Vasospasm, Microvascular Dysfunction Tied to MACE in Nonobstructive CAD

The presence of epicardial coronary spasm and increased microvascular resistance in patients with angina but without obstructive coronary artery disease is associated with an increased risk of major adverse cardiovascular events, according to the results of a small study.

Patients with coronary spasm and a high index of microcirculatory resistance (IMR) had a significantly worse prognosis compared with those without vasospasm and a normal IMR (HR 6.23; 95% CI 1.21-118.48) over a median follow-up of 893 days. Led by Akira Suda, MD, PhD (Tohoku University Graduate School of Medicine, Sendai, Japan), investigators observed no increased risk of cardiac death, nonfatal MI, or hospitalization for unstable angina among patients with vasospastic angina and a normal IMR nor among those without vasospasm but with microvascular resistance.   

The new study, which included 113 men and 74 women, highlights the growing awareness of nonobstructive CAD in patients with chest pain, according to experts. Viviany Taqueti, MD (Brigham and Women’s Hospital, Boston, MA), who wrote an editorial accompanying the study, said the findings provide yet more data “elucidating the impact of coronary microcirculation on macrovascular disease prognosis.”

Colin Berry, MBChB (University of Glasgow, Scotland), who was not involved in the study, urged caution when interpreting the study, noting to TCTMD that it lacks precision and accuracy given that it included just 187 patients with chest pain symptoms (and/or ECG abnormalities) and nonobstructive CAD on coronary angiography. During follow-up, only nine patients were hospitalized for angina and one patient died from cardiovascular causes.

Most of the time, it’s: ‘Angiogram done, next.’ Tom Ford

Nonetheless, the new data underline the importance of recognizing patients with angina symptoms who don’t present with obstructive CAD.

“Cardiology teaching has focused on obstructive coronary disease, and we have great treatments for patients with atherosclerosis and patients with obstructive disease,” Berry said. “We have great preventive therapies with statins and antiplatelet drugs. For those with obstructive disease, we have stents and bypass surgery. For patients with angina who don’t have these ‘physician-empowering’ features, the prioritization of these patients—both in the clinic and in research—greatly diminishes. In other words, our attention drops off. There is much less information about these patients.”

He noted that most patients who present with angina but without obstructive CAD are women.

“I’m really starting to reappraise my thinking about ischemic heart disease,” said Berry. “In obstructive coronary disease, both men and women can be affected, of course, but it preponderantly affects men. Small-vessel disease preponderantly affects women. If we’re using an anatomical strategy—that is, angiography—to identify obstructive disease, it favors a positive bias to diagnosing men. If we’re systematically not testing for small-vessel disease, it’s a systematic negative bias against women.”

Challenging the Cutoff for Microvascular Angina

In their paper, published in the November 12, 2019, issue of the Journal of the American College of Cardiology, Suda and colleagues argue against the conventional definition of microvascular angina, which is typically defined as an IMR > 25. The Cox proportional hazard analysis showed that a high IMR was significantly correlated with MACE, but the optimal IMR cutoff for identifying patients at risk for clinical events was 18.0 based on the receiver-operating characteristics curve analysis.

Tom J. Ford, MBChB (Central Coast Local Health District/Gosford Hospital, New South Wales, Australia), who led the CorMicA study along with Berry, said the Japanese report challenges the established diagnostic IMR threshold for microvascular angina. “We don’t really know what the cutoff should be for normal versus abnormal IMR and obviously that’s very important,” he told TCTMD, adding that whether an IMR of 18 or higher should define microvascular angina in non-Japanese patients needs to be tested in further studies.

For a general or interventional cardiologist, Ford said one of the most important findings is that roughly three-quarters of patients without obstructive CAD had coronary vasomotor dysfunction, which is similar to the rate observed in CorMicA.

“The vast majority of these patients, if they’re well selected, have cardiac vasospastic or functional coronary disorders that would explain their chest pain,” he said. In addition, the study also showed that a large proportion of patients with vasospastic angina—nearly 50%—also have a high index of microvascular resistance. Despite this, Ford said, the cardiology community still struggles with the treatment of patients with nonobstructive disease given that they often have other health issues.

“As a community, we know these patients are around and we’ve seen this for decades,” said Ford. “The trouble is, within this population, there are patients who have definite vasospasm or functional disorders, but there’s also an awareness that a lot of these patients also have other functional noncardiac issues. They could have psychosocial distress, they might have anxiety or depression. The field has been potentially put off from investigating these patients because of a bias where we don’t feel comfortable managing these patients that have other noncardiac issues.”

To TCTMD, Udo Sechtem, MD (Robert Bosch Krankenhaus, Stuttgart, Germany), who was not involved in the study but has studied nonobstructive CAD, said diagnostic measurements of IMR or coronary flow reserve, show interventional cardiologists “that there is life beyond the stenosis.” He said it’s very common to encounter patients with chest pain but without obstructive CAD. Depending on the study or database, roughly 50% of patients undergoing coronary angiography do not have an obstructed coronary artery.

There is life beyond the stenosis. Udo Sechtem   

When an interventionalist takes a patient to the catheterization lab and the angiogram reveals no coronary blockage, there is the assumption somebody made a mistake or that the patient is a “psychiatric case,” said Sechtem. Right now, though, the additional testing required to further investigate the causes of chest pain in these patients is performed infrequently.

“Most of the time, it’s: ‘Angiogram done, next,’” agreed Ford. “But if we really think about our patients, this guy or girl really deserves an answer. I don’t think this [testing] is for everyone, but if you look hard enough at the right patients [without obstructive CAD], a large proportion do have disorders. Depending on the patient, if you know who is on the table, a lot of them do want to know if it’s a functional coronary disorder and are they taking the right treatment.”

On the other hand, some patients are satisfied with knowing there is no obstructive CAD and they don’t need revascularization, particularly if they aren’t suffering from frequent angina, he said.  

Stopping Angina Medication in SCOT-HEART

Berry served as a site investigator for SCOT-HEART—which showed that a workup strategy using coronary CT angiography (CTA) was superior to standard care in patients with chest pain—and pointed out that angina medication was discontinued in patients without obstructive CAD in that trial. As a result, CTA was associated with smaller improvements in angina frequency and quality of life compared with standard care, a finding that was published in Heart in 2017.

That paper, according to Berry, was largely unappreciated by the cardiology community. The United Kingdom’s National Institute for Health and Care Excellence (NICE) recently recommended CTA as the first-line test for patients with stable CAD. “I can’t get my head around how you can have these guideline recommendations—with CT given primacy over other tests—where the strategy actually makes quality of life worse,” he said.

The likely explanation for the attenuated quality of life is that SCOT-HEART included a large proportion of patients with angina but without obstructive CAD and that angina medication was halted after CTA ruled out significant coronary stenosis, said Berry.

To TCTMD, Sechtem said cardiologists need to learn to think in a different way about CAD, but there is currently no financial incentive for further diagnostic testing. “Everything in the world of interventional cardiology is against doing extra tests in these patients,” he said. “This is why it’s not done. The quickest way to ensure it’s done immediately is to put a price tag on this. If provocative testing would be rewarded financially, I think it would be done.”

Berry sees trials like CorMicA as empowering for interventional cardiologists, noting that use of diagnostic guidewires for the assessment of microvascular disease is right up their alley. In the present study, the investigators also showed that the administration of intracoronary fasudil, a selective Rho-kinase inhibitor, significantly ameliorated IMR in patients with epicardial coronary spasm and microcirculatory resistance.

For Berry, it’s a novel concept that allows interventionalists to perform personalized medicine right in the cath lab. Still, he acknowledges the need for more evidence to support decision-making and the additional resources required for assessing microvascular function. He is currently leading the Cor-CTCA study, which is attempting to determine if coronary function parameters aid in diagnosis of CAD over standard care after obstructive CAD has been ruled out by CT angiography. So far, 200 of the planned 250 patients have been enrolled in the trial.