International Journal of Cardiology 172 (2014) 59–63
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Leukoaraiosis and ambulatory blood pressure load in a healthy elderly cohort study: The PROOF study John Avet a,b, Vincent Pichot c,d, Jean-Claude Barthélémy c,d, Bernard Laurent e,f, Arnauld Garcin c,d, Frédéric Roche c,d, Sébastien Celle c,d,⁎ a
Service de radiologie, CHU Nord, 42055 Saint-Étienne, France Service de médecine nucléaire, CHU Nord, 42055 Saint-Étienne, France Service de Physiologie Clinique et de l'Exercice, Pôle NOL, CHU Nord, 42055 Saint-Étienne, France d EA 4607 SNA-EPIS, Faculté de Médecine Jacques Lisfranc, Université Jean Monnet, PRES Université de Lyon42023 Saint-Étienne, France e Service de neurologie, Pôle NOL, Université Jean Monnet, CHU Nord, 42055 Saint-Étienne, France f Inserm U1028, Central Integration of Pain Lab, Université Claude Bernard Lyon 1, France b c
a r t i c l e
i n f o
Article history: Received 29 July 2013 Received in revised form 11 October 2013 Accepted 18 November 2013 Available online 23 November 2013 Keywords: Hypertension Leukoaraiosis Aging
a b s t r a c t Background: Old age and hypertension are consistently reported to be the main risk factors of leukoaraiosis. The association between white matter lesions (WMLs) and other cardiovascular risk factors (CVRF) remains controversial. We evaluated the association between CVRF and WMLs in a cohort study and determined the blood pressure variables that could predict WML severity. Methods: 830 subjects (65 +/− 1 years of age, 60% women) from the PROOF study, with a reliable ABPM and brain MRI, were included. The exclusion criteria included prior myocardial infarction, stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, and pacing. White matter changes on MRI were defined as hyperintensities N 5 mm on FLAIR images. We used the total degree of WML (range: 0–30) by adding the region-specific scores of both hemispheres. Results: Linear regression analyses demonstrated a significant relationship between total leukoaraiosis score and 24 h systolic blood pressure (SBP), 24 h diastolic BP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis score and clinical SBP, clinical DBP, or nocturnal DIP. There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors. Based on a ROC curve analysis, we identified the optimal threshold separating high-risk WML patients for a mean 24 h SBP above 123 mm Hg (p b 0.05). Conclusions: Even moderate increases in 24 h SBP promote arteriolar fragility of the cerebral white matter in a population aged 65. The prognostic implications of such abnormalities in asymptomatic and moderate cardiovascular risk populations remain to be evaluated. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction White-matter lesions (WMLs) are frequently observed on cerebral magnetic resonance imaging (MRI) of elderly patients, even when they have no apparent neurological symptoms [1], and are an important prognostic factor for stroke [2], cognitive impairment, dementia [3,4], and premature death. WMLs are associated with degenerative changes in brain arterioles that are related to atherosclerosis. This suggests that cerebral arteriosclerosis of the penetrating vessels is a major factor in the pathogenesis of ischemic WMLs [5]. Old age and hypertension are consistently reported to be the main risk factors [6–8] for these lesions. ⁎ Corresponding author at: Service de physiologie clinique, Niveau 6, CHU de SaintÉtienne, 42055 Saint-Étienne, France. Tel.: +33 4 77 82 83 00; fax: +33 4 77 82 84 47. E-mail address: [email protected] (S. Celle). 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.11.052
Both average systolic blood pressure (BP) and the variability of systolic blood pressure have been linked to the presence of WMLs [9], although the results vary somewhat across published studies [10,11]. Twentyfour-hour ambulatory blood pressure monitoring (ABPM) has become an important tool that is used to improve the diagnosis and management of hypertension [12]. It is known that ABPM more strongly correlates with hypertension-related organ damage and cardiovascular events than do office blood pressure measurements [13]. The association between WMLs and other cardiovascular risk factors, such as type 2 diabetes, dyslipidemia or metabolic syndrome, remains controversial [14,15]. To our knowledge, no prospective study has examined the relationship between tobacco use, dyslipidemia, metabolic syndrome and WMLs in the elderly. The aim of this study was to evaluate the associations between cardiovascular risk factors and WMLs in an elderly French cohort (i.e., the
60
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63
PROOF study cohort) in subjects free of patent cerebrovascular disease and to determine the blood pressure parameters (measured using ABPM) that are most highly correlated with WMLs. 2. Methods 2.1. The PROOF study The PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) study is a large representative community survey of older adults who were recruited from the town of Saint-Étienne (France) and aged 65 years at the inclusion date [16]. The population of the study was selected among healthy volunteers who were expected to be at a low risk for cardiac or cerebrovascular events. The exclusion criteria were prior myocardial infarction, prior stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, cardiac pacing, and diseases limiting life expectancy to b5 years. The final population sample included 1011 subjects (60% of women). Detailed primary and secondary objectives of the PROOF study have been published elsewhere. In summary, the PROOF study was conducted to assess the role of decline in autonomic nervous system activity as a risk factor for cardiovascular events or death due to any cause. Subject assessment included clinical evaluation at the hospital by a cardiologist, an analysis of cardiovascular risk factors, and a survey of the concomitant therapeutic drugs prescribed to these volunteers. Ambulatory blood pressure and ECG Holter monitoring was then performed on an outpatient basis. Lastly, a brain MRI was conducted in subjects for whom MRI was not contraindicated to ensure the absence of silent stroke. Of the 1011 subjects identified, 830 were included who completed reliable ABPMs and brain MRIs, which allowed for the presence of white matter lesions to be evaluated. The PROOF study was approved by an ERB (CCPRB Rhône-Alpes Loire) and all subjects signed a written informed consent. 2.2. Brain MRI The brain MRIs were obtained using a 1-Tesla clinical MR unit (Magnetom Harmony; Siemens) equipped with an 8-channel phased array coil. The scanning protocol included axial sections of T2-weighted conventional spin-echo (TE = 121 ms, TR = 6620 ms, FOV = 173 ∗ 230 mm2, matrix size 115 ∗ 256) and fluid-attenuated inversion recovery (FLAIR) (TR = 9000 ms, TE = 104 ms, inversion time = 2200 ms, FOV = 173 ∗ 230 mm2, matrix size = 182 ∗ 256) sequences. The slice orientation was the axial plane perpendicular to the posterior margin of the pons, and the slice thickness was 5 mm, with a 1 mm inter-slice gap. Only the FLAIR images were used to rate WMLs in this study because this sequence suppresses the cerebrospinal fluid (CSF) signal and it is sensitive to visualizing hyperintensities. Each scan was screened for other confounding neurological disorders. 2.3. Assessment of WML The degree of WMH severity was rated using the axial FLAIR images via the visual age related white matter changes scale (ARWMC) [17]. White matter changes were defined as ill-defined hyperintensities N5 mm on FLAIR images [18] and were rated as shown in Table 1. Five different regions were rated in the right and left hemispheres separately: 1) the frontal area, which comprised the frontal lobe anterior to the central sulcus; 2) the parietooccipital area, which consisted of the parietal and occipital lobes together; 3) the temporal area, which included the temporal lobe (the border between the parietooccipital and temporal lobes was approximated as the line drawn from the posterior part of the Sylvian fissure to the trigone areas of the lateral ventricles); 4) the infratentorial area, which included the brain stem and cerebellum; and 5) the basal ganglia, which included the striatum, globus pallidus, thalamus, internal and external capsules, and insula. The total degree of WMH (range: 0–30) was calculated by adding the region-specific scores of both hemispheres. All of the visual ratings were centrally conducted by a single rater who was blinded to subjects' clinical information. We did not use semi-automated threshold methods to quantify WMLs. Table 1 The ARWMC rating scale for MRI. Score Definition White matter lesions 0 No lesions 1 Focal lesions 2 Beginning confluence of lesions 3 Diffuse involvement of the entire region, with or without involvement of U fibers Basal ganglia lesions 0 No lesions 1 1 focal lesion N 5 mm 2 More than 1 focal lesion 3 Confluent lesions White matter changes on MRI were defined as bright lesions N5 mm on FLAIR images.
2.4. Blood pressure measurements Clinical blood pressure was defined as the mean of 2 consecutive blood pressure measurements obtained by a physician with a mercury sphygmomanometer after the patient had been lying down for 15 min. Twenty-four-hour ambulatory BP monitoring was assessed using valid, non-invasive auscultatory methods (Diasys Integra, Novacor, Rueil-Malmaison, France) [19]. Measurements were taken on a weekday beginning in the early morning. Automatic measurements were taken every 15 min during daytime and every 30 min during the night from the non-dominant arm. Subjects were instructed to continue their daily activities and regular sleeping habits as normal. Average values of clinical systolic blood pressure (SBP) and diastolic blood pressure (DBP), 24-hour SBP and DBP, awake SBP and DBP, and sleep SBP and DBP were obtained for all of the subjects. Moreover, we calculated systolic and diastolic Dip as Dip = (1 − [sleep BP / awake BP]), pulse pressure (PP) as PP = 24-hour SBP − 24-hour DBP, and mean arterial BP (MAP) as MAP = (24-hour SBP + [2 × 24-hour DBP]) / 3. Hypertension was defined as either being treated (with at least one medication), having a mean DBP N 85 mm Hg and/or mean SBP N 130 mm Hg. An awake SBP N 135 mm Hg and a 24 h SBP N 130 mm Hg were defined as two markers of elevated BP on ABPM. 2.5. Cardiovascular risk factors Risk factors other than blood pressure were evaluated in the PROOF study including the following: biological measures (fasting blood glucose, total cholesterol, HDL and LDL cholesterol, and triglyceride levels) as well as clinical anthropometric measurements (body mass index (BMI), waist circumference (WC), and tobacco smoking). In this study, the following thresholds were used: WC N102 cm for men and N88 cm for women, fasting plasma glucose concentration N6.1 mmol/L or use of hypoglycemic medication, plasma HDL-cholesterol concentration b1.03 mmol/L for men and b1.29 mmol/L for women, and plasma triglycerides concentration N1.69 mmol/L [20]. 2.6. Statistical methods We performed statistical analyses using a linear regression model with each blood pressure measurement (clinical SBP and DBP, ambulatory SBP and DBP, PP, MAP) and common risk factors (age, tobacco use, waist circumference, BMI, fasting blood glucose level, total cholesterol, HDL-cholesterol, LDL-cholesterol, LDL/HDL cholesterol and triglycerides) as dependent variables and leukoaraiosis, gender and hypertension status as independent variables. A linear regression was then performed using the subjects who were free of antihypertensive medications; each blood pressure measurement was used as a dependent variable, and gender and leukoaraiosis were used as independent variables. Common metabolic syndrome thresholds were used to separate our population into two groups: those with metabolic syndrome and those without metabolic syndrome. Student's t-test was applied to compare mean leukoaraiosis scores/severity between these two groups. Using ROC curves, we also attempted to define a blood pressure threshold to discriminate between individuals with low levels of leukoaraiosis and individuals with high levels of leukoaraiosis; these groups were defined using the median leukoaraiosis score observed in the entire sample.
3. Results For a total of 830 subjects, biological measurements, ambulatory blood pressure recordings and validated brain MRIs were obtained. Table 2 presents the characteristics of the population of study and Table 3 summarizes regional leukoaraiosis scores. Evaluating the two subgroups in relation to the known thresholds for fasting blood glucose, WC, BMI, HDL cholesterol, HDL/LDL or triglycerides or blood pressure measurements, the leukoaraiosis score was determined to be significantly different only between subjects with elevated blood pressures or with treatment and normotensive subjects. As expected, leukoaraiosis severity was found higher in subjects under anti-hypertensive medication (p = 0.015). Linear regression analyses revealed a significant relationship between total leukoaraiosis scores and 24 h SBP and 24 h DBP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis scores and clinical SBP, clinical DBP or systolic and diastolic DIP. The relationship between total leukoaraiosis and nighttime DBP approached significance but was non-significant. The total leukoaraiosis score was also significantly associated with PP and MAP. These results are summarized in Table 4. In untreated and supposedly normotensive subjects, the total leukoaraiosis score was significantly associated with all of the BP measurements, except for clinical SBP and DBP, and systolic and diastolic
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63 Table 2 Selected participant characteristics (n = 830 for all of the variables).
Age (years) Waist circumference (cm) BMI (kg/m2) Fasting blood glucose (g/L) Total cholesterol (g) HDL cholesterol (g) LDL cholesterol (g) LDL/HDL Triglycerides (g) Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
Mean
SD
Minimum
Maximum
66.19 85.64 25.26 1.02 2.34 0.58 1.54 1.10 1.26 143.35 87.76 118.87 75.90 123.34 78.70 106.04 68.04 0.14 0.13 42.96 90.23
0.81 11.23 3.70 0.22 0.39 0.16 0.33 0.34 0.53 18.33 10.21 14.27 8.00 14.74 8.37 15.59 8.95 0.08 0.08 10.13 9.36
62.46 57 15 0.70 1.01 0.21 0.54 0.22 0.41 100 60 80 52 80 55 75 44 −0.19 −0.24 19 64
69.85 133 52.2 3.02 3.92 1.81 2.96 2.86 3.41 220 130 181 108 184 114 173 105 0.36 0.35 88 130.33
Table 4 Linear regression between blood pressure and total leukoaraiosis adjusted for gender and hypertension status (n = 830). Significance of Bold Emphasis P-value b 0.05.
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
DIP (Table 5). In treated hypertensive subjects, there were no significant relationships between the leukoaraiosis score and any of the blood pressure variables (Table 6). There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors (current smoking status, fasting blood glucose level, waist circumference, BMI, HDL-cholesterol, HDL/LDL or triglyceride levels). The median leukoaraiosis score was equal to 1 in our population. Using this threshold, the best area under the ROC curve was obtained for the 24 h mean systolic blood pressure (area = 0.5384, p b 0.01). This curve was used to identify the optimal threshold separating highrisk versus low-risk patients for a mean SBP greater than 123 mm Hg. 4. Discussion The present study highlights the strong relationship between systolic blood pressure load (24-hour BP load and daytime BP load) and leukoaraiosis in healthy participants aged 65 years who were free of cardiovascular and cerebrovascular events. The strengths of our study are numerous. First, our study represents the first evaluation to date of the presence of a statistical relationship between leukoaraiosis and moderate cardiovascular risk, which is essential in the primary prevention of cardiovascular and cerebrovascular events. Second, the use of ambulatory blood pressure monitoring allows for more accurate descriptions of BP burden; this appears to be critical for other epidemiological studies [21]. Although this method has been well recognized and validated throughout the world, it remains underused in the diagnosis of hypertension and the assessment of its severity. The lack of a statistically significant relationship between the severity of leukoaraiosis and common clinical blood pressure measurements is troubling considering that the relationship between leukoaraiosis and ambulatory BP is quite strong; this provides further evidence that this ambulatory tool is clinically relevant in daily practice [22,23]. Third,
61
β
[95% CI]
0.0366559 0.0342103 0.108329 0.0904572 0.1134499 0.0909822 0.0833873 0.0701787 0.0108188 0.0049235 0.0760837 0.1081072
[−0.0060533 [−0.0114919 [0.0079346 [0.0073369 [0.0088665 [0.0074036 [0.0023569 [−0.0003307 [−2.286933 [−2.425528 [0.001871 [0.0118958
P-value 0.0184206] 0.0322158] 0.039014] 0.0625662] 0.0387112] 0.0597732] 0.0307171] 0.0487943] 3.146647] 2.803163] 0.0445494] 0.0594799]
0.322 0.352 0.003 0.013 0.002 0.012 0.022 0.053 0.756 0.887 0.033 0.003
we highlight the fact that in our normotensive population of individuals who are regularly medically followed, even a moderate increase in the systolic blood pressure burden led to increased risk of cerebral arteriolar obstruction. ROC curve analysis allowed for us to propose a threshold value of systolic ambulatory BP above which the risk of cerebral arteriolar injuries increases statistically significantly. This threshold is consistent with recent internationally available recommendations proposed for patients with diabetes to slow the progression of renal damage associated with chronic hypertension [24]. This proposed value of mean systolic BP must of course be confirmed according to prospective longitudinal studies that focus on the potential neurocognitive consequences associated with WMLs. Indeed, from an epidemiological perspective, leukoaraiosis may increase the risk of developing cognitive impairment in the elderly; it may also increase the risk of ischemic stroke. These last two points appear to be major endpoints in overall aging in developed countries. Fourth, in the present study, blood pressure appears to be the only cardiovascular risk factor for leukoaraiosis in our selected population. The specific impact of the other factors of metabolic syndrome and even type 2 diabetes was inconsequential compared to that of systolic blood pressure load. This result is not inconsistent with the literature in this area. Abnormalities of glycemic control may induce neuronal damage more frequently than vascular fragility [25]. We have recently demonstrated that the mean 24-hour systolic blood pressure was associated with reduced focal gray matter volumes of the neocortex [26]. These results were observed independently of both the presence of leukoaraiosis and its severity as evaluated using the same method used in the present study. Thus, it appears likely that hypertension may accelerate neurodegeneration with or without arteriolar lesion. A link between the two diseases (WM lesions, focal GM atrophy) could not be formally established as per a pathophysiological hypothesis. Various issues remain unclear. The mechanism involved in vascular white matter lesions [27] has also been studied; however, the results of these investigations are beyond the scope of our epidemiological and descriptive study. Our results are most likely not applicable to a general unselected population. The limited age span of our population restricts the impact of our results to 65 year old people. The prevalence of current smoking status and type 2 diabetes was low in our population, and the role of these risk factors may have been underestimated. In addition, the favorable impact of antihypertensive
Table 3 The distribution of leukoaraiosis levels in the studied PROOF subpopulation (n = 830).
0 1 2 3
Left frontal
Right frontal
Left parietooccipital
Right parietooccipital
Left temporal
Right temporal
Left basal ganglia
Right basal ganglia
Left subtentorial
Right subtentorial
480 229 98 23
476 249 82 23
584 149 68 29
624 130 52 24
822 6 2 0
822 8 0 0
798 24 7 1
786 36 7 1
817 8 4 1
817 9 3
62
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63
Table 5 Linear regression between blood pressure and total leukoaraiosis adjusted for gender in untreated subjects (n = 534). Significance of Bold Emphasis P-value b 0.05.
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
β
[95% CI]
0.0634398 0.0655655 0.1160561 0.1077257 0.1178378 0.0995333 0.1133248 0.1188029 −0.0211583 −0.0510752 0.077128 0.1214629
[−0.00405 [−0.0067666 [0.0068288 [0.0075997 [0.00691 [0.0043085 [0.0061231 [0.0113848 [−4.369796 [−5.268187 [−0.0023999 [0.0115679
P-value 0.0269446] 0.0483823] 0.0456794] 0.076545] 0.0438365] 0.0695469] 0.0434377] 0.0737035] 2.626104] 1.307839] 0.0514262] 0.0708658]
0.147 0.139 0.008 0.017 0.007 0.027 0.009 0.008 0.625 0.237 0.074 0.007
therapy that is typically prescribed for primary prevention of leukoaraiosis in hypertensive patients is not fully known [28–30]. Some authors have noted that antihypertensive medication may have potential deleterious effects in elderly patients with WM disease and an increased risk of lacunar cerebral lesion due to postural or sustained hypotension [31]. We report that, in the present study, the degree of leukoaraiosis is more severe in treated hypertensive subjects than in others which can be explained by a longer duration of hypertensive disease and a higher initial BP burden leading to irreversible WM lesions; a relationship between leukoaraiosis and increased systolic blood pressure load was not observed in our subpopulation of treated hypertensive subjects. The number of subjects included in this group is most likely insufficient to definitively affirm the lack of a correlation. We also found a highly significant association between pulse pressure and the presence and/or severity of leukoaraiosis in our population of normotensive or hypertensive men and women. However, pulse pressure does not appear to be a better predictor of the presence or severity of leukoaraiosis than systolic blood pressure. Similarly, in our elderly subjects, neither the amplitude of dipping during the night nor the absence of dipping appears to play an essential role in arteriolar damage of the white matter. Regardless, this variable did not appear to be more significant in our statistical analyses than systolic blood pressure. This point raises important issues present in the literature. Indeed, large dipping or the absence of dipping has been previously suggested to represent a phenomenon related to distal arteriolar obstruction in hypertensive patients. However, the authors of this previous work were interested in the study of hypertensive populations [32]. Our normotensive subjects may not have the same susceptibility to cerebral white matter damage that is associated with large amplitude variations in systolic blood pressure.
Table 6 Linear regression between blood pressure and total leukoaraiosis adjusted for gender in treated subjects (n = 296 for all of the BP measurements).
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
β
[95% CI]
−0.0055246 −0.0103385 0.0855174 0.0632151 0.0965978 0.0775059 0.035015 −0.002507 0.0564332 0.0903959 0.0668056 0.0806149
[−0.0210964 [−0.0395325 [−0.0070684 [−0.0215484 [−0.0044682 [−0.0149703 [−0.0155439 [−0.0410608 [−2.220514 [−0.9222366 [−0.0149402 [−0.0127346
P-value 0.0191731] 0.0330288] 0.0451242] 0.0713262] 0.0464524] 0.0734364] 0.0289081] 0.0393536] 6.518193] 7.736263] 0.0559762] 0.0674664]
0.925 0.860 0.152 0.292 0.106 0.194 0.555 0.967 0.334 0.122 0.256 0.180
5. Study limitation The limitations of our study include cross-sectional design, the selection of a population at 65 years of age with moderate cardiovascular risk who had never clinically presented with a cardiovascular or cerebrovascular event, and the low rate of severe and uncontrolled hypertension. In addition, our population had normal cognitive function at the time of participation [33]. Moreover, in another paper concerning the PROOF study [34], we demonstrated a modest statistical relationship between diastolic blood pressure and the level of executive functioning in these volunteers. It should be noted that there was no impact of the systolic blood pressure load on executive functioning. Achieving a reliable ABPM is not always possible, and it may bias our interpretation of the results. However, we systematically re-evaluated ABP monitoring in instances in which the number of measurements was low (less than 50 measures per 24 h) during the first visit. A methodological limitation is represented by visual analysis of the severity of leukoaraiosis. Several recent epidemiological studies have used quantitative methods to evaluate the total volume of leukoaraiosis in the white matter. This technique may enable the identification of the relationship between leukoaraiosis progression over time in hypertensive subjects and reduced increases in WM lesion volume in hypertensive patients whose blood pressure is controlled with medication [9]. 6. Conclusions The role of hypertension in the development of leukoaraiosis in the elderly is well recognized. However, we demonstrate in the present study that even moderate increases in the 24 h systolic blood pressure load promote arteriolar fragility of the cerebral white matter. The prognostic implications of these abnormalities in the asymptomatic and moderate cardiovascular risk populations remain unclear. Ambulatory blood pressure monitoring appears once again to outperform other clinical measures currently used to predict the risk of cerebrovascular complications, including leukoaraiosis. Acknowledgements This study was supported by a grant from the French Minister of Health (Programme Hospitalier de Recherche Clinique, Délégation Régionale à la Recherche Clinique, CHU Saint-Étienne; PHRC National 1998 et PHRC National 2002), the Association de Recherche SYNAPSE, and by a grant from the Société Française d'Hypertension Artérielle (Bourse 2008). References [1] Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666. [2] Wong TY, Klein R, Sharrett AR, et al. Study ARICIAR in C. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002;288:67–74. [3] Au R, Massaro JM, Wolf PA, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch Neurol 2006;63:246–50. [4] Schmidt R, Ropele S, Enzinger C, et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian Stroke Prevention Study. Ann Neurol 2005;58:610–6. [5] Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. [6] Dufouil C, de Kersaint-Gilly A, Besançon V, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001;56:921–6. [7] de Leeuw F-E, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125:765–72. [8] Guo X, Pantoni L, Simoni M, et al. Blood pressure components and changes in relation to white matter lesions: a 32-year prospective population study. Hypertension 2009;54:57–62. [9] Godin O, Tzourio C, Maillard P, Mazoyer B, Dufouil C. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study. Circulation 2011;123:266–73.
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63 [10] Puisieux F, Monaca P, Deplanque D, et al. Relationship between leuko-araiosis and blood pressure variability in the elderly. Eur Neurol 2001;46:115–20. [11] Sierra C, Sierra A de L, Mercader J, Gómez-Angelats E, Urbano-Márquez A, Coca A. Silent cerebral white matter lesions in middle-aged essential hypertensive patients. J Hypertens 2002;20:519–24. [12] Mancia G, Backer GD, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. [13] Mancia G, Parati G. The role of blood pressure variability in end-organ damage. J Hypertens Suppl 2003;21:S17–23. [14] Manschot SM, Brands AMA, van der Grond J, et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006;55:1106–13. [15] Schmidt R, Launer LJ, Nilsson L-G, et al. Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004;53:687–92. [16] Barthelemy JC, Pichot V, Dauphinot V, et al. Autonomic nervous system activity and decline as prognostic indicators of cardiovascular and cerebrovascular events: the “PROOF” study. Study design and population sample. Associations with sleeprelated breathing disorders: the “SYNAPSE” Study. Neuroepidemiology 2007;29: 18–28. [17] Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;32:1318–22. [18] Fazekas F, Kleinert R, Offenbacher H, et al. The morphologic correlate of incidental punctate white matter hyperintensities on MR images. AJNR Am J Neuroradiol 1991;12:915–21. [19] O'Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001;322: 531–6. [20] Assoumou H-GN, Bertholon F, Barthélémy J-C, et al. Alteration of baroreflex sensitivity in the elderly: the relationship with metabolic syndrome components. Int J Cardiol 2012;155:333–5. [21] Gosse P, Dauphinot V, Roche F, Pichot V, Celle S, Barthelemy J-C. Prevalence of clinical and ambulatory hypertension in a population of 65-year-olds: the PROOF study. J Clin Hypertens (Greenwich) 2010;12:160–5.
63
[22] Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005;111:1777–83. [23] Ohkubo T, Kikuya M, Metoki H, et al. Prognosis of “masked” hypertension and “white-coat” hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the Ohasama study. J Am Coll Cardiol 2005;46:508–15. [24] International Society for Chronobiology, American Association of Medical Chronobiology and Chronotherapeutics, Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk, Hermida RC, Smolensky MH, Ayala DE, et al. Ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals. Chronobiol Int 2013;30:355–410. [25] Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 2013;37:1346–62. [26] Celle S, Annweiler C, Pichot V, et al. Association between ambulatory 24-hour blood pressure levels and brain volume reduction: a cross-sectional elderly populationbased study. Hypertension 2012;60:1324–31. [27] Jellinger KA. Pathology and pathophysiology of vascular cognitive impairment. A critical update. Panminerva Med 2004;46:217–26. [28] Cherubini A, Lowenthal DT, Paran E, Mecocci P, Williams LS, Senin U. Hypertension and cognitive function in the elderly. Am J Ther 2007;14:533–54. [29] Paglieri C, Bisbocci D, Caserta M, et al. Hypertension and cognitive function. Clin Exp Hypertens 2008;30:701–10. [30] Sörös P, Whitehead S, Spence JD, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat Rev Neurol 2013;9:174–8. [31] Fagard RH, Cort PD. Orthostatic hypotension is a more robust predictor of cardiovascular events than nighttime reverse dipping in elderly. Hypertension 2010;56:56–61. [32] Verdecchia P, Angeli F, Mazzotta G, et al. Day–night dip and early-morning surge in blood pressure in hypertension: prognostic implications. Hypertension 2012;60:34–42. [33] Sforza E, Roche F, Thomas-Anterion C, et al. Cognitive function and sleep related breathing disorders in a healthy elderly population: the SYNAPSE study. Sleep 2010;33:515–21. [34] Beauchet O, Herrmann FR, Annweiler C, et al. Association between ambulatory 24hour blood pressure levels and cognitive performance: a cross-sectional elderly population-based study. Rejuvenation Res 2010;13:39–46.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Leukoaraiosis and ambulatory blood pressure load in a healthy elderly cohort study: The PROOF study John Avet a,b, Vincent Pichot c,d, Jean-Claude Barthélémy c,d, Bernard Laurent e,f, Arnauld Garcin c,d, Frédéric Roche c,d, Sébastien Celle c,d,⁎ a
Service de radiologie, CHU Nord, 42055 Saint-Étienne, France Service de médecine nucléaire, CHU Nord, 42055 Saint-Étienne, France Service de Physiologie Clinique et de l'Exercice, Pôle NOL, CHU Nord, 42055 Saint-Étienne, France d EA 4607 SNA-EPIS, Faculté de Médecine Jacques Lisfranc, Université Jean Monnet, PRES Université de Lyon42023 Saint-Étienne, France e Service de neurologie, Pôle NOL, Université Jean Monnet, CHU Nord, 42055 Saint-Étienne, France f Inserm U1028, Central Integration of Pain Lab, Université Claude Bernard Lyon 1, France b c
a r t i c l e
i n f o
Article history: Received 29 July 2013 Received in revised form 11 October 2013 Accepted 18 November 2013 Available online 23 November 2013 Keywords: Hypertension Leukoaraiosis Aging
a b s t r a c t Background: Old age and hypertension are consistently reported to be the main risk factors of leukoaraiosis. The association between white matter lesions (WMLs) and other cardiovascular risk factors (CVRF) remains controversial. We evaluated the association between CVRF and WMLs in a cohort study and determined the blood pressure variables that could predict WML severity. Methods: 830 subjects (65 +/− 1 years of age, 60% women) from the PROOF study, with a reliable ABPM and brain MRI, were included. The exclusion criteria included prior myocardial infarction, stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, and pacing. White matter changes on MRI were defined as hyperintensities N 5 mm on FLAIR images. We used the total degree of WML (range: 0–30) by adding the region-specific scores of both hemispheres. Results: Linear regression analyses demonstrated a significant relationship between total leukoaraiosis score and 24 h systolic blood pressure (SBP), 24 h diastolic BP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis score and clinical SBP, clinical DBP, or nocturnal DIP. There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors. Based on a ROC curve analysis, we identified the optimal threshold separating high-risk WML patients for a mean 24 h SBP above 123 mm Hg (p b 0.05). Conclusions: Even moderate increases in 24 h SBP promote arteriolar fragility of the cerebral white matter in a population aged 65. The prognostic implications of such abnormalities in asymptomatic and moderate cardiovascular risk populations remain to be evaluated. © 2013 Published by Elsevier Ireland Ltd.
1. Introduction White-matter lesions (WMLs) are frequently observed on cerebral magnetic resonance imaging (MRI) of elderly patients, even when they have no apparent neurological symptoms [1], and are an important prognostic factor for stroke [2], cognitive impairment, dementia [3,4], and premature death. WMLs are associated with degenerative changes in brain arterioles that are related to atherosclerosis. This suggests that cerebral arteriosclerosis of the penetrating vessels is a major factor in the pathogenesis of ischemic WMLs [5]. Old age and hypertension are consistently reported to be the main risk factors [6–8] for these lesions. ⁎ Corresponding author at: Service de physiologie clinique, Niveau 6, CHU de SaintÉtienne, 42055 Saint-Étienne, France. Tel.: +33 4 77 82 83 00; fax: +33 4 77 82 84 47. E-mail address: [email protected] (S. Celle). 0167-5273/$ – see front matter © 2013 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.ijcard.2013.11.052
Both average systolic blood pressure (BP) and the variability of systolic blood pressure have been linked to the presence of WMLs [9], although the results vary somewhat across published studies [10,11]. Twentyfour-hour ambulatory blood pressure monitoring (ABPM) has become an important tool that is used to improve the diagnosis and management of hypertension [12]. It is known that ABPM more strongly correlates with hypertension-related organ damage and cardiovascular events than do office blood pressure measurements [13]. The association between WMLs and other cardiovascular risk factors, such as type 2 diabetes, dyslipidemia or metabolic syndrome, remains controversial [14,15]. To our knowledge, no prospective study has examined the relationship between tobacco use, dyslipidemia, metabolic syndrome and WMLs in the elderly. The aim of this study was to evaluate the associations between cardiovascular risk factors and WMLs in an elderly French cohort (i.e., the
60
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63
PROOF study cohort) in subjects free of patent cerebrovascular disease and to determine the blood pressure parameters (measured using ABPM) that are most highly correlated with WMLs. 2. Methods 2.1. The PROOF study The PROOF (PROgnostic indicator OF cardiovascular and cerebrovascular events) study is a large representative community survey of older adults who were recruited from the town of Saint-Étienne (France) and aged 65 years at the inclusion date [16]. The population of the study was selected among healthy volunteers who were expected to be at a low risk for cardiac or cerebrovascular events. The exclusion criteria were prior myocardial infarction, prior stroke, heart failure, atrial fibrillation, type 1 diabetes mellitus, cardiac pacing, and diseases limiting life expectancy to b5 years. The final population sample included 1011 subjects (60% of women). Detailed primary and secondary objectives of the PROOF study have been published elsewhere. In summary, the PROOF study was conducted to assess the role of decline in autonomic nervous system activity as a risk factor for cardiovascular events or death due to any cause. Subject assessment included clinical evaluation at the hospital by a cardiologist, an analysis of cardiovascular risk factors, and a survey of the concomitant therapeutic drugs prescribed to these volunteers. Ambulatory blood pressure and ECG Holter monitoring was then performed on an outpatient basis. Lastly, a brain MRI was conducted in subjects for whom MRI was not contraindicated to ensure the absence of silent stroke. Of the 1011 subjects identified, 830 were included who completed reliable ABPMs and brain MRIs, which allowed for the presence of white matter lesions to be evaluated. The PROOF study was approved by an ERB (CCPRB Rhône-Alpes Loire) and all subjects signed a written informed consent. 2.2. Brain MRI The brain MRIs were obtained using a 1-Tesla clinical MR unit (Magnetom Harmony; Siemens) equipped with an 8-channel phased array coil. The scanning protocol included axial sections of T2-weighted conventional spin-echo (TE = 121 ms, TR = 6620 ms, FOV = 173 ∗ 230 mm2, matrix size 115 ∗ 256) and fluid-attenuated inversion recovery (FLAIR) (TR = 9000 ms, TE = 104 ms, inversion time = 2200 ms, FOV = 173 ∗ 230 mm2, matrix size = 182 ∗ 256) sequences. The slice orientation was the axial plane perpendicular to the posterior margin of the pons, and the slice thickness was 5 mm, with a 1 mm inter-slice gap. Only the FLAIR images were used to rate WMLs in this study because this sequence suppresses the cerebrospinal fluid (CSF) signal and it is sensitive to visualizing hyperintensities. Each scan was screened for other confounding neurological disorders. 2.3. Assessment of WML The degree of WMH severity was rated using the axial FLAIR images via the visual age related white matter changes scale (ARWMC) [17]. White matter changes were defined as ill-defined hyperintensities N5 mm on FLAIR images [18] and were rated as shown in Table 1. Five different regions were rated in the right and left hemispheres separately: 1) the frontal area, which comprised the frontal lobe anterior to the central sulcus; 2) the parietooccipital area, which consisted of the parietal and occipital lobes together; 3) the temporal area, which included the temporal lobe (the border between the parietooccipital and temporal lobes was approximated as the line drawn from the posterior part of the Sylvian fissure to the trigone areas of the lateral ventricles); 4) the infratentorial area, which included the brain stem and cerebellum; and 5) the basal ganglia, which included the striatum, globus pallidus, thalamus, internal and external capsules, and insula. The total degree of WMH (range: 0–30) was calculated by adding the region-specific scores of both hemispheres. All of the visual ratings were centrally conducted by a single rater who was blinded to subjects' clinical information. We did not use semi-automated threshold methods to quantify WMLs. Table 1 The ARWMC rating scale for MRI. Score Definition White matter lesions 0 No lesions 1 Focal lesions 2 Beginning confluence of lesions 3 Diffuse involvement of the entire region, with or without involvement of U fibers Basal ganglia lesions 0 No lesions 1 1 focal lesion N 5 mm 2 More than 1 focal lesion 3 Confluent lesions White matter changes on MRI were defined as bright lesions N5 mm on FLAIR images.
2.4. Blood pressure measurements Clinical blood pressure was defined as the mean of 2 consecutive blood pressure measurements obtained by a physician with a mercury sphygmomanometer after the patient had been lying down for 15 min. Twenty-four-hour ambulatory BP monitoring was assessed using valid, non-invasive auscultatory methods (Diasys Integra, Novacor, Rueil-Malmaison, France) [19]. Measurements were taken on a weekday beginning in the early morning. Automatic measurements were taken every 15 min during daytime and every 30 min during the night from the non-dominant arm. Subjects were instructed to continue their daily activities and regular sleeping habits as normal. Average values of clinical systolic blood pressure (SBP) and diastolic blood pressure (DBP), 24-hour SBP and DBP, awake SBP and DBP, and sleep SBP and DBP were obtained for all of the subjects. Moreover, we calculated systolic and diastolic Dip as Dip = (1 − [sleep BP / awake BP]), pulse pressure (PP) as PP = 24-hour SBP − 24-hour DBP, and mean arterial BP (MAP) as MAP = (24-hour SBP + [2 × 24-hour DBP]) / 3. Hypertension was defined as either being treated (with at least one medication), having a mean DBP N 85 mm Hg and/or mean SBP N 130 mm Hg. An awake SBP N 135 mm Hg and a 24 h SBP N 130 mm Hg were defined as two markers of elevated BP on ABPM. 2.5. Cardiovascular risk factors Risk factors other than blood pressure were evaluated in the PROOF study including the following: biological measures (fasting blood glucose, total cholesterol, HDL and LDL cholesterol, and triglyceride levels) as well as clinical anthropometric measurements (body mass index (BMI), waist circumference (WC), and tobacco smoking). In this study, the following thresholds were used: WC N102 cm for men and N88 cm for women, fasting plasma glucose concentration N6.1 mmol/L or use of hypoglycemic medication, plasma HDL-cholesterol concentration b1.03 mmol/L for men and b1.29 mmol/L for women, and plasma triglycerides concentration N1.69 mmol/L [20]. 2.6. Statistical methods We performed statistical analyses using a linear regression model with each blood pressure measurement (clinical SBP and DBP, ambulatory SBP and DBP, PP, MAP) and common risk factors (age, tobacco use, waist circumference, BMI, fasting blood glucose level, total cholesterol, HDL-cholesterol, LDL-cholesterol, LDL/HDL cholesterol and triglycerides) as dependent variables and leukoaraiosis, gender and hypertension status as independent variables. A linear regression was then performed using the subjects who were free of antihypertensive medications; each blood pressure measurement was used as a dependent variable, and gender and leukoaraiosis were used as independent variables. Common metabolic syndrome thresholds were used to separate our population into two groups: those with metabolic syndrome and those without metabolic syndrome. Student's t-test was applied to compare mean leukoaraiosis scores/severity between these two groups. Using ROC curves, we also attempted to define a blood pressure threshold to discriminate between individuals with low levels of leukoaraiosis and individuals with high levels of leukoaraiosis; these groups were defined using the median leukoaraiosis score observed in the entire sample.
3. Results For a total of 830 subjects, biological measurements, ambulatory blood pressure recordings and validated brain MRIs were obtained. Table 2 presents the characteristics of the population of study and Table 3 summarizes regional leukoaraiosis scores. Evaluating the two subgroups in relation to the known thresholds for fasting blood glucose, WC, BMI, HDL cholesterol, HDL/LDL or triglycerides or blood pressure measurements, the leukoaraiosis score was determined to be significantly different only between subjects with elevated blood pressures or with treatment and normotensive subjects. As expected, leukoaraiosis severity was found higher in subjects under anti-hypertensive medication (p = 0.015). Linear regression analyses revealed a significant relationship between total leukoaraiosis scores and 24 h SBP and 24 h DBP, daytime SBP and DBP and nighttime SBP. No significant relationship was found between leukoaraiosis scores and clinical SBP, clinical DBP or systolic and diastolic DIP. The relationship between total leukoaraiosis and nighttime DBP approached significance but was non-significant. The total leukoaraiosis score was also significantly associated with PP and MAP. These results are summarized in Table 4. In untreated and supposedly normotensive subjects, the total leukoaraiosis score was significantly associated with all of the BP measurements, except for clinical SBP and DBP, and systolic and diastolic
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63 Table 2 Selected participant characteristics (n = 830 for all of the variables).
Age (years) Waist circumference (cm) BMI (kg/m2) Fasting blood glucose (g/L) Total cholesterol (g) HDL cholesterol (g) LDL cholesterol (g) LDL/HDL Triglycerides (g) Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
Mean
SD
Minimum
Maximum
66.19 85.64 25.26 1.02 2.34 0.58 1.54 1.10 1.26 143.35 87.76 118.87 75.90 123.34 78.70 106.04 68.04 0.14 0.13 42.96 90.23
0.81 11.23 3.70 0.22 0.39 0.16 0.33 0.34 0.53 18.33 10.21 14.27 8.00 14.74 8.37 15.59 8.95 0.08 0.08 10.13 9.36
62.46 57 15 0.70 1.01 0.21 0.54 0.22 0.41 100 60 80 52 80 55 75 44 −0.19 −0.24 19 64
69.85 133 52.2 3.02 3.92 1.81 2.96 2.86 3.41 220 130 181 108 184 114 173 105 0.36 0.35 88 130.33
Table 4 Linear regression between blood pressure and total leukoaraiosis adjusted for gender and hypertension status (n = 830). Significance of Bold Emphasis P-value b 0.05.
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
DIP (Table 5). In treated hypertensive subjects, there were no significant relationships between the leukoaraiosis score and any of the blood pressure variables (Table 6). There was also no significant relationship between leukoaraiosis and other recognized cardiovascular risk factors (current smoking status, fasting blood glucose level, waist circumference, BMI, HDL-cholesterol, HDL/LDL or triglyceride levels). The median leukoaraiosis score was equal to 1 in our population. Using this threshold, the best area under the ROC curve was obtained for the 24 h mean systolic blood pressure (area = 0.5384, p b 0.01). This curve was used to identify the optimal threshold separating highrisk versus low-risk patients for a mean SBP greater than 123 mm Hg. 4. Discussion The present study highlights the strong relationship between systolic blood pressure load (24-hour BP load and daytime BP load) and leukoaraiosis in healthy participants aged 65 years who were free of cardiovascular and cerebrovascular events. The strengths of our study are numerous. First, our study represents the first evaluation to date of the presence of a statistical relationship between leukoaraiosis and moderate cardiovascular risk, which is essential in the primary prevention of cardiovascular and cerebrovascular events. Second, the use of ambulatory blood pressure monitoring allows for more accurate descriptions of BP burden; this appears to be critical for other epidemiological studies [21]. Although this method has been well recognized and validated throughout the world, it remains underused in the diagnosis of hypertension and the assessment of its severity. The lack of a statistically significant relationship between the severity of leukoaraiosis and common clinical blood pressure measurements is troubling considering that the relationship between leukoaraiosis and ambulatory BP is quite strong; this provides further evidence that this ambulatory tool is clinically relevant in daily practice [22,23]. Third,
61
β
[95% CI]
0.0366559 0.0342103 0.108329 0.0904572 0.1134499 0.0909822 0.0833873 0.0701787 0.0108188 0.0049235 0.0760837 0.1081072
[−0.0060533 [−0.0114919 [0.0079346 [0.0073369 [0.0088665 [0.0074036 [0.0023569 [−0.0003307 [−2.286933 [−2.425528 [0.001871 [0.0118958
P-value 0.0184206] 0.0322158] 0.039014] 0.0625662] 0.0387112] 0.0597732] 0.0307171] 0.0487943] 3.146647] 2.803163] 0.0445494] 0.0594799]
0.322 0.352 0.003 0.013 0.002 0.012 0.022 0.053 0.756 0.887 0.033 0.003
we highlight the fact that in our normotensive population of individuals who are regularly medically followed, even a moderate increase in the systolic blood pressure burden led to increased risk of cerebral arteriolar obstruction. ROC curve analysis allowed for us to propose a threshold value of systolic ambulatory BP above which the risk of cerebral arteriolar injuries increases statistically significantly. This threshold is consistent with recent internationally available recommendations proposed for patients with diabetes to slow the progression of renal damage associated with chronic hypertension [24]. This proposed value of mean systolic BP must of course be confirmed according to prospective longitudinal studies that focus on the potential neurocognitive consequences associated with WMLs. Indeed, from an epidemiological perspective, leukoaraiosis may increase the risk of developing cognitive impairment in the elderly; it may also increase the risk of ischemic stroke. These last two points appear to be major endpoints in overall aging in developed countries. Fourth, in the present study, blood pressure appears to be the only cardiovascular risk factor for leukoaraiosis in our selected population. The specific impact of the other factors of metabolic syndrome and even type 2 diabetes was inconsequential compared to that of systolic blood pressure load. This result is not inconsistent with the literature in this area. Abnormalities of glycemic control may induce neuronal damage more frequently than vascular fragility [25]. We have recently demonstrated that the mean 24-hour systolic blood pressure was associated with reduced focal gray matter volumes of the neocortex [26]. These results were observed independently of both the presence of leukoaraiosis and its severity as evaluated using the same method used in the present study. Thus, it appears likely that hypertension may accelerate neurodegeneration with or without arteriolar lesion. A link between the two diseases (WM lesions, focal GM atrophy) could not be formally established as per a pathophysiological hypothesis. Various issues remain unclear. The mechanism involved in vascular white matter lesions [27] has also been studied; however, the results of these investigations are beyond the scope of our epidemiological and descriptive study. Our results are most likely not applicable to a general unselected population. The limited age span of our population restricts the impact of our results to 65 year old people. The prevalence of current smoking status and type 2 diabetes was low in our population, and the role of these risk factors may have been underestimated. In addition, the favorable impact of antihypertensive
Table 3 The distribution of leukoaraiosis levels in the studied PROOF subpopulation (n = 830).
0 1 2 3
Left frontal
Right frontal
Left parietooccipital
Right parietooccipital
Left temporal
Right temporal
Left basal ganglia
Right basal ganglia
Left subtentorial
Right subtentorial
480 229 98 23
476 249 82 23
584 149 68 29
624 130 52 24
822 6 2 0
822 8 0 0
798 24 7 1
786 36 7 1
817 8 4 1
817 9 3
62
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63
Table 5 Linear regression between blood pressure and total leukoaraiosis adjusted for gender in untreated subjects (n = 534). Significance of Bold Emphasis P-value b 0.05.
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
β
[95% CI]
0.0634398 0.0655655 0.1160561 0.1077257 0.1178378 0.0995333 0.1133248 0.1188029 −0.0211583 −0.0510752 0.077128 0.1214629
[−0.00405 [−0.0067666 [0.0068288 [0.0075997 [0.00691 [0.0043085 [0.0061231 [0.0113848 [−4.369796 [−5.268187 [−0.0023999 [0.0115679
P-value 0.0269446] 0.0483823] 0.0456794] 0.076545] 0.0438365] 0.0695469] 0.0434377] 0.0737035] 2.626104] 1.307839] 0.0514262] 0.0708658]
0.147 0.139 0.008 0.017 0.007 0.027 0.009 0.008 0.625 0.237 0.074 0.007
therapy that is typically prescribed for primary prevention of leukoaraiosis in hypertensive patients is not fully known [28–30]. Some authors have noted that antihypertensive medication may have potential deleterious effects in elderly patients with WM disease and an increased risk of lacunar cerebral lesion due to postural or sustained hypotension [31]. We report that, in the present study, the degree of leukoaraiosis is more severe in treated hypertensive subjects than in others which can be explained by a longer duration of hypertensive disease and a higher initial BP burden leading to irreversible WM lesions; a relationship between leukoaraiosis and increased systolic blood pressure load was not observed in our subpopulation of treated hypertensive subjects. The number of subjects included in this group is most likely insufficient to definitively affirm the lack of a correlation. We also found a highly significant association between pulse pressure and the presence and/or severity of leukoaraiosis in our population of normotensive or hypertensive men and women. However, pulse pressure does not appear to be a better predictor of the presence or severity of leukoaraiosis than systolic blood pressure. Similarly, in our elderly subjects, neither the amplitude of dipping during the night nor the absence of dipping appears to play an essential role in arteriolar damage of the white matter. Regardless, this variable did not appear to be more significant in our statistical analyses than systolic blood pressure. This point raises important issues present in the literature. Indeed, large dipping or the absence of dipping has been previously suggested to represent a phenomenon related to distal arteriolar obstruction in hypertensive patients. However, the authors of this previous work were interested in the study of hypertensive populations [32]. Our normotensive subjects may not have the same susceptibility to cerebral white matter damage that is associated with large amplitude variations in systolic blood pressure.
Table 6 Linear regression between blood pressure and total leukoaraiosis adjusted for gender in treated subjects (n = 296 for all of the BP measurements).
Clinical SBP (mm Hg) Clinical DBP (mm Hg) 24-hour SBP (mm Hg) 24-hour DBP (mm Hg) Awake SBP (mm Hg) Awake DBP (mm Hg) Asleep SBP (mm Hg) Asleep DBP (mm Hg) Systolic DIP (mm Hg) Diastolic DIP (mm Hg) PP (mm Hg) MAP (mm Hg)
β
[95% CI]
−0.0055246 −0.0103385 0.0855174 0.0632151 0.0965978 0.0775059 0.035015 −0.002507 0.0564332 0.0903959 0.0668056 0.0806149
[−0.0210964 [−0.0395325 [−0.0070684 [−0.0215484 [−0.0044682 [−0.0149703 [−0.0155439 [−0.0410608 [−2.220514 [−0.9222366 [−0.0149402 [−0.0127346
P-value 0.0191731] 0.0330288] 0.0451242] 0.0713262] 0.0464524] 0.0734364] 0.0289081] 0.0393536] 6.518193] 7.736263] 0.0559762] 0.0674664]
0.925 0.860 0.152 0.292 0.106 0.194 0.555 0.967 0.334 0.122 0.256 0.180
5. Study limitation The limitations of our study include cross-sectional design, the selection of a population at 65 years of age with moderate cardiovascular risk who had never clinically presented with a cardiovascular or cerebrovascular event, and the low rate of severe and uncontrolled hypertension. In addition, our population had normal cognitive function at the time of participation [33]. Moreover, in another paper concerning the PROOF study [34], we demonstrated a modest statistical relationship between diastolic blood pressure and the level of executive functioning in these volunteers. It should be noted that there was no impact of the systolic blood pressure load on executive functioning. Achieving a reliable ABPM is not always possible, and it may bias our interpretation of the results. However, we systematically re-evaluated ABP monitoring in instances in which the number of measurements was low (less than 50 measures per 24 h) during the first visit. A methodological limitation is represented by visual analysis of the severity of leukoaraiosis. Several recent epidemiological studies have used quantitative methods to evaluate the total volume of leukoaraiosis in the white matter. This technique may enable the identification of the relationship between leukoaraiosis progression over time in hypertensive subjects and reduced increases in WM lesion volume in hypertensive patients whose blood pressure is controlled with medication [9]. 6. Conclusions The role of hypertension in the development of leukoaraiosis in the elderly is well recognized. However, we demonstrate in the present study that even moderate increases in the 24 h systolic blood pressure load promote arteriolar fragility of the cerebral white matter. The prognostic implications of these abnormalities in the asymptomatic and moderate cardiovascular risk populations remain unclear. Ambulatory blood pressure monitoring appears once again to outperform other clinical measures currently used to predict the risk of cerebrovascular complications, including leukoaraiosis. Acknowledgements This study was supported by a grant from the French Minister of Health (Programme Hospitalier de Recherche Clinique, Délégation Régionale à la Recherche Clinique, CHU Saint-Étienne; PHRC National 1998 et PHRC National 2002), the Association de Recherche SYNAPSE, and by a grant from the Société Française d'Hypertension Artérielle (Bourse 2008). References [1] Debette S, Markus HS. The clinical importance of white matter hyperintensities on brain magnetic resonance imaging: systematic review and meta-analysis. BMJ 2010;341:c3666. [2] Wong TY, Klein R, Sharrett AR, et al. Study ARICIAR in C. Cerebral white matter lesions, retinopathy, and incident clinical stroke. JAMA 2002;288:67–74. [3] Au R, Massaro JM, Wolf PA, et al. Association of white matter hyperintensity volume with decreased cognitive functioning: the Framingham Heart Study. Arch Neurol 2006;63:246–50. [4] Schmidt R, Ropele S, Enzinger C, et al. White matter lesion progression, brain atrophy, and cognitive decline: the Austrian Stroke Prevention Study. Ann Neurol 2005;58:610–6. [5] Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol 2010;9:689–701. [6] Dufouil C, de Kersaint-Gilly A, Besançon V, et al. Longitudinal study of blood pressure and white matter hyperintensities: the EVA MRI Cohort. Neurology 2001;56:921–6. [7] de Leeuw F-E, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain 2002;125:765–72. [8] Guo X, Pantoni L, Simoni M, et al. Blood pressure components and changes in relation to white matter lesions: a 32-year prospective population study. Hypertension 2009;54:57–62. [9] Godin O, Tzourio C, Maillard P, Mazoyer B, Dufouil C. Antihypertensive treatment and change in blood pressure are associated with the progression of white matter lesion volumes: the Three-City (3C)-Dijon Magnetic Resonance Imaging Study. Circulation 2011;123:266–73.
J. Avet et al. / International Journal of Cardiology 172 (2014) 59–63 [10] Puisieux F, Monaca P, Deplanque D, et al. Relationship between leuko-araiosis and blood pressure variability in the elderly. Eur Neurol 2001;46:115–20. [11] Sierra C, Sierra A de L, Mercader J, Gómez-Angelats E, Urbano-Márquez A, Coca A. Silent cerebral white matter lesions in middle-aged essential hypertensive patients. J Hypertens 2002;20:519–24. [12] Mancia G, Backer GD, Dominiczak A, et al. 2007 guidelines for the management of arterial hypertension: the task force for the management of arterial hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). J Hypertens 2007;25:1105–87. [13] Mancia G, Parati G. The role of blood pressure variability in end-organ damage. J Hypertens Suppl 2003;21:S17–23. [14] Manschot SM, Brands AMA, van der Grond J, et al. Brain magnetic resonance imaging correlates of impaired cognition in patients with type 2 diabetes. Diabetes 2006;55:1106–13. [15] Schmidt R, Launer LJ, Nilsson L-G, et al. Magnetic resonance imaging of the brain in diabetes: the Cardiovascular Determinants of Dementia (CASCADE) Study. Diabetes 2004;53:687–92. [16] Barthelemy JC, Pichot V, Dauphinot V, et al. Autonomic nervous system activity and decline as prognostic indicators of cardiovascular and cerebrovascular events: the “PROOF” study. Study design and population sample. Associations with sleeprelated breathing disorders: the “SYNAPSE” Study. Neuroepidemiology 2007;29: 18–28. [17] Wahlund LO, Barkhof F, Fazekas F, et al. A new rating scale for age-related white matter changes applicable to MRI and CT. Stroke 2001;32:1318–22. [18] Fazekas F, Kleinert R, Offenbacher H, et al. The morphologic correlate of incidental punctate white matter hyperintensities on MR images. AJNR Am J Neuroradiol 1991;12:915–21. [19] O'Brien E, Waeber B, Parati G, Staessen J, Myers MG. Blood pressure measuring devices: recommendations of the European Society of Hypertension. BMJ 2001;322: 531–6. [20] Assoumou H-GN, Bertholon F, Barthélémy J-C, et al. Alteration of baroreflex sensitivity in the elderly: the relationship with metabolic syndrome components. Int J Cardiol 2012;155:333–5. [21] Gosse P, Dauphinot V, Roche F, Pichot V, Celle S, Barthelemy J-C. Prevalence of clinical and ambulatory hypertension in a population of 65-year-olds: the PROOF study. J Clin Hypertens (Greenwich) 2010;12:160–5.
63
[22] Sega R, Facchetti R, Bombelli M, et al. Prognostic value of ambulatory and home blood pressures compared with office blood pressure in the general population: follow-up results from the Pressioni Arteriose Monitorate e Loro Associazioni (PAMELA) study. Circulation 2005;111:1777–83. [23] Ohkubo T, Kikuya M, Metoki H, et al. Prognosis of “masked” hypertension and “white-coat” hypertension detected by 24-h ambulatory blood pressure monitoring 10-year follow-up from the Ohasama study. J Am Coll Cardiol 2005;46:508–15. [24] International Society for Chronobiology, American Association of Medical Chronobiology and Chronotherapeutics, Spanish Society of Applied Chronobiology, Chronotherapy, and Vascular Risk, Hermida RC, Smolensky MH, Ayala DE, et al. Ambulatory blood pressure monitoring recommendations for the diagnosis of adult hypertension, assessment of cardiovascular and other hypertension-associated risk, and attainment of therapeutic goals. Chronobiol Int 2013;30:355–410. [25] Ho N, Sommers MS, Lucki I. Effects of diabetes on hippocampal neurogenesis: links to cognition and depression. Neurosci Biobehav Rev 2013;37:1346–62. [26] Celle S, Annweiler C, Pichot V, et al. Association between ambulatory 24-hour blood pressure levels and brain volume reduction: a cross-sectional elderly populationbased study. Hypertension 2012;60:1324–31. [27] Jellinger KA. Pathology and pathophysiology of vascular cognitive impairment. A critical update. Panminerva Med 2004;46:217–26. [28] Cherubini A, Lowenthal DT, Paran E, Mecocci P, Williams LS, Senin U. Hypertension and cognitive function in the elderly. Am J Ther 2007;14:533–54. [29] Paglieri C, Bisbocci D, Caserta M, et al. Hypertension and cognitive function. Clin Exp Hypertens 2008;30:701–10. [30] Sörös P, Whitehead S, Spence JD, Hachinski V. Antihypertensive treatment can prevent stroke and cognitive decline. Nat Rev Neurol 2013;9:174–8. [31] Fagard RH, Cort PD. Orthostatic hypotension is a more robust predictor of cardiovascular events than nighttime reverse dipping in elderly. Hypertension 2010;56:56–61. [32] Verdecchia P, Angeli F, Mazzotta G, et al. Day–night dip and early-morning surge in blood pressure in hypertension: prognostic implications. Hypertension 2012;60:34–42. [33] Sforza E, Roche F, Thomas-Anterion C, et al. Cognitive function and sleep related breathing disorders in a healthy elderly population: the SYNAPSE study. Sleep 2010;33:515–21. [34] Beauchet O, Herrmann FR, Annweiler C, et al. Association between ambulatory 24hour blood pressure levels and cognitive performance: a cross-sectional elderly population-based study. Rejuvenation Res 2010;13:39–46.
