Driver gene mutations including TET2, DNMT3A, and JAK2V617F, will lead to aberrant clone expansions in hematopoietic stem cells (HSCs) that increasingly give rise to mutant progeny leukocytes. The mutant leukocytes display altered immune responses, shifting the balance away from a healing and towards an overt inflammatory response involving the increased expression of IL-6, IL-1β, and TNFα in addition to other immune cell perturbations. These mutant leukocytes promote myocardial cardiac dysfunction, hypertrophy and fibrosis, and accelerate the progression of heart failure.