United States: A fresh investigative endeavor has conclusively addressed a long-standing contention in medical circles, establishing that mutations associated with clonal hematopoiesis significantly amplify the susceptibility to atherosclerosis.
While classical risk determinants for cardiovascular complications—such as hypertension, hypercholesterolemia, diabetes, obesity, smoking, and sedentary lifestyles—are well-documented, the emergence of clonal hematopoiesis introduces a novel factor. This condition arises from acquired mutations in hematopoietic stem cells and has now been correlated with a higher propensity for cardiovascular episodes, according to reports.
Until recently, uncertainty prevailed regarding whether clonal hematopoiesis was a precursor or a mere consequence of cardiovascular disease. However, a groundbreaking study in Nature Medicine, spearheaded by researchers at the Centro Nacional de Investigaciones Cardiovasculares (CNIC), has resolved this pivotal question. The study cements clonal hematopoiesis as a direct contributor to atherosclerosis, which manifests as plaque accumulation within arterial walls—a precursor to the majority of cardiovascular afflictions.
In an additional investigation published in the European Heart Journal, CNIC researchers proposed an ancient pharmacological remedy, colchicine, as a cornerstone of tailored therapeutic approaches aimed at mitigating the deleterious effects of clonal hematopoiesis linked to TET2 gene mutations. These findings will be presented at the European Society of Cardiology Congress in London, UK.
Somatic Mutations and Their Role in Atherosclerosis Development
The adult human body produces an astronomical number of blood cells each day. The sheer frequency of this process inevitably leads to the accumulation of DNA alterations in these proliferating cells, referred to as somatic mutations—mutations that are acquired, not inherited. While the vast majority of these mutations are benign, some confer a competitive edge to the affected cells, enabling them to proliferate and form clonal populations, a phenomenon known as clonal hematopoiesis.
Previous studies had already hinted at clonal hematopoiesis as a potential risk factor for cardiovascular disease. However, the precise nature of the relationship had remained opaque. As noted by Dr. José Javier Fuster, the lead investigator of the Nature Medicine study and head of CNIC’s “Novel Mechanisms of Atherosclerosis” program, some research suggested that somatic mutations associated with clonal hematopoiesis actively contributed to the pathogenesis of cardiovascular disease, accelerating the advancement of atherosclerosis. Others hypothesized the inverse—that atherosclerosis itself stimulated clonal hematopoiesis by increasing hematopoietic stem cell proliferation, thereby expanding the mutated blood cell population, according to reports.
The Nature Medicine study dispels this ambiguity through an extensive longitudinal examination of data from the PESA-CNIC-Santander cohort. PESA, which stands for the Progression of Early Subclinical Atherosclerosis, is a forward-looking investigation involving over 4,000 ostensibly healthy middle-aged participants, each undergoing regular assessments with cutting-edge imaging technologies since 2010, to monitor the onset and progression of asymptomatic atherosclerosis.
This collaboration between CNIC and Santander Bank has already contributed immensely to our understanding of cardiovascular disease. Its longitudinal framework and distinct methodology rendered it an ideal platform to explore the intricate interplay between clonal hematopoiesis and atherosclerosis, explained Dr. Valentín Fuster, CNIC’s General Director and the principal investigator of the PESA study.
Utilizing state-of-the-art high-sensitivity DNA sequencing, the researchers detected somatic mutations in blood samples and tracked the emergence and progression of atherosclerosis using advanced, non-invasive imaging techniques on the PESA participants. According to José Javier Fuster, the study was a multidisciplinary endeavor involving experts from basic science, cardiology, bioinformatics, genomics, and clinical trial units at CNIC.
Reportedly, the study’s conclusions were unequivocal: participants with mutations linked to clonal hematopoiesis at the study’s outset exhibited a higher likelihood of developing atherosclerosis in subsequent years. Crucially, the presence or severity of atherosclerosis did not impact the proliferation of mutated blood cells. As co-first author Miriam Díez-Díez clarified, these findings indicate that while mutations drive atherosclerosis development, the reverse is not true. Co-first author Beatriz L. Ramos-Neble added that future investigations would aim to explore how other factors, such as genetic predispositions or lifestyle choices, may influence the interplay between clonal hematopoiesis and cardiovascular disease.
Colchicine: An Ancient Solution for a Modern Cardiovascular Dilemma
Among the various mutations linked to clonal hematopoiesis, those affecting the TET2 gene are particularly well-characterized. A pivotal 2017 study published in Science by Dr. José Javier Fuster’s team demonstrated that TET2 mutations expedite the progression of atherosclerosis in animal models. The recent study, featured in the European Heart Journal, illustrates that the adverse effects of TET2 mutations on cardiovascular health can be mitigated through the administration of colchicine, an anti-inflammatory drug.
The CNIC team’s experiments showed that colchicine administration to animals harboring TET2 mutations significantly slowed atherosclerosis progression, bringing it in line with rates observed in non-mutated animals. Meanwhile, a parallel study by the Broad Institute revealed that human patients with TET2 mutations who had received colchicine treatment for unrelated conditions had a reduced risk of heart attacks compared to untreated individuals with similar mutations.
Colchicine has been utilized for millennia in traditional medicine and is currently approved for treating inflammatory conditions such as gout. According to Dr. María Ángeles Zuriaga, the primary author of the European Heart Journal study, colchicine is widely available, affordable, and endorsed by the FDA and the European Medicines Agency for preventing cardiovascular disease. Thus, there are few barriers to its potential use in combating the cardiovascular risks posed by TET2 mutations, according to the reports.
Dr José Javier Fuster emphasized that this study lays a critical foundation for personalized cardiovascular medicine. “Since each mutated gene in clonal hematopoiesis operates through distinct mechanisms, tailored interventions will likely be necessary to neutralize their effects. This research underscores colchicine’s potential in addressing the risks associated with TET2 mutations. Nevertheless, further clinical trials are required to definitively confirm its efficacy in affected individuals.”