Author + information
- Published online October 29, 2018.
- Scott W. Sharkey, MD∗ ()
- ↵∗Address for correspondence:
Dr. Scott W. Sharkey, Minneapolis Heart Institute Foundation, 920 East 28th Street, Suite 100, Minneapolis, Minnesota 55407.
Takotsubo syndrome now commands broad recognition in the realm of acute cardiac conditions. Within the diverse clinical profile of takotsubo syndrome, an important minority experience profound acute heart failure including cardiogenic shock (1–4). Takotsubo syndrome is characterized by sudden loss of regional left ventricular (LV) contraction, often involving substantial myocardial mass. Ejection fraction is acutely reduced to 30% to 40%, typically below that observed with acute myocardial infarction (1–5). LV stroke volume is reduced by 40% and cardiac output by 25%, with tachycardia frequently contributing to maintenance of the latter (5). As well, LV diastolic function is impaired with significant elevation of LV end-diastolic pressure (1). Therefore, it is not surprising that cardiogenic shock occurs in 10% to 15% of takotsubo patients, usually within 72 h of admission, and often of magnitude requiring pharmacologic or mechanical circulatory support (1–5). Cardiogenic shock is most commonly encountered in those with severely reduced LV ejection fraction, with incidence similar to that of shock in acute myocardial infarction (1–4). Coexisting acute illnesses, acting as takotsubo triggers (e.g., sepsis), may aggravate hemodynamic instability (1).
Importantly, dynamic LV outflow tract obstruction, present in 15% to 20% of takotsubo patients, often contributes to shock; peak systolic gradients >100 mm Hg have been observed (1–4). Outflow tract obstruction is the consequence of basal LV hypercontraction in combination with proximal septal hypertrophy (septal bulge), a relatively common anatomic finding in older patients. Severe mitral regurgitation caused by systolic anterior motion of the mitral leaflets may aggravate shock. In some circumstances, conventional treatments for shock may provoke or worsen LV outflow tract obstruction, in the case of inotropic agents by increasing basal LV contractility, and in the case of an intra-aortic balloon pump by decreasing LV size, thereby resulting in unintentional exacerbation of shock.
Early (1 month) mortality in takotsubo shock has ranged from 11% to 29%, with cause of death frequently influenced by coexisting acute illnesses, yet with normalization of LV ejection fraction in survivors (1,3). Effective management strategies for takotsubo shock are unknown, therefore treatment has been modeled on that of shock in acute myocardial infarction, including the use of inotropic drugs, an approach with unproven efficacy. Furthermore, whether patients with takotsubo shock have a natural history and outcome different from that of patients with acute myocardial infarction associated shock is largely unknown.
In this context, the nicely detailed report from the multicenter Registry on Takotsubo Syndrome (RETAKO) in this issue of JACC: Heart Failure (6) represents an important contribution to the fund of knowledge regarding cardiogenic shock in this unique condition. Among the 711 patients, cardiogenic shock occurred in 81 (11%), a frequency consistent with other contemporary studies (1–4). Among those with shock, hospital mortality was 11 of 81 (14%), only 2 hospital deaths were attributed to cardiovascular causes, and the 70 survivors experienced normalization of LV ejection fraction (61 ± 6%). Considering these findings with those from smaller earlier studies, a profile of takotsubo shock emerges that differs from that of shock associated with acute myocardial infarction, in which hospital mortality may exceed 50%, mostly attributed to intractable pump failure, and with compromised ejection fraction in many survivors. The relatively more favorable hospital survival among patients with takotsubo shock may reflect the presence of largely reversible myocardial injury (i.e., stunning), a hallmark of takotsubo events.
Nonetheless, in the RETAKO report, cardiogenic shock emerged as the most powerful predictor of long-term nonsurvival, with 10-year mortality approaching 30%. This influence was most pronounced during hospitalization and diminished substantially thereafter. For example, 11 of 22 (50%) of shock-associated deaths occurred during initial hospitalization, and the remainder over 10-year follow-up, with cardiovascular causes accounting for the minority (6 of 22; 27%). In contrast, a 2016 study reported greater long-term shock associated mortality (67%) at 3.6-year follow-up, with virtually all deaths attributed to cardiovascular events (3). This study was limited by small size (n = 22), older patient age (77 years), and frequency of cardiopulmonary resuscitation (64%). As well, referral center status may have introduced bias toward greater illness severity. Considering this conflicting information, it remains uncertain whether long-term mortality in patients with takotsubo cardiogenic shock represents a primary cardiac process or a noncardiac process imposed by the prognosis of a coexisting condition.
The authors emphasize the independent takotsubo contribution of LV outflow tract obstruction to shock occurrence (odds ratio: 4.6). Therefore, evaluation of patients with takotsubo shock should include echocardiographic visualization of the LV outflow tract and mitral valve leaflets, together with measurement of outflow tract systolic gradient at cardiac catheterization or noninvasively with Doppler echocardiography. The presence and severity of outflow tract obstruction often varies over time, therefore serial evaluation may be necessary.
Among the 711 takotsubo patients included in this study, inotropic class drugs were used during hospitalization in 84 (12%), a frequency consistent with that of other studies (1–4). Inotropic drugs, in particular catecholamines, are commonly used in the intensive care unit and the surgical arena to treat hypotension complicating a variety of illnesses and surgical procedures. To that end, it is conceivable these agents, under certain circumstances, act in synergy with a coexisting acute illness to trigger takotsubo events.
Could inotropic agents administered as treatment of takotsubo shock increase hospital mortality? In the RETAKO report, inotropic drugs were used in 11% of survivors versus 59% of nonsurvivors (p < 0.001; Online Table 6 in Almendro-Delia et al. ), although this variable was apparently not included in the multivariable analysis of hospital mortality. A 2015 report (n = 1,750) noted catecholamine administration was a more powerful predictor of hospital mortality (odds ratio: 9.7) than age, LV ejection fraction, or troponin level, although coexisting illness severity was not examined in that analysis (7). Considering these observations, and with knowledge catecholamines likely play a role in the pathophysiology of takotsubo events, their use as treatment for hemodynamic instability in this condition should be limited or avoided altogether.
Finally, this report highlights the intriguing relationship of male gender to both cardiogenic shock and long-term mortality, an association noted in several previous studies (1,3,4). In reconciling this observation, it is reasonable to consider that the physiologic stress unique to an acute physical illness is necessary to trigger takotsubo events in most males, illnesses that may in turn contribute to hemodynamic instability and also negatively influence survival.
Despite the notable work by the RETAKO investigators, considerable uncertainty remains regarding cardiogenic shock in takotsubo syndrome, in particular: 1) Does catecholamine administration adversely affect survival or delay takotsubo recovery? Might early mechanical support, for example with extracorporeal membrane oxygenation, improve survival in some circumstances?; 2) Is shock-associated mortality related to the takotsubo event itself, a noncardiovascular illness, or a combination of both? Does cause of death in-hospital differ from that post-hospital? Might some of the long-term mortality reflect other age-related cardiac disease processes?; 3) Are there long-term consequences beyond mortality, such as late deterioration of systolic function, diastolic heart failure, or serious arrhythmia?; and 4) To what extent is takotsubo shock influenced by noncardiac factors, such as septic shock or vasoplegia from a neurologic catastrophe or a surgical procedure?
Although cardiogenic shock represents a major obstacle during the clinical course of takotsubo syndrome, long-term survival with complete recovery of LV contraction is not uncommon even when shock is profound, therefore extraordinary supportive measures may be appropriate in the absence of a nonsurvivable coexisting illness.
↵∗ Editorials published in JACC: Heart Failure reflect the views of the authors and do not necessarily represent the views of JACC: Heart Failure or the American College of Cardiology.
Dr. Sharkey has reported that he has no relationships relevant to the contents of this paper to disclose.
- 2018 American College of Cardiology Foundation
- Citro R.,
- Rigo F.,
- D'Andrea A.,
- et al.
- Medeiros K.,
- O'Connor M.J.,
- Baicu C.F.,
- et al.
- Almendro-Delia M.,
- Núñez-Gil I.J.,
- Lobo M.,
- et al.,
- for the RETAKO Investigators
- Templin C.,
- Ghadri J.R.,
- Napp L.C.