New Risk Factors for Aortic Stenosis

Genetic horizons

Aortic Stenosis (AoS) is the most common acquired aortic valve disease and for which surgery is indicated in developed countries. According to the most recent publications, the disease affects 2 to 5% of the elderly population, with an annual incidence of severe AoS cases around 4-7% per year in patients over 65 years of age. As the population ages these numbers tend to increase over the years. Just as cardiovascular diseases increase with age, other chronic-degenerative diseases such as cancers (solid or hematological) also increase. New studies have been looking for common denominators among these diseases. In this regard, a deepening of genetics has been taking place correlating to cardiovascular diseases.

Clonal hematopoiesis of undetermined potential in English clonal haematopoiesis of indeterminate potential (CHIP) arises when hematopoietic stem cells from healthy individuals acquire mutations in conducting genes commonly mutated in hematological neoplasms. The cells carrying these mutations expand and can form detectable clones in peripheral blood. When we have more than 2% of mutated leukocytes in peripheral blood, we define CHIP, and this situation affects more than 10% of septuagenarians. It has recently been demonstrated that in this population with CHIP we have observed an increase in mortality from all causes, and for cardiovascular diseases this finding is twice as high as in the general population that does not have such mutations.

In North America, Europe and to a lesser extent in other countries where Brazil is included, aortic valve heart disease of calcific etiology has predominated. Calcific aortic valve disease (CVAD) describes a wide clinical spectrum of the disease, ranging from thickening and early fibrosis of the leaflets to accentuated calcification with major stenosis with hemodynamic impairment leading to a decline in left ventricular function. Once attributed to age-related degeneration, we now understand that traditional cardiovascular risk factors are also associated with CVD, such as atherosclerosis, high LDL, hypertension, smoking, diabetes and chronic kidney disease.

Studies have shown similar mechanisms in the pathogenesis of atherosclerosis and CVD, including mechanisms associated with inflammatory cells such as macrophages and T cells that mediate the thickening and calcification of the leaflets. In these studies, mice with mutations that increase susceptibility to atherosclerosis were designed to have CHIP mutations in myeloid cells when compared to animals without the mutations, after undergoing an atherogenic diet they had a considerably increased number of atherosclerotic lesions.

In a recent unpublished publication on the subject in the European Heart Journal, Mas-Peiro et al. aim to deepen the understanding of the roles of CHIP and inflammation in heart disease, with a focus on calcified valve disease and severe aortic stenosis. A cohort study was carried out with 279 patients with aortic stenosis treated with transcatheter aortic valve replacement (TAVR), where patients with mutations in the two most common genes of the CHIP driver, DNMT3a and TET2, were observed, in comparison with populations of the same age without CHIP, and demonstrate that the presence of these mutations is associated with worse results, including increased mortality during an average follow-up period of 8 months. Of the 279 patients in the cohort, 93 (33%) had DNMT3a or TET2 mutations. Patients with the mutations had a three-fold increase in cardiovascular mortality compared to non-CHIP patients. In the Mas-Peiro study with CVD, these mutations act through divergent mechanisms that converge in the increase of various aspects of inflammation.

The explanation for what happens with these conductive mutations in CHIP patients may lie in the fact that an increased number of non-classical monocytes is expressed in the circulation, which are the ones that express CD14dim and CD 16 ++, the same ones that are expressed in the activation of inflammation with release of high levels of pro-inflammatory cytokines, including tumor necrosis factor (TNF) α, IL-1β and IL-8. The results of this first study corroborate the hypothesis that somatic mutations in hematopoietic cells due to mutations in the DNMT3A and TET2 genes may be significantly associated with the progression of degenerative aortic stenosis with a worse clinical outcome in the medium term, even after successful valve replacement. by TAVR. Future studies will have to validate these findings in larger cohorts and test whether targeted anti-inflammatory therapy can be a valuable treatment strategy in patients with a DNMT3A or TET2 driver with severe degenerative aortic stenosis undergoing TAVR.

Notes:

  • Aortic stenosis is an age-related disease, in this sense with the aging of the population, we will have an explosion of cases in the coming years worldwide including Brazil.
  • In addition to the classic factors known as SAH, DLP, DM and CKD, genetic factors related to some specific mutations appear.
  • We know that we do not have drug therapy for severe AoS at the present time. Perhaps testing immunotherapy is the future, we don’t know yet, but we at The Valve Club are vigilant in the development of this story.

Suggested literature:

  1. Lin, A. E., Libby, P., & Ebert, B. L. (2019). A new opening on aortic stenosis: predicting prognosis with clonal haematopoiesis. European Heart Journal.
  2. Mas-Peiro, S., Hoffmann, J., Fichtlscherer, S., Dorsheimer, L., Rieger, M. A., Dimmeler, S., Zeiher, A. M. (2019). Clonal haematopoiesis in patients with degenerative aortic valve stenosis undergoing transcatheter aortic valve implantation. European Heart Journal.

 

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