Tilburg University
Psychological triggers of acute cardiac events
Smeijers, L.
Publication date:
2015
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Smeijers, L. (2015). Psychological triggers of acute cardiac events. Ridderprint.
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Psychological Triggers of Acute Cardiac Events
ISBN 978-94-6299-098-2
Nie knieze nie zeuren
Das hartstikke fout
Vergeet nie te leven
Want straks ben de oud
-Opa Sanders
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P145
Psychological distress and personality factors in emotionally triggered acute coronary syndromes Emotional, neurohormonal and hemodynamic responses to mental stress in Tako-Tsubo Cardiomyopathy Psychological distress and personality factors in Tako-Tsubo Cardiomyopathy General Discussion Dutch summary / Nederlandse samenvatting Acknowledgements / DankwoordAbout the author
CHapter 5
CHapter 6
CHapter 7
CHapter 8
CHAPTER 1
GENERAL INTRODUCTION
Cardiovascular Diseases
Cardiovascular diseases (CVD) are a group of disorders of the heart and blood vessels. CVD is the number one cause of death globally 1 and approximately 30% of all global deaths are the result of CVD. Over 17 million people died of CVD worldwide in 2008 alone 2. In the Netherlands, mortality rates are comparable, with 28% of the total deaths resulting from CVD 3.The largest proportion of global CVD-related deaths (7.3 million, 42%) result from coronary artery disease (CAD) 2. In the Netherlands, CAD accounted for 25% of the cardiovascular deaths in 20133. Other manifestations of CVD that are a common cause of hospital admission are arrhythmias, heart failure (decreased pump function of the heart) and stroke. CAD is a gradual disease process resulting from atherosclerosis; build-up fatty deposits and other cells in the inner walls of the coronary blood vessels4.Due to plaque growth, the coronary arteries become narrowed, which may result in ischemic chest pain (i.e., angina pectoris). Myocardial infarction (MI) is the primary acute manifestation of CAD and results from an acute blockage of the coronary arteries that prevents blood from flowing to the heart muscle by either a thrombus (blood clot) or rupture of an atherosclerotic plaque. The underlying atherosclerotic disease process may progress until symptoms such as angina pectoris occur but it is not unusual that MI is the first manifestation of the disease. Symptoms of MI include for example pain or discomfort in the chest, radiating to the arms, left shoulder, jaw or back, in addition to shortness of
Cardiac and Non-Cardiac Chest Pain
In the United States, more than 6 million patients are admitted to an
emergency department annually with chest pain as the primary complaint 5.
Chest pain may suggest CAD as the primary cause of the symptoms. Cardiac chest pain may result from myocardial ischemia, which develops when cardiac demands
exceed the oxygen supply of the heart muscle 6. Myocardial ischemia usually
results from inadequate coronary blood flow as a result of a critical narrowing or blockage in the coronary arteries, and/or coronary spasm. When cardiac demand increases (e.g., increased heart rate, blood pressure or contractility of the heart muscle), then the reduced coronary supply may result in myocardial ischemia as a result of an imbalance between coronary supply and cardiac demand. However, a cardiac etiology is found in less than one-third of patients who present themselves with chest pain as the primary complaint 7, 8. Approximately half of the patients without a cardiac explanation for their symptoms are diagnosed
with active gastro-esophageal disease or anxiety disorders 9. Consequently,
a large group of patient remains without an explanation for their symptoms 10, 11.
These patients are eventually discharged without a cardiac or other diagnosis and are often referred to as patients with non-cardiac chest pain (NCCP). The high prevalence of NCCP, combined with the need to perform a range of diagnostic tests (e.g., serial electrocardiograms, cardiac enzyme testing in blood, exercise test, coronary angiogram) to rule out cardiac pathology, which often require overnight hospital admission, results in a major burden on the healthcare system. The biological mechanisms involved in chest pain with ‘normal’ coronary arteries (i.e., minimal (<50%) or no narrowing) are not well understood and
may include coronary spasm 12 and impaired endothelial functioning 13 as well
as cardiac microvascular disease 14. Evidence suggests that psychological and
NCCP is generally considered to imply the absence of CAD as documented using diagnostic tests such as coronary angiography. However, these diagnostic tools cannot rule out other ‘cardiac’ conditions such as transient coronary spasm and microvascular disease. In addition, clinically significant CAD may result in symptoms other than chest pain (e.g., dyspnea, general malaise and other ‘angina equivalents’). Thus, the term ‘non-cardiac’ lacks sufficient precision to unambiguously describe a specific patient group. The term NCCP will nonetheless be used in this dissertation because of its heuristic value in identifying patients in whom a clear cardiac diagnosis for current symptoms cannot be identified.
Anxiety, depression and general psychological distress are among the
primary psychological factors involved in both cardiac and non-cardiac chest pain15. NCCP is associated with high anxiety levels 16-19 and the estimated prevalence of panic disorder in NCCP ranges from 16% to 52% 20, which is substantially higher than in the general population (1.5-3.5%) 21. In addition, these psychological factors are associated with increased symptom awareness and adverse health behaviors that can increase vulnerability for NCCP 22, 23. NCCP and other symptoms that may
suggest cardiac pathology such as palpitations, dizziness, dyspnea or fainting may therefore be the result of a psychological vulnerability and an individual’s misinterpretation of symptoms related to psychological distress.
Long-Term Risk Factors
Well-established risk factors for CAD include health behaviors such as tobacco use, unhealthy diet and physical inactivity. These health behaviors may result in obesity, elevation of blood pressure, high blood glucose and adverse
lipids profiles. These conditions are referred to as intermediate risk factors 4.
In clinical practice, targeting these health behavior-related factors is important in reducing the risk of CAD and the modification of health behaviors results in major
Chronic psychological conditions can also influence the gradual
progression of cardiovascular disease 25, 26. ‘Stress’, a term associated with
definitional problems but widely used in the literature 6, has been associated
with a higher risk of developing CAD and its clinical manifestations such as MI
and other acute coronary syndromes (ACS) 27, 28. Several studies, including
meta-analyses showed an association between depression 29-31 and anxiety 32 with
the development of CAD and its clinical manifestations such as MI and sudden cardiac death. In addition, psychological factors have been associated with adverse prognosis in CAD patients 33-35. Evidence suggests a dose-response relationship between the severity of psychological distress with cardiovascular outcomes 28. Psychological risk factors may have direct physiological effects that result in CAD progression, but adverse CAD outcomes may also be mediated by adverse health
behaviors (e.g. smoking) and intermediate risk factors (e.g. hypertension) 6.
The link between psychological risk factors and the development and progression of CAD involves a complex interaction of biobehavioral mechanisms including traditional risk factors, lifestyle factors, treatment adherence, alterations in the autonomic nervous system, neurohormones (catecholamines and hypothalamic
pituitary adrenal (HPA) axis functioning), platelet activation, and inflammation 36.
Short Term Risk Factors: Triggers
external stimulus, emotional state or activity that produces acute physiological or pathophysiological changes leading directly to the onset of an acute (cardiac)
event 37. Some investigators (e.g., Muller and colleagues 38) make a distinction
between ‘triggers’ and acute risk factors, the latter being defined as a transient physiological change, such as a surge in arterial pressure that may result in (i.e. ‘trigger’) acute disease onset. Therefore, acute risk factors may represent the physiological consequence of a triggering emotion or activity. For purposes of this dissertation, we refer to triggers as short-term risk factors, as they are associated with immediate increases in the risk of cardiac events.
Reports on the incidence of triggers of myocardial infarction (MI) vary
from 10% 39 to 88% 40. The most common triggers include physical activity and
emotional distress. Physical triggers include activities involving vigorous exertion and emotional triggers include for example having a fierce argument, experiencing
high levels of fear, and other events that result in intense negative emotions 41-43.
Triggers can be investigated using case-crossover methodology (See Box 1). A higher risk of MI has been documented immediately following episodes of vigorous physical exertion with relative risks ranging from 3.3 to 6.1 44-46. A recent meta-analysis by Mostofsky et al. 47
found a 4.7 (95%CI=2.5-9.0) times higher risk of ACS in the 2 hours following outbursts of anger. Other
documented triggers of MI include sexual activity 48, 49 and bereavement 50, as
well as chemical exposures including coffee 51, marijuana 52and cocaine 53.
Less well documented triggers include psychological states such as anxiety 43 and
Box 1. The Case-Crossover Design
The case-crossover design has been developed to assess the change in the risk of an acute event during a brief hazard period
after exposure to a transient risk factor 55. It can be used to answer
the question: “Was this event triggered by something unusual that
happened just before?” 56. The case-crossover design applies best
under the following conditions: 1) exposure is intermittent, 2) the effect on risk is immediate and transient, and 3) the outcome is
abrupt 56.
The case-crossover design uses control times, rather than control persons. To calculate risks, the exposure frequency during a brief hazard period just before outcome onset is compared with exposure frequencies during control times. Control information for each patient is based on his or her past exposure experience and each case serves as its own control. Two types of control data are frequently used: (a) usual annual frequency of exposure and (b) frequency of exposure in the control period on the day before onset. The case-crossover design eliminates confounding by determinants that are constant within individuals over sampling time, such as
Mechanisms of Triggers
Whereas long-term risk factors contribute to the gradual progression of atherosclerosis, triggers represent the final step in the pathophysiological
process resulting in MI and other ACS 58. The physiological processes that occur
in response to experiencing a trigger may include increased cardiac demand (i.e., increased heart rate, blood pressure and cardiac contractility) and decreased coronary supply resulting from vasoconstriction, coronary spasm and/or blood viscosity. The acute supply/demand imbalance may result in acute transient myocardial ischemia and related angina symptoms. Acute triggers can also reduce coronary supply by blood clot formation resulting from platelet activation, hyper-coagulability (increased tendency towards blood clot formation) and an
unfavorable coagulation/fibrinolysis balance 58, 59.
These processes may ultimately result in plaque disruption and thrombosis that directly cause acute MI. However, even in the absence of an occlusive thrombus, experiencing triggers may result in adverse cardiac outcomes including ventricular fibrillation and sudden cardiac death, by elevated
catecholamine levels and increased cardiac sympathetic activation 59, potentially
combined with transient ischemia.
A Trigger Prone Condition
in Cardiovascular Medicine:
Tako-Tsubo Cardiomyopathy
A relatively rare cardiac condition that is characterized by a high prevalence
of emotional and physical triggers is Tako-Tsubo Cardiomyopathy (TTC) 41, 60, 61.
Up to 75% of the patients with TTC report emotional and/or physical distress
as a triggering factor prior to TTC 60. The prevalence of TTC ranges from 0.7% to
4.9% in patients admitted with symptoms suggesting ACS 62-64. TTC is much more
common in women than men and most women with TTC are postmenopausal65.
The most common presentation of TTC includes chest pain and/or dyspnea with ST-segment elevation or T-wave inversion suggestive of MI, with minimal biochemical markers of myocardial tissue damage (i.e., at most mild increase in troponin levels) 60. However, these signs and symptoms develop in the absence of obstructive CAD 41, 60, 61. Typical to this syndrome is the apical ballooning of the left ventricle 66, 67 as shown in Figure 1, alhtough inverted TTC has been described with akinesia and ballooning of the basal segments of the left ventricle 68, 69. A wide range of terminology is used to describe this phenomenon including ‘apical ballooning syndrome’, ‘broken heart syndrome’, ‘stress cardiomyopathy’, ‘ampulla cardiomyopathy’, ‘neurogenic stunning’ and ‘transient left ventricular
apical ballooning’ 70. TTC was first described in Japan in 1990 71, 72. The name
Tako-Tsubo is derived from the Japanese word for an octopus trapping pot with a round bottom and narrow neck, which resembles the apical ballooning of the left
Figure 1. Diastolic and systolic freeze frames from a left ventriculogram of a
patient with TTC illustrating apical ballooning 67
TTC is clinically different from other cardiac conditions in which obstructive CAD is typically absent, such as Variant or Prinzmetal’s angina, cardiac syndrome X (i.e., myocardial ischemia without underlying CAD), and transient coronary spasm, primarily because of the characteristically pronounced left ventricular defects in TTC. TTC is completely reversible and hemodynamic stabilization and standard therapy invariably leads to recovery within days and in
rare cases within months 61. The optimal treatment of Tako-Tsubo has not been
established. Because the presentation of TTC mimics that of MI, initial diagnostic evaluation and clinical management are directed towards the treatment of ACS, including ECG monitoring and echocardiography, often combined with administration of aspirin, heparin and β-adrenergic blocking agents.
The pathophysiological mechanisms involved in TTC are not well understood. Substantial increases in circulating catecholamine levels have been observed in the acute phase of TTC, suggesting exaggerated sympathetic
stimulation as a causal factor 41, 73. However, not all studies have found elevated
catecholamine levels in acute TTC 74. Psychological characteristics may be of
The prevalence estimates of prodromal depression and anxiety disorders in TTC range from 21-60% 60, 75-78. The high prevalence of emotional triggers suggests that some individuals may be particularly vulnerable to experiencing TTC following a physiological or psychological trigger.
Aims of this Dissertation: Addressing
the Knowledge Gaps in Triggers of
Acute Cardiac Events
The general aim of this dissertation is to thoroughly investigate the importance of psychological triggers in clinical cardiology. The majority of
research on triggers has focused on ACS 37 and no studies have examined the triggers of the large patient population presenting to the emergency room and acute coronary care with NCCP. Furthermore, research on negative emotions as potential triggers has primarily focused on anger, and the role of other emotions such as anxiety and sadness is yet to be determined. One aim of this dissertation is therefore to address these knowledge gaps.
Although literature is available on the short term risk associated with
potential triggers 43-45, 49, 52, 53, 79, no studies have assessed the consequences of triggers for long-term prognosis. Therefore, this dissertation will not only quantify the magnitude of the risk associated with triggers for ACS and NCCP, but also determine the association of triggers with prognosis in the subsequent years after hospital admission. This knowledge is essential to long-term risk stratification of patients with a triggered cardiac event.
Little is known about the demographic, clinical and psychological characteristics of patients who experience a trigger prior to hospital admission for cardiac symptoms. Clinical characteristics of patients with high physical
Only one study assessed the factors associated with triggering by anger 46 and
Outline of the Dissertation and
Study Design
Studies used
For this dissertation, data from three research projects were used: two projects were developed specifically for purposes of this dissertation and one existing data-base project was used to conduct a prospective cohort study (see Figure 2). All three projects were approved by the Institutional Review Boards of the participating hospitals and universities and all patients provided written informed consent prior to participation.
TRIGGERS Study
The TRIGGERS study was developed to investigate the risk of behavioral and emotional triggers of hospital admission in patients with suspected cardiac disease. The study was conducted between October 2012 and July 2014 at the TweeSteden Hospital, Tilburg, the Netherlands. Patients were included immediately after hospital admission and inclusion criteria were 1) symptoms suggestive of acute cardiac pathology, 2) age between 18 and 80 years, and 3) ability to answer questionnaires and participate in an interview. Details andresults of this study are presented in Chapters 2 and 5.
Second, patients participated in an extensive structured interview assessing negative emotions and physical activity levels prior to the onset of their symptoms. Of the 805 patients who completed the first questionnaire, 521 were interviewed. Interviewers were trained and unaware of the patients’ diagnosis. Finally, patients completed a second questionnaire to obtain information on psychological distress and personality factors using standardized questionnaires. The general approach used in this project involves a case-crossover design to examine triggers and a case-control design to examine differences between patients with triggered events versus patients who did not report a trigger prior to hospitalization. The TRIGGERS study adds to the current literature by thoroughly examining multiple emotional exposures including anger, anxiety and sadness and by examining emotional and physical triggers in NCCP.
TAKO Study
The study consisted of an experimental stress protocol and extensive assessment of psychological factors. The stress protocol consisted of an anger recall speech task, a mental arithmetic task and low-grade supine bicycle physical exertion. During the tasks, measurements were obtained for emotional, neurohormonal (catecholamines and HPA-axis hormones) and hemodynamic (echocardiography-based cardiac function, blood pressure and heart rate) responses. Levels of emotional and physiological measures during psychological and physical stress were compared to baseline rest measures. The protocol concluded with a structured interview and patients filled out a questionnaire assessing psychological distress and personality factors.
For this project, two types of designs were used. The stress response analyses compare the emotional, neurohormonal and hemodynamic measures between groups during each phase of the experiment, and involve a mixed model with patient status (TTC, healthy controls and heart failure controls) as between-groups factor and the repeated emotional, neurohormonal and hemodynamic measures as within-subject factor. Comparison between the TTC and the two control groups on the various psychological characteristics are
examined using multivariate analyses of variance using group status as between-subjects factor. Results from this study are presented in Chapters 6 and 7.
Determinants of Myocardial
Infarction Onset Study (ONSET)
in the study. Patients were interviewed to assess potential triggers and data on psychological triggers was available for 2176 patients. The cohort was then
prospectively followed-up for 10 years for all-cause mortality. Chapters 3 and 4
present the results of this study.
Consistent with the approach in the Triggers study, the ONSET study uses a case-control design to examine differences between patients with versus without a triggered event. The predictive value of triggered versus non-triggered events will be examined using a longitudinal follow-up design.
Outline
Triggers: Risk and Prognosis
The first two data-based Chapters (2 and 3) of this dissertation address the risks of hospital admission associated with emotional and physical triggers, and the consequences of experiencing triggers for long-term prognosis. Chapter 2describes data from the TRIGGERS study and, using a case-crossover design, determines the risk associated with hospital admission after experiencing high levels of negative emotions or physical activity. This study sample includes both patients with CVD as well as patients with NCCP and the risks associated with potential triggers will be investigated for both groups.
The long-term consequences of experiencing ACS as a result of a
triggering event are unknown. Chapter 3 describes the association of emotional
Clinical and Psychological Characteristics
Associated with Triggers
Once the importance of triggers is determined in terms of immediate risk and long-term prognostic value, it becomes relevant to know about the characteristics of patients who experience these specific triggers prior to
hospitalization. Chapter 4 describes data from the ONSET study, investigating
the demographic and clinical characteristics associated with experiencing high levels of negative emotions and physical activity prior to MI. The psychological profile, in terms of psychological distress and personality, of patients who report
triggers prior to hospitalization will be examined in Chapter 5, using data from
the TRIGGERS study.
A Trigger Prone Condition in Cardiovascular
Medicine: Tako-Tsubo Cardiomyopathy
An in-depth investigation of TTC, a condition characterized by a high prevalence of emotional triggers, is examined in Chapters 6 and 7 using data from
the TAKO study. In Chapter 6 an experimental design will be used to determine
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??
CHAPTER 2
Acute negative emotions and
physical activity as triggers
of cardiac and non cardiac
hospital admission
Loes Smeijers; Elizabeth Mostofsky;
Jos W Widdershoven; Lotte van Dammen;
Liesbeth de Vos; Willem J. Kop
Abstract
Aims
Acute physical and psychological stressors can trigger myocardial infarction. This study determined the prevalence and relative risk of acute exposure to negative emotions and high levels of physical activity preceding hospital admission for cardiac evaluation. We examined whether risks differ between patients with cardiac versus non-cardiac discharge diagnoses.Methods
This case-crossover study involved 521 patients (mean age 61.8±11.2, 31.5% women) admitted with acute cardiac complaints. Negative emotions (anxiety, anger, and sadness) and physical activity levels were assessed using structured interviews. Relative risks (RR) and 95% confidence intervals (CI) were based on the two-hour pre-admission hazard period compared to each patient’s usual frequency levels in the previous year.Results
High negative emotions occurred in 32 patients (6.1%) during the 2-hour hazard period, and high physical activity occurred in 43 patients (8.3%) patients. Exposure to negative emotions was associated with an elevated risk of hospital admission in patients with a cardiac diagnosis (RR=6.40, 95%CI=3.97-10.30) and this association was even stronger for patients with a non-cardiac diagnosis (RR=12.37, 95%CI=6.78-22.54,
p interaction=0.090). Physical activity was also associated with an acute increased
risk of hospital admission in patients with cardiac (RR=4.89, 95%CI=3.35-7.14) and
non-cardiac (RR=5.07, 95%CI=2.96-8.69) diagnoses (p interaction=0.951).
Conclusion
Introduction
Each year, a large number of patients is admitted to the emergency room with acute chest pain or angina equivalents. Approximately one-third of these admissions involves patients who receive a diagnosis of myocardial infarction or another cardiovascular condition 1, leaving a large group of patients who are discharged without a cardiac diagnosis. Physical and psychological stressors can act as triggers of cardiovascular events such as acute coronary syndromes (ACS) and stroke 2, 3. However, little is known about acute exposures that can act as triggers of hospitalization for patients who experience cardiac symptoms but do not have a cardiovascular discharge diagnosis. A ‘trigger’ is an activity, emotional state or external stimulus that produces acute physiological or pathophysiological changes leading directly to the onsetof an acute medical event and can therefore be considered an acute risk factor 3.
The triggering potential of high physical activity and psychological distress has
been well-established in ACS 4-9. High-intensity physical activity is associated with a
six-fold increased risk of MI in the subsequent hours 4, 9. A recent meta-analysis found
a substantially higher risk of ACS in the 2 hours following outbursts of anger (RR=4.74,
95%CI=2.50-8.99) 7. Anxiety 5 and depression 10 are also elevated immediately prior
to MI relative to control periods.
No research has focused on the acute risk factors in patients who are admitted for cardiac observation but who are subsequently discharged without a cardiac diagnosis. This is an important knowledge gap because of the large proportion of
patients with acute cardiac symptoms in whom a cardiac etiology cannot be found1.
Hospital admission for non-cardiac chest pain is a major burden on the health care system. Because 23-38% of patients with non-cardiac chest paint report high levels
of anxiety 11, 12 and 16-52% present with panic disorder 13, it is plausible that acute
In this study, we assessed the prevalence of negative emotions (anxiety, anger, sadness) and physical activity levels immediately preceding hospital admission for acute cardiac symptoms. The second objective was to examine whether the risks of these potential triggers differ between patients with compared to those without a cardiac discharge diagnosis. Based on the existing literature we expected negative emotions to be more strongly associated with admissions for non-cardiac diagnoses compared to cardiac diagnoses.
Methods
Study Population
Between October 2012 and July 2014, patients admitted to the Cardiology Department were enrolled in the TRIGGERS study. Inclusion criteria were: 1) symptoms and signs resulting in admission for differential diagnosis of (acute) cardiac disease, 2) age between 18 and 80 years, and 3) ability to answer questionnaires and participate in an interview. The study was conducted at the TweeSteden Hospital, Tilburg, the Netherlands (>2000 annual admission to cardiology per year). The protocol was approved by the Institutional Review Board (#NL41272.028.12). This study complies with the Declaration of Helsinki and all patients provided informed consent prior to participating in the study.
Procedure
Interview-based data were collected during hospital admission (N=191) or by telephone (N=330) if patients were discharged before the interview could be scheduled.
Trained interviewers conducted a standardized interview to obtain information about potential triggers including anxiety, anger, sadness and physical activity in addition to the time, place and nature of symptoms prior to admission. The interview also assessed standard psychological measures (depression and panic disorder; not described in this paper). Interviewers were unaware of the patient’s diagnosis and whether a cardiac etiology was found to explain the symptoms and subsequent hospital admission.
Exposure Assessment
Exposure to anxiety, anger, sadness and physical activity was assessed using scales based on the Onset Study Anger Scale, with values ranging from
1 for no exposure to 7 for high levels of exposure 5. Patients were asked to
indicate their level of exposure to each of the potential triggers during the 1, 2, 3 and 24 hours prior to symptom onset (e.g., “In the hour prior to the onset of your symptoms, how angry were you on a scale from 1 to 7”). Exposure scales were visualized as thermometers. Consistent with the literature on the acute
impact of negative emotions and physical activity 5, patients were considered
exposed if they reported a peak level of ≥5, indicating ‘very anxious, angry, sad’
or ‘heavy physical activity’ in the two hours prior to symptom onset 4, 5. In order to
maximize statistical power, we examined the impact of exposure to any negative emotion, including anxiety, anger or sadness. In sensitivity analyses, we examined the association for each of these emotions separately. In the primary analyses, we used usual frequency of each exposure during the past year as reference (e.g., “How often did you experience level 5 during the past year?”). Consistent with the literature on triggering exposures prior to ACS, we also conducted matched-pair analyses using negative emotion and physical activity levels at
Clinical Assessment of Cardiac vs.
Non-Cardiac Diagnosis
Two physicians independently extracted discharge diagnosis from the hospital medical records and indicated whether the admission was related to a cardiac or non-cardiac diagnosis. Diagnoses were based on standard clinical criteria using ECG, coronary angiography and biochemistry assessments. Cardiac diagnoses included MI with ST-segment elevation (STEMI), MI without ST-segment elevation (non-STEMI), coronary artery disease, unstable or stable angina, heart failure, ventricular arrhythmia, atrial fibrillation, Tako-Tsubo cardiomyopathy and pericarditis.
Non-cardiac diagnoses included non-cardiac chest pain or other symptoms suggesting cardiac disease such as dyspnea and palpitations. The primary defining characteristic of NCCP in this study was the absence of CAD (based on coronary angiography or non-inducibility of ischemia by exercise or pharmacological testing). A prior history of MI or coronary revascularization was not exclusionary for NCCP as current discharge diagnosis as long as the current admission could not be attributed to underlying CAD or another cardiac pathology (see Chapter 1 for additional discussion about the definition of NCCP). Medical records were used to obtain information about history of MI, percutaneous coronary intervention (PCI), angina, heart failure, atrial fibrillation, and evaluations for non-cardiac chest pain. Information was also obtained about cardiovascular risk factors (prior diagnosis of hypertension, diabetes mellitus or hypercholesterolemia), family history of cardiovascular disease and medication use.
Study Design
The case-crossover design assesses the risk of an acute event during a brief hazard period after exposure to a transient risk factor 14, 15. Patients werephysical activity. Control information for each patient is based on his or her past exposure experience. In this study we used two types of reference data: (a) usual annual frequency of exposure and (b) exposure during the same time on the day prior to symptom onset. The primary analyses used the usual annual frequency as reference 4, 5. Usual frequency was computed as the sum of exposure frequency to level 5, 6 and 7 during the past year. Based on previous literature, we used the two-hour hazard period immediately before the onset of symptoms as the acute exposure phase and compared this hazard period with usual annual frequency. For the matched-pair analysis we used the 1-hour hazard period because no data were available for the 25-26 hour time period prior to symptom onset. Both usual frequency and matched-pair methodologies have been used previously in studies examining triggers of acute cardiovascular events 4, 5.
Statistical Analysis
Data are presented as mean ± standard deviation or N and percentages. In the primary analysis, we compared high levels (≥5) of negative emotions or physical activity during the two hour exposure period prior to symptom onset with the expected frequency of exposure based on usual frequency (≥5) during the prior year using methods for cohort studies with sparse data in each stratum. Mantel-Haenszel incidence ratios were used to estimate relative risks. For the matched-pair analyses, we used conditional logistic regression to compare whether the person reported negative emotions or physical activity in the hourprior to symptom onset with exposure at the same time on the prior day 14.
Results
Characteristics of the study sample are shown in Table 1. Among 521 patients (mean age 61.8±11.2 years, 31.5% women), 354 (67.9%) were diagnosed with a cardiac diagnoses (STEMI, N=104; non-STEMI, N=102; unstable angina, N=13; coronary artery disease, N=38, other cardiac conditions, N=97) and 167 (32.1%) patients received a non-cardiac discharge diagnosis. Patients diagnosed with a cardiac condition were more likely to be male (73.4% vs. 58.1%,
p<0.001), current smokers (28.0% vs. 14.4%, p=0.001), drink alcohol (69.1% vs.
59.6%, p=0.033), and use anticoagulant medication (29.7% vs. 20.5, p=0.027)
compared to patients who did not have a cardiac diagnosis.
Negative Emotions
Of the 354 patients with a cardiac diagnosis, 19 patients (5.4%) reported exposure to high levels of negative emotions during the two-hour hazard period prior to symptom onset. Most patients reported anxiety (13 patients, 3.7%), followed by sadness (7 patients, 2.0%) and anger (6 patients, 1.7%). For the 167 patients without a cardiac diagnosis, these frequencies were 13 (7.8%), 10 (6.0), 5 (3.0%) and 4 (2.4%), respectively. 7 (2.0%) patients with a cardiac diagnosis and 6 (3.6%) with a non-cardiac diagnosis experienced more than one of these negative emotions.
As shown in Figure 1, negative emotions were associated with an elevated risk of hospital admission in patients with a cardiac diagnosis (RR=6.40, 95%CI=3.97-10.30) and in patients without a cardiac diagnosis (RR=12.37, 95%CI=6.78-22.54). The risk associated with negative emotions was higher in patients without a cardiac diagnosis compared to patients with a cardiac diagnosis
(p interaction=0.090). When examining the emotions anxiety, anger and sadness
separately, relative risks were higher with larger confidence intervals (Table 2). In a sensitivity analysis comparing admission for non-cardiac diagnosis with admissions for ACS (instead of all cardiac diagnoses), the associations were stronger among patients with non-cardiac conditions compared to
estimates for ACS admissions (negative emotions (p interaction=0.019),
anxiety (p interaction=0.046), anger (p interaction=0.018) and sadness (p
interaction=0.291)).
Results for matched-pair analyses are displayed in Table 3. When
p interaction=0.330) (Table 3). There were very few exposed cases in this analysis and the results should therefore be interpreted with caution. Exploratory analyses using only patients with ACS showed similar relative risks compared to the group including all cardiac etiologies (e.g., heart failure, atrial fibrillation).
Physical Activity
Discussion
This study shows that hospital admissions for both cardiac and non-cardiac conditions are often preceded by high levels of negative emotions and physical activity in the two-hours prior to symptom onset. The association between negative emotions and hospital admission was stronger for patients with non-cardiac conditions compared to patients with a cardiac diagnosis.
The prevalence of acute stressors in the two-hours prior to symptom onset and the associations between these stressors and cardiac outcomes are comparable to prior research. In our study, 1.7% of the cardiac diagnoses were preceded by anger in the two hours prior to symptom onset and 6.2% were preceded by physical activity in during the hour prior to symptom onset
(Table 2). These estimates are similar to the MI Onset study 4, 5 prevalence of anger
(2.4%) and physical activity (4.4%) and also comparable to the SHEEP study 8, 9
(anger 2.3%; physical activity 6.4%). The present findings are also consistent with prior studies showing that episodes of negative emotions are associated with
an acute higher risk of ACS 4, 5, 8, 9 although our findings are somewhat higher
than in prior reports. It is possible that our estimates are higher because of how negative emotions were assessed. For acute exposure, participants identified the level of emotion they experienced during each time period. For usual exposure, patients were asked how frequently they experienced each level of emotion, from the highest to the lowest level, which may have resulted in over-reporting of immediate exposures and under reporting of the usual frequency, thus leading to somewhat higher risk estimates than previously reported.
This study adds to the literature by showing that negative emotions and physical activity are short-term risk factors for patients admitted for non-cardiac conditions. About one third of the patients was discharged without a cardiac diagnosis. This number is lower compared to prevalence estimates reported in the literature, stating that about two thirds of the patients are not diagnosed
with a cardiac condition 1, 16. One reason for this discrepancy is that the inclusion
differential diagnosis and patients who presented at the emergency room but who were clearly not having a cardiac condition were not further evaluated by cardiac emergency physicians. It is also possible that patients with non-cardiac conditions were discharged relatively soon after admission and hence they were not approached to participate in the study. The present sample may therefore not be representative for all patients presenting at the emergency room with cardiac symptoms. However, NCCP patients who undergo a range of diagnostic tests and make more extensive use of healthcare facilities pose a high burden on the healthcare system and these patients are likely to be well represented in our sample. Among the negative emotions, acute high levels of anxiety might be of particular importance in ACS. The present findings show that anxiety is the most common preceding emotion prior to both cardiac and non-cardiac conditions and associated with the highest risk for admission (Table 2). The association between anxiety and hospital admission was stronger for non-cardiac conditions compared to cardiac conditions. However, since both groups reported these exposures, it is unlikely that knowledge on levels of emotions immediately prior to symptom onset will directly facilitate early differential diagnosis.
The mechanisms involved in psychological and behavioral triggering of
cardiovascular events likely involve both physiological and biological processes2, 3.
The onset of MI might occur when a vulnerable, but not necessarily flow-limiting stenotic atherosclerotic plaque, is disrupted in response to stress-induced hemodynamic changes resulting in increased cardiac demand and reduced myocardial supply. Thereafter, hemostatic processes and vasoconstriction
determine whether an occlusive thrombus develops 17, 18. Strike et al. studied
14 ACS patients who experienced acute negative emotions in the 2 hours before symptom onset and 20 ACS patients who did not experience negative emotions
prior to ACS using psychophysiological stress testing 19. Patients whose ACS was
platelet activation and impaired hemodynamic recovery in response to a mental challenge protocol compared to patients with an ACS that was not preceded by these psychological factors. These findings indicate that biological hyper-arousal may in part explain the predictive value of negative emotions as triggers of ACS.
In terms of the mechanisms in patients with non-cardiac conditions, it is possible that hyper-responsiveness to physical symptoms and symptom amplification contribute to patients seeking medical care. It has been previously shown that 16-70% of patients with non-cardiac chest pain have diagnosed panic disorders 13, 20, 33-50% have anxiety disorders and 11-22% have mood disorders20, 21. Therefore, these individuals may be more likely to seek medical care regardless of recent exposure and may have heightened symptom awareness 22. The present study shows that acutely elevated levels of negative emotions increase the risk of symptoms that suggest cardiac disease, leading to hospitalization of patients who ultimately have a non-cardiac discharge diagnoses. Future studies are needed to examine the differences between NCCP patients with versus without a history of cardiac disease.
as noted in Table 1, the two groups differed with respect to sex, smoking status and alcohol consumption. It is also possible that personality factors and other stable psychological traits differentially infuence pre-admission recall of emotions. In addition, the induction period for cardiac vs. non-cardiac admissions may be different. The concerns related to the NCCP group are partly related to the definitional problems associated with NCCP, which is a ‘diagnosis by exclusion’. Third, the questions used to assess the usual frequency of exposure differ by necessity from the questions assessing the short-term exposure during the 2-hour hazard period. For usual exposure, patients reported about the frequency of experiencing each specific level whereas for the short-term exposure the level of exposure during a specific time frame was reported. This could have resulted in bias in terms of under as well as overestimation of usual level of exposure. Despite these limitations, the study has many strengths. This is the first investigation to rigorously evaluate whether exposures that are associated with an acutely higher risk of cardiovascular events are similar for people admitted for non-cardiac reasons. In addition, multiple emotions were assessed using structured interview techniques, enabling assessment of a composite score for negative emotions and exploratory analyses on the relative importance of anxiety, anger and sadness.
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??
CHAPTER 3
Association between high
levels of anxiety, anger and
physical exertion immediately
prior to myocardial infarction
with mortality during 10 years
follow-up
Loes Smeijers; Elizabeth Mostofsky;
Geoffrey H. Tofler; James E. Muller;
Willem J. Kop; Murray A. Mittleman
Abstract
Background
Acute exposure to high levels of anxiety, anger and physical exertion are associated with a high risk of triggering myocardial infarction (MI) in the following two hours. It is not known whether patients who have an MI immediately following short-term physical and emotional exposures have a poor long-term prognosis compared to patients with an MI that is not preceded by such exposures.
Objectives
To evaluate whether heavy physical exertion and high levels of anger or anxiety immediately prior to MI onset are associated with 10-year all-cause mortality.
Methods
We conducted a prospective cohort study of 2176 MI patients from the multicenter Determinants of Myocardial Infarction Onset Study (age=60.1±12.5 years, 29.2% women). Exposures to potential triggers during the 2 hours prior to MI onset were assessed using structured interviews. We defined heavy physical exertion
as activities with ≥6 metabolic equivalents and high anger and anxiety as a >90th
percentile score on the Spielberger State-Trait Personality Inventory. Ten-year all-cause mortality was assessed using the US National Death Index. Cox proportional hazards models adjusted for demographic variables and health characteristics were used to calculate hazard ratios (HR) and 95% confidence intervals (CI).
