PRECLINICAL STUDY
Development of Mild Aortic Valve Stenosis in a Rabbit Model of Hypertension
Luis A. Cuniberti, PhD*,*,
Pablo G. Stutzbach, FACC, MD ,
Eduardo Guevara, FACC, MD,
Gustavo G. Yannarelli, MSc*,
Rubén P. Laguens, MD, PhD and
Roberto R. Favaloro, MD, PhD
* Lipid and Atherosclerosis Research Laboratory, Department of Pathology, Favaloro University, Buenos Aires, Argentina
Institute of Cardiology and Cardiovascular Surgery of the Favaloro Foundation, Buenos Aires, Argentina
Manuscript received August 22, 2005;
revised manuscript received October 6, 2005,
accepted December 13, 2005.
* Reprint requests and correspondence: Dr. Luis A. Cuniberti, Laboratorio de Investigación en Lípidos y Aterosclerosis, Universidad Favaloro, Solis 453, 4to piso, (C1078AAI), Buenos Aires, Argentina (Email: cuniberti{at}favaloro.edu.ar).
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Abstract
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OBJECTIVES: This study was designed to investigate the association between hypertension and aortic valve stenosis (AVS) in a rabbit model.
BACKGROUND: Degenerative AVS is a prevalent disease in elderly persons. Its molecular mechanisms remain unclear, in part because of the absence of experimental models. Epidemiologic data suggest a link between hypertension and AVS. However, there has been no evidence of a cause-effect relationship.
METHODS: New Zealand White rabbits were divided into two groups: 1) animals (n = 20) instrumented according to one-kidney/one-clip hypertensive model; and 2) control animals (n = 10) sham operated. Echocardiography (S12 MHz) was used to assess aortic valve (AV) morphology and function as well as left ventricular mass at baseline and after two and four months of hypertension.
RESULTS: Blood pressure and left ventricular mass increase were highly significant in the animal model but not in controls at two months, without noticeable AV function abnormalities. After 4 months, however, 14 hypertensive survived animals showed a 14.6% reduction of AV area (0.240 ± 0.063 cm2 vs. 0.205 ± 0.060 cm2, p < 0.05), a 19.6% increase of AV thickness (0.056 ± 0.011 cm vs. 0.067 ± 0.010 cm, p < 0.001), a 40.4% increase of transvalvular mean gradient (5.35 ± 2.26 mm Hg vs. 7.51 ± 3.73 mm Hg, p < 0.05) and a 63.6% increase of transvalvular maximal gradient (10.56 ± 3.68 mm Hg vs. 17.28 ± 10.95 mm Hg, p < 0.05). Control animals did not show significant changes.
CONCLUSIONS: We report a novel experimental model of AVS in rabbits that may prove useful in studying the progression of the disease and the efficacy of new treatments. The present findings support the hypothesis of a causal link between hypertension and AVS.
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Abbreviations and Acronyms
| | AV = aortic valve | | AVS = aortic valve stenosis | | HDL = high-density lipoprotein | | HTA = hypertension | | LV = left ventricular | | PWT = posterior wall thickness | | RWT = relative wall thickness |
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Aortic valve stenosis (AVS) is a chronic progressive condition and is the most common form of acquired valve heart disease in developed countries (1). Despite the incidence of degenerative AVS and its increasing associated morbidity and mortality, the molecular and cellular mechanisms of this disorder remain unclear, in part because of the absence of appropriate experimental models (2–4). Epidemiologic studies have identified several atherosclerotic risk factors for the progression and outcome of AVS, including age, smoking, high cholesterol levels, low high-density lipoprotein cholesterol levels, hypertension (HTA), lipoprotein(a) levels, and diabetes (5–12). Although recent observations have reinforced the suggested association between HTA and the development of AVS (13,14), comorbidities associated with high blood pressure (high blood cholesterol, hyperinsulinemia, and so on) might be relevant confounding factors pathologically related to AVS progression, and so far no certain evidence of a causal link has been found. In fact, emerging animal models of AVS have focused on the development of AVS essentially using hypercholesterolemic conditions as valvular insult (15–17).
Histologic studies show that an early step in the progression of AVS is oxidized lipid and lipoprotein depositions, macrophage and T-lymphocyte infiltration, and microscopic calcification, particularly in the aortic side of the valve (18,19). This prominent feature fits with the notion that arterial segments subjected to turbulent blood flow, such as those at branch points or arterial surfaces of aortic valve cups, show a predisposition to lesion development that is intensified by hypertension (20–22). A possible mechanism that could explain the deleterious effects of HTA is, at least in part, the synergy between elevated blood pressure and other atherogenic stimuli to induce oxidative stress (23). The striking correlation between disturbed blood flow patterns and atherosclerosis has led to various recent studies (24,25) in an attempt to define a mechanistic role for hemodynamics forces in the pathogenesis of AVS.
We hypothesized that sustained hypertension per se could lead to valve damage with abnormalities in the valve’s morphology and function. Therefore, the aim of the present study was to investigate the development of AVS in a rabbit model of hypertension.
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Methods
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Animals.
Thirty adult New Zealand White rabbits (weight 2.7 to 3.2 kg) were randomly divided into two groups: 1) hypertensive animals (n = 20) induced by one-kidney/one-clip Goldblatt model (26), and 2) sham-operated normotensive controls (n = 10) with unilateral nephrectomy and contralateral renal artery non-clipping. Animals were housed in individual cages, quarantined for seven days before surgery, fed normal chow and water ad libitum, and treated according to the Guide for the Care and Use of Laboratory Animals published by the U.S. National Institutes of Health.
Direct blood pressure measurements and blood samples were obtained from all animals before the surgical procedure and two and four months thereafter through catheterization of the central ear artery. Serum samples were immediately frozen and kept at –80°C until laboratory determinations were carried out.
Echocardiography.
Transthoracic echocardiography was performed by applying standard practice guidelines at baseline and at two and four months of follow-up. Animals were sedated with an intramuscular injection of ketamine (20 mg/kg) and xilazine (1 mg/kg). Ultrasound images were obtained with a 12-MHz phased-array probe connected to a Sonos 5500 echograph (Philips Medical Imaging, Andover, Massachusetts). A parasternal short-axis view at the mid left ventricular (LV) level was used to measure the following parameters: LV end-systolic and end-diastolic dimensions and ventricular septum and LV posterior wall thickness. The LV mass was measured by M-mode echocardiography with the use of the Devereux formula (27). Relative wall thickness (RWT) was measured as RWT = 2 x (PWT/LVIDd). The peak and mean aortic valve flow velocities were determined by continuous-wave Doppler echocardiography by systematically sampling the flow from different windows and averaging the values for four to five beats. The maximal instantaneous gradient across the aortic valve and the mean gradient were derived from aortic Doppler velocities by the modified Bernoulli equation. The aortic valve area was measured by the standard continuity equation in the same manner as in humans with suspected AVS (28). To minimize the intra- and inter-assay variability, all echocardiographic imaging and analyses were carried out by the same investigator, who was kept blind regarding group allocation of individual animals throughout the study.
Histology.
After four months’ follow-up, rabbits received a lethal anesthetic dose; the hearts were excised; and the aortic valves were immediately dissected free of surrounding tissue, rinsed in phosphate-buffered saline, and prepared for macroscopic evaluation. One suitable leaflet from each aortic valve was fixed in 4% neutral-buffered formalin and processed for paraffin embedding. Serial cross-sections (5-µm thick) were prepared with hematoxylin and eosin and Masson’s trichromic staining for histologic analysis.
Statistical analysis.
Continuous variables are expressed as mean ± SD. Repeated-measurement one-way analysis of variance with the post hoc Newman-Kleus test was used for intragroup comparisons to assess changes in blood pressure levels and echocardiographic parameters over time. The unpaired t test was used for intergroup comparisons. A probability value <0.05 was considered statistically significant.
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Results
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Clinical and laboratory characteristics.
All rabbits in the control group remained alive to the end of the study, whereas six animals in the hypertensive group died prematurely (five from histologically verified hemorrhagic stroke and one from nonverified cause). Rabbits in group 1 uniformly developed hypertension within two to three weeks from surgery. As shown in Table 1, at two months systolic and diastolic blood pressure levels significantly increased by 36.3% and 47%, respectively. Systolic, but not diastolic, blood pressure levels additionally increased to 56.9% over baseline at four months. Blood pressure levels did not change in control animals throughout the study period. Body weight increased similarly in animals from the control and the hypertensive groups (3.7 ± 0.5 kg and 3.7 ± 0.6 kg, respectively, p = NS). Total plasma cholesterol levels were transiently and slightly higher after surgery to a similar extent in the control and the hypertensive group, but they remained within the normal range throughout the study (92.8 ± 32.7 mg/dl and 93.2 ± 19.8 mg/dl, respectively, p = NS).
Echocardiographic evaluation of AVS progression.
As shown in Table 2, the thickness of ventricular septum and the LV posterior wall, as well as RWT and LV mass, showed a highly significant increase after two and four months in the hypertensive group. At this time, aortic valve (AV) area significantly decreased by 14.6% (0.240 ± 0.063 cm2 vs. 0.205 ± 0.060 cm2, p < 0.05), whereas AV thickness, transvalvular mean gradient, and transvalvular maximal gradient significantly increased 19.6% (0.056 ± 0.011 cm vs. 0.067 ± 0.010 cm, p < 0.001), 40.4% (5.35 ± 2.26 mm Hg vs. 7.51 ± 3.73 mm Hg, p < 0.05), and 63.6% (10.56 ± 3.68 mm Hg vs. 17.28 ± 10.95 mm Hg, p < 0.05), respectively, in the hypertensive group. None of these echocardiographic changes was evident in the control group (Fig. 1). An intergroup comparison at four months revealed that the hypertensive condition was associated with valve thickening (26.4%, p < 0.001), increased transvalvular mean gradient (81.4%, p < 0.05), increased transvalvular maximal gradient (88.9%, p < 0.05), and a nonsignificant reduction of AV area (13.1%).
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Figure 1 Effect of hypertension (HTA) on aortic valve by echocardiographic assessment. Transthoracic echocardiography was used to measure the following morphologic and functional parameters at baseline and at two and four months of follow-up: valve thickness (A), aortic valve area (AVA) x continuity (B), maximal gradient (C), and mean gradient (D) in hypertensive (left) and control rabbits (right).
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Association between severity of hypertension and AVS.
As shown in Table 3, at four months of follow-up there were positive associations between systolic blood pressure and echocardiographic measures of LV remodeling such as septum thickness (p < 0.0001), posterior wall thickness (p < 0.05), and LV mass (p < 0.0005). Similarly, significant associations were observed between systolic blood pressure and measures of AVS, including valve thickness (p < 0.005) and maximal and mean gradients (p < 0.01 and p < 0.05, respectively). Finally, AV area changes did not correlate with a hypertensive state (p = 0.10).
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Table 3. Relationship Between Echocardiographic Parameters and Systolic Blood Pressure at Four Months of Follow-Up
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Macroscopic and histologic evaluation.
Visual examination of excised aortic valves from hypertensive animals revealed a progressive degeneration of the leaflet morphology during follow-up. Whereas valves from control animals had a clear glistening appearance (Fig. 2A), those from hypertensive animals presented signs of tissue hypertrophy (Figs. 2B and 2C). Microscopic analysis showed a prominent lesion development on the aortic side of the valve characterized by inflammation nodules extending to the aortic base and to the tip region of the leaflets (Fig. 3).
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Figure 2 Aortic valve photographs from rabbits over study period. The aortic valve is shown from the ascending aorta. (A) Control after four months; (B) hypertension (HTA) after two months; (C) HTA after four months. The control aortic valves have a clear glistening appearance, whereas valves from hypertensive animals show marked signs of tissue hypertrophy after four months.
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Figure 3 Light microscopy of rabbit aortic valves after four months with Masson trichrome stain. A1 and B1 = control; A2 and B2 = hypertension. (A) Low-magnification view (x25); (B) high-magnification view (x400). Aortic valves from hypertensive animals are characterized by increased valve thickness and development of inflammation nodules.
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Discussion
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The progression of calcified AVS has long been considered a "wear and tear" phenomenon—a consequence of aging coupled with increased hemodynamic/biomechanical stresses on the aortic valve. For most of the patients progressing to severe stenosis, surgical intervention is required (29,30). More recently, classical risk factors for atherosclerotic disease were implicated as accelerating conditions of AVS. Although an association between hypertension and AVS has been reported almost uniformly in multiple clinical studies (5,6,12–14,31), most of these observations have been limited by small sample size; possible selection bias; nonrandomization; cross-sectional nature; retrospective study design; and comorbidities associated with hypertension, such as hypercholesterolemia, insulin resistance, obesity, and so on.
To our knowledge, this study is the first to demonstrate a direct association between experimental hypertension and development of aortic stenosis without the potential influence of common clinically relevant confounding factors. The comparable results obtained by morphologic valve assessment, combined with functional echocardiographic analysis and histopathology examination, support our conclusions.
The association between hypertension and aortic valve disease may find several explanations. Pathogenically, hypertension may intensify the recognized hemodynamic disturbances that affect the aortic side of the valve (25,32), and this degenerative process could be accelerated in our study by the coupled high cardiac frequency of the rabbit.
A prominent characteristic of degenerative aortic valvular stenosis in humans is the presence of inflammatory infiltrates composed of macrophages, T-cells, and lipids, particularly in the fibrosa, the anatomic layer of the valve located immediately below the endothelium on the aortic side of the valve (18). It is noteworthy that these characteristics are strikingly similar to the histologic findings in our model of inflammatory nodules in the aortic side of the valves, which suggest that the valvular lesions induced by hypertension in the rabbit well reproduce one of the major early features of human valvular disease. Yet the precise subcellular/molecular mechanisms responsible for the increased site-specific inflammatory activity of the valves remain to be clarified.
In this study, we cannot exclude that various humoral/metabolic modifications inherent to the experimental model might have contributed to the development of valvular disease, including electrolyte imbalances, hyperreninemia, hyperaldosteronemia, other neurohormonal changes, or a mild loss of renal function. Yet, one or more of these parameters are also commonly altered in patients with hypertension, which makes the model even more evocative of the human condition.
Another advantage of this study as compared to other previous experimental models of AVS is its use of two-dimensional Doppler echocardiography as the test of choice to assess valve morphology and to quantify the extent of changes in valvular function. This is pertinent in that this diagnostic tool is considered the "noninvasive gold standard" for the diagnosis of aortic valve stenosis (33). This approach was recently proposed by Drolet et al. (16) and was successfully reproduced in the present study.
Although the ultrasonographic cardiac assessment of small animals may raise practical difficulties and inaccuracies, the method may be useful and show fair reproducibility in middle-size animals such as the rabbits weighing around 2.7 kg used in this protocol.
Unlike other previously published models of hypertension induced by acute pressure overload (34,35), the model used in this study more suitably reproduces a chronic hypertensive state (36). Some of our notable findings can be summarized as follows: 1) a drop in transvalvular gradients at two months, which indicates that intraventricular pressure is conserved in hypertensive early state; and 2) a heterogeneous response to sustained hypertension in terms of mean gradient and valve leaflet thickening, which indicates that valvular susceptibility to hemodynamic damage has a significant interindividual variability. This heterogeneous response likely mimics the clinical condition epidemiologically associated with progression of valvular aortic stenosis.
Although the present findings support a role for high blood pressure in the pathogenesis of mild AVS, further experiments using other hypertensive models of experimental chronic hypertension in different animal species should be performed to confirm this association. Moreover, longer term studies (6 to 12 months) are required to evaluate whether the early lesions induced by hypertension in our model will ultimately result in advanced disease with progressive leaflet thickening and eventually calcification and severe aortic valve stenosis.
Finally, a role of atherogenic lipoproteins as risk factors, not only for classical atherosclerosis but also for aortic valve stenosis, has recently been emphasized, and this notion is supported by several sources of data. First, at least three experimental models of hypercholesterolemia-induced valve calcification and stenosis were recently reported (15–17); second, high blood lipids are epidemiologically associated with progression of AVS; and third, there is some controversial evidence that progression of AVS can be reduced by statins owing to their lipid-lowering activity and/or some of their pleiotropic effects.
Although in the studies reported herein the animals were normolipidemic, we cannot exclude a pathogenic role of blood lipids. Indeed, hypertension augments infiltration of macromolecules, proteins, and lipoproteins through the endothelial barrier and promotes vascular oxidative stress (23), potentially augmenting the susceptibility of the vessel even to physiologic plasma levels of atherogenic lipoproteins. Thus, we speculate that lipids beneath a hypertensive state, even within the normal range, may represent a continuous risk factor for AVS. Furthermore, it could be interesting to assess the ability of statins to prevent the progression of mild AVS in the hypertensive-normolipidemic rabbit model presented in this study.
In summary, we report here an experimental animal model of acquired AVS induced by high blood pressure, which may prove useful to investigate the precise mechanisms underlying the association between hypertension and AVS and the efficacy of different medical treatments to delay, or even hinder, the advancement of the disease.
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Acknowledgments
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The authors thank Dr. María I. Besanson and Pedro Iguain for veterinarian assistance, technicians Julio Martinez and Fabian Gauna for assistance during surgical procedures, and Dr. Pablo Werba, MD, for his review of the manuscript.
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Footnotes
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This work was supported by grant CID 107 from Favaloro University.
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Abstract
Methods