Torsades de Pointes in Takotsubo Cardiomyopathy with QT Prolongation

Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is characterized by reversible left ventricular apical ballooning associated with emotional or physiologic stress, mimicking acute myocardial infarction in the absence of significant coronary artery disease at angiography. Although the prognosis for patients with Takotsubo cardiomyopathy is relatively good, it is reported to be associated with long QT syndrome and torsades de pointes (TdP) which is a fatal polymorphic ventricular tachyarrhythmia. However, only QT prolongation abnormalities is not enough to induce TdP, and other factors associated with Takotsubo cardiomyopathy seem to be needed for the induction of TdP. In this chapter, the mechanism of TdP in Takotsubo cardiomyopathy with QT prolongation is discussed.


Introduction
Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is characterized by reversible left ventricular apical ballooning associated with emotional or physiologic stress, mimicking acute myocardial infarction in the absence of significant coronary artery disease at angiography.Although the prognosis for patients with Takotsubo cardiomyopathy is relatively good, it is reported to be associated with long QT syndrome and torsades de pointes (TdP) which is a fatal polymorphic ventricular tachyarrhythmia.However, only QT prolongation abnormalities is not enough to induce TdP, and other factors associated with Takotsubo cardiomyopathy seem to be needed for the induction of TdP.In this chapter, the mechanism of TdP in Takotsubo cardiomyopathy with QT prolongation is discussed.

Takotsubo cardiomyopathy
Takotsubo cardiomyopathy, or stress-induced cardiomyopathy, is a disease exhibiting an acute left ventricular apical ballooning of unknown cause (Kawai et al., 2007).Many cases with takotsubo cardiomyopathy are associated with preceded emotional or physiologic stress.In this disease, the left ventricle takes on the appearance of a Japanese octopus fishing pot called a takotsubo.In takotsubo cardiomyopathy, left ventricular dysfunction is reversible, i.e., it recovers within a few weeks (Figure 1).Other signs include ECG changes, including ST-segment elevation, abnormal Q wave, and T-wave inversions (Figure 2), which mimicks acute myocardial infarction but there is no significant coronary artery disease at angiography (Kawai et al., 2007, Tsuchihashi et al., 2001, Kurisu et al. , 2002 ).Several pathophysiological mechanisms have been proposed to explain the features of this syndrome, such as multivessel coronary vasospasm, abnormalities in coronary microvascular function, and catecholamine-mediated cardiotoxicity (Akashi et al, 2002, Kurisu et al, 2003, Sansen V & Holvoet G., 2007).Studies on 123I-metaiodybenzylguanidine suggested the existence of cardiac autonomic damage and/or accelerated cardiac sympathetic nervous function in patients with Takotsubo cardiomyopathy (Akashi et al, 2004, Burgdorf et al, 2008).Nef, et al (Nef et al, 2007) reported that there were contraction bands, increase in fibrosis, and the regional accumulation of inflammatory cells in biopsied specimen of myocardium in acute phase of Takotsubo cardiomyopathy, and they suggested that these findings were similar to those associated with catecholamine cardiotoxicity.These data suggest that catecholamine-mediated cardiotoxicity may be the most plausible cause of Takotsubo cardiomyopathy although the precise aetiology and pathophysiology of this syndrome remain unknown.Takotsubo cardiomyopathy occurs most frequently in women over 50 years of age.The reason for the much more common occurrence in post-menopausal women is unclear.Several explanations have been proposed.Sex hormones may exert important influences on the sympathetic neurohormonal axis (Hinojosa-Laborde et al, 1999) and on coronary vasoreactivity (Sader & Celermajer, 2002).Women appear also to be more vulnerable to sympathetically mediated myocardial stunning (Lambert et al, 2002), and post-menopausal alteration of endothelial function in response to reduced estrogen levels has been advocated as a possible alternative explanation (Taddei et al, 1996).

Long QT syndrome (QT prolongation) and torsades de pointes
The Long QT syndrome (LQTS) is originally a hereditary disorder in which most affected family members have delayed ventricular repolarization manifest on the electrocardiogram (ECG) as QT prolongation (Moss et al, 1985).The disorder is associated with an increased propensity to arrhythmogenic syncope, polymorphic ventricular tachycardia (torsades de pointes), and sudden arrhythmic death.LQTS is due to mutations involving principally the myocyte ion-channels, and this monogenetic disorder has an autosomal-dominant inheritance pattern.Since the 3 genes were identified for the 3 major genotypes, a total of 13 forms of LQTS have been reported (Shimizu W & Horie M.).Recently, mutations in the caveolin-3 gene (CAV3) have been linked with the congenital long QT syndrome (LQT9), and mutations in caveolar-localized ion channels may contribute to other inherited arrhythmias.Caveolin-3 is the essential scaffolding protein of caveolae which are specialized membrane microdomains enriched in cholesterol and sphingolipids which are present in multiple cell types including cardiomyocytes.Along with the essential scaffolding protein caveolin-3, a number of different ion channels and transporters have been localized to caveolae in the heart.Mutations in caveolar-localized ion channels may contribute to other inherited arrhythmias, and changes in the caveolar microdomain in acquired heart disease may also lead to dysregulation and dysfunction of ion channels, altering the risk of arrhythmias in conditions such as heart failure (Balijepalli & Kamp, 2008).This indicate that abnormality or damage of structural elements of cardiomyocyte may also induce QT prolongation and arrhythmia.Long QT syndrome can be also divided into idiopathic (congenital) and acquired forms.QT intervals vary according to age, sex, and heart rate, and acquired long QT syndrome describes pathologic QT interval prolongation.Acquired long QT syndrome can arise in response to various drugs, electrolyte abnormalities (e.g., hypokalemia, hypomagnesemia) and significant bradyarrhythmias.It also becomes a risk of arrhythmogenic syncope, polymorphic ventricular tachycardia (torsades de pointes), and sudden arrhythmic death.Torsade de pointes (TdP) is a life-threatening arrhythmia that develops as a consequence of a reduction in the repolarization reserve of cardiac cells leading to amplification of electrical heterogeneities in the ventricular myocardium as well as to the development of early after depolarization-induced triggered activity.Autonomic nervous system may have important role in the initiation of Tdp (Coumel, 1993).The level of adrenergic drive is required for the occurrence of Tdp, and it also produces a sinus tachycardia that would prevent QT prolongation.Autonimic tone influences the QT interval directly by affecting the action potential duration and indirectly by modulating the RR interval.These indicate that the interactions between heart rate and sympathetic nervous activity are complex.Fujiki et al (Fujiki et al, 2001) suggested that the sympathovagal imbalance may have an important role in the dynamic change in the QT interval and initiation of Tdp in patients with long QT syndrome.In patients with acquired long-QT syndrome, Locati et al (Locati et al, 1995) reported that both adrenergic-and pause-dependent mechanisms may have a synergistic role in the genesis of Tdp.Women are more prone to develop TdP than men either congenital or acquired LQTS, and it is similar to the sex difference of occurrence of Takotsubo cardiomyopathy.Although the precise mechanism has not been clarified, female hormone may exert the influence on cardiac repolarization process (Kurokawa et al, 2009).

Torsades de pointes in takotsubo cardiomyopathy with QT prolongation
The presence of QT interval prolongation has been discussed in patients with Takotsubo cardiomyopathy (Abe et al., 2003, Desmet et al., 2003, Matsuoka et al., 2003), and there have been 17 reported cases of QT interval prolongation and torsades de pointes (TdP) associated with Takotsubo cardiomyopathy (Denney et al., 2005, Sasaki et al., 2006, Okada T, et al., 2007 [in Japanese], Nault et al., 2007, Boulouffe et al., 2007, Patel et al., 2007, Kurisu et al., 2008, Furushima et al., 2008, Hirose et al., 2008, Ghosh et al., 2009, Mahida et al., 2009, Inoue et al., 2009, Kawano et al., 2010, Purvis et al., 2009, Yamada et al., 2011 ) (Figure 2) (Table 1).Considering the 17 previous cases reported in the literature, QT prolongation in Takotsubo cardiomyopathy has been attributed to hypokalemia (n= 3), bradycardia associated with atrioventricular (AV) block (n=4), idiopathic long QT syndrome (n=2), hypokalemia plus antiarrhythmic therapy (n=1), and hypokalemia plus idiopathic long QT syndrome (n=1), hypokalemia and hypomagnesemia (n=1), hyponagnesemia (n=1), and antibiotic (n=1) in 14 cases, and there was no specific factor associated with QT prolongation in 3 cases.The vasospasm provocation test was performed in only 3 cases, and vasospasm was not induced in any of these cases.Hypokalemia or hypomagnesemia is one of the most important risk factor because it is present in 7 of 17 (41%) case.Badycardia associated with AV block is also one of the important factor because its presence in 4 of 17 (24%) cases.These observations suggest that electrolyte imbalances and bradycardia are a risk factor for the development of torsades de pointes in patients with Takotsubo cardiomyopathy.However, only QT prolongation is not enough to induce TdP.Oscillations of the RR interval or the short-long-short (or the long-short) sequence precede the initiation of TdP in patients with acquired prolongation of repolarization (Locati et al., 1995).In most cases of TdP, frequent premature ventricular contraction (PVC)s create long-short sequence, i.e., a VPC generates a post-extrasystolic pause, the following regular beat shows marked QT prolongation from which a subsequent PVC arise, and this beat initiates TdP.Triggered activity originating from early after-depolarization or phase 2 reentry has been suggested as the cause of the PVC which induces long-short initiating sequence and can be the first beat of TdP.However, there is another unique pattern of the initiating of TdP in Takotsubo cardiomyopathy (Kawano et al., 2010,).It seems that premature atrial contraction (PAC) followed by QRS on T wave can also induced reentrant ventricular tachycardia directly (Figure 3).The peak of T wave is known as the vulnerable period of the ventricle.Depolarization at this phase may easily induce unstable reentrant mechanism especially in the case with prominently increased dispersion of repolarization such as long QT syndrome.This mechanism of TdP is also very rare in long QT syndrome.Moreover, that case had already had mild QT prolongation with hypokalemia and PAC before the occurrence of Takotsubo cardiomyopathy.This suggests that other factors associated with Takotsubo cardiomyopathy is needed for the induction of TdP.Prolongation of action potential duration (APD) due to abnormal ion channel current causes QT prolongation.Dispersion of APD or repolarizaion is thought to be one of the mechanisms of occurrence of Tdp, and Furushima et al. (Furushima et al., 2008) reported abnormal LV reporlarization gradient in a patient with Takotsubo cardiomyopathy.Taken together, dispersion of APD or repolarization in Takotsubo cardiomyopathy as well as QT prolongation may be important in the occurrence of TdP.Adrenergic stimulation may be also related to TdP in Takotsbo cardiomyopathy because catecholamine excess and neurogenic myocardial stunning are thought to be one of the the most plausible causes of Takotsubo cardiomyopathy.On the other hands, TdP may be one of the trigger of Takotsubo cardiomyopathy in long QT syndrome.Although it occurs most frequently in women over 50 years of age, recent study demonstrated that men with Takotsubo cardiomyopathy-associated QT interval prolongation are at risk for TdP, and that most patients with Takotsubo cardiomyopathyassociated TdP have risk factors for TdP other than the female sex and systolic dysfunction (Samuelov-Kinori, 2009).

Conclusion
We usually pay attention to ventricular arrhythmia in other cardiomyopathy, i.e., hypertrophic cardiomyopathy and dilated cardiomyopathy.And we have to also consider the importance of PAC as well as VPC as the initiator of TdP, the life-threatening arrhythmia in Takotsubo cardiomyopathy .

Acknowledgment
I thank editors of Internal Medicine for their excellent advice to discuss the mechanisms of torsasede de pointes in Takotsubo cardiomyopathy.

References
Abe Y, Kondo M, Matsuoka R, Araki M, Dohyama K, Tanio H. Assessment of clinical features in transient left ventricular apical ballooning.J Am Coll Cardiol 41: 737-742, 2003 Akashi YJ, Nakazawa K, Sakakibara M, Miyake F, Sasaka K. Reversible left ventricular dysfunction "takotsubo" cardiomyopathy related to catecholamine cardiotoxicity.J Electrocardiol 35: 351-6, 2002 Coronary angiography showed no significant coronary stenosis of the left (A) and right (B)coronary arteries.Left ventriculography demonstrated akinesis of apex of the left ventricle on admission (C, enddiastolic phase; D, end-systolic phase) and showed recovered apical wall motion of the left ventricle about three weeks after admission(C, end-diastolic phase; D, end-systolic phase).

Fig. 1 .
Fig. 1.Coronary angiography and left ventriculography on admission and about three weeks after the admission

Table 1 .
Reports of Takotsubo Cardiomyopathy with Torsades de Pointes M male, F female, BA bronchial asthma, LQTS idiopathic long QT syndrome, HT hypertension