READERS’ COMMENTS Cardiac Arrest in Takotsubo Cardiomyopathy We are interested in the recent metaanalysis by Singh et al1 concerning takotsubo cardiomyopathy (TTC) as it relates to cardiac arrest. Obviously, the investigators of that study, by retrospectively reviewing short series and single case reports, could not obtain definitive data about “the natural history” of this disease entity. However, their review was, indeed, important to clarify some current information regarding the mechanisms and incidence of cardiac arrest in TTC. We would like to point out the following facts about this rare and puzzling syndrome: 1. Most likely, most deaths after the onset of TTC occur in the very early stage of an event. Unfortunately, this phase is rarely witnessed by physicians; it generally occurs outside the hospital, lasts for only a few minutes, and has a high mortality rate. Cases that occur in the hospital may be more revealing than those in which the patient is admitted to the hospital 1 to 12 hours after the onset of TTC. 2. In studying the mechanism and consequences of TTC, the best available evidence is derived from clinical experimentation aimed at reproducing TTC during the recovery phase. The best technique for this purpose is acetylcholine (ACH) testing of endothelial dysfunction.2 In a significant percentage of patients recovering from TTC, ACH testing reveals severely increased spasticity of many epicardial branches in the TTCaffected area, which frequently leads to reproduction of the original segmental myocardial dysfunction (Figure 1). Often, total occlusion is elicited by routine ACH test doses, and this is the time when the risk is highest for the onset of ventricular fibrillation. If given early, intracoronary nitroglycerin infusion consistently and immediately resolves the spastic responses (coronary and myocardial). In our short series, we have seen both cardiac

Figure 1. After experiencing emotional stress, a 72-year-old man developed TTC with a typical presentation. Cineangiography did not show critical coronary artery disease at baseline; after ACH testing (A), however, angiography showed extreme narrowing of epicardial vessels, which resolved after immediate administration of intracoronary nitroglycerin (B).

Figure 2. A 44-year-old man had a history of recurrent chest pain at rest that was relieved by sublingual nitroglycerin tablets. Eventually, he had an episode of sudden death, from which he was resuscitated at home. An echocardiogram suggested the presence of typical apical cardiomyopathy of both the right and left ventricles, but that condition was not recognized by the original medical team. An implantable automatic defibrillator was implanted. Because of recurrent angina, the patient underwent catheter coronary angiography, including an ACH test, 3 months after his cardiac arrest. The ACH test was very positive for TTC, inducing severe and diffuse spastic narrowing of the right and left coronary arteries. View A shows the result of ACH testing at 50 mg, and view B shows full disappearance of spasm after intracoronary nitroglycerin administration. Treatment with a calcium antagonist, L-arginine, and long-acting nitrates relieved spontaneous angina. As of 6-month follow-up examination, the patient did not require any more nitrate therapy.

standstill and ventricular tachycardia, but no patient has required electrical cardioversion, and spasm has persisted only for 30 to 60 seconds. Rarely can such early coronary spasm be documented at the time of these patients’ admission to the hospital, but the theory that spasm is responsible for inducing TTC myocardial stunning and arrhythmias is quite compelling, even

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on the basis of our early, singlecenter experience. The condition is not inducible in every TTC patient. In fact, an episode of TTC seems to induce immunity, by an unknown mechanism, consistent with clinical experience (5% to 10% probability of recurrence). Our attempt to co-ordinate a multicenter prospective study is encountering serious difficulties, mainly because many


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clinicians believe that the catecholamine/stress theory is correct and adequate; however, this theory has never been proved, catecholamine levels in TTC are not usually tested, and only w5% of pheochromocytoma patients have TTC.3,4 3. It is likely that many more TTC patients die out of the hospital, before medical attention can be instituted. Autopsy studies involving TTC are rare and not demonstrative; these facts lead to under-reporting of early mortality. 4. Recent attempts to produce TTC experimentally in animal models were based on the catecholamine theory, but they failed to show some typical features of human TTC: mortality was quite high (15% to 40% instead of w2%), dyskinesia was atypical of TTC, and acquired residual immunity (so that recurrence and reinducibility of TTC are rare after an event) was not demonstrated.3 5. During the past few years, we have used ACH to study patients presenting with a cardiac arrest preceded by chest pain. These early studies have revealed an unexpected high probability of endothelial dysfunction (Figure 2) accompanying a pattern of reversible severe, diffuse coronary narrowing similar to that seen in TTC. We encourage TTC investigators to follow similar protocols to confirm a promising lead in explaining this fascinating and puzzling entity, which was first described almost 25 years ago by Dote et al5 as “[m]yocardial stunning due to multivessel simultaneous coronary spasms.” Singh et al suggest that “patients with cardiac arrest after TTC do not require an automatic implantable cardioverterdefibrillator, because the risk of recurrent cardiac arrest is extremely low.” We believe that ACH testing could provide both interesting pathophysiological clues and valuable, objective prognostic indications regarding the risk of recurrence, as relatable to endothelial dysfunction. Paolo Angelini, MD Carlo Uribe, MD Houston, Texas 21 April 2015

1. Singh K, Carson K, Hibbert B, Le May M. Natural history of cardiac arrest in patients with takotsubo cardiomyopathy. Am J Cardiol 2015;115:1466e1472. 2. Angelini P. Transient left ventricular apical ballooning: a unifying pathophysiologic theory at the edge of Prinzmetal angina. Catheter Cardiovasc Interv 2008;71:342e352. 3. Angelini P, Tobis JM. Is high-dose catecholamine administration in small animals an appropriate model for takotsubo syndrome? Circ J 2015;79:897. 4. Tobis J. Takotsubo syndrome: a call to action. Catheter Cardiovasc Interv 2013;82:914. 5. Dote K, Sato H, Tateishi H, Uchida T, Ishihara M. Myocardial stunning due to simultaneous multivessel coronary spasms: a review of 5 cases. J Cardiol 1991;21:203e214.

Single-Coil Implantable Cardioverter Defibrillator Leads Remained the Preferred Option We read the article by Shariff et al,1 suggesting a higher failure rate of single-coil compared with dual-coil Sprint Quattro implantable cardioverter defibrillator (ICD) leads. However, we have concerns regarding the investigators’ conclusions and the level of confidence with which they are expressed. The investigators present a singlecenter study relying on retrospective analysis of data collected in the course of routine clinical care in which they found a higher rate of ICD lead failure in single-coil compared with dual-coil Sprint Quattro models. A major limitation of the analysis is the short mean follow-up of only 3.4 years for dual-coil leads and 1.3 years for single-coil leads, despite a study period of almost 14 years. This limitation is illustrated by inspection of the Kaplan-Meier survival curve, which shows that only 7 single-coil leads remained at risk at 4 years. In contrast, an analysis of the Multicenter Automatic Defibrillator Implantation Trial with Cardiac Resynchronization Therapy (MADIT-CRT) trial, which, although post hoc, enjoyed the benefit of using prospectively collected clinical trial data found no difference between singleand dual-coil models in the crude or adjusted incidence of RV leaderelated complications.2 Although the proportion of single-coil leads in this analysis was small (162/1,783 vs 631/1,651 in the present study), potentially limiting power, mean follow-up duration was substantially longer (40 vs 25.9 months).

Although the single- and dual-coil groups were similar with respect to age and gender, the single-coil group had a higher mean ejection fraction, a known association with ICD lead failure.3 Other patient variables known to be associated with an increased risk of ICD lead failure in other models, such as previous lead failure,4,5 hypertrophic cardiomyopathy, arrhythmogenic right ventricular dysplasia and channelopathies,4 rightsided implant, and subpectoral position,6 may also confound results. Implant technique has an important influence on long-term lead survival, and certain approaches, such as cephalic vein access, have been associated with lower failure rates in some ICD leads.3 These preferences likely co-segregate with selection of single- or dual-coil leads in a single center with a limited number of operators. Last, the analysis the investigators quote in support of the assertion that single-coil Riata leads have worse survival than dual-coil leads included only 30 single-coil leads7 and as such is vulnerable to a type I error. Although conductor externalization has been found to be more common in single-coil 8Fr models, we are not aware of any other reports that single coil are more likely than dual-coil Riata leads to display “electrical” abnormalities: many analyses have been limited by the small number of single-coil leads implanted. Although the conclusion drawn in the abstract is appropriately circumspect, in the text the association is said to have been “demonstrated” and “documented.” It must be emphasized that observational data such as those presented are hypotheses generating and that such definite statements are inappropriate. Given the limitations described earlier, the increased complexity and complication rate seen with extraction of dual-coil ICD leads (as acknowledged by the investigators),8,9 the increased risk of venous obstruction,10 similarity in defibrillation threshold with modern waveforms,11 and the lack of clinical benefit in several studies including a prespecified analysis of the landmark Sudden Cardiac Death in Heart Failure trial,12 the weight of evidence is in favor of single-coil ICD leads remaining the appropriate choice for the great majority of patients. Edmond M. Cronin, MB, MRCPI, CCDS Steven L. Zweibel, MD, CCDS Hartford, Connecticut 23 March 2015

Cardiac Arrest in Takotsubo Cardiomyopathy.

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