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Hypertrophic remodeling and increased arterial stiffness in patients with intracranial aneurysms
Atherosclerosis 211 (2010) 486–491
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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Hypertrophic remodeling and increased arterial stiffness in patients with intracranial aneurysms David Maltete a,1 , Jeremy Bellien b,1 , Lucie Cabrejo a , Michele Iacob b , Franc¸ois Proust c , Bruno Mihout a , Christian Thuillez b , Evelyne Guegan-Massardier a , Robinson Joannides b,∗ a Department of Neurology, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France b Department of Pharmacology, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France c Department of Neurosurgery, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France
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Article history: Received 8 February 2010 Received in revised form 21 March 2010 Accepted 1 April 2010 Available online 13 April 2010 Keywords: Intracranial aneurysm Pathophysiology Carotid artery Elasticity Haemodynamics
a b s t r a c t Objective: Because an underlying arteriopathy might contribute to the development of intracranial aneurysms (IAs), we assessed the elastic properties of proximal conduit arteries in patients with IA. Methods: In 27 patients with previous ruptured IA and 27 control subjects matched for age, gender and BMI, we determined arterial pressure, internal diameter, intima-media thickness (IMT), circumferential wall stress (CWS) and elastic modulus (wall stiffness) in common carotid arteries using applanation tonometry and echotracking. Moreover, carotid augmentation index (AIx, arterial wave reflections) and carotid-to-femoral pulse wave velocity (PWV, aortic stiffness) were assessed. Results: Compared with controls, patients with IA exhibited higher brachial and carotid systolic and diastolic blood pressures, with similar brachial but higher carotid artery pulse pressure (35 ± 6 mm Hg vs. 41 ± 8 mm Hg, P = 0.014). Moreover, patients have higher PWV (7.8 ± 1.2 m s−1 vs. 8.3 ± 1.1 m s−1 , P = 0.048) and AIx (15.8 ± 10.8% vs. 21.1 ± 8.5%, P < 0.001) which contributes to increase carotid blood pressures. Furthermore, carotid IMT was higher in patients (546 ± 64 m vs. 642 ± 70 m, P < 0.001) without difference in diameter suggesting an adaptive hypertrophy. However, patients display a lower CWS (61.6 ± 9.2 kPa vs. 56.9 ± 10.3 kPa, P = 0.007) and no correlation between IMT and pulse pressure (r = 0.152, P = NS) in contrast to controls (r = 0.539, P < 0.001) showing the contribution of a pressure-independent process. Finally, despite this lesser CWS, elastic modulus was increased in patients (310 ± 105 kPa vs. 383 ± 174 kPa, P = 0.026). Conclusion: This study demonstrates that patients with IA display a particular carotid artery phenotype with an exaggerated hypertrophic remodeling and altered elastic properties. Thus, a systemic arteriopathy might contribute, together with the arterial wall fatiguing effect of the increased pulsatile stress, to the pathogenesis of IA. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The rupture of intracranial aneurysms (IAs) generally occurs at young age and causes a subarachnoidal haemorrhage (SAH) leading to severe morbidity and high mortality [1,2]. Despite intensive researches, the pathogenesis of IA remains unclear but could be related to a disrupted balance between local high haemody-
∗ Corresponding author at: Département de Pharmacologie, Institut de Biologie Clinique, INSERM U644, IFRMP 23, CHU de Rouen, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 90 30; fax: +33 2 32 88 91 16. E-mail address: [email protected] (R. Joannides). 1 Both authors contribute equally to the study. 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.04.002
namic stresses and vascular wall strength at the sites of arterial bifurcations in particular within the circle of Willis. A defect in the extracellular matrix, which contributes to the elasticity of the arterial wall as well as the control of cell proliferation [3–5], is a likely factor involved. Indeed, IAs are more common in heritable connective tissue disorders and abnormalities in the structural proteins of the extracellular matrix, mainly elastin and collagen fibers, have been observed in aneurysm patients without known heritable diseases [6]. Because these abnormalities were found not only in the intracranial wall of many ruptured aneurysms but also in skin biopsies [7], and unaffected intracranial and peripheral conduit arteries [8,9], IAs might not be a localized disease but rather represent a more general disease of the extracellular matrix [7].
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Under these conditions, the geometrical and mechanical properties of arteries not directly concerned by aneurysm formation may be affected as previously observed in heritable connective tissue disorders [10,11]. However, few data are available and the results obtained are conflicting. Ex vivo experiments suggested no major changes in the elastic properties of intracranial and extracranial arteries obtained from patients with IA [12]. In contrast, an increased augmentation index in carotid arteries of patients with IA which may be related to altered arterial elastic properties was observed in vivo [13]. Indeed, assuming the measured pressure as resulting from the sum of forward and reflected pressure waves, the augmentation index represents the impact of arterial wave reflections on the magnitude of systolic blood pressure and pulse pressure in proximal conduit arteries and its increase can be related to (1) a longer systolic ejection time which increases the likelihood that arterial wave reflections will return to the proximal aorta during systole, (2) an early return of arterial wave reflections due to a decrease in proximal conduit artery distensibility and/or a shorter distance to reflecting sites, and (3) an increase in the magnitude of arterial wave reflections mainly determined by the peripheral vascular resistance and the geometric discontinuity of the successive arterial segments [14,15]. The aim of the present study was thus to assess in vivo the elastic properties of two proximal conduit arteries, the common carotid artery and the aorta, and to evaluate the determinants of the arterial wave reflections in patients with an antecedent of ruptured IA compared with control subjects in order to support or not the presence of an underlying systemic arteriopathy.
2. Methods 2.1. Subjects Twenty seven patients with an antecedent of ruptured IA (median delay at exploration: 5 [IQ: 2–7] years) documented by cerebral angiography and who received surgical treatment at the local Department of Neurosurgery were recruited for the study. Patients with IA were questioned for clinical personal and familial signs, i.e. history of ocular (dislocation of lenses, retinal detachment, glaucoma, maculopathy or cataracts), cardiovascular (valves defects), renal (hematuria, incidental discovery of hypertension, renal insufficiency or cystic kidney) and skin (easy bruising) abnormalities, suggestive of a hereditary connective tissue disorder. Moreover, they were carefully examined for classical features of: (i) Marfan syndrome (very tall, disproportionately long extremities, long, narrow face, pectus excavatum, scoliosis, flat feet, and joint hyperlaxity); (ii) Ehlers-Danlos type IV syndrome (facial dysmorphy, translucent skin, ecchymoses and haematomas); (iii) polycystic kidney disease (abdominal mass); (iv) or pseudoxanthoma elasticum (yellow-white small flat papules). None of the patients included have polycystic kidney disease, symptoms or familial history suggesting Marfan syndrome, Ehlers-Danlos syndrome type IV or pseudoxanthoma elasticum. In addition, patients with diabetes (fasting glycaemia > 1.26 g/L), untreated or complicated arterial hypertension, renal failure (creatinemia > 120 mol/L) or heart failure and any medical history or clinical symptoms of atherosclerosis (stroke, transient cerebral ischaemia, coronary artery disease or peripheral vascular disease) were excluded from the study. The inaugural event was SAH in all patients. A single aneurysm was found in 23 patients and predominantly affected the anterior communicating artery (n = 10); the remainder had multiple lesions. Familial antecedent of IA was found in 3 patients and abnormalities of the circle of Willis in 4 patients. Twenty seven control subjects carefully matched for age, sex, body mass index, total, LDL and HDL cholesterol
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and triglycerides were recruited. None of them had personal or familial history of cerebrovascular disease, aneurysm or heritable connective tissue disorder. The study has been carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association, and has been approved by the local ethical committee. All participants gave written informed consent. 2.2. Investigated parameters 2.2.1. Pulse wave analysis Brachial blood pressures were measured on the right arm using an oscillometric device (Omron HEM-705CP, Colson). After 10 min resting, blood pressure was measured over the brachial artery 3 times at 5-min intervals. Radial artery pressure waveforms of the same arm were recorded non-invasively by applanation tonometry using a pencil-type probe incorporating a high-fidelity Millar strain gauge transducer (SPT-301, Millar Instruments) and were calibrated using systolic and diastolic brachial pressures [10,11,16–19]. Radial artery waveforms were processed with dedicated software (SphygmoCor version 7, AtCor Medical) allowing to calculate an averaged radial artery waveform and derive a corresponding central aortic pressure waveform using a validated generalised transfer function. Aortic pressure waveforms were subjected to further analysis by the SphygmoCor software to identify the time to the shoulder of the first and second pressure wave components during systole. The pressure at the shoulder of the first component was identified as P1 height (forward pressure wave), and the pressure difference between this point and the maximal pressure during systole (augmentation: P) was identified as the reflected pressure wave. Augmentation index (AIx) was defined as the ratio of augmentation to central pulse pressure: AIx = (P/PP) × 100, where PP is pulse pressure. Pulse pressure amplification (PPA) was expressed as the ratio of central pulse pressure (CPP) to peripheral (radial) pulse pressure (PPP): PPA = PPP/CPP. Moreover, the time to return of the reflection wave of the aortic waveform was automatically calculated from the beginning of systole to the inflection point [19]. Furthermore, the right and left common carotid artery pressure waveforms were directly recorded by applanation tonometry, calibrated from diastolic pressure and the mean blood pressure determined by the integration of radial waveform, and similarly analyzed [10,11,16,18,19]. Carotid-to-femoral pulse wave velocity (PWV), an index of aortic stiffness, was determined by simultaneous measurement of pressure waves at the carotid and femoral arteries with sensitive pressure transducers (Complior SP, Artech-Medical) [10,11,16–19]. Briefly, the surface distance between the carotid and femoral recording sites was measured, and the pressure wave transit time was calculated using a footof-the-wave to foot-of-the-wave method. PWV was calculated by dividing the distance to the distal site by the pressure wave transit time. 2.2.2. Common carotid artery geometry Internal diameter (iD) and intima-media thickness (IMT) were measured on the far wall of the right and left common carotid arteries, 1 cm beneath the bifurcation, with high-resolution echotracking (Wall Track System, Esaote Pie Medical) as previously described [10,11,16]. The measurements were performed three times on each side and averaged. The repeatability coefficient (RC), defined by the British Standard Institution, was determined in the first 22 patients with IA to assess the intra-observer repeatability of internal diastolic diameter and IMT measurements. Calculated RC were 357 m for diameter and 30 m for IMT which was in agreement with previous published data [20,21]. Wall-to-lumen ratio was calculated in diastole as 2·IMT/iD.
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Fig. 1. Bar graphs show the values of carotid artery internal diastolic diameter (A) and intima-media thickness (B) in control subjects and in patients with intracranial aneurysms. Results are mean ± SD.
2.2.3. Common carotid artery elastic properties Circumferential wall stress (CWS) was calculated according to Lamé’s equation as CWS = (MBP·iD)/(2·IMT), where MBP and iD are mean blood pressure and internal diameter respectively [10,11,16]. Arterial compliance and distensibility were estimated through the variations in arterial cross-sectional area (A) and blood pressure (P), assuming the lumen to be circular. The cross-sectional compliance coefficient was calculated as CC = A/P and crosssectional distensibility coefficient as DC = A/A·P where A is the diastolic lumen area, A is the stroke change in lumen area, and P is the local pulse pressure measured with applanation tonometry [10,11,16]. The incremental Young’s elastic modulus (Einc), an index of the carotid wall material stiffness, was calculated as Einc = [3(1 + A/WCSA)]/DC, where A is the lumen area, WCSA is the wall-cross sectional area and DC is the cross-sectional distensibility [10,11,16]. 2.3. Statistical analysis Statistical analyses were performed by using SYSTAT package (version 8.0, SPSS Inc.). Data are expressed as mean ± SD. Demographic and radial artery parameters were analyzed using one-way ANOVA with group as factor and subject as cofactor. PWV was analyzed using one-way ANOVA with group as factor and subject and age as cofactors. Carotid artery parameters were compared by twoway ANOVA with group and site of measurement as factor and subject as cofactor. Pearson correlation analysis was performed to determine the relation between carotid artery IMT and local pulse pressure in patients with IA and in control subjects. A value of P < 0.05 was considered statistically significant. 3. Results 3.1. Demographic parameters Baseline characteristics of patients with IA and control subjects are presented in the Supplementary Table S1. There was no difference between group for age, sex ratio, BMI, smoking habit, total, LDL and HDL cholesterol, triglycerides and fasting glucose. Brachial systolic and diastolic blood pressures were higher in patients. However, there was no significant difference between groups for the number of treated mild to moderate hypertensive subjects, the nature and the duration of the antihypertensive treatments. Furthermore, there was no significant difference between groups for the number of hypercholesterolemic subjects and lipid lowering agents.
3.2. Pulse wave analysis The pulse wave analysis parameters are presented in Table 1. Peripheral and central aortic systolic, diastolic and mean blood pressures were higher in patients with IA compared with control subjects. In addition, central pulse pressure but not peripheral pulse pressure was significantly higher in patients. According with these findings, pulse pressure amplification was lesser in patients compared with controls. There was not significant difference between groups for heart rate or ejection duration. Furthermore, P1 height was similar but the central systolic pressure wave augmentation and the augmentation index were higher in patients compared with controls. PWV was increased in patients but this difference was no more significant when mean blood pressure (P = 0.775) or central pulse pressure (P = 0.697) are taken as covariate into analysis. According with this increase in PWV, the time to return of arterial wave reflections was reduced in patients. Indeed, the difference in the time to return was no more significant when PWV is taken as covariate into analysis (P = 0.135). Furthermore, the difference between groups for the augmentation index persisted when PWV (P = 0.045) or the time to reflection (P = 0.045) are taken as covariate into analysis but disappeared when diastolic blood pressure is introduced into the statistical model (P = 0.2).
3.3. Common carotid artery geometry and biomechanical properties In each group, there was no significant difference for all measured parameters between left and right measurements and thus, the data presented are the combined values of both sites of measurement. In agreement with the derived aortic data, carotid systolic, diastolic, mean blood pressures, pulse pressure and augmentation index were higher in patients compared with controls (Table 2). Diastolic internal diameter was not significantly different between groups whereas IMT was significantly higher in patients (Fig. 1). The difference between groups for IMT persisted after adjustment for carotid mean, systolic and pulse pressure (all P < 0.05). In addition, correlation analysis showed that IMT is positively linked with carotid pulse pressure in controls but not in patients (Fig. 2). As a result of the arterial wall thickening occurring without change in diameter, the wall-to-lumen ratio was significantly lesser in patients compared with controls. The stroke change in diameter was lower in patients. Despite of the increase in carotid mean blood pressure and IMT, the circumferential wall stress was significantly lesser in patients (Fig. 3). As regards the mechanical properties, despite their lesser circumferential wall stress, patients
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Table 1 Pulse wave analysis in patients with intracranial aneurysms and control subjects. Parameters
Patients with aneurysms (n = 27)
Peripheral SBP, mm Hg Peripheral DBP, mm Hg Peripheral MBP, mm Hg Peripheral PP, mm Hg Central SBP, mm Hg Central DBP, mm Hg Central PP, mm Hg Pulse pressure amplification, ratio Heart rate, bpm Ejection duration, ms P1 height, mm Hg Augmentation, mm Hg Augmentation index, % Tr, ms Aortic pulse wave velocity, m s−1
128 81 98 47 121 82 39 1.22 62 334 27.0 12.1 30.9 142 8.3
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
Control subjects (n = 27)
14 9 10 12 14 10 10 0.11 8 18 7.1 4.4 8.4 10 1.1
115 72 87 42 106 73 32 1.29 63 335 24.2 8.3 25.1 148 7.8
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
13 7 8 10 11 8 7 0.17 8 19 5.6 4.5 11.0 13 1.2
Statistics ANOVA (P) 0.004 0.001 <0.001 0.107 0.001 0.001 0.008 0.008 0.662 0.956 0.180 0.001 0.006 0.038 0.048
Values are mean ± SD. SBP, DBP, MBP and PP indicate respectively systolic, diastolic and mean blood pressure and pulse pressure; Tr, time to return of arterial wave reflections. Table 2 Common carotid artery parameters in patients with intracranial aneurysms and control subjects. Carotid artery parameters
Patients with aneurysms (n = 27)
Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Mean blood pressure, mm Hg Pulse pressure, mm Hg Augmentation index, % Stroke change in diameter, m Wall-to-lumen ratio
122 81 98 41 21.1 405 4.4
± ± ± ± ± ± ±
13 7 9 8 8.5 87 0.6
Control subjects (n = 27) 108 73 87 35 15.8 471 5.3
± ± ± ± ± ± ±
9 5 6 6 10.8 140 0.7
Statistics ANOVA (P) 0.009 0.042 0.015 0.014 <0.001 <0.001 <0.001
Values are mean ± SD.
Fig. 2. Line graphs show the correlation between carotid artery intima-media thickness and carotid pulse pressure in control subjects () and in patients with intracranial aneurysms (䊉). A positive relationship was observed in control subjects (continuous line, r = 0.539, P < 0.001) but not in patients with aneurysms (dotted line; r = 0.152, P = 0.274).
with IA exhibit a lesser cross-sectional compliance and distensibility and a higher incremental elastic modulus as compared with controls (Fig. 3). Finally, when comparing controls and patients with similar carotid artery systolic and diastolic blood pressures (Supplementary Table S2, n = 17 in each group), the increase in carotid artery IMT and, after adjustment for arterial wall stress, in elastic modulus were still present (both P < 0.05). 4. Discussion The major findings of this study are that patients with IA (1) exhibit an increase in central systolic blood pressure and pulse pressure due to aortic stiffening and increased effect of arterial wave
reflections and (2) display at the level of the carotid artery an arterial wall hypertrophy associated with a marked alteration in elastic properties. First of all, patients with IA exhibited higher peripheral and central systolic, diastolic and mean blood pressures than controls, emphasizing the role of blood pressure elevation in the physiopathology of IA [22]. This was observed although blood pressure remained within normal values with a small and similar number of treated hypertensive patients between groups. Furthermore, the pulse pressure amplification, i.e. the physiological increase in systolic and pulse pressure from central to peripheral arteries, was lesser in patients with IA compared with controls strongly suggesting, in absence of body height difference between groups, an altered cardiovascular coupling [19]. In accordance with the lesser amplification, central but not peripheral pulse pressure was significantly increased in patients with IA. These higher central systolic blood pressure and pulse pressure appear not related to an increase in the forward systolic pressure wave because P1 height was non significantly different between groups. In contrast, the central systolic pressure wave augmentation and the augmentation index were higher in patients demonstrating that an increase in arterial wave reflections mainly contributes to this increase. Our results are thus in accordance with those of Turner and coworkers that shown previously an increased augmentation index in patients with IA although they did not focus on the mechanisms involved [13]. In the present study, neither the left ventricular ejection time nor heart rate were different between groups and thus the increased augmentation index in patients cannot result from an increase in the likelihood that arterial wave reflections will return to the proximal aorta during systole. In contrast, pulse wave analysis revealed the presence of an early time to return of arterial wave reflections in patients compared with controls inducing an early summation of the reflected wave on the forward wave and thus contributing to the higher aortic systolic pressure wave reflections in patients. This early return is related to a decrease in proximal artery distensibility as demonstrated by the slight but significant increase in aortic
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Fig. 3. Bar graphs show the values of carotid artery circumferential wall stress (A), compliance (B), distensibility (C) and elastic modulus (D) in control subjects and in patients with intracranial aneurysms. Results are mean ± SD.
PWV which appears mainly pressure-dependent. Furthermore, a modification in the position of the reflecting sites appears to not play an additional role in the early return of arterial wave reflections since the difference between groups for the time to return of reflection waves did not persist after adjustment for aortic PWV. Finally, because the increase in PWV was modest and the difference between groups for the augmentation index persisted after adjustment for the PWV or the time to reflection, an increase in the magnitude of arterial wave reflections may also be involved. Changes in vascular structure and/or function of reflection sites which are predominantly located at the origin of resistance arterioles might be an explanation for differential patterns of wave reflections [14,15]. In the present work, we observed a higher diastolic blood pressure in patients with IA suggesting an increased peripheral vascular resistance and thus the presence of arteriolar abnormalities which might enhance the magnitude of reflection waves as observed during essential hypertension [23]. Consistent with this hypothesis, the difference between groups for augmentation index did not persist after adjustment for diastolic blood pressure. As regards the carotid arteries, pulse wave analysis directly confirmed the increase in central systolic and pulse pressures and in augmentation index. As stressed by Turner et al. [13], flow patterns within the circle of Willis are influenced by the input blood pressure profiles generated within the extracranial carotid arteries and therefore, this increase in pulsatile mechanical load might contribute to IA development [24]. Indeed, cyclic stress exerts a fatiguing effect on the load-bearing elements of the arterial wall that is dependent of both the number of cycles and the magnitude of wall stress [14] and mathematical models showed, that the blood pressure-dependent wall stress loading of aneurysms is a major
determinant of the time for them to rupture [25]. Furthermore, patients with IAs exhibit an increased carotid artery IMT without significant difference in diameter and thus a higher wall-to-lumen ratio compared to controls. These results suggest an adaptive hypertrophy to pressure overload in patients with IAs. However, the circumferential wall stress was lesser in these patients compared with controls supporting the presence of an exaggerate hypertrophy involving pressure-independent processes. According with this hypothesis, correlation analysis revealed that local pulse pressure is a main determinant of IMT in control subjects, as previously shown in normotensive and hypertensive subjects [26], but not in patients with IA. Such arterial wall hypertrophy and decrease in wall stress were previously reported ex vivo in intracranial arteries of patients with IA even in absence of hypertension but was not yet reported at the level of extracranial arteries [12,27]. As regards the arterial mechanical properties, despite this lesser circumferential wall stress, patients with IA display an altered cross-sectional compliance and distensibility and higher elastic modulus compared with control subjects demonstrating a decrease in arterial chamber deformability and an increase in carotid artery wall material stiffness. These results seem to contrast with one previous ex vivo study showing no change in the pressure-distensibility relationship of the anterior cerebral artery in patients with IA [12]. However, if the associated decrease in wall stress had been considered, the results would have been probably similar to ours showing a decrease in distensibility at each level of wall stress [12]. In this way, when comparing patients and controls matched for carotid blood pressures, the increase in carotid IMT and in wall stress-adjusted increase in elastic modulus were still significant in patients with IA. At last, whether the absence of
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pressure-independent increase in aortic stiffness is related or not to a difference in aortic geometry remains to be clarified. Furthermore, although all the participants suffered an aneurysmal rupture, the arterial thickening and stiffening cannot be the consequence of SAH but rather represent a generalised vasculopathy since it was observed in both the left and right carotid arteries even if the SAH was localized on one side. In addition, In the same way, although not analyzed in the present study, the carotid artery wall hypertrophy and stiffening appeared higher in women with IA compared with men and thus may contribute to the higher incidence of IA and SAH in women [1]. Finally, concerning the mechanism involved, these alterations of arterial structure and function might promote an abnormal responsiveness of the arterial wall to increased haemodynamic stresses thus favoring the formation and rupture of aneurysms. This process may be particularly relevant at the level of intracerebral vessels where external elastic lamina is lacking and perivascular support is lower. Furthermore, although not addressed in the present study, this carotid artery remodeling and stiffening could be related to the defects in the constituents of extracellular matrix, elastin, collagen type 3 and proteoglycans [6–8,28,29]. In particular, defects in elastin is associated with arterial hypertrophy while collagen abnormalities may promote mechanical weakness and IA development [10,11,30]. Thus, our results as well as those obtain in genetic and histomorphological studies support the hypothesis that a complex multifactorial disease caused by the interaction of several inherited and environmental factors promotes IA development [6–8,28,29]. In conclusion, this study demonstrates that patients with an antecedent of IA, in addition to altered cardiovascular coupling and elevated blood pressure, exhibit a particular carotid artery phenotype with an hypertrophic remodeling and altered elastic properties. This particular phenotype supports the hypothesis for a generalised arteriopathy in patients with IAs which might contribute together with the fatiguing effect of increased pulsatile stress on the arterial wall to the pathogenesis of aneurysms. Additional prospective studies are needed to confirm the prognostic role of these alterations on IA development but this may help to identify patients at risk for rupture and thus may represent an important therapeutic target in addition to blood pressure lowering. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.atherosclerosis.2010.04.002. References [1] Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998;29:251–6. [2] Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997;28:660–4. [3] Glagov S, Vito R, Giddens DP, Zarins CK. Micro-architecture and composition of artery walls: relationship to location, diameter and the distribution of mechanical stress. J Hypertens Suppl 1992;10:S101–4. [4] Kresse H, Schönherr E. Proteoglycans of the extracellular matrix and growth control. J Cell Physiol 2001;189:266–74.
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Hypertrophic remodeling and increased arterial stiffness in patients with intracranial aneurysms David Maltete a,1 , Jeremy Bellien b,1 , Lucie Cabrejo a , Michele Iacob b , Franc¸ois Proust c , Bruno Mihout a , Christian Thuillez b , Evelyne Guegan-Massardier a , Robinson Joannides b,∗ a Department of Neurology, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France b Department of Pharmacology, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France c Department of Neurosurgery, CHU-Hopitaux de Rouen & Institut National de la Sante et de la Recherche Medicale (INSERM) U644, Institut Federatif de Recherche Multidisciplinaire sur les Peptides (IFRMP) 23, Institute for Biomedical Research, University of Rouen, France
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Article history: Received 8 February 2010 Received in revised form 21 March 2010 Accepted 1 April 2010 Available online 13 April 2010 Keywords: Intracranial aneurysm Pathophysiology Carotid artery Elasticity Haemodynamics
a b s t r a c t Objective: Because an underlying arteriopathy might contribute to the development of intracranial aneurysms (IAs), we assessed the elastic properties of proximal conduit arteries in patients with IA. Methods: In 27 patients with previous ruptured IA and 27 control subjects matched for age, gender and BMI, we determined arterial pressure, internal diameter, intima-media thickness (IMT), circumferential wall stress (CWS) and elastic modulus (wall stiffness) in common carotid arteries using applanation tonometry and echotracking. Moreover, carotid augmentation index (AIx, arterial wave reflections) and carotid-to-femoral pulse wave velocity (PWV, aortic stiffness) were assessed. Results: Compared with controls, patients with IA exhibited higher brachial and carotid systolic and diastolic blood pressures, with similar brachial but higher carotid artery pulse pressure (35 ± 6 mm Hg vs. 41 ± 8 mm Hg, P = 0.014). Moreover, patients have higher PWV (7.8 ± 1.2 m s−1 vs. 8.3 ± 1.1 m s−1 , P = 0.048) and AIx (15.8 ± 10.8% vs. 21.1 ± 8.5%, P < 0.001) which contributes to increase carotid blood pressures. Furthermore, carotid IMT was higher in patients (546 ± 64 m vs. 642 ± 70 m, P < 0.001) without difference in diameter suggesting an adaptive hypertrophy. However, patients display a lower CWS (61.6 ± 9.2 kPa vs. 56.9 ± 10.3 kPa, P = 0.007) and no correlation between IMT and pulse pressure (r = 0.152, P = NS) in contrast to controls (r = 0.539, P < 0.001) showing the contribution of a pressure-independent process. Finally, despite this lesser CWS, elastic modulus was increased in patients (310 ± 105 kPa vs. 383 ± 174 kPa, P = 0.026). Conclusion: This study demonstrates that patients with IA display a particular carotid artery phenotype with an exaggerated hypertrophic remodeling and altered elastic properties. Thus, a systemic arteriopathy might contribute, together with the arterial wall fatiguing effect of the increased pulsatile stress, to the pathogenesis of IA. © 2010 Elsevier Ireland Ltd. All rights reserved.
1. Introduction The rupture of intracranial aneurysms (IAs) generally occurs at young age and causes a subarachnoidal haemorrhage (SAH) leading to severe morbidity and high mortality [1,2]. Despite intensive researches, the pathogenesis of IA remains unclear but could be related to a disrupted balance between local high haemody-
∗ Corresponding author at: Département de Pharmacologie, Institut de Biologie Clinique, INSERM U644, IFRMP 23, CHU de Rouen, 76031 Rouen Cedex, France. Tel.: +33 2 32 88 90 30; fax: +33 2 32 88 91 16. E-mail address: [email protected] (R. Joannides). 1 Both authors contribute equally to the study. 0021-9150/$ – see front matter © 2010 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2010.04.002
namic stresses and vascular wall strength at the sites of arterial bifurcations in particular within the circle of Willis. A defect in the extracellular matrix, which contributes to the elasticity of the arterial wall as well as the control of cell proliferation [3–5], is a likely factor involved. Indeed, IAs are more common in heritable connective tissue disorders and abnormalities in the structural proteins of the extracellular matrix, mainly elastin and collagen fibers, have been observed in aneurysm patients without known heritable diseases [6]. Because these abnormalities were found not only in the intracranial wall of many ruptured aneurysms but also in skin biopsies [7], and unaffected intracranial and peripheral conduit arteries [8,9], IAs might not be a localized disease but rather represent a more general disease of the extracellular matrix [7].
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Under these conditions, the geometrical and mechanical properties of arteries not directly concerned by aneurysm formation may be affected as previously observed in heritable connective tissue disorders [10,11]. However, few data are available and the results obtained are conflicting. Ex vivo experiments suggested no major changes in the elastic properties of intracranial and extracranial arteries obtained from patients with IA [12]. In contrast, an increased augmentation index in carotid arteries of patients with IA which may be related to altered arterial elastic properties was observed in vivo [13]. Indeed, assuming the measured pressure as resulting from the sum of forward and reflected pressure waves, the augmentation index represents the impact of arterial wave reflections on the magnitude of systolic blood pressure and pulse pressure in proximal conduit arteries and its increase can be related to (1) a longer systolic ejection time which increases the likelihood that arterial wave reflections will return to the proximal aorta during systole, (2) an early return of arterial wave reflections due to a decrease in proximal conduit artery distensibility and/or a shorter distance to reflecting sites, and (3) an increase in the magnitude of arterial wave reflections mainly determined by the peripheral vascular resistance and the geometric discontinuity of the successive arterial segments [14,15]. The aim of the present study was thus to assess in vivo the elastic properties of two proximal conduit arteries, the common carotid artery and the aorta, and to evaluate the determinants of the arterial wave reflections in patients with an antecedent of ruptured IA compared with control subjects in order to support or not the presence of an underlying systemic arteriopathy.
2. Methods 2.1. Subjects Twenty seven patients with an antecedent of ruptured IA (median delay at exploration: 5 [IQ: 2–7] years) documented by cerebral angiography and who received surgical treatment at the local Department of Neurosurgery were recruited for the study. Patients with IA were questioned for clinical personal and familial signs, i.e. history of ocular (dislocation of lenses, retinal detachment, glaucoma, maculopathy or cataracts), cardiovascular (valves defects), renal (hematuria, incidental discovery of hypertension, renal insufficiency or cystic kidney) and skin (easy bruising) abnormalities, suggestive of a hereditary connective tissue disorder. Moreover, they were carefully examined for classical features of: (i) Marfan syndrome (very tall, disproportionately long extremities, long, narrow face, pectus excavatum, scoliosis, flat feet, and joint hyperlaxity); (ii) Ehlers-Danlos type IV syndrome (facial dysmorphy, translucent skin, ecchymoses and haematomas); (iii) polycystic kidney disease (abdominal mass); (iv) or pseudoxanthoma elasticum (yellow-white small flat papules). None of the patients included have polycystic kidney disease, symptoms or familial history suggesting Marfan syndrome, Ehlers-Danlos syndrome type IV or pseudoxanthoma elasticum. In addition, patients with diabetes (fasting glycaemia > 1.26 g/L), untreated or complicated arterial hypertension, renal failure (creatinemia > 120 mol/L) or heart failure and any medical history or clinical symptoms of atherosclerosis (stroke, transient cerebral ischaemia, coronary artery disease or peripheral vascular disease) were excluded from the study. The inaugural event was SAH in all patients. A single aneurysm was found in 23 patients and predominantly affected the anterior communicating artery (n = 10); the remainder had multiple lesions. Familial antecedent of IA was found in 3 patients and abnormalities of the circle of Willis in 4 patients. Twenty seven control subjects carefully matched for age, sex, body mass index, total, LDL and HDL cholesterol
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and triglycerides were recruited. None of them had personal or familial history of cerebrovascular disease, aneurysm or heritable connective tissue disorder. The study has been carried out in accordance with the Declaration of Helsinki (2000) of the World Medical Association, and has been approved by the local ethical committee. All participants gave written informed consent. 2.2. Investigated parameters 2.2.1. Pulse wave analysis Brachial blood pressures were measured on the right arm using an oscillometric device (Omron HEM-705CP, Colson). After 10 min resting, blood pressure was measured over the brachial artery 3 times at 5-min intervals. Radial artery pressure waveforms of the same arm were recorded non-invasively by applanation tonometry using a pencil-type probe incorporating a high-fidelity Millar strain gauge transducer (SPT-301, Millar Instruments) and were calibrated using systolic and diastolic brachial pressures [10,11,16–19]. Radial artery waveforms were processed with dedicated software (SphygmoCor version 7, AtCor Medical) allowing to calculate an averaged radial artery waveform and derive a corresponding central aortic pressure waveform using a validated generalised transfer function. Aortic pressure waveforms were subjected to further analysis by the SphygmoCor software to identify the time to the shoulder of the first and second pressure wave components during systole. The pressure at the shoulder of the first component was identified as P1 height (forward pressure wave), and the pressure difference between this point and the maximal pressure during systole (augmentation: P) was identified as the reflected pressure wave. Augmentation index (AIx) was defined as the ratio of augmentation to central pulse pressure: AIx = (P/PP) × 100, where PP is pulse pressure. Pulse pressure amplification (PPA) was expressed as the ratio of central pulse pressure (CPP) to peripheral (radial) pulse pressure (PPP): PPA = PPP/CPP. Moreover, the time to return of the reflection wave of the aortic waveform was automatically calculated from the beginning of systole to the inflection point [19]. Furthermore, the right and left common carotid artery pressure waveforms were directly recorded by applanation tonometry, calibrated from diastolic pressure and the mean blood pressure determined by the integration of radial waveform, and similarly analyzed [10,11,16,18,19]. Carotid-to-femoral pulse wave velocity (PWV), an index of aortic stiffness, was determined by simultaneous measurement of pressure waves at the carotid and femoral arteries with sensitive pressure transducers (Complior SP, Artech-Medical) [10,11,16–19]. Briefly, the surface distance between the carotid and femoral recording sites was measured, and the pressure wave transit time was calculated using a footof-the-wave to foot-of-the-wave method. PWV was calculated by dividing the distance to the distal site by the pressure wave transit time. 2.2.2. Common carotid artery geometry Internal diameter (iD) and intima-media thickness (IMT) were measured on the far wall of the right and left common carotid arteries, 1 cm beneath the bifurcation, with high-resolution echotracking (Wall Track System, Esaote Pie Medical) as previously described [10,11,16]. The measurements were performed three times on each side and averaged. The repeatability coefficient (RC), defined by the British Standard Institution, was determined in the first 22 patients with IA to assess the intra-observer repeatability of internal diastolic diameter and IMT measurements. Calculated RC were 357 m for diameter and 30 m for IMT which was in agreement with previous published data [20,21]. Wall-to-lumen ratio was calculated in diastole as 2·IMT/iD.
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Fig. 1. Bar graphs show the values of carotid artery internal diastolic diameter (A) and intima-media thickness (B) in control subjects and in patients with intracranial aneurysms. Results are mean ± SD.
2.2.3. Common carotid artery elastic properties Circumferential wall stress (CWS) was calculated according to Lamé’s equation as CWS = (MBP·iD)/(2·IMT), where MBP and iD are mean blood pressure and internal diameter respectively [10,11,16]. Arterial compliance and distensibility were estimated through the variations in arterial cross-sectional area (A) and blood pressure (P), assuming the lumen to be circular. The cross-sectional compliance coefficient was calculated as CC = A/P and crosssectional distensibility coefficient as DC = A/A·P where A is the diastolic lumen area, A is the stroke change in lumen area, and P is the local pulse pressure measured with applanation tonometry [10,11,16]. The incremental Young’s elastic modulus (Einc), an index of the carotid wall material stiffness, was calculated as Einc = [3(1 + A/WCSA)]/DC, where A is the lumen area, WCSA is the wall-cross sectional area and DC is the cross-sectional distensibility [10,11,16]. 2.3. Statistical analysis Statistical analyses were performed by using SYSTAT package (version 8.0, SPSS Inc.). Data are expressed as mean ± SD. Demographic and radial artery parameters were analyzed using one-way ANOVA with group as factor and subject as cofactor. PWV was analyzed using one-way ANOVA with group as factor and subject and age as cofactors. Carotid artery parameters were compared by twoway ANOVA with group and site of measurement as factor and subject as cofactor. Pearson correlation analysis was performed to determine the relation between carotid artery IMT and local pulse pressure in patients with IA and in control subjects. A value of P < 0.05 was considered statistically significant. 3. Results 3.1. Demographic parameters Baseline characteristics of patients with IA and control subjects are presented in the Supplementary Table S1. There was no difference between group for age, sex ratio, BMI, smoking habit, total, LDL and HDL cholesterol, triglycerides and fasting glucose. Brachial systolic and diastolic blood pressures were higher in patients. However, there was no significant difference between groups for the number of treated mild to moderate hypertensive subjects, the nature and the duration of the antihypertensive treatments. Furthermore, there was no significant difference between groups for the number of hypercholesterolemic subjects and lipid lowering agents.
3.2. Pulse wave analysis The pulse wave analysis parameters are presented in Table 1. Peripheral and central aortic systolic, diastolic and mean blood pressures were higher in patients with IA compared with control subjects. In addition, central pulse pressure but not peripheral pulse pressure was significantly higher in patients. According with these findings, pulse pressure amplification was lesser in patients compared with controls. There was not significant difference between groups for heart rate or ejection duration. Furthermore, P1 height was similar but the central systolic pressure wave augmentation and the augmentation index were higher in patients compared with controls. PWV was increased in patients but this difference was no more significant when mean blood pressure (P = 0.775) or central pulse pressure (P = 0.697) are taken as covariate into analysis. According with this increase in PWV, the time to return of arterial wave reflections was reduced in patients. Indeed, the difference in the time to return was no more significant when PWV is taken as covariate into analysis (P = 0.135). Furthermore, the difference between groups for the augmentation index persisted when PWV (P = 0.045) or the time to reflection (P = 0.045) are taken as covariate into analysis but disappeared when diastolic blood pressure is introduced into the statistical model (P = 0.2).
3.3. Common carotid artery geometry and biomechanical properties In each group, there was no significant difference for all measured parameters between left and right measurements and thus, the data presented are the combined values of both sites of measurement. In agreement with the derived aortic data, carotid systolic, diastolic, mean blood pressures, pulse pressure and augmentation index were higher in patients compared with controls (Table 2). Diastolic internal diameter was not significantly different between groups whereas IMT was significantly higher in patients (Fig. 1). The difference between groups for IMT persisted after adjustment for carotid mean, systolic and pulse pressure (all P < 0.05). In addition, correlation analysis showed that IMT is positively linked with carotid pulse pressure in controls but not in patients (Fig. 2). As a result of the arterial wall thickening occurring without change in diameter, the wall-to-lumen ratio was significantly lesser in patients compared with controls. The stroke change in diameter was lower in patients. Despite of the increase in carotid mean blood pressure and IMT, the circumferential wall stress was significantly lesser in patients (Fig. 3). As regards the mechanical properties, despite their lesser circumferential wall stress, patients
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Table 1 Pulse wave analysis in patients with intracranial aneurysms and control subjects. Parameters
Patients with aneurysms (n = 27)
Peripheral SBP, mm Hg Peripheral DBP, mm Hg Peripheral MBP, mm Hg Peripheral PP, mm Hg Central SBP, mm Hg Central DBP, mm Hg Central PP, mm Hg Pulse pressure amplification, ratio Heart rate, bpm Ejection duration, ms P1 height, mm Hg Augmentation, mm Hg Augmentation index, % Tr, ms Aortic pulse wave velocity, m s−1
128 81 98 47 121 82 39 1.22 62 334 27.0 12.1 30.9 142 8.3
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
Control subjects (n = 27)
14 9 10 12 14 10 10 0.11 8 18 7.1 4.4 8.4 10 1.1
115 72 87 42 106 73 32 1.29 63 335 24.2 8.3 25.1 148 7.8
± ± ± ± ± ± ± ± ± ± ± ± ± ± ±
13 7 8 10 11 8 7 0.17 8 19 5.6 4.5 11.0 13 1.2
Statistics ANOVA (P) 0.004 0.001 <0.001 0.107 0.001 0.001 0.008 0.008 0.662 0.956 0.180 0.001 0.006 0.038 0.048
Values are mean ± SD. SBP, DBP, MBP and PP indicate respectively systolic, diastolic and mean blood pressure and pulse pressure; Tr, time to return of arterial wave reflections. Table 2 Common carotid artery parameters in patients with intracranial aneurysms and control subjects. Carotid artery parameters
Patients with aneurysms (n = 27)
Systolic blood pressure, mm Hg Diastolic blood pressure, mm Hg Mean blood pressure, mm Hg Pulse pressure, mm Hg Augmentation index, % Stroke change in diameter, m Wall-to-lumen ratio
122 81 98 41 21.1 405 4.4
± ± ± ± ± ± ±
13 7 9 8 8.5 87 0.6
Control subjects (n = 27) 108 73 87 35 15.8 471 5.3
± ± ± ± ± ± ±
9 5 6 6 10.8 140 0.7
Statistics ANOVA (P) 0.009 0.042 0.015 0.014 <0.001 <0.001 <0.001
Values are mean ± SD.
Fig. 2. Line graphs show the correlation between carotid artery intima-media thickness and carotid pulse pressure in control subjects () and in patients with intracranial aneurysms (䊉). A positive relationship was observed in control subjects (continuous line, r = 0.539, P < 0.001) but not in patients with aneurysms (dotted line; r = 0.152, P = 0.274).
with IA exhibit a lesser cross-sectional compliance and distensibility and a higher incremental elastic modulus as compared with controls (Fig. 3). Finally, when comparing controls and patients with similar carotid artery systolic and diastolic blood pressures (Supplementary Table S2, n = 17 in each group), the increase in carotid artery IMT and, after adjustment for arterial wall stress, in elastic modulus were still present (both P < 0.05). 4. Discussion The major findings of this study are that patients with IA (1) exhibit an increase in central systolic blood pressure and pulse pressure due to aortic stiffening and increased effect of arterial wave
reflections and (2) display at the level of the carotid artery an arterial wall hypertrophy associated with a marked alteration in elastic properties. First of all, patients with IA exhibited higher peripheral and central systolic, diastolic and mean blood pressures than controls, emphasizing the role of blood pressure elevation in the physiopathology of IA [22]. This was observed although blood pressure remained within normal values with a small and similar number of treated hypertensive patients between groups. Furthermore, the pulse pressure amplification, i.e. the physiological increase in systolic and pulse pressure from central to peripheral arteries, was lesser in patients with IA compared with controls strongly suggesting, in absence of body height difference between groups, an altered cardiovascular coupling [19]. In accordance with the lesser amplification, central but not peripheral pulse pressure was significantly increased in patients with IA. These higher central systolic blood pressure and pulse pressure appear not related to an increase in the forward systolic pressure wave because P1 height was non significantly different between groups. In contrast, the central systolic pressure wave augmentation and the augmentation index were higher in patients demonstrating that an increase in arterial wave reflections mainly contributes to this increase. Our results are thus in accordance with those of Turner and coworkers that shown previously an increased augmentation index in patients with IA although they did not focus on the mechanisms involved [13]. In the present study, neither the left ventricular ejection time nor heart rate were different between groups and thus the increased augmentation index in patients cannot result from an increase in the likelihood that arterial wave reflections will return to the proximal aorta during systole. In contrast, pulse wave analysis revealed the presence of an early time to return of arterial wave reflections in patients compared with controls inducing an early summation of the reflected wave on the forward wave and thus contributing to the higher aortic systolic pressure wave reflections in patients. This early return is related to a decrease in proximal artery distensibility as demonstrated by the slight but significant increase in aortic
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Fig. 3. Bar graphs show the values of carotid artery circumferential wall stress (A), compliance (B), distensibility (C) and elastic modulus (D) in control subjects and in patients with intracranial aneurysms. Results are mean ± SD.
PWV which appears mainly pressure-dependent. Furthermore, a modification in the position of the reflecting sites appears to not play an additional role in the early return of arterial wave reflections since the difference between groups for the time to return of reflection waves did not persist after adjustment for aortic PWV. Finally, because the increase in PWV was modest and the difference between groups for the augmentation index persisted after adjustment for the PWV or the time to reflection, an increase in the magnitude of arterial wave reflections may also be involved. Changes in vascular structure and/or function of reflection sites which are predominantly located at the origin of resistance arterioles might be an explanation for differential patterns of wave reflections [14,15]. In the present work, we observed a higher diastolic blood pressure in patients with IA suggesting an increased peripheral vascular resistance and thus the presence of arteriolar abnormalities which might enhance the magnitude of reflection waves as observed during essential hypertension [23]. Consistent with this hypothesis, the difference between groups for augmentation index did not persist after adjustment for diastolic blood pressure. As regards the carotid arteries, pulse wave analysis directly confirmed the increase in central systolic and pulse pressures and in augmentation index. As stressed by Turner et al. [13], flow patterns within the circle of Willis are influenced by the input blood pressure profiles generated within the extracranial carotid arteries and therefore, this increase in pulsatile mechanical load might contribute to IA development [24]. Indeed, cyclic stress exerts a fatiguing effect on the load-bearing elements of the arterial wall that is dependent of both the number of cycles and the magnitude of wall stress [14] and mathematical models showed, that the blood pressure-dependent wall stress loading of aneurysms is a major
determinant of the time for them to rupture [25]. Furthermore, patients with IAs exhibit an increased carotid artery IMT without significant difference in diameter and thus a higher wall-to-lumen ratio compared to controls. These results suggest an adaptive hypertrophy to pressure overload in patients with IAs. However, the circumferential wall stress was lesser in these patients compared with controls supporting the presence of an exaggerate hypertrophy involving pressure-independent processes. According with this hypothesis, correlation analysis revealed that local pulse pressure is a main determinant of IMT in control subjects, as previously shown in normotensive and hypertensive subjects [26], but not in patients with IA. Such arterial wall hypertrophy and decrease in wall stress were previously reported ex vivo in intracranial arteries of patients with IA even in absence of hypertension but was not yet reported at the level of extracranial arteries [12,27]. As regards the arterial mechanical properties, despite this lesser circumferential wall stress, patients with IA display an altered cross-sectional compliance and distensibility and higher elastic modulus compared with control subjects demonstrating a decrease in arterial chamber deformability and an increase in carotid artery wall material stiffness. These results seem to contrast with one previous ex vivo study showing no change in the pressure-distensibility relationship of the anterior cerebral artery in patients with IA [12]. However, if the associated decrease in wall stress had been considered, the results would have been probably similar to ours showing a decrease in distensibility at each level of wall stress [12]. In this way, when comparing patients and controls matched for carotid blood pressures, the increase in carotid IMT and in wall stress-adjusted increase in elastic modulus were still significant in patients with IA. At last, whether the absence of
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pressure-independent increase in aortic stiffness is related or not to a difference in aortic geometry remains to be clarified. Furthermore, although all the participants suffered an aneurysmal rupture, the arterial thickening and stiffening cannot be the consequence of SAH but rather represent a generalised vasculopathy since it was observed in both the left and right carotid arteries even if the SAH was localized on one side. In addition, In the same way, although not analyzed in the present study, the carotid artery wall hypertrophy and stiffening appeared higher in women with IA compared with men and thus may contribute to the higher incidence of IA and SAH in women [1]. Finally, concerning the mechanism involved, these alterations of arterial structure and function might promote an abnormal responsiveness of the arterial wall to increased haemodynamic stresses thus favoring the formation and rupture of aneurysms. This process may be particularly relevant at the level of intracerebral vessels where external elastic lamina is lacking and perivascular support is lower. Furthermore, although not addressed in the present study, this carotid artery remodeling and stiffening could be related to the defects in the constituents of extracellular matrix, elastin, collagen type 3 and proteoglycans [6–8,28,29]. In particular, defects in elastin is associated with arterial hypertrophy while collagen abnormalities may promote mechanical weakness and IA development [10,11,30]. Thus, our results as well as those obtain in genetic and histomorphological studies support the hypothesis that a complex multifactorial disease caused by the interaction of several inherited and environmental factors promotes IA development [6–8,28,29]. In conclusion, this study demonstrates that patients with an antecedent of IA, in addition to altered cardiovascular coupling and elevated blood pressure, exhibit a particular carotid artery phenotype with an hypertrophic remodeling and altered elastic properties. This particular phenotype supports the hypothesis for a generalised arteriopathy in patients with IAs which might contribute together with the fatiguing effect of increased pulsatile stress on the arterial wall to the pathogenesis of aneurysms. Additional prospective studies are needed to confirm the prognostic role of these alterations on IA development but this may help to identify patients at risk for rupture and thus may represent an important therapeutic target in addition to blood pressure lowering. Conflict of interest None. Appendix A. Supplementary data Supplementary data associated with this article can be found, in the online version, at doi:10.1016/j.atherosclerosis.2010.04.002. References [1] Rinkel GJ, Djibuti M, Algra A, van Gijn J. Prevalence and risk of rupture of intracranial aneurysms: a systematic review. Stroke 1998;29:251–6. [2] Hop JW, Rinkel GJ, Algra A, van Gijn J. Case-fatality rates and functional outcome after subarachnoid hemorrhage: a systematic review. Stroke 1997;28:660–4. [3] Glagov S, Vito R, Giddens DP, Zarins CK. Micro-architecture and composition of artery walls: relationship to location, diameter and the distribution of mechanical stress. J Hypertens Suppl 1992;10:S101–4. [4] Kresse H, Schönherr E. Proteoglycans of the extracellular matrix and growth control. J Cell Physiol 2001;189:266–74.
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