The role of complement activation in atherogenesis: the first 40 years

Abstract

The pathogenesis of atherosclerotic inflammation is a multi-step process defined by the interweaving of excess modified lipid particles, monocyte-macrophages populations, and innate immune and adaptive immunity effectors. A part of innate immunity, the complement system, is an important player in the induction and progression of atherosclerosis. The accumulation of either oxidized or enzymatically modified LDL-bound to C-reactive protein or not-prompts complement activation leading to the assembly of the terminal complement C5b-9 complex in the atherosclerotic lesion. The sublytic C5b-9 assembly leads to the activation and proliferation of smooth muscle and endothelial cells, accompanied by the release of various chemotactic, pro-adhesion, and procoagulant cytokines from these cells. Response gene to complement (RGC)-32, an essential effector of the terminal complement complex C5b-9, also affects atherogenesis, propelling vascular smooth muscle cell proliferation and migration, stimulating endothelial proliferation, and promoting vascular lesion formation. A substantial amount of experimental work has suggested a role for the complement system activation during atherosclerotic plaque formation, with the proximal classical complement pathway seemingly having a protective effect and terminal complement contributing to accelerated atherogenesis. All these data suggest that complement plays an important role in atherogenesis.

RVX-208, a BET-inhibitor for treating atherosclerotic cardiovascular disease, raises ApoA-I/HDL and represses pathways that contribute to cardiovascular disease

“…4). Overactivation of the complement pathway has been implicated in plaque development and destabilization [44,45]. Complement activation also influences thrombosis through activation of platelets, promotion of fibrin formation, and impairment of fibrinolysis.…”

Enzymatically modified LDL atherosclerosis and beyond paving the way to acceptance

“…In 1977, it has been demonstrated that free cholesterol activates complement (52) and since then, several reviews summarized the evidence for an important impact of complement activation on atherogenesis (53)(54)(55)(56). Thereby, an unexpectedly large number of pathways are operative that may differentially influence the evolution of the atherosclerotic lesion.…”

Sudden cardiac death in patients with rheumatoid arthritis

“…Conversely, DI Franco et al[ 104 ] found no significant difference in QTc interval duration amongst CIA patients treated with TNFi and rituximab. However, the authors did not report on disease activity and thus there may be have been a large proportion of patients who did not achieve adequate disease control[ 105 ]. In the Diana study, 12 wk of treatment with combination synthetic DMARDs or biologics significantly improved cardiac autonomic dysfunction ( P < 0.05) in both RA and AS patients[ 106 ].…”

“…However, the use of biologics is not without risk, and beyond the well-recognized risks of malignancy and infection, there have been reports of cardiac arrhythmias, in some cases life threatening, particularly following the use of anti-TNF monoclonal antibodies and rituximab[ 105 ]. Case reports have described ventricular arrhythmias[ 108 , 109 ], supraventricular arrhythmias[ 110 , 111 ], and various degrees of heart block[ 112 - 114 ], associated with the use of infliximab, although in one case, the complete heart block did in fact resolve spontaneously[ 112 ].…”

“…Case reports have described ventricular arrhythmias[ 108 , 109 ], supraventricular arrhythmias[ 110 , 111 ], and various degrees of heart block[ 112 - 114 ], associated with the use of infliximab, although in one case, the complete heart block did in fact resolve spontaneously[ 112 ]. It is thought that biologics and in particular TNF inhibiting monoclonal antibodies may be acutely unmasking the inflammation driven myocardial instability that characterizes RA, and other inflammatory conditions[ 105 ]. They could be doing this in one of three ways; firstly by worsening LV function, secondly by reducing coronary blood flow[ 115 ], and thirdly, a mechanism which would be exclusive to monoclonal antibodies, via complement-mediated cytotoxic or inflammatory damage to the myocardium[ 105 , 116 ].…”