In a study published in JAMA cardiology, the data suggested that somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 and DNMT3A, could be significantly associated with the progression and poor prognosis of CHF. The study was led by Dr. Lena Dorsheimer from the Department of Medicine, Goethe University Hospital, Frankfurt, Germany.
A new window has just opened, illuminating a novel and unsuspected aspect of the pathogenesis of heart failure. As we age, we accumulate somatic mutations in bone marrow stem cells that confer a proliferative advantage, yielding clones in the peripheral blood of mutant leukocytes. Unexpectedly, carriers of these clones of mutant leukocytes have a striking increase in the risk of ischemic heart events. Because most individuals with these clones will never develop leukemia during their lifespan, this condition has been termed clonal hematopoiesis of indeterminate potential (CHIP). Clonal hematopoiesis of indeterminate potential mutations commonly arises in a surprisingly restricted set of genes. A consensus cut point of 2%of circulating leukocytes that bear such driver mutations defines CHIP. It is already known that somatic mutations causing clonal expansion of hematopoietic cells (clonal hematopoiesis of indeterminate potential [CHIP]) are increased with age and associated with atherosclerosis and inflammation. Age and inflammation are the major risk factors for heart failure, yet the association of CHIP with heart failure in humans is unknown. Therefore, Dorsheimer and her team of investigators strived to assess the potential prognostic significance of CHIP in patients with chronic heart failure (CHF) owing to an ischemic origin. They examined bone marrow-derived mononuclear cells from 200 patients with CHF by deep targeted amplicon sequencing to detect the presence of CHIP and associated such with long-term prognosis in patients with CHF at University Hospital Frankfurt, Frankfurt, Germany. Data were analyzed between October 2017 and April 2018.
“The novel results reported by Dorsheimer et al. have profound implications for understanding and treating cardiovascular diseases. They magnify the scope of CHIP beyond arterial and venous disease to encompass heart failure. As CHIP links to cardiovascular outcomes independently of traditional risk factors and existing interventions might address some of the consequences of CHIP, stratifying individuals by CHIP status may help achieve the goal of sharpening risk prediction and personalizing the allocation of therapies.”- Dr. Peter Libby, M.D.
The median age of the patients was 65 years. The results showed that forty-seven mutations with a variant allele fraction (VAF) of at least 0.02 were found in 38 of 200 patients with CHF (18.5%). The somatic mutations most commonly occurred in the genes DNMT3A (14 patients), TET2 (9 patients), KDM6A (4 patients), and BCOR (3 patients). Patients with CHIP were older and more frequently had a history of hypertension. During a median follow-up of 4.4 years, a total of 53 patients died, and 23 patients required hospitalization for heart failure. There was a significantly worse long-term clinical outcome for patients with either DNMT3A or TET2 mutations compared with non-CHIP carriers. By multivariable Cox proportional regression analysis, the presence of somatic mutations within TET2 or DNMT3A (HR, 2.1; 95%CI, 1.1-4.0; P = .02, for death combined with heart failure hospitalization) and age (HR, 1.04; 95%CI, 1.01-1.07 per year; P = .005) but not a history of hypertension remained independently associated with adverse outcome. Importantly, there was a significant dose-response association between VAF and clinical outcome.
In this cohort study, the investigators concluded that CHIP had a high prevalence in 200 investigated patients with CHF. While no clinical baseline characteristics associated with CHF were different between CHIP carriers and non-CHIP carriers, except for the mean age, harboring mutations in the most prevalent driver genes associated with CHIP, namely DNMT3A and TET2, was associated with a significant and profound increase in death and rehospitalization for heart failure. Thus, clonal hematopoiesis of indeterminate potential was presented as a newly identified risk factor for impaired long-term survival and increased disease progression in patients with CHF that could be well targetable as a valuable approach to precision medicine in patients with CHF carrying specific mutations encoding for clonal hematopoiesis. Somatic mutations in hematopoietic cells, specifically in the most commonly mutated CHIP driver genes TET2 andDNMT3A, could be significantly associated with the progression and poor prognosis of CHF of ischemic origin. Future studies would have to validate our findings in larger cohorts and address whether targeting specific inflammatory pathways could be valuable for precision medicine in patients with CHF carrying specific mutations encoding for CHIP.
“DNMT3A and TET2 mutations probably influence cardiovascular events by producing epigenetic alterations of gene expression as a consequence of dysregulated DNA methylation. The mechanisms which underlie these previously unsuspected links with heart failure and atherosclerosis outcomes likely include an augmented expression of genes that participate in innate immune signaling. As pharmacologic approaches permit targeting each of the elements in this pathway, these observations promise considerable translational potential.”- Dr. Benjamin L. Ebert, M.D.
In an accompanying editorial, Dr. Peter Libby, Division of Cardiovascular Medicine, Brigham and Women’s Hospital, Harvard Medical School, Boston, Massachusetts wrote, “The novel results reported by Dorsheimer et al. have profound implications for understanding and treating cardiovascular diseases. They magnify the scope of CHIP beyond arterial and venous disease to encompass heart failure. As CHIP links to cardiovascular outcomes independently of traditional risk factors and existing interventions might address some of the consequences of CHIP, stratifying individuals by CHIP status may help achieve the goal of sharpening risk prediction and personalizing the allocation of therapies.” Speaking of the impact of this study, Dr. Benjamin L. Ebert stated, “These 2 most common CHIP genes mutated in this study encode proteins that function in the methylation of cytosine, one of the pyrimidines found in DNA. Hence, DNMT3A and TET2 mutations probably influence cardiovascular events by producing epigenetic alterations of gene expression as a consequence of dysregulated DNA methylation. The mechanisms which underlie these previously unsuspected links with heart failure and atherosclerosis outcomes likely include an augmented expression of genes that participate in innate immune signaling. As pharmacologic approaches permit targeting each of the elements in this pathway, these observations promise considerable translational potential.”
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