Cardiac Magnetic Resonance Unmasks Microvascular Angina

Patrice Wendling

March 07, 2018

New research provides robust evidence that cardiac magnetic resonance (CMR) can noninvasively and accurately detect microvascular coronary obstruction in patients with angina.

In the first of two studies, British researchers identify two diagnostic thresholds for coronary microvascular dysfunction on gadolinium-based stress perfusion CMR that correlate with an elevated index of microcirculatory resistance (IMR) value on the invasive gold standard for assessing flow limitation, fractional flow reserve (FFR).

The second study provides the first prospective validation of stress T1 mapping without contrast agents against invasive FFR for detecting obstructive epicardial coronary artery disease (CAD) (FFR < 0.8) and coronary microvascular dysfunction, defined by FFR of 0.8 or greater and an IMR of 25 U or greater.

"This new noninvasive CMR biomarker offers the unique potential to detect and differentiate between epicardial obstructive CAD and coronary microvascular dysfunction…with excellent interscan and intrascan reproducibility," lead author, Alexander Liu, MBBS, Oxford Centre for Clinical Magnetic Resonance Research at Oxford University, United Kingdom, and colleagues reported.

The authors noted that more than half of patients with angina have nonobstructive coronary arteries on invasive angiography. The ability of stress T1 mapping to noninvasively diagnose and differentiate between epicardial CAD and coronary microvascular disease "may represent a breakthrough" for patients with microvascular dysfunction, who are often reassured of having no significant CAD or are treated empirically with antianginal drugs but experience reduced quality of life and adverse long-term prognosis.

"Overall, the authors should be commended for performing 2 important studies that open new frontiers for myocardial ischemia testing," Theodoros Karamitsos, MD, PhD, from Aristotle University of Thessaloniki, Greece, said in a related editorial, published with the two studies online ahead of the March 6 issue of the Journal of the American College of Cardiology (JACC).

Commenting for | Medscape Cardiology, Manesh R Patel, MD, chief of cardiology at Duke University Health System in Durham, North Carolina, who was not involved in the studies, said, "I don't know if it's a breakthrough yet, but it's an important step forward. It gives us a window into what might be possible."

He said the population at risk with microvascular disease or other issues that simple coronary angiography may not identify is not small, with his own research showing that only about 40% of people electively going to the catheterization lab in the United States have obstructive coronary disease.

"My one caveat is there are a lot of techniques in any one lab or any one machine works well, but they really need to be tested in larger populations and multiple centers so we can show they're reproducible and actually usable in the real world beyond the few places that do these," Patel said.

He noted that a previous study touted that an MRI technique looking at microvascular perfusion would identify more patients with cardiac syndrome X, but the "technique wasn't as reproducible" and "just didn't take off."

T1 Mapping

For the T1 mapping study, Liu and colleagues recruited 60 patients with stable angina referred for coronary angiography and 30 healthy volunteers, who underwent CMR to assess left ventricular function, ischemia (adenosine stress/rest T1 mapping and first-pass perfusion), and infarction (scar imaging with late-gadolinium enhancement). FFR and IMR were assessed within 7 days after CMR.

Adenosine stress and rest T1 mapping were performed before administration of gadolinium-based contrast agents. T1 maps were acquired by using the Shortened Modified Look-Locker Inversion recovery sequence.

In all, 40% of patients had single-vessel angiographic disease, 22% had two-vessel CAD, 8% had three-vessel disease, and 30% no significant CAD. Myocardial scars were present downstream of 9% of coronary arteries.

In healthy controls, resting T1 was normal and T1 reactivity (ΔT1) during stress testing was 6.2%.

In patients with CAD, infarcted segments had elevated resting T1 values and a nearly abolished stress T1 reactivity (ΔT1 0.7%).

Myocardium downstream of nonobstructive coronary arteries with evidence of microvascular dysfunction (FFR ≥ 0.8 and IMR ≥ 25 U) had impaired stress T1 reactivity compared with myocardium with an IMR less than 25 U (3.0% vs 5.0%; P < .001).

This blunted T1 reactivity, however, was significantly higher than the near-abolished T1 reactivity downstream of obstructive epicardial CAD (3.0% vs 0.7%; P < .001), "which enabled distinction between these 2 pathological entities," the authors write.

A stress ΔT1 cutoff of 4.0% downstream of nonobstructive coronary arteries accurately detected microvascular dysfunction on receiver-operating characteristic curve analysis (area under the curve [AUC], 0.95; P < .001), with a specificity, sensitivity, and accuracy of 94%, positive predictive value of 92%, and negative predictive value of 96%.

Finally, stress T1 reactivity (AUC, 0.97) significantly outperformed stress gadolinium-based perfusion for detecting obstructive epicardial CAD when analyzed visually (AUC, 0.85), semi-quantitatively by using the myocardial perfusion reserve index (AUC, 0.87), and by absolute quantification of myocardial blood flow at stress and rest (AUC, 0.91; all comparisons P < .01).

"The T1 mapping is something that can be addressed by any good laboratory with MR, and now we know what we're talking about," JACC editor Valentin Fuster, MD, PhD, director of the Mount Sinai Cardiovascular Institute in New York City, said in an interview.

That said, this is the first time such comparative data have been reported and were produced by cardiac MR experts at Oxford. "In order for us to really begin to use this approach clinically, we need to be convinced that other groups can reproduce the same data," he added.

In his editorial, Karamitsos also called for larger studies to test whether the superiority of stress T1 mapping, which was based on per-vessel analysis data, "also translates into a better diagnostic performance on a per-patient basis in single-vessel or multivessel CAD."

He also noted that there are no head-to-head comparisons with other T1-mapping sequences and that the plethora of T1-mapping methods available generates confusion and uncertainty about whether results of a single study can be confirmed in a similar patient population with a different T1-mapping method.

"Streamlining of the various T1 mapping protocols and developing a unified approach to T1 mapping is one of the most important challenges for the CMR community," he writes.

Novel Diagnostic Thresholds

For the second study, Liu and colleagues recruited 50 patients with angina (mean age, 65 years) referred for angiography and 20 healthy age-matched volunteers, all of whom underwent CMR, including left ventricular function, adenosine stress and rest perfusion, and late-gadolinium enhancement.

During subsequent angiography within 7 days of CMR, 28 patients had significant epicardial CAD and 22 had angiographic nonobstructive CAD (microvascular dysfunction as above; FFR ≥ 0.8 and IMR ≥ 25 U).

Myocardium with IMR less than 25 U had a similar myocardial perfusion reserve index (MPRI) — defined as the stress/rest ratio of myocardial signal intensity upslopes, normalized to the arterial input function — compared with that of normal controls (1.9 vs 2.0; P = .49).

In contrast, myocardium with an IMR of 25 U or greater had impaired MPRI, identical to myocardium downstream of obstructive CAD (1.2 vs 1.2; P = .61).

An MPRI threshold of 1.4 proved optimal for detecting inducible myocardial ischemia from obstructive CAD (AUC, 0.95; P <.001).  

When applied to patients with three-vessel nonobstructive CAD, this threshold accurately detected inducible ischemia due to coronary microvascular dysfunction (AUC, 0.90; P < .0001), with a specificity of 95%, sensitivity of 89%, and accuracy of 92%.

An MPRI threshold of 1.6 yielded a high negative predictive value (95%) and sensitivity (94%) for ruling out significant inducible ischemia due to microvascular dysfunction.

For patients with an MPRI between 1.4 and 1.6, absolute quantification of myocardial blood flow (MBF) during adenosine stress may help characterize microvascular dysfunction. A stress MBF threshold of 2.3 mL/min/g distinguished patients with this milder form of microvascular dysfunction from healthy controls with 100% specificity and 100% positive predictive value (AUC, 0.76; P < .0001).

"A CMR-based combined diagnostic pathway for both epicardial and microvascular CAD deserves further clinical validation," Liu and his colleagues conclude.

"There is no doubt that these novel, noncontrast CMR techniques offer important pathophysiological insights into myocardial ischemia and have a significant diagnostic potential that justifies the conduction of a large-scale study," Karamitsos concluded in his editorial.

The studies and Liu were funded by a British Heart Foundation Clinical Research Training Fellowship grant. Karamitsos, Patel, and Fuster reported no relevant conflicts of interest.

J Am Coll Cardiol. 2018;71:957-968, 969-979, 980-982. Liu T1 mapping: full text; Liu threshold: full text,  Editorial

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