The Molecular Basis of Predicting Atherosclerotic Cardiovascular Disease Risk

Abstract

Atherosclerotic cardiovascular disease (ASCVD) proceeds through a series of stages: initiation, progression (or regression), and complications. By integrating known biology regarding molecular signatures of each stage with recent advances in high-dimensional molecular data acquisition platforms (to assay the genome, epigenome, transcriptome, proteome, metabolome, and gut microbiome), snapshots of each phase of atherosclerotic cardiovascular disease development can be captured. In this review, we will summarize emerging approaches for assessment of atherosclerotic cardiovascular disease risk in humans using peripheral blood molecular signatures and molecular imaging approaches. We will then discuss the potential (and challenges) for these snapshots to be integrated into a personalized movie providing dynamic readouts of an individual's atherosclerotic cardiovascular disease risk status throughout the life course.

Keywords: cardiovascular disease; coronary artery disease; metabolome; proteomics.

Figure 1.. The molecular biology of ASCVD and its peripheral blood signature.

Initiation of atherosclerosis commences with a pro-atherogenic, lipid rich, inflammatory milieu leading to focal inflammation, maladaptive intimal and medial thickening, and endothelial damage. Markers of elevated blood lipid values and systemic inflammation (and their genetic and epigenetic determinants) can be detected in circulating blood. As atherosclerosis progresses, fatty streaks develop into atherosclerotic plaques through migration of smooth muscle cells and lipid accumulation. This process is heavily influenced by the functions of different leukocyte species including macrophage polarization and transition to foam cells and lymphocyte infiltration and proliferation within developing plaques. Programmed leukocyte cell death and micro-calcifications can promote a necrotic core, which, coupled with a thin fibrous cap, are characteristic of ‘vulnerable plaques’ more prone to rupture. Epigenetic, proteomic, and metabolomic fingerprints of developing plaque characteristics can be detected in circulating blood. Molecular imaging and cell-type specific profiling via cell sorting and single cell sequencing may also identify adverse plaque features. Complications of ASCVD primarily occur as a result of critical blockages and/or plaque rupture events (frequently preceded by subclinical intra-plaque hemorrhages) leading to thrombosis and acute organ ischemia. Identification of early signs of vessel occlusion prior to symptom development may be facilitated by assaying high-sensitivity transcriptomic, proteomic, and metabolomic markers in circulating blood.

Figure 2.. Life course integration of multi-dimensional molecular data for ASCVD risk prediction.

A conceptual view of how molecular diagnosis of ASCVD may proceed through the life course. Prevention of atherosclerosis development begins early in the life course with monitoring of standard clinical risk factors, environmental exposures, and deep, dynamic molecular risk profiles integrating information from the various “omics” layers. The connections between different “omic” layers displayed here is simplified for visualization purposes; the ‘post-genetic’ layers (epigenome, transcriptome, proteome, metabolome, microbiome) also influence each other bi-directionally. During early adulthood to mid-life, when atherosclerosis typically develops, personalized molecular risk profiles can inform risk status, leading to personalized treatment recommendations. In individuals with sufficient risk (typically in middle age and older adults), molecular imaging and cell-specific molecular profiling can be deployed to more precisely risk profile individual plaque features, with the goal of informing targeted therapeutic approaches. Lastly, high-sensitivity molecular diagnostics may reveal signs of impending ASCVD complications (e.g., plaque rupture) before clinical symptoms develop, enabling upstream treatment and prevention approaches.