Immune System Signatures Correlate with the Near Term Risk of Developing Atherosclerosis
Atherosclerosis is universal; everyone develops fatty atherosclerotic plaques in their arteries at some point, and to some degree. Plaques narrow blood vessels to impede blood flow, and rupture of unstable plaque causes heart attack, stroke, and embolism. It is the largest cause of human mortality, and at present the best that the medical community can do is to slow down plaque growth. Established therapies based on reducing the amount of cholesterol carried outward from the liver on low-density lipoprotein (LDL) particles produce something like a 15% mortality risk reduction at best, and do not regress plaque to any meaningful degree. Interestingly, the drivers of atherosclerosis are sufficiently complex and varied for there to be a few lucky people who exhibit 10% or more plaque regression in response to some combination of lifestyle change and medication. The flip side of that point is the majority of people who show up in a hospital in the immediate aftermath of a first heart attack or stroke do not in fact exhibit elevated LDL cholesterol, and probably benefit very little from the relentless clinical focus on LDL cholesterol.
It isn't all that easy to assess the degree of plaque present in the early stages of atherosclerosis. Imaging approaches have improved greatly over the past ten to fifteen years, but still struggle to distinguish small amounts of plaque. Little to no assessment takes place in the early stages of the condition. Many people have no idea as to whether or not they are in a high risk group until it is far too late. Simple risk factors are well understood, such as chronic inflammation, being overweight, suffering metabolic disease, and so forth. But as the discovery and continued research into the role of Lp(a) in atherosclerosis risk illustrates, there is a great deal yet to be catalogued of how exactly specific differences in metabolism yield differences in the pace at which atherosclerotic lesions emerge. It remains largely a mystery as to why any given person exhibits a given degree of atherosclerosis.
It does seem plausible that differences in atherosclerosis risk, onset, and progression, could correlate usefully well from specific differences in the configuration of the immune system, some of which are more likely (but not guaranteed) to exist in overweight, chronically inflamed, or metabolically dysfunctional people. Fundamentally, an atherosclerotic lesion is a consequence of macrophage dysfunction. Macrophages are innate immune cells responsible for clearing up excess cholesterol in blood vessel walls, and otherwise repairing damage. A lesion is a macrophage graveyard, perpetually calling in more macrophages, driving them into an inflammatory state, and killing them with its toxic mix of excess cholesterol and other lipids. Macrophages do not operate in a vacuum, however, and are strongly influenced by the activities of cells in other immune compartments. There is plenty of evidence for T cells of the adaptive immune system to affect plaque growth in animal studies, for example.
Age-related structural and functional changes in the arterial wall promote endothelial dysfunction and accelerate atherosclerosis development. Importantly, this process begins long before clinical symptoms appear. During this silent phase, early vascular damage and subclinical atherosclerotic plaque (SAP) formation may already occur but remain undetected. Detecting such early alterations is therefore crucial for improving prevention and enabling timely intervention. Immunological mechanisms and inflammation are increasingly recognized as central drivers of atherogenesis. T cells play a pivotal role in maintaining chronic vascular inflammation. Both CD4+ and CD8+ T-cell subsets modulate plaque biology through pro- and anti-inflammatory effects, whereas regulatory T cells (Tregs) exert protective effects by limiting immune activation and stabilizing plaque. Reduced Treg activity has been linked to accelerated vascular damage. In addition, a broad network of mediators, including cytokines such as Interleukin (I)L-1β, IL-6, IL-18, and tumor necrosis factor-alpha (TNF-α), contributes to endothelial activation, arterial remodeling, and plaque progression. Together with circulating proteins such as growth differentiation factor-15 (GDF-15) and osteoprotegerin (OPG), these immune-related pathways form a complex regulatory network that may provide early insight into emerging vascular vulnerability.
Previous cross-sectional work in a carefully characterized cohort of healthy, medication-free older adults with high cardiorespiratory fitness demonstrated that SAP were accompanied by distinct cellular and molecular immune signatures. Individuals with SAP exhibited hallmarks of immunosenescence, including reduced proportions of naïve CD4+ T cells, expansion of differentiated subsets such as CD4+ and CD8+ central memory cells, elevated inflammatory mediators, molecular features of cellular senescence, and alterations within Treg subpopulations. These findings underscored the pivotal role of immune system alterations in early plaque formation and suggested that immunological profiling may help identify individuals at increased vascular risk before clinical manifestation.
In a three-year longitudinal study, 49 healthy older adults (63.8 ± 3.8 years) underwent carotid ultrasound, T cell phenotyping, serum protein profiling, body composition assessment, and fitness testing at baseline and follow-up. At follow-up, participants were classified as no SAP, new SAP or persistent SAP. We analyzed baseline determinants and within-person changes to predict incident plaque formation. New SAP occurred in 30.3% of those initially plaque-free. At baseline, lower frequencies of CD8+ effector memory (EM) T cells and higher frequencies of CD8+ effector memory re-expressing CD45RA (EMRA) T cells and regulatory T cells (Tregs) were associated with higher odds of new SAP. Over time, expansion of CD8+ EM T cells was the most consistently associated independent variable of new SAP, accompanied by declines in Tregs and in the Treg/Teff ratio. Vascular cell adhesion molecule-1 (VCAM-1) at baseline was an additional independent predictor. Increases in visceral fat and declines in VO2peak were linked to new SAP, but immune markers were more robust than metabolic variables or serum cytokines.