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Eur J Vasc Endovasc Surg 27, 519–524 (2004) doi: 10.1016/j.ejvs.2004.02.023, available online at http://www.sciencedirect.com on

Varicose are Common in Patients with Coronary Ectasia. Just a Coincidence or a Systemic Deficit of the Vascular Wall?

A. E. Androulakis,1* A. A. Katsaros,1 A. N. Kartalis,1 P. N. Stougiannos,1 G. K. Andrikopoulos,1 E. I. Triantafyllidi,1 A. A. Pantazis,1 C. I. Stefanadis2 and I. E. Kallikazaros1

1Department of State Cardiac, and 2Cardiology Clinic of Athens University Medical School, Hippokration Hospital, Athens, Greece

Objectives. Coronary artery ectasia (CAE), an uncommon finding during coronary arteriography, has been associated with the presence of (s) in other parts of the arterial tree including the abdominal . (VV) or phlebectasias are a common disorder of the superficial leg veins. Correlations between arterial and venous ectasias have not been established. We sought to examine whether there is an association between CAE and VV. Methods and results. CAE was diagnosed in 181 patients out of 7510 eligible patients undergoing coronary arteriography within 33 months. The prevalence of VV was significantly higher among patients with CAE (40%) compared to 200 aged- matched patients with but without CAE (17%) and to 201 randomly selected subjects from the general population (23%). In multivariate analysis, CAE was found to be significantly and independently associated with VV (RR ¼ 3.42, 95% confidence interval (CI) 2.24–5.59, p , 0.001). Conclusion. In this study population, VV were more common in patients with CAE than in those without. This association was valid in both univariate and multivariate analysis, suggesting the possible existence of a generalised defect of the entire vascular wall.

Key Words: Coronary artery ectasia; Varicose veins.

Introduction other parts of the arterial tree including the abdominal aorta and peripheral .6–10 Histopathological Epicardial dilatation of the coronary arteries has been studies in CAE have shown that the destruction of the 1 medial musculo-elastic elements accompanies the recognised for decades. The most widely used term 3,11– 13 for this condition is now ‘coronary artery ectasia’ degenerative process. (CAE).2 In early reports many cases of CAE had been Primary varicose veins (VV) of the lower limbs represent abnormal localised or diffuse dilatations of classified as congenital. A portion of acquired CAE has the superficial venous system, mainly of the long and been associated with trauma or inflammatory and short saphenous veins and their tributaries. Looking at connective tissue disorders. Current opinion suggests the relative histological findings, it may be claimed that the majority of CAE is a variant of coronary that there are some interesting similarities between the , regardless of the severity of any pathology of the varicose wall14,15 and that of the possible accompanying stenotic lesions.3–5 However, ectatic coronary arterial wall. In particular, the venous the aetiology of CAE has not been established and it is and its elastic tissue seem to be among not known whether it is a primary endothelial defect, a the key elements involved in varicose veins, just as in pure wall defect or a mixture of both. A generalised CAE. Coexistence of CAE with venous dilatation has deficit of the wall of the entire arterial system has been described, including varicosities of the coronary already been assumed, as associations have been venous tree2 and of the leg veins.10 However, found between CAE and ectasias or in correlations between arterial and venous ectasias have never been studied. Though arteries and veins *Corresponding author. Aristides Androulakis, Department of State Cardiac, Hippokration Hospital, 30 Dodekanisou Str, Vrilissia 152 35 differ substantially in terms of physiology, we sought Athens, Greece. systematically to assess the prevalence of VV in

1078–5884/050519 + 06 $35.00/0 q 2004 Elsevier Ltd. All rights reserved. 520 A. E. Androulakis et al. patients with CAE. Any possible association between as well as those with a history of deep vein . these two entities would suggest a generalized Individuals of group 3 were thought to represent the vascular wall defect. ‘general population’. Patients of group 2 and group 3 were examined for the presence of primary VV in the same way as group 1. Materials and Methods All study patients were evaluated for demographic parameters and for classical risk factors for CAD. The From 01/05/1999 until 31/01/2002, the coronary local ethics committee approved the study protocol angiogram of every new patient undergoing a diag- and all study participants gave written informed nostic or an interventional procedure was reviewed at consent. the time of catheterisation. If coronary aneurysmal disease was suspected, calculations by callipers on still images were immediately performed. CAE was Statistical analysis considered any discrete or fusiform coronary artery dilatation, with a maximal luminal diameter greater Data descriptors are the mean and standard deviation. than 1.5 times the diameter of the adjacent normal Pearson’s chi-squared test, t-test and analysis of segment. When the first investigator characterised the variance, where appropriate, were employed to case as CAE, another examiner was randomly compare the baseline characteristics of the study recruited and separately repeated calculations of groups. Logistic regression analysis was employed to luminal diameters. The patient was selected for the detect possible significant associations between a study only when both investigators were in agreement dichotomous dependent variable (presence of VV) about the classification of CAE. The patient was then and a number of independent ones (age, gender, examined clinically by three physicians among inves- diabetes mellitus, cigarette , hypercholesterol- tigators for the presence of primary VV. All three had emia, , heredity for CAD, Body Mass 2 to confirm the presence of VV for the subject to be Index . 27 kg/m , and the existence of CAE). In characterized as having VV. Primary VV in the lower contrast to the other variables, age was modelled as limbs included any clearly visible, dilated, elongated a continuous variable. Variable selection was termin- or tortuous veins. Small subcutaneous reticular vari- ated when no candidate variables for entry were : ; cosities or intradermal of small venules significant at P , 0 05 and all those selected for entry : : (spider veins) were not classified as VV. Patients with a remained significant at P , 0 10 All tests of statistical history of , congenital heart significance were two-tailed and were considered to be disease, connective tissue disease, previous coronary significant at a 0.05 level of statistical significance. or cardiac surgery were excluded. Patients Statistical analyses were performed with SPSS statisti- who had previously undergone surgical or other cal software (version 8.0, SPSS, Chicago, IL, USA). treatment for varicose veins classified as having VV. The severity of any coronary artery was not considered in the patient selection process. Results During the study period, 11,248 diagnostic cardiac catheterisations and percutaneous coronary interven- The baseline characteristics of the study population tions were performed in 9132 consecutive adult are presented in Table 1. Age and gender were patients at our institution. After the application of comparable among the three study groups. According the exclusion criteria, 7510 patients were eligible for to univariate analysis, cigarette smoking was more the study. Among them, 181 patients (2.4%) were common in catheterised patients (group 1 and group diagnosed as having CAE and comprised group 1. 2) compared to controls (group 3). Diabetes mellitus After the 31st of January 2002, 200 aged and sex- was significantly more prevalent in group 2 than in matched patients were selected in a consecutive both group 1 and group 3, while patients of group 1 manner from catheterised patients and were found had similar prevalence of diabetes with group 3. to have significant coronary artery disease (CAD), but Seventy-three subjects with CAE (58 males and 15 no CAE (group 2). Concurrently, a group of randomly females), were found to have primary VV (40% of enrolled ‘healthy’ individuals, aged and sex-matched group 1 patients). Univariate analysis among group 1 with the group 1, was created from relatives of patients showed that those with VV were younger had hospitalised patients in all the wards of our hospital a lower prevalence of arterial hypertension and a (group 3, n ¼ 201). In the latter two groups, we higher prevalence of family history for CAD than those excluded subjects who were unwilling to participate without VV (Table 2). The frequency of VV among

Eur J Vasc Endovasc Surg Vol 27, May 2004 Varicose Veins and Coronary Artery Ectasia 521

Table 1. Baseline characteristics of the study population

CAE (group 1) n ¼ 181 CAD-no CAE (group 2) n ¼ 200 Controls (group 3) n ¼ 201 p value

Age (years) 56 SD 10 57 SD 10 57 SD 11 0.956 Male gender (%) 142 (79%) 150 (75%) 138 (69%) 0.085 Hypertension (%) 88 (49%) 85 (43%) 78 (39%) 0.150 (%) 72 (40%) 74 (37%) 87 (43%) 0.437 Family history of CAD (%) 40 (22%) 37 (19%) 39 (19%) 0.662 Diabetes (%) 27 (15%) 44 (22%) 25 (12%) 0.028 (%) 63 (35%) 64 (32%) 54 (27%) 0.232 Smoking (%) 107 (59%) 117 (59%) 74 (37%) ,0.001

CAE, coronary artery ectasia; CAD, coronary artery disease. males was 40.8, 14 and 20.3% in group 1, 2 and 3, 11 – 13 typically revealing marked destruction and respectively, whereas among females was 38.5, 24 and reduction of the medial elastic fibres with disrup- 30.2% within group 1, 2 and 3, respectively ( p ¼ ns). tion of the internal and external elastic laminae, In univariate analysis, the frequency of VV was usually out of proportion to the degree of the found to be significantly higher among patients with intimal involvement. The intima almost always CAE, compared both to group 2 and group 3 patients. presents classic atherosclerotic changes. However, Conversely, the prevalence of VV in group 2 patients the primary degenerative mechanisms leading to was not found to be significantly different from that of aneurysmal formation have not been elucidated. the group 3 (Table 3). Immunohistochemical studies of the wall of the In multivariate logistic regression analysis among coronary arteries in CAE have been very few, as in patients catheterised for for CAD a case of a patient with familial hypercholesterolae- (i.e. group 1 and group 2 patients, n ¼ 381) with age, mia, which revealed increased matrix metalloproteinase gender, diabetes mellitus, cigarette smoking, hyper- (MMP) activity within the vessel wall.16 Increased cholesterolemia, hypertension, heredity for CAD, BMI proteolysis and elastolysis by means of MMP over- .27 kg/m2, and the existence of CAE included as production have been consistently reported from covariates, age, hypertension and CAE were signifi- samples of abdominal aortic aneurysms (AAA) and cantly and independently associated with the presence arterial aneurysms in other parts of the body.17 –19 This of VV. The respective relative risks and 95% CIs are MMP overflow within the vessel wall produced by presented in Table 4. According to multivariate numerous cell populations appears to greatly contrib- analysis, CAE was strongly and significantly related ute to the aortic wall degeneration, which leads to to VV increasing the likelihood of VV by a factor of 3.42 expansion. The elaboration of inflammatory cytokines (Table 4). activating proteolysis has been confirmed in AAA.20 There is also evidence for increased vascular smooth muscle cell (VSMC) apoptosis and resultant decreased Discussion VSMC density in aortic aneurysmal tissue.21,22 Previous reports have already shown an increased Coronary aneurysmal disease is found in up to 5% prevalence of CAE in patients with aneurysms in other of autopsies or angiographic examinations and its locations of the arterial tree.6 – 10,12 These associations origin is still an enigma. Histological examination suggest a common pathogenic mechanism for these has been performed in only a minority of cases3, conditions.

Table 2. Baseline characteristics of patients with CAE (group 1, n 5 181) in relation to the presence of VV

VV present ðn ¼ 73Þ No VV ðn ¼ 108Þ p value

Age (years) 53 SD 10 59 SD 9 ,0.001 Within males ðn ¼ 142Þ 58 (41%) 84 (59%) 0.788 Within females ðn ¼ 39Þ 15 (39%) 24 (62%) 0.788 Arterial hypertension ðn ¼ 88Þ 42 (48%) 46 (53%) 0.048 Hypercholesterolemia ðn ¼ 72Þ 32 (44%) 40 (56%) 0.359 Heredity for CAD ðn ¼ 40Þ 23 (58%) 17 (43%) 0.012 Diabetes ðn ¼ 27Þ 10 (37%) 17 (63%) 0.705 Obesity ðn ¼ 63Þ 23 (37%) 40 (64%) 0.444 Smoking ðn ¼ 107Þ 39 (36%) 68 (64%) 0.200

CAE, coronary artery ectasia; VV, varicose veins; CAD, coronary artery disease.

Eur J Vasc Endovasc Surg Vol 27, May 2004 522 A. E. Androulakis et al.

Table 3. Univariate comparisons of the prevalence of VV between reported from specimens simultaneously derived the study groups from tissues of an AAA and coexisting varicosities Presence of VV Absence of VV p value nor from AAA and coexisting CAE. But even if such studies were performed, it appears doubtful whether CAE (group 1) 73 (40%) 108 (60%) ,0.001* CAD-no CAE (group 2) 33 (17%) 167 (84%) 0.104† they could explain the origins of the condition, Controls (group 3) 47 (23%) 154 (77%) ,0.001‡ possibly due to the fact that the time course of the primary events in any structural change within the CAE, coronary artery ectasia; CAD, coronary artery disease; VV, wall of every respective vessel remain vague. While varicose veins. *p value for univariate comparison of group 1 vs. group 2. the timing of the clinical presentation usually differs †p value for univariate comparison of group 2 vs. group 3. between VV, CAE and AAA, it is not known when the ‡p value for univariate comparison of group 1 vs. group 3. initial degenerating process begins, under what In contrast with CAE, vein ectasia, termed as pathophysiological or haemodynamic circumstances, ‘phlebectasia’ or ‘varicose veins’ represent a frequent whether there is a latent period or a certain type of a clinical situation with a widely varying geographical endogenous or exogenous triggering stimulus. Con- appearance. In western countries it has been estimated sequently, it cannot be established whether the to be within the range of 10–40%.23,24 Studies defective process is expressed at the same time in all performed in our geographical area have indicated a vessels and locations of a given vessel or with the same 7–21% prevalence of VV in the general population.25,26 potency within the subclinical period. It is also No one theory explaining the origin of varicosis has unknown whether findings that could be observed been universally accepted. Histological examination of when studying the apparently diseased segments are the varicosities usually shows degeneration, fragmen- relevant to the concurrent findings within the macro- tation and loss of the medial elastic tissue, fragmenta- scopically ‘normal’ parts of the vessel, and vice versa. tion and reshape of the fibre network, On the other hand, supposing that there is a relation accumulation of extracellular matrix widely separ- between aneurysmal vascular entities, more questions ating the hypertrophied medial VSMC and thickening arise than answers have been provided. Patients with of the intima.14,15,27 –30 Dysregulated collagen syn- VV have a familial predisposition, however, no study thesis,31 disturbance of VSMC/extracellular matrix has yet shown horizontal inheritance that could be organisation and progressive remodelling and vari- attributed to a genetic model. Evidence of a familial ation of the thickness and elastic properties of the vein tendency to CAE has been lacking so far. In contrast to wall,32,33 may precede valvular insufficiency. The role previous thoughts that VV are more common in of proteolysis is unclear as not consistency exists about women, recent epidemiological studies show a slightly the level of activation of various MMPs in VV.28,31,33 –36 higher frequency of varicose veins in men than Interestingly, cytokine overproduction has been women, similar to the sex ratio for CAE. The ease of demonstrated in VV, just like in AAA.37 Also, both recognition of VV in contrast to CAE, which is often inhibition of programmed cell death38 as well as asymptomatic requiring coronary for enhanced number of apoptotic cells contributing to diagnosis, may play a role in the above discrepancies. changes in the structural integrity and thus possibly It would be interesting to know the prevalence of VV predisposing to varicosis,39 have been reported in VV. in patients with AAA, the prevalence of CAE in age- Although histological and immunohistochemical and sex-matched patients having VV, as well as if the . similarities exist comparing findings in the wall of high proportion ( 40%) of VV in CAE patients that we aortic aneurysms and of varicose veins, this is observed, is also seen in other populations and insufficient to support a common pathogenic mechan- different ethnic groups. Some modern theories chal- ism. Direct studies in the same patient have not been lenge the role of atherosclerosis as a sine qua non for aneurysmal transformation, regarding it as a coinci- 41,42 Table 4. Multivariate predictors of VV among 381 patients dence a hypothesis that may apply to the develop- catheterised for signs and symptoms indicating CAD (i.e. group ment of varicose veins. The role of autoimmunity as 1 1 group 2) well as of the adventitia as a significant field of RR 95% CI 95% CI p value changes has recently been suggested in the case of (lower) (higher) AAA40 – 42 while basic research has not yet focused on Age 0.96 0.937 0.985 0.002 adventitia in either CAE and VV. Arterial hypertension 1.73 1.07 2.79 0.025 From the epidemiological viewpoint, we noticed a CAE 3.42 2.24 5.59 ,0.001 low prevalence of diabetes mellitus in patients with CAE, coronary artery ectasia; CAD, coronary artery disease; VV, CAE (14.9%) in relation to patients with CAD. This low varicose veins. frequency of diabetes has previously been reported

Eur J Vasc Endovasc Surg Vol 27, May 2004 Varicose Veins and Coronary Artery Ectasia 523 both in patients with AAA43,44 and patients with VV.45 same patient along the time course of these disorders, Interestingly, among our diabetic patients with CAE, an underlying generalised defect of the entire vascular those also presenting VV comprised only one third of wall might be responsible for this observation and this population. Thus, the perception that diabetes merits further study. protects against vascular aneurysms seems to be substantiated by our findings. Regardless all these considerations, our results Acknowledgements show that a condition with unusual arterial dilatation We would like to thank Nicos Labropoulos, PhD, for his helpful may relate to another condition with venous dilata- comments. tion. It is certain that more data are needed to support such a view, with the clinical analogy that exists between arterial aneurysms also expanding to the References venous system. 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