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Psychosomatics 49:309-316, July-August
doi: 10.1176/appi.psy.49.4.309
© 2008 Academy of Psychosomatic Medicine
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Pre-Existing Major Depression Predicts In-Hospital Cardiac Complications After Acute Myocardial Infarction

Jeff C. Huffman, M.D., Felicia A. Smith, M.D., Mark A. Blais, Psy.D., Amy M. Taylor, M.D., James L. Januzzi, M.D., and Gregory L. Fricchione, M.D.

Received January 19, 2007; accepted March 16, 2007. From the Dept. of Psychiatry and the Dept. of Cardiology, Massachusetts General Hospital; Boston, MA; and the Harvard Medical School, Boston, MA. Send correspondence and reprint requests to Jeff C. Huffman, M.D., Massachusetts General Hospital, 55 Fruit Street/Warren 1220C, Boston, MA 02114. e-mail: jhuffman{at}partners.org


  ABSTRACT

 
TOP
 ABSTRACT
INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
BACKGROUND: Depression (MDD) and anxiety have been associated with negative long-term outcomes among patients with acute myocardial infarction (MI). OBJECTIVE: The objective of the study was to determine whether MDD and anxiety preceding MI were associated with in-hospital post-MI cardiac complications. METHOD: Subjects (N=129) underwent psychiatric interviews within 72 hours of MI and were evaluated for five in-hospital cardiac complications (recurrent ischemia, ventricular arrhythmia, ventricular arrhythmia requiring intervention, congestive heart failure, and reinfarction). RESULTS: Current (pre-MI) MDD was a significant and independent predictor of all complications except recurrent ischemia on multivariate regression analysis. In contrast, pre-MI anxiety was not associated with complications. CONCLUSION: These findings underscore the importance of identifying and treating MDD in post-MI patients and those at risk for MI.


  INTRODUCTION

 
TOP
 ABSTRACT
 INTRODUCTION
METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 
Depression and anxiety have been associated with negative long-term outcomes among patients with acute myocardial infarction (MI). Post-MI depression is independently associated with cardiac mortality, approximately doubling the risk of death in the following year, after correction for other risk factors,1,2 and post-MI depression and anxiety have both been associated with increased rates of recurrent cardiac events over this time period.3,4 Nevertheless, there remain major and clinically important aspects of these syndromes that require further study.

First, the vast majority of post-MI depression studies have examined outcomes months and years after the index cardiac event, and there has been little study of the in-hospital effects of post-MI depression. However, the greatest risk of cardiac complications, recurrent cardiac events, and mortality is in the hours and days following MI, usually while the patient is still hospitalized. Depression has been associated with adverse effects on platelet activity, inflammation, and sympathetic nervous system activity,5 and these depression-related effects could increase the risk of cardiac complications during the tenuous post-MI period. Such considerations make the in-hospital impact of post-MI depression an important subject for study.

Furthermore, there has been minimal investigation of strictly diagnosed current major depression (MDD) among in-hospital post-MI patients (that is, patients with ongoing depression that meets full 2-week time criteria and preceded the onset of MI) because most studies have only measured depressive symptoms that are present after the MI.1 Such a distinction between current MDD and briefer depressive symptoms has important clinical implications. Antidepressants are clearly indicated and effective for current MDD in patients with MI;6 in contrast, there is no clear treatment for post-MI depressive symptoms that have been present only for days.

The effects of anxiety immediately preceding MI are also understudied. Longitudinal studies have found that initially healthy patients with elevated levels of anxiety have increased incidence of coronary artery disease (CAD) and acute cardiovascular events.7,8 Furthermore, persistent anxiety has been associated with decreased heart rate variability and abnormal autonomic nervous system activity,9,10 both of which could adversely affect outcomes in the post-MI period. Given these potential consequences of anxiety on cardiovascular outcome, the impact of preexisting anxiety (i.e., present in the days or weeks before MI) on in-hospital cardiac outcomes requires further investigation.

Accordingly, in this study, we evaluated post-MI patients within 72 hours of symptom onset for 1) current MDD, and 2) increased levels of pre-MI anxiety. We then determined whether these symptoms were associated with increased rates of in-hospital cardiac complications.


  METHOD

 
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 ABSTRACT
 INTRODUCTION
 METHOD
RESULTS
 DISCUSSION
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Procedures and Subjects
This prospective observational cohort study was approved by the Institutional Review Board of Massachusetts General Hospital.

Patients admitted to the Massachusetts General Hospital Coronary Care Unit or Cardiac Step-Down Unit between October 2003 and July 2005 with a primary diagnosis of MI were recruited within 72 hours of symptom onset for entrance into the study. Inclusion and exclusion criteria were similar to those of comparable studies of post-MI psychiatric syndromes.2,11,12 Specifically, eligible patients met at least two of the three following criteria of the World Health Organization13 and Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction14 for an acute MI: typical chest pain, elevated cardiac enzymes (troponin T >0.10 ng/ml or CPK-MB >1.5 times the upper limit of the normal range), and electrocardiographic (ECG) changes consistent with MI.

We excluded patients with peri-procedural MIs, those who had cognitive difficulties precluding informed consent or completion of a psychiatric interview, or those too medically unstable to complete the interview. Patients with current substance abuse or dependence (identified by the Structured Clinical Interview [SCID] for Diagnostic and Statistical Manual of Mental Disorders, 4th Edition [DSM–IV]15 modules for substance abuse and dependence) were also excluded to reduce the possibility of substance use as a cause of psychiatric symptoms.

Physician study staff then performed an initial evaluation for each patient. This evaluation included 1) the SCID module (current and lifetime) for MDD; 2) the Beck Depression Inventory–II (BDI–II);16 3) the Beck Anxiety Inventory (BAI)17 for anxiety in the month before the MI; and 4) the Multidimensional Scale of Perceived Social Support (MSPSS).18

We used structured-interview diagnosis of MDD because this is the DSM–IV19-based gold standard for psychiatric diagnosis. We used the BDI–II as an additional measurement of depression because elevated scores on the original Beck Depression Inventory (BDI)16 have been associated with subsequent negative cardiac outcomes in post-MI patients.2,20 We chose to use the BDI–II rather than the BDI because it is the updated version of this instrument and it better matches MDD time criteria (asking about symptoms in the last 2 weeks, rather than 1 week for the BDI); this instrument has been used in a recent, large study of depression in CAD patients.21 We used the BAI for anxiety symptoms because it is a rapid screen for anxiety that has been used in cardiac populations22 and does not overlap significantly with depression, unlike other tools such as the Spielberger State Trait Anxiety Inventory.23

We also measured social support, for two reasons. First, social support could serve as a confounding factor when assessing the effects of mood and anxiety symptoms, and therefore we felt it important to account for social support in our analyses. Also, a recent review has suggested that a limited social support network may be associated with mortality in the year after MI,24 although other studies have found no such association;25 no studies have evaluated the impact of social support on in-hospital outcomes. The MSPSS, a 12-item scale with item scores ranging from 1–7 (total score 12–84, with higher scores indicating greater perceived support), has been used successfully in cardiac populations26 and we used this instrument to measure social support.

Chart Review
At the end of the hospitalization, subjects’ medical records were reviewed to obtain demographic and medical variables to allow statistical analysis to control for the effects of these variables on the development of in-hospital complications. Specifically, we collected information regarding demographic variables (age, gender, and living alone) and medical variables (cardiac risk factors [history of diabetes mellitus, hyperlipidemia, and hypertension, current smoking, and previous MI], peak troponin T levels, and left-ventricular ejection fraction [LVEF]).

Also, the charts were reviewed for in-hospital complications by study staff blinded to patients’ initial interview results. These complications included 1) chest pain with ischemia (defined as chest pain with ECG changes or hypotension); 2) ventricular arrhythmia (defined as ventricular tachycardia [VT] or fibrillation [VF] lasting 4 beats or more); 3) ventricular arrhythmia requiring acute intervention (defined as VT or VF requiring medication or defibrillation); 4) congestive heart failure (CHF; identified either through a diagnosis of CHF in the discharge summary, or both a) chest X-ray consistent with CHF, and b) acute administration of diuretic or other agent to treat CHF); and 5) recurrent MI (defined using the above criteria for MI).

Statistical Analysis
Data analysis was carried out with SPSS for Windows (SPSS for Windows, Release 14.0.1, 2005, Chicago, IL, SPSS Inc.). All statistical tests were two-tailed.

To explore the association between depression/anxiety and the development of in-hospital complications, we used logistic-regression analysis to create a multivariate model for each complication. To avoid overfitting in the regression model, we reduced the number of confounders tested, avoided automatic stepwise regression techniques, and did not dichotomize continuous variables.27

Given the literature consistently linking MI severity and overall cardiac functioning with post-MI complications,28–31 we included peak troponin T and LVEF (representing severity of MI and overall cardiac functioning) in all multivariate analyses. Also, we performed univariate analysis of all other demographic, medical, and psychological variables, and entered into the multivariate logistic regression those variables that were significant (p<0.05) or nearly significant (p≤0.10) predictors of each complication on univariate analysis. All variables included in the logistic regression were entered in hierarchical fashion, with demographic variables (age, gender, living alone) entered in the first block, medical/cardiac variables (all cardiac factors, peak troponin-T, and LVEF) entered in the second block, and all psychological variables (MDD, BAI scores, and MSPSS scores) entered last. Finally, an additional analysis was performed for each complication, substituting BDI–II scores for MDD as the measure of depression.


  RESULTS

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
DISCUSSION
 REFERENCES
 
Patient Characteristics and Outcomes
A total of 180 eligible post-MI patients were approached for participation in the study; 49 (27%) declined or met exclusion criteria. The remaining 131 patients were enrolled in the study, 129 of whom were used in the final data analysis (LVEF was not measured in the remaining 2 patients, and thus these subjects were excluded).

The demographic, medical, and psychiatric characteristics of this cohort are listed in Table 1, and Table 2 lists the primary psychiatric and cardiac outcomes in this cohort. With regard to in-hospital psychiatric measures, 17 of the patients (13%) met criteria for a current major depressive episode; 32 patients (25%) had BDI–II≥14, considered a threshold for clinically significant symptoms (and approximately equivalent to BDI>10, which has been associated with adverse post-MI cardiac outcomes in several studies1,2) and 34 patients (26%) had BAI>10.


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TABLE 1. Baseline and In-Hospital Characteristics of Study Subjects




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TABLE 2. In-Hospital Psychiatric and Cardiac Outcomes



Figure 1 shows complication rates for patients with and without current MDD. Rates of all complications were higher for patients with current MDD (with MDD: recurrent ischemia: 23.5% without MDD: recurrent ischemia, 9.8% ventricular arrhythmia: 52.9% versus 28.6%; ventricular arrhythmia requiring intervention: 29.4% versus 4.5%; CHF 35.3% versus 10.7%; reinfarction 17.6% versus 3.6%).


Figure 1
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FIGURE 1.  Complication Rates With and Without Current MDD


Predictors of Recurrent Chest Pain With Ischemia
Table 3 provides data for all variables significantly associated with in-hospital complications on multivariate analysis. The first complication analyzed was recurrent chest pain with ischemia. On univariate analysis, hypertension (r=0.20; p=0.021), LVEF (r = –0.18; p=0.042), and BAI score (r=0.20; p=0.022) were significantly associated with recurrent ischemia. Also, age and current MDD were included in the multivariate analysis because they trended (p≤0.10) toward significance; peak troponin T was also included as a predetermined variable.


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TABLE 3. Multivariate Analysis of Variables Independently Associated With the Development of In-Hospital Post-MI Cardiac Complications



Logistic regression found that LVEF (odds ratio [OR]: 0.937; p=0.010; 95% confidence interval [CI]: 0.878–0.979) and history of hypertension (OR: 5.81; p=0.010; 95% CI: 1.53–24.48) were significantly associated with recurrent chest pain with ischemia; no psychological variable was independently associated with ischemia. Reanalysis with BDI–II scores rather than MDD as a depression measure found that BDI–II scores did not predict ischemia.

Predictors of Ventricular Arrhythmia
Current MDD (r=0.18; p=0.045) was significantly associated with ventricular arrhythmia on univariate analysis; previous MI (p≤0.10) and peak troponin T and LVEF (predetermined variables) were also included in the multivariate analysis. On multivariate logistic regression, previous MI (OR: 2.41; p=0.040; 95% CI: 1.04–5.56) and current MDD (OR: 3.07; p=0.039; 95% CI: 1.06–8.88) were independent predictors of ventricular arrhythmias. BDI–II scores were not predictive of arrhythmia on reanalysis.

The data were then analyzed when ventricular arrhythmias were limited to those requiring intervention with medication or defibrillation. LVEF (r = –0.27; p=0.002), BDI score (r=0.28; p=0.001), and current MDD (r=0.32; p<0.001) were significantly associated, on univariate analysis, with ventricular arrhythmias requiring intervention; living alone, current smoking (p≤0.10) and peak troponin T were also included in multivariate analysis. When these variables were entered into hierarchical multiple logistic regression, LVEF (OR: 0.891; p=0.007; 95% CI: 0.823–0.971) and current MDD (OR: 26.53; p=0.043; 95% CI: 1.11–632.9) independently predicted ventricular arrhythmias requiring intervention.

Analysis substituting BDI–II scores for MDD did find that the BDI–II scores were associated with ventricular arrhythmia requiring intervention on both univariate (r=0.28; p=0.001) and multivariate analysis (OR: 1.11; p=0.024; 95% CI: 1.08–1.16).

Predictors of Congestive Heart Failure
Univariate analysis found female sex (r = –0.19; p=0.033), advanced age (r=0.20; p=0.025), current smoking (r=0.18; p=0.045), LVEF (r = –0.19; p=0.032), and current MDD (r=0.24; p=0.006) to be significantly associated with CHF; history of hyperlipidemia, current smoking, and BDI score (all p≤0.10), and peak troponin T were also included in the logistic regression.

On multivariate analysis, only current MDD (OR: 15.45; p=0.022; 95% CI: 1.81–161.7) was associated with the development of CHF. BDI–II scores reached near-significance (p≤0.10) on univariate analysis (r=0.17; p=0.057), but were not a significant independent predictor of CHF on multivariate reanalysis.

Predictors of Reinfarction
Only advanced age (r=0.18; p=0.047) and current MDD (r=0.21; p=0.017) had significant univariate associations with recurrent MI; current smoking and low LVEF were also included in the multivariate analysis (p≤0.10), along with peak troponin T. On multivariate analysis, current MDD (OR: 8.44; p=0.023; 95% CI: 1.34–53.2) predicted reinfarction. BDI–II scores were not associated with reinfarction.


  DISCUSSION

 
TOP
 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
REFERENCES
 
This study examined the impact of two psychological variables on in-hospital post-MI cardiac complications: current MDD (i.e., pre-MI depression meeting full diagnostic criteria, including the time criterion of 2 weeks or longer) and pre-MI anxiety.

Overall, current MDD was an independent, non-redundant predictor of ventricular arrhythmia, ventricular arrhythmia requiring intervention, CHF, and reinfarction. When BDI–II scores were substituted for formal MDD diagnosis as a measure of depression, the links between depression and in-hospital complications were substantially weaker. In contrast with depression, preexisting anxiety was not associated with in-hospital complications.

To our knowledge, the in-hospital effects of depression have only been examined in one previous study. In that study, Dickens and colleagues32 found that MDD in the month preceding MI independently predicted a greater degree of CHF among a cohort of 314 first-MI patients; other in-hospital complications were not studied. The inclusion of other in-hospital complications is a strength of the current study.

Many post-MI studies1,2,33 have evaluated depression using a modified screen for MDD that required symptoms only since the onset of hospitalization (usually only several days, rather than the standard 2-week criterion), and did not assess whether depression or MI came first. Another important strength of the current study is that patients diagnosed with depression met the full 2-week time-criterion; as such, it is known that MDD preceded the onset of MI and persisted into the post-MI period.

There has long been discussion regarding whether the link between depression and negative cardiac outcomes is due to behavioral mechanisms (i.e., poor health-maintenance behavior in depressed patients) or to direct physiologic factors. Our results suggest that the link between depression and negative post-MI cardiac outcomes is not solely related to poor health-maintenance behavior, and that direct physiologic mechanisms likely play an important role. Although depressed post-MI patients do have lower rates of medication adherence, exercise, and other secondary prevention-behaviors in the months and years after MI,34 in our study, current MDD was associated with adverse cardiac complications that occurred immediately after MI and before these behaviors would have a significant post-MI impact. In contrast to the more gradual impact of behavior on cardiac health, the physiologic changes associated with MDD (including increased platelet activation, increased inflammation, sympathetic nervous system hyperactivity, and abnormal hypothalamic-pituitary-adrenal axis activation5) would likely be immediate and ongoing in the peri-MI period, potentially contributing to both the onset of MI and post-MI cardiac complications.

These findings regarding patients with current MDD also have implications for depression diagnosis and treatment in two populations of patients. First, by confirming the high frequency and substantial medical impact of current MDD in post-MI patients, our results underscore the need for treatment of this cohort, in whom depression frequently persists over the next year.35,36 Fortunately, treatment of post-MI MDD with selective serotonin reuptake inhibitors (SSRIs) appears both safe and efficacious,6 and post-hoc analysis from the Enhancing Recovery in Patients with Coronary Heart Disease (ENRICHD) trial of patients with post-MI MDD suggests that treatment with SSRIs may also be associated with reduced cardiac mortality,37 although this association has not been confirmed in a prospective study.

Second, our finding that patients with MDD preceding MI had higher complication rates suggests another population for whom systematic assessment and treatment of MDD may be critical: patients at high risk for MI, such as those with multiple cardiac risk factors or a previous MI.

Treatment of MDD initiated in the post-MI period might not have immediate in-hospital effects, but earlier identification and treatment of depression in those at high risk for MI (i.e., "pre-MI treatment") may provide substantial benefit. Indeed, given the association between depression and cardiac events, and the potential cardiovascular benefits of treatment with antidepressants,38 treatment of MDD in our subjects before their MI might have reduced the risk of MI or in-hospital post-MI complications; further study is needed.

The second entity examined in this study was pre-MI anxiety. In previous longitudinal studies, preexisting anxiety has been associated with onset of CAD and with acute cardiovascular events,7,8 but, in our study, pre-MI anxiety was not predictive of in-hospital post-MI complications. In contrast, previous studies have found that post-MI anxiety has been associated with in-hospital complications,39 and, in some studies, poorer longitudinal outcomes.4

The effects of anxiety on sympathetic nervous system activity and other physiologic processes may be both more immediate and more transient than the physiologic effects of depression on the cardiovascular system, and it may be that post-MI anxiety is a more important risk factor for negative in-hospital outcomes than pre-MI anxiety.

This study was limited by the fact that it was performed in a single academic medical setting, on two cardiac units, and included only a moderate number of patients. Although the demographic and medical variables of the sample were generally similar to those of other studies of this population (although with a higher proportion of men), these factors mean that our findings may not be generalizable to all patients. The low death rate of the patients and the necessity of subjects to comprehend and tolerate a 15- to 25-minute series of questions suggest that this cohort was potentially healthier than a typical cohort of post-MI patients, and this may have affected responses or cardiac outcome. Finally, it is not known whether the approximately 25% of patients who declined or were ineligible for the study may have had different patterns of response and cardiac complications.

In conclusion, our study suggests that MDD preceding MI and persisting during the post-MI period is associated with major, clinically relevant, in-hospital cardiac complications; to our knowledge, this is the first report of this relationship. These findings underscore the importance of identifying and promptly treating depression, both among patients with acute MI and those at risk for MI.


  ACKNOWLEDGMENTS

 
The authors thank Sara Nadelman and Rebecca Harley for editorial assistance

This study was supported by the Kaplen Fellowship Award Grant and the Livingston Fellowship Award Grant, both through Harvard Medical School, Boston, MA.


  REFERENCES

 
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 ABSTRACT
 INTRODUCTION
 METHOD
 RESULTS
 DISCUSSION
 REFERENCES
 

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