Progression of Aortic Valve Calcification Association With Coronary Atherosclerosis and Car

ISSN: 1524-4539Copyright © 2001 American Heart Association. All rights reserved. Print ISSN: 0009-7322. OnlineCirculation is published by the American Heart Association. 7272 Greenville Avenue, Dallas, TX 72514DOI: 10.1161/hc4101.0975272001;104;1927-1932 Circulation Werner G. Daniel and Stephan AchenbachKarsten Pohle, Ralph Mäffert, Dieter Ropers, Werner Moshage, Nicolaos Stilianakis,Atherosclerosis and Cardiovascular Risk Factors Progression of Aortic Valve Calcification: Association With Coronary/cgi/content/full/104/16/1927located on the World Wide Web at:The online version of this article, along with updated information and services, is/reprints Reprints: Information about reprints can be found online atjournalpermissions@ 410-528-8550. E-mail:Kluwer Health, 351 West Camden Street, Baltimore, MD 21202-2436. Phone: 410-528-4050. Fax: Permissions: Permissions & Rights Desk, Lippincott Williams & Wilkins, a division of Wolters/subscriptions/Subscriptions: Information about subscribing to Circulation is online atProgression of Aortic Valve Calcification Association With Coronary Atherosclerosis and CardiovascularRisk FactorsKarsten Pohle,MD;Ralph Mäffert,MD;Dieter Ropers,MD;Werner Moshage,MD;Nicolaos Stilianakis,PhD;Werner G.Daniel,MD;Stephan Achenbach,MDBackground—Recent studies demonstrated an influence of atherosclerotic risk factors on the progression of aortic valve stenosis.The extent of aortic valve calcification(AVC)was also found to be a strong predictor of stenosis progression.We investigated the influence of the LDL cholesterol level(LDL),other standard cardiovascular risk factors,and the extent of coronary calcification(CC)on the progression of AVC quantified by electron beam tomography(EBT). Methods and Results—In104patients(64.7Ϯ8years,89male)with an EBT scan positive for AVC,CC and AVC were quantified using a volumetric score.EBT was repeated at a mean interval of15months(10to36months),and the progression of AVC and CC was determined.Patients were divided into2groups according to LDL:group1, LDLՅ3.36mmol/L(130mg/dL),57patients;group2,LDLϾ3.36mmol/L(130mg/dL),47patients.Mean values for CC were546Ϯ932mm3in scan1and665Ϯ1085mm3in scan2for AVC324Ϯ796mm3and404Ϯ1076mm3, respectively.The mean progression of CC was27Ϯ37%(group1,16Ϯ22%;group2,39Ϯ46%,PՅ0.001)and of AVC was25Ϯ38%(group1,9Ϯ22%;group2,43Ϯ44%,PՅ0.001).Conclusions—Quantification of AVC by EBT permits new insights into the progression of aortic valve sclerosis.We observed a strong influence of LDL cholesterol level on the progression of AVC and CC,suggesting that lipid-lowering therapy may decrease the progression of aortic valve calcification.(Circulation.2001;104:1927-1932.)Key Words:imagingⅢheart diseasesⅢlipidsⅢrisk factorsⅢatherosclerosisA ortic valve stenosis has a prevalence of2%to7%in thepopulation above65years of age.1In industrialized countries,aortic valve stenosis is most frequently caused by progressive calcification and degeneration of the aortic cusps.2,3The disease shows a progressive course,especially after the threshold to mild aortic stenosis has been crossed.2,4 Common pathomechanisms of aortic valve stenosis and atherosclerosis have been discussed,and several studies have demonstrated an influence of cardiovascular risk factors on the progression and outcome of aortic valve stenosis,but results have been inhomogeneous as to the relative impor-tance of specific risk factors.5–9Several studies have identi-fied the degree of aortic valve calcification as a strong predictor both for the progression and outcome of aortic stenosis.10,11Presently,there are no accurate methods to quantify the extent of aortic valve calcification;most studies rely on categorical scoring systems derived from echocardio-graphic valve morphology.1,12See p1881Electron beam tomography(EBT)is a cross-sectional imaging technique with high temporal resolution.13,14It has so far mainly been used to sensitively detect and quantify coronary calcifications15–17;several studies used EBT to follow the progression of coronary calcification.An influence of cardiovascular risk factors,especially the LDL cholesterol level,on the degree of coronary calcium progression could be demonstrated.18–22Some studies suggested the use of EBT or computed tomography to detect and quantify aortic valve calcification.23–25A weak correlation between the extent of calcification and the severity of aortic valve stenosis has been described.25We therefore used EBT in a group of104patients to quantify the extent of aortic valve calcification,to determine the rate of progression,and to analyze the influence of cardiovascular risk factors on the course of aortic valve calcification.In addition,we inves-tigated the relationship between the progression of aortic valve calcification and the extent and progression of coronary atherosclerosis,expressed through the amount of coronary calcification.We hypothesized that adults with aortic sclerosis and low levels of LDL cholesterol would have a lower increase in aortic valve and coronary calci-fication,as measured by EBT,compared with those with higher LDL cholesterol levels.Received May30,2001;revision received August6,2001;accepted August9,2001.From the Department of Internal Medicine II(K.P.,R.M.,D.R.W.M.,W.G.D.,S.A.)and Department of Medical Information,Biometry,and Epidemiology(N.S.),University of Erlangen,Germany.Correspondence to Dr Karsten Pohle,Medizinische Klinik II,Universität Erlangen-Nürnberg,Östliche Stadtmauerstr.29,D-91054Erlangen,Germany. E-mail Falk-Karsten.Pohle@rzmail.uni-erlangen.de©2001American Heart Association,Inc.Circulation is available at MethodsPatientsOne hundred four patients (89men and 15women,mean age 64.7Ϯ8years)with aortic valve calcification in EBT were included in the study in a retrospective fashion.The patients were recruited by reviewing 2124EBT studies that had been obtained for detection of coronary artery calcification on an outpatient basis in our centerbetween 1997and 2000.Two hundred seventy two individuals with aortic valve calcification in the EBT scan (volume score Ͼ10mm 3)were identified and invited for a follow-up EBT investigation to assess the progression of coronary and aortic valve calcification.One hundred sixty eight patients with aortic calcification had to be excluded because they refused return for follow-up or for other reasons that did not permit inclusion in the investigation (established diagnosis or symptoms suggestive of coronary artery disease or aortic valve stenosis at the baseline scan,arrhythmias,possible pregnancy,history of renal disease or renal failure [elevated serum creatinine concentrations],or change of lipid-lowering medications within the observation interval).All participating patients gave written informed consent to the investigation,and the study protocol was approved by the institutional ethics committee.Assessment of Cardiovascular Risk FactorsCardiovascular risk factors were determined by interviewing the patients at the time of the follow-up scan.The following risk factors were assessed:patient age (Ն55years),present smoking,hyperten-sion (antihypertensive medication or known and untreated hyperten-sion),and diabetes (use of insulin or oral hypoglycemic agents).In addition,fasting blood samples were taken from all patients,and the serum levels of LDL cholesterol and total cholesterol were measured.Image Acquisition and EvaluationImaging was performed with an Imatron C-150XP EBT scanner (Imatron Inc).Patients were scanned in supine position.After determination of the heart position,40axial cross-sections of the heart were acquired during inspiratory breathhold.Imaging was performed using the high-resolution single slice mode of the scanner with 100-ms exposure time,3-mm slice thickness,and 3-mm table feed between consecutive slices.Image acquisition was triggered to the patient ’s ECG at 40%of the cardiac cycle.Cross-sectional images were reconstructed with a 26-cm field of view using the scanner ’s sharp kernel.To assess the interscan variability of aortic valve calcification measurements by EBT,a second scan was performed in 50patients at the time of the follow-up investigation.After repositioning the patient,the EBT scan was repeated with identical parameters as the first scan,but only 12images were acquired to selectively cover the region of the aorticvalve.Figure 1.Cross-sectional EBT image of a calcified aortic valve (arrow).Arrowheads indicate coronary artery calcifications.Clinical Characteristics of the Patients and Results of Coronary and Aortic Valve Calcification MeasurementsAll PatientsGroup 1,LDL Cholesterol Յ3.36mmol/LGroup 2,LDL Cholesterol Ͼ3.36mmol/LPNo.of patients 1045747Men/women 89/1549/840/7Age,y64.7Ϯ865.8Ϯ763.4Ϯ9NS Present smoker,%44.240.448.9NS Hypertension,%51.050.951.1NS Diabetes,%11.512.310.6NS LDL cholesterol,mmol/L 3.4Ϯ1.12.6Ϯ0.64.4Ϯ0.8Ͻ0.001Coronary calcification Volume score,initial scan 546.8Ϯ932632.9Ϯ1180455.5Ϯ554NS Volume score,follow-up scan 665.1Ϯ1085705.5Ϯ1278620.2Ϯ834NS Percent annualized increase 27.3Ϯ3716.2Ϯ2339.7Ϯ46Ͻ0.001Aortic valve calcifications Volume score,initial scan 324.8Ϯ796239.9Ϯ356427.6Ϯ1116NS Volume score,follow-up scan 404.1Ϯ1076272.8Ϯ409563.5Ϯ1530NS Percent annualized increase24.5Ϯ389.1Ϯ2243.2Ϯ44Ͻ0.001Continuous variables are expressed as mean ϮSD.1928Circulation October 16,2001Acquired images were transferred to an offline workstation (NetraMD,ScImage).Coronary and aortic valve calcifications were defined as areas of at least2contiguous pixels(areaϾ0.51mm2) with a density of130HU or more(see Figure1).Using an interpolated volume score,26the total volumes of coronary and aortic valve calcification were determined.Calcifications of the aortic wall that were immediately connected to calcifications of aortic valve cusps were included in the aortic valve calcification score.To determine interscan variability,the absolute difference of the two aortic valve calcification scores was divided by the mean score and expressed as percent value.To determine the change of aortic valve and coronary artery calcification over time,the initial score was subtracted from the follow-up score and the difference was divided by the initial score and expressed as percent value.This value was divided by the actual number of days between the initial and follow-up scan and multiplied by365to obtain the annualized percent change in aortic valve and coronary calcification. Statistical AnalysisStatistical analysis was performed using a PC-based computer program(SPSS version10.0).To compare the influence of LDL cholesterol levels on the progression of coronary and aortic valve calcification,patients were divided into two groups using an arbi-trary threshold.In group1,the LDL cholesterol level wasՅ3.36mmol/L(130mg/dL);in group2,the LDL cholesterol level wasϾ3.36mmol/L(130mg/dL).Comparisons between groups were performed using the t test for unpaired samples.The relationship between the progression of coronary and aortic valve calcification was analyzed by bivariate correlation using the Pearson coefficient. In addition,stepwise multiple regression analysis was performed to identify independent predictors of the progression of aortic valve and coronary calcification.PՅ0.05was considered to indicate a signif-icant difference.ResultsBaseline Patient CharacteristicsThe mean interval between the initial and follow-up EBT scan was15.3Ϯ5months(range,10to36months).There were no significant differences concerning age,sex,and cardiovascular risk factors between the two patient groups divided according to LDL cholesterol levels.Fifty four patients(39in group1and15in group2)were treated with HMG-CoA reductase inhibitors.The Table shows the patient characteristics in all patients as well as in the subgroups.The mean initial aortic valve calcification score in all104patients was324Ϯ796mm3.The baseline amount of aortic valve calcification was not significantly different in the2patient groups,and it was not associated with any of the other tested cardiovascular risk factors(age,Pϭ0.46;diabetes,Pϭ0.22; hypertension,Pϭ0.52;smoking,Pϭ0.33).All patients had coronary calcifications in the baseline scan(mean score, 541Ϯ929mm3).No significant correlation was found be-tween the amount of coronary and aortic valve calcification in the initial EBT investigation(rϭ0.04,Pϭ0.7). Variability of Aortic ValveCalcification MeasurementsIn50patients,measurement of aortic valve calcification was repeated at the follow-up investigation to determine interscan variability.The mean aortic valve calcification score was 410.5mm3for the first and386.6mm3for the second measurement(Pϭ0.9),resulting in a mean variability of 8.2Ϯ9%and a median variability of6.9%.There was a significant influence of the total amount of aortic valve calcification on interscan variability:Mean and median vari-abilities in the lowest tercile of aortic valve calcification (scoreϽ96.8mm3)were14.3Ϯ11%and11.9%,whereas the mean and median variabilities in the upper tercile of aortic valve calcification(scoreϾ1531.7mm3)were4.8Ϯ6%and 5.9Ϯ5%,respectively(Pϭ0.05).Progression of Aortic Valve andCoronary CalcificationThe mean aortic valve calcification score of all104patients increased from324Ϯ796mm3in the initial scan to 404Ϯ1076mm3in the follow-up scan,corresponding to a mean annualized progression of24.5Ϯ38%.Eighty five patients(82%)showed progression,whereas19patients (18%)showed regression in the amount of aortic valve calcification.There was no significant influence of the amount of aortic valve calcification in the initial scan on the rate of progression.In the lowest tercile(scoreϽ34mm3),the mean progression was39.2Ϯ57%(median18.8),whereas in the upper tercile(scoreϾ274mm3),the mean progression was14.7Ϯ11%(median14.7,Pϭ0.18).The mean coronary artery calcification score increased from546Ϯ932mm3to665Ϯ1085mm3during the study period.The mean annualized progression was27.3Ϯ37%. There was a significant correlation between the annualized progression of coronary and aortic valve calcification (rϭ0.42,PϽ0.001,Figure2).In the upper tercile of annual-ized coronary calcium progression(annual progression Ͼ33.8%),the mean annual increase of aortic valve calcifica-tion was47.3Ϯ33%(median38.6),whereas in the lowest tercile of coronary calcium progression(Ͻ8.3%),the mean annual increase of aortic valve calcium was only9.5Ϯ22% (median6.5,PϽ0.001).Influence of Cardiovascular Risk Factors on the Progression of Aortic Valve CalcificationThere was a significant influence of serum LDL cholesterol levels on the progression both of aortic valve andcoronary Figure2.Scatterplot of percent annualized progression of coro-nary calcifications(x-axis)and aortic valve calcifications(y-axis). Bold line indicates regression line;thin lines,95%CI.Corre-sponding correlation coefficient was rϭ0.42(PϽ0.001).Associ-ated estimate of the regression coefficient was bϭ0.44(95%CI 0.27to0.59,PϽ0.001).Pohle et al Progression of Aortic Valve Calcification1929calcifications (Table,Figures 3A and 3B).Patients were divided according to their LDL cholesterol level,using a predefined value of 3.36mmol/L (130mg/dL)as an arbi-trarily chosen cut point.In patients with a LDL cholesterol level Յ3.36mmol/L (group 1,n ϭ57),the mean annual progression of aortic valve calcification was 9.1Ϯ22%,whereas in patients with LDL cholesterol levels Ͼ3.36mmol/L (group 2,n ϭ47),the mean annual progression was 43.2Ϯ44%(P Ͻ0.001).Correspondingly,the mean an-nual coronary calcium progression was 16.1Ϯ22%(group 1)and 39.7Ϯ46%(group 2),respectively (P Ͻ0.001,Figure 4).We found no influence of smoking,hypertension,diabetes,or patient age on the rate of progression,possibly because of the small size of the respective subgroups.The use of cholesterol-lowering medication by itself had no significant influence on the progression of aortic valve calcification.Fifty four patients were treated with HMG-CoA reductase inhibitors during the follow-up interval;their mean LDL cholesterol level was 2.97Ϯ0.83mmol/L (114.7Ϯ32mg/dL).The mean annual progression of aortic valve calci-fication in these 54patients was 21.5Ϯ44%.The mean LDLcholesterol level in the 50patients not treated with HMG-CoA inhibitors was 3.96Ϯ1.16mmol/L (153.2Ϯ45mg/dL),and these patients displayed a mean annual progression of 27.8Ϯ31%(P ϭ0.4).If,however,the 54patients treated with statins were divided according to their LDL cholesterol level (Յ3.36mmol/L,39patients;Ͼ3.36mmol/L,15patients),a statistically significant difference of annualized aortic valve calcium progression was found (10.1Ϯ26%and 51.1Ϯ65%,P ϭ0.002).Multiple Regression AnalysisStepwise multiple regression analysis was performed for two reasons:to identify predictors of the progression of aortic valve and coronary calcifications and to verify an indepen-dent association between the degree of progression of coro-nary calcifications and the progression of aortic valve calci-fication.For entry into calculation,a univariate probability value of 0.10was set for all parameters.LDL cholesterol levels and age were entered as continuous variables,whereas hypertension,diabetes,and smoking were entered as categor-ical variables.The serum LDL level could be identified as a parameter with an independent influence both on the progression of aortic valve (slope 0.29;95%CI 0.13to 0.46;P ϭ0.001)and coronary calcifications (slope 0.22;95%CI 0.05to 0.39;P ϭ0.01).The overall data fit of the model was R 2ϭ0.11for the progression of aortic valve calcifications and R 2ϭ0.06for the influence on progression of coronary calcifications.When the annualized relative progression of coronary artery calcification was added to the regression analysis,it could be identified as an independent predictor of the pro-gression of aortic valve calcification (slope 0.37;95%CI 0.18to 0.57;P Ͻ0.001)along with the LDL cholesterol level (slope 0.19;95%CI 0.03to 0.36;P ϭ0.02).The overall data fit of this model was R 2ϭ0.22.DiscussionThe degree of aortic valve calcification is of high predictive value concerning the progression and clinical outcome of aortic valve stenosis 10and has also been identified as a predictor of cardiovascular mortality,echocardiographic ev-idence of aortic valve sclerosis being associated with a50%Figure 3.A,Scatterplot of LDL cholesterol level in mmol/L (x-axis)and the percent annualized progression of aortic valve calci fications (y-axis).Bold line indicates regression line;thin lines,95%CI.The corresponding correlation coef ficient was r ϭ0.35(P Ͻ0.001).Associated estimate of the regression coef fi-cient was b ϭ10.55(95%CI 5.09to 16.02,P Ͻ0.001).B,Scat-terplot of LDL cholesterol level in mmol/L (x-axis)and the per-cent annualized progression of coronary calci fications (y-axis).Bold line indicates regression line;thin lines,95%CI.Corre-sponding correlation coef ficient was r ϭ0.25(P ϭ0.01).Associ-ated estimate of the regression coef ficient was b ϭ8.49(95%CI 1.87to 15.12,P ϭ0.01)Figure 4.Box plots of the annualized progression of coronary calci fications and of aortic valve calci fications in the two patient groups divided according to their LDL cholesterol level.Box plots display median,25th and 75th percentile,and the extreme values.1930Circulation October 16,2001increase in the risk of death from cardiovascular causes. Clinical and histopathological data suggest that aortic valve sclerosis and stenosis represent different stages of the same disease.12In our study,we could demonstrate that electron beam tomography permits the quantification of aortic valve calci-fication with high interscan reproducibility.It was demon-strated that aortic valve calcification,even in asymptomatic patients,is progressive,with a mean increase of24.5%per year.In addition,we could show that the degree of progres-sion of aortic valve calcification is influenced by the LDL cholesterol level,and that,independent from risk factors,the progression of aortic valve calcification is more rapid in patients with a rapid progression of coronary artery calcifi-cation,a surrogate marker for the amount of coronary atherosclerotic plaque.27These results strongly add to the findings of previous investigations,which have suggested a similar nature of calcified aortic valve stenosis and coronary artery disease,for example by establishing an association between atherosclerotic risk factors or the presence of coro-nary artery disease and the progression of aortic stenosis5,28,29 or by demonstrating that aortic valves affected by degenera-tive stenosis contain higher amounts of oxidized LDL cho-lesterol and show increased expression of metalloproteinases compared with healthy valves,9,30–32observations that are also made in coronary atherosclerotic plaque.33,34Even though it therefore seems possible that risk factor modifica-tions that have proven to beneficially influence the progres-sion and outcome of coronary artery disease,such as the reduction of LDL cholesterol,may also be able to slow the progression of calcified aortic valve stenosis,this remains to be proven in intervention studies,especially because aortic valve stenosis may be a multifactorial disease28and nonath-erosclerotic risk factors for disease progression have also been identified.29Our study,intended as a first investigation to analyze a possible association between the progression of aortic valve and coronary artery calcification,has several limitations.It is a retrospective analysis in patients who had been referred for coronary calcification scanning and is therefore subjected to selection bias,because patients with cardiovascular risk factors are overrepresented.Even though a significant influ-ence of LDL cholesterol levels on the progression of aortic valve calcification could be demonstrated,the sample size was too small to reliably analyze the effect of other risk factors,such as diabetes,which was only present in a very small subgroup of our patients.Apart from the determination of reproducibility in our study and a small,previously published group of19patients,25no other validations of EBT for the quantification of aortic valve calcification have been performed.However,it is reasonable to assume that the close association that has been found for EBT and histological measurements of coronary artery calcium also should hold true for the aortic valve.35Most importantly,we only assessed aortic valve calcification,and no measurements concerning the functional status of the aortic valve were performed. Patients with symptoms suggestive of severe aortic valve stenosis were excluded from our investigation.However, echocardiographic data were not available in all subjects and,therefore,our patients may have been an inhomogeneous group,consisting of patients with aortic sclerosis without obstruction and patients with asymptomatic,calcified valvu-lar stenosis.Even though other authors have described a weak correlation between the extent of aortic valve calcification and the degree of aortic stenosis,25the data we obtained as to the progression of valve calcification cannot be directly extrapolated to the progression of aortic valve stenosis. 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