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

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.

• Regadenoson (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 (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.

Primary outcomes

• 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 outcomes

• 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.

Sex: All, ages: 18 Years to any

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

Participant flow

Outcome results

• 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. (Primary), Number, Percentage of group with MVD: Hypertrophic Cardiomyopathy 79; Non-ischemic Dilated Cardiomyopathy 33.3; Control 20
• CMR Measurement of Global Perfusion Reserve Ratio (Secondary), Median, ratio: Hypertrophic Cardiomyopathy 2.99 (1.87 to 4.65); Non-ischemic Dilated Cardiomyopathy 3.04 (2.64 to 3.61); Control 3.83 (2.42 to 4.34)
• The Association Between Global Perfusion Reserve (GPR) Ratio and Regional Myocardial Scarring. (Secondary), Mean, Global perfusion reserve ratio: Hypertrophic Cardiomyopathy - Scarring 3.19 +/- 1.71; Hypertrophic Cardiomyopathy - Without Scarring 5.91 +/- 4.09; Non-ischemic Dilated Cardiomyopathy - Scarring 3.16 +/- 0.65; Non-ischemic Dilated Cardiomyopathy - Without Scarring ; Control - Scarring ; Control - Without Scarring 3.53 +/- 1.26

Adverse events

Time frame: Adverse events were assessed during the time of the MR scan.

Limitations and caveats: Slow recruitment led to the end of the study.

• 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. PMID 25311229
• 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. PMID 16631001
• 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. PMID 19356464
• 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. PMID 17314342
• 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. PMID 12505229

• Study Protocol and Statistical Analysis Plan (PDF, 2016-03-01)

• Han Kim, Principal investigator, Duke University