INOCA: A Common, Dangerous, Often Overlooked Cause of Chest Pain

What to do when a patient’s ischemia is not due to coronary artery stenosis

Ischemia with non-obstructive coronary arteries (INOCA) is an increasingly recognized entity involving microvasculature dysfunction and/or vasospasm of the coronary arteries. Because the diagnosis requires specialized expertise and testing, it is frequently missed. But leaving it undiagnosed puts the patient in peril, as INOCA is associated with repeated emergency department visits and hospital admissions, as well as increased incidence of cardiovascular events and death.


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These characteristics have made INOCA an area of great interest for Cleveland Clinic interventional cardiologists Khaled Ziada, MD, and Claire Raphael, MD, PhD.

“Despite poor awareness of INOCA, we now know it is not rare, and that makes it an important topic,” says Dr. Ziada. “Fortunately, we are gaining a better understanding of its mechanisms and how to diagnose and manage it.”

Studies show that more than 50% of patients undergoing invasive angiography — particularly women — do not have obstructive coronary artery disease, with many of them having INOCA.

“I’ve seen many patients who are so grateful for a diagnosis of INOCA after having had their angina symptoms repeatedly dismissed by doctors,” says Dr. Raphael. “Just knowing that their condition is a real entity is a tremendous relief and allows patients to move forward with management.”

A different form of heart disease

Like angina caused by stenosis of the larger coronary arteries, INOCA involves a supply-demand mismatch of myocardial oxygen. Two major mechanisms — microvascular dysfunction and vasospastic disorders — have been identified, as detailed below and illustrated in the figure.

Microvascular dysfunction involves small vessels that supply the myocardium but cannot be seen angiographically. The pathophysiology may be related to vasomotor dysregulation and structural remodeling of the arterioles.


So-called microvascular angina (MVA) is more common in women, especially during middle age. Risk factors are similar to those for atherosclerosis and include smoking, hypertension and dyslipidemia.

PET and MRI criteria have been established for the diagnosis of MVA, but they are not always reliable. Better diagnostic measurements can be performed in the catheterization laboratory: reduced coronary flow reserve and reduced blood flow velocities (using index of microvascular resistance testing) are indicative of MVA and predictive of elevated risk of cardiovascular events and death.

Vasospastic disorders involve spasm of coronary arteries. Hyperreactive smooth muscle cells and dysfunctional endothelium are likely underlying mechanisms. Vasospasm can be transient (causing Prinzmetal angina) or persistent, leading to myocardial infarction.

Vasospastic angina (VSA) more commonly occurs in Asians and men, with smoking being a major risk factor. It can be diagnosed in the catheterization lab, with provocative testing using intracoronary acetylcholine and/or IV ergonovine.

These two INOCA endotypes — MVA and VSA — may overlap, which is associated with a worse prognosis.

“The key is to think about INOCA when we see patients who present with angina but have little or no evidence of plaque in their coronary arteries,” says Dr. Ziada. “Appropriate testing can be done at the same time that we perform angiography.”


Figure. Acetylcholine provocation testing for coronary spasm and microvascular function testing. Top and middle panels demonstrate angiography of the left coronary system before and after intracoronary injection of acetylcholine 50 micrograms. Severe spasm is noted in the mid and distal left anterior descending artery (arrows) in response to the drug. When accompanied by ECG changes and reproduction of the patient’s chest pain, this is diagnostic of vasospastic angina. The bottom panel demonstrates microvascular function testing in a different patient with INOCA. In this case, coronary flow reserve (CFR) calculated using the thermodilution method is abnormal at 1.3 (normal, >2.0 or 2.5). The index of microcirculatory resistance (IMR) is also abnormal at 38 (normal, <25).

Management on multiple fronts

Patients with INOCA need therapy to alleviate their angina symptoms and to address long-term risk of cardiac events. Neither MVA nor VSA can be treated with stents or bypass. Dr. Ziada offers the following guidance on various aspects of management:

  • Pharmacotherapy may be helpful, although traditional anti-anginal medications tend to be less effective in INOCA. Options recommended for MVA are beta-blockers, calcium channel blockers, ranolazine and ivabradine. Options recommended for VSA are calcium channel blockers, long-acting nitrates and nicorandil. For all patients, statins, aspirin, ACE inhibitors and angiotensin II receptor blockers should be considered.
  • Risk factor management should include addressing hypertension, dyslipidemia and diabetes.
  • Lifestyle factors involving nutrition, exercise, weight management, smoking cessation and stress reduction should be emphasized.

An active area of research

Dr. Raphael notes that research is underway on many aspects of INOCA diagnosis and treatment. The large WARRIOR trial (Women’s Ischemia Trial to Reduce Events in Nonobstructive Coronary Artery Disease) is enrolling more than 4,000 patients at multiple sites to assess the impact of intensive medical treatment (high-dose statin, moderate-dose ACE inhibitor, angiotensin II receptor blocker) on death, myocardial infarction, stroke and hospitalization. Participants will be followed for three years, with results expected in 2024.

She is particularly excited about two promising avenues of innovative treatment:

  • Stem cell therapy for MVA. Cleveland Clinic is involved in the ongoing multicenter FREEDOM trial, a double-blind, randomized, placebo-controlled study expected to enroll 105 patients. The therapy arm consists of a single infusion of autologous CD34+ cells into coronary arteries. Patients will be monitored for up to six months for change in angina, exercise time and quality of life. The study is anticipated to be completed later this year. This method was tested in the IMPROvE-CED study on 20 patients with MVA. It was found to be safe, with encouraging outcomes.
  • Coronary sinus reducer. Considerable research is focusing on the implantation of a coronary sinus reducer to treat refractory angina that is not amenable to stent placement. The hourglass-shaped device creates a focal narrowing, increasing pressure in the coronary sinus and thereby improving blood flow to the myocardium. Preliminary trials indicate that implantation is safe and leads to significant reduction of angina. Cleveland Clinic is exploring participation in a clinical trial of this device for refractory INOCA-related angina.

“Our understanding of INOCA is growing quickly, as is physician awareness,” Dr. Raphael observes. “I am hopeful that it will soon be a well-recognized condition with effective therapy options.”

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