Stigmasterol accumulation causes cardiac injury and promotes mortality

Area of Science:

• Cardiovascular Research
• Metabolic Diseases
• Toxicology

Background:

• Cardiovascular disease (CVD) remains a leading cause of death globally.
• Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors effectively lower cholesterol but residual risk factors persist.
• Phytosterolemia, characterized by elevated blood plant sterols, presents a potential, understudied CVD risk.

Purpose of the Study:

• To investigate the cardiovascular impact of phytosterolemia, specifically the role of stigmasterol accumulation.
• To determine if phytosterols cause cardiac injury independent of cholesterol levels.
• To explore the therapeutic potential of inhibiting sterol absorption in phytosterolemia-associated cardiac dysfunction.

Main Methods:

• A mouse model of phytosterolemia was utilized to study cardiac outcomes.
• Plasma cholesterol and phytosterol levels were monitored.
• Cardiac function, fibrosis, and inflammatory cell infiltration were assessed.
• The effect of a sterol absorption inhibitor on cardiac fibrogenesis was evaluated.

Main Results:

• Mice with phytosterolemia exhibited cardiac injury, left ventricle dysfunction, and increased mortality despite a 50% reduction in plasma cholesterol.
• Accumulation of stigmasterol was identified as a key factor in cardiac pathology.
• Phytosterol-induced cardiac fibrosis and macrophage infiltration occurred without significant atherosclerosis.
• Pharmacological inhibition of sterol absorption ameliorated cardiac fibrogenesis.

Conclusions:

• Phytosterolemia, driven by stigmasterol accumulation, induces cardiac fibrosis and dysfunction, leading to increased mortality.
• Cardiac fibrosis, rather than cholesterol-driven atherosclerosis, appears to be the primary mechanism linking phytosterolemia to cardiovascular outcomes.
• Stigmasterol is identified as a potent and independent risk factor for cardiovascular disease.