A. Enbergs, R. Bürger, H. Reinecke, M. Borggrefe, G. Breithardt and S. Kerber

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1 European Heart Journal (2) 21, Article No. euhj , available online at on Prevalence of coronary artery disease in a general population without suspicion of coronary artery disease: angiographic analysis of subjects aged 4 to 7 years referred for catheter ablation therapy A. Enbergs, R. Bürger, H. Reinecke, M. Borggrefe, G. Breithardt and S. Kerber Department of Cardiology and Angiology and Institute for Arteriosclerosis Research, Hospital of the Westfälische Wilhelms-Universität Background The prevalence of coronary vessel wall alterations in the general population is not known. Therefore, the aim of our study was to determine the prevalence of coronary artery disease in persons in whom the underlying disease was not related to coronary artery disease and could therefore be regarded as a near normal population. Methods We included 331 consecutive patients (173 men, 158 women, aged between 4 and 7 years) who were referred for catheter ablation of an accessory pathway (67 4% ) or atrioventricular-node modification (32 6%) and who underwent coronary angiography as part of their routine baseline evaluation before radiofrequency current application. Most of the patients (79%) of this cohort were free of symptoms of coronary artery disease. Based on visual inspection of coronary angiograms in multiple projections, patients were classified to have one-, two- or three-vessel disease if stenoses greater than 5% of lumen diameter were present. In addition, diffuse vessel wall alterations were assessed using two different score systems. Results The prevalence of coronary artery disease in this near normal population was 7 3%, with a significant difference in coronary asymptomatic (3 8%) vs symptomatic patients (17 1%). Mean levels of total cholesterol and other risk factors were not significantly different in patients with coronary artery disease compared to those without. But levels of low-density lipoprotein (LDL) cholesterol and lipoprotein(a) were significantly higher and high-density (HDL) cholesterol lower in patients with a stenosis or extent score higher than zero compared to a score of zero. The values of all vessel scores evaluating the extent of critical and diffuse coronary vessel alterations were very low in patients affected with coronary artery disease, indicating a low degree of diffuse alteration of the vessel wall. Conclusions The prevalence of coronary artery disease with at least one critical stenosis in subjects aged 4 7 years with an average cholesterol level of mg.dl 1 is 7 3%. (Eur Heart J 2; 21: 45 52) 2 European Society of Cardiology Key Words: Coronary stenoses, asymptomatic persons, occult coronary disease. See page 13 for the Editorial comment on this article Introduction The prevalence of coronary vessel wall alterations in the general population is unknown. This is due to the fact that coronary angiography is generally only indicated in patients with a history of coronary artery disease or with Revision submitted 21 June 1999, and accepted 23 June Correspondence: Dr Annette Enbergs, Medizinische Klinik und Poliklinik, Innere medizin C (Kardiologie/Angiologie), Universität Münster, D Münster, Germany X//145+8 $35./ clinical symptoms typical for this disease. Nevertheless, autopsy in individuals who died of non-cardiac causes revealed a high prevalence of one-vessel disease (up to 1%) [1]. To determine the prevalence of coronary artery disease, as well as the degree and the extent of coronary lesions in a cohort of subjects, as nearly representative of the general population as we could obtain, we analysed the coronary angiograms of patients who had routinely undergone coronary angiography before radiofrequency catheter ablation of accessory pathways 2 The European Society of Cardiology

2 46 A. Enbergs et al. or atrioventricular-node modification. We also assessed the differences in risk factors in patients with and without vessel wall alterations. Patients and methods Patients above 4 years of age in whom radiofrequency catheter ablation of an accessory pathway or modification of the atrioventricular-node was planned, underwent coronary angiography to establish a baseline coronary profile before radiofrequency ablation, since some data had suggested that radiofrequency currents might have some effect on coronary vessels. Three hundred and thirty-one consecutive patients, 173 men and 158 women were included. Two hundred and sixtyone patients (79%), 134 men, 127 women, were free of clinical symptoms suggestive of coronary artery disease, the other group of patients (n=7, 39 men, 31 women) were symptomatic, presenting with chest pain unrelated to episodes of tachycardia. The coronary risk profile (weight, height, systolic and diastolic blood pressure, diabetes mellitus, smoking status, lipid profile) and current medication (antiplatelet agents, beta-blockers, ACE inhibitors, nitrates, calciumchannel blockers, lipid lowering drugs) were obtained from the patients records. After intracoronary injection of 2 mg nitroglycerin in either coronary artery to reduce vasomotor tone, multiplane cine coronary angiograms were obtained using the Judkins technique, mostly via a left femoral 5 French sheath. Angiograms included at least five projections of the left and three projections of the right coronary artery tree, with at least two projections each being in a rectangular orientation. Coronary angiograms were independently reviewed by two experienced cardiologists blinded to the patients clinical and laboratory findings. In the presence of stenoses greater than 5% of lumen diameter, coronary angiographic findings were grouped as one- to threevessel disease. The cinefilms were then evaluated using two different score systems which describe the extent and severity of vessel wall alterations [2 4]. (a) Stenosis score: 32 points. The maximum diameter reduction of eight coronary segments (left main stem, left anterior descending artery, main diagonal branch, main septal branch, left circumflex artery, main marginal branch, right coronary artery, right posterior descending branch) was scored with 1 to 4 points according to a luminal narrowing of 1 to 49% (1 point), 5 to 74% (2 points), 75 99% (3 points) or total occlusion (4 points). (b) Extent score: 1 points. This score was developed by Sullivan et al. [2]. According to the proportional length of each vessel segment in the coronary artery tree, segments are graded with different numbers of maximum points: 5 points for the left main stem, 2 for the left anterior descending artery, 1 for the main diagonal branch, 5 for the first septal branch, 2 for the left circumflex artery, 1 for the marginal and posterolateral vessels, 2 for the right coronary artery, and 1 for the right posterior descending branch. The number of points for each segment (irrespective of the degree of the diameter reduction) was expressed as the percentage length of visible lesions within the total segment. Occluded vessels which were filled with contrast medium by collateral flow, were evaluated according to the visible irregularities of the vessel wall. If no collateral flow existed, the mean value of all other vessel segments in this angiogram was transferred to this occluded vessel segment. Statistical evaluation was performed using the Statistical Package for the Social Sciences (SPSS), version 6.1. Bivariate relationships of stenosis and extent scores with other variables were calculated by Pearson correlation coefficients. All P-values are two-tailed. Results The age distribution of the whole cohort is shown in Fig. 1. The mean age was equal in men and women, but a higher proportion of patients symptomatic for coronary artery disease compared to asymptomatic persons was in the group aged 61 to 7 years (27 1 vs 13 8%). Table 1 presents the baseline characteristics including coronary risk factors. Prevalence of risk factors except current smoking was higher in symptomatic than in asymptomatic patients. Levels of total cholesterol and of LDL cholesterol were moderately elevated with no significant differences between male and female patients, but HDL cholesterol was markedly lower in asymptomatic men than in women (45 14 vs 6 17 mg. dl 1 ) paralleled by higher triglyceride levels in asymptomatic men than in women ( vs mg. dl 1 ). Treatment with drugs was very low in the study group with the exception of beta-blockers (4 5%) used as antiarrhythmic agents. 13 6% took antiplatelet agents, mostly in order to reduce the risk of thromboembolic events in connection with the interventional electrophysiological procedure. 6 9% were treated with ACE inhibitors, 3 3% with nitrates, 17 8% with calcium antagonists. 3 3% of the patients received lipid lowering agents. The results of coronary angiography analysis are presented in Table 2 (a) and (b). In the majority of patients (92 7%), there was no coronary artery disease. The prevalence of coronary artery disease (=1 3-vessel disease) in the total group was 7 3%. Twelve patients had one-vessel disease, seven patients two-vessel disease and five patients (only men) had three-vessel disease. The prevalence of coronary artery disease was higher in men in comparison to women (1 4 vs 3 8%) and especially higher in symptomatic patients compared to asymptomatic patients (17 1 vs 3 8%, not shown). The mean values of the coronary scores were very low compared to the maximum values (Table 2 (b)). They

3 Prevalence of CAD in a general population 47 Total (n = 331) Asymptomatic (n = 261) yrs 51 6 yrs 61 7 yrs Symptomatic (n = 7) Figure % Distribution of age in the study population. Table 1 Baseline characteristics of the study population Characteristic Total (n=331) Asymptomatic Men (n=134) Women (n=127) Men (n=39) Symptomatic Women (n=31) General Age (years) Type of arrhythmia (%) WPW syndrome AVNRT History of Hypertension (%) Current smoking (%) Diabetes (%) Hyperlipidaemia (%) Body mass index Blood pressure (mmhg) Systolic Diastolic Serum lipids Cholesterol (mg. dl 1 ) Total cholesterol LDL cholesterol HDL cholesterol Triglycerides (mg. dl 1 ) Lipoprotein(a) (mg. dl 1 ) Total cholesterol/hdl ratio Plus-minus values are means SD. WPW=Wolff Parkinson White; AVNRT=atrioventricularnode reentry tachycardia; LDL=low-density lipoprotein; HDL=high-density lipoprotein. The body-mass index is the weight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per litre, multiply by To convert values for triglycerides to millimoles per litre, multiply by were significantly higher in men than in women (P< 1). The distribution of the extent score is shown in Fig. 2. In Table 3, the baseline variables are compared between patients with at least one stenosis >5%, and to patients without significant stenoses. Patients with coronary artery disease had slightly but not significantly higher levels of total cholesterol ( vs mg. dl 1 ) and lower levels of HDL-cholesterol (43 11 vs mg. dl 1 ). Patients without critical stenoses had very low extent scores (Fig. 3). Scores in patients with coronary artery disease were also low, but the number of affected vessels (stenosis score) and the extension of vessel wall alterations (extent score) was

4 48 A. Enbergs et al. Table 2 (a) Angiographically determined prevalence of coronary artery disease Vessels with at least one stenosis >5% Total (n=331) Men (n=173) Women (n=158) 1-vessel disease 12 (3 6%) 8 (4 6%) 4 (2 5%) 2-vessel disease 7 (2 1%) 5 (2 9%) 2 (1 3%) 3-vessel disease 5 (1 6%) 5 (2 9%) Total prevalence 24 (7 3%) 18 (1 4%) 6 (3 8%) *Score values: Means SD. Table 2 (b) Extent of angiographically documented vessel wall alterations according to the score evaluation Total Men Women Stenosis score ( 32) Total (n=331) * Symptomatic (n=7) Asymptomatic (n=261) Extent score ( 1) Total (n=331) * Symptomatic (n=7) Asymptomatic (n=261) Score values: Means SD; *P< 1 men vs women; P< 5 symptomatic vs asymptomatic in men. significantly larger in this subgroup than in patients without significant stenoses greater than 5% (P< 1, Fig. 4). Regarding baseline variables and serum lipids in relation to scores, systolic and diastolic blood pressure, LDL cholesterol, and lipoprotein(a) as well as the cholesterol/hdl ratio were significantly higher, and HDL cholesterol lower in patients with a stenosis and Table 3 Comparison of baseline variables and serum lipids in patients with and without at least one stenosis >5%* -vessel disease 1 3-vessel disease Baseline variable (n=37) (n=24) Age (years) Body-mass index Blood pressure (mmhg) Systolic Diastolic Serum lipids Cholesterol (mg. dl 1 ) Total LDL HDL Cholesterol/HDL cholesterol ratio Triglycerides (mg. dl 1 ) Lipoprotein(a) (mg. dl 1 ) *Plus-minus values are means SD. All values are age-adjusted. LDL=low-density lipoprotein; HDL=high-density lipoprotein. The body-mass index is the weight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per litre, multiply by To convert values for triglycerides to millimoles per litre, multiply by extent score greater than, compared to patients with a stenosis or extent score of (Table 4 (a) and (b)). The differences remained significant for the subgroup of asymptomatic patients (for blood pressure only a trend), whereas risk factors and lipid levels were not significantly different in symptomatic patients with stenosis and extent scores greater than vs (not shown). Calculating the correlation coefficients, there was a strong correlation only between age and the scores, and Score value % Figure 2 Distribution of the extent score (n=331).

5 Prevalence of CAD in a general population 49 % Score value Figure 3 Distribution of the extent score in patients with -vessel disease (n=37). % Score value Figure 4 Distribution of the extent score in patients with 1 3 vessel disease (n=24). a weak positive correlation between LDL cholesterol, cholesterol/hdl ratio and the stenosis score, between systolic blood pressure, LDL cholesterol, cholesterol/ HDL ratio, lipoprotein(a) and the extent score as well as a negative correlation between HDL cholesterol and both scores (Table 4 (a) and (b)). Discussion It has been difficult to estimate precisely the prevalence of coronary artery disease in the general population, especially in asymptomatic patients: on the one hand, non-invasive tests (exercise-test, thallium-scintigraphy) cannot fully rule out coronary heart disease; on the other hand, invasive diagnostic procedures such as coronary angiography cannot be consecutively performed in an asymptomatic cohort of persons without pathological non-invasive tests or without any evidence of myocardial ischaemia. In our investigation, we achieved systematic coronary angiography in symptomatic as well as in asymptomatic patients. This was realized because our study group consisted of consecutive patients referred for invasive electrophysiological examination and intervention to treat accessory pathways, or to perform atrioventricular node modification. In this special clinical setting, routine coronary angiography seemed mandatory, so that we

6 5 A. Enbergs et al. Table 4 (a) Relation of baseline variables, serum lipids and stenosis-score Stenosis score > 32 r P Baseline variable* (n=28) (n=123) Age (years) ** 75 < 1 Body mass index ns Blood pressure (mmhg) Systolic # 1 8 ns Diastolic # 4 ns Serum lipids Cholesterol (mg. dl 1 ) Total ns LDL # 12 5 HDL # 18 2 Cholesterol/HDL ratio # 15 9 Triglycerides (mg. dl 1 ) ns Lipoprotein(a) (mg. dl 1 ) # 11 7 ns *Plus minus values are means SD; r=correlation coefficient, all values are age-adjusted. LDL=low-density lipoprotein; HDL=high-density lipoprotein. The body-mass index is the weight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per litre, multiply by To convert values for triglycerides to millimoles per litre, multiply by #P< 5; **P< 1. Table 4 (b) Relation of baseline variables, serum lipids and extent-score Extent score > 1 r P Baseline variable* (n=28) (n=123) Age (years) ** 36 < 1 Body mass index ns Blood pressure (mmhg) Systolic # 13 2 Diastolic # 8 ns Serum lipids Cholesterol (mg. dl 1 ) Total ns LDL # 15 9 HDL # 17 3 Cholesterol/HDL ratio Triglycerides (mg. dl 1 ) ns Lipoprotein(a) (mg. dl 1 ) # *Plus-minus values are means SD; r=correlation coefficient, all values are age-adjusted; LDL=low-density lipoprotein; HDL=high-density lipoprotein. The body-mass index is the weight in kilograms divided by the square of the height in meters. To convert values for cholesterol to millimoles per litre, multiply by To convert values for triglycerides to millimoles per litre, multiply by #P< 5; **P< 1. could ascertain the coronary artery status, as regards possible peri-procedural complications, before performing the planned electrophysiological interventional procedure. In conclusion, our analysis enabled us to define the extent of coronary vessel wall alterations in a group of definitely asymptomatic as well as symptomatic subjects. This group was as near as possible representative of male and female persons aged 4 to 7 years in the general population. Concerning our analysis it must be kept in mind that the investigated study group suffers from supraventricular tachycardia. Regarding previous reports, post-mortem analyses of asymptomatic patients who died of causes unrelated to coronary artery disease pointed to an estimated prevalence of coronary artery disease of 4 5%, 6 4% in men and 2 6% in women [5]. A higher prevalence (of 1%) of one-vessel disease has been reported from autopsies in individuals who died of non-cardiac causes [1].

7 Prevalence of CAD in a general population 51 Gensini et al. [6] demonstrated an incidence of 4 5%, (6% in males vs 3 4% in females) in a group of 278 adults undergoing cardiac catheterization with the clinical diagnosis of valvular or congenital heart disease in the absence of symptoms suspicious for coronary artery disease. These patients underwent coronary angiography before necessary cardiac surgery [6]. In further studies coronary angiography was restricted to patients who were asymptomatic but presented with an abnormal ECG, exercise test or thallium scanning. In a study of 5 asymptomatic male subjects, 3 65 years old, 86 persons (1 7%) proceeded to coronary angiography due to pathological non-invasive tests; 67 showed significant coronary artery disease, resulting in a prevalence of coronary artery disease of 1 34% in the whole study population of patients with signs of myocardial ischaemia [7]. Two further investigations including 214 and 139 male persons using exercise testing as a screening method for silent ischaemia reported a prevalence of 2 5% of significant coronary artery disease documented by coronary angiography [8,9]. In another study with a relatively smaller number of patients (129 asymptomatic men), the coincidence of ST-segment depression and coronary artery calcification at fluoroscopy was highly predictive of coronary artery disease at angiography, showing a prevalence of 1% [1] In the elderly and symptomatic patients, a link between radiographically detectable coronary calcium deposits and future events of coronary heart disease seems to be likely [11]. The majority of patients with angiographically normal coronary arteries are negative for coronary calcification at electron beam computed tomography; a low risk of cardiovascular events within the next 2 5 years could be documented for these patients [11]. In the subgroup without angina, coronary calcification was identified by means of computed tomography in only 4% [11]. None of these had significant stenoses on the coronary angiogram. Asymptomatic subjects differ from symptomatic subjects in two regards. According to the data of the Framingham study, asymptomatic subjects (particularly younger) have a relatively low risk of coronary events [12]. In consequence, there is less incentive to screen such patients. Regarding the literature, more information is available about asymptomatic postinfarction patients [13]. Nevertheless, there is some interest in the group of asymptomatic patients since data on silent myocardial ischaemia and sudden death are similar ( 5% prevalence of sudden death due to coronary artery disease in an asymptomatic population [8] ). Two decades ago, assessment in coronary angiographical studies of the sensitivity and specificity in the general population, of asymptomatic subjects without ECG signs of coronary artery disease was discussed theoretically. However, there was no consensus due to the inheritent risks of the procedure at that time [8]. Comparing the risk profile of asymptomatic persons in our study group to the male persons in the prospective cardiovascular Münster study (PROCAM) [14] without evidence for coronary artery disease there are no striking differences. Comparing our symptomatic patients to the male PROCAM persons with clinical evidence of coronary artery disease we find higher levels of risk factors in the PROCAM group. The risk factor levels of patients with one- to three-vessel disease (Table 3) are nearly equal to those of the PROCAM group with clinical evidence of coronary artery disease. This emphasizes that our study group does not comprise of a group of persons presenting with a totally different, highly elevated cardiovascular risk profile. It therefore may be justified to describe our study cohort as a nearly normal population. Concerning the prevalence of coronary artery disease, our analysis not only considered the extent of so-called critically stenosed vessels, but also included an evaluation of diffuse vessel wall alterations using two well established score systems. In the total group of patients, we found a prevalence of 7 3% of coronary artery disease, with at least one critical stenosis greater than 5%, 17 1% in symptomatic and 3 8% in asymptomatic persons. This underscores that in asymptomatic patients critical stenoses are rare. The extent of diffuse vessel wall alterations, as assessed by stenosis and extent scores, can be regarded as considerably low. It is worthwhile mentioning that the overall extent of coronary artery disease was low, even though this study cohort presented with a moderately elevated total cholesterol, a slightly elevated lipoprotein(a) level, a borderline ratio of total to HDL cholesterol and a considerable proportion of smokers and patients with hypertension and elevated body mass index, which is not negligible. From a clinical point of view, our data suggest that persons without clinical evidence of coronary artery disease (no history, no pathological non-invasive test) rarely prove to have significant stenoses even though they present with a moderately elevated risk profile for coronary artery disease. In consequence, patients without clinical evidence for coronary artery disease no longer undergo routine coronary angiography in our department. Our clinical practice has been modified to the following regimen: patients referred for catheter ablation without any symptoms typical of coronary artery disease do not undergo coronary angiography. This diagnostic procedure is only recommended when non-invasive diagnostic procedures are suspicious of coronary artery disease (e.g. regional left ventricular wall abnormalities during transthoracic echocardiography, pathological thallium scintigraphy, etc.) or the patient presents with a high risk profile of cardiovascular risk factors (e.g. serum cholesterol >3 mg. dl 1, excessive smoking, etc). Interpreting the angiographic findings in asymptomatic patients it must be considered that the study group may differ from a representative population sample. This becomes obvious regarding the level of medical treatment within our study group: 6 9% of the patients were treated with ACE inhibitors, 3 3% with nitrates, 17 8% with calcium antagonists, 13 6% with antiplatelet agents and 3 3% of patients received lipid lowering

8 52 A. Enbergs et al. agents. It is likely that this treatment level is higher than the treatment level in a representative study population. Knowing that plaque morphology appears to be most relevant concerning cardiovascular events (myocardial infarction, ischaemic syndromes), we plan to establish a follow-up analysis of these patients to compare the angiographic features of coronary artery disease to the incidence of cardiovascular events in the long-term. It will be interesting to find out whether patients with more diffuse or patients with more focal, critical stenoses have different long-term morbidity and mortality. Since the number of patients in our study group is relatively low concerning the topic of cardiovascular events, mortality and morbidity, a separate analysis is necessary to investigate the clinical course of these patients in a further long-term follow up several years after coronary angiography prior to the ablation procedure. Regarding well known risk factors for coronary artery disease, our data demonstrate that in patients without any critically stenosed arteries, a strong correlation between the extent of diffuse atherosclerotic vessel wall alterations and the absolute level of LDL cholesterol, HDL cholesterol and other risk factors can be confirmed. This underlines that well known risk factors already contribute to the angiographic manifestation of coronary artery disease at a stage when the person themself does not show any clinical manifestation or functional relevance of coronary artery disease. References [1] Davies MJ. Anatomic features in victims of sudden death: coronary artery pathology. Circulation 1992; 85 suppl. I: I-19 I-24. [2] Sullivan DR, Marwick TH, Freedman SB. A new method of scoring coronary angiograms to reflect extent of coronary atherosclerosis and improve correlation with major risk factors. Am Heart J 199; 119: [3] Budde T, Fechtrup C, Bösenberg E et al. Plasma Lp(a) levels correlate with number, severity, and length-extension of coronary lesions in male patients undergoing coronary arteriography for clinically suspected coronary atherosclerosis. Arterioscler Thromb 1994; 14: [4] Enbergs A, Dorszewski A, Luft M, Mönnig G et al. Failure to confirm ferritin and ceruloplasmin as risk factors for the angiographic extent of coronary arteriosclerosis. Cor Art Dis 1998; 9: [5] Diamond GA, Forrester JS. Analysis and probability as an aid in the clinical diagnosis of coronary artery disease. N Engl J Med 1979; 3: [6] Gensini GG, Kelly AE. Incidence and progression of coronary artery disease. Arch Intern Med 1972; 129: [7] Davies B, Ashton WD, Rowlands DJ et al. Association of conventional and exertional coronary heart disease risk factors in 5 apparently healthy men. Clin Cardiol 1996; 19: [8] Erikssen J, Enge I, Forfang K, Storstein O. False positive diagnostic tests and coronary angiographic findings in 15 presumably healthy males. Circulation 1976; 54: [9] Froelicher VF, Thompson AJ, Longo MR Jr, Triebwasser JH, Lancaster MC. Value of exercise testing for screening asymptomatic men for latent coronary artery disease. Prog Cardiovasc Dis 1976; 18: [1] Langou RA, Huang EK, Kelley MJ, Cohn LS. Predictive accuracy of coronary artery calcification and abnormal exercise test for coronary artery disease in asymptomatic men. Circulation 198; 62: [11] Wexler L, Brundage B, Crouse J et al. Coronary artery calcification: pathophysiology, epidemiology, imaging methods and clinical implications. A Statement for Health Professionals from the American Heart Association. Circulation 1996; 94: [12] Anderson KM, Wilson PW, Odell PM, Kannel WB. An updated coronary risk profile: a statement for health professionals. Circulation 1991; 83: [13] Cohn PF. The role of noninvasive cardiac testing after an uncomplicated myocardial infarction. N Engl J Med 1983; 39; 9 3. [14] Assmann G, Schulte H. Relation of high-density lipoprotein cholesterol and triglycerides to incidence of atherosclerotic coronary artery disease (the PROCAM experience). Am J Cardiol 7: