Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG
|ClinicalTrials.gov Identifier: NCT01432626|
Recruitment Status : Completed
First Posted : September 13, 2011
Results First Posted : March 22, 2016
Last Update Posted : March 22, 2016
|First Submitted Date ICMJE||September 7, 2011|
|First Posted Date ICMJE||September 13, 2011|
|Results First Submitted Date||March 21, 2016|
|Results First Posted Date||March 22, 2016|
|Last Update Posted Date||March 22, 2016|
|Study Start Date ICMJE||September 2011|
|Actual Primary Completion Date||December 2014 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Number of Participants Who Had an Abnormal Regional Uptake of I-123 mIBG at Baseline (Acute Phase) and the Number of Participants Who Had an Abnormal I-123 mIBG Uptake on Follow up (Recovery Phase) [ Time Frame: During the acute phase (2-5 days with an expected mean 3 days) and after recovery of cardiac function (6 weeks) ]
Number of participants who had an abnormal regional uptake of I-123 mIBG at baseline (acute phase) and the number of participants who had an abnormal I-123 mIBG uptake on follow up (recovery phase)
|Original Primary Outcome Measures ICMJE
|Change History||Complete list of historical versions of study NCT01432626 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Outcome Measures ICMJE||Not Provided|
|Original Other Outcome Measures ICMJE||Not Provided|
|Brief Title ICMJE||Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG|
|Official Title ICMJE||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.
|Study Type ICMJE||Interventional|
|Study Phase||Not Applicable|
|Study Design ICMJE||Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
|Condition ICMJE||Stress Induced Cardiomyopathy|
|Intervention ICMJE||Drug: I-123 radiolabeled metaiodobenzylguanidine cardiac imaging
All subjects will receive an intravenous injection of 10 mCi (370 MBq) of 123I-mIBG. A ±10% tolerance of the nominal dose will be allowed, thus yielding an acceptable dose range of 9 to 11 mCi (333 to 407 MBq). The investigational medicinal product will be administered in a volume of 5 mL (diluted using 0.9% sodium chloride as needed) and injected over 1 to 2 minutes. The patient will have planar and SPECT imaging performed after the dose is administered. This dosing and imaging procedure will be performed during the acute phase and after the patient has recovered cardiac function, approximately 6 weeks later. This means that each study subject will receive a total of 2 doses of I123-mIBG at 2 different time points.
Other Name: AdreVeiw
|Study Arms||Experimental: Stress Induced Cardiomyopathy Patients
Patients presenting with stress induced cardiomyopathy, after meeting the Mayo criteria (normal coronary anatomy, EKG changes/Enzyme abnormalities, wall motion abnormalities consistent with stress induced cardiomyopathy and no evidence of pheochromocytoma) and signing informed consent, will receive an I123-mIBG scan to determine the sympathetic function of the heart during the acute presentation and after functional recovery.
Intervention: Drug: I-123 radiolabeled metaiodobenzylguanidine cardiac imaging
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE
|Actual Study Completion Date||June 2015|
|Actual Primary Completion Date||December 2014 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT01432626|
|Other Study ID Numbers ICMJE||PRO10080198|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement||
|Responsible Party||Prem Soman, University of Pittsburgh|
|Study Sponsor ICMJE||University of Pittsburgh|
|Collaborators ICMJE||GE Healthcare|
|PRS Account||University of Pittsburgh|
|Verification Date||March 2016|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP