Highlighted Articles - Atherosclerosis March 2016 Issue
17 March 2016
Volume 246 Issue March 2016
By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief)
Circulating levels of low-density lipoprotein cholesterol (LDL), and high-density lipoprotein cholesterol (HDL) are two of the most important risk factors for the development of cardiovascular disease (CVD), the leading cause of death worldwide.
Recently, miRNAs have emerged as critical regulators of cholesterol metabolism and promising therapeutic targets for the treatment of CVD. A great deal of work has established numerous miRNAs as important regulators of HDL metabolism. This includes miRNAs targeting ABCA1, a critical factor for HDL biogenesis and reverse cholesterol transport (RCT), the process through which cells, including arterial macrophages, efflux cellular cholesterol for transport to and removal by the liver.
The most well studied of these miRNAs, miR-33, has been demonstrated to target ABCA1, as well as numerous other genes involved in metabolic function and RCT, and therapeutic inhibition of miR-33 was found to increase HDL levels in mice and non-human primates.
Moreover, numerous studies have demonstrated the beneficial effects of miR-33 inhibition or knockout in reducing atherosclerotic plaque burden. Even a more recent work has identified miRNAs that regulate LDL cholesterol levels, including direct modulation of LDL uptake in the liver through targeting of the LDL receptor. Among these, inhibition of miR-128-1, miR-148a, or miR-185 was found to reduce plasma LDL levels, and inhibition of miR-185 was further demonstrated to reduce atherosclerotic plaque size in ApoE−/− mice.
Due to their ability to target many different genes, miRNAs mediate complex physiologic changes through simultaneous regulation of multiple inter-related pathways. Of particular importance for CVD, inhibition of miR-148a may prove an important therapeutic approach for combating dyslipidemia, as this has been demonstrated to both raise plasma HDL levels and lower LDL levels in mice by targeting both ABCA1 and LDLR, respectively.
In this review, Rotllan and colleagues highlight recent advances in the understanding of the mechanism of miRNAs regulation of cholesterol metabolism and development of atherosclerotic plaques and discuss the potential of anti-miRNA therapies for the treatment and prevention of CVD.
Atherosclerosis is a chronic lipid-driven inflammatory disease of the arterial wall. Interferon gamma (IFNγ) is an important immunomodulatory cytokine and a known pro-atherosclerotic mediator. However, cell-specific targeting of IFNγ or its signalling in atherosclerosis development has not been studied so far.
As macrophages are important IFNγ targets, Boshuizen et al. investigated the involvement of myeloid IFNγ signalling in murine atherosclerosis. Bone marrow was isolated from interferon gamma receptor 2 chain (IFNγR2) wild type and myeloid IFNγR2 deficient mice and injected into lethally irradiated LDLR-/- mice. After recovery, mice were put on a high-fat diet for 10 weeks. Atherosclerotic lesion analysis was then performed and the accompanying liver inflammation assessed.
The results show that even though absence of myeloid IFNγ signalling attenuated the myeloid IFNγ response, no significant differences in atherosclerotic lesion size or phenotype were found. In addition, no effects of IFNγR2 deficiency could be observed, when examining the liver inflammatory state.
Overall, the data presented argue against a role of myeloid IFNγR2 in atherosclerosis development.
The genetic cause and pathogenic mechanism of approximately 20–40% of autosomal dominant hypercholesterolemias (ADH) are unknown. Increased cholesterol intestinal absorption has been associated with ADH. Whether this variation contributes to their pathogenesis is unknown.
Baila-Rueda et al. studied cholesterol absorption (phytosterols and cholestanol serum concentrations) and cholesterol synthesis (desmosterol serum concentration) in 20 families with ADH without causal mutations in LDLR, APOB, PCSK9 or APOE genes (non-FH ADH) selected from 54 non-FH ADH probands with and without hyperabsorption.
They showed that concentrations of cholestanol, sitosterol, campesterol and stigmasterol are higher in affected than in non-affected subjects. In addition, there was a strong co-segregation of hyperabsorption with high LDL cholesterol within hyperabsorber families. In hyperabsorber families, 60.5% of subjects were hyperabsorbers and 76% of them had high LDL cholesterol versus 38.3% and 63% in non-hyperabsorber families, respectively.
In conclusion, most hypercholesterolemic family members with a hyperabsorber proband are hyperabsorbers. These absorption markers are significantly and positively associated with LDL cholesterol, and predispose to high LDL cholesterol in family members.
These data suggest that complex interindividual variation in cholesterol absorption is involved in many non-FH ADH.
n-3 polyunsaturated fatty acid (PUFA) treatment may decrease liver fat in non-alcoholic fatty liver disease (NAFLD), but uncertainty exists on whether this treatment also decreases cardiovascular disease (CVD) risk in NAFLD.
Bathia et al. tested whether 15–18-month n-3 PUFA treatment [docosahexaenoic acid (DHA) and eicosapentaenoic acid] versus placebo decrease carotid intima-media thickness (CIMT) progression, a surrogate marker of CVD risk. In addition, they evaluated whether improvement in markers of NAFLD severity is associated with decreased CIMT progression over time.
In a pre-specified sub-study of the WELCOME (Wessex Evaluation of fatty Liver and Cardiovascular markers in NAFLD with OMacor thErapy) trial (NCT00760513), CIMT was measured using B-mode ultrasound while NAFLD severity was assessed by measuring liver fat percentage (magnetic resonance spectroscopy) and hepatic necro-inflammation (serum cytokeratin-18 (CK-18) concentration), at baseline and end of study.
92 patients completed the study. In the treatment group (n = 45), CIMT progressed by 0.012 mm (IQR 0.005–0.020 mm) compared to 0.015 mm (IQR 0.007–0.025 mm) in the placebo group (n = 47). Reduced CIMT progression in the entire cohort was independently associated with decreased liver fat, reduced CK-18 levels, and antihypertensive usage in multivariable regression analysis after adjusting for all potential confounders. Decreased weight and increased DHA tissue enrichment during the 18-month study were both independently associated with decreased liver fat, but not with CK-18.
In conclusion, the data show that improvement in two markers of NAFLD severity is independently associated with reduced CIMT progression.
Since dyslipidaemia is one of the most important risk factors for coronary heart disease (CHD), lowering of LDL-cholesterol (LDL-C) causes significant reduction in morbidity and mortality, particularly in patients with established CHD.
The aim of this survey was to assess how statins were prescribed in CHD patients at discharge after a coronary event, from hospitals throughout Europe and how the intake of these drugs was reported by the patients, when they were seen more than one year later, in relationship with their achieved LDL-C levels.
To this purpose, Reiner et al. gathered 6648 CHD patients' data from centres in 24 European countries using standardized methods. Lipid measurements were performed in one central laboratory. Patients were divided in three groups: high-intensity statin therapy, moderate- or low-intensity statin therapy and no-statin therapy.
90.4% CHD patients were on statin therapy at the time of discharge from the hospital, which decreased to 86% one year later. Only 37.6% of these patients were prescribed a high-intensity statin at discharge, which even decreased to 32.7% later on. In only 6 countries (all of them high-income countries), the number of patients on a high-intensity statin therapy increased substantially after the hospital discharge. It is worrying that statin therapy was discontinued in 11.6% and that only 19.3% of all CHD patients achieved target values of LDL-C <1.8 mmol/L at the time of the interview.
In conclusion, the authors show that too many CHD patients with dyslipidaemia are still inadequately treated and most of these patients on statin therapy are not achieving the treatment targets. Therapeutic control of LDL-C is clearly related to the intensity of lipid lowering drug regimen after the CHD event, indicating that considerable potential still exists throughout Europe to reduce CHD mortality and morbidity rates through more efficient LDL-C lowering.