Haemostatic and inflammatory alterations in hypertension and hyperlipidaemia, and the impact of angiotensin II

Abstract

The process of atherosclerosis is multifactorial, and endothelial dysfunction is considered to precede atherosclerosis. Angiotensin (Ang) II, the main effector of renin-angiotensinaldosterone system (RAAS), is implicated in hypertension and has been shown to promote atherosclerosis. Familial combined hyperlipidaemia (FCHL) and familial hypercholesterolemia (FH) have been identified as risk factors for increased risk of cardiovascular heart disease and premature death. FCHL has a different phenotype compared to FH, but both lipid disorders are accompanied by subclinical atherosclerosis and endothelial dysfunction. We speculated that patients with hypertension and hyperlipidaemia were more sensitive to the potential proinflammatory and procoagulatory effects of Ang II than healthy individuals. The present research program was set up to investigate the extent to which the RAAS affects the inflammatory and thrombotic properties of individuals with hypertension and hyperlipidaemia.

In Paper I we examined the impact of treatment with the ACE inhibitor ramipril on coagulation in patients with mild-to-moderate hypertension. We observed that ramipril attenuates thrombin generation in essential hypertension by reducing thrombin-antithrombin complex, and tended to reduce fibrinogen levels. In Paper II we wanted to clarify the impact of antihypertensive treatment per se. Therefore, we examined the effects of long-term treatment of ramipril compared to the alpha 1-adrenoceptor blocker doxazosin on inflammation and haemostasis in patients with mild-tomoderate hypertension. We found that antihypertensive treatment seems to exert a minor impact on systemic inflammation. Treatment with ramipril, but not doxazosin, appeared to reduce thrombin generation. This extended our previous findings in paper I suggesting that treatment with ramipril reduces thrombin generation in addition to the effects on blood pressure reduction alone. Drugs blocking the renin-angiotensin-aldosterone system may reduce atherothrombotic complications beyond their effects of lowering blood pressure. We also observed a decrease in t-PA antigen and a tendency to decreased PAI-1 activity in the doxazosin treated group, which would implicate beneficial effects by treatment with doxazosin in hypertensive patients regarding fibrinolysis. This may be of benefit in the treatment of patients with hypofibrinolysis, such as patients with FCHL. In Paper III we examined how an intravenous infusion of Ang II affected inflammation and haemostasis in patients with FCHL and healthy control subjects.

In Paper IV we characterized the studied the patients with FCHL, in paper III, with respect to insulin resistance and in more detail regarding fibrinolysis. We also performed placebo experiments to make it possible to assess the influence of diurnal variations and to verify the stability of the experimental design. We found that FCHL had an increased systolic blood pressure response during infusion of Ang II compared to controls, indicating an increased vascular responsiveness in FCHL. Patients with FCHL exhibited a low-grade chronic inflammation, an impaired fibrinolysis, while the coagulation system seemed intact. FCHL shared several characteristics with the metabolic syndrome, including high triglyceride and low HDL cholesterol levels, insulin resistance and high body mass index. An infusion of Ang II increased systemic inflammation in a similar way in FCHL and controls. Ang II did not have any impact on thrombin generation, in either FCHL or controls. Ang II did not affect fibrinolysis in FCHL, whereas fibrinolysis was enhanced in healthy controls. The different responses to Ang II stimulation probably involved t-PA activity but not PAI-1 activity, and this suggests that patients with FCHL were incapable of increasing fibrinolysis in response to Ang II. We could not observe any short-term effects on PAI-1 activity, in either FCHL or controls. Our findings suggested that patients with FCHL had a low-grade chronic inflammation, impaired fibrinolysis and insulin resistance, contributing to the risk of cardiovascular heart disease and premature death in FCHL. We also suggested that Ang II acted as a proinflammatory and enhanced fibrinolysis, without impact on thrombin generation. However, taking the possible effects of diurnal variations of our coagulation markers, not taken into account in paper III, and analysing the impact of Ang II during the ongoing infusion time, post hoc analyses showed that thrombin generation instead increased, similarly in FCHL and controls. Hence, our new conclusion became that Ang II acts as a prothrombotic agent.

In Paper V we examined how an intravenous infusion of Ang II affected inflammation and haemostasis in patients with FH and healthy controls. We also performed placebo experiments to make it possible to assess the influence of diurnal variations and to verify the stability of the experimental design. We found that patients with FH had higher systolic blood pressure than controls at baseline, whereas blood pressure responses were equal in FH and controls. FH showed an intact fibrinolysis and an increased thrombin generation potential compared to controls, but did not show any convincing signs of an on-going low-grade inflammation. A systemic infusion of Ang II caused an increase in systemic inflammation, fibrinolysis and possibly also thrombin generation similar in FH and control subjects. During Ang II infusion FH exhibited possible signs of an activated anticoagulant system.

Our findings suggested that patients with FH had an affected coagulation system, rather than altered fibrinolysis or inflammation, contributing to the increased risk of cardiovascular heart disease and premature death in FH. Thus, blocking the renin-angiotensin-aldosterone system by an ACE inhibitor may prevent atherothrombotic complications in hypertensive patients beyond the effects on BP by reducing thrombin formation. Different mechanisms may contribute to the increased incidence of cardiovascular complications in patients with FCHL and FH. A beneficial effect of ACE inhibition in patients with FCHL might be to attenuate inflammation in combination with its documented positive influence on insulin resistance, while in patients with FH, may benefit be obtained mainly by reduced thrombin generation.