Placebo-Controlled Trial of High-Dose Atorvastatin in Patients With Severe Cerebral Small Vessel Disease

Lavallée, Philippa C.; Labreuche, Julien; Góngora‐Rivera, Fernando; Jaramillo, Arturo; Brenner, David A.; Klein, Isabelle; Touboul, Pierre‐Jean; Vicaut, Éric; Amarenco, Pierre

doi:10.1161/strokeaha.108.540088

Cited by 36 publications

(34 citation statements)

References 47 publications

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“…Accordingly, the so-called pleiotropic effects of statins in improving endothelial function in stroke patients are discussed to contribute to the proven effect of these drugs in reducing the risk of stroke [43]. Results are inconclusive, however, as no positive direct effect of high-dose statin treatment on endothelium function was observed in a controlled trial in patients with severe cerebral small-vessel disease [44]. In an animal model, systemic administration of endothelial progenitor cells improved long-term outcome after stroke [45].…”

Section: Discussionmentioning

confidence: 99%

Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

Scherbakov¹,

Sandek

Martens‐Lobenhoffer

et al. 2011

Cerebrovasc Dis

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Background: Endothelial dysfunction (ED) is relevant for the development of cerebrovascular and cardiovascular diseases. Asymmetric dimethylarginine (ADMA) competes with L-arginine and has been implicated in the development of ED. Increased levels of ADMA have been found in chronic heart failure (CHF). We hypothesized that peripheral ED in acute ischemic stroke is associated with increased ADMA levels. Methods: We evaluated 60 patients with acute stroke in the territory of the middle cerebral artery. Stroke patients were classified according to the Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification. We compared these patients with patients of similar age without known cardiovascular disease (negative controls, n = 23) and patients with stable, ambulatorily treated CHF (n = 46, left ventricular ejection fraction = 33.8 ± 10.9) with known ED (positive controls). Peripheral endothelial function was assessed by EndoPAT2000 technology using the reactive hyperemia index (RHI). Results: RHI was significantly decreased in stroke and in CHF compared to controls (1.8 ± 0.3 vs. 1.8 ± 0.4 vs. 2.2 ± 0.4, respectively, ANOVA p = 0.01). A decreased RHI was observed in cardioembolic and lacunar infarcts and stroke of undetermined etiology (1.7 ± 0.4, 1.8 ± 0.5 and 1.7 ± 0.3, p < 0.0001). The L-arginine/ADMA ratio was significantly decreased in stroke and in CHF (147.6 ± 31.7 and 126.1 ± 37.9 vs. controls: 161.5 ± 26.1, p < 0.0001) and was lowest in stroke patients in the cardioembolic group (133.0 ± 29.4, p < 0.0001). A lower L-arginine/ADMA ratio was associated with ED in cardioembolic stroke and CHF (r = 0.324, p < 0.05 and r = 0.429, p < 0.0001). Conclusion: Peripheral ED occurs to a similar degree in acute ischemic stroke and CHF. The impaired vasodilator capacity of peripheral arteries reflects the TOAST classification. ADMA may play a role in ED in both acute ischemic stroke and CHF.

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Section: Discussionmentioning

confidence: 99%

Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

Scherbakov¹,

Sandek

Martens‐Lobenhoffer

et al. 2011

Cerebrovasc Dis

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“…We read with great interest the article by Dr Lavallée and colleagues 1 dealing with the effect of the high dose of statin administration on cerebral vasoreactivity in patients with cerebral small vessel disease. The results of their study demonstrated that 3-month treatment with 80 mg atorvastatin per day did not significantly improve brachial and carotid artery endotheliumdependent vasodilatory responses in patients with recent lacunar stroke.…”

Section: To the Editormentioning

confidence: 99%

Statins and Gender-Related Difference in Endothelial Function in Cerebral Small Vessel Disease

Tsuda

2009

Stroke

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Statins and Gender-Related Difference in Endothelial Function in Cerebral SmallVessel Disease To the Editor:We read with great interest the article by Dr Lavallée and colleagues 1 dealing with the effect of the high dose of statin administration on cerebral vasoreactivity in patients with cerebral small vessel disease. The results of their study demonstrated that 3-month treatment with 80 mg atorvastatin per day did not significantly improve brachial and carotid artery endotheliumdependent vasodilatory responses in patients with recent lacunar stroke. The authors also indicated that the same dose of atorvastatin markedly reduced the low-density lipoprotein cholesterol and high-sensitivity C-reactive protein in these patients. The authors propose that, despite a significant reduction in lowdensity lipoprotein cholesterol and high-sensitivity C-reactive protein, there is no positive evidence indicating that a high dose of statin might restore the cerebral microvasculature endothelial dysfunction in patients with cerebral small vessel disease.Numerous studies have shown that estrogen may have beneficial effects on circulatory functions. One of the mechanisms underlying the protective effect of estrogen may be the enhancement of nitric oxide production. There is evidence showing that vascular endothelial function is markedly influenced by estrogen and is improved by hormone replacement therapy in postmenopausal women. 2 In an in vitro study presented earlier, we demonstrated that 17␤-estradiol increased membrane fluidity (a reciprocal value of membrane microviscosity) of erythrocytes and improved the rigidity of cell membranes in postmenopausal women through the nitric oxide-dependent mechanism. 3 Because abnormalities in membrane microviscosity could cause a disturbance in rheological behavior and microcirculation, estrogen deficiency could be involved in the pathogenesis of vascular complications in women. Recently, the role of estrogen in male physiology has also become evident, and normal physiological estrogen, which is converted from testosterone by aromatase, may confer cardiovascular benefits for men. 4 In this context, we speculate that changes in nitric oxide production by sex hormones might modify the effects of statin on endothelial function in patients with lacunar stroke. It was demonstrated that when a low dose of simvastatin was administered to the hypercholesterolemic patients, the incidence of the coronary events was lower in women than in men. 5 Therefore, we would like to know whether gender difference might be related to the magnitudes of the restored endothelial function by the statin in the present study of Dr Lavallée and colleagues. It would be important to assess more precisely the relationships among the statin effect, sex hormone status, and nitric oxide production as well as their contribution to the improvement of endothelial function in patients with cerebral small vessel disease. DisclosuresNone. Kazushi Tsuda, MD, FAHA Cardiovascular and Metabolic Research CenterKansai University of ...

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“…Few drugs have been tested directly for improvement of CVR, but 2 small randomized controlled trials in patients with recent lacunar infarcts did not show any benefit of 3-month use of high-dose atorvastatin and allopurinol on vasoreactivity. 47,48 Another small trial assessing the effect of 1-year lisinopril versus candesartan versus hydrochlorothiazide found no significant between-group differences in vasoreactivity or vasomotor range. 49 Future observational and experimental studies should investigate potential beneficial drug classes, based on aforementioned mechanism in relation to cognition and markers of cerebrovascular permeability, in addition to lacunar stroke.…”

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confidence: 99%

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

Wolters

Bruijn

Hofman

et al. 2016

ATVB

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A bout 44 million people worldwide are living with dementia, and because of a rapidly aging population this number is predicted to nearly double every 20 years until 2050. 1,2 Consequently, the social and economic burden of dementia will increase enormously, unless preventive or curative measures can be established. Cardiovascular health is increasingly acknowledged as a key determinant in prevention of dementia, including Alzheimer disease (AD).3,4 Yet, the mechanism by which vascular damage leads to cognitive decline remains largely unknown.Although many studies have related cognitive function to static markers of cerebrovascular pathology, such as small vessel disease on magnetic resonance imaging and the retinal vasculature, few provide a functional measure of cerebral vascular disease. Cerebral vasoreactivity (CVR) reflects the ability of the cerebral arterioles and capillaries to dilate in response to increased neuronal metabolic demand, 5 and can be quantified in vivo using transcranial Doppler (TCD) or magnetic resonance imaging. Vasoreactivity is essential for maintenance of continuous cerebral perfusion, and impaired vasoreactivity is associated with (cardiovascular) mortality in the general population 6 and risk of stroke in the presence of flow-limiting carotid artery stenosis. 7 In addition, lower vasoreactivity correlates with higher volumes of cerebral white matter lesions, 8 which are strongly associated with cognitive decline and dementia.9 Several small cross-sectional studies have found CVR to be reduced in patients with dementia or mild cognitive impairment compared with healthy controls, 10-12 but its impact on cognitive decline and the risk of dementia is uncertain.We hypothesized that impaired CVR precedes dementia, and aimed to determine the association of CVR with cognitive decline and the risk of dementia in a population-based study.© 2015 American Heart Association, Inc. Materials and MethodsThis study is embedded within the Rotterdam study, an ongoing population-based cohort study in The Netherlands. TCD investigation with induction of hypercapnia was added to the core protocol for the second follow-up examination, from July 1997 to December 1999. Materials and Methods are available in the online-only Data Supplement. ResultsAmong 2569 eligible participants undergoing TCD with induced hypercapnia, no temporal bone window was present on either side in 632 (24.6%) individuals. Measurements could not be completed in 214 (8.3%) cases because of participants feeling anxious or unwell (n=54), lack of time (n=3), or other undocumented causes (n=157). In addition, in 94 participants we failed to obtain a reliable measurement of CVR despite adequate CO 2 induction, thus leaving a total of 1629 cases for analysis. Baseline characteristics of participants in comparison with nonparticipants are shown in Table 1. CVR was strongly impaired in current smokers and to a lesser extent in participants with a history of hypertension or diabetes mellitus. Conversely, higher systolic and diastoli...

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Placebo-Controlled Trial of High-Dose Atorvastatin in Patients With Severe Cerebral Small Vessel Disease

Cited by 36 publications

References 47 publications

Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

Endothelial Dysfunction of the Peripheral Vascular Bed in the Acute Phase after Ischemic Stroke

Statins and Gender-Related Difference in Endothelial Function in Cerebral Small Vessel Disease

Cerebral Vasoreactivity, Apolipoprotein E, and the Risk of Dementia

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