Small Vessels, Big Problems
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《新英格兰医药杂志》
The impressive gains in stroke prevention and treatment seen over the past decade have not been evenly distributed across all types of stroke. Most advances have pertained to the approximately two thirds of symptomatic strokes that are caused by disease of the large arteries (those more than 0.1 mm in diameter) that run from the neck into the skull, the circle of Willis, and the surface of the brain. These large-vessel subtypes of stroke include atherosclerotic narrowing and occlusion of the large neck vessels, aneurysmal rupture and subarachnoid hemorrhage over the brain surface, and thromboembolic occlusion of the major vessel branches (see diagram). The treatment of large-vessel strokes has been facilitated by the ability to identify individual blood-vessel segments that are at risk for occlusion or rupture and to reach them by surgical or endovascular routes or, alternatively, to initiate pharmacologic treatments that can prevent or lyse thromboemboli. The correction of a symptomatic critical stenosis of the internal carotid artery or an expanding aneurysm of the circle of Willis is indeed an important clinical accomplishment, one that dramatically reduces the likelihood of a devastating stroke.
Large-Vessel and Small-Vessel Brain Disease.
The sites of the most common forms of cerebrovascular disease are shown in Panel A. Arteriolosclerosis typically affects small vessels that penetrate the white matter and the deep gray nuclei, whereas cerebral amyloid angiopathy preferentially involves the small arteries and arterioles of the cerebral cortex and gray–white-matter junction. Axial MRI with the use of gradient-echo technique (Panel B) and fluid-attenuated inversion recovery (Panel C) highlight two prominent radiographic features of small-vessel brain disease: hemorrhages (Panel B, dark lesions ) and changes in white matter (Panel C, bright lesions). The images are of a 71-year-old man with probable cerebral amyloid angiopathy.
Unfortunately, clinicians have much less to offer for the prevention of the remaining third of symptomatic strokes, which are caused primarily by disease of the small arteries and arterioles that penetrate the brain cortex and reach the underlying structures of the white and deep gray matter. Small-vessel diseases include arteriolosclerosis (thickening of and damage to the arteriole wall, also referred to as fibrohyalinosis or lipohyalinosis) and cerebral amyloid angiopathy (injury to the vascular wall caused by deposition of the -amyloid peptide). These small-vessel diseases can lead to vessel occlusion with small (lacunar) brain infarction or to vessel rupture with intracerebral hemorrhage.
There is nothing small about the consequences of small-vessel disease. Intracerebral hemorrhage, in particular, represents perhaps the most catastrophic form of stroke. Beyond its role in clinically overt strokes, small-vessel disease is also the predominant underlying cause of silent strokes — brain infarctions that are not in themselves symptomatic but that cumulatively represent a major contributor to cognitive impairment in elderly persons. The Rotterdam Scan Study, for example, found that the rate of dementia was more than doubled in the 20 percent of healthy older subjects (60 to 90 years of age) who had evidence on magnetic resonance imaging (MRI) of silent, mostly lacunar brain infarction.1 Small-vessel diseases also underlie the diffuse changes in white matter revealed by MRI (see diagram) — another emerging and important risk factor for age-related cognitive impairment.
What can be done to treat small-vessel brain disease? The prevention of changes in small, diffuse, inaccessible cerebral vessels is unlikely to be accomplished by the types of surgical or endovascular approaches that have proved effective for large-vessel disease. Instead, treatment will probably require medical therapies that protect the cerebral microvasculature from injury. The control of systemic risk factors for small-vessel disease, such as hypertension and diabetes mellitus, will almost certainly be part of a successful vasculoprotective strategy,2 but these conditions do not account for much small-vessel injury (and indeed appear unrelated to the pathogenesis of cerebral amyloid angiopathy). Recent studies of animal models have identified common molecular components of small-vessel physiology that may also mediate microvascular dysfunction or injury — including angiotensin II, nitric oxide, and reactive oxygen species.3 Each component represents a potential target for vasculoprotective therapy.
The studies by Gould et al. reported in Science4 and in this issue of the Journal (pages 1489–1496) identify a new molecular candidate for involvement in small-vessel brain disease: type IV collagen. Type IV collagen 1 and 2 chains, assembled as a heterotrimer, are a major component of the vascular basement membrane in the brain and elsewhere. Using random mutagenesis in mice, Gould and colleagues found that the deletion of an exon in the gene encoding type IV collagen 1 (Col4a1) prevented the normal assembly and secretion of vascular type IV collagen, resulting in a host of microvascular abnormalities. Among the prominent findings in the mice were increased fragility of brain microvessels in response to stressors such as birth trauma and hypertension, tortuosity of the retinal vessels, and albuminuria. Completing the connections from molecule to mouse to clinical disease, the authors made the striking observation that mutations in the human COL4A1 gene that affect the assembly of type IV collagen also appear to be responsible for some familial forms of intracerebral hemorrhage, white-matter lesions, and retinal-vessel tortuosity.
These studies do not provide evidence that nonfamilial small-vessel disease is caused by abnormalities of type IV collagen or the vascular basement membrane, but this intriguing hypothesis seems worthy of testing. The basement membrane is not only a mechanical support for the vessel wall, but also a rich and complex source of adhesion, vasculotrophic, and signaling factors. It is therefore plausible that even subtle variations in the composition of the vascular basement membrane could affect the long-term risk of microvascular injury. It is notable in this regard that MRI scans of the brains of persons with the COL4A1 mutation described by Gould et al. revealed extensive white-matter lesions, as well as hemorrhages, suggesting that alterations in the basement membrane can cause small vessels in the brain to function abnormally as well as to rupture.
Like many neurologic conditions, small-vessel brain disease is a common and potentially devastating disorder crying out for improved treatment. The good news is that our growing understanding of the molecular components underlying microvascular function and injury, together with the development of sensitive MRI techniques for detecting the effects of damage to small vessels in the brain, form a strong foundation for rational, biologically based clinical trials. There is thus hope that the upcoming decade will see big advances toward big solutions for small-vessel disease.
Source Information
Dr. Greenberg is the codirector of the Neurology Clinical Trials Unit, Massachusetts General Hospital, and associate professor of neurology at Harvard Medical School — both in Boston.
References
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MMB. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215-22.
Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 2005;112:1644-1650.
Iadecola C, Gorelick PB. Hypertension, angiotensin, and stroke: beyond blood pressure. Stroke 2004;35:348-350.
Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 2005;308:1167-1171.(Steven M. Greenberg, M.D.)
Large-Vessel and Small-Vessel Brain Disease.
The sites of the most common forms of cerebrovascular disease are shown in Panel A. Arteriolosclerosis typically affects small vessels that penetrate the white matter and the deep gray nuclei, whereas cerebral amyloid angiopathy preferentially involves the small arteries and arterioles of the cerebral cortex and gray–white-matter junction. Axial MRI with the use of gradient-echo technique (Panel B) and fluid-attenuated inversion recovery (Panel C) highlight two prominent radiographic features of small-vessel brain disease: hemorrhages (Panel B, dark lesions ) and changes in white matter (Panel C, bright lesions). The images are of a 71-year-old man with probable cerebral amyloid angiopathy.
Unfortunately, clinicians have much less to offer for the prevention of the remaining third of symptomatic strokes, which are caused primarily by disease of the small arteries and arterioles that penetrate the brain cortex and reach the underlying structures of the white and deep gray matter. Small-vessel diseases include arteriolosclerosis (thickening of and damage to the arteriole wall, also referred to as fibrohyalinosis or lipohyalinosis) and cerebral amyloid angiopathy (injury to the vascular wall caused by deposition of the -amyloid peptide). These small-vessel diseases can lead to vessel occlusion with small (lacunar) brain infarction or to vessel rupture with intracerebral hemorrhage.
There is nothing small about the consequences of small-vessel disease. Intracerebral hemorrhage, in particular, represents perhaps the most catastrophic form of stroke. Beyond its role in clinically overt strokes, small-vessel disease is also the predominant underlying cause of silent strokes — brain infarctions that are not in themselves symptomatic but that cumulatively represent a major contributor to cognitive impairment in elderly persons. The Rotterdam Scan Study, for example, found that the rate of dementia was more than doubled in the 20 percent of healthy older subjects (60 to 90 years of age) who had evidence on magnetic resonance imaging (MRI) of silent, mostly lacunar brain infarction.1 Small-vessel diseases also underlie the diffuse changes in white matter revealed by MRI (see diagram) — another emerging and important risk factor for age-related cognitive impairment.
What can be done to treat small-vessel brain disease? The prevention of changes in small, diffuse, inaccessible cerebral vessels is unlikely to be accomplished by the types of surgical or endovascular approaches that have proved effective for large-vessel disease. Instead, treatment will probably require medical therapies that protect the cerebral microvasculature from injury. The control of systemic risk factors for small-vessel disease, such as hypertension and diabetes mellitus, will almost certainly be part of a successful vasculoprotective strategy,2 but these conditions do not account for much small-vessel injury (and indeed appear unrelated to the pathogenesis of cerebral amyloid angiopathy). Recent studies of animal models have identified common molecular components of small-vessel physiology that may also mediate microvascular dysfunction or injury — including angiotensin II, nitric oxide, and reactive oxygen species.3 Each component represents a potential target for vasculoprotective therapy.
The studies by Gould et al. reported in Science4 and in this issue of the Journal (pages 1489–1496) identify a new molecular candidate for involvement in small-vessel brain disease: type IV collagen. Type IV collagen 1 and 2 chains, assembled as a heterotrimer, are a major component of the vascular basement membrane in the brain and elsewhere. Using random mutagenesis in mice, Gould and colleagues found that the deletion of an exon in the gene encoding type IV collagen 1 (Col4a1) prevented the normal assembly and secretion of vascular type IV collagen, resulting in a host of microvascular abnormalities. Among the prominent findings in the mice were increased fragility of brain microvessels in response to stressors such as birth trauma and hypertension, tortuosity of the retinal vessels, and albuminuria. Completing the connections from molecule to mouse to clinical disease, the authors made the striking observation that mutations in the human COL4A1 gene that affect the assembly of type IV collagen also appear to be responsible for some familial forms of intracerebral hemorrhage, white-matter lesions, and retinal-vessel tortuosity.
These studies do not provide evidence that nonfamilial small-vessel disease is caused by abnormalities of type IV collagen or the vascular basement membrane, but this intriguing hypothesis seems worthy of testing. The basement membrane is not only a mechanical support for the vessel wall, but also a rich and complex source of adhesion, vasculotrophic, and signaling factors. It is therefore plausible that even subtle variations in the composition of the vascular basement membrane could affect the long-term risk of microvascular injury. It is notable in this regard that MRI scans of the brains of persons with the COL4A1 mutation described by Gould et al. revealed extensive white-matter lesions, as well as hemorrhages, suggesting that alterations in the basement membrane can cause small vessels in the brain to function abnormally as well as to rupture.
Like many neurologic conditions, small-vessel brain disease is a common and potentially devastating disorder crying out for improved treatment. The good news is that our growing understanding of the molecular components underlying microvascular function and injury, together with the development of sensitive MRI techniques for detecting the effects of damage to small vessels in the brain, form a strong foundation for rational, biologically based clinical trials. There is thus hope that the upcoming decade will see big advances toward big solutions for small-vessel disease.
Source Information
Dr. Greenberg is the codirector of the Neurology Clinical Trials Unit, Massachusetts General Hospital, and associate professor of neurology at Harvard Medical School — both in Boston.
References
Vermeer SE, Prins ND, den Heijer T, Hofman A, Koudstaal PJ, Breteler MMB. Silent brain infarcts and the risk of dementia and cognitive decline. N Engl J Med 2003;348:1215-22.
Dufouil C, Chalmers J, Coskun O, et al. Effects of blood pressure lowering on cerebral white matter hyperintensities in patients with stroke: the PROGRESS (Perindopril Protection Against Recurrent Stroke Study) Magnetic Resonance Imaging Substudy. Circulation 2005;112:1644-1650.
Iadecola C, Gorelick PB. Hypertension, angiotensin, and stroke: beyond blood pressure. Stroke 2004;35:348-350.
Gould DB, Phalan FC, Breedveld GJ, et al. Mutations in Col4a1 cause perinatal cerebral hemorrhage and porencephaly. Science 2005;308:1167-1171.(Steven M. Greenberg, M.D.)