Increasing evidence from prospective studies have implicated

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1 Phobic Anxiety and Risk of Coronary Heart Disease and Sudden Cardiac Death Among Women Christine M. Albert, MD, MPH; Claudia U. Chae, MD, MPH; Kathryn M. Rexrode, MD, MPH; JoAnn E. Manson, MD, DPH; Ichiro Kawachi, MD, PhD Background High levels of phobic anxiety have been associated with elevated risks of coronary heart disease (CHD) death and sudden cardiac death (SCD) among men. To the best of our knowledge, no studies have looked at this association among women. Anxiety may influence CHD mortality by increasing the risk of ventricular arrhythmia and SCD. Methods and Results We prospectively examined the relationship between phobic anxiety, as measured by the Crown-Crisp index (CCI), and CHD among women participating in the Nurses Health Study. Among women with no history of cardiovascular disease or cancer in 1988, 97 SCDs, 267 CHD deaths, and 930 nonfatal myocardial infarctions (MI) were documented over 12 years of follow-up. A higher score on the CCI was associated with an increased risk of SCD and fatal CHD but not of nonfatal MI in age-adjusted (P, trend 0.008) and in multivariable models excluding possible biological intermediaries (P, trend 0.03). Multivariable adjustment appeared to attenuate the relations; women who scored 4 or greater on the CCI were at a 1.59-fold (95% CI, 0.97 to 2.60) marginally increased risk of SCD and a 1.31-fold (95% CI, 0.97 to 1.75) marginally increased risk of fatal CHD compared with those who scored 0 or 1. After control for possible intermediaries (hypertension, diabetes, and elevated cholesterol), a trend toward an increased risk persisted for SCD (P 0.06). Conclusions These prospective data suggest that high levels of phobic anxiety are associated with an increased risk of fatal CHD, particularly from SCD. Some but not all of this risk can be accounted for by CHD risk factors associated with phobic anxiety. (Circulation. 2005;111: ) Key Words: death, sudden women arrhythmia stress Increasing evidence from prospective studies have implicated negative emotions anxiety, anger/hostility, and depression as risk factors for the incidence of coronary heart disease (CHD). 1,2 Several mechanisms have been put forward to explain this finding, including the association of negative emotions with deleterious health behaviors (smoking, poor diet, sedentarism), in addition to the potential direct effects of emotional stress on progression of atherosclerosis as well as lowering of thresholds for ventricular arrhythmia and sudden cardiac death (SCD). 2 In several studies, patients with phobic anxiety or panic disorder appeared to have an increased risk of CHD. 3 In 2 prospective cohort studies involving men, 4,5 high levels of phobic anxiety, as measured by a score of 4 or greater on the Crown-Crisp index, were associated with an elevated risk of CHD death but not nonfatal myocardial infarction (MI). In one of these studies, the Health Professionals Follow-Up Study, 5 the excess risk was confined to sudden rather than nonsudden CHD death. Similar results were found in the Normative Aging Study by use of another measure of chronic anxiety. 6 Although the prevalence of anxiety 7 and phobic disorders 8 is known to be twice as high among women, little is currently known about the relationship between phobic anxiety and CHD and/or SCD among women. In the present study of women free of cardiovascular disease (CVD) and cancer in 1988, we prospectively examined whether symptoms of phobic anxiety, as measured by the Crown- Crisp index, were associated with subsequent CHD outcomes, particularly SCD and fatal CHD, over 12 years of follow-up. Methods The Nurses Health Study Cohort The NHS began in 1976, when registered nurses, 30 to 55 years of age, completed a questionnaire about their medical history, CHD risk factors, menopausal status, and lifestyle factors. The cohort has been followed up every 2 years with mailed question- Received July 15, 2004; accepted December 7, From the Division of Preventive Medicine (C.M.A., C.U.C., K.M.R., J.E.M.) and Channing Laboratory (J.E.M., I.K.), Department of Medicine, Brigham and Women s Hospital and Harvard Medical School; the Cardiology Division (C.M.A., C.U.C.), Department of Medicine, Massachusetts General Hospital and Harvard Medical School; and the Departments of Epidemiology (J.E.M.) and Society, Human Development, and Health (I.K.), Harvard School of Public Health, Boston, Mass. Correspondence to Dr Christine Albert, Division of Preventive Medicine, Brigham and Women s Hospital, 900 Commonwealth Ave East, Boston, MA calbert@partners.org 2005 American Heart Association, Inc. Circulation is available at DOI: /01.CIR D 480

2 Albert et al Phobic Anxiety and Risk of CHD and SCD in Women 481 naires that update exposure information and inquire about newly diagnosed medical illnesses. Population for Analysis As part of the 1988 questionnaire, all participants were asked to complete the phobic anxiety scale of the Crown-Crisp experimental index. These questions were included specifically to address the hypothesis that phobic anxiety is a risk factor for SCD and CHD. Because a previous or perceived diagnosis of CVD or cancer may influence the responses to certain items on the Crown-Crisp index (eg, Do you find yourself worrying about getting some incurable illness ), we excluded from the analyses women who reported nonfatal CVD end points (angina, MI, coronary revascularization, or stroke) or cancer (except nonmelanoma skin cancer) before or at the time of the 1988 questionnaire. Of these women, returned the 1988 questionnaire, and completed at least part of the Crown-Crisp index. Of these women, completed at least 6 of 8 questions and were included in the analysis. Assessment of Phobic Anxiety: The Crown-Crisp Index The Crown-Crisp phobia index measures common symptoms of phobic anxiety and has been validated in psychiatric outpatient clinic settings and found to discriminate patients with anxiety disorders and agoraphobia from healthy controls. 9,10 It is a standardized, self-rating inventory of 8 questions with 2 to 3 levels of possible responses to each question, allowing scores ranging from 0 to 16 (with higher scores given to higher levels of phobic anxiety). 9,10 The individual questions and response options are outlined in Table 4. For those with missing data on 1 or 2 questions (n 4148), the total score was divided by the fraction of questions answered and then rounded to the nearest whole number. In keeping with previous studies in health professionals that have used the Crown-Crisp index, 5 we categorized the total score into the following categories: 0 or 1 (reference category), 2, 3, and 4 or higher (highest levels of phobic anxiety). These categories also separated the population into approximate quartiles, as was done in other studies. 4 End Point Ascertainment and Definitions The study end points comprised incident cases of nonfatal MI, fatal CHD, and SCD occurring after the return of the 1988 questionnaire and before June 1, All nurses who reported having a nonfatal MI were asked for permission to review medical records. Medical records were reviewed by physicians who were blinded to exposure status. The follow-up rate for nonfatal events was 98% of the total potential person-years. Myocardial infarction was confirmed by use of World Health Organization criteria: symptoms plus either diagnostic ECG changes or elevated cardiac enzymes. 11 Infarctions that required hospital admission and for which confirmatory information was obtained by interview or letter, but for which no medical records were available, were designated as probable. Analyses including or excluding these events yielded similar results, so we present analyses including these events. Most deaths are reported by next of kin or postal authorities. In addition, at the completion of each mailing cycle, the National Death Index is searched for names of nonrespondents to the questionnaire. Death follow-up is 98% complete. Death certificates are obtained from state vital statistics departments to confirm deaths, and permission to obtain further information from medical records or verbal reports is requested from family members. Deaths are then confirmed for a cardiovascular cause by physician review of medical records. The next of kin is interviewed regarding the circumstances surrounding the death if not adequately documented in the medical record. Fatal CHD was confirmed by hospital records or autopsy or if CHD was listed as the cause of death on the death certificate along with evidence of previous coronary disease and CHD was the most plausible cause of death. We designated as presumed CHD (24% of fatal cases) those in which CHD was the underlying cause on the death certificate but where no medical records surrounding the death were available. The specific details regarding the classification of SCD are described in detail elsewhere. 12 In brief, a cardiac death was considered sudden if the death and/or cardiac arrest that precipitated the terminal event occurred within 1 hour of symptom onset. To increase our specificity for arrhythmic death, we excluded anyone who had evidence of collapse of the circulation (hypotension, exacerbation of congestive heart failure, and/or altered mental status) before the disappearance of the pulse. 13 Statistical Analysis Age-adjusted means or proportions of cardiovascular risk factors were computed across the 4 categories of the Crown-Crisp index. The significance of associations was tested by use of the Mantel- Haenszel 2 test for trend for categorical variables and linear regression for continuous variables. As a test of internal validity of the Crown-Crisp index, we also examined the association between scores on the Crown-Crisp index in 1988 and reported use of anti-anxiety medications in 2000, the first year in which detailed information on these drugs was collected. Cox proportional-hazards models were then used to compute ageand multivariable-adjusted relative risks of SCD, fatal CHD, and nonfatal MI across the 4 categories of the Crown-Crisp index and age-adjusted relative risks associated with responses to individual items on the Crown-Crisp index. For each woman, person-months of follow-up were calculated from the date of return of the 1988 questionnaire to the date of the first end point or death or to June 1, 2000, whichever came first. Two multivariable models were performed (please see legend of Table 2 for the list of variables included in the models). The first multivariable model simultaneously controlled for all CHD risk factors except for those that theoretically might be in the causal pathway (hypertension, diabetes, and elevated cholesterol). The second multivariable model also included these covariates. If information on covariates was missing, then persontime was assigned to a missing category for that covariate. In secondary models, we updated the information on CHD risk factor status over the 12 years of follow-up to determine how much of the effect could be explained by changes in CHD risk factors over the course of the study. If information was missing during a follow-up period, then person-time was assigned to a missing category for that time period. Tests for trend were performed by assigning the median value for each category of the Crown-Crisp index and then modeling this as a continuous variable in separate Cox proportional-hazards models. In addition, we tested for deviation from linearity by comparing models containing the 4 categories of the Crown-Crisp index with those containing a linear term for these categories in a likelihood-ratio test with 2 degrees of freedom. We also explored whether the observed associations were modified by age or were proportional over the follow-up period by adding cross-product terms composed of the Crown-Crisp trend variable with either age or the logarithm of follow-up time into the full multivariable model. Statistical analysis was performed by use of SAS statistical software (SAS Institute Inc), Version 8.2. Results Among women who were free of CVD at baseline in 1988, 27.7%, or the approximate top quartile, scored 4 or greater on the Crown-Crisp index. Scores ranged from 0 to 14 (out of a possible maximum score of 16; see Figure 1 for distribution of scores). Scores on the Crown-Crisp index were associated with several CHD risk factors (Table 1). Women with higher scores were more likely to have a history of diabetes, hypercholesterolemia, or hypertension. They were also more likely to be heavy smokers or obese (body mass index of 30 kg/m 2 ) and were less physically active. In addition, women with higher scores on the Crown-Crisp index in 1988 were more likely to subsequently report regular use of minor tranquilizers (eg, Valium, Xanax, Ativan,

3 482 Circulation February 1, 2005 Figure 1. Distribution of responses to Crown-Crisp index among women free of CVD in Librium) in 2000 (P 0.001). Women who scored 4 or greater on the Crown-Crisp index were 2.7 (95% CI, 2.5 to 3.0) times more likely to report minor tranquilizer use compared with women who scored 0 or 1. During 12 years of follow-up, a total of 930 nonfatal MIs, 97 SCDs, and 267 total CHD deaths occurred among these TABLE 1. Relationship of Crown-Crisp Index Score to Coronary Heart Disease Risk Factors* Among Women Free of Cardiovascular Disease at Baseline in 1988 Crown-Crisp Index Score Variable 0or No. of women (total N ) Age, y (mean) Smoking, % Past Current 1 14 cigarettes/d Current cigarettes/d Current 25 cigarettes/d Reported diagnosis of Diabetes, % High cholesterol, % Hypertension, % Body mass index, mean Parental history of MI before age y, % Alcohol intake, 3 /wk, % Aspirin use, 7 /wk, % Physical activity, total Mets/wk, mean Postmenopausal hormone use, current, % Vitamin supplement use Vitamin E, % Multivitamin, % *Standardized for age to the total cohort. Information ascertained on the 1988 questionnaire. P P women (Table 2). In age-adjusted models, scores on the Crown-Crisp index were directly related to fatal CHD (P, trend 0.001) and to SCD (P 0.008). These relationships were attenuated, but persisted, after control for smoking status, body mass index, alcohol intake, menopausal status, postmenopausal hormone use, parental history of myocardial infarction, and aspirin and Valium use (Table 2, multivariable model 1). With further control for diabetes, hypertension, and hypercholesterolemia, the relationship for fatal CHD was further attenuated, and the P for trend over the 4 categories of the Crown-Crisp index became nonsignificant (Table 2, multivariable model 2). However, even after control for these potential biological mediators in the causal pathway, a trend toward an increased risk persisted for SCD (P 0.06). When we updated the information on CHD risk factor status over the 12 years of follow-up to determine how much of the effect could be explained by changes in CHD risk factors over the course of the study, the relationship with fatal CHD was almost completely attenuated (P, trend 0.30; RR comparing extreme categories 1.10 [95% CI, 0.82 to 1.47]), whereas a marginal trend toward an increased risk of SCD persisted (P, trend 0.08; RR comparing extreme categories 1.42 [95% CI, 0.86 to 2.33]). However, because information on anxiety could not be updated along with CHD risk factor status, the independent association of phobic anxiety in these models is probably underestimated in these updated models. In contrast to the relationships observed above for fatal events, the Crown-Crisp index was not significantly related to nonfatal MI in the age-adjusted model or in the multivariable model that did not include potential biological mediators (Table 2). However, after control for diabetes, hypertension, and hypercholesterolemia, a trend toward a decreased risk over the 4 categories of the Crown-Crisp index emerged (P 0.07). If we updated these and other CHD risk factors over the course of the 12 years of follow-up, this trend became significant (P, trend 0.03; RR comparing extreme categories 0.86 [95% CI, 0.73 to 1.02]). For both fatal CHD and SCD, the elevation in risk appeared to be primarily among women who scored 4 or greater on the phobia index; however, no significant deviations from linearity in the log relative risks were detected in

4 Albert et al Phobic Anxiety and Risk of CHD and SCD in Women 483 TABLE 2. Relative Risks (RR and 95% CI) of CHD in a Cohort of Women Free of CVD at Baseline Followed Up From 1988 to 2000, According to Score on the Crown-Crisp Index Crown-Crisp Index Score 0, P for trend SCD No. of cases Person-years Age-adjusted ( ) 1.18 ( ) 1.77 ( ) Multivariate I* ( ) 1.14 ( ) 1.59 ( ) 0.03 Multivariate ( ) 1.08 ( ) 1.45 ( ) 0.06 Fatal CHD No. of cases Person-years Age-adjusted ( ) 0.99 ( ) 1.55 ( ) Multivariate I* ( ) 0.92 ( ) 1.31 ( ) 0.02 Multivariate ( ) 0.88 ( ) 1.18 ( ) 0.12 Nonfatal MI No. of cases Person-years Age-adjusted ( ) 1.04 ( ) 1.08 ( ) 0.56 Multivariate I* ( ) 0.97 ( ) 0.95 ( ) 0.32 Multivariate ( ) 0.94 ( ) 0.89 ( ) 0.07 *Adjusted for age, smoking status (never, past, current 1 24, 15 24, 25 cigarettes/d), body mass index ( 25, , 30 kg/m 2 ), alcohol intake (0, 5, 5 14, 15 g/d), menopausal status and postmenopausal hormone use (current, past, never), parental history of myocardial infarction before age 60 years (yes vs no), vigorous to moderate activity ( 2, 2 3.9, 4 h/wk), usual aspirin use ( 1/wk, 1 6/wk, and 7 /wk), and valium use ( 1/wk, 1/wk). Adjusted for factors cited above and history of hypertension (yes vs no), hypercholesterolemia (yes vs no), and diabetes (yes vs no). any of the models. In secondary post hoc analyses, we compared women who scored 4 or greater with those who scored less than 4 on the phobia index (Table 3). Women who scored 4 or greater were at a 1.52-fold (95% CI, 1.01 to 2.30; P 0.04) increased risk of SCD and a 1.30-fold (95% CI, 1.02 to 1.67; P 0.04) increased risk of fatal CHD even after adjustment for all of the above covariates. Again, a trend toward a lower risk for nonfatal MI was observed in the women who scored 4 or above. We then explored whether risk varied over the follow-up period by examining the interaction between the logarithm of time and the Crown-Crisp index in the multivariable models. This interaction was of borderline significance for SCD (P 0.06) but did not approach significance for either nonfatal MI or fatal CHD. For SCD, the hazard ratio for the interaction term was positive (1.07; 95% CI, 1.00 to 1.15), indicating that risk may have been higher during the later follow-up period. Figure 2 displays the age-adjusted risk for SCD associated with the Crown-Crisp index by 4-year time periods. In these secondary post hoc analyses, the elevation in risk appeared to be confined primarily to the last 4 years of follow-up, when the majority (52%) of the SCDs occurred (multivariable P, trend 0.004). We then explored whether an interaction with age could explain this varying effect, and there was no evidence for an interaction with age for any of the outcomes. Finally, we examined the age-adjusted associations of the individual items on the phobia scale (Table 4). Four individual items were associated with an elevation in the risk of SCD and fatal CHD: having an unreasonable fear of being in enclosed spaces, feeling panicky in crowds, feeling more relaxed indoors, and feeling uneasy traveling on buses or trains. The first symptom is characteristic of claustrophobia, whereas the latter 3 questions represent typical features of agoraphobia. These 4 items appeared to be more predictive of risk compared with other phobias pertaining to incurable illnesses, relative s safety, or fear of heights (acrophobia). As observed for the composite score, none of the individual items were associated with nonfatal MI (data not shown). Discussion In this large, prospective cohort study of women who were free of reported CVD at baseline, phobic anxiety, as measured by the Crown-Crisp index, was associated with an increase in risk of SCD and fatal CHD but not of nonfatal MI in age-adjusted and multivariable models that excluded potential biological mediators. In these multivariable models, women who scored 4 or greater on the Crown-Crisp index

5 484 Circulation February 1, 2005 TABLE 3. Relative Risks (RR and 95% CI) of CHD From 1988 to 2000 According to Score on the Crown-Crisp Index of >4 Crown-Crisp Index Score 4 4 P SCD No. of cases Age-adjusted ( ) Multivariate I* ( ) 0.02 Multivariate ( ) 0.04 Fatal CHD No. of cases Age-adjusted ( ) Multivariate I* ( ) Multivariate ( ) 0.04 Nonfatal MI No. of cases Age-adjusted ( ) 0.73 Multivariate I* ( ) 0.28 Multivariate ( ) 0.07 *Adjusted for age, smoking status (never, past, current 1 24, 15 24, 25 cigarettes/d), body mass index ( 25, , 30 kg/m 2 ), alcohol intake (0, 5, 5 14, 15 g/d), menopausal status and postmenopausal hormone use (current, past, never), parental history of myocardial infarction before age 60 years (yes vs no), vigorous to moderate activity ( 2, 2 3.9, 4 h/wk), usual aspirin use ( 1/wk, 1 6/wk, and 7 /wk), and valium use ( 1/wk, 1/wk). Adjusted for factors cited above and history of hypertension (yes vs no), hypercholesterolemia (yes vs no), and diabetes (yes vs no). were at a 1.59-fold (95% CI, 0.97 to 2.60) increased risk of SCD and a 1.31-fold (95% CI, 0.97 to 1.75) increased risk of fatal CHD compared with those who scored 0 or 1. After control for these possible intermediaries (hypertension, diabetes, and elevated cholesterol), a trend toward an increased risk persisted only for SCD (P 0.06), indicating that at least part of the observed elevation in risk, particularly for fatal CHD, can be accounted for by these CHD risk factors. In contrast, there was no relationship between phobic anxiety and nonfatal MI in either age-adjusted or multivariable models that excluded potential mediators in the causal pathway, whereas a trend toward a lower risk emerged in multivariable models that controlled for possible mediators (P 0.07). For SCD and fatal CHD, the risk appeared to increase in the fourth quartile, which corresponded to a score of 4 or higher on the phobia index; however, no significant deviations from linearity in the log relative risks were detected in any of the models. Because only 9% of the population scored higher than 4 on the index (Figure 1), we were limited in our ability to determine whether this elevation represented a threshold or whether the risk increased further with higher scores on the index. In secondary post hoc analyses, a score of 4 or greater was associated with a 52% increased risk of SCD and a 30% increased risk of fatal CHD compared with women who scored lower than 4 on the phobia index. Both elevations in risk remained significant even after control for multiple CHD risk factors, including those potentially in the causal pathway. These data are generally consistent with those previously reported on the effect of chronic phobic anxiety on CHD in 3 prospective male cohorts. 4 6 All of these studies reported positive associations with fatal CHD end points and no relationship with nonfatal CHD. The British Northwick Park Heart Study, 4 which included 1457 Caucasian men followed up for 6 years, first reported a significant association between scores on the Crown-Crisp index and fatal CHD. Men who were in the approximate top quartile (score of 5 or greater) had a relative risk of 3.8 (95% CI, 1.6 to 8.6) of fatal CHD. The US Health Professionals Follow-up Study of men confirmed and expanded on these results by specifically examining SCD. 5 Over 2 years of follow-up, high levels of phobic anxiety on the Crown-Crisp index (score of 4 or greater) were associated with a 2.5-fold increase in risk of CHD death, which was entirely because of a 6-fold increase in SCD. The magnitudes of the relative risk elevations in these 2 studies were higher than in the present study; however, the numbers of fatal CHD events (n 40 to 57) and Figure 2. Age-adjusted relative risk of SCD according to scores on Crown- Crisp index by 4-year follow-up periods.

6 Albert et al Phobic Anxiety and Risk of CHD and SCD in Women 485 TABLE 4. Age-Adjusted Relative Risks (RR and 95% CI) of SCD and Fatal CHD From 1988 to 2000 According to Answers to Individual Questions on the Crown-Crisp Index SCD Fatal CHD Do you have an unreasonable fear of being in enclosed spaces such as shops, lifts, etc? Never Sometimes 1.79 ( ) 1.80 ( ) Often 2.22 ( ) 2.51 ( ) Do you find yourself worrying about getting some incurable illness? Never Sometimes 0.92 ( ) 0.95 ( ) Often 0.56 ( ) 1.49 ( ) Are you scared of heights? Not at all Moderately 0.93 ( ) 0.89 ( ) Very 1.22 ( ) 1.33 ( ) Do you feel panicky in crowds? Not at all Moderately 1.51 ( ) 1.22 ( ) Very 2.22 ( ) 3.43 ( ) Do you worry unduly when relatives are late in coming home? No Yes 1.06 ( ) 1.08 ( ) Do you feel more relaxed indoors? Not particularly Sometimes 1.32 ( ) 1.92 ( ) Definitely 3.90 ( ) 2.40 ( ) Do you dislike going out alone? No Yes 1.33 ( ) 1.54 ( ) Do you feel uneasy traveling on buses or trains even if they are not crowded? Not at all A little 1.03 ( ) 1.41 ( ) Definitely 2.91 ( ) 3.44 ( ) SCDs (n 16) were much lower, leading to less stable estimates of risk. The Normative Aging Study also found similar results over a longer follow-up period (up to 28 years) by use of another measure of chronic anxiety found to correlate with the Crown-Crisp index. 6 The differential association with fatal CHD, particularly SCD, versus nonfatal CHD end points in this and previous studies suggests that phobic anxiety may influence cardiovascular risk to a greater extent through direct effects on arrhythmogenesis and fatal ventricular arrhythmias 14 than through effects on atherogenesis 15 and/or thrombosis. Conversion of nonfatal ischemic events to fatal arrhythmic events through proarrhythmic mechanisms associated with chronic phobic anxiety 14 might explain the seemingly paradoxical lower risk of nonfatal MI in the fully controlled multivariable model. A similar phenomenon was reported in the CAST 1 trial, in which the treatment group had a significantly lower nonfatal CHD event rate despite having a higher mortality and SCD rate because of proarrhythmic effects of the IC antiarrhythmic drugs tested. 16 Possible proarrhythmic mechanisms associated with anxiety include alterations in autonomic tone manifested by decreased vagal and increased sympathetic components, thereby increasing the overall susceptibility to ventricular fibrillation. Individuals with high levels of anxiety have reduced heart rate variability compared with normal subjects, 17 which has been shown to predict SCD in the elderly 18 and in patients with heart failure. 19 Also, acute attacks of anxiety or mental stress may trigger episodes of fatal ventricular arrhythmias in susceptible patients. It is well documented that acute increases in the incidence of SCD can occur in populations suffering acute psychological stressors such as

7 486 Circulation February 1, 2005 earthquakes or wars. 20 Potential mechanisms include increases in sympathetic nervous system activity, leading to cardiac instability 21 and an acute increase in susceptibility to ventricular fibrillation and SCD. When we examined the associations between phobic anxiety and risk of CHD over time, only the association with SCD risk appeared to vary by time. The elevation in risk appeared to emerge in the last 4 years of the study, suggesting that the chronic rather than acute effects of anxiety on cardiac electrophysiology may be of greater importance. Alternatively, the increasing association over time might be a consequence of the higher number of events that occurred at the end of the study and the resulting greater power to detect an association. The temporal relationship found for SCD in our study differs from that reported for fatal CHD among men in the Northwick Park Heart Study, in which the association between the Crown-Crisp index and fatal CHD was found to diminish with increasing length of follow-up. 22 Also, in the Health Professionals Follow-up Study, the elevation in SCD risk was found after only 2 years of follow-up. 5 In addition to direct effects on myocardial vulnerability, anxiety may also lead to diabetes, hypertension, and hypercholesterolemia. Chronically elevated catecholamine levels have been shown to increase lipoprotein lipase levels, 23 induce hyperglycemia, 24 and elevate blood pressure. 25 Because these disease states might, at least in part, be biological mediators in the causal pathway of CHD, analyses were performed excluding these variables from the model (multivariable model 1). In these models, the relationship with SCD and fatal CHD remained significant over the 4 categories of the Crown-Crisp index. Control for these potential intermediaries appeared to have a greater impact on the risk estimates for fatal CHD and nonfatal MI than for SCD, suggesting that these mechanisms may be more important in the causal pathway for these end points. In support of this concept, when data on CHD risk factors were updated over time, the relationship with fatal CHD was almost completely attenuated and the trend for SCD persisted. The lower prevalence of CHD among women who suffer SCD found in autopsy and cardiac arrest survivor series may provide a potential explanation for this finding. 26 Finally, symptoms of phobic anxiety may lead to unhealthy lifestyle habits, such as smoking and physical inactivity, which in turn increase the risk of CHD. If such behaviors lie in the causal pathway between anxiety and CHD, then treating them as confounding variables, as was done in the multivariable analyses, might underestimate the overall impact of phobic anxiety on CHD risk. 27 There are several limitations of the present study. As described above, phobic anxiety was directly related to several CHD risk factors, and residual confounding by these risk factors could account for at least part of the association between phobic anxiety and SCD and fatal CHD. Also, phobic anxiety might affect adherence to medical therapies, which could not be controlled for in this analysis. However, if confounding by CHD risk factors and/or medical adherence accounted for all of the association, one would also expect to have observed a positive association between phobic anxiety and nonfatal MI. Another important limitation of the study is the single measure of phobic anxiety, and therefore, the inability to account for changes in phobic anxiety over time, which would tend to obscure associations if the effect is of short duration. However, the score on the Crown-Crisp index was significantly associated with benzodiazepine use 12 years later, supporting the concept that phobic disorders tend to be chronic in nature. 28 Also, we did not find any evidence that associations diminished with increasing length of followup. In contrast, the association appeared to increase for SCD. Finally, this was a relatively healthy population of predominately Caucasian female registered nurses (approximately 96%) who were free of CVD and cancer at study entry, with a relatively low CHD event rate. Therefore, it is unclear whether these results would be generalizable to non- Caucasian or other less healthy populations. However, despite the selective nature of the cohort, we believe that these data represent an important addition to the previous published studies in men, especially given the higher prevalence of phobic and/or anxiety disorders in women. In summary, these prospective data suggest that higher levels of phobic anxiety are associated with an increased risk of fatal CHD, particularly from SCD, but not nonfatal MI. Some but not all of this risk can be accounted for by CHD risk factors and lifestyle factors associated with phobic anxiety. If phobic and/or anxiety disorders increase the risk for SCD in women, then the public health importance of such a finding could be quite substantial. In one general population sample, the prevalence estimates for agoraphobia, simple phobia, and social phobia were 9.0%, 15.7%, and 16.5%, respectively, among women, and rates were twice as high as among men. 8 Prevalence estimates for generalized anxiety disorder are approximately 5% in the general population, and again, the prevalence is estimated to be 2 to 3 times higher in women than in men. 7 Attention and resources directed at the recognition, diagnosis, and treatment of these disorders could potentially reduce SCD incidence in otherwise healthy populations. Acknowledgments This study was supported by the Charles A. Dana Foundation s Brain-Body Invitational Award and by grants HL and CA from the National Institutes of Health. We are indebted to the participants in the Nurses Health Study for their outstanding commitment and cooperation and to Lisa Dunn, Barbara Egan, Karen Corsano, and Gary Chase for their expert and unfailing assistance. We are also indebted to Rimma Dushkes for her technical assistance in preparing the manuscript. References 1. Rozanski A, Blumenthal JA, Kaplan J. Impact of psychological factors on the pathogenesis of cardiovascular disease and implications for therapy. Circulation. 1999;99: Kubzansky LD, Kawachi I. Going to the heart of the matter: negative emotions and coronary heart disease. J Psychosom Res. 2000;48: Coryell W, Noyes R, Hause JD. Mortality among outpatients with anxiety disorders. Am J Psychiatry. 1986;143: Haines AP, Imeson JD, Meade TW. Phobic anxiety and ischaemic heart disease. BMJ. 1987;295: Kawachi I, Colditz GA, Ascherio A, Rimm Eric B, Giovannucci E, Stampfer MJ, Willett WC. Coronary heart disease/myocardial infarction: prospective study of phobic anxiety and risk of coronary heart disease in men. Circulation. 1994;89:

8 Albert et al Phobic Anxiety and Risk of CHD and SCD in Women Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Coronary heart disease/ myocardial infarction: symptoms of anxiety and risk of coronary heart disease: the Normative Aging Study. Circulation. 1994;90: Wittchen HU, Zhao S, Kessler RC, Eaton WW. DSM-III-R generalized anxiety disorder in the National Comorbidity Survey. Arch Gen Psychiatry. 1994;51: Magee WJ, Eaton WW, Wittchen HU, McGonagle KA, Kessler RC. Agoraphobia, simple phobia, and social phobia in the National Comorbidity Survey. Arch Gen Psychiatry. 1996;53: Crown S, Crisp AH. A short clinical diagnostic self-rating scale for psychoneurotic patients: the Middlesex Hospital questionnaire. Br J Psychiatry. 1956;112: Burgess PM, Mazzocco L, Campbell IM. Discriminant validity of the Crown-Crisp experimental index. Br J Psychiatry. 1987;60: Rose GA, Blackburn H. Cardiovascular Survey Methods. WHO Monograph Series No. 58. Geneva, Switzerland: World Health Organization; Albert CM, Chae CU, Grodstein F, Rose LM, Rexrode KM, Ruskin JN, Stampfer MJ, Manson JE. Prospective study of sudden cardiac death among women in the United States. Circulation. 2003;107: Hinkle L, Thaler HT. Clinical classification of cardiac deaths. Circulation. 1982;65: Lown B, Verrier RL, Corbalan R. Psychological stress and threshold for repetitive ventricular response. Science. 1973;182: O Malley PG, Jones DL, Feuerstein IM, Taylor AJ. Lack of correlation between psychological factors and subclinical coronary artery disease. N Engl J Med. 2000;343: Greenberg HM, Dwyer EM, Hochman JS, Steinberg JS, Echt DS, Peters RW. Interaction of ischaemia and encainide/flecainide treatment: a proposed mechanism for the increased mortality in CAST1. Br Heart J. 1995;74: Kawachi I, Sparrow D, Vokonas PS, Weiss ST. Decreased heart rate variability in men with phobic anxiety (data from the Normative Aging Study). Am J Cardiol. 1995;75: La Rovere MT, Pinna GD, Maestri R, Mortara A, Capomolla S, Febo O, Ferrari R, Franchini M, Gnemmi M, Opasich C, Riccardi PG, Traversi E, Cobelli F. Short-term heart rate variability strongly predicts sudden cardiac death in chronic heart failure patients. Circulation. 2003;107: Makikallio TH, Huikuri HV, Makikallio A, Sourander LB, Mitrani RD, Castellanos A, Myerburg RJ. Prediction of sudden cardiac death by fractal analysis of heart rate variability in elderly subjects. J Am Coll Cardiol. 2001;37: Leor J, Poole WK, Kloner RA. Sudden cardiac death triggered by an earthquake. N Engl J Med. 1996;334: Kop WJ, Krantz DS, Nearing BD, Gottdiener JS, Quigley JF, O Callahan M, DelNegro AA, Friehling TD, Karasik P, Suchday S, Levine J, Verrier RL. Effects of acute mental stress and exercise on T-wave alternans in patients with implantable cardioverter defibrillators and controls. Circulation. 2004;109: Haines A, Cooper J, Meade TW. Psychological characteristics and fatal ischaemic heart disease. Heart. 2001;85: Hayward C, Taylor CB, Roth WT, King R, Agras WS. Plasma lipid levels in patients with panic disorder or agoraphobia. Am J Psychiatry. 1992; 142: Anderson RJ, Grigsby AB, Freedland KE, de Groot M, McGill JB, Clouse RE, Lustman PJ. Anxiety and poor glycemic control: a meta-analytic review of the literature. Int J Psychiatry Med. 2002;32: Jonas BS, Franks P, Ingram DD. Are symptoms of anxiety and depression risk factors for hypertension? Longitudinal evidence from the National Health and Nutrition Examination Survey I Epidemiologic Follow-up Study. Arch Family Med. 1997;6: Albert CM, McGovern BA, Newell JB, Ruskin JN. Sex differences in cardiac arrest survivors. Circulation. 1996;93: Hemingway H, Marmot M. Psychosocial factors in the aetiology and prognosis of coronary heart disease: systematic review of prospective cohort studies. BMJ. 1999;318: Robins LN, Locke BZ, Regier DA. Overview: psychiatric disorders in America. In: Robins LN, Regier DA (eds). Psychiatric Disorders in America. New York, NY: Free Press; 1991: