Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG

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.

Inclusion Criteria:

- The subject is ≥18 years of age at study entry.

- The subject is able and willing to comply with study procedures and signed and dated
informed consent is obtained.

- The subject is male, or a female who is either surgically sterile (has a documented
bilateral oophorectomy and/or hysterectomy), postmenopausal (cessation of menses for
more than 1 year), non-lactating, or of childbearing potential for whom the result of
a urine pregnancy test performed at screening is negative.

- The subject's left heart catheterization (obtained as part of the clinical
evaluation) is without clinically significant coronary atherosclerotic disease.

- The subject's echocardiogram (obtained as part of the clinical evaluation) is
consistent with a diagnosis of Takotsubo's Cardiomyopathy.

- The patient's electrocardiogram or cardiac enzymes including troponin or CKMB
(obtained as part of the clinical evaluation) is abnormal.

- The patient does not have a diagnosis or suspicion of Pheochromocytoma.

Exclusion Criteria:

- The subject has previously received I123-MIBG or I131-MIBG.

- The subject has a ventricular pacemaker that routinely functions (>5% paced beats) or
has received defibrillation (either external or via an ICD), anti-tachycardic pacing,
or cardioversion to treat a previous arrhythmic event.

- The subject was previously entered into this study or has participated in any other
investigational medicinal product or medical device study within 30 days of
enrollment.

- The subject has a previous history or suspicion of significant allergic reaction or
anaphylaxis to iodine or iodinated compounds.

- The subject had cardiac revascularization (eg, percutaneous transluminal coronary
angioplasty, PCI, or CABG) or insertion of an ICD within the last 30 days.

- The subject has a serious non-cardiac medical condition associated with significant
elevation of plasma catecholamines including Pheochromocytoma.

- The subject is claustrophobic or has a movement disorder that prevents him/her from
lying still in a supine position for up to an hour at a time.

- The subject has renal insufficiency (serum creatinine > 3.0 mg/dl [265umol/L]).

- The subject has participated in a research study using ionizing radiation in the
previous 12 months.

- The subject has a history of Type I or Type II Diabetes Mellitus with signs of
neurological involvement, signs or symptoms of neurological disease (eg, Parkinson's
Disease, Multiple System Atrophy, Parkinsonian syndromes), or other diseases known to
affect the sympathetic nervous system.