Submitter: Dr.M. Nasir Shamas
Email: nasirshamas@gmail.com
Type: CallPublication
State:
Nation: India
Date: --
RELATIONSHIP OF AGE AND SEX WITH PLASMA LIPOPROTEIN (a) LEVELS IN ACUTE ISCHAEMIC STROKE



M. Nasir Shamas MBBS; MD Senior Resident

Irfan Ali MBBS; MD Senior Resident*

Syed Basharat Hussain MBBS; MD Senior Resident

Moonis Farooq MBBS; MD Senior Resident

Beenish Mushtaq MBBS. Post Graduate Student**





Department of Endocrinology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar India.
*Post Graduate department of Medicine, Govt. Medical College Jammu. India
**Post Graduate department of Community Medicine, Govt. Medical College Jammu, India

Correspondence:

Dr. M. Nasir Shamas Senior Resident, Endocrinology
Sheri-Kashmir Institute of Medical Sciences, Srinagar, J&K India.

Ph: 91-194-2426611 Resi .
M: 91-09419080512/91-09797485600.

Email: nasirshamas@gmail.com / nasirshamas@ yahoo.com

Post Box: House No 8, New Colony Sector B, NIT Road
Nigeen , Srinagar , Kashmir PIN 190006








RELATIONSHIP OF AGE AND SEX WITH PLASMA LIPOPROTEIN (a) LEVELS IN ACUTE ISCHAEMIC STROKE




ABSTRACT

Stroke, the most common life threatening neurological disorder has evolved as the third leading cause of death and foremost cause of disability in western countries. Annually, 15 million people worldwide suffer a stroke resulting in substantial health-care expenditures; the mean lifetime cost resulting from an ischemic stroke is estimated at $140,000 per patient. With time the focus has shifted from the conventional risk factors to the genetic and inflammatory markers as risk factors for stroke. The present study was aimed to ascertain the relationship of age and gender with Lipoprotein (a) levels in patients of acute ischemic stroke. The study was done in 120 subjects including 80 Computerized Tomography (CT) proven patients of acute ischemic stroke and 40 age and sex matched controls. Complete biochemical parameters were carried out on autoanalyzer using standard kits and reagents. Lipoprotein (a) [Lp (a)] was determined by immunoturbidimetric assay. The difference in Lp (a) levels in cases and control subjects distributed in three age groups was (p 0.34, P 0.14, p<0.001) respectively. p< 0.001 being highly significant. However no association was documented between sex and plasma lipoprotein (a) levels in acute ischemic stroke. Hence Lp (a) considered to be a genetic factor is instrumental in causing cerebrovascular arteriosclerosis leading to ischaemic stroke. It can be used as important marker to identify patients at risk of severe stroke and to institute aggressive preventive strategies in future.


KEY WORDS
Ischemic stroke, Age, Sex, Lipoprotein (a), cerebrovascular arteriosclerosis,


















INTRODUCTION

Stroke is defined as rapidly developing clinical symptoms and a sign of focal or at times global loss of cerebral function with symptoms lasting more than 24 hours or leading to death with no apparent reason, other than that of vascular origin(1). It is due to sudden loss of brain function resulting from an interference with the blood supply to the brain. Stroke is the sixth leading cause of Disability Adjusted Life Years (DALY) (2), third most common cause of death in the developed countries(3) with over a 5 million people dying and another 5 million left permanently disabled annually placing a great socio-economic burden on the family and society (4). India will soon have to bear an enormous socioeconomic burden due to the costs of the rehabilitation of stroke survivors; Community surveys from many regions show crude prevalence rates for stroke in the range of 90-222 per 100,000 persons (5). It is important to reduce the impact of stroke in communities by both primary as well as secondary preventive strategies, which include identifying people at risk and thereby appropriate risk factor management. Ischaemic Stroke accounts for 86% of stroke cases and the commonest cause of ischaemic stroke is atherosclerosis, which has been found to be particularly high in Indian population (6). This unusual predisposition to increased atherogenic risk of Indians may be due to our demographic profile, transition in economy and lifestyle changes (7).
There is a substantial void in understanding the pathogenesis of stroke as only 50% of strokes are attributed to conventional risk factors like age, sex, blood pressure, smoking, diabetes mellitus, coronary artery disease and serum Lipids. This perceived dilemma has led to further evaluation, research and subsequent emergence of nontraditional, new and genetic risk factors causing ischaemic stroke. Lipoprotein (a), Fibrinogen, Homocysteine, TNF, D- Dimer, C - reactive protein (CRP) any many others are emerging as newer markers for CAD and associated cerebrovascular disorders (8).
Lipoprotein (a) Lp (a) consists of LDL particle attached with the apo (a) protein by a disulfide bridge. The apo (a) moiety resembles plasminogen (9). Thus providing a connecting link between atherothrombosis and atherosclerosis (10).Density of Lipoprotein (a) ranges from 1.050 – 1.120 gms/ml and its size is 25 nm. It originates in the liver and was first identified in the plasma by Berg in 1963. Lipoprotein (a) is ten times more atherogenic than LDL-C but the mechanism by which it is removed from circulation is still unknown. Plasma levels of Lp (a) > 20-30 mg/dl are repeatedly associated with premature development of atherosclerosis. A link between Lp (a) and atherosclerosis has been confirmed in most of the studies (11) (12). A recent meta-analysis indicates that elevated Lp (a) increases the risk of vascular events by 30% in secondary prevention studies and by 70% in primary prevention studies (13). More than 10 angiographic and case-control studies in India have shown elevated Lp (a) levels to be a powerful risk factor for premature atherosclerosis, especially under the age of 40 years (14) (15).Lipoprotein (a) levels are genetically determined and found to increase slightly with age and show racial variation Many studies have been done which prove that higher plasma Lp (a) levels are associated with increasing age in ischaemic stroke, but the absence of any such data in this region of the world was one of the motivating factors for the present study.



METERIALS AND METHODS
Study population:
The present study is an in hospital study. Patients were recruited from indoor wards of general medicine, outpatient clinics, Neurology clinics and emergency department. Between June 2006 and March 2008, a total of 120 subjects including 80 cases of acute ischemic stroke of various age groups and both sexes were admitted and registered in the study. WHO definition of acute ischemic stroke was considered for the early diagnosis and subsequent confirmation was done by CT scan of head or MRI brain (where ever required). 40 age and sex matched controls (hospital employees and healthy attendants of patients of non vascular diseases) were also included in the study. Inclusion criteria of ischemic stroke patients for enrollment in the study were CT scans showing cerebral infraction and patient admitted with in 12 hours of ischemic stroke. Patients with infective / inflammatory, neoplastic, renal, hepatic, neurodegenerative, collagen vascular diseases, recent myocardial infarction, with in 6 weeks and recurrent stroke were excluded from the study. Similar exclusion criteria were also applied for selected healthy controls. A stepwise approach was formulated for the patients and evaluation was done by means of a Proforma, which consisted of detailed history, examination and investigations. Risk factors for stroke like hypertension, hyperlipidemia, smoking, coronary artery disease, and alcohol were taken into account. Dietary habits and socioeconomic status were also studied. The complete hematological and biochemical investigations including X-ray chest and 12-lead electrocardiogram were done in all patients. In addition, Carotid Doppler and echocardiography was also done where possible.

Lipoprotein (a):

Quantitative determination of Lipoprotein (a) in human serum was done by turbidimetric immunoassay using commercial kit from Diasys Diagnostic System (GmbH) D 65558 from HOLZHEIM, Germany and measurement of antigen antibody reaction was achieved by the end point method using semi-automatic analyzer Biotron-BTR 820 Photometer.


Statistical Analysis:

In the study, all the data are expressed in Mean / ± Standard Error of Mean. SPSS statistical software was used for Statistical Analysis. P-values < 0.05 were considered significant. Pearson’s Correlation was used to find out significant correlation between two variables. ANOVA was applied for categorical variables and for continuous variables Student’s t-test was used.










RESULTS

A total of 120 subjects were included in the study, out of which 80 were patients of ischaemic stroke. 40 healthy subjects served as controls in this study. Plasma Lipoprotein (a) levels were assessed in all subjects besides other investigations as per Proforma. The data of observations is presented and analysed on the following variables.










































Table No: 1. Mean Plasma Lipoprotein (a) levels in cases and controls

Study Group Cases Controls
Mean Plasma Lp(a) 26.7 mg/l 17.04 mg/dl
Observations 80 40

Table No. 1 shows the mean plasma Lipoprotein (a) values in cases and controls. The plasma Lp (a) values in the case group ranged from 3.4-98.7 mg/dl with a mean value of 26.7 mg/dl. In the control group plasma Lp (a) values ranged from 3.5-48 mg/dl with a mean of 17.04 mg/dl. Statistical analysis was done to assess the significance of difference of mean of plasma Lipoprotein(a) values in 80 cases of ischaemic stroke and 40 healthy age and sex matched controls, p value was <0.000 which suggests a statistically significant difference in mean values of plasma Lipoprotein (a) in cases versus controls.






























FIG. A: Bar chart showing plasma Lipoprotein (a) levels distribution in cases and controls.



























Age Distribution

Table No: 2
Age group Cases Controls
<40 Years 21 10
41-60 years 25 13
> 60 Years 34 17
Total 80 40

As shown in Table 2, present study included a total of 80 patients of ischaemic stroke and 40 healthy sex and age matched controls. 21 cases of ischaemic stroke and 10 controls were below 40 years of age, 25 patients and 13 controls belonged to the age group between 41-60 years, whereas 34 patients and 17 controls were above 60 years of age. The mean age of cases was 55.63 years and mean age of controls was 57.13 years.




























Sex Distribution.

Table No: 3
Sex group. Cases Controls
Males 48 24
Females 32 16

Table No. 3 shows the sex distribution in the present study. Among the controls 24 were males and 16 were females. Out of 80 cases 60 %( 48) patients were males and 40% (32) patients were females.





































FIG. B: Bar chart showing Age distribution of cases and controls



























FIG.C: Bar chart showing sex distribution































Relationship between Age and Plasma Lipoprotein (a) levels

Table No: 4.
Age Group Number Mean Lp(a) mg/dl Cases Number Mean Lp(a) mg/dl Controls
<40 21 17.54 10 15.45
41-60 25 23.9 13 17.22
>60 34 34.5 17 17.8

Table No. 4 shows the levels of plasma Lp (a) in three age groups of cases and controls (<40, 41-60, and >60 years). The mean age of ischaemic patients was 55.63 years, the youngest patient presenting at 22 years and the oldest patient presenting at 91 years of age. Of these, 26.25% (21) patients were below 40 years of age group. 31.25% (25) patients were between the age group of 41-60 years and 42.5% (34) patients were above 60 years of age. In 21 patients of ischaemic stroke with less than 40 years of age, Mean plasma Lp (a) level was 17.54 mg/dl and in healthy 10 controls of same age group mean plasma Lp (a) level was 15.45 mg/dl. In 25 patients of Ischaemic stroke of age group of 41-60 years mean plasma Lp (a) level was 23.9 mg/dl and in 13 controls of this age group mean plasma Lipoprotein (a) level was 17.22 mg/dl. In 34 patients of Ischaemic stroke of > 60 years age group mean plasma Lp (a) level was 34.5 mg/dl and in 17 healthy controls of >60 years of age, mean plasma Lp (a) level was found to be 17.8 mg/dl. To assess the statistical significance of the difference of mean between 3 age groups in cases and controls, p value in the age group of >60 years was <0.001 which is highly statistically significant suggesting an association between increased Lp(a) levels and advancing age.

















Relationship between sex and plasma Lipoprotein (a) levels.

Table No: 5.
Sex Group Cases Controls
Number Mean Lp(a) mg/dl Number Mean Lp(a) mg/dl
Male 48 27.4 24 17.22
Female 32 25.7 16 16.75

Table No 5 shows the plasma Lp (a) distribution in two sex groups in cases of ischaemic stroke and age and sex matched healthy controls. In 48 male patients the mean plasma Lp (a) level was 27.4 mg/dl and in 32 female patients mean plasma lipoprotein (a) level was 25.7 mg/dl. In male controls, 24 in number the mean plasma Lp(a) level was 17.22 mg/dl and in 16 female healthy controls plasma Lp(a) level was 16.75 mg/dl. To assess the statistical significance between difference of mean in two sex groups in cases and controls p value was <0.693 in cases and <0.986 in controls both of which are statistically insignificant suggesting that plasma Lp(a) levels were not affected by gender.


























DISCUSSION

Our study is a hospital based case control study to determine the relationship of age and gender with plasma levels of Lipoprotein (a) in 80 patients of ischaemic stroke. Our study shows a highly significant increase in serum Lp(a) levels in cases of ischaemic stroke as compared to healthy controls with a p-value of <0.000.As in our study mean serum Lp(a) levels have been shown to be higher in patients of ischaemic stroke as compared to healthy controls in many studies. Woo et al (16) performed a case control study of 304 Chinese patients and found high serum Lp (a) concentration and low apolipoprotein A-1 concentration in such patients. This study has about (26.25%) patients of young stroke presenting before the age of 40 years. The observation is peculiar to our population as compared to many reports from Asia and study by Olivero U et al (17).The results of our study are also in agreement with a study done by Mehndiratta MM et al (18) who concluded that stroke in young patients accounted for 13.5% (127/940) of all cerebrovascular accidents.

In another study, done by Scanu AM (19), Lipoprotein (a) levels were found to be an independent risk factor for carotid atherosclerosis in subjects younger than 60 years of age. Our study included more number of male patients (60%) than female patients (40%) as supported by the observation of Kurtzke JF (20) who reported that the incidence of atherothrombotic cerebrovascular disease is about 30% higher in males as compared to females. In our study, mean age of patients was 55.63 years (range 22-91 years, median length of hospital stay (irrespective of outcome) was 15 days (3-30 days), mean Lipoprotein(a) levels in plasma were found to be higher in cases of ischaemic stroke (26.7 mg/dl) as compared to controls (17.04 mg/dl). There was no correlation of serum Lipoprotein (a) levels with the outcome in patients of ischaemic stroke.

Thus, best way to reduce plasma Lp (a) is unknown however; some reduction is seen with the use of Niacin. The genetic variations causing raised Lp (a) levels interact with non-genetic factors, resulting in variable susceptibility to the development of atherosclerosis. Due to cumulative effects of elevated Lp (a) with other risk factors like hypertension, elevated serum cholesterol, high BMI values, diabetes mellitus etc, these factors should be taken care of aggressively to prevent occurrence and recurrence of stroke. Thus to summarize, Lipoprotein (a) is a genetic risk factor which increases the risk of vascular atherothrombotic lesions with increasing age and hence increases the risk of stroke in people who have higher levels of Lipoprotein (a).The main shortcoming of present study is that it was a hospital based case-control study and the results cannot be extrapolated to the entire population.








CONCLUSION

Stroke ranks first in frequency and importance among all adult neurological disorders. Keeping in view the magnitude of morbidity and mortality associated with ischaemic stroke, it seems prudent to search for risk factors that predispose to stroke. After obtaining the findings and evaluating these for statistical significance, we conclude that the significant relationship between increasing age and Lipoprotein (a) levels in acute ischaemic stroke. However, gender bears no influence on plasma lipoprotein (a) levels in patients of acute ischemic stroke. Though it is proven and only based on evidence, further long term prospective studies are required in Indian population before we can concretely prove our point.








































REFERENCES

1. Warlow CP, Dennis MS, Van Gijn J, et al. A practical guide to management. Oxford: Blackwell scientific publications Stroke 2000; 34; 45-47.
2. Sethi PK. Stroke- Incidence in India and management of ischemic stroke. Neurosciences 2002; 6 (3): 139-43.
3. Rosamond W, Flegal K, Friday G, et al. Heart disease and stroke statistics — 2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Circulation 2007; 115: e69—e171.
4. Mackay J, Mensah GA. The Atlas of Heart Disease and Stroke. Published by WHO in collaboration with USA’s Centers for Disease Control and Prevention (CDC). 2004.
5. Dalal P, Bhattacharjee M, Vairale J, Bhat P. UN millennium development goals: Can we halt the stroke epidemic in India? Ann Indian Acad Neurol 2007; 10:130-36.
6. Enas EA. Why is there an epidemic of Malignant CAD in young Indians? Asian J of Clin Cardiol 1998: 1: 43-59.
7. Enas EA. Coronary artery epidemic in Indians: A cause for alarm and call for action. JIMA 2000; 98: 694-702.
8. Tanne D, Benderly M, Goldbourt U et al. C Reactive Protein as a Predictor of Incident Ischemic Stroke Among Patients With Preexisting Cardiovascular Disease. Stroke 2006; 37: 1720-24.
9. Scanu AM. Lipoprotein (a): A genetically determined cardiovascular pathogen in search of a function. J Lab Clin Med 1990; 116:142-6.
10. Foody JM, Milberg JA, Robinson K et al. Homocysteine and Lipoprotein (a) Interact to Increase CAD Risk in Young Men and Women. Arteriosclerosis, Thrombosis, and Vascular Biology 2000; 20(2):493- 9.
11. Cremer P, Nagel D, Mann H, et aI. Ranking of Lp (a) as a Cardiovascular risk factor: Results from a 10 year prospective study: in Woodford FP, Uavignon J. Sniderman A (eds): Atherosclerosis X. Amsterdam, Elsevier, 1995, PP 903-07.
12. Nguyen TT, Elletson RD, Hodge DO. Et al. predictive value of electrophoretically detected Lipoprotein (a) for coronary heart disease and cerebrovascular disease in a commonly-based cohort of 9,936 men and women. Circulation 1997:96: 1390-97.
13. Danesh J, Collins R, Peto R. Lipoprotein (a) and coronary heart disease. Meta-analysis of prospective studies. Circulation 2000; 102:1082–85.
14. Enas EA. Lipoprotein (a) is an important genetic risk factor for coronary artery disease in Asian Indians. Am J Cardiol 2001; 88: 201-02.
15. Gambhir JK, Kaur H, Gambhir DS et al. Lipoprotein (a) as an independent risk factor for coronary artery disease in patients below 40 years of age. Ind Heart J 2000; 52:407-10.
16. Woo J, Lau E, Lam CW, et al. Hypertension, Lipoprtein(a) and apolipoprotein A-1 as risk factors for stroke in the Chinese. Stroke 1991; 22:203-08.
17. Oliviero U, Orefice G, Coppola G, et al. Carotid Atherosclerosis and Ischaemic Stroke in young patients. Int Angiol 2002; 21(2):117-22.
18. Mehndiratta MM, Puneet A, Kaushik S, et al. Stroke in young adults. A Study from University hospital in North India. Med Sci Monit 2004; 10(9): CR535-41.
19. Scanu AM, Fless GM. Lipoprotein heterogeneity and biological relevance. J Clin Invest 1990; 85: 1709-15.
20. Kurtzke JF. Epidemiology of cerebrovascular disease. In cerebrovascular survey report for joint council Sub committee on cerebrovascular disease. NINDS and Stroke NHLI (Revised): Whiting Press: 1980; 135-176.