Clinical Impact of Left Ventricular Outflow Tract Obstruction in Takotsubo Cardiomyopathy

Abstract

Background: A hyperdynamic state of the basal left ventricle sometimes results in obstruction of the left ventricular outflow tract (LVOT). However, the prevalence, clinical presentation, and prognostic effect of LVOT obstruction in takotsubo cardiomyopathy (TC) have not been fully evaluated.

Methods and Results: Among 933 consecutive patients who underwent emergency coronary angiography for suspected acute coronary syndrome, 35 patients (3.8%) were diagnosed as TC. The cumulative 3-year incidence of all-cause death, cardiac death, hospitalization for congestive heart failure (CHF), and recurrent TC was 24.2%, 0.0%, 6.5%, and 12.2%, respectively. Among 27 patients with information of a LVOT pressure gradient, LVOT obstruction was present in 9 (33%). The prevalence of moderate to severe mitral regurgitation (67% vs. 11%, P=0.003), CHF (78% vs. 28%, P=0.02), and hypotension (56% vs. 5.6%, P=0.008) was significantly higher in patients with LVOT obstruction than in those without. Nevertheless, the cumulative 3-year incidence of all-cause death was not significantly different between the 2 groups (49.2% vs. 23.0%, P=0.22) with no cardiac deaths in either group. Hospitalization for CHF and recurrent TC were significantly more frequent in patients with LVOT obstruction (25.0% vs. 0.0%, P=0.04, and 25.0% vs. 6.7%, P=0.02).

Conclusions: In 35 consecutive patients with TC, those with significant LVOT obstruction (33%) had a more serious clinical presentation such as CHF and hypotension, but had similar 3-year mortality rate as compared with those without. (Circ J 2015; 79: 839–846)

Takotsubo cardiomyopathy (TC), also called apical ballooning syndrome or stress-induced cardiomyopathy, is characterized by transient systolic left ventricular (LV) dysfunction and abnormal ECG mimicking acute coronary syndrome (ACS).^1–3 The prognosis of TC is reported to be favorable as compared with ACS and most patients recover without specific medical care.⁴ However, the pathophysiology of TC has not been fully elucidated. Several types of TC are distinguished by the location of the LV dysfunction (ie, apical, midventricular and global types).⁵ In the case of apical TC, a hyperdynamic state of the basal segment of the LV sometimes results in obstruction of the LV outflow tract (LVOT).^6–9 In some cases, LVOT obstruction induces mitral regurgitation (MR) and pulmonary edema. However, the prevalence, clinical presentation, and prognostic implications of LVOT obstruction in patients with TC have not been fully evaluated. The aim of the current single-center study was to elucidate the clinical characteristics of TC with LVOT obstruction.

Editorial p 758

Methods

Study Population

Between August 2004 and August 2013, 933 consecutive patients underwent emergency angiography for suspected ACS in Kyoto University Hospital. Based on coronary angiography and left ventriculography (LVG), 35 patients (3.8%) were diagnosed as having TC, excluding 702 true ACS patients with significant coronary stenosis, and 196 patients without significant coronary stenosis or LV systolic dysfunction (Figure 1). LVG was performed after elimination of significant coronary artery stenosis, and the LVOT pressure gradient was evaluated by pullback of the pigtail catheter from the LV apex to aorta after LVG. However, we either did not measure the pressure gradient or lost the data for 8 patients. Therefore, in the current study, we analyzed the characteristics of TC in 35 consecutive patients, but focused on the prevalence, clinical presentation and prognostic effect of LVOT obstruction in 27 patients.

Figure 1.

Study flow chart. ACS, acute coronary syndrome; LVOT, left ventricular outflow tract.

Definitions and Endpoints

TC was defined according to the Mayo Clinic diagnosis criteria as clinical consensus: (1) new ST-segment elevation and/or T-wave inversion on 12-lead ECG, (2) transient systolic dysfunction with segmental hypokinesis, dyskinesis and akinesis of the LV detected by LVG, and (3) no significant coronary artery stenosis on coronary angiography.^1,10,11 LVOT obstruction was defined as LVOT peak-to-peak pressure gradient >20 mmHg.^7,12

Demographic and angiographic data were collected from hospital charts according to prespecified definitions. Follow-up information was obtained by hospital-chart review and/or telephone contact with the patient, relatives, or referring practitioner. The mean clinical follow-up period was 4.7±2.0 years.

The outcome measures evaluated in this study included all-cause death, cardiac death, hospitalization for congestive heart failure (CHF), myocardial infarction (MI), stroke, and recurrent TC. Death was regarded as cardiac in origin unless an obvious non-cardiac cause could be identified. MI was defined according to the definition in the Arterial Revascularization Therapy Study.¹³ Stroke during follow-up was defined as ischemic or hemorrhagic stroke requiring hospitalization with symptoms lasting >24 h. Recurrent TC was diagnosed by transient angiographic or echocardiographic LV dysfunction with characteristic ECG changes.

Statistical Analysis

Continuous variables are presented as mean±standard deviation (SD) or median with interquartile range (IQR), and were compared using the Student’s t-test or Wilcoxon rank sum test based on their distributions. Categorical variables are presented as number and percentage and were compared with the chi-square and Fisher’s exact tests. We used the Kaplan-Meier method to estimate the cumulative incidences of clinical events and assessed the differences with the log-rank test. Statistical analyses were performed using JMP 10 (SAS Institute Inc, Cary, NC, USA) software. All the analyses were 2-tailed, and P<0.05 was considered statistically significant.

Results

Clinical Characteristics

The current study population mainly consisted of elderly patients (median age: 76 years) and was predominantly female (83%) (Table 1). Nearly half of the patients developed TC during hospitalization and half of those were postoperative. Obvious emotional and/or physical stress, which could be attributed as the trigger of TC, was detected in 29 patients (83%) (Table S1). Chest pain was the initial clinical presentation in 23 patients (66%). The prevalence of CHF, defined as New York Heart Association (NYHA) class ≥3 degree or pulmonary capillary wedge pressure ≥18 mmHg, was 40% at onset and 7 patients presented with hypotension (systolic blood pressure ≤90 mmHg). Hemodynamic mechanical support devices such as intra-aortic balloon pumping (IABP) and/or percutaneous cardiopulmonary support were used in 2 patients. Troponin T and H-FABP levels were positive in most patients, although the quantitative value of troponin T was 0.3ng/dl and maximum creatine kinase was only 158 IU/L. Mean LV ejection fraction (LVEF) was 51% and moderate to severe MR, defined as Sellers ≥3 degree, was observed in 11 patients (33%) at initial presentation (Table 1). In the current study, the midventricular type of TC, which spared the apex as the location of LV dyskinesis on LVG, was observed in 5 patients (14%).

Table 1. Baseline Characteristics, Clinical Presentation, Laboratory Findings, and Catheterization Findings of Patients Diagnosed as TC

Variable	All patients (n=35)	With LVOT obstruction (n=9)	Without LVOT obstruction (n=18)	P value
Baseline characteristics
Age (years)	76 (69–82)	72 (67–83)	73 (69–90)	0.54
≥75 years	18 (51%)	3 (33%)	8 (44%)	0.69
Male	6 (17%)	1 (11%)	5 (28%)	0.32
Hypertension	15 (43%)	1 (11%)	8 (44%)	0.09
Dyslipidemia	12 (34%)	1 (11%)	8 (44%)	0.09
Diabetes mellitus	8 (23%)	2 (22%)	3 (17%)	0.55
Current smoking	1 (2.9%)	1 (11%)	0 (0.0%)	0.33
Emotional/physical stress	29 (83%)	6 (67%)	17 (94%)	0.09
Onset in hospital	17 (49%)	4 (44%)	11 (61%)	0.34
Postoperative	8 (23%)	3 (33%)	5 (28%)	0.55
Hemodialysis	1 (2.9%)	0 (0.0%)	0 (0.0%)	1.0
Malignancy	11 (31%)	4 (44%)	4 (22%)	0.23
Atrial fibrillation	3 (8.6%)	2 (22%)	1 (5.6%)	0.25
Clinical presentation
Chest pain	23 (66%)	7 (78%)	9 (50%)	0.17
Heart rate (beats/min)	89 (75–106)	89 (76–96)	93 (78–111)	0.68
Systolic blood pressure	126±33	95±9	136±6	0.0007
≤90 mmHg	7 (20%)	5 (56%)	1 (5.6%)	0.008
Support by IABP/PCPS	2 (5.7%)	2 (22%)	0 (0.0%)	0.10
CHF	14 (40%)	7 (78%)	5 (28%)	0.02
Laboratory findings
WBC (/μL)	9,690±6,240	10,989±2,014	9,406±1,424	0.53
Hemoglobin ≤11 g/dl	11 (31%)	1 (11%)	6 (33%)	0.22
CRP (mg/dl)	0.9 (0.05–6)	0.3 (0.05–8.7)	1.2 (0.05–13.8)	0.29
Maximum CK value (IU/L)	158 (109–399)	324 (109–848)	261 (129–538)	0.66
≥1,000 IU/L	4 (11%)	2 (22%)	2 (11%)	0.67
Positive troponin T	25 (76%) (n=33)	7 (78%)	13 (76%) (n=17)	0.67
Troponin T (ng/ml)	0.3 (0.03–0.6) (n=31)	0.4 (0.1–0.9)	0.3 (0.06–0.7) (n=17)	0.64
Positive H-FABP	25 (78%) (n=32)	7 (78%)	13 (76%) (n=16)	0.94
hBNP (pg/ml)	318 (120–571) (n=30)	123 (654–497) (n=6)	336 (169–624) (n=16)	0.30
Catheterization data
Types of LV dyskinesis
Apical (typical) type	30 (86%)	9 (100%)	14 (78%)	0.17
Midventricular type	5 (14%)	0 (0.0%)	4 (22%)	0.17
Ejection fraction by LVG (%)	51 (42–57)	50 (47–53)	50 (34–59)	0.86
≤40%	8 (23%)	1 (11%)	6 (33%)	0.22
Moderate to severe MR	11 (31%)	6 (67%)	2 (11%)	0.003
LVOT peak gradient	13 (4–50) (n=27)	54 (50–100)	7.5 (4–13)	<0.001

Data are presented as number of patients (prevalence). Continuous variables are presented as mean±SD. CK, creatine kinase; CRP, C-reactive protein; hBNP, human B-type natriuretic polypeptide; H-FABP, heart type fatty acid-binding protein; IABP, intra-aortic balloon pumping; LV, left ventricular; LVDd, LV dimension diastolic; LVDs, LV dimension systolic; LVG, left ventriculography; LVOT, LV outflow tract; MR, mitral regurgitation; PCPS, percutaneous cardiopulmonary support; TC, takotsubo cardiomyopathy; WBC, white blood cells.

All the patients were discharged alive. An episode of torsades de pointes occurred in 1 patient who was treated with inotropic agents for low cardiac output state on day 2. Recovery of both ST-T changes on ECG and LV systolic dysfunction on echocardiography was generally seen after 1 week. Mean LVEF by echocardiography before hospital discharge was 69±13% (n=29).

Regarding the long-term outcome, the cumulative incidence of all-cause death was 0.0% at 30 days, 8.6% at 1 year, and 24.2% at 3 years, and there were no cases of cardiac death during the 3-year follow-up (Figure 2). The cumulative 3-year incidence of hospitalization for CHF was 6.5%, there were no MI events and only 1 ischemic stroke event on day 7 (Table 2). The cumulative incidence of recurrent TC was 2.9% at 30 days, 8.9% at 1 year, and 12.2% at 3 years.

Figure 2.

Kaplan-Meier curves of all 35 patients with takotsubo cardiomyopathy (TC) for (A) all-cause death and cardiac death, (B) hospitalization for congestive heart failure, and (C) recurrent TC.

Table 2. Clinical Outcomes at 3 Years of Patients Diagnosed as TC

	All patients (n=35)	With LVOT obstruction (n=9)	Without LVOT obstruction (n=18)	P value
All-cause death (%)	8 (24.2)	4 (49.2)	4 (23.0)	0.22
Cardiac death	0 (0.0)	0 (0.0)	0 (0.0)	–
Hospitalization for CHF (%)	2 (6.5)	2 (25.0)	0 (0.0)	0.042
Myocardial infarction (%)	0 (0.0)	0 (0.0)	0 (0.0)	–
Stroke (%)	1 (2.9)	0 (0.0)	0 (0.0)	–
Recurrent TC (%)	4 (12.2)	2 (25.0)	1 (6.7)	0.02

Data are presented as number of patients with event (cumulative incidence). Abbreviations as in Table 1.

Effect of LVOT Obstruction

Among the 27 TC patients who had LVOT pressure gradient data, significant LVOT obstruction was observed in 9 patients (33%). LVOT obstruction is a temporary complication and relief of LVOT obstruction was confirmed by echocardiography or catheterization during follow-up in all the patients with LVOT obstruction.

There were no significant differences in most baseline characteristics, including echocardiographic findings and medications, between TC patients with or without LVOT obstruction (Tables 1,3). However, the prevalences of moderate to severe MR (67% vs. 11%, P=0.003), CHF (78% vs. 28%, P=0.01), and hypotension (56% vs. 5.6%, P=0.004) were significantly higher in patients with LVOT obstruction than in patients without.

Table 3. Medications: Taken by Patients Diagnosed as TC

Variable	All patients (n=35)	With LVOT obstruction (n=9)	Without LVOT obstruction (n=18)	P value
Medications at presentation (%)
Aspirin	5 (14)	1 (11)	3 (17)	0.59
Statin	8 (23)	2 (22)	5 (28)	0.57
β-blocker	1 (2.9)	0 (0.0)	0 (0.0)	–
ACEI/ARB	3 (8.6)	2 (22)	1 (5.6)	0.25
Warfarin	2 (5.7)	1 (11)	0 (0.0)	0.33
Medications at discharge (%)
Aspirin	13 (37)	3 (33)	7 (39)	0.56
Statin	14 (40)	2 (22)	9 (50)	0.17
β-blocker	8 (23)	3 (33)	3 (17)	0.30
ACEI/ARB	11 (32)	2 (22)	8 (44)	0.24
Warfarin	4 (11)	2 (22)	2 (11)	0.41

Data are presented as number of patients (prevalence). Continuous variables are presented as mean±SD. ACEI/ARB, angiotensin-converting enzyme inhibitor/angiotensin-receptor blocker. Other abbreviations as in Table 1.

The cumulative 3-year incidence of all-cause death was not significantly different between the 2 groups (49.2% vs. 23.0%, P=0.22) with no cardiac deaths in either group. The cumulative 3-year incidences of hospitalization for CHF and recurrent TC were significantly higher in patients with LVOT obstruction than in those without (25.0% vs. 0.0%, P=0.042, and 25.0% vs. 6.7%, P=0.02, respectively) (Figure 3, Table 2). Of the 2 patients who developed recurrent TC after a first episode of TC with LVOT obstruction, the obstruction occurred in 1 patient without β-blocker use at the time of recurrent TC and did not occur in the other patient who was taking a β-blocker. After a first episode of TC without LVOT obstruction, 1 patient without β-blocker use developed recurrent TC without LVOT obstruction.

Figure 3.

Kaplan-Meier curves of takotsubo cardiomyopathy (TC) patients with and without LVOT obstruction for (A) all-cause death and cardiac death, (B) hospitalization for congestive heart failure, and (C) recurrent TC. LVOT, left ventricular outflow tract.

Discussion

The main findings of the current study are: (1) the long-term outcome of 35 consecutive patients with TC was generally favorable, with no cardiac deaths during 3-year follow-up; (2) significant LVOT obstruction was documented in 33% of patients and was associated with a more severe clinical presentation such as CHF and hypotension; and (3) patients with significant LVOT obstruction as compared with those without had significantly higher cumulative 3-year incidence of hospitalization for CHF and recurrent TC without any difference in 3-year mortality.

TC mimics ACS, presenting as transient LV dysfunction and ST-T changes on ECG.^1–3 The prevalence of TC has been reported as 0.8–2.2% among patients suspected of ACS, and was 3.8% among 933 patients undergoing emergency angiography for suspected ACS in the current study.^6,7,14 The higher prevalence in our study might at least partly be related to the hospital being a generic university hospital with a high prevalence of patients with malignancy and/or postoperative. Indeed, half of the current study population developed TC during hospitalization.

The prognosis of TC patients was favorable with no cardiac deaths during 3-year follow-up, which could be explained by the relatively limited myocardial damage as indicated by the small increases in troponin T and creatine kinase despite the presence of significant LV systolic dysfunction at the initial presentation. The LV systolic dysfunction gradually recovered during the index hospitalization in most patients, although it induced CHF in some patients. In previous reports, CHF occurred in 3–46%, which was consistent with the 40% in the current study.^4,15 Serious ventricular arrhythmia such as torsades de pointes occurred in only 1 patient with inotropic agent use. Because fatal arrhythmia is known to occur in 1.5–6% of cases of TC, we systematically monitored the ECG during hospitalization.^4,14,16,17 Ischemic stroke occurred in 1 patient not taking anticoagulation therapy, a decision that was left to the discretion of the attending physician. The prevalence of ischemic stroke in TC has not been reported in detail. Some case reports show apical thrombus formation before systemic embolization and 1 review of consecutive 569 acute ischemic stroke patients included 7 patients diagnosed as having TC at the time of presentation.^4,18–20 We could not distinguish whether TC might have had been the cause or the result of acute ischemic stroke in that review, but ischemic stroke might not be rare in TC patients. In the current study, the cumulative incidence of recurrent TC gradually increased during the first year and reached 12.2% at 3 years, which seemed to be consistent with previous reports.^1,4,15,16

LVOT obstruction is commonly induced by typical septal hypertrophy of the LV in patients with hypertrophic obstructive cardiomyopathy, but the LVOT obstruction seen in patients with TC is considered to be related to a hyperdynamic state of the basal segment of the LV.²¹ In the current study, LVOT obstruction occurred in 33% of patients, which was consistent with a prevalence of 13–50% in previous reports.^{7,10,12,15,22} Relief of LVOT obstruction was confirmed by echocardiography or catheterization during follow-up in all the patients with LVOT obstruction. This condition has been known as latent LVOT obstruction and dobutamine-stress echocardiography is useful for detecting latent LVOT obstruction without LV hypertrophy.²³ In the current study, we could not identify any baseline characteristics predisposing to the occurrence of LVOT obstruction. Previous reports have suggested relative posterior wall thickening, small end-systolic LVOT diameter, and short end-diastolic mitral leaflet tethering distance on echocardiography at rest as predictors of positive dobutamine-stress echocardiography for latent LVOT obstruction,^23–25 but we could not find this echocardiographic characteristic in patients with LVOT obstruction.

LVOT obstruction is known to induce systolic anterior motion of the anterior mitral leaflet and subsequent significant MR with or without pulmonary edema.^7,12 In the current study, significant MR and CHF were more frequent in patients with LVOT obstruction. Furthermore, significant hypotension and use of hemodynamic support by mechanical devices were more frequent in patients with LVOT obstruction. Despite their more serious clinical presentation, patients with LVOT obstruction as compared with those without had a similar degree of cardiac enzyme elevation and similar 3-year mortality with no cardiac mortality, suggesting that significant LVOT obstruction temporarily influenced the hemodynamic status at the initial presentation of TC but did not cause extensive myocardial damage. Hypotension was either caused by low output with severe LV systolic dysfunction and/or LVOT obstruction. It might be important to note that the use of inotropic agents and IABP might exacerbate hypotension and are contraindicated in patients with significant LVOT obstruction.²⁶ Significant LVOT obstruction needs to be managed by fluid administration and β-blockers to increase the end-diastolic volume and ameliorate the hyperdynamic state of the LV.^27,28 It is crucially important to discriminate LVOT obstruction from LV systolic dysfunction as the primary cause of hypotension. In the current series of patients with TC, a β-blocker was effective in a patient with LVOT obstruction complicated by cardiogenic shock (Figure 4). Furthermore, it was interesting that β-blockers prevented recurrent LVOT obstruction with TC in the current study. These findings might suggest the utility of β-blockers for TC patients with LVOT obstruction, warranting further study with a larger number of patients.

Figure 4.

Case of takotsubo cardiomyopathy (TC) with LVOT obstruction in a previously healthy 77-year-old woman who presented with chest pain and nausea. At hospital admission, her blood pressure was 64/46 mmHg with a systolic ejection murmur. Initial ECG showed extensive ST-segment transition and chest X-ray revealed pulmonary edema (A-1,B). She was diagnosed as having TC by coronary angiography and left ventriculography, which demonstrated normal coronary arteries, and apical ballooning with severe LVOT obstruction (pressure gradient: 96 mmHg) (C,D). Although she underwent intra-aortic balloon pumping for suspected cardiogenic shock with acute coronary syndrome, her blood pressure remained unstable and she received a percutaneous cardiopulmonary support device for hemodynamic support. Negative T wave in the precordial leads appeared the next day and lasted for 4 days (A-2). She was withdrawn from the mechanical support on day 3. Relief of LVOT obstruction by landiolol, a short-acting β-blocker, was confirmed by cardiac catheterization on day 4 and β-blocker therapy was started (E). Left ventricular wall motion gradually recovered without LVOT obstruction. No cardiac events occurred up to 2 years after the onset of TC. LVOT, left ventricular outflow tract.

The pathophysiologic mechanisms of TC are not fully established, but it is reported that plasma catecholamine levels at the time of presentation are remarkably high, induced by the preceding emotional or physical stress.^29–32 The proposed mechanism by which the elevated catecholamines precipitate LV dysfunction is unknown. The possible mechanisms include endothelial damage, microvascular dysfunction, multivessel epicardial or microvascular coronary spasm, and catecholamine-mediated myocardial stunning.^2,27–30,33 In the most reliable hypothesis of catecholamine-mediated myocardial stunning, elevated catecholamines, especially epinephrine, switch β-adrenergic receptors from stimulatory G protein to inhibitory G protein.^30,31 The difference in the distribution of the adrenergic receptors between the base vs. the mid-portion and apex of the LV may induce LV dysfunction that does not closely fit with any coronary artery territory.^27,33 It was convincing that in the current study the prevalence of recurrent TC, which is associated with elevated plasma catecholamine levels, was more frequent in patients with LVOT obstruction, which might be prevented by β-blockers, than in patients without LVOT obstruction.^29–32 We did not measure plasma catecholamine levels in the current study but patients with LVOT obstruction at first TC might have relatively high plasma catecholamine levels or sensitivity. However, the observed higher incidences of hospitalization for CHF and recurrent TC in patients with LVOT obstruction need confirmation by future studies.

Study Limitations

First, the number of patients in this single-center observational study was small. Second, we were missing information on LVOT pressure gradient in a certain number of patients.

Conclusions

In 35 consecutive patients with TC, patients with significant LVOT obstruction (33%) had a more serious clinical presentation such as CHF and hypotension, but had a similar 3-year mortality rate to those without obstruction.

Acknowledgments

We thank all the staff of the Cardiac Catheterization Laboratory in Kyoto University Hospital for their contribution to this study.

Disclosures

None.

Supplementary Files

Supplementary File 1

Table S1. Emotional/physical stress in patients diagnosed as takotsubo cardiomyopathy

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-14-1148

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