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3WS17-5 Remnant lipoprotein and lipoprotein(a) as risk factors of stroke and carotid disease
3WS17
Wednesday October 1, 2003: Workshop Risk Factors of Stroke: Recent Evidence and New Aspects
hemorrhagic strokes. Hypertension is present in approximately 70% of stroke cases. Cigarette smoking doubles the risk of stroke. High plasma cholesterol is associated with the risk of developing ischemic stroke, but only in the individuals under 45 years of age, while there is no association in older groups. Heavy alcohol consumption is clearly associated with an increased risk in stroke but this association is less clear for moderate and light doses. Diabetes is a prominent risk factor for ischemic but not hemorrhagic stroke. It is not clear whether “tight” control of glucose reduces stroke. Detection and improvement on diagnostic procedures of major risk factors for stroke play an important role as well as the improved medical care of individuals at risk. 3WS17-2
Stroke: Blood pressure and blood pressure-lowering therapy
A. Tonkin. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia There is a continuous, log-linear relationship between blood pressure (BP) and risk of both first and recurrent stroke. Cardiovascular disease (CVD) risk approximately doubles with each increment of 20/10 mmHg, above a level of 115/75 mmHg. However, most strokes occur in those with “average” or only mildly elevated levels. In the older trials, testing mainly beta-blockers and diuretics, lowering BP by about 10-12/5-6 mmHg reduced stroke risk by about one third, within a few years. From more recent overview of all trials, also including ACE inhibitors and calcium antagonists, the more BP is lowered, probably the greater the stroke reduction. Particularly, recent trials show that BP lowering protects against both initial and recurrent stroke whether or not BP is “elevated”. Which drug(s)? In ALLHAT, a thiazide was more effective than a calcium channel blocker or ACE inhibitor. In ANBP 2, an ACE inhibitor was superior to a diuretic. However, the cohorts differed; ALLHAT younger, more racially diverse and with more comorbidities. At this time, thiazide diuretics are usually recommended for most as initial treatment. For practical purposes, comorbidities often influence the drug choice of agent and most (63% in ALLHAT) require two or more drugs and in addition, lifestyle modification. Blood pressure is elevated in about 70% of patients with acute stroke. In most, this settles spontaneously. Further data is needed to elucidate the role of BP lowering immediately and in the first two weeks after stroke. Despite the robust evidence base, only about one quarter to a third of hypertensives have adequate BP control. Future research must concentrate on how best to translate the evidence to usual practice. 3WS17-3
Statins in stroke prevention: After ALLHAT and PROSPER, disappointment or reasons to hope?
P. Amarenco. Bichat Hospital, Department of Neurology and Stroke Center, Paris, France
Carotid atherosclerosis and stroke risk
P. Rothwell. University of Oxford, Department of Clinical Neurology, Radcliffe Infirmary, Oxford, United Kingdom Increased carotid artery stiffness, intima-media thickness and early plaque formation are predictors of ischaemic stroke and coronary heart disease in the general population. Early carotid arterial wall disease is also a useful predictor of coronary artery disease on angiography and coronary vascular events. Measures of more advanced disease, such as carotid stenosis and plaque surface irregularity or ulceration on angiography, are predictive of both ischaemic stroke and coronary heart disease in patients with established cerebrovascular disease. In patients with recent TIA or ischaemic stroke in general, the risk of major stroke is highest in the first few days and weeks after the event. This early risk is greatest in patients with carotid stenosis, and is 10-20% in the week after the presenting event. It is essential that preventive treatment is initiated immediately. For example, the benefit derived from carotid endarterectomy is greatest when it is performed within two weeks of the presenting event and falls rapidly thereafter. The decline in benefit with time is particularly prominent in women. The risk of stroke is lower, at about 2% per year, in patients with asymptomatic carotid stenosis. However, the risk is increased in men, in patients with ulcerated plaque and in patients with asymptomatic infarction on brain imaging. The predominant mechanism of ischaemic stroke in patients with carotid stenosis is thomboembolism but there is good evidence that haemodynamic compromise is also important. For example, in patients with severe carotid stenosis, endarterectomy reduces the risk of lacunar stroke as well as cortical stroke, embolic cerebral infarction is most frequent in the arterial border zones, and low blood pressure is associated with a major increase in stroke risk in patients with bilateral carotid stenosis or occlusion. 3WS17-5
Remnant lipoprotein and lipoprotein(a) as risk factors of stroke and carotid disease
S. Uchiyama, M. Iwata. Department of Neurology, Tokyo Women’s Medical University, Tokyo, Japan Remnant lipoprotein (RLP) and lipoprotein (LP)(a) are known to promote atherosclerosis and thrombosis. Molecular structure of Lp(a) is similar to that of plasminogen, which may produce antifibrinolytic and vascular smooth muscle proliferation effects. Many retrospecitve studies have reported increased Lp(a) in patients with ischemic stroke or carotid disease, although it has not yet been proven by any large prospective study that Lp(a) can be a risk factor of stroke. RLP is known to have a potent atherogenetic action, and a quantitative assay as a total of chylomicron remnant and VLDL remnant has recently been developed in Japan. We studied whether these lipoproteins can be risk factors of stroke and carotid disease in 170 consecutive outpatients except those with atrial fibrillation or thrombophilia. RLP was significantly higher in patients with (N=45) than without (N=125) cerebral infarction with stroke episodes (Mann-Whitney’s U test, p = 0.01), while there was no differece in Lp(a) between patients with and without symptomatic cerebral infarction (p = 0.83). In contrast, there was a significant difference in Lp(a) (p = 0.003) but not in RLP (p = 0.26) between patients with (N = 76) and without (N = 94) maximum intima-media thickness (IMT) =/>2.0 mm in carotid bifurcations. Multiple logistic regression analysis showed that RLP is an independent risk factor of symptomatic cerebral infarction [=/>7.5 mg/dl, relative risk (RR) 2.84, 95% confidence interval (CI) 1.26-6.40]. Multivariate regression analysis showed that Lp(a) (p = 0.032) but not RLP (p = 0.518) is significantly correlated with IMT. The results indicate that RLP but not Lp(a) is an independent risk factor of symptomatic cerebral infarction, while Lp(a) but not RLP is an independent risk factor of carotid disease in our series of Japanese patients. 3WS17-6
Genetic risk factors for stroke: Insights into patho-physiology from candidate gene approaches
S.E. Humphries. University College London, United Kingdom Ischaemic and hemorragic stroke are believed to result from both shared and different determinants, and thus the genetic variants that influence these clinical endpoints are likely to differ. Studies involving twins, siblings and families have detected significant evidence for heritability, indicating that genetic determinants are important, but to date their identification is unclear. The specific mutations in several monogenic causes of stroke have been identified, and these give useful insight into pathophysiological processes but these mutations are rare and thus do not contribute significantly to risk
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
WEDNESDAY
Four randomized trials with a statin and one with a fibrate showed modest absolute reduction in stroke incidence in patients with previous myocardial infarction (MI). Reasons for statins’ effect on stroke endpoint are unclear the link between serum cholesterol level (SCL) and stroke has never been fully established. Furthermore, the positive results for statins were mainly in patients with average/low SCL. This suggests nonhypolipidemic effects of these drugs (pleiotropic effects) acting on the biologic promoters of plaque instability. Statins have a good overall safety profile with no increase of hemorrhagic stroke or cancer. They have positive effects in primary prevention of cardiovascular disease in high-risk young and elderly populations. Statins reduced stroke incidence in high-risk (mainly CHD, diabetics and hypertensives) populations with normal baseline blood cholesterol level, which argues for a global cardiovascular risk-based treatment strategy. In patients with prior stroke, statins reduce coronary event incidence (the HPS trial), but it is not proven that statins reduce recurrent stroke incidence in secondary prevention. Based on the evidence from the 4 statin trials, there are no longer discussions that clinicians should consider a statin for all stroke patients with history of MI, even when SCL is in the “normal” range. In patients with ischemic stroke with no history of coronary event, no clear recommendation can be made. SPARCL is an on-going, unique, randomized, placebo-controlled trial to answer this question with aggressive cholesterol lowering with atorvastatin 80 mg/d in patients with stroke and no history of cerebrovascular disease. If current hypotheses are true, we may avoid an extra 20-30 stroke events/1000 patients/2 y with a lipid-lowering agent, adding to the 28 prevented with an antiplatelet agent over 2 y. This would be a significant advance in stroke/vascular dementia prevention.
3WS17-4
187
Wednesday October 1, 2003: Workshop Risk Factors of Stroke: Recent Evidence and New Aspects
hemorrhagic strokes. Hypertension is present in approximately 70% of stroke cases. Cigarette smoking doubles the risk of stroke. High plasma cholesterol is associated with the risk of developing ischemic stroke, but only in the individuals under 45 years of age, while there is no association in older groups. Heavy alcohol consumption is clearly associated with an increased risk in stroke but this association is less clear for moderate and light doses. Diabetes is a prominent risk factor for ischemic but not hemorrhagic stroke. It is not clear whether “tight” control of glucose reduces stroke. Detection and improvement on diagnostic procedures of major risk factors for stroke play an important role as well as the improved medical care of individuals at risk. 3WS17-2
Stroke: Blood pressure and blood pressure-lowering therapy
A. Tonkin. Department of Epidemiology and Preventive Medicine, Monash University, Melbourne, Vic., Australia There is a continuous, log-linear relationship between blood pressure (BP) and risk of both first and recurrent stroke. Cardiovascular disease (CVD) risk approximately doubles with each increment of 20/10 mmHg, above a level of 115/75 mmHg. However, most strokes occur in those with “average” or only mildly elevated levels. In the older trials, testing mainly beta-blockers and diuretics, lowering BP by about 10-12/5-6 mmHg reduced stroke risk by about one third, within a few years. From more recent overview of all trials, also including ACE inhibitors and calcium antagonists, the more BP is lowered, probably the greater the stroke reduction. Particularly, recent trials show that BP lowering protects against both initial and recurrent stroke whether or not BP is “elevated”. Which drug(s)? In ALLHAT, a thiazide was more effective than a calcium channel blocker or ACE inhibitor. In ANBP 2, an ACE inhibitor was superior to a diuretic. However, the cohorts differed; ALLHAT younger, more racially diverse and with more comorbidities. At this time, thiazide diuretics are usually recommended for most as initial treatment. For practical purposes, comorbidities often influence the drug choice of agent and most (63% in ALLHAT) require two or more drugs and in addition, lifestyle modification. Blood pressure is elevated in about 70% of patients with acute stroke. In most, this settles spontaneously. Further data is needed to elucidate the role of BP lowering immediately and in the first two weeks after stroke. Despite the robust evidence base, only about one quarter to a third of hypertensives have adequate BP control. Future research must concentrate on how best to translate the evidence to usual practice. 3WS17-3
Statins in stroke prevention: After ALLHAT and PROSPER, disappointment or reasons to hope?
P. Amarenco. Bichat Hospital, Department of Neurology and Stroke Center, Paris, France
Carotid atherosclerosis and stroke risk
P. Rothwell. University of Oxford, Department of Clinical Neurology, Radcliffe Infirmary, Oxford, United Kingdom Increased carotid artery stiffness, intima-media thickness and early plaque formation are predictors of ischaemic stroke and coronary heart disease in the general population. Early carotid arterial wall disease is also a useful predictor of coronary artery disease on angiography and coronary vascular events. Measures of more advanced disease, such as carotid stenosis and plaque surface irregularity or ulceration on angiography, are predictive of both ischaemic stroke and coronary heart disease in patients with established cerebrovascular disease. In patients with recent TIA or ischaemic stroke in general, the risk of major stroke is highest in the first few days and weeks after the event. This early risk is greatest in patients with carotid stenosis, and is 10-20% in the week after the presenting event. It is essential that preventive treatment is initiated immediately. For example, the benefit derived from carotid endarterectomy is greatest when it is performed within two weeks of the presenting event and falls rapidly thereafter. The decline in benefit with time is particularly prominent in women. The risk of stroke is lower, at about 2% per year, in patients with asymptomatic carotid stenosis. However, the risk is increased in men, in patients with ulcerated plaque and in patients with asymptomatic infarction on brain imaging. The predominant mechanism of ischaemic stroke in patients with carotid stenosis is thomboembolism but there is good evidence that haemodynamic compromise is also important. For example, in patients with severe carotid stenosis, endarterectomy reduces the risk of lacunar stroke as well as cortical stroke, embolic cerebral infarction is most frequent in the arterial border zones, and low blood pressure is associated with a major increase in stroke risk in patients with bilateral carotid stenosis or occlusion. 3WS17-5
Remnant lipoprotein and lipoprotein(a) as risk factors of stroke and carotid disease
S. Uchiyama, M. Iwata. Department of Neurology, Tokyo Women’s Medical University, Tokyo, Japan Remnant lipoprotein (RLP) and lipoprotein (LP)(a) are known to promote atherosclerosis and thrombosis. Molecular structure of Lp(a) is similar to that of plasminogen, which may produce antifibrinolytic and vascular smooth muscle proliferation effects. Many retrospecitve studies have reported increased Lp(a) in patients with ischemic stroke or carotid disease, although it has not yet been proven by any large prospective study that Lp(a) can be a risk factor of stroke. RLP is known to have a potent atherogenetic action, and a quantitative assay as a total of chylomicron remnant and VLDL remnant has recently been developed in Japan. We studied whether these lipoproteins can be risk factors of stroke and carotid disease in 170 consecutive outpatients except those with atrial fibrillation or thrombophilia. RLP was significantly higher in patients with (N=45) than without (N=125) cerebral infarction with stroke episodes (Mann-Whitney’s U test, p = 0.01), while there was no differece in Lp(a) between patients with and without symptomatic cerebral infarction (p = 0.83). In contrast, there was a significant difference in Lp(a) (p = 0.003) but not in RLP (p = 0.26) between patients with (N = 76) and without (N = 94) maximum intima-media thickness (IMT) =/>2.0 mm in carotid bifurcations. Multiple logistic regression analysis showed that RLP is an independent risk factor of symptomatic cerebral infarction [=/>7.5 mg/dl, relative risk (RR) 2.84, 95% confidence interval (CI) 1.26-6.40]. Multivariate regression analysis showed that Lp(a) (p = 0.032) but not RLP (p = 0.518) is significantly correlated with IMT. The results indicate that RLP but not Lp(a) is an independent risk factor of symptomatic cerebral infarction, while Lp(a) but not RLP is an independent risk factor of carotid disease in our series of Japanese patients. 3WS17-6
Genetic risk factors for stroke: Insights into patho-physiology from candidate gene approaches
S.E. Humphries. University College London, United Kingdom Ischaemic and hemorragic stroke are believed to result from both shared and different determinants, and thus the genetic variants that influence these clinical endpoints are likely to differ. Studies involving twins, siblings and families have detected significant evidence for heritability, indicating that genetic determinants are important, but to date their identification is unclear. The specific mutations in several monogenic causes of stroke have been identified, and these give useful insight into pathophysiological processes but these mutations are rare and thus do not contribute significantly to risk
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
WEDNESDAY
Four randomized trials with a statin and one with a fibrate showed modest absolute reduction in stroke incidence in patients with previous myocardial infarction (MI). Reasons for statins’ effect on stroke endpoint are unclear the link between serum cholesterol level (SCL) and stroke has never been fully established. Furthermore, the positive results for statins were mainly in patients with average/low SCL. This suggests nonhypolipidemic effects of these drugs (pleiotropic effects) acting on the biologic promoters of plaque instability. Statins have a good overall safety profile with no increase of hemorrhagic stroke or cancer. They have positive effects in primary prevention of cardiovascular disease in high-risk young and elderly populations. Statins reduced stroke incidence in high-risk (mainly CHD, diabetics and hypertensives) populations with normal baseline blood cholesterol level, which argues for a global cardiovascular risk-based treatment strategy. In patients with prior stroke, statins reduce coronary event incidence (the HPS trial), but it is not proven that statins reduce recurrent stroke incidence in secondary prevention. Based on the evidence from the 4 statin trials, there are no longer discussions that clinicians should consider a statin for all stroke patients with history of MI, even when SCL is in the “normal” range. In patients with ischemic stroke with no history of coronary event, no clear recommendation can be made. SPARCL is an on-going, unique, randomized, placebo-controlled trial to answer this question with aggressive cholesterol lowering with atorvastatin 80 mg/d in patients with stroke and no history of cerebrovascular disease. If current hypotheses are true, we may avoid an extra 20-30 stroke events/1000 patients/2 y with a lipid-lowering agent, adding to the 28 prevented with an antiplatelet agent over 2 y. This would be a significant advance in stroke/vascular dementia prevention.
3WS17-4
187