Source – news medical.net
A recent study published in the journal Nature has shed light on how early cholesterol spikes, known as intermittent hyperlipidemia, accelerate atherosclerosis, the buildup of plaque in the arteries. Conducted by an international team of researchers, the study explored how these cholesterol fluctuations alter the number and behavior of resident-like tissue macrophages, a type of immune cell, contributing to an increased risk of atherosclerotic cardiovascular disease (ASCVD). The researchers aimed to understand the biological mechanisms behind the elevated ASCVD risk associated with early cholesterol exposure and fluctuations.
Cholesterol is well-known for its role in developing atherosclerosis, partly due to its activation of the NLRP3-IL1β pathway, a key inflammatory response mechanism. However, the precise ways in which cholesterol overload triggers the formation of inflammatory plaques remain unclear. Beyond simple cholesterol levels, the study suggests that the duration and timing of cholesterol exposure are significant predictors of ASCVD events. Early accumulation of cholesterol has been linked to a higher risk of cardiovascular diseases, and Cholesterol Fluctuation levels, even among those undergoing statin treatment, have been found to increase the likelihood of ASCVD.
Research Methodology and Findings
The study used various genetically modified mice models to examine the effects of early intermittent hyperlipidemia on atherosclerosis development. These mice, housed in pathogen-free facilities and subjected to controlled conditions, were either fed a late continuous Western diet or an early intermittent Western diet. Despite similar overall cholesterol exposure, mice on the early intermittent diet developed significantly larger atherosclerotic plaques than those on the continuous diet. These larger plaques were also characterized by increased inflammation, higher numbers of macrophages and T cells, and more extensive necrosis, indicating a more severe form of the disease.
Further investigations revealed that gut microbiota, while slightly altered between the two groups after six weeks of diet, played a limited role in accelerating atherosclerosis. Antibiotic treatment only partially reduced the development of plaques in mice fed an early intermittent diet. Additionally, mice lacking adaptive immune cells, such as T and B cells, still showed accelerated atherosclerosis, suggesting that innate immune responses, rather than adaptive ones, are critical in this process. RNA sequencing further revealed significant changes in macrophage gene expression, particularly concerning autophagy and efferocytosis—key processes in maintaining plaque stability.
Conclusions and Implications for Cardiovascular Health
The findings highlight that early and intermittent spikes in cholesterol levels are crucial drivers of atherosclerotic plaque development, even when cumulative cholesterol exposure is equivalent to sustained high cholesterol levels later in life. The study identifies impaired autophagy and efferocytosis in arterial macrophages as key contributors to accelerated atherosclerosis. This impaired function is particularly evident in resident-like macrophages, essential for maintaining arterial health and stability.
The researchers conclude that early-life exposure to high cholesterol has a significant impact on the progression of atherosclerosis, providing a potential explanation for the strong correlation between early cholesterol fluctuations and later cardiovascular events. The study underscores the importance of managing cholesterol levels from an early age to reduce long-term cardiovascular risks, suggesting that early intervention and cholesterol control could be vital strategies for preventing atherosclerosis and its associated complications.
