Tako-tsubo cardiomyopathy (TTC) is a novel cardiac syndrome characterized by transient left ventricular dysfunction, named by Japanese authors owing to the shape of the heart at ventriculogram, resembling the round-bottomed, narrow-necked jar (tsubo) used for trapping the octopus (tako). TTC is of great interest to cardiologists and emergency medicine physicians, since this condition mimics the clinical scenario of acute myocardial infarction (AMI) Citation[1].
The diagnostic criteria include Citation[1]:
• Transient hypokinesis, akinesis, or dyskinesis in the left ventricular mid segments with or without apical involvement; regional wall motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently but not always, a stressful trigger;
• Absence of obstructive coronary disease or angiographic evidence of acute plaque rupture;
• New ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin;
• Absence of myocarditis or pheochromocytoma.
The prevalence among patients with symptoms suggestive of AMI is 0.7–2.5%, TTC is predominant in postmenopausal women, especially after severe emotional and/or physical stress Citation[2].
Time of onset of TTC
Based on the data from a multicenter Italian registry that included more than 90 cases of TTC, we found a chronobiological pattern, with most events occurring during the morning hours and summer months Citation[3]. Based on these findings, we performed a systematic review of the literature (done from January 2000 to January 2010) Citation[4] including studies with at least 30 cases of TTC, and identified 18 studies (total number of cases: 1051) including eight reports from Europe (404 patients; 38.4%), five from the USA (347 patients; 33.1%), four from Asia (265 patients; 25.2%), and one from Australia (35 patients; 3.3%). Seven studies (four from Europe, one each from Asia, Australia and the USA), all accounting for a total of 391 patients, included in their results the time of onset of events Citation[4].
A circadian (morning) and a seasonal (summer) higher frequency of events was found. Moreover, another study from our group reported a Monday preference for TTC onset Citation[5].
Time of onset of AMI
Time of day
Several decades ago, Muller et al. first observed a circadian variation for onset of AMI, characterized by increased morning frequency between 6 and 12 AM Citation[6]. Some years later, a comprehensive meta-analysis considering 30 studies on nonfatal AMI (66,635 cases) and 19 studies on sudden cardiac death (SCD; 5834 cases) reported that nearly 27.7% of morning AMIs and 22.5% of SCDs (accounting for ∼8.8 and 6.8% of all AMIs and SCDs, respectively) were attributable to a morning excess of risk Citation[7]. It is also possible that time of day may have an impact also on clinical outcome of AMI, since we found an excess of fatal cases between 6 and 12 AM, independent of patients’ age, and AMI site or extension Citation[8].
A series of factors capable of increasing oxygen demand and others that reduce oxygen supply are temporally related to the morning hours Citation[9]. The former include: activation of the sympathetic nervous system during the rapid eye movement (REM) phase of sleep, the rise in heart rate (HR) and blood pressure (BP) – the so-called ‘morning blood pressure surge’ – upon awakening and commencing daily activities, and the well-known morning rise in plasma cortisol levels, contributing to the sensitivity of vessels to vasoconstrictor stimuli – just elevated during morning hours by the enhanced plasma catecholamines. On the other hand, morning reduction in myocardial oxygen supply may derive from other causes, such as enhanced vascular tone (and consequently reduced flow), secondary to an increased α-sympathetic vasoconstrictor activity, imbalance between coagulation and fibrinolysis, with increased levels of fibrinogen, plasma viscosity, hematocrit, platelet aggregability and, by contrast, reduced endogenous fibrinolytic activity.
Of course, the combination of these factors is not typically harmful for healthy individuals, but requires the presence of pre-existing coronary disease. In fact, in the presence of coronary stenoses, in the morning hours, the heart is called upon to increase both workload and HR, with the consequence of an increased risk of myocardial ischemia.
Stress
Stress may exert major effects upon the circulatory system of coronary patients, particularly in the morning, acting on the cardiovascular system in multiple ways Citation[10]. For example, experimental and clinical studies showed a direct link between emotional stress and changes in HR, BP, left ventricular stroke work, cardiac output, blood viscosity and coagulation, all factors that could potentially trigger cardiovascular events. Acute coronary syndromes may also be triggered by emotional stress (in 11% of men and 16% of women, the onset of AMI was preceded by an emotional stress) and acute burst of anger that can be responsible of a twofold increased relative risk of acute coronary syndromes within 2 h. Mental stress may inhibit flow-mediated brachial artery vasodilatation, a validated indicator of endothelial function, and the hemodynamic response to mental stimuli. Interestingly, the effect of stress on the human cardiovascular functions is greater in the morning, and is mediated by circadian rhythmic oscillators.
Month & season of the year
Data from the US Second National Registry of Myocardial Infarction reported 53% more cases in the winter than in the summer, and winter was characterized by the highest frequency of fatal cases Citation[11]. With some exceptions, the majority of studies have reported the lowest frequency of AMI onset in the summer and the highest frequency during winter Citation[12]. We recently confirmed this temporal pattern in more than 64,000 consecutive cases of AMI hospitalized between 1998 and 2006 in the Emilia-Romagna region of Italy Citation[13]. Seasonal variation in multiple factors might play a role Citation[13]. One potential unfavorable factor could be the seasonal change in ambient temperature, with consequences on coagulation, BP and endothelial function. Changes in blood viscosity and coagulation, for example, have been described in relation to cold temperature. A relatively hypercoagulable state could be further supported by elevated fibrinogen levels, which show a significant increase during the colder months of the year. Low temperatures may also lead to an increase in BP levels. Endothelial function is also associated with the season and with ambient temperature, and brachial artery flow-mediated vasodilatation is lowest in the winter. Cholesterol levels also exhibit significant seasonal cycles, characterized by winter time peaks in plasma levels of total cholesterol and LDL-cholesterol Citation[14].
Day of the week
Several studies have indicated that Monday represents a critical day for onset of AMI Citation[14], and we recently confirmed the Monday excess (16.1%) and a lower rate on Sunday (11.8%) Citation[13].
The finding of the highest number of events on Monday and a decreasing number from Tuesday to Sunday has suggested a relationship with the beginning of the working week.
Patients’ activity (or change in activity) and environmental influences may play a substantial role in triggering AMI, and employed subjects probably experience a more stressful change from weekend leisure activities to work activities on Mondays, but reported results are not uniform Citation[15]. A recent meta-analysis of 28 community-based studies confirmed a statistically significant excess in coronary events on Mondays in 20 out of 28 studies Citation[16]. The Monday excess in events was observed in both fatal and nonfatal events, in both sexes, and was greater in younger compared with older subjects. However, this meta-analysis showed that, even if greater than zero, the Monday excess in coronary event was small, being calculated as less than one event in 100, with a relative increase of 1%. Such an excess of events appears negligible when compared with those occurring in the morning (+40%) and in winter (+45%).
Time of onset of TTC & AMI: ethiopathology, analogies & differences
The increased morning frequency of TTC is quite similar to that of AMI. It is possible that these two clinical entities share several common underlying risk factors, and circadian rhythms and stress play a pivotal role in the diurnal regulation of multiple cardiovascular parameters. The catecholamine hypothesis relates to the role that increased sympathetic activity triggered by stress and stressful events may play a pivotal role in TTC. Physiological responses induced by stress involve activation of the sympathoadrenal system. Catecholamines, norepinephrine (NE) and epinephrine (E) are among the first compounds released during stress. Catecholamines appear to show a circadian periodicity, with a peak in the morning.
On the other hand, the possible summer preference in the occurrence of TTC is quite different compared with the well-known winter peak of AMI. However, reports on these aspects of TTC are few and not uniform, and the relationships with different geographic areas and possible influence of meteorological data deserve further investigation. In addition, the available data on the circannual periodicity of catecholamines are more heterogenous even though several studies have suggested a summer peak for NE and E excretion.
The Monday preference in onset of TTC parallels that of AMI, but further confirmation in different settings is needed.
Conclusion
Although the clinical onset of TTC seems to exhibit a preferred time of onset during morning hours and summer months, the number of patients considered in the studies is modest, and does not allow us to draw definite conclusions. Thus, time of onset does not represent a useful tool in diagnosing TTC. In a clinical emergency setting when a prompt differential diagnosis between AMI and TTC is needed, clinical factors (typical chest pain, female sex, postmenopausal age, recent stressful events) and instrumental examinations (ECG, transthoracic echocardiography) remain the first diagnostic tools. Ultimately, most patients require urgent coronary angiography to be sure that an acute thrombolysis is not the culprit.
However, the identification of temporal frames characterized by highest frequency of onset, if confirmed on larger populations, could help in tailoring appropriate use of drugs, such as β-blockers, to try to ensure maximal benefit for potentially at-risk individuals during particularly vulnerable periods.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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