International Journal of Cardiology 130 (2008) 180 – 184 www.elsevier.com/locate/ijcard
Acute myocardial infarction preceded by potential triggering activities: Angiographic and clinical characteristics Yafim Brodov a,⁎, Amir Sandach b , Valentina Boyko b , Shlomi Matetzky a , Victor Guetta a , Lori Mandelzweig a , Solomon Behar b b
a Heart Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel Neufeld Cardiac Research Institute, Sackler Faculty of Medicine, Tel Aviv University, Tel Hashomer, Israel
Received 18 January 2007; received in revised form 8 July 2007; accepted 20 July 2007 Available online 18 December 2007
Abstract Background: In an investigation of the relationship between myocardial infarction (MI) preceded by certain activities or events and coronary angiographic data, including the extent of atherothrombotic involvement during acute MI, we hypothesized that when comparing patients with MI that was preceded by potential triggering activities (PTA “+”) to MI without PTA, the former might have a distinct pathogenic basis exhibiting different angiographic and clinical features. Methods: In the framework of a national survey on acute coronary syndromes conducted during a 2-month period in 2002, 662 acute MI patients with complete angiographic data were divided into two groups, according to whether or not they reported the presence of specific unusual events or activities immediately preceding the onset of MI. Results: One hundred and one patients with PTA “+” MI were younger, and included a higher proportion of smokers than their counterparts (n = 561), who were characterized by a higher frequency of hypertension and diabetes. After adjustment for age, gender, prior MI or CABG, diabetes, hypertension, current smoking, serum creatinine level, left ventricular ejection fraction less than 30%, re-ischemia and Killip class II+, 30-day, 6 month and 1-year mortality was similar between the two groups. The incidence of LAD disease (P b 0.01), 3-vessel coronary disease (P b 0.03) and TIMI flow 0 or 1 after coronary angioplasty was significantly lower (P b 0.02) in patients with PTA “+” MI, while infarct-related right coronary artery (RCA) obstruction was significantly higher (OR: 1.7; 95% CI: 1.0–2.9). Conclusion: Further investigation is needed in order to confirm the association between angiographic data and potential triggering activities observed in our study, and to determine the mechanisms responsible for this finding. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Acute myocardial infarction; Coronary angiography; Myocardial infarction with trigger
1. Introduction Previous studies that investigated circadian variations, triggers and unusual life events have provided extensive data on their significant role in precipitating myocardial infarction (MI). Various events, such as emotional stress, heavy physical exertion, bursts of anger, sexual activity, heavy meals and others, have been reported in up to 40% of all ⁎ Corresponding author. Heart Institute, Sheba Medical Center, Tel Hashomer 52621, Israel. Tel.: +972 3 5302604; fax: +972 3 5343888. E-mail address:
[email protected] (Y. Brodov). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.07.173
cases of acute coronary syndromes and nonfatal MI [1]. It has been suggested that the underlying pathogenesis of MI involves mechanisms that increase blood coagulability, platelet aggregation and vasoconstriction. Gender-related differences, such as physical exertion and overeating were more likely to precipitate MI in men, while emotional stress was a more frequent potential trigger of events in women [2]. Age-related trigger differences in anterior and inferior MI have also been reported [3]. Patients with triggered MI have been shown to have a lower prevalence of angina, hypertension and diabetes mellitus compared to patients without triggers.[2–4]. However, the relationship between
Y. Brodov et al. / International Journal of Cardiology 130 (2008) 180–184 Table 1 Type of events according to MI location
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Table 3 Medical and interventional treatment
Events (n = 101)
Anterior MI (N = 38) n, %
Inferior MI (N = 41) n, %
Other MI (N = 22) n, %
P
Emotional stress Heavy physical exertion Heavy meal Anger Sexual activity Two events
13 (34) 15 (39)
15 (37) 7 (17)
7 (32) 6 (27)
0.8 0.09
6 (16) 3 (8) 0 1 (3)
9 (22) 1 (2) 7 (17) 2 (5)
7 (32) 2 (9) 0 0
0.3 0.8 0.005 0.8
MI that was preceded by potential triggering activities (PTA) and coronary angiographic data, including the extent of atherothrombotic involvement during acute MI, has not been thoroughly investigated. We hypothesized that when comparing cases of myocardial infarction for which PTA were reported, with cases of MI without reports of PTA preceding the event, the former might have a distinct pathogenic basis exhibiting different angiographic and clinical features.
Aspirin Ticlopidine, clopidogrel Platelet glycoprotein IIb/ IIIa antagonists Heparin (unfractionated) LMWH β-Blockers Nitrates Diuretics ACE-inhibitors Lipid lowering drugs Antiarrhythmics Digitalis Primary reperfusion Thrombolysis Primary PCI Any PCI Coronary bypass
PTA“+”MI (N = 101), %
PTA“−”MI (N = 561), %
P value
95.0 63.4 29.7
93.0 60.6 17.5
NS NS 0.004
49.5 48.5 77.2 46.5 14.9 61.4 59.4 6.9 1.0 33.7 13.9 19.8 80.2 6.9
49.0 46.0 75.8 61.7 21.0 64.7 67.6 7.5 2.0 34.0 15.2 18.9 73.8 10.2
NS NS NS 0.004 NS NS NS NS NS NS NS NS NS NS
LMWH = low molecular weight heparin.
2. Patients and methods Data were collected on 1490 consecutive patients with acute MI, hospitalized in all operating cardiac departments in Israel during February and March 2002 within the framework of a biennial 2-month survey on acute coronary syndrome, conducted by the Israel Heart Society (ACSIS). Myocardial infarction was diagnosed on the basis of the following criteria: duration of anginal chest pain N 30 min, ST-segment elevation N1 mm in 2 inferior leads, N 2 mm in 3 precordial leads or left bundle branch block and N1 mm in posterior leads, or cardiac enzyme elevation (CPK-MB, Troponin I or Troponin T). On the special survey form for each patient, filled out prospectively by cardiologists during the hospitalization period, a question about the presence or absence of PTA immediately preceding the MI was included,
in addition to clinical, echocardiographic and angiographic data. These activities, or experiences, included emotional stress, bursts of anger, physical exertion, sexual activity and heavy meals. Coronary angiography was performed on 1021 patients, and complete angiographic data were available for 662 of these patients, who formed the current study population. The patients who constituted the PTA “+” group (n = 101), reported the presence of potential triggering activities or experiences immediately before MI, while the remaining 561 patients did not (PTA “−” group). Angiographically significant coronary stenosis was defined as N 50% of luminal diameter stenosis. TIMI coronary flow Table 4 Clinical course and complications PTA“+”MI PTA“−”MI P value (N=101), % (N=561), %
Table 2 Baseline characteristics and risk factors
Age (years) Females (%) Prior angina (%) Prior MI (%) Prior coronary bypass (%) Past PCI (%) Diabetes (%) Hypertension (%) Current smoking (%) Total Cholesterol (mg/dL) LDL-Cholesterol (mg/dL) HDL-Cholesterol (mg/dL) Triglycerides (mg/dL) Body mass index (kg/m2) Blood creatinine (mg/dL)
PTA “+”MI (N = 101)
PTA“−”MI (N = 561)
P value
59.2 ± 11.2 16.8 19.8 18.8 5.0 14.9 23.8 34.7 44.6 191.9 ± 38.5 117.3 ± 36.7 42.0 ± 11.2 174.8 ± 110.6 26.8 ± 3.6 89.8 ± 23.9
62.8 ± 12.4 22.5 38.5 23.0 9.8 18.4 31.7 53.7 33.7 198.3 ± 50.3 124.2 ± 38.6 42.1 ± 11.0 166.1 ± 107.9 27.04 ± 3.7 103.2 ± 50.8
0.007 NS 0.0003 NS NS NS 0.1 0.0004 0.03 NS NS NS NS NS 0.009
PCI — percutaneous coronary intervention.
Pulmonary edema CAVB PAF Stroke Re-infarction Re-ischemia STE MI NSTE MI Peak CPK, mg/L, mean Anterior MI LVEF 30–40% LVEF b30% Killip II+ Hospitalization length (days), mean
3.0 4.0 4.0 1.0 2.0 4.0 54.5 44.5 1183.1 37.6 23.7 4.8 9.9 6.1
7.3 2.3 6.2 0.9 2.5 8.9 49.8 47.9 1124.9 39.0 21.4 10.4 17.6 7.4
CAVB = complete AV block. PAF = paroxysmal atrial fibrillation. STEMI = ST elevation myocardial infarction. NSTEMI = myocardial infarction without ST elevation. LVEF = left ventricle ejection fraction.
NS NS NS NS NS 0.09 NS NS NS NS NS NS 0.05 0.03
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Table 5 Angiographic data
LMCA LAD 3 vessel disease IRA — LAD IRA — CX IRA — RCA
Table 7 Mortality rates PTA“+”MI (n = 101), %
PTA“−”MI (n = 561), %
P value
OR a (95% CI)
Mortality
PTA“+”MI (n = 101)
PTA“−”MI (n = 561)
P value
OR a (95% CI)
3.0 54.5 16.8 26.7 12.9 26.7
8.4 70.6 32.8 24.1 7.7 15.7
NS 0.01 0.03 NS 0.09 0.03
0.5 0.5 0.5 1.0 1.8 1.7
7-day (%) 30-day (%) 6-month (%) 1-year (%)
0 1.0 3.0 3.0
2.1 3.9 5.7 7.1
0.1 0.1 0.2 0.1
– 0.5 (0.1–3.7) 1.1 (0.3–3.8) 0.8 (0.2–2.8)
(0.1–1.3) (0.3–0.9) (0.3–0.9) (0.6–1.7) (0.9–3.6) (1.0–2.9)
IRA = infarct-related artery. LMCA = left main coronary artery. LAD = left anterior descending artery. CX = circumflex artery. RCA = right coronary artery. a After adjustment for age, gender, prior MI, prior CABG, diabetes, hypertension, current smoking, creatinine levels, LVEF b30%, re-ischemia and Killip II+.
assessment, performed on the basis of TIMI flow score [5], was obtained only in patients who underwent PCI. 3. Statistical methods Data were analyzed using SAS software (SAS institute, Cary, NC, USA). Continuous variables were expressed as mean ± SD; chi-square and t tests were used to compare proportions and means, respectively. Two-sided P values were reported. Multivariate analysis of the risk (expressed as odds ratios) of both specific angiographic findings and mortality associated with PTA “+” was performed using logistic regression with adjustment for age, gender, prior MI or CABG, diabetes, hypertension, current smoking, creatinine levels, left ventricular ejection fraction less than 30%, re-ischemia and Killip class II+. 4. Results Among the 101 patients with potential triggering activities recorded (98 patients reported one single event and 3 patients reported two events), the types of PTA were distributed as follows: emotional stress: 35 patients; heavy physical exertion: 28 patients; heavy meals: 22 patients; sexual activity: 7 patients; anger: 6 patients; and 3 patients reported more than one event. Heavy physical exertion was reported as a PTA in 39% and 17% respectively of all PTA patients with anterior or inferior MI (P N 0.09). Sexual activity served as a PTA more frequently among PTA patients with inferior versus anterior MI (P N 0.005) (Table 1). Baseline characteristics and Table 6 TIMI coronary flow before and after PCI
TIMI flow 0, 1 (before PCI) TIMI flow 3 (before PCI) TIMI flow 0, 1 (after PCI) TIMI flow 3 (after PCI)
PTA“+”MI (n = 49) (%)
PTA“−”MI (n = 244) (%)
P value
41.8 51.0 0 91.9
37.8 52.3 8.1 90.3
NS NS 0.02 NS
a After adjustment for age, gender, prior MI, prior coronary bypass, diabetes, hypertension, current smoking, creatinine levels, LVEF b30%, re-ischemia and Killip II+.
coronary risk factors in both types of MI are shown in Table 2. The PTA “+”patients were younger, with a greater proportion of current smokers, while their counterparts included more hypertensive and diabetic patients with higher blood creatinine levels. In-hospital management is presented in Table 3. In the PTA “+” group, 30% of patients were treated with platelet glycoprotein IIb/IIIa antagonists versus only 17% of PTA “−” group (P b 0.004). Patients with PTA “−” presented with higher Killip class and were more likely to develop pulmonary edema, re-ischemia and impaired left ventricular function, although these differences were not statistically significant (Table 4). In 27% of the patients with PTA “+” and 16% of the PTA “−” group, the RCA was the infarct-related artery, OR: 1.7; 95% CI: 1.0−2.9 (Table 5). However, the incidence of LAD disease and 3-vessel coronary disease was significantly lower in the PTA “+” group, OR: 0.5; 95% CI: 0.3–0.9 (Table 5). A statistically significant higher rate of TIMI flow 0 or 1 after coronary intervention was found in patients with no PTA (Table 6). Seven-day, 30-day, 6-month and 1-year mortality tended to be higher in the PTA “−” group, but after adjustment for age, gender, prior MI or CABG, diabetes, hypertension, current smoking, creatinine levels, left ventricular ejection fraction less than 30%, re-ischemia and Killip class II+, the difference in mortality rates between the two groups disappeared (Table 7). 5. Discussion Cardiovascular epidemiology, which has focused on chronic risk factors such as diabetes mellitus, hypertension, hyperlipidemia and others during the past decade, has recently devoted increased attention to acute risk factors or external triggers, which could possibly cause disruption of vulnerable coronary plaque and occlusive thrombus formation, producing acute MI and sudden cardiac death [1]. Strategies for prevention of MI, as well as efforts to stabilize vulnerable or unstable plaque, include elucidation of the mechanism by which acute risk factors or triggers initiate plaque rupture [1]. Since the early 1990s, multiple studies on the role of external triggers such as mental stress [6,7], bursts of anger [8–10], circadian rhythms [11–16], physical exertion [17–20], sexual activity [21–23], disaster [24–26], important sporting events [27,28] and other possible triggers which could precipitate acute MI, have been conducted. According to these studies the
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above-mentioned events could play a causative role in up to 40% of all cases of acute coronary syndromes and nonfatal MI [4]. The MILIS study found that among the triggering events reported, emotional stress was the most common, affecting up to 20% of patients with acute MI, while moderate physical activity was reported in 14% of the same population [4]. Of all potential triggering activities examined in our study, emotional stress and anger were the most common, reaching as much as 40%. In accordance with Culic et al. [2] and the MILIS study, PTA “+” MI in our study was associated with younger age, being male, smoking, and having no previous history of angina, while it was less likely to occur in diabetic and hypertensive patients. Presumably this younger population, with a more active life style, was more exposed to external influences and was also more likely to report a potential triggering activity than were older patients. In another study, Miric et al. showed that anterior infarctions were more frequently associated with physical strain or occurred without any apparent precipitator (67% of all anterior MIs), while inferior infarctions, occurring in 56% of all patients, were found to be triggered more frequently by overeating, emotional or meteorological stress, possibly associated with sudden altered autonomic tone [3]. Our study confirmed a difference between anterior and inferior MI with respect to types of potential triggering activities. Heavy physical exertion preceded anterior MI more frequently, while sexual activity and heavy meals were more likely to precede inferior MI, suggesting that inferior and anterior MIs may have different precipitating mechanisms. In addition, lower mortality rates in patients with “triggered” MI have also been reported [2–4]. A trend towards higher early and late mortality rates during a 1-year follow-up in patients with PTA “−” versus those with PTA “+” MI was observed in our study. This trend, despite lack of differences in enzymaticallyassessed MI size, incidence of anterior or ST elevation MI and lack of difference in clinical management (except platelet glycoprotein IIb/IIIa antagonists use), could possibly be explained by a larger percentage of older hypertensive and diabetic patients, with more extensive coronary disease in the PTA “−” group. However this trend was not maintained after adjustment for baseline characteristics. Angiographic analysis revealed significantly more severe involvement of the LAD in the PTA “−” group of patients, while the infarct-related RCA was more frequently associated with the PTA “+” group. A partial explanation for these findings could be differing sensitivity of the coronary artery to possible triggers, a fact suggested by the relative abundance of cholinergic receptors of the inferior wall of the heart [29]. In addition, under strain or on physical exertion, the risk of plaque rupture increases with consequent occlusion of the coronary artery which, in turn, could precipitate an anterior infarction [17]. Platelet glycoprotein IIb/IIIa antagonists were administered at the discretion of the treating physician on the basis of angiographic evidence of coronary thrombosis or ruptured plaque, which might suggest a higher incidence of thrombotic lesions in patients with PTA “+” . Based on the above, we
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hypothesize that two types of acute MI could exist on two sides of the spectrum of our patients: the relatively younger smokers who had no advanced coronary atherosclerosis but with evidence of thrombotic coronary lesions coupled with a sensitivity to external events, as opposed to older diabetic and/ or hypertensive patients with more extensive atherosclerotic involvement who probably have a decreased sensitivity to external events for the precipitation of MI. Limitations: As no control data were available for cases reporting potential triggering activities, it is not possible to determine whether our data on PTA fulfill the criteria of “triggers,” as defined in the literature. Angiographic data were not available for all patients included in the ACSIS2002 registry, and data on TIMI flow prior to and following the coronary intervention were available for about half of the patients who underwent this procedure. In conclusion, the incidence of LAD disease, 3-vessel coronary disease and TIMI flow 0 or 1 after coronary angioplasty was significantly lower, while, infarct-related RCA obstruction was significantly higher in patients with PTA “+”. Further investigation is needed in order to confirm the association between angiographic data and potential triggering activities observed in our study, and to determine the mechanisms responsible for this finding. References [1] Muller JE, Abela GS, Nesto RW, Tofler GH. Triggers, acute risk factors and vulnerable plaques: the lexicon of a new frontier. J Am Coll Cardiol 1994;23(3):809–13. [2] Culic V, Eterovic D, Miric D, Rumboldt Z, Hozo I. Gender differences in triggering of acute myocardial infarction. Am J Cardiol 2000;85(6): 753–6 A8. [3] Miric D, Eterovic D, Giunio L, et al. Triggers of acute myocardial infarction regarding its site. Int J Cardiol 1997;60:67–71. [4] Tofler GH, Stone PH, Maclure M, et al. Analysis of possible triggers of acute myocardial infarction (the MILIS study). Am J Cardiol 1990;66(1): 22–7. [5] Gibson CM, Cannon CP, Daley WL, et al. TIMI frame count: a quantitative method of assessing coronary artery flow. Circulation 1996;93:879. [6] Stalnikowicz R, Tsafrir A. Acute psychosocial stress and cardiovascular events. Am J Emerg Med 2002;20(5):488–91. [7] Krantz DS, Quigley JF, O'Callahan M. Mental stress as a trigger of acute cardiac events: the role of laboratory studies. Ital Heart J 2001;2(12): 895–9. [8] Mittleman MA, Maclure M, Nachnani M, Sherwood JB, Muller JE. Educational attainment, anger, and the risk of triggering myocardial infarction onset. The Determinants of Myocardial Infarction Onset Study Investigators. Arch Intern Med 1997;157(7):769–75. [9] Mittleman MA, Maclure M, Sherwood JB, et al. Triggering of acute myocardial infarction onset by episodes of anger. Determinants of Myocardial Infarction Onset Study Investigators. Circulation 1995;92(7): 1720–5. [10] Moller J, Hallqvist J, Diderichsen F, Theorell T, Reuterwall C, Ahlbom A. Do episodes of anger trigger myocardial infarction? A casecrossover analysis in the Stockholm Heart Epidemiology Program (SHEEP). Psychosom Med 1999;61(6):842–9. [11] Muller JE. Circadian variation and triggering of acute coronary events. Am Heart J 1999;137(4 Pt 2):S1–8. [12] Johnstone MT, Mittleman M, Tofler G, Muller JE. The pathophysiology of the onset of morning cardiovascular events. Am J Hypertens 1996;9(4 Pt 3):22S–8S.
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