Working…
ClinicalTrials.gov
ClinicalTrials.gov Menu

Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT01432626
Recruitment Status : Completed
First Posted : September 13, 2011
Results First Posted : March 22, 2016
Last Update Posted : March 22, 2016
Sponsor:
Collaborator:
GE Healthcare
Information provided by (Responsible Party):
Prem Soman, University of Pittsburgh

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Stress Induced Cardiomyopathy Drug: I-123 radiolabeled metaiodobenzylguanidine cardiac imaging Not Applicable

  Hide Detailed Description

Detailed Description:

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.


Layout table for study information
Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 10 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Diagnostic
Official Title: The Evaluation of the Pathogenesis of Stress-Induced Cardiomyopathy by I-123 MIBG Imaging
Study Start Date : September 2011
Actual Primary Completion Date : December 2014
Actual Study Completion Date : June 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
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.
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




Primary Outcome Measures :
  1. 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)



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Layout table for eligibility information
Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01432626


Locations
Layout table for location information
United States, Pennsylvania
University of Pittsburgh Medical Center
Pittsburgh, Pennsylvania, United States, 15213
Sponsors and Collaborators
University of Pittsburgh
GE Healthcare
Investigators
Layout table for investigator information
Principal Investigator: Prem Soman, MD University of Pittsburgh Heart Vascular Institute

Layout table for additonal information
Responsible Party: Prem Soman, Principle Investigator, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01432626     History of Changes
Other Study ID Numbers: PRO10080198
First Posted: September 13, 2011    Key Record Dates
Results First Posted: March 22, 2016
Last Update Posted: March 22, 2016
Last Verified: March 2016
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Prem Soman, University of Pittsburgh:
stress induced cardiomyopathy
broken heart syndrome
Takotsubo cardiomyopathy
transient apical ballooning syndrome
apical ballooning cardiomyopathy
stress cardiomyopathy
non-ischemic cardiomyopathy
Additional relevant MeSH terms:
Layout table for MeSH terms
Cardiomyopathies
Takotsubo Cardiomyopathy
Heart Diseases
Cardiovascular Diseases
Ventricular Dysfunction, Left
Ventricular Dysfunction
3-Iodobenzylguanidine
Antineoplastic Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Radiopharmaceuticals