Takotsubo (Stress) Cardiomyopathy and the Anesthesiologist: Enough Case Reports. Let's Try to Answer Some Specific Questions!

Takotsubo cardiomyopathy (also known as takotsubo syndrome, broken heart syndrome, ampulla cardiomyopathy, transient left ventricular apical ballooning, apical ballooning syndrome, transient left ventricular dysfunction syndrome, and stress [induced] cardiomyopathy) was first described in Japan in 1990.1** It was initially characterized by a unique pattern of transient (hours to weeks) wall motion abnormality (“transient left ventricular apical ballooning”) occurring in the absence of significant epicardial coronary artery disease, presenting as an acute coronary syndrome, most frequently in postmenopausal elderly women, often triggered by stressful situations. It has since been observed throughout the world and under various circumstances.†† This condition was first described in the perioperative period in the North American anesthesia literature via case reports that appeared in the September 2006 issues of Anesthesia & Analgesia4 and Anesthesiology.5 Since that time, multiple case reports of periprocedural (e.g., endoscopy, catheterization, and electroconvulsive therapy) and at least 25 to 38 perioperative cases of takotsubo cardiomyopathy have appeared6–23 with the latest in this issue of Anesthesia & Analgesia.24,25 Anesthesiologists may also confront this syndrome while caring for patients with aneurysmal subarachnoid hemorrhage (A-SAH),26–29 pheochromocytoma,30–37 and other critical illnesses.3,38,39 In this issue of Anesthesia & Analgesia, Daly and Dixon24 report on 2 cases of takotsubo cardiomyopathy that occurred in an elderly (76- and 78-year-old) man and woman, which the authors attribute to severe peri-injury pain. Wong et al.25 report on a case presenting immediately preoperatively in a 63-year-old woman scheduled to undergo elective minor surgery. Notably, none of these patients presented with chest pain or dyspnea, but rather with electrocardiographic (ECG) changes (with or without elevated cardiac enzymes). All 3 recovered from the acute phase of this syndrome without complications with supportive management (β-adrenergic blockade, angiotensin-converting enzyme inhibitors, statins, and heparin, with or without clopidogrel) and tolerated subsequent surgery without problems. Both sets of authors have nicely reviewed various aspects of this syndrome, but these case reports raise additional important questions of obvious interest to anesthesiologists. Why did these patients develop this syndrome in the face of an apparent amount of pain or perioperative anxiety that would not be expected to cause cardiac injury in most patients? Is there something unique about pain or how some patients process pain that contributes to the pathogenesis of this syndrome? What is the true incidence of this syndrome during the perioperative period? The authors suggest that it is rare, but is it actually? Why is this syndrome now being reported so frequently (i.e., in this decade)? Was it just missed previously (perhaps because of less-frequent “routine” perioperative use of echocardiography) or has something changed in our clinical environment or patient populations or how we care for them that explains its recent occurrence? Did the perioperative management of these patients (β-adrenergic blockade, aspirin, statins, heparin, with or without clopidogrel) contribute to their recovery or would it have occurred without these therapies? What is the optimal anesthetic management of patients who have recently or remotely experienced takotsubo syndrome? It is now abundantly clear that the observation that takotsubo cardiomyopathy occurs in the perioperative period is no longer unique and therefore further case reports, particularly those that focus on the “basics” of this syndrome, are not likely to help advance our understanding of the condition. Thus, it is highly unlikely that this journal will publish any case reports in the future on its isolated occurrence in 1 or 2 patients, as have been described by Daly and Dixon and Wong et al., unless they provide completely unique insights or are able to provide objective quantitative measurement of factors related to the development of this syndrome (e.g., myocardial catecholamine receptors in an autopsy specimen). As discussed below, it is obvious that what is needed are more specialized or complex approaches that address the many unresolved questions listed above. These range from detailed biochemical/pharmacogenomic approaches to more sophisticated epidemiologic approaches (e.g., case registries to accumulate large numbers of patients). Given that the recent “surge” of information on this syndrome is spread among so many diverse journals, we herein summarize what is known and identify important questions yet to be answered, based on the data presented by the case reports of Daly and Dixon24 and Wong et al.,25 recent systematic40–44 and other review articles and commentaries,2,45–58 and a number of case series.59–74 Finally, we present our suggestions for answering these remaining questions. WHAT IS KNOWN? Bybee and Prasad3 have reviewed the various stress-related cardiomyopathy syndromes, which they describe as occurring in several different contexts: (1) classic takotsubo cardiomyopathy, which presents as an acute coronary syndrome, (2) left ventricular dysfunction associated with acute intracranial disease, especially A-SAH, (3) transient cardiomyopathy, which occurs during other critical illness, especially sepsis, and (4) transient cardiomyopathy associated with pheochromocytoma and exogenous catecholamine administration. Whether in fact these categories represent a spectrum of the same syndrome is not definitely known but is quite likely. In several large series, about 13% (6%–16%) of cases occurred perioperatively, periprocedurally, or were associated with fractures.59,60,67,74 Although the classic pattern of wall motion abnormality observed is hypokinesia or dyskinesia of the distal mid and apical walls of the left ventricle (“apical ballooning”), usually associated with hyperkinesia of the basal segments, several other patterns (described as “variants”) have been reported including isolated midventricular and even basilar (so-called “inverted takotsubo”) hypokinesis. Thus, the apical ballooning pattern is no longer considered pathognomonic of the syndrome. Whether the pattern of transient global hypokinesia can be included in this syndrome has not been clarified. Although its onset is often preceded/precipitated by emotional or physiologic stress (between 45% and 85% of the time), this is not invariable. Furthermore, the onset of the stress may have preceded the presentation by several days, and often, the degree of stress does not seem to be unusual. As discussed by Daly and Dixon24 and Wong et al.,25 the most commonly accepted cause is excessive adrenergic/catecholamine stimulation, which damages cardiomyocytes75 (Fig. 1). Recent reports of its acute precipitation by administration of catecholamines (epinephrine or dobutamine),76,77 its occurrence in patients with pheochromocytoma,32 and its reproduction by infusion of epinephrine in primates78 strongly support this hypothesis. Other case reports have described transient global ventricular dysfunction associated with chest pain, ECG changes, and often troponin release after epinephrine administration (8, 0.75, and 0.1 mg, respectively).79–81 Suk et al.82 recently described a 32-year-old woman who developed the midventricular variant of takotsubo syndrome after anaphylactic shock during general anesthesia, which had been treated with epinephrine (1 mg) before onset of the syndrome, whereas Zubrinich et al.83 reported the occurrence of the classic syndrome in a 76-year-old woman after administration of epinephrine (0.3 mg) via an “EpiPen” for lip angioedema. Interestingly, this patient was receiving chronic treatment with a nonselective β-adrenergic blocker (oxprenolol) at the time. Han and Yeon84 reported a case of probable midventricular variant of takotsubo cardiomyopathy in a 41-year-old man after anaphylaxis treated with epinephrine (0.2 mg). The role of therapeutically administered epinephrine versus sympathetic activation (with catecholamine release) or other mediators precipitated by anaphylaxis per se is conjectural. However, a report by Vultaggio et al.85 of the occurrence of classic takotsubo syndrome in a young woman after anaphylaxis, who did not receive epinephrine, suggests that the former is not essential in the pathogenesis of this syndrome. Finally, as mentioned by Daly and Dixon24 and Wong et al.,25 other factors besides catecholamines may be involved exclusively or additively in the pathogenesis of this syndrome in some patients including transient epicardial coronary thrombosis, coronary artery spasm, coronary microvascular dysfunction, and dynamic left ventricular outflow tract obstruction.Figure 1.: Proposed pathophysiology of takotsubo cardiomyopathy. (Reproduced from Prasad et al.,48 with permission.)Although takotsubo syndrome classically presents with chest pain, dyspnea, and ECG changes, these findings are not invariably present. It is interesting that none of the 3 patients reported by Daly and Dixon24 and Wong et al.25 complained of chest pain (which perhaps was masked by their somatic pain from injury in the former report). This resembles the situation in the majority of cases of perioperative myocardial infarction.86 Other authors have suggested that dyspnea may be a more common presentation in African American women.87,88 The age (62–75 years) and gender predominance (about 80%–100% postmenopausal women) encountered in classic takotsubo syndrome may be less obvious in the variant forms in which patients often are younger and more often male. Although most patients recover without complications after an episode of takotsubo cardiomyopathy, serious complications including congestive heart failure (occurring in as many as 44%–57% of patients),63,67 pulmonary edema often requiring endotracheal intubation and mechanical ventilation, and cardiogenic shock (15%–45% of cases) requiring vasopressor or inotropic therapy27,45,50,60,71,74 and even intraaortic balloon pumping45,50,53,55,60,66,67,71,72,74 do occur. Other complications such as ventricular arrhythmias including torsade de pointes,63,67,89 syncope, cardiac arrest, apical thrombosis, and thromboembolism including stroke, dynamic intraventricular gradients, and obstruction (up to 25%)64 with or without systolic anterior motion of the mitral valve, severe mitral regurgitation, ruptured ventricle, and death (1%–3% but as high as 21%)63 have been reported.55,68,74 Elesber et al.67 at the Mayo Clinic observed a recurrence rate of 11.4% over an average follow-up of 4.4 ± 4.6 years of 100 patients with takotsubo cardiomyopathy (2.9% per year over the first 4 years and 1.3% per year thereafter). Interestingly, only 2 of the 10 patients who experienced a recurrence had an identifiable precipitating event at that time. WHAT IS NOT KNOWN? As noted above, there is no clear explanation for individual susceptibility to takotsubo cardiomyopathy after exposure to a similar degree of emotional or physiologic stress or dose of exogenous catecholamines that usually do not adversely affect most patients. It is not improbable that genetic heterogeneity of the adrenergic receptors, rendering them more or less sensitive to adrenergic stimuli, may explain some of this variability as has been shown for the neurocardiac injury associated with A-SAH90 and sensitivity to β-adrenergic blocking drugs,91,92 but not yet in takotsubo cardiomyopathy.93 Furthermore, the cause or trigger in individuals who develop the syndrome in the absence of an obvious emotional/physiologic stressor is not clear. Although various hypotheses have been proposed, there is no established explanation for the susceptibility of elderly women to this condition or why particular myocardial segments are prone to dysfunction when this cardiomyopathy occurs. Finally, optimal therapy during the acute phase and after the patient has recovered, especially in the perioperative period, is yet to be defined. Because of the presumed role of excess catecholamines in its pathogeneses, avoidance of adrenergic agonists and initiation of antiadrenergic therapy (e.g., β-adrenergic blocking drugs or centrally acting α2 agonists) have been advocated. Clearly, therapy must be individualized based on the clinical presentation. In patients presenting with left ventricular outflow tract obstruction,94 catecholamines are particularly contraindicated. However, it is unclear whether the administration of inotropic drugs to treat systolic dysfunction (heart failure, pulmonary edema, and cardiogenic shock) is harmful (i.e., does it worsen the transiently dysfunctional myocardium or impair full recovery?). And, if inotropic support is needed, is there an inotrope of choice? Padayachee95 suggests that the calcium sensitizer levosimendan may be the best choice. Are there therapies that hasten recovery? A recent primate study suggests that administration of metoprolol after development of epinephrine-induced cardiomyopathy hastens recovery.78 Mechanical support of the circulation (e.g., intraaortic balloon pump and ventricular assist device) is clearly an option to avoid catecholamine use, but not without significant risk for additional complications related to these devices.45,50,53,55,60,66,67,71,72,74 From our review of the literature, it seems likely, but has not been conclusively proven, that a substantial portion of the damage caused by catecholamine toxicity to the myocardium has likely occurred by the time of clinical presentation, and thus administration of antiadrenergic therapy at this time is unlikely to completely reverse injury. Indeed, in a number of reported cases, catecholamines seem to have facilitated recovery in patients with acute left ventricular dysfunction.27,45,50,60,71,74 As in the setting of acute myocardial infarction with significant systolic dysfunction, routine early administration of β-adrenergic blockers may be potentially hazardous, potentially leading to cardiogenic shock.96 How to best prevent perioperative takotsubo cardiomyopathy and whether there is a best anesthetic technique to use in patients who have experienced the syndrome previously (remotely or recently) who now require surgery is unclear. The role of β-blocker therapy in managing these patients is unclear because the dose necessary to block the excessive levels of catecholamines that may precipitate takotsubo cardiomyopathy might not be hemodynamically tolerated. However, it is also likely that a certain percentage of patients who are unusually sensitive to catecholamines will be responsive to prophylactic β-blocker therapy. The possible futility of prophylactic β-blocker therapy is reinforced by the aforementioned case report by Zubrinich83 and by the observation that 26% of the patients in the Rhode Island Registry had been taking β-adrenergic receptor blockers at the time they presented with the syndrome.59 However, abrupt β-adrenergic blocker withdrawal was hypothesized to be the cause of takotsubo cardiomyopathy in a case report of a 56-year-old woman.97 Given the intense interest in the benefits and risks of perioperative β-blockade in prevention of cardiac complications, this is an area in which additional clinical information would be particularly welcomed. WHAT IS NEEDED TO TRY TO ANSWER THESE UNRESOLVED QUESTIONS? 1. Additional case reports describing isolated occurrences of this syndrome unless they provide unique insights into previously undescribed etiology or pathophysiology associated with this syndrome would seem to be of little further value. Whatever term the clinician prefers to describe this syndrome and its variants, it is now a well established one in the perioperative setting. 2. Large population cohort studies to identify/define the incidence, characteristics, and risk factors in perioperative populations, as recommended by Suk et al.,82 are of particular importance. 3. Establishment of perioperative patient registries. The 2 major hospitals in Rhode Island have established such a registry to study all cases of takotsubo cardiomyopathy in that state.59 The anesthesia community is well aware of the registry established by the University of Washington to study perioperative optic ischemia, which has provided valuable information on this rare event. We call on enterprising individuals, institutions, or societies (e.g., Society of Cardiovascular Anesthesiologists and Anesthesia Patient Safety Foundation) to seriously consider the feasibility of establishing a perioperative takotsubo registry. Although it would likely be a logistically difficult endeavor, given the variability in presentation of this syndrome and similarities to other forms of acute coronary syndromes that may present with greater frequency perioperatively, we believe that the information to be gained could be substantial. Given the ongoing interest in prophylactic manipulation of the adrenergic nervous system perioperatively, finding adequate substrate on which to base focused clinical investigations of possible etiologic and pathophysiologic factors would be most important (e.g., pharmacogenomic evaluation of patients sustaining this syndrome). 4. Genetic studies, especially as they relate to adrenergic receptors and their sensitivity to and release of catecholamines, are of particular interest.90–93 5. There is clearly substantial similarity between classic takotsubo cardiomyopathy and the cardiac injury encountered in A-SAH including ECG changes (ST changes, T wave inversion, and prolonged QTc), relatively low levels of troponin release, and transient wall motion abnormalities (although the classic midapical ballooning pattern is less dominant, it has been well described with A-SAH).27,98 Because the latter form of stress cardiomyopathy seems to be more prevalent and more predictable than the sporadic perioperative syndrome, we believe that the characteristics and management strategies used to treat cardiac injury associated with A-SAH are likely directly applicable to perioperative takotsubo cardiomyopathy. In summary, although it is infrequently encountered, takotsubo cardiomyopathy is now a well-established clinical syndrome reported in a variety of clinical settings. Given the abundance of case reports and small clinical series, clinicians working in the perioperative and critical care environments managing patients presenting with acute coronary syndromes, new onset of dyspnea, ECG evidence of myocardial ischemia, or left ventricular failure should be able to distinguish it from acute myocardial dysfunction caused by occlusive epicardial coronary events although most patients will require similar diagnostic testing to rule it in or out. The prognostic implications (e.g., generally more favorable) and therapeutic options (e.g., less clear) seem to be distinctly different. Intraoperative transesophageal echocardiography or perioperative transthoracic echocardiography provide valuable information to establish the diagnosis and guide appropriate hemodynamic therapy especially in the “classic” takotsubo wall motion pattern. We hope that the case reports of Daly and Dixon24 and Wong et al.25 presented in this issue of Anesthesia & Analgesia will be the last of their kind and that future efforts will tackle the considerably more difficult task of providing aggregate data on large groups of patients developing this syndrome or can provide detailed biochemical, physiologic, or pharmacogenomic data on specific patients currently absent from the literature base. AUTHOR CONTRIBUTIONS Both authors had essential roles in the conception of this editorial, examination of the literature, and preparing the manuscript and its revisions. This editorial reflects the opinions of both authors who have each reviewed and approved the final manuscript.