 2016. During the study duration 110 ECAS and 40 ICAS patients were included. The patients and their attendants were explained the purpose of the study and an informed consent was obtained from them or their legal representatives before enrolment in the study. The study was approved by the Institutional Ethics Committee.

Inclusion criteria and case definitions

Acute ischemic stroke patients with large artery stenosis as a mechanism of stroke were included in the study. They were classified as either as ECAS or ICAS. ICAS was defined as significant stenosis in the intracranial arteries including anterior cerebral artery, middle cerebral artery, posterior cerebral artery, basilar artery and intracranial internal carotid, vertebral artery, without significant stenosis of the extracranial carotid and vertebral arteries. ECAS was defined as significant stenosis in the common carotid, extracranial internal carotid and vertebral arteries without significant stenosis of the intracranial arteries. Significant stenosis was defined as presence of more than 50%stenosis of the arterial lumen assessed by 1.5 Tesla MR Angiography.

Exclusion criteria

We excluded patients with lacunar ischemic strokes, those with clinical evidence of cardio-embolic stroke, with clinical or serological evidence of CNS vasculitis, with clinical or biochemical evidence of liver, renal, or thyroid disease, women on contraceptive pills, those with on-going fever or presence of sepsis, with clinical or radiological evidence of malignancy, those with collagen vascular disease or those with CT or MRI Brain showing intracranial bleed. Patients with simultaneous significant (>50%) atherosclerotic stenosis of both extra cranial and intracranial arteries on CT or MRI study were also excluded.

Data collection and data analysis

All patients were subject to recording of a detailed history, general physical examination, a detailed neurological examination. History regarding clinical risk factors profile such as age, sex, hypertension, diabetes mellitus, cardiovascular history, drug history, smoking habits and alcohol intake was also recorded. The following investigations were performed in each case: complete hemogram, fasting blood sugar, postprandial blood sugar, HbA1c levels, renal function tests, lipid profile, plasma Lp (a) levels, MRI brain with angiography. CT angiography of head and neck vessel was done in selected patients to confirm presence of atherosclerotic arterial stenosis exclude non atherosclerotic disease of vessels like vasculitis.

Overnight fasting blood samples were collected for estimation of Lp (a) levels. Lp(a) estimation was done through immunoturbidimetric assay at our laboratory. Lp (a) can also be estimated by Radio Immune Assay, Rosache strips using micro- ELISA, Monoclonal antibodies. The normal values of level of serum Lp (a) are less than 30 mg/dl. The level of serum Lipoprotein (a) more than 30 mg/dl were considered as high level. Parameters of dyslipidaemias were defined according to NCEP ATP III (2005 revision) definition if total cholesterol levels were ≥ 200 mg/dl or triglyceride levels were ≥ 150 mg/dl or LDL levels were>100 mg/dl or HDL levels were <40 mg/dl [5]. Abdominal obesity was defined according to NCEP ATP III (2005 revision) definition for metabolic syndrome, if patient’s waist circumference was ≥ 40 inches in men and ≥ 35 inches in women.

The data were compiled using Microsoft Excel sheet and analysed using SPSS 23 software. Descriptive analysis for numerical data consisted of mean+SD (if normally distributed)/ median and range (if not normally distributed) and for categorical data consists of frequencies and percentage for various parameters. Normality of data was checked using Kolmogorov Smirnov test. A p value of less than 0.05 was considered as statistically significant.

Results

During the study period, 110 patients were included in ECAS and 40 in ICAS group. The median age of patients was 62 years with a range of 31-89 years and 67 years with a range of 34-87 years in ECAS and ICAS groups respectively (p value=0.59). In the ECAS group, there were 76 males and 34 females, compared to 34 and 6 in the IACS group (p value=0.051). Hypertension was found in 72 (65%) in ECAS and 30 (75%) in ICAS group (p value=0.26). Diabetes mellitus was found in 52 (47%) in ECAS and 22 (55%) in ICAS group (p value=0.41). Abdominal obesity was found in 45 (41%) in ECAS and 19 (48%) in ICAS group (p value=0.47). There were 15 (14%) smokers in ECAS group as compared to 9 (23%) in ICAS group (p value=0.19). Significant alcohol intake was present in 13 (12%) and 9 (23%) patients of ECAS and ICAS groups respectively (p value=0.11). Thus age, gender, and the occurrence of hypertension, diabetes mellitus, smoking, and significant alcohol consumption were not statistically different between the ECAS and ICAS groups as shown in Table 1.

Clinical variables	ECAS (n=110)		ICAS (n=40)		p value
Clinical variables	N	%	N	%	p value
1) Gender
Females	34	31%	6	15%	0.051
Males	76	69%	34	85%
2) Past medical history
Hypertension	72	65%	30	75%	0.26
Diabetes mellitus	52	47%	22	55%	0.41
Smoking	15	14%	9	23%	0.19
Alcohol	13	12%	9	23%	0.11
Abdominal obesity	45	41%	19	48%	0.47
3) Age	ECAS (n=110)		ICAS (n=40)		p value
Median value	62 years		67 years		0.593
Range	31-89		34-87		0.593

Table 1: Comparison of clinical profile between extra cranial (ECAS) and intracranial stenosis (ICAS) patients.

Hemispheric large cortical plus subcortical infarcts (53%) and cerebellar infarcts (20%) were more common in ICAS group (p values of <0.05 for both). Whereas cortical watershed (37%) and deep watershed (33%) infarcts were more common in the ECAS group (p values of <0.001 and <0.05 respectively) as shown in Table 2.

Sites of infarction	ECAS (n=110)		ICAS (n=40)		p-value
Sites of infarction	N	%	N	%	p-value
Hemispheric large cortical plus subcortical infarcts	29	26%	21	53%	<0.05
Cortical watershed	41	37%	1	3%	<0.001
Deep watershed	36	33%	5	13%	<0.05
Cerebellar	3	3%	8	20%	<0.05
Brainstem	3	3%	5	13%	0.06

Table 2: Comparison of radiological pro ile between extra cranial (ECAS) and intracranial stenosis (ICAS) patients.

The blood sugar pro ile was similar in the two study groups and the values were statistically not signi icant. High FBS was seen in 47 (43%) of the ECAS and 17 (43%) of the ICAS group (p value=0.98), whereas high PLBS was seen in 46 (42%) of the ECAS and 17 (43%) of the ICAS group (p value=0.94). Similarly high HbA1c levels were seen in 38 (35%) of the ECAS and 12 (30%) of the ICAS group (p value=0.61). Lipid profile was also found to be similar in the two study groups, except low HDL, which was observed in 70 (64%) of the ECAS patients as compared to 17 (43%) of the ICAS patients. This was statistically signi icant with a p value of <0.05 as shown in Table 3.

Laboratory variables	ECAS (n=110)		ICAS (n=40)		p value
Laboratory variables	N	%	N	%	p value
Blood sugar profile
High fasting blood sugar	47	43%	17	43%	0.98
High post-prandial blood sugar	46	42%	17	43%	0.94
High HbA1c	38	35%	12	30%	0.61
Lipid profile
High Cholesterol	30	27%	8	20%	0.36
High low-density lipoprotein	35	32%	8	20%	0.15
Low high-density lipoprotein	70	64%	17	43%	<0.05
High very low-density lipoprotein	26	24%	5	13%	0.26
High triglyceride	25	23%	5	13%	0.31

Table 3: Comparison of laboratory profile between extracranial (ECAS) and intracranial stenosis (ICAS) patients.

We observed that median Lp (a) levels were 38.7 mg/dl (range: 2.1-201 mg/dl) in the ECAS group and 28.4 mg/dl (range: 1.9 to 222 mg/dl) in the ICAS group (p value=0.42). It was also found to be high in 66 (60%) of the ECAS patients and 18 (45%) of the ICAS group, with no significant statistical difference between the two groups (p value=0.11) as shown in Table 4.

Lipoprotein (a) levels	ECAS (n=110)		ICAS (n=40)		p value
Lipoprotein (a) levels	N	%	N	%	p value
High	66	60%	18	45%	0.11
Normal	44	40%	22	55%	0.11
Median value	38.7 mg/dl		28.4 mg/dl		0.42
Range	2.1-201 mg/dl		1.9-222 mg/dl		0.42

Table 4: Comparison of Lipoprotein (a) levels between extra cranial (ECAS) and intracranial stenosis (ICAS) patients.

Discussion

The present study was done to compare the clinical risk factor and biochemical variables between ECAS and ICAS stroke patients and assess the association of raised Lp (a) with ICAS. We also compared the radiological profile among these groups. In our study of 150 stroke patients, 73% had ECAS and 27% had ICAS. Previous reports have observed that ICAS is a more common cause of stroke than ECAS in Asian populations. ICAS accounts for about 33%–50% of ischemic strokes and >50% of transient ischemic attacks (TIAs) in these populations [6].

ICAS was the most common stroke mechanism in the Hyderabad Stroke Registry reported by [7]. As the majority of the world’s population is represented by Asians, ICAS is thus the most common vascular lesion in stroke patients worldwide. However, new studies have indicated increase in ECAS among Asian stroke patients, and though this difference may be lost in the future [8].

Another reason for the lower number of patients with ICAS in our study could be due to the exclusion of patients with simultaneous signi icant (>50%) atherosclerotic stenosis of both extracranial and intracranial arteries.

In the present study, the median age of patients was 62 years with a range of 31-89 years and 67 years with a range of 34-87 years in ECAS and ICAS groups respectively. Srivastva et al observed that intracranial stenosis is more commonly associated with younger age (age<60 years) while extracranial stenosis with older age group (age>60 years) [9]. However, a study by Uehara et al found that older age is risk factor for both extracranial and intracranial stenosis [10].

We observed that 76 (69%) of the ECAS and 34 (85%) of the ICAS were males; however this observation was statistically not signi icant. Li et al showed men had a higher risk of suffering from ICAS with acute ischemic strokes than women, demonstrating that a sex difference existed in ICAS with anterior circulation stroke.

This may be due to the fact that males are the bread winners in majority of India and they are more likely to seek medical care, which suggests cultural bias. In addition, this association of male gender with ECAS could be explained by the fact that men tended to have habits of smoking, alcohol use, and a high calorie and fat intake [11]. Kim et al investigated differences in risk factors between patients with ICAS and ECAS and found patients with ICAS were more o ten young (65.92 ± 11.50) and female (42%) as compared to that in ECAS group (mean age 68.08 ± 9.42 and 21% females) [12].

Hypertension was found to be the most common past medical history, irrespective of the location of stenosis. It was observed that 72 (65%) of the ECAS and 30 (75%) of the ICAS were hypertensive. Diabetes mellitus was seen in 52 (47%) of ECAS and 22 (55%) of ICAS groups making it the next most common risk in our study, followed by abdominal obesity. It should be noted that we could not ind a signi icant association of any comorbid conditions with both ECAS and ICAS. Found the most prevalent risk factors in their study population to be hypertension (77.4%) and reported that hypertension, was non-signi icantly more prevalent in ECAS patients [13]. In a similar study, reported that ECAS had more frequent hypertension (67.5% vs. 53.8% p<0.001) than the patients with ICAS [14]. Reported that hypertension (56.9% in ICAS vs. 28.6% in ECAS) was signi icant risk factors for ICAS [15]. Found DM in 53.9% of their patients and found it to be more common in ICAS patients (55.2%) as compared to ECAS (52.6%), though the dierence was not statistically signi icant [13]. In the study by Kim et al, DM was diagnosed DM in 35.5% with ICAS, 35.8% with ECAS and 36.6% in both ICAS & ECAS, p value=0.9 [12]. NOMASS, Barcelona-ASIA and some other studies have reported DM as more prevalent and important for prognosis in ICAS, but it has not been supported by our or by other studies [16]. DM, a major component of metabolic syndrome, is an established risk factor for ECAS [17]. However, its role in ICAS is yet to be elucidated, and previous studies have yielded controversial results [18]. In the present study, abdominal obesity was found to be present in 41% of ECAS and 48% of ICAS patients, with no statistical difference between them. Jin et al also found no significant difference regarding BMI and waistline between ICAS or non- ICAS groups [15]. Obesity is an established risk factor for stroke, but no other studies have evaluated its association with ICAS or ECAS. Future studies should investigate this association, as South-East Asian population is at a higher risk for metabolic syndrome.

Lee DK, et al. described the possible mechanisms of stroke associated with large-artery Intracranial Atherosclerotic Stenosis (ICAS) as artery-to-artery embolism, hypo-perfusion, branch occlusive disease and a combination of these mechanisms [22]. This was similar our study, where hemispheric large cortical plus subcortical and cerebellar infarcts were observed to be significantly more in ICAS group. The likely mechanism being branch occlusive disease. Derdeyn CP, et al, demonstrated a link between extracranial carotid occlusive disease and hemodynamic impairment, which leads to cortical and internal watershed infarcts, which is consistent with our findings, in which cortical and deep (internal) watershed infarcts are significantly more common in the ECAS group [23].

We observed that serum Lp (a) levels were also found to be similar among ECAS and ICAS patients. Thus, we did not find any correlation between Lp (a) levels and predilection towards ICAS in our study population. Kim et al observed that the median serum Lp (a) levels of the ICAS (32.0, 21.5-48.9 mg/dL), ECAS (35.0, 23.9-48.6 mg/dL), and combined intra and extracranial stenosis (39.3, 21.4-67.0 mg/dL) group were significantly higher than that of the non-cerebral stenosis group (25.3, 13.1-43.7 mg/dL) (p<0.001, respectively, and there was a significant difference of lipoprotein levels between the ICAS and combined group (p=0.047) [19]. The underlying mechanism of involvement of Lp(a) is not clearly understood. It is known that apolipoprotein (a) has a tendency to bind with connective tissue elements, and Lp (a) particle is vulnerable to oxidative modification and scavenger receptor uptake. As a result, Lp (a) could actively promote atherosclerosis [20]. In addition, Lp (a) is associated with endothelial dysfunction [21]. However, these mechanisms need to be verified from future bench research.

There are a few limitations of the study. This was a hospitalbased study. This might introduce some sampling bias. We excluded patients with simultaneous presence of significant (>50%) extracranial and intracranial stenosis. Our sample did not include asymptomatic patients with cerebral artery stenosis. Thus, the results might not be extrapolatable to the general public. Second, the patients were not followed up to analyze the clinical outcome and recurrence of events.

Conclusion

The levels of increased Lp (a) were not significantly different in ECAS and ICAS patients with acute ischemic stroke, as per this study. Thus, we did not find correlation between Lp (a) levels and predilection towards ICAS in our study population.