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Highlighted articles January

Volume 256 Issue January 2017

By Simona Negrini and Arnold von Eckardstein (Editor–in-Chief).

Issue highlights

Articles

    Highlighted articles

    Old challenges and new opportunities in the clinical management of heterozygous familial hypercholesterolemia (HeFH): The promises of PCSK9 inhibitors

    In this review, Arca M. summarizes the challenges in clinical management of subjects with heterozygous familial hypercholesterolemia (HeFH), with a focus on emerging treatments, and highlights the status of HeFH diagnosis and treatment in Italy. HeFH is a common genetic disorder associated with an elevated risk of premature coronary heart disease, stroke, and peripheral vascular disease. Despite the availability of reliable diagnostic criteria, HeFH is underdiagnosed and undertreated worldwide. HeFH is characterized by markedly elevated plasma concentrations of low-density lipoprotein cholesterol (LDL-C), but because of the high baseline levels of LDL-C, the achievement of target LDL-C levels remains a challenge. In recent years, a number of novel therapies to lower LDL-C levels in HeFH have been developed, including the monoclonal antibodies against serine protease proprotein convertase subtilisin/kexin type 9 (PCSK9), alirocumab and evolocumab, which have the potential to reduce LDL-C by an additional 50%–60% when prescribed in combination with standard lipid-lowering drugs.

    Carotid artery plaques and intima medial thickness in familial hypercholesteraemic patients on long-term statin therapy: A case control study

    Statins reduce subclinical atherosclerosis and premature atherosclerotic cardiovascular disease (ASCVD) in patients with familial hypercholesterolemia (FH), although some FH patients still develop ASCVD despite statin therapy. Bos et al. aimed to compare subclinical atherosclerosis in long-term statin-treated FH patients and healthy controls assessed by carotid plaque presence and intima media thickness (C-IMT).

    The association between carotid ultrasonography findings and subclinical coronary atherosclerosis was analyzed in 221 asymptomatic heterozygous FH patients on long-term statin treatment and 103 controls. The authors found that the frequency of carotid plaques and C-IMT did not differ significantly between FH patients and controls, which shows that long-term statin treatment in these FH patients reduces carotid atherosclerosis to a degree observed in the healthy population. Concerning the association between carotid ultrasonography findings and subclinical coronary atherosclerosis, in a subgroup of 49 FH patients who underwent cardiac computed tomography, coronary artery calcification correlated with carotid plaque presence, but not with C-IMT. These findings strongly suggest that sonography of the carotid arteries during follow-up of statin-treated FH patients has limited value.

    Ideal cardiovascular health influences cardiovascular disease risk associated with high lipoprotein(a) levels and genotype: The EPIC-Norfolk prospective population study

    According to the American Heart Association, “ideal cardiovascular health” can be defined on the basis of seven cardiovascular health metrics. Perrot et al. aimed to evaluate the importance of “ideal cardiovascular health” in individuals with high lipoprotein(a), which is a strong genetic risk factor for cardiovascular disease.


    A total of 14,051 participants of the EPIC-Norfolk study were stratified according to a cardiovascular health score. Cox proportional hazards models were used to describe the association between the cardiovascular health score and lipoprotein (a) level or genotype (as estimated by the rs10455872 variant). Little or no differences in serum Lp(a) levels were observed across the seven cardiovascular health metric categories. Among participants with high serum Lp(a) levels, those in the healthiest cardiovascular health score category had an adjusted hazard ratio for cardiovascular disease of 0.33 compared to participants in the unhealthiest cardiovascular health score category. Similar results were obtained when the analysis was conducted considering rs10455872 variants.

    The authors concluded that although Lp(a) levels differ only slightly between categories, an ideal cardiovascular health could substantially reduce cardiovascular disease risk associated with high Lp(a) levels or genotype.

    Low vitamin D does not predict statin associated muscle symptoms but is associated with transient increases in muscle damage and pain

    Low vitamin D (VITD) may contribute to statin-associated muscle symptoms (SAMS). Taylor et al. examined the influence of baseline and change in vitamin D levels in patients with verified statin-associated muscle symptoms (SAMS).

    SAMS was assessed in 120 patients with prior statin muscle complaints in 8-week randomized, double-blind crossover trial using simvastatin 20 mg/d or placebo. 25(OH)vitamin D was measured at each phase of the trial. 35.8% of the patients experienced muscle pain upon simvastatin but none on placebo. Vitamin D levels prior to simvastatin treatment were not different between patients who did or did not develop SAMS, and they were not predictive of SAMS. The proportion of patients classified as either vitamin D-deficient or vitamin D-insufficient did not differ between patients with and without SAMS. Both baseline and on-statin vitamin D levels were inversely related to the change in creatine kinase with statin therapy, independently of SAMS.

    The authors concluded that baseline vitamin D, deficiency/insufficiency of vitamin D, and changes in vitamin D with statin therapy do not predict SAMS. In their editorial, Glueck et al. discussed this paper and some other papers assessing the association between low vitamin D levels and SAMS and, given the major clinical importance of SAMS, they emphasize the need of a large, double-blind, placebo-controlled crossover trial of vitamin D supplementation in patients with SAMS to elucidate the effectiveness of vitamin D supplementation in ameliorating this disease.

    Inhibitory effect of PCSK9 on Abca1 protein expression and cholesterol efflux in macrophages

    Proprotein convertase subtilisin/kexin type 9 (PCSK9) may have extra-hepatic effects on cholesterol homeostasis of vascular macrophages. Adorni et al. investigated the role of PCSK9 in extra-hepatic cholesterol homeostasis of vascular macrophages and, in particular, its influence on the anti-atherogenic process mediated by Abca1 (ATP binding cassette transporter A1).

    To this aim, they exposed wild-type and LDL receptor knock-out mice to human recombinant PCSK9 and evaluated Abca1-mediated cholesterol efflux in mouse peritoneal macrophages; in their experimental setting, expression of Abca1 was stimulated with liver X receptor/retinoid X receptor (LXR/RXR) ligands or acetylated LDL. When exposed to PCSK9, cholesterol efflux mediated by Abca1 was inhibited in wild type mouse peritoneal macrophages, but not in macrophages lacking the LDL receptor. Both Abca1 protein and gene expression levels were inhibited in wild type macrophages.

    The authors concluded that PCSK9 plays a direct role on Abca1-mediated cholesterol efflux through a downregulation of Abca1 gene and Abca1 protein expression and suggested that this extrahepatic effect may influence relevant steps in the pathogenesis of atherosclerosis.

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