Circulating immune cells in atherosclerotic disease Identification of patients at risk

Abstract

Cardiovascular disease is a major cause of death worldwide. The underlying pathology of CVD is atherosclerosis, a lipid-driven, chronic inflammatory disease of the large arteries. The role of the immune system in atherosclerosis is well-established and experimental studies have indicated that different immune cells can play atherogenic or atheroprotective roles in atherosclerotic disease. In this thesis, we reviewed the current literature on white blood cells as well as the white blood cell subtypes, including granulocytes, monocytes and lymphocytes. Our literature analysis showed that total white blood cell count, as well as the neutrophil-to-lymphocyte ratio were significantly associated with the occurrence of adverse cardiovascular manifestations. In addition, we have measured circulating immune cell profiles in patients with severe atherosclerosis, in order to identify patients at risk for recurrent cardiovascular manifestations. We comprehensively analyzed specific monocyte and lymphocyte subtypes in relation to vulnerable plaque characteristics, and in relation to the occurrence of secondary cardiovascular manifestations during follow-up. Surprisingly, although well-established in experimental atherosclerosis, classical monocytes, nor other monocyte subtypes, were related to vulnerable plaque characteristics or associated with the occurrence of secondary cardiovascular events. These findings might indicate that monocytes are mainly implicated in the earlier stages of atherosclerosis instead of the later stage of atherosclerosis. On the other hand, analysis of B lymphocyte subtypes revealed that patients with high numbers of memory B cells were protected against the occurrence of secondary cardiovascular events. As antibody production is an important function of B lymphocytes, we investigated the antibody profile in the serum of atherosclerotic patients. Among different isotypes, we found that IgG4 levels were significantly associated with the occurrence of secondary major cardiovascular events in females, but not in males. These findings confirm that the cardiovascular pathology differs between males and females. Another example of the different pathology between males and females, is given by the fact that women with pregnancy disorders, such as preeclampsia (PE), have increased risk to develop cardiovascular disease later in life. As inflammation is one of the pathological mechanisms that is involved in both PE and atherosclerosis, we investigated if circulating neutrophils were associated to subclinical coronary artery disease in women with a history of PE. We observed no significant differences in neutrophil counts or neutrophil activity in women with coronary atherosclerosis as compared to women without. Nevertheless, women with early PE are at high risk of future CVD and should be closely monitored and treated (if applicable) to prevent early clinical CVD manifestations. In conclusion, we have shown that components of the white blood cell count harbor important information that holds prognostic value to identify men and women at high risk for secondary cardiovascular events. Beyond its biomarker potential, future research might evaluate treatment options that ultimately prevent the occurrence of CVD events.