International Journal of Cardiology 176 (2014) 1362–1364

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International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard

Letter to the Editor

Incidence and clinical characteristics of takotsubo cardiomyopathy post-aneurysmal subarachnoid hemorrhage Thura T. Abd a, Salim Hayek b, Jeh-wei Cheng c, Owen B. Samuels d,e, Ilan S. Wittstein a, Stamatios Lerakis b,⁎ a

Division of Cardiology, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, United States Division of Cardiology, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States Division of Internal Medicine, Department of Medicine, Emory University School of Medicine, Atlanta, GA, United States d Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA, United States e Department Neurology, Emory University School of Medicine, Atlanta, GA, United States b c

a r t i c l e

i n f o

Article history: Received 28 July 2014 Accepted 29 July 2014 Available online 6 August 2014 Keywords: Takotsubo Stress-induced cardiomyopathy Neurogenic stunned myocardium Broken heart syndrome Incidence Subarachnoid hemorrhage

Takotsubo cardiomyopathy (TCMP), also known as stress-induced cardiomyopathy, broken heart syndrome or apical ballooning syndrome, is an increasingly recognized syndrome characterized by reversible left ventricular (LV) dysfunction, electrocardiographic (ECG) changes and release of myocardial enzymes that mimic myocardial infarction in the absence of obstructive coronary artery disease (CAD) [1], attributed to a surge in catecholamine levels precipitated by an acute physical or emotional stressor [2,3]. Stress-induced cardiomyopathy following subarachnoid hemorrhage (SAH) has been described primarily in case reports and small case series [2,4], but data from larger series are lacking. The aim of this study was to report the incidence and describe the clinical characteristics of patients with non-traumatic SAH and evidence of TCMP. We retrospectively identified consecutive patients who were admitted with non-traumatic SAH to the neurologic intensive care unit of Emory University Hospital in Atlanta, Georgia from 2005 to 2011. The severity of neurologic injury was assessed by the Hunt and Hess (H&H) score [5]. Echocardiograms obtained during the admission were reviewed. The diagnosis of TCMP was made using a modified ver-

⁎ Corresponding author at: Emory University Hospital, 1365 Clifton Rd NE, Suite AT-503, Atlanta, GA 30322, United States. Tel.: +1 404 778-5414; fax: +1 404 778 3540. E-mail address: [email protected] (S. Lerakis).

http://dx.doi.org/10.1016/j.ijcard.2014.07.279 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

sion of the Mayo Clinic Criteria [6], requiring the presence of the following four criteria: [1] reduced LV systolic function, [2] the presence of regional wall motion abnormalities that extended beyond a single epicardial vascular distribution [3], complete recovery of regional wall motion abnormalities on follow-up echocardiogram and [4] the presence of either new ECG abnormalities (e.g. ST-segment elevation, T wave inversion, QT prolongation) or elevation of cardiac biomarkers. Patients with akinesis or hypokinesis of LV apical segments with preserved contractility of the basal segments were considered to have the apical variant of TCMP (apical ballooning), while those with akinesis of the basal segments with preserved contractility of the apex and mid-ventricular segments were classified as having reverse TCMP (non-apical ballooning). Clinical characteristics and laboratory data of those who met the criteria for TCMP were reviewed. The study was approved by the Emory Institutional Review Board. Incidence: A total of 2276 patients were admitted with aneurysmal SAH during the study period. Echocardiograms performed during the index hospitalization were available for 828 (36%) patients. Thirty-one patients had reduced LV ejection fraction with regional wall motion abnormalities extending beyond a single epicardial vascular distribution. Twelve were excluded because they did not have a follow-up echocardiogram. Nineteen patients met all the inclusion criteria, estimating an incidence of post-SAH TCMP of 0.8%. Demographics and outcomes: All patients with TCMP were women, mostly white (14, 74%), with a mean age of 45 ± 11 years. Hypertension (53%) and tobacco use (26%) were common. None had a prior history of CAD. One patient was diabetic and one was hyperlipidemic. The mean duration of the hospital stay was 20.6 days (range 6–62). Five (26%) patients with TCMP died during the hospitalization, compared to 315 (14%) of those who did not develop TCMP (p = 0.2). Subarachnoid hemorrhage and cardiac enzymes: All patients had aneurysmal, non-traumatic SAH. The majority of patients with TCMP had moderate to severe SAH as measured by H&H score; with 11 (58%) having a H&H score of ≥4. All patients with TCMP had elevated peak troponin-I level and peak CK-MB levels (Table 1). Those with an H&H score ≥ 4 were younger (40 ± 10 versus 52 ± 10, p = 0.033), and had significantly higher troponin-I levels (7.3 ± 6.5 versus 2.0 ± 1.4 ng/mL, p = 0.026) compared to those with an H&H b4. The correlation between H&H score and Troponin-I levels was positive (r = 0.413, p = 0.079).

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Table 1 Clinical characteristics of patients with SCMP following aneurysmal subarachnoid hemorrhage.

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18 Patient 19

Age (y) EF on EF on Peak Peak CK-MB Vasopressor admission (%) follow-up (%) troponin-I (ng/mL) use (ng/mL)

Takotsubo Aneurysm location type

H&H Survived score admission

43 32 34 43 61 39 50 24 55 35 42 62 50 37 63 44 55 56 32

Reverse Reverse Apical Apical Apical Reverse Apical Apical Apical Apical Apical Apical Apical Apical Reverse Apical Apical Apical Apical

4 5 4 5 4 4 3 4 4 4 4 3 3 4 3 3 1 3 1

20 20 25 30 40 20 45 15 25 15 20 15 10 30 40 20 35 40 45

60 60 60 60 60 50 50 60 50 55 55 55 55 50 55 65 60 55 55

10.7 12.9 12.8 8.43 0.09 20.6 1.1 1.06 3.3 0.27 3.06 1.42 2.2 6.57 3.7 0.29 0.97 2.55 4.14

20 3 28 14 2 51 20 2 59 4 13 12 14 22 29 2 13 13 33

Yes Yes Yes Not reported Yes Yes Yes Yes Yes No Yes No Yes Yes Yes No No Yes Yes

Right anterior communicating artery Left peri-callosal artery Right posterior communicating artery Supra-clinoidal left ICA Left posterior communicating artery Left internal carotid artery/terminus aneurysm Right posterior communicating artery Right middle cerebral artery Left anterior communicating artery Right middle cerebral artery Basilar artery apex Right posterior communicating artery Left PICA Basilar artery apex Left PICA Right anterior communicating artery Right anterior communicating artery Cerebellar Vasculitis related aneurysm

Yes Yes No No Yes No Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes Yes

EF: left ventricular ejection fraction, CK-MB: creatine kinase-MB, H&H: Hunt&Hess score, SCMP: stress-induced cardiomyopathy.

applied here. While still considerable, the incidence of TCMP reported in both studies likely underestimate the true incidence, since only a third of patients had echocardiograms done. While the demographics and clinical characteristics of patients described here are similar to those reported following non-neurologic stressors, there are notable differences: the patients tended to be younger than what is typically reported and had high in-hospital mortality (25%). Previous studies have reported an in-hospital mortality of approximately 1%. This likely reflects the strong impact of SAH on mortality, rather than the contribution of TCMP to outcomes. The extent to which the development of TCMP in this patient population contributed to the high in-hospital mortality rate remains unclear. Female gender is also a major risk factor for the development of TCMP [3,5]. Previous reports have shown that post-menopausal women appear to be particularly at risk, and is thought to be due to a declining level of estrogen, cardiac vagal tone and baroreflex sensitivity with age [7], leading to enhanced sympathetic response to mental stress and catecholamine release [8–10]. While it may seem paradoxical that 58% of the patients

Electrocardiography: ECGs were available for 16 patients. All patients presented with normal sinus rhythm. The most common ECG abnormality was prolonged QTc (≥ 440 ms) in 14 patients (88%) and Twave inversion, primarily in anterior and anterolateral leads (63%) (Table 2). Echocardiography: All patients with TCMP had an initial transthoracic echocardiogram within 0–8 days (mean 1.8 days) of admission. The mean EF was 26% (range 10–45%). Fifteen patients (79.9%) showed the typical apical ballooning pattern of TCMP, while four patients (21.1%) had the apical sparing reverse Takotsubo pattern (Table 1). Patients with reverse Takotsubo pattern had significantly higher Troponin-I levels compared to those with the typical apical pattern (12.0 ± 7.0 versus 3.2 ± 3.6 ng/mL, p = 0.002). Little is known of the incidence and clinical characteristics of TCMP. The estimated incidence in patients with suspected acute coronary syndrome who underwent left heart catheterization range between 1 and 2.5% [2]. In patients presenting with SAH, one smaller series of 178 patients report an incidence of 4.5% [5], using the same Mayo Clinic criteria

Table 2 Electrocardiographic changes in patients with SAH-associated stress-induced cardiomyopathy. Patient

Rhythm

Heart rate (bpm)

T-wave changes

ST segment changes

QTc (ms)

R-wave progression

Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Patient 7 Patient 8 Patient 9 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15 Patient 16 Patient 17 Patient 18 Patient 19

Sinus Sinus Sinus Sinus Sinus Sinus Sinus

115 119 111 80 90 86 54

None Deep inversion, anterolateral None Inversion, anterior None None Deep inversion, inferolateral

489 475 530 456 481 593 510

Poor Normal Poor Normal Normal Poor Poor

Sinus

99

415

Normal

Sinus Sinus Sinus Sinus Sinus Sinus Sinus Sinus

70 92 61 122 114 72 84 106

None Non-specific None None None None None N/A None N/A N/A Depression, inferior None None Non-specific None None None None

503 457 626 464 424 444 465 587

Poor Poor Normal Normal Poor Normal Normal Normal

Inversion, inferior

Deep inversion, anterolateral None Inversion, inferolateral None Deep inversion, inferolateral Deep inversion, anterolateral Inversion, lateral Inversion, anterior

BPM: beats per minute, RWP: R wave progression, SAH: subarachnoid hemorrhage.

Other changes

Left axis deviation Wide broad T wave

Low voltage

Wide broad T wave

Left bundle branch block

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in the current series were ≤45 years old, this finding, is consistent with a recently proposed paradigm suggesting that the degree of sympathetic stimulation required to precipitate myocardial dysfunction is inversely related to the number of individual risk factors [6]. Thus, patients without predisposing risk factors likely require significant adrenergic stimulation – such as that induced by a neurologic catastrophy – to precipitate LV dysfunction, while those with estrogen deficiency or endothelial dysfunction may develop dysfunction with lesser stressors. This study represents the largest case series to date of TCMP following SAH, and several conclusions can be drawn from the findings: TCMP is not a rare complication of aneurysmal SAH and occurs in at least 1% of patients; its occurrence correlates with the severity of neurologic injury; and younger White women represent the majority of affected patients.

Conflict of interest There are no conflicts of interest to disclose.

Acknowledgments None.

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