Cardiovascular Morbidity in Erdheim-Chester Disease (ECD) Patients with and without Cardiac Involvement

Purpose: The understanding of cardiac-involved ECD (ECD-CV) and how this affects outcomes and pre-existing diseases remains limited. We aimed to determine the association, burden, and severity of pre-existing and de novo cardiovascular (CV) comorbidities with ECD-CV compared to patients (pts) without cardiac-involved ECD (ECD-noCV).

Methods: Records of pts with ECD diagnosed from Jan-1990 to Dec-2021, consecutively seen at Mayo Clinic, AZ, FL, and MN were reviewed. Cardiac involvement was diagnosed by imaging. CV comorbidities were captured before and after ECD diagnosis. CTCAE v3.0 based grading system was used to assess CV comorbidities which graded the conditions as mild (grade 1), moderate (grade 2), severe (grade 3), and life-threatening or disabling (grade 4). Chi-square test was used to determine if having ECD-CV worsens pre-existing CV comorbidities in pts with ECD. As per the established methods, the cumulative CV disease burden was defined after considering 8 CV morbidities that are known to have direct structural and functional implications on the heart, including hypertension (HTN), coronary artery disease (CAD), myocardial infarction (MI), congestive heart failure (CHF), atrial fibrillation (afib), pericardial effusion, valvular disease, and conduction disorders. A composite CV morbidity grade was assigned based on the highest grade in one of the 8 CV comorbidities (Oeffinger, NEJM, 2006). Lastly, a multivariant analysis was conducted using the presence of BRAF^V600E mutation, smoking, age ≥ 60 years (yr), conventional vs targeted therapy, and ECD-CV in pts with a composite grade of 4.

Results: Among 106 ECD pts, 38% (n=40) had cardiac involvement. The median age at diagnosis of ECD was 57 yr (range: 49-67); 61% were males. The median follow-up was 5 yr (95% CI: 3.5-6.1), and 4.1 yr (95% CI: 3.2-6.5) for ECD-CV and ECD-noCV pts, respectively p=0.92. The median time of CV diagnoses for the entire cohort before and after ECD diagnosis was 4.8 yr (range: 0.06-42.5) and 3.4 yr (range: 0.05-18.7), respectively. BRAF^V600E mutation was present in 65% (n=26) of ECD-CV vs 42% (n=28) of ECD-noCV, p=0.02. Eight pts with ECD-CV died; one from sudden cardiac death, while 9 ECD-noCV pts died, p=0.39. Smoking was present in 43% (n=18) of ECD-CV pts compared to 24% with ECD-noCV (n=16), p=0.05.

In comparison to ECD-noCV pts, increased prevalence of pre-existing HTN [59% (n=23) vs 35% (n=23), p=0.016] and MI [10% (n=4) vs 2% (n=1), p=0.046] was seen in ECD-CV. There was no difference in hyperlipidemia, diabetes mellitus, CAD, CHF, valvular disease, afib, and conduction disorders among the two cohorts. After ECD diagnosis, de novo diagnosis of hyperlipidemia [67% (n=26) vs 38% (n=25); p=0.004] and CHF [35% (n=14) vs 7% (n=5); p=<0.001] was seen more frequently in ECD-CV pts compared to ECD-noCV. Following the diagnosis of ECD, the severity of pre-existing conditions did not change in pts with or without ECD-CV.

ECD-CV pts had a greater cumulative CV disease burden as the total number of CV morbidities was greater in ECD-CV pts both before and after ECD diagnosis (Table 1). Additionally, pts with ECD-CV had greater severity of CV morbidity (composite grade ≥4) than ECD-noCV before (35% v 3%; p=<0.001) and after (42.5% vs 7.6%; p=<0.001) ECD diagnosis. The composite grade of 4 before ECD diagnosis was most attributable to pericardial effusion (42% in pts with ECD-CV vs 0% in pts with ECD-noCV) and CAD (50% in pts with ECD-CV vs 100% in pts with ECD-noCV); after ECD diagnosis pericardial effusion (42% in pts with ECD-CV vs 0% in pts with ECD-noCV) and CAD (41% in pts with ECD-CV vs 100% in pts with ECD-noCV). After considering BRAF^V600E mutation, age ≥60, smoking, ECD-CV, and first-line therapy (conventional vs targeted therapy), ECD-CV was the only factor independently associated with a composite grade of ≥4, before (OR 25.6, 95% CI: 4.8-137) and after (OR 9.7, 95% CI: 3.0-30.8) ECD diagnosis. Nonetheless, smoking, age >60, and ECD-CV were independent factors associated when considered a composite grade of ≥3, before and after ECD diagnosis.

Conclusion: ECD-CV did not prognosticate pts and did not worsen the pre-existing CV conditions compared to pts with ECD-noCV. However, ECD-CV pts had a higher cumulative CV disease burden and a higher grade of pre-existing and de novo CV morbidities compared to ECD-noCV. The presence of cardiac involvement in ECD was independently associated with a severe cumulative CV disease burden grade.