Abstract

Aims

The patho-physiology of apical ballooning syndrome (ABS) has not been clearly defined. The aim of this study was to determine whether patients with a history of ABS are more likely to develop left ventricular (LV) mid-cavity or outflow tract obstruction, or have a greater regional LV contractile response to an adrenergic stimulus compared with normal controls.

Methods and results

Twenty patients who had recovered from ABS and 15 age-and sex-matched controls had dobutamine stress echocardiography with incremental doses up to 20 µg/kg/min. On average ABS subjects had slightly greater basal LV interventricular septal (1.1 ± 0.24 cm vs. 0.93 ± 0.12, P = 0.03) and posterior wall (1.04 ± 0.16 vs. 0.91 ± 0.11 cm, P = 0.02) diameters compared with controls but LV end-diastolic and end-systolic volumes and LV ejection fraction were similar both at rest and after dobutamine. Regional and global LV contractility, measured with the strain rate and tissue velocity imaging were also similar during the dobutamine infusion up to 10 µg/kg/min in ABS and controls. Mid-LV or LV outflow tract obstruction was not present at rest in any subjects, but was common during peak dobutamine infusion both in the ABS (45%) and controls (53%, P = 0.62).

Conclusions

Dynamic LV obstruction with dobutamine is common in those with and without prior ABS. However, this study did not identify a greater individual predisposition to LV obstruction, or a different regional or global LV contractile response to dobutamine in patients with a history of ABS compared with control subjects.

Introduction

Apical ballooning syndrome (ABS), also known as Tako-tsubo or stress-induced cardiomyopathy, is characterized by acute, reversible apical and mid-left ventricular (LV) akinesis occurring in the absence of obstructive coronary disease. ABS is often triggered by severe emotional or physical stress, and is more common in women.1 Dobutamine and epinephrine can both cause ABS2 confirming an important patho-physiological role of catecholamine excess. The temporal pattern of the wall motion abnormality and diffuse T-wave change on electrocardiogram are consistent with acute stunning of the LV apical myocardium. Dynamic mid-ventricular cavity obstruction3,4 and systolic anterior motion (SAM) of the mitral valve with left ventricular outflow tract (LVOT) obstruction5–7 have been described in acute ABS, and dobutamine has been noted to cause LVOT obstruction in some patients.4,8 These observations have led to the hypothesis that intense adrenergic stimulation may lead to dynamic mid-ventricular and/or LVOT obstruction causing a marked increase in apical LV mechanical wall stress which can result in apical myocardial stunning.4,9,10 It is currently not clear which factors predispose some individuals to develop ABS.10 One possibility is that individual differences in the LV structure could increase the LV outflow obstruction with exposure to excess catecholamines. Individual variations in the anatomy of cardiac innervation or adrenoceptor distribution have also been postulated as possible predisposing factors.10 However, there has been no systematic assessment of the LV morphology or evaluation of the response to beta-adrenergic stimulation in patients who have recovered from ABS compared with normal controls. The aim of this study was to compare LV morphology, the global and regional LV response to beta-adrenergic stimulation and the incidence of inducible mid-LV and LV outflow tract obstruction in patients who have recovered from ABS compared with age- and sex-matched normal controls.

Study population

Twenty patients after recovery from ABS and 15 age- and sex-matched controls were studied. Patients from an Auckland regional research database were approached to participate. ABS patients were studied at least 6 weeks after the episode of ABS. For inclusion patients had to meet the current modified Mayo classification11: (i) transient hypokinesis, akinesis, or dyskinesis in the LV mid-egments with or without apical involvement; regional wall motion abnormalities that extend beyond a single epicardial vascular distribution; and frequently, but not always, a stressful trigger; (ii) the absence of obstructive coronary disease or angiographic evidence of acute plaque rupture; (iii) new ECG abnormalities (ST-segment elevation and/or T-wave inversion) or modest elevation in cardiac troponin; and (iv) the absence of pheochromocytoma and myocarditis. Control patients were recruited by advertisement from the local community and had no history or clinical evidence of cardiovascular disease or valvular heart disease. All patients and controls gave signed informed consent. The study protocol was approved by the regional ethics board.

Study power

We planned a study with 20 ABS and 15 control subjects. Prior published data indicated that the probability of inducible LV obstruction is 0.2. If the true probability of exposure among cases is 0.7, we will be able to reject the null hypothesis that the rates for case and controls are equal with probability (power) of 0.77.

Dobutamine stress echocardiography

Patients and controls were studied at rest and after incremental infusion of intravenous dobutamine—5, 10 and 20 μg/kg/min—in 5 min stages. Beta-blocker medication was withheld for 36 h prior to the study. The studies were performed in the morning and subjects were not fasted. The dobutamine infusion was stopped once the 20 μg/kg/min stage was completed, or earlier if any of the following occurred: 85% of the patient's maximum predicted heart rate was exceeded, intra-ventricular or LVOT obstruction developed, moderate mitral regurgitation (MR) developed, atrial flutter/fibrillation or non-sustained ventricular tachycardia, patient requested discontinuation due to discomfort, 2 mm of new ST depression on the ECG, or other evidence of clinical instability judged by the supervising doctor to necessitate discontinuation.

Echocardiography

Two-dimensional echocardiography was performed using a Vivid 7 Dimension machine (General Electric, Vingmed Ultrasound, Horten, Norway). At rest only, basal LV wall thickness (interventricular septum, IVS and LV posterior wall, LVPW) were obtained from the parasternal views according to standard guidelines12 and the length of the anterior mitral valve leaflet was measured in diastole and the distance from the mitral valve tips to the IVS in late systole. At rest and at each dobutamine stage, standard apical two- and four-chamber and basal and mid-LV short-axis images were obtained. Frame rates were optimized to facilitate analysis of LV strain using speckle tracking software.13 Tissue velocity imaging was obtained at the septal and lateral mitral annulus. Colour Doppler was used to assess the presence of MR. Colour and continuous wave (CW) Doppler were used to evaluate the presence of mid-ventricular (MVO) or LVOT obstruction.

Echo analysis

All echo analysis was performed by an experienced echocardiographer (R.G.) blind to whether subjects were ABS patients or controls. LV end-diastolic and end-systolic volumes and ejection fraction were measured from the apical four-chamber and two-chamber views using the bi-plane Simpson's method.12 2D speckle tracking was used to assess regional myocardial strain in the apical four chamber and basal and mid-LV short-axis acquisitions. Using Echopac system software, 2D speckle tracking analysis was used to derive regional longitudinal and radial strain and the strain rate using a standard 16 segment model. Strain can be considered to be a measure of regional shortening fraction and relates to ejection fraction. The strain rate correlates well with the LV contractility.14 The longitudinal analysis was performed at the baseline, 5 and 10 μg/kg/min stages. For summary purposes, the longitudinal strain and the strain rate obtained from each of the four individual basal, mid, and apical two- and four-chamber segments were averaged to give basal, mid, and apical regional strain and the strain rate, respectively. Global longitudinal strain and the strain rate were obtained by averaging the basal, mid, and apical data. The radial analysis was performed at the baseline and 5 μg/kg/min stages. Image quality was technically suboptimal for analysis at higher doses of dobutamine. The radial strain and the strain rate were derived for the basal and mid-ventricular short-axis acquisitions. For summary purposes, the six short-axis segments at each level were averaged. MR severity was graded 0–4.15 The length of the anterior mitral valve leaflet was measured from the parasternal long-axis view in early diastole. The MV-to-IVS height was the vertical distance from the parasternal long-axis view between the mitral valve leaflet tips and the basal interventricular septum, measured at end systole. LVOT obstruction was defined as the presence of SAM of the mitral valve with a late-systolic peaking (dagger shape) gradient on CW Doppler envelope (peak velocity >3 m/s).16 MVO was defined as the presence of a dagger-shaped late systolic gradient on CW Doppler along the long-axis of the LV that exceeded the basal peak velocity by at least 1 m/s16 in association with colour Doppler localization of the obstruction at the mid-ventricular level.

Statistics

Descriptive statistics for continuous variables were summarized as mean with standard deviation, and median with inter-quartile range. Categorical data are reported by frequency and percentage. Comparisons between groups were performed by the two sample Student's t-test or Mann–Whitney U test (for non-normally distributed data). χ2 test or Fisher exact test was used for categorical variables. All P-values reported were two tailed and a P-value <0.05 was considered significant. Data were analysed using SAS statistical package, version 9.1.3 (SAS Institute, Cary, NC).

Results

Clinical features

Twenty patients with ABS and 15 controls were studied. The baseline characteristics of patients with ABS and controls are summarized in Table 1. For the ABS group, the mean time after the acute episode of ABS was 477 days (range: 37–1557 days). All were women with mean ages of 66.0 ± 10.1 and 61.5 ± 6.8 years, respectively. ABS and controls had similar mean body mass index (26.4 ± 6.3, 26.5 ± 5.4, P = 0.64). The mean systolic blood pressure and prevalence of hypertension were higher in the ABS group, although these differences were not statistically significant. Fifty per cent (n = 10) of ABS patients were taking beta-blocker medication and none of the controls.

Table 1

Baseline clinical characteristics of ABS patients and normal controls

Baseline characteristics ABS (n = 20) Control (n = 5) P-value 
Age (mean ± SD) 66.0 ± 10.1 61.5 ± 6.8 0.15 
Female [n (%)] 20 (100) 15 (100) – 
Ethnicity [n (%)]   0.12 
 European 16 (80) 15 (100)  
 Maori/pacific/other specify 4 (15) 0 (0)  
Height (mean ± SD) 160.3 ± 6.4 161.4 ± 7.5 0.64 
Weight (mean ± SD) 68.2 ± 15.6 69.0 ± 14.2 0.88 
Systolic BP (mean ± SD) 134.2 ± 26.4 125.7 ± 14.0 0.23 
Diastolic BP (mean ± SD) 77.8 ± 8.4 76.5 ± 7.5 0.66 
Heart rate (mean ± SD) 67.6 ± 9.1 63.1 ± 6.9 0.13 
Hypertension [n (%)] 10 (50) 4 (26.7) 0.16 
Medications [n (%)] 
 Aspirin 13 (65) 2 (13.3) 0.01 
 Warfarin 1 (5) 0 (0) 
 Statins 12 (60) 2 (13.3) 0.02 
 Beta-blockers 10 (50) 0 (0) 0.01 
 Calcium channel blockers 3 (15) 0 (0) 0.24 
 ACE inhibitors/ARB 11 (55) 1 (6.67) 0.01 
 Diuretics 2 (10) 0 (0) 0.5 
 Nitrates 1 (5) 0 (0) 
Baseline characteristics ABS (n = 20) Control (n = 5) P-value 
Age (mean ± SD) 66.0 ± 10.1 61.5 ± 6.8 0.15 
Female [n (%)] 20 (100) 15 (100) – 
Ethnicity [n (%)]   0.12 
 European 16 (80) 15 (100)  
 Maori/pacific/other specify 4 (15) 0 (0)  
Height (mean ± SD) 160.3 ± 6.4 161.4 ± 7.5 0.64 
Weight (mean ± SD) 68.2 ± 15.6 69.0 ± 14.2 0.88 
Systolic BP (mean ± SD) 134.2 ± 26.4 125.7 ± 14.0 0.23 
Diastolic BP (mean ± SD) 77.8 ± 8.4 76.5 ± 7.5 0.66 
Heart rate (mean ± SD) 67.6 ± 9.1 63.1 ± 6.9 0.13 
Hypertension [n (%)] 10 (50) 4 (26.7) 0.16 
Medications [n (%)] 
 Aspirin 13 (65) 2 (13.3) 0.01 
 Warfarin 1 (5) 0 (0) 
 Statins 12 (60) 2 (13.3) 0.02 
 Beta-blockers 10 (50) 0 (0) 0.01 
 Calcium channel blockers 3 (15) 0 (0) 0.24 
 ACE inhibitors/ARB 11 (55) 1 (6.67) 0.01 
 Diuretics 2 (10) 0 (0) 0.5 
 Nitrates 1 (5) 0 (0) 

BMI, body mass index; SBP, systolic blood pressure; DBP, diastolic blood pressure; ACE inhibitors, angiotensin-converting enzyme inhibitors; ARB, angiotensin II receptor blocker.

aWilcoxon–Mann–Whitney test, otherwise unpaired t-test for continuous variable or χ2 test or Fisher's exact test for categorical variables.

Resting echocardiography

The resting echo morphology is presented in Table 2. ABS patients on average had slightly larger basal IVS and LVPW (0.93 vs. 1.1 cm and 0.91 vs. 1.04 cm for controls and ABS, respectively), although the majority of ABS cases were still within normal limits and there was considerable overlap between patients and controls. Subjects with ABS also had a lower E/A ratio, consistent with effects of mild LV on diastolic filling. There were no other significant differences on the resting echo between ABS patients and normal controls. In particular, the LV dimensions, volumes, and LV ejection fraction (EF) were similar. There was no resting MR or SAM of the anterior mitral leaflet (SAM) in either group, and both the length of the anterior mitral valve leaflet and the relationship between the mitral valve and the IVS were similar. On regional strain imaging at rest, there were no significant differences in longitudinal or radial strain at the base, mid-ventricle or apex. However, longitudinal strain rate in basal, mid, and apical LV segments was slightly higher in ABS patients than that in the controls. Radial strain rate at both the base and mid-LV did not differ between groups.

Table 2

Resting echocardiographic parameters of ABS patients and controls

Echocardiographic measurement Mean ± SD
 
P-value 
 ABS (n = 20) Control (n = 15)  
LA area (cm215.8 ± 2.81 16.7 ± 2.74 0.32 
IVS (cm) 1.10 ± 0.24 0.93 ± 0.12 0.03 
LVPW (cm) 1.04 ± 0.16 0.91 ± 0.11 0.02 
LVEDV(mL)a 58.4 ± 13.1 59.8 ± 10.7 0.73 
LVESV (mL) 19.3 ± 6.2 21.7 ± 4.7 0.21 
EF (%) 68.1 ± 7.2 63.2 ± 6.8 0.046 
E 0.70 ± 0.18 0.70 ± 0.17 0.93 
E/A 0.89 ± 0.22 1.08 ± 0.25 0.03 
TVI e′ septum (cm/s) 7.80 ± 2.17 8.00 ± 1.25 0.73 
TVI S′ lateral (cm/s)a 8.65 ± 2.35 8.00 ± 1.73 0.65 
TVI S′ septum (cm/s)a 7.10 ± 1.12 6.87 ± 0.74 0.53 
AMVL length 2.13 ± 0.38 2.13 ± 0.27 0.51 
MV to IVS height 1.23 ± 0.39 1.17 ± 0.22 0.62 
Peak LVOT velocity (m/s) 1.35 ± 0.22 1.25 ± 0.17 0.14 
Peak intra-ventricular velocity (m/s)a 1.22 ± 0.58 0.91 ± 0.22 0.04 
Echocardiographic measurement Mean ± SD
 
P-value 
 ABS (n = 20) Control (n = 15)  
LA area (cm215.8 ± 2.81 16.7 ± 2.74 0.32 
IVS (cm) 1.10 ± 0.24 0.93 ± 0.12 0.03 
LVPW (cm) 1.04 ± 0.16 0.91 ± 0.11 0.02 
LVEDV(mL)a 58.4 ± 13.1 59.8 ± 10.7 0.73 
LVESV (mL) 19.3 ± 6.2 21.7 ± 4.7 0.21 
EF (%) 68.1 ± 7.2 63.2 ± 6.8 0.046 
E 0.70 ± 0.18 0.70 ± 0.17 0.93 
E/A 0.89 ± 0.22 1.08 ± 0.25 0.03 
TVI e′ septum (cm/s) 7.80 ± 2.17 8.00 ± 1.25 0.73 
TVI S′ lateral (cm/s)a 8.65 ± 2.35 8.00 ± 1.73 0.65 
TVI S′ septum (cm/s)a 7.10 ± 1.12 6.87 ± 0.74 0.53 
AMVL length 2.13 ± 0.38 2.13 ± 0.27 0.51 
MV to IVS height 1.23 ± 0.39 1.17 ± 0.22 0.62 
Peak LVOT velocity (m/s) 1.35 ± 0.22 1.25 ± 0.17 0.14 
Peak intra-ventricular velocity (m/s)a 1.22 ± 0.58 0.91 ± 0.22 0.04 

LA, left atrium; IVSD, interventricular septum; LVPW, left ventricular posterior wall; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; pw, pulsed-wave; TVI, tissue velocity imaging; AMVL, anterior mitral valve leaflet; MV, mitral valve; LVOT, left ventricular outflow tract.

aWilcoxon–Mann–Whitney test, otherwise unpaired t-test.

Response to dobutamine

The mean peak doses of dobutamine were 19.0 ± 3.1 vs. 18.7 ± 3.5 (P = 0.79) for ABS patients and controls, respectively. Eighteen ABS patients and 13 controls received the maximum dobutamine dose. Dobutamine was stopped because of development of an intraventricular or LVOT obstruction in nine ABS patients and eight controls (Table 3). Dobutamine was stopped because of palpitations in one ABS patient and one control, and for pre-syncope in one ABS patient. No participants developed ischaemic changes on electrocardiogram.

Table 3

Echocardiography at peak dose dobutamine

Measurements at peak dose of dobutamine Mean ± SD
 
P-value 
 ABS (n = 20) Control (n = 15)  
Maximum dose of dobutamine 19.0 ± 3.1 18.7 ± 3.5 0.79 
Systolic BP 156.3 ± 29.1 147.3 ± 11.0 0.21 
Diastolic BP 72.1 ± 16.1 73.5 ± 14.9 0.79 
Heart rate 107.3 ± 15.5 117.9 ± 13.4 0.02 
LVEDV 48.3 ± 13.2 43.2 ± 11.3 0.24 
LVESV 9.6 ± 5.4 7.5 ± 3.2 0.40 
TVI S′ lateral wall 0.16 ± 0.05 0.19 ± 0.04 0.15 
TVI S′ septum 0.15 ± 0.05 0.17 ± 0.03 0.15 
MR [n (%)] 3 (15) 2 (13.3) 1.00 
Peak mid-ventricular velocity 2.16 ± 0.74 2.73 ± 1.02 0.12 
Peak LVOT velocity 2.52 ± 1.16 2.77 ± 0.82 0.04 
Any dynamic outflow tract obstruction [n (%)] 9 (45) 8 (53) 0.63 
Mid-ventricular obstruction [n (%)] 5 (25) 7 (47) 0.18 
LVOT obstruction with SAM [n (%)] 4 (20) 1 (7) 0.37 
Measurements at peak dose of dobutamine Mean ± SD
 
P-value 
 ABS (n = 20) Control (n = 15)  
Maximum dose of dobutamine 19.0 ± 3.1 18.7 ± 3.5 0.79 
Systolic BP 156.3 ± 29.1 147.3 ± 11.0 0.21 
Diastolic BP 72.1 ± 16.1 73.5 ± 14.9 0.79 
Heart rate 107.3 ± 15.5 117.9 ± 13.4 0.02 
LVEDV 48.3 ± 13.2 43.2 ± 11.3 0.24 
LVESV 9.6 ± 5.4 7.5 ± 3.2 0.40 
TVI S′ lateral wall 0.16 ± 0.05 0.19 ± 0.04 0.15 
TVI S′ septum 0.15 ± 0.05 0.17 ± 0.03 0.15 
MR [n (%)] 3 (15) 2 (13.3) 1.00 
Peak mid-ventricular velocity 2.16 ± 0.74 2.73 ± 1.02 0.12 
Peak LVOT velocity 2.52 ± 1.16 2.77 ± 0.82 0.04 
Any dynamic outflow tract obstruction [n (%)] 9 (45) 8 (53) 0.63 
Mid-ventricular obstruction [n (%)] 5 (25) 7 (47) 0.18 
LVOT obstruction with SAM [n (%)] 4 (20) 1 (7) 0.37 

Data are presented as mean ± SD unless otherwise specified.

SBP, systolic blood pressure; DBP, diastolic blood pressure; LVEDV, left ventricular end-diastolic volume; LVESV, left ventricular end-systolic volume; TVI, tissue velocity imaging; MR, mitral regurgitation; LVOT, left ventricular outflow tract; SAM, systolic anterior motion of the anterior mitral leaflet; CW, continuous wave.

The peak heart rate was slightly higher in control patients (107 ± 16 vs. 120 ± 13, P = 0.02). As expected both the LV end-diastolic and LV end-systolic volumes decreased, and LVEF increased, with incremental dobutamine dose (Figure 1). There was no difference in this response between the ABS patients and controls. At peak dobutamine there was also no difference between both groups in septal S′, a global measure of LV contractility. There was similar augmentation of both global and regional LV strain and the strain rate with dobutamine. Achieved longitudinal strain and the strain rate at 10 µg/kg/min, and radial strain and the strain rate at 5 µg/kg/min, were also similar for the two groups (Tables 4 and 5). Radial strain and the strain rate beyond 5 μg/kg/min, and the longitudinal strain beyond 10 μg/kg/min, are not reported due to image quality precluding accurate measurement in some subjects.

Table 4

Longitudinal strain and strain rate at rest and with incremental doses of dobutamine

Dobutamine (µg/kg/min) Mean ± SD
 
Mean ± SD
 
 Strain (%)
 
Strain rate (1/s)
 
 ABS Control P-value ABS Control P-value 
Basal 
 0 −19.02 ± 3.28 −18.93 ± 2.63 0.91 −1.21 ± 0.17 −1.03 ± 0.14 <0.01 
 5 −20.29 ± 2.66 −22.64 ± 2.93 0.02 −1.34 ± 0.24 −1.49 ± 0.18 0.04 
 10 −19.76 ± 3.44 −21.08 ± 2.28 0.21 −1.74 ± 0.37 −1.74 ± 0.2 0.96 
Mid 
 0 −19.12 ± 2.35 −18.53 ± 2.08 0.45 −1.06 ± 0.11 −0.92 ± 0.14 <0.01 
 5 −20.94 ± 2.05 −21.96 ± 1.73 0.13 −1.24 ± 0.17 −1.35 ± 0.11 0.04 
 10 −20.8 ± 2.56 −21.56 ± 2.46 0.39 −1.58 ± 0.26 −1.64 ± 0.22 0.45 
Apical 
 0 −19.01 ± 3.01 −17.47 ± 4.45 0.23 −1.16 ± 0.32 −0.92 ± 0.19 0.02 
 5 −24.18 ± 3.17 −23.97 ± 4.34 0.87 −1.68 ± 0.3 −1.56 ± 0.3 0.27 
 10 −24.59 ± 4.06 −24.23 ± 4.55 0.81 −2.06 ± 0.46 −2.08 ± 0.45 0.73 
Global 
 0 −19.05 ± 1.79 −18.31 ± 2.22 0.28 −1.14 ± 0.16 −0.96 ± 0.13 <0.01 
 5 −21.80 ± 1.98 −22.86 ± 1.91 0.12 −1.42 ± 0.19 −1.47 ± 0.13 0.40 
 10 −21.72 ± 2.39 −22.29 ± 2.36 0.49 −1.79 ± 0.31 −1.82 ± 0.23 0.44 
Dobutamine (µg/kg/min) Mean ± SD
 
Mean ± SD
 
 Strain (%)
 
Strain rate (1/s)
 
 ABS Control P-value ABS Control P-value 
Basal 
 0 −19.02 ± 3.28 −18.93 ± 2.63 0.91 −1.21 ± 0.17 −1.03 ± 0.14 <0.01 
 5 −20.29 ± 2.66 −22.64 ± 2.93 0.02 −1.34 ± 0.24 −1.49 ± 0.18 0.04 
 10 −19.76 ± 3.44 −21.08 ± 2.28 0.21 −1.74 ± 0.37 −1.74 ± 0.2 0.96 
Mid 
 0 −19.12 ± 2.35 −18.53 ± 2.08 0.45 −1.06 ± 0.11 −0.92 ± 0.14 <0.01 
 5 −20.94 ± 2.05 −21.96 ± 1.73 0.13 −1.24 ± 0.17 −1.35 ± 0.11 0.04 
 10 −20.8 ± 2.56 −21.56 ± 2.46 0.39 −1.58 ± 0.26 −1.64 ± 0.22 0.45 
Apical 
 0 −19.01 ± 3.01 −17.47 ± 4.45 0.23 −1.16 ± 0.32 −0.92 ± 0.19 0.02 
 5 −24.18 ± 3.17 −23.97 ± 4.34 0.87 −1.68 ± 0.3 −1.56 ± 0.3 0.27 
 10 −24.59 ± 4.06 −24.23 ± 4.55 0.81 −2.06 ± 0.46 −2.08 ± 0.45 0.73 
Global 
 0 −19.05 ± 1.79 −18.31 ± 2.22 0.28 −1.14 ± 0.16 −0.96 ± 0.13 <0.01 
 5 −21.80 ± 1.98 −22.86 ± 1.91 0.12 −1.42 ± 0.19 −1.47 ± 0.13 0.40 
 10 −21.72 ± 2.39 −22.29 ± 2.36 0.49 −1.79 ± 0.31 −1.82 ± 0.23 0.44 
Table 5

Radial strain and strain rate analysis at rest and with incremental doses of dobutamine

Dobutamine (µg/kg/min) Mean ± SD
 
Mean ± SD
 
 Strain (%)
 
Strain rate (1/s)
 
 ABS Control P-value ABS Control P-value 
Basal 
 0 43.39 ± 13.63 43.09 ± 22.28 0.97 1.84 ± 0.27 1.82 ± 0.50 0.91 
 5 45.83 ± 21.17 53.89 ± 23.15 0.33 2.08 ± 0.67 1.87 ± 0.23 0.26 
 10 53.32 ± 17.14 45.86 ± 16.78 0.30    
Mid 
 0 53.22 ± 29.57 43.34 ± 14.36 0.58 1.55 ± 0.32 1.61 ± 0.29 0.65 
 5 49.04 ± 20.9 59.52 ± 23.15 0.21 1.66 ± 0.37 1.82 ± 0.39 0.26 
 10 48.30 ± 17.58 63.36 ± 15.33 0.05    
Dobutamine (µg/kg/min) Mean ± SD
 
Mean ± SD
 
 Strain (%)
 
Strain rate (1/s)
 
 ABS Control P-value ABS Control P-value 
Basal 
 0 43.39 ± 13.63 43.09 ± 22.28 0.97 1.84 ± 0.27 1.82 ± 0.50 0.91 
 5 45.83 ± 21.17 53.89 ± 23.15 0.33 2.08 ± 0.67 1.87 ± 0.23 0.26 
 10 53.32 ± 17.14 45.86 ± 16.78 0.30    
Mid 
 0 53.22 ± 29.57 43.34 ± 14.36 0.58 1.55 ± 0.32 1.61 ± 0.29 0.65 
 5 49.04 ± 20.9 59.52 ± 23.15 0.21 1.66 ± 0.37 1.82 ± 0.39 0.26 
 10 48.30 ± 17.58 63.36 ± 15.33 0.05    
Figure 1

(A) Changes of basal left ventricular end-diastolic volumes and (B) left ventricular end-systolic volumes with increasing doses of dobutamine in patients with apical ballooning syndrome and normal controls.

Figure 1

(A) Changes of basal left ventricular end-diastolic volumes and (B) left ventricular end-systolic volumes with increasing doses of dobutamine in patients with apical ballooning syndrome and normal controls.

Four (20%) ABS patients and one (6.7%) control patient (P = 0.37) developed SAM and LVOT obstruction with dobutamine. The four patients who developed SAM had a slightly larger basal IVS compared with others patients who did not develop SAM (1.41 vs. 1.13 cm, P < 0.05). The peak trans-LVOT velocities were 2.46 ± 1.16 m/s in the ABS patients and 2.77 ± 0.82 m/s in the control patients. There was associated MR in four of these five cases. In all cases, the SAM and LVOT obstruction resolved within minutes of discontinuation of the dobutamine infusion and the patients were asymptomatic and haemodynamically stable. Transient MVO was common in both groups: five (25%) ABS patients and seven (47%) control (P = 0.69) with mean gradients of 2.16 ± 0.74 and 2.73 ± 1.02 m/s, respectively.

The clinical presentation of the 20 patients on the initial ABS event is presented in Table 6. Three patients were on β-blockers before admission. Four patients presented with pulmonary oedema and one was in cardiogenic shock. More than half of the patients had significant overall impairment of LV systolic function documented either on transthoracic echocardiography or left ventriculogram during the acute phase. Moderate to severe MR was documented in two patients who also had significant dynamic outflow tract obstruction. These two patients also developed SAM and LVOT obstruction with dobutamine. One patient who developed MVO during the test had presented with acute pulmonary oedema and right heart failure during the acute phase; and one patient who developed LVOT obstruction during the test presented with cardiogenic shock during the acute phase. However, the other patients who developed LVOT or MVO during the test did not have a complicated clinical presentation during the acute phase. Four of the 20 ABS patients were admitted with recurrent episodes of ABS after discharge from the index event. Two of the four patients with recurrence developed dynamic outflow tract obstruction during the dobutamine study.

Table 6

Clinical presentation of ABS patients

 Number of ABS patients (n = 20) 
Presenting symptoms [n (%)] 
 Chest pain 18 (90) 
 Dyspnoea 10 (50) 
 Arrhythmia 1 (5) 
 Presyncope/syncope 3 (15) 
 Pulmonary oedema 4 (20) 
 Cardiogenic shock 1 (5) 
Stressor [n (%)] 
 Yes 13 (65) 
 No 7 (35) 
LV function during acute phase [n (%)] 
 Severe 3 (15) 
 Moderate 11 (55) 
 Mild/low-normal 4 (20) 
 Normal 2 (10) 
MR/SAM [n (%)] 2 (10) 
ECG on admission [n (%)] 
 ST elevation 7 (35) 
Medications on admission [n (%)] 
 β-blockers 3 (15) 
 ACE inhibitors 5 (25) 
 Calcium channel blockers 4 (20) 
Recurrence [n (%)] 4 (20) 
 Number of ABS patients (n = 20) 
Presenting symptoms [n (%)] 
 Chest pain 18 (90) 
 Dyspnoea 10 (50) 
 Arrhythmia 1 (5) 
 Presyncope/syncope 3 (15) 
 Pulmonary oedema 4 (20) 
 Cardiogenic shock 1 (5) 
Stressor [n (%)] 
 Yes 13 (65) 
 No 7 (35) 
LV function during acute phase [n (%)] 
 Severe 3 (15) 
 Moderate 11 (55) 
 Mild/low-normal 4 (20) 
 Normal 2 (10) 
MR/SAM [n (%)] 2 (10) 
ECG on admission [n (%)] 
 ST elevation 7 (35) 
Medications on admission [n (%)] 
 β-blockers 3 (15) 
 ACE inhibitors 5 (25) 
 Calcium channel blockers 4 (20) 
Recurrence [n (%)] 4 (20) 

Discussion

This study evaluated for the first time LV structure and function at rest and with adrenergic stimulation in patients who have recovered from ABS, and compared changes to normal controls. No clear differences were found to explain why some individuals are at greater risk of developing ABS. The LV wall thickness was slightly greater in subjects with a history of ABS, but the importance of LV hypertrophy to the patho-physiology of ABS is currently uncertain. Further study is needed to determine whether LV hypertrophy or other factors could predispose to apical myocardial stunning in the setting of an intense adrenergic stimulus.

We6 and others4,10 have suggested that LVOT obstruction, by markedly increasing apical intra-ventricular pressure and wall stress, could predispose to LV apical stunning. In a previous study, a dynamic mid-ventricular gradient was documented by invasive intra-ventricular pressure recording in 18% of patients studied during their admission with ABS.3 Rates of dynamic MVO reported by echocardiography in acute ABS have been similar.17,18 Several small studies have reported dynamic LVOT obstruction on echocardiography performed at the index admission with incidence ranging from 5 to 25%.7,19,20 In virtually all patients studied the mid-ventricular and LVOT obstruction resolved on subsequent studies.3,21 In one study dobutamine infusions induced mid-ventricular or outflow gradients in 28% of ABS patients early after the acute presentation and prior to full recovery of LV function.22 In these studies, most patients did not have intra-ventricular or outflow gradients after presentation with ABS. However, to evaluate a possible causal role of intra-ventricular obstruction evaluation needs to occur during the excess adrenergic stimulation and before myocardial stunning and apical dilation have occurred, or as in this study, after LV function has returned to normal.

MVO has been reported in 15–23% of patients referred for dobutamine stress echocardiography for suspected coronary artery disease.16,23,24 LVOT obstruction outflow tract obstruction was seen in 12% of patients.22 Both mid-ventricular and LVOT obstruction were more likely in women16,23,24 and, as in the current study, LVOT obstruction was more common if mild LV septal hypertrophy was present.6,24 Women on average have a smaller LV and therefore may have a greater predisposition to LV cavity or outflow tract gradients.23,25 In the current study, mid-ventricular or outflow gradients were observed during the dobutamine infusion in almost half of subjects with ABS. It is possible that gradients could have occurred in all subjects with a more intense adrenergic stimulus, as with the event which triggered the acute presentation. However, a similar high prevalence of mid- and outflow gradients occurred during the dobutamine infusion in normal female controls, suggesting that patients with a history of ABS do not have a greater predisposition to intra-ventricular gradients with excess sympathetic activity. This would not exclude the possibility that high intra-ventricular gradients contribute to apical stunning and ballooning, but does suggest additional factors are likely to be important.

It has been suggested patients with ABS may be more sensitive to adrenergic stimulation.26 However, in this study the increase in contractility with a standard dose of dobutamine was similar for subjects with ABS and normal controls suggesting a similar sensitivity of the myocardium to adrenergic stimulation. Regional differences in beta-receptor density have also been suggested as the explanation for the apical distribution of myocardial stunning.27 However, myocardial tissue Doppler imaging during beta-adrenergic stimulation did not identify regional or global differences in myocardial strain or strain rate between patients and controls during the dobutamine infusion. Due to image quality limitations, strain and the strain rate could only be assessed at lower doses of dobutamine. We were therefore unable to assess the differences between the groups which might have been evident only at higher doses. Coronary micro-vascular function may be abnormal in ABS28 but this was not directly evaluated in this study.

In our study women with ABS had a slightly higher longitudinal strain rate at rest. We cannot ascertain whether this was due to differences in resting sympathetic tone, to recent beta-blocker withdrawal, or an intrinsic myocardial difference. A higher rate of chronic anxiety has been reported in ABS.29 Patients with ABS have also been reported to have greater vascular reactivity, decreased endothelial function, and greater increases in catecholamine levels in response to acute mental stress.30

In this study four ABS patients developed significant MR due to SAM during the dobutamine infusion which resolved rapidly after the infusion was stopped. Severe MR due to SAM may be an important mechanism contributing to acute LV failure and shock in 20–40% of patients with ABS3,21 and has been associated with a more adverse clinical course.19

Limitations

Dobutamine was chosen as the adrenergic stimulant because of extensive clinical and safety data in patients with suspected cardiac disease, and because dobutamine has been reported to trigger ABS. The maximum dose of 20 µg/kg/min was half the typically maximum dose used when stress testing for coronary artery disease. We were careful not to use a high dose which might cause ABS. At the moderate doses used, there was no difference in the myocardial performance between patients and controls, but we cannot exclude the possibility of a difference with very intense or more prolonged adrenergic stimulation. We were interested in whether there were consistent and major differences in response to adrenergic stimulation between patients and controls. This study had reasonable power to exclude a 50% difference in the incidence of LV obstruction. Smaller between-group differences cannot be excluded but there was no trend in the ABS group towards more frequent LV obstruction. Nor was there any trend towards a systematic between-group difference in LV response to dobutamine across a range of LV volume and strain rate imaging measures. ABS is relatively rare and this detailed mechanistic study was not large enough to evaluate possible heterogeneity between ABS patients.

Conclusion

The frequent occurrence of the LV outflow obstruction during dobutamine infusion is consistent with the hypothesis that LV mid-cavity and outflow tract gradients during an intense adrenergic stimulus explain the apical distribution of myocardial stunning in ABS. However, this study did not identify a greater individual predisposition to LV obstruction, or a different regional or global LV contractile response to dobutamine in patients with a history of ABS compared with control subjects.

Conflict of interest: none declared.

Funding

This work was supported by National Heart Foundation, New Zealand [grant number #1236] and Middlemore Hospital Cardiology Trust.

Acknowledgements

We thank Sela Takau and Fiona Doull (sonographers), and Jenny White, Pauline Clarke and Gina Barker (research nurses) at Middlemore Hospital for their help during the dobutamine stress echocardiography.

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