Exercise-associated prevention of adult cardiovascular disease in children and adolescents: monocytes, molecular mechanisms, and a call for discovery

Human blood monocytes are heterogeneous and conventionally subdivided into two subsets based on CD16 expression. Recently, the official nomenclature subdivides monocytes into three subsets, the additional subset arising from the segregation of the CD16+ monocytes into two based on relative expression of CD14. Recent whole genome analysis reveal that specialized functions and phenotypes can be attributed to these newly defined monocyte subsets. In this review, we discuss these recent results, and also the description and utility of this new segregation in several disease conditions. We also discuss alternative markers for segregating the monocyte subsets, for example using Tie-2 and slan, which do not necessarily follow the official method of segregating monocyte subsets based on relative CD14 and CD16 expressions.

Persistent pain, impaired mobility and function, and reduced quality of life and mental well-being are the most common experiences associated with musculoskeletal conditions, of which there are more than 150 types. The prevalence and impact of musculoskeletal conditions increase with aging. A profound burden of musculoskeletal disease exists in developed and developing nations. Notably, this burden far exceeds service capacity. Population growth, aging, and sedentary lifestyles, particularly in developing countries, will create a crisis for population health that requires a multisystem response with musculoskeletal health services as a critical component. Globally, there is an emphasis on maintaining an active lifestyle to reduce the impacts of obesity, cardiovascular conditions, cancer, osteoporosis, and diabetes in older people. Painful musculoskeletal conditions, however, profoundly limit the ability of people to make these lifestyle changes. A strong relationship exists between painful musculoskeletal conditions and a reduced capacity to engage in physical activity resulting in functional decline, frailty, reduced well-being, and loss of independence. Multilevel strategies and approaches to care that adopt a whole person approach are needed to address the impact of impaired musculoskeletal health and its sequelae. Effective strategies are available to address the impact of musculoskeletal conditions; some are of low cost (e.g., primary care-based interventions) but others are expensive and, as such, are usually only feasible for developed nations. In developing nations, it is crucial that any reform or development initiatives, including research, must adhere to the principles of development effectiveness to avoid doing harm to the health systems in these settings.

The aim of this study was to analyze the yet ill-defined relationship of distinct human monocyte subsets with cardiovascular outcomes in a broad patient population at cardiovascular risk. Monocytes, the most abundant immune cell type found in atherosclerotic plaques, are crucial promoters of atherogenesis. Three distinct human monocyte subsets exist: classical CD14++CD16-, intermediate CD14++CD16+, and nonclassical CD14+CD16++ monocytes. Immunomodulation of distinct monocyte subsets has recently been discussed as a new therapeutic avenue in atherosclerosis. Cardiovascular events in 951 subjects referred for elective coronary angiography were prospectively analyzed. Monocyte subset analysis was performed using flow cytometry, blinded to patients' clinical characteristics, and patients were categorized according to quartiles of total monocyte and monocyte subset counts. The primary endpoint was defined a priori as the first occurrence of cardiovascular death, acute myocardial infarction, or nonhemorrhagic stroke. Endpoint adjudication was done blinded to monocyte subset distribution. During a mean follow-up period of 2.6 ± 1.0 years, 93 patients experienced the primary endpoint. In univariate Kaplan-Meier analysis, counts of total (p = 0.010), classical CD14++CD16- (p = 0.024), and intermediate CD14++CD16+ (p < 0.001) monocytes predicted the primary endpoint, whereas nonclassical monocytes did not (p = 0.158). After full adjustment for confounders, CD14++CD16+ monocytes remained the only monocyte subset independently related to cardiovascular events (fourth vs. first quartile: hazard ratio: 3.019; 95% confidence interval: 1.315 to 6.928; p = 0.009). CD14++CD16+ monocytes independently predicted cardiovascular events in subjects referred for elective coronary angiography. Future studies will be needed to elucidate whether CD14++CD16+ monocytes may become a target cell population for new therapeutic strategies in atherosclerosis. Copyright © 2012 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.