Stress Induced Cardiomyopathy Clinical Trial
Official title:
The Evaluation of the Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG Imaging
Objective: The objective of this pilot study is to characterize the cardiac uptake patterns
of I-123 mIBG in stress-induced (Takotsubo's) cardiomyopathy.
Hypothesis: Perturbations in sympathetic innervation are the underlying pathogenesis of
stress induced cardiomyopathy and will result in abnormalities in I-123 mIBG cardiac
imaging. Thus, planar and SPECT I-123 MIBG imaging will provide insight into the
pathogenesis of stress-induced cardiomyopathy, and may lead to the development of more
specific diagnostic criteria.
Study design: This proposal is for a prospective pilot study to characterize perturbations
in cardiac sympathetic innervation in patients with stress induced cardiomyopathy by
performing planar and SPECT I-123 MIBG imaging during the acute presentation and after
recovery of LV function.
Background: Since the initial Japanese description of Takotsubo's cardiomyopathy in 1991 as
a transient systolic dysfunction of the apical or mid left ventricular segments in the
absence of obstructive coronary artery disease, stress induced cardiomyopathy has been
increasingly recognized in the Unites States. Takotsubo's cardiomyopathy accounts for 1.2 to
2.2 percent of all cases of acute coronary syndrome. The current American Heart Association
Statistical Update estimates that approximately 1.2 million Americans will experience an
acute coronary event in 2010. Based on this estimate, between 15 and 26 thousand Americans
will have stress induced cardiomyopathy annually. Takotsubo's cardiomyopathy has also been
described in stroke and critically ill patients. Post menopausal women are disproportionally
affected, accounting for 80 to 100 percent of the patient population. These patients
classically present with signs of acute heart failure or acute coronary syndrome after a
severe emotional stress. The presentation may include chest pain, shortness of breath,
elevated troponin enzymes, ST segment elevations, deep T-wave inversions, ventricular
arrhythmias, pulmonary edema or elevated biomarkers. Cardiac catheterization reveals
angiographically normal coronary arteries while the ventriculogram and the echocardiogram
shows apical ballooning with basal hyperkinesis. While the majority of patients recover
complete function within few days to two weeks, up to eight percent of the patients will die
from the acute heart failure.
The etiology of stress-induced cardiomyopathy remains speculative. Catecholamine excess
leading to microvascular dysfunction or direct cardiomyocyte toxicity is hypothesized as the
most likely etiology. This hypothesis is supported by the fact that most patients with
Takotsubo's cardiomyopathy experience an intense physical or emotional stress. Furthermore,
several other observations support this hypothesis. First, catecholamines levels are
elevated in patients with stress induced cardiomyopathy at presentation when compared to
patients with acute coronary syndrome. Second, multi-vessel coronary vasospasm and transient
myocardial perfusion defects have been identified repeatedly in this population. Third,
myocardial biopsies show myocarditis, interstitial fibrosis and mononuclear infiltrates,
signs consistent with catecholamine toxicity. Fourth, in a mouse model, elevated epinephrine
levels cause a switch from beta-2 adrenoreceptor mediated Gs protein signaling to Gi protein
signaling, which is negatively inotropic. These findings all support the theory that there
is altered sympathetic activity in patients with stress induced cardiomyopathy.
Thus, based on the existing knowledge base of this intriguing disease, an imaging approach
that specifically evaluates the sympathetic activation state of the myocardium would appear
to be ideally suited to further explore pathophysiology. I-123 radiolabeled
metaiodobenzylguanidine, (mIBG) imaging allows for direct analysis of cardiac sympathetic
function because it is structurally similar to norepinephrine (NE), and is transported into
the cardiac sympathetic neurons by human norepinephrine transporter 1 ( hNET1), in the
synaptic cleft. Unlike NE, mIBG is not metabolized by monoamine oxidase or catechol-o-methyl
transferase. mIBG requires an intact myocardial sympathetic nervous system for uptake, is
stored in the presynaptic vesicles and is released by stimulation with acetylcholine.
Experimental manipulation of cardiac sympathetic function alters mIBG uptake and
distribution. Planar imaging acquisition enables evaluation of sympathetic activation, while
SPECT characterizes regional abnormalities. Measurement of the heart to mediastinal ratio
during early and delayed planimetry assesses the initial uptake and washout of the tracer.
mIBG uptake follows one of three general patterns: good uptake and retention, good uptake
with washout or poor uptake. The different patterns likely represent the level of
sympathetic activation, increase in sympathetic tone and heart failure-induced damage to the
myocardial sympathetic nervous system. mIBG uptake is altered in patient with diabetic
neuropathy, congestive heart failure, myocardial infarction. The uptake and washout patterns
correlate with severity of neuropathy, severity of congestive heart failure, congestive
heart failure treatment response, improvement in ejection fraction, cardiac death and
ventricular arrhythmogenic potential.
Preliminary data in patients with Takotsubo's cardiomyopathy has shown decrease in mIBG
uptake with an increased washout in the acute phase, with improved retention after left
ventricular functional recovery. Furthermore, regional decrease in tracer uptake corresponds
to the regional wall motion abnormalities. However, a systematic exploration of mIBG uptake
patterns in consecutive patients with Takotsubo's cardiomyopathy has not been performed. Of
note, PET imaging with 11C Hydroxyephedrine has described similar sympathetic dysfunction in
Takotsubo's cardiomyopathy.
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Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Diagnostic