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Highlighted articles July

Volume 262 Issue June 2017

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

Several new interventions have been developed for the control of cardiovascular risk factors. Their clinical utility towards prevention of cardiovascular events and reduction of cardiovascular morbidity and mortality as well as total mortality is only starting to emerge. This issue of Atherosclerosis contains several publications on the clinical impact of new regimen, which facilitate smoking cessation or lower blood pressure or LDL cholesterol levels. Moreover, results from preclinical research on news targets are reported.

Issue highlights


    Highlighted articles

    Effects of varenicline and nicotine replacement therapy on arterial elasticity, endothelial glycocalyx and oxidative stress during a 3-month smoking cessation program

    The effects of medically-aided smoking cessation on vascular function and oxidative stress are not fully clarified.

    To gain further insights on this mechanism, Ikonomidis et al. evaluated the effects of a 3-month pharmacologically-assisted smoking cessation program on a study population consisting of 188 current smokers randomized to varenicline or nicotine replacement treatment (NRT) for a 3-month period. They assessed: (i) augmentation index (Aix) and pulse wave velocity (PWV), (ii) perfusion boundary region (PBR) of sublingual microvasculature (an index of the endothelial glycocalyx thickness), (iii) the exhaled CO, and (iv) the malondialdehyde (MDA) and protein carbonyls (PC) plasma levels, as markers of oxidative stress, at baseline and after 3 and 12 months.

    After 3 months of treatment, Aix, CO, MDA, and PC were decreased in all subjects, while PWV remained unchanged. Endothelial glycocalyx integrity showed a greater improvement in the varenicline than NRT treatment group, in parallel with a greater CO reduction. At 1-year follow-up, Aix, MDA, PC, and PBR were further improved in subjects who abstained from smoking, while these markers, together with PWV, deteriorated in relapsed smokers.

    The results showed that a smoking cessation program using varenicline or NRT for 3 months resulted in a decrease of CO, oxidative stress, arterial stiffness and restored endothelial glycocalyx. These effects were more evident after varenicline treatment, likely because of a greater CO reduction, and were maintained after 1 year only in subjects who abstained from smoking.

    Safety and performance of the second generation EnligHTN™ Renal Denervation System in patients with drug-resistant, uncontrolled hypertension

    Catheter-based renal denervation for the treatment of drug-resistant hypertension has been intensively investigated in recent years. To date, only limited data have been published using multi-electrode radiofrequency ablation systems that can deliver lesions with a pre-determined pattern.

    Worthley et al. aimed at evaluating the safety and performance of the second generation EnligHTN™ Renal Denervation System by performing a first-in-human, prospective, multi-center, non-randomized study on 39 patients with drug-resistant hypertension. The primary safety and performance objectives were to characterize, from baseline to 6 months post procedure, the rate of serious procedural and device related adverse events, as adjudicated by an independent Clinical Events Committee, and the reduction of office systolic blood pressure.

    Renal artery denervation, using the second generation EnligHTN multi-electrode system significantly reduced office blood pressure from baseline to 1, 3, 6, 12, 18 and 24 months by 19/7, 26/9, 25/7, 23/7, 25/8 and 27/9 mmHg, respectively. No serious device or procedure related adverse events affecting the renal arteries or renal function occurred through 24 months of follow-up.

    Renal denervation with the second generation EnligHTN™ System was efficacious at reducing blood pressure 24 months post renal denervation. Future studies will need to address the utility of this system against an appropriate sham based comparator.

    How many familial hypercholesterolemia patients are eligible for PCSK9 inhibition?

    Familial hypercholesterolemia (FH) is a high cardiovascular risk condition. Less than 20% of patients achieve the low-density lipoprotein (LDL) targets despite high-intensity lipid-lowering therapy. Although PCSK9 inhibitors improve control and reduce cardiovascular events, official recommendations for their use are restrictive.

    Masana et al. aimed at assessing the number of FH patients suitable for PCSK9 inhibition according to the European guidelines. A total of 2685 FH patients, with a minimum of 6-month follow-up, included in the Dyslipidemia Registry of the Spanish Arteriosclerosis Society, were sorted according to the intensity of their lipid-lowering therapy (LLT) and LDL cholesterol levels achieved. The number of patients who met the recommendations for PCSK9 inhibition treatment, according to the European Atherosclerosis Society (ESC/EAS), Spanish Arteriosclerosis Society and the European Medicines Agency, was calculated.

    In total, 1573 patients were on high-intensity LLT, 607 were on moderate-intensity statins, 82 were on low-intensity LLT, and 423 were neither on statins nor on ezetimibe in the last registered visit. The mean LDL reduction among those on high-intensity LLT was 54%. Ninety-one percent of patients on high-intensity LLT had an LDL below 5.2 mmol/L, 53% below 3.4 mmol/L, and 23% below 2.6 mmol/L. Only 12% of FH patients with cardiovascular disease achieved 1.8 mmol/L. Despite this, only 17% of patients qualified for PCSK9 inhibition according to ESC/EAS guidelines.

    In conclusion, these results suggest that for patients exposed to high cardiovascular risk, such as FH patients, who have extreme difficulties to achieve LDL targets, wider access to PCSK9 inhibitor therapy is warranted.

    New role of PCSK9 in atherosclerotic inflammation promotion involving the TLR4/NF-κB pathway

    Proprotein convertase subtilisin/kexin 9 (PCSK9) has emerged as a popular target in the development of new cholesterol-lowering drugs and therapeutic interventions for atherosclerosis. PCSK9 accelerates atherosclerosis through mechanisms beyond the degradation of the hepatic low-density lipoprotein receptor.

    Several clinical studies suggested that PCSK9 is involved in atherosclerotic inflammation. Tang et al. aimed at investigating the role of PCSK9 in vascular inflammation. They analyzed whether PCSK9 silencing via transduction with the lentivirus-mediated PCSK9 shRNA (LV-PCSK9 shRNA) vector affects the formation of vascular lesions in hyperlipidemia-induced atherosclerosis in apolipoprotein E knockout (apoE KO) mice. Moreover, the effect of PCSK9 on oxLDL-induced macrophages inflammation was assessed in vitro using LV-PCSK9 and LV-PCSK9 shRNA inducing PCSK9 overexpression and PCSK9 silencing, respectively.

    Immunohistochemical analysis showed that PCSK9 expression was increased within the atherosclerotic plaques in apoE KO mice. Silencing of PCSK9 in these mice led to the development of less aortic atherosclerotic plaques compared with the control group. These lesions also showed a reduced number of macrophages and decreased expression of vascular inflammation regulators, such as tumor necrosis factor-α, interleukin 1 beta, monocyte chemoattractant protein-1, toll-like receptor 4 and nuclear factor kappa B (NF-κB). The authors further showed that PCSK9 overexpression in macrophages increased the secretion of oxLDL-induced proinflammatory cytokines. PCSK9 overexpression upregulated TLR4 expression and increased p-IκBα levels, IkBα degradation, and NF-κB nuclear translocation to macrophages, while PCSK9 knockdown had the opposite effects in oxLDL-treated macrophages.

    These results show that interference with PCSK9 suppresses atherosclerosis directly by decreasing vascular inflammation and inhibiting the TLR4/NF-κB signaling pathway without affecting plasma cholesterol levels in high-fat diet-fed apoE KO mice. PCSK9 may be an inflammatory mediator in the pathogenesis of atherosclerosis.

    Proprotein convertase furin/PCSK3 and atherosclerosis: New insights and potential therapeutic targets

    Furin, a member of the mammalian proprotein convertases family, can promote the proteolytic maturation of proproteins. Furin is predominantly present in certain cell types of human atherosclerotic lesions and neointima in animal models, including vascular smooth muscle cells, endothelial cells and mononuclear inflammatory cells. Evidence suggests that furin participates in the initiation and progression of atherosclerosis through regulation of lipid and cholesterol metabolism, inflammatory response, blood pressure and the formation of atherosclerotic lesions. In this review, Ren et al. describe the roles of furin in atherosclerosis and give insights into the prevention and treatment of atherosclerosis and cardiovascular diseases.

    Recombinant adeno-associated virus vector carrying the thrombomodulin lectin-like domain for the treatment of abdominal aortic aneurysm

    Thrombomodulin (TM), through its lectin-like domain (TMD1), sequesters proinflammatory high-mobility group box 1 (HMGB1) to prevent it from engaging the receptor for advanced glycation end-product (RAGE) that sustains inflammation and tissue damage.

    In a previous study, Lai et al. demonstrated that short-term treatment with recombinant TM containing all the extracellular domains inhibits HMGB1-RAGE signaling and confers protection against CaCl2-induced abdominal aortic aneurysm (AAA) formation. In this study, the authors attempted to further optimize TM domains, as a potential therapeutic agent for AAA, using the recombinant adeno-associated virus (AAV) vector.

    To this aim, the therapeutic effects of recombinant TMD1 (rTMD1) and recombinant AAV vectors carrying the lectin-like domain of TM (rAAV-TMD1) were evaluated in the CaCl2-induced AAA model and angiotensin II-infused AAA model, respectively.

    In the CaCl2-induced model, treatment with rTMD1 suppressed the tissue levels of HMGB1 and RAGE, macrophage accumulation, elastin destruction and AAA formation, and the effects were comparable to a mole-equivalent dosage of rTMD123. In the angiotensin II-infused model, a single intravenous injection of rAAV-TMD1, resulting in a persistently high serum level of TMD1 for at least 12 weeks, effectively attenuated AAA formation, with suppression of HMGB1 and RAGE levels, and inhibition of proinflammatory cytokine production, macrophage accumulation, matrix metalloproteinase activities and oxidative stress in the aortic wall.

    These findings corroborate the therapeutic potential of the TM lectin-like domain in AAA. The attenuation of angiotensin II-infused AAA by one-time delivery of rAAV-TMD1 provides a proof-of-concept validation of its application as potential gene therapy for aneurysm development.

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