Innate immune cells in the pathophysiology of calcific aortic valve disease: lessons to be learned from atherosclerotic cardiovascular disease?

Calcific aortic valve disease (CAVD) is the most common valvular disease in the developed world with currently no effective pharmacological treatment available. CAVD results from a complex, multifactorial process, in which valvular inflammation and fibro-calcific remodelling lead to valve thickening and cardiac outflow obstruction. The exact underlying pathophysiology of CAVD is still not fully understood, yet the development of CAVD shows many similarities with the pathophysiology of atherosclerotic cardiovascular disease (ASCVD), such as coronary artery disease. Innate immune cells play a crucial role in ASCVD and might also play a pivotal role in the development of CAVD. This review summarizes the current knowledge on the role of innate immune cells, both in the circulation and in the aortic valve, in the development of CAVD and the similarities and differences with ASCVD. Trained immunity and clonal haematopoiesis of indeterminate potential are proposed as novel immunological mechanisms that possibly contribute to the pathophysiology of CAVD and new possible treatment targets are discussed.

Differences in thrombin and plasmin generation potential between East African and Western European adults: The role of genetic and non-genetic factors.

BACKGROUND: Geographic variability in coagulation across populations and their determinants are poorly understood. OBJECTIVE: To compare thrombin (TG) and plasmin (PG) generation parameters between healthy Tanzanian and Dutch individuals, and to study associations with inflammation and different genetic, host and environmental factors. METHODS: TG and PG parameters were measured in 313 Tanzanians of African descent living in Tanzania and 392 Dutch of European descent living in the Netherlands and related to results of a dietary questionnaire, circulating inflammatory markers, genotyping, and plasma metabolomics. RESULTS: Tanzanians exhibited an enhanced TG and PG capacity, compared to Dutch participants. A higher proportion of Tanzanians had a TG value in the upper quartile with a PG value in the lower/middle quartile, suggesting a relative pro-coagulant state. Tanzanians also displayed an increased normalized thrombomodulin sensitivity ratio, suggesting reduced sensitivity to protein C. In Tanzanians, PG parameters (lag time and TTP) were associated with seasonality and food-derived plasma metabolites. The Tanzanians had higher concentrations of pro-inflammatory cytokines, which correlated strongly with TG and PG parameters. There was limited overlap in genetic variation associated with TG and PG parameters between the two cohorts. Pathway analysis of genetic variants in the Tanzanian cohort revealed multiple immune pathways that were enriched with TG and PG traits, confirming the importance of co-regulation between coagulation and inflammation. CONCLUSIONS: Tanzanians have an enhanced TG and PG potential compared to Dutch individuals, which may relate to differences in inflammation, genetics and diet. These observations highlight the importance of better understanding of the geographic variability in coagulation across populations.