Methods

The Determinants of Myocardial Infarction Onset Study (MIOS) was a multicenter cohort study of patients with confirmed AMI. In the first phase of the MIOS (August 1989 to September 1994), 1,937 patients were enrolled in 45 community hospitals and tertiary care medical centers in the United States. In the second phase (October 1994 to September 1996), the study was expanded to 64 medical centers across the United States, and an additional 1,949 patients were enrolled. Altogether, 3,886 patients (2,627 men and 1,259 women, mean age 61.4 years) were interviewed a median of 4 days (range 0 to 30) after sustaining an AMI. For inclusion in the study, the patients were required to meet all the following criteria: English-speaking, ≥1 creatine kinase level greater than the upper limit of normal for the clinical laboratory performing the test, positive MB isoenzymes, an identifiable onset of pain or other symptoms typical of infarction, and the ability to complete a structured interview. The institutional review board at each participating center approved the protocol, and each patient provided informed consent.

As previously described, detailed chart reviews and patient interviews were conducted by trained research personnel. Standard demographic and risk factor data were collected for coronary artery disease (CAD). The interview identified the time, place, and quality of the AMI pain and other symptoms. If the patients reported that they had experienced any chest pain in the week preceding the acute onset, they were classified as having premonitory symptoms. The subjects were also asked to report the timing of their last exposure to several potential triggers and to estimate the usual frequency of these factors in the year preceding AMI onset. We used the onset anger scale to measure the outbursts of anger. The patients were shown a chart of 7 levels of anger and reported the timing of their last episode of anger at each level and their usual frequency of anger outbursts at each level in the previous year. They were also asked about their anger levels during each of the 26 hours before AMI onset. The patients were considered exposed if they reported an anger level of ≥5 during the window of interest. In another study, 25 subjects completed the onset anger scale at admission for ischemic stroke, and they were interviewed again within 6 days. The intraclass correlation for the usual frequency of anger outbursts was excellent (0.93).

The State-Trait Personality Inventory (STPI) is a well-validated measure with strong psychometric properties. It consists of six 10-item self-report scales for measuring state and trait anxiety, anger, and curiosity. The subjects reported how often they experienced a particular feeling by rating themselves using a 4-point frequency scale: (1) almost never, (2) sometimes, (3) often, and (4) almost always. The 10-item scale measuring anger during the 24 hours before AMI was used as an indicator of a tendency toward anger feelings. Although cutoff values that relate to clinical diagnostic categories have not been established, a score of >11 points on the anger scale and 21 points on the anxiety scale corresponded to the 75th percentile of the scores in our sample.

The MIOS used a case-crossover design, a variation of the case-control design appropriate when a transient exposure (outbursts of anger) is associated with an acute change in the risk of an acute outcome (nonfatal AMI). Because the control information for each subject was determined from their own previous exposure experience, self-matching eliminated confounding by risk factors constant within the subjects during the sampling period but that often differ between study subjects. Because we have previously shown that the transiently increased AMI risk after episodes of anger extends for ≤2 hours, we compared a patient’s report of anger episodes in the 2 hours before AMI onset (the hazard period) with the same patient’s report of anger in the previous year (the control period). In a sensitivity analysis, we compared the scores from the onset anger scale in the 2 hours before AMI onset with the anger intensity in the same 2 hours on the day before the AMI (pair-matched intervals). We also performed a similar analysis for the STPI scores of anger adjusted for anxiety above the 75th percentile. Anger episodes were assumed to be rare enough that the hazard periods did not overlap.

Each subject in a case-crossover study formed their own stratum and thus was their own control. For the primary analysis, the ratio of the observed exposure frequency in the hazard period to the expected frequency using the control information about anger outbursts in the previous year was used to calculate estimates of the rate ratio as a measure of relative risk (RR). To calculate the expected frequency of exposure in the case period, we multiplied the usual annual frequency of anger outbursts by the hypothesized window of its physiologic effect (2 hours in the primary analysis) to estimate the amount of person-time exposed to anger. The unexposed person-time was calculated by subtracting this value from the number of hours in 1 year. The data were analyzed using methods for cohort studies with sparse data in each stratum. As a sensitivity analysis, we used conditional logistic regression to compare each patient’s exposure during the hazard period to their exposure at the same point on the day before AMI onset.

We examined whether the triggering effect was greater for higher anger levels in the 2 hours before AMI onset compared with the risk for lower anger levels by estimating the RR for levels 4, 5, 6, and 7 on the onset anger scale and testing for a linear component of trend using a chi-square test for linear trend. We then calculated the incremental change in risk for each unit increase in anger. We stratified the patients by the demographic, clinical, pharmacologic, psychological, and behavioral factors and compared the RRs using a Wald test for homogeneity. The potential modifiers included gender, age (<50, 50 to 69, and ≥70 years), educational attainment (less than high school, completed high school, some college), previous CAD (defined as a history of AMI or angina pectoris), diabetes, hypertension (yes/no), aspirin use, β-blocker use (yes/no), trait anger score less than versus greater than the 75th percentile, weekly physical activity (<3 vs ≥3 times per week), and coffee intake (0, 1 to 4, ≥5 times per week). We conducted several sensitivity analyses. In the first sensitivity analysis, we restricted the analysis to participants reporting no other potential triggers (i.e., physical activity, caffeine, alcohol, tobacco) in the 2 hours before AMI onset. It is possible that premonitory symptoms evoke feelings of anger rather than the anger eliciting AMI onset, resulting in reverse causation bias. Therefore, we conducted a sensitivity analysis restricted to the participants who reported no premonitory symptoms. In the final sensitivity analysis, we conducted separate analyses for each phase of the study. All reported p values are 2 sided.

Results

The population characteristics are listed in Table 1 . Of the 3,886 study participants, 1,484 (38%) reported outbursts of anger in the previous year. Of these 1,484 participants, 617 (42%) reported that the outbursts occurred less than once per month, 271 (18%) reported outbursts more than once per month, 340 (23%) reported outbursts more than once per week, and 256 (17%) reported outbursts at least daily. Of the 3,886 participants, 110 (2.8%) reported episodes of anger in the 2 hours before AMI onset. The most frequent causes of anger outbursts were family (38%), conflicts at work (25%), and commuting (6%).

The risk of AMI was 2.43 (95% confidence interval [CI] 2.01 to 2.90; p <0.001) times higher in the 2 hours after self-reported outbursts of moderate or extreme anger compared with at other times. Rather than a similar risk at any level of self-reported moderate or high anger, Figure 1 shows a dose–response relation, with greater AMI risk for each increment in anger intensity (p for trend <0.001). Compared with other times, the risk of AMI was greater in the 2 hours after feeling “moderately angry, so hassled it shows in your voice” (RR 1.68, 95% CI 1.39 to 2.03). The association was even greater after feeling “very angry, body tense, clenching fists or teeth” (RR 2.27, 95% CI 1.83 to 2.82) and after feeling “furious, almost out of control, very angry, pound table, slam door” (RR 2.91, 95% CI 1.97 to 4.30). The risk was strongest after feeling “enraged! lost control, throwing objects, hurting yourself or others” (RR 4.50, 95% CI 2.77 to 7.30).

RR for the risk of AMI in the 2 hours after anger episodes by the anger level according to the onset anger scale. Error bars indicate 95% CIs; dashed line , the baseline risk. The sample size represents the number of participants reporting anger at that level in the 2 hours before the index AMI.

Concordant with the original study, the RR was lower among regular users of β blockers than among nonusers. The RR was lower among those with a CAD history than among those without a CAD history. Even among those who were not regular β-blocker users, the RR was lower among the patients with a CAD history (RR 1.83, 95% CI 1.17 to 2.85) than those without a CAD history (RR 3.08, 95% CI 2.45 to 3.88; p for homogeneity = 0.02). No other statistically significant differences by any of the other prespecified potential modifiers were observed ( Table 2 ). We did not have enough data to further stratify these subgroups to determine whether other patient characteristics were responsible for the heterogeneity in the observed RRs. In a sensitivity analysis restricted to participants who did not report exposure to other potential triggers (i.e., physical activity, caffeine, alcohol, tobacco) in the 2 hours before AMI onset, the association was less but remained statistically significant (RR 1.88, 95% CI 1.46 to 2.42; p <0.001); the associations were also less but remained statistically significant in the sensitivity analyses restricted to participants with no premonitory symptoms (RR 2.34, 95% CI 1.92 to 2.85; p <0.001). The results were similar for the first and second phases of the study.

Table 2

Relative risk (RR) and 95% confidence intervals (CIs) for acute myocardial infarction (AMI) within 2 hours of anger outburst according to patient characteristics

Characteristic	Exposed in Previous Year (n)	Exposed in Previous 2 h (n)	RR (95% CI)	p for Chi-Square Test for Homogeneity
All patients	3,886	110	2.43 (2.01–2.92)
Gender
Men	2,627	73	2.26 (1.79–2.84)	0.26
Women	1,259	37	2.83 (2.04–3.93)
Age (yrs)
<50	766	36	1.93 (1.36–2.72)	0.19
50–69	1,982	62	2.85 (2.23–3.64)
≥70	1,135	12	2.35 (1.40–3.96)
Education
Less than high school	924	32	3.54 (2.45–5.11)	0.03
Completed high school	2,161	52	1.96 (1.51–2.55)
Some college	801	26	2.67 (1.79–3.98)
Frequency of weekly activity
<3	3,264	73	2.20 (1.75–2.76)	0.11
≥3	622	37	3.05 (2.20–4.25)
Smoking status
Never smoker	1,017	25	2.56 (1.74–3.75)	0.79
Former smoker	1,558	29	2.17 (1.49–3.14)
Current smoker	1,278	55	2.49 (1.91–3.25)
Body mass index >30 (kg/m 2 )
Yes	986	36	2.37 (1.69–3.32)	0.89
No	2,859	73	2.42 (1.93–3.04)
History of diabetes
Yes	758	16	1.94 (1.20–3.13)	0.31
No	3,128	94	2.54 (2.07–3.11)
History of hypertension
Yes	1,698	47	2.56 (1.89–3.47)	0.63
No	2,188	63	2.33 (1.84–2.96)
History of AMI
Yes	1,005	19	1.71 (1.11–2.64)	0.08
No	2,808	88	2.65 (2.14–3.27)
History of angina pectoris
Yes	955	19	1.75 (1.12–2.71)	0.09
No	2,931	91	2.65 (2.15–3.25)
History of CAD (AMI or angina pectoris)
Yes	1,443	28	1.63 (1.14–2.33)	0.006
No	2,443	82	2.92 (2.34–3.65)
STPI score
<75th percentile	1,486	28	2.19 (1.53–3.14)	0.51
≥75th percentile	469	34	2.58 (1.83–3.64)
Aspirin
Yes	1,549	43	2.57 (1.91–3.45)	0.64
No	2,337	67	2.34 (1.84–2.98)
β Blocker
Yes	834	14	1.42 (0.87–2.32)	0.02
No	3,052	96	2.71 (2.21–3.32)

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