Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG
Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG
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.
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.