Abstract
Clonal hematopoiesis of indeterminate potential (CHIP)-associated mutations, which are also commonly observed in Myelodysplastic syndrome (MDS), have been linked to an increased risk of cardiovascular disease (CVD). However, the burden and risk factors of CVD in the context of MDS remain poorly characterized. This study aimed to assess the frequency of CVD and its associated risk factors, including CHIP-associated mutations, in patients with MDS and related myeloid disorders.MethodsThis bidirectional cohort study was conducted in King Chulalongkorn Memorial Hospital, Thailand. We included patients diagnosed with unexplained cytopenia, MDS or myelodysplastic syndrome/myeloproliferative neoplasms (MDS/MPN) who underwent targeted next-generation sequencing between January 2015 and March 2025. Patients with therapy-related MDS, and classical MPN (essential thrombocytosis, polycythemia Vera and primary myelofibrosis) were excluded. The primary outcome was the frequency of composite cardiovascular events, defined as myocardial infarction, ischemic stroke, or cardiovascular death. Secondary outcomes included the identification of risk factors associated with CVD and the assessment of association between mutations and cardiovascular events.ResultsA total of 196 participants were enrolled. The majority were diagnosed with MDS (77.2%), followed by ICUS (7.6%), MDS/MPN (7.6%), and CCUS (7.6%). The median follow-up duration was 33.8 months (IQR 28.8-36.7). CVD events were observed in 51 patients (26%), a higher incidence compared to the 17–20% observed in the age-matched general population. Most CVD events occurred prior to the diagnosis of MDS, with a median time from myocardial infarction (MI) to MDS of 71 months (IQR, 9–156) and from stroke to MDS of 21 months (IQR, 3–101.5). Seventeen patients (8.7%) developed CVD after the diagnosis of MDS. The median time from MDS diagnosis to MI and stroke was 6 months (IQR, 4–18) and 17 months (IQR, 2–36), respectively. In terms of cardiovascular risk factors, 29.6% of patients were diagnosed with type 2 diabetes mellitus, 40.3% had hypertension, and 37.8% had dyslipidemia. Additionally, 18.3% of the patients had a history of smoking. Regarding treatment history, 43.4% of patients had received azacitidine, and 31.1% had received erythropoiesis stimulating agents (ESA), and 5.6% underwent bone marrow transplantation. CHIP-associated mutations were identified in 47% of the cohort. The most frequently mutated genes were TET2 (13.3%), ASXL1(13.3%), SRSF2(12.2%), and SF3B1 (10.7%), respectively. Notably, gene mutations were present in 59% of patients with CVD compared to 50% of those without (p=0.3). Among specific mutations, TET2mutations were significantly more frequent in patients with CVD than in those without (21.6% vs. 10.3%; p = 0.042). Age > 70 years at diagnosis, anemia (defined as hemoglobin < 10 g/dL), and history of smoking were independently associated with an increased risk of CVD events (adjusted OR 2.99, 95% CI 1.01–8.85, p = 0.048; aOR 4.23, 95% CI 1.22–14.55, p = 0.022; and aOR 5.32, 95% CI 1.18–23.92, p = 0.029, respectively). TET2 mutations were also associated with an increased risk of CVD (OR 2.38, 95% CI 1.01–5.60, p = 0.046). However, the variant allele frequency (VAF) of CHIP-associated mutations was not significantly associated with CVD risk.Patients with CVD had significantly shorter overall survival compared to those without CVD (median overall survival: 27 vs. 56 months; p = 0.006). Furthermore, lower-risk MDS (R-IPSS ≤ 3.5) was independently associated with reduced all-cause mortality (aOR 0.16, 95% CI 0.027–0.91, p = 0.039). ConclusionCVD was more prevalent in patients with MDS than in the general population. Age > 70 years at diagnosis, anemia and history of smoking emerged as independent risk factors for CVD. TET2 mutations were also linked to an increased risk of CVD. Patients with cardiovascular comorbidities demonstrated poorer overall survival, underscoring the need for proactive cardiovascular risk assessment and management in individuals with MDS.
