Inflammation plays an important role in cardiovascular disease (CVD) development. The NOD-like receptor protein-3 (NLRP3) inflammasome contributes to the development of atherosclerosis in animal models. Components of the NLRP3 inflammasome pathway such as interleukin-1β can therapeutically be targeted. Associations of genetically determined inflammasome-mediated systemic inflammation with CVD and mortality in humans are unknown. We explored the association of genetic NLRP3 variants with prevalent CVD and cardiovascular mortality in 538 167 subjects on the individual participant level in an explorative gene-centric approach without performing multiple testing. Functional relevance of single-nucleotide polymorphisms on NLRP3 inflammasome activation has been evaluated in monocyte-enriched peripheral blood mononuclear cells (PBMCs). Genetic analyses identified the highly prevalent (minor allele frequency 39.9%) intronic NLRP3 variant rs10754555 to affect NLRP3 gene expression. rs10754555 carriers showed significantly higher C-reactive protein and serum amyloid A plasma levels. Carriers of the G allele showed higher NLRP3 inflammasome activation in isolated human PBMCs. In carriers of the rs10754555 variant, the prevalence of coronary artery disease was significantly higher as compared to non-carriers with a significant interaction between rs10754555 and age. Importantly, rs10754555 carriers had significantly higher risk for cardiovascular mortality during follow-up. Inflammasome inducers (e.g. urate, triglycerides, apolipoprotein C3) modulated the association between rs10754555 and mortality. The NLRP3 intronic variant rs10754555 is associated with increased systemic inflammation, inflammasome activation, prevalent coronary artery disease, and mortality. This study provides evidence for a substantial role of genetically driven systemic inflammation in CVD and highlights the NLRP3 inflammasome as a therapeutic target. rs10754555 associates with higher NLRP3 mRNA expression and NLRP3 inflammasome activation, which induces the release of IL-1β and IL-18. This leads to systemic inflammation, higher risk for coronary artery disease, and cardiovascular mortality.

Plasma aldosterone levels have been shown to be associated with adverse clinical outcomes after ST-elevation myocardial infarction (STEMI). We investigated whether aldosterone levels in patients presenting with STEMI or non-STEMI, are predictive of mortality during prolonged follow-up. Aldosterone levels were assayed in plasma taken from 583 patients within 24–96 h following acute myocardial infarction (MI). The median plasma aldosterone level was 108 pmol/L and all values were below the upper limit of the normal range (800 pmol/L) except for five patients (0.9%). Aldosterone tertile was significantly associated with increasing plasma levels of NTproBNP (N-terminal pro-B-type natriuretic peptide), BNP (B-type natriuretic peptide), epinephrine, and endothelin-1 (P ≤ 0.010), but not ANP (atrial natriuretic peptide). Patients in the lowest aldosterone tertile had a significantly better survival, over 5 years’ follow-up, than those in the upper two tertiles (P = 0.0023). Multivariable analysis showed that aldosterone was a significant predictor of survival following adjustment for established predictors (tertile 1 vs. tertile 3; hazard ratio = 2.19, P = 0.018). Patients with above-median levels of both NTproBNP and aldosterone had significantly greater mortality than the remaining patients (above-median 39.8%, other patients ≥25.3% mortality, P ≥ 0.026). Plasma aldosterone levels post-MI are independent predictors of survival and hospitalization for heart failure over a 5-year-follow-up period.