We have read Ghadri et al' s article published in the issue of April 7, 2014 (1), which provide a very useful review to help us better understand Takotsubo cardiomyopathy (TTC), a sometimes puzzling disorder. In the "TTC TYPES" section, the authors state that TTC often affect different left ventricular (LV) regions in the recurrent episodes. The similar findings have been reported repetitively by other studies (2, 3) and found in our own TTC patients. A consistent theme appears to emerge is that recurrent TTC tends to change its original LV contractile pattern, to avoid significant hemodynamic compromise induced by the previous episode. This brings up an interesting question: does the heart have a mind of its own, to use memory imprint to protect itself?

TTC has several unique clinical features: 1) in spite of sometimes grave presentation, it usually improves without residual cardiac impairment, 2) although most patients with TTC appear to have poorer systolic function than those with acute myocardial infarction (AMI), their LV filling pressures are paradoxically lower, 3) There is significant discrepant hemodynamic features between LV and Right ventricle (RV) (4-6). The prevalence of RV involvement in TTC is largely underestimated, particularly when RV apex has not been imaged sufficiently in the echocardiographic examinations. In our TTC patients, regardless of various LV regional involvement, RV contractile pattern in is very constant (4-6): the basilar and middle segments of RV are hyperkinetic, but the apical segment is hypokinetic (reverse McConnell's sign, 4). The hyperkinesis of RV likely represents an adaptive physiologic response to the low LV filling pressure in TTC, to maintain cardiac output. Tethering of RV apex to an akinetic LV apex accounts for reduced RV apical motion. This characteristic RV contractile feature helps clinically differentiate TTC and AMI (6). More importantly, this significantly different, but also reciprocally dependent functional status between LV and RV provides us a hint to explore the unique pathophysiology underlying TTC.

Recent research shows that TTC is likely mediated by a switching of epinephrine signaling transduction through the pleiotropic ?2-adrenergic receptor from canonical stimulatory G-protein-activated cardiostimulant to inhibitory G-protein-activated cardiodepressant pathways (7). Clinical evidence also suggests that TTC is likely evolved as a self-protective strategy to limit catecholamine-induced myocardial injury and reduce hemodynamic compromise. During the acute phase of TTC, an active LV dilation will lower filling pressure, not only protecting the vulnerable myocardium within LV, but also preventing an abrupt increase in pulmonary capillary wedge pressure and pulmonary edema. Meanwhile, the less vulnerable myocardium, including RV and basilar LV walls, are activated. These myocardial portions likely form a temporarily alternative functional conduit that detours blood flow towards left ventricular outflow tract (LVOT), to help maintain cardiac output, until the excessive catecholamine surge subsides. This well-programmed interventricular discrepancy/dependency helps maintain benign clinical courses during the most acute TTC episodes. Heart failure/cardiogenic shock will not occur unless some structural (e.g. basal septal hypotrophy) or functional (e.g. dynamic LVOT obstruction) abnormalities significantly interrupt this otherwise harmony machinery. In recurrent TTC episodes, the heart can learn and adjust its contractile pattern to avoid affecting this key "rescue" system, and avoid hemodynamic compromise happening again. Therefore, maintaining appropriate LV filling pressure and avoiding dynamic LVOT obstruction should be the main therapeutic strategies during the acute phase of TTC (6). Unnecessary cardiac catheterization and inappropriate pressor (such as dobutamine) treatment will potentially disrupt the heart's self protective mechanism, and results in adverse outcome.

Reference 1. Ghadri JR, Ruschitzka F, L?scher TF, et al. Takotsubo cardiomyopathy: still much more to learn. Heart. 2014 Apr 7. doi: 10.1136/heartjnl-2013- 304691

2. Xu B, Williams PD, Brown M, et al. Takotsubo cardiomyopathy: does recurrence tend to occur in a previously unaffected ventricular wall region? Circulation. 2014;129: e339-340 3. Kaushik M, Alla VM, Madan R, et al. Recurrent stress cardiomyopathy with variable regional involvement: insights into etiopathogenetic mechanisms. Circulation. 2011;124:e556-e557. 4. Liu K, Carhart R. "Reverse McConnell's Sign?": A Unique Right Ventricular Feature of Takotsubo Cardiomyopathy. Am J Cardiol 2013;11:1232 -1235. 5. Boppana S, Bhatta L, Liu K. Reversible Tricuspid Regurgitation in Acute and Chronic Cardiomyopathies: Medical Management vs. Surgical Intervention? J Am Coll Cardiol Img 2013;6:920-921. 6. Liu K Krone RJ. What truly causes the adverse outcome of Tako-Tsubo cardiomyopathy? Lessons learned from echocardiography. J Am Coll Cardiol Img 2014; (in press). 7. Paur H, Wright PT, Sikkel MB, et al. High levels of circulating epinephrine trigger apical cardiodepression in a ?2-adrenergic receptor/Gi -dependent manner: a new model of Takotsubo cardiomyopathy. Circulation 2012; 126:697-706.

Conflict of Interest:

None declared

The developers1 of the first rigorous predictive model for mortality after transcatheter aortic valve implantation (TAVI) have overcome the limitations of the previous surgical scores. While EuroSCORE I is an old and redundant model based on data of 1995 and derived from a highly heterogeneous patient group with different operations, techniques and demographics, this predictive model is based on new results of a remarkably homogeneous population (72,4% >80 years of age and all treated with TAVI procedures).1 Moreover, while EuroSCORE II developers included variables that were not significantly associated with the event by multivariate regression and did not analyze some important variables2, Iung et al1 studied a wide variety of variables including only those significantly associated with mortality. In addition, while in traditional cardiac surgery there is a great disparity in results between centers which can hamper the accuracy of any predictive model, in this study there was no difference according to the center.1 However, and despite all these strengths, the discriminatory power evaluated by C-index in the validation cohort was the same as that observed when the old EuroSCORE was used (0,59). This disappointing result means that the ability to distinguish or separate those who will die after TAVI from those who will not is the same between a score created 15 years ago to predict mortality after traditional surgery and a score created nowadays and based on patients who underwent TAVI. In fact, taking into account that a C-statistic of 0.5 indicates no predictive ability, a value of 0,59 does not seem to be very favorable. This is more pronounced when we consider that the promising results published by the authors of the EuroSCORE II (C-statistic of 0,81) proved again to be disappointing when the external validation of the model was assessed by independent researchers2. We agree with Ribeiro and Rod?s-Cabau3 when noting that this new model is more accurate than some surgical scores. However, EuroSCORE II has shown in some studies4 great calibration and better discrimination power (C- statistic of 0,66). These authors consider the smaller number of patients compared with surgical scores as a reason that could explain this enormous limitation. We complete agree with this suggestion and we would like to note that, while this system has been created based on a multivariate analysis of 28 variables (Table 2, those with p<0,2) in a development group of 2552 patients (253 deaths), EuroSCOCRE II was created using 26 variables in 12673 patients (587 deaths). Moreover, these authors wonder whether a predictive model for octogenarian patients would be more reliable taking into account a medium-term follow up. This suggestion is supported by some works that have already confirmed this finding in traditional surgery.5 Therefore, many more patients should be included in future models and the performance of the system at mid-term follow up should be always tested. However, the creation of an efficient and reliable predictive model for TAVI seems to be one of the biggest challenges facing cardiologist and cardiac surgeons.

REFERENCES 1. Iung B, Laou?nan C, Himbert D et al. Predictive factors of early mortality after transcatheter aortic valve implantation: individual risk assessment using a simple score. Heart. 2014 Apr 16. doi: 10.1136/heartjnl -2013-305314. 2. Barili F, Pacini D, Capo A et al. Does EuroSCORE II perform better than its original versions? A multicentre validation study. Eur Heart J 2013;34:22-9. 3. Ribeiro HB, Rod?s-Cabau J. The multiparametric FRANCE-2 risk score: one step further in improving the clinical decision-making process in transcatheter aortic valve implantation. Heart. 2014 Apr 23. doi: 10.1136/heartjnl-2014-305806. 4. Durand E, Borz B, Godin M et al. Performance Analysis of EuroSCORE II Compared to the Original Logistic EuroSCORE and STS Scores for Predicting 30-Day Mortality After Transcatheter Aortic Valve Replacement. Am J Cardiol 2013;111:891-7. 5. Leontyev S, Walther T, Borger MA et al. Aortic valve replacement in octogenarians: utility of risk stratification with EuroSCORE. Ann Thorac Surg. 2009;87:1440-5.

Conflict of Interest:

None declared

We read with great interest the article by Di Maria et al. [1], describing the importance of right ventricular (RV) performance, especially RV stroke work (RVSW) in children with pulmonary arterial hypertension (PAH). The authors investigated the relation between echocardiographic measurements of RV function and the "gold standard" of right heart catheterization in children and found that the RVSW strongly correlates with non-invasive data of RV function [1]. The authors concluded that RVSW correlates with outcome parameters, e.g. abnormal WHO class, and mortality, in children with PAH. We completely agree with the findings of Di Maria et al. [1] and want to emphasize the importance of echocardiographic evaluation, e.g. tricuspid annular peak systolic excursion (TAPSE) for longitudinal management of pediatric patients with PAH. Di Maria et al. compared data of patients with adverse outcomes to patients with WHO class I-III, of different age groups: median 16.9 versus 11.8 years (table 1) and found no statistically significant difference of TAPSE (mean values 1.3 versus 1.5 cm, respectively) between those groups [1]. In our opinion their data would have been more promising and statistically significant, if the authors would have compared their TAPSE data with already existing normative data of TAPSE [2] (comparing 1.5 to 2.14 cm for 12 years of age, and 1.3 cm to 2.45 cm for 17 years of age). This might highlight the importance of their data for future pediatric PAH follow ups. We want to encourage the prospective use of echocardiography for routine assessment of RV systolic function in pediatric PAH patients.

References 1.) Di Maria MV, Younoszai AK, Mertens L, Landeck BF 2nd, Ivy DD, Hunter KS, Friedberg MK. RV stroke work in children with pulmonary arterial hypertension: estimation based on invasive haemodynamic assessment and correlation with outcomes. Heart 2014 Apr 29. doi: 10.1136/heartjnl-2013- 305298 [Epub ahead of print].

2.) Koestenberger M, Nagel B, Ravekes W, Avian A, Heinzl B, Fandl A, et al. Tricuspid annular peak systolic velocity (S') in children and young adults with pulmonary artery hypertension secondary to congenital heart diseases, and in those with repaired tetralogy of Fallot: echocardiography and MRI data. J Am Soc Echocardiogr 2012; 25: 1041-9.

Conflict of Interest:

None declared

To the editor: We read the article by Quinn et al1on the effects of prehospital 12-lead ECG (PHECG) on processes of care and mortality with great interest. The authors conclude that when a PHECG was used, patients with ST-elevation myocardial infarction and non-ST elevation myocardial infarction had better survival compared to those without. Interestingly, among the determinants associated with PHECG use, the authors identify female patients to be less likely to have a PHECG than male patients.

When the authors discuss possible explanations to the sex differences in PHECG use, they suggest that the predominately male emergency medical services workers might be reluctant to perform a PHECG on female patients because of the need for intimate exposure. Furthermore female patients might also be less willing to agree to a PHECG compared to men. We argue that a more plausible explanation is uncontrolled confounding of presenting symptoms and type of myocardial infarction.

When we analysed a similar ST-elevation myocardial infarction and non -ST elevation myocardial infarction population in the Swedish comprehensive SWEDEHEART2 register we found an odds ratio for women vs. men to receive a PHECG comparable to that in the article by Quinn et al: (SWEDEHEART: OR=0.89; 95 % CI 0.87-0.92) vs. (Quinn et al: OR=0.87; 95% CI 0.86-0.89). In Sweden 64% of the ambulance specialist nurses were male (The National Board of Health and Welfare).

In accordance with previous findings3 we found women to report chest pain as their presenting symptom in a lesser degree than men, 77.5% vs. 84.8%. Patients with atypical MI symptoms (e.g. no chest pain) are less likely to receive a PHECG compared to patients with chest pain, in SWEDEHEART 12.6% vs. 35.1%. When stratifying according to presenting symptoms, the sex differences almost disappeared, table 1. In addition non -ST elevation myocardial infarction patients are less likely to receive a PHECG compared to ST-elevation myocardial infarction patients, in SWEDEHEART 23.4% vs. 46.4%. Non-ST elevation myocardial infarction occurs more frequently than ST-elevation myocardial infarction in female patients, in SWEDEHEART 38.0% vs. 33.6%. Similarly in the Myocardial Ischaemia National Audit Project (MINARP) cohort4 which Quinn et al analysed. After stratification of presenting symptom and myocardial infarction type, the sex differences completely disappeared.

We believe that if Quinn et al controls for presenting symptom and myocardial infarction type, the difference in PHECG use among men and women will disappear.

Kristina Klerdal1 Christoph Varenhorst2 Stefan James2 Lars Alfredsson1 Hans Blomberg3 Tahereh Moradi1,4

1Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Sweden

2Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center, Uppsala University, Uppsala, Sweden

3Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden

4Centre for Epidemiology and Social Medicine, Health Care Services, Stockholm County Council, Sweden

Contributors TM acquisition of data. KK conceived the letter, analysed the data and wrote the first draft. CV, SJ, LA, HB and TM contributed with editing of the content and specifics of the letter. All authors reviewed and approved the final product.

Correspondence to MSc Kristina Klerdal, Unit of Cardiovascular Epidemiology, Institute of Environmental Medicine, Karolinska Institutet, Box 210, SE-171 77 Stockholm, Sweden; Kristina.Klerdal@ki.se

Competing interest None

REFERENCES 1 Quinn T, Johnsen S, Gale CP, et al. Effects of prehospital 12-lead ECG on processes of care and mortality in acute coronary syndrome: a linked cohort study from the Myocardial Ischaemia National Audit Project. Heart 2014;100:944-50. 2 Jernberg T, Attebring MF, Hambraeus K, et al. The Swedish Web-system for enhancement and development of evidence-based care in heart disease evaluated according to recommended therapies (SWEDEHEART). Heart 2010;96:1617-21. 3 Coventry LL, Finn J, Bremner AP. Sex differences in symptom presentation in acute myocardial infarction: a systematic review and meta- analysis. Heart Lung 2011;40:477-91. 4 Gale CP, Cattle BA, Woolston A, et al. Resolving inequalities in care? Reduced mortality in the elderly after acute coronary syndromes. The Myocardial Ischaemia National Audit Project 2003-2010. Eur Heart J. 2012;33:630-9.

? Table 1 Prehospital 12-lead electrocardiogram (PHECG) use and sex in patients who came via emergency medical services

Overall PHECG No PHECG OR estimate 95% CI

women vs. men All patients (n)

81,190 25,210 55,980

Female

36.5% 34.8% 37.3% 0.89 0.87 to 0.92

Patients chest pain* (n)

66,695 23,389 43,306

Female

34.5% 34.0% 34.7% 0.97 0.94 to 1.00

STEMI

24,450 12,062 12,388

Female

32.4% 32.3% 32.4% 0.99 0.94 to 1.05

NSTEMI

42,245 11,327 30,918

Female

35.7% 35.8% 35.7% 1.01 0.96 to 1.05

Patients atypical symptoms* (n)

11,799 1,487 10,312

Female

45.9% 45.1% 46.0% 0.96 0.86 to 1.08

STEMI

2,030 363 1,667

Female

46.3% 43.0% 47.0% 0.85 0.68 to 1.07

NSTEMI

9,769 1,124 8,645

Female

45.9% 45.8% 45.9% 1.00 0.88 to 1.13

STEMI, ST-elevation myocardial infarction; NSTEMI, non ST-elevation myocardial infarction Crude odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analysis. *Patients with missing information on presenting symptoms were deleted.

Conflict of Interest:

None declared