Clonal Hematopoiesis in Clinical and Experimental Heart Failure With Preserved Ejection Fraction

Abstract

BACKGROUND: Clonal hematopoiesis (CH), which results from an array of nonmalignant driver gene mutations, can lead to altered immune cell function and chronic disease, and has been associated with worse outcomes in patients with heart failure (HF) with reduced ejection fraction. However, the role of CH in the prognosis of HF with preserved ejection fraction (HFpEF) has been understudied. This study aimed to characterize CH in patients with HFpEF and elucidate its causal role in a murine model. METHODS: Using a panel of 20 candidate CH driver genes and a variant allele frequency cutoff of 0.5%, ultradeep error-corrected sequencing identified CH in a cohort of 81 patients with HFpEF (mean age, 71±6 years; ejection fraction, 63±5%) and 36 controls without a diagnosis of HFpEF (mean age, 74±7 years; ejection fraction, 61.5±8%). RESULTS: Compared with controls, there was an enrichment of TET2 -mediated CH in the HFpEF patient cohort (12% versus 0%, respectively; P =0.02). In the HFpEF cohort, patients with CH exhibited exacerbated diastolic dysfunction in terms of E/e′ (14.9 versus 11.7, respectively; P =0.0096) and E/A (1.69 versus 0.89, respectively; P =0.0206) compared with those without CH. The association of CH with exacerbated diastolic dysfunction was corroborated in a validation cohort of 59 individuals with HFpEF. In accordance, patients with HFpEF with CH and age ≥70 years exhibited worse prognosis in terms of 5-year cardiovascular-related hospitalization rate (hazard ratio, 5.06; P =0.042) compared with patients with HFpEF without CH and age ≥70 years. To investigate the causal role of CH in HFpEF, nonconditioned mice underwent adoptive transfer with Tet2 –wild-type or Tet2 -deficient bone marrow and were subsequently subjected to a high-fat diet/L-NAME (N ω -nitro-l-arginine methyl ester) combination treatment to induce features of HFpEF. This model of Tet2 -CH exacerbated cardiac hypertrophy by heart weight/tibia length and cardiomyocyte size, diastolic dysfunction by E/e′ and left ventricular end-diastolic pressure, and cardiac fibrosis compared with the Tet2 –wild-type condition. CONCLUSIONS: CH is associated with worse heart function and prognosis in patients with HFpEF, and a murine experimental model of Tet2 -mediated CH displays greater features of HFpEF.

Clonal Hematopoiesis and Incident Heart Failure With Preserved Ejection Fraction

“…Third, while this study benefited from the inclusion of racially diverse cohorts, certain demographic groups were still not represented. However, recent case-control studies that mainly involved participants with demographics different from those in the present study (eg, White male participants) found consistent associations between CHIP or TET2 CHIP and HFpEF, suggesting that our findings may generalize to other demographic groups. Fourth, while WGS enables large-scale genetic analyses in population-based cohorts, it has limited sensitivity to detect CHIP with VAF less than 10% .…”

“…CHIP had increased diastolic dysfunction, ventricular hypertrophy, and cardiac fibrosis in comparison with control mice. 23 Our results corroborate and extend these findings by showing that TET2 CHIP was associated with incident HFpEF in a population-based sample, identifying TET2 CHIP as a strong and independent risk factor for new-onset HFpEF. Additional work using targeted sequencing is needed to determine an optimal VAF threshold for the prognostic significance of TET2-driven clonal hematopoiesis in HFpEF and to define pragmatic approaches for incorporating CHIP as a clinical risk factor for HFpEF.…”

“…Similarly, in a case-control study of 81 individuals with HFpEF vs 36 controls, Cochran et al found that those with HFpEF were significantly enriched for TET2 CHIP. The same study found that mice modeled for TET2 CHIP had increased diastolic dysfunction, ventricular hypertrophy, and cardiac fibrosis in comparison with control mice . Our results corroborate and extend these findings by showing that TET2 CHIP was associated with incident HFpEF in a population-based sample, identifying TET2 CHIP as a strong and independent risk factor for new-onset HFpEF.…”

“…In a recent study including 358 individuals with incident HF and 347 age- and sex-matched control participants, CHIP was associated with higher natriuretic peptide levels, with subgroup analyses suggesting a nominally increased risk of incident HFpEF but not HFrEF among individuals younger than 65 years with vs without CHIP . Similarly, in a case-control study of 81 individuals with HFpEF vs 36 controls, Cochran et al found that those with HFpEF were significantly enriched for TET2 CHIP. The same study found that mice modeled for TET2 CHIP had increased diastolic dysfunction, ventricular hypertrophy, and cardiac fibrosis in comparison with control mice .…”

“…natriuretic peptide levels, with subgroup analyses suggesting a nominally increased risk of incident HFpEF but not HFrEF among individuals younger than 65 years with vs without CHIP. 22 Similarly, in a case-control study of 81 individuals with HFpEF vs 36 controls, Cochran et al 23 found that those with HFpEF were significantly enriched for TET2 CHIP. The same study found that mice modeled for TET2…”