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Cardiovascular disease (CVD) still being the most common cause of death in worldwide. In spite of development of new lipid-lowering therapies which optimize low-density lipoprotein cholesterol (LDL-c) levels, recurrence of CVD events implies addressing factors related with residual cardiovascular (CV) risk. The key determinants of residual CV risk include triglyceride-rich lipoproteins (TRLs) and remnant cholesterol (RC), lipoprotein(a) [Lp(a)] and inflammation including its biochemical markers such as high sensitivity C reactive protein (hs-CRP). On the other hand, unhealthy lifestyle habits, environmental pollution, residual thrombotic risk and the residual metabolic risk determined by obesity and type 2 diabetes (T2D) have a specific weight in the residual CV risk. New pharmacologic therapies and pathways are being explored such as inhibition of apolipoprotein C-III (apoC-III) and angiopoietin-related protein 3 (ANGPTL3) in order to explore if a reduction in TRLs and RC reduce CVD events. Therapeutic target of inflammation plays an attractive way to reduce the atherosclerotic process and to date, approved therapies as colchicine plays a beneficial effect in chronic inflammation and residual CV risk. Lp(a) constitutes one of the most residual CV risk factor due to linkage with CVD and aortic valve stenosis. New and hopeful treatments including antisense oligonucleotides (ASO) and small-interfering ribonucleic acid (siRNA) which interfere in LP(a) codification have been developed to achieve an adequate control in Lp(a) levels. This review points out the paradigms of residual CV risk, discus how we should manage their features and summarize the different therapies targeting each residual CV risk factor., Competing Interests: Declaration of Competing Interest F.G-D has given talks, attended conferences, and participated in trials sponsored by Ferrer, Esteve, Boehringer Ingelheim, Eli Lilly and Company, Daiichi Sankyo, Amgen, Viatris and Sanofi. M.R-C has given talks, attended conferences, and participated in trials sponsored by Astra-Zeneca, Boehringer Ingelheim, Eli Lilly and Company, Menarini and Rovi. N.K has given talks, attended conferences and participated in trials sponsored by Amgen, Astra Zeneca, Boehringer Ingelheim, Elpen, Libytec, Novartis, Novo Nordisk, Sanofi and Viatrix. J.D-L has given talks and participated in trials sponsored by Ferrer, Novo-Nordisk, Boehringer Ingelheim, Esteve, and Viatris. P.P-M has given talks and participated in trials sponsored by Ferrer, Novo-Nordisk, Boehringer Ingelheim, Amgen, Daiichi Sankyo, Esteve, and Viatris., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

One of the newly recognized types of cell death is ferroptosis which is related to the accumulation of iron and lipid-reactive oxygen species. Ferroptosis is considered a programmed cell death with a different mechanism from apoptosis, necrosis, and autophagy. Emerging evidence suggests that ferroptosis may occur in the context of cardiovascular disease (CVD), cancer, neurodegenerative diseases, and non-alcoholic fatty liver disease (NAFLD). Statins are the first-line therapy for dyslipidemia. The suppression of the HMG-CoA reductase by statins leads to decreased expression of glutathione peroxidase 4 (GPX4), a key regulator of lipid peroxidation, which in turn results in lipid ROS production and induction of ferroptosis. Experimental data suggest that statins may act as anti-cancer drugs by enhancing tumor cells' ferroptosis. In contrast, statins have also been reported to mitigate ferroptosis in animal models of myocardial ischemia-reperfusion and heart failure. This mini-review presents statin effects on the ferroptosis pathway, based on up-to-date in vivo and in vitro research. Furthermore, the potential impact of these effects on cardiometabolic diseases (e.g., CVD and NAFLD) and cancer is briefly discussed. Overall, there is a need for future studies focusing on statin-induced changes in ferroptosis as a therapeutic approach to such diseases., Competing Interests: Declaration of competing interest Nothing to declare in relation to this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Non-Alcoholic Fatty Liver Disease (NAFLD) is a common condition affecting around 10-25% of the general adult population, 15% of children, and even > 50% of individuals who have type 2 diabetes mellitus. It is a major cause of liver-related morbidity, and cardiovascular (CV) mortality is a common cause of death. In addition to being the initial step of irreversible alterations of the liver parenchyma causing cirrhosis, about 1/6 of those who develop NASH are at risk also developing CV disease (CVD). More recently the acronym MAFLD (Metabolic Associated Fatty Liver Disease) has been preferred by many European and US specialists, providing a clearer message on the metabolic etiology of the disease. The suggestions for the management of NAFLD are like those recommended by guidelines for CVD prevention. In this context, the general approach is to prescribe physical activity and dietary changes the effect weight loss. Lifestyle change in the NAFLD patient has been supplemented in some by the use of nutraceuticals, but the evidence based for these remains uncertain. The aim of this Position Paper was to summarize the clinical evidence relating to the effect of nutraceuticals on NAFLD-related parameters. Our reading of the data is that whilst many nutraceuticals have been studied in relation to NAFLD, none have sufficient evidence to recommend their routine use; robust trials are required to appropriately address efficacy and safety., Competing Interests: Declaration of Competing Interest Manfredi Rizzo: speakers bureau: Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; consultant to Amgen, Astra Zeneca, Boehringer Ingelheim, Eli Lilly, Meda, Mylan, Merck Sharp & Dohme, Novo Nordisk, Roche Diagnostics, Sanofi, and Servier; Medical and Scientific Advisor, Europe East and South at Novo Nordisk; Peter E. Penson has received honoraria and/or travel reimbursement for events sponsored by AKCEA, Amgen, AMRYT, Link Medical, Mylan, Napp, Sanofi; Niki Katsiki; Dimitri P. Mikhailidis has given talks, acted as a consultant or attended conferences sponsored by Amgen and Novo Nordisk; Peter P. Toth: speakers bureau: Amgen, Esperion, Kowa, Merck, Novo-Nordisk; consultant to Amarin, bio89, Kowa, Merck, Resverlogix, Theravance; Maciej Banach: speakers bureau: Amgen, Herbapol, Kogen, KRKA, Polpharma, Mylan/Viatris, Novartis, Novo-Nordisk, Sanofi-Aventis, Teva, Zentiva; consultant to Amgen, Daichii Sankyo, Esperion, Freia Pharmaceuticals, Novartis, Novo-Nordisk, Polfarmex, Sanofi-Aventis; Grants from Amgen, Mylan/Viatris, Sanofi and Valeant; CMO at Nomi Biotech Corporation Ltd.; all other authors have no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Purpose of Review: Obesity is a chronic disease, a major public health problem due to its association with non-communicable diseases and all-cause mortality. Indeed, people with obesity are at increased risk for a variety of obesity-related disorders including hypertension, dyslipidemia, type 2 diabetes mellitus, cardiovascular disease, and several cancers. Many popular diets with very different macronutrient composition, including the Mediterranean diet (MD), have been used, proposed, and studied for prevention and management of obesity. In particular, MD has been the subject of countless studies over the years and now boasts a large body of scientific literature. In this review, we aimed to update current knowledge by summarizing the most recent evidence on the effect of MD on obesity and obesity-related disorders., Recent Findings: The negative effects of obesity are partly reversed by substantial weight loss that can be achieved with MD, especially when low-calorie and in combination with adequate physical activity. In addition, the composition of MD has been correlated with an excellent effect on reducing dyslipidemia. It also positively modulates the gut microbiota and immune system, significantly decreasing inflammatory mediators, a common ground for many obesity-related disorders. People with obesity are at increased risk for a variety of medical disorders including hypertension, dyslipidemia, type 2 diabetes mellitus, and cardiovascular disease. Therefore, there is an inevitable need for measures to manage obesity and its related disorders. At this point, MD has been proposed as a valuable nutritional intervention. It is characterized by a high consumption of vegetables, fruit, nuts, cereals, whole grains, and extra virgin olive oil, as well as a moderate consumption of fish and poultry, and a limited intake of sweets, red meat, and dairy products. MD proves to be the healthiest dietary pattern available to tackle obesity and prevent several non-communicable diseases, including cardiovascular disease and type 2 diabetes., (© 2022. The Author(s).)

The risk of atherosclerotic cardiovascular disease (ASCVD) is strongly related to lifetime exposure to low-density lipoprotein (LDL)-cholesterol in longitudinal studies. Lipid-lowering therapy (using statins, ezetimibe and PCSK9 inhibitors) substantially ameliorates the risk and is associated with long-term reduction in cardiovascular (CV) events. The robust evidence supporting these therapies supports their continued (and expanding) role in risk reduction. In addition to these 'conventional' therapeutics, while waiting for other innovative therapies, growing evidence supports the use of a range of 'nutraceuticals' (constituents of food prepared as pharmaceutical formulations) including preparations of red yeast rice (RYR), the product of yeast (Monascus purpureus) grown on rice, which is a constituent of food and is used in traditional Chinese medicine. The major active ingredient, monacolin K, is chemically identical to lovastatin. RYR preparations have been demonstrated to be safe and effective in reducing LDL-C, and CV events. However, surprisingly, RYR has received relatively little attention in international guidelines - and conventional drugs with the strongest evidence for event reduction should always be preferred in clinical practice. Nevertheless, the absence of recommendations relating to RYR may preclude the use of a product which may have clinical utility in particular groups of patients (who may anyway self-prescribe this product), what in the consequence might help to reduce population CV risk. This Position Paper of the International Lipid Expert Panel (ILEP) will use the best available evidence to give advice on the use of red-yeast rice in clinical practice., Competing Interests: Conflict of Interest NA., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Microvascular dysfunction is the key element in the pathogenesis of systemic sclerosis (SSc), whereas the contribution of large and medium size vessel abnormalities is yet to be established. The aim of the present study is to assess the association between micro- and macrovascular function by utilizing a broad spectrum of assessments of vascular performance., Methods: We included consecutive, consenting SSc patients who underwent nailfold video capillaroscopy (NVC) for microcirculation evaluation. Peripheral and central systolic and diastolic blood pressure, carotid intima-media thickness (cIMT), aortic augmentation index (AIx) corrected for a heart rate of 75 beats per minute (AIx-75), and carotid-femoral pulse wave velocity (PWV) were also performed to assess macrovascular function. Cardiovascular risk disease (CVD) algorithms were also calculated and included in the analysis., Results: A total of 81 patients (6 males) were studied with mean age 55.44 ± 13.40 years. Reduced capillary density was inversely correlated with arterial stiffness (Alx-75) and augmentation pressure (r =  - 0.262, p = 0.018, and r =  - 0.249, p = 0.025 respectively). Alx was significantly lower in the early compared to late pattern (28.24 ± 11.75 vs 35.63 ± 10.47, p = 0.036). A significant trend was found among NVC patterns with Alx-75 values being higher with the progression of microangiopathy towards the "late" group (26.36 ± 10.90 vs 30.81 ± 11.59 vs 35.21 ± 7.90, p = 0.027 for trend). Similarly, Framingham risk score and Atherosclerotic Cardiovascular Disease score were progressively higher across the worsening NVC patterns (4.10 ± 4.13 vs 2.99 ± 2.72 vs 6.36 ± 5.65, p = 0.023, and 6.99 ± 7.18 vs 5.63 ± 4.41 vs 12.09 ± 9.90, p = 0.019, respectively, for trends). Finally, QRISK3 (10-year cardiovascular disease risk) and ASCVD (Atherosclerotic Cardiovascular Disease) scores were inversely correlated with the number of capillaries (r =  - 0.231, p = 0.048, and r =  - 0.260, p = 0.038 respectively)., Conclusion: These data suggest that CVD risk scores and macrovascular parameters are strongly correlated with microvasculopathy in patients with SSc. Key Points • Microangiopathy is the hallmark of SSc, but the relationship between subclinical atherosclerosis and small vessel disease remains unknown. • Arterial stiffening and CVD risk scores are positively associated with the degree of progression of peripheral microvasculopathy assessed with NVC. • The results of the study suggest an association between NVC abnormalities and higher CVD risk in SSc patients., (© 2021. International League of Associations for Rheumatology (ILAR).)

Limited data suggests possible gender-specific association between serum uric acid (SUA) and cardiovascular disease (CVD) incidence. The aim of the present analysis was to evaluate the association between SUA levels and 10-year CVD incidence (2002-2012) in the ATTICA study participants. Overall, 1687 apparently healthy volunteers, with SUA measurements, residing in the greater metropolitan Athens area (Greece), were included. Multivariable Cox-regression models were used to estimate the hazard ratios for SUA in relation to 10-year CVD incidence. Receiver operating curve analysis was conducted to detect optimal SUA cut-off values. Participants in the 2nd and 3rd SUA tertile had 29 and 73% higher 10-year CVD incidence compared with those in the 1st tertile ( p < 0.001). In gender-specific analysis, only in women SUA was independently associated with CVD incidence; women in the 3rd SUA tertile had 79% greater 10-year CVD event risk compared to their 1st tertile counterparts. Obese in the 3rd SUA tertile had 2-times higher CVD incidence compared to those in the 1st tertile. Similar findings were observed in metabolically healthy (vs. unhealthy) and metabolically healthy obese. SUA thresholds best predicting 10-year CVD incidence was 5.05 and 4.15 mg/dL (0.30 and 0.25 mmol/L) in men and women, respectively. In conclusion, increased SUA levels were independently related to 10-year CVD event rate in women, obese and metabolically healthy individuals. SUA could predict 10-year CVD incidence even at low levels. Further studies are warranted to identify SUA cut-off values that may improve the detection of individuals at higher CVD risk in clinical practice., Competing Interests: NK has given talks, attended conferences and participated in trials sponsored by Angelini, Astra Zeneca, Bausch Health, Boehringer Ingelheim, Elpen, Mylan, Novo Nordisk, Sanofi and Servier. DPM has given talks and attended conferences sponsored by Amgen, Novo Nordisk and Libytec. CC has given talks sponsored by Astra Zeneca, Boehringer Ingelheim, Elpen, Sanofi and Roche Diagnostics. MK, DBP, CP declare no conflict of interest. MK and DBP are the Guest Editors of this journal, given their roles as Guest Editors, had no involvement in the peer-review of this article and had no access to information regarding its peer-review., (© 2021 The Author(s). Published by IMR Press.)

Purpose of Review: Hypercholesterolemia is a major risk factor for cardiovascular diseases. Administration of statins represents the cornerstone of the prevention and treatment of cardiovascular disease, with demonstrated long-term safety and efficacy. This review aims to revisit statin intolerance mechanisms, as well as to discuss new data and therapeutic options., Recent Findings: Although statins are well tolerated, myopathy and other adverse effects are a challenging problem, being the main reason for poor adherence to treatment and failure in lowering cardiovascular risk. Statin intolerance is the subject of ongoing research, as these drugs are widely used. There are alternative options of treatment if statin intolerance emerges, that is, lowering the dose, intermittent dosages, and/or combining a statin with other drugs, such as ezetimibe, proprotein convertase subtilisin-kexin type 9 inhibitors, bempedoic acid, angiopoietin-like 3 protein inhibitors, and nutraceuticals. If even the lowest statin dose cannot be tolerated, a nonstatin regimen is recommended to reduce LDL cholesterol levels., Summary: Treatment options in statin intolerance include combinations of a lower dose of statin with other lipid-lowering regimens or only nonstatin drugs in the presence of complete intolerance. New hypolipidemic therapies that address gene editing are emerging, and may prove useful in the future., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The present narrative review focuses on the up-to-date clinical data on the correlations between olive oil consumption and cardiovascular (CV) diseases (i.e., CHD, stroke, and peripheral artery disease)., Recent Findings: Olive oil contains monounsaturated fats, several antioxidant phenols, and other micronutrients that mediate CV-protective effects via improvements in oxidative stress, endothelial dysfunction, inflammation, thrombosis, blood pressure, and lipid and carbohydrate metabolism. High consumption of olive oil, and in particular the extra-virgin, which is rich in phenolic antioxidants, has been suggested to prevent against coronary heart disease (CHD). The olive oil-induced cardioprotection was further supported by the findings of a very recent analysis of 2 large US prospective cohort studies showing that a higher olive oil intake was related to a lower risk of CV morbidity and mortality after 24 years of follow-up and that replacement of dairy fat, margarine, butter, or mayonnaise with the equivalent amount of olive oil significantly reduced CV risk. There is evidence for associations between olive oil consumption and lower risk for CV diseases. Both health policy makers and physicians should be aware of these associations and thus promote the intake of olive oil in both primary and secondary prevention settings to minimize individual's CV risk.

Context: Elevated levels of lipoprotein (a) [Lp(a)] are an independent risk factor for premature cardiovascular disease (CVD). Flaxseed (Linum usitiatissimum L.) is a rich source of alpha-linolenic acid, phytoestrogens, and lignans and has been shown to improve several cardiovascular risk factors, although the overall effect on Lp(a) is unknown., Objective: The study intended to assess the impact of flaxseed on plasma Lp(a) levels through a meta-analysis of the results of randomized controlled trials (RCTs)., Design: PubMed-Medline, Scopus, Embase, and Google Scholar databases were searched using the following search terms in titles and abstracts: flaxseed OR Linum usitatissimum OR lignin OR linseed AND lipoprotein(a) OR lipoprotein (a) OR Lp(a) OR Lp (a)., Results: Of the 48 RCTs, 6 were eligible for inclusion, and the results suggested a significant decrease in plasma Lp(a) levels-standardized mean difference: -0.22, 95% confidence interval: -0.41 to -0.04, P = .017-following supplementation with flaxseed-containing products., Conclusions: This finding highlights the potential clinical significance of flaxseed supplementation for patients who are at risk of a high residual CVD despite intensive statin therapy, patients with hyperliporoteinemia(a), and patients who prefer natural remedies for CVD prevention in the context of a healthy lifestyle. Further RCTs are needed to establish the role of flaxseed-containing products on lowering Lp(a).

Mitochondria provide energy to the cell during aerobic respiration by supplying ~95% of the adenosine triphosphate (ATP) molecules via oxidative phosphorylation. These organelles have various other functions, all carried out by numerous proteins, with the majority of them being encoded by nuclear DNA (nDNA). Mitochondria occupy ~1/3 of the volume of myocardial cells in adults, and function at levels of high-efficiency to promptly meet the energy requirements of the myocardial contractile units. Mitochondria have their own DNA (mtDNA), which contains 37 genes and is maternally inherited. Over the last several years, a variety of functions of these organelles have been discovered and this has led to a growing interest in their involvement in various diseases, including cardiovascular (CV) diseases. Mitochondrial dysfunction relates to the status where mitochondria cannot meet the demands of a cell for ATP and there is an enhanced formation of reactive-oxygen species. This dysfunction may occur as a result of mtDNA and/or nDNA mutations, but also as a response to aging and various disease and environmental stresses, leading to the development of cardiomyopathies and other CV diseases. Designing mitochondria-targeted therapeutic strategies aiming to maintain or restore mitochondrial function has been a great challenge as a result of variable responses according to the etiology of the disorder. There have been several preclinical data on such therapies, but clinical studies are scarce. A major challenge relates to the techniques needed to eclectically deliver the therapeutic agents to cardiac tissues and to damaged mitochondria for successful clinical outcomes. All these issues and progress made over the last several years are herein reviewed., (© 2020 Wiley Periodicals LLC.)

Hyperuricemia, has been traditionally related to nephrolithiasis and gout. However, it has also been associated with the development of type 2 diabetes mellitus (T2DM) and cardiometabolic and cardiovascular diseases. Pathophysiologically, elevated serum uric acid (SUA) levels may be associated with abnormal lipid and glucose metabolism. In this narrative review, we consider the associations between hyperuricemia, hyperglycemia, atherosclerosis and thrombosis. Furthermore, we comment on the available evidence linking elevated SUA levels with the incidence and outcomes of coronary heart disease, stroke, peripheral artery disease and non-alcoholic fatty liver in subjects with T2DM. The effects of antidiabetic drugs (e.g. metformin, pioglitazone, sulfonylureas, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium-glucose cotransporter 2 inhibitors and insulin) on SUA concentrations are also reviewed., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiovascular disease (CVD) remains the first cause of mortality in Western countries. Among cardiometabolic risk factors, dyslipidemia, and especially high low-density lipoprotein cholesterol (LDL-C) concentrations, have been extensively linked to the development and progression of atherosclerosis and to CVD events. Recent evidence has shown that the prevention of unhealthy dietary habits and sedentarism is crucial in the management of dyslipidemia. In this sense, a number of scientific societies recommend the adherence to certain healthy dietary patterns (DPs), such as the Mediterranean diet (MedDiet), the Dietary Approaches to Stop Hypertension (DASH), the Portfolio diet, the Vegetarian diet, the Nordic diet and low-carbohydrate diets, as well as increased physical activity between others. This nutritional and lifestyle advice could be adopted by government bodies and implemented in different health programs as a reliable way of providing health-care professionals with efficient tools to manage cardiometabolic risk factors and thus, prevent CVD. In this narrative review, we will discuss recent data about the effects of nutrition on dyslipidemia, mainly focusing on high LDL-C concentrations and other lipid particles related to atherogenic dyslipidemia such as triglycerides (TG) and non-high density lipoprotein cholesterol (non-HDL-C), that are related to CVD. On the other hand, we also comment on other cardiometabolic risk factors such as type 2 diabetes mellitus (T2DM), high blood pressure (HBP), inflammation and endothelial dysfunction. This review includes food groups as well as different healthy DPs.

Introduction: The links between flavonoid intake and mortality were previously evaluated in epidemiological studies. The aim of the present study was to perform a systematic review and meta-analysis of cohort studies evaluating the link of flavonoid consumption with total and cause-specific mortality. Methods: Prospective cohort studies reporting flavonoid intake and mortality data published up to 30th April 2019 (without language restriction) were searched using PubMed, Scopus and EMBASE database. Generic inverse variance methods and random effects models were used to synthesize pooled and quantitative data. Sensitivity analysis was also performed by a leave-one-out method. Results: Overall, 16 articles met the inclusion criteria (nine studies were performed in Europe, five in the USA, one in Asia and one in Oceania); a total of 462,194 participants (all adults aged >19 years) with 23,473 mortality cases were included in the final analysis. The duration of follow-up ranged from 4.8 to 28 years. Most of the studies assessed flavonoid intake using food frequency questionnaires, whereas four studies used interviews and 1 study used 4-day food records. The meta-analysis showed that flavonoid consumption was inversely and significantly associated with total (relative risk (RR): 0.87, 95% confidence interval (CI) = 0.77-0.99) and cardiovascular disease mortality risk (RR: 0.85, 95%CI = 0.75-0.97), but not cancer (0.86, 95%CI = 0.65-1.14) mortality risk. These findings remained robust in sensitivity analyses. Conclusions: The present findings highlight the potential protective role of flavonoids against total and cause-specific mortality. These results support the recommendations for flavonoid-rich foods intake to prevent chronic diseases.

Background: Insulin response to diet might predict the risk of mortality; however, the evidence is limited. We prospectively evaluated the link between the dietary hyperinsulinemia index (DHI) and dietary insulin resistance index (DIRI) with all-cause and cause-specific (cardiovascular disease [CVD] and cancer) mortality. Methods: The National Health and Nutrition Examination Survey (1999-2010) database was used. Vital status through December 31, 2011, was ascertained. Stepwise linear regression models consisted of 39 macro/micronutrients applied, and fasting plasma C-peptide for the DHI and triglyceride/high-density lipoprotein cholesterol ratio (TG/HDL-C) for the DIRI were used. Adjusted Cox regression (followed by propensity score matching) was performed to determine the hazard ratios (HRs) and 95% confidence interval (95% CIs). Results: Overall, 22,246 participants were included (mean age = 47.8 years; 48.9% men). There was a significant increasing risk of mortality across the quartiles of DHI, i.e., participants with a highest score of DHI (Q4) had a greater risk of all-cause (HR: 1.21, 95% CI: 1.17-1.26), CVD (HR: 1.17, 95% CI: 1.07-1.29), and cancer (HR: 1.15, 95% CI: 1.08-1.23) mortality compared with the first quartile (Q1; p  < 0.001 for all comparisons). Similarly, participants in the highest DIRI quartile (Q4) had 23% and 31% higher risk of all-cause and CVD mortality, respectively, compared with Q1, while the association between cancer mortality and DIRI was non-significant (HR: 0.88, 95% CI: 0.35-2.61). Conclusions: These findings highlight, for the first time, the detrimental role (association) of insulinemia and insulin resistance potential of diet on all-cause and cause-specific mortality. Our findings support the role of C-peptide and TG/HDL-C ratio as cost-effective and practical biomarkers in clinical settings. These results need to be confirmed to establish their implications.

Proton pump inhibitors (PPIs) are among the most widely prescribed agents, either for treatment or prophylaxis of gastrointestinal (GI) disease, that are often administered for prolonged or chronic use. Patients with cardiovascular (CV) disease frequently receive PPIs for prophylaxis against GI bleeding due to common use of antithrombotic drugs. Over the last several years there is a growing number of reports associating chronic PPI use with a variety of serious CV and non-CV adverse effects. In this context, PPI use has been independently associated with an increased risk of CV morbidity (myocardial infarction, stroke, other CV events) and mortality. However, the critique remains that these data do not largely derive from randomized controlled trials. On the other hand, in certain conditions, the benefits of PPIs may outweigh the risks of adverse CV effects. As the indications for prolonged, particularly lifelong, prophylactic use of PPIs are not compelling and in the light of evidence of serious CV and other adverse effects, clinicians have to reconsider such long-term use of these drugs. Importantly, histamine 2 blockers have not been found to be associated with increased CV risk and thus may be an alternative therapeutic option in certain patients. These issues are amply discussed together with the potential mechanisms of these pleiotropic and off-target effects of PPIs, which are also depicted in an illustrative schema; data are also presented on differential effects of specific agents involved, alternative modes of therapy available, and relevant current guidelines on this issue., Competing Interests: Declaration of Competing Interest AAM, TAM, HM and ASM declare no conflict of interest. NK has given talks, attended conferences and participated in trials sponsored by Amgen, Angelini, Astra Zeneca, Bausch Health, Boehringer Ingelheim, Elpen, Mylan, NovoNordisk, Sanofi, Servier and WinMedica., (Copyright © 2019 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

Arterial stiffness (AS) is considered an independent predictor of cardiovascular disease (CVD) events. Among lipid lowering drugs, statins have a beneficial effect on AS, independent of their hypolipidaemic effect. Based on 3 meta-analyses and other studies, this effect is compound- and doserelated. Potent statins at high doses are more effective than less powerful statins. Ezetimibe (± statin) also seems to decrease AS in patients with dyslipidaemia. Fibrates have no effect on AS. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have data that beneficially affect all AS risk factors, suggesting a beneficial effect on artery compliance. However, there is no direct measurement of their effect on AS indices. In patients with dyslipidaemia, prescribing high dose statins (± ezetimibe) will not only decrease low-density lipoprotein cholesterol levels but also improve AS (in addition to other effects). This effect on AS may contribute to the observed reduction in vascular events., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cardiovascular disease (CVD) remains the major cause of death and disability worldwide, and residual risk after implementing all current therapies is still high. In this context, the latest (2016) European Cardiology Society/European Atherosclerosis Society guidelines recommend that triglyceride (TG)-lowering drugs should be used in high-risk patients with TGs levels >2.3 mmol/L (200 mg/dL), after lifestyle measures fail to lower them. After several neutral CVD outcome trials with n-3 fatty acids, the Reduction of Cardiovascular Events with EPA-Intervention Trial met its primary end point, that is, among patients with elevated TGs levels despite the use of statins, the risk of ischemic events, including cardiovascular death, was significantly lower in those who received 4 g of icosapent ethyl daily. In this review, we comment on the findings of previous and recently published randomized controlled CVD outcome trials assessing n-3 fatty acids supplementation. Both efficacy and safety, as well as future perspectives, are discussed.

Hypoglycaemia represents an important side effect of insulin therapy and insulin secretagogues. It can occur in both type 1 and type 2 diabetes mellitus patients. Also, some associations between hypoglycaemia and cardiovascular (CV) risk have been reported. Several mechanisms may be involved, including the sympathoadrenal system, hypokalaemia, endothelial dysfunction, coagulation, platelets, inflammation, atherothrombosis and impaired autonomic cardiac reflexes. This narrative review discusses the associations of hypoglycaemia with CV diseases, including coronary heart disease (CHD), cardiac arrhythmias, stroke, carotid disease and peripheral artery disease (PAD), as well as with dementia. Severe hypoglycaemia has been related to CHD, CV and all-cause mortality. Furthermore, there is evidence supporting an association between hypoglycaemia and cardiac arrhythmias, potentially predisposing to sudden death. The data linking hypoglycaemia with stroke, carotid disease and PAD is limited. Several factors may affect the hypoglycaemia-CV relationships, such as the definition of hypoglycaemia, patient characteristics, co-morbidities (including chronic kidney disease) and antidiabetic drug therapy. However, the association between hypoglycaemia and dementia is bilateral. Both the disorders are more common in the elderly; thus, glycaemic goals should be carefully selected in older patients. Further research is needed to elucidate the impact of hypoglycaemia on CV disease., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Little is known about the association between dietary choline intake and mortality. We evaluated the link between choline consumption and overall as well as cause-specific mortality by using both individual data and pooling prospective studies by meta-analysis and systematic review. Furthermore, adjusted means of cardiometabolic risk factors across choline intake quartiles were calculated. Data from the National Health and Nutrition Examination Survey (1999-2010) were collected. Adjusted Cox regression was performed to determine the risk ratio (RR) and 95 % CI, as well as random-effects models and generic inverse variance methods to synthesise quantitative and pooling data, followed by a leave-one-out method for sensitivity analysis. After adjustments, we found that individuals consuming more choline had worse lipid profile and glucose homeostasis, but lower C-reactive protein levels (P < 0·001 for all comparisons) with no significant differences in anthropometric parameters and blood pressure. Multivariable Cox regression models revealed that individuals in the highest quartile (Q4) of choline consumption had a greater risk of total (23 %), CVD (33 %) and stroke (30 %) mortality compared with the first quartile (Q1) (P < 0·001 for all comparison). These results were confirmed in a meta-analysis, showing that choline intake was positively and significantly associated with overall (RR 1·12, 95 % CI 1·08, 1·17, I2 = 2·9) and CVD (RR 1·28, 95 % CI 1·17, 1·39, I2 = 9·6) mortality risk. In contrast, the positive association between choline consumption and stroke mortality became non-significant (RR 1·18, 95 % CI 0·97, 1·43, P = 0·092, I2 = 1·1). Our findings shed light on the potential adverse effects of choline intake on selected cardiometabolic risk factors and mortality risk.

A growing interest has emerged in the beneficial effects of plant-based diets for the prevention of cardiovascular disease, diabetes and obesity. The Mediterranean diet, one of the most widely evaluated dietary patterns in scientific literature, includes in its nutrients two fluid foods: olive oil, as the main source of fats, and a low-to-moderate consumption of wine, mainly red, particularly during meals. Current mechanisms underlying the beneficial effects of the Mediterranean diet include a reduction in inflammatory and oxidative stress markers, improvement in lipid profile, insulin sensitivity and endothelial function, as well as antithrombotic properties. Most of these effects are attributable to bioactive ingredients including polyphenols, mono- and poly-unsaturated fatty acids. Polyphenols are a heterogeneous group of phytochemicals containing phenol rings. The principal classes of red wine polyphenols include flavonols (quercetin and myricetin), flavanols (catechin and epicatechin), anthocyanin and stilbenes (resveratrol). Olive oil has at least 30 phenolic compounds. Among them, the main are simple phenols (tyrosol and hydroxytyrosol), secoroids and lignans. The present narrative review focuses on phenols, part of red wine and virgin olive oil, discussing the evidence of their effects on lipids, blood pressure, atheromatous plaque and glucose metabolism.

Introduction : Cardiovascular disease (CVD) frequently co-exists with chronic kidney disease (CKD). Patients with concomitant CVD and CKD are at very high risk of CVD events. Areas covered : This narrative review discusses the use of hypolipidaemic drugs in patients with both CVD and CKD. Current guidelines are considered together with the evidence from randomised controlled clinical trials. Expert opinion : Statins are the first-line lipid-lowering therapy in patients with CVD and CKD. Some statins require dose adjustments based on renal function, whereas atorvastatin does not. Ezetimibe can be prescribed in patients with CVD and CKD, usually combined with a statin. According to current guidelines, statin±ezetimibe therapy should not be initiated, but should be continued, in dialysis-treated CKD patients. Fenofibrate (dose adjusted or contra-indicated according to renal function) and omega 3 fatty acids lower triglyceride levels; whether they also exert cardiorenal benefits in patients with CVD and CKD remains to be established. The use of proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors, cholesterol-reducing nutraceuticals, bempedoic acid and apabetalone in such patients should be investigated. Patients with concomitant CVD and CKD should be treated, in terms of lipid-lowering therapy, early and intensively to minimize their very high risk and possibly, progression of CKD.

Aims: Little is known about the long-term association between low-carbohydrate diets (LCDs) and mortality. We evaluated the link between LCD and overall or cause-specific mortality using both individual data and pooled prospective studies., Methods and Results: Data on diets from the National Health and Nutrition Examination Survey (NHANES; 1999-2010) were analysed. Multivariable Cox proportional hazards were applied to determine the hazard ratios and 95% confidence intervals (CIs) for mortality for each quartile of the LCD score, with the lowest quartile (Q1-with the highest carbohydrates intake) used as reference. We used adjusted Cox regression to determine the risk ratio (RR) and 95% CI, as well as random effects models and generic inverse variance methods to synthesize quantitative and pooled data, followed by a leave-one-out method for sensitivity analysis. Overall, 24 825 participants from NHANES study were included (mean follow-up 6.4 years). After adjustment, participants with the lowest carbohydrates intake (quartile 4 of LCD) had the highest risk of overall (32%), cardiovascular disease (CVD) (50%), cerebrovascular (51%), and cancer (36%) mortality. In the same model, the association between LCD and overall mortality was stronger in the non-obese (48%) than in the obese (19%) participants. Findings on pooled data of nine prospective cohort studies with 462 934 participants (mean follow-up 16.1 years) indicated a positive association between LCD and overall (RR 1.22, 95% CI 1.06-1.39, P < 0.001, I2 = 8.6), CVD (RR 1.13, 95% CI 1.02-1.24, P < 0.001, I2 = 11.2), and cancer mortality (RR 1.08, 95% CI 1.01-1.14, P = 0.02, I2 = 10.3). These findings were robust in sensitivity analyses., Conclusion: Our study suggests a potentially unfavourable association of LCD with overall and cause-specific mortality, based on both new analyses of an established cohort and by pooling previous cohort studies. Given the nature of the study, causality cannot be proven; we cannot rule out residual bias. Nevertheless, further studies are needed to extend these important findings, which if confirmed, may suggest a need to rethink recommendations for LCD in clinical practice., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2019. For permissions, please email: journals.permissions@oup.com.)

Gender differences in the pathophysiology of atherosclerosis, cardiovascular risk factors, and diagnosis of coronary artery disease and valvular heart disease are well known. Such differences have also been outlined in the management and outcomes after acute coronary syndromes and valvular repair. Regarding the atherosclerotic process, pathological experimental studies suggest that plaque composition and burden may differ by gender. Female gender is associated with worse outcomes in the case of ischemic heart disease and, compared with men, women are less likely to undergo interventional cardiac procedures and sustain worse outcomes. In the setting of valvular heart disease (VHD), transcatheter aortic valve implantation (TAVI) and percutaneous edge-to-edge mitral valve repair are now well-established procedures with high success rates. In women with moderate to severe aortic stenosis, subgroup analyses in TAVI trials have demonstrated gender-related differences suggesting female gender as beneficial in terms of short-, mid-, and long-term outcomes. Similarly, several studies reported different procedural challenges and outcomes in males and females following surgical and percutaneous mitral valve repair. These diverse findings emphasize the necessity to provide gender-specific analyses of interventional methods. This review highlights gender differences in the epidemiology, pathophysiology, treatment options and clinical outcomes of the conditions mentioned above., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background and Aims: We aimed to evaluate the link between inflammatory score [consisting of C-reactive protein (CRP) and white blood cells], serum uric acid (SUA) and atherogenic index of plasma (AIP) and the cardiovascular health (CVH) score., Methods: We used the cross-sectional National Health and Nutrition Examination Survey database. Statistical analyses accounted for the survey design and sample weights., Results: Overall, there were 23,004 participants (mean age = 47.2 years, 46.5% males). Participants with an ideal CVH level had the highest ratio of poverty to income (3.62%, p < 0.001), as well as lower levels of CRP, SUA and AIP (p < 0.001 for all comparisons). In adjusted linear regression, a significant negative association was observed between inflammatory score (β = -0.052, p < 0.001), SUA (β = -0.041, p < 0.001) and AIP (β = -0.039, p < 0.001) and CVH score, i.e. participants with a better (greater) CVH score had a lower inflammatory score. Results from adjusted logistic regression showed reduction in the likelihood of "high-risk atherosclerosis" (defined as AIP ≥0.21) [intermediate: odds ratio (OR) = 0.90, 95% confidence interval (CI):0.85-0.95, ideal: OR = 0.81, 95%CI: 0.74-0.88] and "high CVD risk" (defined as CRP ≥3 mg/l) [intermediate: OR = 0.86, 95%CI:0.73-0.98, ideal: OR = 0.82, 95%CI:0.69-0.95] across the categories of CVH., Conclusions: Our findings highlight that CVH metrics were associated with inflammatory score, SUA and AIP. Furthermore, participants with a better CVH score had a lower CVD risk. These results reinforce the importance of implementing healthy behaviours as proposed by the American Heart Association. If confirmed in clinical trials, this knowledge may have implications for CVD prevention and management., (Copyright © 2018. Published by Elsevier B.V.)

Background: Obesity frequently co-exists with type 2 diabetes mellitus (T2DM), leading to the socalled "diabesity epidemic". The metabolic syndrome (MetS), a cluster of central obesity, hypertension, dysglycemia, insulin resistance and/or atherogenic dyslipidemia, as well as non-alcoholic fatty liver disease (NAFLD), a hepatic manifestation of MetS, has been associated with increased cardiovascular disease (CVD), T2DM and chronic kidney disease (CKD) incidence. However, the association between obesity, MetS (including NAFLD) and diabetic microvascular complications is less evident., Methods: The present narrative review discusses the associations of obesity, MetS and NAFLD with diabetic kidney disease (DKD), diabetic retinopathy (DR) and diabetic peripheral neuropathy (DPN) as well as cardiac autonomic neuropathy (CAN). The available data on the effects of lifestyle measures and bariatric surgery on these diabetic complications are also briefly discussed., Results: Overall, both obesity and MetS have been related to DKD, DR and DPN, although conflicting results exist. Links between NAFLD and diabetic microvascular complications have also been reported but data are still limited. Lifestyle intervention and bariatric surgery may prevent the development and/or progression of these microvascular complications but more evidence is needed., Conclusion: Clinicians should be aware of the frequent co-existence of MetS and/or NAFLD in T2DM patients to prevent or treat these metabolic disorders, thus potentially minimizing the risk for both CVD and diabetic microvascular complications., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Transition to menopause is associated with an increase in cardiovascular disease (CVD) risk, mainly attributed to lipid and glucose metabolism dysregulation, as well as to body fat redistribution, leading to abdominal obesity. Indeed, epidemiological evidence suggests that both early menopause (EM, defined as age at menopause <45 years) and premature ovarian insufficiency (POI, defined as age at menopause <40 years) are associated with 1.5-2-fold increase in CVD risk. Menopausal hormone therapy (MHT) exerts a favorable effect on CVD risk factors (with subtle differences regarding oestrogen dose, route of administration, monotherapy or combination with progestogen and type of progestogen). Concerning CVD morbidity and mortality, most studies have shown a beneficial effect of MHT in women at early menopausal age (<10 years since the final menstrual period) or younger than 60 years. MHT is strongly recommended in women with EM and POI, as these women, if left untreated, are at risk of CVD, osteoporosis, dementia, depression and premature death. MHT has also a favorable benefit/ risk profile in perimenopausal and early postmenopausal women, provided that the patient is not at a high CVD risk (as assessed by 10-year calculation tools). Transdermal oestrogens have a lower risk of thrombosis compared with oral regimens. Concerning progestogens, natural progesterone and dydrogesterone have a neutral effect on CVD risk factors. In any case, the decision for MHT should be individualized, tailored according to the symptoms, patient preference and the risk of CVD, thrombotic episodes and breast cancer., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Psoriasis (Pso) is a chronic inflammatory immune-mediated skin disease associated with several comorbidities. Despite the growing number of studies providing evidence for the link between Pso and Cardiovascular (CV) disorders, there are still many unsolved questions, dealing with the role of the skin disease as an independent risk factor for CV events, the influence of Pso severity and duration on CV damage, the presence of Psoriatic Arthritis (PsA) as a predictor of increased CV mortality and morbidity and the detection of reliable clinical, laboratory and/or instrumental parameters to stratify CV risk in psoriatic patients. Moreover, it remains to clarify if the early treatment of the dermatosis may lower CV risk. In this paper we will try to provide answers to these queries in the light of the updated data of the literature., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Postprandial hypertriglyceridaemia, defined as an increase in plasma triglyceride-containing lipoproteins following a fat meal, is a potential risk predictor of atherosclerotic cardiovascular disease and other chronic diseases. Several non-modifiable factors (genetics, age, sex and menopausal status) and lifestyle factors (diet, physical activity, smoking status, obesity, alcohol and medication use) may influence postprandial hypertriglyceridaemia. This narrative review considers the studies published over the last decade that evaluated postprandial hypertriglyceridaemia. Additionally, the genetic determinants of postprandial plasma triglyceride levels, the types of meals for studying postprandial triglyceride response, and underlying conditions (e.g. familial dyslipidaemias, diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver and chronic kidney disease) that are associated with postprandial hypertriglyceridaemia are reviewed; therapeutic aspects are also considered., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Residual vascular risk exists despite the aggressive lowering of Low-Density Lipoprotein Cholesterol (LDL-C). A contributor to this residual risk may be elevated fasting, or non-fasting, levels of Triglyceride (TG)-rich lipoproteins. Therefore, there is a need to establish whethe a standardised Oral Fat Tolerance Test (OFTT) can improve atherosclerotic Cardiovascular (CV) Disease (ASCVD) risk prediction in addition to a fasting or non-fasting lipid profile. An expert panel considered the role of postprandial hypertriglyceridaemia (as represented by an OFTT) in predicting ASCVD. The panel updated its 2011 statement by considering new studies and various patient categories. The recommendations are based on expert opinion since no strict endpoint trials have been performed. Individuals with fasting TG concentration <1 mmol/L (89 mg/dL) commonly do not have an abnormal response to an OFTT. In contrast, those with fasting TG concentration ≥2 mmol/L (175 mg/dL) or nonfasting ≥2.3 mmol/L (200 mg/dL) will usually have an abnormal response. We recommend considering postprandial hypertriglyceridaemia testing when fasting TG concentrations and non-fasting TG concentrations are 1-2 mmol/L (89-175 mg/dL) and 1.3-2.3 mmol/L (115-200 mg/dL), respectively as an additional investigation for metabolic risk prediction along with other risk factors (obesity, current tobacco abuse, metabolic syndrome, hypertension, and diabetes mellitus). The panel proposes that an abnormal TG response to an OFTT (consisting of 75 g fat, 25 g carbohydrate and 10 g proteins) is >2.5 mmol/L (220 mg/dL). Postprandial hypertriglyceridaemia is an emerging factor that may contribute to residual CV risk. This possibility requires further research. A standardised OFTT will allow comparisons between investigational studies. We acknowledge that the OFTT will be mainly used for research to further clarify the role of TG in relation to CV risk. For routine practice, there is a considerable support for the use of a single non-fasting sample., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The past decade has witnessed considerable progress in the field of lipids. New drugs have been "rapidly" developed and some of these drugs have already been evaluated in event-based large trials. This evidence has led to the guidelines recommending new, more aggressive treatment goals for low-density lipoprotein cholesterol (LDL-C) levels. Although LDL-C remains the principal goal for cardiovascular disease (CVD) risk reduction, there has also been considerable interest in other lipid variables, such as high-density lipoprotein cholesterol, triglycerides, and lipoprotein(a). Statin intolerance is now considered a very important topic in daily clinical practice. This has resulted in more attention focusing on non-statin drugs [e.g., ezetimibe and proprotein convertase subtilisin/kexin 9 (PCSK9) inhibitors] and statin-related side effects. The latter mainly involve muscles, but there is also a need to consider other adverse effects associated with statin use (e.g., new onset diabetes). New specific areas of statin use have attracted interest. For example, statin-loading before procedures (e.g., coronary stenting), the prevention of stroke, and the treatment of non-alcoholic fatty liver disease (NAFLD). Statins will remain the most widely used drugs to treat dyslipidaemia and decrease CVD risk. However, we also need to briefly consider some other lipid-lowering drugs, including those that may become available in the future.

Leptin, an adipokine that is implicated in the control of food intake via appetite suppression, may also stimulate oxidative stress, inflammation, thrombosis, arterial stiffness, angiogenesis and atherogenesis. These leptin-induced effects may predispose to the development of cardiovascular diseases. In the present review we discuss the evidence linking leptin levels with the presence, severity and/or prognosis of both coronary artery disease and non-cardiac vascular diseases such as stroke, carotid artery disease, peripheral artery disease (PAD) and abdominal aortic aneurysms (AAA) as well as with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). Leptin levels have been positively associated with the presence, severity, extent and lesion complexity of coronary atherosclerosis as well as with the presence, severity and poor clinical outcomes of both ischemic and hemorrhagic strokes. But conflicting results also exist. Furthermore, leptin was reported to independently predict common carotid intima-media thickness and carotid plaque instability. A link between hyperleptinemia and PAD has been reported, whereas limited data were available on the potential association between leptin and AAA. Elevated leptin concentrations have also been related to CKD incidence and progression as well as with insulin resistance, T2DM, micro- and macrovascular diabetic complications. Statins and antidiabetic drugs (including sitagliptin, metformin, pioglitazone, liraglutide and empagliflozin) may affect leptin levels. Further research is needed to establish the potential use (if any) of leptin as a therapeutic target in these diseases.

Introduction: The elderly population (i.e. aged ≥ 65 years) is increasing worldwide. Ageing is associated with a higher incidence and prevalence of cardiovascular disease (CVD). Areas covered: The prevalence of CVD risk factors including type 2 diabetes mellitus, hypertension and dyslipidaemia also increases with advancing age, contributing to the higher absolute CVD risk observed in the elderly. The present narrative review comments on the associations of dyslipidaemia with CVD as well as the effects of lifestyle measures and lipid-lowering drugs on lipids and CVD risk with a special focus on the elderly population. Individual treatment goals and therapeutic options according to current guidelines are also reviewed. Finally, we discuss special characteristics of the elderly that may influence the efficacy and safety of drug therapy and should be considered before selection of hypolipidaemic pharmacotherapy. Expert commentary: There may be a greater CVD benefit in older patients following drug therapy compared with younger ones. Treatment goals and therapeutic options should be individualized according to current guidelines. Specific characteristics that may influence the efficacy and safety of drug therapy in the elderly should be considered in relation to dyslipidaemia treatment.

Women are often excluded/underrepresented in clinical trials; sometimes, the number of men/women participants or separate analysis by sex are not reported. A robust body of evidence demonstrated that several life-threatening acute cardiovascular diseases, for example, acute myocardial infarction, sudden cardiac death, cardiac arrest, rupture or dissection of aortic aneurysms, and stroke, exhibit a circadian periodicity with a morning peak. An analysis of 20 years of chronobiologic studies (44% of them, accounting for 85% of total cases, with separate analysis by sex) confirmed that morning hours are a critical time of onset of acute cardiovascular diseases in men and women., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In recent years, there has been growing interest in the possible use of nutraceuticals to improve and optimize dyslipidemia control and therapy. Based on the data from available studies, nutraceuticals might help patients obtain theraputic lipid goals and reduce cardiovascular residual risk. Some nutraceuticals have essential lipid-lowering properties confirmed in studies; some might also have possible positive effects on nonlipid cardiovascular risk factors and have been shown to improve early markers of vascular health such as endothelial function and pulse wave velocity. However, the clinical evidence supporting the use of a single lipid-lowering nutraceutical or a combination of them is largely variable and, for many of the nutraceuticals, the evidence is very limited and, therefore, often debatable. The purpose of this position paper is to provide consensus-based recommendations for the optimal use of lipid-lowering nutraceuticals to manage dyslipidemia in patients who are still not on statin therapy, patients who are on statin or combination therapy but have not achieved lipid goals, and patients with statin intolerance. This statement is intended for physicians and other healthcare professionals engaged in the diagnosis and management of patients with lipid disorders, especially in the primary care setting., (© The Author(s) 2017. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Type 2 diabetes mellitus (T2DM) is associated with several cardiovascular (CV) risk factors such as insulin resistance, obesity, hypertension, dyslipidaemia, non-alcoholic fatty liver disease as well as platelet and haemostatic abnormalities increasing the risk of thrombosis. Therefore, T2DM patients are at an increased risk for CV disease (CVD). Areas covered: This narrative review discusses the treatment of T2DM. This includes lifestyle measures (diet, exercise and smoking cessation) as well as hypolipidaemic, antihypertensive, weight reducing, antiplatelet and glucose lowering drugs. The focus is on the effects of these therapeutic strategies on CVD risk. Randomized controlled clinical trials (RCTs) reporting CVD outcomes with such drugs in T2DM patients are also reviewed. Expert opinion: Apart from current guidelines, the findings of RCTs on CVD outcomes in T2DM patients should be taken into consideration in daily clinical practice. Multiple risk factors should be targeted simultaneously in such high-risk patients in order to efficiently reduce the risk of CV events.

Non-alcoholic fatty liver disease (NAFLD), the most common liver disease, is characterized by accumulation of fat (>5% of the liver tissue), in the absence of alcohol abuse or other chronic liver diseases. It is closely related to the epidemic of obesity, metabolic syndrome or type 2 diabetes mellitus (T2DM). NAFLD can cause liver inflammation and progress to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis or hepatocellular cancer (HCC). Nevertheless, cardiovascular disease (CVD) is the most common cause of death in NAFLD/NASH patients. Current guidelines suggest the use of pioglitazone both in patients with T2DM and in those without. The use of statins, though considered safe by the guidelines, have very limited use; only 10% in high CVD risk patients are on statins by tertiary centers in the US. There are data from several animal studies, 5 post hoc analyses of prospective long-term survival studies, and 5 rather small biopsy proven NASH studies, one at baseline and on at the end of the study. All these studies provide data for biochemical and histological improvement of NAFLD/NASH with statins and in the clinical studies large reductions in CVD events in comparison with those also on statins and normal liver. Ezetimibe was also reported to improve NAFLD. Drugs currently in clinical trials seem to have potential for slowing down the evolution of NAFLD and for reducing liver- and CVD-related morbidity and mortality, but it will take time before they are ready to be used in everyday clinical practice. The suggestion of this Expert Panel is that, pending forthcoming randomized clinical trials, physicians should consider using a PPARgamma agonist, such as pioglitazone, or, statin use in those with NAFLD/NASH at high CVD or HCC risk, alone and/or preferably in combination with each other or with ezetimibe, for the primary or secondary prevention of CVD, and the avoidance of cirrhosis, liver transplantation or HCC, bearing in mind that CVD is the main cause of death in NAFLD/NASH patients., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Sodium-glucose cotransporter 2 inhibitors (SGLT2i) are a novel category of oral antidiabetic drugs that inhibit renal glucose reabsorption and increase renal glucose excretion, thus lowering plasma glucose levels. This unique mechanism of SGLT2i action is insulin independent, thus improving glycemic control without promoting hypoglycemia in the absence of exogenously administered insulin., Methods: The present narrative review addresses the putative associations between SGLT2i and several cardiovascular (CV) and microvascular risk factors, as well as their effects on cardiac and renal function., Results: SGLT2i improve several CV risk factors, including fasting and postprandial plasma glucose levels, lipids, blood pressure, body weight, serum uric acid and arterial stiffness. These drugs may also favorably modulate cardiac and renal function via their effects on inflammation, oxidative stress, diuresis, fluid and sodium retention, myocardial function, vascular resistance and 'fuel' metabolism. In the EMPA-REG OUTCOME study, the first published large CV outcome SGLT2i trial, empagliflozin significantly reduced the primary composite outcome (i.e. CV death, nonfatal myocardial infarction or stroke) and all-cause death as well as hospitalization for heart failure. In addition, empagliflozin was associated with a slower progression of kidney disease and lower rates of clinically relevant renal events than was placebo when added to standard care in patients at high CV risk., Conclusion: Multiple metabolic benefits may account for the positive clinical outcomes in the EMPA-REG OUTCOME study. Ongoing CV outcome trials involving other SGLT2i will help establish whether the reported CV and microvascular risk benefits are compound-specific or drug class effects., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.)

Aims: Specialized nurses estimated the HeartScore in an urban Greek population by recognizing cardiovascular disease (CVD) risk factors in the setting of the Onassis Cardiovascular Prevention Program (OCPP). They also provided nursing consultation and assessed the clinical and biochemical characteristics of the studied population., Methods and Results: Individuals were recruited through TV announcements and via the website of the Onassis Cardiac Surgery Centre. All participants visited the Onassis Cardiac Centre from 20 September to 30 October 2011. Overall, 2,145 individuals were included in the study. CVD risk was calculated by the HeartScore and serum total cholesterol was measured (mean: 193±43 mg/dl). Although 33% of the participants reported dyslipidaemia, only 17% were on hypolipidaemic treatment. Hypertension and dyslipidaemia frequency increased with age., Conclusion: In the present study, specialized nurses estimated the HeartScore in a Greek urban population. The majority of the studied population was undiagnosed and untreated. These results highlight the necessity for both primary and secondary prevention programs that can be carried out by specialized nurses. Such programs may improve the diagnosis and treatment of CVD risk factors; early initiation and optimization of therapy as well as management of drug intolerance (e.g. statins) can contribute to CVD risk reduction.