Lower diurnal HPA-axis activity in male hypertensive and coronary heart disease patients predicts future CHD risk

Background Coronary heart disease (CHD) and its major risk factor hypertension have both been associated with altered activity of the hypothalamus-pituitary-adrenal (HPA)-axis but the biological mechanisms underlying prospective associations with adverse disease outcomes are unclear. We investigated diurnal HPA-axis activity in CHD-patients, hypertensive (HT) and healthy normotensive men (NT) and tested for prospective associations with biological CHD risk factors. Methods Eighty-three male CHD-patients, 54 HT and 54 NT men repeatedly measured salivary cortisol over two consecutive days. Prospective CHD risk was assessed by changes between baseline and follow-up in the prothrombotic factors D-dimer and fibrinogen, the pro-inflammatory measures interleukin (IL)-6, tumor necrosis factor-alpha (TNF-α), and acute phase protein C-reactive protein (CRP), as well as blood lipids in terms of total cholesterol (tChol)/high-density-lipoprotein cholesterol (HDL)-ratio. We aggregated coagulation and inflammatory measures to respective indices. Results The groups differed in repeated daytime cortisol (dayCort) secretion ( p =.005,η 2 p =.03, f =0.18) and cortisol awakening response (CAR) ( p =.006,η 2 p =.03, f =0.18), with similarly lower overall dayCort and CAR in CHD-patients and HT, as compared to NT. The groups differed further in cortisol at awakening ( p =.015,η 2 p =.04, f =0.20) with highest levels in HT ( p ´s≤.050), and in diurnal slope between waking and evening cortisol ( p =.033,η 2 p =.04, f =0.20) with steepest slopes in HT ( p ´s≤.039), although in part not independent of confounders. Lower aggregated dayCort and CAR in terms of area-under-the-curve (AUC) independently predicted increases in future overall CHD risk (AUC dayCort : p =.021,η 2 p =.10, f =0.33;AUC CAR : p =.028,η 2 p =.09, f =0.31) 3.00 ± 0.06( SEM ) years later, with risk prediction most pronounced in fibrinogen (AUC dayCort : p =.017,Δ R 2 = 0.12;AUC CAR : p =.082). Conclusion We found evidence for an HPA-axis hypoactivity in CHD and HT with lower diurnal HPA-axis activity predicting increases in cardiovascular risk as evidenced by increases in circulating levels of biomarkers of atherothrombotic risk. Down-regulation of basal HPA-axis activity may contribute to the pathogenesis of atherosclerosis and thrombosis in CHD via effects on coagulation.