One of the most common chief complaints for ER visits in the U.S. is chest pain, which accounts for more than seven million hospital visits per year. More than one million of these patients will have cardiac catheterizations performed. A significant number of patients receiving invasive coronary angiography for stable angina have a condition known as ischemia with non-obstructive coronary arteries (INOCA).
One of INOCA patients’ most outspoken advocates, Khaled Ziada, MD, frequently encounters this in his research and practice as an interventional cardiologist at Cleveland Clinic’s Heart, Vascular and Thoracic Institute. According to Dr. Ziada, many patients with INOCA receive invasive angiography to examine their epicardial arteries without more in-depth investigation.
“The angiogram was the beginning of our understanding of coronary disease,” he said. “But now we've gone beyond that and now we're understanding more physiologic concepts — not just the pipe, so to speak — but the function of the artery and a deeper understanding of the structure of the artery.”
While initially thought to be an uncommon phenomenon, research has shown that INOCA can be found in as many as 65% of women and 32% of men who undergo invasive coronary angiography for stable angina. When these types of patients go undiagnosed, it can have a major impact on both patients and health care systems. Untreated patients with INOCA have an increased risk of major adverse cardiac events, such as a MI, stroke, cardiovascular death, and all-cause mortality. They’re also more likely to develop diastolic dysfunction and heart failure.
“When you see a lot of patients with what we think is real angina and you don't see anything on the angiograms, this is when you have to think about whether it’s coronary spasm, or microvascular dysfunction,” Dr. Ziada said. “And they both fall under the bigger title of INOCA. For those patients who have mild or no obstruction on angiograms, we can now go further with the testing. For microvascular dysfunction, we can measure things like coronary flow reserve, indices of microvascular resistance, and blood flow velocity. And if we suspect a vasospastic disorder, we can perform acetylcholine challenges to determine if there are coronary spasms with associated ECG changes.”
Dr. Ziada’s team is currently researching the difference between the two coronary microvascular disease (CMD) endotypes — structural and functional CMD — in order to define normal parameters and identify potential noninvasive diagnostic tools. His team is also looking into associations between echo findings and microvascular tests to form a deeper understanding of functional CMD and its relationship to HFpEF, or heart failure with preserved ejection fraction.
The microvasculature has become an important area of focus for physicians worldwide, and the magnitude of understanding its significance cannot be overstated, Dr. Ziada pointed out. Focus on the epicardial arteries is vital, but so is focus on the microcirculation. Endothelial dysfunction can also be a significant contributor to INOCA.
“Microvascular dysfunction is a phenomenon that starts with endothelial dysfunction,” Dr. Ziada said. “The endothelium is a magical organ, which doesn't get enough credit because it's microscopic, and people think of arteries more as pipes, but they're actually living structures that are very sophisticated. So when you lose endothelial function, it’s one of the fundamental underlying pathologies of microvascular dysfunction.”
Understanding the intricacies of the microvasculature has become one of Dr. Ziada’s areas of focus because so many patients with untreated angina have been referred to him over the years. His work with INOCA patients has been an extremely rewarding aspect to his research and practice in interventional cardiology.
“I think one of the biggest values of working in this area is just validating some of the patients about what they're feeling, and that their symptoms are actually real problems and medical issues that need to be addressed and not just in their imagination,” he said. “Because I think that's the impression patients get when they’re dismissed.”
Dismissal is a common thread among many patients with INOCA; their angiography is normal, so many clinicians mistakenly assume that the issue is not cardiac in origin.
These specific types of patients are what first led Dr. Ziada into this area of research. He began his work with INOCA patients at the University of Kentucky Women’s Heart Center, where he remembers seeing many women who were symptomatic yet unable to find a physician who could help them find a definitive diagnosis. He understands that many of these patients have been told repeatedly by physicians that their chest pain is non-cardiac in nature, yet after receiving angiograms, they continue to experience symptoms of chest pressure, chest pain, chest discomfort, and dyspnea.
According to a recent study, led by investigators at the Smidt Heart Institute at Cedars-Sinai, almost half of the patients surveyed in the study reported living with INOCA symptoms (chest pain, chest pressure, chest discomfort, shortness of breath) for one to 10 years before receiving an INOCA diagnosis. Nearly 78% of patients in the study reported being told that their symptoms weren’t cardiac, and 54% had been told their symptoms were due to gastroesophageal reflux disease. Almost 32% had been referred to a psychiatrist, and the majority of patients had been told that “although their symptoms of INOCA may be unpleasant, they could not die from INOCA or have a heart attack” (66%).
Although there is far more understanding of this condition today than there was a decade ago, it is constantly evolving with ongoing research.
“Unfortunately, this is an area that a lot of physicians are not very well-versed in,” Dr. Ziada said. “And we really need to have more emphasis on this, not even in cardiology, but in internal medicine, and during residency and fellowship training, to expose trainees to the concept that patients who do not have large vessel disease on a heart cath or a coronary angiogram doesn't necessarily mean that they don't have coronary disease, but they have it in a different form. We need to look beyond the idea that we are sort of marrying coronary artery disease with the angiogram.”
Recognizing that patients with INOCA need therapy to alleviate their angina symptoms, and to address long-term risk of cardiac events, Dr. Ziada makes several recommendations. Statins, aspirin, ACE inhibitors, and angiotensin II receptor blockers should be considered for all INOCA patients. Additional recommendations address either microvascular or vasospastic disorders. Options for microvascular angina include beta-blockers, calcium channel blockers, ranolazine, and ivabradine. Options for vasospastic angina include long-acting nitrates, calcium channel blockers, and nicorandil. Lifestyle modifications such as weight loss and exercise are also an extremely important aspect of INOCA treatment, along with effective management of diabetes, hypertension, and dyslipidemia.
Because angina in microvascular disease and coronary spasm cannot be treated with stents or bypass grafting, Dr. Ziada emphasized the importance for these types of patients to understand that their condition cannot be treated in the same way as patients with obstructive coronary disease.
“It’s a much more collaborative approach, and the more patients are engaged in their care, and the more they understand their condition, the better their outcomes,” Dr. Ziada said.
Providing the proper treatment regimen for INOCA patients can mean a world of difference for a patient who is suffering with daily episodes of angina, according to Dr. Ziada.
“There is evidence that by doing these tests and by directing the therapy according to the result of these tests, we can improve patients' symptoms and we can improve quality of life,” he said. “We don't have to accept having chest pain and not being able to address it in the proper way.”
Illustration by April Brust