Relationship between aortic valve calcification and aortic atherosclerosis: a transoesophageal echocardiography study

INTRODUCTION: Clinical and laboratory data provide an increasing amount of information regarding the common aetiopathogenetic background of acquired heart defects with calcification and arterial atherosclerosis. AIM: To evaluate the relationship between presence and severity of calcifications of the aortic semilunar valves and the intensity of atherosclerotic lesions in the aorta and aortic stiffness (AS). METHODS: The study group comprised 80 subjects (49 males and 31 females) aged 72.2 (+/-8.0) years with an aortic valve defect found on echocardiography. Patients were divided into two subgroups depending on the severity of valvular disease. Subgroup I comprised 42 patients with small valvular lesions (0--absence of calcification of the valve, or +--trivial valvular calcifications, possible to find on detailed evaluation of the valve). Subgroup II consisted of 38 patients with intense calcifications (++--large, easily found valve calcifications, +++--massive calcifications affecting leaflet mobility). All patients underwent transoesophageal echocardiography to evaluate atherosclerotic lesions in the aorta. The assessment included the following: location of the lesions in the aorta, intimal thickness, presence of calcifications and mobile parts of plaques and possible associated thrombi. Aortic stiffness was also measured using the formula: AS=log (SBP/DBP)/Ao(max)-Ao(min)/Ao(min). RESULTS: Atherosclerotic plaques were more frequent in patients with more prominent calcifications of the aortic valve (19 vs 10 patients, p <0.05). Intimal thickness was larger in patients with more pronounced valve calcifications (3.9+/-0.8 mm vs 2.2+0.6 mm, p <0.05). Presence of calcifications in the aortic wall was also more frequent in patients from group II, as they were found in 10 subjects compared to only 3 cases in group I. Mobile plaque parts were observed in 3 patients from group II; also thrombi were found in 3 individuals from this group. Patients with more prominent calcifications of the aortic valve had decreased aortic wall elasticity (AS 5.5+/-1.2 cm vs 3.4+/-0.9 cm, p <0.05). CONCLUSIONS: Severity of aortic valve calcification indicates simultaneous changes in the thoracic aorta. Stiffness of the aortic wall is greater in patients with a more pronounced defect of the aortic valve. Prevalence of atherosclerosis risk factors is increased in patients with aortic valve defect, enhanced atherosclerosis and rigidity of the aorta. Defect of the aortic valve and increased aortic rigidity may be different manifestations of atherosclerosis.     

Development of mild aortic valve stenosis in a rabbit model of hypertension.

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.     

Mitral and aortic valve sclerosis/calcification and carotid atherosclerosis: results from 1065 patients

This study assesses whether aortic valve sclerosis (AVS) and mitral annulus calcification (MAC) are associated with carotid artery atherosclerosis, independently of traditional cardiovascular risk factors. A total of 1065 patients underwent both echocardiography and carotid artery ultrasound scanning. AVS and MAC were defined as focal areas of increased echogenicity and thickening of the aortic leaflets or mitral valve annulus. Carotid artery atherosclerosis was defined as presence/absence of any atherosclerotic plaque or presence/absence of plaque >50 %. Of 1065 patients (65 ± 9 years; 38 % female) who comprised the study population, 642 (60 %) had at least one atherosclerotic plaque. AVS, but not mitral valve sclerosis; was associated with the presence of carotid atherosclerosis (odds ratio (OR) 1.9, 95 % confidence interval (CI) 1.2–3.9; P = 0.005) and the degree of carotid atherosclerosis (OR 2.1, 95 % CI 1.2–3.9; P = 0.01) in a multivariate model including age, gender, previous ischemic heart disease, hypertension, dyslipidemia, smoking, diabetes, family cardiovascular history, left ventricular size, mass, and ejection fraction, and left atrial size. AVS is a significant predictor of carotid atherosclerosis, independently of other cardiovascular clinical and echocardiographic risk factors.     

Aortic valve sclerosis, mitral annular calcium, and aortic root sclerosis as markers of atherosclerosis in men

Aortic valve sclerosis (AVS) and mitral annular calcium (MAC) as detected by transthoracic echocardiography have been associated with atherosclerosis. Aortic root sclerosis (ARS) may have a similar association, but has not been studied. This study evaluates, by transesophageal echocardiography, the association of AVS, MAC, and ARS with aortic atheromatous disease and cardiovascular disease. Multiplane transesophageal echocardiography with evaluation of AVS, MAC, ARS, and aortic atheromatous disease by 2 experienced observers unaware of clinical data was performed in 157 male patients > or =50 years old. The presence of cardiovascular disease, defined as coronary, carotid, or peripheral artery disease, was determined by specific criteria. The prevalence of AVS, MAC, ARS, and aortic atheromatous disease was 42%, 30%, 48%, and 71%, respectively. The presence of AVS, MAC, or ARS was highly associated with aortic atheromatous disease (odds ratio 4.9 to 12.0, confidence interval 1.4 to 35.8, p <0.001). ARS was also associated with cardiovascular disease (odds ratio 2.2, confidence interval 1.0 to 4.5, p = 0.038). The presence of AVS, MAC, or ARS had a sensitivity of 77%, specificity of 72%, a positive predictive value of 88%, and a negative predictive value of 55% for aortic atheromatous disease. We concluded that the prevalence of AVS, MAC, or ARS by transesophageal echocardiography in men is common, and their presence is highly associated with aortic atheromatous disease and coronary, carotid, or peripheral artery disease.     

Aortic valve sclerosis as a marker of active atherosclerosis

Aortic sclerosis is a calcific disease of the aortic valvular leaflets defined as focal leaflet thickening without significant obstruction to left ventricular outflow. Several clinical factors are associated with calcific aortic valve disease, including male sex, smoking, hypertension, age, hypercholesterolemia, and diabetes. Histologic and biochemical studies suggest similarities between the mechanisms involved in the development of aortic sclerosis and atherosclerosis, suggesting these two diseases may share common pathophysiologic mechanisms. In a recent prospective trial, the presence of aortic sclerosis was associated with an approximately 50% increase in cardiovascular mortality and myocardial infarction, even after correction for age, gender, known coronary artery disease, and clinical factors associated with a aortic sclerosis.     

Development of aortic valve sclerosis or stenosis in rabbits: role of cholesterol and calcium

BACKGROUND AND AIM OF THE STUDY: Aortic valve sclerosis is fairly common and is currently seen as a marker of systemic atherosclerosis. For unclear reasons only a minority of those sclerotic valves will evolve to become stenotic suggesting that atherogenic factors alone are insufficient to explain the development of valve stenosis. We had reported in a model of cholesterol fed rabbits that a combination of high cholesterol with vitamin D supplementation was necessary to induce valve stenosis and significant calcium deposition whereas high cholesterol alone only induced a sclerosis of the valve. In this study, we further evaluated the role of vitamin D treatment in the development of aortic valve disease (sclerosis or stenosis) in this rabbit model. METHODS: Rabbits were divided in 4 groups followed for 12 weeks: 1) no treatment; 2) cholesterol-enriched diet, 3) cholesterol-enriched diet + vitamin D2 (VD; 50000IU, daily) 4) VD alone for 12 weeks. Echocardiographic assessment of the aortic valve was done at baseline, and every 4 weeks thereafter. Aortic valve area, maximal and mean transvalvular gradients were recorded and compared over time. Immunohistological study of the valves of AS rabbits was also realized for several classical atherosclerosis markers. RESULTS: Vitamin D2 treated animal did not develop any stenosis of the valve despite increased echogenicity due to diffuse calcium deposits on the leaflets without any atherosclerotic lesions. Only the combination of high cholesterol with VD resulted in a decrease of aortic valve area. Immunohistological analysis of aortic valves from VD rabbits showed the presence of calcium deposits, T-cell infiltration in addition to positive labeling for alpha-smooth muscle cell actin. We did not observe macrophage infiltration in aortic valve leaflets of VD rabbits. CONCLUSION: Hypercholesterolemia or vitamin D supplements alone could not induce aortic valve stenosis in our animal model whereas the combination resulted in a decreased aortic valve area. These findings support the hypothesis that a combination of atherosclerotic and calcifying factors is necessary to induce aortic valve stenosis in this model.     

Chlamydia pneumoniae-induced atherosclerosis in a rabbit model

In order to establish a causative relationship between Chlamydia pneumoniae and atherosclerosis, animal models have been proposed. In a rabbit model, arterial intimal thickening has been induced by direct intravascular and intranasal inoculation with C. pneumoniae. C. pneumoniae infection can induce significant acceleration of atherosclerosis in a mildly hyperlipidemic rabbit model but is prevented by treatment with azithromycin. Together these preliminary rabbit experiments suggest that C. pneumoniae may play a causative role in atherosclerosis. More animal studies are underway that are designed to address further mechanistic and therapeutic questions regarding the association between C. pneumoniae and atherosclerosis.     

Vaccine-induced antibodies inhibit CETP activity in vivo and reduce aortic lesions in a rabbit model of atherosclerosis

Using a vaccine approach, we immunized New Zealand White rabbits with a peptide containing a region of cholesteryl ester transfer protein (CETP) known to be required for neutral lipid transfer function. These rabbits had significantly reduced plasma CETP activity and an altered lipoprotein profile. In a cholesterol-fed rabbit model of atherosclerosis, the fraction of plasma cholesterol in HDL was 42% higher and the fraction of plasma cholesterol in LDL was 24% lower in the CETP-vaccinated group than in the control-vaccinated group. Moreover, the percentage of the aorta surface exhibiting atherosclerotic lesion was 39.6% smaller in the CETP-vaccinated rabbits than in controls. The data reported here demonstrate that CETP activity can be reduced in vivo by vaccination with a peptide derived from CETP and support the concept that inhibition of CETP activity in vivo can be antiatherogenic. In addition, these studies suggest that vaccination against a self-antigen is a viable therapeutic strategy for disease management.     

Cardiac valve papillary fibroelastomas: clinical, histological and immunohistochemical studies and a physiopathogenic hypothesis

BACKGROUND AND AIM OF THE STUDY: Cardiac papillary fibroelastoma (CPF) is a rare and histologically benign tumor, but may have a malignant propensity for life-threatening complications; thus, surgical removal is justified. Case histories were reviewed of four patients who underwent surgical management after diagnosis of CPF located on aortic (n = 2) or mitral (n = 2) valves. Our aim was to provide explanations for the clinical diversity of the lesions and, using histological and immunohistochemical methods, to hypothesize the genesis of these tumors. METHODS: Among four patients with a diagnosis of valvular CPF, two had previous and recent history of neurological embolic symptoms with small echographically located tumors attached to the ventricular side of aortic cusps. Two other patients (one with paroxysmal atrial fibrillation, one with no neurological or rhythmically related stroke) had CPFs located on the posterior or anterior mitral leaflets. RESULTS: Surgical excision was performed with a conservative valve-sparing approach. Histological and specific immunohistochemical (IHC) studies were conducted on all samples. The postoperative course was uneventful, and histological analysis confirmed the diagnosis of CPF with typical fronds characterized by three successive layers. In the first two patients there was correlation between neurological events and the presence of thrombus aggregated on the injured superficial endothelial layer. In the other patients, no endothelial damage or thrombus was found. IHC studies showed dysfunction of the superficial endothelium, a centrifugal mesenchymal cellular migration arising from the central layer to the superficial layer with differentiation steps, the presence of dendritic cells in the intermediate layer, and remnants of cytomegalovirus (CMV) in the intermediate layer. CONCLUSION: Despite their benign histological aspect, and independent of their size, CPFs justify surgical excision because of their high potential to systemic embolization. In most cases, valve sparing management is possible with no observed recurrence after complete excision. The presence of dendritic cells and CMV strongly suggests the possibility of a virus-induced tumor, therefore evoking the concept of a chronic form of viral endocarditis.     

实验性动脉粥样硬化动物模型研究概况

动脉粥样硬化(AS)是严重危害人类健康的常见心血管系统疾病。建立实验性AS模型在该病的发生机制、病理变化及药物疗效等实验研究中起着重要作用。本文分别以鹌鹑、豚鼠、小鼠、大鼠、家兔、小型猪为载体,对以不同方法建立的AS动物模型进行整理归纳,比较分析了各种动物模型的特点,为今后更好的建立AS动物模型提供参考。     

The association of hypertension and aortic valve sclerosis

Background. Aortic valve sclerosis (AVS), a condition of thickening and calcification of the normal trileaflet aortic valve without the obstruction to left ventricular outflow, is likely the initial stage in the development of aortic stenosis and is associated with an increased incidence of cardiovascular events. The objective of this study is to critically review the data on the association of blood pressure and hypertension with AVS. Methods. A systematic search of MEDLINE and EMBASE (to June 2004) was conducted using the keywords hypertension and aortic valve. All English language papers were examined if they dealt with hypertension and AVS. All studies were included for analysis if they had a control group. Results. Three population-based, cross-sectional studies with a total sample size of 6450 individuals showed a consistent and significant relationship between hypertension and AVS with an odds ratio (OR) ranging from 1.23 to 1.74. Smaller case-control studies with a total sample size of 1609 individuals did not show consistent results but the OR ranged from 1.75 to 2.38. Only one small study (n = 188) showed fewer cases with hypertension and AVS than in the control group. Hypertension was a significant factor remaining in multivariate analysis after consideration of age and other risk factors in several cross-sectional studies. In contrast, other studies with blood pressure measurements consistently showed no increased blood pressures in the presence of AVS. However, these studies did not examine the prevalence of AVS within age-adjusted blood pressure levels. Conclusions. Cross-sectional population-based studies present evidence of an association between hypertension and AVS with an OR between 1.23 and 1.74. The major limitation in establishing a causal relationship is the failure to demonstrate a gradient of risk between increasing blood pressure and increasing incidence of AVS. In addition, the literature is confounded by the wide variety of definitions for AVS as well as hypertension. At this time, further data is required to conclude that there is a causal relationship between AVS and elevated blood pressure.     

Progression of aortic valve sclerosis and aortic valve stenosis: what is the role of statin treatment?

BACKGROUND: It has recently been suggested that statins could slow the progression of aortic stenosis, but this hypothesis has not been validated in large series. Moreover, there is little information about the role of statin treatment in patients with aortic valve sclerosis. METHODS: From our database 1988--2002, we retrospectively identified 1136 consecutive patients with aortic valve sclerosis (peak aortic velocity [Vmax] > 1.5 and < 2 m/s), or mild to moderate aortic stenosis (Vmax 2.0-3.9 m/s) and with > or = 2 echocardiographic studies > or = 6 months apart; 121 (11 %) were treated with statins. As a control group we randomly selected 121 age-gender-matched patients not treated with statins, with similar initial Vmax. RESULTS: The mean follow-up duration was 54+/-34 months in the statin group, and 50+/-33 months in controls (p = 0.35). There were no differences between statin-treated patients and controls with respect to age, gender, and prevalence of hypertension. More patients in the statin group had documented hypercholesterolemia, diabetes, or had proven coronary artery disease. Overall, the rate of change of Vmax was not different between statin-treated patients and controls (0.13+/-0.24 vs 0.14+/-0.19 m/s/year, p = 0.72). However, in the subgroup of patients with aortic valve sclerosis (n = 52, 26 statin-treated, 26 controls), the rate of change of Vmax was significantly lower in statin-treated patients (0.04+/-0.04 vs 0.08+/-0.06 m/s/year, p = 0.007). CONCLUSIONS: The results of our retrospective study show that statins could be beneficial in retarding the progression of valvular aortic sclerosis to aortic stenosis. This suggests that statins retard the progression of aortic valve lesion in its early stage, a finding that may have important implications in the management of this very common disease.     

Progression and regression of atherosclerosis in APOE3-Leiden transgenic mice: an immunohistochemical study

Apolipoprotein E3-Leiden (APOE3-Leiden) transgenic mice develop hyperlipidemia and are highly susceptible to diet-induced atherosclerosis. We have studied the progression and regression of atherosclerosis using immunohistochemistry. Female transgenic mice were fed a moderate fat diet to study atherosclerosis over a longer time period. Fatty streaks arose in the intima and consisted of lipid filled macrophages which differed in origin. All macrophages expressed the macrophage scavenger receptor while two thirds expressed sialoadhesin and were positive for an antibody recognizing marginal zone macrophages (MOMA-1). All macrophages were negative for the scavenger receptor MARCO and 50% were positive for CD4. Small fatty streaks contained CD-3 positive T-lymphocytes which were for more than 70% CD4-positive. ICAM-1 was positive both in atherosclerotic and control mice. In early plaques, fibrosis was observed on the luminal and medial site of the foam cells while smooth muscle cells were only observed in the fibrous cap. To study regression, we used a high fat, high cholesterol diet to rapidly induce atherosclerosis (14 weeks). The animals were then fed normal chow. Subsequently, atherosclerosis was assayed over time (4, 8, 16 weeks). Cholesterol levels dropped in 4 weeks to control levels.The animals did not show a significantly decrease in plaque size over time. but the percentage macrophages was significantly smaller in the animals after 4 weeks. In conclusion, the APOE3-Leiden mouse is a useful model to study the progression and regression of atherosclerosis.     

Are degenerative changes in the aortic valve an additional important marker of atherosclerosis?

BACKGROUND AND AIM: Degenerative changes of the mitral annulus are associated with atherosclerotic disease. It has recently been suggested that degenerative changes in the aortic valve may also be associated with atherosclerosis. The intima-media thickness of the carotid arteries has been used as one of the best and earliest markers of atherosclerosis. The aim of this study was to evaluate whether the additional presence of degenerative changes in the aortic valve in coronary patients with mitral annular degenerative disease reflects different degrees of intima-media thickness as assessed by carotid ultrasonography. METHODS: The study group included 55 patients admitted for myocardial infarction who presented with degenerative changes of the mitral annulus assessed by echocardiography. Exclusion criteria were moderate or severe valvular heart disease and chronic renal failure. All patients underwent echocardiography, cardiac Doppler and carotid ultrasonography. Based on the echocardiographic findings, two sub-groups were formed: 1--with degenerative changes of the aortic valve; and 2--without degenerative changes of the aortic valve. Carotid ultrasonography was performed with a 7.5-10 MHz linear transducer and the following parameters were evaluated: 1--bilateral measurement of intima-media thickness in the common carotid artery; 2-- incidence of atheromatous plaques in the carotid arteries, and 3--incidence of >50% lesion in the internal carotid arteries assessed by pulsed Doppler (Vmax >125 cm/s). RESULTS: Thirty-three patients (aged 71.6 +/- 7.1 years), 21 men and 12 women, did not present degenerative changes in the aortic valve. The other group consisted of 22 individuals (aged 72.9 +/- 6.8 years), 14 men and 8 women, who did have such changes. Differences in age and gender distribution between the two groups were not significant. Patients with degenerative aortic valve disease had greater intima-media thickness than the control group (1.6 +/- 0.3 mm versus 1.3 +/- 0.4 mm, p < 0.001). Fifteen (68%) patients with aortic degenerative disease had plaques in the carotid arteries compared to 11 (33%) patients in the control group (p < 0.05). No significant differences were found between the two groups regarding the incidence of >50% atherosclerotic lesion in the internal carotid artery (22% versus 12%; NS). CONCLUSIONS: Patients with degenerative changes in the aortic valve presented significantly greater intima-media thickness and a higher incidence of atherosclerotic plaques than the control group, suggesting that their presence may constitute an additional important marker of severity of atherosclerotic disease.     

Prevalence of aortic valve prolapse with bicuspid aortic valve and its relation to aortic regurgitation: a cross-sectional echocardiographic study

Although aortic valve prolapse (AVP) has been suggested as a cause of aortic regurgitation (AR) in patients with bicuspid aortic valves, neither the frequency of AVP nor its relation to AR in this setting has been defined. To assess these relations, 64 patients with bicuspid aortic valves diagnosed by 2-dimensional echocardiography and 20 normal subjects, similarly distributed according to age and sex, were studied. The presence and degree of AVP were defined using 3 quantitative terms: aortic valve prolapse distance (AVPD), area (AVPA) and volume (AVPV). Each was corrected (c) for patient size with reference to the diameter of the aorta at the level of insertion of the valve cusps. In normal subjects, the AVPDc averaged 0.09 +/- 0.06 (range 0 to 0.16) and the AVPAc averaged 0.08 +/- 0.06 cm (range 0 to 0.15). In patients with bicuspid aortic valves, the AVPDc averaged 0.26 +/- 0.10 (range 0.11 to 0.59, p = 0.00005 vs normal subjects), whereas the AVPAc averaged 0.35 +/- 0.17 cm (range 0.05 to 0.90, p = 0.00005 vs normal subjects). When the AVPDc criteria were used, 81% of the bicuspid valves were abnormal; when the AVPAc criteria were used, 87% were abnormal. The degree of prolapse defined by the AVPVc, which considers both cusp area and degree of apical displacement, was significantly greater for patients with bicuspid aortic valve with clinical AR than for those without (p = 0.008). However, because of the overlap between groups, there was no point at which this measure uniquely separated patients with and without AR.(ABSTRACT TRUNCATED AT 250 WORDS)     

实验性高胆固醇血症与家兔腹主动脉粥样硬化的关系研究

目的　研究实验性高胆固醇血症与家兔腹主动脉粥样硬化的关系 ,评价胆固醇在家兔腹主动脉粥样硬化形成中的作用。方法　对 16只雄性家兔分别于高脂饲料喂饲前及 12周后进行腹主动脉超声检查 ,测量腹主动脉内膜 -中层厚度的最大值 (IMTm) ,测定血清总胆固醇 (TC)、高密度脂蛋白胆固醇 (HDL- c)、低密度脂蛋白胆固醇(L DL- c) ,计算 TC与 HDL- c之比 (C/ H) ,取腹主动脉做病理切片测量动脉 IMTm。结果　 12周后家兔腹主动脉IMTm值明显增高 ,TC、L DL - c、C/ H明显升高。 IMTm与 L DL - c及 C/ H呈正相关。 IMTm的超声与病理测值之间无显著性差异 ,并高度一致。结论　高胆固醇是动脉粥样硬化的重要危险因素 ,其中的 HDL- c及 L DL- c在总胆固醇中所占比例的变化与动脉粥样硬化病变的形成密切相关 ,超声方法检测活体家兔腹主动脉 IMT准确可行。