The correlation between the severity of peripheral arterial disease and carotid occlusive disease

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1 The correlation between the severity of peripheral arterial disease and carotid occlusive disease Tayler H Long a, Michael H Criqui b, Eduard E Vasilevskis c, Julie O Denenberg b, Melville R Klauber b and Arnost Fronek d Abstract: Peripheral arterial disease (PAD) and carotid occlusive disease (COD) are both known to be specific manifestations of atherosclerosis. Because they both have a common cause, it is reasonable to hypothesize that they should correlate with each other to a certain extent, and previous studies have shown that there is a correlation between the prevalence of PAD and COD. The purpose of this study was to determine whether a correlation exists between the severity of PAD and the severity of COD by retrospectively looking at a group of 203 patients who underwent non-invasive testing for suspicion of PAD at the San Diego VA Hospital or UCSD Medical Center, and who also had a non-invasive duplex carotid scan. The severity of PAD was assessed by segmental blood pressure ratios (leg segment/arm ratio) in each leg taken at the toe, ankle, and below the knee, as well as the peak flow velocity of the posterior tibial artery. The severity of COD was assessed by duplex ultrasound scans of six distinct segments of the carotid artery system: the right and left common, internal, and external carotid arteries. Correlation analysis showed r = 0.23 (p = 0.001) when comparing a PAD aggregate standard score with the number of diseased carotid arteries ( 50% stenosis), and r = 0.23 (p = 0.001) when comparing a PAD aggregate standard score with an average COD score. Because about 50% of the patients had undergone surgical intervention on their leg or carotid arteries, another correlation analysis restricted to patients with no surgical interventions (n = 97) was performed. The above correlations were slightly attenuated in this analysis, r = 0.21 (p = 0.043) and r = 0.17 (p = 0.092), respectively. The results indicate that there is a modest but significant correlation between the severity of PAD and the severity of COD in a population with a high prevalence of both. Key words: cardiovascular events; cardiovascular risk factors; carotid artery disease; duplex ultrasonography; non-invasive diagnosis; peripheral arterial disease Introduction The association between manifestations of atherosclerotic cardiovascular disease (CVD) in various arterial beds has been evaluated in numerous studies employing several types of study design. The rationale for expecting a correlation among different arterial beds is the systemic nature of atherosclerosis. Specifically, peripheral arterial disease (PAD) and carotid occlusive disease (COD) have been evaluated to determine how they correlate with each other and with other manifestations of atherosclerosis in several different types of study. These include cross-sectional CVD morbidity studies of symptomatic patients 1,2 ; cross-sectional CVD studies of both symptomatic and asymptomatic patients, with PAD as the reference group 3 9 and with COD as the reference group 6,10 12 ; and CVD prospective morbidity studies with PAD as the reference group, and with COD as the reference group. 16,17 CVD prospective mortality has also been evaluated with PAD as the refera University of Texas, South Western Medical Center, Dallas, TX, b University of California, San Diego, Department of Family & Preventive Medicine, La Jolla, CA, c Oregon Health Sciences University, School of Medicine, Portland, OR, d University of California, San Diego, Department of Surgery and Bio-Engineering, La Jolla, CA, USA Address for correspondence: Michael H Criqui, University of California, San Diego, 9500 Gilman Drive, La Jolla, CA , USA. ence group, 13,18 21 and with COD as the reference group. 17,22 24 These studies in general show a strong correlation between the presence of atherosclerosis in a given arterial bed and the co-prevalence or subsequent development of atherosclerosis in another arterial bed. However, these studies do not address the correlation of the degree of severity of atherosclerosis in two or more arterial beds. There are to our knowledge only two cross-sectional (and no prospective) studies that have directly correlated the severity of two forms of atherosclerosis. An abstract by Wofford et al noted a significant correlation (p ) between COD severity by B-mode ultrasound and CHD stenosis 50% in one or more vessels at angiography. 25 However, the direct correlation between carotid B-mode score and the number of diseased coronary vessels was of only borderline significance (p = 0.10). A second study by Klop et al found a high co-prevalence of COD with PAD, but failed to find a significant correlation between the degree of internal carotid stenosis and PAD severity. 26 These authors evaluated only the internal carotid artery. The goal of our study was to employ a graded definition of PAD and COD in a group of non-invasive vascular laboratory patients and to determine the correlation of the severity of these two conditions. In order to assess the full extent of atherosclerosis more accurately, we assessed PAD by four separate non-invasive tests in each leg and evaluated COD in the internal, external, and common carotid arteries. Arnold X(99)VM289OA

2 136 TH Long et al Methods Study population Between 1990 and 1994, patients seen in the previous 10 years at either the San Diego Veterans Hospital (SDVA) or the University of California, San Diego Medical Center hospital (UCSDMC) vascular laboratories were invited to return for a new, comprehensive, non-invasive vascular examination of the lower extremities as well as an evaluation of their CVD risk factors. In addition, a comprehensive retrospective review of these patients medical records was carried out in order to find all non-invasive duplex examinations of the carotid arteries between 1985 and This report is limited to those patients who had a new, non-invasive lower extremity examination as part of our study between 1990 and 1994 and who had a non-invasive carotid examination between 1985 and The overall population of 508 comprised all subjects studied for PAD during the preceding 15 years who had survived, could be located and were willing to enter the study. This population is representative of vascular laboratory patients who were studied for suspicion of having PAD and remained in the same general geographic location. Of these 508 subjects, 203 had had a carotid duplex examination between 1985 and 1995 and within 5 years of their PAD assessment. This group of 203 is representative of patients who were studied for suspicion of having COD in addition to PAD. Some 72.4% of patients had their PAD and COD examinations within 2 years of each other, 25.0% 2 4 years apart, and 2.6% 4 5 years apart. Non-invasive PAD testing Data were collected on segmental blood pressure ratios (segment/arm) at three levels of the lower extremity (below knee, ankle, and toe). Additionally, peak flow velocity by Doppler ultrasound was measured in the posterior tibial artery (peak PT). In an analysis from a population based study, Feigelson assessed the sensitivity, specificity, positive predictive value, and negative predictive value for each individual segmental blood pressure ratio used in this study as well as the peak flow velocity of the posterior tibial artery. 27 Toe/brachial index (TBI) had a 40.5% sensitivity, 99.4% specificity, 87.8% positive predictive value, and 94.3% negative predictive value. Ankle/brachial index (ABI) had a 39.6% sensitivity, 99.0% specificity, 80.0% positive predictive value, and 94.0% negative predictive value. Below knee/brachial index (BKBI) had a 40.7% sensitivity, 99.4% specificity, 88.1% positive predictive value, and 94.2% negative predictive value. Peak posterior tibial flow had a 70.3% sensitivity, 99.8% specificity, 97.0% positive predictive value, and 97.0% negative predictive value. In addition, Feigelson was able to show that the ABI and peak PT when considered in parallel gave an 89% sensitivity, 99% specificity, 90% positive predictive value, 99% negative predictive value, and 98% overall accuracy for large vessel PAD compared with the entire battery of tests. Feigelson s analysis using ABI and peak PT in parallel only showed the sensitivity, specificity, and predictive values for detecting the presence of disease. Our study was concerned with the severity of PAD. Thus, we used a combination of four non-invasive tests (peak PT, BKBI, ABI, and TBI) that individually had been shown by Feigelson to have good sensitivity, specificity, and predictive values, relative to all the non-invasive tests of the lower extremity, in an attempt to gain a good assessment of the severity of PAD. BKBI, ABI, and TBI Systolic blood pressure was recorded in both arms with a brachial cuff and photoplethysmographic sensor on the third finger of each hand, and the higher of the two pressures was used as the arm pressure. The ratio of arm systolic blood pressure to the systolic pressure recorded by cuffs at the toe, just above the ankle, and just below the knee was recorded by the sphygmomanometric technique and a photoplethysmographic sensor attached to the toe. 28 The photoplethysmographic sensor technique has been shown to produce results identical to Doppler ultrasound for both arm and leg pressures, 29 and has the advantage of allowing simultaneous pressure determination. All toe, ankle, and below knee/brachial indices greater than 1.15 were converted to 1.15 because such values frequently represent stiff walled arteries (e.g. calcified arteries) and do not correlate with the severity of actual stenosis at higher indices. Peak PT The Doppler effect produced by backscattered ultrasound from red blood cells in motion was used to measure flow velocity in the posterior tibial artery. 30 All peak PT measurements above 11 cm/s were converted to 11 cm/s because variability in flow velocities above 10 cm/s does not correlate with actual stenosis (Criqui, unpublished data.) Overall PAD severity Severity was measured along a continuous scale by adding up the standard scores of all eight measurements (four from each leg). Standard scores were calculated by finding the study population s mean and standard deviation for each method of measurement (TBI, ABI, BKBI, and peak PT). Each patient s measurement for each leg was then given a standard score based on how far their measurement deviated from the mean. For example, if a patient had a TBI in their left leg that was 1 standard deviation above the mean for TBI, they were given a score of 1 for that measurement. If they had a right ABI that was 1.5 standard deviations below the mean, they were given a standard score of 1.5 for that measurement. The standard scores of all eight measurements (four from each leg) were then added up to give a composite standard score of PAD severity for each patient. The composite PAD score was then multiplied by 1 in order to create a severity score that corresponded with the COD score such that a low score corresponded to less disease. The range for the PAD leg score was 5.43 to Non-invasive COD testing Data on the carotid arteries was obtained from radiology and vascular laboratory records of each patient from 1985 to 1995 at the SDVA and UCSDMC hospitals. Only patients who had a non-invasive carotid artery evaluation using a duplex scanner were included in the study. In a meta-analysis of several studies on duplex ultrasound, Reed found that the concordance of carotid duplex ultrasound with carotid arteriogram had a sensitivity that ranged from 87.0% to 95.8%, a specificity of 81.8% to 96.6%, a positive

3 Correlation between the severity of PAD and COD 137 predictive value of 86.8% to 98.6%, and negative predictive value of 81.5% to 88.9%. 31 The present study uses noninvasive carotid duplex examinations that were conducted over a period of 10 years, in which a variety of different sonographers and readers evaluated the various patients. The reliability of using data from different sonographers and readers was studied by O Leary et al who found insignificant differences between sonographer and reader evaluations of carotid duplex examinations. 32 The severity of COD was assessed by duplex ultrasound scans of six distinct parts of the carotid artery system, which included the right and left common, internal, and external carotid arteries. Each of the six arteries were scored in one of five categories according to their percentage of diameter stenosis. Information on plaque morphology was not included due to the inconsistent reporting of this information. The five stenosis categories were 0 49%, 50 74%, 75 89%, 90 99%, and total occlusion. These categories were based on standard image and flow criteria for the common, internal, and external carotid arteries. 33,34 Rather than smaller increments, 0 49% was used because the imaging studies did not consistently report stenosis less than 50%. Additionally, a stenosis of less than 50% is generally considered to be not hemodynamically significant. Each of the categories was given a score ranging from 0 to 4, with 0 representing 0 49% and 4 representing total occlusion. The severity of COD was evaluated in two separate ways: (1) the average score of the entire carotid artery system using the 0 to 4 scoring system (range: ); and (2) the total number of the six carotid arteries in each patient with a stenosis greater than 49% (i.e. a score of 1 or greater) (range: 0 6). Previous PAD and COD interventions Questions were asked concerning the type, anatomic locations, and date of previous surgeries and/or angioplasties for PAD and COD. In addition to statistical analysis of the whole study population, patients who had arterial intervention in either the legs or carotids were analyzed separately from patients who had not had previous intervention at the time of the study. Statistics Correlation analyses controlling for age and sex, including those between the severity of PAD and COD, were determined using the Pearson correlation coefficient. Spearman s rank order correlation was used to correlate PAD and COD while controlling for age, sex, HDL cholesterol, exercise, pack-years of cigarettes, systolic blood pressure (SBP), and history of diabetes. A t-test was used to determine if there was a significant difference in the group average for the leg standard score, average carotid score, and number of diseased arteries among each group of patients with and without a history of TIA, stroke, and heart attack. All analyses were conducted using the SAS statistical package. Results Many of the patients had severe cardiovascular disease, often in several systems, and many were disabled. Table 1 Table 1 Comparison of patients with a carotid duplex examination with patients without a carotid duplex examination. Patients with duplex Patients without duplex Ethnicity comparison (n = 203) (n = 303) Caucasian 182 (89.7%) 259 (85.5%) Hispanic 8 (3.9%) 20 (6.6%) African American 7 (3.4%) 16 (5.3%) Native American 4 (2%) 6 (2%) Asian/Pacific Islander 1 (0.5%) 0 (0%) Other 1 (0.5%) 2 (0.7%) Sex (n = 203) (n = 305) Male 189 (93.1%) 259 (84.9%) Female 14 (6.9%) 46 (15.1%) Age (n = 203) (n = 305) Maximum Minimum Mean Education (n = 203) (n = 305) Some high school or less 46 (22.7%) 64 (21.0%) High school graduate 53 (26.1%) 65 (21.3%) Some college or tech school 63 (31.0%) 117 (38.4%) College graduate or more 41 (20.2%) 59 (19.3%) Hospital breakdown (n = 203) (n = 295) UCSDMC 21 (10.4%) 28 (9.5%) SDVA 181 (89.6%) 267 (90.5%) Carotid pulse (n = 203) (n = 305) Maximum 4 4 Minimum Mean Carotid bruit (n = 203) (n = 305) Yes 80 (39.4%) 54 (17.7%) No 123 (60.6%) 251 (82.3%) Carotid surgery (n = 203) (n = 305) Yes 31 (15.3%) 15 (4.9%) No 172 (84.7%) 290 (95.1%) Leg surgery (n = 203) (n = 305) Yes 87 (42.9%) 98 (32.1%) No 116 (57.1%) 207 (67.9%) History of heart attack (n = 201) (n = 302) Yes 69 (34.3%) 87 (28.8%) No 120 (59.7%) 198 (65.6%) Uncertain 12 (6.0%) 17 (5.6%) History of stroke (n = 202) (n = 304) Yes 61 (30.2%) 62 (20.4%) No 135 (66.8%) 232 (76.3%) Uncertain 6 (3.0%) 10 (3.3%) History of TIA (n = 202) (n = 304) Yes 38 (18.8%) 33 (10.9%) No 147 (72.8%) 251 (82.6%) Uncertain 17 (8.4%) 20 (6.6%) compares the 203 patients in the study group with the 305 patients not studied because they had not had a previous carotid duplex examination. The age, sex, ethnicity, education profile and hospital of the study group and non-study group were similar. There was a higher percentage of carotid bruits, vascular surgeries and histories of heart attacks, transient ischemic attacks (TIA), and strokes in the

4 138 TH Long et al study group than in the non-study group, which was expected because the study group had a higher suspicion for diffuse atherosclerotic disease. Overall, the 203 patients used in this study were demographically comparable with the patients who were not included in the study. Table 2 shows that the mean, median, and standard deviation of the PAD standard score for the 203 patients in the study group did not significantly differ from the that of the 305 non-study patients without carotid scans. The PAD standard score of the study patients who did not have a history of vascular surgery had a lower mean and median, demonstrating less severe disease, than the study group as a whole, which was expected because patients who did not have surgery were most likely to have less severe disease. Also, in patients with surgery, disease could recur in the surgically corrected leg, and such patients were more likely to have significant disease in the other leg. The mean, median, and standard deviation of the average carotid score and the number of diseased carotid arteries was similar for the study group as a whole and the subset of patients in the study group who did not have vascular surgery (Table 2). An analysis of our COD scoring system using everyone in the study showed that the average carotid score strongly correlated with the number of diseased carotid arteries (r = 0.90, p ). Figure 1 shows the results of the correlation analysis of all the patients in the study comparing the PAD aggregate standard score with the number of arteries that had greater than 50% stenosis, adjusting for age and sex (n = 193, r = 0.23, p = ). Ten patients were missing complete data on their legs so a PAD standard score could not be generated. Figure 2 shows the same analysis when comparing the average carotid score with the PAD aggregate standard score, adjusting for age and sex (n = 193, r = 0.23, p = ). Table 2 Comparison of patients by PAD standard score and carotid duplex data. Duplex Duplex Patients patients patients without without a duplex history of vascular surgery PAD standard score (n = 193) (n = 97) (n = 288) Maximum Minimum Mean Median Standard deviation Average carotid score (n = 203) (n = 97) Maximum Minimum 0 0 Mean Median Standard deviation No. of diseased carotid (n = 203) (n = 97) arteries Maximum Minimum 0 0 Mean Median Standard deviation About 50% of the patients had some sort of surgical intervention on their carotid or leg arteries that may have confounded the results. Therefore, another correlation analysis was done using patients with no surgical interventions (n = 97). Comparing the PAD aggregate standard score with the number of arteries that had greater than 50% stenosis resulted in an age- and sex-adjusted correlation coefficient of 0.21 (p = 0.043) (Figure 3). Comparing the PAD aggregate standard score with the average carotid score resulted in an age- and sex-adjusted correlation coefficient of 0.17 (p = 0.092) (Figure 4). Additional correlation analyses were done comparing the leg (right or left) with the most severe disease with the side of the carotid system (right or left) with the most severe disease. Perhaps surprisingly, this did not significantly improve the correlation results. The leg with the least severe disease was also correlated with the side of the carotid system with the least severe disease. No significant correlation was found. Correlation analyses were also done between the PAD standard score and the average carotid score, and between PAD and the number of diseased carotid arteries, while adjusting for age, sex, and several known CVD risk factors (HDL, pack-years, exercise, systolic blood pressure, and history of diabetes) (Table 3). These risk factors were included because they had a p 0.20 when correlated independently with PAD and COD. Risk factor adjustment resulted in only minor changes: r = 0.22 (n = 183, p = ) for the PAD aggregate standard score versus the number of diseased carotid arteries and r = 0.21 (n = 183, p = ) for the PAD aggregate standard score versus the average carotid score. For patients with no surgical intervention, the results after risk factor adjustment again only showed minor change: r = 0.21 (n = 90, p = 0.058) for the PAD aggregate standard score versus the number of arteries and r = 0.15 (n = 90, p = 0.18) for the PAD aggregate standard score versus the average carotid score. Table 4 shows the group mean scores for leg standard score, average carotid score, and the number of diseased carotids for each group of patients with and without a history of TIA, stroke, and heart attack. There was a significantly higher group mean average carotid score among patients with a history of TIA (0.55, n= 38) compared with those without a history of TIA (0.35, n = 167) (p = 0.015). The difference in the group mean number of diseased carotids for patients with and without TIA was close to significance (with TIA 1.76, n = 38; without TIA 1.35, n = 167; p = 0.11). The difference in the group mean leg standard score for patients with and without a history of stroke was also close to significance (with stroke 0.54, n = 57; without stroke 0.33, n = 136; p = 0.055). All other PAD and COD score group mean comparisons for clinical events did not reach statistical significance, but all but one (PAD score among patients with or without TIA) were in the expected direction, supportive of the hypothesis that atherosclerosis is a systemic disease. We did separate analyses correlating the PAD standard score with the two types of COD severity scoring among groups of patients with and without a history of TIA, stroke, and heart attack, respectively. For patients with a history of TIA the correlation results were: PAD score versus number of diseased carotids n = 37, r = 0.43,

5 Correlation between the severity of PAD and COD 139 Figure 1 Scattergram of PAD standard score by number of diseased carotid arteries: all patients. Figure 2 Scattergram of PAD standard score by average carotid score: all patients. Figure 3 Scattergram of PAD standard score by number of diseased carotid arteries: patients without surgical intervention.

6 140 TH Long et al Figure 4 Scattergram of PAD standard score by average carotid score: patients without surgical intervention. Table 3 Correlations between PAD standard score and carotid duplex results. All patients in study Adjusted for age and sex Adjusted for age, sex, and risk factors a r p r p PAD standard score versus (n = 193) (n = 183) no. of diseased carotids PAD standard score versus (n = 193) (n = 183) average carotid score Patients with no surgical intervention PAD standard score versus (n = 97) (n = 90) no. of diseased carotids PAD standard score versus (n = 97) (n = 90) average carotid score a Adjusted risk factors include HDL, exercise, pack-years, SBP, and history of diabetes. Table 4 PAD and COD scores in patients with and without histories of transient ischemic attack (TIA), stroke, and myocardial infarction (MI). Histories (mean score) PAD Average No. of standard carotid diseased score score carotids With TIA (n = 37) (n = 38) (n = 38) Without TIA (n = 156) (n = 167) (n = 167) t-statistic p-value With stroke (n = 57) (n = 61) (n = 61) Without stroke (n = 136) (n = 144) (n = 144) t-statistic p-value With MI (n = 65) (n = 69) (n = 69) Without MI (n = 128) (n = 136) (n = 136) t-statistic p-value p = ; PAD score versus average carotid score n = 37, r = 0.49, p = For patients without a history of TIA the correlation results were: PAD score versus number of diseased carotids n = 156, r = 0.19, p = 0.018; PAD score versus average carotid score n = 156, r = 0.16, p = For patients with a history of stroke the correlation results were: PAD score versus number of diseased carotids n = 57, r = 0.25, p = 0.06; PAD score versus average carotid score n = 57, r = 0.30, p = For patients without a history of stroke the correlation results were: PAD score versus number of diseased carotids n = 136, r = 0.22, p = 0.011; PAD score versus average carotid score n = 136, r = 0.17, p = For patients with a history of heart attack the correlation results were: PAD score versus number of diseased carotids n = 65, r = 0.14, p = 0.26; PAD score versus average carotid score n = 65, r = 0.23, p = For patients without a history of heart attack the correlation results were: PAD score versus number of diseased carotids n = 128, r = 0.27, p = ; PAD score versus average carotid score n = 128, r = 0.25, p =

7 Correlation between the severity of PAD and COD 141 Discussion The results of the correlation analysis comparing the severity of PAD with COD show a modest but significant correlation between the two disease processes, which was hypothesized based on the amount of evidence demonstrating an overlap in the prevalence of PAD and COD. 1,2,6 9,11,12 This correlation persisted even when subjects with carotid or leg surgery were excluded from the analysis, though p-values were less significant primarily due to smaller numbers. What is surprising is that the correlation is not as strong as we might have expected considering the perceived notion that atherosclerosis is a systemic disease. This might be due to several potential biases in the study. One potential bias is selective survival, where patients with severe disease died of clinical events related to their disease, and only those with less severe disease survived to be included in the study. This could lead to a more homogenous study population and a weaker correlation between the severity of PAD and COD. The study population is representative of primarily elderly (mean age 68.5 years) Caucasian males living in San Diego who have been evaluated for high suspicion of both PAD and COD at either a VA hospital or a university medical center. This is not a true representation of the community, but it is a population that is at high risk for developing manifestations of atherosclerosis. The homogeneity of the population likely reduced the strength of the correlation because there was less variability in risk factor and disease severity compared with the general population. Therefore, a study looking at the general population might find a stronger correlation between the severity of PAD and COD than was found in this study. Selective survival might also explain the finding that cardiovascular clinical events (TIA, stroke, and heart attack) correlated weakly with the severity of PAD or COD except for TIA and average carotid score (Table 4). Among the 203 patients studied there was a history of TIA in 18.8%, stroke in 30.2%, and heart attack in 34.3% (Table 1). Therefore, the population did not lack clinical events, but the severity of disease did not appear to correlate significantly with such events even though it has been shown to correlate in population studies 13,14 and a clinical study. 1 Another potential bias with this study, which may account for the correlation results, is that non-invasive techniques were used to assess for stenosis as a means of determining disease severity. This may not clearly reflect the systemic nature of atherosclerosis because a patient may have several atherosclerotic plaques throughout an arterial system. In the absence of clinical or hemodynamic evidence of stenosis, such a patient would be considered disease free in our study. A study using angiography, the gold standard in assessing PAD and COD, would be better at assessing true stenosis, but would still not determine the amount of atherosclerotic plaques. An autopsy study would be the best means of determining the systemic extent of atherosclerosis and the correlation of disease severity among the various arterial beds. One final potential bias is that the patients evaluated were not randomly selected from the original population of 508. Instead, only those who had had carotid duplex scans were used because COD data was needed to compare with PAD data. Tables 1 and 2 compare the population used in the study with the population that did not have carotid duplex scans. The two groups were similar in age, ethnicity, education, hospital site, and carotid and leg standard score. Overall, there was more CVD in the study population, which was expected in a group referred for carotid evaluation. While the above biases might reduce the correlation between PAD and COD, we did note that there was a high correlation between the presence of PAD and COD. This is readily apparent from the fact that most of our patients had some disease at their evaluations for PAD and COD and supports the results of many earlier studies. 1,2,6 9,11,12 Therefore, the correlation between disease severity may only be modest, but the correlation between prevalence of disease is significant. One interesting result that contributes to our assessment of correlation between PAD and COD severity is that the correlation was found to be stronger in groups of patients who had a history of TIA or stroke. This suggests that among patients who have COD severe enough to cause clinical symptoms, there is a stronger correlation between PAD and COD than in those who do not have clinical symptoms. This was not apparent when we looked at patients with and without a history of heart attack, suggesting that severity only correlates when the patient has a clinical event that is secondary to the disease being correlated. Thus, among patients with clinical events related to the disease being correlated (COD), the severity correlation was stronger than when looking at asymptomatic patients. The results of the correlation analyses between PAD and COD severity are congruent with the concept of atherosclerosis as a systemic disease, but their limited strength is most likely due to selective survival and the homogeneity of the population. Adjusting for risk factors reduced the correlation slightly, which was as expected because the risk factors contribute to disease severity. Future prospective population studies that look at disease severity and risk factors over time might be useful in eliminating some of these biases, resulting in potentially stronger correlations. Earlier studies have shown a strong association between the prevalence of PAD and COD. 1,2,6 9,11,12 Our study was consistent with these earlier prevalence studies because some disease was found at most of our patients PAD and COD evaluations suggesting that there is a strong correlation between the prevalence of PAD and COD despite a weaker severity correlation. In summary, our study extended previous studies by looking at the correlation between the severity of PAD and COD. Despite the potential biases in this study, we found a modest, but significant, correlation. Acknowledgements The authors would like to thank Ms Linda Sridhar for assistance in the manuscript preparation. This study was supported by NIH Grant HL 42973, NIH-NCRR GCRC Program Grant M01 RR 00827, NIH Summer Short Term Research Grant 5T 35 HL07491, and an American Heart Association, California Affiliate Student Summer Research Fellowship.

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