Abstract
Takotsubo syndrome (TS), also known as broken heart syndrome and neurogenic stunned myocardium, is an acute cardiac disease entity characterized by a clinical picture mimicking that of an acute coronary syndrome. The pathogenesis of TS has not been established yet. Among the most often debated pathologic mechanisms of TS are as follows: first, multi-vessel coronary spasm; second, myocardial microvascular dysfunction; third, aborted myocardial infarction caused by transient thrombotic occlusion of a long wrap-around left anterior descending artery; fourth, left ventricular outflow tract obstruction; fifth, blood-borne catecholamine cardiac toxicity; and sixth, cardiac sympathetic disruption and norepinephrine seethe and spillover. The aim of this review is to provide a thorough analysis of the literature data coming mainly from the neurological literature and dealing with the pathogenesis of TS. Substantial evidence challenging the first five hypotheses and arguing in favor of the hypothesis that acute cardiac sympathetic eruption and norepinephrine seethe and spillover is causing TS in predisposed patients is presented.
1
Introduction
Takotsubo syndrome (TS), also known as neurogenic stunned myocardium, is characterized by a clinical presentation resembling that of acute coronary syndrome; a reversible typically regional ventricular wall motion abnormality with a characteristic circular pattern, which is incongruent with the coronary artery supply region; and a coronary angiography showing no identifiable coronary artery culprit lesion to account for the observed regional ventricular wall motion abnormality . The term “tsubo” or “takotsubo” was introduced by Sato et al. in 1990 and 1991 to describe the shape of the left ventricle during systole in patients presented with a clinical picture of myocardial infarction and no obstructive coronary artery disease ( Fig. 1 ). Takotsubo is a pot with a round base and narrow neck used in Japan for trapping octopuses (Tako = octopus and Tsubo = pot). In fact, the disease had been reported under different names including currently used terms a long time before 1990 . Rees and Lutkins used the term “broken heart” in 1967 when they reported on the results of a survey of the death rate among 903 relatives of patients dying in a semirural area of Wales. A typical case of broken heart syndrome with documented cardiac image of left ventricular ballooning during systole was reported 1986, 4 years before the introduction of the term takotsubo . This case was diagnosed as “acute myocarditis” but “catecholamine myocarditis” could not be excluded. Cebelin and Hirsch in 1980 reported on human stress cardiomyopathy, 10 years before the introduction of the term takotsubo.
The disease has special predilection for elderly menopausal women . The condition affects typically the left ventricle (but the right ventricle may also be involved) and may be localized to the apical, mid-apical, mid-ventricular, and basal parts of the left ventricle ( Fig. 2 ). Focal and global left ventricular involvement has also been reported . The disease may occur in the setting of severe emotional stress, often after the sudden death of a loved one—hence the alternative name “broken heart syndrome” . Countless physical stress factors ranging from the most severe diseases as subarachnoid hemorrhage (SAH) and sepsis to the most physiological activities as sexual intercourse may trigger the disease . SAH, brain death and other intracranial disease processes are currently well-recognized trigger factors for TS and are among the diseases and injuries, which have provided a great contribution to the understanding of the pathogenesis of TS . In this report, a systematic review of the literature data coming mainly from the neurological literature and dealing with the pathogenesis of TS, is presented.
2
Pathogenesis of TS
The etiology of TS has not yet been fully elucidated. Among the most frequently debated pathologic mechanisms underlying TS are the following: first, multi-vessel coronary spasm; second, myocardial microvascular dysfunction; third, aborted myocardial infarction caused by transient thrombotic occlusion of a long wrap-around left anterior descending artery (LAD); fourth, left ventricular outflow tract (LVOT) obstruction; fifth, blood-borne catecholamine cardiac toxicity; and sixth, local cardiac sympathetic disruption and norepinephrine seethe and spillover (a state of extreme sympathetic activation with excessive surge of noradrenaline at the cardiac nerve terminals resulting in noradrenaline overflow spilling over the myocardium) .
Three other hypothetical pathologic mechanisms have also been mentioned in the literature. Evidence supporting these hypotheses is insufficient. Lyon et al. in a report about TS suggested a pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. They believe that high levels of circulating epinephrine trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from Gs protein to Gi protein signaling via the ß 2 -adrenoceptor. This switch to ß 2 -adrenoceptor-Gi protein signaling protects against the proapoptotic effects of intense activation of ß 1 -adrenoceptors and has also a negative inotropic myocardial effect leading to ventricular wall motion abnormality. Cocco and Chu , in a review article, claim that hypoplastic branching of the coronary arteries in the apical region of the heart may explain the apical localization of the left ventricular wall motion abnormality in TS. Regional differences in ß-adrenergic receptor density and sympathetic innervation with increased responsiveness of the left ventricular apical myocardium to adrenergic stimuli have been proposed by other investigators as potential explanation for the unique pattern of contractile dysfunction observed in TS .
Substantial literature data that, with persuasive reasons, challenge the first five proposed hypotheses and argue in favor of the causal link between the local cardiac sympathetic eruption and norepinephrine seethe and spillover and TS are presented.
2.1
Data challenging the first five proposed pathologic mechanisms
2.1.1
First: multi-vessel coronary spasm
Sato et al. , who introduced the term takotsubo 1990 and 1991 described the left ventricular dysfunction as myocardial stunning caused by multi-vessel coronary spasm. They described five patients with a clinical picture of myocardial infarction without atherosclerotic obstructive coronary artery stenosis. Two of the five patients had spontaneous diffuse multi-vessel coronary spasm. They could induce multi-vessel coronary spasm after ergonovine administration in two of the remaining three patients.
Spontaneous multi-vessel epicardial coronary spasm is not a consistent finding in patients with TS and has been reported in only 2% of patients with TS . Multi-vessel coronary vasospasm could be induced after acetylcholine administration in only 21% of patients with TS in one study and in 24 (28.6%) of 84 patients in another study . Ongoing ST elevation and the absence of coronary artery spasm during coronary angiography; long-lasting ST elevation (hours to days) and slight elevation of myocardial infarction biomarkers are not in favor of severe ischemia caused by multi-vessel coronary spasm . Challenging the coronary spasm hypothesis is the fact that the regions of wall motion abnormalities are incongruent to the coronary artery supply region . The normal coronary angiography and the demonstration of normal myocardial perfusion in the akinetic/hypokinetic ventricular segments by myocardial contrast echocardiography in TS in the face of ongoing ST-segment elevation challenge both multi-vessel coronary spasm and myocardial microvascular dysfunction . First-pass perfusion cardiac magnetic resonance imaging (C-MRI) has not shown any evidence of focal perfusion abnormalities corresponding to specific vascular territory . The localization of left ventricular dysfunction at the basal region in inverted TS and the recurrence of TS with different localization in the same patient argue against multi-vessel coronary spasm hypothesis .
2.1.2
Second: myocardial microvascular dysfunction
Sadamatsu et al. could document a diminished coronary flow reserve using Doppler guide wire in patients with TS. Others have demonstrated elevated thrombolysis in myocardial infarction (TIMI) frame counts and abnormal TIMI myocardial perfusion grades in patients with TS . These results were confirmed by other investigators suggesting that myocardial microvascular dysfunction may contribute to the pathogenesis of TS . However, several findings challenge the pathogenetic potential of myocardial microvascular dysfunction in causing TS. Signs of myocardial microvascular dysfunction are not consistent findings in patients with TS. In a considerable number of cases, coronary angiography failed to reveal the slow-flow phenomenon, even in the presence of ongoing ST elevation . Against the microvascular dysfunction theory is the induction of TS with dobutamine, which in fact has a vasodilatory effect . First-pass perfusion C-MRI has not shown any evidence of focal perfusion abnormalities in other studies . Finally, myocardial microvasular dysfunction during the acute phase of TS does not need to be a direct evidence of causation because impairment of microcirculation may be secondary to the myocardial dysfunction caused by TS.
2.1.3
Third: aborted infarction caused by a transient thrombosis in a long wrap-around LAD
Ibanez et al. reported on evidence of disrupted atherosclerotic plaque in a long wrap-around LAD studied by intravascular ultrasound (IVUS) in five patients with TS. These findings have not been uniformly supported. Disrupted atherosclerotic plaque could not be confirmed by a study of 10 patients with TS undergone IVUS . Delgado et al. , in studying patients with TS by IVUS, found no evidence of culprit lesion in LAD. Similarly the course of the LAD in the same study failed to account for the characteristic left ventricular apical ballooning seen in TS. In the majority of patients with TS (73%), the LAD does not fulfil the criteria of long wrap-around LAD . The localization of left ventricular ballooning at the basal or mid-ventricular region in TS and other apical sparing TS argues against aborted infarction in a long wrap-around LAD as demonstrated in Fig. 3 showing an apical sparing left mid-ventricular variant of TS in a patient with wrap-around LAD. Long-lasting (hours or even days) ST-segment elevation in patients with TS challenges strongly the hypothesis of aborted myocardial infarction, in which rapid resolution of ST elevation is an important feature .
Another feature, found in TS, which could not be explained by the proposed ischemic hypothesis, is the myocardial histopathology. The contraction band necrosis (also known as myofibrillar degeneration and coagulative myocytolysis) is a characteristic histopathologic feature in TS, distinct in several major respects from coagulation necrosis, the fundamental lesion in myocardial infarction . Worth mentioning is the fact that an acute coronary ischemic insult, as any other physical stress factor, may trigger TS .
2.1.4
Fourth: left ventricular outflow tract obstruction
LVOT obstruction may be found in some patients with TS and may be one of the causes of cardiogenic shock in TS. El mahmoud et al. in a study of 32 patients with TS demonstrated a relatively high prevalence of LVOT obstruction (25%). It has been suggested that patients with localized sigmoid septum and smaller ventricles may be predisposed to severe mid-cavity obstruction during periods of excessive sympathetic stimulation. Theoretically, this LVOT obstruction could result in apical subendocardial ischemia and ballooning due to a large pressure gradient between the apex and base of the left ventricle. However the vast majority of patients with TS do not have LVOT obstruction. The right ventricular dysfunction that occurs in a substantial number of patients with TS could not be explained by LVOT obstruction . The left intraventricular pressure gradient does not provide a reasonable explanation for the basal and mid-ventricular variants of TS . In fact, the LVOT obstruction observed in some patients with TS is most likely a complication rather than the underlying cause of the wall motion abnormality.
2.1.5
Fifth: blood-borne catecholamine cardiac toxicity
Clinically, a considerable number of patients with TS lack a history of antecedent emotional or physical triggering stress factor . Although male more than female populations are exposed to stress situations as in war conditions, TS predominantly affects elderly postmenopausal women . Studies have not uniformly shown elevated plasma catecholamine levels and have produced conflicting results. A markedly increased as well as nearly normal systemic plasma concentration of norepinephrine has been measured during the acute phase of TS . Greenhoot and Reichenbach have reported that stimulation of the midbrain reticular formation in cats has produced cardiac lesions similar to those seen in patients with SAH. That the cardiac lesions seen were not blood-borne catecholamine cardiac toxicity was supported by the finding of identical lesions in adrenalectomized animals. The relationship of the nervous system to the “myocarditis” that occurs after adrenaline administration has been studied. The incidence of the myocardial lesions was significantly reduced in rats that had their spinal cords severed at C7–T1 prior to adrenaline administration. This indicates that the administered adrenaline was not the causative agent but rather a trigger factor . The combination of the evidence provided above and the systematized circumferential ballooning pattern of TS ( Fig. 4 ) indicates that the blood-borne catecholamines are not primarily causing TS but rather triggering the cardiac sympathetic system to cause TS .
2.2
Trigger, epiphenomenon, or a complication
Sufficient data casting a shadow on the causal link between the aforementioned five debated hypotheses and TS have been presented. It is important not to forget that some of the above five debated pathologic mechanisms as coronary spasm and acute coronary syndrome may, as any other physical stress, trigger TS . Administration of catecholamines accidentally or during therapeutic and diagnostic measures may trigger TS . Surge of catecholamine discharge in diseased conditions as phaeochromocytoma is a well-recognized physical trigger factor for TS . Pheochromcytoma-induced TS is characterized by increased complications including cardiogenic shock and multiorgan failure which can be explained by the presence of overwhelming catecholamine surge.
Myocardial microvascular dysfunction, epicardial coronary spasm and increased catecholamines may be epiphenomena associated with the diseases that have triggered TS . LVOT obstruction may be a complication of the apical or mid-apical form of TS occurring especially in predisposed women in the presence of abnormal myocardial functional architecture, such as localized mid-ventricular septal thickening .
2.3
Sixth: data in favor of local cardiac sympathetic disruption hypothesis
The two main findings that solidly argue in favor of the involvement of the local cardiac sympathetic nervous system in causing the ventricular wall motion abnormality in TS are as follows: (A) a convergent evidence of disruption of the local cardiac sympathetic nerve endings with local norepinephrine seethe and spillover into the ventricular myocardial tissue ; and (B) the characteristic systematized circular pattern of ventricular wall motion abnormality, which is unrelated to the coronary arterial system and appears most likely following the cardiac sympathetic supply system .
A: cardiac sympathetic nerve disruption and norepinephrine spillover.
- 1.
Cardiac sympathetic over-activation in animal and human studies: There is a clear association between the psychologic state of mind and the development of TS. The frequent association of TS with sudden and deep emotional stress suggests that the mechanism of transient ventricular myocardial dysfunction might be sympathetically mediated . An emotional or a physical stressor has been reported in about 70% of patients with TS . There are sufficient data in both animal and human studies that indicate hyper-activation of the cardiac sympathetic nervous system in TS . In animal studies, brain and stellate ganglion stimulation, induction of experimental intracranial hemorrhage caused ECG changes resembling that caused by mid-apical type of TS; and induced myocardial changes reminding that of TS. These changes could be prevented either by surgical (spinal cord transection or severing) or pharmacological (reserpine, propranolol) sympathectomy . Ueyama et al. have shown that left ventricular apical ballooning can be reproduced in rats subjected to immobilization stress (which is an animal model for emotional test) and this effect can be attenuated with adrenoceptor blockade. In human studies, a variety of intracranial diseases and injuries irrespective of the lesion localization may trigger the development of TS . This may occur through an increase in the intracranial pressure and hyper-activation of the cardiac sympathetic nervous system . Beta-adrenoceptor blockers have been shown to have cardioprotective effects in intracranial diseases and injuries in some studies . Zhu et al. have reported on a patient with electroconvulsive therapy (ECT)-induced myocardial stunning with a clinical picture consistent with TS. The condition recurred during repeat ECT in spite of nitrate and calcium channel therapy. On the other hand labetalol (beta- and alpha-blocker) given intravenously to block the effect of sympathetic surge prevented the recurrence of TS during repeated ECT. Liang et al. in one study have shown that preadmission beta-blockers were associated with decreased incidence of neurogenic stunned myocardium in aneurysmal SAH. One hundred thirty of 234 patients had echocardiograms on or shortly after admission, and 18 of these developed neurogenic stunned myocardium (13.8%). None of the 22 patients taking prehospital beta-blockers developed neurogenic stunned myocardium. The rapid appearance and disappearance of the electrocardiographic changes with perturbations of the nervous system strongly suggests that these effects are due to neural rather than humoral factors . Decreased heart rate variability and findings consistent with increased sympathetic tone and cardiac autonomic dysfunction have been described in patients with TS and neurogenic-stunned myocardium . Bonnemeier et al. have shown indications of differential activation of the left stellate ganglion and left cardiac sympathetic nerves in patients presenting with apical ballooning and the right stellate ganglion and right cardiac sympathetic nerves in patients presenting with mid-ventricular ballooning types of TS. TS has been reported after dobutamine administration for therapeutic or diagnostic purposes. In one study, three of nine patients with TS experienced the onset of symptoms while receiving standard doses of intravenous dobutamine during stress echocardiography. One patient had apical TS and two patients had mid-ventricular TS. Dobutamine is a sympathomimetic agent, predominantly a ß 1 -adrenergic agonist and has mild vasodilataory effects. The reports of dobutamine-induced TS further implicate enhanced sympathetic stimulation in the pathogenesis of TS .
- 2.
Cardiac sympathetic denervation: Iodine 123 meta-iodobenzylguanindine ( 123 I-MIBG) is an imaging tracer that can be used to assess the cardiac sympathetic function. There is substantial evidence for cardiac sympathetic denervation in regions with wall motion abnormalities in patients with TS detected by 123 I-MIBG scintigraphy. Banki et al. studied 42 patients with SAH with echocardiography, myocardial scintigraphy with technitiun sestamibi (MIBI) and 123 I-MIBG imaging to assess myocardial perfusion and sympathetic innervation respectively. All patients with interpretable scans ( N = 41) had normal MIBI uptake. Twelve subjects had either global ( n = 9) or regional ( n = 3) absence of 123 I-MIBG uptake. In comparison with patients with normal 123 I-MIBG uptake, those with evidence of functional denervation were more likely to have regional wall motion abnormalities (92% versus 52%, p = 0.03) and cardiac troponin I levels > 1 μg/L (58% versus 21%, p = 0.029). The investigators concluded that left ventricular systolic dysfunction in humans with SAH is associated with normal myocardial perfusion and abnormal sympathetic innervations. Cardiac sympathetic denervation may be explained by excessive release of norepinephrine from myocardial sympathetic nerve terminals, which could damage the myocytes and the nerve terminals. Burgdorf et al. studied 10 patients with TS with 123 I-MIBG scintigraphy. They showed regional alterations in myocardial sympathetic innervation in the form of decreased heart to mediastinum ratio and increased washout rate. The study indicated impaired sympathetic neurotransmitter uptake in the hypokinetic/akinetic apical LV segments in patients with TS. The cardiac sympathetic nerve endings have also been assessed by 11 C hydroxyephedrine positron emissions tomography (PET) in a patient with TS. The tracer uptake was reduced in the majority of the mid segments and several of the apical and basal segments on the 11 C hydroxyephedrine images, suggesting sympathetic abnormality .
- 3.
Cardiac sympathetic norepinephrine spillover: Greenhoot and Reichenbach have reported on ECG changes and cardiac myofibrillar degeneration in patients with SAH. Both the ECG changes and the cardiac lesions could be reproduced in cats given mesencephalic reticular formation stimulation. The investigators observed that the cell injury occasionally was seen adjacent to the nerves with more normal structure at a distance. Adrenalectomy did not protect the heart. The investigators concluded that the ECG changes and the cardiac lesions were due to the release of cateholamines from adrenergic nerve endings in the heart. Mertes et al. have demonstrated increased myocardial interstitial, but not plasma, norepinephrine release after brain death induction in pigs. Kume et al. have also demonstrated elevated norepinephrine levels in the coronary sinus in five patients with TS, suggesting increased local myocardial catecholamine release. Norepinephrine spillover from the cardiac sympathetic nerve terminals can decrease myocyte viability through cyclic adenosine monophosphate-mediated calcium overload, resulting histologically in contraction band necrosis which is one of the histopathologic features of TS .
B: The pattern of the regional ventricular wall motion abnormality
The left ventricular wall motion abnormality in TS has a characteristic regional and systematized pattern. It affects the ventricular myocardium circumferentially ( Fig. 4 ) with a sharp transition between the affected (stunned) and the normal or hyperkinetic myocardium resulting in a conspicuous left ventricular ballooning during systole . Two-dimensional speckle-tracking echocardiography has shown a circular systolic dysfunction in the acute phase of TS . The heart is densely innervated with sympathetic nerves, which are distributed on a regional basis. The pattern of ventricular wall motion abnormality in TS appears to follow the sympathetic projections from the left and right stellate and caudal ganglia . The regional pattern of the left ventricular systolic dysfunction after SAH was studied in 30 patients by Zaroff et al. . The authors observed that many of the wall motion patterns did not match the coronary artery disease but correlated with the distribution of the myocardial sympathetic nerve terminals providing an indirect evidence for a neurally mediated mechanism of cardiac injury. Worth mentioning, there are only two cardiac supply systems which are involved in the ventricular wall motion abnormality on a regional basis and in a systematized pattern and these are the coronary arterial and the neural supply systems. Convincing evidence that challenges the coronary arterial system being the cause of ventricular wall motion abnormality in TS has been presented in this paper. As a result, the most likely cause for the ventricular wall motion abnormality in TS is the disruption of the neural supply system. The different varieties of TS are most likely due to involvement of different branches of the cardiac sympathetic system in the disease process. Unfortunately, the anatomical distribution of the various branches of the cardiac sympathetic nervous system has not been mapped out yet in order to specify the branch or branches of the cardiac sympathetic nerves involved in TS. This may have facilitated categorization of the different patterns of TS (apical, mid-apical, mid-ventricular, basal, focal and global) according to the sympathetic branch involved in a manner analogous to that of coronary artery occlusion causing anterior, inferior, lateral and true posterior myocardial infarction.
2
Pathogenesis of TS
The etiology of TS has not yet been fully elucidated. Among the most frequently debated pathologic mechanisms underlying TS are the following: first, multi-vessel coronary spasm; second, myocardial microvascular dysfunction; third, aborted myocardial infarction caused by transient thrombotic occlusion of a long wrap-around left anterior descending artery (LAD); fourth, left ventricular outflow tract (LVOT) obstruction; fifth, blood-borne catecholamine cardiac toxicity; and sixth, local cardiac sympathetic disruption and norepinephrine seethe and spillover (a state of extreme sympathetic activation with excessive surge of noradrenaline at the cardiac nerve terminals resulting in noradrenaline overflow spilling over the myocardium) .
Three other hypothetical pathologic mechanisms have also been mentioned in the literature. Evidence supporting these hypotheses is insufficient. Lyon et al. in a report about TS suggested a pathophysiological hypothesis to explain catecholamine-induced acute myocardial stunning. They believe that high levels of circulating epinephrine trigger a switch in intracellular signal trafficking in ventricular cardiomyocytes, from Gs protein to Gi protein signaling via the ß 2 -adrenoceptor. This switch to ß 2 -adrenoceptor-Gi protein signaling protects against the proapoptotic effects of intense activation of ß 1 -adrenoceptors and has also a negative inotropic myocardial effect leading to ventricular wall motion abnormality. Cocco and Chu , in a review article, claim that hypoplastic branching of the coronary arteries in the apical region of the heart may explain the apical localization of the left ventricular wall motion abnormality in TS. Regional differences in ß-adrenergic receptor density and sympathetic innervation with increased responsiveness of the left ventricular apical myocardium to adrenergic stimuli have been proposed by other investigators as potential explanation for the unique pattern of contractile dysfunction observed in TS .
Substantial literature data that, with persuasive reasons, challenge the first five proposed hypotheses and argue in favor of the causal link between the local cardiac sympathetic eruption and norepinephrine seethe and spillover and TS are presented.
2.1
Data challenging the first five proposed pathologic mechanisms
2.1.1
First: multi-vessel coronary spasm
Sato et al. , who introduced the term takotsubo 1990 and 1991 described the left ventricular dysfunction as myocardial stunning caused by multi-vessel coronary spasm. They described five patients with a clinical picture of myocardial infarction without atherosclerotic obstructive coronary artery stenosis. Two of the five patients had spontaneous diffuse multi-vessel coronary spasm. They could induce multi-vessel coronary spasm after ergonovine administration in two of the remaining three patients.
Spontaneous multi-vessel epicardial coronary spasm is not a consistent finding in patients with TS and has been reported in only 2% of patients with TS . Multi-vessel coronary vasospasm could be induced after acetylcholine administration in only 21% of patients with TS in one study and in 24 (28.6%) of 84 patients in another study . Ongoing ST elevation and the absence of coronary artery spasm during coronary angiography; long-lasting ST elevation (hours to days) and slight elevation of myocardial infarction biomarkers are not in favor of severe ischemia caused by multi-vessel coronary spasm . Challenging the coronary spasm hypothesis is the fact that the regions of wall motion abnormalities are incongruent to the coronary artery supply region . The normal coronary angiography and the demonstration of normal myocardial perfusion in the akinetic/hypokinetic ventricular segments by myocardial contrast echocardiography in TS in the face of ongoing ST-segment elevation challenge both multi-vessel coronary spasm and myocardial microvascular dysfunction . First-pass perfusion cardiac magnetic resonance imaging (C-MRI) has not shown any evidence of focal perfusion abnormalities corresponding to specific vascular territory . The localization of left ventricular dysfunction at the basal region in inverted TS and the recurrence of TS with different localization in the same patient argue against multi-vessel coronary spasm hypothesis .
2.1.2
Second: myocardial microvascular dysfunction
Sadamatsu et al. could document a diminished coronary flow reserve using Doppler guide wire in patients with TS. Others have demonstrated elevated thrombolysis in myocardial infarction (TIMI) frame counts and abnormal TIMI myocardial perfusion grades in patients with TS . These results were confirmed by other investigators suggesting that myocardial microvascular dysfunction may contribute to the pathogenesis of TS . However, several findings challenge the pathogenetic potential of myocardial microvascular dysfunction in causing TS. Signs of myocardial microvascular dysfunction are not consistent findings in patients with TS. In a considerable number of cases, coronary angiography failed to reveal the slow-flow phenomenon, even in the presence of ongoing ST elevation . Against the microvascular dysfunction theory is the induction of TS with dobutamine, which in fact has a vasodilatory effect . First-pass perfusion C-MRI has not shown any evidence of focal perfusion abnormalities in other studies . Finally, myocardial microvasular dysfunction during the acute phase of TS does not need to be a direct evidence of causation because impairment of microcirculation may be secondary to the myocardial dysfunction caused by TS.
2.1.3
Third: aborted infarction caused by a transient thrombosis in a long wrap-around LAD
Ibanez et al. reported on evidence of disrupted atherosclerotic plaque in a long wrap-around LAD studied by intravascular ultrasound (IVUS) in five patients with TS. These findings have not been uniformly supported. Disrupted atherosclerotic plaque could not be confirmed by a study of 10 patients with TS undergone IVUS . Delgado et al. , in studying patients with TS by IVUS, found no evidence of culprit lesion in LAD. Similarly the course of the LAD in the same study failed to account for the characteristic left ventricular apical ballooning seen in TS. In the majority of patients with TS (73%), the LAD does not fulfil the criteria of long wrap-around LAD . The localization of left ventricular ballooning at the basal or mid-ventricular region in TS and other apical sparing TS argues against aborted infarction in a long wrap-around LAD as demonstrated in Fig. 3 showing an apical sparing left mid-ventricular variant of TS in a patient with wrap-around LAD. Long-lasting (hours or even days) ST-segment elevation in patients with TS challenges strongly the hypothesis of aborted myocardial infarction, in which rapid resolution of ST elevation is an important feature .
