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Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve

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: NCT03249272
Recruitment Status : Terminated (Sponsor withdrew funding)
First Posted : August 15, 2017
Results First Posted : March 24, 2020
Last Update Posted : September 16, 2020
Sponsor:
Information provided by (Responsible Party):
Duke University

Brief Summary:
The aim of this study is to assess microvascular function as determined by a cardiovascular magnetic resonance measurement of whole-heart (global) perfusion reserve. The goal is to determine the prevalence of MVD in two common forms of non-ischemic cardiomyopathy, hypertrophic cardiomyopathy (HCM) and idiopathic dilated cardiomyopathy (IDCM). The hypothesis that an optimized technique will provide robust detection of MVD and that a multifaceted approach will provide new insights into the pathophysiology of MVD, including the influence of myocardial scarring upon the presence and severity of MVD.

Condition or disease Intervention/treatment Phase
Hypertrophic Cardiomyopathy Non-ischemic Dilated Cardiomyopathy Microvascular Ischaemia of Myocardium Drug: Regadenoson Drug: Adenosine Phase 4

Detailed Description:

Coronary microvascular dysfunction (MVD) has been implicated as an important marker of cardiac risk and has been thought to directly contribute to the pathogenesis of a wide variety of cardiomyopathies. For instance, MVD is believed to cause ischemia (with reduction in coronary flow reserve) in patients with hypertrophic cardiomyopathy (HCM) despite the presence of angiographically normal epicardial coronary arteries. The implication is that MVD in HCM may lead to the ventricular arrhythmias, sudden death, and heart failure. Similarly, patients with idiopathic dilated cardiomyopathy (IDCM) have blunted coronary flow reserve, which appears to be independently associated with poor prognosis.

Several etiologic mechanisms have been proposed to explain the occurrence of MVD, including structural and functional abnormalities1:

  1. increased microvascular resistance due to reduced vascular luminal caliber.
  2. reduced density of microvessels associated with replacement scarring.
  3. inappropriate vasoconstrictor responses.
  4. inadequate vasodilator responses.

Unfortunately, these mechanisms are difficult to study in humans since no technique currently allows the direct visualization of the coronary microcirculation in vivo. Thus, MVD has been largely studied using non-invasive imaging techniques, such as positron emission tomography (PET) or single photon emitted computed tomography (SPECT).

Although these methods have provided insight into MVD, much remains unknown. For example, even the prevalence of MVD in patients with various types of cardiomyopathy is unclear, with different studies showing widely different rates.

Cardiovascular magnetic resonance (CMR) is increasingly being used in clinical practice to evaluate cardiac disease. CMR employs a multifaceted imaging approach with separate techniques used to acquire separate sets of raw data, providing information on cardiac morphology, function, regional myocardial ischemia, scarring, and global myocardial perfusion reserve. The advantage of this approach is that image artifacts in one set of data will not affect the quality of the other datasets, and the datasets in combination can be used to distinguish separate pathophysiologies that could confound image interpretation. For example, perfusion defects could be due to ischemia or scar tissue, but since the investigators will obtain both perfusion images and scar images, the investigators will be able to resolve the etiology. Additionally, CMR provides high spatial resolution (over 10-fold higher than PET), and hence partial volume affects will be kept to a minimum and variability in measurements will be reduced.

The aim of this study is to assess microvascular function as determined by a cardiovascular magnetic resonance measurement of whole-heart (global) perfusion reserve. The goal is to determine the prevalence of MVD in two common forms of non-ischemic cardiomyopathy, hypertrophic cardiomyopathy (HCM) and idiopathic dilated cardiomyopathy (IDCM). The hypothesis that an optimized technique will provide robust detection of MVD and that a multifaceted approach will provide new insights into the pathophysiology of MVD, including the influence of myocardial scarring upon the presence and severity of MVD.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 31 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Participants undergoing cardiovascular magnetic resonance stress testing will be recruited and randomized to receive either regadenoson or adenosine.
Masking: Single (Outcomes Assessor)
Masking Description: The reader of the CMR scan will be blinded to the stress agent used.
Primary Purpose: Basic Science
Official Title: Microvascular Dysfunction in Nonischemic Cardiomyopathy: Insights From CMR Assessment of Coronary Flow Reserve
Actual Study Start Date : September 5, 2017
Actual Primary Completion Date : March 31, 2019
Actual Study Completion Date : March 31, 2019


Arm Intervention/treatment
Active Comparator: Hypertrophic cardiomyopathy Drug: Regadenoson
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.

Drug: Adenosine
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.

Active Comparator: Non-ischemic dilated cardiomyopathy Drug: Regadenoson
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.

Drug: Adenosine
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.

Active Comparator: Control Drug: Regadenoson
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.

Drug: Adenosine
Microvascular disease will be considered present if regional perfusion defects are observed or global perfusion reserve is reduced. For the assessment of microvascular disease, the adenosine and regadenoson groups will be combined, as the medications are considered interchangeable.




Primary Outcome Measures :
  1. Prevalence of Microvascular Dysfunction (MVD) by a CMR Measurement of Whole-heart (Global) Perfusion Reserve Ratio in Patients With Hypertrophic Cardiomyopathy, Non-ischemic Cardiomyopathy, and Controls. [ Time Frame: The prevalence of MVD will be determined based on the findings at the time of the scan on Day 1 of the study. ]

    Prevalence of microvascular dysfunction as determined by the CMR measure of global perfusion reserve ratio (GPR) in each these patient groups. MVD was considered present when either GPR was <2.0 or regional stress perfusion abnormalities were present.

    In order to calculate this ratio, coronary sinus flow was measured twice:

    1. prior to the the administration of adenosine/regadenoson
    2. during the administration of adenosine/regadenoson

    GPR is a ratio of coronary sinus flow during the administration adenosine/regadenoson divided by the baseline coronary sinus flow measured prior to the administration.

    Regional perfusion abnormalities will be assessed at the time of adenosine/regadenoson administration.



Secondary Outcome Measures :
  1. CMR Measurement of Global Perfusion Reserve Ratio [ Time Frame: The global perfusion ratio will be calculated from the measurements obtained at the time of the scan on Day 1 of the study. ]

    Comparison of the CMR measure of global perfusion reserve ratio (GPR) in each these patient groups.

    In order to calculate this ratio, coronary sinus flow was measured twice:

    1. prior to the the administration of adenosine/regadenoson
    2. during the administration of adenosine/regadenoson

  2. The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. [ Time Frame: Both global perfusion ratio and the presence of regional scarring will be determined/measured from the images obtained during the scan on Day 1 of the study. ]
    Relationship between global perfusion reserve ratio and regional myocardial scarring.



Information from the National Library of Medicine

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

Inclusion Criteria:

  • Men or women aged 18 years or older

Cardiomyopathy patients

  • Patients presenting for CMR with the clinical diagnosis of hypertrophic cardiomyopathy based on left ventricular wall thickness of at least ≥15 mm in the absence of any other cardiac or systemic cause of hypertrophy
  • Patients presenting for CMR with the clinical diagnosis of idiopathic dilated cardiomyopathy based upon left ventricular ejection fraction ≤40%, LV end-diastolic diameter ≥55 mm or left ventricular end-systolic diameter ≤45 mm, and the absence of coronary stenoses on angiography.

Control patients

  • Patients presenting for CMR without evidence of obstructive coronary artery disease either by coronary angiography or stress testing.

Exclusion Criteria:

  • Decompensated heart failure or hemodynamic instability
  • Prior coronary revascularization (PCI or CABG) or myocardial infarction (as evidenced by previously elevated CPK-MB or troponin levels)
  • Accelerating angina or unstable angina
  • Inability to physically tolerate MRI or implanted objects that are MRI incompatible
  • Inability to provide written informed consent obtained at time of study enrollment.
  • Severe claustrophobia
  • Advanced heart block or sinus node dysfunction
  • Hypersensitivity or allergic reaction to regadenoson or adenosine
  • Hypotension
  • Active bronchospasm or history of hospitalization due to bronchospasm
  • History of seizures
  • Recent cerebrovascular accident
  • Use of dipyridamole within the last 5 days
  • Contraindication to aminophylline
  • Severe renal insufficiency with estimated glomerular filtration rate <30 ml/min/ 1.73 m2
  • Pregnant or nursing

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): NCT03249272


Locations
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United States, North Carolina
Duke Cardiovascular Magnetic Resonance Center
Durham, North Carolina, United States, 27110
Sponsors and Collaborators
Duke University
Investigators
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Principal Investigator: Han Kim Duke University
  Study Documents (Full-Text)

Documents provided by Duke University:
Publications:
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Responsible Party: Duke University
ClinicalTrials.gov Identifier: NCT03249272    
Other Study ID Numbers: Pro00082447
First Posted: August 15, 2017    Key Record Dates
Results First Posted: March 24, 2020
Last Update Posted: September 16, 2020
Last Verified: August 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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Cardiomyopathies
Cardiomyopathy, Hypertrophic
Cardiomyopathy, Dilated
Ischemia
Pathologic Processes
Heart Diseases
Cardiovascular Diseases
Aortic Stenosis, Subvalvular
Aortic Valve Stenosis
Heart Valve Diseases
Cardiomegaly
Adenosine
Regadenoson
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Arrhythmia Agents
Vasodilator Agents
Purinergic P1 Receptor Agonists
Purinergic Agonists
Purinergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Adenosine A2 Receptor Agonists