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Purpose of Review: The aim of this review was to provide an overview of the role of novel biomarkers in metabolic syndrome, their association with cardiovascular risk and the impact of bariatric surgery on these biomarkers., Recent Findings: Metabolic syndrome encompasses an intricate network of health problems, and its constituents extend beyond the components of its operational definition. Obesity-related dyslipidaemia not only leads to quantitative changes in lipoprotein concentration but also alteration in qualitative composition of various lipoprotein subfractions, including HDL particles, rendering them proatherogenic. This is compounded by the concurrent existence of obstructive sleep apnoea (OSA) and nonalcoholic fatty liver disease (NAFLD), which pave the common pathway to inflammation and oxidative stress culminating in heightened atherosclerotic cardiovascular disease (ASCVD) risk. Bariatric surgery is an exceptional modality to reverse both conventional and less recognised aspects of metabolic syndrome. It reduces the burden of atherosclerosis by ameliorating the impact of obesity and its related complications (OSA, NAFLD) on quantitative and qualitative composition of lipoproteins, ultimately improving endothelial function and cardiovascular morbidity and mortality., Summary: Several novel biomarkers, which are not traditionally considered as components of metabolic syndrome play a crucial role in determining ASCVD risk in metabolic syndrome. Due to their independent association with ASCVD, it is imperative that these are addressed. Bariatric surgery is a widely recognized intervention to improve the conventional risk factors associated with metabolic syndrome; however, it also serves as an effective treatment to optimize novel biomarkers., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: Guidelines for cholesterol-lowering treatment generally include extensive review of epidemiological and clinical trial evidence. However, the next logical step, the translation of evidence into clinical advice, occurs not entirely by reasoning, but by a form of consensus in which the prejudices and established beliefs of the societies with interests in cardiovascular disease convened to interpret the evidence are prominent. Methods, which are the subject of this review, have, however, been developed by which clinical trial evidence can be translated objectively into best practice., Recent Findings: Guidelines differ in their recommended goals for cholesterol-lowering treatment in the prevention of atherosclerotic cardiovascular disease (ASCVD). Proposed goals are LDL-cholesterol 2.6 mmol/l (100 mg/dl) or less in lower risk, LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less in higher risk, non-HDL-cholesterol decrease of at least 40% or LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. Evidence from clinical trials of statins, ezetimibe and proprotein convertase subtilisin/kexin type 9-inhibitors can be expressed in simple mathematical terms to compare the efficacy on ASCVD incidence of clinical guidance for the use of cholesterol-lowering medication. The target LDL-cholesterol of 2.6 mmol/l (100 mg/dl) is ineffective and lacks credibility. Cholesterol-lowering medication is most effective in high-risk people with raised LDL-cholesterol. The best overall therapeutic target is LDL-cholesterol 1.8 mmol/l (70 mg/dl) or less or decreased by at least 50% whichever is lower. The use of non-HDL-cholesterol as a therapeutic goal is less efficacious. Aiming for LDL-cholesterol 1.4 mmol/l (55 mg/dl) or less as opposed to 1.8 mmol/l produces only a small additional benefit. Evidence for apolipoprotein B targets in hypertriglyceridaemia and in very high ASCVD risk should be more prominent in future guidelines., Summary: The LDL-cholesterol goal of 2.6 mmol/l or less should be abandoned. Percentage decreases in LDL-cholesterol or non-HDL-cholesterol concentration are better in people with initial concentrations of less than 3.6 mmol/l. The LDL-cholesterol target of 1.8 mmol/l is most effective when initial LDL-cholesterol is more than 3.6 mmol/l in both primary and secondary prevention., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The role of lipoprotein (a) in atherogenesis has been the subject of argument for many years. Evidence that it is raised in familial hypercholesterolaemia has been disputed not least because a mechanism related to low density lipoprotein (LDL) receptor mediated catabolism has been lacking. Whether lipoprotein (a) increases the already raised atherosclerotic cardiovascular disease (ASCVD) risk in familial hypercholesterolaemia is also more dubious than is often stated. We review the evidence in an attempt to provide greater clarity., Recent Findings: Lipoprotein (a) levels are raised as a consequence of inheriting familial hypercholesterolaemia. The mechanism for this is likely to involve increased hepatic production, probably mediated by PCSK9 augmented by apolipoprotein E. The extent to which raised lipoprotein (a) contributes to the increased ASCVD risk in familial hypercholesterolaemia remains controversial.Unlike, for example, statins which are effective across the whole spectrum of LDL concentrations, drugs in development to specifically lower lipoprotein (a) are likely to be most effective in people with the highest levels of lipoprotein (a). People with familial hypercholesterolaemia may therefore be in the vanguard of those in whom theses agents should be exhibited., Summary: Inheritance of familial hypercholesterolaemia undoubtedly increases the likelihood that lipoprotein (a) will be raised. However, in familial hypercholesterolaemia when ASCVD incidence is already greatly increased due to high LDL cholesterol, whether lipoprotein (a) contributes further to this risk cogently needs to be tested with drugs designed to specifically lower lipoprotein (a)., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Purpose of Review: The role of non-HDL-C in the identification and management of lipid disorders is not clearly defined, although UK guidelines recommend its wider use in assessing the need for lipid-lowering therapy and as a treatment target., Recent Findings: We examined the implications of the use of non-HDL-C as opposed to LDL-C in 253 people with hypercholesterolaemia before treatment and 573 after treatment in whom fasting total serum cholesterol, HDL-C and LDL-C had been recorded and the diagnosis of heterozygous familial hypercholesterolemia (heFH) was investigated by genetic testing. The difference and the limits of agreement between non-HDL-C and LDL-C calculated using the Friedewald formula were assessed in those with and without heFH-causing mutations., Summary: There were 147 mutation-positive and 106 mutation-negative pretreatment participants and 395 mutation-positive and 178 mutation-negative patients receiving treatment. The difference between non-HDL-C and LDL-C pretreatment in mutation-positive people (mean LDL-C 7.73 mmol/l) was 0.67 mmol/l (95% CI 0.62-0.73) and posttreatment (mean LDL-C 4.71 mmol/l) was 0.62 mmol/l (95% CI 0.59-0.65) with wide limits of agreement of -0.02 to 1.37 and 0.07-1.18 mmol/l, respectively. Among patients with heterozygous familial hypercholesterolaemia, use of estimated LDL-C derived from non-HDL-C in place of calculated LDL-C may result in diagnostic misclassification and difficulty in assessing the true reduction in LDL-C with treatment, because of the wide inter-individual limits of agreement around the mean difference between non-HDL-C and LDL-C.

Purpose of Review: Non-HDL cholesterol was originally conceived as a therapeutic target for statin treatment in hypertriglyceridaemia when apolipoprotein B100 assays were not widely available. Recently non-HDL cholesterol has been recommended to replace LDL cholesterol in the clinical management of dyslipidaemia routinely in general medical practice. This is misguided., Recent Findings: Non-HDL cholesterol is heterogeneous, constituting a mixture of triglyceride-rich VLDL, intermediate density lipoprotein and LDL in which small dense LDL is poorly represented and to which VLDL cholesterol contributes increasingly as triglyceride levels rise. This makes it unsuitable as a goal of lipid-lowering treatment or as an arbiter of who should receive such treatment. Results of trials designed to lower LDL cholesterol are not easily translated to non-HDL cholesterol. Fasting is no longer thought essential for screening the general population for raised LDL cholesterol. ApoB100 measurement also does not require fasting even in rarer more extreme lipoprotein disorders encountered in the Lipid Clinic, provides greater precision and specificity and overcomes the problems posed by LDL and non-HDL cholesterol. It is more easily interpreted both in diagnosis and as a therapeutic goal and it includes SD-LDL., Summary: If we are to discourage use of LDL cholesterol, it should be in favour of apoB100 not non-HDL cholesterol.

Purpose of Review: Acquired hypocholesterolaemia occurs more commonly than inherited hypocholesterolaemia but has received little attention in the literature. In this review, we discuss the causes and underlying mechanisms of acquired hypocholesterolaemia and its relevance to safety of therapeutically induced decreased LDL cholesterol levels., Recent Findings: Hypocholesterolaemia is increasingly identified as cholesterol testing becomes more widespread in the assessment of cardiovascular risk. Lower therapeutic targets for LDL cholesterol are also being achieved more regularly with the introduction of more intensive cholesterol-lowering regimens. Acquired hypocholesterolaemia may be the presenting feature of treatable diseases. Understanding its mechanisms may also provide new treatment approaches for neoplastic disease, such as breast cancer, and infections, such as tuberculosis., Summary: When hypocholesterolaemia is discovered, it is important to identify its cause. Further research into the pathogenesis of hypocholesterolaemia may provide new therapies for primary diseases underlying it.

Purpose of Review: In randomized clinical trials, reduction in cardiovascular disease (CVD) risk with cholesterol-lowering drugs correlates with the LDL cholesterol decrease. However, because the majority have investigated a fixed statin dose, current guidelines disagree about the use of statin dose titration or non-statin adjunctive cholesterol-lowering drugs., Recent Findings: We conducted a meta-analysis of all randomized controlled trials with CVD end-points, comparing two intensities of lipid-lowering regimens within the same population, using varying statins doses and/or potency, ezetimibe or PCSK9 inhibitors and compared the observed number of patients needed to be treated for 10 years to prevent one CVD event (NNT) with NNT predicted from trials of predominantly single-dose statin.Some 75439 participants in 10 randomized studies were included. The mean 10-year CVD risk in controls was around 50% and the incremental mean LDL cholesterol decrease 0.95 mmol/l (36.7 mg/dl). Observed NNT closely correlated with those predicted from predominantly single-dose statin trials [18.2 and 17.1; Pearson R=0.844 (P=0.001)]. When pre-treatment LDL cholesterol exceeded 4 mmol/l (155 mg/dl), achieving a target LDL cholesterol of 1.8 mmol/l (70 mg/dl) was the most effective strategy. At lower pre-treatment levels, fixed-dose statin equivalent to atorvastatin 80 mg daily was superior. The target of 40% reduction in non-high density lipoprotein cholesterol was least effective regardless of pre-treatment LDL cholesterol., Summary: We conclude that when initial LDL cholesterol exceeds 4 mmol/l and absolute CVD risk demands it, a target value of 1.8 mmol/l should be achieved, if necessary by adding ezetimibe and/or PCSK9 inhibitors to statin treatment.

Purpose of Review: The purpose is to discuss recent developments in the understanding of lipoprotein metabolism in diabetes, the cardiovascular risk associated with both type 1 and type 2 diabetes, recently published guidelines on the management of this risk, concerns over the use of statin treatment in diabetes, and other therapeutic options., Recent Findings: Diabetic dyslipidaemia can be gross with massive hypertriglyceridemia, or subtle with a lipid profile which would be regarded as normal in a nondiabetic patient, but which hides underlying increases in atherogenic subfractions of LDL (e.g., small dense LDL, glycated LDL) and remnant lipoproteins. Statins can decrease these without the clinician being aware from routine biochemistry. In type 2 diabetes, HDL cholesterol levels are often reduced, whereas in type 1, insulin can raise HDL, but its antiatherogenic properties are compromised. Dyslipidaemia and hypertension predate the onset of glycaemia of diabetic proportions (metabolic syndrome). Obese people can thus die of diabetes before they develop it. Obesity should be prevented and treated. Statins decrease the risk of cardiovascular disease in diabetes or metabolic syndrome regardless of whether glycaemia worsens., Summary: One unassailable truth is that statin therapy is beneficial and should rarely, if ever, be withheld.

Purpose of Review: To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL., Recent Findings: Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties., Summary: The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.

Purpose of Review: Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism., Recent Finding: Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects., Summary: Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.

Purpose of Review: Despite being both the longest known and the most prevalent genetic risk marker for atherosclerotic cardiovascular disease (CVD), little progress has been made in agreeing a role for lipoprotein (a) [Lp(a)] in clinical practice and developing therapies with specific Lp(a)-lowering activity. We review barriers to progress, and discuss areas of controversy which are important to future research., Recent Findings: Epidemiological and genetic studies have supported a causal role for Lp(a) in accelerated atherosclerosis, independent of other risk factors. Progress continues to be made in the understanding of Lp(a) metabolism, and Lp(a) levels, rather than apolipoprotein (a) isoform size, have been shown to be more closely related to CVD risk. Selective Lp(a) apheresis has offered some evidence that Lp(a)-lowering can improve cardiovascular end-points., Summary: We have acquired a great deal of knowledge about Lp(a), but this has not yet led to reductions in CVD. This is at least partially due to disagreement over Lp(a) measurement methodologies, its physiological role and the importance of the elevations seen in renal diseases, diabetes mellitus and familial hypercholesterolaemia. Renewed focus is required to bring assays into clinical practice to accompany new classes of therapeutic agents with Lp(a)-lowering effects.

Purpose of Review: Guidelines seeking to deploy statin treatment rely heavily on the use of estimates of absolute cardiovascular disease (CVD) risk as an arbiter of who should receive statins. We question whether this is an effective strategy unless the LDL-cholesterol (LDL-C) response is also considered., Recent Findings: Recently, meta-analyses of randomized clinical trials of statins have revealed that CVD risk decreases linearly by 22% for each 1 mmol/l reduction in LDL-C. Calculation of the number needed to treat with statins to prevent one CVD event using both the pretreatment absolute CVD risk and the LDL-C response that can be achieved is thus possible. Application of this evidence reveals that many people (including younger ones) with high LDL-C levels can benefit more than people currently receiving statin treatment solely on the basis of their absolute CVD risk, whereas others at higher CVD risk, but with lower LDL-C, will derive little benefit. This does not seem to have been adequately considered in recent clinical guidelines., Summary: A simple additional mathematical step in risk assessment to take account of the LDL-C response to statins and provide knowledge of number needed to treat would greatly improve individual management, cost-effectiveness and the population impact of statins.

Purpose of Review: HDL cholesterol concentration is inversely correlated with cardiovascular disease and has a wide range of functions involved in many systems. The purpose of this review is to summarize HDL functionality, its relevance to atherosclerosis and factors affecting HDL functions., Recent Findings: The contribution of HDL to reverse cholesterol transport may not be as great as first envisaged. However, it still plays an important role in cholesterol efflux from peripheral tissues. The capacity of HDL to promote cellular cholesterol efflux in an ex-vivo model has been reported to correlate more closely with carotid intima-media thickness than HDL cholesterol concentration. Recently, a variety of other functions of HDL have been described including antimicrobial, antioxidant, antiglycation, anti-inflammatory, nitric oxide--inducing, antithrombotic and antiatherogenic activity and immune modulation as well as a potential role in glucose homeostasis, diabetes pathophysiology and complications., Summary: HDL has a wide range of functions some of which are independent of its cholesterol content. Its cargo of apolipoproteins, various proteins and phospholipids contributes most to its various functions. These functions are affected by a number of genetic, physiological and pathological factors.

Purpose of Review: To highlight the potential importance of glycation as an atherogenic modification of LDL, factors determining glycated apolipoprotein B in vivo and susceptibility of LDL to glycation in vitro. We also discuss the distribution of glycated apolipoprotein B across different LDL subfractions in healthy controls, patients with type 2 diabetes and metabolic syndrome., Recent Findings: Small, dense LDL, which is known to be most closely associated with atherogenesis, is more preferentially glycated in vivo and more susceptible to glycation in vitro than more buoyant LDL. Glycation and oxidation of LDL appear to be intimately linked. In patients with type 2 diabetes, plasma glycated apolipoprotein B correlated with small, dense LDL apolipoprotein B, but not with HbA1c. Glycated apolipoprotein B is significantly lower in statin-treated type 2 diabetes compared with those not on statins., Summary: Glycation of LDL occurs chiefly because of the nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine of which apolipoprotein B is rich. Higher concentrations of glycated LDL are present in diabetes than in nondiabetic individuals and metabolic syndrome. Even in nondiabetic individuals, however, there is generally more circulating glycated LDL than oxidatively modified LDL. Probably, oxidation and glycation of LDL are partially interdependent and indisputably coexist, and both prevent LDL receptor-mediated uptake and promote macrophage scavenger receptor-mediated LDL uptake. The recognition that LDL glycation is at least as important as oxidation in atherogenesis may lead to improvements in our understanding of its mechanism and how to prevent it.

Purpose of Review: To highlight the potential importance of glycation as an atherogenic modification of LDL in both diabetic and nondiabetic people., Recent Findings: Small dense LDL which is known to be most closely associated with atherogenesis is more susceptible to glycation than more buoyant LDL. Glycation and oxidation of LDL appear to be intimately associated., Summary: Glycation of LDL occurs chiefly due to the nonenzymatic reaction of glucose and its metabolites with the free amino groups of lysine in which LDL is rich. Higher concentrations of glycated LDL are present in diabetic than in nondiabetic individuals, but even in the latter, there is generally more circulating glycated LDL than oxidatively modified LDL. Probably, oxidation and glycation of LDL are at least partially interdependent, but both prevent LDL receptor-mediated uptake and promote macrophage scavenger receptor uptake. The recognition that LDL glycation is at least as important as oxidation in atherogenesis may lead to improvements in our understanding of its mechanism and how to prevent it.

Purpose of Review: Blood lipoprotein profiles in early life are known to be related to and predictive of those in adulthood, but little is known about their determinants. Genetic and environmental influences affect cord blood lipoproteins, but how this occurs and the relative contribution of these influences to the overall profile in healthy newborns remains uncertain., Recent Findings: This review discusses findings from a range of earlier and more recent studies, and summarizes the key influences on cord blood lipoproteins. In particular, we review the potential contribution of maternal blood total cholesterol levels during pregnancy and the increased maternal transmission in newborns of mothers with diabetes., Summary: In cord blood, cholesterol levels are lower than in adults and the relative proportion present in HDL as opposed to LDL is much higher. The currently available evidence suggests that several factors influence the composition of cord blood lipoproteins. Although inheritance of major monogenic disorders can affect cord lipids in general, the genetic contribution appears to be minimal, although effects of the proprotein convertase subtilisin/kexine type 9 gene (PCSK9) need fuller exploration in this regard in certain ethnic groups. Evidence is summarized that maternal lipoprotein levels, particularly those due to diet or induced by pregnancy, influence cord lipid levels. Placental insufficiency and other conditions affecting fetal growth and the mode of delivery may also influence cord lipoprotein concentrations. How maternal glucose tolerance during pregnancy affects cord blood lipoproteins remains unclear. In view of increasing evidence that cardiovascular risk may have prenatal antecedents, this would seem to be an important area for further investigation.

Purpose of Review: The antioxidant activity of high-density lipoprotein is largely due to the paraoxonase 1 located on it. Experiments with transgenic paraoxonase 1 knock-out mice indicate the potential for this enzyme to protect against atherogenesis. This effect of high-density lipoprotein in decreasing low-density lipoprotein lipid peroxidation is maintained for longer than that of antioxidant vitamins and could thus be more protective. Several important advances in the field of paraoxonase research have occurred during this review period, not least the discovery that two other members of the paraoxonase gene family, PON2 and PON3, may also have important antioxidant properties. Significant advances have been made in understanding the basic biochemical function of paraoxonase 1 and the discovery of possible modulators of its activity., Recent Findings: Decreased coronary heart disease risk associated with polymorphisms of paraoxonase 1, which are most active in lipid peroxide hydrolysis, as revealed by meta-analysis is likely to be an underestimate of the true contribution of paraoxonase 1 to coronary heart disease because these polymorphisms explain only a small component of the variation in paraoxonase 1 activity. It is a very important observation, however, because genetic influences are not likely to be confounded by other factors linked with both coronary heart disease and diminished paraoxonase 1 activity., Summary: Although advances have been made in research into the paraoxonase family and atherosclerosis, much more needs to be done. Paraoxonase 1 is much the most extensively researched and strategies will hopefully emerge to increase its activity and provide a more satisfactory test of the antioxidant hypothesis of atherosclerosis than antioxidant vitamins have done.

The protective effect of HDL against the development of atherosclerosis appears to be multifaceted involving a number of mechanisms. One of the major mechanisms is, however, the ability of HDL to decrease, directly or indirectly, the lipid peroxidation of LDL. The hydrolysis of lipid peroxides by PON1 makes a major contribution to this effect of HDL. Evidence is accumulating that the PON1 activity of human serum can be modulated by a variety of natural compounds and that these may increase or decrease the protective ability of PON1 and therefore of HDL on which it is exclusively located. Modulations of PON1 that enhance its activity may help to delay the atherosclerotic process.

Paraoxonase (PON1) hydrolyses organophosphate insecticides and nerve gases and is responsible for determining the selective toxicity of these compounds in mammals. Human PON1 has two genetic polymorphisms giving rise to amino-acid substitutions at positions 55 and 192. The 192 polymorphism is the major determinant of the PON1 activity polymorphism towards organophosphates. However, the 55 polymorphism also modulates activity. Ex vivo, the PON1 polymorphisms are important in determining the capacity of HDL to protect LDL against oxidative modification in vitro and this may explain the relationship between the PON1 alleles and coronary heart disease in case-control studies. In recent case-control studies serum PON1 concentration and activity were also found to be decreased in coronary heart disease (CHD) independent of the PON1 polymorphism, and in diabetes serum PON1 specific activity decrease is also independent of the PON1 genetic polymorphism. HDL from transgenic mice lacking PON1 fails to protect LDL against oxidative modification. Thus PON1 may be a determinant of resistance to the development of atherosclerosis by protecting lipoproteins against oxidative modification, perhaps by hydrolysing phospholipid and cholesteryl-ester hydroperoxides.

Human serum paraoxonase is located on an HDL. It has the capacity to retard the accumulation of lipid peroxides in LDL under oxidizing conditions in vitro. Paraoxonase has a genetic polymorphism that results in a single amino acid substitution. Evidence indicates that both the serum concentration of paraoxonase and an individual's genotype are related to plasma lipid and lipoprotein concentrations, and possibly also to coronary heart disease, implicating paraoxonase in the development of atherosclerosis.