| Background: Degeneration of aortic valve is now the most frequent cause of aortic valve replacement in western countries and they frequently occur in old patients. Calcific aortic stenosis is present in 2-3% of adults over 65 years, and irregular aortic valve thickening without obstruction to left ventricular outflow is present in about 25% of elderly adults. Previously, degeneration of aortic valve was thought of as a degenerative disease and a natural consequence of aging. Even if degeneration of aortic valve is accompanied by cardiocerebral diseases due to atherosclerosis, it is considered as a coincidence. However, recently, histopathologic and clinical studies suggest similarities between the mechanisms involved in the development of degenerative lesion and atherosclerosis, suggesting these two diseases may share common pathophysiologic mechanisms. In addition, it is considered as anotherform of atherosclerosis beyond vascular wall. Several clinical risk factors are associated with degeneration of aortic valve, including male sex, smoking, hypertension, age, hypercholesterolemia, and diabetes mellitus. Recent retrospective trials have suggested a role for hydroxymethymethylglutary- coenzyme A (HMG-CoA) reductase inhibitors (also known as statins) in slowing the progression of degenerative lesion of aortic valve. Patients taking stains had a 62% lower rate of aortic valve calcium accumulation than did patients not receiving stains. Using stains can reduce the prevalence of calcific aortic valve disease and decrease notably the population receiving aortic valve replacement. Furthermore, some researchers have thought that calcific aortic valve stenosis in the elderly can be an endstage of degeneration of aortic valve. Degenerative lesion of aortic valve and atheroscleros s have much common in histopathology, for example, lipids accumulation, inflammatory cells infiltration including macrophages and T- lymphocytes and calcium deposition. More recent studies have suggested that the presence of degenerative lesion may also be associated with increased cardiovascular morbidity and mortality. Therefore, it is reasonable that degeneration of aortic valve is named as aortic valve sclerosis (AVS). Most scholars have replaced 'degeneration of aortic valve' with AVS in some recent publications.In the retrieved literatures on the relationships between AVS and coronary artery disease (CAD), only Tolstrop classified AVS by transesophageal echocardiography (TEE). The study indicated as follows: different AVS subtypes have great difference in the value ofprediction and diagnosis for CAD. Diffuse and mixed sclerosis in AVS group have higher sensitivity and speciality for the diagnosis of CAD than localized and nonnodular sclerosis. However, researches on classification of AVS by transthoratic echocardiography (TTE) have not been reported up to date in the publications. Therefore, if AVS is classified by TTE and the value of prediction and diagnosis for CAD may be demonstrated, it will have important clinical significance. Atherosclerosis is considered a generalized disease, mainly manifested in the entire vasculature, an association between peripheral vascular diseases has well established. Researches have suggested that the degree of carotid atherosclerosis can reflect the degree of a generalized atherosclerosis, especially for coronary atherosclerosis. The carotid artery intima-media wall thickness (IMT) has been reported to be a useful marker for the presence of CAD. Ultrasonography, a valid, simple, safe and noninvasive technique for the assessment of extracoronary atherosclerosis. Because carotid artery has some advantages including a superficial place, ittle interference with ultrasound and better ultrasonogram, at present, it has also been one of the most valuable windows in evaluating non-invasive atherosclerosis. However, the accurate relationship between AVS and atherosclerosis has not yet been confirmed to this day, and comparative studies on the histopathologic characterizations of aortic valve, aortic wall and coronary artery have been rarely reported.In our research, we rule out those patients with reheumatic heartdisease, congenital aortic valve abnormality, infective endocarditis, prosthetic aortic valve and idiopathic cardiomyopathy after detailed history taking, physical examination, chest X-ray and routine echocardiography. On the basis of them, we divided study subjects into two groups, that is, AVS group (patients with aortic valve sclerosis) and No-AVS group (patients without aortic valve sclerosis).Objectives: The aim of this study: l.to evaluate clinical risk factors associated with AVS group, including: age, gender, body weight index, blood pressure, serum lipids and blood glucose. 2.to evaluate the diagnostic value of aortic valve sclerosis in general for coronary artery disease, and to evaluate the diagnostic value of aortic valve sclerosis in variable morphologic types for coronary artery disease-, 3.to evaluate the association of aortic valve sclerosis and carotid atherosclerosis. 4.to identify the histopathological and immunohistochemical characterization of aortic valve sclerosis.5.to evaluate the similarities and differences of histopathologic characterizations among aortic valve, aortic wall and coronary artery specimens between both AVS and non-AVS patients.Methods:1.Study populatoion: The study population consisted of 138 patients (91 men and 47women; mean age 63.7+12.5 years) with suspected coronary artery disease (CAD) between February 2002 and December 2003 at department of cardiology, the Second Hospital of Shandong University.Forty-three had a previous myocardial infarction. Thirty-five patients had stable angina pectoris. Fifty-one patients hadan atypical angina pectoris. Nine patients have accepted the coronary artery bypass grafting (CABG). 7 of them come from AVS group, the rest come from No-AVS group.All patients were affirmed by coronary angiography. Patients with rheumatic valvular disease, congenital aortic valve abnormality, bicuspid aortic valves, infective endocarditis, prosthetic valves, or idiopathic cardiomyopathy, were excluded from this study.2.Risk factors and serum examination: After risk factors for coronary artery disease such as age, sex, hypertension, hypercholesterolemia, diabetes mellitus, and history of smoking were recorded, each subject underwent a complete physical examination. Blood pressure was measured twice using the sphygmomanometer in the sitting position, with 5-10 minutes apart, and averaged. Body weight index (BWI) was measured according to the weight and height (kg/m2). Venous blood samples were obtained after overnight fast. Levels of total cholesterol (TC), triglyceride (TG), high-density lipoprotein cholesterol (HDL-c), low-density lipoprotein cholesterol (LDL-c) and lipoprotein cholesterol (a) [Lp (a)] were determined using an automatic enzymatic technique. In addition, fasting glucose level was measured, and if needed, a glucose tolerance test was followed.3.Echocardiography: All patients underwent transthoratic echocardiography with a Toshiba Power Vision 6000 imaging system. Two-dimensional assessment of the aortic valve was performed on the basis of the parasternal long-axis and short-axis views. Aortic valvesclerosis (AVS) was defined by focal areas of increased echogenicity and thickening of the aortic valve leaflets.Aortic stenosis was defined as thickened leaflets with reduced systolic opening on two-dimensional imaging, and with an increased velocity across the aortic valve ^ 2.5m/s. The location and extent of AVS was defined. Also, the number of affected cusps was recorded. Four morphologic types of AVS were identified: type I, localized, non-nodular sclerosis; type II, localized, nodular sclerosis; type III, diffuse sclerosis;type IV, mixed sclerosis. In addition, aortic regurgitation was observed with color flow imaging. Left ventricular myocardial mass (LVM) and left ventricular ejection fraction (LVEF) were calculated using Devereux' formula and B-mode Simpson' s method, respectively.4.Carotid artery ultrasound: The carotid artery ultrasound scanning with a 6-llMHz imaging transducer was performed. The patients's head position,sonographer position,scanning,and scanning angle sequence were all standardized.The extracranial carotid artery was evaluated at 3 1-cm segments,the common carotid,the carotid bifurcation,and the internal carotid artery. Intima-media wall thickness, systolic peak velocity (Vmax),end-diastolic velocity (Vmin), mean velocity (Vmen), resistance index (RI) and pulse index (PI) were measured. We defined as the carotid atherosclerosis plaque when IMT ^ 2mm.5.Coronary angiography: Coronary angiography in multiple views was performed according to the standard Judkins technique. At least five-views, including two orthogonal views, were acquired forthe left coronary artery and at least two orthogonal views for the right coronary artery. The percent of diameter stenosis was determined by quantitative coronary angiography. In all patients, the presence of CAD was determined as: ^50% luminal diameter narrowing in^ 1 vessel by coronary angiography.6.Tissue acquisition and preparation: Aortic valve leaflets with varying degrees of macroscopic disease were obtained: including surgical specimens from patients undergoing aortic valve replacement for aortic stenosis with multivessel CAD, autopsy cases with CAD and autopsy cases with a noncardial desease. Specimens were fixed with Formalin. When necessary, decalcification was performed with formic acid. Specimens were examined for leaflet thickening, cellularity, and the presence of adipose cells using hematoxylin and cosin staining.Immunohistochemical analysis were performed using (Streptavidin/Peroxidase) directed against macrophages and T-lymphocytes.7.Statistical analysis: Data were entered into Excel and analyzed with SPSS version 10.0. Continuous measures are expressed as the mean value ± SD. Continuous variables are analyzed by using the Student t test. Dichotomous variables are compared by chi-square analysis. A value of P<0.05 was considered statistically significant.Results: All 138 patients completed the study successfully. Of these, 58 subjects were diagnosed as having AVS (AVS group), and 80 subjects were diagnosed as No-AVS (No-AVS group).1.Baseline patient characteristics: On average, patients in AVSgroup were 4 years older than in No-AVS group (67.8 + 12.5 vs 63.5 ± 11.6, P <0.05). The significant differences were found in history of hypertension, previous myocardial infarction, and hypertension between two groups (P<0.05). There existed no significant differences in gender distribution, body weight index, history of diabetes mellitus and smoking (P>0.05).2.Blood pressure and lipids-related factor assessment: Between AVS group and No-AVS groups, significant differences were found in systolic blood pressure(13 8.6 ± 18.8 vs 131.3 + 15.3, P<0.05). TG,TC,and LP(a)were increased in the AVS group,compared with Non-AVS group(2.33 + 1.6 vs 1.62+1.0, P<0.05; 5.73 + 1.1 vs 5.18 + 1.3, P<0.05; 316.9 + 199.5 vs 206.5 + 172.7,P<0.01).AVS group had a lower serum concentration of HDL-c (1.06 + 0.47 vs 1.29 + 0.34, P<0.01). However ,there no significant differences in diastolic blood pressure,LDL-c and fasting glucose(80.5 + 1 2.5 vs 79.8 + 11.9, P>0.05; 2.85 + 0.98 vs 2.93±0.95, P>0.05; 6.16 + 2.49, vs5.74± 1.91; P>0.05).3.Echocardiographic findings: LVEF was lower in patients with AVS than in those whithout AVS,but there was not significant difference in statistics(64.4 +13.1 vs 67.3 + 9.3, P>0.05). LVMW was increased in the AVS group,compared with No-AVS group(163.5 + 42.7 vs 152.7 + 39.3, P<0.05). The transaortic flow velocity was higher in patients with AVS than in those No-AVS (1.52 + 0.47 vs 1.16 + 0.21,P<0.01). 17 patients (29.3%) in AVS group were found with valvular aortic stenosis and 5 patients with severe aortic valuestenosis. The prevalence of aortic regurgitation was significantly higher in AVS group than in No-AVS group (48.3 % vs 23.8 %,P<0.05). Of 58 AVS patients, 10 cases were defined as I type, 6 cases II type, 21 cases III type and 22 cases IV type.4.Carotid artery ultrasound findings: IMT in AVS group was thicker than that in No-AVS groups(?<0.05).The prevalence of carotid atherosclerosis was higher in AVS group compared with that in No-AVS groups(P<0.05).There were not significant differences in the common carotid diameter,the maximum velocity, the minimum velocity, the mean velocity,the resistance index and the pulus index between two groups (allP>0.05) .5.Coronary angiography findings: Of 138 patients, significant coronary artery stenosis was found in 60 patients (43.5%). In AVS group, 37 patients had CAD (63.8%) , 13 patients (35.1%) having single vessel disease,24 patients(64.9%) having multivessel disease. In No-AVS group, 23 patients (28.8%) had CAD, 15 patients (65.2%) having single vessel disease, 8 patients (34.8%) having multivessel disease. Of 42 patients with III type and IV type AVS, 33 patients had coronary artery disease. In general, the sensitivity, specificity, positive predictive value and negative predictive value of AVS in diagnosing CAD were 63.8%, 71.3%, 61.7% and 73.1%, respectively. Furthermore, when III type and IV type AVS combined together, the sensitivity, specificity, positive and negative predictive values were 78.6%, 71.3%, 58.9% and 84.6%, respectively. The presence of type III or IV AVS was significantly correlated with CAD. When comparedto cases with normal aortic valves, diffuse and mixed nodular sclerosis was significantly correlated with CAD (P<0.01). The prevalence of cardiovascular risk factors was similar among all four AVS types.6.Histopathology and immunohistochemistry Of AVS: 5 in 7 surgical specimens were derived from patients undergoing aortic valve replacement for aortic stenosis and coronary artery disease, AVS were found in a advanced stage. It can be seen that aortic valves were milky white, obviously-thicken modulus, rough and uneven in their surfaces, and white calcium masses and light yellow lipid accumulation in their sections at the same time. Under microscope this lesion is characterized by disappear of endothelial cells on the aortic side of the valves, subendothelial thickening of the collagen fibers, large calcific nodules and neutral lipids. The predominant celluar components of these lesions are lymphocytes, a small number of macrophages (including lipid-laden foam cells) -. cholesterol crystals and new capillaries. Immunohistochemistry were shown with remarkably reduced macrophages and T-lymphocytes. Another 2 specimens were derived from autopsy case with sudden death due to CAD. AVS were found in an early stage. It can be seen that aortic valves were diffusely-thicken, little smooth and tough in their surfaces, and there were no calcium nudulus and light yellow lipid accumulation in their sections at the same time. Under microscope the lesion is characterized by endothelial cells disruption on the aortic side of the valves and subendothelial thickening of the collagen fiberlayers. The subendothelial elastic lamina is displaced by the lesion. In these lesions, a large number of new capillaries and cholosterol crystals can be seen and the predominant celluar components are macrophages and lymphocytes. The inflammatory cells tend to be located near the surface of the lesions. Smooth muscle cells and calcium depositions are less common. Immunohistochemistry were shown with lots of macrophages and T-lymphocytes in and near the lipid vesicula.7. 3 patients with No-AVS have no abnormality in aortic valve histopathology,including normal valve thickness,intact endothelial and ventricular muscle layer,no remarkable lipid components and imflammatory cells.Immunocytochemistry showed the presence of isolated macrophages or T-lymphocytes.Conclusions:(1). Clinical risk factors associated with aortic valve sclerosis or stenosis are similar to those with carotid and coronary artery atherosclerosis. These factors include older age, hypertension, and elevated serum levels of triglyceride, total cholesterol and lipoprotein (a) . In addition, decreased serum high density lipoprotein (HDL-c) levels correlated significantly with AVS.(2). Patients with AVS have higher prevalence of carotic and coronary atherosclerosis than those with No-AVS.(3). There was a high diagnostic valve of AVS for CAD, especially when III and IV types AVS combined together.(4). Advanced AVS is characterized by multiplicated fibers,increased collagen proteins and serious calcium nodules, whereas early and mid-term AVS are characterized by lipid deposition and inflammatory cells infiltration.(5). TTE has a important clinical value of diagnosis and classification for AVS.
|
PDF Full Text Request