OR

IGIN

AL

AR

TIC

LE

Original Article

Therapy for Triggered Acute Risk Prevention:A Study of Feasibility

Elizabeth Shaw, MBBS a, Geoffrey H. Tofler, MD FRACP a,∗, Thomas Buckley, MSc b,Beata Bajorek, PhD a and Michael Ward, PhD FRACP a

a Royal North Shore Hospital, University of Sydney, Australiab University of Technology Sydney, Australia

Background: Heavy physical exertion, emotional stress, heavy meals and respiratory infection transiently increase therisk of myocardial infarction, sudden death and stroke, however it remains uncertain how to use this information fordisease prevention.

Aims: We determined the feasibility of taking targeted medication for the hazard duration of a triggering activity toreduce risk.

Methods: After a run-in training period over 1 month, 17 healthy subjects recorded for 1 month all episodes of physicaland emotional stress, heavy meal and respiratory infection. For each episode, they were instructed to take either aspirin100 mg and propranolol 10 mg (for physical exertion and emotional stress) or aspirin 100 mg alone (for respiratory infectionand heavy meal) and record adherence with taking medication. Subjects performed exertion while wearing a heart ratem

w(c

ii

K

I

AbfrisbtoMO

R2

∗LfE

©A

onitor, once during the run-in period, and once 30 min after taking propranolol and aspirin.Results: Based on study diary subjects reliably documented triggers with 94% adherence. Designated medicationas also reliably taken, with 88% adherence. Propranolol taken prior to exertion resulted in a lower peak heart rate

128 ± 38 versus 149 ± 21, p < 0.01) compared to similar exercise during the run-in period. Over two-thirds (71%) of subjectsonsidered that it was feasible to continue taking medication in this manner.

Conclusions: The study indicates that potential triggers of acute cardiovascular disease can be reliably identified, andt is feasible and acceptable to take targeted medication at the time of these triggers. These findings encourage furthernvestigation of the potential role of this therapeutic strategy.

(Heart, Lung and Circulation 2009;18:347–352)© 2009 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society of Australia and New

Zealand. Published by Elsevier Inc. All rights reserved.

eywords. Myocardial infarction; Trigger; Stress; Beta-blocker; Aspirin

ntroduction

relationship has long been recognised between acutestressors and cardiovascular events, although it has

een difficult to demonstrate causal links. Studies haveound that heavy physical exertion, acute emotional stress,espiratory infection and heavy meals can transientlyncrease the relative risk of myocardial infarction (MI),udden cardiac death and stroke by 2- to 10-fold overasal risk [1–7]. In the Onset study, heavy physical exer-

ion within 1 h of MI was associated with a relative riskf 5.9 over baseline [1] while in patients with ST-elevationI, there was a 10-fold increase in relative risk [8]. In thenset study, anger in the two hour period before MI was

eceived 23 July 2008; received in revised form 23 October008; accepted 17 February 2009; available online 1 May 2009

Corresponding author at: Royal North Shore Hospital, Steonards 2065, N.S.W., Australia. Tel.: +61 2 99266359;

ax: +61 2 99067807.-mail address: gtofler@nsccahs.health.nsw.gov.au (G.H. Tofler).

associated with a relative risk of 4.0 compared with theday before [2], while in another study, the relative riskwas nine-fold [9]. Acute anxiety has been associated witha transient doubling of relative risk [2] while populationstressors such as earthquakes, missile attacks and somesporting finals, have also been associated with increasedMI [10,11]. An increased risk of MI occurs with respiratoryinfection, particularly during the first three days (relativerisk for MI 4.9) [5]. Heavy meal has also been associatedwith a transient four-fold increase in relative risk of MI [6].

Although these stressors can trigger MI, it remainsunclear how this information can be used for preven-tion. The current pharmacological strategy for preventionis based on long-term daily therapy. To complement thisapproach, we recently proposed a strategy with five poten-tial approaches for prevention of triggered acute risk [10].One proposed approach was to take targeted medicationacutely at the time of a potential trigger. However, beforesuch an approach could be considered clinically applica-ble, several steps would be required. A first step, whichwas the purpose of the present study, was to investigate

2009 Australasian Society of Cardiac and Thoracic Surgeons and the Cardiac Society ofustralia and New Zealand. Published by Elsevier Inc. All rights reserved.

1443-9506/04/$36.00doi:10.1016/j.hlc.2009.02.008

OR

IGIN

AL

AR

TIC

LE

348 Shaw et al. Heart, Lung and CirculationTherapy for triggered acute risk prevention 2009;18:347–352

whether such an approach was feasible and acceptable toindividuals.

The specific aims were to determine whether healthysubjects could reliably identify and document episodes ofheavy physical exertion, emotional stress, heavy meals andrespiratory infection; whether subjects could reliably takespecific medication (propranolol and/or aspirin) at thetime of the triggering activity; whether beta-blocker takenbefore heavy physical exertion in a person’s home envi-ronment would reduce heart rate response; and whetherthis approach was practical and acceptable to participants.

Methods

Study PopulationNineteen healthy subjects aged 30–75 provided writteninformed consent for the study, which was approved bythe Institutional Human Research Ethics Committee. Par-ticipants were excluded if they had contraindications toaspirin or beta-blocking agents, asthma, diabetes, pepticulcer or increased bleeding risk. Other exclusion criteriawere resting heart rate <60 bpm, not in sinus rhythm, sys-tolic blood pressure <110 mmHg, any regular medication(except hormone replacement or oral contraceptives) orany significant illness.

Run-in Period

Table 1. Rating Scales Used to Estimate the Level of PhysicalActivity, Anger and Anxiety, Heavy Meal and RespiratoryInfection.

Exertion chart1. Sleeping, reclining—sunbathing, lying watching TV2. Sitting—eating, reading, deskwork, sitting watching TV,

highway driving3. Very light—office work, city driving, personal care,

standing in line, strolling in park4. Light normal breathing—mopping, slow walking (e.g.

shopping), bowling, sweeping, gardening with powertools

5. Moderate, deep breathing—normal walking, golfing onfoot, ballroom dancing, slow biking, fishing, slow dancing

6. Vigorous, panting—slow jogging, speed walking, tennis,swimming, fast biking, mowing with a push-powermower, heavy gardening, picking up garbage, shoveling

7. Heavy, gasping/much sweat—running, fast jogging,moving boulders, mixing cement, competitive basketball,touch football

8. Extreme, peak exertion—sprinting, fast running, joggingup-hill, aggressive sports with frequent sprinting and norest, pushing or pulling with all your might, unusuallyextreme work

Anger chart1. Calm2. Busy, but not hassled3. Mildly angry, irritated and hassled, but it does not show4. Moderately angry, so hassled it shows in your voice5. Very angry, body tense, clenching fists or teeth6. Furious or enraged, almost out of control or out of

control, pound table, slam door

Anxiety chart1. Calm2. Busy, but not hassled3. Mildly anxious, But it does not show4. Moderately anxious, such that it shows in your voice or

demeanour5. Very anxious, body shaking, feel your pulse racing6. Panicked almost out of control or out of control

What is considered a heavy mealAll take-away food (other than sushi)All restaurant meals (other than conscious effort for

low-fat, small portioned meal)A home-cooked meal containing fried food, fatty cuts of

meat, full cream desserts/cakes

Respiratory infectionTwo or more symptoms of headache, sore throat, fever,

cough or nasal discharge, joint discomfort.

Bolded levels of physical and emotional stress were entered in the diaries.Adapted from Refs. [1,2].

at onset or within 30 min prior to an anticipated stres-sor; moderate to heavy physical activity – aspirin (100 mg)plus propranolol (10 mg); moderate to severe anger oranxiety – aspirin plus propranolol; heavy meal – aspirinonly; respiratory infection – aspirin only. Subjects notedin the diary whether and when they took the studymedication.

24 h Heart Rate MonitorFor one 24-hour period during the run-in and study peri-ods, participants wore a heart rate monitor (Polar S610i),during which they performed an episode of physical exer-tion. During the study period, subjects were instructed toperform the same or similar physical activity as during

During a run-in period over one month, subjects wereinstructed on how to identify and record specific triggersin a pocket-sized event diary. Using scales derived fromthe Onset study [1,2], the subjects recorded only moresevere episodes of physical activity and emotional stressthat have been associated with an increased relative riskof MI. For instance, subjects recorded exertion equivalentto ≥6 Metabolic equivalents, anger events of level 4–6, i.e.from “moderately angry, so hassled it shows in your voice”to “furious or enraged, almost out of control or out of con-trol.” Heavy meal and respiratory infection were definedas in Table 1. Participants were encouraged to maintainusual daily activities and behaviour.

Medication PackagingTo enable medication to be readily accessible and not inter-fere with daily activity, subjects were provided with smallflat plastic sealable bags (6.5 cm × 7.5 cm) that could bekept in a wallet or purse, or with their event diary in atrouser pocket or bag.

Study ProtocolDuring the run-in period, participants were instructed inrecording episodes of heavy physical activity, emotionalstress (anger and anxiety), heavy meals and respiratoryinfection. In the first week, subjects were telephoned atleast once by an investigator to address any questions andremained available.

Prior to the study period, the investigator providedinstruction on the appropriate response to a triggeringactivity. In addition to completing the event diary, sub-jects were instructed to take the following oral medication

OR

IGIN

AL

AR

TIC

LEHeart, Lung and Circulation Shaw et al. 349

2009;18:347–352 Therapy for triggered acute risk prevention

run-in although during the study period, they took aspirinand propranolol, 30 min prior to the monitored activity.

Regular ExercisersDuring the run-in period, nine subjects were identifiedwho exercised ≥4 times a week and were classified asregular exercisers. Since heavy exertion in regular exer-cisers is associated with only a small increase in relativerisk [1,8], the nine regular exercisers were instructed to nottake medication for exertion, although they still recordedeach episode. The exception was that during the heart ratemonitoring during the study period, these subjects wererequired to take study medication prior to exertion. Adher-ence with taking medication for triggers was assessedthrough the event diary and self-report in an end-of-studyquestionnaire.

Study PopulationOf the 19 subjects recruited, one subject, a 49-year-oldman without medical background, withdrew after fivedays of run-in when he expressed reluctance to completethe diary. This subject had not recorded any triggers. Asecond subject, a 48-year-old female nurse, successfullycompleted the run-in period, but did not participate inthe study period because she was commenced on dailyaspirin by her doctor.

SCct<auawan

R

ST(nc

TDrmi

PAwtuw

Table 2. Baseline Characteristics of the Study Participants.

Age mean (range) in years 45.2 (30–64)Age group, n (%)

30–44 8 (47%)45–59 7 (41%)60–75 2 (12%)

Gender, n (%)Male 7 (41%)Female 10 (59%)

Height mean (range) in cm 169 (155–197)Weight mean (range) in kg 76 (54–102)Heart rate mean (range) in bpm 72 (60–85)

Smoker, n (%)Current 4 (23%)Ex-smoker 3 (18%)Never smoked 10 (59%)

Marital status, n (%)Married 6 (35%)Divorced 2 (12%)De-facto 4 (24%)Never married 5 (29%)

Employment, n (%)Full-time 14 (82%)Part-time 2 (12%)Not employed 1 (6%)

Occupation, n (%)Health professionals (incl. medical student) 8 (47%)Non-health professionals 9 (53%)

Emotional StressWork conflict, deadlines and equipment malfunction wereleading causes of anger and anxiety.

Anger: During the study period, 3 of 17 subjects reported≥1 anger event. All anger events were unanticipated.

Anxiety: During the study period, 5 of 17 subjectsreported ≥1 anxiety event. Six percent of anxiety eventswere anticipated.

Heavy meals: Fifteen of 17 subjects in the study periodreported at least one heavy meal.

Respiratory infection: Two of 17 subjects reported a respi-ratory infection during the study phase. Both subjects tookaspirin daily during their infections.

24-hour Heart Rate MonitorDuring the heart rate monitoring period, 14 of the 17subjects performed almost identical types of exercise inboth phases (stationary bike, treadmill or lifting weights).In the remaining subjects, one went for a more strenu-ous run during the study period than the run-in, anotherperformed push-ups and sit-ups in the run-in periodbut performed speed walking during the study period.Another walked up stairs in the run-in, and spent twicethe time exercising in the study period than during therun-in. The maximum and average heart rates duringexertion were lower in the study period (30 min afterpropranolol 10 mg and aspirin 100 mg) than during therswe

tatistical Analysisomparison of peak and average heart rate during exer-

ise between Phase 1 and 2 was performed using paired-test or Wilcoxon rank-sum test (SigmaStat). p-values0.05 were considered statistically significant. Analyses fordherence with medication were conducted such that reg-larly exercising subjects were considered to have takenppropriate medication for their physical exertion onlyhen the correct response was to take medication. We

lso compared results for the subjects with medical versuson-medical background.

esults

ubject Characteristics (Table 2)en women (59%) and seven men (41%) aged 30–64 years45.1 ± 8.8) completed the study period. Nine subjects didot have a health care background while eight had a healthare background (seven nurses and one medical student).

riggering Events during the Study Perioduring the one month study period, the 17 subjects

eported a total of 158 physical exertion events, 103 heavyeals, 11 anger events, 15 anxiety events and 2 respiratory

nfections.

hysical Activitylmost all (99.2%) reported episodes of physical exertionere anticipated activities such as speed walking, running,

raining exercises and gym workouts. There were threenanticipated events (e.g. a subject ran to catch a train toork).

un-in (128 ± 38 versus 149 ± 21, p < 0.01) and (96 ± 28 ver-us 111 ± 16, p = 0.007). This difference was also significanthen we only analysed subjects who reported identical

xercise during the run-in and study periods.

OR

IGIN

AL

AR

TIC

LE

350 Shaw et al. Heart, Lung and CirculationTherapy for triggered acute risk prevention 2009;18:347–352

AdherenceSubjects reported an average adherence of 94% in com-pleting the diary when they had a triggering event duringthe study period. Adherence with taking appropriate med-ication when indicated was 88% based on diary entries,with 14 of the 17 subjects able to achieve >80% adherence.Based on self-report with the end-of-study question-naire, adherence with taking indicated medication was89%. Non-adherence only represented failure to take theindicated medication as instructed. No subject took med-ication when it was not indicated. Of the three subjectswith <80% adherence, one was a regular exerciser whoseonly trigger was one heavy meal event for which she forgotto take study medication. Another did not contact inves-tigators for further medication when she had insufficientaspirin to cover four of her nine heavy meals. A third hadan episode of anxiety at night which awoke her but shedid not get out of bed to take the indicated study medi-cation. This subject also had six anxiety episodes duringexams for which she did not take study medication, andforgot to take medication for two heavy meals. Adherencefor taking medication based on diaries for the individ-ual triggers were: physical activity 100%, heavy meals90%, anger 91%, anxiety 60%, and respiratory infection100%. The lower adherence rate for anxiety was largelybecause of the participant previously described who didnot take medication for any of seven episodes of anxi-

Discussion

The study found that it was feasible and acceptable forhealthy subjects to take medication at the time of or shortlybefore triggering activities that in prior studies have beenlinked to a transient increase in risk of MI, sudden death,and stroke. The potential triggers evaluated were heavyphysical exertion, anger and anxiety, heavy meal and res-piratory infection, since these have been associated withan increased relative risk of MI [1–7]. There was 88%adherence with taking medication based on event diaries.Subjects who achieved <80% adherence mainly forgot, orin one case, ran out of study medication. No subject tookmedication when it was not indicated. Non-health profes-sionals were equally successful in trigger recognition andmedication adherence as health professionals. Two thirdsof subjects felt that they would be able to take medica-tion using this approach in the future and that it wouldbe feasible for the general population to follow the proto-col. When taking beta-blocker prior to exertion, subjectshad a lower heart rate, consistent with prior studies [12].The significant heart rate reduction was observed withlow dose propranolol (10 mg) taken 30 min prior to theexertion.

The study pharmacotherapy was chosen based on thepathophysiologic processes associated with the triggers.Acute physical and emotional stress has been linked toelevations in heart rate and blood pressure, reduced elec-

ety.

Triggering events were easily categorised by 82% of sub-jects, while one found difficulty distinguishing the level ofseverity of anger and anxiety.

Subject SatisfactionAll subjects agreed (either strongly 65% or moderatelystrongly 35%) that the packaging made it easy to use themedication when indicated. Completing the diary helpedsubjects to remember to take study medication (47%strongly agreed, 18% moderately agreed and 29% mildlyagreed). Seventy-one percent considered (29% strongly,18% moderately and 24% mildly) that they would be ableto sustain taking medication for triggering events in thefuture, while 71% thought the strategy used in this studywould be feasible for the general population (35% stronglyagreed, 18% moderately and 18% mildly). No adverseeffects of medication were reported. One subject felt morerelaxed than expected after taking medication prior to ananticipated stressful talk.

Effect of Health Care BackgroundThe presence or absence of a health care background didnot significantly influence the results. Completion ratesfor triggering events in the diary during the study periodwere 95% for health care background and 93% for non-health care background. Adherence in taking medicationwas 85% based on self-report for subjects with a healthcare background compared to 93% in non-health profes-sionals. Based on event diaries, the adherence was 82%and 94% in those with and without health care back-ground, respectively.

trical stability, platelet activation and a procoagulant state,endothelial dysfunction and plaque rupture [13]. Respira-tory infection also leads to a prothrombotic state [14,15].Some studies have found a prothrombotic response to afatty meal, reduced vascular reactivity and increased heartrate [16–18].

Beta-blockers provide the most compelling evidence forprotection against physical and emotional triggers of MI[12,19,20–22]. Andrews found that propranolol reducedischaemia associated with increased heart rate by 65%,and those not associated with heart rate increases by 45%[23]. By reducing flow velocity and turbulence at regionsof high circumferential tensile stress, beta-blockers couldreduce endothelial damage and plaque rupture [24].Beta-blockers also reduce arrhythmic risk by attenuatingtransmembrane fluxes due to catecholamine surges [25].

Aspirin preferentially reduced the morning peak of MIthat corresponds with a morning peak of platelet reactivity[26]. Aspirin inhibits epinephrine-induced platelet aggre-gation within 15 min [27,28]. Subjects taking aspirin had areduced relative risk for anger triggering MI [2].

In the present study, we focused on medication withrapid onset of action. However, the hazard intervalassociated with respiratory infection or longer acting psy-chological stress, such as bereavement, can last over daysto months, where other therapy such as statins may beof benefit. In some individuals already receiving aspirin,clopidogril could be considered [29] or alternatively anincrease in aspirin may help counter the prothromboticmilieu associated with a trigger. In those already onbeta-blockers, additional heart rate lowering may notbe indicated. However, underutilisation and suboptimal

OR

IGIN

AL

AR

TIC

LEHeart, Lung and Circulation Shaw et al. 351

2009;18:347–352 Therapy for triggered acute risk prevention

long-term adherence for evidence-based therapies, suchas beta-blockers, is well recognised [30,31].

The present approach may also be applicable to otheridentified triggers of MI such as days of heavy pollutionwhich are associated with a prothrombotic state [10]. Emo-tional stress is often a precipitant of TakoTsubo cardiomy-opathy, and its effects could potentially be ameliorated bythe present approach [11]. Having aspirin and propranololavailable would also potentially enable them to be takenif a subject developed chest pain symptoms of MI.

LimitationsWe relied on the subjects to record the occurrence ofstressors and the taking of study medications, and did notconduct pill counts. However, there was close agreementbetween diary entries made at the time of the stressor,and self-report at the end-of-study questionnaire. For theheart rate evaluation, we asked subjects to take propra-nolol 30 min prior to exercise. Although the effect wouldnot have been maximal at 30 min, the expected heart ratelowering was still significant. There may be bias towardsa reduced heart rate if subjects performed less strenuousexercises while on propranolol or if a training effect waspresent, however 14 of 17 subjects performed almostidentical exercise in both Phases, and the differenceswere significant when the analysis was restricted to the1wbsoaemirtwrpfttnosawtmp

sfnpicd

directed therapy include the informal use of beta-blockersfor performance anxiety, prophylactic nitroglycerin forexercise-induced angina and “pill in the pocket” strate-gies for supraventricular tachycardia. A transient increasein risk has to be balanced by the low absolute risk for anypotential trigger to cause MI.

Conclusion

Healthy subjects successfully identified potential trigger-ing activities of physical exertion, acute emotional stress,heavy meals and respiratory infection, and had an 88%adherence rate in filling out diaries and taking medica-tion appropriately. The reduced heart rate during exercisewith propranolol, support the efficacy of beta-blockadeduring periods of increased adrenergic activity. Whilesome of the results may appear intuitive based on normalbehaviour (e.g. the ability to identify an episode of anger ora heavy meal), acute preventive therapy would represent anovel approach to prevention that would complement cur-rent chronic daily therapy. Study of the feasibility of thisapproach in higher risk subjects is required. Ultimately,large numbers of randomised individuals would berequired to test whether short-term management of acutetriggering activities would lower the occurrence of MI,sudden deaths and stroke. The present study suggests thatit is feasible and practical to take medication at the time ofacute triggering events, and supports further investigationo

R

4 with almost identical exercise. For anger and anxiety,hich are often unanticipated, propranolol would note immediately effective, however the hazard period ofevere acute psychological stressors often extends beyondne hour, and in the Onset Study, was two hours fornger, which would include a period of drug effect [2]. Wexcluded subjects with known illness or taking regularedication. Future studies are required in higher risk

ndividuals, including elderly people and those takingegular medication. While there were no safety issues inhe present study, medication overuse as well as underuseould raise potential safety concerns. While the relative

isk during a trigger may be significantly increased com-ared to baseline periods, the most important information

or clinical significance is the absolute difference in riskhe activity produces. For instance, it has been estimatedhat the absolute risk that a 50-year-old non-smoking,on-diabetic man will experience an MI is approximatelyne chance in a million per hour, and 10-fold higher inomeone with prior MI [10]. In a low risk individual, even10-fold increase in relative risk of a brief, rare triggerith a hazard interval of one hour may only increase the

ransient absolute risk from one in a million to 10 in aillion. In this instance, the potential for benefit from

rophylactic therapy would be very low.Although two thirds considered the approach to be fea-

ible and practical, some individuals will not be suitedor the self-awareness and understanding required. Cog-itive impairment and depression will also contribute tooor adherence to medication. Nonetheless this approach

s consistent with efforts to involve patients in theirare. While adherence in higher risk subjects cannot beetermined from this study, other examples of patient-

f the potential role of triggered acute risk prevention.

eferences

[1] Mittleman MA, Maclure M, Tofler GH, Sherwood JB, Gold-berg RJ, Muller JE. Triggering of acute myocardial infarctionby heavy physical exertion. Protection against triggeringby regular exertion. Determinants of Myocardial InfarctionOnset Study Investigators. N Engl J Med 1993;329:1677–83.

[2] Mittleman MA, Maclure M, Sherwood JB, Mulry RP, ToflerGH, Jacobs SC, Friedman R, Benson H, Muller JE. Trigger-ing of acute myocardial infarction onset by episodes of anger.Circulation 1995;92:1720–5.

[3] Hallqvist J, Moller J, Ahlbom A, Diderichsen F, Reuterwall C,de Faire U. Does heavy physical exertion trigger myocardialinfarction? A case-crossover analysis nested in a population-based case-referent study. Am J Epidemiol 2000;151:459–67.

[4] Moller J, Theorell T, de Faire U, Ahlbom A, Hallqvist J.Work related stressful life events and the risk of myocardialinfarction. Case-control and case-crossover analyses withinthe Stockholm heart epidemiology program. (SHEEP). J Epi-demiol Community Health 2005;59:23–30.

[5] Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Val-lance P. Risk of myocardial infarction and stroke after acuteinfection or vaccination. N Engl J Med 2004:2611–8.

[6] Lipovetsky N, Hod H, Roth A, Kishon Y, Sclarovsky S, GreenMS. Heavy meals as a trigger for a first event of the acute coro-nary syndrome: a case-crossover study. IMAJ 2004;6:728–31.

[7] Strike PC, Steptoe A. Behavioural and emotional triggers ofacute coronary syndromes: a systematic review and critique.Psychosom Med 2005;67:179–86.

[8] Giri S, Thompson PD, Kiernan FJ, Clove J, Fram DB, MitchelJF, Hirst JA, McKay RG, Waters DD. Clinical and angiographiccharacteristics of exertion-related acute myocardial infarc-tion. JAMA 1999;282:1731–6.

OR

IGIN

AL

AR

TIC

LE

352 Shaw et al. Heart, Lung and CirculationTherapy for triggered acute risk prevention 2009;18:347–352

[9] Moller J, Hallqvist J, Diderichsen F, Theorell T, Reuter-wall C, Ahlbom A. Do episodes of anger trigger myocardialinfarction? A case-crossover analysis in the StockholmHeart Epidemiology Program (SHEEP). Psychosom Med1999;61:842–9.

[10] Tofler GH, Muller JE. Triggering of acute cardiovascu-lar disease and potential preventive strategies. Circulation2006;114:1863–72.

[11] Wilbert-Lampen U, Leistner D, Greven S, Pohl T, Sper S,Volker C, Guthlin D, Plasse A, Knez A, Kuchenhoff J, SteinbeckG. Cardiovascular events during world cup soccer. N Engl JMed 2008;358:475–83.

[12] Frishman WH. Multifactorial actions of beta-adrenergicblocking drugs in ischemic heart disease: current concepts.Circulation 1983;67:11–8.

[13] Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute riskfactors and vulnerable plaques: the lexicon of a new frontier.J Am Coll Card 1994;23:809–13.

[14] Naghavi M, Wyde P, Litovsky S, Madjid M, Akhtar A, NaguibS, Siadaty MS, Sanati S, Casscells W. Influenza infectionexerts prominent inflammatory and thrombotic effects on theatherosclerotic plaques of apolipoprotein E-deficient mice.Circulation 2003;107:762–8.

[15] Visseren FL, Bouwman JJ, Bouter KT, Diepersloot RJ, de GrootPH, Erkelens DW. Procoagulant activity of endothelial cellsafter infection with respiratory viruses. Thromb Haemost2000;84:319–24.

[16] Miller GJ, Martin JC, Webster J, Wilkes H, Miller NE,Wilkinson WH, Meade TW. Association between dietaryfat intake and plasma factor VII coagulant activity—a pre-

[

[

[

[

[21] Tofler GH, Muller JE, Stone PH, Forman S, Solomon RE, Knat-terud GL, Braunwald E. Modifiers of timing and possibletriggers of acute myocardial infarction in the Thrombolysisin Myocardial Infarction Phase II (TIMI II) Study Group. J AmColl Card 1992;20:1049–55.

[22] Mangano DT, Layug EL, Wallace A, Tateo I, for the Multicen-ter Study of Perioperative Ischaemia Research Group. Effectof atenolol on mortality and cardiovascular morbidity afternoncardiac surgery. N Engl J Med 1996;335:1713–20.

[23] Andrews TC, Fenton T, Toyosaki N, Glasser SP, Young PM,MacCallum G, Gibson RS, Shook TL, Stone PH, for theAngina and Silent Ischemia Study Group (ASIS). Subsets ofambulatory myocardial ischemia based on heart rate activity.Circulation 1993;88:92–100.

[24] Richardson PD, Davies MJ, Born GV. Influence of plaque con-figuration and stress distribution on fissuring of coronaryatherosclerotic plaques. Lancet 1989;2:941–4.

[25] Brown MJ, Brown DC, Murphy MB. Hypokalemia from �-2receptor stimulation by circulating epinephrine. N Engl J Med1983;309:1414–9.

[26] Ridker PM, Manson JE, Buring JE, Muller JE, Hennekens CH.Circadian variation of acute myocardial infarction and theeffect of low-dose aspirin in a randomized trial of physicians.Circulation 1990;82:897–902.

[27] Folts JD, Rowe GG. Epinephrine potentiation of in vivostimuli reverses aspirin inhibition of platelet thrombus for-mation in stenosed canine coronary arteries. Thromb Res1988;50:507–16.

[28] Jimenez AH, Stubbs ME, Tofler GH, Winther K, Williams GH,Muller JE. Rapidity and duration of platelet suppression by

[

[

[

dictor of cardiovascular mortality. Atherosclerosis 1986;60:269–77.

17] Vogel RA, Corretti MC, Plotnick GD. Effect of a single high-fatmeal on endothelial function in healthy subjects. Am J Cardiol1997;79:350–4.

18] Baliga RR, Burden L, Sidhu MK, Rampling MW, Kooner JS.Effects of components of meals (carbohydrate, fat, protein) incausing postprandial exertional angina pectoris. Am J Cardiol1997;79:1397–400.

19] Peters RW, Muller JE, Goldstein S, Byington R, FriedmanLM. Propranolol and the morning increase in the fre-quency of sudden cardiac death (BHAT Study). Am J Cardiol1989;63:1518–20.

20] Deedwania PC, Carbajal EV. Role of Beta blockade in the treat-ment of myocardial ischaemia. Am J Cardiol 1997;80:23J–8J.

enteric-coated aspirin in healthy young men. Am J Cardiol1992;69:258–62.

29] The Clopidogril in Unstable Angina to Prevent RecurrentEvents Trial Investigators. Effects of clopidogril in additionto aspirin in patients with acute coronary syndromes withoutST-segment elevation. N Engl J Med 2001;345:494–502.

30] Miller RR, Li Y-F, Sun H, Kopjar B, Sales AE, PinerosSL, Fihn SD. Underuse of cardioprotective medications inpatients prior to acute myocardial infarction. Am J Cardiol2003;92:209–11.

31] Newby LK, Allen LaPointe NM, Chen AY, Kramer JM,Hammill BG, DeLong ER, Muhlbaier LH, Califf RM. Long-term adherence to evidence based secondary preventiontherapies in coronary artery disease. Circulation 2006;113:203–12.