Relation between Cardiovascular Disease Risk Markers and Brain Infarcts Detected by Magnetic Resonance Imaging in an Elderly Population €m, MD, PhD,* Ruta Nylander, MD,* Lars Lind, MD, PhD,† Johan Wikstro Bertil Lindahl, MD, PhD,†‡ Per Venge, MD, PhD,† Anders Larsson, MD, PhD,† € o €v, MD, PhD,xk Lars Berglund, PhD,‡ H €m, MD, PhD,* Johan Arnl akan Ahlstro Lars Johansson, PhD,*{ and Elna-Marie Larsson, MD, PhD*

Background: Established cardiovascular risk markers, such as hypertension, are associated with increased risk of brain infarcts. The newer markers N-terminal pro-brain natriuretic peptide, troponin I, C-reactive protein, and cystatin C may affect the risk of cardiovascular events and potentially, thereby, also stroke. We investigated the association between established and new risk markers for cardiovascular disease and brain infarcts detected by magnetic resonance imaging (MRI) at age 75. Methods: Four hundred six randomly selected subjects from the Prospective Investigation of the Vasculature in Uppsala Seniors study were examined with MRI of the brain at age 75. Blood samples, measurements, and dedicated questionnaires at age 70 were used for analysis of risk markers. A history of diseases had been obtained at age 70 and 75. MRI was evaluated regarding lacunar and cortical infarcts. Univariate associations between outcomes and risk markers were assessed with logistic regression models. Results: One or more infarcts were seen in 23% of the subjects (20% had only lacunar infarcts, 1% had only cortical infarcts, and 2% had both). Hypertension (odds ratio [OR] 2.6, 95% confidence interval [CI] 1.4, 4.7) and obesity (OR 1.3; CI 1.0, 1.8) were significantly associated with increased risk of brain infarction. The newer risk markers were not significantly associated with the brain infarcts. Conclusions: The new markers were not associated with the predominantly lacunar infarcts in our 75-year-old population, why troponin I and NT-proBNP may be associated mainly with cardioembolic infarcts as shown recently. Key Words: Magnetic resonance—stroke—lacunar infarctions—risk factors—hypertension. Ó 2015 by National Stroke Association

From the *Department of Radiology, Oncology and Radiation Science, Uppsala University, Uppsala; †Department of Medical Sciences, Uppsala University, Uppsala; ‡Uppsala Clinical Research Centre, Uppsala University, Uppsala; xDepartment of Public Health and Caring Sciences, Uppsala University, Uppsala; kSchool of Health and Social Studies, Dalarna University, Falun; and {AstraZeneca, Gothenburg, Sweden. Received June 5, 2014; revision received August 13, 2014; accepted August 25, 2014. Address correspondence to Ruta Nylander, Department of Radiology, Akademiska Sjukhuset, SE 751 85, Uppsala, Sweden. E-mail: [email protected]. 1052-3057/$ - see front matter Ó 2015 by National Stroke Association http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2014.08.027

312

Introduction Established cardiovascular risk markers, such as hypertension, diabetes, obesity, and smoking, are associated with an increased risk of stroke.1,2 Early detection and treatment of these risk markers, and preventive efforts to reduce smoking, could reduce the risk of stroke.1,2 Many studies have investigated the association of established cardiovascular risk factors with brain infarcts in populations.2-5 Among these risk factors, hypertension is most widely associated with stroke1,5 and with silent brain infarcts.2,4 Cortical and lacunar infarcts may have different risk factor profiles because

Journal of Stroke and Cerebrovascular Diseases, Vol. 24, No. 2 (February), 2015: pp 312-318

RISK FACTORS AND BRAIN INFARCTS ON MRI

cortical infarcts often are caused by large-vessel disease and lacunar infarcts by small-vessel disease.6 Cardioembolic infarcts are usually large and include the cortex but may sometimes be lacunar.7,8 Silent brain infarcts are detected in approximately 20% of healthy elderly people, and most of the silent infarcts are lacunar.2 The location of a brain infarct in the acute stage determines if it is symptomatic (ie, recognized) or silent, and because cortical infarcts are larger than lacunar they are more often symptomatic. Thus, a difference in risk factor profile is more dependent on the type of infarct than if it is symptomatic or silent. B-type natriuretic peptide (NT-proBNP), a neurohormone secreted from the cardiac ventricles, is a recognized marker of myocardial wall tension and established biochemical marker of increased mortality and morbidity in cardiovascular events.9,10 Cardiac troponin (troponin I) is an intracellular protein involved in heart muscle contraction and is a biochemical marker of myocardial damage.11 C-reactive protein (CRP) is a marker of inflammation, involved in endothelial inflammatory response, predicting stroke and cardiovascular events.10,12,13 Cystatin C is mainly used as a marker of renal function and has been reported as a strong predictor of cardiovascular death in elderly people.10 The addition of NT-proBNP, troponin I, CRP, and cystatin C to the established risk factors for cardiovascular disease was reported to improve risk stratification for death from cardiovascular causes in elderly men.10 Troponin I and NT-proBNP were recently found to be independently related to increased risk of stroke, systemic embolism, and vascular event mortality in a population with atrial fibrillation.11,14 In a review and meta-analysis, NTproBNP was found to have a reasonable accuracy in the diagnosis of cardioembolic stroke.7 The ‘‘new’’ markers have, however, not been investigated regarding the risk of different types of brain infarcts seen on magnetic resonance imaging (MRI). The aim of the present study was to investigate the associations between established cardiovascular risk factors and 4 new risk markers and brain infarcts detected on MRI in a 75-year-old population.

Materials and Methods

313

Out of 964 subjects, 827 agreed and gave written informed consent to participate in the study. From this cohort, 406 randomly selected subjects (210 men) underwent MRI of the brain at the age of 75 years.

Risk Markers Cardiovascular risk factor/marker data were obtained from blood samples and measurements performed at age 70, from the patient clinical records, and from dedicated questionnaires in the PIVUS study at age 70 and 75. This information was used for the statistical analysis of association with the cerebral infarcts. The following variables obtained at age 70 were assessed: systolic blood pressure (SBP), diastolic blood pressure [DBP], hypertension prevalence (SBP $ 140 mm Hg, DBP $ 90 mm Hg, or the use of antihypertensive medication), diabetes mellitus (defined as fasting blood sugar . 6.1 mmol/L or history of diabetes mellitus), body mass index (weight divided by the square of the height), waist circumference, current smoking (daily), former smoking (nonsmoker with history of smoking), total smoking (current and former smoking), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, serum triglyceride, lipid-lowering treatment, NT-proBNP, troponin I, CRP, and cystatin C. All subjects were investigated in the morning after an overnight fast. No medication or smoking was allowed after midnight. After recordings of height, weight, waist, and hip circumference, blood pressure measurements and blood sampling were performed with the subjects lying supine in a quiet room.16 Blood pressure was measured by a calibrated mercury sphygmomanometer in the noncannulated arm to nearest mm Hg after at least 30 minutes of rest, and the average of 3 recordings was used. Lipid variables and fasting blood glucose were measured by standard laboratory techniques. NT-proBNP was measured using the Elecsys proBNP sandwich immunoassay on an Elecsys 2010 instrument (Roche Diagnostics, Roche Diagnostics Scandinavia AB, Bromma, Sweden). Troponin I was analyzed using the high-sensitive ARCHITECT STAT hsTnI assay on an Architect i2000SR platform. CRP, cystatin C, etc., were analyzed on the Architect 8000 Instrument (Abbott Diagnostics, Lake Forest, IL).

Ethics Statement The Regional Ethical Review Board in Uppsala, Sweden, approved the study, and all subjects provided written informed consent.

Study Population We studied 406 subjects at the age of 75 years from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study.15 The subjects had been chosen in a randomized manner from the register of the municipality.

Stroke Verification The subjects answered a questionnaire at age 70 and 75 regarding the history of diseases. If hospital-treated stroke was indicated, the diagnosis was validated by the hospital records.

Image Acquisition Imaging was performed at age 75 on a 1.5 T MRI system (Gyroscan Intera; Philips Medical Systems, Best, The

R. NYLANDER ET AL.

314

Netherlands) with a 25 mT/m gradient system. MRI of the brain was performed using a quadrature head coil (receive only). The protocol included sagittal 3dimensional T1-weighted gradient echo images (magnetization-prepared rapid gradient echo; repetition time 8.6 ms, echo time 4 ms, slice thickness 1.2 mm, pixel size .94 3 .94 mm), transverse proton density, and transverse T2-weighted (T2-w) turbo spin echo images (repetition time 3000 ms, echo time 21, and 100 ms, echo train length 16, pixel size .94 3 .94 mm, slice thickness 3 mm).

Table 1. Number of subjects with brain infarcts Type of infarct

Cortical only

Lacunar only

Both

Sum

SBI RBI Sum

5 1 6

68 13 81

5 3 8

78 17 95

Abbreviations: RBI, recognized brain infarct; SBI, silent brain infarct.

Image Analysis For assessment of the images, a PACS workstation (Carestream PACS; Carestream Health, Inc., Rochester, NY) was used. The cerebral MR images were assessed by a neuroradiologist who was blinded to information of any previous disease. Lacunar infarcts were defined as hypointense foci (3-15 mm size), on 3-dimensional T1-weighted images. They were further defined to be isointense on proton density–weighted and hyperintense on T2-w images, surrounded by white matter or subcortical gray matter and not located in areas with a high prevalence of widened perivascular spaces. Recognized brain infarcts were infarcts seen on MRI and associated with clinical symptoms reported by the patients in the questionnaire and thereafter verified by data in the clinical patient record by an experienced clinician. Silent brain infarcts were infarcts seen on MRI without reported clinical symptoms.

Statistical Analysis Data were presented as means, standard deviations, and minimum and maximum values for continuous variables and as numbers and percentages for dichotomous variables. Univariate associations and associations adjusted for gender, between outcomes and risk markers, were assessed with logistic regression models. Furthermore, in multiple logistic regression models, we sought to find independent risk markers among statistically significant risk markers in the univariate analyses. Results from the logistic regression models were presented in forest plots as estimated odds ratios with 95% confidence intervals (CIs) of a 1 standard deviation increase for continuous risk markers and of a 1-unit increase for dichotomous variables. All statistical tests and CIs were 2 sided, and a statistically significant result was declared if the CI did not include unity. No adjustments for multiple tests were made in this exploratory study. All analyses were performed with the statistical program package, SAS 9.3 (SAS Institute, Inc., Cary, NC).

hemorrhage on MRI. In 9 (33%) of these subjects, no infarct could be seen on MRI. On MRI, 95 of 406 (23%) subjects had 1 or more infarcts, 81 of 406 (20%) had only lacunar infarcts, 6 of 406 (1%) had only cortical infarcts, and 8 of 406 (2%) had both lacunar and cortical infarcts (Table 1). Out of the whole population, 78 (19%) subjects had infarcts on MRI without a history of stroke, that is, silent brain infarcts, and 17 (4%) had recognized infarcts. Lacunar infarcts were more common than cortical infarcts among both recognized and silent brain infarcts (Table 1). Most lacunar infarcts were located in the basal ganglia, the corona radiata, and the cerebellum. The cortical infarcts were located in the middle and posterior cerebral artery territories, in the watershed area between the anterior and middle cerebral arteries and in the cerebellum. The largest size of infarction measured 52 3 25 mm in the axial plane. Seven subjects with a history of stroke had both lacunar and cortical infarcts, and it was difficult to tell which of them were symptomatic. Descriptive data regarding risk markers are shown in Table 2. The gender-adjusted odds ratios [ORs] for increased risk of any type of brain infarcts are shown in Figure 1. SBP (OR 1.6, 95% CI 1.2, 2.0), DBP (OR 1.4, CI 1.1, 1.8), hypertension prevalence (OR 2.6, CI 1.4, 4.7), body mass index (OR 1.3, CI 1.0, 1.6), and waist circumference (OR 1.4, CI 1.0, 1.8) were significantly associated with any type of infarct. The same markers except body mass index were significantly associated with lacunar infarcts. The newer markers NT-proBNP, troponin I, CRP, and cystatin C were not significantly associated with the brain infarcts. In multiple logistic models, SBP and abdominal obesity were independently associated with both lacunar infarcts and any type of infarct. Standardized ORs with 95% CI for increased risk of any type of brain infarct were 1.4 for both SBP and waist circumference.

Discussion Results In our study population, 27 (7%) subjects had a verified history of stroke, out of which 17 (63%) had infarcts and 1 had a parenchymal defect after a previous intracerebral

The present study showed that hypertension and obesity at age 70 were significantly and independently associated with brain infarcts on MRI at age 75. The investigated new risk markers were not associated with brain

RISK FACTORS AND BRAIN INFARCTS ON MRI

Table 2. Risk markers in the study population (406 subjects, former smoking only 367 subjects) at age 70 Variable

Statistics

SBP (mm Hg), mean (SD) 148.9 (21.3) DBP (mm Hg), mean (SD) 78.6 (10.0) Hypertension prevalence, n (%) 291 (72) Diabetes, n (%) 38 (9) BMI (kg/m2), mean (SD) 27.0 (3.9) Waist (cm), mean (SD) 91.1 (10.9) Smoking: current, n (%) 36 (9) Smoking: former, n (%) 156 (43) Smoking: total, n (%) 192 (48) HDL cholesterol (mmol/L)*, 1.40 (1.20, 1.70) median (quartiles) LDL cholesterol (mmol/L), 1.50 (.41) mean (SD), n (%) Triglycerides* (mmol/L), 1.13 (.87, 1.51) median (quartiles) Lipid-lowering treatment, n (%) 56 (14) NT-proBNP (ng/L), median 99.77 (56.35, 165.55) (quartiles) Troponin I (ng/L), median 6 (4, 9) (quartiles) CRP (mg/L), median (quartiles) 1.84 (.93, 3.31) Cystatin C (mg/L), median .86 (.79, .96) (quartiles) Recognized brain infarcts, n (%) 18 (4) Silent brain infarcts, n (%) 83 (21) Abbreviations: BMI, body mass index; CRP, C-reactive protein; Cys C, cystatin-C; DBP, diastolic blood pressure; HDL, highdensity lipoprotein; LDL, low-density lipoprotein; NT-proBNP, terminal pro-brain natriuretic peptide; SBP, systolic blood pressure. *Logarithmic values.

infarcts. Knowledge of risk markers for cerebral infarcts is important for potential treatment of high-risk patients to reduce the burden of stroke and silent brain infarcts.

Brain MRI Findings In our study population, one or more brain infarcts were seen in 23% of the subjects. Out of all subjects, 4% had recognized and 19% had silent brain infarcts on MRI. This is in agreement with previous studies showing a prevalence of silent brain infarcts from 8% to 28% within age ranges 34-97 years.2 Our study is unique with regard to the homogenous age of 75 years of all subjects. Both silent and recognized lacunar infarcts were in our subjects predominantly located in the basal ganglia, thalamus, and the corona radiata. It has been shown that the main location of acute symptomatic (recognized) lacunar infarcts is the primary motor and sensory pathways, and lacunar infarcts in other locations are usually silent.17 Lacunar infarcts are often the residuals of slightly larger acute lesions, which have shrunk leaving small cavities/lacunes.17 In our population, we evaluated old lacunar infarcts that may, thus, have been slightly larger

315

in the acute phase. Because the lacunar infarcts are small, the symptoms are highly dependent on the exact location at the acute stage. It has been shown that approximately 20% of patients can be misclassified regarding the subtype of infarct based on clinical symptoms only,18 why imaging is important for adequate determination of infarct type. Most of the cortical infarcts in our population were located in the middle cerebral artery territory. Because of the small number of patients with recognized cortical infarcts only and, in addition, 7 patients with a history of stroke and both cortical and lacunar infarcts (Table 1), no conclusions can be drawn regarding the location of recognized cortical infarcts in our study. It could be discussed if the silent brain infarcts really represent definite infarction. In our study, there were lacunar and a few cortical infarcts without clinical stroke. The cortical infarcts were radiologically evident, and the lacunar infarcts were like in most studies defined as focal lesions with diameter 3-15 mm with well-defined signal properties and location on MRI. Thus, the silent brain infarcts in our study have a typical MRI appearance of definite infarcts although we do not have any histopathologic confirmation. In our population, 9 subjects (2%) had a verified history of stroke without any infarct seen on MRI, not even at a second evaluation when the clinical findings were revealed to the neuroradiologist who had performed the image assessment. This is expected because it has been shown that up to 30% of patients with lacunar stroke syndromes do not have a visible small infarct on imaging.19 Small subcortical infarcts may evolve into a lacunar cavity or a hyperintense lesion without apparent cavitation on T2-w images or can even regress totally without any visually detectable lesion on MRI.20 Because the location and size of a brain infarct at the acute stage is the most important factor to determine if it will become symptomatic or silent, we think that it is more relevant to compare cortical and lacunar infarcts than recognized and silent ones with regard to risk factor profiles. Most silent infarcts are lacunar because of the smaller size and, thus, less risk for damage of motor or sensory pathways unless they are located precisely in eloquent regions. It is also more likely that cortical and lacunar infarcts have different risk factor profiles because of the presumed etiology of large-vessel and small-vessel disease (perforating arteriolar abnormality), respectively.21 Many embolic infarcts have a cardiac origin, and these infarcts are often large and multiple and predominate in the middle cerebral artery territory, but cardiac embolism may sometimes result in lacunar infarction (in up to 5% of cases).8 However, single small deep infarcts may be caused by intrinsic small-vessel disease despite the presence of concomitant atrial fibrillation.22 Cortical and lacunar infarcts may, thus, have a mixed etiology, why an adequate risk factor analysis of

R. NYLANDER ET AL.

316 OR (95 % CI)

SBP

1.55 ( 1.22, 1.96)

DBP

1.42 ( 1.12,1.80 )

Hypertension prevalence

2.56 (1.40 , 4.69)

Diabetes

1.82 ( 0.89, 3.72)

BMI

1.29 ( 1.03, 1.63)

Waist

1.36 ( 1.06, 1.75)

Smoking: Current

1.55 ( 0.73,3.30 )

Smoking: Former

0.81 ( 0.49, 1.34)

Smoking: Total

0.92 ( 0.58, 1.47)

HDL

0.80 ( 0.62, 1.04)

LDL

1.01 (0.80 , 1.28)

Triglycerides

1.00 ( 0.79, 1.26)

Lipid-lowering treatment

0.69 ( 0.33, 1.42)

NT-ProBNP

1.22 ( 0.97, 1.54)

Troponin I

0.94 ( 0.74, 1.19)

CRP

1.17 ( 0.93, 1.47)

Cystatin C

1.18 ( 0.94, 1.48)

0

1

2

3

4

subgroups may provide different results in different studies. Interestingly, a recent study showed a better long-term prognosis for patients’ nondisabling stroke and large-vessel disease than for such patients with small-vessel disease despite similar vascular risk factors at baseline.23 The patients with small-vessel disease had a higher risk especially of recurrent nonfatal stroke. It has also been shown that coexisting small-vessel disease predicts poor long-term outcome in stroke patients with intracranial large artery atherosclerosis.24 In addition, prior symptomatic lacunar stroke is predictive of recurrent ischemic stroke.25 These findings may imply that optimal preventive treatment may be important also in individuals with lacunar infarctions that were previously regarded as more benign than cortical ones.

Established Cardiovascular Risk Markers Hypertension was in our study related to any type of brain infarct. This is in agreement with previous studies, where hypertension is a well-established risk factor, which is strongly associated with all types of brain infarcts.2-4 Other studies have shown that hypertension is strongly associated with silent brain infarcts, which are most often lacunar2,4,26-28 and also with recognized lacunar infarcts.3 Thus, hypertension and small-vessel disease are important factors for the pathogenesis of lacunar infarcts.2

Figure 1. Gender-adjusted odds ratios for any brain infarct. Odds ratios are standardized for continuous variables. Total smoking is defined as current and/or former smoking. Abbreviations: BMI, body mass index; CI, confidence interval; CRP, C-reactive protein; Cys C, cystatin-C; DBP, diastolic blood pressure; HDL, high-density lipoprotein; LDL, lowdensity lipoprotein; NT-proBNP, terminal probrain natriuretic peptide; OR, odds ratio; SBP, systolic blood pressure.

5

Diabetes showed increased OR for risk of brain infarcts in our study, but this was not statistically significant (Fig 1). In a previous study, hypertension, diabetes, and smoking were associated with recognized lacunar infarcts.3 Diabetes was a significant risk factor for all subtypes of ischemic brain infarcts on MRI in another study.29 It has also been shown that glucose intolerance is associated with an increased risk for stroke on MRI.30 The population-based Rotterdam Scan study showed a significant association between diabetes and silent brain infarctions.30 In addition, a study of 360 asymptomatic hypertensive subjects with or without diabetes showed that the prevalence of silent brain infarctions was significantly higher among the hypertensive patients who also had diabetes,26 whereas we only found an association between hypertension and brain infarcts. Thus, our results have the same trend as previous studies although not statistically significant. The reason for this could be different criteria for diabetes and for silent brain infarcts, different study populations, different imaging technique used, or different infarct definition applied. A systematic review of previous studies showed that the apparent excess of hypertension and diabetes among lacunar compared with nonlacunar infarction patients disappeared when only studies using risk factor–free classifications were included,21 and this result has been supported by more recent investigations.22,23 We could

RISK FACTORS AND BRAIN INFARCTS ON MRI

not compare infarct subtypes with regard to different risk factors because of the small number of cortical infarcts in our population. Smoking was not significantly associated with any type of brain infarct in our study. However, smoking was one of the risk factors for recognized lacunar infarcts in a previous study,3 but there was no strong association with silent brain infarcts. Another study showed that smoking alone was not a significant risk factor for silent brain infarcts.4 The silent brain infarcts were predominant in our study, so our results are in agreement with these studies. Smoking may be difficult to assess correctly because of the fact that self-reported smoking habits could be uncertain. HDL cholesterol has shown an inverse relation to stroke in most epidemiologic studies,1 and in agreement with this, we found that low HDL cholesterol was associated with increased OR for brain infarcts, but it was not statistically significant. The LDL cholesterol was not significantly associated with brain infarcts in our study. A previous study showed that serum cholesterol (total cholesterol, LDL cholesterol, and non-HDL cholesterol) showed a significant association with silent brain infarcts.28 In this study, there was no gender bias with regard to different types of infarcts. In a previous study of unrecognized myocardial infarction in relation to cerebral ischemic lesions in the PIVUS cohort, men with recognized myocardial infarctions had an increased prevalence of cortical and lacunar brain infarcts, whereas women with unrecognized myocardial infarction had more cortical brain infarcts.31

New Cardiovascular Risk Markers NT-proBNP is a marker released in response to myocardial stretch and is valuable for diagnosis of heart failure and a marker of increased mortality and morbidity in cardiovascular events.16,32 It has also been shown to be strongly associated with cardioembolic stroke.7 Cardiac troponins, intracellular proteins involved in heart muscle contraction, are biochemical markers of myocardial damage.7 Troponins are used as biomarkers to detect acute coronary syndrome and may also be elevated in other diseases, such as renal failure, atrial fibrillation, and acute stroke.33 Elevated troponin in acute ischemic stroke patients without concomitant acute coronary syndrome may be because of different reasons that stress the heart.33 CRP is a marker of inflammation, involved in endothelial inflammatory response, predicting stroke and cardiovascular events.12,16 Cystatin C is mainly used as a marker of renal function and has been reported as a strong predictor of cardiovascular death in elderly people.10 All the 4 markers mentioned earlier significantly predicted death from cardiovascular causes in a longitudinal population-based study of a large male cohort.10 These new risk markers have not been extensively investigated

317

with regard to the risk of different types of brain infarcts seen on MRI. None of these new risk markers16 were significantly related to brain infarcts in our study. However, in a recent article, troponin I and NT-proBNP were found to be independently related to increased risk of stroke and mortality in a population with atrial fibrillation32 and a review and meta-analysis showed that NTproBNP has a strong association with cardioembolic stroke.7 Because most of the infarcts found in our study were asymptomatic and lacunar, they were most likely not of cardioembolic origin. This implies that troponin I and NT-proBNP are associated mainly with cardioembolic infarcts. A previous study showed that NTproBNP were elevated after acute ischemic brain infarct,9,14 which was not investigated in our project. No acute infarcts were seen in our study. Another study has shown that NT-proBNP was elevated in two thirds of acute stroke patients, whereas elevated cardiac troponin levels were found only in a small number of patients with acute brain infarcts. However, neither NT-proBNP nor cardiac troponins could predict the clinical outcome of acute ischemic stroke if other risk factors are considered.11

Limitations Although our sample size is rather large (406 individuals), it is not large enough to completely exclude that also the newer risk factors are related to brain infarcts. However, the CIs for most of the variables are rather narrow, and therefore, we do not consider this to be of major concern. Another limitation of this study is the difficulty to analyze subgroups of infarcts because of the small number of cortical infarcts, which was not predicted when the study evaluation of our large population was designed. Only 6 subjects had cortical infarcts without concomitant lacunar infarcts, and this group is too small for a relevant statistical comparison with regard to risk markers. Further studies with larger populations would be of interest for further investigation of risk marker profiles in different types of infarcts.

Conclusions Elderly subjects with the established risk markers, hypertension and obesity, had a significantly increased risk of brain infarction, whereas the newer markers were not associated with the predominantly lacunar infarcts in our study population. Thus, troponin I and NT-proBNP may be associated mainly with cardioembolic infarcts as recently shown.

References 1. Goldstein LB, Bushnell CD, Adams RJ, et al. Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart

R. NYLANDER ET AL.

318

2.

3.

4.

5.

6. 7.

8.

9.

10.

11.

12.

13.

14.

15.

16.

17.

18.

Association/American Stroke Association. Stroke 2011; 42:517-584. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol 2007; 6:611-619. Kim MH, Moon JS, Park SY, et al. Different risk factor profiles between silent brain infarction and symptomatic lacunar infarction. Eur Neurol 2011;65:250-256. Das RR, Seshadri S, Beiser AS, et al. Prevalence and correlates of silent cerebral infarcts in the Framingham offspring study. Stroke 2008;39:2929-2935. Yoon PW, Gillespie CD, George MG, et al. Control of hypertension among adults—National Health and Nutrition Examination Survey, United States, 2005-2008. Morb Mort Weekly Report Surv Summ 2012;61:19-25. Wardlaw JM. What causes lacunar stroke? J Neurol Neurosurg Psychiatry 2005;76:617-619. Yang HL, Lin YP, Long Y, et al. Predicting cardioembolic stroke with the B-type natriuretic peptide test: a systematic review and meta-analysis. J Stroke Cerebrovasc Dis 2014;23:1882-1889. Arboix A, Alio J. Acute cardioembolic cerebral infarction: answers to clinical questions. Curr Cardiol Rev 2012; 8:54-67. Sharma JC, Ananda K, Ross I, et al. N-terminal proBrain natriuretic peptide levels predict short-term poststroke survival. J Stroke Cerebrovasc Dis 2006;15:121-127. Zethelius B, Berglund L, Sundstrom J, et al. Use of multiple biomarkers to improve the prediction of death from cardiovascular causes. N Engl J Med 2008;358:2107-2116. Etgen T, Baum H, Sander K, et al. Cardiac troponins and N-terminal pro-brain natriuretic peptide in acute ischemic stroke do not relate to clinical prognosis. Stroke 2005;36:270-275. van Dijk EJ, Prins ND, Vermeer SE, et al. C-reactive protein and cerebral small-vessel disease: the Rotterdam Scan Study. Circulation 2005;112:900-905. Cook NR, Buring JE, Ridker PM. The effect of including C-reactive protein in cardiovascular risk prediction models for women. Ann Intern Med 2006;145:21-29. Idris I, Hill R, Ross I, et al. N-terminal probrain natriuretic peptide predicts 1-year mortality following acute stroke: possible evidence of occult cardiac dysfunction among patients with acute stroke. Age Ageing 2010;39:752-755. Lind L, Fors N, Hall J, et al. A comparison of three different methods to determine arterial compliance in the elderly: the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. J Hypertens 2006;24:1075-1082. Hansen T, Ahlstrom H, Wikstrom J, et al. A total atherosclerotic score for whole-body MRA and its relation to traditional cardiovascular risk factors. Eur Radiol 2008; 18:1174-1180. Wardlaw JM, Smith C, Dichgans M. Mechanisms of sporadic cerebral small vessel disease: insights from neuroimaging. Lancet Neurol 2013;12:483-497. Potter G, Doubal F, Jackson C, et al. Associations of clinical stroke misclassification (’clinical-imaging dissocia-

19.

20.

21.

22.

23.

24.

25.

26.

27.

28.

29.

30.

31.

32.

33.

tion’) in acute ischemic stroke. Cerebrovasc Dis 2010; 29:395-402. Doubal FN, Dennis MS, Wardlaw JM. Characteristics of patients with minor ischaemic strokes and negative MRI: a cross-sectional study. J Neurol Neurosurg Psychiatry 2011;82:540-542. Moreau F, Patel S, Lauzon ML, et al. Cavitation after acute symptomatic lacunar stroke depends on time, location, and MRI sequence. Stroke 2012;43:1837-1842. Jackson C, Sudlow C. Are lacunar strokes really different? A systematic review of differences in risk factor profiles between lacunar and nonlacunar infarcts. Stroke 2005;36:891-901. Park YS, Chung PW, Kim YB, et al. Small deep infarction in patients with atrial fibrillation: evidence of lacunar pathogenesis. Cerebrovasc Dis 2013;36:205-210. Achterberg S, Pruissen DM, Kappelle LJ, et al. Risk of vascular events after nondisabling small and large vessel cerebral ischemia. Cerebrovasc Dis 2013;36:190-195. Fu JH, Chen YK, Chen XY, et al. Coexisting small vessel disease predicts poor long-term outcome in stroke patients with intracranial large artery atherosclerosis. Cerebrovasc Dis 2010;30:433-439. Hart RG, Pearce LA, Bakheet MF, et al. Predictors of stroke recurrence in patients with recent lacunar stroke and response to interventions according to risk status: secondary prevention of small subcortical strokes trial. J Stroke Cerebrovasc Dis 2014;23:618-624. Eguchi K, Kario K, Shimada K. Greater impact of coexistence of hypertension and diabetes on silent cerebral infarcts. Stroke 2003;34:2471-2474. Vermeer SE, Den Heijer T, Koudstaal PJ, et al. Incidence and risk factors of silent brain infarcts in the populationbased Rotterdam Scan Study. Stroke 2003;34:392-396. Asumi M, Yamaguchi T, Saito K, et al. Are serum cholesterol levels associated with silent brain infarcts? The Seiryo Clinic Study. Atherosclerosis 2010;210:674-677. Cui R, Iso H, Yamagishi K, et al. Diabetes mellitus and risk of stroke and its subtypes among Japanese: the Japan public health center study. Stroke 2011;42:2611-2614. Stamler J, Vaccaro O, Neaton JD, et al. Diabetes, other risk factors, and 12-yr cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial. Diabetes Care 1993;16:434-444. Barbier CE, Nylander R, Themudo R, et al. Prevalence of unrecognized myocardial infarction detected with magnetic resonance imaging and its relationship to cerebral ischemic lesions in both sexes. J Am Coll Cardiol 2011; 58:1372-1377. Marini C, Totaro R, Carolei A. Long-term prognosis of cerebral ischemia in young adults. National Research Council Study Group on Stroke in the Young. Stroke 1999;30:2320-2325. Anders B, Alonso A, Artemis D, et al. What does elevated high-sensitive troponin I in stroke patients mean: concomitant acute myocardial infarction or a marker for high-risk patients? Cerebrovasc Dis 2013;36:211-217.

Relation between cardiovascular disease risk markers and brain infarcts detected by magnetic resonance imaging in an elderly population.

Established cardiovascular risk markers, such as hypertension, are associated with increased risk of brain infarcts. The newer markers N-terminal pro-...
174KB Sizes 1 Downloads 5 Views