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Heart and lung, a dangerous liaison-Tako-tsubo cardiomyopathy and respiratory diseases: A systematic review.

AIM
To investigate the possible association between Tako-tsubo cardiomyopathy (TTC)-a reversible clinical condition mimicking an acute myocardial infarction characterized by multifactorial pathophysiologic mechanisms- and respiratory system diseases.


METHODS
We systematically searched PubMed and EMBASE medical information sources, to identify the different triggering causes, limiting our search to articles in English. The search keywords were: "tako-tsubo cardiomyopathy", "takotsubo", "takotsubo cardiomyopathy", "broken heart syndrome", "stress-induced cardiomyopathy", "apical ballooning syndrome", and "ampulla cardiomyopathy in combination with respiratory diseases, lung, pulmonary disease. For each kind of disease, we registered: author, year and country of study, patient sex, age, concurring situation, and outcome.


RESULTS
Out of a total of 1725 articles found, we selected 37 papers reporting a total of 38 patients. As expected, most patients were women (81.6%), mean age was 65 ± 10 years. Outcome was favorable in 100% of cases, and all the patients have been discharged uneventfully in a few days.


CONCLUSION
An association between respiratory diseases and TTC is likely to exist. Patients with severe respiratory diseases, due to the high dosages of β2-agonists used or to the need of invasive procedures, are highly exposed to the risk of developing TTC.

posed to the risk of developing TTC. Thus, in these patients a certain caution should maintained, along with a special alertness in suspecting and recognizing this particular disease.

Tako-tsubo cardiomyopathy (broken heart syndrome)
Tako-Tsubo cardiomyopathy (TTC) is a reversible clinical condition mimicking an acute myocardial infarction (AMI) [1] . The original Japanese term "tako-tsubo" indicates the particular shape of the end-systolic left ventricle in ventriculography resembling that of the round-bottom and narrow-neck pot used for trapping octopuses [2] . Other terms have been used to define this cardiac entity, i.e., "apical ballooning", "acute stress cardiomyopathy" or "broken heart". Typical presentation involves chest pain and/or dyspnea, transient ST-segment elevation on the electrocardiogram (ECG), and a modest increase in cardiac troponin [3] .
The Mayo clinic diagnostic criteria include: (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; (2) absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (3) new ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin and, and (4) absence of myocarditis or pheochromocytoma [1] .
Although TTC is still underdiagnosed, the current prevalence estimate is approximately 1% to 3% (even 6% to 9% in women) of all acute coronary syndromes [4] . The mean age ranges from around 60 to 75 years, both in men and women [5] , but its occurrence is much more likely (approximately 90%) in postmenopausal women [6] . After a first finding on a large cohort of patients in Italy [7] , a precise temporal periodicity has been reported, characterized by highest occurrence peaks during morning hours and summer months [8][9] . Interestingly, quite similar to AMI, Monday seems to be a critical day for onset [10] .
Even if TTC is frequently characterized by dramatic clinical presentation and urgent presentation to the Emergency Department, the prognosis is generally favorable, with a rapid short-term improvement of left ventricle systolic function [11] . According to several studies, in-hospital mortality rates range from 0% to 8% [4] , with higher mortality rates for males than females [12] .
Multifactorial pathophysiologic mechanisms are likely to be involved, but the most accepted pathogenic hypothesis considers a rapid elevation of circulating catecholamine, triggered by emotional and/or physical stress, as a key mechanism [13][14] . In fact, the major determinants of sympathetically mediated myocardial reversible dysfunction in patients with TTC include all the direct effects of catecholamines upon the myocardium, i.e. cellular damage, contraction band necrosis, defects in perfusion, altered cellular metabolism, and negative inotropic effects of epinephrine via stimulation of the cardioprotective β2adrenergic receptors-Gi signaling pathway [15] . It has been recently shown that the apical ventricular region has a greater β2:β1 adrenoceptor ratio, with a higher responsiveness and vulnerability to sympathetic stimulation [16] . Again, the different occurrence of wall motion abnormalities could be explained by interindividual anatomical differences in the distribution of β-adrenergic receptors [17,18] .

Broken heart and broken lung: Is there a relationship?
The clinical onset of TTC is usually preceded by an emotional and/or physical stress with a similar distribution in approximately two-thirds of the patients. A long list of stressors has been reported, and this is continuously updated. Men seem to be more prone to physical stress and women to emotional stress [19] . Among emotional stressors, for example, death or severe illness of a family member, receiving bad news, financial loss, move to a new residence, natural disasters, dispute or litigation, car accident, assault, surprise party, public speaking, and so on [3] . Among physical stressors, surgery, cardiovascular procedures, medications and illicit drugs, and medical conditions, including gastroenterologic, endocrine, hematologic, renal, infectious, and neurologic diseases [3] . Thus, we aimed to more-in-depth investigate the relationships between TTC and respiratory diseases.

MATERIALS AND METHODS
We systematically searched PubMed and EMBASE medical information sources, to identify the different triggering causes, limiting our search to articles in English. The search keywords were: "TTC", "takotsubo", "takotsubo cardiomyopathy", "broken heart syndrome", "stressinduced cardiomyopathy", "apical ballooning syndrome" and "ampulla cardiomyopathy in combination with respiratory diseases, lung, pulmonary disease. Further papers were sought by means of manual search of secondary sources, including references from primary articles. For each kind of disease, we collected a set of data, including author, year of publication, country where the study was performed, and patient sex, age, concurring situation, and outcome.

RESULTS
Out of a total of 1725 articles found (1341 with the precise MeSH term (Takotsubo cardiomyopathy), we selected 37 papers reporting a total of 38 patients (Table 1).

Chronic obstructive pulmonary disease
Chronic obstructive pulmonary disease (COPD)is relatively frequently associated with TTC. In a retrospective analysis of a large cohort of approximately 17000 patients with diagnostic angiographies in Hamburg, Germany, Hertting et al [20] , out of the 32 cases of TTC found that 14 (44%) had COPD or asthma. Since 72% of these patients were taking β-mimetics, the authors postulated that this kind of medication could have acted as preconditioning factor for the cardiomyopathy or aggravated the sympathetic nervous system stress. In fact, several other cases of TTC in patients with β2-stimulators abuse have been reported [21][22][23] . Multiple admissions for COPD exacerbations may act as a trigger [24][25] , alone or in combination with emotional stressors, i.e., unexpected death of a son [26] , severe financial problems [27][28][29] , or family dispute [30] .

Asthma
Similarly to COPD, acute asthmatic attack may trigger TTC [31] , and pharmacological treatments may potentiate such an effect [32][33] . Abuse of nasal decongestants in the course of allergic rhinitis has also been reported [34] . TTC episodes have also been described in the case of relapsing polychondritis with symptoms of intractable bronchial asthma [35] , allergic asthma secondary to cephalosporin use [36] , abuse of coffee to cope with jet lag [37] , and also concomitant abuse of cocaine [38] . In the latter case, the TTC cardiotoxic effect could have been potentiated by catecholamines [39] .

Pulmonary embolism
Arterial systemic embolization represents frequent complication during TTC. Mitsuma et al [40] studied the clinical characteristics and complications of 21 consecutive patients with TTC in Japan. Thromboembolism was found in 3 patients, 1 with ventricular thrombus and 2 with cardioembolic stroke. However, cases of pulmonary thromboembolism have been reported in elderly women as a consequence of acute pyelonephritis [41] , and a popliteal vein thrombosis after a long distance travel [42] .

Malignancies, invasive procedures and surgery
On the one hand, an association of TTC with malignancies has been hypothesized, potentially as a result of paraneoplastic phenomena [43] . On the other, surgery and invasive procedures represent severe physical stressors capable to trigger TTC onset. Several cases of TTC events in patients with lung malignancies undergoing pulmonary resection have been reported [44][45][46] , and also after lung transplantation for end-stage fibrosis [47] or cardiopulmonary bypass [48] . Again, other cases were associated with intubation [49] , debridement of central airways neoplastic invasion with rigid bronchoscopy [50] , and even after a simple bronchoalveolar lavage [51] .

Miscellaneous
Several other diseases or condition have been shown to trigger TTC. Among these, pneumothorax [52] , pulmonary hypertension [53] also after attempt at treatment [54] , pneumonia with sepsis [55] , and pulmonary edema secondary to stressful events [56,57] . A TTC episode occurred after acute dyspnea secondary to the stress of scuba diving in a 51-year-old woman (at the third immersion, as her level-3 diving examination), has been reported [58] . Finally, 2 singular episodes of dyspnea occurred in ultraoctuagenarians, both of them triggering a TTC episode: A bad coughing since "pill went down the wrong way" in a 82-year-old lady [59] , and a sudden dyspnea occurred in a 81-year-old man during an adulterous sexual intercourse with a young lady [60] .

DISCUSSION
If the question is: "Does an association between respiratory diseases and TTC exist" the answer is yes. On the one hand, patients with severe respiratory diseases, such as asthma or COPD, are exposed to a high risk of developing TTC in the course of critical exacerbations, when they are also compelled to assume high dosages of β2agonists. On the other hand, patients with lung cancer are often exposed to invasive procedures, both diagnostic and surgical, that may be relevant in predisposed subjects. Patients with acute respiratory symptoms or diseases should always be approached with caution in the event of invasive procedures or surgery, keeping in mind the possible acute cardiologic complications.

ACKNOWLEDGMENTS
We are indebted with Mrs Francesca Molinari and Mrs Cristina Rinaldi, from the University of Ferrara Library Staff, and with Mrs Claudia Righini and Mrs Manuela Zappaterra, from the Health Science Library of the Azienda Ospedaliera-Universitaria of Ferrara, for their precious support in collecting currently unavailable bibliographic material from extrenal sources.

Background
Tako-Tsubo cardiomyopathy (TTC) is a reversible clinical condition mimicking an acute myocardial infarction. Its onset is characterized by multifactorial pathophysiologic mechanisms, and stress may paly a crucial role.

Research frontiers
Patients with acute respiratory symptoms or diseases should be approached with caution in the event of invasive procedures or surgery, keeping in mind the possible acute cardiologic complications and the availability of managing abilities.

Innovations and breakthroughs
This is the first study evaluating the association between respiratory diseases and TTC.

Applications
More attention in either suspecting and recognizing TTC, and managing it.

Terminology
TTC is a reversible clinical condition mimicking an acute myocardial infarction. The original Japanese term "tako-tsubo" indicates the particular shape of the end-systolic left ventricle in ventriculography resembling that of the roundbottom and narrow-neck pot used for trapping octopuses.

Peer review
The authors have reviewed the association between respiratory diseases and Tako-Tsubo cardiomyopathy by searching case reports in world wide. They initially described general features of TTC, then discussed about relationship between TTC and respiratory disorders, including chronic obstructive pulmonary disease, asthma, pulmonary embolism, malignancies, invasive procedures, and miscellaneous. This article is well searched and summarized, and may provoke attention of TTC not only to cardiologists but also to pulmonologists and anesthesiologists.