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ORIGINAL ARTICLES |
From the Departments of Psychiatry and Behavioral Sciences (L.L.W., J.A.B., J.R.T.D., M.A.B.) and Medicine (C.B.M., M.H.S.), Duke University, Durham, North Carolina.
Address correspondence and reprint requests to Lana L. Watkins, PhD, Department of Psychiatry and Behavioral Sciences, Box 3119, Duke Medical Center, Durham, NC 27710. E-mail: watki017{at}mc.duke.edu
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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Methods: Phobic anxiety level was measured using the Crown-Crisp phobic anxiety scale in 940 patients (660 men, 280 women) hospitalized for diagnostic cardiac catheterization between April 1999 and June 2002. Depressive symptomatology was assessed using the Beck Depression Inventory. Patients were followed for a median follow-up period of 3 years, and the occurrence of ventricular arrhythmias was determined through review of medical records.
Results: Ventricular arrhythmias occurred in 97 patients and were significantly related to higher phobic anxiety after statistical adjustment for established medical and demographic determinants of arrhythmias (odds ratio = 1.40; p = .012). Depressive symptomatology was significantly correlated with phobic anxiety (r = 0.44, p < .001) and was also related to ventricular arrhythmias (odds ratio = 1.40; p = .006). The composite of depression and phobic anxiety predicted ventricular arrhythmias with a larger effect size than either depression or phobic anxiety score alone (odds ratio = 1.6, 95% confidence interval, 1.2–2.1, p = .002).
Conclusions: Both phobic anxiety and depressive symptomatology predict ventricular arrhythmias in patients with CAD and may share a common factor predictive of ventricular arrhythmias.
Key Words: phobic anxiety • coronary disease • sudden death • arrhythmias
Abbreviations: CAD = coronary artery disease; SCD = sudden cardiac death; MI = myocardial infarction; LVEF = left ventricular ejection fraction; BDI = Beck Depression Inventory; NSVT = nonsustained ventricular tachycardia; susVT = sustained ventricular tachycardia; V-fib = ventricular fibrillation; BMI = body mass index; ICD = internal cardiodefibrillator device.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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Phobic anxiety, measured from the eight-item phobic anxiety subscale of the Crown-Crisp experiential index, appears to be particularly predictive of mortality, with relative risks ranging from 3.0 to 3.8 (4,5). The majority of the items on the phobic subscale are related to symptoms of agoraphobia (concerns of going out alone, concerns of being in crowds) and simple phobias (fear of heights) with some association with generalized anxiety disorder (worrying when relatives are late coming home). Validity studies have shown that elevated scores on the phobic anxiety subscale successfully discriminate phobic disorders from other diagnostic groups in psychiatric patients (9,10).
One mechanism proposed to explain the adverse effects of phobic anxiety on mortality is an increased vulnerability to arrhythmias. This mechanism is supported by findings that phobic anxiety increases the risk of sudden cardiac death (SCD), defined as death within 1 hour of symptom onset (4). An arrhythmic mechanism is also supported by the known relationship between anxiety and increased sympathetic and decreased parasympathetic cardiac control (11–17). To date, however, there have been no prior studies in which the relationship between phobic anxiety and ventricular arrhythmias has been directly examined.
The primary goal of the present study was to evaluate whether phobic anxiety is associated with ventricular arrhythmias. Findings of a relationship between phobic anxiety and ventricular arrhythmias would lend support to the hypothesis that an arrhythmic mechanism underlies the increased risk of SCD observed with high phobic anxiety. A secondary goal of this study was to determine whether the association between phobic anxiety and arrhythmias is independent of the effects of comorbid depression.
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METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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As shown in Figure 1, 8028 of the 9162 patients undergoing left heart cardiac catheterization during this period were available for screening, and approximately 75% of these patients did not qualify for the study. The leading reason for excluding patients was insignificant CAD, which was found in 2549 patients. An additional 2159 patients were excluded because they had experienced an acute MI and/or revascularization procedure in the prior month, 736 were excluded because medical chart review indicated that they were not in normal sinus rhythm at the time of enrollment, and 627 were not approached because of medical, physical, or psychiatric complications that would affect the patient's ability to participate in the interview (e.g., ventilator-dependency, stroke-related aphasia, language conflict, psychosis). Approximately half of the remaining qualified patients declined to participate (n = 1003). Of the 954 enrolled patients, 14 patients were unable to complete the phobic anxiety scale as a result of time constraints, leaving 940 patients for the primary analyses. During the follow-up period, an additional 39 patients withdrew or were lost to follow up over the follow-up period; however, partial information (median of 2 years of follow up) was available for 31 of these patients. There were no differences in age, race, left ventricular ejection fraction (LVEF), or MI history between the enrolled patients and the patients who were eligible but refused to take part in the study; however, the group who refused to participate contained a significantly larger number of females (38% female versus 30% female; p < .05).
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Assessment of Phobic Anxiety
Phobic anxiety was measured using the phobic anxiety subscale of the Crown-Crisp experiential index (18), a self-rating scale containing eight questions primarily related to agoraphobia and simple phobias (for example, "Do you dislike going out alone?" and "Are you scared of heights?"). For each question, there are two to three levels of possible responses (with values ranging from 0–2), allowing total scores to range from zero to 16. The phobic anxiety subscale has been shown to have acceptable internal reliability (19) and moderate discriminant validity (10,18,20).
The eight questions were administered to patients by a trained research assistant during hospitalization for coronary angiography. In 65% of patients, the phobic scale was administered on the same day as coronary angiography; in the remaining patients, the scale was administered 1 to 4 days after angiography. There were no differences in phobic anxiety scores between patients evaluated on the day of coronary angiography and the remaining patients. Because one of the eight questions on the phobic scale asks about worries related to medical illness ("Do you find yourself worrying about getting some incurable illness?"), we asked the patients to consider only noncardiac illnesses to minimize the impact of their coronary disease on the phobic anxiety score.
Assessment of Depressive Symptomatology
Depressive symptomatology was measured using the original version of the Beck Depression Inventory (BDI). The BDI is a 21-item self-report rating inventory that measures characteristic symptoms of depression for a total depression score ranging from zero to 72 (21). A score of 10 or greater is considered a cutoff for clinically significant depression (22). In this sample, BDI scores ranged from zero to 46 (mean: 7.3, median: 6.0, standard deviation [SD]: 6.6). Twenty-eight percent of the BDI scores were greater than 10. BDI scores were significantly correlated with phobic anxiety scores (r = 0.44, p < .001).
Cardiac Variables
At the time of enrollment, cardiac catheterization results were used to determine LVEF and the number of coronary arteries with 
75% stenosis. A composite estimate of the extent of CAD was also derived from the Duke CAD index, an anatomically derived index based on the number of diseased vessels, the extent of disease in each vessel, the percent stenosis of the proximal left anterior descending artery, and the presence/absence of left main disease (23). Data describing how the patient was treated (medically, percutaneous transluminal coronary angioplasty, or coronary bypass grafting surgery), type of medications, comorbid conditions, and cardiovascular risk factors (lipid profile, smoking history, body weight, blood pressure) were obtained from medical records.
End Points
Patients were contacted by telephone at 6 months, 1 year, and annually thereafter for up to 4 years from the time of phobic anxiety assessment to identify rehospitalizations. If patients were unavailable at the time of the follow-up call, information regarding hospitalizations was gathered from the next of kin. Discharge summaries (and when necessary for clarification, admission history, emergency room notes, electrocardiograms, and daily progress reports) were obtained for each hospitalization reported by the patient; this included hospitalizations outside of Duke. Retrieval of medical records was completed in 901 patients; 39 patients withdrew or were lost during the follow-up period; therefore, only partial information was available for those 39 patients. The mean follow-up period for the cohort as a whole was 34 ± 13 months (median follow-up period: 36 months) and ended for all patients in June 2004. Predefined primary end points were major arrhythmic events defined as nonsustained ventricular tachycardia (NSVT), sustained ventricular tachycardia (susVT), or ventricular fibrillation (V-fib). Although less serious than the sustained arrhythmias, the occurrence of NSVT has been associated with increased risk of mortality independently of left ventricular dysfunction (24,25). Arrhythmia information was obtained from review of medical records from all cardiac hospitalizations reported by patients, including the hospitalization period during which they were enrolled and each subsequent hospitalization during the follow-up period. All staff involved in gathering and classifying arrhythmia information was blinded to the anxiety status of the individual.
Statistical Analysis
As a preliminary analysis, we examined the correlates of phobic anxiety using chi-squared tests or Pearson correlations as appropriate. We also examined the correlates of ventricular arrhythmias. To estimate the relation between phobic anxiety and the risk of arrhythmia, we conducted a logistic regression with the continuous phobic anxiety score as the predictor of interest. We selected LVEF, age, gender, minority status, and history of arrhythmias a priori as covariables in the model. Continuous variables (ie, phobic anxiety, age, and LVEF) were centered and scaled to their interquartile range. This rescaling produces an odds ratio that compares a typical patient in the middle of the upper half of the predictor's distribution with a typical patient in the middle of the lower half of the distribution. All predictors were maintained in the model regardless of statistical significance. Further covariables were not included in the model to prevent overfitting (26). Additional analyses were conducted to evaluate the contribution of depression symptomatology to the phobic anxiety/ventricular arrhythmia relationship. In these analyses, the BDI score was added to the model in the presence and absence of the phobic anxiety score. In addition, the combined effects of depression and anxiety were evaluated by evaluating the predictive value of a composite index of BDI and phobic anxiety created by converting the BDI and phobic anxiety scores to z-scores (ie, standardizing the scores to a mean of zero and a SD of one) and adding them together with unit weighting.
To optimize the power of the logistic regression model, we included all follow-up data regardless of the length of follow up and also included an offset term that accounts for individual differences in follow-up time. Following Harrell, we conducted preliminary analyses in which we examined the assumptions of linearity (using splines and residual plots), additivity (testing interactions using a pooled test), and influential data points (using Harrell's, which influence function in S-Plus). All assumptions were reasonably met. We also estimated the internal validity of the model using bootstrap.
Solely for the purposes of facilitating comparisons for a clinical perspective, phobic anxiety scores were categorized by tertiles, resulting in "low," "medium," and "high" phobic anxiety corresponding to phobic anxiety scores of zero to 1 (reference category), 2 to 3, and 4. The categories were then compared with respect to potential correlates with a one-way analysis of variance using Tukey's HSD test as a follow-up test (see Table 1).
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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During the enrollment hospitalization, 57% were treated medically, 27% of the patients underwent coronary artery bypass grafting, and 16% underwent percutaneous transluminal coronary angioplasty. Of the 940 patients enrolled, 4 had pacemakers, 2 had combined pacemaker/internal cardiodefibrillator (ICD) devices, and 9 had ICD devices. Prescribed medications were as follows: beta-blockers (80%), angiotensin converting enzyme-inhibiting drugs (69%), lipid-lowering drugs (63%), long-lasting nitrates (46%), diuretics (37%), calcium channel blockers (23%), digitalis-like drugs (8%), antiplatelet drugs (9%), coumadin (6%), and antiarrhythmics (2%). In addition, 20% of the cohort was taking antidepressants (defined as drugs that work through inhibition of serotonin and/or norepinephrine metabolism) and 12% were taking antianxiety medications (defined as benzodiazepines, nonbenzodiazepine hypnotic agents, and anxiolytic drugs from the azaspirodecanedione class such as buspirone).
Correlates of Phobic Anxiety
Scores on the phobic anxiety scale were positively skewed and spanned the full range of the phobic anxiety scale (from zero to the maximum possible score of 16). Women reported higher phobic anxiety than men (women: 4.1 ± 3.2, n = 286; men: 2.5 ± 2.4, n = 654; correlation with female gender: r = 0.24, p < .0001). Phobic anxiety scores were also affected by minority status (r = 0.08, p = .002) and body mass index (BMI) (r = 0.10, p = .002). Approximately half of the patients with phobic anxiety scores in the highest tertile were obese (defined as a BMI of 30 kg/m2) compared with one third of the patients with scores in the lowest tertile. Patients with higher phobic anxiety scores were also more likely to be younger (r = –0.13, p < .0001) and to have less severe CAD, as estimated by the Duke CAD anatomic index (r = –0.06, p = .023). Phobic anxiety was unrelated to LVEF (r = –0.004, p = .91) or to systolic blood pressure (r = –0.01, p = .76) and tended to be related to lower diastolic blood pressure (r = –0.06, p = .057).
Phobic anxiety was significantly correlated with use of antianxiety and antidepressant medications (r = 0.11, p = .001; r = 0.18, p < .0001, respectively). Phobic anxiety was also significantly correlated with use of antihypertensive drugs (diuretics: r = 0.08, p = .016; calcium channel blockers: r = 0.10, p < .002). In addition, phobic anxiety was related to the presence of a history of hypertension (r = 0.10, p < .002), but was unrelated to duration of treatment of hypertension. There was no relationship between phobic anxiety and use of antiischemic medications. Table 1 illustrates the demographic and clinical differences in patients with "low," "medium," and "high" phobic anxiety based on a tertile split of the phobic anxiety scores.
Correlates of Ventricular Arrhythmias
Ventricular arrhythmias were documented in 97 of the 940 patients (10.3%). Roughly half (47%) of these patients had a history of arrhythmias. Univariate analyses showed that history of arrhythmias (r = 0.30, p < .0001), low LVEF (r = –0.24, p < .0001), and age (r = 0.09, p = .006) were predictors of ventricular arrhythmias. Male gender and minority status were not significantly related to ventricular arrhythmias (p = .11 and .14, respectively). Fifty-two patients experienced ventricular arrhythmias during the enrollment hospitalization; these arrhythmic events were predominantly asymptomatic short runs of NSVT, although 14 patients experienced sustained ventricular tachycardia and three patients experienced ventricular fibrillation during the enrollment hospitalization. After discharge from the enrollment hospitalization, there were an additional 59 arrhythmic events; 13 of these occurred in patients with ventricular arrhythmias during their enrollment hospitalization. The arrhythmic events occurring after discharge were primarily sustained arrhythmias (64% of the arrhythmias were susVT and/or V-fib).
Logistic regression modeling revealed that phobic anxiety was significantly related to ventricular arrhythmias after adjusting for the clinical and demographic predictors of arrhythmias (LVEF, age, gender, minority status, and history of arrhythmias). The odds ratio (OR), scaled to a three-point increase in phobic anxiety, was 1.4 (95% confidence interval [CI], 1.1–1.8, p = .012). Among the adjustment covariables, history of arrhythmia was the strongest predictor of later arrhythmia (OR: 12.0; p < .0001) followed by LVEF (OR: 0.28; p < .0001) and age (OR: 1.5, p = .003). Being male was associated with higher likelihood of arrhythmia (OR: 1.8), but was not statistically significant (p = .065); similarly, minority status (vs. whites) was positively associated with arrhythmia (OR: 1.6), but also was not statistically significant (p = .103). The internal validity of the model was good with a bootstrap corrected R-square of 0.146 compared with a naïve R-square value of 0.166, indicating only small optimism (approximately 0.02) in the model fit.
Four percent (n = 39) of patients withdrew or were lost to follow up over the follow-up period; however, partial (average of 2 years of follow up) was available for 31 of these patients. Not including the 39 individuals with missing follow-up data did not alter the relationship between phobic anxiety and arrhythmias (OR for phobic anxiety: 1.4, p = .020).
To evaluate the potential contribution of comorbid depression to the association between phobic anxiety and ventricular arrhythmias, BDI score was added to the model containing the clinical and demographic predictors of arrhythmias (LVEF, age, gender, minority status, and history of arrhythmias). BDI scores were available for 97% of the patients (n = 916). In this subset of patients, BDI score was a predictor of arrhythmias with an OR of 1.4 (95% CI, 1.1–1.9, p = .006). When phobic anxiety was added to this model, neither phobic anxiety nor BDI score was a significant predictor of arrhythmias (phobic anxiety—OR: 1.3, 95% CI, 0.98–1.8, p = .11; BDI score—OR: 1.3, 95% CI, 0.99–1.7, p = .054). This mutual decrement in effect size and increase in standard error reflects the correlation between the two predictors and, when taken together with the fact that the variables predict in isolation, suggests that they share predictive power. To explore this issue further, we examined the predictive value of a composite index of BDI and phobic anxiety. This composite score predicted ventricular arrhythmias with a slightly larger effect size than either the BDI or phobic anxiety score alone (OR: 1.6, 95% CI, 1.2–2.1, p = .002), suggesting that phobic anxiety and depression share a common factor predictive of ventricular arrhythmias.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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The current findings that the magnitude of the relationship between phobic anxiety and ventricular arrhythmias is attenuated after adjusting for the effects of depression suggest that part of the effects of phobic anxiety may be attributable a factor shared with comorbid depression. Similarly, the relationship between depression and ventricular arrhythmias was weakened by adjustment for phobic anxiety. A unit-weighted composite of phobic anxiety and depression exhibited a somewhat larger relation with ventricular arrhythmias than either variable in isolation. Taken together, these findings imply that phobic anxiety and depression share a component that is predictive of arrhythmias and that the composite may have captured the underlying shared construct more reliably or perhaps more comprehensively. A role for stress or negative affect is supported by evidence from laboratory-based studies in which mental stress increases the frequency of ventricular premature beats (27). Self-reported distress has also been associated with increased ventricular ectopy in post-MI patients and in patients with congestive heart failure (28,29).
Classification of cardiac deaths as sudden or nonsudden is intrinsically difficult as a result of the fact that many cardiac deaths are unwitnessed and the duration of symptoms is not ascertainable. In the absence of precise subjective and clinical information (e.g., chest pain, cardiac enzymes, electrocardiography changes), it is often not possible to know with certainty whether underlying ischemia or pulmonary emboli can be ruled out as the precipitating cause of death. This lack of precision may explain why several large prospective studies have found the anxiety-SCD relationship to become nonsignificant after adjustment for potential confounding variables (3,5,30). The present findings suggest that an arrhythmic mechanism underlies, at least in part, the excess risk attributable to phobic anxiety.
The magnitude of risk of arrhythmias associated with phobic anxiety in the present study (OR: 1.4) was lower than the risk of mortality reported by earlier studies in male cohorts (4,5). For example, Haines et al. reported that men who scored a 2, 3 to 4, or 5 (of a maximum possible score of 16) on the phobic anxiety scale showed a relative risk of cardiac mortality of 1.3, 2.5, and 3.8, respectively, compared with men who scored zero or 1 (5). Similar magnitudes of risk of mortality and SCD were reported by Kawachi et al. in the U.S. male health professional study of 33,999 men (4). The lower risk estimates found in this study may be attributable to the fact that medically treated patients with CAD were evaluated rather than community-dwelling men; ß-blockers are well-known to protect against arrhythmias (31), and the majority of patients in this study (80%) were taking ß-blockers. The lower estimates of risk of arrhythmias found in the current study may also be in part the result of the fact that approximately one third of the current cohort was women. A recent evaluation of the effects of phobic anxiety on SCD in the Nurses' Health Study cohort showed that women with high phobic anxiety show substantially lower levels of SCD risk attributable to phobic anxiety than reported in male cohorts (phobic anxiety scores 4 were associated with a relative risk of 1.45 when compared with women who scored a zero or 1) (30).
Although the present study found a significant relationship between phobic anxiety and arrhythmia risk, there was no evidence that patients with phobic anxiety had a greater number of cardiac risk factors or more severe cardiovascular disease. These findings are consistent with previous evidence that individuals with high anxiety tend to be seek health care more readily and are more vigilant of somatic symptoms (32). There was also no evidence that the risk attributable to phobic anxiety in the current study was secondary to difference in medications as beta-blocker use and antiarrhythmic medication use was similar in patients with low and high levels of phobic anxiety.
The current findings of a relationship between phobic anxiety and ventricular arrhythmias are consistent with previous findings of a relationship between anxiety and increased mortality (3–5,8); however, they contrast with findings of one study that reported an association between anxiety and lower mortality in 5057 men and women referred for routine exercise testing (33). In this study, the reduced mortality associated with anxiety was maintained after adjusting for several predictors of mortality primarily derived from the exercise tolerance test; however, because coronary angiograms were not performed, it was not possible to determine whether the anxious group showed less CAD. Patients with elevated anxiety who are referred for diagnostic cardiac catheterization are more likely to be free of underlying significant angiographic coronary disease than patients with lower anxiety; therefore, it is likely that the lower mortality associated with anxiety in this group may have been secondary to less severe CAD (34).
One limitation of the present study is that level of phobic anxiety may have been influenced by arrhythmias or other events occurring during the enrollment hospitalization. However, phobic anxiety is a stable measure of an individual's tendency to respond to certain environmental situations (fear of heights, fear of crowded places, fear of using public transportation) as anxiety-provoking and is therefore considered to be influenced little by events related to the hospitalization. In the current study, phobic anxiety levels were not different in patients evaluated before versus after cardiac catheterization. It is also unlikely that the occurrence of arrhythmias altered phobic anxiety level because in the majority of cases, the arrhythmias that occurred during the enrollment hospitalization were asymptomatic NSVT and therefore not observed by the patient. Finally, phobic anxiety was unrelated to the length of follow up (p = .89), suggesting that it is unlikely that the relationship between phobic anxiety and arrhythmia is confounded by length of follow up and consequent number of rehospitalizations.
A second limitation of the present study is that we assessed phobic anxiety using a self-report scale of phobic anxiety symptoms rather than interviewing patients to establish the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition-based psychiatric diagnoses. Early validation studies have demonstrated that high scores on the phobic subscale of the Crown-Crisp experiential index discriminate psychiatric patients with and without phobic symptoms (9,10) and that the phobic anxiety scale differentiates anxiety and phobic neuroses from obsessive-compulsive and depressive neuroses (p < .01) (9). There is also some evidence that high phobic anxiety is found in patients with panic disorder and leads to the avoidance of specific fear-provoking situations (35). Taken together with findings of a relationship between acute increases in psychological stress and ventricular ectopy reported by Lown and colleagues (27), these findings suggest that situational or environmental triggers may trigger autonomic symptoms (blood pressure, heart rate, respiratory rate changes) that could precipitate arrhythmias.
In summary, the present findings suggest that both phobic anxiety and depressive symptomatology are associated with increased risk of arrhythmias in patients with CAD. Findings that the composite of phobic anxiety and depression predict ventricular arrhythmias more strongly than each alone suggests that depression and phobic anxiety share a common factor predictive of arrhythmias. These findings support an arrhythmic mechanism underlying the increased risk of cardiac mortality associated with phobic anxiety and depression.
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NOTES |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONNOTESREFERENCES |
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Received for publication June 29, 2005; revision received April 18, 2006.
DOI:10.1097/01.psy.0000228342.53606.b3
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