Cardiovascular Disease in Myeloproliferative Neoplasms: JACC: CardioOncology State-of-the-Art Review

Abstract

Myeloproliferative neoplasms are associated with increased risk for thrombotic complications. These conditions most commonly involve somatic mutations in genes that lead to constitutive activation of the Janus-associated kinase signaling pathway (eg, Janus kinase 2, calreticulin, myeloproliferative leukemia protein). Acquired gain-of-function mutations in these genes, particularly Janus kinase 2, can cause a spectrum of disorders, ranging from clonal hematopoiesis of indeterminate potential, a recently recognized age-related promoter of cardiovascular disease, to frank hematologic malignancy. Beyond thrombosis, patients with myeloproliferative neoplasms can develop other cardiovascular conditions, including heart failure and pulmonary hypertension. The authors review the pathophysiologic mechanisms of cardiovascular complications of myeloproliferative neoplasms, which involve inflammation, prothrombotic and profibrotic factors (including transforming growth factor-beta and lysyl oxidase), and abnormal function of circulating clones of mutated leukocytes and platelets from affected individuals. Anti-inflammatory therapies may provide cardiovascular benefit in patients with myeloproliferative neoplasms, a hypothesis that requires rigorous evaluation in clinical trials.

Keywords: ASXL1, additional sex Combs-like 1; CHIP, clonal hematopoiesis of indeterminate potential; DNMT3a, DNA methyltransferase 3 alpha; IL, interleukin; JAK, Janus-associated kinase; JAK2, Janus kinase 2; LOX, lysyl oxidase; MPL, myeloproliferative leukemia protein; MPN, myeloproliferative neoplasm; STAT, signal transducer and activator of transcription; TET2, tet methylcytosine dioxygenase 2; TGF, transforming growth factor; atherosclerosis; cardiovascular complications; clonal hematopoiesis; myeloproliferative neoplasms; thrombosis.

Graphical abstract

Figure 1

Spectrum of Disorders of Myelopoiesis Oversimplified schema of the spectrum of disorders of myelopoiesis. Hematopoietic stem cells can acquire somatic mutations that can lead to myeloproliferative neoplasms (MPNs) directly or through mutations of clonal hematopoiesis of indeterminate potential (CHIP). Although MPN driver mutations can be present in CHIP, variant allele expansion or other genetic insults can result in MPN from CHIP. MPNs can progress to more aggressive disorders including myelodysplastic syndromes and acute leukemia. Additionally, myelofibrosis can be primary (primary myelofibrosis) or secondary (progression from essential thrombocythemia and polycythemia vera). CHIP similarly can lead to myelodysplastic syndrome (MDS) or acute leukemia through additional genetic insults. ASXL1 = additional sex Combs-like 1; CALR = calreticulin; DNMT3a = DNA methyltransferase 3 alpha; JAK2 = Janus kinase 2; LOX = lysyl oxidase; MPL = myeloproliferative leukemia protein; TET2 = tet methylcytosine dioxygenase 2; TGFβ = transforming growth factor–β.

Central Illustration

Pathophysiology of Cardiovascular Disease in Myeloproliferative Neoplasms Arrows indicate relationships. Circulating myeloid neoplastic cells contribute to atherosclerosis and thrombosis via production of inflammatory cytokines, neutrophil extracellular trap formation, and plaque infiltration. Heart failure in myeloproliferative neoplasm mediated by arterial thrombosis (myocardial infarction) and accelerated pathologic remodeling. Extramedullary hematopoiesis can lead to high-output heart failure and pulmonary hypertension.

Figure 2

Fibrogenic Mediators Promote Bone Marrow Fibrosis in Myeloproliferative Neoplasms Arrows indicate relationships. Neoplastic megakaryocytes in myeloproliferative neoplasms secrete transforming growth factor–β and lysyl oxidase, which promote bone marrow fibrosis. Lysyl oxidase oxidizes platelet-derived growth factor (PDGF) receptors on the surface of stromal cells and megakaryocytes, which enhances ligand affinity to receptors and promotes proliferation of neoplastic megakaryocytes. Lysyl oxidase also exerts effects on platelets and increases platelet activation and adhesion to collagen.