Frederick Epstein1
1University of Virginia, United States
Synopsis
Coronary microvascular disease (CMD) is an important cause of myocardial ischemia, a central mechanism underlying heart failure with preserved ejection fraction, and an important risk factor for major adverse cardiac events and mortality. This presentation reviews pharmacological methods to modulate the coronary microvessels and their use in MR imaging to detect and quantify CMD. Specific methods covered include adenosine first-pass gadolinium-enhanced MRI, adenosine T1 mapping, arterial spin labeling, and LNAME T1 mapping. Studies applying these methods in obese and diabetic patients are reviewed, as are studies in animal models of CMD that investigate biological disease mechanisms and novel therapies.
Background
Historically, ischemic heart disease has been essentially equated with obstructive coronary artery disease (CAD) caused by atherosclerosis of the large epicardial coronary vessels. However, in the past decade increased attention has been given to coronary microvascular disease (CMD), which is now understood to be an important cause of myocardial ischemia (1), a central mechanism underlying heart failure with preserved ejection fraction (HFpEF) (2), and an important risk factor for major adverse cardiac events and mortality (3).
CMD is defined as an impairment of the ability of the coronary microvessels to react (typically to dilate) in response to pharmacologic vasoactive compounds. The most common vasodilator for CMD assessment is adenosine, which causes adenosine-receptor-mediated and endothelial-independent dilation of the coronary arterioles. In healthy subjects, adenosine causes a 3-4-fold increase in coronary flow and myocardial perfusion relative to the resting state, leading to a normal coronary flow reserve (CFR) or myocardial perfusion reserve (MPR) in the range of 3 to 4. Given this normal range, CMD is typically defined as adenosine-induced CFR or MPR < 2.5. While adenosine is the most commonly used vasodilator, it is not the only one. Regadenason is another vasodilator that is selective for the adenosine A2A receptor, and it has fewer side effects. Also, for invasive catheter-based assessments of CFR, in addition to the adenosine response, intracoronary acetylcholine is often used to assess endothelial-dependent vasodilation. While CMD can refer to both endothelial-dependent and endothelial-independent impairments of microvascular reactivity, the endothelial-independent impairment, probed using adenosine, has stronger associations with adverse outcomes and diastolic dysfunction (4) and accounts for most data relating CMD to outcomes and HFpEF (3).
While a reduction in CFR or MPR is indicative of CMD, it is not specific for CMD, as stenoses of the epicardial coronary arteries can also reduce CFR and MPR. Thus, the diagnosis of CMD can be made when MPR is reduced in the absence of significant CAD. Also, while CAD often leads to focal reductions in adenosine myocardial perfusion in specific coronary territories (which are readily detected visually), CMD is global in nature, visual detection is very challenging, and quantitative assessment of MPR is essential. MRI methods to assess CMD
The most common way to assess CMD by imaging is to perform quantitative perfusion imaging under rest and adenosine stress conditions, either using PET or MRI. Using MRI, quantitative myocardial perfusion imaging is typically performed using a dual-contrast first-pass sequence for acquisition of both the arterial input function and the tissue function after injection of a bolus of gadolinium (5). After acquiring images at rest and stress, quantitative perfusion analysis using the Fermi-function deconvolution method (6) is applied to the rest and stress images to quantify myocardial perfusion at both conditions, and MPR is computed as stress perfusion divided by rest perfusion. As an example, quantitative first-pass MRI has detected CMD in patients with type 2 diabetes or metabolic syndrome and normal coronary arteries by quantifying a lower MPR compared to age-matched healthy controls ((2.21 [1.95,2.69] vs. 2.93 [2.763.19], p < 0.001) (7).
Non-contrast T1 mapping at rest and with adenosine is another technique to assess CMD. In this method, adenosine-induced coronary vasodilation leads to an increase in myocardial blood volume (MBV), and because the T1 of blood is greater than the T1 of myocardium, the increase in MBV is reflected as an increase in the aggregate T1 of heart tissue, an effect referred to as adenosine T1 reactivity. Using adenosine T1 mapping, compared with normal control subjects, patients with chronic kidney disease (a contraindication for gadolinium) had a blunted adenosine T1 reactivity (ΔT1 of 4.0 ± 4.8% vs. 7.1 ± 3.8%; p ≤ 0.001) (8), indicative of CMD.
For preclinical studies in small animals aimed at understanding biological mechanisms of CMD or testing new therapies for CMD, due to the high heart rate and small size of the animals, cardiac arterial spin labeling (ASL) is preferred over first-pass MRI to quantify myocardial perfusion and MPR (9,10). Our group has shown, using ASL at rest and with adenosine, that mice fed a high-fat high-sucrose diet (HFHSD) have impaired MPR and represent a diet-induced model of CMD (11). Further, we have shown that treatment with eplerenone provides partial protection against CMD in HFHSD mice (11).
Lastly, a novel experimental MRI method to assess endothelial-dependent coronary microvascular dysfunction is LNAME T1 mapping (12). LNAME (N(G)-Nitro-L-arginine methyl ester) is a nitric oxide synthase (NOS) inhibitor that causes the coronary microvessels to constrict and also increases their permeability. We have shown that T1-mapping after LNAME administration detects an increase in T1 which is mediated through endothelial NOS, and that the LNAME T1 response is diminished in mice fed a high fat diet, indicative of coronary microvascular endothelial dysfunction (12). Summary
In summary, the clinical importance of CMD is increasingly recognized, and perfusion MRI and T1 mapping applied at rest and during application of vasoactive compounds that modulate the coronary microvessels enables the detection of normal or impaired coronary microvascular function. This presentation reviews MRI methods to assess CMD and discusses their application to various scenarios involving clinical or experimental CMD. Acknowledgements
NIH NIBIB R01 001763
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