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3WS17-1 Stroke risk factors: Recent evidence and new aspects
186 3WS16-2
3WS17
Wednesday October 1, 2003: Workshop Risk Factors of Stroke: Recent Evidence and New Aspects
Molecular genetics of experimental hypertension: An update
N. Samani. University of Leicester, Department of Cardiology, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom It is over a decade since the first quantitative trait locus (QTL) regulating blood pressure was mapped in a genetic model of hypertension. The location of several such QTLs are now known, as are the location of QTLs for related traits such as left ventricular mass, stroke susceptibility, kidney failure and metabolic syndrome. However, progress towards identification of the causal genes has been slow and illustrates the difficulties in positional cloning of quantitative traits. Nonetheless, through the narrowing of the QTL containing regions by the construction of increasingly refined congenic strains, the availability of the rat genome sequence and the use of tools such as gene expression profiling by microarrays, progress is being made. This paper will provide an update on the current state of play and discuss the relevance of identifying such QTLs in experimental models to the genetic basis of human essential hypertension. 3WS16-3
Recent advances in the genetics of human blood pressure
S. Harrap. Department of Physiology, University of Melbourne, Parkville, Vic., Australia The potential for discovery of underlying genetic explanations for common conditions such as hypertension is a major justification for the human genome project. Hopes have been raised for personalised molecular prognostic and therapeutic strategies. After the inconsistencies of candidate gene analyses, it was hoped that genome scans might provide some unified answers. However, the biggest and most recent genome searches, the US Family Blood Pressure Program and the UK BRIGHT studies have found scant evidence of genes that determine hypertension, let alone the DNA variants (alleles) within these genes. Previous genome searches have struggled for consensus. It is possible that the identities of genetic causes are mysterious because they are numerous, of small individual impact and distributed unevenly between populations, consistent with the so-called Common Disease/Rare Allele (CD/RA) paradigm. Current, and possibly future genetic strategies might fail to amass comprehensive and proven catalogues of blood pressure alleles, without which reliable genetic diagnosis is tenuous. However, it is likely that a variety of genes and alleles operate through common physiological mechanisms – a Common Disease/Common Mechanism (CD/CM) paradigm. Even the discovery of a single proven allele could lead to the definition of relevant and possibly novel physiological targets for blood pressure control. Accordingly, the future of genetics is more likely to be more effective in finding mechanisms than molecules and more useful for prevention and treatment than for diagnosis prevention and treatment than in diagnosis. 3WS16-4
Hypolipidemic drugs, blood pressure, heart rate variability and sympathetic activity
R. Ceska. IIIrd Department of Internal Medicine, University Hospital, Prague, Czech Republic Treatment of dyslipidaemia represents a reasonable approach in the prevention and treatment of cardiovascular diseases. Although it is generally accepted that the lipid lowering is responsible for the majority of the beneficial effects of the treatment, there are also a data demonstrating positive effects of lipid-lowering drugs beyond cholesterol lowering. These, pleiotropic effects of statins, but also fibrates and some new hypolipdemic agents (e.g. ezetimibe) are intensively studied. In addition to the influence on CRP and other markers of inflammation, parameters of coagulation as well as endothelial dysfunction markers, the effects of statins and fibrates on blood pressure, insulin resistency or on the sympathetic activity are investigated. We discuss the common pathways leading to dyslipidaemia and hypertension and the effects of diet and lipid-lowering drugs on correcting blood pressure. Both, statins and fibrates have demonstrated a capability to lower blood pressure significantly in some small-scale clinical trials. However, the data from large-scale intervention trials are either absent or ambiguous. Lipidlowering drugs influence arterial wall structure and hence pulse wave velocity. In the FAT (Fenofibrate vs Atorvastatin Trial) we proved positive effect of both drugs on heart rate variability. So far, an explanation of these positive effects of lipid lowering drugs beyond cholesterol drugs is not known. Just some hypothesis, e.g. the influencing of sympathetic activity or/and insulin resitency are available.
Anyway, lipid lowering may provide an additional method of correcting hypertension in some high-risk patients and it has also the other positive effects on cardiovascular risk. 3WS16-5
Renin-angiotensin systems and vasculature: Focusing on insulin’s action
M. Tuck. UCLA School of Medicine, Los Angeles, CA, USA Several recent clinical trials show that blocking of renin-angiotensin system (RAS) by angiotensin converting inhibitor (ACEI) or angiotensin II receptor antagonist (ARB) could reduce cardiovascular events independent of blood pressure reduction. Especially, RAS blockades are effective for patients with multiple coronary risks and metabolic syndrome based on insulin resistance as recommended in JNC VII. It is well known that activation of RAS in vascular wall is playing an important role in the progression of vascular hypertrophy and atherosclerosis. Thus, RAS blockades would be effective to protect or reduce vascular events. Our laboratory paid attention to the relationship between RAS and insulin’s action in the vasculature. We revealed that high level of insulin, i.e. hyperinsulinemia in vivo, could accelerate renin substrate and finally angiotensin II production and induce vascular smooth muscle cell (VSMC) growth. Vascular endothelial cells (EC) could protect against insulin induced VSMC growth, however, high level of insulin could induce ACE activation in EC. This activated ACE might promote the conversion of angiotensin I to II and cell growth under high insulin state. These mechanisms would be underlying in vascular protective effects of ACEI or ARB in patients with metabolic syndrome. 3WS16-6
Identification of angiotensin receptor antagonists with PPARγ modulating activity: Implications for treatment of the metabolic syndrome
T. Kurtz. University of California, San Francisco, Department of Laboratory Medicine, San Francisco, CA, USA The metabolic syndrome is a common clinical disorder characterized by the clustering of multiple risk factors for diabetes and cardiovascular disease including insulin resistance, dyslipidemia, and increased blood pressure. Given the major impact of this syndrome on cardiovascular disease morbidity and mortality, the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value. Although ACE inhibitors have been reported to improve insulin sensitivity and decrease the incidence of new onset diabetes, apparently via kinin/nitric oxide pathways, the results with ARBs have been equivocal. In clinical trials, the lower incidence of new diabetes in patients treated with an ARB versus patients treated with a beta blocker or diuretic appears to have been due to a prodiabetic effect of the comparator agents rather than an antidiabetic effect of AII receptor blockade. However, only a few ARBs have been tested for their ability to prevent diabetes in high risk patients. Moreover, given known structural differences among the various ARBs, it is possible that these agents may differ in their effects on metabolic risk factors despite similar effects on BP. We have found that two of the clinically available ARBs can activate the peroxisome proliferator activated receptor gamma (PPAR), a nuclear receptor that plays a key role in glucose and lipid metabolism and that represents an important target for antidiabetic drugs. These ARBs also promote adipogenesis and increase the expression of known PPAR target genes as predicted for agents that increase PPAR activity. These findings suggest a number of opportunities for developing improved therapeutic approaches to the metabolic syndrome as well as type 2 diabetes and other clinical disorders that may be influenced by activity of the renin angiotensin system, PPAR, or both.
3WS17 RISK FACTORS OF STROKE: RECENT EVIDENCE AND NEW ASPECTS 3WS17-1
Stroke risk factors: Recent evidence and new aspects
M. Cubrilo. University Dept., Internal Medicine OB Sveti Duh, Croatia Risk factors for stroke can be classified as modifiable (hypertension, hyperlipidemia, smoking, excessive alcohol consumption, diabetes, atrial fibrillation, hyperhomocystinemia, increased fibrinogen and C reactive protein) and non modifiable (age, gender, family history and ethnicity). Lifestyle treatable risk factors for stroke include: physical inactivity, obesity, poor diet/nutrition, stress, and drug abuse. Hypertension is the leading cause of both ischemic and
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
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
3WS17
Wednesday October 1, 2003: Workshop Risk Factors of Stroke: Recent Evidence and New Aspects
Molecular genetics of experimental hypertension: An update
N. Samani. University of Leicester, Department of Cardiology, Clinical Sciences Wing, Glenfield Hospital, Leicester, United Kingdom It is over a decade since the first quantitative trait locus (QTL) regulating blood pressure was mapped in a genetic model of hypertension. The location of several such QTLs are now known, as are the location of QTLs for related traits such as left ventricular mass, stroke susceptibility, kidney failure and metabolic syndrome. However, progress towards identification of the causal genes has been slow and illustrates the difficulties in positional cloning of quantitative traits. Nonetheless, through the narrowing of the QTL containing regions by the construction of increasingly refined congenic strains, the availability of the rat genome sequence and the use of tools such as gene expression profiling by microarrays, progress is being made. This paper will provide an update on the current state of play and discuss the relevance of identifying such QTLs in experimental models to the genetic basis of human essential hypertension. 3WS16-3
Recent advances in the genetics of human blood pressure
S. Harrap. Department of Physiology, University of Melbourne, Parkville, Vic., Australia The potential for discovery of underlying genetic explanations for common conditions such as hypertension is a major justification for the human genome project. Hopes have been raised for personalised molecular prognostic and therapeutic strategies. After the inconsistencies of candidate gene analyses, it was hoped that genome scans might provide some unified answers. However, the biggest and most recent genome searches, the US Family Blood Pressure Program and the UK BRIGHT studies have found scant evidence of genes that determine hypertension, let alone the DNA variants (alleles) within these genes. Previous genome searches have struggled for consensus. It is possible that the identities of genetic causes are mysterious because they are numerous, of small individual impact and distributed unevenly between populations, consistent with the so-called Common Disease/Rare Allele (CD/RA) paradigm. Current, and possibly future genetic strategies might fail to amass comprehensive and proven catalogues of blood pressure alleles, without which reliable genetic diagnosis is tenuous. However, it is likely that a variety of genes and alleles operate through common physiological mechanisms – a Common Disease/Common Mechanism (CD/CM) paradigm. Even the discovery of a single proven allele could lead to the definition of relevant and possibly novel physiological targets for blood pressure control. Accordingly, the future of genetics is more likely to be more effective in finding mechanisms than molecules and more useful for prevention and treatment than for diagnosis prevention and treatment than in diagnosis. 3WS16-4
Hypolipidemic drugs, blood pressure, heart rate variability and sympathetic activity
R. Ceska. IIIrd Department of Internal Medicine, University Hospital, Prague, Czech Republic Treatment of dyslipidaemia represents a reasonable approach in the prevention and treatment of cardiovascular diseases. Although it is generally accepted that the lipid lowering is responsible for the majority of the beneficial effects of the treatment, there are also a data demonstrating positive effects of lipid-lowering drugs beyond cholesterol lowering. These, pleiotropic effects of statins, but also fibrates and some new hypolipdemic agents (e.g. ezetimibe) are intensively studied. In addition to the influence on CRP and other markers of inflammation, parameters of coagulation as well as endothelial dysfunction markers, the effects of statins and fibrates on blood pressure, insulin resistency or on the sympathetic activity are investigated. We discuss the common pathways leading to dyslipidaemia and hypertension and the effects of diet and lipid-lowering drugs on correcting blood pressure. Both, statins and fibrates have demonstrated a capability to lower blood pressure significantly in some small-scale clinical trials. However, the data from large-scale intervention trials are either absent or ambiguous. Lipidlowering drugs influence arterial wall structure and hence pulse wave velocity. In the FAT (Fenofibrate vs Atorvastatin Trial) we proved positive effect of both drugs on heart rate variability. So far, an explanation of these positive effects of lipid lowering drugs beyond cholesterol drugs is not known. Just some hypothesis, e.g. the influencing of sympathetic activity or/and insulin resitency are available.
Anyway, lipid lowering may provide an additional method of correcting hypertension in some high-risk patients and it has also the other positive effects on cardiovascular risk. 3WS16-5
Renin-angiotensin systems and vasculature: Focusing on insulin’s action
M. Tuck. UCLA School of Medicine, Los Angeles, CA, USA Several recent clinical trials show that blocking of renin-angiotensin system (RAS) by angiotensin converting inhibitor (ACEI) or angiotensin II receptor antagonist (ARB) could reduce cardiovascular events independent of blood pressure reduction. Especially, RAS blockades are effective for patients with multiple coronary risks and metabolic syndrome based on insulin resistance as recommended in JNC VII. It is well known that activation of RAS in vascular wall is playing an important role in the progression of vascular hypertrophy and atherosclerosis. Thus, RAS blockades would be effective to protect or reduce vascular events. Our laboratory paid attention to the relationship between RAS and insulin’s action in the vasculature. We revealed that high level of insulin, i.e. hyperinsulinemia in vivo, could accelerate renin substrate and finally angiotensin II production and induce vascular smooth muscle cell (VSMC) growth. Vascular endothelial cells (EC) could protect against insulin induced VSMC growth, however, high level of insulin could induce ACE activation in EC. This activated ACE might promote the conversion of angiotensin I to II and cell growth under high insulin state. These mechanisms would be underlying in vascular protective effects of ACEI or ARB in patients with metabolic syndrome. 3WS16-6
Identification of angiotensin receptor antagonists with PPARγ modulating activity: Implications for treatment of the metabolic syndrome
T. Kurtz. University of California, San Francisco, Department of Laboratory Medicine, San Francisco, CA, USA The metabolic syndrome is a common clinical disorder characterized by the clustering of multiple risk factors for diabetes and cardiovascular disease including insulin resistance, dyslipidemia, and increased blood pressure. Given the major impact of this syndrome on cardiovascular disease morbidity and mortality, the availability of antihypertensive agents that also improve insulin resistance and dyslipidemia could be of considerable clinical value. Although ACE inhibitors have been reported to improve insulin sensitivity and decrease the incidence of new onset diabetes, apparently via kinin/nitric oxide pathways, the results with ARBs have been equivocal. In clinical trials, the lower incidence of new diabetes in patients treated with an ARB versus patients treated with a beta blocker or diuretic appears to have been due to a prodiabetic effect of the comparator agents rather than an antidiabetic effect of AII receptor blockade. However, only a few ARBs have been tested for their ability to prevent diabetes in high risk patients. Moreover, given known structural differences among the various ARBs, it is possible that these agents may differ in their effects on metabolic risk factors despite similar effects on BP. We have found that two of the clinically available ARBs can activate the peroxisome proliferator activated receptor gamma (PPAR), a nuclear receptor that plays a key role in glucose and lipid metabolism and that represents an important target for antidiabetic drugs. These ARBs also promote adipogenesis and increase the expression of known PPAR target genes as predicted for agents that increase PPAR activity. These findings suggest a number of opportunities for developing improved therapeutic approaches to the metabolic syndrome as well as type 2 diabetes and other clinical disorders that may be influenced by activity of the renin angiotensin system, PPAR, or both.
3WS17 RISK FACTORS OF STROKE: RECENT EVIDENCE AND NEW ASPECTS 3WS17-1
Stroke risk factors: Recent evidence and new aspects
M. Cubrilo. University Dept., Internal Medicine OB Sveti Duh, Croatia Risk factors for stroke can be classified as modifiable (hypertension, hyperlipidemia, smoking, excessive alcohol consumption, diabetes, atrial fibrillation, hyperhomocystinemia, increased fibrinogen and C reactive protein) and non modifiable (age, gender, family history and ethnicity). Lifestyle treatable risk factors for stroke include: physical inactivity, obesity, poor diet/nutrition, stress, and drug abuse. Hypertension is the leading cause of both ischemic and
XIIIth International Symposium on Atherosclerosis, September 28–October 2, 2003, Kyoto, Japan
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