INOCA May Be at the Root of Angina for Many Long-COVID Patients

For a substantial portion of patients experiencing long COVID and new-onset chest pain, ischemia with nonobstructive coronary arteries (INOCA) appears to be the underlying cause of their angina, according to a 20-patient series out of Spain. Moreover, medical therapy tailored to what was driving the INOCA was able to significantly reduce patients’ symptom burden.

The results were published recently as a research letter in JACC: Cardiovascular Interventions.

Lead author Javier Escaned, MD, PhD (Hospital Clínico San Carlos, Madrid, Spain), said that given their group’s work on INOCA and invasive physiological testing more generally, the findings don’t come as a complete surprise. Escaned and colleagues had already, since November 2017, been tracking patients who underwent angiography due to angina but had obstructive disease ruled out by that test or through physiological assessment.

But, of course, post-COVID chest pain is a novel area that’s just begun to be explored.

When the investigators enrolled their first patient who had angina symptoms after recovering from her viral infection, in mid-2020, it was known that “COVID is an endothelial disease,” Escaned noted, highlighting a European Heart Journal paper that was an early voice on the topic. Another early report, published in JAMA, specified angina as the dominant symptom in long COVID, affecting 25% of patients with the condition.

Now, 4 years later, “we do hope that with vaccination there is less occurrence of [angina after COVID-19], but still this is something that may ruin the life of a patient,” said Escaned. “The most important thing at this stage is that physicians are aware that in those patients who have long COVID that this particular aspect can be [addressed] and improve quality of life.”

The most important thing at this stage is that physicians are aware that in those patients who have long COVID that this particular aspect can be [addressed] and improve quality of life. Javier Escaned

Colin Berry, MBChB, PhD (University of Glasgow, Scotland), principal investigator for the CorMicA trial of INOCA patients as well as an expert on COVID-19’s sequelae, told TCTMD that these data provide welcome perspective. With long COVID, which affects relatively few people in comparison to other diseases, it can be hard to obtain research funding, he said. The current study gets beyond that obstacle by being part of a larger, ongoing project.

When gauging the prevalence of angina in long COVID, “selection is an important consideration,” Berry noted. But many “patients are being referred to me with these symptoms,” he said, estimating that about 10% of long COVID patients he encounters report chest pain.

A takeaway from the new study is “the demonstration that chest pain in long COVID can have an objective basis for being angina,” said Berry. It provides “a mechanistic explanation, albeit in 20 patients, that the symptoms they’re reporting are actually angina and they are actually due to small-vessel disease and they can actually improve with treatment. That, I think, is quite an important message.”

Beta-blockers and Calcium Channel Blockers

Escaned et al homed in on 140 patients with suspected INOCA enrolled between June 2020 and December 2021—in this group, 20 patients (14.3%) had new-onset chest pain after a documented case of COVID-19.

Mean age among these 20 individuals was 56 years, and 70% were female. Their angina symptoms appeared at a median of 31 days after COVID diagnosis. For 40%, the angina occurred only during exercise, while 30% had symptoms only at rest and 25% had symptoms both at rest and during exercise.

Fourteen of the patients underwent noninvasive testing for detection, with positive results for 79% of those individuals.

All underwent invasive physiological testing, which occurred at a median of 186 days after chest-pain onset. Testing consisted of both endothelium-dependent evaluation with acetylcholine and endothelium-independent assessment with adenosine, based on thermodilution or Doppler, to measure coronary flow reserve (CFR) and microcirculatory resistance (MR).

In the end, 16 patients (80%) were diagnosed with INOCA and presented with endothelium-dependent abnormalities: epicardial spasm in 56% and microvascular in 44%. These abnormalities were seen in combination with other endothelium-independent impairment for as many as half the patients: 25% with low CFR, 38% with high MR, and 38% with both low CFR and high MR.

The researchers offer several ideas on how COVID-19 leads to these abnormalities. “SARS-CoV-2 has a strong affinity for vascular endothelial cells (VECs) due to the high density of ACE2 angiotensin-converting enzyme II receptors. Dysregulation of VEC may affect myocardial blood flow control, causing epicardial or arteriolar vasospasm, which may last for months after SARS-CoV-2 exposure,” they write. “Furthermore, inflammation and increased permeability associated with endothelial dysfunction may cause structural changes in the microvasculature, leading to decreased microvascular conductance.”

“The next step,” said Escaned, was to ask how patients might be treated. “And that was very easy—we followed the same recipe, so to speak, that was followed in the CorMicA study.” He stressed that the ability to tailor treatment to the angina’s cause was key.

For patients with epicardial or microvascular spasm, first-line treatment was calcium channel blockers with or without nitrates. For those with impaired CFR and/or MR, the first-line treatment was beta-blockers. All of the INOCA patients were advised to take statins, ACE inhibitors, and ARBs and make lifestyle changes.

By a median follow-up of 214 days, patients had significant improvements in Seattle Angina Questionnaire scores for angina frequency (+17 points; P= 0.003) as well as stability (+20 points; P =  0.004).

The prescriptions need to be bespoke. Colin Berry

One reason this physiology-based approach to INOCA diagnosis in long COVID hadn’t, prior to their study, been widely explored is because “there are not many groups in the world that are doing acetylcholine testing,” Escaned noted.

Using the right test to determine whether that chest pain is in fact due to INOCA, Berry said, is “very helpful.” A diagnosis “gives the individual information [and] understanding. . . . It gives them access to literature—there’s patient support materials out there,” he explained.

A diagnosis also allows treatment to be based on the actual cause of symptoms, Berry continued. “One does wish to be cautious to be prescribing angina medication in anyone, but also in long COVID. I think having objective information—such as invasive coronary function tests, or alternatively with noninvasive tests such as stress perfusion MRI or even a treadmill exercise test—to correlate with symptoms is helpful and relevant” for decision-making, especially in patients who have multisystem long-COVID symptoms and may be susceptible to headaches, changes in the ability to taste, and other side effects.

“The prescriptions need to be bespoke,” he urged, adding, though, that noninvasive diagnostic testing may suffice for many patients, if that first result is positive. “If it’s a negative result with unexplained symptoms, then refer to the cath lab.”

Both Escaned and Berry said it’s not yet known if angina in patients with long COVID will eventually resolve, though this possibility can’t be ruled out. “What we’ve seen so far,” Escaned said, “is that at least it can be improved.” Other symptoms, like muscle tiredness and mental fog, could stick around even if the angina goes away, he added.

Escaned said that their group is currently recruiting for a 100-patient randomized trial of INOCA in long COVID. The aim is to show that medical treatment is more effective at relieving angina symptoms when based on the findings of intracoronary functional tests.