Cardiac and genetic predictors of cardiovascular risk in patients with myelodysplastic syndromes

Myelodysplastic syndromes (MDS) comprise a spectrum of clonal blood cancers characterized by ineffective clonal hematopoiesis and the risk of progression to acute myeloid leukemia (AML) [1]. The median age at MDS diagnosis is approximately 76 years old [2]. Therapeutic options have remained limited for MDS, especially for low-risk patients, for whom long-term survival remains poor despite a lower risk of progression to leukemia [3]. While complications of cytopenias (i.e. infection) and progression to AML are major causes of MDS mortality, identifying other modifiable risk factors for death may substantially improve survival in MDS patients. Clonal hematopoiesis of indeterminant potential (CHIP) is characterized by recurrent somatic mutations that result in identifiable clonal cell architecture, but without dysplasia or cytopenia to fulfill the diagnostic criteria for MDS [4]. Many recurrent somatic mutations seen in CHIP are also seen in MDS, and include those affecting epigenetic modifiers (e.g. TET2, ASXL1), signaling pathways (e.g. JAK2, RUNX1) and DNA damage repair (e.g. TP53) [5–7]. The presence of CHIP is associated with an increase in all-cause mortality and cardiovascular disease (CVD) risk as defined by coronary heart disease and ischemic stroke [5]. In particular, mutations in DNMT3A, TET2, ASXL1 and JAK2 may be associated with CVD risk [6]; for instance, somatic mutations in TET2 appear to increase atherosclerotic plaque size via IL-1B expression by macrophages harboring these mutations [8]. Recently, we have shown that patients with MDS, who have similar mutations to those seen in the CHIP population, have an increased mortality attributed to CVD compared to the ageand sex-matched US population, suggesting a common underlying pathophysiology between these patient groups [9]. In this study, we sought to specifically characterize CVD events among MDS patients and correlate these events with cardiovascular risk factors and MDS-associated somatic mutations, with particular attention paid to mutations characteristically seen in CHIP. We identified patients 18 years or older with an MDS diagnosis who were treated at Massachusetts General Hospital and who underwent next generation sequencing (NGS)-based mutation testing during the course of their disease, which was performed between 2015 and 2017. Mutational testing was performed as part of routine clinical care using the NGS-based Heme SNaPshot and Rapid Heme Panel Assays [10,11]. MDS disease risk was assessed using the Revised International Prognostic Scoring System (IPSS-R) based on patient attributes at the time of MDS diagnosis [3]. CVD risk was assessed at the time of MDS diagnosis using the American College of Cardiology/American Heart Association Pooled Cohort risk equation (‘ASCVD score’), which incorporates a patient’s age, gender, race, blood pressure, cholesterol levels and history of diabetes, smoking or hypertension. Although this score was developed to provide an estimate of the 10-year atherosclerotic cardiovascular disease risk as primary prevention for patients without CVD, it integrates a number of known risk factors for CVD and may therefore reflect general cardiac risk, even though it cannot be used to provide 10-year risk estimates for those patients with prior cardiac disease or high risk factors [12]. The medical record was interrogated for CVD events using a validated search algorithm from QPIDmed (Queriable Patient Inference Dossier) informatics platform version 2.2 [13,14] and categorized as (1) coronary artery disease (CAD; defined by documentations of ‘ST-elevation MI’ [STEMI], ‘non-ST-elevation MI’ [NSTEMI], ‘ischemic cardiomyopathy’ or history of