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

NCT ID: NCT03249272

Last Updated: 2020-09-16

Basic Information

• Recruitment Status: TERMINATED
• Clinical Phase: PHASE4
• Total Enrollment: 31 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2017-09-05
• Study Completion Date: 2019-03-31

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.

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.

Conditions

Hypertrophic Cardiomyopathy; Non-ischemic Dilated Cardiomyopathy; Microvascular Ischaemia of Myocardium

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: BASIC_SCIENCE
• Blinding Strategy: SINGLE

Study Groups

Hypertrophic cardiomyopathy

Group Type: ACTIVE_COMPARATOR

Regadenoson

Intervention Type: DRUG

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.

Adenosine

Intervention Type: DRUG

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.

Non-ischemic dilated cardiomyopathy

Group Type: ACTIVE_COMPARATOR

Regadenoson

Intervention Type: DRUG

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.

Adenosine

Intervention Type: DRUG

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.

Control

Group Type: ACTIVE_COMPARATOR

Regadenoson

Intervention Type: DRUG

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.

Adenosine

Intervention Type: DRUG

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.

Interventions

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.

Intervention Type: 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.

Intervention Type: DRUG

Eligibility 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

• Minimum Eligible Age: 18 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Duke University

OTHER

Sponsor Role: lead

Responsible Party

Responsibility Role: SPONSOR

Principal Investigators

Han Kim

Role: PRINCIPAL_INVESTIGATOR

Duke University

Locations

Duke Cardiovascular Magnetic Resonance Center

Durham, North Carolina, United States

Countries

United States

References

Camici PG, d'Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nat Rev Cardiol. 2015 Jan;12(1):48-62. doi: 10.1038/nrcardio.2014.160. Epub 2014 Oct 14.

Reference Type: BACKGROUND

PMID: 25311229 (View on PubMed)

Klem I, Heitner JF, Shah DJ, Sketch MH Jr, Behar V, Weinsaft J, Cawley P, Parker M, Elliott M, Judd RM, Kim RJ. Improved detection of coronary artery disease by stress perfusion cardiovascular magnetic resonance with the use of delayed enhancement infarction imaging. J Am Coll Cardiol. 2006 Apr 18;47(8):1630-8. doi: 10.1016/j.jacc.2005.10.074. Epub 2006 Mar 27.

Reference Type: BACKGROUND

PMID: 16631001 (View on PubMed)

Klem I, Greulich S, Heitner JF, Kim H, Vogelsberg H, Kispert EM, Ambati SR, Bruch C, Parker M, Judd RM, Kim RJ, Sechtem U. Value of cardiovascular magnetic resonance stress perfusion testing for the detection of coronary artery disease in women. JACC Cardiovasc Imaging. 2008 Jul;1(4):436-45. doi: 10.1016/j.jcmg.2008.03.010.

Reference Type: BACKGROUND

PMID: 19356464 (View on PubMed)

Camici PG, Crea F. Coronary microvascular dysfunction. N Engl J Med. 2007 Feb 22;356(8):830-40. doi: 10.1056/NEJMra061889. No abstract available.

Reference Type: BACKGROUND

PMID: 17314342 (View on PubMed)

Choudhury L, Mahrholdt H, Wagner A, Choi KM, Elliott MD, Klocke FJ, Bonow RO, Judd RM, Kim RJ. Myocardial scarring in asymptomatic or mildly symptomatic patients with hypertrophic cardiomyopathy. J Am Coll Cardiol. 2002 Dec 18;40(12):2156-64. doi: 10.1016/s0735-1097(02)02602-5.

Reference Type: BACKGROUND

PMID: 12505229 (View on PubMed)

Provided Documents

Document Type: Study Protocol and Statistical Analysis Plan

View Document

Other Identifiers

Pro00082447

Identifier Type: -

Identifier Source: org_study_id