Jesse Weinberger

Lipid Lowering by Simvastatin Induces Regression of Human Atherosclerotic Lesions Two Years’ Follow-Up by High-Resolution Noninvasive Magnetic Resonance Imaging

Background—Statins are widely used to treat hypercholesterolemia and atherosclerotic disease. Noninvasive MRI allows serial monitoring of atherosclerotic plaque size changes. Our aim was to investigate the effects of lipid lowering with simvastatin on atherosclerotic lesions. Methods and Results—A total of 44 aortic and 32 carotid artery plaques were detected in 21 asymptomatic hypercholesterolemic patients at baseline. The effects of statin on these atherosclerotic lesions were evaluated as changes versus baseline in lumen area (LA), vessel wall thickness (VWT), and vessel wall area (VWA) by MRI. Maximal reduction of plasma total and LDL cholesterol by simvastatin (23% and 38% respectively;P <0.01 versus baseline) was achieved after ≈6 weeks of therapy and maintained thereafter throughout the study. Significant (P <0.01) reductions in maximal VWT and VWA at 12 months (10% and 11% for aortic and 8% and 11% for carotid plaques, respectively), without changes in LA, have been reported. Further decreases in VWT and VWA ranging from 12% to 20% were observed at 18 and 24 months. A slight but significant increase (ranging from 4% to 6%) in LA was seen in both carotid and aortic lesions at these later time points. Conclusion—The present study demonstrates that maintained lipid-lowering therapy with simvastatin is associated with significant regression of established atherosclerotic lesions in humans. Our observations indicate that lipid-lowering therapy is associated with sustained vascular remodeling and emphasize the need for longer-term treatment.

Elevated Anticardiolipin Antibody Titer Is a Stroke Risk Factor in a Multiethnic Population Independent of Isotype or Degree of Positivity

BACKGROUND AND PURPOSE Previous studies have produced conflicting results regarding the putative association between anticardiolipin antibodies (aCL) and infarction in the general stroke population. These inconsistencies may be a function of sample size and methodological differences among the studies. The purpose of the present study, the largest case-control study of this issue to date, was to assess aCL status as an independent risk factor for ischemic stroke in a multiethnic, urban population. METHODS We obtained aCL titers in 524 hospitalized acute stroke patients and 1020 community controls enrolled in the Minorities Risk Factors and Stroke Study. The results were interpreted as negative (</=22.9 IgG phospholipid [GPL] or 10.9 IgM phospholipid [MPL] units), low positive (22.9 to 30.0 GPL or 10.9 to 15.0 MPL units), or high positive (>30.0 GPL or 15.0 MPL units). Odds ratios (ORs) were adjusted for age, sex, race/ethnicity, history of diabetes, hypertension, atrial fibrillation, coronary artery disease, and current cigarette smoking. RESULTS A positive aCL titer was present in 11% (111/1020) of controls and 34% (180/524) of cases. The adjusted OR for any positive aCL titer was 4.0 (95% CI, 3.0 to 5.5). For any positive IgG aCL titer this value was 3.9 (95% CI, 2.8 to 5.5), and for any positive IgM aCL titer it was 3.4 (95% CI, 2.1 to 5.5). There were no significant differences in ORs associated with high- or low-positive IgG or IgM aCL titers. CONCLUSIONS In the largest study of its kind to date, aCL antibodies were demonstrated to be independent stroke risk factors across the 3 ethnic groups studied, conferring a 4-fold increased risk of ischemic stroke. IgG and for the first time IgM aCL were each shown to be associated with increased stroke risk. The prevalence of these antibodies and the stroke risk associated appear greater than previously reported.

Mechanisms in lacunar infarction.

Background and Purpose Lacunes are thought to occur in patients with hypertension or diabetes mellitus as a result of small-vessel disease. This study evaluated the importance of other stroke mechanisms in a population of patients with lacunar infarction. Methods We evaluated 108 consecutive patients with a lacune in the lenticulostriate distribution for other stroke risk factors such as carotid and cardiac disease. Results Hypertension was present in 68% of the patients and diabetes mellitus in 37%; both occurred in 28% and neither occurred in 23%. Noninvasive carotid studies identified atherosclerotic plaque as a possible embolic source in 23%. By previously established criteria, 18% were at high risk for cardioembolism. Of those with hypertension or diabetes mellitus, 36% were at risk for a carotid or cardiac embolus. Of those without hypertension or diabetes mellitus, 32% had a possible carotid or cardiac etiology. Conclusions The high incidence of carotid and cardiac disease in those with and without hypertension or diabetes mellitus suggests the importance of other stroke mechanisms in this population. Patients with lacunar infarction should therefore be evaluated for other causes of stroke that may be treatable.

Nerve terminal damage in cerebral ischemia: protective effect of alpha-methyl-para-tyrosine.

Mongolian gerbils were treated with alpha-methyl-para-tyrosine methyl ester (AMPT, a tyrosine hydroxylase inhibitor), in order to decrease brain levels of catecholamines. Six hours later, unilateral ischemic stroke was induced by ligation of the left common carotid artery. The delayed degeneration of nerve terminals was studied sixteen hours later by measuring the high-affinity uptake of radiolabeled transmitters by isolated synaptosomes. Dopamine, serotonin and glutamate terminals were studied. AMPT-treated gerbils were compared to untreated (no AMPT) animals; 220 gerbils were studied. AMPT pretreatment (100, 250 and 400 mg/kg) produced a dose-dependent protection of all three types of nerve terminals. In the absence of AMPT pretreatment, the uptake of radiolabeled transmitters by the ischemic hemisphere, expressed as a percentage of that seen in the contralateral (unaffected) side of the brain, was as follows (mean +/- SEM): 27.3 +/- 5.2% for dopamine terminals, 49.5 +/- 6.2% for serotonin terminals, and 42.7 +/- 5.3% for glutamate terminals. Protection was essentially complete at a dose of 400 mg AMPT per kg. The number of animals with significant damage to nerve terminals was reduced from 38.5% in untreated animals to 11.1% in animals treated with AMPT 400 mg/kg. Although the nerve terminals were protected, gerbils still showed the behavioral signs of unilateral stroke due to the permanent occlusion of the left carotid. These results indicate that endogenous dopamine may play a significant role in ischemic damage to nerve terminals in the cerebrum.

Carotid Stenosis in Patients With Atrial Fibrillation: Prevalence, Risk Factors, and Relationship to Stroke in the Stroke Prevention in Atrial Fibrillation Study

BACKGROUND Several mechanisms contribute to the increased stroke rate of patients with atrial fibrillation (AF). We assessed the frequency of carotid artery stenosis in patients with AF and its relationship to stroke during aspirin or warfarin therapy. METHODS Carotid ultrasonography was done in 676 patients with AF enrolled in the Stroke Prevention in Atrial Fibrillation Study to detect cervical carotid stenosis of 50% or more of the luminal diameter. The presence of carotid stenosis was correlated with patient features and subsequent stroke during a mean of 2.6 years of follow-up. RESULTS In patients with AF who were older than 70 years, the frequency of carotid stenosis was 12% in men and 11% in women. Carotid stenosis was independently associated with systolic hypertension (relative risk, 2.4; P = .002), diabetes (relative risk, 1.8; P = .04), and tobacco use (relative risk, 1.8; P = .02). Carotid stenosis did not add significantly to prediction of stroke when analyzed with other clinical risk factors for stroke in patients with AF (relative risk, 1.3; 95% confidence interval, 0.5 to 3.6; P = .55). CONCLUSIONS Carotid artery stenosis of 50% or more occurs in about 12% of elderly patients with AF, reflecting the substantial prevalence of hypertension and diabetes in these patients. Carotid stenosis was not usefully predictive of stroke in patients with AF who were given aspirin or warfarin. Routine ultrasonography to detect carotid stenosis does not appear warranted in patients with AF without previous symptoms of brain ischemia.

Nerve terminal damage in cerebral ischemia: greater susceptibility of catecholamine nerve terminals relative to serotonin nerve terminals.

The energy-dependent uptake of (3H)-dopamine (DA), (3H)-norepinephrine (NE) and (3H)-serotonin (5-HT) was measured in synaptosomes isolated from either the whole cerebral hemispheres or the striata of gerbils after cerebral ischemia. Ischemic stroke was induced in the Mongolian gerbil by left common carotid ligation. Uptake values in the affected hemisphere (expressed as a percent of the corresponding control hemisphere) were 32.6% for DA, 35.1% for NE, and 52.0% for 5-HT, 16 hours after stroke. The differential reduction in uptake of the catecholamines relative to 5-HT was significant (p less than 0.005). This differential persisted when measures were made on isolated striata from the ischemic and control hemispheres. In the latter measurements, uptake of DA was 20.7% of control and uptake of 5-HT was 44.7% of control. Uptake of both DA and NE were significantly reduced in animals exhibiting milder circling behavior, while uptake of 5-HT was not. There was no significant reduction of uptake in animals subjected to left common carotid ligation not exhibiting signs of stroke. These studies indicate a selective sensitivity of catecholamine nerve terminals to damage in ischemic stroke.

Factors contributing to stroke in patients with atherosclerotic disease of the great vessels: the role of diabetes.

The incidence of carotid artery disease and cerebrovascular symptoms were determined in 102 consecutive patients with peripheral arterial disease. Symptoms were correlated with risk factors of age, hypertension, smoking and diabetes and with the extent of disease at the carotid bifurcation. The incidence of stroke with permanent neurological deficit was twice as high in diabetics as in non-diabetics with equivalent atherosclerotic vascular disease (p less than .05). In women, the incidence of stroke was three times higher in diabetics (p less than .02). The number of transient ischemic attacks was significantly higher in non-diabetics (p less than .02). The total number of ischemic episodes in diabetics and non-diabetics was equivalent. This indicates that diabetics are more prone to irreversible destruction of ischemic brain tissue regardless of the nature of the circulatory disturbance.

Morphologic and dynamic changes of atherosclerotic plaque at the carotid artery bifurcation: Sequential imaging by real time B-mode ultrasonography

Occurrence of new symptoms of focal cerebrovascular disease, including completed cerebral infarction, transient cerebral ischemic attack and amaurosis fugax, was correlated with changes in size and morphology of atherosclerotic plaques at the carotid artery bifurcation visualized by real time B-mode ultrasonography. Bilateral serial images of 246 plaques in 123 patients were made in a time interval of 9 to 35 months between initial and follow-up studies. There was a significantly higher incidence of symptoms ipsilateral to plaques that grew [30 (25%) of 121] than of symptoms ipsilateral to plaques that diminished or remained unchanged [8 (8%) of 98] (p less than 0.001). Plaques that became hemodynamically obstructive by causing disruption of laminar flow or reduction of distal perfusion pressure at the ophthalmic artery were associated with a higher frequency of symptoms [12 (40%) of 30] than were nonobstructive plaques [26 (13%) of 201] (p less than 0.001). There was also a strong association between symptoms and plaque configuration. Mural plaques growing in a crescentic configuration along the wall of the carotid bifurcation between the first and second examination had a higher incidence of symptoms [22 (40%) of 56] than did plaques that grew but maintained a nodular configuration [8 (12%) of 65] (p less than 0.001), although the same proportion of each became hemodynamically obstructive. Sequential visualization of atherosclerotic plaques by real time B-mode ultrasonography of the carotid bifurcation may provide a method for studying the pathogenesis of arterial thrombosis.

A New Noninvasive Technique for Imaging Atherosclerotic Plaque in the Aortic Arch of Stroke Patients by Transcutaneous Real-Time B-Mode Ultrasonography An Initial Report

BACKGROUND AND PURPOSE Aortic arch atherosclerotic plaque is a probable source of atheroembolic stroke. Transesophageal echocardiography (TEE) has been used to image the aorta of patients with stroke to identify atherosclerotic plaque. TEE is moderately invasive and does not always visualize plaques present in the distal ascending aorta and proximal aortic arch. METHODS In the current study, transcutaneous B-mode ultrasonography was performed to image the aortic arch through a lateral supraclavicular window, and the results were compared with those of TEE in 20 patients. The aorta was subdivided into the proximal ascending (PAsc), distal ascending (DAsc), proximal aortic arch (PAA), and distal aortic arch (DAA) to be certain the plaques identified by each technique were the same. Plaques were characterized as simple (<4 mm thick) or complex (>4 mm thick). RESULTS In the PAsc, 8 simple plaques were identified with TEE but not with B-mode. In the DAsc, 1 complex plaque was identified with both techniques, and B-mode identified 1 additional complex and 1 simple plaque. In the PAA, 6 simple and 5 complex plaques were identified by both techniques, and TEE identified 1 additional complex plaque. In the DAA, TEE identified 2 simple and 2 complex plaques; B-mode identified 3 complex plaques. CONCLUSIONS B-mode imaging compared favorably with TEE in identification of plaques in the aortic arch and distal ascending aorta, although it could not identify simple plaques in the proximal ascending. B-mode could visualize plaques not seen by TEE in the distal ascending aorta. B-mode ultrasonography is complementary to TEE in performance of a comprehensive assessment of plaque in the aortic arch and provides a noninvasive method for sequential studies of plaques that can be visualized.

The Differential Effect of Ischemia on the Active Uptake of Dopamine, γ-Aminobutyric Acid, and Glutamate by Brain Synap to somes

Abstract: Ischemic stroke was induced in the Mongolian gerbil by left common carotid ligation. No change in uptake of [3H]dopamine, [3H]γ‐aminobutyric acid ([3H]GABA), or [14C]glutamate in synaptosomes obtained from the ischemic hemisphere was observed for up to 8 h. At 16 h after ligation, marked decrements in uptake were observed in animals showing hemiparesis: Uptake values expressed as a percent of the corresponding control hemisphere were 15.2% for dopamine, 28.0% for GABA, and 47.5% for glutamate. The differential sensitivity of dopamine terminals compared with glutamate terminals was highly significant. Separate experiments performed with synaptosomes isolated from the corpus striatum showed that the greater sensitivity to damage was intrinsic to the dopamine nerve terminal and not the result of regional variations in ischemic damage in brain. No bilateral effect of ischemia on dopamine uptake was evident. In animals exhibiting milder behavioral deficits (circling), a smaller and comparable decrement in uptake of dopamine, GABA, and glutamate was evident at 16 h, whereas animals not affected behaviorally showed no decrement at 16 h. Following uptake, the subsequent fractional release of neurotransmitter stimulated by 60 mM‐potassium ions was not affected at any time point studied. Therefore, the loss in uptake at 16 h probably represents overt destruction of nerve terminals. Experiments with urethane used in place of pentobarbital for anesthesia during carotid occlusion showed that “protection” by pentobarbital was not a factor in the delayed response to ischemia. These results show that damage or destruction of nerve terminals is a delayed event following ischemia and that dopamine terminals are intrinsically more sensitive than glutamate terminals.