A new study added heart failure with preserved ejection fraction (HFpEF) to the growing list of cardiovascular diseases associated with clonal hematopoiesis of indeterminate potential (CHIP), which already includes atherosclerotic cardiovascular diseases (ASCVD).
But what exactly is CHIP and what potential value does it have for CVD risk and management?
CHIP is an age-related condition characterized by clonal expansion of blood stem cells with leukemia-associated mutations in individuals without evidence of hematological malignancy. Approximately 10% of people aged 70 and older are estimated to be affected by CHIP.
Initially described as a risk factor for hematological, particularly myeloid, malignancies, CHIP has recently emerged as a new risk factor for cardiovascular diseases.
CHIP leads to the formation of proinflammatory immune cells, which can exacerbate ASCVD and induce or accelerate heart failure.
„The association between CHIP and HFpEF may be particularly relevant as the prevalence of HFpEF is increasing due to the aging population,“ said José J. Fuster, PhD, Coordinator of the Novel Mechanisms of Atherosclerosis Program, Spanish National Center for Cardiovascular Research, Madrid, Spain, according to theheart.org | Medscape Cardiology.
Previous studies that investigated CHIP and heart failure, however, either focused on general heart failure without distinguishing between the subtypes of preserved and reduced ejection fraction, or examined their prognostic significance within established heart failure and not the development of future heart failure.
To address this gap, researchers based in Boston recently examined the connections between CHIP and the two most common gene-specific CHIP subtypes (TET2 and DNMT3A CHIP) with incident HFpEF and HF with reduced ejection fraction (HFrEF).
In two racially diverse cohorts totaling 8090 adults, TET2 CHIP was independently associated with a >twofold higher risk of an HFpEF event. In contrast, there were no significant associations between CHIP and HFrEF events.
„The funding our research suggests previously described associations between CHIP and the future development of heart failure may be primarily driven by HFpEF,“ said Dr. Michael Honigberg from the Cardiocular Research Center and Center for Genomic Medicine at Massachusetts General Hospital in Boston.
Furthermore, the „most distinct signal for an association with HF“ was observed with TET2 CHIP, the second most common subtype of CHIP in the population. This finding is consistent with a recent study reporting a relative enrichment of TET2 CHIP in a small human HFpEF cohort,“ added Honigberg.
Fuster stated that the association between CHIP and aging „increases the potential clinical relevance of this study, as CHIP is common in older individuals and may therefore contribute to the pathophysiology of HFpEF in a high proportion of patients.“
However, he cautioned that the results need to be validated in other studies.
„In addition, the awareness that the effects of CHIP are heterogeneous, as mutations in different genes have different effects on the cardiovascular system and act through different mechanisms. Further studies will be necessary to analyze the gene-specific effects on HFpEF. This will also be the case,“ Fuster added.
Honigberg said the results could be helpful in developing new targeted treatment strategies, at least for the subgroup of patients with HFpEF.
Based on several lines of evidence, the mechanism linked to TET2 CHIP in CVD seems to be enhanced inflammation, he explained.
For example, in a sub-study of the CANTOS trial, patients with atherosclerosis and TET2 CHIP who received canakinumab appeared to have a „disproportionate benefit“ in preventing cardiovascular events compared to the overall study population, Honigberg said.
„HFpEF is a particularly challenging condition with limited effective therapies. Our findings support the notion that targeted anti-inflammatory therapies may prevent and/or treat HFpEF through TET2 CHIP. Of course, this hypothesis needs to be tested in prospective randomized studies,“ said Honigberg.
„The CHIP field has rapidly evolved and is an exciting area of research,“ added Fuster. „However, I personally believe that there is still a lot of work to be done before it is ready for primetime in the clinical setting.“
„Although the association between CHIP and CVD is clear, evidence-based interventions to mitigate the increased CVD risk associated with these mutations are still lacking. Without effective interventions, the value of screening for CHIP as a risk factor may be limited,“ Fuster noted.
„For example, in the context of HFpEF, we do not really know if CHIP mutation carriers may respond positively to modern HF medications or require new personalized approaches. Further research and ultimately clinical studies are needed,“ he added.
Honigberg disclosed relationships with Genentech, Miga Health, CRISPR Therapeutics, and Comanche Biopharma. Fuster had no relevant disclosures.