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Aortic stiffness and pulse pressure amplification in Wistar-Kyoto and spontaneously hypertensive rats

¹Institut National de la Santé et de la Recherche Médicale, EMI-U0107, Paris, France; ²Centre d'Investigations Préventives et Cliniques, Paris, France; ³Paris Nord University, Laboratory of Nutrition, Metabolic Diseases and Cardiovascular Prevention, Bobigny, France; and ⁴Paris-Descartes University 5, AP-HP, Diagnosis Center, Hôtel-Dieu Hospital, Paris, France

Submitted 10 July 2006 ; accepted in final form 18 January 2007

	ABSTRACT

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In humans, increased body weight and arterial stiffness are significantly associated, independently of blood pressure (BP) level. The finding was never investigated in rodents devoid of metabolic disorders as spontaneously hypertensive rats (SHR). Using simultaneous catheterization of proximal and distal aorta, we measured body weight, intra-arterial BP, heart rate and their variability (spectral analysis), aortic pulse wave velocity (PWV), and systolic and pulse pressure (PP) amplifications in unrestrained conscious Wistar-Kyoto (WKY) rats and SHR between 6 and 24 wk of age. Aortic proximal systolic and diastolic pressure, PP, and mean BP were significantly higher in SHR than in WKY rats and increased significantly with age (with the exception of PP). PP amplification increased with age but did not differ between strains. PWV was significantly associated with heart rate variability. PWV was significantly higher (via two-way variance analysis) in SHR than in WKY rats (strain effect) and increased markedly with age in both strains (age effect). Adjustment of PWV to mean BP attenuated markedly both the age and the strain effects. After adjustment for body weight, either alone or associated with mean BP, the age effect was not more significant, but the strain effect was markedly enhanced. In conscious unanesthetized SHR and WKY rats, aortic stiffness is consistently associated with body weight independent of age and mean BP. An intervention study should consider in the objectives systolic BP and PP amplifications measured in conscious animals, central control of body weight, and autonomic nervous system.

pulse wave velocity; body weight; conscious rat; autonomic nervous system

In the past, most studies on the mechanical properties of large arteries in populations with increased body weight were performed in humans or rodents with major metabolic disorders, such as diabetes mellitus or insulin resistance, and less in subjects with an excess of fat in proportion to lean body mass (32, 45). Few studies have been reported in populations in which hypertension was considered as the major and unique hallmark of the disease, as in spontaneously hypertensive rats (SHR). Thus studies indicating the statistical links between changes in arterial stiffness and in body weight during the development of animal hypertension are totally lacking. Of course, the weight gain associated with development differs from that associated with obesity, with both lean body mass and fat mass contributing to body weight during development.

Our group (16) has recently shown that, during SHR development, age and body weight were two factors susceptible to statistical and independent association with increased carotid arterial stiffness (16). In this study, increased mean blood pressure (MBP) was a significant but slight modulator of increased arterial stiffness, as shown from multiple statistical regression analysis (16, 29). However, such findings were observed in anesthetized rats, thus raising several problems. First, the statistical links between carotid artery stiffness and body weight were established only on the basis of local (carotid artery) and not on regional or systemic measurements of arterial elasticity. Second, as a consequence of increased arterial stiffness and altered wave reflections, systolic BP (SBP) and pulse pressure (PP) in rats are known to be higher in peripheral than in central arteries (28). This particularity is important to consider for the evaluation of BP in any hypertensive rodent and complicates considerably the diagnosis of increased arterial stiffness independent of MBP, mostly when animals are studied under anesthesia. Finally, in our previous experiments, no evaluation of BP and heart rate (HR) variability was performed, although this parameter may constitute an indirect but useful index reflecting the contribution of the adrenergic system at the early phase of development to obesity or hypertension or to increased arterial stiffness in SHR (13, 16, 29).

The purpose of this study was, in conscious SHR between 6 and 24 wk of age, to determine body weight, BP, aortic pulse wave velocity (PWV), SBP and PP amplifications, and SBP and HR variabilities in comparison to Wistar-Kyoto (WKY) rats. Our working hypothesis is that, during such periods, increased arterial stiffness in SHR is more consistently associated with body weight than with age, MBP, or HR variability. Our final goal is to determine in which conditions an intervention study in SHR could establish firmly a cause-and-effect relationship between increased body weight and increased arterial stiffness and possibly involve an activation of the autonomic nervous system.

	MATERIALS AND METHODS

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Animals. Male normotensive WKY rats (n = 35) and age-matched male SHR (n = 27) were obtained from Charles River France (L'Arbresle, France). Life span in such animals is 18 mo in SHR and 27 mo in WKY rats (50). The study was performed at the 6th, 12th, and 24th wk of age. Rats were acclimatized for 1 wk before the experiments. The animals were maintained at 22–24°C with lights on from 0600 to 1800 and received standard chow (A03; UAR) and tap water ad libitum. All procedures were conducted in accordance with and approved by the Animal Ethics Committee of the Institut National de la Santé et de la Recherche Médicale and conformed to the Guide for the Care and Use of Laboratory Animals, published by the National Institutes of Health.

PWV and BP measurements. The technique for measurement of PWV in rats is adapted from that described by others (11, 18, 24, 36, 44). For intra-arterial BP recording in conscious rats, we constructed polyethylene catheters [a PE-10 (2 cm length, 0.28 mm ID, 0.61 mm OD; Clay Adams, Parsippany, NJ) fused to a PE-50 (15 cm length, 0.58 mm ID, 0.96 mm OD; Guerbet, Louvres, France)] filled with heparinized 0.9% NaCl (50 U/ml). These kinds of catheters provide an optimum dynamic response with negligible resonance (41). Moreover, in the present study, the validity of BP measurement was verified with the use of parallel Millar catheters. In a separate experiment, BP was recorded in anesthetized WKY rats with a 3-Fr Mikro-Tip pressure transducer catheter (model SPR-330; Millar Instruments, Houston, TX) introduced into the descending aorta via the left carotid artery. As shown in Fig. 1, the two pressure waveforms were quite similar. Other groups have observed similar results in rats when a catheter or a Millar Mikro-Tip transducer was alternatively used (24).

View larger version (11K): [in this window] [in a new window]   Fig. 1. Comparison of the waveforms of proximal blood pressure recorded in Wistar-Kyoto (WKY) rats, by means of a Millar Mikro-Tip transducer (top) and a catheter connected to a pressure transducer (bottom).

View larger version (13K): [in this window] [in a new window]   Fig. 2. Schematic illustration of the measurement of pulse wave velocity (PWV) in the rat. PWV is the ratio between the distance (D) between the tips of the 2 catheters and the difference between the time at the minimal values of proximal and distal blood pressure (T). The blood pressure signals are from a 24-wk-old WKY rat.

BP signals were analyzed beat to beat by means of Chart version 5.2 software in 20 s of recording corresponding to 100–150 cardiac cycles. This software allows detection of the time at the minimal value (foot) of proximal and distal BP and the minimal (diastolic) and maximal (systolic) BP and calculates the MBP and PP. HR was also automatically detected. The difference between the time at the minimal value of proximal and distal aortic BPs yielded the transit time (ms). PWV was calculated as the aortic distance between the tips of the two catheters (an index of aortic length) divided by the transit time (expressed in cm/s) (Fig. 2). BP amplification was calculated as the difference between distal minus proximal SBP, diastolic BP (DBP), MBP, or PP and expressed in absolute and percent values. The -index, an index of arterial stiffness poorly influenced or not influenced by BP level, was calculated according to the following formula: 2.11 x (PWV²/DBP) (11, 22). In contrast to other studies that determined PWV on a maximum of 10 cardiac cycles, in the present experiments, for each rat, PWV and all other parameters (see Table 1) were calculated in 100–150 consecutive cardiac cycles, and the results were averaged.

Statistical analyses. Results are presented as means ± SE. General linear models, including age, strain, and age x strain interaction, were used to evaluate the influence of age and strain and their interaction on the different hemodynamic variables. Additional adjustments to MBP and body weight were performed for the study of PWV and -index, to evaluate the respective contribution of these parameters. To evaluate the major determinants of PWV, stepwise regression analysis was used. Variables entered in the model were age, weight, MBP, HR, LF-SBP, HF-PI, and LF/HF-PI (12). The statistical analysis was performed with NCSS 6.0 package software (Hintze JL, Kaysville, UT). P < 0.05 was considered statistically significant.

	RESULTS

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Table 1 shows in rats the changes in body weight and aortic proximal hemodynamic parameters as a function of age and strain. Body weight increased with age and was lower in SHR than in WKY rats. The elevation of body weight with age tended to be more important among WKY rats than among SHR (P interaction = 0.063). SBP, DBP, and MBP increased with age in both strains, but the increase was markedly higher in SHR than in WKY rats, resulting in significant interactions (Table 1). PP was higher (P < 0.0001) in SHR than in WKY rats but was not modified by age. HR was higher in SHR than in WKY rats (P < 0.0001) and was markedly reduced with age (P < 0.0001), resulting in a significant interaction (P = 0.0156).

SBP amplification (mmHg or %) was present to the same extent in SHR and WKY rats and increased markedly with age (P = 0.0012 and P = 0.0041) (Table 1), whereas no significant amplification and no change of amplification with age were observed for DBP and MBP (data not shown). PP amplification (either in mmHg or %) increased significantly (P = 0.0001; P = 0.0031) with age and did not differ between strains. Adjustment of PP amplification (mmHg) to MBP did not modify such results. Note that, after adjustment to body weight, the increase in PP amplification with age disappeared (data not shown). Aortic length increased with age (P < 0.0001), but this increase did not differ between strains.

In Table 2, no significant age and strain effects were reported for the -index. PWV increased with age (P < 0.0001) (age effect) and was significantly higher in SHR than in WKY rats (P < 0.0035) (strain effect). After adjustment to MBP, the age effect was attenuated (P < 0.02) and the strain effect even disappeared (P = 0.08). Adjustment to body weight alone or to body weight and MBP together highly attenuated the age effect (P < 0.05) and highly increased the strain effect (P < 0.0001; P < 0.003) (Table 2). The results from the stepwise regression analysis performed in SHR and WKY rats indicated that PWV was significantly associated with body weight, MBP, and HR but not with age (Table 3).

View larger version (14K): [in this window] [in a new window]   Fig. 3. A: correlations between aortic PWV and weight. , Spontaneously hypertensive rats (SHR) (r = 0.58, P = 0.0024); , WKY rats (r = 0.70, P < 0.0001). B: correlations between aortic pulse PWV and high frequency of pulse interval (HF-PI). , SHR (r = –0.17, P = 0.433); , WKY rats (r = –0.42, P = 0.028).

	DISCUSSION

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In the past, several studies have noted significantly different changes in body weight between normotensive and hypertensive rats but never integrated such observations in the mechanisms of increased arterial stiffness (3, 21, 40, 52). In contrast, the present study had several important particularities. First, the investigation was entirely performed in unrestrained and conscious SHR and WKY rats. Second, aortic PWV was measured between the proximal and the distal portion of the aorta, using adequately validated catheters and transducers with a high degree of resolution and reproducibility. Third, in this report, the changes in body weight were known, by definition, to be devoid of consistent associations with insulin resistance, diabetes mellitus, and/or atherosclerosis (32, 45). Thus the statistical links between body weight and arterial stiffness in conscious animals could be firmly evaluated during vascular development.

A major finding of this study was that, in SHR and WKY rats, SBP and PP were physiologically higher in peripheral than in central arteries for the same MBP (29). This finding is the consequence of the propagation of pressure wave along the arterial tree, with changes in the timing and amplitude of wave reflections at any given local value of the arterial tree (29). Because SBP and PP amplifications require the development of wave reflections and thus the presence of consistent vascular discontinuities at the levels of arterial and arteriolar bifurcations (23), SBP and PP amplifications should develop progressively with age, increasing mostly between weeks 6 and 24, although to a lesser extent before week 6. In younger animals, this finding is in relation with the well-established age-related increase in aortic length and therefore the increase in body weight (Table 2). Interestingly, after body weight adjustment, SBP and PP amplifications in rats were no more related to age but only to body weight, confirming that a certain degree of increase in body weight and arterial length is necessary for the development of wave reflections. Finally, the presence of SBP and PP amplifications in rats suggests that the diagnosis of hypertension needs caution, particularly when direct or indirect BP measurements are done at the site of peripheral (tail) arteries (15). Furthermore, ambulatory BP measurements should be performed at the site of the carotid artery rather than at the site of the abdominal aorta to avoid any disturbance of pressure wave transmission (15, 17).

In the present investigation, it was possible, on the basis of statistical evaluations of arterial stiffness or SBP and PP amplifications, to dissociate the role of body weight from that of age and MBP during arterial development. However, the cause-and-effect relationships between arterial stiffness and other parameters cannot be firmly established from a simple regression analysis. Thus the general interpretation should take into account human data from recent studies on body weight, adiposity, and arterial stiffness.

Indeed, although the increase in body weight associated with development may differ from that associated with obesity per se, similar associations between arterial stiffness and body weight have been reported in normal weight as well as obese young and older subjects. In young healthy adults, weight changes are directly related to PWV changes (25, 46). Similar results have been reported in obese children and in young and older adults (38, 47). The positive association that we observed between PWV and body weight independent of age is in line with these data in humans.

In humans, increased body weight has been adversely associated with arterial stiffness not only in adults (10, 34, 37, 47) but also in children and in adolescents (25, 38). Some evidence has even emerged in both younger and older adults suggesting that weight gain accumulated in the trunk is the most adverse with regard to arterial stiffness, whereas weight gain accumulated peripherally (i.e., in the limbs) and lean mass can be protective with regard to arterial stiffness (10). Furthermore, although few studies have examined the impact of weight loss on arterial stiffness in subjects with hypertension and moderate increases in body weight, these subjects have shown an improved arterial stiffness after weight reduction (2, 37, 49). In addition, weight change is consistently associated with vascular stiffness in young and older adults independently of MBP level and degree of adiposity (46). Such findings reinforce the adverse role of excessive body weight on arterial stiffness. Importantly, the reduction of body weight is constantly associated with a reduction in the size of adipocytes but not in their number (51). Finally, a reduction of HR is constantly noted in all of these intervention studies (9, 17, 20, 30). It has been proposed that adipocytes may produce excessive amounts of cytokines, causing insulin resistance, inflammation, or dyslipidemia and even hypercoagulability, all of them being potentially linked to changes in vascular structure and function (31). Mostly, many compounds such as insulin and leptin have been shown to develop consistent effects on arterial stiffness and wave reflections (19, 31).

In the present investigation, the statistical association that we observed between PWV and HF-PI is of interest (8). Of interest is also the trend to a negative correlation between PWV and baroreceptor gain, as we observed in the whole population of rats (r = –0.25, P = 0.082) and particularly in WKY rats (r = –0.36, P = 0.062). Indeed, an inverse relationship between arterial stiffness and baroreceptor sensitivity has been reported in humans (33, 43). BP and HR variability are quite general but traditional markers of autonomic functions, which are able to reflect alterations of the sympathovagal balance, as previously validated in animals (1, 14, 42). At the early phase of hypertension in SHR, increases in body weight and adrenergic activity are consistently associated (13). During the vascular development of such animals, norepinephrine and nitric oxide are known to contribute to optimization of arterial distensibility (5, 26). Furthermore, studies of human vascular smooth muscle cells have shown that adrenergic stimulation directly modulates indexes of vascular elasticity through changes in transforming growth factor-₁ expression, fibronectin, and extracellular matrix protein synthesis of arterial elastin and collagen fibers (48). Our present finding of a significant association between PWV and HF-PI might also indicate subtle links between arterial stiffness and activation of the autonomic nervous system, such as those observed in rat models of obesity involving ventromedial hypothalamic lesions and/or central actions of leptin (17, 39). Finally, it is worth noting that, in humans, increased HR variability is significantly associated with reduced arterial distension (7).

In conclusion, a number of studies in humans and rats suggest consistent associations between body weight and arterial stiffness, independent of age, MBP, and HR. In rats, such associations are observed in the absence of major metabolic disorders. An intervention study involving starvation and/or overfeeding seems relevant in rats to demonstrate a cause-and-effect relationship between the two studied parameters. Nevertheless, this experiment should also consider the following conditions: 1) stiffness and BP measurements should be performed in conscious animals, 2) hormonal and/or pharmacological compounds acting on arterial stiffness and wave reflections such as insulin and leptin should be used as pathophysiological tools, and 3) an evaluation of the changes in the autonomic nervous system, principally in its central compartment, is important to consider (17, 35).

	ACKNOWLEDGMENTS

 
We thank Anne Safar for fruitful discussion.

Present addresses: E. Cosson, Paris Nord University, Laboratory of Nutrition, Metabolic Diseases and Cardiovascular Prevention, Bobigny F-93000, France; M. Herisse and D. Laude, INSERM, Unité 652, Paris F-75270, France; H. Dabire, INSERM, Unité 660, Maisons-Alfort F-94704, France.

	FOOTNOTES

 

Address for reprint requests and other correspondence: H. Dabire, INSERM, Unité 660, ENVA-Bâtiment Ferrando, 7 Ave. du Général de Gaulle, Maisons-Alfort F-94704, France (e-mail: hdabire{at}vet-alfort.fr)

The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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