European Journal of Echocardiography Advance Access published online on June 20, 2008
European Journal of Echocardiography, doi:10.1093/ejechocard/jen192
Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2008. For permissions please email: journals.permissions@oxfordjournals.org
Takotsubo cardiomyopathy: pathogenetic insights and myocardial perfusion kinetics using myocardial contrast echocardiography
Luis Afonso*,
Khaled Bachour,
Khaled Awad and
Greg Sandidge
Division of Cardiology, 3990 John R, 8 Brush, Harper University Hospital, Wayne State University, Detroit Medical Center, Detroit, MI 48201, USA
Received 19 March 2008; accepted after revision 30 May 2008.
* Corresponding author. Tel:+1 313 745 2620; fax: +1 313 993 8627. E-mail address: lafonso{at}med.wayne.edu
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Abstract
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Transient apical ballooning syndrome or Takotsubo cardiomyopathy
(TC) is a novel acute cardiac syndrome, characterized by regional
systolic dysfunction involving the apex and mid-ventricular
segments, with hyperkinesis of the basal segments. Mid-ventricular
ballooning cardiomyopathy (MVBC) is a recently recognized variant
of TC. Both disorders share the same precipitating factors,
clinical features and course; however, unlike TC, MVBC is characterized
by ballooning and akinesis of the mid-ventricular segments with
hypercontractility of the basal and apical segments. While the
precise pathogenetic mechanism of this disorder remains elusive,
microvascular dysfunction from excessive catecholamine release
has been implicated. We report findings on regional contractile
dysfunction (strain imaging), myocardial blood flow (semi-quantitative),
and perfusion kinetics using myocardial contrast echocardiography
in a series of three illustrative cases of TC.
Keywords: Takotsubo cardiomyopathy; Myocardial contrast echocardiography; Myocardial perfusion; Apical ballooning syndrome; Microvascular
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Case 1
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A 46-year-old male was admitted with status epilepticus. The
electrocardiogram (ECG) revealed sinus tachycardia and T-wave
inversion in the lateral leads. Peak Troponin I (cTnI) was 0.55
ng/mL (<0.4). A 2D-echocardiogram showed severe left ventricular
(LV) systolic dysfunction, an ejection fraction (EF) of 20%,
akinesis of the mid-ventricular segments and preserved contractility
of the apex and basal segments, suggestive of mid-ventricular
ballooning cardiomyopathy (MVBC), a variant of Takotsubo cardiomyopathy
(TC). Coronary angiography was normal. On 2D strain imaging,
akinesis and paradoxical strain of the mid-ventricular segments
was noted (
Figure 1,
Supplementary material online, video 1).
Myocardial contrast echocardiography (MCE) revealed preserved
perfusion and contrast wash-in in the apical and basal segments
of the left ventricle with delayed replenishment evident in
the mid-segments. Time intensity curves showed significant attenuation
of plateau video intensity (VI) consistent with decreased myocardial
blood volume (MBV) and flow in the mid-segments (
Figure 2A and
B,
Supplementary material online, video 2). Plateau VI after
wash-in curve fitting assessed using triggered intervals in
end-systole (when the arterioles and veins are devoid of blood)
was attenuated in the mid-segments relative to the base and
apex (
Figure 3), representing diminished capillary cross-sectional
volume in these areas. A repeat echocardiogram performed 4 weeks
later revealed complete resolution of systolic dysfunction (EF,
50–55%) and regional wall motion abnormalities.
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Figure 1 Two-dimensional longitudinal strain curves and corresponding parametric image (2D and colour-anatomic M-mode) showing dyskinesis (paradoxical strain) of the mid-inferior septum (light blue trace), and severe hypokinesis of the mid-lateral wall (dark blue trace) with preserved contractility at the apex and base.
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Figure 2 (A) Contrast replenishment traces in the basal inferior septum (yellow), mid-inferior septum (blue), apex (red), and mid-inferolateral wall (green), timed immediately following a high-energy ultrasound pulse. Fitted replenishment curves are then used to calculate A and β for each segment. (B) Representative regions of interest (ROI) in the myocardium where replenishment was assessed.
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Figure 3 Wash in curve fitting using triggering intervals depicting attenuated plateau contrast levels in the midventricular segments during end-systole (myocardium devoid of arteriolar and venous blood), a surrogate indicator of reduced capillary blood volume in these areas.
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Case 2
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A 38-year-old premenopausal female with history of chronic obstructive
pulmonary disease, severe wheezing, and hypoxia was intubated
upon arrival. ECG at presentation showed sinus tachycardia,
and right bundle branch block, but no ischaemic changes. She
was admitted to the intensive care unit with a diagnosis of
chronic obstructive pulmonary disease exacerbation. Initial
serum cTnI was 1.34 ng/mL. Two-dimensional echocardiogram showed
hypokinesis, involving the LV apex and distal segments. Cardiac
catheterization revealed normal coronary arteries. MCE revealed
decreased capillary blood volume and flow in the apical and
mid-ventricular segments and sparing of the basal segments.
The patient’s respiratory status improved, and she was
extubated and discharged after complete clinical recovery. Complete
resolution of regional and global systolic dysfunction (EF,
65%) was evident on a follow-up surface echocardiogram done
2 months post-discharge.
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Case 3
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A 52-year-old postmenopausal female admitted for further workup
of her chest tightness. The initial ECG was remarkable for sinus
tachycardia, T-wave inversion in the lateral leads, and prolongation
of the QT interval. On subsequent ECG’s, the T-wave inversion
spread to involve the inferior leads and the troponin peaked
at 2.0 ng/mL. A 2D-echo revealed dilatation and akinesis involving
apical and mid-ventricular segments, hyperkinesis of the basal
segments, and an EF of 20%, findings consistent with TC. Cardiac
catheterization revealed no abnormalities. MCE showed a decrease
in capillary blood flow and volume in the akinetic areas with
delayed contrast replenishment (wash-in post-high power flash),
sparing the basal segments. A repeat 2D echo, 2 weeks later,
revealed an EF of 45%, resolution of the apical dilatation with
mild residual apical and mid-ventricular hypokinesis. A repeat
MCE study showed near-normalization of perfusion parameters
in affected areas. None of the patients described in our series
had evidence of right ventricular systolic dysfunction.
Qualitative and quantitative assessment
Myocardial contrast echocardiography was performed using bolus injections of Definity (Bristol-Myers Squibb, Billerica, MA, USA) and low mechanical index real-time harmonic imaging (Vivid & scanner, GE Vingmed). Time intensity curves were sampled offline [regions of interest (ROI) of 6 mm x 3 mm], using the Echo PAC work station. Images for 2D strain (speckle tracking) were acquired at a frame rate of 70–80 frames per second. Two-dimensional strain entails spatial and temporal tracking of adjacent naturally occurring acoustic markers or ‘speckles’ from standard black and white echocardiographic images. Deformation is calculated on a frame–frame analysis of speckle displacement, yielding angle-independent parameters of myocardial contraction, namely longitudinal, transverse, and radial strain and strain rate.1
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Results
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A summary of mean bubble velocity represented by the slope of
the replenishment curve (
β) and plateau intensity values
(
A) for representative ROI’s in the myocardium are summarized
in
Table 1. Corresponding peak longitudinal 2D strain values
(manual mapping in respective ROI’s) are also depicted.
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Discussion
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Takotsubo cardiomyopathy is a novel syndrome characterized by
transient, acute-onset ventricular systolic dysfunction, in
the absence of epicardial coronary artery disease. Although
predominantly described in postmenopausal women, reports of
this entity in younger adults and children exist in the literature.
2–5 Emotional or physical stress is the usual triggering event.
The most common clinical presentations of TC are chest pain
(68%) and dyspnea (18%) while the most frequent electrocardiographic
findings are ST-segment elevation (81%), followed by T-wave
abnormalities (64%) and Q waves (31%).
3 Histological findings
on endomyocardial biopsy include focal myocytolysis, mononuclear
infiltrates, and contraction band necrosis without evidence
of myocarditis.
6
Although the precise cause and mediators of myocardial injury in TC remain unclear, a host of pathophysiological mechanisms have been implicated, including epicardial multivessel spasm, microvascular spasm, acute coronary syndrome with reperfusion, myocarditis, and transient obstruction of the LV outflow tract. Multivessel spasm has been demonstrated inconsistently even following provocation,7–9 with intracoronary ergonovine or acetylcholine and probably does not explain MVBC, a variant of TC that spares the apex but affects the mid-ventricular segments10 (e.g. Case 1).
Excessive sympathetic stimulation and catecholamine release3,6,11 appear to be central to the pathogenesis of TC. Ueyama et al.12 induced transient LV apical ballooning in rats exposed to emotional stress but were unable to reproduce these effects after pre-treatment with 
- and β-adrenoreceptor blockers. Plasma catecholamine and neuropeptide levels were significantly higher among patients with TC than among those with Killip class III myocardial infarction.6 Akashi et al.13 performed serial 123I-metaiodobenzlguanidine serial (123I-MIBG) myocardial scintigraphy in eight patients with TC during the index admission, and at 3 months follow-up. On the basis of heart–mediastinum ratios and higher radioisotope washout rates in the initial compared with follow-up scans, they suggested that cardiac hypersympathetic activity and neurogenic myocardial stunning could be the operant mechanisms in the genesis of TC. MIBG is structurally similar to norepinephrine and utilizes the same uptake and storage mechanisms. 123I-MIBG scintigraphy was developed to evaluate cardiac sympathetic nervous function (sympathetic nerve density), and a decreased uptake denotes adrenergic dysfunction.
Similarly, radiolabelled 123I-metyl-iodophenyl pentadecanoic acid (BMIPP) uptake is impaired in the setting of transient cardiac dysfunction, reflecting a reduction in myocardial long-chain fatty acid utilization. Using rest 201Tl and 123I-BMIPP dual-isotope myocardial SPECT imaging, Kurisu et al.14 reported a discrepancy between myocardial perfusion and fatty acid metabolism, further reinforcing the ‘myocardial stunning’ concept. Myocardial fatty acid metabolism was impaired to a greater extent than myocardial perfusion in the early stages and, although this discrepancy improved during follow-up, metabolic impairment persisted beyond resolution of systolic dysfunction.14 A reduction in regional glucose uptake out of proportion to the myocardial perfusion abnormality was also demonstrated in TC using 13N-ammonia (flow tracer) and 18F-fluorodeoxyglucose positron emission tomography, providing further corroborative evidence of myocardial stunning and microcirculatory disruption.15
Multiple factors modulate coronary blood flow including epicardial coronary diameter, antegrade perfusion pressure, vasospasm, wall stress, and the integrity of the coronary microcirculation. Microvascular function in TC has been showed to be deranged by several techniques including angiographic Thrombolysis In Myocardial Infarction trial (TIMI) frame count14 (reflecting increased coronary vascular resistance), TIMI myocardial perfusion grades,16 MCE,17,18 and coronary perfusion/flow reserve as assessed by nuclear imaging,19–21 transthoracic22 and intracoronary Doppler techniques.23–25
Myocardial contrast echocardiography can be rapidly performed by the bedside and repeated serially if needed, for monitoring myocardial perfusion. Upadya et al.18 first reported a perfusion defect in an elderly woman (using real-time low-mechanical index MCE) that resolved within 72 h. More recently, Azzareli et al.17 described a similar case and demonstrated normalization of the perfusion abnormalities during follow-up, using time intensity curves.17
Myocardial contrast echocardiography utilizes gas-filled microbubbles that are very effective in scattering ultrasound due to their very small radius (<5 µm), a property that also accounts for similarities between microbubble and erythrocyte rheology. Ultrasound scattered by microbubbles can be quantified using VI to evaluate the integrity of the microvasculature, particularly capillary flow and density.
For assessing resting capillary blood flow, a steady state of contrast infusion has to be first achieved. Subsequently, a high-energy ultrasound pulse(s) is delivered to destroy myocardial microbubbles, followed by low-mechanical index imaging to assess its rate of reappearance, a surrogate measure of erythrocyte velocity (1 mm s–1 at rest). The change in the VI over time is then fitted into a monoexponential curve that represents the replenishment phase of contrast flow, and from that curve several parameters are then derived. The relation between the change in the VI and time can be represented by the following function:
where
y is the
VI at time
t,
A is the plateau VI, and
β is the rate constant
that represents the rate of rise of VI.
26 The value
A is proportional
to the microvascular cross-sectional area and MBV in the surveyed
myocardium, whereas
β correlates with the myocardial blood
flow velocity within the myocardial region of interest.
26
Our patients demonstrated significantly attenuated A and β values in affected myocardial regions compared with spared segments that manifested normal replenishment and contractile patterns (Table 1). The decreased MBV and velocity in affected segments is consistent with arteriolar vasoconstriction,27 resulting in a marked loss of capillary bed volume as evidenced by the end-systolic triggered plateau intensity wash in curves. The presence of normal epicardial coronary vessels and lack of conformity of contractile or perfusion abnormalities to known coronary artery distributions argue against epicardial spasm being the causative mechanism of microvascular dysfunction. Finally, the severity and extent of perfusion abnormalities (MCE) matched impairments in segmental contractile function (manual spatial mapping of video intensity) and improved in parallel during follow-up (Case 3). These and other data from the literature discussed above lend further credence to catecholamine-induced stunning as the primary underlying pathophysiological mechanism responsible for TC. However, it is still unclear whether myocardial stunning ensues from the hyperadrenergic state (accompanying arteriolar vasoconstriction and profound reduction of coronary flow) or from the direct toxic effects of catecholamine on myocytes. Finally, the vulnerability and predominant involvement of the LV apex is intriguing and needs to be addressed by future research.
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Conclusion
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The pathophysiology of TC/MVBC remains poorly understood. First,
our findings confirm that disruption of microvascular integrity
appears to be the proximate underlying mechanism of contractile
dysfunction in TC. Secondly, the attenuation of myocardial blood
flow velocity seems to accompany a reduction in cross-sectional
capillary bed volume in segments demonstrating contractile dysfunction.
Finally, our illustrative cases also highlight the feasibility
and unique ability of MCE to rapidly and inexpensively quantify
myocardial perfusion, profile perfusion kinetics, and contractile
abnormalities by the bedside. Technique simplicity allows for
serial assessment of coronary flow, facilitating future research
in the pathogenesis of this intriguing entity. To the best of
our knowledge, these are the first reported cases of MVBC or
TC to profile myocardial flow kinetics (qualitatively and semi-quantitatively)
using MCE and contractile abnormalities with 2D (speckle tracking)
strain imaging.
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Supplementary data
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Supplementary data is available at European Journal of Echocardiography online.
Conflict of interest: none declared.
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Abstract
Case 1