ABSTRACT: Objectives. The present study was designed to delineate and compare the clinical characteristics of patients with apical and non-apical takotsubo syndrome in a high-volume U.S. hospital. Background. A comparison between apical and non-apical variants of the “broken heart,” or takotsubo syndrome, has not been performed in the United States. Methods. From 2004 through 2007, patients with takotsubo syndrome were identified according to the following criteria: acute chest pain with electrocardiographic changes or elevation of cardiac enzymes, absence of significant coronary narrowing, left ventricular (LV) segmental akinesia (“ballooning”), with or without antecedent stressful events. Based upon the location of LV ballooning, the patients were divided into two subgroups: apical and non-apical. Results. Of 38 patients (age 64 ± 12 years) fulfilling the inclusion criteria, 84% were women, 79% had documented stressors, 76% had apical and 24% non-apical LV ballooning. When compared to non-apical subjects, apical patients presented predominantly with ST-elevation, had a higher incidence of hypertension, had significantly higher levels of Troponin T (8.5 ± 6.7 ng/ml vs. 3.4 ± 2.1 ng/ml, respectively; p = 0.032), and lower ejection fraction (31 ± 9% vs. 43 ± 5%, respectively; p Methods
This observational study was conducted at our high-volume, U.S. medical center on all patients who presented from 2004 through 2007 with AMI and were diagnosed with normal coronary arteries during cardiac catheterization. The study was approved by the hospital’s institutional review board, and data were collected and analyzed according to a predetermined protocol.
Patients were identified as having transient LV ballooning syndrome based upon the following criteria: 1) acute chest pain with ST-segment elevation and/or T-wave inversion and/or elevated cardiac enzymes; 2) coronary arterial narrowing Results
A total of 38 patients were identified as having transient LV ballooning syndrome (age 64 ± 12 years). Patients were predominantly female (84%) in their post-menopausal age, with 79% having documented antecedent emotional or physical stressful events (Table 1). Figures 2 and 3 show examples of echocardiographic and magnetic resonance imaging of patients with classical LV ballooning syndrome, respectively.
Of patients fulfilling inclusion criteria for takotsubo cardiomyopathy, 76% demonstrated classic LV apical ballooning, and 24% showed atypical, non-apical LV ballooning silhouettes (on right anterior-oblique imaging). For both groups, the mean ages at presentation were similar (65 ± 13 years vs. 62 ± 10 years; p = 0.53), and a female preponderance was observed (79% and 100%, for apical and non-apical, respectively). All patients had at least one coronary risk factor. The prevalence of hypertension was higher in the apical group (76% vs. 33%, respectively; p = 0.04). Six (21%) patients in the apical group and none in the non-apical group had a prior history of coronary artery disease (CAD).
Interestingly, a past history of a similar reversible takotsubo episode was reported in 3 patients in the apical group and in 1 patient in the non-apical group. One patient in each group had a prior history of cerebrovascular disease, and 3 patients in the apical group also had a prior history of peripheral vascular disease. Three patients in the non-apical and none in apical group had chronic kidney disease (33% vs. 0%, respectively; p = 0.01). Two non-apical and 3 apical patients had hypothyroidism.
The majority of patients (79%) had documented antecedent stressors including recent personal or family members’ diagnosis of severe illness (or death), upcoming or recent job interview, hospitalization, surgery and building or moving homes. In the apical group, 15 patients had experienced emotional and 8 had physical stressors, with no reportable stressors in 6 patients. In the non-apical group, 5 had emotional, 2 had physical and 2 had no documented stressors.
The most common initial presenting symptom was chest pain in both groups. In the apical group, 1 patient presented with seizures secondary to ventricular tachycardia (VT), 2 presented with pulmonary edema, and another with cardiogenic shock. For the apical-ballooning group, 19 patients (66%) presented with ST-elevation myocardial infarction (STEMI), and 10 patients (34%) presented with non-STEMI. In the non-apical group, 6 patients (67%) were diagnosed with non-STEMI, 2 (33%) with unstable angina, and none with STEMI. Cardiac enzyme elevation was significantly higher in the apical group compared to the non-apical group (Troponin T: 8.5 ± 6.7 ng/ml vs. 3.4 ± 2.1 ng/ml, respectively; p = 0.032).
Electrocardiographic (ECG) findings. In the non-apical group, 6 patients had T-wave inversions, 1 had left bundle branch block, and 5 had a prolonged QT interval at the time of presentation. In the apical group, 19 patients had ST-elevation, 1 had ST depression, 7 had T-wave inversions, 1 had peaked T-waves and 6 had a prolonged QT interval at initial presentation. Five patients developed T-wave inversions in subsequent ECG recordings (Figure 4). While the non-apical group presented mostly with T-wave inversions (67% vs. 24%, respectively; p = 0.04), the apical group had ST-elevation as the most common initial ECG presentation (66% vs. 0%, respectively; p = 0.04). The prevalence of a prolonged QT interval tended to be higher in the non-apical group (56% vs. 21%, respectively; p = 0.088).
Angiographic findings. By definitional design, obstructive CAD was absent in all patients. Those with apical akinesia and basal hyperkinesia, consistent with the classic takotsubo appearance, were subclassified into the apical group, while those with basal or midventricular akinesia/hypokinesia (inverted takotsubo or apical-sparing pattern) were allocated to the non-apical group (Figure 5).
In-hospital clinical course. All patients in both groups were treated with a standard anti-ischemic regimen including aspirin, beta-blockers, angiotensin-converting enzyme inhibitors/angiotensin receptor-blockers and nitroglycerin, as allowed by the hemodynamic parameters. Eight patients (28%) in the apical and 3 (33%) in the non-apical group received glycoprotein IIb/IIIa inhibitors, and 1 patient in the apical group received thrombolytic therapy. LV systolic function was significantly lower in the apical group compared to the non-apical group (ejection fraction [EF]: 31 ± 9% vs. 43 ± 5%, respectively; p Discussion
To the best of our knowledge, this is the first report comparing the clinical presentation and in-hospital course of American patients with apical and non-apical variants of the “broken heart,” or takotsubo cardiomyopathy. Our data suggest that even though both apical and non-apical ballooning are variants of the same syndrome, the clinical presentation, in-hospital course and the extent of complications may be quite different between these two groups. Understanding and anticipating the distinct clinical features of each subgroup may aid clinicians to better care for this patient population, especially in early stages when most complications tend to occur.
In concordance with other studies,3,4 the majority of our patients in both groups were post-menopausal females. Although the striking preponderance of women may suggest a gender-specific susceptibility to stress-related myocardial dysfunction, the basis for this observation is unknown. Estrogen has many potential benefits on coronary flow, myocyte calcium-handling and microvascular function, which might explain why post-menopausal women are more susceptible.20 Ueyama et al21 demonstrated that estradiol diminished the pathologic emotional stress-induced heart rate accelerations in rats. The withdrawal of protection from this tachycardic response may contribute to the observed post-menopausal predilection. As there have been no studies on the hormonal status of affected female patients, the role of menopause or hormone replacement therapy remains only speculative.
The lower prevalence of hypertension in the non-apical group in our study is concordant with data reported by Hahn and associates.22 Four patients in our study had a prior history of reversible takotsubo syndrome, which is likewise reminiscent of recent published literature.19–22 Kurowski and coworkers19 demonstrated the likelihood of recurrent takotsubo episodes in the same patient; interestingly, the specific variant of LV dysfunction (apical vs. non-apical) may differ upon recurrence.25
Moreover, in our study, the majority of patients in the apical group had ST-elevation at the time of presentation, compared to T-wave inversion in the non-apical group. This observation is likewise consistent with other published reports on classical and atypical variants of takotsubo syndrome.19,23,26 The prevalence of a prolonged QT interval tended to be higher in our non-apical group, an observation reported by previous investigators.6,27,28 Small increases in cardiac biomarkers are observed in takotsubo cardiomyopathy, with troponin elevation being the most common abnormality.4,8,23 In the present series, the mean peak troponin level was greater, and the LVEF was significantly lower in the apical versus the non-apical group. This is contrary to two published studies demonstrating similar mean EFs in both groups.19,22
Predisposing emotional and physical stressors were noted in most patients in both groups. Stress (emotional, physical or physiological) may contribute to enhanced sympathetic activity, resulting in an elevation of plasma catecholamine levels. Alternatively, high levels of norepinephrine may be released directly into the myocardium by local sympathetic nerve terminals. Catecholamine excess can confer direct cardiac toxicity by increasing myocardial oxygen demands while reducing supply through epicardial coronary spasm,9,29 plaque rupture,30 transient dynamic LVOT obstruction31,32 or microvascular spasm. Emotional and physical stresses are known to alter microvascular function, coagulation cascade and markers of inflammation.33,34
In their review, Donohue and colleagues35 summarized the prevalence of complications: cardiogenic shock in 6.5% of patients, congestive heart failure in 3.8%, VT in 1.6% and death in 3.2%. In our study, 5.3% of the patients developed cardiogenic shock, 7.9% had pulmonary edema, 5.3% had VT, 2.6% had LV thrombus, 2.6% had LVOT obstruction and 2.6% (1 patient) died. Interestingly, all these complications and adverse cardiovascular events occurred only in the apical group, underscoring the need to understand the two variants of takotsubo syndrome as differential diagnoses of ACS.
Previous literature has indicated that, upon survival of the acute index event, nearly all patients can expect a full clinical and myocardial functional recovery.23 Thus, it is important to monitor these patients in the acute phase of the syndrome in order to identify those likely to progress to cardiogenic shock and/or display life-threatening arrhythmias. For patients in shock, a low threshold should exist for IABP counterpulsation, as this may be a potentially life-saving measure in these otherwise salvageable patients. In general, treatment is supportive and should follow standard post-MI and heart failure protocols.
Although myocardial sensitivity to adrenergic stimulation is generally enhanced in the apical region,36 the heterogeneous cardiac nerve distribution37 has provided compensatorily lower norepinephrine content at the apex than at the base.38 Alternatively, the apex may not be more vulnerable to catecholamine excess than the mid-ventricle or the base in all patients. Rather, individual variations in regional myocardial susceptibility may determine the location of regional wall-motion abnormality. Moreover, a base-to-apex myocardial perfusion gradient is an alternative explanation for selective apical involvement in patients with apical ballooning. This myocardial perfusion gradient has been found in patients with coronary risk factors, but who have no clinical evidence of CAD.39
In their nuclear imaging report, Cimarelli and coinvestigators40 evaluated apical and midventricular variants of takotsubo cardiomyopathy, revealing severe contractile dysfunction with hypometabolic activity of the involved segments. A similar pattern was observed with a decreased uptake of I-123 MIBG (iodine 123 metaiodobenzylguanidine) and F-18 FDG (fluorine 18 fluorodeoxyglucose). These defects corresponded to segmental wall-motion abnormalities with preserved coronary blood flow consistent with myocardial stunning. Catecholamine-mediated myocardial insulin resistance may be responsible for reduced F-18 FDG uptake in hypokinetic areas. Differential densities of sympathetic receptors between the basal and apical regions of the left ventricle may explain the difference between the classic and variant forms.
At present, the pathophysiology of takotsubo syndrome remains unknown. Initially, multivessel epicardial coronary spasm had been implicated.1 However, a more recent investigation6 revealed that even acetylcholine provocation could elicit angiographic spasm in only a minority of these patients. Wittstein et al9 suggested excess sympathetic stimulation to be a hallmark of takotsubo syndrome, potentially accounting for the reversibly “stunned” myocardium. In their study, Nef and associates41 performed systematic gene expression profiling by micro-array analysis in 3 takotsubo patients during the acute phase and after functional recovery. They proposed that oxidative stress, possibly triggered by excess catecholamines, may pose a significant contribution to the pathophysiology of takotsubo cardiomyopathy.
Study limitations. As this is a somewhat rare clinical entity, our study sample size was relatively small, precluding statistical significance in some assessed parameters. Alternatively, the lack of observed differences may simply represent the overall similarities among all patients with this condition. Another shortcoming of this study is its lack of long-term follow up. However, the focus of our assessment was to delineate and compare the clinical characteristics and in-hospital course of both variants of this condition in U.S. patients. Nonetheless, the dramatic in-hospital clinical recovery in the vast majority of our patients is consistent with previous international series reporting benign long-term outcomes.
Conclusions
The “broken heart” syndrome, or takotsubo cardiomyopathy, is an important differential diagnosis of acute MI and appears to involve predominantly post-menopausal women in the setting of major emotional or physical stress. Apical and non-apical ballooning subgroups may represent different manifestations of a single syndrome. When compared with non-apical ballooning, the apical-ballooning group may represent a more severe subset characterized by more heart failure and an increased rate of cardiac complications.
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