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Lipoprotein and apolipoprotein profile in men with ischemic stroke: Role of lipoprotein (a), triglyceride-Rich lipoproteins, and apolipoprotein E polymorphism
Abstract
The role of lipoprotein abnormalities in the development of ischemic cerebrovascular disease has not been sufficiently clarified. The aim of this study was to identify the lipoprotein profile in ischemic cerebrovascular disease and the possible role of apolipoprotein E polymorphism.
The relation between the concentrations of lipoprotein(a), intermediate density lipoproteins, apolipoprotein A-I, apolipoprotein B, apolipoprotein E, and other lipoproteins was studied in 100 men with ischemic cerebrovascular disease (48 atherothrombotic, 28 lacunar, and 24 of unknown type) and in 100 healthy age-matched men as a control group.
Patients with ischemic cerebrovascular disease had significantly higher levels of lipoprotein(a), lipids carried by intermediate density lipoproteins, and low density lipoprotein cholesterol and lower levels of high density lipoproteins than control subjects. Patients with atherothrombotic infarction had higher total serum cholesterol and low density lipoprotein cholesterol concentrations than patients with lacunar infarction. To assess lipoprotein abnormalities in normolipidemic subjects, a subgroup of 38 patients with ischemic cerebrovascular disease and 53 control subjects, both with serum cholesterol levels < 5.2 mmol/l (200 mg/dl) and triglycerides < 2.3 mmol/l (200 mg/dl), was analyzed. Serum lipoprotein(a), lipids carried by very low density lipoproteins and intermediate density lipoproteins, and low density lipoprotein triglycerides were significantly higher in normolipidemic patients compared with normolipidemic control subjects, whereas high density lipoprotein cholesterol levels were lower. Apolipoprotein E polymorphism in our ischemic cerebrovascular patients differed from that of the control group, with the epsilon 4 allele being more prevalent.
Increased serum lipoprotein(a) levels and intermediate density lipoprotein abnormalities together with decreased high density lipoprotein levels are major risk factors for ischemic cerebrovascular disease, even in normocholesterolemic and normotriglyceridemic subjects. Finally, the epsilon 4 allele could probably be a predisposing genetic marker for ischemic cerebrovascular disease.
... [45][46][47] Several authors agree on the influence of the apoE polymorphisms in the lipid metabolism. 48,49 However, this study does not show any association between apoE polymorphisms and increased levels of TC and LDL-C or reduced levels of HDL-C, even with the significantly higher frequency of the APOE*4 allele in patients. Nevertheless, the Framingham Offspring Study, with a lower prevalence of the APOE*4 allele in postmenopausal women in relation to those in premenopause, showed an association between higher LDL-C levels and an increase in the mortality risk for patients ...
... 60 Several authors have agreed about the influence of apoE polymorphisms on the metabolism of lipids. 48,49 The different isoforms of apoE interfere in the lipoproteic lipase activity during the conversion of VLDL to LDL. 51 Kinetic studies have shown a faster catabolization of apoE4 compared with apoE2, which is slower than apoE3. 7,61 The apoE4 was associated with a faster removal of TG only in non-CAD individuals, and so, the difference may be attributed to lower TG fasting levels in this group as moderate increases in fasting TG constitute an impaired postprandial response. ...
This study confirms the association of risk factors for coronary artery disease (CAD) and the apoE polymorphisms, specifically related to the APOE*4 allele, with coronary disease in postmenopausal women. Significantly altered values of the lipid profile were found in patients when compared with controls, independent of the presence of the APOE*4 allele. However, the controls showed higher high-density lipoprotein cholesterol (HDL-C) levels and reduced triglyceride (TG) levels, differing significantly from patients. In this case, the study of subgroups, considering the APOE*3/3 and APOE*3/4 genotypes, suggests that the APOE*4 allele is not implicated in the variations of the lipid profile of patients and determined an increase in the production levels of HDL-C and a reduction in TG highly benefiting the control group compared with APOE*3/3 genotype. The metabolic kinetics of TG, although with the same pattern between groups, and the presence of the APOE*4 allele are suggested to be associated with accelerated clearance compared with APOE*3 allele in non-CAD group.
... It is generally accepted that atherosclerotic lesions are initiated via the enhancement of LDL uptake by monocytes and macrophages [4,5]. Allelic variants for apolipoproteins such as APOB, APOCIII and APOE, as well as the cholesterol ester transfer protein (CETP) and the lipoprotein lipase (LPL), play a key role in lipoprotein metabolism and are linked to the development of atherosclerosis and increased vascular risk [6][7][8][9][10][11][12][13]. ...
... Different variations affecting the amino acid sequence (exonic polymorphisms) or the level of genetic expression (promoter region polymorphisms) of genes encoding apolipoproteins have been observed in several studies [6][7][8][9][10]. These genetic variations are related to total cholesterol, low-density lipoproteins, triglycerides, and vascular disorders [33,34]. ...
Introduction:
The study of variations in genes involved in the different events that trigger the atherogenic process, such as lipid metabolism (modification of LDL-cholesterol), endothelial function and hypertension, immune response (recruitment of macrophages and foam cell formation) and stability of atherosclerotic plaques (thrombosis), established the risk for suffering a vascular disorder. A total of 2455 cases over 50 years of age were genotyped for a panel of 19 SNPs in 15 genes encoding for proteins involved in the atherogenic process. This study shows the relevance of polymorphisms in APOB (odds ratio (OR), 1.17; 95% confidence interval (95% CI), 0.74-1.85), APOC3 (OR, 1.33; 95% CI, 0.82-2.17) and APOE (OR, 1.75; 95% CI, 1.09-2.80), as genetic risk markers for hypercholesterolemia; polymorphisms in ACE (OR, 1.68; 95% CI, 0.32-8.77) and AGT (OR, 1.74; 95% CI, 0.97-3.14) for hypertension; and in APOE*3/*4 (OR, 2.06; 95% CI, 1.70-2.51) and APOE*4/*4 (OR, 3.08; 95% CI, 1.85-5.12) as unambiguous markers of dementia.
Result:
Our results also showed the transversal importance of proinflammatory cytokines in different stages of atherogenesis, with special relevance of IL6 (OR, 1.39; 95% CI, 0.56-3.49) and TNF (OR, 1.40; 95% CI, 0.92-2.15) related to hypercholesterolemia and hypertension. The set of markers involved in this genetic risk panel makes it a powerful tool in the management of patients with different vascular disorders.
... Most studies used patients with completed strokes. There was an equal sex distribution in all studies except for the report by Pedro-Botet et al (9), which assessed men only. Two of the studies were Japanese (19,22), one was from Canada (15), and the remainders were European (8 -11, 18, 23). ...
... Two of the studies were Japanese (19,22), one was from Canada (15), and the remainders were European (8 -11, 18, 23). Three reports demonstrated a positive association between the apoE4 allele and ischemic CVD (two European (9,23), and one Japanese (19). Kessler et al (18) found that E4 allele is more common in CVD patients with large-vessel atherosclerosis than in those with other types of CVD. ...
The possible association of apolipoprotein E (apoE) DNA polymorphism with ischemic cerebrovascular disease was evaluated in 65 patients who had suffered completed stroke or transient ischemic attack and 330 healthy controls. ApoE genotypes were determined by restriction isotyping/MADGE analysis. Significant difference in apoE genotype frequencies between case and control group was observed (p<0.01). Patients affected by ischemic stroke had higher frequency of E4 allele and lower E2 allele than age-matched control subjects. Compared with persons without E4 allele, carriers of an E4 allele had 2.1 times higher risk of incident stroke. Our results indicate that the apoE gene polymorphism may be a risk factor for the development of ischemic cerebrovascular disease in Serbian population..
... [14] They found that the E4 allele carrier had a 2.34-fold increase risk of ischemic stroke (OR = 2.34; 95% CI: 1.92-2.86). Our results are similar to the results in the ischemic stroke patients in Spanish, [15] Italian, [16] Chinese, [17] and German [18] studies. The E3/E4 genotype was found to be a risk for developing ischemic stroke, whereas the homozygote E3 was protective in our study cohort. ...
Context: Studies from the different ethnic regions of the world have reported variable results on association of APOE gene polymorphismin stroke. Aim: The aim of this study is to find out the possible association of APOE polymorphism in stroke patients in ethnic Bengalipopulation. Settings and Design: A prospective case–control study was undertaken in the Department of Neurology, Burdwan MedicalCollege, Burdwan, West Bengal, India, over a period of 3 years. Methods: We collected 10 ml venous blood samples from 148 clinicallyand radiologically diagnosed acute stroke patients (80 of ischemic stroke and 68 of intracerebral hemorrhage) and consecutive 108 ethnicage- and sex-matched controls, in ethylenediaminetetraacetic acid vials after informed written consent. Genomic DNA was prepared atS.N. Pradhan Centre of Neurosciences, University of Calcutta, Kolkata, India. Exotic single-nucleotide polymorphisms (rs429358, rs 7412)were analyzed by polymerase chain reaction-restriction fragment length polymorphism for genotype of APOE. Results: The frequencies ofdifferent APOE allele among 80 ischemic stroke patients were 5.6% (n = 9) for E2, 75.68% (n = 121) for E3, and 18.7% (n = 30) for E4.The E3 allele is significantly over-represented (P = 0.004) in controls compared to the patients (88% in controls vs 75.6% ischemic strokepatients and 80% hemorrhagic patients). A significantly high frequency of APOE4 allele was observed in ischemic (18.7%) and hemorrhagicpatients (11%) compared to controls (8%). The E4 allele plays a major risk for developing ischemic stroke [odds ratio (OR) = 2.744; 95%confidence interval (CI): 1.43–5.10] and E3 plays a protective role for hemorrhagic stroke (OR = 0.53; 95% CI: 0.29–0.96), while E4 alleleplays a nonsignificant (P = 0.31) increase in trend in hemorrhage stroke (OR = 1.4). Conclusions: There is significant association of APOEgene polymorphism in stroke patients of ethnic Bengali population. The E4 allele increases significant risk for development of ischemic strokes,and it also plays nonsignificant increase in trend in hemorrhagic strokes.Keywords: Apolipoprotein E, hemorrhage stroke, ischemic stroke, polymorphisms, stroke
(PDF) AnnIndianAcadNeurol234504-688707 190750 2. Available from: https://www.researchgate.net/publication/368357897_AnnIndianAcadNeurol234504-688707_190750_2 [accessed Feb 08 2023].
... Sreedhar K et al. [5] showed that high levels of serum LDL cholesterol had significant risk of ischemic stroke in the non-diabetics. Botet et al. [18] and Hachinski et al. [14] showed positive correlation between LDL cholesterol levels and risk of stroke. Kurth T et al. [19] 2007 showed remarkable increase in serum LDL levels in ischemic stroke patients. ...
Background. The amount of evidence regarding the relation between serum lipids, lipoproteins and cerebrovascular accident is not adequate. The atherogenecity of diabetics and non-diabetics are different. Therefore, non-diabetic patients were included in the study.
Objective. To study lipid abnormalities in non-diabetic stroke patients in our setup.
Methods. The study was carried out at the Department of General Medicine, BMCH, Chitradurga, during the period from June 2020 to December 2020. The lipid profile and the fasting blood sugar rates of 50 stroke patients without diabetes were studied. Their serum samples were assessed for fasting blood glucose (FBG), total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL) and high-density lipoprotein cholesterol (HDL) by using standard biochemical methods.
Results. The age distribution of the subjects was from 19 to 72 years with a mean age of patients 54.8±15.75 years. Among patients 31 (62%) were males and 19 (38%) were females. Among the study subjects 58% were hypertensive, 76% were smokers, 32% were alcoholics and 34% had family history of cerebrovascular accident. Among ischemic stroke group, the most common deranged value in the ischemic group was decreased HDL deranged in 54.1% of patients; the second most common deranged value – increased VLDL deranged in 40.5%. Among the hemorrhagic group the most common deranged value was also decreased HDL, which was deranged in 46.1% of patients and the second most common deranged value – increased total cholesterol, which was deranged in 53.8% patients.
Conclusion. Lipid profile should be considered while predicting the risk of stroke.
... The study found that Apo B is of paramount importance and contributes to the formation of triglycerides, LDL cholesterol, and Apo B associated with IS [18]. Besides exploring the potential role of the Apo E polymorphism in ischemic cerebrovascular abnormalities, the 4 alleles may predispose to ischemic cerebrovascular disease [19]. Additionally, increased serum levels of Apo B and an increased Apo B/apoA1 ratio correlate with IS and intracranial atherosclerotic disease. ...
Background: Stroke is one of the leading causes of death worldwide and has different characteristics. Different physiopathological mechanisms characterize the different subtypes of ischemic stroke. In this study, we investigated the correlation between serum levels of autophagy-5 protein, Apo-lipoprotein B-48, and oxidative stress markers in patients with ischemic stroke.
Methods and results: We enrolled 100 participants, including 50 ischemic stroke (IS) patients as the case group and 50 healthy individuals as the control group. Then, we conducted a case-control study at Imam Reza Hospital from March 2019 to April 2020. We quantified the serum levels of ATG5, Apo B-48, and oxidative stress markers in both groups. And we evaluated the incremental diagnostic value of these factors by receiver operating characteristic analysis (ROC) in both groups. The mean serum levels of ATG5, Apo B-48, and oxidative stress markers were higher in the case group than in the control group, with a p–value of less than 0.0001 (p <0.0001).
Conclusions: Serum levels of ATG5, Apo B-48, Malonaldehyde (MDA), total oxidative stress (TOS), and total antioxidant capacity (TAC) in patients with IS can be used as novel biomarkers to predict or therapeutically modulate patients with IS.
... we conclude that the study group was largely affected by abnormal LDL levels than that of control group. Botet et al and Hachinski et al in their studies have found positive correlation 23 between LDL Cholesterol levels and risk of ischaemic stroke . ...
Dyslipidemia in non diabetic stroke
... [23][24][25] The study led by David Meyers, at the University of Kansas Medical Centre, USA, suggested that men who donate blood may lower their risk of heart attack and other cardiac illness by about 30%. [26][27][28] Aims and objectives Blood or plasma donations have a direct effect on plasma protein concentration, including plasma viscosity and lipid profile; [22,29,30] however, there is a paucity of reports on the effect of blood donation on plasma lipid profile in this environment. This study therefore aims to assess the effect of blood donation on lipid profile. ...
Background and Objectives: Regular blood donations seem to be beneficial to the health of donors in many ways. There is evidence to suggest that blood donation lowers blood viscosity and alters lipid profile, which is an acceptable parameter for assessing the risk of coronary heart disease. The objective of this study was to assess the pattern in changes of lipid profiles and hematocrit due to blood donation. Methods: This was a cross-sectional study, which comprises 289 apparently healthy male blood donors who were recruited as family replacement and nonvoluntary donors. Those who were ineligible for donation were excluded. Fasting venous blood samples were collected serially before phlebotomy, 1 h, 3 days, 6 days, 9 days, and 12 days after phlebotomy. Lipid profile and hematocrit were estimated appropriately. Results: The mean hematocrit, total cholesterol (T-Chol), low-density lipoprotein-cholesterol (LDL-C), high-density lipoprotein-Chol (HDL-C), very low-density lipoprotein-cholesterol (VLDL-C), and triglycerides before donations were 32 ± 8 years, 0.46 ± 0.05, 5.04 ± 0.81 mmol/l 2.93 ± 0.56 mmol/l 1.35 ± 0.24 mmol/l, 0.76 ± 0.14 mmol/l, and 1.65 ± 0.29 mmol/l, respectively. Postdonation results indicated an increased in HDL-C and decreased in all the remaining parameters with time. There are statistically significant differences between the levels of the HDL-C (P < 0.001), T-Chol: HDL ratio (P < 0.001), LDL-C (P < 0.001), and T-Chol (P < 0.001) before and at 12 days after blood donations. There was also a decrease in VLDL-C (P = 0.061), triglyceride (P = 0.092), and hematocrit values (P = 0.056), which was not statistically significant. Conclusion: These findings indicated that blood donation may be beneficial to donors, on the short term, since there is decreasing serum T-Chol, LDL-C, VLDL-C, and triglycerides and increasing serum HDL-C concentration. Long-term effects need to be determined in this cohort of donors.
... [14] They found that the E4 allele carrier had a 2.34-fold increase risk of ischemic stroke (OR = 2.34; 95% CI: 1.92-2.86). Our results are similar to the results in the ischemic stroke patients in Spanish, [15] Italian, [16] Chinese, [17] and German [18] studies. The E3/E4 genotype was found to be a risk for developing ischemic stroke, whereas the homozygote E3 was protective in our study cohort. ...
Context:
Studies from the different ethnic regions of the world have reported variable results on association of APOE gene polymorphism in stroke.
Aim:
The aim of this study is to find out the possible association of APOE polymorphism in stroke patients in ethnic Bengali population.
Settings and design:
A prospective case-control study was undertaken in the Department of Neurology, Burdwan Medical College, Burdwan, West Bengal, India, over a period of 3 years.
Methods:
We collected 10 ml venous blood samples from 148 clinically and radiologically diagnosed acute stroke patients (80 of ischemic stroke and 68 of intracerebral hemorrhage) and consecutive 108 ethnic age- and sex-matched controls, in ethylenediaminetetraacetic acid vials after informed written consent. Genomic DNA was prepared at S.N. Pradhan Centre of Neurosciences, University of Calcutta, Kolkata, India. Exotic single-nucleotide polymorphisms (rs429358, rs 7412) were analyzed by polymerase chain reaction-restriction fragment length polymorphism for genotype of APOE.
Results:
The frequencies of different APOE allele among 80 ischemic stroke patients were 5.6% (n = 9) for E2, 75.68% (n = 121) for E3, and 18.7% (n = 30) for E4. The E3 allele is significantly over-represented (P = 0.004) in controls compared to the patients (88% in controls vs 75.6% ischemic stroke patients and 80% hemorrhagic patients). A significantly high frequency of APOE4 allele was observed in ischemic (18.7%) and hemorrhagic patients (11%) compared to controls (8%). The E4 allele plays a major risk for developing ischemic stroke [odds ratio (OR) = 2.744; 95% confidence interval (CI): 1.43-5.10] and E3 plays a protective role for hemorrhagic stroke (OR = 0.53; 95% CI: 0.29-0.96), while E4 allele plays a nonsignificant (P = 0.31) increase in trend in hemorrhage stroke (OR = 1.4).
Conclusions:
There is significant association of APOE gene polymorphism in stroke patients of ethnic Bengali population. The E4 allele increases significant risk for development of ischemic strokes, and it also plays nonsignificant increase in trend in hemorrhagic strokes.
... Couderc et al [20] observaron una asociación significativa entre ECV y niveles bajos de ApoE; la isomorfa ApoE2 podría constituir un factor de riesgo en combinación con otros factores de riesgo de ECV. Hallazgos similares, pero en asociación con ApoE4, habían sido descritos por Pedro-Botet et al [21]. Más recientemente, Aalto-Setala et al [22] estudiaron una posible asociación entre aterosclerosis de las arterias cervicales y polimorfismos de los genes de ApoA-I, C-III, B y E y de enzima convertidora de la angiotensina (ACE). ...
... This finding was similar to study by Roquer et al. 12 where they found that the mean age of affected patients was higher in women. 20,22 Male patients in the age group of 50-59 yrs and female patients in the age group of 50-59 and 60-69 yrs suffering from ischaemic stroke had low serum HDL cholesterol levels (<40mg% according to ATP -III guidelines). Among haemorrhagic stroke patients serum HDL cholesterol was low in the age group of 40-49 and 50-59 yrs in males. ...
Background: To study serum lipid profile in non-diabetic patients with stroke and to determine whether there is any significant correlation between them and to compare the serum lipid profile between ischaemic and haemorrhagic group. Design: Case control study.Methods: The current study was done in the Department of Medicine VIMSAR, Burla, Odisha. Total 100 patients of completed stroke (Ischaemic63 and haemorrhagic37) and 30 controls were included in the study. All cases were adult (more than 14 years of age). Patients with suspected embolic stroke, diabetes (Type 1 and 2) and patients on lipid lowering drugs were excluded from the study. Routine investigations and fasting serum lipid profile was done.Results: 45 patients had elevated serum total cholesterol levels out of which 75.56% had Ischaemic stroke and 24.49% had haemorrhagic stroke. 24 cases had elevated serum Triglyceride levels of which 66.67% had Ischaemic stroke and 29.17% had haemorrhagic stroke. 76.47% of cases having elevated serum LDL cholesterol suffered from Ischaemic stroke where as 20.59% had haemorrhagic stroke.Conclusions: A statistically positive correlation was found between serum total cholesterol, Triglyceride, LDL levels and the risk of stroke.
... However, other different reasons may also explain the high rate of APOE-ε4, and the APOE-ε4/ε4 genotype in our population. The APOE-ε4 allele is highly associated with an aberrant increase in LDL-family lipoproteins and cholesterol, which promotes the risk of developing atherosclerosis and vascular disorders [13][14][15][16][17][18][19][20], which may be explained by the significant rate of disorders with a vascular component represented in our population. Some of the individuals belonging to the 15% carrying dementia-related disorders were diagnosed with AD, although a high proportion of them had a vascular component rather than neurodegenerative. ...
Introduction:
Cardiovascular and neurodegenerative disorders are among the major causes of mortality in the developed countries. Population studies evaluate the genetic risk, i.e. the probability of an individual carrying a specific disease-associated polymorphism. Identification of risk polymorphisms is essential for an accurate diagnosis or prognosis of a number of pathologies.
Aims:
The aim of this study was to characterize the influence of risk polymorphisms associated with lipid metabolism, hypertension, thrombosis, and dementia, in a large population of Spanish individuals affected by a variety of brain and vascular disorders as well as metabolic syndrome.
Material & method:
We performed a cross-sectional study on 4415 individuals from a widespread regional distribution in Spain (48.15% males and 51.85% females), with mental, neurodegenerative, cerebrovascular, and metabolic disorders. We evaluated polymorphisms in 20 genes involved in obesity, vascular and cardiovascular risk, and dementia in our population and compared it with representative Spanish and European populations. Risk polymorphisms in ACE, AGT(235), IL6(573), PSEN1, and APOE (specially the APOE-ε4 allele) are representative of our population as compared to the reference data of Spanish and European individuals.
Conclusion:
The significantly higher distribution of risk polymorphisms in PSEN1 and APOE-ε4 is characteristic of a representative number of patients with Alzheimer's disease; whereas polymorphisms in ACE, AGT(235), and IL6(573), are most probably related with the high number of patients with metabolic syndrome or cerebrovascular damage.
... The possible role of hypertriglyceridaemia and changes in VLDL composition as risk factors for coronary heart disease remain a matter of dispute [26][27][28]. In recent years several authors have tended to consider triglyceride-rich lipoproteins, par- ticularly IDL abnormalities, and high levels of Lp(a) as cardiovascular risk factors [27,[29][30][31][32][33]. Concerning CRF patients on haemodialysis, after other concomitant causes of dyslipidaemia have been excluded, lipoprotein profile is currently well defined and consists of low-to-normal LDL cholesterol levels, mild-tomoderate hypertriglyceridaemia, increased VLDL, IDL and Lp(a) levels, together with a decrease in HDL [9][10][11][12][13]. ...
Background
There are no specific recommendations for management of dyslipidaemia in patients with chronic renal failure (CRF) on haemodialysis, in which atherosclerosis is a common cause of morbidity and mortality. The aim of the present study was to analyse different approaches based on low-density lipoprotein (LDL) cholesterol (measured and calculated with a formula), non-high-density lipoprotein (HDL) cholesterol, and HDL cholesterol levels in the clinical management of dyslipidaemia in haemodialysis patients.
Methods
Calculated LDL cholesterol by the Friedewald formula was compared with measured LDL cholesterol after separation by ultracentrifugation n 101 male patients with CRF on haemodialysis and in 101 healthy control subjects.
Results
Calculated LDL cholesterol coincided with measured LDL cholesterol, with less than 10% error, in 54 patients (53.4%) and in 75 controls (74.2%). Calculated LDL cholesterol was overestimated, with an error of 10% or more with respect to measured LDL cholesterol, in 37.6% of patients and in 23.7% of controls, and underestimated in 8.9% and 1.9% respectively. Despite a good correlation between calculated and measured LDL cholesterol, the intraclass correlation coefficients demonstrate a poor concordance between calculated and measured LDL cholesterol, both in patients and controls. Only 17 patients were at non-HDL cholesterol level risk defined as higher than 4.28 mmol/l. HDL cholesterol levels lower than 0.9 mmol/l were found in 70% of patients and in 23% of controls.
Conclusions
LDL or non-HDL cholesterol levels may not be appropriate for management of lipoprotein abnormalities in CRF patients. Further studies must clarify whether HDL cholesterol may be the best lipoprotein parameter for evaluating cardiovascular risk in these patients.
... Pedro-Botet et al. 25 and Hachinski et al. 23 have found positive correlation between LDL-C levels and risk of ischemic stroke. Treatment with cholesterol-lowering medications and changes in LDL-C level over time may have attenuated the risk in stroke population, and lipid measurements at several points may be a better marker of stroke risk. ...
Background: Stroke is one of the most frequent causes of death and disability worldwide and has significant clinical and socioeconomic impact. Hyperlipidemia and inflammation play major roles in atherothrombosis and in stroke. This study is conducted to compare the high sensitive C-reactive protein (hs-CRP) levels and the lipid profile parameters between stroke patients and control group and demonstrate correlation between markers, neurological deficit, and short-term outcome.
Methods: We have studied a total 162 patients according to inclusion criteria. Serum level of hs-CRP and lipid profile estimated and correlated with neurological deficit and short-term outcome.
Results: We found stroke patients had significantly higher levels of hs-CRP, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL), and low level of high-density lipoprotein (HDL) than control. When we compared ischemic and hemorrhagic stroke (HS), data show increased level of triglyceride, LDL and HDL, and decreased the level of hs-CRP in ischemic stroke group than HS group. However, the National Institutes of Health Stroke Scale (NIHSS) score significantly higher in HS as compared to ischemic stroke at the time of admission and on the 7th day.
Conclusion: Thus, continuous clinical observation is necessary for clear differentiation of those changes. Furthermore, the determination of some reliable soluble markers of neuronal damage in blood and cerebrospinal fluid in the early infarction period would be much easier and more useful for tracking the course and prognosis of the disease and for any appropriate therapeutic approach.
... However, studies to date have produced conflicting results as to the importance of apolipoprotein E alleles in predisposition to ischaemic stroke (Table 5). In small case-control or cross-sectional studies, both the ε2/ε3 genotype (Couderc et al., 1993;de Andrade et al., 1995;Schmidt et al., 1997) and the ε4 allele (Pedro-Botet et al., 1992;Kessler et al., 1997;Margaglione et al., 1998) have been over-represented in patients with ischaemic stroke. Other groups have examined the role of the apolipoprotein E genotype in modulating the outcome of cerebral infarction as this lipoprotein appears to be an important regulator of lipid turnover within the brain and of neuronal membrane maintenance and repair. ...
Ischaemic stroke can be caused by a number of monogenic disorders, and in such cases stroke is frequently part of a multisystem disorder. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL), due to mutations in the NOTCH: 3 gene, is increasingly appreciated as a cause of familial subcortical stroke. The genetics and phenotypes of monogenic stroke are covered in this review. However, the majority of cases of ischaemic stroke are multifactorial in aetiology. Strong evidence from epidemiological and animal studies has implicated genetic influences in the pathogenesis of multifactorial ischaemic stroke, but the identification of individual causative mutations remains problematic; this is in part limited by the number of approaches currently available. In addition, genetic influences are likely to be polygenic, and ischaemic stroke itself consists of a number of different phenotypes which may each have different genetic profiles. Almost all human studies to date have employed a candidate gene approach. Associations with polymorphisms in a variety of candidate genes have been investigated, including haemostatic genes, genes controlling homocysteine metabolism, the angiotensin-converting enzyme gene, and the endothelial nitric oxide synthase gene. The results of these studies, and the advantages and limitations of the candidate gene approach, are presented. The recent biological revolution, spurred by the human genome project, promises the advent of novel technologies supported by bioinformatics resources that will transform the study of polygenic disorders such as stroke. Their potential application to polygenic ischaemic stroke is discussed.
... 10 M Bewn and Durrington in 1990 suggested that Lp (a) would become critical when other factors, particularly LDL, had led to the development of significant atheroma. 11 Pedro-Botet et al 1992 recently reported that increased serum Lp (a) levels and IDL abnormalities together with decreased HDL levels are major factors for stroke. 12 Masao Nagayama in 1993 in their study found that patients with Lacunar stroke had only slightly elevated serum Lp (a) levels than the control group, but still significant. ...
... There is overwhelming convincing evidences relating hypercholesterolemia, increased LDL cholesterol, decreased HDL cholesterol and increased total cholesterol and HDL cholesterol ratio (TC/HDL) with CAD but their relation to CVD is controversial. Some studies showed positive correlation of ICVD with total cholesterol, LDL cholesterol, TAG and (TC/HDL) but negative correlation with HDL cholesterol 9,10,11 . In contrast, several other studies reported no association between stroke and total cholesterol, LDL cholesterol, HDL cholesterol, TAG 12,13,14 . ...
... Gene Ontology Annotation (GOA) analysis demonstrated that the three proteins are categorized by ''lipid binding'' (P < 0.05). Several studies have demonstrated that perturbation of lipid metabolism may be involved in the pathophysiology of both MDD [31,32,75,78] and stroke [53,58,64]. This study is the first to report that ApoA-IV and ApoC-II levels were significantly altered in PSD subjects as compared to stroke subjects, indicating that the dysregulation of lipid metabolism may play an important role in the pathophysiology of PSD. ...
Background:
Post-stroke depression (PSD) is the most common psychiatric complication facing stroke survivors and has been associated with increased distress, physical disability, poor rehabilitation, and suicidal ideation. However, the pathophysiological mechanisms underlying PSD remain unknown, and no objective laboratory-based test is available to aid PSD diagnosis or monitor progression.
Methods:
Here, an isobaric tags for relative and absolute quantitation (iTRAQ)-based quantitative proteomic approach was performed to identify differentially expressed proteins in plasma samples obtained from PSD, stroke, and healthy control subjects.
Results:
The significantly differentiated proteins were primarily involved in lipid metabolism and immunoregulation. Six proteins associated with these processes--apolipoprotein A-IV (ApoA-IV), apolipoprotein C-II (ApoC-II), C-reactive protein (CRP), gelsolin, haptoglobin, and leucine-rich alpha-2-glycoprotein (LRG)--were selected for Western blotting validation. ApoA-IV expression was significantly upregulated in PSD as compared to stroke subjects. ApoC-II, LRG, and CRP expression were significantly downregulated in both PSD and HC subjects relative to stroke subjects. Gelsolin and haptoglobin expression were significantly dysregulated across all three groups with the following expression profiles: gelsolin, healthy control>PSD>stroke subjects; haptoglobin, stroke>PSD>healthy control.
Conclusions:
Early perturbation of lipid metabolism and immunoregulation may be involved in the pathophysiology of PSD. The combination of increased gelsolin levels accompanied by decreased haptoglobin levels shows promise as a plasma-based diagnostic biomarker panel for detecting increased PSD risk in post-stroke patients.
... Además, se ha demostrado que la edad a la que sucede el episodio es menor en varones portadores del alelo apoE4 41 , que son los que presentan una mayor tasa de mortalidad por episodios coronarios 42 . Algunos estudios muestran que dicho alelo es más frecuente en los individuos que han sufrido un accidente cerebrovascular 43 , aunque no siempre se haya confirmado ni probado su posible relación con la enfermedad vascular periférica [44][45][46][47] . Finalmente, estudios de cohorte han comprobado un aumento de la prevalencia de cardiopartía isquémica asociado al alelo apoE4, tanto en varones como en mujeres 48 , y también se ha descrito un aumento de la mortalidad por dicha enfermedad en las personas portadoras de este alelo, sin que dicho incremento estuviera en relación con los valores lipídicos 49 . ...
The apolipoprotein E (ApoE) plays an important role in lipid metabolism; This apoprotein presents three major isoforms (apoE2; apoE3 and apoE4) that modulate lipid levels; Carriers of the apoE4 allele have higher total and LDL-cholesterol plasma concentration and a greater coronary risk; particularly for myocardial infarction; Nevertheless; not all the people with this allele develop the disease; which suggests that other genetic or environmental factors are necessary for its total expression; In this review; we will analyze the importance of several polymorphisms in the apoE gene promoter region; as well as various environmental factors; including diet; in the association of this gene with lipid metabolism and cardiovascular risk
... As far as Lp(a), we found no significant differences between patients and control subjects. Existing data in literature indicate this lipoprotein as a sure marker for CHD and CVD (45,(59)(60)(61)(62)(63)(64)(65)(66)(67)(68), while contrasting results are still found for PVD patients (69-71) not selected according to clinical stages. Based on our sample, our results might be explained by the characteristics of the patients studied : all were stage II with no history of acute events within the last 6 months. ...
The aim of the study was to provide a detailed apolipoproteic profile in stage II peripheral vascular disease (PVD) patients and to ascertain whether lower ankle/ arm pressure index (API) values were associated with a worse profile.
Apolipoproteins of 83 stage II PVD patients (average age 64.7 ± 9.3 years) were selected and compared with those of a group of 44 normal control subjects, similar in terms of age, sex, and smoking and eating habits. Neither PVD patients nor controls had ever received lipid-lowering agents or defined dietary treatment. A diagnosis of PVD was confirmed by an API of <0.85. Arteriopathic patients were also split into two groups, depending on their API values, similar in terms of age, sex and smoking habits: API values of one group (n = 38) were ≥0.6, those of the other group (n = 45) were <0.6. The following biohumoral parameters were considered: fasting glycemia, total cholesterol, triglycerides (TGs); high-density lipoprotein cholesterol (HDL-C); low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), total cholesterol (TC)/HDL-C (TC/ HDL-C), Apoproteins (Apos) AI, AII, B, CII, CIII, and E; and lipoprotein a [Lp(a)].
HDL-C and Apo AI were lower ( p < 0.01), while TC/ HDL-C ratios, Apo B, and Apo CII were higher ( p < 0.01) in PVD patients compared with controls. The comparison between the two PVD groups with different API values showed higher blood TG and VLDL-C values for the patients with lower API values (p < 0.05), indicating a relationship between hypertriglyceridemia and greater arterial damage. Key Words: Peripheral arterial occlusive disease-Triglyceride-Lipoprotein a.
... Other studies have demonstrated that the apoE4 allele and the AA genotype of beta-fibrinogen G/A-455 polymorphism occurred more frequently in patients with stroke resulting from stenosis of large, brain-supplying vessels, while the apolipoprotein E epsilon 2 allele carriers had a lower risk of stroke. [88][89][90] Another genetically determined factor, the plasminogen activator inhibitor-1 (PAI-1), has been incriminated in the development of stroke. In a study of 558 patients with stroke and 172 controls, the PAI-1 activity was significantly higher in patients with stroke (n = 245) both at presentation (11.6 U/mL) and after 3 months (11.8 U/mL), in paired samples, than in control subjects ( These characteristics have been classified into those describing the overall distribution of grey tones (overall brightness) and those that describe the spatial variation of the grey tones of the plaque in the image.93 ...
The aim of this review is to present the current knowledge regarding stroke. It will appear in three parts (in part II the pathogenesis, investigations, and prognosis will be presented, while part III will consist of the management and rehabilitation). In the current part (I) the definitions of the clinical picture are presented. These include: amaurosis fugax, vertebrobasilar transient ischemic attack, and stroke (with good recovery, in evolution and complete). The role of the following risk factors is discussed in detail: age, gender, ethnicity, heredity, hypertension, cigarette smoking, hyperlipidemia, diabetes mellitus, obesity, fibrinogen and clotting factors, oral contraceptives, erythrocytosis and hematocrit level, prior cerebrovascular and other diseases, physical inactivity, diet and alcohol consumption, illicit drug use, and genetic predisposition. In particular, regarding the carotid arteries, the following characteristics are analyzed: atheroma, carotid plaque echomorphology, carotid stenosis, presence of ulcer, local variations in surface deforma bility, pathological characteristics, and dissection. Finally the significance of the cerebral collateral circulation and the conditions predisposing to cardioembolism and to cerebral hemorrhage are presented.
... 34 ApoE4 may also be a predisposing genetic marker for ischemic cerebrovascular disease. 35 The E2 and/or the E4 alleles may be risk factors for cerebral amyloid angiopathy independent of their influence on the risk for Alzheimer disease, but this remains controversial. 36,37 Subjects with an apoE2 or apoE4 allele were found to be at greater risk for intracranial hemorrhage independent of environmental risk factors in 1 study. ...
Genetic causes of disease, including stroke, range from classic mendelian (a single gene leads to disease) to complex (multiple genes contribute to risk for disease in combination with other genetic and/or environmental factors). One method of identifying genetic risk factors is the candidate gene association study, in which a given polymorphism in a gene of interest is compared between cases or controls; if the polymorphism is more common in affected subjects, a contribution to risk for disease is implied. A candidate gene is usually selected because the gene product is intuitively related to the disease process. Further studies in other populations will reveal whether findings from both association and candidate gene studies can be generalized. Because stroke includes multiple clinically relevant subgroups, the appropriate phenotyping approach is not yet known. It also is unclear whether the biological factors contributing to risk for one type of stroke are the same as those for the other types or whether these are biologically differing entities. Medical risk factors for stroke, such as hypertension, and shared risk factors between stroke and cardiovascular disease, for example, suggest that biological processes overlap across related disorders. Despite the complex biological questions that remain to be answered regarding stroke etiology and risk, genetic studies are of value to elucidate risk factors for stroke, give us clues regarding targets for interventional therapies, and give us insight into the process leading to clinical stroke of all types.
Single gene disorders that cause stroke include hemoglobinopathies, dyslipoproteinemias, and cardioembolic disorders.1,2 Family history of ischemic stroke is a major risk factor for the disease.1,3 Ethnicity is also a risk factor; age-standardized mortality rates for stroke are higher among blacks than whites.4 Family history is an independent risk factor for subarachnoid hemorrhage.5 Most clinicians separate stroke into ischemic and …
OBJECTIVE: Strokes are among the leading causes of death worldwide and have different characteristics. Different physiopathological mechanisms characterize the numerous subtypes of ischemic stroke. In this study, we investigated the relationship between serum levels of autophagy-5 protein, apolipoprotein B-48, and oxidative stress markers in patients with ischemic stroke.
METHODS: For this study, 100 participants were recruited, of which 50 were patients with ischemic stroke (IS) and 50 were healthy individuals. We conducted a case-control study at Imam Reza Hospital from March 2019 to April 2020. Serum levels of ATG5, apo B-48, and oxidative stress markers were determined in both groups. Our Receiver Operating Characteristic Analysis (ROC) evaluated the additional diagnostic value of these factors in both groups.
RESULTS: Diabetes, smoking, age, sex, alcohol consumption, weight, and height did not differ significantly between the two groups (p > 0.05). However, the two groups had significant differences in hypertension and body mass index (BMI) (p < 0.05). Fifty-four percent (27 patients) of patients with IS had ischemic stroke in large vessels, while 46% (23 patients) had ischemic stroke in small vessels. Serum levels of ATG5, apo B-48, and oxidative stress markers were higher in the case group than in the control group (p < 0.0001).
CONCLUSIONS: In patients with IS, serum levels of ATG5, apoB-48, malonaldehyde (MDA), total oxidative stress (TOS), and total antioxidant capacity (TAC) can be used as novel biomarkers to predict or treat the disease.
Background
It has been suggested that human T-cell lymphotropic virus type 1 (HTLV-1) infection can affect the lipid profile. Therefore, in this study, the main apolipoproteins and HTLV-1 regulatory factors were assessed in infected subjects.
Methods and results
A cross-sectional study was performed on 12 adult T-cell leukemia/lymphoma (ATLL) and 10 HAM/TSP patients, and 10 HTLV-1 asymptomatic carriers (ACs). The peripheral blood mononuclear cells (PBMCs) were assessed for proviral load (PVL) measurement and the expression of HBZ, ABCA, APOA, and APOE, using the qRT-PCR, Taqman method.
The ABCA1 expression level in the ATLL group was significantly higher than ACs and HAM/TSP, (P = 0.034 and P = 0.019, respectively). The APOA1 expression, in ATLL (0.89 ± 0.30) and HAM/TSP patients (0.31 ± 0.25), was lower than HTLV-1 ACs (1.15 ± 0.63); but not significant. The APOE expression in the ACs' group (22.66 ± 7.88) was strongly higher than ATLL (0.003 ± 0.0004) and HAM/TSP (1.81 ± 0.60) subjects (P = 0.007 and P = 0.012, respectively); ATLL and HAM/TSP groups had no significant differences (P = 0.957). All of the ATLL patients expressed HBZ, but not Tax, on the other hand more than 70% of HAM/TSPs and ACs expressed Tax but only one AC and one HAM/TSP patient expressed HBZ. The PVL median in ATLL patients was higher (2983.87 ± 1797.07copies/10⁴PBMCs), than ACs (17.00 ± 10.00copies/10⁴) (P = 0.016), and HAM/TSP (314.00 ± 185.00) (P = 0.05).
Conclusions
The HBZ probably altering the expression of ABCA1 and APOE, which particularly, can deteriorate the lipid profile in ATLL patients. The importance of APOE in healthy condition and its negative correlation with PVL in ATLL patients could be a novel target in therapy.
Introduction:
Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS.
Methods:
To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations.
Results:
A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene ε4 mutation and IS was confirmed (ε4 vs. ε3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; ε2/ε4 vs. ε3/ε3: pooled OR = 1.233, 95% CI, 1.056-1.440; ε3/ε4 vs. ε3/ε3: pooled OR = 1.340, 95% CI, 1.165-1.542; ε4/ε4 vs. ε3/ε3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE ε4 carriers vs. non-ε4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE ε4 mutation showed a dose-response correlation with IS risk (ε4/ε4 vs. ε2/ε4: pooled OR = 1.625; 95% CI, 1.281-2.060; ε4/ε4 vs. ε3/ε4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis.
Conclusions:
These observations reveal that specific APOE ε4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE ε4 mutation was related to SAD subtype onset without a cumulative effect.
The role of lipoprotein-A [Lp (a)] as a risk factor for stroke is less well documented than for coronary heart disease. Hence, we conducted a systematic review and meta-analysis for the published observational studies in order to investigate the association of Lp (a) levels with the risk of stroke and its subtypes. In our meta-analysis, 41 studies involving 7874 ischemic stroke (IS) patients and 32,138 controls; 13 studies for the IS subtypes based on TOAST classification and 7 studies with 871 Intracerebral hemorrhage (ICH) cases and 2865 control subjects were included. A significant association between increased levels of Lp (a) and risk of IS as compared to control subjects was observed (standardized mean difference (SMD) 0.76; 95% confidence interval (CIs) 0.53–0.99). Lp (a) levels were also found to be significantly associated with the risk of large artery atherosclerosis (LAA) subtype of IS (SMD 0.68; 95% CI 0.01–1.34) as well as significantly associated with the risk of ICH (SMD 0.65; 95% CI 0.13–1.17) as compared to controls. Increased Lp (a) levels could be considered as a predictive marker for identifying individuals who are at risk of developing IS, LAA and ICH.
p> Pendahuluan: Stroke adalah penyebab utama kecacatan jangka panjang dengan dampak klinis dan sosial ekonomi yang signifikan di seluruh dunia. Hiperlipidemia dan inflamasi memainkan peranan penting dalam patofisiologi stroke iskemik. Meskipun high-sensitivity C-Reactive Protein (hs-CRP) dan kadar lipid merupakan penentu risiko penyakit pembuluh darah, kekuatan penggunaan biomarker ini dalam penentuan prognosis stroke iskemik belum dapat dipastikan. Penelitian ini bertujuan untuk mengetahui hubungan kadar hs-CRP dan profil lipid pada pasien stroke iskemik akut di Rumah Sakit Universitas Sebelas Maret dan memahami hubungan antara biomarker tersebut dengan outcome jangka pendek.
Metode penelitian: Penelitian cross-sectional dilakukan pada 34 pasien dengan serangan stroke iskemik pertama kali. Profil lipid dan hs-CRP diukur pada hari pertama masuk rumah sakit. Defisit neurologis diukur menggunakan National Institutes of Health Stroke Scale (NIHSS) dan outcome diukur menggunakan Barthel Index pada hari ke-7 perawatan di unit stroke . Selanjutnya, kadar serum hs-CRP dan profil lipid dianalisis korelasinya dengan defisit neurologis dan outcome jangka pendek.
Hasil penelitian: Pasien stroke iskemik memiliki kadar hs-CRP, kolesterol total (TC), trigliserida (TG), low-density lipoprotein (LDL) yang lebih tinggi; serta kadar high-density lipoprotein (HDL) yang lebih rendah dari kriteria normal. Berdasarkan uji korelasi Pearson, LDL memiliki korelasi signifikan dengan NIHSS (r = 0,447; p = 0,008) sedangkan hs-CRP memiliki korelasi signifikan yang lebih kuat dengan Barthel Index daripada NIHSS (r = -0,412; p = 0,015). TC dan HDL juga memiliki korelasi signifikan dengan NIHSS.
Kes impulan: Penelitian ini menunjukkan bahwa profil lipid dan hs-CRP dapat digunakan sebagai prediktor prognosis outcome stroke iskemik akut.
Introduction: Stroke is the leading cause of long-term disability with significant clinical and socioeconomic impact worldwide. Hyperlipidemia and inflammation play major roles in ischemic stroke. While high-sensitivity C-Reactive Protein (hs-CRP) and lipid levels are established risk determinants for vascular disease, the relative strength of these biomarkers for ischemic stroke is uncertain. The purpose of this study is to investigate the association of hs-CRP levels and lipid profile in acute ischemic stroke patients and understand correlation between those markers and short-term outcome.
Methods: This was a cross-sectional study of 34 first-timer ischemic stroke patients. Lipid profiles and hs-CRP were measured on admission day. The neurological deficit was quantified using National Institutes of Health Stroke Scale (NIHSS) and outcome was quantified using Barthel Index at the 7th day in stroke unit. Serum level of hs-CRP and lipid profile were estimated and correlated with neurological deficit and short-term outcome.
Results: Ischemic stroke patients had higher levels of hs-CRP, total cholesterol (TC), triglyceride (TG), low-density lipoprotein (LDL); and lower level of high-density lipoprotein (HDL) than normal criteria. Based on Pearson correlation test, LDL had significant correlation with NIHSS (r=0.447; p=0.008) while hs-CRP had stronger significant correlation with Barthel Index than NIHSS (r=-0.412; p=0.015). TC and HDL also had significant correlation with NIHSS.
Conclusions: This research suggests that lipid profile and hs-CRP can be used as predictors of prognosis for acute ischemic stroke outcome. Keywords: Barthel index, C-reactive protein, National Institutes of Health Stroke Scale, lipid profile, ischemic stroke.</p
Over the last forty years considerable evidence has been gathered in support of the hypothesis that amino acids are among the most important neurotransmitters within the central nervous system. The development of compounds that inhibit the actions of these recently described neurotransmitters led to the identification of several subtypes of amino acid receptor. Recognition of the neurotoxic effects mediated by excitatory amino acids (EAAs) has prompted investigation of the role of these naturally occurring substances in the processes that culminate in irreversible neuronal injury and death. The observation that EAA receptor antagonists protect neurons from the toxic effects of hypoxia and potent EAA receptor agonists has stimulated interest in the potential therapeutic use of this new class of drug in neurodegenerative disorders. These include stroke, head injury, epilepsy, Parkinson's and Alzheimer's diseases, motorneurone disease, Huntington's Chorea and the neurological sequelae of the acquired immunodeficiency syndrome (AIDS). Surgical procedures performed with the aid of cardiopulmonary bypass (CPB) represent a novel human model of diffuse neuronal injury. Advances in both technology and surgical technique have brought about a steady decline in the mortality and morbidity associated with such cardiac surgery. The fall in the incidence of major perioperative neurological sequelae (brain death, coma, stroke, seizures and altered conscious level) has paralleled that of other complications. Despite this apparent improvement in outcome, formal neuropsychological testing reveals that a significant proportion of patients sustain persistent deficits in cognitive function after otherwise successful surgery. Amongst the many factors implicated in the genesis of this phenomenon, the delivery of microemboli to the cerebral microcirculation during CPB, appears to be one of the most important. This thesis reviews some of the historical landmarks in the evolution of coronary artery bypass surgery (CABS); discusses the neurological consequences of cardiac surgery and reviews the evidence for a role for amino acids in neurotransmission and neurotoxicity. The hypothesis that the incidence and severity of neuropsychological deficits after CPB can be reduced by Remacemide, a selective inhibitor of excitotoxic amino acids, is examined in a detailed study of patients undergoing CABS. Evidence for pharmacological neuroprotection is presented in this first reported use of an EAA antagonist in this clinical setting.
The present research aimed at studying association between Apo E polymorphism and certain types of stroke and also association factors of lipid profile’s results and different types of stroke it depends on sex and conditions of living in typical West Siberian megapolis (Novosibirsk).
The causes of brain stroke were registered in representative population with population about 150 000 in according to standarts of WHO program MONICA and previous program «Register of stroke». From 2003 to 2007 among new registered and repeated causes of stroke was form at random 15% sample (261 patients). The average age of stroke attack is 61,3 ± 1,0 for men and 61,3 ± 1,0 for women.
Independent influence of APOE gene's genotypes polymorphism on development at different stroke patients has not been revealed.
Background:
Hypertension-induced microvascular brain injury is a major vascular contributor to cognitive impairment and dementia. We hypothesized that chronic hypoxia promotes the hyperphosphorylation of tau and cell death in an accelerated spontaneously hypertensive stroke prone rat model of vascular cognitive impairment.
Methods:
Hypertensive male rats (n = 13) were fed a high salt, low protein Japanese permissive diet and were compared to Wistar Kyoto control rats (n = 5).
Results:
Using electron paramagnetic resonance oximetry to measure in vivo tissue oxygen levels and magnetic resonance imaging to assess structural brain damage, we found compromised gray (dorsolateral cortex: p = .018) and white matter (corpus callosum: p = .016; external capsule: p = .049) structural integrity, reduced cerebral blood flow (dorsolateral cortex: p = .005; hippocampus: p < .001; corpus callosum: p = .001; external capsule: p < .001) and a significant drop in cortical oxygen levels (p < .05). Consistently, we found reduced oxygen carrying neuronal neuroglobin (p = .008), suggestive of chronic cerebral hypoperfusion in high salt-fed rats. We also observed a corresponding increase in free radicals (NADPH oxidase: p = .013), p-Tau (pThr231) in dorsolateral cortex (p = .011) and hippocampus (p = .003), active interleukin-1β (p < .001) and neurodegeneration (dorsolateral cortex: p = .043, hippocampus: p = .044). Human patients with subcortical ischemic vascular disease, a type of vascular dementia (n = 38; mean age = 68; male/female ratio = 23/15) showed reduced hippocampal volumes and cortical shrinking (p < .05) consistent with the neuronal cell death observed in our hypertensive rat model as compared to healthy controls (n = 47; mean age = 63; male/female ratio = 18/29).
Conclusions:
Our data support an association between hypertension-induced vascular dysfunction and the sporadic occurrence of phosphorylated tau and cell death in the rat model, correlating with patient brain atrophy, which is relevant to vascular disease.
Sasang Constitutional Medicine is a major branch of Korean Traditional Oriental Medicine. The differences of disease susceptibility to be shown in Sasang constitution may be due to genetic factors. Therefore, we examined interrelationship among cerebral infarction (CI), apolipoprotein E (apoE) gene polymorphism, and Sasang constitutional classification. ApoE is a key protein modulating the highly atherogenic apoB containing lipoproteins and is a candidate gene for the development of coronary artery disease (CAD). The {\varepsilon}2\;and/or\;{\varepsilon}4 alleles were the first to be implicated in premature CAD, which resulted in this polymorphism being extensively studied. We investigated the association between apoE genotype and CI by case-control study in a Korean population. We also classified CI patients and control group into groups according to Sasang Constitutional Medicine. 196 CI patients and 379 controls without CI were examined. ApoE genotype was determined by 8% polyacrylamide gel separation after DNA amplification. A significant difference in the apoE genotype distribution was observed in the CI patients compared with that in controls (X^{2}=14.920, df=4, P=0.005). Also, the frequency of Taeumin constitution in patients with CI was significantly higher than that in controls (58.0% vs. 36.9%; P alleles. No differences in the apoE genotypes frequencies were observed in the Taeumin compared with that in the other constitutions. In addition, we investigated whether the DD genotype of angiotensin converting enzyme (ACE) gene, a candidate gene for CI, was associated with CI, Taeumin constitution, and apoE polymorphism. As a result, the frequency of Taeumin constitution was significantly higher in CI patients with both apoE {\varepsilon}3/{\varepsilon}4 and ACE ID/DD genotypes than in the remaining Sasang constitutions (14.5% vs. 8.3% and 0%) (X^{2}=13.521, df=6, P=0.035). In summary, we concluded that the apoE polymorphism is a major risk factor for CI in Koreans and the ACE ID/DD genotype enhanced the relative risk for CI in the subjects with apoE {\varepsilon}3/{\varepsilon}4 genotype and Taeumin constitution.
The association between apolipoprotein E (apoE) gene polymorphism and ischemic cerebrovascular disease (ICVD) has been controversial. These controversies may be due to inaccurate classification of patients and ethnic differences. The aim of the present study was to assess the relationship between apoE gene polymorphism and the development of ICVD in a population from Korea. We investigated 136 patients with ICVD and 357 controls without ICVD. No differences in the apoE genotypes frequencies (X^{2} = 3.660, df = 5, P = 0.454) and even in the alleles frequencies (X^{2} = 1.946, df = 2, P = 0.378) were observed in the ICVD patients compared with that in controls. The data have been compared with data found in other population groups. However, the risk of ICVD associated with apoE {\varepsilon}3/{\varepsilon}4 genotype was increased nearly 3-fold in subjects possessing the history of diabetes mellitus (OR 3.3, 95% CI 1.2-9.4, P = 0.026). We concluded that the apoE polymorphism is not associated with ICVD at least in the Korean population, but the apoE frequencies found in this study differ significantly from those obtained in Japanese.
In Western countries, acute myocardial infarction and stroke, are major causes of morbidity and mortality (1). An occlusive coronary thrombus on an ulcerated atherosclerotic plaque in the coronary arteries is the central event in more than 90% of patients with Q-wave myocardial infarction (2). The underlying abnormality in non-Q-wave infarctions is a ruptured atherosclerotic plaque, which acts as a nidus for the deposition and activation of platelets. Atherosclerotic changes in the carotid and vertebrobasilar arteries resemble those of coronary arteries (3). These lesions may progress to local occlusions, but most often do not become symptomatic until embolization to more distal arteries takes place (ischemic stroke). In the cerebral arteries, vessel wall and lumen may be normal until the artery is occluded by an embolus from a more proximal arterial lesion or from the heart (4). Rather than to emboli, occlusion of the small penetrating arteries is often due to degenerative changes of the vessels or to extracranial large-artery disease (5).
Cytochrome oxidase has been used in the past as a marker of neuronal activity. We propose that cytochrome oxidase may also serve as a useful marker for predicting potential neurodegeneration, particularly following chronic brain hypoperfusion. This proposal is based on a series of experiments in rats subjected to mild chronic brain hypoperfusion and tested at determined time points for regional cytochrome oxidase activity, visuo-spatial memory, reactive astrocytosis, neurodegenerative changes and microtubule associated protein 2 (MAP-2). The results of these experiments suggest the following scenario: four weeks following chronic brain hypoperfusion, regional cytochrome oxidase activity is reduced in parallel with spatial memory function although no neurodegenerative changes are seen anywhere in the brain, despite an increased density of astrocytes in the hippocampus. After 8 weeks of ischemia, neurodegenerative changes are still absent but spatial memory remains depressed while the postsynaptic dendritic marker MAP-2 shows loss of immunostaining in the apical dendrites of CA1 neurons (suggesting continued metabolic dysfunction of these neurons). Twelve weeks after brain hypoperfusion, some neurodegenerative signs begin to be seen in CA1 neurons with continued MAP-2 reduction and reactive gliosis. If rats with chronic brain hypoperfusion are kept for 25 weeks, neuronal loss and extended hippocampal neurodegeneration with cortical atrophy can be seen. Neuronal loss and extension of neurodegeneration 25 weeks after chronic brain hypoperfusion are dependent on factors: age of animal, severity of the chronic ischemic insult and of ischemia. We suggest that the chronologic progression of memory dysfunction, gliosis and MAP-2 loss following mild but chronic brain hypoperfusion are due to lowered mitochondrial oxidative phosphorylation and reduced energy metabolism, initially in ischemic-sensitive neurons, such as in CA1. This energy metabolic down-regulation which is reflected by depressed cytochrome oxidase activity in the CA1 region, appears to precede neurodegenerative changes of CA1 neurons by many weeks. Cytochrome oxidase may be an important pathogenetic precursor of neurodegenerative pathology, particularly Alzheimer’s disease which shares many of the anatomic and cognitive deficits seen in the rat model.
This chapter deals with the neuroprotective effects of estrogen in the aging human brain. In the clinical arena, estrogen is the best studied of the gonadal steroids and is the gonadal steroid most relevant to human illness. The protective effects are considered both in the context of normal aging and several common disorders affecting the aging brain—cerebrovascular disease, Alzheimer's, and Parkinson's. The clinical studies cited pertain only to women, primarily because the midlife loss of estrogen is a natural phenomenon unique to women. During their reproductive years, women are exposed to high concentrations of estrogens cyclicly produced in the ovaries. After menopause, which occurs at a mean age of approximately 51 years, ovarian estrogen production ceases. Residual estrogens are produced in low concentrations from androgen precursors formed in the adrenal glands and the atrophic ovaries.
Stroke is a leading cause of death and morbidity throughout the world. Numerous medical conditions are associated with stroke and predispose individuals to cerebrovascular disease. Hematologic disorders are a frequent cause. Several important disorders that involve the coagulation cascade, including protein C and S deficiencies, antithrombin III deficiency, and protein C resistance, are examined. Additionally, the relationship between the immune system and stroke is considered. Various circulating proteins such as homocysteine, lipoprotein (a), and cryoglobulins are linked to stroke and are discussed, as also are sickle cell disease, conditions that perturb coagulation such as malignancy, and medication use and the risk of stroke. The relationship between genetics and stroke is considered with regard to stroke evaluation and therapies in the future.
Introduction: Magnesium deficiency is known to have adverse effects on the composition of blood lipids in such a way that the development of atherosclerosis is promoted. Objectives: Hence it was decided to investigate the effects of magnesium (Mg) deficiency on cerebrovascular system. The role of hypomagnesemia on serum LDL in cerebrovascular accident (CVA) cases was also evaluated. Materials and Methods: 45 cases of stroke and 45 age and sex matched controls in the age group of 40-80 years were included in the study. Fasting blood samples were collected and serum magnesium and LDL were estimated by auto-analyzer. The results were analyzed using Student's 't' test and Pearson's correlation. Results: The values of serum LDL were significantly increased in cerebrovascular accident cases when compared to controls (p <0.001). The values of magnesium were significantly decreased in cases when compared to controls (p <0.001). Highly significant negative Pearson's correlation between serum LDL and magnesium in cases was obtained (r value: -0.936), (p<0.001). Conclusion: From this study, it is concluded that Mg deficiency can be a risk factor for cerebrovascular atherosclerosis which can cause CVA. The above mentioned parameters (Mg and LDL) are good indicators for prognosis of CVA.
Elevated plasma levels of Lp(a) do seem to influence the progression of atherosclerosis. Evidence is emerging that certain apo(a) isoforms may be more atherogenic than others, and in transgenic mice free apo(a) has been shown to be associated with accelerated atherosclerosis. Currently it is not known whether treating elevated Lp(a) levels will reduce progression of atherosclerosis and, as therapeutic options are limited, mass screening of Lp(a) levels in populations is not indicated. The presence of raised Lp(a) levels, however, warrants aggressive treatment to reduce other cardiovascular risk factors. Continuing research to investigate the relationship of the apo(a) gene to other genes, including the plasminogen gene and apo(a)-related genes, will add further information pertaining to the evolution, function, regulation and clinical implications of Lp(a).
Background: Non-HDL cholesterol is a potential newer risk factor for cerebrovascular diseases (CVD). Objective: To explore the association of non-HDL cholesterol with cerebrovascular disease. Methods: This case control study was carried out in the Department of Biochemistry, BSMMU, Dhaka during the period of January to December 2007 to evaluate the association of non-HDL cholesterol with CVD in Bangladeshi population. A total number of 135 subjects of both sexes were grouped as Group-I (CVD cases) and Group-II (Healthy controls). Group-I include 85 cases of which 59 were ischaemic cerebrovascular diseases (ICVD) and 26 were haemorrhagic cerebrovascular diseases (HCVD). By taking the history and doing clinical examination and laboratory investigations, diabetes mellitus, malignant disease, renal disease, liver disease and diuretic medication were excluded from study subjects. Serum non-HDL cholesterol was measured in all study subjects. Statistical analysis was performed by using SPSS for windows version 12.0. Mean values of the findings were compared between groups. One way ANOVA test and multiple comparison (Bonferroni‘t’) test were used to see the level of significance. Results: Serum non-HDL cholesterol found significantly increased in CVD, ICVD and HCVD cases in comparison to control subjects. But ICVD and HCVD cases did not differ with respect to serum non-HDLcholesterol. Conclusion: The result shows that elevated non-HDL cholesterol is associated with CVD. Prospective study with large sample size is required to evaluate the elevated Non-HDL cholesterol as a risk factor of CVD. Key words: Non-HDL cholesterol; Cerebrovascular disease; Ischaemic cerebrovascular disease; Haemorrhagic cerebrovascular disease. DOI: 10.3329/bjms.v9i3.6469 Bangladesh Journal of Medical Science Vol.09 No.3 July 2010, pp.143-149
Lipoprotein(a) (Lp(a)), an LDL-like particle containing apo(a), a highly glycosylated protein, is a significant genetic risk factor for coronary heart disease (CHD). Lp(a) phenotypes are characterized into single-band and double-band phenotypes according to electrophoretic mobility compared to that of apo B-100. The first goal was to assess whether Lp(a) phenotype influences the concentrations and metabolism of other serum lipoproteins. A second focus was to evaluate the effect on Lp(a) concentrations of substituting medium chain saturated fat for a polyunsaturated, baseline diet. In this two-way cross-over study 18 females are a baseline, polyunsaturated fat diet (PolySat en% ratio = 10.511.9) for 1 week, and then a high saturated fat diet for 4 weeks (PolySat en% ratio = 3.419.8) providing either 14 energy % medium chain triglycerides (MCT) 8:0 + 10:0 or 12:0, whereas monounsaturated fat was held constant. Subjects with double-band Lp(a) phenotypes had higher (P = 0.000) Lp(a) levels on the baseline diet compared to single-band phenotypes. Both diets decreased serum Lp(a) concentration about 30% (P < 0.05) but raised serum LDL-C about 11%. On the baseline diet, Lp(a) polymorphism did not affect serum LDL-cholesterol levels or receptor-mediated uptake and degradation of LDL. In a two-way ANOVA 8:0 + 10:0 and 12:0 had significantly different effects on change in serum HDL-C concentrations and LDL receptor activity in MNC, but Lp(a) polymorphism had no effect on the variables measured in this study. These results suggest that the response of LDL and Lp(a) levels to the two saturated fat diets were independent of each other. Lp(a) polymorphism did not seem to influence LDL metabolism.
Cognitive impairment is one of the major symptoms of
dementia. The main cognitive functions acc orientation to time
and place, recall and memory, attention, language, calculation,
and visual construction. Impairment of cognitive functions influences
the ability of an individual to live independently, and it diminishes
the quality of life. In addition to the consequences for an individual,
cognitive impairment imposes a major burden on the health care
system because it induces an increased risk of institutionalization and
hospitalization.
Although cognlttve impairment is a less severe disorder than dementia,
it is much more common. In a representative papu lation of
subjects over 65 years of age, the prevalence of cognitive impairment
was 15.8%, whereas the prevalence of dementia was 4.2%.' The risk of
cognitive impairment rises exponentially with age. Therefore, we may
expect an increase in the number of people with cognitive impairment
in our aging society. At present, there acc a number of medications that
can delay the progression of dementia and that can stabilize cognitive
function. However, no cure or prevention for these disorders has been
found yet. Therefore, it is important to identify modifiable risk factors
for cognitive impairment and dementia. If these risk factors can be
found, preventive intervention may become feasible.
In contrast to ischemic heart diseases, the relationship between serum cholesterol and cerebrovascular diseases has been equivocal. This contradiction is due to the heterogeneous nature of strokes, therefore the lipid-stroke relationship should be analyzed considering subtypes of cerebrovascular diseases. Focusing mostly on the results of research in humans, we summarize the current view on the relationship between serum cholesterol and cerebrovascular diseases. In this review, we give an overview on epidemiological data, diagnostic methods and results of some clinical therapeutic trials. We focus on the role of cholesterol in large-vessel (carotid) atherosclerosis, small-vessel cerebral diseases (lacunar infarcts, leukoaraiosis and cerebral microbleeds) and on the effects of cholesterol on the microvascular system, evaluated by studies on cerebrovascular reactivity. We also enlist new diagnostic and therapeutic approaches that may have a role in the management of patients with atherosclerotic cerebrovascular diseases in the future.
Until recently, intracranial atheromatosis was a probably underdiagnosed clinicopathological entity that was rarely studied in depth. In the last years the advance and expansion in the use of non-invasive diagnostic tools have led intracranial atheromatosis to the front page among the most prevalent causes of stroke worldwide. Important efforts have been accomplished with the aim of identifying markers of poor outcome, which, besides the underlying mechanisms of cerebral ischemia in these patients, are the most important factors on which clinical and therapeutic decisions should be based. To date, the therapeutic armamentarium is scarce and far from optimun, regarding medical and endovascular measures. In this review we address the most important aspects of the natural history and cure treatment of intracranial atheromatosis.
Stroke is a complex genetic trait, rather than a simple monogenic disorder. This chapter introduces the approaches to current stroke genetic research. In addition, the chapter discusses inherited diseases causing stroke. Common stroke refers to age-related stroke in the general population. Finding stroke genes help in understanding cerebrovascular pathophysiology, providing targets for stroke prevention, and developing genetic tests to identify high-risk individuals. An important genetic etiology of stroke is inherited diseases causing cerebrovascular disease. Although stroke may not be the primary manifestation of the inherited disorders, there may be a strong family history of stroke or stroke in young patients. These inherited diseases may have associated physical or metabolic findings that provide clues, and genetic tests can confirm the diagnosis. Many of these diseases may be the result of sporadic mutations, so there may not always be a family history. These strategies can also be applied to study the genetics of cerebral hemorrhage, including intracerebral hemorrhage and subarachnoid hemorrhages, intracranial aneurysms, and other vascular malformations. There are several inherited diseases associated with cerebral hemorrhage and vascular malformations. Further advancements in research will hopefully yield genetic tests to identify high-risk individuals for hemorrhage and therapeutic targets for disease prevention.
Objective: To determine whether a specific apolipoprotein E (APOE) allele is a predictor for ischemic cerebrovascular disease (ICVD). Background: The role of APOE in atherosclerosis has been a focus of intensive research. The APOE ε4 allele is overrepresented in Alzheimer's disease, atherosclerosis, ischemic heart disease, and ICVD. Also, ε4 carriers have higher cholesterol levels than non-ε4 carriers. Methods: We performed a prospective, longitudinal study on patients who have ICVD. The patients were recruited from St. Mary Hospital, Korea, and investigated for ICVD through interviews and by reviewing their medical records and neuroimaging studies. APOE genotypes were determined for each patient. Results: 20 of the 91 enrolled patients had recurrent ICVD, yielding a 3-year cumulative recurrence rate of 22%. Carriers of the ε4 allele had a 3-year recurrence rate of 53%, as compared with only 16% for patients who had the APOE non-ε4 allele (the risk ratio was 4.11; the 95% CI was 1.49–11.32; P
Treger I, Froom P, Ring H, Friedman G. Association between apolipoprotein E4 and rehabilitation outcome in hospitalized ischemic stroke patients. Arch Phys Med Rehabil 2003;84:973–6.
Context
Next to Alzheimer disease, vascular dementia is the second most common
form of dementia in the elderly, yet few specific risk factors have been identified.Objective
To investigate the relationship of plasma lipids and lipoproteins to
dementia with stroke.Design and Setting
Prospective longitudinal community-based study over a 7-year period
(1991-1998).Participants
A total of 1111 nondemented participants (mean [SD] age, 75.0 [5.9]
years) were followed up for an average of 2.1 years (range, 1-7.8 years).Main Outcome Measure
Incident dementia with stroke according to standardized criteria, by
baseline levels of total plasma cholesterol and triglycerides, low-density
lipoprotein (LDL) cholesterol, LDL levels corrected for lipoprotein(a), high-density
lipoprotein cholesterol, lipoprotein(a), and apolipoprotein E genotype.Results
Two hundred eighty-six (25.7%) of the 1111 subjects developed dementia
during follow-up; 61 (21.3%) were classified as having dementia with stroke
and 225 (78.7%) as having probable Alzheimer disease. Levels of LDL cholesterol
were significantly associated with an increased risk of dementia with stroke.
Compared with the lowest quartile, the highest quartile of LDL cholesterol
was associated with an approximately 3-fold increase in risk of dementia with
stroke, adjusting for vascular risk factors and demographic variables (relative
risk [RR], 3.1; 95% confidence interval [CI], 1.5-6.1). Levels of LDL corrected
for lipoprotein(a) were an even stronger predictor of dementia with stroke
in the adjusted multivariate analysis. Compared with the lowest quartile,
the RR of dementia with stroke for the highest quartile of lipoprotein(a)–corrected
LDL cholesterol was 4.1 (95% CI, 1.8-9.6) after adjusting for vascular factors
and demographic variables. Lipid or lipoprotein levels were not associated
with the development of Alzheimer disease in our cohort.Conclusions
Elevated levels of LDL cholesterol were associated with the risk of
dementia with stroke in elderly patients. Further study is needed to determine
whether treatment of elevated LDL cholesterol levels will reduce the risk
of dementia with stroke.
Figures in this Article
Vascular dementia is considered the second major cause of dementia after
Alzheimer disease in Western populations.1
While the role of coincident vascular disease in patients with Alzheimer disease
has received attention,2 the origin of vascular
dementia remains unclear. Previously we found that an apolipoprotein E ∊4
(APOE ∊4) allele increased the risk of dementia
with stroke in a population-based case-control investigation.3APOE could influence the pathogenesis of dementia with
stroke through its effects on lipid metabolism and atherosclerosis,4 but the relationship between lipids and the risk of
dementia in the presence or absence of the APOE ∊4
allele has not been investigated. Plasma lipids and lipoprotein fractions
were studied in a multiethnic elderly population to test the hypothesis that
dyslipidemia could be an independent risk factor for the development of dementia
with stroke.
This new, sensitive, specific "sandwich"-type enzyme-linked immunosorbent assay (ELISA) for quantifying lipoprotein(a) [Lp(a)] in human serum and in ultracentrifugal lipoprotein fractions is based on use of a monoclonal antibody raised against apolipoprotein(a) as coating protein and a polyclonal antibody, raised against either apo B or against Lp(a) and conjugated with peroxidase, for detection of bound Lp(a). Mean intra- and interassay CVs for assay of 16 samples were 3.0% and 5.6%, respectively. Sample pretreatment with urea did not enhance Lp(a) immunoreactivity, and treatment with nonionic detergents decreased binding to the monoclonal antibody. Results correlated well (r = 0.99, n = 38) with those by radial immunodiffusion (RID). The ELISA assay, however, detects amounts corresponding to Lp(a) contents of 10 to 1000 mg/L in plasma samples diluted 1000-fold, compared with 100-500 mg/L for RID. For 92 normolipidemic subjects, the mean Lp(a) concentration was 120 (SD 130) mg/L. In patients undergoing coronary angiography, Lp(a) concentrations increased with the severity of the disease but were not correlated with either HDL cholesterol, triglycerides, apo A-I, or apo B, and only weakly with plasma cholesterol and apo A-II. These two correlations were even weaker in normal subjects, and only the correlation with total cholesterol was valid. Lp(a), measured at birth and at seven days and six months, steadily increased with age. This assay is well suited for measuring Lp(a) in plasma and in lipoprotein fractions and also for screening programs evaluating this significant genetic risk factor for the development of atherosclerosis.
We describe an ultracentrifugation method for isolating the different lipoprotein classes relatively quickly. In this method the very-low-density lipoproteins are first separated by non-density-adjusted ultracentrifugation. The resulting infranatant material is then stained with Coomassie Brilliant Blue R-250 and ultracentrifuged in a density gradient. The intermediate-density lipoproteins (IDL), low-density lipoproteins, and high-density lipoproteins fractions are separated by aspiration from the top of the tube. This method can be used to separate, analyze, and quantify lipoproteins, including anomalous lipoproteins such as the IDL. The CVs for the present method never exceeded 15%.
Apolipoprotein (apo) B containing lipoproteins and their remnants which are enriched in cholesterol are atherogenic in humans. These particles are metabolized by a complex process that is regulated by a number of different factors [1]. These include the assembly and secretion of triglyceride-rich apo B containing lipoprotein particles, intravascular lipolysis of the triglycerides, exchange of lipids and proteins between lipoprotein particles, and catabolism of the remnants of these apo B containing particles by receptor-mediated endocytosis. Two important modulating factors in the regulation of the catabolism of these remnants particles are apo E and the cell surface receptors with which it interacts.
We estimated the serum levels of lipoprotein(a) [Lp(a)] of 87 patients suffering from ischemic cerebrovascular disease (ICVD) (50 men, 37 women; mean age, 66.7 f 10.9 years; median, 66) and of 66 healthy controls (33 men, 33 women; mean age, 62.2 k 11.1; median, 63). The Lp(a) serum levels of the ICVD group (mean, 20.5 k 23 mg/dl; median, 9.5) were significantly elevated compared with those of controls (mean, 14.2 k 23.1 mg/dl; median, 5). In a smaller submouu, limiting the age range to 30 to 60 vears. I. the difference in the Lp(a) serum levels between the ICVD patients and the controls was even highly significant (p < 0.001).
The development and generalization of CT or MRI in patients with acute stroke has allowed to refine the knowledge on the topography of cerebral infarcts, which was based on autopsy studies. Still more interesting is the attempt to correlate the different topographic patterns with the underlying causes of infarct, because it may be of help in establishing the etiologic diagnosis strategies in individual patients.Copyright © 1991 S. Karger AG, Basel
Serum lipoprotein(a) [Lp(a)] was determined in 205 patients (71 ± 10 years; mean age ± SD) with acute stroke and in 204 nonhospitalized referent subjects in the 60- to 80-year age range. Lp(a) levels were significantly higher in the stroke patients (median 87 vs. 63 mg/l; p = 0.002). Within the group of stroke patients, Lp(a) levels were similar among men and women, correlated modestly with age (r = 0.15; p = 0.04) and increased only marginally through the first days after stroke. Patients with concomitant ischemic heart disease tended to have higher Lp(a) than those without coronary disease (median 103 vs. 71 mg/l; p = 0.07). Hypertensive patients had higher levels than normotensives (97 vs. 73 mg/l; p = 0.02) and this relation between hypertension and Lp(a) was particularly strong among patients below 65 years of age (p = 0.01). Median Lp(a) level was 75 mg/l in patients not on beta blocker treatment, 103 mg/l in patients on selective beta blockers and 150 mg/l in those on nonselective beta blockers. In a multiple regression model, the use of beta blockers was a predictor of high Lp(a) levels (p = 0.03) that was independent of other clinical variables.
Plasma lipid and lipoprotein levels were determined in a continuous series of 50 patients (36 males and 14 females), mean age around 50 years, with a clinical diagnosis of transient ischemic attacks (TIAs). TIA was defined as a sudden episode of focal cerebrovascular insufficiency, with complete resolution of the symptoms within 24 h. TIAs are considered an important prognostic symptom for ischemic cerebrovascular diseases, being manifest in approximately 45% of the patients later undergoing a complete stroke.Plasma total cholesterol levels did not differ in these patients, when compared with a similar series of patients of the same age and sex, free of cerebrovascular lesions. A slight elevation of mean triglyceride levels was detected in the patients of both sexes, as well as higher incidence of type IV hyperlipoproteinemia. The most significant finding, however, observed only in male TIA patients, was that of significantly reduced high density lipoprotein (HDL)-cholesterol levels. This reduction (−19.7% compared to the control group) is similar to that recently reported for patients with clear-cut ischemic cerebrovascular disease. The detection of decreased HDL-cholesterol levels in male TIA patients may be of considerable significance for a prognostic evaluation of this biochemical parameter.
The body cholesterol pool increases with decreasing plasma-high-density-lipoprotein (H.D.L.) but is unrelated to the plasma concentrations of total cholesterol and other lipoproteins. This finding supports existing evidence that H.D.L. facilitates the uptake of cholesterol from peripheral tissues and its transport to the liver for catabolism and excretion. Plasma-H.D.L., is reduced in several conditions associated with an increased risk of future ischaemic heart-disease (I.H.D.), namely hypercholesterolaemia, hypertriglyceridaimia, male sex, obesity, and diabetes mellitus, while subjects with existing clinical I.H.D. have lower levels of H.D.L. than healthy subjects within the same community. It is proposed that a reduction of plasma-H.D.L. concentration may accelerate the development of atherosclerosis, and hence I.H.D., by impairing the clearance of cholesterol from the arterial wall.
Plasma-levels of major lipids (cholesterol, triglyceride, high-density-lipoprotein cholesterol), two major apolipoproteins (apo-B and apo-A1), and two ratios (total-cholesterol/apo-B and apo-A1/apo-B) were studied in 218 survivors of myocardial infarction and 160 controls. Apolipoproteins were as good as lipids as discriminators between the populations under the age of 50 and better in the sixth to eighth decades.. Furthermore, values of total-cholesterol/apo-B and apo-A1/apo-B obtained from controls and normolipaemic survivors of myocardial infarction gave a bimodal distribution. The protein moiety of lipoproteins is a better discriminator than lipids between atherosclerotic subjects and controls.
Lipid and lipoprotein values, including fasting triglycerides and high density lipoproteins (HDL), low density lipoproteins (LDL) and total cholesterol levels, were obtained on 2,815 men and women aged 49 to 82 years chiefly between 1969 and 1971 at Framingham. In the approximately four years following the characterization of lipids, coronary heart disease developed in 79 of the 1,025 men and 63 of the 1,445 women free of coronary heart diseases. At these older ages the major potent lipid risk factor was HDL cholesterol, which had an inverse association with the incidence of coronary heart disease (p less than 0.001) in either men or women. This lipid was associated with each major manifestation of coronary heart disease. These associations were equally significant even when other lipids and other standard risk factors for coronary heart disease were taken into consideration. A weaker association with the incidence of coronary heart disease (p less than 0.05) was observed for LDL cholesterol. Triglycerides were associated with the incidence of coronary heart disease only in women and then only when the level of other lipids was not taken into account. At these ages total cholesterol was not associated with the risk of coronary heart disease.
Serum lipoproteins were determined 8-12 weeks after the onset of ischemic cerebro-vascular disease (ICD) in 61 patients, 38 males and 23 females, before the age of 55. The results were compared with those of a matched control material. The diagnosis was based on clinical findings, CSF spectrophotometry, computer tomography, and angiography. Hyperlipoproteinemia was no common finding in these young and middle-aged patients with ICD. The normal mean total serum cholesterol concentration was the result of a slight increase in VLDL cholesterol and a concomitant HDL cholesterol reduction. In men, the HDL cholesterol concentration was lower than expected for any VLDL-TG concentration. The mean value of the HDL cholesterol concentration in the patients was 18% lower than in the control group. On agarose electrophoresis the lipoprotein variants "late prebeta", "sinking prebeta" and "rapid beta" lipoproteins could be demonstrated in the same frequency as in controls. There was no significant correlation between the degree of atherosclerosis, estimated by angiography, and any serum lipoprotein fraction. Several recent studies have stressed the importance of a low HDL concentration as an independent risk factor for atherosclerosis. The decreased HDL cholesterol levels found in the present material require further attention to the possible beneficial role of HDL in ICD.
Lipids and lipoproteins were analysed in forty-one survivors of stroke, aged less than 65 years, and the same number of age and sex matched controls without vascular disease. The stroke subjects had no evidence of coronary artery or peripheral vascular disease. High density lipoprotein cholesterol was significantly lower (1.19 +/- 0.06 mmol/l) in the stroke subjects than the controls (1.47 +/- 0.07 mmol/l). Triglyceride was also elevated in the stroke subjects, but this was confined to those who were taking antihypertensive treatment which included beta-blockers and/or thiazides. The low levels of high density lipoprotein in stroke were independent of hypertension or its treatment. Thus low levels of high density lipoprotein appear to be associated with cerebrovascular disease, while elevated triglyceride is a complication of anti-hypertensive therapy.
Data from 694 patients hospitalized with stroke were entered in a prospective, computer-based registry. Three hundred and sixty-four patients (53 percent) were diagnosed as having thrombosis, 215 (31 percent)as having cerebral embolism 70 (10 percent) as having intracerebral hematoma, and 45 (6 percent) as having subarachnoid hemorrhage from aneurysm or arteriovenous malformations. The 364 patients diagnosed as having thrombosis were divided into 233 (34 percent of all 694 patients) whose thrombosis was thought to involve a large artery and 131 (19 percent) with lacunar infarction. Many of the findings in this study were comparable to those in previous registries based on postmortem data. New observations include the high incidence of lacunes and cerebral emboli, the absence of an identifiable cardiac origin in 37 percent of all emboli, a nonsudden onset in 21 percent of emboli, and the occurrence of vomiting at onset in 51 percent and the absence of headache at onset in 67 percent of hematomas.
A protein determination method which involves the binding of Coomassie Brilliant Blue G-250 to protein is described. The binding of the dye to protein causes a shift in the absorption maximum of the dye from 465 to 595 nm, and it is the increase in absorption at 595 nm which is monitored. This assay is very reproducible and rapid with the dye binding process virtually complete in approximately 2 min with good color stability for 1 hr. There is little or no interference from cations such as sodium or potassium nor from carbohydrates such as sucrose. A small amount of color is developed in the presence of strongly alkaline buffering agents, but the assay may be run accurately by the use of proper buffer controls. The only components found to give excessive interfering color in the assay are relatively large amounts of detergents such as sodium dodecyl sulfate, Triton X-100, and commercial glassware detergents. Interference by small amounts of detergent may be eliminated by the use of proper controls.
Sixty-one male patients with ischemie thrombotic cerebrovascular disease (ITCVD) and 61 age-matched controls were studied to determine the interrelationships between the primary risk factors of ITCVD. Impaired carbohydrate metabolism in ITCVD was reflected in the significantly greater number of abnormal oral glucose tolerance tests (GTT) and type IV lipoprotein abnormalities when compared to controls. Elevated uric acid and triglyceride levels also were observed in ITCVD. Glucose and immunoreactive insulin (IRI) response curves in ITCVD were elevated and exhibited delayed peaks despite the normal or abnormal classification of GTT, indicating that insulin is ineffective in restoring glucose to normal levels. In the ITCVD and control groups with abnormal GTT the free fatty acid (FFA) levels were elevated at fasting and lacked the characteristic rebound at two hours observed in subjects with normal GTT, supporting the theory of a glucose-FFA cycle and its role in carbohydrate disturbances.
Lipids, lipoproteins, apolipoproteins (apo) and apo E polymorphism were determined in 101 men with chronic renal failure (CRF) were were on hemodialysis and 101 healthy controls matched for age and sex. Patients with CRF on hemodialysis had significantly higher levels of serum triglycerides, very-low-density lipoprotein (VLDL) cholesterol, intermediate-density lipoproteins (IDL), and lower levels of low- and high-density lipoproteins (LDL and HDL, respectively) than controls. Regarding apolipoproteins, serum apo B concentrations were decreased. Apo C-III concentrations in sera and in VLDL and HDL fractions were significantly increased in 35 hemodialysis patients compared with 32 controls. Seventy-eight of the 101 CRF patients had normal serum cholesterol and triglycerides (less than 5.2 mmol/liter and less than 2.3 mmol/liter, respectively). However, this subgroup also showed a significant increase in VLDL-triglycerides and serum apo E concentration in addition to changes observed in the group as a whole. Apo E polymorphism in our study population did not differ from that reported for other European populations. According to the different apo E phenotypes, lipids and lipoprotein composition showed no significant differences in controls or patients. We conclude that accumulation of triglyceride-rich lipoproteins in patients with CRF on hemodialysis may thus be at least in part related to the enrichment of apo C-III in VLDL and HDL fractions. Lipoprotein profile in hemodialysis patients, including those with normal serum cholesterol and triglyceride levels, is consistent with high cardiovascular risk.
The role of lipoprotein disturbances in the development of peripheral vascular disease (PVD) has not been sufficiently clarified.
The relations among concentrations of intermediate density lipoproteins (IDL), apoprotein (apo) B, apo E, and other lipoproteins were studied in 102 men with PVD and 100 healthy men who formed the control group. Patients with PVD had significantly higher levels of serum triglycerides, very low density lipoprotein (VLDL) cholesterol, VLDL triglycerides, VLDL proteins, IDL cholesterol, and IDL triglycerides and lower levels of high density lipoproteins (HDL) than controls. Serum cholesterol and triglycerides were normal in 30 patients (cholesterol, less than 5.2 mmol/l; triglycerides, less than 2.3 mmol/l), who had significant increases in IDL triglycerides and significant decreases in HDL cholesterol compared with the 47 controls, who had normal cholesterol and triglyceride levels. Patients with more severe distal involvement showed higher cholesterol and triglycerides carried by IDL and a greater reduction in HDL cholesterol. Smoking patients with PVD showed increased VLDL cholesterol and VLDL triglycerides and lower HDL concentrations. Apo E polymorphism in our study population does not differ from that reported for other European populations. Alleles epsilon 2 and epsilon 4 had a major impact on serum triglycerides and VLDL lipids in our patients with PVD.
Lipoprotein disturbances are a major risk factor for PVD. IDL abnormalities play an important role in the development and severity of PVD and should also be considered a vascular risk factor in normocholesterolemic and normotriglyceridemic patients.
A large segment of the population is modifying its dietary cholesterol intake to achieve a healthier life-style. However, all individuals do not respond equally. We have investigated the effects that that two physiologically important polymorphisms in the apolipoprotein (apo) E and B genes have on the responses of plasma lipid, lipoprotein, and apolipoprotein levels to a high-cholesterol diet. Over a 6-wk period, individuals were prescribed two diets, one consisting of 300 mg dietary cholesterol/d for 3 wk and one consisting of 1,700 mg dietary cholesterol/d for 3 wk. Total cholesterol, low-density-lipoprotein cholesterol (LDL-C), and apo B levels were significantly increased on the high-cholesterol diet. Average total cholesterol (numbers in parentheses are SDs) went from 167.6 (23.4) mg/dl on the low-cholesterol diet to 190.8 (36.2) mg/dl on the high-cholesterol diet; LDL-C went from 99.9 (24.8) mg/dl to 119.2 (33.4) mg/dl, and apo B went from 74.9 (24.5) mg/dl to 86.8 (29.5) mg/dl. In 71 individuals, the frequencies of the apo epsilon 2, epsilon 3, and epsilon 4 alleles were .09, .84, and .07, respectively. The frequency of the longer, apo B signal peptide allele (5'beta SP27) was .68. Apo epsilon 2/3 individuals had significantly lower LDL-C levels than did epsilon 3/3 homozygotes, on both the low-cholesterol diet (LDL-C lower by 21 mg/dl) and the high-cholesterol diet (LDL-C lower by 27 mg/dl). Average triglyceride levels were significantly different among apo B signal peptide genotypes, with the 5'beta SP27/37 homozygotes having the lowest levels (70 mg/dl). When individuals were switched from the low-cholesterol diet to the high-cholesterol diet, in no case were the average responses in lipid levels significantly different among apo E or B genotypes. Therefore, these gene loci do not have a major effect on the response of lipid levels to increased dietary cholesterol.
We analyzed the serum concentrations of lipids and lipoproteins and the prevalence of other risk factors in a case-control study of 304 consecutive Chinese patients with acute stroke (classified as cerebral infarction, lacunar infarction, or intracerebral hemorrhage) and 304 age- and sex-matched controls. For all strokes we identified the following risk factors: a history of ischemic heart disease, diabetes mellitus, or hypertension; the presence of atrial fibrillation or left ventricular hypertrophy; a glycosylated hemoglobin A1 concentration of greater than 9.1%; a fasting plasma glucose concentration 3 months after stroke of greater than 6.0 mmol/l; a serum triglyceride concentration 3 months after stroke of greater than 2.1 mmol/l; and a serum lipoprotein(a) concentration of greater than 29.2 mg/dl. We found the following protective factors: a serum high density lipoprotein-cholesterol concentration of greater than 1.59 mmol/l and a serum apolipoprotein A-I concentration of greater than or equal to 106 mg/dl. The patterns of risk factors differed among the three stroke subtypes. When significant risk factors were entered into a multiple logistic regression model, we found a history of hypertension, a high serum lipoprotein(a) concentration, and a low apolipoprotein A-I concentration to be independent risk factors for all strokes. The attributable risk for hypertension was estimated to be 24% in patients aged greater than or equal to 60 years. In this population, in which cerebrovascular diseases are the third commonest cause of mortality, identification of risk factors will allow further studies in risk factor modification for the prevention of stroke.
Application of uniform methods for measuring the apolipoprotein (apo) E polymorphism and plasma cholesterol levels in nine populations (Tyrolean, Sudanese, Indian, Chinese, Japanese, Hungarian, Icelandic, Finnish, and Malay) revealed significant heterogeneity among them in apo E type frequencies and mean cholesterol levels. The major apo E types in all populations were E3/2 (frequency range from 7.0% in Indians to 16.9% in Malays), E3/3 (frequency range from 39.8% in Sudanese to 72.1% in Japanese), and E3/4 (frequency range from 11.3% in Japanese to 35.9% in Sudanese). Mean cholesterol levels ranged from 144.2 mg/dl in the Sudanese to 228.5 mg/dl in the Icelandics. Two-way analysis of variance of the effect of population and apo E type on cholesterol levels showed no significantly interaction effect, indicating that the effects of apo E type on cholesterol levels do not differ significantly among the populations. The overall average excess for the epsilon 2 allele was -14.12 mg/dl (range -31.63 to -8.82 mg/dl); for the epsilon 3 allele, 0.04 mg/dl (range -1.87 to 1.58 mg/dl; and for the epsilon 4 allele, 8.14 mg/dl (range -1.71 to 13.31 mg/dl). Despite the apparent heterogeneity in these values, especially for the epsilon 4 allele, comparison of the average excesses by a method of repeated sampling with random permutations revealed no significant difference in effects among populations. These data indicate that a given apo E allele acts in a relatively uniform manner in different populations despite differences in genetic background and environmental factors.
We review the definition, pathogenesis, natural history, and prognosis and describe the first experimental model of lacunes. Defined pathologically or radiologically, lacunes are small cerebral infarcts which become cystic and are caused by occlusion of small arteries. The clinical definition of lacune is confused. The word "lacune" means a small stroke. While the immediate mortality rate from a small stroke is low, many patients are unable to return to work and the long-term prognosis is guarded. Photochemical damage to the carotid artery of rats produces microemboli to the brain, resulting in cavitary lesions resembling lacunes in humans. The "lacune hypothesis" is a fallacy because small cerebral infarcts are not caused solely by a combination of hypertension and small vessel disease, and the various "lacunar syndromes" are simply small strokes which should be investigated as such.
We tested the hypothesis that hypertension is more common and cardiac embolism less common in patients with lacunar infarction than in patients with other types of cerebral infarction. We studied risk factor profiles in a series of 102 consecutive patients with a lacunar infarct and 202 consecutive patients with a carotid artery-distribution infarct involving the cortex registered in the Oxfordshire Community Stroke Project, a community-based study of first-ever stroke. The two groups did not differ in the prevalence of prestroke hypertension (defined in a number of ways) or in the prevalence of markers of sustained hypertension. The presence of atrial fibrillation and a history of myocardial infarction, particularly during the 6 weeks before the stroke, were significantly more common in the group with carotid-distribution infarcts involving the cortex. There was no significant difference in the prevalence of other accepted risk factors for ischemic stroke, including previous transient ischemic attack, cervical bruit, diabetes mellitus, peripheral vascular disease, or cigarette smoking. Our results suggest that hypertension is no more important in the development of lacunar infarction than it is in the development of other types of ischemic stroke that are presumed to be due to atherosclerotic thromboembolism in a major cerebral artery. Our data support the autopsy evidence that cardioembolic occlusion is an unusual cause of lacunar infarction.
Blood levels of triglycerides, total cholesterol, isolated lipoprotein fractions (VLDL-LDL- and HDL-cholesterol) and apoproteins (Apo-A1 and Apo-B) were examined in multi-infarct dementia, senile dementia of the Alzheimer type, ischemic stroke associated with carotid atherosclerosis and in control subjects. Forty patients divided into 10 consecutive patients for each group were studied. Alzheimer patients showed mean total cholesterol and Apo-B values significantly higher than control subjects. Apo-B was significantly higher in stroke patients than in controls. The mean lowest HDL-cholesterol (HDL-c) value was observed in stroke patients. No significant differences in mean HDL-c levels were found between patients with multi-infarct and Alzheimer dementia.
In a community-based study of 301 subjects from 61 nuclear families, two distinct phenotypes (denoted A and B) were identified by nondenaturing gradient gel electrophoretic analysis of low density lipoprotein (LDL) subclasses. Phenotype A was characterized by predominance of large, buoyant LDL particles, and phenotype B consisted of a major peak of small, dense LDL particles. Previous analysis of the family data by complex segregation analysis demonstrated that these phenotypes appear to be inherited as a single-gene trait. In the present study, the phenotypes were found to be closely associated with variations in plasma levels of other lipid, lipoprotein, and apolipoprotein measurements. Specifically, phenotype B was associated with increases in plasma levels of triglyceride and apolipoprotein B, with mass of very low and intermediate density lipoproteins, and with decreases in high density lipoprotein (HDL) cholesterol, HDL2 mass, and plasma levels of apolipoprotein A-I. Thus, the proposed genetic locus responsible for LDL subclass phenotypes also results in an atherogenic lipoprotein phenotype.
We examined the relation between the serum total cholesterol level and the risk of death from stroke during six years of follow-up in 350,977 men, 35 to 57 years of age, who had no history of heart attack and were not currently being treated for diabetes mellitus. The diagnosis of stroke and the type of stroke were obtained from death certificates. Using proportional-hazards regression to control for age, cigarette smoking, diastolic blood pressure, and race or ethnic group, we found that the six-year risk of death from intracranial hemorrhage (International Classification of Diseases, ninth edition [ICD-9], categories 431 and 432) was three times higher in men with serum cholesterol levels under 4.14 mmol per liter (160 mg per deciliter) than in those with higher cholesterol levels (P = 0.05 by omnibus test across five cholesterol levels). On the other hand, a positive association was observed between the serum cholesterol level and death from nonhemorrhagic stroke (P = 0.007). The inverse association of the serum cholesterol level with the risk of death from intracranial hemorrhage was confined to men with diastolic blood pressure greater than or equal to 90 mm Hg, in whom death from intracranial hemorrhage is relatively common. We conclude that there is an inverse relation between the serum cholesterol level and the risk of death from hemorrhagic stroke in middle-aged American men, but that its public health impact is overwhelmed by the positive association of higher serum cholesterol levels with death from nonhemorrhagic stroke and total cardiovascular disease (ICD-9 categories 390 through 459).
Lipoprotein mass concentrations were measured by analytical ultracentrifugation in a subset of 57 hypercholesterolaemic male participants in the National Heart, Lung, and Blood Institute Type II Coronary Intervention Study. 2-year changes in levels of intermediate-density lipoproteins (IDL) of flotation rate 12-20 were strongly predictive of progression of coronary artery disease at 5 years. Changes in serum mass concentrations of low-density lipoproteins (LDL; flotation rate 0-12), very-low-density lipoproteins (VLDL; flotation rate 20-400), high-density lipoproteins (HDL), and the HDL2 and HDL3 subfractions did not differ significantly between men with and without definite progression of coronary artery disease. The relation of IDL mass to disease progression remained significant (p less than 0.05) after adjustment for group assignment to cholestyramine treatment or placebo and was only slightly reduced (p less than or equal to 0.06) by adjustment for changes in LDL mass concentrations. Changes in IDL mass and ratios of HDL-cholesterol to total-cholesterol or LDL-cholesterol were inversely correlated and had a similar ability to predict progression. The findings are consistent with earlier evidence that IDL are directly involved in the development of coronary artery disease and suggest that ratios of HDL-cholesterol to total-cholesterol or LDL-cholesterol may be indicators of coronary disease risk partly owing to relations with IDL metabolism.
We investigated the relation of plasma lipids to the risk for ischemic stroke by comparing clinical and biochemical characteristics of survivors of cortical (n = 48) and lacunar (n = 36) brain infarction. By analysis of variance, no differences were observed in the concentrations of total cholesterol, triglycerides, low density lipoprotein cholesterol, very low density lipoprotein cholesterol, or apoproteins A1 and B. Patients with lacunar infarction, however, had higher concentrations of high density lipoprotein (HDL)-cholesterol than patients with cortical stroke. This HDL-cholesterol difference was due primarily to a strikingly low HDL-cholesterol content in white patients with cortical stroke. These data suggest that previously demonstrated differences in HDL-cholesterol concentrations between patients with ischemic stroke and control subjects without stroke may apply to patients with cortical but not lacunar infarction. Separation of cerebral infarction into subtypes based on mechanism may help clarify lipid-related risk factors in cerebrovascular disease.
Attempts were made to prepare antisera monospecific for Lp(a) lipoprotein and to investigate the distribution of subjects according to plasma levels of Lp(a) in Japanese controls and patients with coronary heart disease or cerebral infarction. Positive plasma reactions to the double diffusion test for Lp(a) (Ouchterlony) were observed in 32.3% of the healthy Japanese subjects, which is similar to results previously reported in western countries. The plasma threshold level of 17 mg/dl was considered an appropriate point for dividing subjects into positive and negative groups depending on reactions to the double diffusion test. When subjects were divided into two groups at 17 mg/dl, a significant association was found between a high plasma level of Lp(a) and either coronary heart disease or cerebral infarction in the distribution of the cortical artery. These results suggest that Lp(a) may play an important part as a risk factor for coronary heart disease and cerebral infarction.
To evaluate the role of lipoprotein(a) (Lp(a] in patients with cerebrovascular disease (CVD), lipid parameters were compared with a control group (CO). Additionally, the Lp(a) serum levels were investigated in a coronary artery disease (CAD) group. The CO was made up of 37 healthy persons (age: 54.5 +/- 7.7, 26 males and 11 females), the CVD group included 46 patients with sustained transient ischemic attack (TIA) prolonged reversible ischemic neurologic deficits (PRIND) and cerebral infarction (CI) (age: 53.6 +/- 9.7, 32 males and 14 females), and the CAD group was made up of 28 survivors of myocardial infarctions (age: 52.5 +/- 8.1, 18 males and 10 females). The median values of Lp(a) in CVD were significantly higher than in the CO (p less than 0.01) and did not differ significantly from the CAD. Total TC, HDL-C, TG, LDL-C and the ratio of LDL-C/HDL-C did not show any significant difference between the control and cerebrovascular disease group. For quantification of the vascular lesions of the carotid system, a Duplex Doppler score system was used. The score correlated with Lp(a) in patients between 40 to 65 years of age (r = 0.34, p less than 0.01). Thus, we conclude that Lp(a) is not only a risk factor for CAD but also for CVD.
We estimated the serum levels of lipoprotein(a) [Lp(a)] of 87 patients suffering from ischemic cerebrovascular disease (ICVD) (50 men, 37 women; mean age, 66.7 +/- 10.9 years; median, 66) and of 66 healthy controls (33 men, 33 women; mean age, 62.2 +/- 11.1; median, 63). The Lp(a) serum levels of the ICVD group (mean, 20.5 +/- 23 mg/dl; median, 9.5) were significantly elevated compared with those of controls (mean, 14.2 +/- 23.1 mg/dl; median, 5). In a smaller subgroup, limiting the age range to 30 to 60 years, the difference in the Lp(a) serum levels between the ICVD patients and the controls was even highly significant (p less than 0.001).
The classification and metabolism of human apolipoproteins and lipoproteins are reviewed. Fourteen well-characterized apolipoproteins are present in human plasma. The structures and physiological functions of several of them have been elucidated, and defects in individual apolipoproteins lead to characteristic abnormalities in lipoprotein metabolism. Metabolism of apo B-containing lipoproteins involves lipolysis and intravascular remodeling of triglyceride-rich chylomicrons and very-low-density lipoproteins secreted by the intestine and liver, respectively. After metabolism, the remnant particles are removed from the plasma by the liver or peripheral cells by means of specific lipoprotein receptors. The return of cholesterol from peripheral cells to the liver by 'reverse cholesterol transport' may occur directly via high-density lipoproteins or, following exchange, by very-low-density or low-density lipoproteins. Determination of the functional roles of apolipoproteins, lipolytic enzymes, and lipoprotein receptors provides a conceptual framework for understanding lipoprotein metabolism and analyzing molecular defects in dyslipoproteinemic patients.
A variety of lipids, lipoprotein (Lp) lipids and APO-Lp were measured in 72 patients of both sexes suffering from cerebrovascular arteriopathy and compared with a control group matched for age and sex. The best discriminators by univariate analysis were serum concentrations of APO-AI, followed by APO-AII, high density lipoprotein phospholipids and HDL cholesterol (HDL-C). Low density lipoprotein cholesterol and serum APO-B values were lower in the patients than in the controls. With APO-AI only, patients and controls could be classified with 88-91% certainty. By combination of some of the variables which were selected by a stepwise discriminant analysis, several models were calculated resulting in 93-97% segregation of patients from controls. By multivariate analysis, APO-AI, APO-AII, HDL-C, and triglycerides in combination with the blood pressure or the body weight index were independent variables (in a mathematical sense). By comparing the present data with published results of previous studies it is concluded that cerebral atherosclerosis differs from other forms of atherosclerosis by several major risk indicators.
The apo E locus contributes to determining the variation in plasma cholesterol levels of healthy and diseased populations. It also influences the expression of hyperlipidemia and appears to modulate the susceptibility to atherosclerosis in a complex multifactorial interaction. There is evidence that the presence of apo E2 is protective, whereas that of apo E4 predisposes to coronary artery disease. The burden of proof, however, lies on future, well-designed clinical trials and prospective studies. The study of the biological significance of the apo E polymorphism in humans has emphasized the importance of gene-gene and gene-environment interactions in the pathogenesis of hyperlipidemia and atherosclerosis. The apo E polymorphism involves the coding region of the apo E gene and results in alterations of the gene product which, in turn, either directly or secondarily affect the metabolic fate of the lipoprotein particles. Rapid advances in knowledge over the last decade have provided a metabolic explanation for the observation of the opposite effects of the epsilon 4 and the epsilon 2 alleles on lipoprotein levels. Apo E2 has lower receptor binding affinity which results in delayed clearance of apo E2-bearing lipoprotein particles from plasma. Apo E4 is distributed differently from apo E3 between VLDL and HDL, is degraded more rapidly than apo E3, and may enhance the catabolism of E4-bearing particles, leading to other alterations in lipoprotein metabolism which result in elevated levels of LDL. In view of the significant opposite impacts of the epsilon 4 and the epsilon 2 alleles on plasma LDL cholesterol concentrations, it is evident that determination of the apo E phenotype will become a useful adjunct to the assessment of the cardiovascular risk profile of an individual. In addition, the relationship between the epsilon 2 allele and type III hyperlipoproteinemia provides a valuable model for the study of complex genetic interactions in the pathogenesis of hyperlipidemia. The further study of apo E and its interactions shows great promise for a deeper comprehension of the pathogenesis of atherosclerosis.
Although blood lipids and lipoproteins are strongly related to coronary atherosclerosis, their association with cerebrovascular atherosclerosis is less clear. A review of more than 20 publications in which a relation was sought between plasma lipid and lipoprotein concentrations and cerebrovascular atherosclerosis leads to the general conclusion that such a relation exists and that it is stronger in older than in younger individuals. A relation was found between blood lipids and/or lipoproteins and the extent and/or severity of cerebrovascular atherosclerosis in all but three of 26 reviewed studies. However, the specific nature of the relation is obscure because the various studies cannot easily be compared with one another. Interstudy variations in lipoprotein fraction analyzed, methodology for the analysis of lipids and lipoproteins, arterial segment examined, population sampled, control selection in case-control studies, statistical analytic approach taken, and methodology for the assessment of arterial disease preclude pooled analyses. There is a clear need for further evaluation of this relation using standardized and up-to-date methodologies both for analyses of lipids and lipoproteins and for assessment of cerebrovascular disease in symptom-free volunteers as well as in symptomatic patients.
We present epidemiologic, etiologic, and clinical data for 1,000 consecutive patients with a first stroke (cerebral infarction or hemorrhage) admitted to the Centre Hospitalier Universitaire Vaudois since 1982. The patients were evaluated using a standard protocol of tests (computed tomography, Doppler ultrasonography, and electrocardiography in all patients, as well as angiography and specific cardiac investigations in selected patients). Each case was coded prospectively into a computerized registry. We believe that the Lausanne Stroke Registry is the first registry with complete computed tomography and Doppler ultrasonography data on all patients, which allows correlation between clinical findings, presumed etiology, and stroke location. Although the Lausanne Stroke Registry is not population-based, it gives a good estimate of the stroke-related problems in patients admitted to a primary-care center since our hospital is the sole acute-care facility for stroke in the Lausanne area.
Recent studies have shown that heterogeneity of human plasma low-density lipoproteins (LDL) is, in part, the result of production of different LDL products from two subspecies of intermediate-density lipoproteins (IDL). Cholesterol-enriched forms of both IDL species are found in plasma of patients with atherogenic dyslipidemias (familial hypercholesterolemia and type 3 hyperlipoproteinemia) and have physical properties similar to the major species in plasma of cholesterol-fed monkeys. Patients with familial combined hyperlipidemia have been shown to have increased plasma levels of IDL and of a smaller, denser LDL subclass (LDL-IIIA) that appears to be a metabolic product of the smaller IDL subspecies. Results from the NHLBI Type II Coronary Intervention study have supported a link between the small IDL-LDL pathway and coronary disease, in that 2-year changes in levels of these species were associated with disease progression. Furthermore, therapeutic reductions in IDL levels were correlated with increases in high-density lipoprotein cholesterol. Thus variation in IDL levels might influence coronary disease risk by both a direct effect and indirectly by affecting LDL particle number and possibly high-density lipoprotein metabolism.
We determined the frequencies of genetic apolipoprotein E isoforms in 570 survivors of myocardial infarction, all with demonstrable coronary heart disease, as compared with 624 healthy persons. In controls, E-4/E-3 heterozygosity was associated with total cholesterol concentrations of 1985 (SD 364) mg/L and low-density lipoprotein (LDL)-cholesterol concentrations of 1306 (SD 332) mg/L. Significantly lower values, 1811 (SD 312) mg/L and 1121 (SD 274) mg/L, respectively, were observed for E-3/E-2 heterozygous persons. In survivors of myocardial infarction, the respective values were significantly higher than in controls, differing between E-4/E-3 and E-3/E-2 heterozygous patients by 233 and 220 mg/L, respectively. Moreover, E-4/E-3 heterozygosity was accompanied by earlier age of myocardial infarction (48.8 +/- 7.4 years) as compared with E-3/E-2 heterozygosity (53.4 +/- 6.9 years) and E-3/E-3 homozygosity (51.2 +/- 7.7 years). Evidently, apolipoprotein E polymorphism can contribute to total and LDL-cholesterol concentrations in serum, thereby affecting risk of coronary heart disease and myocardial infarction.
The death rate from stroke in the United States has declined by 50 percent over the past decade, the evidence pointing to a reduction in the incidence of stroke as the responsible factor, not improved survival after stroke. The striking decrease in the mortality rate over this brief span suggests that modifiable environmental factors are important in the occurrence of stroke. Central to the decline in stroke mortality has been the identification of hypertension as the principal risk factor for stroke, whether due to hemorrhage or infarction, and the demonstration in controlled clinical trials that treatment of hypertension reduces the . . .
The first report from the Framingham Study that demonstrated an inverse relationship between high-density lipoprotein cholesterol (HDL-C) and the incidence of coronary heart disease (CHD) was based on four years of surveillance. These participants, aged 49 to 82 years, have now been followed up for 12 years, and this report shows that the relationship between the fasting HDL-C level and subsequent incidence of CHD does not diminish appreciably with time. Since a second measurement of HDL-C is available eight years after the initial determination, the relationship of HDL-C measurements on the same subjects at two points in time is examined. This second HDL-C measurement is also used in a multivariate model that includes cigarette smoking, relative weight, alcohol consumption, casual blood glucose, total cholesterol, and blood pressure. It is concluded that even after these adjustments, nonfasting HDL-C and total cholesterol levels are related to development of CHD in both men and women aged 49 years and older. Study participants at the 80th percentile of HDL-C were found to have half the risk of CHD developing when compared with subjects at the 20th percentile of HDL-C.
Studies were undertaken to determine whether there is an association between elevated levels of intermediate-density lipoproteins (IDL) (Sf 12-60 lipoproteins) and coronary artery disease. Forty-five to sixty-five-year-old men with objectively documented coronary artery disease (n = 58) who were free of known risk factors (diabetes, hypertension, obesity, hyperuricemia, and hypercholesterolemia) were compared with similar men who were free of coronary artery disease (n = 52). Smokers could not be excluded. The coronary artery disease group had a higher rate of cigarette smoking (NS, due to large variations); higher concentrations of triglycerides in their plasma (p = .003) and higher levels of very low-density lipoproteins (VLDL) (p = .007), IDL (p = .016), and low-density lipoproteins (LDL) (p = .04); as well as somewhat lower levels of high-density lipoprotein (HDL) cholesterol (p = .04). Chi-squared analysis demonstrated a strong association between coronary artery disease and IDL apolipoprotein (apo) B (p = .006), coronary artery disease and IDL triglyceride (p = .032), and coronary artery disease and IDL apo B times IDL triglyceride (p = .006) when the top quintile of the population was compared with the bottom quintile for each of these variables. Stepwise logistic regression analysis resulted in rejection of an association between coronary artery disease and HDL cholesterol, plasma triglyceride, VLDL triglyceride, or LDL triglyceride. However, it did show that coronary artery disease was most strongly associated with smoking and that the second strongest association was with IDL.(ABSTRACT TRUNCATED AT 250 WORDS)
There is increasing agreement about the atherogenicity of intermediate density lipoprotein (IDL). In order to determine whether normocholesterolemic diabetics are at a higher risk of atherosclerosis, cholesterol concentrations in three subclasses of triglyceride-rich lipoprotein fraction (Sf 12-400) were examined. Their plasma triglyceride and cholesterol levels were limited to below 150 and 250 mg/dl, respectively. They were divided into 3 groups according to their treatment: insulin injection (group I), sulphonylurea (group S) and diet alone (group D). Age-matched healthy normolipidemic non-obese subjects served as controls (group C). Triglyceride-rich lipoproteins were separated by ultracentrifugation: very low density lipoprotein (VLDL), Sf 60-400; intermediate density lipoprotein (IDL1), Sf 20-60; IDL2; Sf 12-20. Cholesterol concentrations in total plasma, VLDL, IDL2 and high density lipoprotein (HDL) were all identical in every group. A significant increase in cholesterol concentration was found in IDL1 of groups S and D. Low density lipoprotein-cholesterol of group I was also increased. These findings indicate an increased risk factor in normolipidemic diabetics.
A rapid flat gel isoelectric focusing method has been developed for the determination of apolipoprotein E phenotypes. Isoelectric focusing in 5% polyacrylamide flat gel with 8 mol/l urea and 2.8% pharmalyte (pH 4-6.5) was carried out at 3,000 V and 4 degrees C for 1 h under a constant power of 30 W. The separation of apolipoprotein E isoproteins was good and the isoelectric points were determined. Using this method, the apolipoprotein E phenotype frequency was examined in the Japanese population, and a higher frequency of phenotype E3/3 and a lower frequency of phenotype E3/2 were found in Japanese than those reported for the German, American or English population. In our focusing system the cut-off point of apolipoprotein E2/E3 ratio between the phenotype E3/3 and E3/2 was assumed to be approximately 0.9. These results indicate that this method may be useful for the determination of apolipoprotein E phenotypes.
An association of blood lipids with the development of atherothrombotic brain infarction under age 60 is demonstrated. This is based on 18 years' surveillance of 5,209 men and women, of whom 52 men and 59 women developed brain infarction. The relationship under age 60 was statistically significant only for men.
Triglyceride-rich pre-beta and cholesterol-rich beta lipoprotein were both related to the incidence of premature brain infarctions. Regardless of associated lipoprotein pattern, risk was proportional to serum cholesterol value, under age 60. On the other hand, pre-beta lipoprotein was unrelated to risk when associated cholesterol was taken into account.
At any lipid value risk of brain infarction varied greatly depending on the number and intensity of other contributors. Blood lipids are best considered as an ingredient of a stroke profile, and in the absence of other contributors to risk the influence of lipid is feeble.