Age-Related Somatic Mutations Implicated in Cardiovascular Death

Cardiovascular death had a strong tie to the somatic mutations that often accrue with aging in people with subclinical atherosclerosis, an observational study found.

For asymptomatic people who had atherosclerosis detected by carotid ultrasound, the additional presence of clonal hematopoiesis (CH) — the expansion of hematopoietic stem cells caused by acquired somatic mutations — was associated with increased risk of cardiovascular death (HR 1.50, 95% CI 1.12-2.00) and overall all-cause mortality (HR 1.42, 95% CI 1.11-1.81) over a 12-year follow-up.

Cumulative 12-year survival rates were lower with CH than without it, at 53% versus 65% for cardiovascular death and 41% versus 52% for all-cause death (log-rank P=0.003 for both), reported Christoph Binder, MD, PhD, of the Medical University of Vienna, Austria, and colleagues from their secondary analysis of the ICARAS study.

Moreover, CH and high-degree carotid stenosis together were predictive of cardiovascular mortality, study authors emphasized in their report, published in the Journal of the American College of Cardiology.

Case in point: a person with greater than 50% carotid stenosis and concomitant CH had a 60% elevated risk of mortality over the median 12 years (adjusted HR 1.60, 95% CI 1.08-2.38); over half of such patients died, compared with 27% of those with the same stenosis but no CH detected, according to Binder’s team.

“These findings provide strong evidence for using CH as a stratifying tool in the setting of asymptomatic carotid stenosis,” commented Pradeep Natarajan, MD, MMSC, and Tiffany Bellomo, MD, both of Massachusetts General Hospital and Harvard Medical School in Boston, in an accompanying editorial.

CH had previously been linked to atherosclerotic cardiovascular disease in studies of vascular inflammation and ischemic strokes. “Notably, this [ischemic stroke] risk conferred by CH is equal in magnitude to established clinical factors such as smoking, hypertension, hyperlipidemia, or diabetes,” Natarajan and Bellomo pointed out.

“The presence of a CH variant may serve as a valuable predictive marker for identifying asymptomatic patients at highest risk for progression to symptomatic carotid disease-causing stroke, supporting earlier surgical intervention,” the editorialists suggested.

CH is understood to be the underlying cause of certain hematological malignancies or to represent a premalignant state. When encountered in the general population without an obvious disease phenotype such as myelodysplasia or blasts in the bone marrow, it is known as CH of indeterminate potential (CHIP).

“The incidence of CHIP strongly correlates with age and the frequency of mutant clones is estimated to be about 5% at 60 years of age, increasing to approximately 20% in individuals aged >90 years. While CHIP was shown to elevate the risk of developing a hematological malignancy approximately 10-fold, progression rates to myeloid malignancies in CHIP carriers are still relatively low (0.5%-1%/y),” Binder and colleagues wrote.

They noted that most CHIP-relevant mutations have been reported in the genes DNMT3A, TET2, ASXL1, and JAK2. Thus, they screened for CH in their study by deep sequencing of selected genomic regions within these genes.

The study population was the prospectively enrolled ICARAS cohort of people with indications for sonographic carotid examinations who turned out to have asymptomatic carotid atherosclerosis on duplex sonography.

The main finding of ICARAS had been that inflammatory biomarkers can predict the progression of carotid atherosclerosis in people who were initially asymptomatic.

The secondary analysis focused on 968 participants (median age 69.2 years, 63% men) who had targeted resequencing done to screen for CH. These somatic mutations were detected in 13.7% of the cohort and, as expected, were increasingly prevalent at older age, rising from 7.7% in those under age 50 to 42.9% in the over-90 group.

Binder’s group reported that the association of CH and cardiovascular mortality was more pronounced in older patients and independent of inflammation as measured by high-sensitivity CRP. “Thus, the effects of CH described herein possibly involve other inflammatory pathways.”

Study authors acknowledged that they did not look for all possible CH variants for their study.

“Given that the paramount concern regarding medical management of asymptotic carotid stenosis is the development of a massive stroke, further investigation may focus on using CH variants to predict risk of any stroke occurrence in a designated follow-up period,” Natarajan and Bellomo suggested.

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