Abstract-We hypothesized that age-linked changes in the composition and elastic properties of the arterial wall occur earlier in hypertensive than in normotensive rats. We evaluated the consequences of hypertension and aging on aortic mechanics, geometry, and composition in 3-, 9-, and 15-month-old awake Wistar-Kyoto rats (WKY) (normotensive) and spontaneously hypertensive rats (SHR) (hypertensive). The elastic modulus of the thoracic aorta, calculated from aortic pulse wave velocity and geometry, was higher in young and adult SHR than in age-matched WKY, as was wall stress; however, isobaric pulse wave velocity and pulse wave velocity-pressure curves were similar. Elastic modulus, isobaric pulse wave velocity, and the slope of the pulse wave velocity-pressure curve dramatically increased in old SHR compared with age-matched WKY; there was no further elevation of blood pressure or wall thickness. Fibrosis did not develop with age in SHR, and the ratio of elastin to collagen decreased in a similar fashion with aging in both strains.In conclusion, although elastic properties of the aortic wall are not intrinsically modified in young and adult SHR in comparison to age-matched WKY, aging is associated with a dramatic stiffening of the aortic wall in old SHR but not in WKY. Changes in blood pressure, aortic wall geometry, or scleroprotein composition do not appear to explain this age-linked aortic stiffening in SHR, suggesting that other mechanisms of disorganization of the media may be involved. Key Words: elastin Ⅲ collagen Ⅲ elasticity Ⅲ stress Ⅲ aging Ⅲ hypertension, experimental A ging produces many vascular changes, one of the most important being a progressive rise in arterial stiffness. 1,2 The thickness of the media increases with age because of smooth muscle cell hypertrophy and fibrosis. The elastic fiber network develops longitudinal fissures, transverse breaks, and fragmentation. Such structural modifications (fibrosis and degradation of elastin) lead to a decrease in elasticity. 3 Hypertension also may produce an increase in large-artery stiffness, 4,5 at least when elastic properties are measured at a hypertensive level. 6 -9 However, previous experiments on the effects of hypertension were performed mainly in young or adult subjects, 6 -9 and the consequences of a combination of hypertension and aging on the elastic properties of the aortic wall remain unexplored. 10,11 The first objective of the present study was to evaluate the elastic properties of the aorta of 3-, 9-, and 15-month-old normotensive Wistar-Kyoto rats (WKY) and hypertensive spontaneously hypertensive rats (SHR). This was done by analyzing in awake animals the relationships between (1) pulse wave velocity and central mean aortic blood pressure under a wide range of pressure and (2) elastic modulus and circumferential wall stress. We hypothesized that age-linked mechanical alterations of the arterial wall will occur earlier in SHR than in normotensive rats. Our second objective was to study possible links between elastic properties...

Abstract-In Marfan syndrome, mutations of the fibrillin gene (FBN1) lead to aneurysm of the thoracic aorta, making the aortic wall more susceptible to dissection, but the precise sequence of events underlying aneurysm formation is unknown. We used a rodent model of Marfan syndrome, the mgR/mgR mouse (with mgR: hypomorphic FBN1 mutation), which underexpresses FBN1, to distinguish between a defect in the early formation of elastic fibers and the later disruption of elastic fibers. The content of desmosine plus isodesmosine was used as an index of early elastogenesis; disruption of elastic fibers was analyzed by histomorphometry. Because disruption of the medial elastic fibers may produce aortic stiffening, so amplifying the aneurysmal process, we measured thoracoabdominal pulse wave velocity as an indicator of aortic wall stiffness. Both mgR/mgR and wild-type (C57BL/6J-129SV) strains were normotensive, and wall stress was not significantly modified because the increase in internal diameter (0.80Ϯ0.06 vs 0.63Ϯ0.03 mm in wild type, PϽ0.05) was accompanied by increased medial cross-sectional area. The aortic wall stiffened (4-fold increase in the elastic modulus-to-wall stress ratio). Desmosine content was not modified (mgR/mgR 432Ϯ31 vs wild type 492Ϯ42 g/mg wet weight, PϾ0.05). Elastic fibers showed severe fragmentation: the percentage of the media occupied by elastic fibers was 18Ϯ3% in mgR/mgR mice vs 30Ϯ1% in wild-type mice, with the number of elastic segments being 1.9Ϯ0.2 vs 1.4Ϯ0.1ϫ10 Ϫ6/mm 2 in the wild type (both PϽ0.05). In conclusion, underexpression of FBN1 in mice leads to severe elastic network fragmentation but no change in cross-linking, together with aortic dilatation. This result suggests that fragmentation of the medial elastic network and not a defect in early elastogenesis is 1 of the determinants of aortic dilatation in Marfan syndrome. Key Words: fibrillin-1 Ⅲ elastic modulus Ⅲ aneurysm Ⅲ desmosines Ⅲ elastic fibers M arfan syndrome is a dominantly inherited disorder characterized by cardiovascular, skeletal, and ocular abnormalities. 1 The cardiovascular manifestations include aortic root dilatation and dissection that result in rupture of the vessel wall and premature death. Marfan syndrome has been associated with mutations of the gene coding for fibrillin-1 (FBN1), the major constituent of extracellular microfibrils. 2 However, the link between FBN1 deficiency and the development of aneurysm is not yet clearly established.Early ideas were based on the regulatory role played by microfibrils in the organized deposition of tropoelastin molecules during elastogenesis. 3 It was suggested that FBN1 mutations prevented normal cross-linking (formation of desmosine cross-bridges), leading to disorganized microfibrillar assembly, and that this weakened the mechanical strength of the media. This hypothesis was recently challenged by homologous gene-targeting experiments in the mouse, 4 which indicated that FBN1 microfibrils were predominantly engaged in global tissue homeostasis rather than in elasti...

In elderly patients, aortic stiffness is a major determinant of increased end-systolic stress leading to left ventricular (LV) hypertrophy with impaired cardiac performance. However, in a rat model of aortic elastocalcinosis (induced by vitamin D 3-nicotine [VDN] treatment), brief exposure (1 month) to increased aortic stiffness modified neither cardiac function nor cardiac structure. Here we report the impact of longer exposure (3 months) to aortic stiffness. Three months after induction of aortic stiffness, aortic characteristic impedance was measured in awake rats, 8 control and 10 VDN. Stroke volume was measured (electromagnetic probe) at baseline and after acute volume overload. LV weight/body weight ratio, collagen, and myosin heavy chain (MHC) contents were determined. Although aortic characteristic impedance increased (controls, 322; VDN rats, 508 10 3 dyne s/cm 5 ; P0.0248), stroke volume was maintained in VDN rats at baseline (controls, 22318; VDN, 21113 L) and after volume overload (controls, 37814; VDN, 33815 L). However, LV weight/body weight ratio (controls, 1.540.07; VDN, 1.730.05 g/kg; P0.0397) and LV collagen content (controls, 314; VDN, 524 g/g dry wt; P0.0192) increased. A shift from-MHC (controls, 822%; VDN, 693%; P0.0056) to-MHC (controls, 182%; VDN, 313%; P0.0056) was also observed. Three months' exposure to increased aortic stiffness in VDN rats induced LV hypertrophy with moderate interstitial fibrosis and a shift in the MHC-isoform pattern. Such structural adaptation maintains LV performance. (Hypertension. 1999;34:63-69.) Key Words: heart failure ventricular fibrosis, left myosin hypertrophy, left ventricular cardiac afterload rats I n elderly patients, increased cardiac mass is linked to increased aortic stiffness. 1 With age, decreased aortic elasticity leads to increased aortic impedance and wave reflection velocity, which in turn lead to increased end-sys-tolic stress, diminished cardiac performance, and left ventric-ular (LV) hypertrophy. 2 However, the increase in aortic impedance in humans is generally associated with increased mean pressure and therefore with increases in both the compliance and resistance components of cardiac afterload. The possibility that aortic stiffness alone could be a major determinant of increased end-systolic stress leading to cardiac dysfunction 1,3 is an attractive hypothesis in that it opens up new horizons in the treatment of cardiovascular pathologies related to aging, such as isolated systolic hypertension, in which mean arterial blood pressure is often normal. 4 However, experiments conducted to confirm this hypothesis in animal models or in the elderly have provided contradictory results. While some authors concluded that an acute decrease in aortic compliance leads to a decrease in cardiac performance, 5 others observed only minor changes in cardiac function. 6,7 Similarly, modest declines in resting stroke volume and cardiac output have been observed in some, but not all, elderly people following vascular stiffness associated or not associate...

Abstract-With aging, the aortic wall becomes stiffer. This could be because of changes in wall stress or composition. We investigated whether a specific change in wall composition, ie, accumulation of advanced glycation end products (AGEs) on the extracellular matrix, is a major factor. We measured aortic mechanics, geometry, and composition in 3-, 10-, 15-, 20-, and 30-month-old inbred normotensive Wistar-Glaxo/Rijswick rats and in a group of 30-month-old rats treated from 20 months onward with aminoguanidine (AG, 42 mg/kg per day), an inhibitor of AGE formation. Thoracoabdominal aortic (pressure) pulse-wave velocity (PWV) increased progressively with age (44% from 3 to 30 months). This age-related increase in aortic PWV was not related to changes in wall stress. For all ages, central (and peripheral) aortic mean blood pressures were not statistically different. Dilatation occurred (18% increase in internal diameter from 3 to 30 months), but this was accompanied by outward hypertrophic remodeling, with an increase in the medial cross-sectional area of 95% and in the ratio of medial thickness to internal diameter of 29%. Wall stress decreased with age (Ϫ34%). There was an increase in the ratio of elastic modulus (calculated from the Moens-Korteweg equation) to wall stress (calculated from the Lamé equation, 117% from 3 to 30 months), suggesting that a change in the composition of the wall is responsible for the age-linked increase in wall stiffness. Dry weight decreased slightly but significantly (Ϫ14%) with age. Total protein, elastin, collagen, and nonscleroprotein protein [totalϪ (elastinϩcollagen)] contents did not change with age, but calculated densities of all 4 were halved (as the medial cross-sectional area doubled). The elastin/collagen ratio was statistically similar at all ages. The only significant effect of AG treatment was a fall in PWV (Ϫ20%), leading to a fall in the elastic modulus/wall stress ratio (Ϫ27% at 10 months of AG treatment versus 30 months of no treatment). In conclusion, the age-related increase in aortic wall stiffness is prevented by 10 months of treatment with AG, which has no effect on wall stress or composition, suggesting that AG may improve aortic wall stiffness by lowering the degree of AGE-induced cross-linking of the extracellular matrix scleroproteins, such as collagen. (Hypertension. 2001;38:943-948.)