Nonobstructive CAD remains vexing, especially in women

Evidence of myocardial ischemia with nonobstructive CAD is a major clinical problem that affects more women than men. It is now evident that coronary microvascular dysfunction contributes to this condition, and is commonly underdiagnosed because of limitations in conventional diagnostic methods. Even when detected, ischemia with nonobstructive CAD, also known as INOCA, becomes problematic for the patient and the cardiologist because there are no dedicated guideline-recommended management strategies. Progress has been made in recent years, which allows detection of coronary microvascular dysfunction by invasive and noninvasive imaging tests. These can be used to determine possible causes of persistent anginal symptoms, even in the absence of obstructive coronary plaque.

“Managing angina and ischemia relies on detecting obstructive CAD, as supported by evidence-based guidelines including medical and revascularization therapy. However, about two in three women and one in four men with such findings don’t have obstructive CAD and their outcomes are not benign, yet we have no guideline-based evidence to direct their management,” Cardiology Today Chief Medical Editor Carl J. Pepine, MD, MACC, eminent scholar emeritus and professor in the division of cardiovascular medicine at University of Florida, Gainesville, said in an interview.

It has now become clear that patients with nonobstructive CAD have increased risk for adverse CV event rates and morbidity, and it is important for cardiologists to understand that nonobstructive CAD is not benign, experts told Cardiology Today.

“We shouldn’t focus only on the stenosis,” Janet Wei, MD, FACC, assistant professor andcardiologist at the Barbra Streisand Women’s Heart Center in the Cedars-Sinai Smidt Heart Institute and a Cardiology Today Next Gen Innovator, said in an interview. “If they have plaque, they are at risk.”

Recent research has demonstrated that patients with nonobstructive plaque can also have ischemia, which can be related to coronary spasm, endothelial abnormalities and coronary microvascular dysfunction, alone or in combination.

“You can have ischemia without an obstructive lesion and you can have a MI even without obstruction,” Martha Gulati, MD, MS, FACC, FAHA, FASPC, cardiologist and chief of the division of cardiology at the University of Arizona in Phoenix, told Cardiology Today.

Challenges of diagnosis

Imaging technology has progressed significantly over the last decade and recent long-term outcome studies have shown that nonobstructive CAD is an important, but a poorly understood issue. Characterizing the burden of plaque in these patients through novel imaging approaches may help cardiologists identify and treat those at risk for cardiac events.

Imaging technologies to diagnose nonobstructive CAD lagged compared with that for diagnosis of obstructive CAD. Most diagnostic testing is designed to detect obstructive disease, rather than other causes for ischemia in patients with nonobstructive plaque.

Even methods to diagnose obstructive plaque have their issues. In 398,978 patients who underwent coronary angiography, a little more than one-third had obstructive CAD, as published in The New England Journal of Medicine in 2010. This shows a low diagnostic yield for the condition that is more visible in tests.

“Invasive coronary angiography, which is typically used to identify obstructive CAD, often misses diffuse atherosclerosis and small-vessel disease because of limitations in technique resolution,” Viviany R. Taqueti, MD, MPH, FACC, cardiologist and cardiovascular imaging specialist at Brigham and Women’s Hospital and assistant professor at Harvard Medical School, told Cardiology Today.

Noninvasive CCTA both increases test sensitivity for the diagnosis of CAD and enables characterization of plaque morphology, and research is ongoing to apply this technique to better characterize risk in patients with nonobstructive CAD.

Whereas CCTA allows more sensitive assessment of atherosclerotic plaque to better diagnose nonobstructive CAD, quantitative functional tests like PET/CT allow more sensitive assessments of cardiac ischemia to diagnose coronary microvascular dysfunction.

PET is a noninvasive and clinically-integrated technique with a robust and growing evidence base supporting its prognostic value in symptomatic patients.

“We now recognize that coronary microvascular dysfunction often coexists with nonobstructive CAD in our symptomatic patients, and this has important management implications for ischemic heart disease, especially in women,” Taqueti said.

Coronary blood flow reserve (CFR) may provide a missing link in understanding how certain patients with nonobstructive CAD manifest increased levels of CV risk. Taqueti led a study published recently in Circulation, in which symptomatic patients with impaired CFR by PET had increased risk for future cardiac events even without the presence of obstructive plaque. This effect was especially evident in patients who had severely reduced CFR but no obstructive CAD, a worrisome pattern more common in women.

“PET can give us coronary flow reserve, which provides information about microvascular dysfunction, but PET is not widely available and it’s not always reimbursed by insurance. Those are the issues,” Puja K. Mehta, MD, FACC, FAHA, assistant professor of medicine in the division of cardiology at Emory University School of Medicine, director of women’s translational cardiovascular research at Emory Women’s Heart Center and Cardiology Today Next Gen Innovator, said in an interview.

Exercise treadmill stress testing can point to microvascular dysfunction, but it is not as sensitive or specific as adding PET testing or Doppler echocardiography. Transthoracic Doppler-based echocardiographic coronary flow reserve can determine blood flow, although it is not routinely done in the United States. It also provides a regional rather than a global assessment.

Cardiac MRI can also be used to calculate “myocardial perfusion reserve” analogous to coronary flow reserve, but this expertise is not widely available. So, myocardial perfusion reserve index is used, which may help to diagnose microvascular dysfunction in patients with nonobstructive CAD.

Although there are a few imaging technologies that can help diagnose nonobstructive CAD in patients, there are still some knowledge gaps, particularly in the steps to take to diagnose and treat patients.

What is known, unfortunately, is that nonobstructive CAD is often associated with poor outcomes. In a study published in Arteriosclerosis, Thrombosis, and Vascular Biology in 2015, patients in the CONFIRM registry who had nonobstructive CAD had an increased risk for mortality. Those patients who were treated with statins at baseline had significantly reduced mortality over follow-up.

‘Opportunities for intervention’

As advancements have been made in the diagnosis of nonobstructive CAD, treatment targets have been suggested, but a guideline-based treatment plan does not exist for most of these patients.

Some other trials have evaluated the effects of specific agents on coronary flow reserve. Intermediate-sized trials have been positive, but large randomized trials have not yet occurred.

“We have identified through the WISE investigation two important treatment targets for coronary microvascular dysfunction, and they are atherosclerosis — the vast majority of these women have coronary atherosclerotic plaque — and ... ischemia with abnormal flow reserve, causing abnormal stress testing and angina,” C. Noel Bairey Merz, MD, FACC, FAHA, FESC, director of the Barbra Streisand Women’s Heart Center at Cedars-Sinai Smidt Heart Institute and a Cardiology Today Editorial Board Member, said in an interview.

Bairey Merz and colleagues also published a study in the European Heart Journal in 2015, which found that ranolazine (Ranexa, Gilead Sciences) was not effective in treating angina in patients with nonobstructive CAD, but it was beneficial in a prespecified subgroup of patients who had a low coronary flow reserve.

Patients with low coronary flow reserve and endothelial dysfunction can also be treated with ACE inhibitors and statins, as they have been shown to improve endothelial function.

Angina can also be treated with alpha- or beta-blockers such as carvedilol and nebivolol (Bystolic, Forest Labs), in addition to cardiac rehabilitation and exercise.

“It’s important because it’s still stable ischemic heart disease even if it’s nonobstructive disease,” Mehta told Cardiology Today. “They would qualify for cardiac rehab, which we know is underutilized in women.”

For those with suspected vasospastic angina, calcium channel blockers such as amlodipine, verapamil, diltiazem and long-acting nitrates can be used.

Stress management and stress reduction may also help treat patients with angina, especially for patients with depression and anxiety, which are highly prevalent in women and associated with adverse outcomes.

Guideline-based treatments are used for patients with ischemic heart disease and MI, in addition to cardiac rehab.

Statins can be used to treat patients with atherosclerotic plaque to prevent progression or even regress plaque and decrease risk for future MIs and cardiac death by stabilizing the plaque while decreasing LDL and inflammation.

“Generally speaking, use of a high-intensity statin in patients who have extensive amounts of CAD independent of whether it’s obstructive is really important,” Taqueti said. “The modern ability to image atherosclerotic plaque directly, even subclinically, is revolutionizing how we as cardiologists approach ‘primary’ versus ‘secondary’ prevention. These once important distinctions are becoming obsolete.”

Sometimes, patients are taken off their statin or other cholesterol medications if the coronary angiogram is perceived to be normal, even in the presence of nonobstructive plaque, so it is critical for cardiologists to treat these patients as if they have CAD and manage them accordingly, experts said.

Although there is an overlap between patients with nonobstructive CAD and coronary microvascular disease, a specific management plan does not exist for patients with microvascular disease or even for those with INOCA.

Current knowledge “gives us hopefully many more opportunities for intervention, but only if we recognize it and only if we take the initiative at that time to treat those women aggressively and with a secondary prevention focus in terms of medications and lifestyle changes to try to lower their future CV risk,” Gulati said.

Knowledge gaps remain, research continues

With as much as there is known regarding the diagnosis and treatment of patients with nonobstructive CAD, there is still a lot to be discovered.

Having a standard process for imaging patients with INOCA is necessary, especially to avoid unnecessary tests in these patients. For example, it would be helpful for cardiologists to know whether a particular test or one of several possible tests should be used to detect diastolic dysfunction.

Randomized controlled trials are needed to provide evidence for future guidelines for patients specifically with INOCA. The most recent guidelines for management of patients with stable ischemic heart disease were published in 2012 by the American College of Cardiology Foundation/American Heart Association task force. However, guidelines have since been updated in Europe.

Pepine, Bairey Merz and colleagues recently received funding for the WARRIOR trial (see Sidebar below), which may provide some essential evidence to inform guidelines.

“If a woman has a low [atherosclerotic] CVD risk score, she may not be prescribed a high-intensity statin if she has no obstructive plaque on her angiogram,” Wei said. “The WARRIOR study will help us determine in a rigorous randomized trial if we should or should not treat symptomatic women with nonobstructive plaque using statins or ACE inhibitors.”

There remains a knowledge gap regarding the treatment of patients with nonobstructive CAD or microvascular disease. PCSK9 inhibitors can play an important role in patients who require LDL lowering beyond a statin, in addition to its anti-inflammatory benefits, although that has yet to be analyzed in patients with nonobstructive CAD. If successful, this strategy could especially benefit women, who have a lot of potentially residual inflammatory risk. More research also needs to be done for sodium-glucose cotransporter 2 (SGLT2) inhibitors, some of which are known to reduce risk for CVD events in patients with diabetes.

Sanofi is evaluating a novel Rho-kinase inhibitor, SAR407899, in patients with coronary microvascular angina and low coronary flow reserve, experts said.

Syndromes overlap

Coronary microvascular dysfunction appears to be a complex syndrome that could be associated with a number of adverse conditions, and more must be learned about the basis for the relationships, experts told Cardiology Today.

An important factor that must be analyzed in the setting of microvascular dysfunction is mental stress and autonomic function, especially in women, experts said.

Stress-related, or takotsubo cardiomyopathy, which may be a severe manifestation of coronary microvascular dysfunction, is another condition that must be researched further, according to Bairey Merz.

HF with preserved ejection fraction has become increasingly recognized by cardiologists, and new research from Taqueti and colleagues published in the European Heart Journal showed that coronary microvascular dysfunction was independently associated with diastolic dysfunction, low-level troponin injury and HFpEF hospitalization. HFpEF is more prevalent in women than men, and often associated with hypertension, diabetes and other CV risk conditions, but dedicated therapies have not been found.

“These are overlapping clinical syndromes, which may share some pathophysiologic mechanisms,” Taqueti told Cardiology Today. “Nonobstructive atherosclerosis, inflammation and endothelial dysfunction may contribute to coronary microvascular ischemia, myocardial injury and impaired myocardial relaxation. Small but chronic insults over time may lead to adverse events such as HFpEF, even in the absence of obstructive CAD. It’s the new frontier of cardiology and a lot of exciting work is going to come.”

Although nonobstructive CAD is seen more in women compared with men, their representation in preclinical trials like animal and cell studies was not required by the NIH until 2016, at the prompting of an editorial published in Nature in 2014 on how women were not included in research.

“We’ve been talking for many years about including women in the clinical trials, but we also need to be thinking about sex in the preclinical trials and making sure that there’s female cell lines, female animal studies being represented so that we do find out earlier if there’s things that we’re seeing in animal models that can potentially be translated to humans,” Gulati said.

Focus on increased awareness

As more focus is directed toward nonobstructive CAD, it is important for cardiologists to recognize symptoms occurring even in the absence of obstructive plaque and to treat patients based on those symptoms. Withholding treatment in these patients may result in future cardiac events, experts said.

Moving forward, increasing awareness to both cardiologists and patients is critical to properly diagnose and treat nonobstructive CAD.

“We need to take away the stigma of heart disease,” Wei told Cardiology Today. “We need to convey this message to break the barrier for women to seek help. We need to increase awareness that nonobstructive CAD does lead to heart attacks and can contribute to HF. We need to increase the education in both the clinical community and the patients.” – by Darlene Dobkowski

• References:
• Bairey Merz CN, et al. Eur Heart J. 2016;doi:10.1093/eurheartj/ehv647.
• Chow BJ, et al. Arterioscler Thromb Vasc Biol. 2015;doi:10.1161/ATVBAHA.114.304351.
• Clayton JA, et al. Nature. 2014;doi:10.1038/509282a.
• Patel MR, et al. N Engl J Med. 2010;doi:10.1056/NEJMoa0907272.
• Pepine CJ, et al. J Am Coll Cardiol. 2015;doi:10.1016/j.jacc.2015.08.876.
• Taqueti VR, et al. Circulation. 2017;doi:10.1161/CIRCULATIONAHA.116.023266.
• Taqueti VR, et al. Eur Heart J. 2017;doi:10.1093/eurheartj/ehx721.

• For more information:
• C. Noel Bairey Merz, MD, FACC, FAHA, FESC, can be reached at Advanced Health Sciences Pavilion, A3600, 127 S. San Vicente Blvd., Los Angeles, CA 90048; email: noel.baireymerz@cshs.org.
• Martha Gulati, MD, MS, FACC, FAHA, FASPC, can be reached at University of Arizona College of Medicine, 550 E. Van Buren St., Phoenix, AZ 85004; email: marthagulati@email.arizona.edu.
• Puja K. Mehta, MD, FACC, FAHA, can be reached at Emory Clinical Cardiovascular Research Institute, 1462 Clifton Road NE, Suite 505, Atlanta, GA 30322; email: puja.kiran.mehta@emory.edu.
• Carl J. Pepine, MD, MACC, can be reached at Cardiology Today, 6900 Grove Road, Thorofare, NJ 08086; email: carl.pepine@medicine.ufl.edu.
• Viviany R. Taqueti, MD, MPH, FACC, can be reached at Brigham and Women’s Hospital, 75 Francis St., ASBI L1-037G, Boston, MA 02115; email: vtaqueti@bwh.harvard.edu.
• Janet Wei, MD, FACC, can be reached at Barbra Streisand Women’s Heart Center at Cedars Sinai Heart Institute, 8631 W. 3rd St., Los Angeles, CA 90048; email: janet.wei@cshs.org.

Disclosures: Bairey Merz and Pepine are investigators for the WARRIOR trial, which is funded by the U.S. Department of Defense; they report no other relevant financial disclosures. Gulati and Taqueti report no relevant financial disclosures. Mehta reports she has conducted research for Gilead and Sanofi. Wei reports she has received grant support not relevant to this topic.