- Email: [email protected]
cardiac arrhythmias: A quintet needing exploration
International Journal of Cardiology 203 (2016) 259–261
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Takotsubo syndrome/QTc interval prolongation/myocardial edema/ cardiac sympathetic denervation/cardiac arrhythmias: A quintet needing exploration John E. Madias ⁎ Icahn School of Medicine at Mount Sinai, New York, NY, United States Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY, United States
a r t i c l e
i n f o
Article history: Received 14 October 2015 Accepted 18 October 2015 Available online 19 October 2015
To the Editor: It has been reported that patients with Takotsubo syndrome (TTS) develop prolongation of the QTc interval [1], which is associated with ventricular arrhythmias (VA) (monomorphic and polymorphic ventricular tachycardia, and ventricular fibrillation). However in one recent study reporting on 56 patients with TTS, “only 1 patient had a proved malignant VA and that patient succumbed to it” with “the QT interval noted to be 498 ms at the time of the event” [2]. The incidence of VA in TTS has been reported in some case series to be 1% to 1.5% [3], and felt to be uncommon [4,5]. There is a paucity of data regarding the precise association with QTc prolongation, based on characterization of the natural course of QTc prolongation, frequently recorded electrocardiograms (ECGs), or better continuous ECG monitoring, documentation of all VA, including non-sustained episodes, evaluation of the QTc in temporal proximity with each episode of VA based on the closest recorded ECG, or better on continuous ECG monitoring data analysis. It has been observed that some patients develop VA in the acute phase, even before the emergence of QTc prolongation [1,6], but the bulk of VA is seen in the subacute phase of TTS, at the time that QTc prolongation has occurred [1]. Indeed the same authors hypothesized that the patients with early VA represent cases of cardiac arrest who suffered TTS as a result of the stresses from the episode of sudden death and the ensuing cardiac resuscitation [1], further facilitated by the use of catecholamines [9]. In reference to the mechanism of VA in TTS some feel that it is similar to the one operating in the setting of acute myocardial infarction, and ⁎ Division of Cardiology, Elmhurst Hospital Center, 79–01 Broadway, Elmhurst, NY 11373, United States. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2015.10.155 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
based on myocardial re-entry [1], while others consider this unlikely, and favor “catecholaminergic, automatic, or fascicular tachycardias, with related cytosolic calcium overload” [2,8] inciting mechanisms. The opinion of the latter stems from the data about tissue level characterization deriving from magnetic resonance imaging, showing absence of scar formation [7]. However this author has expressed the notion that myocardial edema (ME) developing in patients with TTS could have a “patchy” distribution, and thus engender the prerequisite substrate for the emergence of re-entry and VA. Cardiac magnetic resonance imaging based ME has been widely documented in patients with TTS, with a causal association with QTc prolongation, attributed to a left ventricular apicobasal distribution gradient of ME [10–13]. Most of these studies have been carried out a few days after admission with TTS. Indeed ME and prolonged QTc persist for many weeks during convalescence, and during which time period the patients do not experience VA. To explain this counterintuitive phenomenon some authors have hypothesized that the mechanism of early and late VA in TTS may be different [1]. However also one wonders whether the consolidation or confluence and homogenization of ME, with plausible clear demarcation of myocardial regions with and without ME, mitigate the myocardial re-entry potential, thus leading to the paucity or rarity of VA several days after admission with TTS. Studies with 123I-metaiodobenzlguanidine (MIBG) myocardial scintigraphy in patients with TTS have documented transient cardiac autonomic sympathetic denervation (CASD) [14–16], in regions also afflicted with regional akinesis/dyskinesis/hypokinesis, and ME. Since MIBG imaging has been implemented ~ 1 to 2 weeks in patients with TTS, it is not known whether CASD is an early finding in the disease process, or it constitutes an epiphenomenon after TTS has been fully manifest. Be as it may the influence of CASD on the emergence of VA has not been addressed. VA are most probably facilitated via the autonomic nervous system direct effects of a heightened activity of its sympathetic component and withdrawal of its parasympathetic limb on the cardiomyocytes [2], and indirectly by the sympathetic nervous system's promotion of QTc prolongation [1]. However it should be understood that the issue of the influence of the autonomic sympathetic nervous system on the QT-interval, irrespective of TTS, is not conclusively settled, and it should be considered independently of the influence of the heart rate; indeed one may hypothesize that this is taken care by the Bazzet's formula correction, but this is only correct for a narrow range of heart rate changes. For example in normal subjects, increase in the
260
Correspondence
heart rate during exercise or atropine administration (both states with substantial vagal inhibition), is associated with shortening of QTinterval, while isoproterenol administration leads comparatively to less shortening, revealing that there are influences of the autonomic nervous system on the QT-interval, independent of the ones, imparted by the increase in the heart rate per se (e.g., by cardiac pacing) [17]. These authors observed that women (important for TTS) showed greater shortening of QT-interval than men during all the above 3 interventions, and discussed the discrepancies in the literature, and methodological problems in QT-interval measurements, where the U-wave is either included or excluded in the measurements [17]. Diurnal variation of the QT-intervals are large, with lengthening of the QT-intervals during sleep in pacemaker-dependent patients with normally autonomic nervous system innervated hearts, and are dependent on both changes in autonomic tone and concentration of the circulating catecholamines during sleep [18]. In contrast, the anatomically and functionally permanently denervated hearts of patients with orthotopic cardiac transplantation, showed markedly blunted variation of the QT-intervals, again with the longest QT-intervals noted during sleep [18], attributed to the changes in circulating catecholamines, to which they respond appropriately [19]. That there is shortening of the QT-intervals, independent of the effects imparted by the increase in the heart rates, has been shown previously [20]. However canine studies with sympathetic nervous system stimulation of short and long duration, and infusion of epinephrine and norepinephrine of short and long duration, produced both shortening and lengthening of QT-intervals [20]. In patients with diabetic neuropathy, and thus completely and permanently denervated hearts, due to associated autonomic nervous system neuropathy, there was no diurnal variation in the QT-intervals noted [18]. This was due to complete anatomical and functional neuropathy in long-term diabetics with peripheral neuropathy [18], who have also the additional problem of low concentrations of blood circulating catecholamines, and blunted response to catecholamines during orthostasis, with an inverse correlation of the severity of peripheral neuropathy and blood levels of circulating catecholamines [21]. The state of sleep with its associated QT-interval prolongation is characterized by a decreased frequency of VA compared with the wakened state with its attendant shortened QT-intervals, for both normal subjects, and patients with ischemic heart disease [18]. VA occurs both in association with sympathetic activation and/or vagal withdrawal engendered shortening of the QT-interval [18], and in states with congenital and acquired QTinterval prolongation (drugs, hypokalemia, TTS) [1,22,23]. In reference to long QT interval syndromes, although etiological influences emanating from the autonomic sympathetic nervous system have been initially invoked, subsequently it has been found that mutations encoding a host of potassium and sodium channels impacting cardiomyocytes are the real culprit for the long QT syndromes [24]. Also stimulation of the sympathetic nerves and released norepinephrine may cause depending on their intensity, both long or short QT-intervals [24]. The complex condition of TTS is ushered by an early operating cardiac autonomic seethe, and subsequently evolves in a state characterized by regional development of apicobasal ME gradient [12]. The former promotes shortening of the QT-intervals [17], while the latter induces the characteristic long QT-intervals of TTS [1,12]. One could postulate that the natural course of the length of QT-interval in TTS is modulated by a dynamic interplay of the declining in intensity activation of the sympathetic activity, and the increasing development of ME. The important issue of VA in TTS is still surrounded by controversy. The range of prevalence is wide [1,2,25], but probably influenced by the variation and duration of monitoring practices, and possible nondetection of transient self-limited episodes of asymptomatic VA [1]. It is possible that the mechanism of VA vary over the clinical course of TTS [1,25], and that several mechanisms may be operating in concert at a given time. The role of the long QTc interval in the causation of VA needs further confirmation; there are many patients with very long QTc intervals, particularly many days after the inception of TTS, without
documentation of any ventricular ectopy. Although ME, and its apicobasal distribution [10–13] underlies the development of QTc prolongation, the exact impact, if any, of ME on arrhythmogenesis has not been dealt with. Finally the role of the cardiac autonomic sympathetic nervous system on VA, particularly in the subacute phase of TTS is still unexplored. Does CASD, involving myocardial regions with mechanical dysynchrony and ME, have an impact on the causation of VA? Also does the heightened activity of the central nervous system have an impact on cardiac arrhythmogenesis? There is a lot of work on this, carried out many years before the description of TTS [26,27], indicating that the central nervous system has the capacity of injuring the cardiomyocytes and cause VA. Indeed the brain–heart disconnection, due to irreversible damage of the brain has led to amelioration of the ECG abnormalities observed, when the brain–heart connection was intact [26,27]. To quote this author [26,27] verbatim, “the electrocardiographic abnormalities usually improve, often dramatically, with death by brain criteria. In fact, any circumstance that disconnects the brain from the heart (e.g., cardiac transplantation, severe autonomic neuropathies caused by amyloidosis or diabetes, stellate ganglionectomy for treatment of the long QT syndrome) blunts neurocardiac damage of any cause”. This was the impetus for the ongoing exploration whether the prevalence of diabetes mellitus (particularly of the type associated with peripheral neuropathy) is low in patients presenting with TTS [28]. Thus, any disconnection of the brain–heart link, either central (due to permanent terminal brain damage) or peripheral (due to transient CASN) could have an ameliorating effect on VA, which in the first case is of course clinically irrelevant. Along this stream of thoughts, it may be contributory to explore whether the rare neuropathic diabetic patients with TTS have a low prevalence of VA. There is little doubt that clinical and experimental explorations of the Takotsubo syndrome/QTc interval prolongation/myocardial edema/cardiac sympathetic denervation/cardiac arrhythmias quintet, may turn out to be scientifically fruitful. Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Madias, T.P. Fitzgibbons, A.A. Alsheikh-Ali, et al., Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes, Heart Rhythm. 8 (2011) 555–561. [2] M. Gopalakrishnan, H. Abdallah, D. Villines, et al., Predictors of short- and long-term outcomes of Takotsubo cardiomyopathy, Am. J. Cardiol. 116 (10) (Nov 2015) 1586–1590. [3] K. Bybee, T. Kara, A. Prasad, A. Lerman, G. Barsness, R. Wright, Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction, Ann. Intern. Med. 141 (2004) 858 (e865). [4] S. Pant, A. Deshmukh, K. Mehta, A. Badheka, Burden of arrhythmias in patients with Takotsubo cardiomyopathy (apical ballooning syndrome), Int. J. Cardiol. 70 (2012) 64 (e6818). [5] S. Sharkey, J. Lesser, M. Menon, M. Parpart, Spectrum and significance of electrocardiographic patterns, troponin levels and thrombolysis in myocardial infarction frame count in patients with stress (Takotsubo) cardiomyopathy and comparison to those in patients with anterior STEMI, Am. J. Cardiol. 101 (2008) 1723 (e1728). [6] A. Kucia, C. Neil, T. Nguyen, Evolution of ECG changes in Takotsubo cardiomyopathy: arrhythmias first, QT prolongation later? Heart Lung Circ. Abstr. 19S (2010) S104. [7] I. Syed, A. Prasad, J. Oh, M. Martinez, D. Feng, A. Motiei, Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging, Int. J. Cardiovasc. Imaging 24 (2008) 875–882. [8] F. Syed, S. Asirvatham, J. Francis, Arrhythmia occurrence with Takotsubo cardiomyopathy: a literature review, Europace 13 (2011) 780–788. [9] J.E. Madias, Is the worse outcome associated with epinephrine in resuscitated patients due to Takotsubo syndrome? Int. J. Cardiol. 182 (Mar 1 2015) 223. [10] F. Migliore, A. Zorzi, M.P. Marra, et al., Myocardial edema underlies dynamic T-wave inversion (Wellens' ECG pattern) in patients with reversible left ventricular dysfunction, Heart Rhythm. 8 (2011) 1629–1634. [11] A. Zorzi, M. Perazzolo Marra, F. Migliore, et al., Relationship between repolarization abnormalities and myocardial edema in atypical Tako-Tsubo syndrome, J. Electrocardiol. 46 (2013) 348–351. [12] M. Perazzolo Marra, A. Zorzi, F. Corbetti, et al., Apicobasal gradient of left ventricular myocardial edema underlies transient T-wave inversion and QT interval
Correspondence
[13]
[14]
[15]
[16]
[17]
[18]
prolongation (Wellens' ECG pattern) in Tako-Tsubo cardiomyopathy, Heart Rhythm. 10 (2013) 70–77. F. Migliore, A. Zorzi, M. Perazzolo Marra, S. Iliceto, D. Corrado, Myocardial edema as a substrate of electrocardiographic abnormalities and life-threatening arrhythmias in reversible ventricular dysfunction of Takotsubo cardiomyopathy: imaging evidence, presumed mechanisms, and implications for therapy, Heart Rhythm. 12 (2015) 1867–1877. Y.J. Akashi, K. Nakazawa, M. Sakakibara, F. Miyake, H. Musha, K. Sasaka, 123I-MIBG myocardial scintigraphy in patients with “Takotsubo” cardiomyopathy, J. Nucl. Med. 45 (2004) 1121–1127. C. Burgdorf, K. von Hof, H. Schunkert, V. Kurowski, Regional alterations in myocardial sympathetic innervation in patients with transient left-ventricular apical ballooning (Tako-Tsubo cardiomyopathy), J. Nucl. Cardiol. 15 (2008) 65–72. D. Caldeira, L.R. Lopes, S. Carmona, C. Gomes, I. Cruz, J. Santos, et al., Takotsubo cardiomyopathy, beyond ventriculography and classical bidimensional echocardiography, Int. J. Cardiol. 182 (2015) 381–383. A.R. Magnano, S. Holleran, R. Ramakrishnan, J.A. Reiffel, D.M. Bloomfield, Autonomic nervous system influences on QT interval in normal subjects, J. Am. Coll. Cardiol. 39 (2002) 1820–1826. R.S. Bexton, H.O. Vallin, A.J. Camm, Diurnal variation of the QT interval-influence of the autonomic nervous system, Br. Heart J. 55 (1986) 253–258.
261
[19] D.S. Cannom, A.K. Rider, E.B. Stinson, D.C. Harrison, Electrophysiologic studies in the denervated transplanted human heart. II. Response to norepinephrine, isoproterenol and propranolol, Am. J. Cardiol. 36 (1975) 859–866. [20] J.A. Abildskov, Adrenergic effects on the QT interval of the electrocardiogram, Am. Heart J. 92 (1976) 210–216. [21] N.J. Christensen, Plasma catecholamines in long-term diabetics with and without neuropathy and in hypophysectomized subjects, J. Clin. Invest. 51 (1972) 779–787. [22] S. Viskin, Long QT syndromes and torsade de pointes, Lancet 354 (1999) 1625–1633. [23] P.J. Kannankeril, D.M. Roden, Drug-induced long QT and torsade de pointes: recent advances, Curr. Opin. Cardiol. 22 (2007) 39–43. [24] M.J. Janse, Historical vignette: the long QT syndrome and the sympathetic nerves, Heart Rhythm. 1 (2004) 284. [25] K.H. Brown, R.G. Trohman, C. Madias, Arrhythmias in Takotsubo cardiomyopathy, Card. Electrophysiol. Clin. 7 (2015) 331–340. [26] M.A. Samuels, The brain–heart connection, Circulation 116 (2007) 77–84. [27] M.A. Samuels, Neurally induced cardiac damage. Definition of the problem, Neurol. Clin. 11 (1993) 273–292. [28] J.E. Madias, Low prevalence of diabetes mellitus in patients with Takotsubo syndrome: a plausible ‘protective’ effect with pathophysiologic connotations, Eur. Heart J. Acute Cardiovasc. Care (Feb 11 2015) (pii: 2048872615570761, Epub ahead of print).
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Correspondence
Takotsubo syndrome/QTc interval prolongation/myocardial edema/ cardiac sympathetic denervation/cardiac arrhythmias: A quintet needing exploration John E. Madias ⁎ Icahn School of Medicine at Mount Sinai, New York, NY, United States Division of Cardiology, Elmhurst Hospital Center, Elmhurst, NY, United States
a r t i c l e
i n f o
Article history: Received 14 October 2015 Accepted 18 October 2015 Available online 19 October 2015
To the Editor: It has been reported that patients with Takotsubo syndrome (TTS) develop prolongation of the QTc interval [1], which is associated with ventricular arrhythmias (VA) (monomorphic and polymorphic ventricular tachycardia, and ventricular fibrillation). However in one recent study reporting on 56 patients with TTS, “only 1 patient had a proved malignant VA and that patient succumbed to it” with “the QT interval noted to be 498 ms at the time of the event” [2]. The incidence of VA in TTS has been reported in some case series to be 1% to 1.5% [3], and felt to be uncommon [4,5]. There is a paucity of data regarding the precise association with QTc prolongation, based on characterization of the natural course of QTc prolongation, frequently recorded electrocardiograms (ECGs), or better continuous ECG monitoring, documentation of all VA, including non-sustained episodes, evaluation of the QTc in temporal proximity with each episode of VA based on the closest recorded ECG, or better on continuous ECG monitoring data analysis. It has been observed that some patients develop VA in the acute phase, even before the emergence of QTc prolongation [1,6], but the bulk of VA is seen in the subacute phase of TTS, at the time that QTc prolongation has occurred [1]. Indeed the same authors hypothesized that the patients with early VA represent cases of cardiac arrest who suffered TTS as a result of the stresses from the episode of sudden death and the ensuing cardiac resuscitation [1], further facilitated by the use of catecholamines [9]. In reference to the mechanism of VA in TTS some feel that it is similar to the one operating in the setting of acute myocardial infarction, and ⁎ Division of Cardiology, Elmhurst Hospital Center, 79–01 Broadway, Elmhurst, NY 11373, United States. E-mail address: [email protected].
http://dx.doi.org/10.1016/j.ijcard.2015.10.155 0167-5273/© 2015 Elsevier Ireland Ltd. All rights reserved.
based on myocardial re-entry [1], while others consider this unlikely, and favor “catecholaminergic, automatic, or fascicular tachycardias, with related cytosolic calcium overload” [2,8] inciting mechanisms. The opinion of the latter stems from the data about tissue level characterization deriving from magnetic resonance imaging, showing absence of scar formation [7]. However this author has expressed the notion that myocardial edema (ME) developing in patients with TTS could have a “patchy” distribution, and thus engender the prerequisite substrate for the emergence of re-entry and VA. Cardiac magnetic resonance imaging based ME has been widely documented in patients with TTS, with a causal association with QTc prolongation, attributed to a left ventricular apicobasal distribution gradient of ME [10–13]. Most of these studies have been carried out a few days after admission with TTS. Indeed ME and prolonged QTc persist for many weeks during convalescence, and during which time period the patients do not experience VA. To explain this counterintuitive phenomenon some authors have hypothesized that the mechanism of early and late VA in TTS may be different [1]. However also one wonders whether the consolidation or confluence and homogenization of ME, with plausible clear demarcation of myocardial regions with and without ME, mitigate the myocardial re-entry potential, thus leading to the paucity or rarity of VA several days after admission with TTS. Studies with 123I-metaiodobenzlguanidine (MIBG) myocardial scintigraphy in patients with TTS have documented transient cardiac autonomic sympathetic denervation (CASD) [14–16], in regions also afflicted with regional akinesis/dyskinesis/hypokinesis, and ME. Since MIBG imaging has been implemented ~ 1 to 2 weeks in patients with TTS, it is not known whether CASD is an early finding in the disease process, or it constitutes an epiphenomenon after TTS has been fully manifest. Be as it may the influence of CASD on the emergence of VA has not been addressed. VA are most probably facilitated via the autonomic nervous system direct effects of a heightened activity of its sympathetic component and withdrawal of its parasympathetic limb on the cardiomyocytes [2], and indirectly by the sympathetic nervous system's promotion of QTc prolongation [1]. However it should be understood that the issue of the influence of the autonomic sympathetic nervous system on the QT-interval, irrespective of TTS, is not conclusively settled, and it should be considered independently of the influence of the heart rate; indeed one may hypothesize that this is taken care by the Bazzet's formula correction, but this is only correct for a narrow range of heart rate changes. For example in normal subjects, increase in the
260
Correspondence
heart rate during exercise or atropine administration (both states with substantial vagal inhibition), is associated with shortening of QTinterval, while isoproterenol administration leads comparatively to less shortening, revealing that there are influences of the autonomic nervous system on the QT-interval, independent of the ones, imparted by the increase in the heart rate per se (e.g., by cardiac pacing) [17]. These authors observed that women (important for TTS) showed greater shortening of QT-interval than men during all the above 3 interventions, and discussed the discrepancies in the literature, and methodological problems in QT-interval measurements, where the U-wave is either included or excluded in the measurements [17]. Diurnal variation of the QT-intervals are large, with lengthening of the QT-intervals during sleep in pacemaker-dependent patients with normally autonomic nervous system innervated hearts, and are dependent on both changes in autonomic tone and concentration of the circulating catecholamines during sleep [18]. In contrast, the anatomically and functionally permanently denervated hearts of patients with orthotopic cardiac transplantation, showed markedly blunted variation of the QT-intervals, again with the longest QT-intervals noted during sleep [18], attributed to the changes in circulating catecholamines, to which they respond appropriately [19]. That there is shortening of the QT-intervals, independent of the effects imparted by the increase in the heart rates, has been shown previously [20]. However canine studies with sympathetic nervous system stimulation of short and long duration, and infusion of epinephrine and norepinephrine of short and long duration, produced both shortening and lengthening of QT-intervals [20]. In patients with diabetic neuropathy, and thus completely and permanently denervated hearts, due to associated autonomic nervous system neuropathy, there was no diurnal variation in the QT-intervals noted [18]. This was due to complete anatomical and functional neuropathy in long-term diabetics with peripheral neuropathy [18], who have also the additional problem of low concentrations of blood circulating catecholamines, and blunted response to catecholamines during orthostasis, with an inverse correlation of the severity of peripheral neuropathy and blood levels of circulating catecholamines [21]. The state of sleep with its associated QT-interval prolongation is characterized by a decreased frequency of VA compared with the wakened state with its attendant shortened QT-intervals, for both normal subjects, and patients with ischemic heart disease [18]. VA occurs both in association with sympathetic activation and/or vagal withdrawal engendered shortening of the QT-interval [18], and in states with congenital and acquired QTinterval prolongation (drugs, hypokalemia, TTS) [1,22,23]. In reference to long QT interval syndromes, although etiological influences emanating from the autonomic sympathetic nervous system have been initially invoked, subsequently it has been found that mutations encoding a host of potassium and sodium channels impacting cardiomyocytes are the real culprit for the long QT syndromes [24]. Also stimulation of the sympathetic nerves and released norepinephrine may cause depending on their intensity, both long or short QT-intervals [24]. The complex condition of TTS is ushered by an early operating cardiac autonomic seethe, and subsequently evolves in a state characterized by regional development of apicobasal ME gradient [12]. The former promotes shortening of the QT-intervals [17], while the latter induces the characteristic long QT-intervals of TTS [1,12]. One could postulate that the natural course of the length of QT-interval in TTS is modulated by a dynamic interplay of the declining in intensity activation of the sympathetic activity, and the increasing development of ME. The important issue of VA in TTS is still surrounded by controversy. The range of prevalence is wide [1,2,25], but probably influenced by the variation and duration of monitoring practices, and possible nondetection of transient self-limited episodes of asymptomatic VA [1]. It is possible that the mechanism of VA vary over the clinical course of TTS [1,25], and that several mechanisms may be operating in concert at a given time. The role of the long QTc interval in the causation of VA needs further confirmation; there are many patients with very long QTc intervals, particularly many days after the inception of TTS, without
documentation of any ventricular ectopy. Although ME, and its apicobasal distribution [10–13] underlies the development of QTc prolongation, the exact impact, if any, of ME on arrhythmogenesis has not been dealt with. Finally the role of the cardiac autonomic sympathetic nervous system on VA, particularly in the subacute phase of TTS is still unexplored. Does CASD, involving myocardial regions with mechanical dysynchrony and ME, have an impact on the causation of VA? Also does the heightened activity of the central nervous system have an impact on cardiac arrhythmogenesis? There is a lot of work on this, carried out many years before the description of TTS [26,27], indicating that the central nervous system has the capacity of injuring the cardiomyocytes and cause VA. Indeed the brain–heart disconnection, due to irreversible damage of the brain has led to amelioration of the ECG abnormalities observed, when the brain–heart connection was intact [26,27]. To quote this author [26,27] verbatim, “the electrocardiographic abnormalities usually improve, often dramatically, with death by brain criteria. In fact, any circumstance that disconnects the brain from the heart (e.g., cardiac transplantation, severe autonomic neuropathies caused by amyloidosis or diabetes, stellate ganglionectomy for treatment of the long QT syndrome) blunts neurocardiac damage of any cause”. This was the impetus for the ongoing exploration whether the prevalence of diabetes mellitus (particularly of the type associated with peripheral neuropathy) is low in patients presenting with TTS [28]. Thus, any disconnection of the brain–heart link, either central (due to permanent terminal brain damage) or peripheral (due to transient CASN) could have an ameliorating effect on VA, which in the first case is of course clinically irrelevant. Along this stream of thoughts, it may be contributory to explore whether the rare neuropathic diabetic patients with TTS have a low prevalence of VA. There is little doubt that clinical and experimental explorations of the Takotsubo syndrome/QTc interval prolongation/myocardial edema/cardiac sympathetic denervation/cardiac arrhythmias quintet, may turn out to be scientifically fruitful. Conflicts of interest The authors report no relationships that could be construed as a conflict of interest. References [1] C. Madias, T.P. Fitzgibbons, A.A. Alsheikh-Ali, et al., Acquired long QT syndrome from stress cardiomyopathy is associated with ventricular arrhythmias and torsades de pointes, Heart Rhythm. 8 (2011) 555–561. [2] M. Gopalakrishnan, H. Abdallah, D. Villines, et al., Predictors of short- and long-term outcomes of Takotsubo cardiomyopathy, Am. J. Cardiol. 116 (10) (Nov 2015) 1586–1590. [3] K. Bybee, T. Kara, A. Prasad, A. Lerman, G. Barsness, R. Wright, Systematic review: transient left ventricular apical ballooning: a syndrome that mimics ST-segment elevation myocardial infarction, Ann. Intern. Med. 141 (2004) 858 (e865). [4] S. Pant, A. Deshmukh, K. Mehta, A. Badheka, Burden of arrhythmias in patients with Takotsubo cardiomyopathy (apical ballooning syndrome), Int. J. Cardiol. 70 (2012) 64 (e6818). [5] S. Sharkey, J. Lesser, M. Menon, M. Parpart, Spectrum and significance of electrocardiographic patterns, troponin levels and thrombolysis in myocardial infarction frame count in patients with stress (Takotsubo) cardiomyopathy and comparison to those in patients with anterior STEMI, Am. J. Cardiol. 101 (2008) 1723 (e1728). [6] A. Kucia, C. Neil, T. Nguyen, Evolution of ECG changes in Takotsubo cardiomyopathy: arrhythmias first, QT prolongation later? Heart Lung Circ. Abstr. 19S (2010) S104. [7] I. Syed, A. Prasad, J. Oh, M. Martinez, D. Feng, A. Motiei, Apical ballooning syndrome or aborted acute myocardial infarction? Insights from cardiovascular magnetic resonance imaging, Int. J. Cardiovasc. Imaging 24 (2008) 875–882. [8] F. Syed, S. Asirvatham, J. Francis, Arrhythmia occurrence with Takotsubo cardiomyopathy: a literature review, Europace 13 (2011) 780–788. [9] J.E. Madias, Is the worse outcome associated with epinephrine in resuscitated patients due to Takotsubo syndrome? Int. J. Cardiol. 182 (Mar 1 2015) 223. [10] F. Migliore, A. Zorzi, M.P. Marra, et al., Myocardial edema underlies dynamic T-wave inversion (Wellens' ECG pattern) in patients with reversible left ventricular dysfunction, Heart Rhythm. 8 (2011) 1629–1634. [11] A. Zorzi, M. Perazzolo Marra, F. Migliore, et al., Relationship between repolarization abnormalities and myocardial edema in atypical Tako-Tsubo syndrome, J. Electrocardiol. 46 (2013) 348–351. [12] M. Perazzolo Marra, A. Zorzi, F. Corbetti, et al., Apicobasal gradient of left ventricular myocardial edema underlies transient T-wave inversion and QT interval
Correspondence
[13]
[14]
[15]
[16]
[17]
[18]
prolongation (Wellens' ECG pattern) in Tako-Tsubo cardiomyopathy, Heart Rhythm. 10 (2013) 70–77. F. Migliore, A. Zorzi, M. Perazzolo Marra, S. Iliceto, D. Corrado, Myocardial edema as a substrate of electrocardiographic abnormalities and life-threatening arrhythmias in reversible ventricular dysfunction of Takotsubo cardiomyopathy: imaging evidence, presumed mechanisms, and implications for therapy, Heart Rhythm. 12 (2015) 1867–1877. Y.J. Akashi, K. Nakazawa, M. Sakakibara, F. Miyake, H. Musha, K. Sasaka, 123I-MIBG myocardial scintigraphy in patients with “Takotsubo” cardiomyopathy, J. Nucl. Med. 45 (2004) 1121–1127. C. Burgdorf, K. von Hof, H. Schunkert, V. Kurowski, Regional alterations in myocardial sympathetic innervation in patients with transient left-ventricular apical ballooning (Tako-Tsubo cardiomyopathy), J. Nucl. Cardiol. 15 (2008) 65–72. D. Caldeira, L.R. Lopes, S. Carmona, C. Gomes, I. Cruz, J. Santos, et al., Takotsubo cardiomyopathy, beyond ventriculography and classical bidimensional echocardiography, Int. J. Cardiol. 182 (2015) 381–383. A.R. Magnano, S. Holleran, R. Ramakrishnan, J.A. Reiffel, D.M. Bloomfield, Autonomic nervous system influences on QT interval in normal subjects, J. Am. Coll. Cardiol. 39 (2002) 1820–1826. R.S. Bexton, H.O. Vallin, A.J. Camm, Diurnal variation of the QT interval-influence of the autonomic nervous system, Br. Heart J. 55 (1986) 253–258.
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