Persistent inflammation and mechanical injury associated with cholesterol crystal accretion within atherosclerotic plaques typically precedes plaque disruption (rupture and/or erosion) and thrombosis--often the terminal events of atherosclerotic cardiovascular disease. To elucidate the mechanisms of these events, the atherosclerotic rabbit model provides a unique and powerful tool that facilitates studies of atherogenesis starting with plaque buildup to eventual disruption. Examination of human coronary arteries obtained from patients who died with myocardial infarction demonstrates evidence of cholesterol crystals perforating the plaque cap and intimal surface of the arterial wall that can lead to rupture. These observations were made possible by omitting ethanol, an avid lipid solvent, from the tissue processing steps. Importantly, the atherosclerotic rabbit model exhibits a similar pathology of cholesterol crystals perforating the intimal surface as seen in ruptured human plaques. Local and systemic inflammatory responses in the model are also similar to those observed in humans. The strong parallel between the rabbit and human pathology validates the atherosclerotic rabbit model as a predictor of human pathophysiology of atherosclerosis. Thus, the atherosclerotic rabbit model can be used with confidence to evaluate diagnostic imaging and efficacy of novel anti-atherosclerotic therapy.
Cholesterol crystals have long been recognized as part of atherosclerotic plaques. They have been visualized by light microscopy as empty spaces or imprints where crystals were once present and then dissolved by tissue processing. Thus, until now, their role in atherosclerosis and plaque rupture had been considered to be inert. However, by the processing of tissue without ethanol it was possible to visualize their extensiveness and potential role in tissue injury. Also, it was demonstrated that cholesterol expands in volume when crystallizing from the liquid to the solid state, which is the presumed cause of plaque rupture by sharp-tipped crystals growing out of the plaque’s necrotic core. Specifically, in patients who died of myocardial infarction, all culprit coronary lesions had extensive cholesterol crystals perforating the fibrous cap and intima, while those patients who died of other causes and had plaques did not have crystals perforating the cap and intima. Additionally, cholesterol crystals traveling downstream from the plaque rupture site can scrape the endothelium and promote vasospasm. Moreover, cholesterol crystals lodging into the muscle can trigger an inflammation with necrosis independent of circulatory compromise or ischemia. These findings suggest that cholesterol crystals could play a critical role in plaque rupture, as well as vascular and myocardial injury.
The global burden of heart failure has reached epidemic proportions with tremendous health and economic consequences. Sodium glucose cotransporter 2 inhibitors, vericiguat, and omecamtiv mecarbil are novel agents that promise to blunt the high residual risk of heart failure with reduced ejection fraction. We review the vast knowledge base that has rapidly materialized for these agents and is poised to shape the current and future trends and recommendations in heart failure pharmacotherapy.
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