Reply: Perspectives and Limitations of the Studies of the Association Between Heart Failure and Cancer.

We thank Drs Brahmbhatt and colleagues and Dr Menon and Mr Ahmad for their constructive comments on our paper.

We agree with Dr Brahmbhatt and colleagues that clonal hematopoiesis of indeterminate potential (CHIP) may be a possible mechanism linking cancer and cardiovascular disease. Indeed, CHIP-related variants both confer a proliferative advantage to hematopoietic progenitors and amplify the inflammatory response of the innate immune system. The proinflammatory phenotype of mature myeloid cells carrying CHIP-related variants might contribute to the enhanced atherosclerotic burden and increased risk for cardiovascular events observed in animal models and patients with CHIP. Accordingly, one recent exploratory analysis suggested that in the CANTOS (Cardiovascular Risk Reduction Study [Reduction in Recurrent Major CV Disease Events]) trial, the effect of interleukin-1-beta inhibition with canakinumab on major adverse cardiovascular events was greater in patients with CHIP due to TET2 variants. In addition, in rodent models of pressure overload–induced heart failure (HF), CHIP-related activation of the Nod-like receptor protein 3 inflammasome worsened maladaptive left ventricular remodeling, indicating that the inflammatory state associated with CHIP has detrimental effects on cardiac function even in the absence of atherosclerosis. Overall, experimental and clinical evidence implicates CHIP in the pathogenesis of both cardiovascular disease and hematologic malignancies.

As pointed out by Dr Menon and Mr Ahmad, one limitation of our analysis is that our study population is rather homogeneous with respect to ethnicity and geography. Nonetheless, our results are corroborated by similar analyses performed in diverse regions, including the United States, Denmark, and Japan., Furthermore, we were unable to differentiate between HF with reduced and preserved ejection fraction, which is certainly relevant given the differences in etiology and pathophysiology of these 2 entities. However, we did include men and assessed whether sex influenced the excess risk for cancer in the HF population. In addition, and consistent with the study by Roderburg et al, we observed that patients with HF had a greater risk for incident head and neck cancers (HR: 1.35; 95% CI: 1.15-1.59) and increased mortality with cancers arising in the head and neck (HR: 1.92; 95% CI: 1.33-2.78) (reported in Supplemental Tables 7 and 8).