Abstract Body (Do not enter title and authors here): Introduction: Aging and inflammation are both important risk factors of heart failure with preserved ejection fraction (HFpEF). However, a potential mechanistic link between them in HFpEF pathogenesis remains unknown. Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition characterized by the clonal expansion of hematopoietic stem cell (HSCs) bearing mutations in certain driver genes and is associated with increased inflammation and elevated risk of cardiovascular diseases. However, our understanding of the role of CHIP in HFpEF remains limited.
Methods and Results: We evaluated the prevalence and clinical impact of CHIP in two independent and well-annotated HFpEF cohorts. We compared a single-center registry of deeply phenotyped HFpEF cases at UT Southwestern with age- and sex-matched controls from the Dallas Heart Study (N=108 each), observing that the prevalence of CHIP was significantly higher in HFpEF patients as compared to matched controls (25% vs 19%). We also discovered that TET2 is the most frequently mutated gene in this population (63% in HFpEF vs 40% in controls), while DNMT3A mutations were underrepresented (30% vs 45%). We validated these findings in an external cohort of HFpEF patients from the TOPCAT trial (N=213). Importantly, we discovered that the presence of CHIP is independently associated increased risk of heart failure hospitalization and all-cause mortality (adjusted HR 2.07, 95% CI: 1.01-4.22, p = 0.046).
To determine whether CHIP causally links with HFpEF, mice received Tet2 knockout (KO) vs wildtype bone marrow, and were subjected to a well-established “two-hit” HFpEF induction model. Despite similar systemic responses, the Tet2 KO group manifested exacerbated diastolic dysfunction. This effect is Tet2 specific, as mice harboring HSCs loss of Dnmt3a did not develop such phenotype. Bulk and single-cell RNASeq analyses revealed that HFpEF induction led to an expansion of pro-inflammatory and pro-fibrotic macrophage subsets in the heart, which was exacerbated by CHIP. There is an enrichment of NLRP3/ IL1b inflammatory genes in the Tet2 KO group, and NLRP3 deficiency in HSCs attenuates the phenotype of Tet2 KO-associated HFpEF.
Conclusion: Our results reveal that TET2-mediated CHIP is highly prevalent in HFpEF patients and directly promotes HFpEF pathogenesis. CHIP status could serve as a marker for risk stratification and targeted anti-inflammatory therapies in patients with HFpEF.