(Stress) Cardiomyopathy

Stress cardiomyopathy is a disease characterized by an acute systolic dysfunction of the left ventricle of the heart which is fully reversible and does not affect basal segments of the left ventricle. It is not accompanied by significant stenoses of the coronary arteries and it is caused by a preceding stressful situation. This article provides an overview of the ethiopathogenesis, diagnostic and therapeutic methods. Finally, we present a case report of our patient who suffers from a rare form of the midventricular type of stress cardiomyopathy.


Takotsubo (Stress) Cardiomyopathy
To the Editor: Templin et al. (Sept.3 issue) 1 highlight the fact that takotsubo cardiomyopathy is associated with a substantial rate of adverse events.With this in mind, an important aspect that the authors do not discuss is the prevalence of dynamic left ventricular outflow tract obstruction (LVOTO).3][4] This association is important because the coexistence of hemodynamically significant LVOTO and acute left ventricular systolic dysfunction poses a major therapeutic challenge, since the accepted management strategy for either condition alone (i.e., negative inotropy and increased afterload for LVOTO or positive inotropy and reduced afterload for acute left ventricular dysfunction) is potentially catastrophic in the other.Thus, it has been speculated that some patients with takotsubo cardiomyopathy and LVOTO may be best treated with early extracorporeal mechanical circulatory support. 5Do the authors have any data regarding the prevalence of LVOTO and its management?Given the unsurpassed wealth of data they have accrued on takotsubo cardiomyopathy, this would seem to be an excellent opportunity to more accurately characterize a potentially devastating complication.
Golden Jubilee National Hospital Glasgow, United Kingdom j .dalzell@ nhs .net No potential conflict of interest relevant to this letter was reported.

DOI: 10.1056/NEJMc1512595
To the Editor: In their article on clinical observations from the International Takotsubo Registry, Templin et al. report 30-day mortality of 5.9% among patients with takotsubo cardiomyopathy.In addition, 12.2% of patients received catecholamine-based inotropes.These proportions are higher than those recently reported by the Swedish Health Care Registry on Heart Disease (SWEDEHEART) (4.1% and 5.6%, respectively), 1 and we think that the high short-term mortality could be partially explained by the liberal use of inotropes.
To date, no randomized clinical trial has investigated pharmacologic treatment strategies in patients with takotsubo cardiomyopathy.3][4] Templin et al. found that the rate of catecholamine treatment was considerably higher among men than among women (21.0% vs. 11.2%),which corresponded to a higher 30-day mortality among men than among women (12.2% vs. 5.2%).Thus, it would therefore be valuable if the authors could indicate whether the use of catecholamines is an independent predictor of death (after appropriate adjustment for cofounders) in their registry.Bjorn Redfors, M.D., Ph.D. Elmir Omerovic, M.D., Ph.D.

DOI: 10.1056/NEJMc1512595
To the Editor: Templin and colleagues report substantial long-term morbidity and mortality among patients with takotsubo cardiomyopathy.
In their diagnosis of this condition according to Mayo Clinic criteria, they do not clarify how they ruled out myocarditis.Myocarditis may present with apical ballooning that mimics takotsubo cardiomyopathy. 1 Indeed, the inclusion of patients with atypical forms, particularly the focal type, may have further increased the risk of enrolling patients with myocarditis.Among patients who have left ventricular dysfunction, an increase in troponin levels, and normal coronary arteries, myocarditis cannot be reasonably ruled out without endomyocardial biopsy or cardiac magnetic resonance imaging (MRI). 2 Myocardial edema without delayed enhancement is a typical feature of takotsubo cardiomyopathy, 3 which allows for distinction from myocarditis on MRI.
The possible inclusion of patients with myocarditis in the study could have substantially increased the event rate.Caforio and colleagues reported a 6-year rate of death or heart transplantation of 27% among patients with biopsyproven myocarditis, with biventricular dysfunction at presentation and the presence of virus on genomic analysis of myocardium being the best predictors of an adverse outcome. 4Thus, the exclusion of myocarditis is crucial to refining the patient population and assessing the prognosis of patients with takotsubo cardiomyopathy.Maurizio Pieroni, M.D., Ph.D. Leonardo Bolognese, M.D.

DOI: 10.1056/NEJMc1512595
The authors reply: In response to the comments of Dalzell: LVOTO occurs in approximately 20% of patients with takotsubo cardiomyopathy 1 and may also develop later during the acute phase.It can be precipitated by inotropes and poses a substantial risk to the patient.Therefore, careful evaluation for the presence of a pressure gradient during angiography should be performed, as well as serial echocardiography to systematically rule out the development of LVOTO later during hospitalization. 2Unfortunately, this approach has been implemented by only few centers, and because of the mostly retrospective nature of our registry, we cannot provide data on the incidence and prognostic value of LVOTO.As outlined by Dalzell, the administration of inotropes potentially increases the pressure gradient during LVOTO, which also holds true for intraaortic counterpulsation.Although prospective data on short-term management of takotsubo cardiomyopathy are lacking, active left ventricular unloading by microaxial pumps 3 appears to be attractive to support left ventricular dysfunction and to reduce the pressure gradient at the same time in such patients.
Redfors and Omerovic emphasize the risk of catecholamines for treating takotsubo cardiomyopathy.In a multivariate analysis in our cohort, the use of catecholamines was a strong and independent predictor of in-hospital death (Fig. 1A).The risk of death associated with catecholamines was very high but did not differ according to sex (Fig. 1B and 1C), which suggests that other factors are responsible for the observed difference in mortality between men and women.Our retrospective analysis may have been influenced by selection bias and other factors.However, we agree that catecholamines of any nature should be administered with great caution, not only because of their potential role in the pathogenesis of takotsubo cardiomyopathy but also because of the risk of hemodynamic worsening (e.g., by the precipitation of LVOTO).
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Copyright © 2015 Massachusetts Medical Society.All rights reserved.
Pieroni and Bolognese emphasize the need for ruling out myocarditis in the diagnosis of takotsubo cardiomyopathy.Indeed, since MRI was not broadly available at the beginning of our study, it was not possible to use MRI data in a meaningful fashion.Patients with focal takot-subo cardiomyopathy in our study shared most features with other patients with this condition (e.g., age, sex, and triggers), making myocarditis unlikely.However, we agree that differentiation between focal takotsubo cardiomyopathy and myocarditis is challenging.Cardiac MRI is suf- Panel A shows predictors of in-hospital death in patients with takotsubo cardiomyopathy, as determined by means of logistic regression in multivariate analysis.LVEF denotes left ventricular ejection fraction, QTc QT interval corrected for heart rate, and ULN upper limit of normal range.Panel B shows Kaplan-Meier estimates of rates of death among men and women, according to receipt of catecholamines, as calculated by means of the log-rank test.Panel C shows the relative risk of in-hospital death among men and women according to receipt of catecholamines, as determined by logistic regression.P = 0.95 for the comparison between men and women with respect to the relative risk of death.The New England Journal of Medicine Downloaded from nejm.org at HAUPTBIBLIOTHEK UNIV ZUERICH on September 13, 2021.For personal use only.No other uses without permission.
Copyright © 2015 Massachusetts Medical Society.All rights reserved.
ficient to distinguish the acute coronary syndrome, takotsubo cardiomyopathy, and myocarditis in most cases and adds valuable information, such as the presence of right ventricular involvement and intraventricular thrombi. 4Thus, in addition to current diagnostic criteria, we recommend the use of cardiac MRI in patients with suspected takotsubo cardiomyopathy.

Acute Methotrexate-Induced Crystal Nephropathy
2][3] Despite the frequency of acute renal failure and the occurrence of distinct urinary crystals in this context, 4,5 the presence of these crystals in human tissues has not been clearly documented.Here, we describe crystals within the kidney tubules of a patient with methotrexate-induced nephropathy.
A 52-year-old man with an aggressive B-cell lymphoma was prescribed intravenous methotrexate (1.20 g per square meter of body-surface area over a 1-hour period, followed by 0.24 g per square meter over a 23-hour period) on day 10 of a regimen of CODOX-M (dexamethasone, cyclophosphamide, doxorubicin, vincristine, rituximab, cytarabine, methotrexate, and leucovorin).The creatinine concentration in serum was below 50 µmol per liter (0.57 mg per deciliter) before the infusion, but it increased to 116 µmol per liter (1.31 mg per deciliter) approximately 20 hours after the infusion and reached 465 µmol per liter (5.26 mg per deciliter) 4 days later (Fig. 1A).A small number of methotrexate-like crystals were also observed in the patient's urine (Fig. 1B and 1C) in the absence of risk factors for drug-induced precipitation or other causes of crystal nephropathy.
Examination of a renal-biopsy specimen obtained 7 days after the infusion revealed severe acute tubular injury with numerous intratubular and interstitial deposits of unique appearance (Fig. 1D-1J).These deposits were made up of compact or needle-shaped golden crystals arranged in annular structures (Fig. 1D and  1E); they were positive on methenamine silver staining (Fig. 1H) and displayed blue or gold birefringence under polarized light (Fig. 1F and  1G).Von Kossa and alizarin red stains were negative, the glomeruli appeared normal, and scarring was minimal (not shown).
Our findings indicate that intratubular crystal formation does occur in humans during the course of methotrexate-induced acute renal failure (this has previously been suspected in nonhuman primates; see the Supplementary Appendix, available with the full text of this letter at NEJM.org) and document the morphologic features of methotrexate-induced crystal nephropathy.In this regard, certain types of urinary crystals are known to form or to undergo structural modifications in the bladder or after micturition because of changes in pH, temperature, or bacterial activity.
This case also shows that acute renal failure can occur even in the absence of toxic methotrexate levels in plasma 24 to 48 hours after infusion (Fig. 1A).For this reason, and because The New England Journal of Medicine Downloaded from nejm.org at HAUPTBIBLIOTHEK UNIV ZUERICH on September 13, 2021.For personal use only.No other uses without permission.
Copyright © 2015 Massachusetts Medical Society.All rights reserved.

Figure 1 .
Figure 1.Use of Catecholamines and Risk of In-Hospital Death among Patients with Takotsubo Cardiomyopathy.
Caforio AL, Calabrese F, Angelini A, et al.A prospective study of biopsy-proven myocarditis: prognostic relevance of clinical and aetiopathogenetic features at diagnosis.Eur Heart J 2007; 28: 1326-33.