phytosterols and Fibrosis

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.

Topics: Animals; Arrhythmias, Cardiac; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cytokines; Death, Sudden, Cardiac; Fibrosis; Heart Failure; Hypercholesterolemia; Inflammation; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Knockout; Phytosterols

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.

Topics: Animals; Atherosclerosis; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP Binding Cassette Transporter, Subfamily G, Member 8; Cell Survival; Dietary Supplements; Fibrosis; Human Umbilical Vein Endothelial Cells; Humans; Hypercholesterolemia; Intestinal Diseases; Lipid Metabolism, Inborn Errors; Lipoproteins; Male; Mice; Mice, Inbred C57BL; Mice, Knockout; Myocardium; Phytosterols; Stigmasterol; Ventricular Dysfunction, Left

The aim of this study was to evaluate the relationship between cholesterol metabolism and coronary plaque vulnerability.. Cholesterol homeostasis, defined as the balance between absorption and synthesis, influences the progression of coronary atherosclerosis.. Consecutive stable angina pectoris patients (N = 80) not receiving any lipid-lowering therapy were divided into 2 groups based on the presence of in vivo thin cap fibroatheroma (TCFA) in de novo target vessels assessed by the combined use of virtual histology intravascular ultrasound and optical coherence tomography.. Patients with in vivo TCFA (n = 42) showed a higher campesterol-to-lathosterol ratio (3.36 [interquartile range, 2.10 to 4.26] vs. 1.50 [1.20 to 2.50], p < 0.0001). The campesterol-to-lathosterol ratio, low-density lipoprotein (LDL) cholesterol, and high-sensitivity C-reactive protein (hsCRP) were positively correlated with the percentage of necrotic core volume (r = 0.520, p < 0.0001; r = 0.520, p < 0.0001; and r = 0.539, p < 0.0001, respectively) and negatively correlated with thinnest fibrous cap thickness (r = -0.566, p < 0.0001; r = -0.530, p < 0.0001; and r = -0.358, p = 0.007, respectively) . The independent predictors of the incidence of TCFA were the campesterol-to-lathosterol ratio (odds ratio: 3.989, 95% confidence interval: 1.688 to 9.428; p = 0.002), LDL cholesterol (odds ratio: 1.425, 95% confidence interval: 1.023 to 1.985; p = 0.03), hsCRP (odds ratio: 1.025, 95% confidence interval: 1.003 to 1.047; p = 0.02), and the percentage of necrotic core volume (odds ratio:1.084, 95% confidence interval: 1.012 to 1.161; p = 0.02).. Enhanced absorption and reduced synthesis of cholesterol may be related to coronary plaque vulnerability.

Topics: Aged; Angina, Stable; Biomarkers; C-Reactive Protein; Chi-Square Distribution; Cholesterol; Cholesterol, HDL; Cholesterol, LDL; Coronary Artery Disease; Coronary Vessels; Disease Progression; Female; Fibrosis; Humans; Linear Models; Logistic Models; Male; Middle Aged; Multivariate Analysis; Necrosis; Odds Ratio; Phytosterols; Plaque, Atherosclerotic; Predictive Value of Tests; Prognosis; Risk Factors; Rupture, Spontaneous; Tomography, Optical Coherence; Ultrasonography, Interventional

Dilated cardiomyopathy (DCM) in A/J mice homozygous for the spontaneous thrombocytopenia and cardiomyopathy (trac) mutation results from a single base pair change in the Abcg5 gene. A similar mutation in humans causes sitosterolemia with high plant sterol levels, hypercholesterolemia, and early onset atherosclerosis. Analyses of CD3+ and Mac-3+ cells and stainable collagen in hearts showed inflammation and myocyte degeneration in A/J-trac/trac mice beginning postweaning and progressed to marked dilative and fibrosing cardiomyopathy by 140 days. Transmission electron microscopy (TEM) demonstrated myocyte vacuoles consistent with swollen endoplasmic reticulum (ER). Myocytes with cytoplasmic glycogen and irregular actinomyosin filament bundles formed mature intercalated disks with normal myocytes suggesting myocyte repair. A/J-trac/trac mice fed lifelong phytosterol-free diets did not develop cardiomyopathy. BALB/cByJ-trac/trac mice had lesser inflammatory infiltrates and later onset DCM. BALB/cByJ-trac/trac mice changed from normal to phytosterol-free diets had lesser T cell infiltrates but persistent monocyte infiltrates and equivalent fibrosis to mice on normal diets. B- and T-cell-deficient BALB/cBy-Rag1(null) trac/trac mice fed normal diets did not develop inflammatory infiltrates or DCM. We conclude that the trac/trac mouse has many features of inflammatory DCM and that the reversibility of myocardial T cell infiltration provides a novel model for investigating the progression of myocardial fibrosis.

Topics: Animals; ATP Binding Cassette Transporter, Subfamily G, Member 5; ATP-Binding Cassette Transporters; Cardiomyopathy, Dilated; Disease Models, Animal; Echocardiography; Female; Fibrosis; Histocytochemistry; Inflammation; Lipoproteins; Male; Mice; Mice, Transgenic; Microscopy, Electron; Monocytes; Myocardium; Myofibrils; Phytosterols; T-Lymphocytes