Leveraging a Clinical HFpEF Program to Better Understand Its Pathophysiology: Role of CHIP in HFpEF

Heart failure with preserved ejection fraction (HFpEF), previously also known as “diastolic heart failure” or “stiff heart,” has emerged as the most common type of HF among older adults. However, effective therapies for HFpEF remain limited due to a poor understanding of its underlying mechanisms. Aging and inflammation are both important risk factors of HFpEF. Clonal hematopoiesis of indeterminate potential (CHIP) is a common age-related condition characterized by the clonal expansion of blood cells bearing mutations in certain driver genes. It is associated with increased inflammation and elevated risk of cardiovascular diseases. However, our understanding of the role of CHIP in HFpEF remains limited.

At #AHA24, we reported the prevalence and prognostic implications of CHIP in two independent and well-annotated HFpEF cohorts: the UTSW HFpEF cohort and the TOPCAT trial cohort. The former included participants from the UTSW HFpEF clinic, a state-of-the-art clinical program focused on improving medical care and quality of life for patients with chronic HFpEF with a passion for understanding the disease and patients better. Patients referred to the UTSW HFpEF clinic undergo detailed phenotyping, including exercise hemodynamic assessments to confirm the diagnosis, and are invited to participate in further prospective diagnostic testing. This evaluation includes an exercise test, physical function assessments, and biobanking to allow for future investigations.

In the study reported at #AHA24, we found that the prevalence of CHIP was significantly higher in HFpEF patients as compared to matched controls, and that ten-eleven translocation-2 (TET2) was the most frequently mutated gene in this population. Importantly, in the TOPCAT trial cohort, a multicenter cohort of patients with chronic HFpEF, we found that the presence of CHIP was independently associated with increased risk of heart failure hospitalization and all-cause mortality, suggesting that CHIP is a novel independent risk factor in HFpEF. We further performed mechanistic studies using animal models and demonstrated that TET2 mutation-mediated CHIP directly promotes HFpEF via pro-inflammatory pathways. Based on these results, we believe that CHIP status could serve as a novel marker for risk stratification and targeted anti-inflammatory therapies in patients with HFpEF.