Cath Lab Exercise Test Flags Coronary Microvascular Dysfunction

Marlene Busko

November 28, 2019

PHILADELPHIA — In patients with angina but no obstructive coronary artery disease (CAD), low coronary flow reserve (CFR) detected in the cath lab can provide a clear diagnosis of coronary microvascular dysfunction (CMD), researchers report.

CMD — defined as a CFR < 2.5 — correlated with poor exercise performance on a supine bike test as well as adenosine-induced myocardial ischemia on a stress magnetic resonance imaging (MRI) test.  

The study by Haseeb Rahman, PhD, a postdoctoral research fellow at Kings College London, UK, and colleagues was published online November 11 in Circulation, just ahead of the American Heart Association Scientific Sessions 2019, where Rahman also presented a substudy and was a finalist in the Samuel A. Levine Early Career Clinical Investigator Award Competition. The study was funded by the British Heart Foundation and the UK National Institute for Health Research.

The main study showed that a simple test in the cath lab to measure CFR "identifies a group of patients who are unable to adapt to exercise and other stresses during day-to-day activities," senior and corresponding author Divaka Perera, MD, a cardiologist at Guy's & St Thomas' Hospital and professor of interventional cardiology, King's College London, told | Medscape Cardiology.

The takeaway message for cardiologists, he said, is: "Don't stop when an angiogram shows that the large arteries have no blockages. Go on to do this simple test, which ought to add no more than 15 to 20 minutes extra, to measure the CFR and microvascular resistance."

This would enable clinicians to "diagnose and manage this large patient group" with angina, chest pain on exertion, but no large coronary blockages "better than we are currently doing," he said.

In the European Society of Cardiology guidelines, the recommendation for measuring CFR in patients with angina and nonobstructive CAD has just been upgraded from 2B, that is, may be useful in some patients, to 2A, should be considered in most patients.

They expect that the American Heart Association/American College of Cardiology guidelines, "will follow suit soon," Perera said.

"It is clear that the coronary microvasculature represents the next frontier in the invasive assessment of coronary physiology," William F. Fearon, MD, professor of medicine, and director of interventional cardiology at Stanford University, California, and Bernard De Bruyne, MD, a cardiologist at Cardiovascular Center Aalst, Belgium, and Lausanne University Hospital, Switzerland, write in an accompanying editorial.

"CMD is common," and this study confirmed that "it can be assessed invasively in the cath lab using wire-based techniques," Fearon told | Medscape Cardiology in an email.

However, he is not yet convinced of the existence of "structural" and "functional" subtypes of CMD, which the researchers propose.

Supine Bicycle Exercise Test, Adenosine-Vasodilation MRI Scan

"About 40% of patients with angina have no blockages on an angiogram, and identifying those with abnormal blood flow responses to exercise is crucial for diagnosis and initiating appropriate therapy," Rahman | Medscape Cardiology in an email.

CFR, the ratio of maximum achievable coronary blood flow and blood flow at rest, indicates the ability of the heart to increase blood supply in response to increased demand, such as during exercise, and is normally above 3 and sometimes even above 4, Perera explained.

It is used to diagnose CMD, he noted, but "the precise meaning of having a low CFR in the absence of blockages in the large arteries was not clear."

The researchers enrolled 85 patients with stable angina and nonobstructive CAD who had chest pain on exertion and were undergoing elective diagnostic angiography at their center. The patients were a mean age of 57 and 78% were women.

The cath lab had a special set-up with a supine bicycle on the cath table. The patients had angiography via the right radial artery at rest and while they pedaled the bike.

The interventionalists used a dual intracoronary wire to measure distal coronary blood pressure and average peak flow velocity from Doppler ultrasound in the left anterior descending artery at rest and during supine bicycle pedaling.

Microvascular resistance was calculated as coronary perfusion pressure divided by flow velocity.

At another visit, patients had a myocardial MRI scan with adenosine-mediated vasodilation that simulates the effect of exercise.

Researchers quantified global myocardial blood flow at rest and after hyperemia induced by intravenous adenosine.

About half of participants, 45 patients (53%), had CMD (defined as CFR < 2.5), and the remaining patients (controls) had CFR ≥ 2.5.

More patients in the CMD group than in the control group had inducible myocardial ischemia (82% vs 22%).

Patients in the CMD group also had a lower myocardial perfusion reserve than those in the control group (2.01 vs 2.68; P < .001).

In the controls, perfusion efficiency improved going from rest to exercise and was unchanged during hyperemia.

In contrast, in patients with CMD, perfusion efficiency decreased during both forms of stress.

Functional vs Structural CMD

The researchers propose a new classification for CMD subtypes — functional and structural.

They report that within the CMD cohort, 62% of patients had "functional" CMD with a normal minimal microvascular resistance and 38% of patients had "structural" CMD with elevated hyperemic microvascular resistance.

In roughly two thirds — the functional CMD group — diminished vasodilator reserve was due to abnormal perfusion at rest, rather than inability to vasodilate in response to stress. Only roughly a third — the structural CMD group — fit the traditional paradigm of abnormal flow at maximum stress.

This "is an arbitrary distinction that is being introduced for the first time by these authors," Fearon pointed out.

"The 'functional' CMD patients are those with abnormal CFR due to a high resting flow," he said. "It is not clear to me that this group even has CMD. We will need to await more data to determine the relevance, if any, of this distinction."

"I agree that functional CMD doesn't appear to have the previously recognized features of CMD (ie, high microvascular resistance even during peak stress as we saw in our structural CMD group)," Perera said.

But they do have the same end result — "low CFR, ischemia on MRI, maladaptation to exercise, and angina that limits their quality of life," he said, which is why the group called it "functional" CMD.

More research is needed, Perera agrees, to see if functional disease precedes the structural phenotype or if they are distinct conditions that have different long-term outcomes. They have already embarked on the next steps to validate these findings and move the research forward, he said.

Acetylcholine-Induced Vasodilation

At the AHA Scientific Sessions, Rahman reported results from a follow-up study in a subset of 30 patients from the main study, who also had pharmacological vasodilation using acetylcholine.

This provides information about endothelial function, he said, whereas the more widely used test of vasodilation with adenosine gives insight into smooth muscle function.

They found that 23% of controls with normal response to adenosine had ischemia induced by acetylcholine, seen on high-resolution MRI.

Much of this is driven by endothelial dysfunction, "and therefore this, too, is an important group to characterize in clinical practice," the researchers write.

Patients with both endothelial and smooth muscle dysfunction had the highest rate of inducible ischemia.

"The presence of isolated endothelial dysfunction also identifies a group with a high prevalence of inducible ischemia and exercise pathology, demonstrating the pivotal role of acetylcholine testing when making a diagnosis" of CMD, the authors conclude.  

Taken together, the two studies reveal that "tiered use of both vasodilators adenosine and acetylcholine are crucial to accurately identify those with microvascular angina," Rahman said.

The group recently published a suggested diagnostic algorithm for patients with angina and nonobstructive CAD seen in the cath lab.

Circulation. Published online November 11, 2019. Article, Editorial

American Heart Association (AHA) Scientific Sessions 2019: Abstract 113. Presented November 16, 2019

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