Phytosterol accumulation results in ventricular arrhythmia, impaired cardiac function and death in mice.

Heart failure (HF) and cardiac arrhythmias share overlapping pathological mechanisms that act cooperatively to accelerate disease pathogenesis. Cardiac fibrosis is associated with both pathological conditions. Our previous work identified a link between phytosterol accumulation and cardiac injury in a mouse model of phytosterolemia, a rare disorder characterized by elevated circulating phytosterols and increased cardiovascular disease risk. Here, we uncover a previously unknown pathological link between phytosterols and cardiac arrhythmias in the same animal model. Phytosterolemia resulted in inflammatory pathway induction, premature ventricular contractions (PVC) and ventricular tachycardia (VT). Blockade of phytosterol absorption either by therapeutic inhibition or by genetic inactivation of NPC1L1 prevented the induction of inflammation and arrhythmogenesis. Inhibition of phytosterol absorption reduced inflammation and cardiac fibrosis, improved cardiac function, reduced the incidence of arrhythmias and increased survival in a mouse model of phytosterolemia. Collectively, this work identified a pathological mechanism whereby elevated phytosterols result in inflammation and cardiac fibrosis leading to impaired cardiac function, arrhythmias and sudden death. These comorbidities provide insight into the underlying pathophysiological mechanism for phytosterolemia-associated risk of sudden cardiac death.

Stigmasterol accumulation causes cardiac injury and promotes mortality.

Cardiovascular disease is expected to remain the leading cause of death worldwide despite the introduction of proprotein convertase subtilisin/kexin type 9 inhibitors that effectively control cholesterol. Identifying residual risk factors for cardiovascular disease remains an important step for preventing and clinically managing the disease. Here we report cardiac injury and increased mortality occurring despite a 50% reduction in plasma cholesterol in a mouse model of phytosterolemia, a disease characterized by elevated levels of dietary plant sterols in the blood. Our studies show accumulation of stigmasterol, one of phytosterol species, leads to left ventricle dysfunction, cardiac interstitial fibrosis and macrophage infiltration without atherosclerosis, and increased mortality. A pharmacological inhibitor of sterol absorption prevents cardiac fibrogenesis. We propose that the pathological mechanism linking clinical sitosterolemia to the cardiovascular outcomes primarily involves phytosterols-induced cardiac fibrosis rather than cholesterol-driven atherosclerosis. Our studies suggest stigmasterol is a potent and independent risk factor for cardiovascular disease.