International Journal of Cardiology 178 (2015) 40–43
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
McConnell's sign — An insight into the pathogenesis of Takotsubo syndrome? Yangzhen Shao a,b,⁎, Björn Redfors a,b, Anwar Ali a, Eduardo Bossone c, Alexander Lyon d, Elmir Omerovic a,b a
Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden Cardiology Unit, Azienda Ospedaliera-Universitaria of Salerno, 84131 Salerno, Italy d NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK b c
a r t i c l e
i n f o
Article history: Received 20 October 2014 Accepted 22 October 2014 Available online 23 October 2014 Keywords: Takotsubo syndrome McConnell's Sign Ventricular wall-stress Segmental myocardial akinesia
1. Introduction Takotsubo syndrome (TTS), also known as stress-induced cardiomyopathy, is an acute cardiac syndrome. The unique characteristics of TTS are that one or more circumferential cardiac segments are stunned out of contraction in the absence of an explanatory coronary lesion [1]. Although the peculiar myocardial akinesia can affect any part of the ventricular wall, two common patterns of TTS are apical akinesis (the typical TTS) and basal akinesis (the inverted pattern) [2]. The pathogenesis underlying Takotsubo syndrome is incompletely understood. Several mechanisms have been proposed for the development of TTS, including overstimulation of the β2-adrenoceptor-Gi pathway [3], acute coronary microvascular and endothelial dysfunction [4], aborted myocardial infarction with spontaneous recanalisation [5], acute metabolic stunning [6], lipotoxicity [1,7], acute left ventricular outflow tract obstruction (LVOTO) and abnormal ventriculo-arterial coupling [8]. One critical shortcoming of some of these proposed mechanisms is that they are not able to elucidate why myocardial akinesia in TTS is usually segmental and circumferential. Although the gradient distribution of β-adrenoceptors or sympathetic nerves in the heart may explain why catecholamine-induced myocardial akinesia can be apical or basal, such physiological properties, including genetic profiles, currently fail to ⁎ Corresponding author at: Bruna stråket 16, 413 45 Gothenburg, Sweden. E-mail address: [email protected] (Y. Shao).
http://dx.doi.org/10.1016/j.ijcard.2014.10.143 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
explain why different anatomical variants of TTS can recur in one patient [9]. 2. McConnell's sign associates with elevated afterload and mimics inverted Takotsubo McConnell's sign is a characteristic echocardiographic finding of the regional dysfunction of the right ventricle in pulmonary embolism (PE) [10]. Fig. 1 shows the typical pattern of McConnell's sign in a patient with acute PE: a distinct bulge (indicating akinesis) in the mid-free wall of the right ventricle during a systole, whilst the apex is spared from dysfunction and contracts into a peak cone. The unique pattern of cardiac contractile dysfunction in PE has certain features which resemble inverted Takotsubo syndrome (Fig. 1). Acute embolic occlusion of a large pulmonary artery causes an abrupt increase in pulmonary artery pressure, and thus an elevated afterload for the right ventricle. This may lead to increased wall-stress and akinesia in the basal myocardium, thus explaining McConnell's sign [11]. Similarly, in a preclinical model we identified that the inverted TTS variant was associated with high afterload [8]. We were able to induce variant patterns of TTS by catecholamines, which have different effects on afterload. Low afterload seems to restrictively precipitate the development of typical TTS (apical akinesia), whilst high afterload leads to inverted TTS variant. Moreover, interfering with the effects of a catecholamine on blood pressure alters the pattern of TTS that is supposed to be induced by the catecholamine [8]. We hypothesize that the level of ventricular afterload may influence which cardiac segment is subjected to increased wall-stress and thus circumferential akinesia. However, how an afterload affects wall-stress only in a certain cardiac segment, but not the other parts of or the entire ventricular wall, is unclear. 3. Sequential contraction may determine how the ventricular afterload affects wall-stress in a restricted segmental distribution The ventricular myocardium is sequentially stimulated to contract and eject blood from the ventricular cavity. The myocardium is highly organised in three layers. The endocardial layer goes in helix-strand ascending, whilst the epicardial myofibres are helix-strand descending. The middle layer is circular and parallel to the ventricular equator, and perpendicular to the apical–basal axis (Fig. 2A) [12]. The helical-strand
Y. Shao et al. / International Journal of Cardiology 178 (2015) 40–43
41
Fig. 1. A similar pattern of myocardial dysfunction develops in pulmonary embolism (PE) and inverted Takotsubo syndrome. In both conditions, the apex contracts and forms a peak cone (yellow arrows), whilst the base and the mid-free wall are stunned out of contraction and paradoxically bulge out during systole (blue arrows). The left picture is an echocardiograph of the characteristic myocardial dysfunction in the right ventricle in the setting of PE (McConnell's sign). The right picture is left ventricular end systolic ventriculography in the setting of inverted Takotsubo. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
muscles generate circumferential torsion forces that rotate the epicardium and endocardium in opposite directions (along the long axis), whilst contraction of the circular muscles contributes to radial contraction. Contraction of these cardiac muscle layers produces different vectors
of peak strain (see Fig. 2B), which are well-coordinated in ejection of blood from the cavity during systole. Sequential electrical activation of these cardiac muscles is potentially important for the efficiency of ventricular systole. Based upon the anatomy of the bundle of His and
Fig. 2. Arrangement of the ventricular muscles and strength patterns after muscle contraction. Cardiac muscles are highly organised in three layers. The epicardium is helix-descending and the endocardium is helix-ascending. Contraction of these helix muscles generates strengths of helix-ascending (green arrows), strengths towards the base along the long axis (red arrows), and clockwise circumferential strengths (blue arrows). The mid-ventricular muscles are circular and are on the planes of the short axis. Contraction of the circular muscles produces strengths pointing to the centre on the plans of the short axis (purple arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
42
Y. Shao et al. / International Journal of Cardiology 178 (2015) 40–43
Purkinje fibre system cardiac contraction usually starts at the apex and advances towards the base [12]. During systole transmural pressure passively imposed on cardiac segments may be continuously changed. More specifically, during the isovolumetric contraction of a systole, wall-stress in the basal myocardium is progressively raised due to the earlier contractions of the apex and the mid-ventricular wall. For the purpose of the present discussion, wall-stress passively imposed on a cardiac segment is termed preload wall-stress. In the setting of PE or inverted TTS, where afterload is elevated, high intraventricular pressure is required to open the pulmonary/aortic valve. This will introduce increased transmural pressure and preload wall-stress to the basal myocardium. If the preload wall-stress exceeds the limitation that basal myofibres can afford, contraction of the myofibres is disrupted, possibly explaining basal akinesia in PE and inverted TTS. Perhaps contractile band rupture observed in the hearts of TTS patients [13] is due to a cardiac segment contracting against such an extremely increased preload wall-stress that the myofibres get ruptured. However, low afterload seems to distribute preload wall-stress differently from high afterload. Because the aortic valve opens when intraventricular pressure exceeds the pressure of the aortic artery, transmural pressure and preload wall-stress in the basal myocardium are unlikely to reach a high level in the condition of low afterload. This probably explains why the base can be spared from akinesis in typical Takotsubo, where the afterload is severely decreased. However, with a strong inotropic and chronotropic drive of catecholamines, intensive and rapid contraction of the base may precipitate outflow obstruction and cause an increase in wall-stress of the apical myocardium. Indeed, outflow obstruction has been recorded in 25% of patients with typical TTS [14]. Perhaps outflow obstruction is one pivotal factor in determining how low-afterload introduces increased wall-stress only to the apical or apical–middle myocardium. However, because the apex usually contracts before the base, how the base is able to contract before the apex and obstructs the outflow is not clear. We hypothesize that the characteristic twisting and rotating contraction of the heart may be relatively delayed in the apex, compared with the circumferential contraction in the base, when heart frequency is significantly accelerated. 4. Increased wall-stress triggers myocardial stunning, possibly by myocardial overstretch How increased wall-stress results in myocardial akinesia has not been completely determined. One mechanism proposed for McConnell's cardiac dysfunction is localised ischemia as a result of increased wall-stress in the free wall of the right ventricle [11]. Elevated wall-stress increases oxygen consumption [15,16] and perhaps results in a relative myocardial ischemia due to a demand–supply mismatch. We believe that a similar demand–supply mismatch also occurs in the setting of TTS, where coronary blood flow is not significantly decreased but energy demand is severely increased [17]. However, ischemia may not be the major cause of the cardiac stunning in TTS, though it does cause cardiac dysfunction. The myofibres are likely overstretched in the cardiac area bearing intensively increased wall tension/stress. Overstretch-induced contractile dysfunction [18] may be the onset of TTS myocardial stunning. Overdistention of myofibres reduces contractility, due to a series of stretch-induced abnormalities, e.g., sarcomere overstrain, fewer cross-bridges between myosin and actin, stretch-induced currents [19], cytoplasmic calcium alteration [20], and instability of membrane potential [21]. In addition, repeated passive stretching of the myocardium in the affected cardiac zone tends to produce progressive lengthening of the myofibres — so-called stretch-induced ‘creep’ and ‘softening’ [18,22]. These effects may contribute to explain the unique deformation of paradoxical spherical bulging during systole in the akinetic cardiac area, which is observed in McConnell's sign and TTS. We have hypothesized that TTS myocardial stunning occurs as the heart alters metabolism to preserve energy for basic
non-contractile cellular survival during severe oxygen insufficiency by shutting down mechanical cardiac activity [17]. Overstretch may be one mechanism potentiating the myocardium to cease the mechanical contraction. In conclusion, McConnell's sign describes the unique cardiac dysfunction observed in pulmonary embolism. The mechanism is associated with increased wall-stress of the mid-free right ventricular wall as a result of abruptly increased pulmonary artery pressure. A similar mechanism may be involved in the development of inverted Takotsubo. The development of inverted TTS in a preclinical model is closely associated with a high afterload, whilst typical TTS (apical ballooning) was usually observed in the context of a low afterload. Sequential contraction of cardiac muscles may be crucial in determining whether the base or apex is subjected to increased wall-stress (and thus akinesia) in the condition of high or low afterload. Increased wall-stress, resulting in myocardial akinesia, may lead to overstretch-triggered myocardial stunning. Ischemia-related myocardial dysfunction as a result of increased wallstress may interact with these mechanisms and promote the development of myocardial stunning.
References [1] Y. Shao, B. Redfors, M. Scharin Tang, H. Mollmann, C. Troidl, S. Szardien, C. Hamm, H. Nef, J. Boren, E. Omerovic, Novel rat model reveals important roles of betaadrenoreceptors in stress-induced cardiomyopathy, Int. J. Cardiol. 168 (3) (2013) 1943–1950. [2] Y. Shao, B. Redfors, A.R. Lyon, A. Rosengren, K. Swedberg, E. Omerovic, Trends in publications on stress-induced cardiomyopathy, Int. J. Cardiol. 157 (2012) 435–436. [3] H. Paur, P.T. Wright, M.B. Sikkel, M.H. Tranter, C. Mansfield, P. O'Gara, D.J. Stuckey, V.O. Nikolaev, I. Diakonov, L. Pannell, H. Gong, H. Sun, N.S. Peters, M. Petrou, Z. Zheng, J. Gorelik, A.R. Lyon, S.E. Harding, High levels of circulating epinephrine trigger apical cardiodepression in a beta2-adrenergic receptor/gi-dependent manner: a new model of Takotsubo cardiomyopathy, Circulation 126 (2012) 697–706. [4] F. Crea, P.G. Camici, C.N. Bairey Merz, Coronary microvascular dysfunction: an update, Eur. Heart J. 35 (2014) 1101–1111. [5] M.H. Tranter, P.T. Wright, M.B. Sikkel, A.R. Lyon, Takotsubo cardiomyopathy: the pathophysiology, Heart Fail. Clin. 9 (2013) 187–196 (viii–ix). [6] K. Obunai, D. Misra, A. Van Tosh, S.R. Bergmann, Metabolic evidence of myocardial stunning in takotsubo cardiomyopathy: a positron emission tomography study, J. Nucl. Cardiol. 12 (2005) 742–744. [7] Y. Shao, B. Redfors, M. Stahlman, M.S. Tang, A. Miljanovic, H. Mollmann, C. Troidl, S. Szardien, C. Hamm, H. Nef, J. Boren, E. Omerovic, A mouse model reveals an important role for catecholamine-induced lipotoxicity in the pathogenesis of stressinduced cardiomyopathy, Eur. J. Heart Fail. 15 (2013) 9–22. [8] B. Redfors, A. Ali, Y. Shao, J. Lundgren, L.M. Gan, E. Omerovic, Different catecholamines induce different patterns of takotsubo-like cardiac dysfunction in an apparently afterload dependent manner, Int. J. Cardiol. 174 (2014) 330–336. [9] A.M. From, G.S. Sandhu, V.T. Nkomo, A. Prasad, Apical ballooning syndrome (Takotsubo cardiomyopathy) presenting with typical left ventricular morphology at initial presentation and mid-ventricular variant during a recurrence, J. Am. Coll. Cardiol. 58 (2011) e1. [10] M.V. McConnell, S.D. Solomon, M.E. Rayan, P.C. Come, S.Z. Goldhaber, R.T. Lee, Regional right ventricular dysfunction detected by echocardiography in acute pulmonary embolism, Am. J. Cardiol. 78 (1996) 469–473. [11] R.P. Sosland, K. Gupta, Images in cardiovascular medicine: Mcconnell's sign, Circulation 118 (2008) e517–e518. [12] P.P. Sengupta, V.K. Krishnamoorthy, J. Korinek, J. Narula, M.A. Vannan, S.J. Lester, J.A. Tajik, J.B. Seward, B.K. Khandheria, M. Belohlavek, Left ventricular form and function revisited: applied translational science to cardiovascular ultrasound imaging, J. Am. Soc. Echocardiogr. 20 (2007) 539–551. [13] Y.J. Akashi, D.S. Goldstein, G. Barbaro, T. Ueyama, Takotsubo cardiomyopathy: a new form of acute, reversible heart failure, Circulation 118 (2008) 2754–2762. [14] R. El Mahmoud, N. Mansencal, R. Pilliere, F. Leyer, N. Abbou, P. Michaud, O. Nallet, F. Digne, P. Lacombe, S. Cattan, O. Dubourg, Prevalence and characteristics of left ventricular outflow tract obstruction in Tako-tsubo syndrome, Am. Heart J. 156 (2008) 543–548. [15] H. Abe, W. Holt, T.A. Watters, S. Wu, W.W. Parmley, N. Schiller, C. Higgins, J. Wikman-Coffelt, Mechanics and energetics of overstretch: the relationship of altered left ventricular volume to the frank-starling mechanism and phosphorylation potential, Am. Heart J. 116 (1988) 447–454. [16] T. Delhaas, T. Arts, F.W. Prinzen, R.S. Reneman, Regional fibre stress-fibre strain area as an estimate of regional blood flow and oxygen demand in the canine heart, J. Physiol. 477 (Pt 3) (1994) 481–496. [17] B. Redfors, Y. Shao, A. Ali, E. Omerovic, Are the different patterns of stress-induced (Takotsubo) cardiomyopathy explained by regional mechanical overload and demand: supply mismatch in selected ventricular regions? Med. Hypotheses 81 (2013) 954–960. [18] S.W. Downing, E.B. Savage, J.S. Streicher, D.K. Bogen, G.S. Tyson, L.H. Edmunds Jr., The stretched ventricle. Myocardial creep and contractile dysfunction after
Y. Shao et al. / International Journal of Cardiology 178 (2015) 40–43 acute nonischemic ventricular distention, J. Thorac. Cardiovasc. Surg. 104 (1992) 996–1005. [19] L.D. Weise, A.V. Panfilov, A discrete electromechanical model for human cardiac tissue: effects of stretch-activated currents and stretch conditions on restitution properties and spiral wave dynamics, PLoS One 8 (2013) e59317. [20] P. Tavi, C. Han, M. Weckstrom, Mechanisms of stretch-induced changes in [Ca2+]i in rat atrial myocytes: role of increased troponin C affinity and stretch-activated ion channels, Circ. Res. 83 (1998) 1165–1177.
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[21] Y. He, J. Xiao, Y. Yang, Q. Zhou, Z. Zhang, Q. Pan, Y. Liu, Y. Chen, Stretch-induced alterations of human kir2.1 channel currents, Biochem. Biophys. Res. Commun. 351 (2006) 462–467. [22] J.L. Emery, J.H. Omens, A.D. McCulloch, Biaxial mechanics of the passively overstretched left ventricle, Am. J. Physiol. 272 (1997) H2299–H2305.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
McConnell's sign — An insight into the pathogenesis of Takotsubo syndrome? Yangzhen Shao a,b,⁎, Björn Redfors a,b, Anwar Ali a, Eduardo Bossone c, Alexander Lyon d, Elmir Omerovic a,b a
Department of Molecular and Clinical Medicine, Institute of Medicine, Gothenburg University, Sweden Department of Cardiology, Sahlgrenska University Hospital, Gothenburg, Sweden Cardiology Unit, Azienda Ospedaliera-Universitaria of Salerno, 84131 Salerno, Italy d NIHR Cardiovascular Biomedical Research Unit, Royal Brompton Hospital, London, UK b c
a r t i c l e
i n f o
Article history: Received 20 October 2014 Accepted 22 October 2014 Available online 23 October 2014 Keywords: Takotsubo syndrome McConnell's Sign Ventricular wall-stress Segmental myocardial akinesia
1. Introduction Takotsubo syndrome (TTS), also known as stress-induced cardiomyopathy, is an acute cardiac syndrome. The unique characteristics of TTS are that one or more circumferential cardiac segments are stunned out of contraction in the absence of an explanatory coronary lesion [1]. Although the peculiar myocardial akinesia can affect any part of the ventricular wall, two common patterns of TTS are apical akinesis (the typical TTS) and basal akinesis (the inverted pattern) [2]. The pathogenesis underlying Takotsubo syndrome is incompletely understood. Several mechanisms have been proposed for the development of TTS, including overstimulation of the β2-adrenoceptor-Gi pathway [3], acute coronary microvascular and endothelial dysfunction [4], aborted myocardial infarction with spontaneous recanalisation [5], acute metabolic stunning [6], lipotoxicity [1,7], acute left ventricular outflow tract obstruction (LVOTO) and abnormal ventriculo-arterial coupling [8]. One critical shortcoming of some of these proposed mechanisms is that they are not able to elucidate why myocardial akinesia in TTS is usually segmental and circumferential. Although the gradient distribution of β-adrenoceptors or sympathetic nerves in the heart may explain why catecholamine-induced myocardial akinesia can be apical or basal, such physiological properties, including genetic profiles, currently fail to ⁎ Corresponding author at: Bruna stråket 16, 413 45 Gothenburg, Sweden. E-mail address: [email protected] (Y. Shao).
http://dx.doi.org/10.1016/j.ijcard.2014.10.143 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
explain why different anatomical variants of TTS can recur in one patient [9]. 2. McConnell's sign associates with elevated afterload and mimics inverted Takotsubo McConnell's sign is a characteristic echocardiographic finding of the regional dysfunction of the right ventricle in pulmonary embolism (PE) [10]. Fig. 1 shows the typical pattern of McConnell's sign in a patient with acute PE: a distinct bulge (indicating akinesis) in the mid-free wall of the right ventricle during a systole, whilst the apex is spared from dysfunction and contracts into a peak cone. The unique pattern of cardiac contractile dysfunction in PE has certain features which resemble inverted Takotsubo syndrome (Fig. 1). Acute embolic occlusion of a large pulmonary artery causes an abrupt increase in pulmonary artery pressure, and thus an elevated afterload for the right ventricle. This may lead to increased wall-stress and akinesia in the basal myocardium, thus explaining McConnell's sign [11]. Similarly, in a preclinical model we identified that the inverted TTS variant was associated with high afterload [8]. We were able to induce variant patterns of TTS by catecholamines, which have different effects on afterload. Low afterload seems to restrictively precipitate the development of typical TTS (apical akinesia), whilst high afterload leads to inverted TTS variant. Moreover, interfering with the effects of a catecholamine on blood pressure alters the pattern of TTS that is supposed to be induced by the catecholamine [8]. We hypothesize that the level of ventricular afterload may influence which cardiac segment is subjected to increased wall-stress and thus circumferential akinesia. However, how an afterload affects wall-stress only in a certain cardiac segment, but not the other parts of or the entire ventricular wall, is unclear. 3. Sequential contraction may determine how the ventricular afterload affects wall-stress in a restricted segmental distribution The ventricular myocardium is sequentially stimulated to contract and eject blood from the ventricular cavity. The myocardium is highly organised in three layers. The endocardial layer goes in helix-strand ascending, whilst the epicardial myofibres are helix-strand descending. The middle layer is circular and parallel to the ventricular equator, and perpendicular to the apical–basal axis (Fig. 2A) [12]. The helical-strand
Y. Shao et al. / International Journal of Cardiology 178 (2015) 40–43
41
Fig. 1. A similar pattern of myocardial dysfunction develops in pulmonary embolism (PE) and inverted Takotsubo syndrome. In both conditions, the apex contracts and forms a peak cone (yellow arrows), whilst the base and the mid-free wall are stunned out of contraction and paradoxically bulge out during systole (blue arrows). The left picture is an echocardiograph of the characteristic myocardial dysfunction in the right ventricle in the setting of PE (McConnell's sign). The right picture is left ventricular end systolic ventriculography in the setting of inverted Takotsubo. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
muscles generate circumferential torsion forces that rotate the epicardium and endocardium in opposite directions (along the long axis), whilst contraction of the circular muscles contributes to radial contraction. Contraction of these cardiac muscle layers produces different vectors
of peak strain (see Fig. 2B), which are well-coordinated in ejection of blood from the cavity during systole. Sequential electrical activation of these cardiac muscles is potentially important for the efficiency of ventricular systole. Based upon the anatomy of the bundle of His and
Fig. 2. Arrangement of the ventricular muscles and strength patterns after muscle contraction. Cardiac muscles are highly organised in three layers. The epicardium is helix-descending and the endocardium is helix-ascending. Contraction of these helix muscles generates strengths of helix-ascending (green arrows), strengths towards the base along the long axis (red arrows), and clockwise circumferential strengths (blue arrows). The mid-ventricular muscles are circular and are on the planes of the short axis. Contraction of the circular muscles produces strengths pointing to the centre on the plans of the short axis (purple arrows). (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this article.)
42
Y. Shao et al. / International Journal of Cardiology 178 (2015) 40–43
Purkinje fibre system cardiac contraction usually starts at the apex and advances towards the base [12]. During systole transmural pressure passively imposed on cardiac segments may be continuously changed. More specifically, during the isovolumetric contraction of a systole, wall-stress in the basal myocardium is progressively raised due to the earlier contractions of the apex and the mid-ventricular wall. For the purpose of the present discussion, wall-stress passively imposed on a cardiac segment is termed preload wall-stress. In the setting of PE or inverted TTS, where afterload is elevated, high intraventricular pressure is required to open the pulmonary/aortic valve. This will introduce increased transmural pressure and preload wall-stress to the basal myocardium. If the preload wall-stress exceeds the limitation that basal myofibres can afford, contraction of the myofibres is disrupted, possibly explaining basal akinesia in PE and inverted TTS. Perhaps contractile band rupture observed in the hearts of TTS patients [13] is due to a cardiac segment contracting against such an extremely increased preload wall-stress that the myofibres get ruptured. However, low afterload seems to distribute preload wall-stress differently from high afterload. Because the aortic valve opens when intraventricular pressure exceeds the pressure of the aortic artery, transmural pressure and preload wall-stress in the basal myocardium are unlikely to reach a high level in the condition of low afterload. This probably explains why the base can be spared from akinesis in typical Takotsubo, where the afterload is severely decreased. However, with a strong inotropic and chronotropic drive of catecholamines, intensive and rapid contraction of the base may precipitate outflow obstruction and cause an increase in wall-stress of the apical myocardium. Indeed, outflow obstruction has been recorded in 25% of patients with typical TTS [14]. Perhaps outflow obstruction is one pivotal factor in determining how low-afterload introduces increased wall-stress only to the apical or apical–middle myocardium. However, because the apex usually contracts before the base, how the base is able to contract before the apex and obstructs the outflow is not clear. We hypothesize that the characteristic twisting and rotating contraction of the heart may be relatively delayed in the apex, compared with the circumferential contraction in the base, when heart frequency is significantly accelerated. 4. Increased wall-stress triggers myocardial stunning, possibly by myocardial overstretch How increased wall-stress results in myocardial akinesia has not been completely determined. One mechanism proposed for McConnell's cardiac dysfunction is localised ischemia as a result of increased wall-stress in the free wall of the right ventricle [11]. Elevated wall-stress increases oxygen consumption [15,16] and perhaps results in a relative myocardial ischemia due to a demand–supply mismatch. We believe that a similar demand–supply mismatch also occurs in the setting of TTS, where coronary blood flow is not significantly decreased but energy demand is severely increased [17]. However, ischemia may not be the major cause of the cardiac stunning in TTS, though it does cause cardiac dysfunction. The myofibres are likely overstretched in the cardiac area bearing intensively increased wall tension/stress. Overstretch-induced contractile dysfunction [18] may be the onset of TTS myocardial stunning. Overdistention of myofibres reduces contractility, due to a series of stretch-induced abnormalities, e.g., sarcomere overstrain, fewer cross-bridges between myosin and actin, stretch-induced currents [19], cytoplasmic calcium alteration [20], and instability of membrane potential [21]. In addition, repeated passive stretching of the myocardium in the affected cardiac zone tends to produce progressive lengthening of the myofibres — so-called stretch-induced ‘creep’ and ‘softening’ [18,22]. These effects may contribute to explain the unique deformation of paradoxical spherical bulging during systole in the akinetic cardiac area, which is observed in McConnell's sign and TTS. We have hypothesized that TTS myocardial stunning occurs as the heart alters metabolism to preserve energy for basic
non-contractile cellular survival during severe oxygen insufficiency by shutting down mechanical cardiac activity [17]. Overstretch may be one mechanism potentiating the myocardium to cease the mechanical contraction. In conclusion, McConnell's sign describes the unique cardiac dysfunction observed in pulmonary embolism. The mechanism is associated with increased wall-stress of the mid-free right ventricular wall as a result of abruptly increased pulmonary artery pressure. A similar mechanism may be involved in the development of inverted Takotsubo. The development of inverted TTS in a preclinical model is closely associated with a high afterload, whilst typical TTS (apical ballooning) was usually observed in the context of a low afterload. Sequential contraction of cardiac muscles may be crucial in determining whether the base or apex is subjected to increased wall-stress (and thus akinesia) in the condition of high or low afterload. Increased wall-stress, resulting in myocardial akinesia, may lead to overstretch-triggered myocardial stunning. Ischemia-related myocardial dysfunction as a result of increased wallstress may interact with these mechanisms and promote the development of myocardial stunning.
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