Dirk Sander

Relationship Between Circadian Blood Pressure Patterns and Progression of Early Carotid Atherosclerosis A 3-Year Follow-Up Study

BackgroundArterial hypertension is a major risk factor for cardiovascular damage. The results of several studies suggest that target organ damage is greater in hypertensive persons with high blood pressure variability. Methods and ResultsDuring 3.3 years of follow-up, we studied the relationship between circadian blood pressure changes and the progression of early carotid atherosclerosis in 286 patients aged >55 years. Blood pressure patterns were evaluated with a long-term blood pressure monitor, and the extent of atherosclerosis was measured as the intima-media wall thickness (IMT) of the common carotid artery. Patients were subdivided according to blood pressure variability. The progression of IMT was significantly greater in the patients with increased systolic blood pressure variability (0.11 mm/y [95% CI 0.09 to 0.14] versus 0.05 mm/y [0.03 to 0.08];P <0.005) even after adjustment for other risk factors. Multivariate regression analysis revealed the daytime systolic blood pressure variability to be the best predictor for the progression of IMT. Raised daytime systolic blood pressure variability (>15 mm Hg) is associated with an increased relative risk of the development of early atherosclerosis (3.9 [1.4 to 11.1];P <0.01) and of cardiovascular events (1.87 [1.08 to 3.20];P <0.01). ConclusionsThe daytime systolic blood pressure variability is a strong predictor of early carotid atherosclerosis progression and is useful to define the risk-benefit ratio of therapeutic approaches.

Carotid intima-media thickness progression to predict cardiovascular events in the general population (the PROG-IMT collaborative project) : a meta-analysis of individual participant data

BACKGROUND Carotid intima-media thickness (cIMT) is related to the risk of cardiovascular events in the general population. An association between changes in cIMT and cardiovascular risk is frequently assumed but has rarely been reported. Our aim was to test this association. METHODS We identified general population studies that assessed cIMT at least twice and followed up participants for myocardial infarction, stroke, or death. The study teams collaborated in an individual participant data meta-analysis. Excluding individuals with previous myocardial infarction or stroke, we assessed the association between cIMT progression and the risk of cardiovascular events (myocardial infarction, stroke, vascular death, or a combination of these) for each study with Cox regression. The log hazard ratios (HRs) per SD difference were pooled by random effects meta-analysis. FINDINGS Of 21 eligible studies, 16 with 36,984 participants were included. During a mean follow-up of 7·0 years, 1519 myocardial infarctions, 1339 strokes, and 2028 combined endpoints (myocardial infarction, stroke, vascular death) occurred. Yearly cIMT progression was derived from two ultrasound visits 2-7 years (median 4 years) apart. For mean common carotid artery intima-media thickness progression, the overall HR of the combined endpoint was 0·97 (95% CI 0·94-1·00) when adjusted for age, sex, and mean common carotid artery intima-media thickness, and 0·98 (0·95-1·01) when also adjusted for vascular risk factors. Although we detected no associations with cIMT progression in sensitivity analyses, the mean cIMT of the two ultrasound scans was positively and robustly associated with cardiovascular risk (HR for the combined endpoint 1·16, 95% CI 1·10-1·22, adjusted for age, sex, mean common carotid artery intima-media thickness progression, and vascular risk factors). In three studies including 3439 participants who had four ultrasound scans, cIMT progression did not correlate between occassions (reproducibility correlations between r=-0·06 and r=-0·02). INTERPRETATION The association between cIMT progression assessed from two ultrasound scans and cardiovascular risk in the general population remains unproven. No conclusion can be derived for the use of cIMT progression as a surrogate in clinical trials. FUNDING Deutsche Forschungsgemeinschaft.

Evaluation of C-Reactive Protein Measurement for Assessing the Risk and Prognosis in Ischemic Stroke: A Statement for Health Care Professionals From the CRP Pooling Project Members

Background and Purpose— Several studies have shown, in different populations, that modest elevation of plasma C-reactive protein (CRP) in the range seen in apparently healthy individuals is a strong predictor of future vascular events. Elevated plasma CRP concentrations are also associated with an increased risk of cerebrovascular events and an increased risk of fatal and nonfatal cardiovascular events in ischemic stroke patients. These epidemiological and clinical observations suggest that determination of plasma CRP concentrations could be used as an adjunct for risk assessment in primary and secondary prevention of cerebrovascular disease and be of prognostic value. The aim of this review is to summarize the evidence for CRP as an independent predictor of cerebrovascular events in at-risk individuals and ischemic stroke patients and to consider its usefulness in evaluating prognosis after stroke. Summary of Review— CRP fulfils most of the requirements of a new risk and prognostic predictor, but several issues await further confirmation and clarification before this marker can be included in the routine evaluation of stroke patients and subjects at risk for cerebrovascular disease. Potentially important associations have been established between elevated plasma CRP concentrations and increased efficacy of established therapies, particularly lipid-lowering therapy with statins. Conclusion— At present, there is not sufficient evidence to recommend measurement of CRP in the routine evaluation of cerebrovascular disease risk in primary prevention, because there is insufficient evidence as to whether early detection, or intervention based on detection, improves health outcomes, although shared risk of cardiovascular disease indicates this may be of value. In secondary prevention of stroke, elevated CRP adds to existing prognostic markers, but it remains to be established whether specific therapeutic options can be derived from this.

Prognostic Relevance of Early Serial C-Reactive Protein Measurements After First Ischemic Stroke

Background and Purpose— Recent studies described an association between elevated levels of C-reactive protein (CRP) and outcome after ischemic stroke. We investigated the impact of early serial CRP measurements in hyperacute ischemic stroke on long-term outcome. Methods— One hundred twenty-seven consecutive patients without thrombolysis with a first ischemic stroke no more than 12 hours after symptom onset were examined. Serial CRP measurements were done at admission (CRP 1), within 24 hours (CRP 2), and within 48 hours (CRP 3) after symptom onset. In addition to several cerebrovascular risk factors, the 1-year outcome and the lesion volumes of initial diffusion-weighted images were determined. Results— The CRP concentration increased significantly during the first 48 hours after symptom onset (CRP 1, 0.86 mg/dL [95% CI, 0.69 to 1.02]; CRP 2, 1.22 mg/dL [95% CI, 0.88 to 1.55]; CRP 3, 1.75 mg/dL [95% CI, 1.25 to 2.25];P =0.003). Multiple logistic regression analysis identified Barthel Index score at admission and CRP 2 and 3 as independent predictors of an unfavorable outcome. Kaplan-Meier analysis revealed a significantly higher rate of end point events (adjusted odds ratio, 3.9 [95% CI, 1.4 to 10.7];P =0.008) only in patients with elevated CRP 2 concentrations. Conclusions— The CRP level measured within 12 hours after symptom onset of an acute ischemic stroke is not independently related to long-term prognosis. In contrast, a CRP increase between 12 and 24 hours after symptom onset predicts an unfavorable outcome and is associated with an increased incidence of cerebrovascular and cardiovascular events.

Physical Activity and Incident Cognitive Impairment in Elderly Persons: The INVADE Study

BACKGROUND Data regarding the relationship between physical activity and cognitive impairment are limited and controversial. We examined whether physical activity is associated with incident cognitive impairment during follow-up. METHODS As part of a community-based prospective cohort study in southern Bavaria, Germany, 3903 participants older than 55 years were enrolled between 2001 and 2003 and followed up for 2 years. Physical activity (classified as no activity, moderate activity [<3 times/wk], and high activity [> or =3 times/wk]), cognitive function (assessed by the 6-Item Cognitive Impairment Test), and potential confounders were evaluated. The main outcome measure was incident cognitive impairment after 2 years of follow-up. RESULTS At baseline, 418 participants (10.7%) had cognitive impairment. After a 2-year follow-up, 207 of 3485 initially unimpaired subjects (5.9%) developed incident cognitive impairment. Compared with participants without physical activity, fully adjusted multiple logistic regression analysis showed a significantly reduced risk of incident cognitive impairment after 2 years for participants with moderate or high physical activity at baseline (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.37-0.87 [P = .01]; and OR, 0.54; 95% CI, 0.35-0.83 [P = .005]; respectively). Further subanalysis including participants (n = 2029) without functional impairment and without prodromal phase of dementia resulted in an even higher reduction of risk of incident cognitive impairment for participants with moderate or high physical activity (OR, 0.44; 95% CI, 0.24-0.83 [P = .01]; and OR, 0.46; 95% CI, 0.25-0.85 [P = .01]; respectively) compared with no activity. CONCLUSION Moderate or high physical activity is associated with a reduced incidence of cognitive impairment after 2 years in a large population-based cohort of elderly subjects.

Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke

Objective: To evaluate the prognostic impact of early pathologic sympathetic activation after stroke. Methods: The authors examined 112 consecutive patients (mean age, 69 years; 60 men) with their first brain infarction. A pathologic sympathetic activation was presumed if the initial norepinephrine level exceeds 300 pg/mL. In addition, involvement of the insular cortex, nighttime blood pressure changes, and several cardiovascular risk factors were determined. One-year outcome measures were mortality rate, cardiovascular and cerebrovascular events, and activities of daily living (Barthel index and Rankin score). Results: Norepinephrine levels greater than 300 pg/mL, nighttime blood pressure increases, and insular involvement were associated with a lower Barthel index (p < 0.005) at the 1-year follow-up. By stepwise logistic regression analysis, insular infarction, serum norepinephrine concentration, right-sided infarction, and nighttime blood pressure increase were significant and independent predictors of an unfavorable functional outcome. Cox regression analysis showed a higher rate of cardiovascular and cerebrovascular events (hazard ratio, 2.9; 95% CI, 1.07; 6.83; p < 0.04) in patients with initially increased norepinephrine concentrations. Conclusions: The involvement of the insular cortex, the occurrence of a pathologic nighttime blood pressure increase, and an initially increased serum norepinephrine concentration are independent predictors of poor long-term outcome.

Changes of circadian blood pressure patterns after hemodynamic and thromboembolic brain infarction.

We investigated the changes of circadian blood pressure patterns after thromboembolic and hemodynamic brain infarction and evaluated the relation between circadian blood pressure variation, infarct location, and activation of the autonomic nervous system after thromboembolic stroke. Methods Repeated 24-hour blood pressure measurements were performed in 45 patients with proven first-ever brain infarctions of different origins. Evaluation of serum norepinephrine concentration, prolongation of the QT interval, and degree of cardiac arrhythmias were used to determine the extent of sympathetic activation after thromboembolic stroke. Results Whereas circadian blood pressure variation was significantly increased after hemodynamic infarction compared with a control group (diastolic, −25.2±4.5% versus −13.8±6.5%; P<.005), a clearly reduced variation was observed after thromboembolic infarction (diastolic, −5.2±6.9%). Blood pressure variation was positively related to serum norepinephrine concentration (r=.79; P<01) after thromboembolic infarction. Patients with involvement of the insular cortex showed a nocturnal rise of blood pressure significantly more frequently (66.7% versus 11.8%; p<.005) and had higher norepinephrine levels (540±110 pg/mL versus 290±178 pg/mL; P<.01) than patients without insular cortex infarction, indicating increased sympathetic activity. This was associated with a significantly more frequent occurrence of QT prolongation and cardiac arrhythmias. Conclusions The observed differences in circadian blood pressure patterns may (1) help to distinguish the pathophysiological basis of the stroke, (2) help to explain worsening in some cases of hemodynamic stroke, (3) confirm the importance of the insular cortex for sympathetic activation, and (4) identify subgroups of patients with increased risk of myocardial infarction and arrhythmia.

Disturbance of venous flow patterns in patients with transient global amnesia

Transient global amnesia (TGA) is an inability to form new memories. The pathophysiology and cause of TGA have not been defined. We examined the changes of internal jugular venous flow patterns in 21 patients with TGA and 21 age-matched and sex-matched controls using duplex ultrasonography during two Valsalva manoeuvres (blocking venous return through the superior vena cava). During both manoeuvres a retrograde flow component was seen significantly more frequently in the TGA group than in the controls. Ten patients reported Valsalva-like activities preceding TGA. In these patients a retrograde flow component took place more frequently than in those who did not report preceding Valsalva-like activities. Our results lend support to the hypothesis that TGA may be attributable to venous congestion, and consequent venous ischaemia to bilateral diencephalic or hippocampal structures.

Bilateral grey-matter increase in the putamen in primary blepharospasm

Background: Primary blepharospasm is a focal dystonia characterised by excessive involuntary closure of the eyelids. The pathophysiology of primary blepharospasm is unresolved. Aim: To pinpoint grey-matter changes that are associated with primary blepharospasm. Methods: 16 right-handed patients with primary blepharospasm (mean age 67.4 (SD 4.3) years; 12 women) were compared with 16 healthy volunteers matched for sex and age. High-resolution T1-weighted magnetic resonance imaging of each participant was obtained and analysed by voxel-based morphometry, a method to detect regionally specific differences in grey matter between patients and control group. To evaluate whether the identified grey-matter changes were correlated with the duration of primary blepharospasm or botulinum neurotoxin treatment (BoNT), separate regression analyses were carried out. Results: In patients with primary blepharospasm, grey-matter increase in the putamina was observed, whereas regression analyses did not indicate a correlation between grey-matter increases and the duration of primary blepharospasm or BoNT. Grey-matter decrease was detected in the left inferior parietal lobule; here regression analyses of grey-matter decrease showed a significant (p = 0.013) correlation of grey-matter decrease with the duration of BoNT. Conclusions: The data suggest structural changes in primary blepharospasm and point to a crucial role of the putamen for the pathophysiology of this focal dystonia.

Bilateral thalamic gray matter changes in patients with restless legs syndrome.

Restless legs syndrome (RLS) is a common neurological disorder of a primary unpleasant sensation with an urge to move the legs occurring at rest. The etiology of idiopathic RLS is unknown and structural cerebral abnormalities have so far not been detected. We studied 51 right-handed patients with an idiopathic restless legs syndrome in two independent samples (Regensburg RLS-group: n = 28, Munich RLS-group: n = 23) and compared them to 51 sex- and age-matched healthy volunteers. High-resolution T1-weighted magnetic resonance imaging (MRI) of each subject was obtained and analyzed using voxel-based morphometry (VBM) to detect regionally specific differences in gray matter between patients and controls. Conjunction analysis was used to combine results from both centers. In patients with idiopathic RLS, both study centers observed independently a bilateral gray matter increase in the pulvinar. In the conjunction analysis including all patients and controls from both study centers, a significant gray matter increase in the pulvinar bilaterally (right: x = 16, y = -21, z = 12, Z = 4.57; left: x = -16, y = -24, z = 12, Z = 4.10) was present. This is the first demonstration of structural changes in the brain of patients with idiopathic RLS. These changes in thalamic structures are either involved in the pathogenesis of RLS or may reflect a consequence of chronic increase in afferent input of behaviorally relevant information.