Abnormal Coronary Reactivity in Women Portends Added CV, Death Risk in the Next Decade

Among middle-aged women, signs of abnormal coronary reactivity (CR) independently predict the risk of death and MACE over as long as a decade, according to a new analysis from the Women’s Ischemia Syndrome Evaluation (WISE) study.

The idea that abnormal CR may be at the root of women’s often atypical presentation isn’t new. But the possibility that it might serve as such an early harbinger of poor outcomes could lead the way toward useful screening tools for female patients with angina but no obstructive coronary artery disease (ANOCA), Ahmed AlBadri, MD (Emory University School of Medicine, Atlanta, GA), and colleagues suggest.

“Given the relatively young age of this cohort, identifying patients who are at higher risk due to impaired compared with normal reactivity becomes of paramount importance, specifically in women with no obstructive CAD,” they say.

Importantly, this “study provides evidence that impaired microvascular function involving endothelial-dependent or independent pathways, or even both, predicts the adverse cardiovascular outcomes in women with signs and symptoms of ischemia but no obstructive coronary artery disease,” AlBadri told TCTMD. Compared with earlier studies, it involves lower-risk patients, a focus on women, and lengthier follow-up, he added.

It’s a reminder for “clinicians [to] recognize that these patients who do get ignored a lot actually have something” worth paying attention to, he said.

Findings from the National Heart, Lung, and Blood Institute-sponsored study were published online ahead of the February 19, 2019, issue of the Journal of the American College of Cardiology.

Long-term Predictive Power

The researchers analyzed data on 224 women (mean age 55 years) with signs and symptoms of ischemia who underwent CR testing via various measures, including coronary flow reserve, coronary blood flow, and coronary dilation in response to intracoronary (IC) acetylcholine and nitroglycerin. They tracked outcomes including all-cause mortality, MACE (cardiovascular death, MI, stroke, and heart failure), and hospitalization for angina.

Testing identified abnormal results for coronary flow reserve in 38% of women, for coronary blood flow in 49%, and for change in cross-sectional area in response to acetylcholine in 55% and in response to nitroglycerine in 57%. Of these women with abnormal results, 30% had minimal CAD (20% to 50% stenosis) and 19% had significant CAD (> 50% stenosis). Half had no CAD (< 20% stenosis).

Over a median follow-up of 9.7 years, there were 129 events, including 18 cardiovascular deaths, eight MIs, and 11 strokes. After adjustment for CV risk factors, low coronary flow reserve predicted a higher risk of MACE (HR 1.06; 95% CI 1.01-1.12), while low coronary blood flow was linked to increases in both MACE (HR 1.11; 95% CI: 1.03 to 1.20) and mortality (HR 1.12; 95% CI 1.01-1.24). Poorer response to IC acetylcholine, meanwhile, was associated with a greater risk of being hospitalized for angina (HR 1.05; 95% CI 1.02-1.07). Epicardial IC nitroglycerin dilation did not appear to influence outcomes, however.

In Search of Simpler Tools

Altogether, the results indicate that “evaluation of CR abnormality can identify those at higher risk of adverse outcomes in the absence of significant CAD,” AlBadri et al conclude.

“The main clinical implication of our findings is to endorse efforts toward reliably identifying patients who have angina due to impaired CR,” they say, adding that “in current practice, efforts toward routine invasive assessment of CR are hampered by time, expertise, and cost. Though these procedures are relatively safe, they require experienced operators familiar with the protocols and techniques. Validation of simpler invasive protocols and noninvasive tools would be needed to appropriately diagnose the majority of these patients.”

To TCTMD, AlBadri noted that this sort of testing does get used at large academic medical centers, where there are efforts to train clinicians from other hospitals. Emory hosts symposiums dedicated to CR testing, for example, and welcomes visitors who want to learn more about the protocols, he said.

“So it is expanding. The problem is there are no specific guidelines to categorize or identify these patients and no really easy or user-friendly tool to screen these patients as well. That’s the challenge for now,” he commented.

Two options already being explored are the use of positron emission tomography myocardial perfusion imaging with quantification of coronary reserve and cardiac MR with measurement of the myocardial perfusion reserve index, AlBadri said. “It’s not invasive, and abnormal results have a relationship with adverse outcomes. Invasive testing is very comprehensive and provides way more details, but that’s at the expense [of being] uncomfortable for the patient.”

Beyond the development of easier-to-use tools, the question of which women should be screened is still unanswered. “There are big knowledge gaps in this field, including the pathophysiology, the phenotyping of these patients, and importantly the management. So I think the efforts to establish evidence-based diagnostic and therapeutic guidelines are really needed,” he stressed.

In an editorial, Nanette K. Wenger, MD (Emory University School of Medicine), agrees that female patients could benefit from a more sex-specific approach. “Women often have microvascular angina with impaired coronary flow reserve and/or vasospasm, such that traditional diagnostic strategies sufficient to detect obstructive epicardial CAD may be inadequate for many women, necessitating additional investigation to define the etiology of their angina,” she writes.

“Although women have less anatomic obstructive coronary disease than men,” Wenger continues, “this does not translate into fewer ischemic events, with the major contributor to adverse outcomes being abnormal coronary reactivity due to diffuse endothelial dysfunction and plaque erosion.”

Importantly, female patients with chest pain but no angiographically apparent CAD “do not represent a low-risk group,” she stresses. “As long as ischemic heart disease is considered synonymous with obstructive coronary atherosclerosis, we miss the opportunity to prevent, diagnose, and treat a substantial portion of women with ischemic heart disease, those with nonobstructive coronary disease or coronary microvascular dysfunction.”

No specific means exist to prevent the development of abnormal CR, or to treat it once it develops, Wenger says, so therapy instead focuses on promoting a healthy lifestyle, managing comorbidities, and generally trying to reduce CV risk. She, too, calls for diagnostic strategies that are noninvasive, feasible, and limit radiation exposure.

AlBadri agreed that the best management for these patients is unclear, though research has provided some clues. “Other than prevention, there is specific treatment targeting each pathway,” he explained. For endothelial dysfunction, both medical therapy with aspirin, ACE inhibitors, statins, and L-arginine supplements and aerobic exercise can be helpful, AlBadri suggested. For abnormal coronary flow reserve, the list includes beta-blockers, nitrates, and antianginal medications.