Cardiac Rupture in Takotsubo Cardiomyopathy: A Systematic Review

Abstract

Background:

Takotsubo cardiomyopathy (TSC) and its complications, such as cardiac rupture (CR), are increasingly being reported in the literature. CR is associated with rapid clinical decline and is uniformly fatal if not surgically repaired. To identify patients who developed CR we performed an analysis of all available indexed cases in the literature and compared them with a control group of patients with TSC without rupture.

Hypothesis:

Takotsubo cardiomyopathy patients with cardiac rupture do not differ significantly from those without rupture.

Methods:

MEDLINE (2009) was searched for all TSC case reports with CR. Eleven case reports were identified. Using a random sampling method, we selected 12 case reports of TSC without rupture (control). We included our patient with TSC with rupture as the 12th case of TSC cohort with CR (CR group). Demographic and clinical characteristics were compared between CR group and control.

Results:

All patients in the TSC group with rupture were female and were significantly older than controls. TSC group with rupture had significantly higher frequency of ST elevation in lead II and absence of T‐wave inversion in lead V5 on hospital admission than controls. Mean ejection fraction, systolic blood pressure, and double product, a measure of oxygen demand, was significantly higher in the rupture group compared to controls. The CR group was associated with less frequent use of β‐blocker as compared to controls.

Conclusions:

CR as a complication of TSC could be more common than recognized. Higher double product and ejection fraction suggest higher fluctuation of intracardiac pressure and may cause CR in TSC. Use of β blockers in TSC may provide protection against CR. © 2011 Wiley Periodicals, Inc.

The authors have no funding, financial relationships, or conflicts of interest to disclose.

Introduction

Takotsubo cardiomyopathy (TSC) is a condition characterized by transient left ventricular apical ballooning, electrocardiographic changes, and mild elevation in cardiac biomarkers without evidence of occlusive coronary artery disease. The clinical outcome in these patients is usually good, but cardiogenic shock, life‐threatening arrhythmias, and cardiac rupture (CR) have been reported.1, 2, 3 CR remains often a fatal illness unless recognized expeditiously and repaired surgically. However, the underlying mechanism of CR in TSC is not well understood. We performed a systematic review of available literature and compared the clinical characteristics of patients who ultimately ruptured with a control group of patients with TSC without rupture.

Methods

Ovid MEDLINE (1950–2009) was searched for case reports with search terms “Takotsubo cardiomyopathy,” “Takotsubo syndrome,” “stress cardiomyopathy,” “ampullary cardiomyopathy,” and “broken heart syndrome.” A total of 375 case reports were identified with “human” and “English” as limits. Eleven case reports of TSC were identified with CR. All case reports were published during the years 2004 to 2009. To obtain a control group for comparison we searched MEDLINE for case reports with the same search terms spanning 2004 to 2009. We chose a random sampling method using a random number generator to select case reports. If the article matching the random number was not a case report, we looked for successively higher‐numbered articles until a case report was found. This method gave each case report equal probability of being selected as a control. Twelve cases of TSC where patients did not have rupture were chosen as the nonrupture group (control). We had 12 cases (including our patient) of TSC with CR (CR group) and 12 cases of TSC without rupture (control). Clinical parameters were compared between the 2 groups (CR vs control). When data was missing, we contacted the authors from both groups via email or direct mail for missing data. In 13 instances new information was provided and used in the analysis.

Demographic and clinical variables of the 2 groups were analyzed using SPSS version 13.0 (SPSS, Inc., Chicago, IL). Data was expressed as mean ± standard deviation. Continuous variables were compared using the Student t test, and categorical variables were compared using the Pearson χ ² test. Double product was calculated as systolic blood pressure (BP) multiplied by heart rate. Left ventricular (LV) peak systolic pressure was estimated by the addition of LV gradient and systolic BP.

Results

The CR group was entirely female with an average age of 76 ± 9 years. Mean presentation to CR duration was 74 ± 70 hours. Ten out of 12 CR patients (83%) died. Fifty percent (5) of the deaths occurred before 48 hours, and 90% of deaths occurred within 187 hours (approximately 8 days). Rupture was confirmed on autopsy in 5, diagnosed by catheterization in 2, and suspected by echocardiography in 5 patients. Out of the 12 reported cases, 2 had ventricular septum, 2 had right ventricular wall, and 7 had LV free wall rupture. Authors for the remaining case did not report the site of rupture. The location of rupture was reported to be LV apex in 2, anterior wall in 1, posterior wall in 1, and apico‐posterior wall in 1 patient.

The CR group was significantly older than the control group (76 years vs 60 years, P = 0.01). Presenting symptoms (dyspnea or chest pain) were similar between the 2 groups. Peak creatine phosphokinase (CPK) and troponin I were higher in the rupture group than in controls, but reached statistical significance only for CPK (461 IU/L vs 247 IU/L, P = 0.04 [approximately 4.0‐vs 1.6‐fold upper limit of normal]). The CR group had significantly higher frequency of ST elevation in inferior leads (especially lead II) and absence of T‐wave inversion in lateral lead (especially V5) compared to control. Fifty percent of the patients in rupture group had persistence of ST elevation until the event (P = 0.005) (Table 1).

Table 1.

Comparison of Variables Between Cardiac Rupture Group and Control.

Parameters	CR Group, Mean ± SD (No.)	Control, Mean ± SD (No.)	Significance, P value (α = 0.05)
Demography
Age, y	76 ± 9 (12)	60 ± 16 (12)	0.01
Asian, %	72 ± 46 (11)	25 ± 45 (10)	0.02
Presentation
Emotional stress, %	33 ± 49 (12)	25 ± 45 (12)	0.67
Dyspnea, %	33 ± 49 (12)	33 ± 49 (12)	1.00
Chest pain, %	66 ± 49 (12)	42 ± 51 (12)	0.23
Laboratory
Peak, CPKIU/L	461 ± 256 (9)	247 ± 99 (6)	0.04
Peak troponin I, µg/L	7.6 ± 8 (4)	3.6 ± 6 (7)	0.43
Admission ECG, %
ST elevation in inferior lead II	50 ± 52 (12)	0 ± 0 (12)	0.003
T‐wave inversion in lateral lead V5	0 ± 0 (12)	50 ± 52 (12)	0.003
Persistent ST elevation	50 ± 51 (12)	0 ± 0 (11)	0.005
Medications use, %
β‐blockers	36 ± 50 (11)	86 ± 37 (7)	0.03
Cardiac hemodynamic variable
SBP, mm Hg	135 ± 21 (8)	105 ± 27 (6)	0.04
DBP, mm Hg	80 ± 9.6 (8)	62 ± 17 (6)	0.03
HR, beats/min	87 ± 17 (7)	78 ± 23 (6)	0.46
Mean arterial pressure, mm Hg	98 ± 12 (8)	76 ± 199 (6)	0.02
Double product (SBP*HR), mm Hg, beats/min	11676 ± 2846 (8)	7966 ± 2387 (5)	0.03
EF on admission, %	38 ± 8 (7)	27 ± 7 (9)	0.03
LVOT gradient, mm Hg	25 ± 40 (7)	4.2 ± 10 (6)	0.24
Peak LV systolic pressure (SBP + LVOT gradient), mm Hg	151 ± 41 (7)	109 ± 23 (6)	0.03

Abbreviations: CPK, creatine phosphokinase; CR, cardiac rupture; DBP, diastolic blood pressure; ECG, electrocardiogram; EF, ejection fraction; HR, heart rate; LV, left ventricle; LVOT, left ventricular outflow tract; SBP, systolic blood pressure; SD, standard deviation.

There were also significant differences in several hemodynamic parameters. The CR group had higher BP, double product, and LV ejection fraction (EF) as compared to the control group. Additionally, LV peak systolic BP was higher for the CR group than for control (151 mm Hg vs 109 mm Hg, P = 0.03) (Table 1).

Discussion

All patients in CR group were female. Females typically contribute upto 93% of the TSC cohort.4 Possible explanations have included postmenopausal state, and smaller LV chamber and outflow tract.5, 6 The CR group was almost 15 years older than the control group. Among all 24 patients, age was not correlated with either systolic or diastolic BP but showed a trend towards correlation with double product (r = 0.54, P = 0.06). A more definitive explanation of role of age in TSC remains to be investigated. CR was more frequent in Asians (72% vs 25%, P = 0.02) but is likely due to reporting bias.

ST elevation and T‐wave inversion in TSC are known to be transient,7 with higher voltage ST elevations in V4–V6 than in V1–V3 because of predominant apical involvement.8 In the TSC rupture group, ST elevations were more frequent in the inferior leads, and T‐wave inversion was less frequent in the lateral leads as compared to the control group. Persistent ST elevations were more common in the CR group than in the control group (50% vs 0%, P = 0.005), and it has been suggested that persistent ST elevation in TSC may be a harbinger of rupture.9 In the CR group, ST elevations were usually noted in inferior, high lateral, and precordial leads (Table 2).

Table 2.

Brief Description of Cardiac Rupture Cases in Takotsubo Cardiomyopathy

Study	Age (y)	Initial Complaint	Initial EKG Features	Initial Echo Finding	Cardiac Catheterization Finding	Last Echo Finding
Akashi 200418	70	CD	SR, STE in lead I, II, III, aVL, aVF, V2–V6	TSC‐ like contraction, no LVOT gradient	Normal CA with TIMI 3 flow, TSC like contraction, EF 51%	PE
Ishida 200515	67	CP	STE in lead I, aVL and V2–V5 without reciprocal ST depression	Apical ballooning LVOT gradient 110 mm Hg	Extensive akinesis from apex to mid portion, TSC‐ like contraction	PE, compressed right atrium
Izumi 200810	79	CP and dyspnea	STE in V2–V5	25 × 12 mm VSD	Normal CA, TSC‐like contraction	Repaired VSD, LV wall motion normal
Ieva 200916	65	CP and dyspnea	SR and STE in the anterior leads	Extensive akinesis from the mid to apical LV and a basal hyperkinesis with 30% ejection fraction	No significant CA stenosis, apical ballooning	PE with collapse of the right heart chambers, suggesting cardiac tamponade
Mafrici 20061	87	CP and dyspnea	STE in inferior and V2–V6	TSC‐like contraction	No significant CA stenois, TSC‐like contraction	Massive PE with collapse of right and left heart chambers, cardiac tamponade, LV free wall rupture
Ohara 20052	79	CP	STE in I, aVL, V1–V5, depression III, and aVF, abnormal Q in V1–V4	Akinesis of LV apical wall	No stenotic CA lesion, TSC‐like contraction, EF 31%	PE
Our Case	62	Dizziness	STE in I, II, V5–V6	Akinesis of mid to distal ventricle, EF 35%, LVOT gradient 70 mm Hg	Noncritical lesion in LAD, TSC‐like contraction	Not done
Sacha 200711	81	CD	STE in precordial and limb leads	Not done	No significant CA stenosis, TSC‐like contraction, no LVOT gradient	Not done
Sakai 200519	84	Anorexia	STE in II, III, aVF and V3–5, abnormal Q waves in II, III, aVF and V1–V4 with RBBB	Apical asynergy, ventriculo septal perforation	No significant CA stenosis, TSC‐like contraction	Not done
Shinozaki 200720	90	CD	STE in I, aVL, V1–V4	TSC‐like contraction	Intact CA	Cardiac tamponade due to LV free wall rupture
Stollberger 20099	71	Seizure	STE in II,III, aVF, V5–V6	Akinesia of LV apex, apical septum, apical posterior wall, MR	Not done	PE
Yamada 200621	71	Shoulder and back pain	SR with ST‐segment elevation in leads V4–6 and abnormal Q waves in leads V4–5	TSC‐like contraction	No CA stenosis, TSC‐like contraction	Anechoic zone around the heart, suggesting PE due to cardiac rupture

Abbreviations: CA, coronary artery; CD, chest discomfort; CP, chest pain; EF, ejection fraction; LV, left ventricle; LVOT, left ventricular outflow tract; MR, Mitral Regurgitation; PE, pericardial effusion; RBBB, right bundle branch block; SR, sinus rhythm; STE, ST‐segment elevation; TIMI, thrombolysis in myocardial infarction; TSC, takotsubo cardiomyopathy; VSD, ventricular septal defect; LAD, Left Anterior Descending artery.

Pathology findings at the rupture site were reported in 4 TSC cases. Izumi et al.10 found new myocardial infarction and loss of nuclei at the rupture site. Ohara et al.2 discovered the presence of inflammatory infiltrates and myocytic necrosis. Sacha et al.11 reported that transmyocardial myocardial necrosis with hemorrhage, mononulcear lymphocytic infiltrations, fused foci of coagulation necrosis, and contraction band necrosis were noticed at the rupture site. In our case, the rupture site demonstrated necrotic fibers exhibiting increased eosinophilic staining, loss of cross striations (contraction band necrosis), along with PMN neutrophilic infiltration. Surrounding the tear, diffuse patchy infarction of myocardial fibers were seen as well. These histopathology findings, including the contraction bands seen in 2 cases, besides being seen in high catecholamine states, can also be seen after myocardial infarction.12 These pathology findings imply a prolonged or irreversible process leading to necrosis and CR, possibly due to demand ischemia driven by high adrenergic state and/or intracardiac gradient. However, TSC is typically a transient condition, and therefore it is difficult to conclusively implicate acute myocardial infarction (AMI) as the etiology of rupture in TSC.

The TSC rupture group had higher systolic BP, diastolic BP, higher double products, and LV ejection fractions. These findings may signify that CR may be related to higher LV intramural pressure and wall stress. Of note, the finding of higher EF in the TSC rupture group is in contrast to rupture in AMI, which is often associated with larger infarct size and likely lower EF.13 Higher LV EF in the CR group is probably associated with higher fluctuation (amplitude) of intracardiac pressure. LV outflow tract (LVOT) gradient can cause increased LV wall stress. In 1 study, up to 18% of TSC cases demonstrated outflow tract obstruction in the acute phase.14 Our patient had gradient up to 70 mm Hg. LVOT gradients were available for 7 TSC rupture patients and for 6 controls. Three patients in CR group and 1 in the control group had elevated LVOT gradient (125 mm Hg, Ishida et al.15 13 mm Hg in Ieva et al.16 70 mm Hg in our case, and 25 mm Hg in Metzl et al.17 A 2‐way tabulation suggests rupture to be frequent, up to 75% in patients with gradient compared to 44% in patients without gradient (P = 0.31).

The CR group was less frequently treated with β‐blockers than controls. Although the role of β‐blockers in CR due to acute myocardial infarction is well proven, its role in treating TSC is not well defined. Nef et al have suggested that β‐blocker may prevent TSC recurrence and fatal outcome.3 TSC is associated with plasma catecholamine elevation.5 Catecholamines can cause preferential toxicity of the cardiac apex, making it balloon out and allow basal segments to contract vigorously.4 The hypercontractile base can create LVOT gradient and oxygen mismatch.4 The present findings suggest that β‐blockers may be useful in TSC patients, particularly if they have an elevated LVOT gradient. In this setting, β‐blockers plus peripheral vasoconstrictors may be better than direct inotropic vasopressors in correcting hypotension.

Limitations

There are several limitations of our systematic review. The numbers are relatively small and power is therefore limited. Although a random sampling method was used to generate nonrupture controls, publication bias may be present. Contraindications to β‐blockers could not be assessed. Also, data points were obtained by reviewing the literature; partial reporting or absence of simultaneous measurement could increase the margin of error.

Conclusion

CR is a rare but important complication of TSC. In this study, risk factors for rupture in TSC patients are female gender; older age; persistent ST elevation; higher systolic BP, diastolic BP, and EF; double product; and LV peak systolic pressure. These hemodynamic findings in CR patients suggest that higher intracardiac pressures predispose TSC patients to CR. Based on this, we speculate that the use of β‐blockers in TSC may provide protection against CR.