Novel Understanding of Takotsubo Syndrome

Transcription

1 REVIEW ARTICLE Novel Understanding of Takotsubo Syndrome Mika Watanabe, 1 MD, Masaki Izumo, 1 MD and Yoshihiro J Akashi, 1 MD Summary Takotsubo cardiomyopathy is described as a transient reversible cardiomyopathy which typically occurs in older women after emotional or physical stress. This cardiomyopathy is also recognized as a syndrome because it develops in conjunction with various diseases. Since the clinical presentation of takotsubo syndrome (TTS) is similar to acute coronary syndrome (ACS), TTS should be distinguished from ischemic heart disease. Although the pathophysiology of TTS has not well been established, a number of its specific features have been suggested. The predictor of mortality in TTS is still unknown. In this review article, we describe a series of treatment decisions in TTS. (Int Heart J 2018; 59: ) Key words: Apical ballooning, Catecholamine, Acute coronary syndrome, Heart failure, Stress T akotsubo cardiomyopathy is described as a transient reversible cardiomyopathy which typically occurs in older women after emotional or physical stress. 1-4) This cardiomyopathy is also recognized as a syndrome because it develops in conjunction with various diseases. 5) Since the clingoogleical presentation of takotsubo syndrome (TTS) is similar to acute coronary syndrome (ACS), TTS should be distinguished from ischemic heart disease. Although the pathophysiology of TTS has not well been established, a number of its specific features suggest that TTS may be caused by catecholamine-induced microvascular spasm or by direct catecholamine-associated myocardial toxicity. 6) The predictor of mortality in TTS is still unknown. In this review article, we describe a series of treatment decisions in TTS. Epidemiology TTS was first described in the literature in 1990 by Sato, et al. from Japan. 7) Since 2000, many case reports have been published around the world. Earthquakes have been regarded as a trigger to increase the prevalence of acute myocardiopathy, and currently it is believed that TTS should also be included. In fact, approximately half of the patients with ACS in Japan were diagnosed as having TTS. 8) One study from the United States showed that TTS was diagnosed in approximately 0.02% of all hospitalized patients. 9) Women have higher odds of developing TTS than men (odd ratio, 8.8). Women aged 55 years and older have 4.8 times higher odds for developing TTS than women younger than 55. Smoking, alcohol abuse, anxiety states, and hyperlipidemia are commonly associated with the prevalence of TTS. The peak incidence of hospitalization for TTS is in the spring 10,11) or summer. 9,12) Japanese researchers reported that the peak of TTS onset was in the autumn and late winter in Japan. 13) According to the Diagnosis Procedure Combination data presented by Isogai, et al., 14) there is no seasonal rule for the onset of TTS. Pathophysiology Various etiologies are presumed to cause TTS, including coronary vasospasm, plaque rapture, microcirculatory dysfunction, loss of female hormones, metabolic disturbances, and catecholamine hypothesis, although no consensus with respect to pathophysiology has yet been reached. It is reported that approximately 30% of TTS is associated with coronary vasospasm. 15) Coronary vasospasm is less likely to trigger TTS because of a discrepancy between TTS and stunned myocardium in the pathological findings. The wall motion of TTS is similar to that of myocardial ischemia after plaque rapture; however, the wall motion of TTS extends beyond a single coronary vascular bed and it has no coronary occlusion. Plaque rapture is excluded from the cause of TTS in several guidelines. The leading hypothesis of the pathophysiology is catecholamine cardiotoxicity. One study demonstrated that the plasma levels of catecholamine among TTC patients were 2 to 3 times the values among myocardial infarction patients. 6) Biased agonism of epinephrine for β2 adrenoceptor (AR) Gs at low and Gi at high concentrations underpins the acute apical cardiodepression observed in TTS, with an apical-basal gradient in β2ars explaining the differential regional responses (Figure). 5) Epinephrinespecific β2ar-gi signaling may have evolved as a cardioprotective strategy to limit catecholamine-induced myocardial toxicity during acute stress. 16) A recent experimental From the 1 Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Kawasaki, Japan. Address for correspondence: Yoshihiro J. Akashi, MD, Division of Cardiology, Department of Internal Medicine, St. Marianna University School of Medicine, Sugao, Miyamae-ku, Kawasaki, Kanagawa , Japan. yoakashi-circ@umin.ac.jp Received for publication October 13, Revised and accepted October 24, Released in advance online on J-STAGE March 5, doi: /ihj All rights reserved by the International Heart Journal Association. 250

2 March 2018 TAKOTSUBO SYNDROME 251 Figure. Pathophysiological model for acute apical dysfunction in Takotsubo syndrome. A: Left ventricular systolic performance under normal conditions of perfusion, afterload (e.g., 120 mmhg), and β-adrenoceptor activation. B: The acute phase of Takotsubo syndrome can be characterized by peripheral vasoconstriction, leading to increased afterload and transient high left ventricular end-systolic pressure (e.g., 200 mmhg), acute coronary artery vasospasm causing myocardial ischemia, and a subsequent reduction in cardiac output with systemic hypotension complicated by direct catecholamine-mediated myocardial stunning in the apex where the β-adrenoceptor gradient is the highest. Adapted without modification from Akashi, et al. with permission. 5) study suggested that β-adrenergic signaling and a high sensitivity to catecholamines could be associated with the onset of this syndrome; the enhanced reduction of integration in meta-iodobenzylguanidine myocardial scintigraphy supports this hypothesis. 17,18) Kurisu, et al. demonstrated that coronary blood flow was severely impaired in all coronary arteries in agreement with left ventricular (LV) asynergy immediately after onset. Even though coronary blood flow was improved, the impairment remained after resolution of the takotsubolike LV dysfunction. 19) Therefore, coronary microvascular impairment has a potential to trigger TTS. 20) Since many postmenopausal women suffer from TTS, a lack of estrogen seems to affect the pathogenesis of TTS. 21,22) No current or proven pathophysiological mechanism exists to explain TTS; many hypotheses are still being investigated. Contractile Pattern Stiermaier, et al. evaluated the prognostic impact of different ballooning patterns in 285 patients with TTS. 23) The patients with typical apical ballooning were significantly older and had a higher prevalence of diabetes mellitus than those with atypical ballooning. The initial LV ejection fraction was significantly lower in apical ballooning but recovered to normal values in both groups. Although 28-day mortality did not differ significantly, typical apical ballooning was associated with increased 6- month and long-term mortality rates. After complete recovery of LV function, the prognosis was similar in patients with typical and atypical ballooning patterns. 23) As well as the classic apical variant of TTS, other forms have been described, including the midventricular, basal, and focal forms. 24) TTS can be triggered by not only negative but also positive life events. While the patient characteristics are quite similar, the midventricular type is more prevalent among the happy heart syndrome than among the broken heart syndrome. 25) Right ventricular (RV) involvement is relatively common and reversible. RV involvement has a negative impact on hospital stay and morbidity; its identification can help predict hemodynamic instability ) Clinical Presentation The predominant symptom on admission is chest pain, followed by dyspnea and syncope; meanwhile, some patients have no symptoms. Less common symptoms, such as pulmonary edema, may sometimes occur, whereas cardiac arrest, cardiogenic shock, and serious ventricular arrhythmias are quite rare. Nonspecific symptoms, including weakness, cough, and fever also have been reported. 26,29) Recurrent TTS is infrequent; one study has demonstrated that the recurrence rate is highest within the first 4 years, approximately 2.9% per year, and the recurrence rate over 4 years is 11.4% after initial presentation. 30) The average recurrence rate is reported to be approximately 3.8%. 5) Diagnosis There are several guidelines with which to diagnose TTS. The criteria proposed by the Mayo Clinic are the most commonly used around the world, 31) even though TTS was first reported and named in Japan. Every criterion proposes the exclusion of significant organic stenosis or spasm of a coronary artery; however, the recent guidelines suggest that obstructive coronary artery disease is frequently observed in patients with TTS. The wall motion abnormalities usually extend to the territory of the involved coronary arteries. CT coronary angiography is employed as alternative imaging to exclude coronary stenosis when the presentation is delayed or the patient is pain free and stable on admission. The current state of knowledge on TTS according to the European Society of Cardiology Working Group is presented in Table I. 32)

3 252 Watanabe, ET AL March 2018 Table I. Diagnostic Criteria for Takotsubo Syndrome Diagnostic criteria 1. Transient regional wall motion abnormalities of LV or RV myocardium which are frequently, but not always, preceded by a stressful trigger (emotional or physical). 2. The regional wall motion abnormalities usually* extend beyond a single epicardial vascular distribution, and often result in circumferential dysfunction of the ventricular segments involved. 3. The absence of culprit atherosclerotic coronary artery disease including acute plaque rupture, thrombus formation, and coronary dissection or other pathological conditions to explain the pattern of temporary LV dysfunction observed (e.g. hypertrophic cardiomyopathy, viral myocarditis). 4. New and reversible electrocardiography (ECG) abnormalities (ST-segment elevation, ST depression, LBBB, T-wave inversion, and/or QTc prolongation) during the acute phase (3 months). 5. Significantly elevated serum natriuretic peptide (BNP or NT-proBNP) during the acute phase 6. Positive but relatively small elevation in cardiac troponin measured with a conventional assay (i.e. disparity between the troponin level and the amount of dysfunctional myocardium present). 7. Recovery of ventricular systolic function on cardiac imaging at follow-up (3-6 months). *Acute, reversible dysfunction of a single coronary territory has been reported. Left bundle branch block may be permanent after Takotsubo syndrome, but should also alert clinicians to exclude other cardiomyopathies. T-wave changes and QTc prolongation may take many weeks to months to normalize after recovery of LV function. Troponin-negative cases have been reported, but are atypical. Small apical infarcts have been reported. Bystander subendocardial infarcts have been reported, involving a small proportion of the acutely dysfunctional myocardium. These infarcts are insufficient to explain the acute regional wall motion abnormality observed. Adapted from Lyon AR, et al. with permission. 32) Laboratory Findings The plasma levels of both epinephrine and norepinephrine are remarkably increased in patients with TTS. Several studies have suggested that the markedly elevated catecholamine levels might be the main pathogenic factor. 6,33,34) Cardiac enzymes, such as troponin T and CK- MB, are slightly increased in TTS, although the levels are lower than those in AMI. 32) One study demonstrated an elevated troponin level in 87.0% of the patients with TTS. 24) Since TTS is a disease that primarily causes distention of the ventricles and is characterized by reversible myocardial dysfunction without necrosis, a greater increase in plasma BNP rather than troponin T or CK-MB has been demonstrated in TTS compared with AMI. 34) Thus, plasma BNP levels are usually greater in TTS than in STEMI; the ratio of BNP to peak troponin levels may differentiate TTS from STEMI. 35) In-hospital mortality is influenced by the peak concentration of troponin I and overall mortality is affected by cardiogenic shock and the elevation of BNP during admission. The assessment of troponin I and BNP will help the prognostication of TTS patients in daily clinical practice. 36) Electrocardiographic Findings ST-segment elevation is observed in almost all patients with TTS in the acute stage. Subsequently, T-wave inversion occurs; QT prolongation and transient Q waves can be seen. It is difficult to distinguish patients with TTS from those with acute anterior AMI based on ECG findings. A difference in ECG findings between TTS and AMI has been demonstrated. Patients with anterior AMI have ST-segment elevation in leads V2 - V4. 37,38) The combination of fewer appearance of abnormal Q waves and no reciprocal changes and ST-segment elevation in leads V4-6 to V1-3 1 had a greater specificity (100%) and overall accuracy (91%) than either criteria. 39) Echocardiography The typical findings of takotsubo-like LV ballooning consist of akinesis, hypokinesis, or dyskinesis of the apical and middle segments of the LV and preserved or hyperkinesia of the basal segments. LV myocardial dysfunction of TTS characterized by symmetric wall motion abnormalities involving the mid-ventricular segments of the anterior, inferior, and lateral walls over the apical segment should be considered peculiar to TTS and included in the differential diagnosis of TTS and ACS. These findings support the hypothesis of diffuse ventricular dysfunction secondary to myocardial stunning underlying the pathogenesis of TTS. 40,41) RV apical akinesia during echocardiographic examination makes the diagnosis of this syndrome very likely. 42) The median LV ejection fraction on the initial echocardiogram was 20% (interquartile range, 15 to 30%). A reduced LV ejection fraction (mean value, 40.7 ± 11.2%) was noted in 86.5% of patients with TTS on admission but in only 54.2% of patients with an ACS. 24) The assessment of LV ejection fraction is also important in the management of TTS because LV ejection fraction and wall motion abnormalities are closely associated with major adverse events. 43) In addition, the evaluation of LV outflow obstruction, valve disease, and pulmonary hypertension in TTS management is indispensable. Echocardiography simply and easily depicts the wall motion abnormalities in their acute phase. Since the diagnosis of TTS is sometimes challenging, it is favorable to perform echocardiography to identify slight clinical changes. Nuclear Imaging In the first nuclear study, technetium-99 m-tetrofosmin and 123 I-b-methyliodophenyl pentadecanoic acid ( 123 I-BMIPP) were administered to patients without coronary disease who revealed stunned myocardium after contrast medium administration. 39) The total defect score (TDS) was higher in the acute phase compared with the

4 March 2018 TAKOTSUBO SYNDROME 253 Table II. Differences in CMR Features of Takotsubo Syndrome, Acute Myocardial Infarction and Acute Myocarditis Takotsubo syndrome Myocardial infarction Myocarditis Site of wall motion abnormality Concentric mid- and apical LV wall Follows expected epicardial coronary artery distribution Usually global unless regional edema/lge is severe Myocardial edema Typically transmural in a concentric Subendocardial or transmural at Subepicardial, mid-myocardial or mid and apical LV wall distri- bution sites of wall motion abnormalities transmural Left ventricular impairment Yes: typically impaired ejection Yes: typically impaired ejection Yes, but may show only mild/ borderline fraction with elevated indexed end systolic volume fraction with elevated indexed end systolic volume low normal ejection frac- tion Right ventricular impairment > 33% of patients May be seen, particularly if right coronary artery territory involved Rarely impacts on right ventricular function LGE Maybe (10e40%) Yes Often Site of LGE Concentric transmural mid and apical LV wall Typically subendocardial or transmural in recognized epicardial coronary artery distribution Mid-myocardial or subepicardial in a focal non-coronary artery distribution Type of LGE Low-intensity LGE Bright LGE Low-intensity or Bright LGE Microvascular obstruction No Maybe No Resolution at 3 months Yes No Potentially but may show residual myocardial fibrosis and impairment CMR indicates cardiac magnetic resonance; LV, left ventricular; LGE, late gadolinium enhancement. Quoted from Abbas A, et al. with permission. 46) sub-acute and chronic phases. Kurisu, et al. presented that the TDS of thallium-201 was lower than that of 123 I- BMIPP in the acute phase. 40) The most recent study conducted by Matsuo, et al. proposed that the TDS of 123 I- BMIPP in patients with TTS is much lower than that in those with AMI. 41) TTS is presumed to be associated with catecholamine abnormality; several studies in the literature describe 123 I- MIBG. Owa, et al. reported that the recovery of 123 I- MIBG uptake was slower than that of other tracers. 42) 123 I- MIBG imaging combined with myocardial perfusion scintigraphy depicts abnormal myocardial sympathetic innervation in a pattern consistent with one of the variants of TTC in the absence of a myocardial perfusion abnormality or scar. 43,44) 123 I-MIBG imaging also may prevent excessive adrenal and ectopic catecholamine secretion while using whole body imaging with the same tracer, such as pheochromocytoma. 45) Since 123 I-MIBG myocardial scintigraphic imaging is quite useful for following cardiac sympathetic activity in patients with TTS, the Task Force on TTS of the Heart Failure Association of the European Society of Cardiology insists in their position statement that the recovery of ventricular systolic dysfunction on cardiac images at follow-up is required for an accurate diagnosis of this syndrome. 46) Cardiac Computed Tomography (CCT) CCT has high negative predictive values and lower risk than coronary angiography ) The exclusion of coronary obstruction is necessary for diagnosing TTS; thus, CCT is a significant examination. Some studies support the role of CTT angiography in the clinical course of TTS. According to the Japanese Guidelines for TTS diagnosis, urgent coronary angiography is desirable for imaging during the acute stage. Coronary angiography is also necessary during the chronic stage to confirm the presence or absence of a significant stenotic lesion and a lesion involved in the abnormal pattern of ventricular contraction. 26) In fact, CCT is used for diagnosis in the acute phase. 50) Cardiac Magnetic Resonance (CMR) CMR imaging is useful for the evaluation of wall motion abnormalities. It also detects reversible (inflammation, ischemic edema) and irreversible (necrosis/fibrosis) injuries. Eitel, et al. reported that CMR imaging showed complete normalization of LV ejection fraction and inflammatory markers in the absence of significant fibrosis in all TTS patients. 44) Late gadolinium enhancement (LGE) on CMR usually represents fibrosis. In myocardial infarction, the distribution of LGE is subendocardial or transmural, indicating the extent of infarction. In nonischemic cardiomyopathy, there may be an isolated midwall or subepicardial pattern of enhancement and myocarditis produces a patchy distribution of LGE among other manifestations on CMR. However, minor LGE can be found in patients with TTS. It has been reported that minor LGE is present in approximately 9% of the patients with TTS when LGE is defined at a cutoff value of > 3 SD above the mean. 44) Meanwhile, Mitchell, et al. 45) reported the usefulness of CMR for assessing myocardial viability and prognosis in TTS. They demonstrated that a lack of delayed enhancement represented a lack of irreversible myocardial damage and predicted functional recovery. Although CMR can be performed noninvasively, it is not suitable for urgent examinations because a lot of time is required for scanning. 45) Therefore, it illustrates the potential of multiple detector computed tomography for the noninvasive differentiation of TTS from ACS. CMR is quite useful for providing an accurate diagnosis or TTS and is also helpful to rule out ACS and myocarditis (Table II). 46)

5 254 Watanabe, ET AL March 2018 Treatment There are no specific options for the LV failure characterizing TTS because cardiac function is normalized within a few weeks. A position statement indicated a suggestive stratification for TTS patients in ) A risk stratification in patients with TTS is also proposed in the statement. High risk patients should be treated in an intensive care unit. Treatment is determined by the complications during the acute phase. When shock occurs, intravenous fluids, inotropic agents, or intra-aortic balloon pumping (IABP) have been established as additional support for the circulation. However, IABP is not suitable for patients with LV outflow obstruction because of a worsening pressure gradient. The administration of angiotensin-converting enzyme inhibitors or angiotensin receptor blockers is reported to potentially decrease the recurrence rate of TTS. 47) Although the use of β-adrenoceptor blockers in the acute phase of TTS is still a matter of debate, 48) the combination of both angiotensin-converting enzyme inhibitors or angiotensin receptor blockers and β-adrenoceptor blockers would be an effective regimen with which to prevent the recurrence of TTS. 49) Prognosis One study reported that patients with TTS had a poor prognosis relative to survival prediction. 50) Thirty-day mortality in TTS was 4.1%, which was similar to that in ACS. 51) The long-term mortality in TTS was poor compared with that in ACS; the representative predictors were men, diabetes, and Killip > 3. 52) The presence of physical triggers is closely associated with higher troponin levels on admission and low EF. 24) The recurrence rate of TTS is reported to be 5-11% and the duration ranges from 3 months to 14 years. 30,53) The main cause of TTS is physical and psychological stress; thus, avoiding stress is vital to prevent reoccurrence. In addition, successful treatment of primary illness has a good prognosis because most deaths with TTS in hospital are derived from non-cardiac disease. Conclusion Not only cardiologists but also non-cardiologists need to fully understand TTS because this syndrome occurs in various situations. TTS is a reversible disease; when the treatment of acute complication is successful, it will lead to a good prognosis. Hence, we should fully understand the mechanism of TTS and provide appropriate treatment. The exact pathophysiology or cause of reoccurrence has not been fully clarified; however, physical and psychological stress influence TTS. Clinicians should treat the primary disease appropriately to prevent the occurrence of TTS. Disclosures Conflicts of interest: None. References 1. Tsuchihashi K, Ueshima K, Uchida T, et al. Transient left ventricular apical ballooning without coronary artery stenosis: a novel heart syndrome mimicking acute myocardial infarction. 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