Coronary Microvascular Dysfunction May Predict Heart Disease in Rheumatoid Arthritis

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Cardiovascular disease (CVD) is a leading cause of death in patients with rheumatoid arthritis (RA). Patients with RA have a 1.5 times increased risk for heart attack compared with the general population.

Although the treatment of RA has advanced significantly, the ability to prevent cardiovascular events hasn’t followed. A study in Arthritis Care & Research suggests coronary microvascular dysfunction may be a predictor of heart disease in this population, as has been shown in people with diabetes and the general population. Researchers have not yet been able to pinpoint what clinicians should measure to capture excess cardiovascular risk among patients with RA.¹

Higher Risk of Mortality

“When we think about CVD we usually focus on coronary arteries and cholesterol,” says lead author Katherine Liao, MD, MPH, associate professor of medicine at Harvard Medical School, Boston. “Researchers have found that in both diabetes and the general population, dysfunction of the smaller vessels in the heart, known as the coronary micro­vasculature, leads to a higher risk for cardiac mortality.”

The researchers compared RA patients with those who have diabetes, a group of patients in whom coronary microvascular dysfunction is an established cause of cardiac mortality. They looked at whether microvascular dysfunction in the heart exists in patients with RA. If so, is it tied to cardiac and all-cause mortality?

Study Parameters

Dr. Liao

The researchers undertook a retrospective cohort study using data obtained from all patients undergoing stress myocardial perfusion positron emission tomography (PET) scans between 2006 and 2017 at Brigham and Women’s Hospital, Boston.

All patients with a normal stress test were included in the study. Patients with known coronary artery disease, a history of myocardial infarction, coronary revascularization, transplantation or moderate to severe valve disease were excluded. Others not included were those with abnormal PET scans showing they already had obstructive coronary artery disease.

Pertinent patient information, such as biologic and non-biologic disease-modifying anti-rheumatic drug use, was obtained through medical records. Data on diabetes treatments, other traditional CVD risk factors, as well as medications used for primary and secondary CVD prevention, were also added. Coronary flow reserve (CFR; the ability of the coronaries to increase blood flow under stress) was calculated using the registry. Coronary microvascular dysfunction was defined as CFR <2.0.

“The data we use to calculate CFR and detect [coronary microvascular dysfunction] are, in many cases, obtained routinely as part of the cardiac stress test,” says Dr. Liao. “Since the main reason to undergo a stress test is to look for blockages in the coronary arteries and not microvascular function, we are not routinely pulling data on [coronary microvascular dysfunction].”

The cohort included 73 subjects with RA and 441 with diabetes who met the inclusion or exclusion criteria. The mean age was similar in both groups: 63 years. The proportion of women was higher in RA than in diabetes (73% vs. 56%, respectively). Those with diabetes had higher prevalence of hypertension and dyslipidemia. Eighteen percent had concurrent RA and diabetes.

Significant Survival Differences

Dr. McFarlane

Among those normal perfusion scans, the prevalence of coronary microvascular dysfunction was similar in both groups (P=0.2). However, significant differences were seen in survival when stratified by CFR <2, when compared with those ≥CFR 2. Each group of patients with CFR <2 had higher mortality rates (P<0.0001).

Coronary microvascular dysfunction was associated with increased risk for all-cause mortality in RA (HR 2.4, 95% confidence interval [CI] 1.4, 4.2). Increased cardiac-related death rates were similar to diabetes.

The group assessed increases in risk for all-cause mortality. In both RA and diabetes, having a low CFR was associated with risk for all-cause mortality after adjusting for age, gender and CV risk factors (HR 2.4, 95% CI 1.4, 4.2). None of the other measured covariates, tested individually in the base model, changed the HR by >5%.

“We know in diabetes that microvascular dysfunction leads to excess mortality,” says Dr. Liao. “We found in RA that patients in our population with cardiac microvascular dysfunction had the same degree of dysfunction and the same all-cause and cardiac mortality as those with diabetes.”

No significant changes in associations between CFR and mortality were found when the model was further adjusted to account for statin use, body mass index and prednisone use at baseline (HR 2.33, 95% CI 1.36, 3.98). Sensitivity analysis excluding patients with concurrent RA and diabetes diagnoses saw a similar relationship between CFR <2 and mortality (HR 2.47, 95% CI 1.48, 4.47)

Consider Inflammation

Dr. Liao notes that although we know inflammation is associated with increased cardiovascular risk in RA, more work is needed to define the mechanisms linking the two. This study’s results suggest a mechanism or pathway whereby inflammation leads to dysfunction in the small cardiac vessels, and this dysfunction over time is associated with increased mortality. The impact of repeated inflammation on the small vessels in the heart is something clinicians should be thinking about when considering heart disease risk in their RA patients and potential RA treatment options to control inflammation.

“Right now we use general population-based calculators, such as Framingham, which underestimate the risk because they don’t take inflammation into account,” says Dr. Liao. “In the future, screening for CVD in RA may include directly measuring the impact of inflammation using information available from routine cardiac stress tests. In many cases, the data may already be there; we just need to extract and calculate information to assess for [coronary microvascular dysfunction].”

CVD & Cardiac Outcomes

Isabel M. McFarlane, MD, FACP, is a clinical assistant professor in the Department of Medicine at SUNY Medical Center, Brooklyn, N.Y. She believes this study is important because it sheds new light on the association of coronary microvascular dysfunction with cardiac outcome in RA.

“It has long been recognized that RA patients have 1.5-fold increase in CV events compared with the general population and [that] risk is similar to the diabetic population,” she says. “This study provides new supporting evidence that impaired coronary flow reserve detected in normal perfusion scans can hint at a higher risk for all-cause mortality and fatal cardiac events among RA patients.”

Systemic inflammation with endothelial cell activation and cytokine expression are crucial to development of atherosclerosis. This, in turn, leads to the increased risk in cardiac events seen among RA patients.

“This study is likely to have important implications for the practicing physician in the assessment of myocardial blood flow, particularly with a readily available assessment tool,” says Dr. McFarlane. “Cardiac perfusion PET scans calculate coronary flow reserve, a surrogate for cardiac microvascular dysfunction, that physicians can use to implement aggressive therapeutic interventions aiming to control inflammation in RA and educate patients in better management of CV risk factors.”

Kurt Ullman is a freelance writer based in Indiana.

Reference

1. Liao KP, Huang J, He Z, et al. Coronary microvascular dysfunction in rheumatoid arthritis compared to diabetes mellitus and association with all-cause mortality. Arthritis Care Res (Hoboken). 2019 Nov 9;10.1002/acr.24108. [Online ahead of print]