Clonal hematopoiesis of indeterminate potential (CHIP) represents a new risk factor for heart failure, according to a new meta-analysis of five previous trials. CHIP refers to the presence of clonal molecular genetic or cytogenetic changes in blood or bone marrow cells in the absence of signs of hematological neoplasm and absence of cytopenia. The incidence of CHIP increases with age. While CHIP was detected only in rare cases in persons under 50 years of age, risk rises rapidly with age and is suggested to affect 10% to 20% of people aged 70 to 80 years. The analysis, published online Monday and in the July 6 issue of the Journal of the American College of Cardiology, suggests that age-related CHIP is associated with adverse health outcomes, including incident heart failure (HF) in asymptomatic individuals. “Our findings identify CHIP as a potentially important novel age-related risk factor for HF, consistent with previous findings of the role of CHIP as a risk factor for age-related atherosclerotic CVD more broadly,” said the authors, led by Bing Yu, PhD, from the University of Texas Health Science Center at Houston. “If confirmed, these findings ultimately may have potential implications for development or targeting of anti-inflammatory therapies such IL-1beta or NLRP3 inflammasome inhibitors in HF patients,” they said. Study details Yu and colleagues noted that age-related CHIP – defined as clonally expanded leukemogenic sequence variations – particularly in DNMT3A, TET2, ASXL1, and JAK2 in asymptomatic individuals – has previously been associated with cardiovascular events, including recurrent HF. As such, the new study set out to evaluate the role of CHIP in incident HF. CHIP status was obtained from whole exome or genome sequencing of blood DNA in participants without prevalent HF or hematological malignancy from five prospective population-based studies with a pooled population of 56,597 individuals. Of 56,597 individuals, 3,406 (6%) had CHIP at baseline, and 4,694 developed HF (8.3%) over up to 20 years of follow-up. CHIP was associated with a 25% increased risk of HF (hazard ratio [HR]: 1.25; 95% confidence interval [CI]: 1.13-1.38) with consistent associations across cohorts, said Yu and colleagues, noting that the ASXL1, TET2, and JAK2 sequence variations were each associated with an increased risk of HF, whereas DNMT3A sequence variations were not associated with HF. Secondary analyses suggested large CHIP – defined as variant allele frequency of greater than 10% – was associated with a greater risk of HF (HR: 1.29; 95% CI: 1.15-1.44), and the associations for CHIP on HF with and without prior coronary heart disease were homogenous. Unprecedented insight Writing in an accompanying editorial, José J. Fuster, PhD, from the Centro Nacional de Investigaciones Cardiovasculares (CNIC), Spain, said that advances in DNA sequencing techniques are enabling unprecedented insight into the relevance of acquired mutations in cancer and noncancerous conditions. Indeed, he noted that a 70-year-old individual may carry approximately 1 million mutations in protein-coding genes in the pool of hematopoietic stem cells. “Whereas most of these mutations are neutral or deleterious to cell function, leading to their demise, some mutations provide a selective advantage that leads to the progressive clonal expansion of the mutant cell over the years.” Fuster said the new findings expand understanding of the clinical implications of this clonal hematopoiesis by demonstrating that CHIP is associated with a 25% increased risk of incident HF, independent of traditional CVD risk factors – adding that the association between CHIP and HF was comparable in individuals with and without coronary heart disease. “This observation is relevant, because it suggests a direct connection between CHIP and cardiac dysfunction, arguing against the possibility that this association merely reflects the strong connection between CHIP and atherosclerosis or the long-lasting effects of myocardial ischemia on the hematopoietic system.” The editorialist added that gene-specific analysis demonstrating mutations in DNMT3A were not associated with HF results support the emerging idea that CHIP mutations in different genes are not equivalent, and that the clinical significance of this phenomenon depends on the specific mutated gene. “Indeed, mutations in TET2, JAK2, and ASXL1 were separately associated with a 1.5- to 2.5-fold increase in the risk of incident HF,” he noted. Sources: Yu B, Roberts MB, Raffield LM, et al. Supplemental Association of Clonal Hematopoiesis With Incident Heart Failure. J Am Coll Cardiol 2021;78:42-52. Fuster JJ. Clonal Hematopoiesis and Incident Heart Failure Risk: The Clone Wars Reach the Myocardium. J Am Coll Cardiol 2021;78:53-5.