Association Between Systemic Vasculitis and Coronary Microvascular Dysfunction in the Absence of Obstructive Coronary Artery Disease

Systemic vasculitides are a heterogeneous group of autoimmune diseases characterized by vessel wall damage, endothelial injury, and systemic inflammation. Several vasculitides are associated with both an elevated risk of cardiovascular disease and increased morbidity and mortality.¹ The cardiovascular disease burden in vasculitis is attributed to both an excess burden of traditional cardiovascular risk factors and systemic inflammation but remains poorly studied. Although systemic inflammation is a known risk factor for cardiovascular disease, the mechanisms underlying these associations are not well understood. Coronary flow reserve (CFR) is a powerful quantitative imaging marker of clinical cardiovascular risk. CFR provides a robust and reproducible clinical measure of the integrated hemodynamic effects of epicardial coronary artery disease, diffuse atherosclerosis, vessel remodeling, and coronary microvascular dysfunction (CMD) on myocardial tissue perfusion.² Systemic inflammation is a driver of atherosclerosis and endothelial cell dysfunction and is felt to be a key mediator of this constellation of abnormalities, which can impact the entire coronary vasculature.³ Therefore, using a case (vasculitis n=26)control (risk factor matched n=72) study design, we investigated the prevalence and severity of CMD by measuring CFR using positron emission tomography (PET) myocardial perfusion imaging in patients with systemic vasculitis without overt obstructive coronary artery disease.

We retrospectively identified subjects across the spectrum of vasculitis who underwent symptom-prompted rest/stress myocardial perfusion PET. Patients with prior coronary artery bypass grafting, an abnormal myocardial perfusion study (summed stress score >3), or left ventricular ejection fraction <40% were excluded. A control group without vasculitis was selected from the Brigham PET registry in an approximate 1:3 ratio of cases versus control from the same population and matched on age, gender, and cardiovascular risk factors (Table 1). CFR was calculated as the ratio of myocardial blood flow (mL[min·g]) at peak stress compared with rest. CMD was defined as CFR <2. Quantitative measures of myocardial blood flow and CFR were recorded by a single experienced operator blinded to patient data. The presence and extent of coronary artery calcium (CAC) was assessed using qualitative visual analysis of the low-dose, noncontrast computed tomography scan obtained for attenuation correction of the PET images.⁴ A linear mixed model for continuous variables and conditional regression for dichotomous variables were used to demonstrate the matching between vasculitis and control patients and to compare hemodynamics, myocardial blood flow, and prevalence of coronary vasomotor dysfunction. Fisher exact test was used for CAC assessment between groups. P<0.05 was considered statistically significant. The study was approved by the Mass General Brigham Institutional Review Board and conducted in accordance with institutional guidelines. The authors declare that all supporting data are available within the article.

Table 1.

Patient Characteristics and Cardiovascular Hemodynamics

Cohort characteristics	Vasculitis (n=26)		Control (n=72)	P value
Age at PET, y	62 (18)		61 (17)	0.24
Time from vasculitis diagnosis to PET, y (median, IQR)	6.5 (2.9–14.2)		n/a	n/a
Female, n (%)	18 (69%)		46 (64%)	0.99
Vasculitis characteristics
Large vessel (eg, giant cell arteritis, Takayasu), n (%)	13 (50%)		n/a	n/a
Medium vessel (eg, polyarteritis nodosa, Kawasaki arteritis), n(%)	2 (8%)		n/a	n/a
Small vessel (eg, ANCA-associated vasculitis, Henoch-Schonlein Purpura), n (%)	11 (42%)		n/a	n/a
Cardiovascular risk factors*	At diagnosis	At PET	At PET
Hypertension, n (%)	12 (46%)	20 (71%)	53 (74%)	0.47
Obesity, n (%)	3 (12%)	2 (32%)	24 (33%)	0.84
Diabetes, n (%)	3 (12%)	5 (20%)	16 (22%)	0.99
Dyslipidemia, n (%)	4 (15%)	15 (58%)	46 (64%)	0.99
Known CAD, n (%)	0 (0%)	1 (4%)	1 (1%)	0.48
Cardiac imaging findings
Resting heart rate, bpm	69 (16)		69 (11)	0.9
Peak heart rate, bpm	89 (17)		92 (19)	0.7
Resting systolic blood pressure, mm Hg	148 (26)		144 (24)	0.7
Peak systolic blood pressure, mm Hg	140 (28)		137 (25)	0.6
Coronary artery calcium, n (%)†
None	8 (31)		33 (46)	0.6
Mild-moderate	12 (50)		27 (37)
Severe	5 (21)		12 (17)
Rest myocardial blood flow, ml/min/g	1.0 (0.3)		1.0 (0.3)	0.8
Stress myocardial blood flow, ml/min/g	2.1 (0.6)		2.6 (1.0)	0.008
Rest coronary vascular resistance, mmHg/mL per gram per minute	106.3 (38)		103.8 (34)	0.8
Stress coronary vascular resistance, mmHg/mL per gram per minute	46.8 (13)		39.5 (13)	0.01
Coronary flow reserve, mL(min·g)	2.1 (0.5)		2.6 (0.7)	0.003
CMD, n (%)	10 (38%)		11 (15%)	0.004

ANCA indicates antineutrophilic cytoplasmic antibody; CAD, coronary artery disease; CMD, coronary microvasculature dysfunction; CV, cardiovascular; IQR, interquartile range; MAP, mean arterial blood pressure; and PET, positron emission tomography.

^*CV risk factors were recorded at the time of the PET scan by the past medical history in the electronic medical record.

^†Degree of coronary artery calcium categorized as none, mild-moderate, or severe between vasculitis patients (n=25) and controls (n=72). Coronary vascular resistance=MAP/myocardial blood flow.

We included 26 consecutive vasculitis cases and 72 controls (Table 1). The most common vasculitides were giant cell arteritis (10, 38%), antineutrophil cytoplasmic antibody-associated vasculitis (8, 31%), and Takayasu arteritis (3, 12%). The median (interquartile range) time between diagnosis and PET was 6.5 (2.9–14.2) years. Seven (27%) cases had active vasculitis at the time of PET. The cases and controls were well-matched with a mean age of 62 and 61 years, respectively; the majority of patients were female (72% and 65%, respectively). Cardiovascular risk factors were uncommon except dyslipidemia (58% vasculitis versus 64% controls) and hypertension (71% and 74%, respectively). Cardiovascular symptoms (chest pain, dyspnea) at the time of cardiac PET were common and comparable in both groups: 73% (19/26) of vasculitis patients and 69% (50/72) of the controls. Impaired CFR, here reflecting CMD, was abnormal in 38% (10/26) of vasculitis cases compared to 15% (11/72) of controls. The mean (SD) CFR was 19% lower in vasculitis cases versus controls (2.1 [0.5] versus 2.6 [0.7]; P=0.003). To account for the contribution of diffuse atherosclerosis on CFR in the systemic vasculitidies, we assessed the presence and severity of CAC. Approximately one-third of the vasculitis patients and controls had no CAC, and the proportion of patients with significant atherosclerosis (severe CAC) was low and similar in both groups (Table 1). These results suggest that vasculitis patients, compared to similar-matched patients, did not have evidence of a higher atherosclerotic burden but nonetheless had more coronary vasomotor dysfunction.

Previous studies in systemic vasculitis have shown evidence of vascular inflammation that associates with broad coronary artery diseas00bse characteristics. Vascular endothelial injury is an early event in atherosclerosis, and prior studies have demonstrated that brachial artery flow-mediated endothelium-dependent vasodilation is impaired in systemic vasculitis and can improve with immunosuppression therapy.⁵ Our data suggest that patients with vasculitis also have more prevalent and more severe CMD than age-matched, sexmatched, and risk factor–matched patients, supporting a potential role for inflammation in driving coronary vasomotor abnormalities. Limitations include the lack of vasculitis disease severity, heterogeneity among the vasculitidies, and treatment history. Only a small portion of the cohort had active vasculitis at the time of the PET (21%, 7/26), and whether coronary vascular function would be further compromised during active disease is not known. Due to the small sample, we were not able to investigate differences between the vasculitidies. Future prospective studies are needed to examine CMD across vasculitis clinical severity and subtype and whether reducing systemic inflammation can lead to improved coronary microvascular function and cardiovascular outcomes.