Carotid Intima-Media Thickness Progression as Surrogate Marker for Cardiovascular Risk: Meta-Analysis of 119 Clinical Trials Involving 100 667 Patients.

BACKGROUND: To quantify the association between effects of interventions on carotid intima-media thickness (cIMT) progression and their effects on cardiovascular disease (CVD) risk. METHODS: We systematically collated data from randomized, controlled trials. cIMT was assessed as the mean value at the common-carotid-artery; if unavailable, the maximum value at the common-carotid-artery or other cIMT measures were used. The primary outcome was a combined CVD end point defined as myocardial infarction, stroke, revascularization procedures, or fatal CVD. We estimated intervention effects on cIMT progression and incident CVD for each trial, before relating the 2 using a Bayesian meta-regression approach. RESULTS: We analyzed data of 119 randomized, controlled trials involving 100 667 patients (mean age 62 years, 42% female). Over an average follow-up of 3.7 years, 12 038 patients developed the combined CVD end point. Across all interventions, each 10 µm/y reduction of cIMT progression resulted in a relative risk for CVD of 0.91 (95% Credible Interval, 0.87-0.94), with an additional relative risk for CVD of 0.92 (0.87-0.97) being achieved independent of cIMT progression. Taken together, we estimated that interventions reducing cIMT progression by 10, 20, 30, or 40 µm/y would yield relative risks of 0.84 (0.75-0.93), 0.76 (0.67-0.85), 0.69 (0.59-0.79), or 0.63 (0.52-0.74), respectively. Results were similar when grouping trials by type of intervention, time of conduct, time to ultrasound follow-up, availability of individual-participant data, primary versus secondary prevention trials, type of cIMT measurement, and proportion of female patients. CONCLUSIONS: The extent of intervention effects on cIMT progression predicted the degree of CVD risk reduction. This provides a missing link supporting the usefulness of cIMT progression as a surrogate marker for CVD risk in clinical trials.

Patients with ventricular assist device and cerebral entrapment-Supporting skullcap reimplantation.

Effects of cranioplasty (CP) and skullcap reimplantation after decompressive craniectomy (DC) for cerebral hemorrhage or malignant brain infarction in patients with left ventricular assist device (LVAD) support as bridge to transplantation has not been surveyed yet. The aim of this study was to evaluate outcome and management after CP when aiming for transplantation. Data were collected from our prospective institutional database including all patients undergoing LVAD implantation between 2010 and 2019. Six patients needed CP procedures and were included. Our analysis focused on postoperative outcome, survival, and facilitation of heart transplantation. Study endpoints included also all-cause mortality. From a total of 1010 LVAD implantations during analysis period in our center, six bridge-to-transplantation LVAD patients [median age at LVAD implantation: 32.5 years (IQR: 24.8-39.5 years); four male, HVAD, n = 3; HM II, n = 1; HM 3, n = 2] underwent CP with imminent entrapment secondary to cerebral hemorrhage or malignant infarction. Primary heart failure etiology was myocarditis (n = 2), dilated (n = 2), or ischemic (n = 2). Median INTERMACS class was 1.5 (IQR; 1.0-2.8). Median time on LVAD support to DC procedure was 33 months (IQR: 16-48 months). The indication for DC was intraparenchymal hemorrhage (n = 4), subdural hematoma (n = 1), and malignant middle cerebral artery infarction (n = 1). After a median time of 4 months (IQR: 3.3-4.0 months, range; 2.0-10 months) post DC procedure, CP was subsequently performed without profound neurologic disabilities in all patients. After median time of 26 months (IQR: 21-42 months) follow-up, three patients successfully received heart transplantation, one patient could undergo LVAD explantation for myocardial recovery, and the remaining two patients are still on the list awaiting heart transplantation. CP procedure with skullcap reimplantation is feasible and can be safely performed in LVAD patients, which subsequently may even be eligible for heart transplantation with beneficial prognosis.

Glial Fibrillary Acidic Protein Serum Levels Distinguish between Intracerebral Hemorrhage and Cerebral Ischemia in the Early Phase of Stroke.

BACKGROUND: Recent studies have suggested that glial fibrillary acidic protein (GFAP) serum concentrations distinguish between intracerebral hemorrhage (ICH) and ischemic stroke (IS) shortly after symptom onset. In this prospective multicenter trial we validated GFAP in an independent patient cohort and assessed the quantitative relationship between GFAP release, bleeding size, and localization. METHODS: We included patients with a persistent neurological deficit (NIH Stroke Scale ≥4) suggestive of stroke within 6 h of symptom onset. Blood samples were drawn at hospital admission. GFAP serum concentrations were measured using an electrochemiluminometric immunoassay. Primary endpoint was the final diagnosis established at hospital discharge (ICH, IS, or stroke mimic). RESULTS: 202 patients were included (45 with ICH, 146 with IS, 11 stroke mimics). GFAP concentrations were significantly higher in ICH than in IS patients [median (interquartile range) 0.16 µg/L (0.04-3.27) vs 0.01 µg/L (0.01-0.01), P <0.001]. A GFAP cutoff of 0.03 µg/L provided a sensitivity of 77.8% and a specificity of 94.2% in distinguishing ICH from IS and stroke mimics [ROC analysis area under the curve 0.872 (95% CI, 0.802-0.942), P <0.001]. GFAP serum concentrations were positively correlated with ICH volume. Lobar ICH volumes were larger and thus associated with higher GFAP concentrations as compared to deep ICH. CONCLUSIONS: Serum GFAP was confirmed to be a biomarker indicating ICH in patients presenting with acute stroke symptoms. Very small ICH may be missed owing to less tissue destruction.

Prediction of asymptomatic carotid artery stenosis in the general population: identification of high-risk groups.

BACKGROUND AND PURPOSE: Because of a low prevalence of severe carotid stenosis in the general population, screening for presence of asymptomatic carotid artery stenosis (ACAS) is not warranted. Possibly, for certain subgroups, screening is worthwhile. The present study aims to develop prediction rules for the presence of ACAS (>50% and >70%). METHODS: Individual participant data from 4 population-based cohort studies (Malmö Diet and Cancer Study, Tromsø Study, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study; totaling 23 706 participants) were pooled. Multivariable logistic regression was performed to determine which variables predict presence of ACAS (>50% and >70%). Calibration and discrimination of the models were assessed, and bootstrapping was used to correct for overfitting. RESULTS: Age, sex, history of vascular disease, systolic and diastolic blood pressure, total cholesterol/high-density lipoprotein ratio, diabetes mellitus, and current smoking were predictors of stenosis (>50% and >70%). The calibration of the model was good confirmed by a nonsignificant Hosmer and Lemeshow test for moderate (P=0.59) and severe stenosis (P=0.07). The models discriminated well between participants with and without stenosis, with an area under the receiver operating characteristic curve corrected for over optimism of 0.82 (95% confidence interval, 0.80-0.84) for moderate stenosis and of 0.87 (95% confidence interval, 0.85-0.90) for severe stenosis. The regression coefficients of the predictors were converted into a score chart to facilitate practical application. CONCLUSIONS: A clinical prediction rule was developed that allows identification of subgroups with high prevalence of moderate (>50%) and severe (>70%) ACAS. When confirmed in comparable cohorts, application of the prediction rule may lead to a reduction in the number needed to screen for ACAS.

Diagnostic accuracy of plasma glial fibrillary acidic protein for differentiating intracerebral hemorrhage and cerebral ischemia in patients with symptoms of acute stroke.

BACKGROUND: Glial fibrillary acidic protein (GFAP) is a biomarker candidate indicative of intracerebral hemorrhage (ICH) in patients with symptoms of acute stroke. GFAP is released rapidly in the presence of expanding intracerebral bleeding, whereas a more gradual release occurs in ischemic stroke. In this study the diagnostic accuracy of plasma GFAP was determined in a prospective multicenter approach. METHODS: Within a 1-year recruitment period, patients suspected of having acute (symptom onset<4.5 h before admission) hemispheric stroke were prospectively included into the study in 14 stroke centers in Germany and Switzerland. A blood sample was collected at admission, and plasma GFAP was measured by use of an electrochemiluminometric immunoassay. The final diagnosis, established at hospital discharge, was classified as ICH, ischemic stroke, or stroke mimic. RESULTS: The study included 205 patients (39 ICH, 163 ischemic stroke, 3 stroke mimic). GFAP concentrations were increased in patients with ICH compared with patients with ischemic stroke [median (interquartile range) 1.91 µg/L (0.41-17.66) vs 0.08 µg/L (0.02-0.14), P<0.001]. Diagnostic accuracy of GFAP for differentiating ICH from ischemic stroke and stroke mimic was high [area under the curve 0.915 (95% CI 0.847-0.982), P<0.001]. A GFAP cutoff of 0.29 µg/L provided diagnostic sensitivity of 84.2% and diagnostic specificity of 96.3% for differentiating ICH from ischemic stroke and stroke mimic. CONCLUSIONS: Plasma GFAP analysis performed within 4.5 h of symptom onset can differentiate ICH and ischemic stroke. Studies are needed to evaluate a GFAP point-of-care system that may help optimize the prehospital triage and management of patients with symptoms of acute stroke.

Complication rates using balloon-expandable and self-expanding stents for the treatment of intracranial atherosclerotic stenoses : analysis of the INTRASTENT multicentric registry.

INTRODUCTION: Using balloon-expandable stents (BES) for treatment of intracranial stenoses, high inflation pressures and rigidity of the device are regarded as major drawbacks limiting feasibility and safety of the procedure. Self-expanding stents (SES) were developed to facilitate lesion access and to allow for less aggressive dilatation. We analyzed data of the INTRASTENT multicentric registry to assess whether self-expanding stents significantly reduced peri-interventional complication rates. METHODS: Records of intracranial stent procedures were entered consecutively into the registry. Datasets were divided into two groups according to the type of stent used. For outcome measurement, we chose three categories: TIA/minor stroke [modified Rankin score (mRS) <2], disabling stroke, and patient death. Clinical outcome was compared between BES and SES. We analyzed types of adverse events occurring in each group in addition. RESULTS: Of 409 atherosclerotic lesions, 254 were treated with BES and 155 with SES. Technical success rates were 97.6% and 98.7%, respectively. Adverse event rates were 4.9%, 3.7%, and 0.8% for TIA/nondisabling stroke, disabling stroke, and death in the BES group compared with 5.3%, 6.0%, and 4.0% in the SES group. The differences were not statistically significant. We observed more perforator strokes after use of BES, but thromboembolic events occurred more often in the SES treatment group. CONCLUSION: Data of the INTRASTENT registry do not support the hypothesis that introduction of SES lowered the overall complication rate of intracranial stent procedures. There might be an advantage using self-expanding stents in vessel segments with important perforating arteries.

Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis.

CONTEXT: The evidence that measurement of the common carotid intima-media thickness (CIMT) improves the risk scores in prediction of the absolute risk of cardiovascular events is inconsistent. OBJECTIVE: To determine whether common CIMT has added value in 10-year risk prediction of first-time myocardial infarctions or strokes, above that of the Framingham Risk Score. DATA SOURCES: Relevant studies were identified through literature searches of databases (PubMed from 1950 to June 2012 and EMBASE from 1980 to June 2012) and expert opinion. STUDY SELECTION: Studies were included if participants were drawn from the general population, common CIMT was measured at baseline, and individuals were followed up for first-time myocardial infarction or stroke. DATA EXTRACTION: Individual data were combined into 1 data set and an individual participant data meta-analysis was performed on individuals without existing cardiovascular disease. RESULTS: We included 14 population-based cohorts contributing data for 45,828 individuals. During a median follow-up of 11 years, 4007 first-time myocardial infarctions or strokes occurred. We first refitted the risk factors of the Framingham Risk Score and then extended the model with common CIMT measurements to estimate the absolute 10-year risks to develop a first-time myocardial infarction or stroke in both models. The C statistic of both models was similar (0.757; 95% CI, 0.749-0.764; and 0.759; 95% CI, 0.752-0.766). The net reclassification improvement with the addition of common CIMT was small (0.8%; 95% CI, 0.1%-1.6%). In those at intermediate risk, the net reclassification improvement was 3.6% in all individuals (95% CI, 2.7%-4.6%) and no differences between men and women. CONCLUSION: The addition of common CIMT measurements to the Framingham Risk Score was associated with small improvement in 10-year risk prediction of first-time myocardial infarction or stroke, but this improvement is unlikely to be of clinical importance.

Adiponectin level as a consequence of genetic variation, but not leptin level or leptin: adiponectin ratio, is a risk factor for carotid intima-media thickness.

BACKGROUND AND PURPOSE: The adipocytokines adiponectin and leptin have been suggested as risk factors for cardiovascular disease, including stroke, acting through atherosclerosis. However, studies have provided conflicting results in underpowered cohorts with some suggesting that the leptin:adiponectin ratio is a better predictor of risk. We examined these associations with carotid intima-media thickness (IMT), a marker of early atherosclerosis and arterial remodeling and an independent predictor of stroke. We also examined association between genetic variants in the leptin and adiponectin genes and IMT. METHODS: Adiponectin and leptin levels were determined in 990 individuals from the community Carotid Atherosclerosis Progression Study. Five variants in the gene encoding adiponectin and 7 in the gene encoding leptin were genotyped and their effects on circulating levels assessed. Both were then correlated with IMT. RESULTS: Adiponectin levels negatively correlated with IMT (-0.079, P=0.013). There was no correlation between leptin levels or leptin:adiponectin ratio and IMT. Two variants in the ADIPOQ gene encoding adiponectin were associated with altered adiponectin levels, 1 of which (rs266729) was associated with IMT. There was also an interaction with body mass index (P=0.019) with the association being present in obese subjects (P=0.02). CONCLUSIONS: Our results support a causal role for adiponectin in early carotid IMT and suggest it may act through interaction with obesity. In contrast, we found no evidence of a role for leptin and no evidence that leptin:adiponectin ratio is a better predictor of risk that adiponectin levels alone.

Pituitary function and IGF-I levels following ischemic stroke.

BACKGROUND: Pituitary dysfunction is a known complication of traumatic brain injury and subarachnoidal hemorrhage but there are few data about pituitary dysfunction as a complication of ischemic stroke. METHODS: We prospectively studied patients 66-274 days after an ischemic stroke, evaluating the prevalence of pituitary dysfunction (by combined releasing hormone testing: GHRH, CRH), stroke severity, outcome and incidence of anxiety and depression. RESULTS: Thirty-two patients (82%) presented with some degree of pituitary dysfunction with predominantly impaired growth hormone response (79.5%) and secondary adrenal failure (14.6%). Abnormal anxiety and/or depression was found in 28.3 and 32.7% of the patients. NIHSS (National Institute of Health Stroke Scale) varied between 1 and 15. Improvement in neurological deficit (ΔNIHSS) correlated significantly with NIHSS at baseline (p < 0.001) but not with pituitary function. CONCLUSIONS: Patients with ischemic stroke may suffer from pituitary dysfunction with predominantly impaired growth hormone response and secondary adrenal failure. We suggest that patients who suffer from stroke should undergo pituitary testing.

Is carotid intima media thickness useful for individual prediction of cardiovascular risk? Ten-year results from the Carotid Atherosclerosis Progression Study (CAPS).

AIMS: Carotid intima media thickness (cIMT) is an intermediate phenotype of early atherosclerosis that independently predicts vascular events. It is often suggested that cIMT be used as a screening tool to select subjects with an elevated event risk. Whether cIMT adds information to traditional risk models has so far received little investigation. METHODS AND RESULTS: The 10-year follow-up of 4904 subjects from the Carotid Atherosclerosis Progression Study (CAPS) without pre-existing vascular disease included cardiovascular events and total mortality. Using Cox models and reclassification statistics, we investigated the usefulness of cIMT in individual risk prediction beyond the Framingham and the SCORE models, using risk strata of 0-5, 5-10, 10-20, and >or=20% over 10 years. Carotid intima media thickness was significantly and independently predictive for cardiovascular events. Compared with a model using the Framingham risk factors, a second model that included the common carotid-IMT led to the reclassification of 357 subjects (8.1%). In 107 subjects (30.0%), this reclassification was correct as confirmed with the actual outcome over 10 years. Net reclassification improvement was -1.41% (P = NS); integrated discrimination improvement was 0.04% (P = NS). More subjects were shifted to lower than to higher risk categories by the inclusion of cIMT. Analyses including other endpoint definitions, other carotid segments, and the SCORE risk model for baseline prediction did not result in consistently better risk prediction with cIMT. CONCLUSION: Despite cIMT being predictive for cardiovascular endpoints, it did not consistently improve the risk classification of individuals. Carotid intima media thickness may not be useful for the risk stratification of individuals in the general population.

Perioperative Psychological Interventions in Heart Surgery­Opportunities and Clinical Benefit.

BACKGROUND: Heart surgery is a source of high levels of emotional distress for the patient. If the stress experience is not adequately compensated, it can have a negative impact on postoperative recovery, as can untreated comorbid mental disorders. METHODS: A selective literature review on emotional distress and mental comorbidities in heart surgery patients and a scoping review on the spectrum and effectiveness of perioperative psychological interventions to compensate and reduce the stress experience. RESULTS: Mental factors such as depressive symptoms or anxiety disorders are associated with an elevated risk of postoperative morbidity and mortality in patients treated for heart disease. Mental comorbidities occur more frequently in these patients than in the general population. Following the manifestation of chronic heart disease (CHD), for example, 15-20% of the patients display severe depressive disorders. A few psychotherapeutic interventions to reduce anxiety and depression, emotional distress, consumption of analgesics, and extubation time have been found effective, with low to moderate evidence quality. Many different psychological interventions have proved useful in clinical practice, including multimodal, multiprofessional interventions incorporating medications, education, sports, and exercise as well as psychosocial therapy including stress management. Individual psychotherapy during the period of acute inpatient treatment after myocardial infarction is also effective. CONCLUSION: Because psychosocial factors are important, the current guidelines recommend systematic screening for mental symptoms and comorbidities in advance of heart transplantation or the implantation of ventricular assist devices (VAD). Acute psychotherapeutic interventions to reduce mental symptoms can be offered in the perioperative setting.

Prevalence of asymptomatic carotid artery stenosis in the general population: an individual participant data meta-analysis.

BACKGROUND AND PURPOSE: In the discussion on the cost-effectiveness of screening, precise estimates of severe asymptomatic carotid stenosis are vital. Accordingly, we assessed the prevalence of moderate and severe asymptomatic carotid stenosis by age and sex using pooled cohort data. METHODS: We performed an individual participant data meta-analysis (23 706 participants) of 4 population-based studies (Malmö Diet and Cancer Study, Tromsø, Carotid Atherosclerosis Progression Study, and Cardiovascular Health Study). Outcomes of interest were asymptomatic moderate (> or =50%) and severe carotid stenosis (> or =70%). RESULTS: Prevalence of moderate asymptomatic carotid stenosis ranged from 0.2% (95% CI, 0.0% to 0.4%) in men aged <50 years to 7.5% (5.2% to 10.5%) in men aged > or =80 years. For women, this prevalence increased from 0% (0% to 0.2%) to 5.0% (3.1% to 7.5%). Prevalence of severe asymptomatic carotid stenosis ranged from 0.1% (0.0% to 0.3%) in men aged <50 years to 3.1% (1.7% to 5.3%) in men aged > or =80. For women, this prevalence increased from 0% (0.0% to 0.2%) to 0.9% (0.3% to 2.4%). CONCLUSIONS: The prevalence of severe asymptomatic carotid stenosis in the general population ranges from 0% to 3.1%, which is useful information in the discussion on the cost-effectiveness of screening.

In-hospital complication rates after stent treatment of 388 symptomatic intracranial stenoses: results from the INTRASTENT multicentric registry.

BACKGROUND AND PURPOSE: Stenting is increasingly used as an adjunct to medical therapy in symptomatic intracranial stenoses. High periprocedural adverse event rates are one of the limitations of endovascular treatment. Data from the INTRASTENT multicentric registry should demonstrate in-hospital complications at the current stage of clinical development of the stent procedure. METHODS: Participating centers entered the records of all their consecutive intracranial stent procedures into the database. To determine the clinical outcome in the acute phase, we distinguished transient ischemic attack/nondisabling stroke (modified Rankin Scale <2), disabling stroke, death, and intracranial hemorrhage as clinical complications and analyzed whether they were associated with patient- or stenosis-related risk factors. RESULTS: Data from 372 patients with 388 stenoses proved 4.8% disabling strokes and 2.2% deaths. Transient or minor events were detected in 5.4% of the cases. Hemorrhagic events (3.5%) occurred more frequently after treatment of middle cerebral artery stenoses (P=0.004) and were associated with significantly higher morbidity and mortality rates. Ischemic strokes by compromise of perforating branches were detected mainly in the posterior circulation. However, the overall rate of severe adverse events was not dependent from location, degree, and morphology of the stenosis or from patient's age, gender, vascular risk factors, or type of qualifying event. CONCLUSIONS: The complication rates within the registry are within the limits of previously published data. Severe adverse events were equally distributed between potential risk groups with similar rates but different types of main complications in the anterior and posterior circulation.

Individual progression of carotid intima media thickness as a surrogate for vascular risk (PROG-IMT): Rationale and design of a meta-analysis project.

Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data. Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points. Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan.

Reproducibility and diagnostic accuracy of substantia nigra sonography for the diagnosis of Parkinson's disease.

OBJECTIVE: Transcranial sonography (TCS) shows characteristic hyperechogenicity of the substantia nigra (SN) in patients with Parkinson's disease (PD). Although this feature is well established, sufficient observer reliability and diagnostic accuracy are prerequisites for advancements of this method. METHODS: The authors investigated both aspects in a cross-sectional study with four blinded TCS raters in 22 PD patients and 10 healthy controls. RESULTS: As expected, the authors found significant bilateral SN hyperechogenicity in PD patients. Quantitative computerised SN planimetry had a substantial intra- (intraclass correlation coefficient (ICC) 0.97 and 0.93 respectively for both hemispheres) and inter-rater reliability (ICC 0.84 and 0.89), while visual semiquantitative echogenicity grading of the SN revealed a moderate intrarater (weighted kappa 0.80 ipsilateral and 0.74 contralateral) and slight (0.33) to fair (0.51) inter-rater reliability only. Diagnostic accuracy measured as the area under the curve of receiver-operating characteristics plots was highest in TCS of the SN opposite the clinically most affected body side (planimetry 0.821, echogenicity grading 0.792) with a hyperechogenic area of 0.24 cm(2) as the optimum cut-off value for the differentiation between PD and controls (sensitivity 79%, specificity 81%). CONCLUSIONS: The data demonstrate that the observer variability of SN planimetry is low in the hands of experienced investigators. This approach also offers adequate diagnostic accuracy. The authors conclude that reliable SN TCS data on PD can be achieved in clinical routine and multicentre trials when standardised analysis protocols and certain quality criteria of brain parenchyma sonography are met.

Predictors of acute poststroke seizures.

BACKGROUND: In this study, we tried to identify predictors of acute poststroke seizures (aPSS) in stroke patients. METHODS: We analyzed a large prospective hospital-based stroke registry in Germany. 58,874 patients with the diagnosis of transient ischemic attack (TIA), ischemic stroke (IS) or intracerebral hemorrhage (ICH) were admitted within 24 h after symptom onset. Predictors for aPSS were identified using multivariate regression analysis adjusted for age, gender, stroke severity, vascular risk factors, acute nonneurologic infection, history of TIA and length of hospital stay. RESULTS: aPSS occurred in 0.7% of patients with TIA (mean duration of hospitalization 8 days), in 2.2% of patients with IS (12 days) and in 5.1% of patients with ICH (13 days). A lower age, a higher stroke severity, acute nonneurologic infection, a history of diabetes mellitus and a history of preceding TIA were identified to be independent predictors of aPSS in IS, whereas younger age, acute infection and a history of TIA were found predictive for aPSS in ICH. CONCLUSIONS: This study characterized so far unknown predictors of aPSS and may help to improve the identification of patients with a high risk of aPSS.

Progression of conventional cardiovascular risk factors and vascular disease risk in individuals: insights from the PROG-IMT consortium.

AIMS: Averaged measurements, but not the progression based on multiple assessments of carotid intima-media thickness, (cIMT) are predictive of cardiovascular disease (CVD) events in individuals. Whether this is true for conventional risk factors is unclear. METHODS AND RESULTS: An individual participant meta-analysis was used to associate the annualised progression of systolic blood pressure, total cholesterol, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol with future cardiovascular disease risk in 13 prospective cohort studies of the PROG-IMT collaboration (n = 34,072). Follow-up data included information on a combined cardiovascular disease endpoint of myocardial infarction, stroke, or vascular death. In secondary analyses, annualised progression was replaced with average. Log hazard ratios per standard deviation difference were pooled across studies by a random effects meta-analysis. In primary analysis, the annualised progression of total cholesterol was marginally related to a higher cardiovascular disease risk (hazard ratio (HR) 1.04, 95% confidence interval (CI) 1.00 to 1.07). The annualised progression of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol was not associated with future cardiovascular disease risk. In secondary analysis, average systolic blood pressure (HR 1.20 95% CI 1.11 to 1.29) and low-density lipoprotein cholesterol (HR 1.09, 95% CI 1.02 to 1.16) were related to a greater, while high-density lipoprotein cholesterol (HR 0.92, 95% CI 0.88 to 0.97) was related to a lower risk of future cardiovascular disease events. CONCLUSION: Averaged measurements of systolic blood pressure, low-density lipoprotein cholesterol and high-density lipoprotein cholesterol displayed significant linear relationships with the risk of future cardiovascular disease events. However, there was no clear association between the annualised progression of these conventional risk factors in individuals with the risk of future clinical endpoints.

Abrupt shift of the pattern of diurnal variation in stroke onset with daylight saving time transitions.

BACKGROUND: Stroke onset shows a pattern of diurnal variation, with a peak in morning hours. Rhythmic changes in blood pressure, hormones, and other parameters have been suggested as underlying mechanisms, but exogenous factors such as increasing physical activity after awakening may also be of relevance. To characterize the impact of external clock changes on the rhythmic variation in stroke onset, this parameter was recorded in patients during transition periods into and out of Daylight Saving Time (DST). METHODS AND RESULTS: The present study was based on a prospective stroke registry in Germany that contains time points of stroke onset from 44 251 patients admitted between 2000 and 2005. To achieve a uniform timeline, time points of stroke onset were set back from Central European Summer Time (CEST) to Central European Time (CET) for patients admitted during DST periods. Compared with the last week before the clock change, transition to or from DST resulted in an immediate shift of stroke onset time points within the first week after the clock change in reference to the uniform timeline (transition from CET to CEST -60 minutes for the time points in both the 25th and 50th percentiles of the diurnal pattern, P<0.001; transition from CEST to CET +60 minutes for the time points in both the 25th and 50th percentiles, P<0.001; patients pooled on a weekly basis). A significant shift was already present the first and second day after the transitions (ie, Monday and Tuesday). CONCLUSIONS: Transition to or from DST is coupled with an immediate shift in the time pattern of stroke onset. This strengthens the idea that exogenous factors associated with awakening are important determinants of the pattern of diurnal variation of stroke onset, because entrainment of the human circadian clock within hours is unlikely.

Genetic variation in the leukotriene pathway and carotid intima-media thickness: a 2-stage replication study.

BACKGROUND AND PURPOSE: The recent finding that genetic variation in the leukotriene biosynthesis pathway may confer an increased risk of ischemic stroke and atherosclerosis has implicated the leukotriene family as potential mediators of cardiovascular disease. Using a 2-stage replication design, we have examined whether polymorphisms in 8 genes related to this pathway are associated with early atherosclerosis and remodeling as measured by carotid artery intima-media thickness. METHODS: We assessed 969 individuals from the Carotid Atherosclerosis Progression Study (CAPS), a community based study of normal subjects, for 39 variants in the leukotriene pathway. Significant associations and gene-environment interactions were found for 21 variants in the initial cohort and were examined in the next 1905 consecutive cases from the same CAPS population. RESULTS: No replicable association between any individual polymorphism and carotid intima-media thickness itself was present after correction for multiple testing. A single gene-environment interaction was replicated between rs17222814 on bifurcation intima-media thickness and alcohol consumption exceeding 30 grams per day. CONCLUSIONS: The genetic variants we examined in the leukotriene biosynthesis pathway have little effect on early atherosclerosis and remodeling risk as determined by carotid intima-media thickness. Our study cannot exclude them as being risk factors for more advanced stages in the atherosclerotic process.

Future demographic trends decrease the proportion of ischemic stroke patients receiving thrombolytic therapy: a call to set-up therapeutic studies in the very old.

BACKGROUND AND PURPOSE: Thrombolytic therapy with tissue plasminogen activator (tPA) is rarely applied to ischemic stroke patients aged 80 years and above. As future demographic trends will increase the proportion of older stroke patients, the overall tPA treatment rate may decrease. The aim of the present analysis was to provide an estimate of the future number of ischemic stroke patients and the fraction thereof receiving tPA. METHODS: In 2005, n=12 906 hospitalized ischemic stroke patients were included into a large registry covering the Federal State of Hesse, Germany. Age- and gender-specific frequency rates for ischemic stroke and tPA therapy were calculated based on the registry and the respective population data. Population projections until 2050 were derived from the Hessian Bureau of Statistics. RESULTS: Assuming constant age- and gender-specific stroke incidence rates and treatment strategies, the total number of ischemic stroke patients will rise by approximately 68% until 2050, whereas the proportion of tPA-treated ischemic stroke patients will decrease from 4.5% to 3.8% in the same time frame (relative decrease 16%; chi(2) P<0.001). CONCLUSIONS: Future demographic changes will reduce tPA treatment rates. Therapeutic studies focusing on very old stroke patients are necessary to counteract this trend.