The takotsubo syndrome (TS) is defined by a constellation of clinical observations in a subgroup of patients with acute coronary syndromes. Separating patients with TS from the general population with acute ischemic events are 2 important findings: obstructive coronary artery disease is missing, but the sine qua non is a distinctive pattern of abnormal left ventricular contraction. As with many newly recognized clinical syndromes, TS seems not to conform to accepted pathogenetic mechanisms. Thus, physicians are challenged to identify previously unrecognized mechanisms of disease. Two schools of thought have emerged in this regard. Most consider its pathogenesis to be a stress-induced neurohormonal phenomenon, while a smaller but substantial group believe that the transient occlusion of an epicardial coronary artery is responsible and that the syndrome is simply an unusual manifestation of coronary atherosclerosis. This editorial outlines briefly the evidence for each of these positions and presents a novel construct that may encompass the 2 views. Central to this unifying hypothesis is the belief that a neurohormonal surge triggers the hallmark left ventricular contraction abnormality, the sine qua non of the TS. In conclusion, the authors postulate that this pattern will result regardless of the state of the epicardial coronary arteries and can be observed in patients with angiographically normal coronary arteries, as well as those with obstructed or occluded arteries.
A distinctive subset of patients with acute coronary syndromes (ACS) has attracted attention because of 2 cardinal features. First, the signs and symptoms of myocardial ischemia occur in the absence of obstructive coronary artery disease. Hardly unique, this association has been reported in 3% to 13% of patients with ACS. It is the second feature, a distinctive abnormality of left ventricular (LV) contraction, that provides the syndrome with its name and its claim to be a unique entity. The Japanese investigators who first described its appearance were struck by the resemblance of the systolic shape of the ventricle on ventriculography to the short, narrow neck and round bottom of the trap used by Japanese fisherman to capture octopi. The Japanese name for the octopus trap, takotsubo, has been attached to the syndrome.
The takotsubo contraction abnormality consists of akinesia or dyskinesia of the apical and/or midventricular segments of the left ventricle together with hypercontractility of the base. This ventriculographic pattern separates patients with takotsubo syndrome (TS) from others with ACS. They are otherwise remarkably virtually similar. Thus, one can argue that this distinctive and usually transient contraction pattern is the sine qua non of the TS.
The TS is uncommon in patients with ACS. In our experience with 893 patients with suspected ACS who underwent emergent or urgent cardiac catheterization from January 1 to December 31, 2008, 95 (10.6%) had no obstructive disease on coronary arteriography. Of that number, 83 had normal LV function on ventriculography, and 12 had explanations other than acute ischemia for the observed abnormality. Of the remaining 31, 15 (1.7%) on blinded review had typical takotsubo contractions and thus had both of the cardinal features of TS. Similar results were reported by Kurowski et al, who found this association in 1.2% of consecutive patients with troponin-positive ACS.
Two schools of thought regarding the pathogenesis of TS have emerged. Many adhere to the position of Ibanez et al, who, after a review of the subject in 2006, concluded that TS “may actually be the paradigm of spontaneously aborted myocardial infarction resulting from an acute atherosclerotic event with rapid and complete lysis of the thrombus.” Most, however, believe the distribution of the LV contraction abnormality cannot be accounted for by transient interruption of flow in a single epicardial coronary artery and must therefore be caused by a neurohormonal surge affecting the small coronary vessels or the myocardium directly. This argument is reinforced by 2 other observations. First, an episode of physical or psychological stress very frequently seems to trigger the onset of TS. Second, women, particularly postmenopausal women, seem to be a susceptible population, accounting for 90% or so of all affected patients. This female preponderance stands in contrast to the predilection of coronary atherosclerosis for men. The arguments for the neurohormonal hypothesis are persuasive enough that TS has also been called “stress cardiomyopathy.”
Data Supporting the Transient Occlusion of ≥1 Epicardial Coronary Artery
Advocates of this pathogenetic theory point out that temporary coronary occlusion by thrombosis or coronary spasm may play a role in the genesis of acute myocardial infarction. Moreover, Oliva et al demonstrated that transient occlusion by spasm of ≥1 coronary artery can be responsible for “Prinzmetal angina” (i.e., typical pain of myocardial ischemia occurring at rest and accompanied by ST-segment elevation). Importantly, they found coronary artery spasm in normal and diseased epicardial arteries.
It is probably a stretch to ascribe the “octopus trap” contraction pattern to the vascular territory of any of the major coronary arteries. Ibáñez et al, however, argued that transient left anterior descending coronary artery (LAD) occlusion, particularly in 1 that “wraps around” the LV apex, can produce the characteristic contraction pattern of the TS. They contended that the distribution of the LAD has not been sufficiently defined, and unless there is careful selection of appropriate angiographic projections, the extent of its distribution may not be defined.
Those investigators further supported this opinion with intravascular ultrasound studies. Using this technique in 5 consecutive typical TS patients, they demonstrated coronary atherosclerosis in all, and importantly, in each of the 5, they found ruptured plaques in the mid LAD. Unfortunately, their findings have not to our knowledge been replicated, for very practical reasons. To do so will require a significant number of intracoronary ultrasound studies. Even in this hospital, in which intracoronary ultrasound examinations are readily available, interventional cardiologists do not often conduct them in acutely ill patients or those being studied nights or weekends. We have encountered a small number of patients with ST-segment elevation myocardial infarctions with ultrasound images of “ruptured plaques” and angiographically normal coronary arteries.
Moreover, several investigators have reported examples of multivessel coronary artery spasm that seem to account for the characteristic contraction pattern of TS. Angelini pointed out that this postulation could account for the association of TS with stress. Thus, there is ample reason to believe that the temporary occlusion of an epicardial coronary artery can occur in angiographically normal as well as in atherosclerotic vessels either from thrombus or spasm.
Data Supporting a Neurohormonal Basis for Takotsubo Syndrome
When specifically sought, a psychologically or physically stressful event is just short of universal in the time immediately preceding the onset of symptoms of TS. In a recent comprehensive review, Sharkey et al reported that 89% of patients fulfilling takotsubo criteria had such triggers immediately preceding the cardiovascular symptoms. Although an association between psychologically stressful events and ACS in general has long been recognized, in TS the connection seems unusually strong.
In keeping with a neurohormonal basis for TS are reports indicating that when noncardiac illnesses impose a severe physiologic stress, a LV contraction abnormality akin to the takotsubo pattern has been found. The consistent association of stress with this distinctive contraction pattern logically points to consideration of the role of the sympathetic nervous system in its pathogenesis.
Linking the central nervous system and cardiac abnormalities is not a new concept. Electrocardiographic changes, cardiac biomarker abnormalities, and LV contraction abnormalities are well known to accompany central nervous system events. Samuels recently reviewed the known and potential interactions of the autonomic nervous system and the heart. Although he was primarily interested in the manifestations of cardiac injury associated with central nervous system events, he pointed to evidence of excessive sympathetic activity as a source for not only cardiac arrhythmias but also myocardial injury.
Moreover, there is clinical evidence of cardiac injury in states known to be associated with increased catecholamine levels. Electrocardiographic changes and LV contraction abnormalities on echocardiography have been found in patients with pheochromocytoma. Furthermore, a typical LV contraction abnormality and symptoms of myocardial ischemia were found in a patient after cocaine use, a condition known to be associated with catecholamine excess.
It seems plausible that individual susceptibility to the myocardial effects of a stress-fueled neurohormonal “jolt” will vary widely, because the physical and psychological stressors commonly cited are ubiquitous and TS is uncommon. The marked preponderance of women, particularly those who are postmenopausal, in most TS cohorts strongly suggests a gender-based variation. Of the 136 patients with TS in the review by Sharkey et al, 130 were female. Furthermore, 90% of the patients were aged >50 years.
In this context, it is perhaps pertinent to note the work of Sung et al and Komesaroff et al, suggesting that estrogen therapy attenuates the response of the vasculature to catecholamines or to mental stress in postmenopausal women.
Further evidence for the importance of catecholamines in this syndrome was provided by Wittstein et al. They studied catecholamine levels in 19 patients who were admitted with cardiac symptoms and LV dysfunction after severe psychological trauma. Only 1 of the 19 had obstructive coronary disease. They found levels of plasma catecholamines on admission in patients with TS to be markedly higher than in 7 control patients with Killip class III myocardial infarction. They postulated that “exaggeration of sympathetic stimulation is probably central to the cause” of the TS. Others have also found catecholamine levels in patients with TS compared to those with myocardial infarction.
Thus, there is strong evidence favoring participation of the sympathetic nervous system and excessive catecholamine levels in the pathogenesis of TS. The location of the action of these vascular agents remains to be determined. Although most adrenergic nerve endings are thought to be located around the base of the left ventricle, there is some evidence that the apex has a greater density of receptors, making it more susceptible to catecholamine-induced microvascular dysfunction and to direct myocyte toxicity. The characteristic midventricular and apical contraction abnormalities have also been attributed to a “base to apex perfusion gradient.”
Data Supporting a Neurohormonal Basis for Takotsubo Syndrome
When specifically sought, a psychologically or physically stressful event is just short of universal in the time immediately preceding the onset of symptoms of TS. In a recent comprehensive review, Sharkey et al reported that 89% of patients fulfilling takotsubo criteria had such triggers immediately preceding the cardiovascular symptoms. Although an association between psychologically stressful events and ACS in general has long been recognized, in TS the connection seems unusually strong.
In keeping with a neurohormonal basis for TS are reports indicating that when noncardiac illnesses impose a severe physiologic stress, a LV contraction abnormality akin to the takotsubo pattern has been found. The consistent association of stress with this distinctive contraction pattern logically points to consideration of the role of the sympathetic nervous system in its pathogenesis.
Linking the central nervous system and cardiac abnormalities is not a new concept. Electrocardiographic changes, cardiac biomarker abnormalities, and LV contraction abnormalities are well known to accompany central nervous system events. Samuels recently reviewed the known and potential interactions of the autonomic nervous system and the heart. Although he was primarily interested in the manifestations of cardiac injury associated with central nervous system events, he pointed to evidence of excessive sympathetic activity as a source for not only cardiac arrhythmias but also myocardial injury.
Moreover, there is clinical evidence of cardiac injury in states known to be associated with increased catecholamine levels. Electrocardiographic changes and LV contraction abnormalities on echocardiography have been found in patients with pheochromocytoma. Furthermore, a typical LV contraction abnormality and symptoms of myocardial ischemia were found in a patient after cocaine use, a condition known to be associated with catecholamine excess.
It seems plausible that individual susceptibility to the myocardial effects of a stress-fueled neurohormonal “jolt” will vary widely, because the physical and psychological stressors commonly cited are ubiquitous and TS is uncommon. The marked preponderance of women, particularly those who are postmenopausal, in most TS cohorts strongly suggests a gender-based variation. Of the 136 patients with TS in the review by Sharkey et al, 130 were female. Furthermore, 90% of the patients were aged >50 years.
In this context, it is perhaps pertinent to note the work of Sung et al and Komesaroff et al, suggesting that estrogen therapy attenuates the response of the vasculature to catecholamines or to mental stress in postmenopausal women.
Further evidence for the importance of catecholamines in this syndrome was provided by Wittstein et al. They studied catecholamine levels in 19 patients who were admitted with cardiac symptoms and LV dysfunction after severe psychological trauma. Only 1 of the 19 had obstructive coronary disease. They found levels of plasma catecholamines on admission in patients with TS to be markedly higher than in 7 control patients with Killip class III myocardial infarction. They postulated that “exaggeration of sympathetic stimulation is probably central to the cause” of the TS. Others have also found catecholamine levels in patients with TS compared to those with myocardial infarction.
Thus, there is strong evidence favoring participation of the sympathetic nervous system and excessive catecholamine levels in the pathogenesis of TS. The location of the action of these vascular agents remains to be determined. Although most adrenergic nerve endings are thought to be located around the base of the left ventricle, there is some evidence that the apex has a greater density of receptors, making it more susceptible to catecholamine-induced microvascular dysfunction and to direct myocyte toxicity. The characteristic midventricular and apical contraction abnormalities have also been attributed to a “base to apex perfusion gradient.”
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