Bioinformatic characterization and automated detection of metabolically activated monocyte subpopulations in dyslipidemia.

Abstract

Atherosclerosis, a chronic inflammatory disease of the arteries, is primarily driven by the accumulation of low-density lipoproteins (LDL) and remnant lipoprotein particles, which initiate an inflammatory response in areas of arteries exposed to disturbed non-laminar blood flow, particularly at arterial branch points (1, 9, 14, 16). This condition is a leading cause of atherosclerotic cardiovascular disease (ASCVD), which includes heart attacks, strokes, and peripheral arterial disease (1, 13). Pathophysiologically, atherosclerosis progresses through a series of well-defined stages. It begins with the retention of lipoproteins in the arterial intima, where these particles undergo modification and trigger chronic inflammation (1, 11, 14). This inflammatory response leads to the formation of nascent fatty streaks, which gradually develop into fibrous plaques and complex lesions prone to rupture (1, 8). Endothelial dysfunction -triggered by factors such as LDL, smoking, diabetes, and hypertension- disrupts the endothelial barrier, increasing vascular permeability and allowing immune cells and lipoproteins to infiltrate the arterial wall (1, 11, 13, 25). Monocytes transmigrate into the intima, differentiate into macrophages, ingest modified lipids, and transform into foam cells, marking the onset of early fatty streak lesions (1, 11, 12, 13, 15, 28). As the disease advances, lesions become increasingly complex, characterized by a necrotic core, a thin fibrous cap, abundant lipids, and an infiltration of inflammatory cells, particularly macrophages. These features render plaques vulnerable to rupture, which can lead to thrombosis and potential life-threatening events such as myocardial infarction and stroke (1, 11, 12). Factors like matrix metalloproteinases (MMPs), myeloperoxidase, and high shear stress further contribute to plaque instability (1, 11). In advanced plaques, impaired efferocytosis leads to the accumulation of apoptotic cells, resulting in the expansion of the necrotic core and exacerbation of inflammation (1, 11, 16).6 Cardiovascular diseases (CVDs) exert a profound global impact, with the World Health Organization (WHO) reporting that CVDs are the leading cause of death worldwide (13). In 2019, CVDs accounted for an estimated 17.9 million deaths, representing 32% of all global mortality (3, 4, 6). Of these, 85% were attributed to heart attacks and strokes (4). In the United States, heart disease has been the leading cause of death since 1921, with approximately 610,000 deaths annually attributed to cardiovascular conditions. Coronary heart disease alone is responsible for over 370,000 deaths each year (1, 2), 19 million deaths attributed to CVDs worldwide in 2020 (5). Stroke continues to rank as the fifth leading cause of death in the U.S. and remains a significant contributor to long-term disability in adults (1). In Mexico, CVDs are similarly the leading cause of mortality and disability, particularly among vulnerable populations such as those living in poverty, older adults, and individuals with comorbid conditions (3). According to the National Institute of Statistics and Geography (INEGI), CVD accounted for 841,318 deaths in 2022, with ischemic heart disease being the primary cause, followed by intracerebral hemorrhage and ischemic stroke (19). Projections for 2024 indicate no significant changes in these statistics. According to INEGI´s press release number 26/24, dated January 24, 2024, projects that heart diseases will remain the leading cause of mortality nationwide. Preliminary data for January to June 2023 recorded 97,187 deaths, with final statistics to be released in November 2024 (19). Despite advances in managing dyslipidemia and other risk factors, ASCVD remains the leading of death globally (7, 8). The chronic accumulation of atherosclerotic plaques within the arterial intima results in significant stenosis, restricting blood flow and leading to critical tissue hypoxia (8, 14). The aggregation of LDL in the intima and its subsequent pathological modifications are key events that facilitate the adhesion and infiltration of monocytes and lymphocytes into the arterial wall, thereby accelerating the progression of atherosclerosis (11, 14, 15). Understanding the complex pathophysiology of atherosclerosis and its epidemiological impact is essential for developing effective prevention and treatment strategies. This underscores the importance of identifying novel subpopulations of7 monocytes and macrophages involved in the disease process, particularly in patients with dyslipidemia, to gain insights into the early stages of atherosclerotic plaque formation and progression (10, 11, 14).