Hypertrophic Cardiomyopathy, Microvascular Ischaemia of Myocardium, Non-ischemic Dilated Cardiomyopathy
Conditions
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.
Interventions
DRUGAdenosine
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.
DRUGRegadenoson
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.
Sponsors
Duke University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
BASIC_SCIENCE
Masking
SINGLE (Outcomes Assessor)
Masking description
The reader of the CMR scan will be blinded to the stress agent used.
Intervention model description
Participants undergoing cardiovascular magnetic resonance stress testing will be recruited and randomized to receive either regadenoson or adenosine.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. | 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
| Measure | Time frame | Description |
|---|---|---|
| CMR Measurement of Global Perfusion Reserve Ratio | 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 |
| The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. | 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. |
Countries
United States
Participant flow
Pre-assignment details
Due to the slow pace of recruitment, the sponsor withdrew funding for the study. Of the expected 75 participants, 31 were recruited. As was pre-specified, the regadenoson and adenosine groups were combined for analysis as these interventions are interchangeable.
Participants by arm
| Arm | Count |
|---|---|
| Hypertrophic Cardiomyopathy Microvascular dysfunction (MVD) will be categorized as present based upon the presence of one of the following:
1. Global perfusion reserve (GPR) \< 2.0.
* Coronary sinus blood flow (CS) with velocity-encoded CMR will be measured during maximal vasodilation and at rest. GPR was calculated as the ratio of stress CS to rest CS blood flow.
2. The presence of regional perfusion abnormalities on visual assessment of first pass perfusion images.
The prevalence will be calculated by dividing the number of hypertrophic cardiomyopathy patients with MVD by the total number of patients with hypertrophic cardiomyopathy. | 19 |
| Non-ischemic Dilated Cardiomyopathy Microvascular dysfunction (MVD) will be categorized as present based upon the presence of one of the following:
1. Global perfusion reserve (GPR) \< 2.0.
* Coronary sinus blood flow (CS) with velocity-encoded CMR will be measured during maximal vasodilation and at rest. GPR was calculated as the ratio of stress CS to rest CS blood flow.
2. The presence of regional perfusion abnormalities on visual assessment of first pass perfusion images.
The prevalence will be calculated by dividing the number of non-ischemic dilated cardiomyopathy patients with MVD by the total number of patients with non-ischemic dilated cardiomyopathy. | 6 |
| Control Patients Microvascular dysfunction (MVD) will be categorized as present based upon the presence of one of the following:
1. Global perfusion reserve (GPR) \< 2.0.
* Coronary sinus blood flow (CS) with velocity-encoded CMR will be measured during maximal vasodilation and at rest. GPR was calculated as the ratio of stress CS to rest CS blood flow.
2. The presence of regional perfusion abnormalities on visual assessment of first pass perfusion images.
The prevalence will be calculated by dividing the number of control patients with MVD by the total number of control patients. | 6 |
| Total | 31 |
Baseline characteristics
| Characteristic | Hypertrophic Cardiomyopathy | Total | Control Patients | Non-ischemic Dilated Cardiomyopathy |
|---|---|---|---|---|
| Age, Continuous | 46.1 years STANDARD_DEVIATION 17.7 | 50.3 years STANDARD_DEVIATION 15.9 | 53.2 years STANDARD_DEVIATION 5.7 | 60.6 years STANDARD_DEVIATION 12.2 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 2 Participants | 4 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 16 Participants | 26 Participants | 5 Participants | 5 Participants |
| Region of Enrollment United States | 19 Participants | 30 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Female | 5 Participants | 12 Participants | 5 Participants | 2 Participants |
| Sex: Female, Male Male | 14 Participants | 19 Participants | 1 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk |
|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 3 |
| other Total, other adverse events | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 3 |
| serious Total, serious adverse events | 0 / 10 | 0 / 9 | 0 / 2 | 0 / 4 | 0 / 3 | 0 / 3 |
Outcome results
Primary
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.
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.
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.
Population: Due to the slow pace of recruitment, the sponsor withdrew funding for the study. Of the expected 75 participants, 31 were recruited. As was pre-specified, the regadenoson and adenosine groups were combined for analysis as these interventions are interchangeable.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Hypertrophic Cardiomyopathy | 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. | 79 Percentage of group with MVD |
| Non-ischemic Dilated Cardiomyopathy | 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. | 33.3 Percentage of group with MVD |
| Control | 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. | 20 Percentage of group with MVD |
Secondary
CMR Measurement of Global Perfusion Reserve Ratio
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
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.
Population: As was pre-specified, the regadenoson and adenosine groups were combined for analysis as these interventions are interchangeable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Hypertrophic Cardiomyopathy | CMR Measurement of Global Perfusion Reserve Ratio | 2.99 ratio |
| Non-ischemic Dilated Cardiomyopathy | CMR Measurement of Global Perfusion Reserve Ratio | 3.04 ratio |
| Control | CMR Measurement of Global Perfusion Reserve Ratio | 3.83 ratio |
Secondary
The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring.
Relationship between global perfusion reserve 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.
Population: As was pre-specified, the regadenoson and adenosine groups were combined for analysis as these interventions are interchangeable. One of the control patients was not able to hold his/her breath, and no image was acquired for stress perfusion myocardial flow. Thus, global perfusion reserve could not be calculated.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Hypertrophic Cardiomyopathy | The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. | 3.19 Global perfusion reserve ratio | Standard Deviation 1.71 |
| Non-ischemic Dilated Cardiomyopathy | The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. | 5.91 Global perfusion reserve ratio | Standard Deviation 4.09 |
| Control | The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. | 3.16 Global perfusion reserve ratio | Standard Deviation 0.65 |
| Control - Without Scarring | The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. | 3.53 Global perfusion reserve ratio | Standard Deviation 1.26 |