VASECTOMY, INFLAMMATION, ATHEROSCLEROSIS AND LONG-TERM FOLLOWUP FOR CARDIOVASCULAR DISEASES: NO ASSOCIATIONS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY

0022-5347/02/1671-0204/0 THE JOURNAL OF UROLOGY® Copyright © 2002 by AMERICAN UROLOGICAL ASSOCIATION, INC.®

Vol. 167, 204 –207, January 2002 Printed in U.S.A.

VASECTOMY, INFLAMMATION, ATHEROSCLEROSIS AND LONG-TERM FOLLOWUP FOR CARDIOVASCULAR DISEASES: NO ASSOCIATIONS IN THE ATHEROSCLEROSIS RISK IN COMMUNITIES STUDY SEAN A. COADY, A. RICHEY SHARRETT, ZHI-JIE ZHENG, GREGORY W. EVANS* GERARDO HEISS

AND

From the Division of Epidemiology and Clinical Applications, National Heart, Lung, and Blood Institute, Bethesda, Maryland, Cardiovascular Health Branch, National Center for Chronic Disease Prevention and Health Promotion, Centers for Disease Control and Prevention, Atlanta, Georgia, and Department of Public Health Sciences, Wake Forest School of Medicine, Winston-Salem and Department of Epidemiology, School of Public Health, University of North Carolina, Chapel Hill, North Carolina

ABSTRACT

Purpose: Although human studies have failed to reveal an increased risk of clinical cardiovascular disease in men who undergo vasectomy, the possibility exists that an association may be detectable only after a long followup, or it may be more evident for subclinical than clinical disease. We assessed the association of vasectomy with inflammation and coagulation factors, carotid intimal-medial thickness, carotid plaque, prevalent peripheral arterial disease, and incident coronary heart disease and stroke in the Atherosclerosis Risk in Communities cohort. Materials and Methods: Included in the study were 3,957 white men 45 to 64 years old who were free of coronary heart disease at the Atherosclerosis Risk in Communities (ARIC) baseline examination in 1987 to 1989. Data on vasectomy was collected at baseline by self-reporting. High resolution B-mode ultrasound was done to assess carotid intimal-medial thickness and carotid plaque. The cohort was followed an average of 9 years for incident cardiovascular events. Results: Average time since vasectomy was 16 years. Approximately 20% of the population had undergone vasectomy 20 years or more ago at baseline. Multivariate analysis showed no association of vasectomy status with inflammation or coagulation factors, peripheral arterial disease, carotid plaque, carotid far wall thickness, incident coronary heart disease or stroke. Associations were unaffected by the time since vasectomy. Conclusions: There is no evidence in this population based sample of men indicating that vasectomy is related to atherosclerosis even after more than 20 years of followup. KEY WORDS: testis, vasectomy, cardiovascular diseases, atherosclerosis

To date observational studies in men have failed to detect an association of vasectomy with clinical cardiovascular disease.1– 6 The proposed pathogenesis involved endothelial injury as a result of circulating immune complexes derived from antisperm antibodies. Others have detected at least transiently higher titers of antisperm antibodies and circulating immune complexes in men with vasectomy.7, 8 Although none of the previous observational studies has shown an association, decreased lower limb artery distensibility was noted in 1.9 Only a few of the previous studies have considered the self-selecting nature of vasectomy and none examined the relationship using direct measures of atherosclerosis in men. We assessed the association of vasectomy with inflammation and coagulation factors, prevalent carotid arterial wall thickness, carotid plaque, peripheral arterial disease, incident myocardial infarction, fatal coronary heart disease, coronary bypass or angioplasty and stroke in white men participating in the Atherosclerosis Risk in Communities Study (ARIC). MATERIALS AND METHODS

The ARIC study recruited and examined 15,792 residents of 4 American communities, including Forsyth County, North Carolina, Jackson, Mississippi, Minneapolis, Minnesota and Washington County, Maryland. The Jackson cohort included exclusively black men and women, while the cohorts from the

other 3 communities were derived from a population based sample.10 The Jackson cohort and black men in Forsyth county were excluded from study since the low rate of vasectomy in these participants (21 of 1,619 or 1.5%) yielded numbers inadequate for analysis. Participants were 45 to 64 years old at baseline and included 5,418 white men. Vasectomy status and age at vasectomy were determined at baseline examination by interviewer administered questionnaire. Vasectomy information was also obtained approximately 3 years later at the second ARIC examination. The 16 participants who underwent interim vasectomy were retained in the baseline no vasectomy group due to inadequate numbers for analysis. In those without interim vasectomy interexamination agreement was 99.8% for present-absent vasectomy. Prevalent coronary heart disease and stroke were also ascertained at baseline as a self-reported, physician diagnosed heart attack, stroke or transient ischemic attack, history of coronary surgery or coronary angioplasty, or electrocardiography diagnosis of unrecognized myocardial infarction. Current smoking, income and education were assessed by interviewer administered questionnaire. Diabetes was defined as a fasting blood glucose value of at least 126 mg./dl. or hypoglycemic drug use. The details of ARIC procedures for B-mode ultrasound have been previously published.11, 12 Mean far wall thickness averaged for the common carotid, bifurcation and internal carotid arteries bilaterally was used in our analysis as a measure of atherosclerotic burden. Atherosclerotic plaque at any site was defined as wall thickness in excess of 1.5 mm. or

Accepted for publication August 24, 2001. Financial interest and/or other relationship with Pfizer and Organon. 204

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TABLE 1. Select characteristics of white men with or without vasectomy adjusted for age and ARIC community Factor No. participants Mean age at vasectomy ⫾ SD (95% CI) Mean yrs. since vasectomy ⫾ SD (95% CI) Mean ARIC community age ⫾ SD (95% CI) Mean white blood count ⫾ SD (95% CI) Mean % neutrophils (95% CI) Mean % lymphocytes (95% CI) Mean % monocytes (95% CI) Mean % eosinophils (95% CI) Mean % basophils (95% CI) Mean secs. activated partial thromboplastin time ⫾ SD (95% CI) Mean ␮g./ml. protein C ⫾ SD (95% CI) Mean % factor VII activity ⫾ SD (95% CI) Mean % antithrombin III activity ⫾ SD (95% CI) Mean % factors VIII: C activity ⫾ SD (95% CI) Mean mg./dl. fibrinogen ⫾ SD (95% CI) Mean % von Willebrand’s factor ⫾ SD (95% CI) Mean mm. Hg systolic pressure ⫾ SD (95% CI) % Hypertension lowering medication (95% CI) % Less than high school education (95% CI) % Income less than $35,000 (95% CI) % Current smoking (95% CI) % Diabetes % Peripheral arterial disease % Carotid plaque Mean mm. carotid intimal-medial thickness ⫾ SD (95% CI)

Vasectomy 1,050 37.5 ⫾ 5.39 (37.1–37.8) 15.7 ⫾ 5.39 (15.4–16.1) 53.2 ⫾ 5.65 (52.9–53.6) 6.2 ⫾ 1.9 (6.1–6.4) 61.3 ⫾ 8.1 (60.7–61.8) 30.1 ⫾ 7.6 (29.6–30.7) 6.0 ⫾ 2.4 (5.9–6.2) 2.3 ⫾ 2.0 (2.2–2.4) 0.5 ⫾ 0.65 (0.45–0.54) 29.4 ⫾ 3.0 (29.3–29.6) 3.0 ⫾ 0.6 (3.0–3.1) 111.9 ⫾ 24.1 (110.4–113.4) 106.9 ⫾ 20.5 (105.7–108.2) 120.3 ⫾ 32.3 (118.3–122.2) 288.6 ⫾ 62.7 (284.8–292.4) 109.4 ⫾ 43.05 (106.8–112.0) 118.8 ⫾ 15.45 (117.8–119.7) 13.5 (11.5–15.8) 10 (8.3–12.1) 29.6 (26.8–32.7) 21.7 (19.2–24.4) 5.5 (4.3–7.2) 1 (0.6–1.9) 37.5 (34.4–40.6) 0.77 ⫾ 0.19 (0.76–0.78)

luminal encroachment, heterogenous texture or an irregular intimal surface.13 Ankle blood pressure was measured in 1 randomly selected leg with the participant prone.14 The ankle-brachial index was calculated as the average of 2 resting ankle systolic pressure readings divided by the average of 2 brachial systolic readings. Assay procedures for lipids and hemostatic factors have been previously published.15 Prevalent peripheral arterial disease was defined as an ankle-brachial index of 0.9 or less, self-reported pain in the lower extremities while walking that was relieved within 10 minutes of standing still, or by self-reported angioplasty in the lower extremities. The determination and diagnosis of incident events have been described previously.16 Briefly, hospitalization was ascertained by yearly telephone contact with participants or relatives, or by hospital surveys. Trained abstractors recorded relevant data from hospital records, including cardiac enzyme and electrocardiography information. Unrecognized myocardial infarction was identified by electrocardiography changes initially detected at clinic examination.17 Deaths were identified by yearly followup, hospital

No Vasectomy

p Value

2,907 55.0 ⫾ 5.63 6.4 ⫾ 1.9 61.1 ⫾ 8.1 30.3 ⫾ 7.6 6.1 ⫾ 2.4 2.3 ⫾ 2.0 0.5 ⫾ 0.65 29.5 ⫾ 3.0

(54.8–55.3) (6.3–6.5) (60.7–61.4) (29.9–30.6) (6.0–6.2) (2.2–2.3) (0.47–0.53) (29.4–29.6)

0.0001 0.0314 0.5500 0.6584 0.4301 0.6592 0.7902 0.4064

3.1 ⫾ 0.6 (3.0–3.1) 111.1 ⫾ 23.9 (110.3–112.0) 108.6 ⫾ 20.4 (107.9–109.3) 122.4 ⫾ 32.1 (121.2–123.5) 292.1 ⫾ 62.2 (289.9–294.4) 112.9 ⫾ 42.74 (111.3–114.4) 120.3 ⫾ 15.34 (119.7–120.8) 17.0% (15.6–18.5) 15.5% (14.2–17.0) 41.1% (39.3–43.0) 24.0% (22.4–25.6) 8.1% (7.1–9.2) 1.8% (1.4–2.5) 39.3% (37.5–41.2) 0.79 ⫾ 0.19 (0.78–0.80)

0.2866 0.3928 0.0247 0.0716 0.1183 0.0245 0.0072 0.0141 0.0001 0.0001 0.0538 0.0107 0.0778 0.3130 0.0123

surveys and state vital statistics files, and they were investigated by collecting relevant information from hospital records, death certificates, autopsy reports, informants, coroners and regular participant physicians. Diagnoses required review and adjudication by a physician committee. Incident myocardial infarction-fatal coronary heart disease was defined as definite or probable myocardial infarction or definite fatal coronary heart disease. The broader Incident coronary heart disease definition included myocardial infarction-fatal coronary heart disease plus unrecognized myocardial infarction, or hospitalized coronary artery bypass surgery or angioplasty. Incident ischemic stroke was defined as definite or probable hospitalization for embolic or thrombotic stroke. Adjusted means for continuous traits were estimated using standard regression techniques.18 For discrete variables logistic regression was used to estimate the adjusted prevalence of each trait.18 Logistic regression was also done to derive adjusted odds ratios for the association of vasectomy with peripheral arterial disease and carotid plaque. Cox proportional hazards models were used to estimate hazard rate

Mean carotid intimal-medial thickness with 95% CI (whiskers) by vasectomy status and time since vasectomy adjusted for ARIC community, age, low and high density lipoprotein cholesterol, triglycerides, systolic blood pressure, hypertension medication, current smoking, diabetic status, von Willebrand’s factor, education and income.

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ratios for incident events.19 The assumption of proportionality was evaluated from weighted Schoenfield residuals, as discussed by Grambsch and Therneau.20 To investigate the time since vasectomy participants with vasectomy were categorized into 1 of 3 groups based on years at baseline since vasectomy, including 12 years or less, 13 to 19, or 20 years or greater. Cutoff points were selected to provide adequate numbers for analysis as well as easily recognizable intervals. The cutoffs correspond to approximately the 30th and 80th percentile points in the distribution. All analysis were completed using a commercially available software package. White men accounted for approximately 98% of the vasectomies in ARIC. Therefore, the population analyzed was restricted to white men. Subjects were excluded from study due to prevalent coronary heart disease or stroke (in 434), unknown or incomplete covariate data (in 747), triglycerides greater than 400 mg./dl. or fasting less than 8 hours (in 252) and with an ankle-brachial index of greater than 1.5 (in 28) due to measurement artifact reflecting rigid or calcified arterial walls. Since prevalent events were excluded from analysis and vasectomy may be associated with them, we evaluated possible biases caused by these exclusions. The association of vasectomy with ARIC field center, hypertensive medication, education, income, current smoking, diabetic status, prevalent peripheral arterial disease or plaque was evaluated in the population under study and the excluded population. Only for peripheral arterial disease was a potentially meaningful difference identified. The vasectomyperipheral arterial disease odds ratio was 1.1 in the excluded population compared with 0.5 in the study population. However, incorporating all excluded participants into analysis did not alter any study conclusion. RESULTS

After study exclusions 3,957 white men remained for analysis. A total of 1,050 vasectomies were performed at an average age of 37 years. Average time since vasectomy was 16 years (range 1 to 38). The vasectomy prevalence was 21% in Washington county, 26% in Forsyth county and 32% in Minneapolis. Men with vasectomy were significantly younger, had lower systolic blood pressure and a thinner carotid arterial wall than those without vasectomy (table 1). Men with a vasectomy were also less likely to have diabetes or be on hypertensive medication and they tended to have higher education and income (table 1). No statistical difference was detected for total cholesterol, low or high density lipoprotein cholesterol, or triglycerides (data not shown). Potential thrombotic complications of vasectomy have previously been suggested.21 Other ARIC based studies described associations of blood coagulation factors with incident coronary heart disease22 and stroke.23 After adjusting for age and ARIC center vasectomy status was associated with a significantly lower leukocyte count, antithrombin III and von Willebrand’s antigen (%) (table 1). Vasectomy status was unrelated to the neutrophil, lymphocyte, monocyte, eosino-

phil or basophil count and was also unrelated to factor VIII, fibrinogen, activated partial thromboplastin time, protein C or factor VII. After additional adjustment for education (high school or not), income less than $35,000 (yearly or not), current smoking and diabetic status only von Willebrand’s antigen remained marginally significant (data not shown, p ⫽ 0.05). On multivariate analysis adjusted for age, ARIC field center, education and income, vasectomy status was unrelated to prevalent peripheral arterial disease in 82 cases or to carotid plaque (table 2 and figure). Vasectomy was also unrelated to carotid artery thickness (data not shown, p ⬎0.05). Categorizing vasectomy status by time since vasectomy also failed to reveal any evidence of an association. At an average followup of 9 years there were 172 incident myocardial infarction-fatal coronary heart disease cases, 258 incident coronary heart disease cases and 88 incident strokes. No association was detected in vasectomy status or time since vasectomy with any incident event (table 2). Associations of prevalent and incident events remained null after further adjustment for lipid factors, systolic blood pressure, hypertension medication, von Willebrand’s factor, current smoking and diabetic status (data not shown). Effect modification in multivariate models was examined with respect to vasectomy status and current smoking, diabetic status, hypertensive medication and lipid factors. No evidence for effect modification was noted except for smoking and average carotid far wall thickness. Carotid thickness was significantly greater in current smokers without vasectomy than in the other 3 vasectomy plus smoking groups. DISCUSSION

Our study of the large ARIC cohort supports previous findings of no association of vasectomy with coronary, cerebral or peripheral clinical manifestations of atherosclerotic disease. It extended these results of no association to markers of subclinical disease, such as carotid far wall thickness and early or more advanced plaque. A limitation of earlier studies was the inability to address concerns that an atherosclerotic response resulting from vasectomy may have a prolonged quiescent period detectable only after long followup.1 Approximately 20% of the ARIC cohort had undergone vasectomy 20 or more years earlier and even they were not at elevated risk. In addition, the effect of vasectomy was not modified by factors, such as diabetes, blood lipids or hypertensive medication. The association of vasectomy status with carotid far wall thickness was modified by current smoking status. However, the direction of the interaction implied decreased rather than enhanced risk. The ARIC study also provided the opportunity to examine associations of vasectomy with inflammatory and blood coagulation factors. Associations were null or negative, providing key evidence against the mechanism hypothesized to explain the adverse effects of vasectomy. Vasectomy is a medical procedure that is generally self-

TABLE 2. ARIC community adjusted associations with prevalence or incidence of select cardiovascular traits in white men by vasectomy status and years since vasectomy Time Since Vasectomy Trait

Vasectomy

No. participants Prevalent events odds ratio (95% CI): Peripheral arterial disease Carotid plaque Incident events hazard rate ratio (95% CI): Myocardial infarction, fatal coronary heart disease Coronary heart disease Stroke

1,050

p Value

12 Yrs. or Less

p Value

307

13–19 Yrs.

p Value

499

20⫹ Yrs.

p Value

244

0.4 (0.1–1.4) 1.0 (0.8–1.1)

0.14 0.56

0.2 (0.0–1.6) 1.2 (0.9–1.5)

0.14 0.19

0.8 (0.3–1.8) 0.8 (0.7–1.0)

0.54 0.13

0.7 (0.2–1.8) 0.9 (0.7–1.2)

0.42 0.62

1.1 (0.8–1.5)

0.60

0.8 (0.5–1.5)

0.58

1.2 (0.8–1.8)

0.36

1.1 (0.7–1.9)

0.68

0.9 (0.7–1.1) 0.7 (0.4–1.3)

0.25 0.31

0.8 (0.5–1.3) 1.1 (0.4–2.8)

0.43 0.85

0.9 (0.7–1.3) 0.6 (0.2–1.5)

0.69 0.26

0.8 (0.5–1.2) 0.7 (0.2–1.9)

0.27 0.46

VASECTOMY, INFLAMMATION, ATHEROSCLEROSIS AND FOLLOWUP FOR CARDIOVASCULAR DISEASE

selected by patients as a method of contraception. Men with vasectomy tend to be healthier than those without vasectomy.2 Even in the Physicians Health Study, which is a cohort relatively homogenous for education and socioeconomic status, men with vasectomy were less likely to have diabetes or hypertension and more likely to exercise regularly.1 Thus, in our series despite adjusting for education and income the possibility exists that an association of vasectomy status with cardiovascular disease was masked by residual confounding. However, adverse effects of vasectomy seem unlikely given the consensus of null findings in previous studies and the extension of null findings in our study to subclinical atherosclerosis and the proposed pathogenic mechanism.

11. 12. 13.

14.

The authors thank the staff and participants in the ARIC study for their important contributions to this study. 15. REFERENCES

1. Manson, J. E., Ridker, P. M., Spelsberg, A. et al: Vasectomy and subsequent cardiovascular disease in US physicians. Contraception, 59: 181, 1999 2. Giovannucci, E., Tosteson, T. D., Speizer, F. E. et al: A long-term study of mortality in men who have undergone vasectomy. N Engl J Med, 326: 1392, 1992 3. Wallace, R. B., Lee, J., Gerber, W. L. et al: Vasectomy and coronary disease in men less than 50 years old: absence of association. J Urol, 126: 182, 1981 4. Rimm, A. A., Hoffmann, R. G., Anderson, A. J. et al: The relationship between vasectomy and angiographically determined atherosclerosis in men. Prev Med, 12: 262, 1983 5. Petitti, D. B., Klein, R., Kipp, H. et al: Vasectomy and the incidence of hospitalized illness. J Urol, 129: 760, 1983 6. Walker, A. M., Jick, H., Hunter, J. R. et al: Vasectomy and nonfatal myocardial infarction: continued observation indicates no elevation of risk. J Urol, 130: 936, 1983 7. Alexander, N. J., Fulgham, D. L., Plunkett, E. R. et al: Antisperm antibodies and circulating immune complexes of vasectomized men with and without coronary events. Am J Reprod Immunol Microbiol, 12: 38, 1986 8. Mullooly, J. P., Wiest, W. M., Alexander, N. J. et al: Vasectomy, serum assays, and coronary heart disease symptoms and risk factors. J Clin Epidemiol, 46: 101, 1993 9. Campbell, W. B., Slack, R. W., Clifford, P. C. et al: Vasectomy and atherosclerosis: an association in man? Br J Urol, 55: 430, 1983 10. The Atherosclerosis Risk in Communities (ARIC) Study: design

16.

17. 18. 19. 20. 21. 22.

23.

207

and objectives. ARIC Investigators. Am J Epidemiol, 129: 687, 1989 Bond, M. G., Barnes, R. W., Riley, W. A. et al: High resolution B-mode ultrasound scanning methods in the Atherosclerosis Risk in Communities (ARIC) study. J Neuroimag, 1: 68, 1991 Riley, W. A., Barnes, R. W., Bond, M. G. et al: High resolution B-mode ultrasound reading methods in the Atherosclerosis Risk in Communities cohort. J Neuroimag, 1: 172, 1991. Li, R., Duncan, B. B., Metcalf, P. A., Crouse, J. R., III et al: B-mode-detected carotid artery plaque in a general population. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Stroke, 25: 2377, 1994 Zheng, Z. J., Sharrett, A. R., Chambless, L. E. et al: Associations of ankle-brachial index with clinical coronary heart disease, stroke and preclinical carotid and popliteal atherosclerosis: the Atherosclerosis Risk in Communities (ARIC) study. Atherosclerosis, 131: 115, 1997 Brown, S. A., Hutchinson, R., Morrisett, J. et al: Plasma lipid, lipoprotein cholesterol, and apoprotein distributions in selected US communities. The Atherosclerosis Risk in Communities (ARIC) study. Arterioscler Thromb, 13: 1139, 1993 White, A. D., Folsom, A. R., Chambless, L. E. et al: Community surveillance of coronary heart disease in the Atherosclerosis Risk in Communities (ARIC) study: methods and initial two years’ experience. ARIC Investigators. J Clin Epidemiol, 49: 223, 1996 Rautaharja, P. M., Warren, J. W. and Jain, U.: Cardiac infarction injury score: an electrocardiographic coding scheme for ischemic heart disease. Circulation, 64: 249, 1981 Neter, J., Kutner, M. H., Nachtsheim, C. J. et al: Applied Linear Statistical Models. Chicago: Richard D. Irwin, Inc., 1996 Lawless, J. F.: Statistical Models and Methods For Lifetime Data. New York: John Wiley & Sons, Inc., 1982 Grambsch, P. M. and Therneau, T. M.: Proportional hazards tests and diagnostics based on weighted residuals. Biometrika, 81: 515, 1994. Roberts, H. J.: Delayed thrombophlebitis and systemic complications after vasectomy: possible role of diabetogenic hyperinsulinism. J Am Geriatr Soc, 16: 267, 1968 Folsom, A. R., Wu, K. K., Rosamond, W. D. et al: Prospective study of hemostatic factors and incidence of coronary heart disease: the Atherosclerosis Risk in Communities (ARIC) study. Circulation, 96: 1102, 1997 Folsom, A. R., Rosamond, W. D., Shahar, E. et al: Prospective study of markers of hemostatic function with risk of ischemic stroke. Atherosclerosis Risk in Communities (ARIC) Study Investigators. Circulation, 100: 736, 1999