Reply

I appreciated the very encouraging comments by the author Madias, published on-line ahead of print on November 18 2013 in the Journal . The author has accurately described my conclusion from the pathophysiology of takotsubo syndrome, which I have published , as “An adrenergic cardiac chemical neuritis/myocarditis”. I would like to emphasize that this acute “cardiac chemical neuritis/myocarditis” with its typical pattern of left ventricular wall motion abnormality represents only the tip of an iceberg, under which lurks the subclinical, milder forms with transient (hours) left ventricular dysfunction and the lethal ones, which kill the patients before reaching medical care. The clinical continuum of takotsubo syndrome is most likely very broad. A typical example for that is takotsubo syndrome triggered by subarachnoid hemorrhage and other intracranial hemorrhage. Forty to seventy percent of patients with subarachnoid hemorrhage develop pathological ECG changes, 10%–45% develop elevation of myocardial infarction biomarkers, 10%–28% develop left ventricular dysfunction and 8% of patients with intracranial hemorrhage have focal myocytolysis on autopsies . The left ventricular dysfunction in subarachnoid hemorrhage has shown to have features consistent with takotsubo syndrome. It will be reasonable to consider the ECG changes and/or the elevation of myocardial infarction biomarkers without left ventricular dysfunction in patients with intracranial bleeding as a mild form in the clinical spectrum of takotsubo syndrome.

Response to the comments/inquiries of the author: 1) It is the term broken heart, a nomenclature currently used for emotionally triggered takotsubo syndrome, which has been described by Rees and Lutkins in 1967. It is accurate as the author has mentioned in his comments on the work of Cannon 1942 that preceded the more recent descriptions. Cannon in 1942 actually published a paper entitled “Vodoo death” in which he reported anecdotal experiences of death from fright as death by “bone pointing” in Australia or as breaking “tapu” in New Zeeland. In fact, the role of psychological stress in sudden death extends as far back as dying suddenly while in the grips of grief, horror, humiliation or enjoyment. It has been described in biblical times. The folklore has recognized the condition for centuries. Sir Henry Wotton, who was an English author and diplomat, wrote upon the death of Sir Albert Morton’s wife about 400 years ago “ He first deceased; she for a little tried to live without him, liked it not, and died ” . 2) The literature evidence relating the autonomic parasympathetic participation as a cause of takotsubo syndrome is inadequate. 3) It is hard to believe that the long-lasting ST-elevation in some patients with takotsubo syndrome is due to myocardial ischemia including myocardial microvascular dysfunction because in such a case it should lead to massive elevation of myocardial infarction biomarkers and to delayed myocardial gadolinium enhancement on cardiac magnetic resonance imaging. This is usually not the case in takotsubo syndrome. Furthermore the histopathological finding of myofibrillar degeneration (also known as coagulative myocytolysis and contraction band necrosis) in takotsubo syndrome is distinct in several major respects from coagulation necrosis, the major lesion in myocardial infarction. The evolution of ST elevation into giant T-wave inversion while having the same degree of left ventricular dysfunction is not in favor of the fact that the ST elevation is caused by ventricular dysfunction. I feel that the ECG changes are most probably a neurally induced phenomena. Furthermore, the ECG changes may continue far beyond normalization of the left ventricular function. 4) Theoretically, the author has right that there may be a possibility of left ventricular outlet obstruction early in the process and that the right ventricular involvement may have been preceded by right ventricular outlet obstruction. Up to my knowledge, the right ventricular outlet obstruction in takotsubo syndrome has not been reported in the literature. In addition to the fact that the majority of patients with takotsubo syndrome have not left ventricular outlet obstruction, this theory cannot explain the left ventricular apical sparing types of takotsubo syndrome as mid-ventricular, mid-basal, or basal, which together constitute a substantial number of patients with takotsubo syndrome . 5) Wittstein and colleagues have demonstrated marked elevations of plasma catecholamines and metanephrines in 13 patients with emotionally induced TS within 1–2 days of symptom onset, with elevation persisting for 5–7 days after the initial event. This marked elevation of catecholamines and metanephrines has not been reproduced by other investigators. The absence of an elevation in the 24-h urine catecholamine levels early after admission in one study makes the transient elevation of catecholamines less likely . 6) Post-ischemic myocardial stunning especially that induced by left anterior descending artery (LAD) ischemia and takotsubo syndrome triggered by emotional or other non-cardiac physical stress factors have identical clinical presentation, ECG changes (usually ST-elevation, T-wave inversions and long QTc time), left ventricular dysfunction, which is usually reversible within days or weeks, and even myocardial scintigraphic findings. We have even observed during the last years that the left ventricular dysfunction caused by post-ischemic myocardial stunning extends beyond the territories of the coronary culprit artery and had typical ballooning pattern as that of takotsubo syndrome . Chao et al. reported on the pattern of left ventricular dysfunction induced by acute occlusion of the LAD. They found that 26% of patients, who presented with anterior ST-elevation myocardial infarction because of acute LAD occlusion had left ventricular contraction pattern typical for that of takotsubo syndrome . Interestingly, the majority of these patients were females. Consequently, the currently used diagnostic criteria for takotsubo syndrome may lead to exclusion of substantial number of patients, who actually have takotsubo syndrome; they undoubtedly need to be revised.