👤 Boris Delpire

Ageing endurance athletes have a higher prevalence of coronary artery disease (CAD) on coronary CT angiography (CCTA) than healthy controls, despite similarly low conventional cardiovascular risk. The predictive value of lipoprotein(a) [Lp(a)] for CAD in these low-risk individuals remains unclear. The Master@Heart study included 558 men (aged 45-70 years) without known cardiovascular risk factors: 191 lifelong athletes, 191 late-onset athletes, and 176 healthy controls. CCTA assessed coronary artery calcification (CAC) and plaques. The association between Lp(a) and subclinical CAD was assessed using logistic regression analysis to estimate odds ratios (ORs), adjusted for cardiovascular risk factors. Lp(a) was analysed dichotomously (<125 vs. >125 nmol/L) and continuously (per 10 nmol/L increase). 76 participants (13.6%) had elevated Lp(a) levels (>125 nmol/L). Elevated Lp(a) was significantly associated with age-specific CAC percentile≥75 (OR 1.80, p=0.049) and ≥1 mixed plaque (OR 1.76, p=0.046). Other CAD measures all tended to be more prevalent in those with elevated Lp(a). In the continuous analysis, Lp(a) was significantly associated with CAC>100 (OR 1.03, p=0.045), CAC percentile≥75 (OR 1.04, p=0.014), and ≥1 mixed or non-calcified plaque (OR 1.03, p=0.029).Lp(a) and prevalence of elevated Lp(a) were similar across lifelong athletes, late-onset athletes, and controls (p=0.586 and p=0.724, respectively). No significant interaction was found between Lp(a) and the exercise groups in predicting CAD. Lp(a) is independently associated with subclinical CAD in ageing endurance athletes and healthy controls, despite similarly low conventional cardiovascular risk. Lp(a) does not explain the higher CAD prevalence in lifelong athletes compared to controls, but may enhance risk stratification in this low-risk population. Show less

Thiazide-sensitive sodium chloride cotransporter (NCC) plays an important role in maintaining blood pressure. Aldosterone is known to modulate NCC abundance. Previous studies reported that dietary salts modulated NCC abundance through either WNK4 [with no lysine (k) kinase 4]-SPAK (Ste20-related proline alanine-rich kinase) or WNK4-extracellular signal-regulated kinase-1 and -2 (ERK1/2) signaling pathways. To exclude the influence of SPAK signaling pathway on the role of the aldosterone-mediated ERK1/2 pathway in NCC regulation, we investigated the effects of dietary salt changes and aldosterone on NCC abundance in SPAK knockout (KO) mice. We found that in SPAK KO mice low-salt diet significantly increased total NCC abundance while reducing ERK1/2 phosphorylation, whereas high-salt diet decreased total NCC while increasing ERK1/2 phosphorylation. Importantly, exogenous aldosterone administration increased total NCC abundance in SPAK KO mice while increasing DUSP6 expression, an ERK1/2-specific phosphatase, and led to decreasing ERK1/2 phosphorylation without changing the ratio of phospho-T53-NCC/total NCC. In mouse distal convoluted tubule (mDCT) cells, aldosterone increased DUSP6 expression while reducing ERK1/2 phosphorylation. DUSP6 Knockdown increased ERK1/2 phosphorylation while reducing total NCC expression. Inhibition of DUSP6 by (E)-2-benzylidene-3-(cyclohexylamino)-2,3-dihydro-1H-inden-1-one increased ERK1/2 phosphorylation and reversed the aldosterone-mediated increments of NCC partly by increasing NCC ubiquitination. Therefore, these data suggest that aldosterone modulates NCC abundance via altering NCC ubiquitination through a DUSP6-dependent ERK1/2 signal pathway in SPAK KO mice and part of the effects of dietary salt changes may be mediated by aldosterone in the DCTs. Show less