Advances in biological therapies for dyslipidemias and atherosclerosis.

Atherosclerosis is a multifactorial disease influenced by genetics, lifestyle and environmental factors. Despite therapeutic advances that reduce the risk of cardiovascular events, atherosclerosis-related diseases remain the leading cause of mortality worldwide. Precise targeting of genes involved in lipoprotein metabolism is an emerging approach for atherosclerosis prevention and treatment. This article focuses on the latest developments, clinical potential and current challenges of monoclonal antibodies, vaccines and genome/transcriptome modification strategies, including antisense oligonucleotides, genome/base editing and gene therapy. Multiple lipid lowering biological therapies have already been approved by the FDA with impressive results to date, while many more promising targets are being pursued in clinical trials or pre-clinical animal models.

The Impact of Obesity on the Association between Vitamin D Deficiency and Cardiovascular Disease.

The aim of this article is to review the literature regarding the relationship between vitamin D deficiency and cardiovascular disease (CVD) and its modification in the presence of obesity. Despite the strong association between vitamin D status and cardiovascular outcomes, vitamin D supplementation trials in the general population have failed to decrease the incidence of cardiovascular events and mortality. A comprehensive study of the published literature and a comparison with experimental data lead to the conclusion that obesity, due to its high prevalence and strong association with both vitamin D deficiency and CVD, may act as a critical confounder, which is responsible for the different results on this association. Adoption of a vitamin D preventive supplementation strategy for CVD is unlikely to yield any benefit to the general population. However, it might be particularly useful in obese adults with increased risk for CVD.

Effects of omega-3 polyunsaturated fatty acids on fibrosis, endothelial function and myocardial performance, in ischemic heart failure patients.

BACKGROUND & AIMS: Polyunsaturated fatty acids (PUFAs) may affect the cardiovascular system with a multiplicity of mechanisms. We assessed the effects of omega-3 PUFAs supplements on inflammation, fibrosis, left ventricle performance and endothelial function of ischemic heart failure (HF) patients. METHODS: In this double-blind, placebo controlled, cross-over trial we enrolled 31 patients with ischemic HF, followed by a 6-week wash-out period. Omega-3 PUFAs (2 g daily, 8 weeks) were administered PO in the intervention arm. Left ventricle ejection fraction (EF), global longitudinal strain and the ratio E/e' (early ventricular filling to early mitral annulus velocities)were measured. Endothelial function was evaluated by flow mediated dilation and myocardial fibrosis by soluble ST2. High sensitive C Reactive protein (hsCRP) levels were measured as an inflammatory marker. RESULTS: Treatment with omega-3 PUFA, compared to placebo, improved: left ventricle EF (percent increased by 4.7% vs 1.7%); global longitudinal strain (decreased by -10.6% vs -2.3%); the E/e' ratio (decreased by -9.47% vs -2.1%); ST2 levels (decreased by -4.53% vs -2.37%); flow mediated dilation (percent increased by 44% vs. 11% and hsCRP levels (decreased by -6.13% vs 4.35%) (p < 0.05 for all). CONCLUSION: Short term treatment with omega-3 PUFAs in subjects with stable ischemic HF improved inflammatory and fibrotic status as well as endothelial function in parallel with systolic and diastolic performance of left ventricle. These findings provide further insights regarding the impact of omega-3 PUFAs administration on left ventricle performance indices, systemic inflammation and fibrosis biomarkers in patients with ischemic HF.

The Impact of Omega 3 Fatty Acids in Atherosclerosis and Arterial Stiffness: An Overview of their Actions.

BACKGROUND: Fatty acids are common dietary nutrients particularly in economically developed countries. Research has revealed that omega-3fatty acids exert beneficial effects in the progression of atherosclerosis and cardiovascular disease. Moreover, eicosapentaenoic acid and docosahexaenoic acid possess a number of biological actions which improve cardio-metabolic health. Omega-3 fatty acids display remarkable anti-oxidant, anti-inflammatory, anti-thrombotic and anti-arrhythmogenic actions. Furthermore, they improve the levels of triglycerides, glucose metabolism and endothelial function. METHODS: The aim of this review article is to present physical, biochemical and biological properties of omega-3 fatty acids and summarize the most important mechanisms of action on arterial wall properties and arterial stiffness in atherosclerosis. RESULTS: Omega-3 fatty acids may prevent the progression of atherosclerosis. Endothelial dysfunction and arterial stiffness can be regulated by the supplementation of omega-3 fatty acids. CONCLUSION: The mechanisms of action of omega-3 fatty acids on cardiovascular health and arterial stiffening have been established. However, further research is needed in order to translate the conflicting results among the studies and improve the therapeutic options of cardiovascular disease.

Olive Oil-related Anti-inflammatory Effects on Atherosclerosis: Potential Clinical Implications.

BACKGROUND AND OBJECTIVE: Atherosclerosis is characterized by a chronic low-grade inflammatory process which can result in atherothrombosis and a number of cardiovascular diseases (CVD). It is believed to be caused by multiple processes that involve inflammation and immunity. Mediterranean Diet (MedD) has been discovered to possess anti-inflammatory properties and associated with a reduction in the CVD risk and mortality. Its main component, extra-virgin olive oil (EVOO), is believed to be largely responsible for these effects and therefore, has been investigated in various studies. The present review article aims to summarize the available literature on the antiinflammatory and cardio-protective effects of EVOO. METHODS: A search based on the key concepts "olive oil", "atherosclerosis", "inflammation" and "cardiovascular disease" was performed to retrieve relevant studies and articles on the association between the consumption of EVOO and the levels of inflammatory biomarkers as well as CVD incidence and mortality from online databases; Pubmed, Embase and Cochrane Library. RESULTS: Consumption of EVOO is associated with a reduction in inflammatory biomarkers and molecules implicated in atherosclerosis as well as CVD incidence and mortality as well as other complications such as heart failure and atrial fibrillation. Moreover, these anti-inflammatory and cardioprotective effects of EVOO are mostly attributable to its high content of polyphenol molecules. CONCLUSION: Currently available evidence supports the anti-inflammatory and cardio-protective roles of EVOO. However, there is limited amount of available randomized controlled trials especially lacking those investigating the use of EVOO as secondary prevention, heterogeneity of study design, limited generalization to wide population groups, and inability to determine the minimum intake of EVOO required to clinically achieve the anti-inflammatory and cardioprotective effects. Therefore, more highquality randomized controlled trials still need to be carried out to overcome these challenges to further assess the health benefits of EVOO consumption and potentially translate it into clinical practice as primary or secondary prevention of atherosclerosis-related conditions.

The impact of dietary flavonoid supplementation on smoking-induced inflammatory process and fibrinolytic impairment.

BACKGROUND AND AIMS: Smoking is associated with increased inflammatory process and impairment of fibrinolytic status. Concord grape juice (CGJ), a rich source of flavonoids, can modify cardiovascular risk factors. We aimed to evaluate the impact of CGJ on smoking-induced impairment of inflammatory and fibrinolytic status in healthy smokers. METHODS: We studied the effect of a 2-week oral treatment with CGJ in 26 healthy smokers on three occasions (day 0: baseline, day 7 and day 14) in a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm) and 20 min after (Sm20) cigarette smoking. Serum levels of intercellular adhesion molecule-1 (sICAM-1) and plasminogen activator inhibitor 1 (PAI-1) were measured as markers of inflammatory and fibrinolytic status, respectively. RESULTS: Treatment with CGJ reduced pSm sICAM-1 levels (p < 0.001), while placebo had no impact on ICAM-1 levels (p = 0.31). Moreover, treatment with CGJ decreased pSm values of PAI-1 (p < 0.001) while placebo had no impact on PAI-1 levels (p = 0.89). Smoking induced an elevation in PAI-1 levels after smoking compared to pro-smoking levels in all study days and in both arms (CGJ and placebo) of the study (p < 0.001 for all). Interestingly, CGJ compared to placebo, attenuated the acute smoking increase in sICAM-1 and PAI-1 levels (p < 0.001 and p = 0.005 respectively). CONCLUSIONS: CGJ consumption improved inflammatory and fibrinolytic status in healthy smokers and attenuated acute smoking induced increase in ICAM-1 and PAI-1 levels. These findings shed further light on the favorable effects of flavonoids in cardiovascular health.

Omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect in adults with metabolic syndrome.

OBJECTIVES: Metabolic syndrome (MetS) is associated with adverse cardiovascular events, and impaired vascular function. In this study we evaluated the effects of omega-3 polyunsaturated fatty acids (PUFAs) supplementation on vascular function, inflammatory and fibrinolytic process in subjects with MetS. METHODS: We studied the effect of a 12 weeks oral treatment with 2 g/day of omega-3 PUFAs in 29 (15 male) subjects (mean age 44 ± 12 years) with MetS on three occasions (day0: baseline, day 28 and day 84). The study was carried out on two separate arms (PUFAs and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. The diagnosis of MetS was based on the guidelines of Adult Treatment Panel III definition. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness. Serum levels of interleukin-6(IL-6) and plasminogen activator inhibitor-1(PAI-1) were measured by ELISA. RESULTS: Treatment with PUFAs resulted in a significant improvement from day 0 to 28 and 84 in FMD and PWV (p < 0.001 for all). Nevertheless, treatment with placebo resulted in no significant changes in FMD (p = 0.63) and PWV (p = 0.17). Moreover, PUFAs treatment, compared to placebo, decreased IL-6 levels (p = 0.03) and increased PAI-1 levels (p = 0.03). Finally, treatment with PUFAs resulted in a significant decrease in fasting triglyceride levels from day 0 to 28 and 84 (p < 0.001) and in serum total cholesterol levels (p < 0.001). CONCLUSIONS: In subjects with MetS, treatment with omega-3 PUFAs improved endothelial function and arterial stiffness with a parallel antiinflammatory effect.

Consumption of a boiled Greek type of coffee is associated with improved endothelial function: the Ikaria study.

OBJECTIVE: The association of coffee consumption with cardiovascular disease remains controversial. Endothelial function is associated with cardiovascular risk. We examined the association between chronic coffee consumption and endothelium function in elderly inhabitants of the island of Ikaria. METHODS: The analysis was conducted on 142 elderly subjects (aged 66-91 years) of the Ikaria Study. Endothelial function was evaluated by ultrasound measurement of flow-mediated dilation (FMD). Coffee consumption was evaluated based on a food frequency questionnaire and was categorized as 'low' (< 200 ml/day), 'moderate' (200-450 ml/day), or 'high' (> 450 ml/day). RESULTS: From the subjects included in the study, 87% consumed a boiled Greek type of coffee. Moreover, 40% had a 'low', 48% a 'moderate' and 13% a 'high' daily coffee consumption. There was a linear increase in FMD according to coffee consumption ('low': 4.33 ± 2.51% vs 'moderate': 5.39 ± 3.09% vs 'high': 6.47 ± 2.72%; p = 0.032). Moreover, subjects consuming mainly a boiled Greek type of coffee had a significantly higher FMD compared with those consuming other types of coffee beverages (p = 0.035). CONCLUSIONS: Chronic coffee consumption is associated with improved endothelial function in elderly subjects, providing a new connection between nutrition and vascular health.

Effects of Ω-3 fatty acids on endothelial function, arterial wall properties, inflammatory and fibrinolytic status in smokers: a cross over study.

BACKGROUND: Smoking is associated with endothelial dysfunction and arterial stiffness. Supplementation of Ω-3 PUFAs is associated with better prognosis. Aim of this study was to evaluate the effects of Ω-3 polyunsaturated fatty acids (PUFAs) supplementation on smoking-induced impairment of arterial function. METHODS: We studied the effect of a 12 weeks oral treatment with 2gr/day of Ω-3 PUFAs in 20 healthy smokers on three occasions (day 0:baseline, day 28 and day 84). The study was carried out on two separate arms (Ω-3 fatty acids and placebo), according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before (pSm), immediately and 20min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD) of the brachial artery. Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) as a measure of arterial wave reflections. Circulating levels of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6) and plasminogen activator inhibitor-1 (PAI-1) were measured. RESULTS: Compared with placebo, Ω-3 PUFAs treatment resulted in a significant improvement in pSm values of FMD (p<0.05), AIx (p<0.001) and PWV (p<0.01). Although, acute cigarette smoking decreased FMD and caused an increase in AIx and PWV, Ω-3 PUFAs treatment blunted the acute smoking-induced impairment of FMD (p<0.001), AIx (p<0.05) and PWV (p<0.05) and significantly decreased levels of TNFα (p<0.05) and IL-6 (p=0.01) and increased levels of PAI-1 (p=0.05). CONCLUSIONS: Ω-3 PUFAs improved endothelial function and the elastic properties of the arterial tree in healthy smokers, with a parallel anti-inflammatory effect.

The impact of oral L-arginine supplementation on acute smoking-induced endothelial injury and arterial performance.

BACKGROUND: Smoking is associated with endothelial dysfunction and increased inflammatory status. The amino acid L-arginine, improves endothelial function in patients with cardiovascular risk factors. We investigated the effect of L-arginine on vascular function and inflammatory process in healthy smokers at rest and after acute smoking. METHODS: We studied the effect of L-arginine and/or placebo in 12 healthy young smokers on three occasions (day 0, day 1, and day 3). The study was carried out on two separate arms, one with L-arginine (3 x 7 g/day) and one with placebo, according to a randomized, placebo-controlled, double-blind, cross-over design. Measurements were carried out before, immediately after, and 20 min after cigarette smoking. Endothelial function was evaluated by flow-mediated dilation (FMD). Carotid-femoral pulse wave velocity (PWV) was measured as an index of aortic stiffness and augmentation index (AIx) and as a measure of arterial wave reflections. Serum soluble intercellular adhesion molecule-1 (sICAM-1) was measured. RESULTS: Compared to placebo, L-arginine improved FMD (P < 0.01 at day 1 and P < 0.05 at day 3). L-Arginine reduced PWV and AIx at both days 1 and 3 (P < 0.05 vs. baseline). L-Arginine blunted the acute smoking-induced increase of AIx at both day 1 (P < 0.05) and day 3 (P < 0.01), and prevented the smoking-induced elevation of PWV at day 3 (P < 0.05). Importantly, L-arginine reduced sICAM-1 at days 1 and 3 (P < 0.05 for both vs. baseline). CONCLUSIONS: Oral L-arginine improves endothelial function and vascular elastic properties of the arterial tree during the acute phase of smoking, an effect accompanied by reduced sICAM-1 levels in these subjects.

L-Arginine, the substrate for NO synthesis: an alternative treatment for premature atherosclerosis?

L-Arginine is the substrate of endothelial nitric oxide synthase (eNOS) and the main precursor of nitric oxide (NO) in the vascular endothelium. L-Arginine improves endothelial function in patients with hypercholesterolemia, hypertension and smokers, while its role in diabetes remains unclear. Oral supplementation of L-arginine leads to a significant improvement of endothelium-dependent forearm vasodilation in hypercholesterolemic patients, while intravenous infusion of L-arginine improves endothelial function in healthy smokers. L-Arginine has anti-hypertensive properties, although its effects on endothelial function in hypertensive patients needs further evaluation. In conclusion, L-arginine administration may be useful in patients with premature atherosclerosis.