In 1980, the National Heart Lung and Blood Institute

Transcription

1 Original Contributions Geographic Patterns in Overall and Specific Cardiovascular Disease Incidence in Apparently Healthy Men in the United States David Q. Rich, ScD, MPH; J. Michael Gaziano, MD, MPH; Tobias Kurth, MD, ScD Background and Purpose Residence in the Southeastern United States (US) has been linked to increased stroke incidence and mortality. However, data on regional variability in overall cardiovascular disease (CVD) and specific coronary heart disease incidence are sparse. Methods We assessed the risk of major CVD (nonfatal stroke, nonfatal myocardial infarction, or death from CVD) and specific CVD associated with region of residence (Northeast, Southeast, Midwest, and West) in apparently healthy male participants of the Physicians Health Study. Subjects were aged 40 to 84, most were white (93%), and had no previous CVD at baseline. We used residence in the Northeast as the reference group and proportional hazards models to adjust for potential confounding. Results We found no difference in risk of major CVD between regions of residence. Further, we found no consistent association between myocardial infarction and CVD death and region of residence. In contrast, we found a significantly increased risk of total stroke (HR, 1.22; 95% CI, 1.02 to 1.47) associated with residence in the Southeast compared with the Northeast. This relative risk was further increased for ischemic stroke (HR, 1.30; 95% CI, 1.06 to 1.58). We saw no difference in risk of any outcome when categorizing state of residence into tertiles based on mean winter temperature, mean summer temperature, or into 2 groups based on latitude. Conclusions In this homogenous and well-characterized cohort of US male physicians, we found greater incidence of ischemic stroke, but not other vascular events among those living in the Southeastern US, compared with other regions. (Stroke. 2007;38: ) Key Words: cardiovascular disease epidemiology ischemic stroke myocardial infarction In 1980, the National Heart Lung and Blood Institute classified the 11 states (Indiana, Kentucky, Tennessee, Mississippi, Alabama, Georgia, South Carolina, North Carolina, Virginia, Arkansas, and Louisiana) with stroke mortality rates 10% higher than the national average (ie, 65 deaths/ persons) as the Stroke Belt, and has since funded research to reduce the risk of stroke in this region. 1 Others have also identified the Stroke Belt, reporting similar disparities in stroke mortality rates. 2 4 Howard et al 5 documented a national decline in stroke mortality, predicting regional variability to persist with other regions emerging with high stroke rates. The National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study found the highest stroke incidence rates in the Southeast United States (US) compared with other regions. 6 In white males 45 to 74 years of age, risk associated with the Southeastern US was not attenuated after adjusting for conventional stroke risk factors. Further, there was no difference in incidence rates between subjects residing inside and outside standard metropolitan statistical areas. 6 However, stroke subtype was not assessed and the only control for socioeconomic status was education level. The Southeast has also been associated with higher mortality rates from congestive heart failure, 7 higher prevalence of self-reported heart disease, 8 and greater prevalence of hypertension among black females, 9 white men, as well as black men and women, 10 compared with other regions. In contrast, the West has been associated with increased incidence of ischemic heart disease, compared with the Southeast, Northeast, and Midwest regions. 11 Increased stroke incidence has been reported in several studies in the colder months and in other studies during the warmer months. Others have found no seasonal differences in stroke rates. 12 Seasonal variation in ischemic stroke incidence, if real, may reflect the influence of acute changes in temperature on known stroke risk factors (eg, blood pressure, blood clotting time, fibrinogen levels, etc). 12 Other potential Received January 25, 2007; final revision received March 29, 2007; accepted April 4, From Department of Epidemiology (D.Q.R.), University of Medicine and Dentistry of New Jersey School of Public Health, Piscataway, NJ; Division of Aging (D.Q.R., J.M.G., T.K.) and Division of Preventive Medicine (J.M.G., T.K.), Brigham & Women s Hospital, Boston, Mass; Massachusetts Veterans Epidemiology Research and Information Center (J.M.G.), Boston VA Healthcare System, Boston, Mass; Department of Epidemiology (T.K.), Harvard School of Public Health, Boston, Mass. Correspondence to Tobias Kurth, MD, ScD, Brigham and Women s Hospital, Division of Aging, 1620 Tremont Street, Boston, MA tkurth@rics.bwh.harvard.edu 2007 American Heart Association, Inc. Stroke is available at DOI: /STROKEAHA

2 2222 Stroke August 2007 explanations for this increased stroke risk associated with residence in the Southeast include residual confounding caused by lifestyle factors and factors correlated with weather conditions. We therefore aimed to prospectively evaluate the association between geographic region of residence and incidence of overall and specific cardiovascular disease (CVD), using data from a well-characterized cohort of mostly white, apparently healthy, US male physicians, aged 40 to 84 years, and free of CVD at baseline. Materials and Methods Study Population The Physicians Health Study is a completed randomized trial designed to test the benefits and risks of aspirin (325 mg every other day) or beta-carotene (50 mg every other day) in the primary prevention of cardiovascular disease and cancer among apparently healthy men aged 40 to 84 at baseline in The methods and results of the Physicians Health Study have been described in detail previously. 13,14 Post-trial follow-up is continuing. 15 All participants gave informed consent. The Institutional Review Board of Brigham and Women s Hospital approved the Physicians Health Study. For this analysis, we included follow-up information through February 28, 2004 (maximum of 22.5 years of follow-up). As of that date, follow-up was 97% complete. At baseline, subjects completed a questionnaire detailing information on cardiovascular risk factors and lifestyle habits. Of the original trial cohort, we excluded 702 participants who did not reside within the 50 US states or in Washington DC. Of these subjects, we retained only those subjects with complete information on age at baseline, frequency of smoking, exercise, and alcohol intake, height, weight, previous diagnoses of hypertension (diagnosis of hypertension or systolic blood pressure 140 mm Hg or diastolic blood pressure 90 mm Hg), elevated cholesterol (diagnosis of high cholesterol or cholesterol 240 mg/100 ml), diabetes, and family history of myocardial infarction (MI) before age 60, and those without a coronary revascularization procedure before receiving the baseline questionnaire procedure. This left subjects for analysis. Geographic Region Using the state listed in subjects baseline mailing address, we categorized subjects into the 4 geographic regions Northeast, Southeast, Midwest, and West (Table 1) according to the 2000 US Census. 16 Outcome Ascertainment Every 6 months in the first year and annually thereafter, participants self-reported incidence of study outcomes, including CVD events. Medical records were obtained for all reported cardiovascular end points and reviewed by an Endpoints Committee of physicians, except coronary revascularization procedures. The occurrence of MI was confirmed if symptoms met World Health Organization criteria and if the event was associated with abnormal levels of cardiac enzymes or diagnostic electrocardiograms. Nonfatal stroke was confirmed if the participant had a new focal neurologic deficit of vascular origin and sudden onset that persisted for 24 hours. Strokes were classified as ischemic, hemorrhagic, or unknown after review of all available information including diagnostic testing, such as brain scans. This classification had a high interrater agreement ( 0.82). 17 Cardiovascular deaths were confirmed by autopsy reports, death certificates, medical records, and information obtained from next of kin or family members. We evaluated the following outcome events: major CVD (a combined end point composed of nonfatal stroke, nonfatal MI, or death from CVD), total MI, total stroke, ischemic stroke, death from CVD, and reports of coronary revascularization procedures (bypass surgery or percutaneous coronary angioplasty). There were too few hemorrhagic strokes to create a separate category for this analysis. Statistical Analysis Incidence Rates Within each region, we calculated crude CVD incidence rates. Next, we calculated age standardized CVD incidence rates by region, using the age distribution of the Northeast as the standard. Main Analyses We used Cox proportional hazards models to estimate the risk of major CVD, specific major CVD, as well as ischemic stroke and coronary revascularization procedures associated with geographic region, adjusting for potential confounding factors. Indicator variables were generated for age at baseline (40 to 49, 50 to 69, and 70), frequency of alcohol intake (once per day or more, once per month through 6 times per week, rarely/never), smoking (never, past, current 1 to 19 cigarettes per day, or current 20 cigarettes per day), exercise frequency (once per day or more, 1 to 6 per week, 1 to 3 per month, rarely/never), body mass index (weight in kg divided by height in meters squared; 25, 25 to 29, 30), history of cholesterol 240 mg/dl, history of hypertension (defined as before), and parental history of MI before age 60. Sensitivity Analyses In a first sensitivity analysis, we re-categorized geographic region into 2 groups (Stroke Belt versus non-stroke Belt). Additionally, we re-categorized geographic region into 2 groups based on latitude. Second, we gathered the monthly mean ambient temperature measurements from all monitoring stations in the US that were in operation every year from 1982 to 2002 (Earth Info, Boulder, Colo). We then computed winter mean (December to February) and summer mean (June to August) temperatures for each state. We then re-categorized geographic region into 3 groups based on winter mean temperature, and then again into 3 groups based on summer mean temperature (Table 1). Results Study subjects were predominantly white (93%). At baseline, the subjects were middle aged (mean SD, ), predominantly never smokers (51%), and past smokers (39%), with a mean body mass index of kg/m 2.A large proportion was classified as overweight (38%) or obese (4%). Subjects generally exercised to sweat at least once per week (73%), and 25% drank daily whereas 15% drank rarely or never. Some subjects were previously diagnosed with elevated cholesterol (12%), hypertension (24%), diabetes (2%), or had a family history of MI before age 60 (10%). There appeared to be little difference in the prevalence of these risk factors and cardiovascular events by geographic region (Table 2). During a mean follow-up time ( SD) of years, subjects experienced 2607 major CVD events, 1018 strokes of which 846 were classified as ischemic stroke, 1247 MIs, 2479 coronary revascularization procedures, and 995 CVD deaths. Incidence Rates by Region The Southeast and Midwest had higher crude and agestandardized major CVD, total stroke, ischemic stroke, coronary revascularization, and CVD death incidence rates compared with the Northeast (Table 3). MI age-standardized incidence rates were lowest in the Southeast, whereas major CVD, stroke, ischemic stroke, and coronary revascularization rates were highest in that region (Table 3).

3 Rich et al Geographic Patterns and Cardiovascular Disease 2223 TABLE 1. States in Each Geographic Classification Grouping Main Analysis 2000 United States Census Northeast Southeast Midwest West Sensitivity analyses 1980 National Heart Lung and Blood Institute Report Stroke belt Not stroke belt Latitude States Maine, New Hampshire, Vermont, Massachusetts, Connecticut, Rhode Island, New York, New Jersey, Pennsylvania Delaware, Maryland, Washington DC, Virginia, West Virginia, Kentucky, Tennessee, North Carolina, South Carolina, Georgia, Florida, Alabama, and Mississippi Ohio, Michigan, Indiana, Illinois, Wisconsin, Minnesota, North Dakota, South Dakota, Nebraska, Kansas, Iowa, Missouri, Oklahoma, Arkansas, Louisiana, Texas Montana, Idaho, Wyoming, Colorado, New Mexico, Arizona, Utah, Nevada, Washington, Oregon, California, Alaska, Hawaii Indiana, Kentucky, Tennessee, Virginia, North Carolina, South Carolina, Georgia, Alabama, Mississippi, Louisiana, Arkansas Other 39 states plus Washington DC North South Mean winter temperature Lowest (region 1) Middle (region 2) Highest (region 3) Mean summer temperature Lowest (region 1) Middle (region 2) Highest (region 3) Main Analyses In unadjusted analyses, the Southeast was associated with significantly decreased risk of MI, and marginally significant (P 0.10) increased risk of coronary revascularization, and ischemic stroke, compared with the Northeast. The Midwest was also associated with significantly increased risk of coronary revascularization procedures compared with the Northeast. There were no other significant associations between geographic region and other CVD outcomes (Table 4). After adjustment for potential confounding factors, the Southeast was no longer associated with significantly decreased risk of MI compared with the Northeast. However, the Southeast was associated with significantly increased risks of total stroke (HR, 1.22; 95% CI, 1.02 to 1.47) and ischemic stroke (HR, 1.30; 95% CI, 1.06 to 1.58) compared with the Northeast (Table 4). Furthermore, we found significantly increased risk of coronary revascularization with residence in the Southeast and the Midwest. Washington, Oregon, Idaho, Montana, Wyoming, Colorado, Utah, North Dakota, South Dakota, Nebraska, Kansas, Missouri, Alaska, Iowa, Minnesota, Wisconsin, Michigan, Illinois, Indiana, Ohio, Pennsylvania, New Jersey, New York, Connecticut, Rhode Island, Massachusetts, New Hampshire, Vermont, Maine Hawaii, California, Nevada, Arizona, New Mexico, Oklahoma, Texas, Arkansas, Louisiana, Tennessee, Mississippi, Alabama, Georgia, Florida, South Carolina, North Carolina, Kentucky, West Virginia, Virginia, Maryland, Washington DC, Delaware Alaska, Colorado, Iowa, Illinois, Maine, Michigan, Minnesota, Montana, North Dakota, Nebraska, New Hampshire, New York, Ohio, South Dakota, Vermont, Wisconsin, Wyoming Connecticut, Delaware, Idaho, Indiana, Kansas, Kentucky, Massachusetts, Maryland, Missouri, New Jersey, Nevada, Pennsylvania, Rhode Island, Utah, Washington, Washington DC, West Virginia Alabama, Arkansas, Arizona, California, Florida, Georgia, Hawaii, Louisiana, Mississippi, North Carolina, New Mexico, Oklahoma, Oregon, South Carolina, Tennessee, Texas, Virginia Alaska, Colorado, Idaho, Massachusetts, Maine, Michigan, Minnesota, Montana, North Dakota, New Hampshire, New York, Oregon, Rhode Island, Vermont, Washington, Wisconsin, Wyoming California, Connecticut, Delaware, Iowa, Illinois, Indiana, Kentucky, Maryland, Nebraska, New Jersey, Nevada, Ohio, Pennsylvania, South Dakota, Utah, Washington DC, West Virginia Alabama, Arkansas, Arizona, Florida, Georgia, Hawaii, Kansas, Louisiana, Missouri, Mississippi, North Carolina, New Mexico, Oklahoma, South Carolina, Tennessee, Texas, Virginia Sensitivity Analyses Compared with the rest of the US, residence in the Southeast was associated with marginally significantly increased risk of total stroke (HR, 1.16; 95% CI, 1.00 to 1.34) and significantly increased risk of ischemic stroke (HR, 1.20; 95% CI, 1.02 to 1.41). The Southeast was also associated with significantly decreased risk of MI (HR, 0.86; 95% CI, 0.75 to 0.99), but not coronary revascularization (HR, 1.08; 95% CI, 0.98 to 1.19), compared with the rest of the US. Residence in the Southeast was not associated with risk of major CVD or CVD death (data not shown). Furthermore, compared with the rest of the US, residence in the Midwest was not associated with any of the evaluated outcomes (data not shown). Because we found significantly increased risk of ischemic stroke but not for MI and coronary revascularization, we limited further sensitivity analyses to the ischemic stroke outcome only. First, residence in the Stroke Belt was associated with marginally significantly increased risk of ischemic

4 2224 Stroke August 2007 TABLE 2. Distribution of Covariates by US Region Characteristic Northeast, Southeast, Midwest, West, Participants 4360 (24) 3734 (21) 5357 (30) 4476 (25) Age, y (mean SD) Mean systolic blood pressure, mm Hg Mean diastolic blood pressure, mm Hg History of hypertension 1085 (25) 897 (24) 1252 (23) 1014 (23) History of diabetes 112 (3) 93 (3) 130 (2) 85 (2) Diagnosed cholesterol 240 mg/dl 576 (13) 396 (11) 611 (11) 530 (12) Parental history of MI before age 60 y 407 (9) 390 (10) 486 (9) 426 (10) Alcohol use Daily 1153 (26) 865 (23) 1192 (22) 1204 (27) 1 per month to 1 per day 2695 (62) 2278 (61) 3287 (61) 2531 (57) Rarely or never 512 (12) 591 (16) 878 (16) 741 (17) Smoking Never 2133 (49) 1827 (49) 2661 (50) 2454 (55) Past 1789 (41) 1466 (39) 2064 (39) 1629 (36) Current (1 19 per day) 166 (4) 136 (4) 205 (4) 167 (4) Current (20 per day) 272 (6) 305 (8) 427 (8) 226 (5) Exercise to sweat Daily 191 (4) 224 (6) 268 (5) 291 (7) At least 1 per week 2629 (60) 2614 (70) 3707 (69) 3096 (69) 1 3 per month 714 (16) 490 (13) 733 (14) 587 (13) Rarely or never 826 (19) 406 (11) 649 (12) 502 (11) Body mass index, kg/m (57) 2126 (57) 3005 (56) 2756 (62) 25 to (39) 1448 (39) 2113 (39) 1574 (35) (4) 160 (4) 239 (4) 146 (3) Subgroup percentages may not sum to 100% because of rounding. Physician s Health Study ( ) n stroke (HR, 1.17; 95% CI, 0.98 to 1.40) compared with the rest of the US. When we categorized region of residence based approximately on latitude, the South was not associated with increased risk of ischemic stroke (HR, 1.00; 95% CI, 0.87 to 1.14) compared with the North. Next, we ranked states into tertiles based on each state s mean winter temperature. Compared with the region with the lowest mean winter temperatures (region 1: mean, 4.6 C; state s mean winter temperature ranged from 9.0 C to 0.9 C), neither the region with the next highest mean winter temperatures (region 2: 1.3 C; range, 0.6 C to 3.5 C; HR, 1.00; 95% CI, 0.85 to 1.17) nor the region with the highest mean winter temperatures (region 3: 9.0 C; range, 4.3 C to 22.6 C; HR, 0.88; 95% CI, 0.74 to 1.06) was associated with increased risk of ischemic stroke. Last, we ranked states into tertiles based on each state s mean summer temperature. Compared with the region with the lowest mean summer temperatures (region 1: mean, 19.7 C; state s mean summer temperature ranged from 11.4 C to 21.6 C), neither the region with the next highest mean summer temperatures (region 2: 23.0 C; range, 21.7 C to 24.5 C; HR, 0.97; 95% CI, 0.81 to 1.15) nor the region with the highest mean summer temperatures (region 3: 26.1 C; range, 24.6 C to 27.6 C; HR, 0.90; 95% CI, 0.77 to 1.06) was associated with increased risk of ischemic stroke. Discussion In this well-characterized cohort of mostly white, apparently healthy, US male physicians, aged 40 to 84, with no CVD or cancer at baseline, we did not find increased risk of major CVD associated with region of residence in any analysis. When we examined individual CVD events, we found significantly increased risk of total stroke and ischemic stroke associated with the Southeast that was not attenuated after adjusting for conventional CVD risk factors. We were also able to replicate the pattern of increased stroke in the Southeastern US (ie, Stroke Belt) seen in previous mortality and incidence studies, as well as when using an alternative definition of Stroke Belt (North Carolina, South Carolina, Georgia, Alabama, Tennessee, Mississippi, Louisiana, Arkansas; data not shown), but not with any region when classified by latitude or mean seasonal temperature. In contrast, we found no consistent association between geographic region and risk of MI or CVD death. Our data suggested an association between residence in the Southeast and Midwest with coronary revascularization procedures,

5 Rich et al Geographic Patterns and Cardiovascular Disease 2225 TABLE 3. Crude and Age-Standardized Incidence Rates (per 1000 person-years) by Region Outcome Type Northeast n 4360 Southeast n 3734 Midwest n 5357 West n 4476 Major cardiovascular disease* (n 2607) Crude Age-standardized Total stroke (n 1018) Crude Age-standardized Ischemic stroke (n 846) Crude Age-standardized MI (n 1247) Crude Age-standardized Coronary revascularization (n 2479) Crude Age-standardized CVD death (n 995) Crude Age-standardized *A major cardiovascular event was defined as any first of the following events: nonfatal stroke, nonfatal MI, or death from cardiovascular cause. Includes reports of bypass surgery or percutaneous coronary angioplasty. Physician s Health Study ( ) n which were, however, attenuated and no longer statistically significant in our sensitivity analyses. The increased risk of ischemic stroke in the Southeast region may be attributable to differences in other regional environmental conditions or lifestyle factors not included in this analysis. Our stroke risk estimates for the Southeast region for predominantly white, male, physicians 40 to 84 years of age (HR, 1.22; 95% CI, 1.02 to 1.47), were slightly lower than those reported by Gillum and Ingram 6 for white males 45 to 74 years of age (HR, 1.41; 95% CI, 1.02 to 1.92). Unadjusted TABLE 4. Unadjusted and Adjusted HR and 95% CIs for Overall and Specific CVD Associated With Residence in Each US Region Northeast Southeast Midwest West Outcome (n 4360) (n 3734) (n 5357) (n 4476) Major cardiovascular disease* (n 2607) (n 633) (n 557) (n 793) (n 624) Unadjusted ( ) 1.01 ( ) 0.95 ( ) Adjusted ( ) 1.07 ( ) 1.07 ( ) Total stroke (n 1018) (n 243) (n 234) (n 311) (n 230) Unadjusted ( ) 1.04 ( ) 0.92 ( ) Adjusted ( ) 1.13 ( ) 1.03 ( ) Ischemic stroke (n 846) (n 197) (n 200) (n 260) (n 189) Unadjusted ( ) 1.07 ( ) 0.93 ( ) Adjusted ( ) 1.17 ( ) 1.05 ( ) MI (n 1247) (n 323) (n 232) (n 372) (n 320) Unadjusted ( ) 0.93 ( ) 0.96 ( ) Adjusted ( ) 0.96 ( ) 1.05 ( ) Coronary revascularization (n 2479) (n 568) (n 542) (n 780) (n 589) Unadjusted ( ) 1.12 ( ) 1.00 ( ) Adjusted ( ) 1.15 ( ) 1.08 ( ) CVD death (n 995) (n 233) (n 214) (n 314) (n 234) Unadjusted ( ) 1.09 ( ) 0.97 ( ) Adjusted ( ) 1.20 ( ) 1.14 ( ) *A major cardiovascular event was defined as any first of the following events: nonfatal stroke, nonfatal MI, or death from cardiovascular cause. Adjusted for age, alcohol consumption, smoking status, exercise frequency, body mass index, history of elevated cholesterol 240 mg/dl, previous diagnosis of hypertension, previous diagnosis of diabetes, and family history of MI before age 60. Physician s Health Study ( ) n

6 2226 Stroke August 2007 stroke incidence rates were markedly lower in our study, compared with Gillum and Ingram. 6 This likely reflects that our cohort only included physicians. On average, physicians are considered to be of higher socioeconomic status, to have healthier lifestyles, better diets, better access to health care services, and more frequent use of preventive health care, compared with nonphysicians. Another explanation why our incidence rates are lower is that our study was conducted from 1982 to 2004, whereas the study period in the study by Gillum and Ingram 6 was much earlier (1971 to 1987). Because stroke mortality rates have declined over time, 5 and assuming incidence rates followed a similar pattern, we would expect to see lower incidence rates in our study. A possible reason for the observed association between residence in the Southeastern US and incidence of ischemic stroke is diet. In the third National Health and Nutrition Examination Survey, the Southeast region had the highest blood pressures values, the highest intakes of monounsaturated and polyunsaturated fatty acids, cholesterol, and sodium, and the lowest intake of fiber and several vitamins and minerals 18 compared with the other three regions. We had no detailed information on dietary intake at baseline in the Physicians Health Study. However, statistical adjustment using available information on vegetable and milk intake made little difference (data not shown). The National Health and Nutrition Examination Survey III reported lower mean serum selenium levels among people residing in the Southern US compared with the other 3 US regions. 19 Selenium levels have previously been inversely associated with risk of nonfatal MI and fatal CHD, 20 total, cardiovascular, and stroke mortality, 21 and directly associated with coronary revascularization procedures. 20 Studies of temperature and stroke incidence have been inconsistent, with some finding no association, others reporting associations with cold months, and others with warm months. 12 One study found no difference in stroke incidence rates between days with abrupt changes in weather conditions and those without such changes. 22 We ranked states based on mean winter temperature, mean summer temperature and latitude. Although we found no association with geographic region based on either latitude or seasonal mean temperature, other characterizations of the regional variability in temperature or other weather conditions may be associated with increased risk of ischemic stroke. Our study had several strengths, including the large number of outcome events and participants, prospective method of data collection, and the homogenous nature of our cohort, which reduced confounding by many sociodemographic factors. Furthermore, with the exception of coronary revascularization, all outcome events were confirmed after medical record review. Several limitations should be considered when interpreting out results. The mailing address given by each subject at baseline was used to classify each subject into US regions. This mailing address could have been the subject s home or the subject s work address. Some subjects may work and live in different cities and states, which could be important if we were examining local variability in CVD incidence. However, it is unlikely that subjects worked and lived in different census regions; therefore, this likely did not result in substantial misclassification of census region. If a few cases of misclassification did in fact occur, this was likely nondifferential with respect to outcome, resulting in underestimation of risk. If subjects moved during follow-up from other regions (cold weather states in the Northeast and Midwest) to the Southeast (eg, Florida, South Carolina, etc), this would have made the regions incidence rates more similar. Therefore, this also would have led to an underestimate of the risk of ischemic stroke associated with residence in the Southeast. These findings are directly generalizable to middle-aged to older, white, US males of higher socioeconomic status. However, gender and racial differences in stroke mortality 3 and stroke incidence 6,23 have been demonstrated. Therefore, it is likely that different racial and gender groups may have markedly different ischemic stroke incidence rates in the same region of residence. Thus, these analyses should be replicated in women and nonwhites. In summary, in this large, prospective cohort of apparently healthy, mostly white, US male physicians, we found no evidence of regional differences in risk of major CVD. In further analyses, we found consistent significantly increased risk of total and ischemic stroke, but not other vascular events associated with living in the Southeast compared with the Northeast or the rest of the US, after adjustment for traditional CVD risk factors. Acknowledgments The authors are indebted to the participants of the Physician s Health Study for their outstanding commitment and cooperation, and to the entire Physicians Health Study staff for their expert and unfailing assistance. Sources of Funding The study was supported by NCI grants CA and CA 40360, and NHLBI grants HL and HL None. Disclosures References 1. United States National Heart, Lung, and Blood Institute. Stroke Belt Initiative. Project accomplishments and lessons learned. Available at: Accessed March 26, Lanska DJ. Geographic distribution of stroke mortality in the United States: to Neurology. 1993;43: Casper ML, Wing S, Anda RF, Knowles M, Pollard RA. The shifting stroke belt: changes in the geographic pattern of stroke mortality in the United States, 1962 to Stroke. 1995;26: Perry HM, Roccella EJ. Conference report on stroke mortality in the southeastern United States. Hypertension. 1998;31: Howard G, Howard VJ, Katholi C, Oli MK, Huston S. Decline in US stroke mortality: an analysis of temporal patterns by sex, race, and geographic region. Stroke. 2001;32: Gillum RF, Ingram DD. Relation between residence in the southeast region of the United States and stroke incidence: The NHANES I Epidemiologic Followup Study. Am J Epidemiol. 1996;144: Center for Disease Control and Prevention. Changes in mortality from heart failure United States, MMWR Morb Mortal Wkly Rep. 1998;47: Gillum RF. Prevalence of cardiovascular and pulmonary diseases and risk factors by region and urbanization in the United States. J Natl Med Assoc. 1994;86:

7 Rich et al Geographic Patterns and Cardiovascular Disease Roccella EJ, Lenfant C. Regional and racial differences among stroke victims in the United States. Clin Cardiol. 1989;12:IV18 IV Obisesan TO, Vargas CM, Gillum RF. Geographic variation in stroke risk in the United States. Region, urbanization, and hypertension in the Third National Health and Nutrition Examination Survey. Stroke. 2000;31: Garg R, Madans JH, Kleinman JC. Regional variation in ischemic heart disease incidence. J Clin Epidemiol. 1992;45: Connor MD. Does the weather influence stroke incidence? Stroke. 2002; 33: Hennekens CH, Buring JE, Manson JE, Stampfer M, Rosner B, Cook NR, Belanger C, LaMotte F, Gaziano JM, Ridker PM, Willett W, Peto R. Lack of effect of long-term supplementation with beta carotene on the incidence of malignant neoplasms and cardiovascular disease. N Engl J Med. 1996;334: Steering Committee of the Physicians Health Study Research Group. Final report on the aspirin component of the ongoing Physicians Health Study. Steering Committee of the Physicians Health Study Research Group N Engl J Med. 1989;321: Christen WG, Gaziano JM, Hennekens CH. Design of Physicians Health Study II a randomized trial of beta-carotene, vitamins E and C, and multivitamins, in prevention of cancer, cardiovascular disease, and eye disease, and review of results of completed trials. Ann Epidemiol. 2000; 10: US Bureau of the Census. Summary population and housing characteristics census of population and housing. Part Available at: Accessed March 26, Berger K, Kase CS, Buring JE. Interobserver agreement in the classification of stroke in the physicians health study. Stroke. 1996;27: Hajjar I, Kotchen T. Regional variations of blood pressure in the United States are associated with regional variations in dietary intakes: the NHANES-III data. J Nutr. 2003;133: Niskar AS, Paschal DC, Kieszak SM, Flegal KM, Bowman B, Gunter EW, Pirkle JL, Rubin C, Sampson EJ, McGeehin M. Serum selenium levels in the US population: Third National Health and Nutrition Examination Survey, Biol Trace Elem Res. 2003;91: Yoshizawa K, Ascherio A, Morris JS, Stampfer MJ, Giovannucci E, Baskett CK, Willett WC, Rimm EB. Prospective study of selenium levels in toenails and risk of coronary heart disease in men. Am J Epidemiol. 2003;158: Virtamo J, Valkeila E, Alfthan G, Punsar S, Huttunen JK, Karvonen MJ. Serum selenium and the risk of coronary heart disease and stroke. Am J Epidemiol. 1985;122: Field TS, Hill MD. Weather, Chinook, and stroke occurrence. Stroke. 2002;33: Sacco RL, Boden-Albala B, Gan R, Chen X, Kargman DE, Shea S, Paik MC, Hauser WA. Stroke incidence among white, black, and Hispanic residents of an urban community: the Northern Manhattan Stroke Study. Am J Epidemiol. 1998;147: