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Background: Heart failure (HF) is characterized by cardiac functional and structural alterations, progressively leading to clinical symptoms and signs. Certain neurohormonal systems (i.e. the sympathetic nervous system, the reninangiotensin-aldosterone system and the natriuretic peptide system) as well as interactions between endothelial, monocytes/macrophages and myocardial cells are involved in the process. Methods: The present narrative review discusses the relationships between lipids, statins and HF. Results: Lipid metabolism is involved in cardiac function. Inflammation, oxidative stress, endothelial and platelet dysfunction, activation of neurohormonal systems, adverse cardiac remodeling, haemodynamic disorders and arrhythmogenesis predispose to HF development and progression. Statins have been shown to reduce HF incidence possibly via their pleiotropic actions on the above mentioned mechanisms. Other cardiovascular (CV) risk factors affecting HF prevalence and outcomes include metabolic syndrome, non-alcoholic fatty liver disease, chronic kidney disease, hyperuricaemia, epicardial fat and increased arterial stiffness that are improved following statin therapy. Conclusion: Lipid disorders are involved in HF development and progression. Statins may beneficially affect these disorders as well as other CV risk factors linked to HF. However, the impact of statins in patients with established HF has yet to be determined. Further studies are needed to unveil potential benefits of statin therapy (or some statins) in specific groups of HF patients.

Statins exert beneficial effects on cardiovascular [CV] outcomes as well as on inflammation and oxidative stress. The widespread use of statins for both primary and secondary CV disease prevention is based on the evidence from large randomized controlled trials. The benefits of statin treatment outweigh any harm in high risk patients. In this narrative review, we provide an update on several aspects of statin treatment based on the most recent evidence in this field.

Statins remain the cornerstone of hypolipidaemic drug treatment. The recent American College of Cardiology (ACC)/American Heart Association (AHA) lipid guidelines suggest using percent reductions of low density lipoprotein cholesterol (LDL-C), according to cardiovascular disease (CVD) risk, rather than specific LDL-C targets. These guidelines raised concerns and other Societies (US, International, European) have not endorsed them. The implementation of previous guidelines in clinical practice is suboptimal due to attitudes of physicians and restrictions in health care systems. Monoclonal antibodies that inhibit proprotein convertase subtilisin/ kexin type 9 (PCSK9), which degrades the LDL receptor, like alirocumab and evolocumab, are in phase 3 trials. These drugs are suitable for statin intolerant or resistant patients, heterozygous familial hypercholesterolaemia (HeFH) and some forms of homozygous FH (HoFH). Mipomersen (antisense oligonucleotide against apolipoprotein B) and lomitapide (microsomal triglyceride transfer protein blocker) have already been approved for HoFH. Eventually, silencing micro-RNA oligonucleotides may also become available. The repair or silencing of genes implicated in hyperlipidaemia and/or atherosclerosis is also on the horizon. If the new therapeutic options mentioned above prove to be effective and safe then by combining them with statins and/or ezetimibe we should be able to effectively control acquired or hereditary dyslipidaemias and substantially further reduce CVD morbidity and mortality.

Cardiovascular disease (CVD) claims more lives than any other disease in the Western World [1]. In US, it is estimated that there was a decline in CVD-related deaths from 1980 to 2000 [1,2]. Nearly half (44%) of this drop resulted from population-wide risk factor reduction (smoking), whereas another (47%) resulted from medical treatment targeting patients at risk or with established atherosclerosis [1,2]. In contrast, only 5% of the reduction in deaths was estimated to be due to revascularization in patients with established CVD [1,2]. No changes in the dietary intake of fat (total, saturated and polyunsaturated) and cholesterol were recorded from 1988-1994 to 2007-2008 [3]. However, the age-adjusted use of cholesterol-lowering medications increased from 1.6 to 12.5% (P < 0.001) [3]. Data suggest that changes in dietary fat intake had minimal contribution to the observed trend in mean concentrations of total cholesterol, while the increased use of cholesterollowering medications was estimated to account for most of the change [3]. The INTERHEART study showed that 9 CVD risk factors - smoking, dyslipidemia, diabetes mellitus (DM), hypertension, abdominal obesity, stress, poor diet, physical inactivity, and excess alcohol consumption - are associated with > 90% of the CVD risk [4]. All the above suggest that despite the substantial effort to inform the public on the benefit of modifying reversible CVD risk factors this has no practical effect, because people are not keen to change their lifestyle on a longterm basis. This led the Centers for Disease Control to design the Million Hearts Initiative, an effort aimed to prevent 1 million myocardial infarctions and strokes over the next 5 years [1, 5]. Moreover, this contributed in embracing the concept of ideal CVD health by the American Heart Association (AHA) among its strategic goals for 2020 [6]. This concept was intended to focus on the promotion of a healthy lifestyle and the adoption of a multi-factorial pharmacological intervention, aimed to improve the CV health of all Americans by 20%, in order to reduce deaths from myocardial infarctions and strokes by 20% by 2020 [6]. All the above seem to have played a significant role in the composition of the new ACC/AHA lipid guidelines [7]. As stated by the authors of the guidelines, they focused on statins and only briefly mentioned other hypolipidemic drugs, because only statins have shown a clearly defined clinical benefit [7]. Also, the ACC/AHA guidelines risk assessment was based on an equation that appears to overestimate CVD risks by 75-150%, roughly doubling the actual risk [7-9]. Based on the new ACC/AHA guidelines, it is probable that 40-50% of the 46 million middle-aged Americans targeted for statin treatment by the ACC/AHA guidelines do not actually need these drugs [7,9]. It may have been the aim of the panel to protect the US population from a greater CVD incidence that is a consequence of the ever increasing prevalence of obesity [10]. By 2015, the prevalence of CVD in US will be 38% [10]. Obesity, hypertension, dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome (MetS) are driving CVD risks [10]. Despite the fact that 70% of US adults are overweight or obese, diet quality continues to deteriorate, leading to the fact that at present more than half of US adults have significant lipid abnormalities [10]. All the above point to the necessity to further inform physicians about CVD risk factors and update the information on the pathogenesis and the recent (as well as the near future) advances in the treatment of dyslipidemias and atherosclerosis. In this issue of the Journal, several articles consider recent advances in novel and established CVD risk factors, mainly those related to lipids, aiming to prevent or treat fatal or non-fatal CVD. The current and future therapeutic options targeting residual CVD risk have been summarized in a multidisciplinary manner. Familial hypercholesterolemia (FH) is a fairly common hereditary lipid disorder that is characterized by a marked increase in low-density lipoprotein cholesterol (LDL-C) levels and premature CVD [11]. The diagnosis of FH is usually based on LDL-C levels, clinical signs and the family history; genetic testing can also be used to confirm the diagnosis [11]. The emphasis of treatment is now on the 4 classes of newer and promising lipid-lowering drugs already or yet to be, available for the treatment of FH. The apolipoprotein-B synthesis inhibitors (mipomersen - as a weekly subcutaneous injection), and the microsomal transfer protein inhibitors (lomitapide - oral administration) have already been approved for homozygous FH (HoFH) and are commercially available in US and Europe, but it remains uncertain whether they will obtain approval for use in patients with heterozygous FH (HeFH) or in the general population [11]. The problem with these drugs is that, besides local irritation at the injection site (for mipomersen), there exists a risk of hepatotoxicity and fat accumulation in the liver; a black box warning exists for both mipomersen and lomitapide regarding the risk for transaminase elevations and hepatic steatosis [11]. Monoclonal antibodies that inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), which degrades the LDL receptor, are in phase 3 trials, and are expected to be commercially available within the next two years [11]. At present, they seem to have an excellent safety profile, while local irritations and liver related side-effects are not reported [11]. With anti PCSK9 antibodies, the LDL receptor has a longer life and removes greater amounts of LDL-C from the blood. Evolocumab and alirocumab (PCSK9 inhibitors administered as a subcutaneous injection every 2- 4 weeks) seem to be able to treat HeFH or reduce the need for LDL apheresis in some forms of HoFH that have a degree of LDL receptor function [11]. On the other hand, specific high density lipoprotein cholesterol (HDL-C) defects may lead to atherosclerosis and in this case only genetic intervention may be of help [12]. The cholesterol ester transfer protein (CETP) inhibitors, which substantially increase HDL-C, had off-target side-effects and 2 of them (torcetrapib and dalcetrapib) have been withdrawn from phase III trials. Anacetrapib and evacetrapib continue to be investigated [12]. At present several HDL-raising agents are being evaluated, including two CETP inhibitors, gene therapies, enzyme replacement therapies, Apo AI mimetics, antagonists against some microRNAs (miRs) and peroxisome proliferator-activated receptors (PPAR)-based therapies [12]. Triglycerides (TGs) are likely to play a role in atherogenesis and significantly increase CVD risk. Hypertriglyceridemia in the fasting or postprandial state, related to a high non-HDL-C level, represents a metabolic disorder due to insulin resistant (IR) states such as inappropriate lifestyle, obesity, MetS and T2DM [13]. The latest guidelines by the Joint European Societies recognize the importance of treating hypertriglyceridemia to prevent CVD and acute pancreatitis, with fibrates being the first choice in drug therapy after lifestyle changes [13]. However, it is not only the quantity of lipid CVD risk factors that matters; the quality of lipoprotein particles also plays a role in atherogenesis. Small dense LDL (sdLDL) sub-fractions are highly atherogenic and small HDL particles may not perform reverse cholesterol transfer as effectively as other HDL fractions [14,15]. From dyslipidemia defined by the routine markers (i.e. total cholesterol, LDL-C, HDL-C and TGs) to atherosclerosis there are a number of steps involving other molecules such as lipoprotein-associated phospholipase A2 (Lp-PLA2), also named as platelet-activating factor (PAF)- acetylhydrolase [16]. Lp-PLA2 is a 45-kDa protein of 441 amino acids, and it is one of several PAF acetylhydrolases; in the blood it travels mainly with LDL, while less than 20% is associated with HDL [16]. It is an enzyme produced by inflammatory cells and it hydrolyzes oxidized phospholipids in LDL. It is considered a marker of atherosclerosis but it may also play an important role in the pathogenesis of atherogenesis [16]. An advantage of this marker is the low biological variation and high vascular specificity [16]. In contrast to LDL-Lp-PLA2, the clinical relevance of HDL-Lp-PLA2 has not been extensively explored, despite data supporting an antiatherogenic role of this enzyme. In a recent prospective study involving patients with overt CVD, HDL-Lp-PLA2 was inversely associated with future cardiac mortality, independently of conventional risk factors [16]. Specific LDL-Lp-PLA2 inhibitors are already available and are being evaluated [16]. Mixed dyslipidemia is an increasingly common lipid disorder across different ethnic groups especially with increasing IR as a result of obesity, MetS and T2DM. The presence of TG-rich lipoproteins and increased sdLDL particles, well known as the atherogenic lipid triad or dyslipidemia, is higher in many ethnic groups including Indian Asians [17]. In high risk populations, such as South Asians, where genetic factors interplay with the environment to lead to premature CVD, early and aggressive intervention is required. Awareness of the problem and lifestyle intervention such as increased physical activity and dietary modification are likely to improve the lipid profile and reduce other CVD risk factors [17]. Moreover, lipid lowering therapies have an important role especially in high risk individuals as they have been proved to reduce CVD morbidity and mortality [17]. With regard to the relation between lifestyle and CVD risk, low to moderate alcohol consumption is associated with beneficial effects on CVD risk. This effect may be mediated by reducing the risk for several metabolic diseases and modifying established and emerging vascular risk factors. In contrast, heavy and binge drinking has been related to increased risk of all the above metabolic conditions, leading to increased CVD risk [18]. Data from a plethora of studies show that apoB levels and the apoB/apoA-I ratio are strongly and independently associated with CVD risk compared with conventional lipids, lipoproteins and lipid ratios [19]. However, there are some drawbacks. ApoB has not been evaluated as a primary treatment target in statin trials, but several post-hoc analyses of statin trials suggest that apoB may not only be a risk marker but also a better treatment target than LDL-C. Also, apoB has not been included in algorithms for calculation of global risk [19]. Even after LDL-C goal attainment, there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the reninangiotensin system (RAS) was investigated. Data from clinical trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone [20]. This benefit is probably related to effects of the two drug categories on endothelial function, vascular inflammation and atheromatous plaques [20]. These effects are, at least in part, driven by mediators, the miRs, which are implicated in the pathogenesis and clinical manifestations of atherosclerosis [20]. Some miRs are favorably affected by statins and others by RAS inhibition. However, a miR family (miR-146a/b), related to coronary artery plaque destabilization is beneficially affected by the statin and RAS inhibition combination only [20]. These data suggest that statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, MetS, and/or T2DM to achieve full clinical benefit [20]. Most of the actions described above are mediated through the “pleiotropic” effects of statins. Indeed it seems that many lipid-lowering agents, mainly statins, exert anti-inflammatory, antithrombotic and antihypertensive actions, which appear to be mostly independent from their effects on the lipid profile [21]. These “pleiotropic” actions may contribute to the observed reduction in CVD events [21]. Regarding other lipid-lowering agents, it is unclear whether the effects on inflammation, thrombosis or blood pressure play a role in their antiatherogenic potential. Adherence to statin treatment is not ideal because it depends on many factors such as the health system, physician education, patient awareness and patient willingness to comply on a long-term basis [22]. Discontinuation of statins after an acute coronary event is associated with higher total mortality and this may represent a biological rebound and/or a risk-treatment mismatch phenomenon, where treatment is withdrawn from very ill patients. It is increasingly apparent that statin non-adherence is an important modifiable risk factor for CV outcomes, and all efforts should be made to improve adherence to statin therapy in both primary and secondary preventions [22]. There are several interventions targeting different barriers to statin adherence; the most successful strategy should capitalize on the physician-patient partnership, and may involve tailoring the intervention to the patient’s need and non-adherence risk assessment, as opposed to a program integrating different strategies [22]. While awaiting further research, at present statin use should only be withdrawn under judicious clinical supervision [22]. There might also be a problem with iatrogenic dyslipidemia, after administration of drugs for other diseases. Some hypoglycemic medications, most notably rosiglitazone, can be associated with dyslipidemia [23]. Antihypertensive medications reduce CVD risk, but some, such as diuretics or older beta-blockers, can cause hypertriglyceridemia [23]. Estrogens administered orally can be associated with a severe hypertriglyceridemia. Currently-used antipsychotic medications have a significant association with hypertriglyceridemia, IR, obesity, MetS and T2DM. Clinicians must be aware of the dyslipidemias caused by these medications and know how to manage them, even in many cases treating a secondary dyslipidemia with another medication as in the case of HIV infection rather than trying to switch treatment of the infection [23].All the traditional CVD risk factors such as hypertension, dyslipidemia, obesity, MetS, DM, and smoking can lead to early arterial stiffness (AS) which has been linked with an increased risk of CVD events [24]. AS increases with aging; early vascular aging is a contributor to CVD events [24]. Statins can reduce AS not only in patients with dyslipidemia but also in those with a variety of CVD risk factors, such as hypertension, obesity, MetS, and T2DM [24]. The effects of combining statins with antihypertensive drugs or other strategies to attenuate arterial aging are very promising but need further investigation [24]. Finally, the future holds significant promise [25] for example, the use of human monoclonal antibodies against PCSK9 [25,26]. These drugs are suitable for statin intolerant or resistant patients, HeFH, some forms of HoFH, increased Lp(a), and as co-administration with statins in patients that cannot reach their lipid goals [26]. Another example is silencing specific miRs, related with the pathogenesis of atherosclerosis and its clinical manifestations, using specific antisense oligonucleotides, some of which are already available at an experimental level [25,26]. Finally, repairing or silencing genes implicated in hyperlipidemia and/or atherosclerosis though genetic engineering holds promise [25,26]. This has already been carried out in animal models [25,26]. Aspects of New Therapeutic Interventions in Lipid-Related Cardiovascular Risk Factors are not Covered in this Issue. It is not feasible in a single issue of the Journal to comment on all novel developments in lipid- and non- lipid-related treatment of the clinical manifestations of atherosclerosis. Some remain to be analyzed in future issues of the Journal. However, we will briefly mention some of these topics in this editorial. A major issue is the administration of statins in patients with chronic liver diseases (CLD), such as non-alcoholic fatty liver disease (NAFLD), chronic hepatitis B (HBV), chronic hepatitis C (HCV), and primary biliary cirrhosis (PBC). Until recently this was a “forbidden fruit” [27]. However, the Liver Expert Panel of the National Lipid Association Statin Safety Task Force clearly stated that this is not so [27], and that liver-related side-effects are uncommon during statin therapy; increased serum activities of liver enzymes, mainly alanine transaminase (ALT) are reported in 0.5% of patients, while acute liver failure is seen in 1 case/1 million patient-years [27]. The incidence of these adverse effects in patients with CLD, HBV, HCV, PBC and NAFLD is likely to be low suggesting that CLD does not induce liver-related statin intolerance [27]. In fact in chronic viral hepatitis, statin treatment facilitates clearance of virus B or C by antiviral drugs, and reduces the risk for cirrhosis and hepatocellular carcinoma [28]. Statins can enhance NAFLD resolution and reduce the excess CVD risk related with NAFLD [29,30]. It has also been shown that statin therapy in patients with HBV, after the acute phase, is safe [31], while in patients with chronic HCV infection statins may contribute to the quicker clearance of the virus from the blood through the reduction of HCV mRNA [28,31]. Statins are also safe and have a beneficial effect in the prognosis of PBC [32] and they also reduce the risk of cirrhosis [27] and hepatocellular carcinoma [33]. Besides liver-related morbidity and mortality, statin treatment may also exert a substantial beneficial effect on CVD risk in patients with NAFLD [34-38]. In the GREACE (n = 1600) and ATTEMPT (n = 1,123) prospective survival studies, atorvastatin treatment not only contributed to NAFLD resolution (reduction in liver enzyme activities and ultrasonographic resolution of fatty liver), but also reduced the associated CVD risk twice as much as in those without NAFLD at baseline [34-36]. These results were supported by a post hoc analysis of the IDEAL (n = 8,888) trial [37], and by a pilot biopsy-based study with rosuvastatin monotherapy [38]. High CVD risk patients with NAFLD should probably not be deprived of statin treatment, because of the fear of liver enzyme elevation [27,35,37]. Another issue is the use of statins in elderly patients. Data suggest that statin treatment is safe in older patients and that the clinical benefit (in terms of relative risk reduction of CVD mortality as well as CVD morbidity) increases with increasing patient age [39,40]. This is because the percentage and the absolute number of CVD events prevented are increasingly higher with older patients [39]. This seems to be so even if only CVD and total mortality in the very elderly patients (>80 years old) are taken into consideration [41]. Another issue is statin administration in patients with impaired renal function. Patients with chronic kidney disease (CKD) are exposed to excess CVD risk [42], to the extent that CKD is considered as a CHD equivalent [43]. Statins are necessary in the treatment of these patients; however, most of these drugs are cleared in the kidney and should not be prescribed in patients with CKD stage 3 or greater [44]. Less than 2% of atorvastatin or fluvastatin are metabolized in the kidneys and these could be prescribed in any stage of CKD [44]. In the GREACE study, CHD patients that were not treated with a statin, glomerular filtration rate (GFR) declined over a period of 3 years, while atorvastatin treatment not only prevented this decline but significantly improved renal function, and substantially reduced the additional CVD risk, in a manner independent of its hypolipidemic effect [45]. Even the periprocedural statin administration in CVD patients undergoing percutaneous coronary intervention or CKD patients undergoing angiography, with or without intervention may prevent contrast-induced acute kidney injury [46]. The relationship between statins and CKD may be quite complex [47,48]. There is also a need to consider the role of lipid lowering drugs other than statins (e.g. ezetimibe and colesevelam) [49,50]. In conclusion, recent advances in the pathophysiology of atherosclerosis and novel drug options will result in a more effective treatment of atherosclerotic disease. Hopefully, residual CVD will decrease but it is unlikely that we will become immortal!

Statins effectively reduce cardiovascular disease (CVD) morbidity and mortality. However, even after low-density lipoprotein cholesterol goal attainment there is a residual CVD risk. To reduce this risk, combining statins with drugs acting on the renin-angiotensin system (RAS) was investigated. The GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE), Japanese Coronary Artery Disease (JCAD), Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) and The Assessing the Treatment Effect in Metabolic Syndrome Without Perceptible Diabetes (ATTEMPT) trials suggest that the statin plus RAS inhibition combination reduces CVD events more than a statin alone and considerably more than RAS inhibition alone. This benefit seems to be related to effects on endothelial function, vascular inflammation and the initiation, progression and rupture of atheromatous plaques. These effects are, at least in part, driven by mediators, the microRNAs (miRs), that are implicated in the pathogenesis and clinical manifestations of atherosclerosis (e.g. restoration of endothelial function and attenuation of vascular inflammation). Some miRs are favourably affected by statins and others by RAS inhibition. There is a miR family (miR-146a/b), related to coronary artery plaque destabilization that is beneficially affected by both statins and RAS inhibition. Statins and RAS inhibition combination should be routinely prescribed in high risk patients with CVD, hypertension, obesity, metabolic syndrome, and/or diabetes to maximize clinical benefit.

Low to moderate alcohol intake has been associated with beneficial effects on the heart and the vasculature, including improvements in several established and emerging cardiovascular disease (CVD) risk factors as well as reduced risk for several metabolic diseases, CVD morbidity and mortality. Binge and heavy drinking exert the opposite effects, leading to increased risks for all the above conditions. With regard to beverage type, there is some evidence supporting red wine superiority in cardioprotection, although other beverages have also been reported to exert beneficial metabolic and vascular effects when consumed in moderate amounts. In this narrative review we discuss the associations between alcohol consumption and CVD morbidity and mortality. Alcohol-induced effects on established and emerging CVD risk factors are also discussed taking into consideration different drinking patterns. Physicians should screen for excessive alcohol use and advise individuals to limit their alcohol intake to moderate amounts (up to 20-30 g/day for men and 10-20 g/day for women), preferably consumed with meals. The question of whether alcohol intake should be encouraged as a measure to prevent CVD remains unanswered.

Psoriasis is a chronic systemic inflammatory disease characterized by topical skin lesions as well as an increased risk for cardiovascular disease (CVD). There is also increasing evidence that patients with psoriasis are more prone to several CVD risk factors (hypertension, obesity, dyslipidemia and smoking), non-cardiac vascular diseases (carotid, peripheral artery and chronic kidney disease) and metabolic co-morbidities (type 2 diabetes mellitus, metabolic syndrome, non-alcoholic fatty liver disease and obstructive sleep apnea) compared with the general population. The associations are even greater in patients with severe psoriasis and those with psoriatic arthritis. Insulin resistance, endothelial dysfunction and obesity induced by several adipokines and inflammatory cytokines are proposed as the common mechanisms linking psoriasis with CVD, vascular risk factors and metabolic diseases. The present narrative review considers the associations between psoriasis (and psoriatic arthritis) with CVD, vascular risk factors and metabolic diseases. Drugs that reduce CVD risk and improve metabolic parameters may also beneficially affect psoriasis severity and prognosis. Furthermore, anti-psoriatic drugs can exert different effects on CVD risk and metabolic co-morbidities. Therefore, physicians should be aware of these associations in order to adequately monitor and treat psoriatic patients.

The metabolic syndrome (MetS) is characterized by a cluster of risk factors including central obesity, hypertension, dyslipidemia and insulin resistance, The MetS is associated with an increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Several international organizations have defined MetS using different diagnostic criteria that produced discrepancies in the results of previous studies, thus leading to the latest Joint Interim Societies (JIS) MetS definition. Other risk factors than the diagnostic criteria that have been associated with MetS include lipid abnormalities, uric acid, liver function, prothrombotic factors, cytokines, adipokines, vitamin D, arterial stiffness, polycystic ovary syndrome and obstructive sleep apnea. Apart from CVD and T2DM, MetS has been related to non-cardiac vascular diseases and in particular to stroke, carotid artery disease, peripheral artery disease, chronic kidney disease, atherosclerotic renal artery stenosis and abdominal aortic aneurysms. In this narrative review, the associations of these diseases with MetS and its components will be discussed. These associations may further increase CVD risk in MetS patients, highlighting the importance of treating such high-risk individuals early and “to target”. In this context, multifactorial treatment including a statin has been proven beneficial, and thus should be considered, in MetS patients.

The prevalence of type 2 diabetes mellitus (T2DM) is increasing worldwide. T2DM is associated with both microvascular (neuropathy, nephropathy and retinopathy) and macrovascular complications [coronary artery disease (CAD), stroke, carotid artery disease and peripheral artery disease (PAD)]. Apart from acting on diabetic dyslipidemia, statins were shown to exert beneficial effects on several diabetic complications as well as other cardiovascular (CVD) risk predictors such as endothelial dysfunction, inflammation, oxidative stress, chronic kidney disease (CKD), non-alcoholic fatty liver disease (NAFLD), metabolic syndrome (MetS), obstructive sleep apnea syndrome (OSAS) and hyperuricemia. Several clinical trials involving T2DM patients have reported significant reductions in coronary and cerebrovascular events following statin treatment. However, a modest statin-related risk of new-onset diabetes (NOD) has been reported but that did outweigh the benefit of CVD risk reduction in high-risk individuals. Overall, statin use is beneficial and should be recommended in diabetic patients to target their increased CVD risk.

Microalbuminuria (MA), excessive albumin excretion in the urine, is defined in different ways. MA is more prevalent among patients with diabetes mellitus (DM) and/or hypertension and correlates with adverse renal and cardiovascular (CV) outcomes. Several cross-sectional and prospective studies have demonstrated a positive association between MA and CV outcomes in the general population but also specific populations such as patients with previous MI and hypertensives. The relationship between MA and hypertension is of particular importance. Increased urine albumin excretion (UAE) has been associated with left ventricular hypertrophy (LVH), subclinical markers of atherosclerosis and vascular dysfunction. Metabolic syndrome (MetS), insulin resistance (IR), inflammatory markers, lipid parameters and measures of obesity also correlate with increased UAE. Accumulating evidence suggests that a UAE value lower than the “traditionally” considered microalbuminuric threshold is associated with increased CV risk. The revision of MA definition according to the levels which confer increased CV risk in the general population should probably be considered. Further prospective studies with uniform methods of urine collection and UAE measurement as well as consistent threshold values and units may provide additional information regarding MA (or low-grade albuminuria) as a predictor of CV outcomes.

After the withdrawal of troglitazone and rosiglitazone, pioglitazone remains the sole thiazolidinedione (TZD) still available. Pioglitazone is efficacious in improving glycemic control and reduce the risk of cardiovascular events. Although generally well-tolerated, pioglitazone was withdrawn by some national medicines agencies (e.g. in France and Germany) due to reports of increased incidence of bladder cancer. In this article, we review the literature on the association between pioglitazone and cancer in several sites, including the bladder. Pioglitazone, like other TZDs, increased differentiation, inhibited growth and proliferation, while provoked apoptosis in various cancer cells, including bladder cancer, in vitro and in vivo. However, a rat-specific carcinogenic effect of pioglitazone on the bladder was noted in vivo. Clinical data for the risk of various cancer sites mostly come from observational studies and are subject to bias. An increased risk for bladder cancer by pioglitazone was suggested by retrospective analyses. This risk was associated with the time of exposure and the age, by identifying 24 months and 65 years, respectively, as time ‘thresholds’ above which this risk becomes relevant. In contrast, no increased risk for bladder cancer was associated with pioglitazone in randomized clinical trials. Pioglitazone was associated with increased incidence of melanoma and non-Hodgkin lymphoma and decreased risk of renal cancer in one cohort study. These findings need to be re-evaluated on a prospective basis. There is no convincing evidence that pioglitazone increases or decreases the risk of cancer in other sites. In contrast, it was suggested that this drug may be useful either in the treatment of cancer complications or as an adjunct to chemotherapeutic agents. Considering the clinical benefit from the use of pioglitazone it is reasonable to wait until data from ongoing clinical trials are available before reaching definitive conclusions. Nevertheless, the potential for increased risk of bladder cancer should be taken into consideration, especially in the presence of other risk factors for bladder carcinogenesis (e.g. smoking).

Elevated serum uric acid (SUA) levels (i.e. hyperuricaemia) have been associated with metabolic syndrome (MetS) and cardiovascular disease (CVD) morbidity and mortality. Elevated SUA levels predict the onset of type 2 diabetes (T2DM). SUA levels are increased during the early stages of impaired glucose metabolism. Furthermore, in diabetic patients, hyperuricaemia has been linked to both micro- and macrovascular complications. The present review considers: (1) SUA levels in patients with MetS, type 1 diabetes and T2DM; (2) the mechanisms that influence SUA levels in these patients; (3) the potential links between SUA and diabetic complications. The effect on SUA levels of drugs commonly prescribed for T2DM and the risk of uric acid nephrolithiasis in patients with MetS or DM are also briefly discussed.

As the population becomes more obese and the prevalence of diabetes and the metabolic syndrome increases, low-density lipoprotein-cholesterol (LDL-C) may lose its value as a sole predictor for cardiovascular risk among lipids. Combined dyslipidemia is typically characterized by elevations in LDL-C and triglyceride levels, often accompanied by decreased high-density lipoproteincholesterol (HDL-C) concentrations and increased levels of small, dense LDL. This common disorder results from overproduction of hepatically synthesized apolipoprotein B in very low-density lipoproteins. In the last few years most of the international scientific guidelines as well as several expert panels have confirmed that LDL-C represents the primary or even the only target of treatment. Yet, increasing evidence suggests moving away from a LDL-C target-based approach to a more tailored treatment approach. For example, non- HDL-C has been introduced in the last few years as a target of treatment.

Even though hydrochlorothiazide (HCTZ) and chlorthalidone are frequently considered interchangeable antihypertensive agents, they appear to differ both in their blood pressure lowering efficacy and in their effects on the lipid profile and on serum potassium, uric acid and glucose levels. More importantly, in randomized controlled trials, chlorthalidone was equally or more effective than other antihypertensive agents in cardiovascular risk reduction whereas treatment with HCTZ yielded conflicting results. Although there are no randomized trials comparing the effects of these two agents on cardiovascular events, retrospective data from the Multiple Risk Factor Intervention Trial suggest that chlorthalidone might reduce cardiovascular morbidity more than HCTZ. However, current guidelines do not consistently recommend one or the other and it remains to be established which one is the diuretic of choice.

Normal aerobic metabolism is associated with reactive oxygen species (ROS) that can damage cellular macromolecules. Analogous free radicals are formed by exposure to ionizing radiation and many dietary products are considered to contain free radical generators. During the past 15 years epidemiological studies and animal experiments have identified bilirubin as a molecule at the crossroads of the protection of the body against ROS. The studies have focused on bilirubin as a biomarker of arterial disease. This review assesses the current state of evidence and sets the data in context. There is no definitive evidence from prospective studies of a causal protective effect from bilirubin in arterial disease or that various genetic polymorphisms, (particularly the 7/7 UGT1A1 repeat polymorphism) impacts coronary artery disease. There is no definitive evidence that high bilirubin levels confer protection against cancer. There is some preliminary evidence that bilirubin may have a protective effect in lung disease and stroke, but the reports have yet to be confirmed. The role of various genotypes of UGT1A1 and HMOX1, if any, in cancer is unclear.

Several cross-sectional studies have reported a relationship between elevated serum activity of liver enzymes [e.g. alanine aminotransferase (ALT) and gamma-glutamyltransferase (γGT)] and metabolic syndrome (MetS) and/or diabetes mellitus (DM). Raised serum activity of liver enzymes independently predicted the future development of MetS and DM as well as cardiovascular (CV) events and/or total/CV mortality in prospective studies. However, this association was not consistently demonstrated and it appears to be independent of alcohol intake. Even though these associations can be partly attributed to non-alcoholic fatty liver disease (NAFLD) and insulin resistance, there may be additional underlying mechanisms that contribute to the increased CV risk (e.g. inflammation and oxidative stress). The association of γGT with atherosclerotic plaque is of particular importance. The present review considers the link between serum liver enzyme activities and vascular risk. The links with DM and MetS are also discussed.

Cholelithiasis is a common disease worldwide. The majority of gallstones can occur when the bile is supersaturated with cholesterol. Dyslipidaemia, obesity, insulin resistance are associated with an increased risk for cholesterol gallstone formation as well as with vascular risk. Statins and ezetimibe are used to treat dyslipidaemia and appear to have some effect on bile composition and cholesterol gallstone formation. Statin (e.g. pravastatin, simvastatin, fluvastatin and lovastatin) monotherapy or combined with ursodeoxycholic acid (UDCA) have shown reductions in bile cholesterol saturation, preventing gallstone formation and even dissolving pre-existing stones. However, this effect was not consistently reported in all studies. Statin use has also been associated with a reduced risk for cholecystectomy in 2 large epidemiological studies. Ezetimibe was shown to have a beneficial action against cholelithiasis in animal studies but data in humans - although promising - are very limited. The effect of these drugs on gallstone disease warrants further investigation in large human trials. We also consider the links between cholelithiasis, vascular risk and the use of lipid lowering drugs.

Ischemic heart disease (IHD) is a leading cause of mortality and morbidity in most developed countries. Many studies revealed gender differences in the presentation, prevalence, and clinical outcomes of IHD. Compared with females, ST-segment elevation myocardial infarction is more often diagnosed in men. They also have a higher prevalence of IHD. These findings indicate that gender may have an important influence on IHD. Appropriate prevention, rapid diagnosis, and optimal treatment may essentially improve the care of all patients. It is therefore necessary to take into account gender differences in the features of IHD between males and females.

Platelet activation is a link in the pathophysiology of diseases prone to thrombosis and inflammation. Numerous platelet markers, including mean platelet volume (MPV), have been investigated in connection with both thrombosis and inflammation. This review considers MPV as a prognostic and therapeutic marker as well as the factors influencing its measurement. Established cardiovascular risk factors, such as smoking, hypertension, dyslipidemia, and diabetes, can influence MPV, depending on confounding factors. Low-grade inflammation is one such factor. Evidence, particularly derived from prospective studies and a meta-analysis, suggest a correlation between an increase in MPV and the risk of thrombosis. High MPV associates with a variety of established risk factors, cardio- and cerebrovascular disorders, and low-grade inflammatory conditions prone to arterial and venous thromboses. High-grade inflammatory diseases, such as active rheumatoid arthritis or attacks of familial Mediterranean fever, present with low levels of MPV, which reverse in the course of antiinflammatory therapy. Lifestyle modification, antihypertensive, lipid-lowering and diet therapies can also affect MPV values, but these effects need to be investigated in large prospective studies with thrombotic endpoints.

Transsexualism refers to individuals that identify themselves as members of the opposite gender and who strive to acquire the physical appearance and psychosocial role compatible with that gender. Gender reassignment therapy is applied through hormonal treatment ± surgical intervention in addition to psychological support. Hormone treatment for male-to-female transsexuals includes estrogen supplementation ± suppression of androgen secretion or action. Sex hormones are important determinants of the metabolic profile. The impact on cardiovascular disease appears to be gender-related but overall evidence remains conflicting. Gender reassignment therapy has been associated with elevated triglyceride concentrations, often accompanied by an increase in high density lipoprotein levels, reduced circulating homocysteine (Hcy), uric acid and creatinine levels as well as an adverse effect on glycemic control. Markers of inflammation, oxidative stress and endothelial function are also affected in various ways, while alterations in hemostatic and fibrinolytic factors favor thrombosis (arterial and/or venous). Male-to-female transsexuals may be adversely affected by both estrogen administration and androgen deprivation, as reported in prostate cancer. Therefore, vascular risk factor screening and potential intervention may be required prior to and during gender reassignment therapy (both hormone and surgical).

In addition to bone homeostasis, vitamin D is involved in the physiological functions of several tissues and its insufficiency may contribute to various disorders. Vitamin D status seems to be associated with each of the components of metabolic syndrome (MetS), as well as MetS overall. We review these associations as well as the effects of vitamin D supplementation on MetS.

In a review [1] published in this journal in 2014 we updated the role of statin treatment in patients with type 2 diabetes mellitus (T2DM). This is an important topic because the prevalence of T2DM is increasing and this disease is associated with a high risk of cardiovascular disease (CVD) as well as microvascular complications [1]. The relationship between T2DM and statins is further complicated since these drugs can cause new onset diabetes (NOD) although there is an overall benefit in terms of preventing vascular events [1, 2]. The cost implications of T2DM in terms of quality of life as well as providing healthcare are obvious. This is a brief update of our earlier review [1] based on recently published data.

Coronary heart disease (CHD) is the leading cause of death in the developed world in both men and women. Elevated low-density lipoprotein cholesterol (LDL-C) levels are strong and independent vascular risk factors in both genders. Statins effectively decrease LDL-C levels, reduce vascular morbidity and mortality and are an essential component of CHD preventive strategies. However, women are less likely to be prescribed statins than men in both primary and secondary prevention settings. It was argued that there is no conclusive evidence showing that statins are beneficial for the prevention of vascular disease in women, particularly in those without established CHD. This review summarizes the evidence regarding the effects of statins in the prevention of CHD in women. Accumulating data suggest that statins are equally effective in both men and women. The lack of significant effects in some studies appears to be primarily due to the under-representation of women and the ensuing lack of statistical power. Current guidelines for the prevention of vascular disease also recommend a similar management of dyslipidemia in both men and women. Therefore, statin treatment should be implemented with the same criteria and with the same goals in both genders.

The present review considers the potential pleiotropic effects of statins and the evidence indicative of the “real world” benefit from these effects in patients with cardiovascular disease (CVD). Some of these cholesterol-independent effects of statins involve improved endothelial function, stability of atherosclerotic plaques, attenuation of oxidative stress and inflammation, as well as inhibition of the thrombogenic response. Clinical evidence from early statin administration in acute coronary syndromes and in revascularisation procedures is reported. Moreover, the “metabolic” effects of statin treatment, such as renal function improvement and reduction in serum uric acid levels, in patients with stable coronary heart disease are discussed. Evidence suggests that in high CVD risk patient groups pleiotropic effects of statins may play a role in the reduction of morbidity and mortality. However, this concept requires proof in appropriately designed trials that will include clinically relevant end points in order to set specific targets in new CVD-related biomarkers, in addition to lipid levels, that should be used to fully assess the statin contribution to CVD treatment.

Atherosclerosis is a multifactorial and long-lasting process in humans. Therefore, animal models where more rapid changes occur can be useful for the study of this process. Among such models are the apolipoprotein (apo) E knock out mice. Apo E deficient mice show impaired clearing of plasma lipoproteins and they develop atherosclerosis in a short time. The current review considers lipid metabolism and inflammation as well as nutritional and pharmacological agents affecting atherosclerosis, using the apo E knock out mouse model.

In the last 50 years, several experimental models of abdominal aortic aneurysms (AAAs) have been described. These models have aided scientists and physicians to understand the pathophysiological mechanisms underlying AAA development and progression. In addition, they have served as means for the development of a number of conservative (such as doxyxycline, marimastat and propranolol) and surgical treatment options for the management of AAAs. In the last few years, experimental models have contributed in the development of novel endovascular techniques for the treatment of AAAs. Animal models of endovascular grafts and percutaneous techniques comprise an essential step for the successful clinical application of these procedures. Additionally, they may comprise part of the training process for vascular surgeons. The different experimental AAA models are briefly presented and their clinical significance is discussed. Experimental models play an essential role in the field of research for the development of more successful therapeutic alternatives for the management of AAAs.

Statins are pluripotent agents exhibiting multiple non-lipid-lowering actions. Besides their established role in the management of hypercholesterolemia, statins may also have beneficial actions in other pathological conditions, namely: a) osteoporosis and osteoporosis- related bone fractures, b) cancer, c) solid organ transplantation, d) cerebrovascular events (transient ischemic attack and stroke episodes), e) various neurological disorders, such as Alzheimers disease, Parkinsons disease and multiple sclerosis, f) cardiac arrhythmias and heart failure, g) renal diseases, h) rheumatoid arthritis, i) autoimmune diseases, j) sepsis, and k) allergic asthma. We reviewed the literature searching for studies that support or oppose the use of statins in each proposed indication. In some of these emerging indications, a role for statin treatment is more firmly set; for others, current evidence is more controversial. Future trials may reveal more convincing evidence that will make statin use necessary in the therapeutic management of several diseases.

The beneficial effect of antihypertensive treatment on the risk of major vascular events is well established. Several trials comparing older and newer drugs in the treatment of primary hypertension suggested that it is the blood pressure achieved, rather than choice of the drug that determines most of the primary outcomes. Beta-blockers have been widely used to treat hypertension and are still recommended as first-line drugs in guidelines. However, recent meta-analyses of trials (either placebo-controlled or using drug comparisons) involving atenolol (a popular beta-blocker), have cast doubt on the suitability of atenolol as a first-line antihypertensive drug. We consider the mechanisms which might be responsible for the inferiority of atenolol in preventing vascular morbidity and mortality in patients with primary hypertension. This knowledge may help design drugs that are not only more effective in achieving blood pressure targets but that also markedly decrease vascular events.

Thiol-containing compounds have an essential role in many biochemical reactions due to their ability to be easily oxidised and then quickly regenerated. Main representatives are glutathione, lipoic acid and thioredoxin which are synthesised de novo in mammalian cells. N-acetylcysteine and Bucillamine are synthetic thiols which have been administered in experimental and clinical studies for treatment of conditions associated with oxidative stress. Ischemia and reperfusion (I/R) injury is characterised by significant oxidative stress, characteristic changes in the antioxidant system and organ injury leading to significant morbidity and mortality. I/R occurs in a variety of clinical settings such as liver resection, organ transplantation, haemorrhagic shock with fluid resuscitation, heart surgery, myocardial infarction followed by reperfusion and laparoscopic surgery. In these circumstances, the administration of antioxidant agents such as thiols, could provide protection from the harmful effects of I/R injury. However, the ability of thiol compounds to reduce free radicals is associated with the formation of thiyl radicals and the rate and efficiency of removal of thiyl radicals has a critical effect on antioxidant or prooxidant actions of thiols in the cells. The aim of this review is to present the mechanisms by which thiols act as antioxidants and signalling molecules and the experimental and clinical evidence regarding their role in I/R injury with a particular emphasis on liver I/R. The current evidence suggests that thiols ameliorate I/R injury and that their clinical significance should be further evaluated in large scale randomised clinical trials.

There is growing evidence that the components of the haemostatic system play a significant role in the development and progression of atherosclerosis and its complications. Lipidlowering interventions have been associated with a significant reduction of morbidity and mortality. However, the improvement in cardiovascular risk seen in several clinical trials is incompletely explained by cholesterol reduction. Therefore, the benefit from lipid lowering drugs may involve non-lipid mechanisms. These include beneficial effects on the arterial wall, improved endothelial function and a favourable influence on blood rheology and thrombogenesis. In this review, we consider the influence of lipid-lowering interventions on rheological and haemostatic parameters as well as the potential clinical relevance of these effects.