False Utopia of One Unifying Description of the Vulnerable Atherosclerotic Plaque: A Call for Recalibration That Appreciates the Diversity of Mechanisms Leading to Atherosclerotic Disease

Abstract

Atherosclerosis is a complex disease characterized by the formation of arterial plaques with a broad diversity of morphological phenotypic presentations. Researchers often apply one description of the vulnerable plaque as a gold standard in preclinical and clinical research that could be applied as a surrogate measure of a successful therapeutic intervention, despite the variability in lesion characteristics that may underly a thrombotic occlusion. The complex mechanistic interplay underlying progression of atherosclerotic disease is a consequence of the broad range of determinants such as sex, risk factors, hemodynamics, medications, and the genetic landscape. Currently, we are facing an overwhelming amount of data based on genetic, transcriptomic, proteomic, and metabolomic studies that all point to heterogeneous molecular profiles of atherosclerotic lesions that lead to a myocardial infarction or stroke. The observed molecular diversity implies that one unifying model cannot fully recapitulate the natural history of atherosclerosis. Despite emerging data obtained from -omics studies, a description of a natural history of atherosclerotic disease in which cell-specific expression of proteins or genes are included is still lacking. This also applies to the insights provided by genome-wide association studies. This review will critically discuss the dogma that the progression of atherosclerotic disease can be captured in one unifying natural history model of atherosclerosis.

Women, lipids, and atherosclerotic cardiovascular disease: a call to action from the European Atherosclerosis Society

“…Integrative systems biology approaches revealed clear differences in gene networks between the sexes. 104 , 105 Female plaque contained more networks associated with SMC phenotypic modulation and endothelial mesenchymal transition, whereas male plaques exhibited pathways associated with immunoreactivity. 105 Consistent with this, carotid endarterectomy specimens from women showed less inflammatory infiltrates, smaller necrotic cores, and enhanced SMC and collagen content.…”

The accumulation of erythrocytes quantified and visualized by Glycophorin C in carotid atherosclerotic plaque reflects intraplaque hemorrhage and pre-procedural neurological symptoms

“…Such an investigation would further enhance our understanding of the role of erythrocytes and intraplaque bleeding and its localization within atherosclerotic plaques, offering valuable insights for clinical risk stratification and targeted therapeutic interventions. Another point that needs to be addressed is that the concept around the ‘vulnerable’ plaque has evolved, and the classification of atherosclerotic plaques is more complex than previously thought 36 . The diversity and complexity of lesion types go beyond the perceived overall plaque phenotypes, thus the presence of one specific plaque feature probably does not determine outcome.…”

Translational opportunities of single-cell biology in atherosclerosis

“…A collaborative effort of unprecedented magnitude is required to collate data from multiple patients, disease stages, treatment regime and vascular beds to represent real-life heterogeneity with sufficient granularity to achieve translational usefulness. 109 Growing improvements in medical treatment and increasing use of percutaneous endovascular procedures pose a time limit for the window of opportunity for vascular single-cell biology. No human vascular tissue sample should go to waste in the next decade, as it is becoming more and more precious.…”