Published online before print April 8, 2004, doi: 10.1161/01.STR.0000126476.10473.47
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(Stroke. 2004;35:1061.)
© 2004 American Heart Association, Inc.
Original Contributions |
Editorial Comment—Not All Hypertensive Subjects Have Similar Risks for White Matter Lesions: Influence of Genetic Factors
Stroke and Memory Departments, Hôpital Roger Salengro, Lille, France
White matter lesions (WML) are frequently found on magnetic resonance imaging (MRI) scans in stroke patients, in patients with cognitive decline or dementia, and in healthy—usually elderly—subjects who have vascular risk factors, especially arterial hypertension.1 However, many neurologists in their clinical practice have seen elderly subjects with a long history of improperly treated arterial hypertension who have only few WML. They have met also middle-aged subjects, with less severe, more recent, and properly treated arterial hypertension with already extensive WML. These clinical findings suggest that not all hypertensive subjects have similar risks of WML.
Genetic factors may explain differences in the susceptibility of the cerebral white matter to arterial hypertension: (1) cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is clearly identified as a genetic disease due to a mutation in the Notch 3 gene, in which severe WML occur at an early stage of the disease in young subjects, even in the absence of vascular risk factors;2 (2) other genetic disorders may also lead to severe WML in the absence of vascular factors, eg, CARASIL (the R indicating recessive) and other nonNotch type angiopathies,3 familial amyloid angiopathies,4 hereditary endotheliopathy with retinopathy nephropathy and stroke,5 and cerebroretinal angiopathies;6 and (3) a greater correlation between the volumes of WML is observed between monozygotic twins than between dizygotic twins.7
Among the various genes that potentially predispose to WML in the presence of arterial hypertension, the apolipoprotein E (APOE) gene is one of the best candidates: (1) the APOE which is encoded by the APOE gene plays a crucial role in lipid metabolism and neuronal repair after injury of any type; (2) the 
4 allele of the APOE gene is associated with the presence of vascular risk factors,8 vascular events, and cognitive impairment;9 (3) the 4 allele of the APOE gene modulates the severity of Aß amyloid deposits in animal models10 and in humans,11 especially in patients with white matter changes;12 and (4) 4 homozygotes exhibit more extensive WML than other genotypes.13
In the current issue of Stroke, De Leeuw and coworkers present their investigation of the interactions between the APOE genotype and blood pressure levels in the pathogenesis of subcortical and periventricular WML in 971 subjects participating in the Rotterdam community-based study. They found that APOE 4 carriers have significantly more subcortical WML than APOE 33 carriers, irrespective of their level of blood pressure. Subjects with arterial hypertension and at least one APOE 4 allele had the highest amount of WML, but the interaction was significant only for subcortical WML. They conclude that the coexistence of an 4 allele and arterial hypertension is strongly associated with the presence of subcortical WML, while neither hypertension alone nor the presence of an 4 allele alone are. This interaction may reflect a decreased capacity for neuronal repair in the presence of 1 or 2 4 alleles.
The results of this study support the hypothesis that the effect of arterial hypertension on the cerebral white matter is enhanced in 4 carriers. It may be a clue for explaining why middle-aged subjects with arterial hypertension are more likely to develop Alzheimer’s disease 15 years later:14 those hypertensive middle-aged subjects with 4 allele might develop more extensive WML, independently from the development of Alzheimer lesions, leading to an anticipation of the clinical onset of dementia because of the summation of Alzheimer lesions and WML.15
This study opens a door for a selective prevention in high-risk subjects: lowering blood pressure might be more beneficial in 4 carriers, and an effective prevention of the development of WML might be beneficial in terms of prevention of cognitive decline, dementia, and stroke. These data are of major importance for understanding the interaction between arterial hypertension and WML, but they cannot influence our practice as a result yet without raising ethical questions. With the presence of at least one 4 allele being associated with a higher risk of Alzheimer’s disease, is it reasonable to look for this marker of increased risk in the presence of arterial hypertension unless an effective pathogenic treatment of the disease is available? For the moment, the best we can do is to treat all treatable vascular risk factors, to decrease the risks of vascular events, including stroke, and of cognitive impairment, including Alzheimer’s disease associated with vascular lesions. The result provided by the Rotterdam study, however, leads to exciting perspectives for a more selective prevention in those patients who are the most likely to have cerebral consequences of arterial hypertension. Other genetic predisposing factors that can make hypertensive subjects prone to develop WML should also be studied and will raise less ethical issues: the D allele of the angiotensin-converting enzyme gene may be one of them because of its association with lacunar stroke, a subtype of ischemic stroke sharing the same underlying small-vessel disease than WML.16
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