Reacción a "CNIC team proposes a new cardiovascular risk factor and a drug to reduce its effects"

Both articles are very interesting. Specifically, the article published in Nature Medicine demonstrates that clonal hematopoiesis precedes and predicts the development of arteriosclerosis, which supports/suggests a causal role and opens new avenues to consider it as having a predictive/prognostic value and to develop new treatments.

There are, however, a number of nuances that need to be considered:

• Clonal hematopoiesis is already known at least as a 'risk marker' associated with the development of atherosclerosis. However, a 'risk marker' may not be a 'risk factor'. For example, elevated C-reactive protein [CRP] is associated with the development of atherosclerosis (it is a risk marker), but does not cause atherosclerosis (subjects with elevated CRP genetically do not have more atherosclerosis). In contrast, elevated LDL cholesterol or elevated lipoprotein (a) are causative agents of arteriosclerosis. Therefore, although this is not the first time the association has been described, this publication reinforces the potential role of clonal hematopoiesis in the development of arteriosclerosis.

• Descriptive epidemiological studies can never establish demonstrations of causality, only association. That said, the prospective PESA study [on which the article in Nature Medicine is based] demonstrates that clonal hematopoiesis can be detected in patients before the development of arteriosclerosis and that arteriosclerosis develops more intensely in subjects with clonal hematopoiesis. Although this temporal association suggests a causal role, such a strong statement cannot be made. It cannot be ruled out that clonal hematopoiesis is an epiphenomenon and that there is another cause that may on the one hand favor the development of mutations that are expressed as clonal hematopoiesis and on the other an accelerated arteriosclerosis (without the former being the cause of the latter).

Having made these clarifications, the combination of the two articles suggests a very interesting avenue of intervention. Although colchicine has been proposed as a treatment for 'residual inflammatory risk', its effect is modest and we still need better tools to reduce the development of arteriosclerosis, which is, together with cancer, the main cause of death in our country.

We need markers that identify patients in whom colchicine treatment offers potentially greater beneficial effects. The problem with cheap drugs is that the industry will never promote a quality clinical trial, which is why the leadership of independent research groups with public support (such as the CNIC in Spain or several centers in Canada that are evaluating colchicine treatment) is important.