Attitudes and actions: A survey to assess statin use among Finnish patients with increased risk for cardiovascular events.

BACKGROUND: Statins are the first-line treatment for lowering serum cholesterol and preventing coronary artery disease (CAD). Patients who fail to comply with the prescribed statin treatment face a markedly increased risk for cardiovascular events. OBJECTIVE: The aim of the article was to study the subjective factors, which modulate persistence with and adherence to statin therapy among Finnish patients at high risk for cardiovascular events. METHODS: A total of 1022 Finnish adults diagnosed with CAD, diabetes, hypertension, or severe hereditary dyslipidemia completed an electronic questionnaire survey during a visit in 1 of the 84 community pharmacies participating in the study. RESULTS: Thirty-four percent of the survey respondents were diagnosed with CAD or severe hereditary dyslipidemia and 82% were current or former statin users. Prevalence of nonpersistence with statin therapy was 15% among CAD patients and 17% among respondents without the diagnosis. Most of the nonpersistent statin users had discontinued the medication without consultation of a physician. None of the studied sociodemographic background factors were associated with persistence with statin therapy. Instead, experienced adverse effects, fear of adverse effects, perceived lack of need, and difficulties in use of a statin emerged as powerful predictors of nonpersistence. Awareness of treatment goals was low, and strikingly, public discussion about adverse effects of statins had induced nearly every third discontinuation of statin treatment. CONCLUSION: Several subjective, potentially modifiable reasons for nonpersistence were identified from the patient perspective. Improved utilization of patient-centered approaches in pharmacologic management of cardiovascular risks is necessary to improve adherence, and ultimately, treatment outcomes.

Phytosterol-mediated inhibition of intestinal cholesterol absorption in mice is independent of liver X receptor.

SCOPE: Previous studies have proposed that phytosterols activate liver X receptors (LXR) in the intestine, thereby reducing intestinal cholesterol absorption and promoting fecal cholesterol excretion. METHODS AND RESULTS: In the present study, we examined the effects of dietary phytosterol supplementation on intestinal cholesterol absorption and fecal neutral sterol excretion in LXRαß-deficient mice, and wild-type mice treated with synthetic high-affinity LXRαß agonists. LXRαß deficiency led to an induction of intestinal cholesterol absorption and liver cholesterol accumulation. Phytosterol feeding resulted in an approximately 40% reduction of intestinal cholesterol absorption both in wild-type and LXRαß-deficient mice, reduced dietary cholesterol accumulation in liver and promoted the excretion of fecal cholesterol-derived compounds. Furthermore, phytosterols produced additive inhibitory effects on cholesterol absorption in mice treated with LXRαß agonists. CONCLUSIONS: Our data confirm the effect of LXR in regulating intestinal cholesterol absorption and demonstrate that the cholesterol-lowering effects of phytosterols occur in an LXR-independent manner.

USF1 deficiency activates brown adipose tissue and improves cardiometabolic health.

USF1 (upstream stimulatory factor 1) is a transcription factor associated with familial combined hyperlipidemia and coronary artery disease in humans. However, whether USF1 is beneficial or detrimental to cardiometabolic health has not been addressed. By inactivating USF1 in mice, we demonstrate protection against diet-induced dyslipidemia, obesity, insulin resistance, hepatic steatosis, and atherosclerosis. The favorable plasma lipid profile, including increased high-density lipoprotein cholesterol and decreased triglycerides, was coupled with increased energy expenditure due to activation of brown adipose tissue (BAT). Usf1 inactivation directs triglycerides from the circulation to BAT for combustion via a lipoprotein lipase-dependent mechanism, thus enhancing plasma triglyceride clearance. Mice lacking Usf1 displayed increased BAT-facilitated, diet-induced thermogenesis with up-regulation of mitochondrial respiratory chain complexes, as well as increased BAT activity even at thermoneutrality and after BAT sympathectomy. A direct effect of USF1 on BAT activation was demonstrated by an amplified adrenergic response in brown adipocytes after Usf1 silencing, and by augmented norepinephrine-induced thermogenesis in mice lacking Usf1. In humans, individuals carrying SNP (single-nucleotide polymorphism) alleles that reduced USF1 mRNA expression also displayed a beneficial cardiometabolic profile, featuring improved insulin sensitivity, a favorable lipid profile, and reduced atherosclerosis. Our findings identify a new molecular link between lipid metabolism and energy expenditure, and point to the potential of USF1 as a therapeutic target for cardiometabolic disease.

Chronic intermittent psychological stress promotes macrophage reverse cholesterol transport by impairing bile acid absorption in mice.

Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids. C57Bl/6J mice exposed to intermittent stress for 5 days exhibited increased transit through the large intestine and enhanced fecal bile acid excretion. Of the transcription factors and transporters that regulate bile acid homeostasis, the mRNA expression levels of the hepatic farnesoid X receptor (FXR), the bile salt export pump (BSEP), and the intestinal fibroblast growth factor 15 (FGF15) were reduced, whereas those of the ileal apical sodium-dependent bile acid transporter (ASBT), responsible for active bile acid absorption, remained unchanged. Neither did the hepatic expression of cholesterol 7α-hydroxylase (CYP7A1), the key enzyme regulating bile acid synthesis, change in the stressed mice. Evaluation of the functionality of the m-RCT pathway revealed increased fecal excretion of bile acids that had been synthesized from macrophage-derived cholesterol. Overall, our study reveals that chronic intermittent stress in mice accelerates m-RCT specifically by increasing fecal excretion of bile acids. This novel mechanism of m-RCT induction could have antiatherogenic potential under conditions of chronic stress.

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice.

Reverse cholesterol transport (RCT) pathway from macrophage foam cells initiates when HDL particles cross the endothelium, enter the interstitial fluid, and induce cholesterol efflux from these cells. We injected [(3)H]cholesterol-loaded J774 macrophages into the dorsal skin of mice and measured the transfer of macrophage-derived [(3)H]cholesterol to feces [macrophage-RCT (m-RCT)]. Injection of histamine to the macrophage injection site increased locally vascular permeability, enhanced influx of intravenously administered HDL, and stimulated m-RCT from the histamine-treated site. The stimulatory effect of histamine on m-RCT was abolished by prior administration of histamine H1 receptor (H1R) antagonist pyrilamine, indicating that the histamine effect was H1R-dependent. Subcutaneous administration of two other vasoactive mediators, serotonin or bradykinin, and activation of skin mast cells to secrete histamine and other vasoactive compounds also stimulated m-RCT. None of the studied vasoactive mediators affected serum HDL levels or the cholesterol-releasing ability of J774 macrophages in culture, indicating that acceleration of m-RCT was solely due to increased availability of cholesterol acceptors in skin. We conclude that disruption of the endothelial barrier by vasoactive compounds enhances the passage of HDL into interstitial fluid and increases the rate of RCT from peripheral macrophage foam cells, which reveals a novel tissue cholesterol-regulating function of these compounds.

Resveratrol administration or SIRT1 overexpression does not increase LXR signaling and macrophage-to-feces reverse cholesterol transport in vivo.

The natural polyphenol resveratrol has cardiometabolic protective properties. Resveratrol has been reported to be an activator of NAD+-dependent deacetylase sirtuin 1 (SIRT1), which may regulate liver X receptor (LXR) activity, thereby upregulating the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, the effects of resveratrol and SIRT1 overexpression on RCT from macrophages-to-feces in vivo in C57BL/6 mice were determined. [³H]cholesterol-labeled mouse macrophages were injected intraperitoneally into mice treated with intragastric doses of the well-known LXR agonist T0901317, resveratrol, or a vehicle solution, and radioactivity was determined in plasma, liver, and feces. T0901317-treated mice presented increased [³H]cholesterol in plasma and HDL 48 h after the label injection. Treatment with T0901317 also increased liver ABCA1, G1, and G5 gene expression and reduced intestinal cholesterol absorption which were changes that were associated with a 2.8-fold increase in macrophage-derived [³H]cholesterol in feces. In contrast, resveratrol treatment had no effect on liver LXR signaling or fecal [³H]cholesterol excretion. A separate experiment was conducted in SIRT1 transgenic mice. Liver LXR-target gene expression and magnitude of macrophage-derived [³H]cholesterol in plasma, liver, and feces of SIRT1 transgenic mice did not differ from those of wild-type mice. We conclude that neither resveratrol administration nor SIRT1 overexpression upregulate liver LXR-target genes and macrophage-to-feces RCT in vivo.

Acute psychological stress accelerates reverse cholesterol transport via corticosterone-dependent inhibition of intestinal cholesterol absorption.

RATIONALE: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood. OBJECTIVE: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. METHODS AND RESULTS: C57Bl/6J mice were exposed to restraint stress for 3 hours to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [(3)H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [(3)H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [(14)C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator-activated receptor-α increased, and that of the sterol influx transporter Niemann-Pick C1-like 1 decreased. The stress-dependent effects on RCT rate and peroxisome proliferator-activated receptor-α gene expression were fully mimicked by administration of the stress hormone corticosterone (CORT) to nonstressed mice, and they were blocked by the inhibition of CORT synthesis in stressed mice. Moreover, the intestinal expression of Niemann-Pick C1-like 1 protein decreased when circulating levels of CORT increased. Of note, when either peroxisome proliferator-activated receptor α or liver X receptor α knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma CORT increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. CONCLUSIONS: Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT.

Mast cell activation in vivo impairs the macrophage reverse cholesterol transport pathway in the mouse.

OBJECTIVE: Chymase released by activated mast cells degrades high-density lipoproteins. We evaluated whether local activation of mast cells would attenuate cholesterol efflux from neighboring macrophage foam cells, thereby disrupting the entire in vivo pathway of macrophage-specific reverse cholesterol transport (RCT). METHODS AND RESULTS: C57Bl/6J mice received intraperitoneal injections of the mast cell-degranulating compound 48/80 to induce peritoneal mast cell activation, human apolipoprotein A-I (apoA-I) to stimulate RCT, and [(3)H]cholesterol-labeled J774 macrophages for measurement of the rate of RCT. After 3 hours, (3)H-radioactivity was measured in the intestinal lumen contents. Activation of mast cells in the peritoneal cavity depleted human apoA-I pre-ß-migrating species, impairing the ability of the peritoneal fluid to efficiently promote cholesterol efflux from cultured macrophages. Moreover, intact but not chymase-treated (proteolyzed) apoA-I accelerated the transfer of macrophage-derived (3)H- radioactivity to the intestinal contents. Importantly, stimulation of RCT by human apoA-I was fully blocked by 48/80 in mast cell-competent wild-type C57Bl/6J mice but not in mast cell-deficient W-sash c-kit mutant mice. The ability of intraperitoneally administered phospholipid vesicles to promote RCT in wild-type mice was not blocked by 48/80, supporting the notion that mast cell-dependent proteolysis of the intraperitoneally administered apoA-I was responsible for RCT inhibition. CONCLUSIONS: Overall, our results suggest that tissue-specific activation of mast cells with ensuing release of chymase is able to proteolytically inactivate apoA-I in the microenvironment of the activated mast cells, thus locally impairing the initiation of macrophage RCT in vivo.