Comparative Analysis of Atherogenic Lipoproteins L5 and Lp(a) in Atherosclerotic Cardiovascular Disease.

PURPOSE OF REVIEW: Low-density lipoprotein (LDL) poses a risk for atherosclerotic cardiovascular disease (ASCVD). As LDL comprises various subtypes differing in charge, density, and size, understanding their specific impact on ASCVD is crucial. Two highly atherogenic LDL subtypes-electronegative LDL (L5) and Lp(a)-induce vascular cell apoptosis and atherosclerotic changes independent of plasma cholesterol levels, and their mechanisms warrant further investigation. Here, we have compared the roles of L5 and Lp(a) in the development of ASCVD. RECENT FINDINGS: Lp(a) tends to accumulate in artery walls, promoting plaque formation and potentially triggering atherosclerosis progression through prothrombotic or antifibrinolytic effects. High Lp(a) levels correlate with calcific aortic stenosis and atherothrombosis risk. L5 can induce endothelial cell apoptosis and increase vascular permeability, inflammation, and atherogenesis, playing a key role in initiating atherosclerosis. Elevated L5 levels in certain high-risk populations may serve as a distinctive predictor of ASCVD. L5 and Lp(a) are both atherogenic lipoproteins contributing to ASCVD through distinct mechanisms. Lp(a) has garnered attention, but equal consideration should be given to L5.

The pathophysiology of excess plasma-free cholesterol.

PURPOSE OF REVIEW: Several large studies have shown increased mortality due to all-causes and to atherosclerotic cardiovascular disease. In most clinical settings, plasma HDL-cholesterol is determined as a sum of free cholesterol and cholesteryl ester, two molecules with vastly different metabolic itineraries. We examine the evidence supporting the concept that the pathological effects of elevations of plasma HDL-cholesterol are due to high levels of the free cholesterol component of HDL-C. RECENT FINDINGS: In a small population of humans, a high plasma HDL-cholesterol is associated with increased mortality. Similar observations in the HDL-receptor deficient mouse (Scarb1 -/- ), a preclinical model of elevated HDL-C, suggests that the pathological component of HDL in these patients is an elevated plasma HDL-FC. SUMMARY: Collective consideration of the human and mouse data suggests that clinical trials, especially in the setting of high plasma HDL, should measure free cholesterol and cholesteryl esters and not just total cholesterol.

Serum opacity factor rescues fertility among female Scarb1-/- mice by reducing HDL-free cholesterol bioavailability.

Human female infertility, 20% of which is idiopathic, is a public health problem for which better diagnostics and therapeutics are needed. A novel cause of infertility emerged from studies of female mice deficient in the HDL receptor gene (Scarb1). These mice are infertile and have high plasma HDL cholesterol (C) concentrations, due to elevated HDL-free cholesterol (FC), which transfers from HDL to all tissues. Previous studies have indicated that oral delivery of probucol, an HDL-lowering drug, to female Scarb1-/- mice reduces plasma HDL-C concentrations and rescues fertility. Additionally, serum opacity factor (SOF), a bacterial virulence factor, disrupts HDL structure, and bolus SOF injection into mice reduces plasma HDL-C concentrations. Here, we discovered that delivering SOF to female Scarb1-/- mice with an adeno-associated virus (AAVSOF) induces constitutive SOF expression, reduces HDL-FC concentrations, and rescues fertility while normalizing ovary morphology. Although AAVSOF did not alter ovary-FC content, the ovary-mol% FC correlated with plasma HDL-mol% FC in a fertility-dependent way. Therefore, reversing the abnormal plasma microenvironment of high plasma HDL-mol% FC in female Scarb1-/- mice rescues fertility. These data provide the rationale to search for similar mechanistic links between HDL-mol% FC and infertility and the rescue of fertility in women by reducing plasma HDL-mol% FC.

Serum opacity factor normalizes erythrocyte morphology in Scarb1-/- mice in an HDL-free cholesterol-dependent way.

Compared with WT mice, HDL receptor-deficient (Scarb1-/-) mice have higher plasma levels of free cholesterol (FC)-rich HDL and exhibit multiple pathologies associated with a high mol% FC in ovaries, platelets, and erythrocytes, which are reversed by lowering HDL. Bacterial serum opacity factor (SOF) catalyzes the opacification of plasma by targeting and quantitatively converting HDL to neo HDL (HDL remnant), a cholesterol ester-rich microemulsion, and lipid-free APOA1. SOF delivery with an adeno-associated virus (AAVSOF) constitutively lowers plasma HDL-FC and reverses female infertility in Scarb1-/- mice in an HDL-dependent way. We tested whether AAVSOF delivery to Scarb1-/- mice will normalize erythrocyte morphology in an HDL-FC-dependent way. We determined erythrocyte morphology and FC content (mol%) in three groups-WT, untreated Scarb1-/- (control), and Scarb1-/- mice receiving AAVSOF-and correlated these with their respective HDL-mol% FC. Plasma-, HDL-, and tissue-lipid compositions were also determined. Plasma- and HDL-mol% FC positively correlated across all groups. Among Scarb1-/- mice, AAVSOF treatment normalized reticulocyte number, erythrocyte morphology, and erythrocyte-mol% FC. Erythrocyte-mol% FC positively correlated with HDL-mol% FC and with both the number of reticulocytes and abnormal erythrocytes. AAVSOF treatment also reduced FC of extravascular tissues to a lesser extent. HDL-FC spontaneously transfers from plasma HDL to cell membranes. AAVSOF treatment lowers erythrocyte-FC and normalizes erythrocyte morphology and lipid composition by reducing HDL-mol% FC.

Bempedoic acid in patients with type 2 diabetes mellitus, prediabetes, and normoglycaemia: A post hoc analysis of efficacy and glycaemic control using pooled data from phase 3 clinical trials.

AIM: To evaluate the effect of bempedoic acid on glycaemic and lipid variables in patients with hypercholesterolaemia. METHODS: A patient-level pooled analysis of four phase 3, randomized, double-blind, placebo-controlled trials evaluated changes in glycaemia, change from baseline in LDL-C, and adverse events. Patients (N = 3621) on maximally tolerated statins were randomized 2:1 to oral bempedoic acid 180 mg or placebo once daily for 12 to 52 weeks with the results analysed by baseline glycaemic status (diabetes, prediabetes, or normoglycaemia). RESULTS: The annual rate of new-onset diabetes for bempedoic acid versus placebo in patients with normoglycaemia at baseline (n = 618) was 0.3% versus 0.8%, and for patients with prediabetes at baseline (n = 1868) it was 4.7% versus 5.9%. In patients with diabetes or prediabetes, bempedoic acid significantly (P < .0001) reduced HbA1c by -0.12% and -0.06%, respectively, and did not worsen fasting glucose versus placebo. Bempedoic acid significantly and consistently lowered LDL-C levels versus placebo, regardless of baseline glycaemic status (placebo-corrected difference range, -17.2% to -29.6%; P < .001 for each stratum). The safety of bempedoic acid was comparable with placebo and similar across glycaemic strata. CONCLUSIONS: Bempedoic acid significantly lowered LDL-C across glycaemic strata and did not worsen glycaemic variables or increase the incidence of new-onset diabetes versus placebo over a median follow-up of 1 year.

High Free Cholesterol Bioavailability Drives the Tissue Pathologies in Scarb1-/- Mice.

Objective: Overall and atherosclerosis-associated mortality is elevated in humans with very high HDL (high-density lipoprotein) cholesterol concentrations. Mice with a deficiency of the HDL receptor, Scarb1 (scavenger receptor class B type 1), are a robust model of this phenotype and exhibit several additional pathologies. We hypothesized that the previously reported high plasma concentration of free cholesterol (FC)-rich HDL in Scarb1-/- mice produces a state of high HDL-FC bioavailability that increases whole-body FC and dysfunction in multiple tissue sites. Approach and Results: The higher mol% FC in Scarb1-/- versus WT (wild type) HDL (41.1 versus 16.0 mol%) affords greater FC bioavailability for transfer to multiple sites. Plasma clearance of autologous HDL-FC mass was faster in WT versus Scarb1-/- mice. FC influx from Scarb1-/- HDL to LDL (low-density lipoprotein) and J774 macrophages was greater ([almost equal to]4x) than that from WT HDL, whereas FC efflux capacity was similar. The higher mol% FC of ovaries, erythrocytes, heart, and macrophages of Scarb1-/- versus WT mice is associated with previously reported female infertility, impaired cell maturation, cardiac dysfunction, and atherosclerosis. The FC contents of other tissues were similar in the two genotypes, and these tissues were not associated with any overt pathology. In addition to the differences between WT versus Scarb1-/- mice, there were many sex-dependent differences in tissue-lipid composition and plasma FC clearance rates. Conclusions: Higher HDL-FC bioavailability among Scarb1-/- versus WT mice drives increased FC content of multiple cell sites and is a potential biomarker that is mechanistically linked to multiple pathologies.

Mammalian Target of Rapamycin: A Metabolic Rheostat for Regulating Adipose Tissue Function and Cardiovascular Health.

The complex relationship between diet and metabolism is an important contributor to cellular metabolism and health. Over the past few decades, a central role for mammalian target of rapamycin (mTOR) in the regulation of multiple cellular processes, including the response to food intake, maintaining homeostasis, and the pathogenesis of disease, has been shown. Herein, we first review our current understanding of the biochemical functions of mTOR and its response to fluctuations in hormone levels, like insulin. Second, we highlight the role of mTOR in lipogenesis, adipogenesis, ß-oxidation of lipids, and ketosis of carbohydrates, lipids, and proteins. Special attention is paid to recent advances in mTOR signaling in white versus brown adipose tissues. Finally, we review how mTOR regulates cardiovascular health and disease. Together, these insights define a clearer picture of the connection between mTOR signaling, metabolic health, and disease.

Lipid-modifying activity of curcuminoids: A systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: The aim of this systematic review and meta-analysis was to determine and clarify the impact of curcuminoids on serum lipid levels. METHODS: Randomized controlled trials (RCTs) investigating the effects of curcuminoids on plasma lipids were searched in PubMed-Medline, Scopus, Web of Science databases (from inception to April 3rd, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on lipid concentrations. RESULTS: A meta-analysis of 20 RCTs with 1427 participants suggested a significant decrease in plasma concentrations of triglycerides (WMD: -21.36 mg/dL, 95% CI: -32.18, -10.53, p < 0.001), and an elevation in plasma HDL-C levels (WMD: 1.42 mg/dL, 95% CI: 0.03, 2.81, p = 0.046), while plasma levels of LDL-C (WMD: -5.82 mg/dL, 95% CI: -15.80, 4.16, p = 0.253) and total cholesterol (WMD: -9.57 mg/dL, 95% CI: -20.89, 1.75, p = 0.098) were not altered. The effects of curcuminoids on lipids were not found to be dependent on the duration of supplementation. CONCLUSION: This meta-analysis has shown that curcuminoid therapy significantly reduces plasma triglycerides and increases HDL-C levels.

Scavenger receptor B1 (SR-B1) profoundly excludes high density lipoprotein (HDL) apolipoprotein AII as it nibbles HDL-cholesteryl ester.

Reverse cholesterol transport (transfer of macrophage-cholesterol in the subendothelial space of the arterial wall to the liver) is terminated by selective high density lipoprotein (HDL)-cholesteryl ester (CE) uptake, mediated by scavenger receptor class B, type 1 (SR-B1). We tested the validity of two models for this process: "gobbling," i.e. one-step transfer of all HDL-CE to the cell and "nibbling," multiple successive cycles of SR-B1-HDL association during which a few CEs transfer to the cell. Concurrently, we compared cellular uptake of apoAI with that of apoAII, which is more lipophilic than apoAI, using HDL-[3H]CE labeled with [125I]apoAI or [125I]apoAII. The studies were conducted in CHO-K1 and CHO-ldlA7 cells (LDLR-/-) with (CHO-SR-B1) and without SR-B1 overexpression and in human Huh7 hepatocytes. Relative to CE, both apoAI and apoAII were excluded from uptake by all cells. However, apoAII was more highly excluded from uptake (2-4×) than apoAI. To distinguish gobbling versus nibbling mechanisms, media from incubations of HDL with CHO-SR-B1 cells were analyzed by non-denaturing PAGE, size-exclusion chromatography, and the distribution of apoAI, apoAII, cholesterol, and phospholipid among HDL species as a function of incubation time. HDL size gradually decreased, i.e. nibbling, with the concurrent release of lipid-free apoAI; apoAII was retained in an HDL remnant. Our data support an SR-B1 nibbling mechanism that is similar to that of streptococcal serum opacity factor, which also selectively removes CE and releases apoAI, leaving an apoAII-rich remnant.

Monocyte-to-HDL-cholesterol ratio as a prognostic marker in cardiovascular diseases.

Inflammation and lipid accumulation are two basic hallmarks of atherosclerosis as a chronic disease. Inflammation not only is a local response but can also be considered as a systemic process followed by an elevation of inflammatory mediators. Monocytes are a major source of proinflammatory species during atherogenesis. In atherosclerosis, modified low-density lipoproteins (LDLs) are removed by macrophages; these are recruited in the vessel wall, inducing the release of inflammatory cytokines in inflamed tissue. Hence, inflammatory cholesterol ester-loaded plaque is generated. High-density lipoprotein-cholesterol (HDL-C) exhibits antiatherosclerotic effects by neutralizing the proinflammatory and pro-oxidant effects of monocytes via inhibiting the migration of macrophages and LDL oxidation in addition to the efflux of cholesterol from these cells. Furthermore, HDL plays a role in suppressing the activation of monocytes and proliferation-differentiation of monocyte progenitor cells. Thus, accumulation of monocytes and reduction of HDL-C may participate in atherosclerosis and cardiovascular diseases (CVD). Given that the relationship between the high number of monocytes and low HDL-C levels has been reported in inflammatory disorders, this review focused on understanding whether the monocyte-to-HDL ratio could be a convenient marker to predict atherosclerosis development and progression, hallmarks of CV events, instead of the individual monocyte count or HDL-C level.

Effect of fibrates on glycemic parameters: A systematic review and meta-analysis of randomized placebo-controlled trials.

AIMS: The aim of this meta-analysis of randomized placebo-controlled clinical trials was to assess the effect of fibrates on glycemic parameters. MATERIALS AND METHODS: Only randomized placebo-controlled trials investigating the impact of fibrate treatment on glucose homeostasis markers were searched in PubMed-Medline, SCOPUS, Web of Science and Google Scholar databases (from inception to April 11, 2017). A random-effects model and generic inverse variance method were used for quantitative data synthesis. Sensitivity analysis was conducted using the leave-one-out method. A weighted random-effects meta-regression was performed to evaluate the impact of potential confounders on glycemic parameters. RESULTS: This meta-analysis of data from 22 randomized placebo-controlled clinical trials involving a total of 11,402 subjects showed that fibrate therapy significantly decreased fasting plasma glucose (WMD: -0.28 mmol/L, 95% CI: -0.42, -0.14, p < 0.001), insulin levels (WMD: -3.87 pmol/L, 95% CI: -4.97, -2.78, p < 0.001) and insulin resistance (HOMA-IR, WMD: -1.09, 95% CI: -1.71, -0.47, p = 0.001), but with no effect on HbA1c (WMD: 0.01%, 95% CI: -0.18, 0.19, p = 0.955). All analyses were robust in the leave-one-out sensitivity analysis except for insulin levels that showed a non-significant result (WMD: -0.84 pmol/L, 95% CI: -6.36, 4.68, p = 0.766) following omission of one of the included trials. CONCLUSION: This meta-analysis has shown that fibrate treatment significantly decreases fasting plasma glucose, insulin levels, and HOMA-IR indicating additional clinical therapeutic benefits.

ABCA1-Derived Nascent High-Density Lipoprotein-Apolipoprotein AI and Lipids Metabolically Segregate.

OBJECTIVE: Reverse cholesterol transport comprises cholesterol efflux from ABCA1-expressing macrophages to apolipoprotein (apo) AI, giving nascent high-density lipoprotein (nHDL), esterification of nHDL-free cholesterol (FC), selective hepatic extraction of HDL lipids, and hepatic conversion of HDL cholesterol to bile salts, which are excreted. We tested this model by identifying the fates of nHDL-[3H]FC, [14C] phospholipid (PL), and [125I]apo AI in serum in vitro and in vivo. APPROACH AND RESULTS: During in vitro incubation of human serum, nHDL-[3H]FC and [14C]PL rapidly transfer to HDL and low-density lipoproteins (t1/2=2-7 minutes), whereas nHDL-[125I]apo AI transfers solely to HDL (t1/2<10 minutes) and to the lipid-free form (t1/2>480 minutes). After injection into mice, nHDL-[3H]FC and [14C]PL rapidly transfer to liver (t1/2=≈2-3 minutes), whereas apo AI clears with t1/2=≈460 minutes. The plasma nHDL-[3H]FC esterification rate is slow (0.46%/h) compared with hepatic uptake. PL transfer protein enhances nHDL-[14C]PL but not nHDL-[3H]FC transfer to cultured Huh7 hepatocytes. CONCLUSIONS: nHDL-FC, PL, and apo AI enter different pathways in vivo. Most nHDL-[3H]FC and [14C]PL are rapidly extracted by the liver via SR-B1 (scavenger receptor class B member 1) and spontaneous transfer; hepatic PL uptake is promoted by PL transfer protein. nHDL-[125I]apo AI transfers to HDL and to the lipid-free form that can be recycled to nHDL formation. Cholesterol esterification by lecithin:cholesterol acyltransferase is a minor process in nHDL metabolism. These findings could guide the design of therapies that better mobilize peripheral tissue-FC to hepatic disposal.

Acylation of lysine residues in human plasma high density lipoprotein increases stability and plasma clearance in vivo.

Although human plasma high density lipoproteins (HDL) concentrations negatively correlate with atherosclerotic cardiovascular disease, underlying mechanisms are unknown. Thus, there is continued interest in HDL structure and functionality. Numerous plasma factors disrupt HDL structure while inducing the release of lipid free apolipoprotein (apo) AI. Given that HDL is an unstable particle residing in a kinetic trap, we tested whether HDL could be stabilized by acylation with acetyl and hexanoyl anhydrides, giving AcHDL and HexHDL respectively. Lysine analysis with fluorescamine showed that AcHDL and HexHDL respectively contained 11 acetyl and 19 hexanoyl groups. Tests with biological and physicochemical perturbants showed that HexHDL was more stable than HDL to perturbant-induced lipid free apo AI formation. Like the reaction of streptococcal serum opacity factor against HDL, the interaction of HDL with its receptor, scavenger receptor class B member 1 (SR-B1), removes CE from HDL. Thus, we tested and validated the hypothesis that selective uptake of HexHDL-[3H]CE by Chinese Hamster Ovary cells expressing SR-B1 is less than that of HDL-[3H]CE; thus, selective SR-B1 uptake of HDL-CE depends on HDL instability. However, in mice, plasma clearance, hepatic uptake and sterol secretion into bile were faster from HexHDL-[3H]CE than from HDL-[3H]CE. Collectively, our data show that acylation increases HDL stability and that the reaction of plasma factors with HDL and SR-B1-mediated uptake are reduced by increased HDL stability. In vivo data suggest that HexHDL promotes charge-dependent reverse cholesterol transport, by a mechanism that increases hepatic sterol uptake via non SR-B1 receptors, thereby increasing bile acid output.

Streptococcal serum opacity factor promotes cholesterol ester metabolism and bile acid secretion in vitro and in vivo.

Plasma high density lipoprotein-cholesterol (HDL-C) concentrations negatively correlate with atherosclerotic cardiovascular disease. HDL is thought to have several atheroprotective functions, which are likely distinct from the epidemiological inverse relationship between HDL-C levels and risk. Specifically, strategies that reduce HDL-C while promoting reverse cholesterol transport (RCT) may have therapeutic value. The major product of the serum opacity factor (SOF) reaction versus HDL is a cholesteryl ester (CE)-rich microemulsion (CERM), which contains apo E and the CE of ~400,000 HDL particles. Huh7 hepatocytes take up CE faster when delivered as CERM than as HDL, in part via the LDL-receptor (LDLR). Here we compared the final RCT step, hepatic uptake and subsequent intracellular processing to cholesterol and bile salts for radiolabeled HDL-, CERM- and LDL-CE by Huh7 cells and in vivo in C57BL/6J mice. In Huh7 cells, uptake from LDL was greater than from CERM (2-4X) and HDL (5-10X). Halftimes for [(14)C]CE hydrolysis were 3.0±0.2, 4.4±0.6 and 5.4±0.7h respectively for HDL, CERM and LDL-CE. The fraction of sterols secreted as bile acids was ~50% by 8h for all three particles. HDL, CERM and LDL-CE metabolism in mice showed efficient plasma clearance of CERM-CE, liver uptake and metabolism, and secretion as bile acids into the gall bladder. This work supports the therapeutic potential of the SOF reaction, which diverts HDL-CE to the LDLR, thereby increasing hepatic CE uptake, and sterol disposal as bile acids.

Neo High-Density Lipoprotein Produced by the Streptococcal Serum Opacity Factor Activity against Human High-Density Lipoproteins Is Hepatically Removed via Dual Mechanisms.

Injection of streptococcal serum opacity factor (SOF) into mice reduces the plasma cholesterol level by ∼40%. In vitro, SOF converts high-density lipoproteins (HDLs) into multiple products, including a small HDL, neo HDL. In vitro, neo HDL accounts for ∼60% of the protein mass of the SOF reaction products; in vivo, the accumulated mass of neo HDL is <1% of that observed in vitro. To identify the underlying cause of this difference, we determined the fate of neo HDL in plasma in vitro and in vivo. Following incubation with HDL, neo HDL-PC rapidly transfers to HDL, giving a small remnant, which fuses with HDL. An increased level of SR-B1 expression in Huh7 hepatoma cells and a reduced level of LDLR expression in CHO cells had little effect on neo HDL-[3H]CE uptake. Thus, the dominant receptors for neo HDL uptake are not LDLR or SR-B1. The in vivo metabolic fates of neo HDL-[3H]CE and HDL-[3H]CE were different. Thirty minutes after the injection of neo HDL-[3H]CE and HDL-[3H]CE into mice, plasma [3H]CE counts were 40 and 53%, respectively, of injected counts, with 10 times more [3H]CE appearing in the livers of neo HDL-[3H]CE-injected than in those of HDL-[3H]CE-injected mice. These data support a model of neo HDL-[3H]CE clearance by two parallel pathways. At early post-neo HDL-[3H]CE injection times, some neo HDL is directly removed by the liver; the remainder transfers its PC to HDL, leaving a remnant that fuses with HDL, which is also hepatically removed more slowly. Given that SR-B1 and SOF both remove CE from HDL, this novel mechanism may also underlie the metabolism of remnants released by hepatocytes following selective SR-B1-mediated uptake of HDL-CE.

The effect of statin therapy on heart failure events: a collaborative meta-analysis of unpublished data from major randomized trials.

AIMS: The effect of statins on risk of heart failure (HF) hospitalization and HF death remains uncertain. We aimed to establish whether statins reduce major HF events. METHODS AND RESULTS: We searched Medline, EMBASE, and the Cochrane Central Register of Controlled Trials for randomized controlled endpoint statin trials from 1994 to 2014. Collaborating trialists provided unpublished data from adverse event reports. We included primary- and secondary-prevention statin trials with >1000 participants followed for >1 year. Outcomes consisted of first non-fatal HF hospitalization, HF death and a composite of first non-fatal HF hospitalization or HF death. HF events occurring <30 days after within-trial myocardial infarction (MI) were excluded. We calculated risk ratios (RR) with fixed-effects meta-analyses. In up to 17 trials with 132 538 participants conducted over 4.3 [weighted standard deviation (SD) 1.4] years, statin therapy reduced LDL-cholesterol by 0.97 mmol/L (weighted SD 0.38 mmol/L). Statins reduced the numbers of patients experiencing non-fatal HF hospitalization (1344/66 238 vs. 1498/66 330; RR 0.90, 95% confidence interval, CI 0.84-0.97) and the composite HF outcome (1234/57 734 vs. 1344/57 836; RR 0.92, 95% CI 0.85-0.99) but not HF death (213/57 734 vs. 220/57 836; RR 0.97, 95% CI 0.80-1.17). The effect of statins on first non-fatal HF hospitalization was similar whether this was preceded by MI (RR 0.87, 95% CI 0.68-1.11) or not (RR 0.91, 95% CI 0.84-0.98). CONCLUSION: In primary- and secondary-prevention trials, statins modestly reduced the risks of non-fatal HF hospitalization and a composite of non-fatal HF hospitalization and HF death with no demonstrable difference in risk reduction between those who suffered an MI or not.

Apolipoprotein AI deficiency inhibits serum opacity factor activity against plasma high density lipoprotein via a stabilization mechanism.

The reaction of Streptococcal serum opacity factor (SOF) against plasma high-density lipoproteins (HDL) produces a large cholesteryl ester-rich microemulsion (CERM), a smaller neo HDL that is apolipoprotein (apo) AI-poor, and lipid-free apo AI. SOF is active versus both human and mouse plasma HDL. In vivo injection of SOF into mice reduces plasma cholesterol ∼40% in 3 h while forming the same products observed in vitro, but at different ratios. Previous studies supported the hypothesis that labile apo AI is required for the SOF reaction vs HDL. Here we further tested that hypothesis by studies of SOF against HDL from apo AI-null mice. When injected into apo AI-null mice, SOF reduced plasma cholesterol ∼35% in 3 h. The reaction of SOF vs apo AI-null HDL in vitro produced a CERM and neo HDL, but no lipid-free apo. Moreover, according to the rate of CERM formation, the extent and rate of the SOF reaction versus apo AI-null mouse HDL were less than that against wild-type (WT) mouse HDL. Chaotropic perturbation studies using guanidine hydrochloride showed that apo AI-null HDL was more stable than WT HDL. Human apo AI added to apo AI-null HDL was quantitatively incorporated, giving reconstituted HDL. Both SOF and guanidine hydrochloride displaced apo AI from the reconstituted HDL. These results support the conclusion that apo AI-null HDL is more stable than WT HDL because it lacks apo AI, a labile protein that is readily displaced by physicochemical and biochemical perturbations. Thus, apo AI-null HDL is less SOF-reactive than WT HDL. The properties of apo AI-null HDL can be partially restored to those of WT HDL by the spontaneous incorporation of human apo AI. It remains to be determined what other HDL functions are affected by apo AI deletion.

Statin Intolerance: the Clinician's Perspective.

Muscle problems and other adverse symptoms associated with statin use are frequent reasons for non-adherence and discontinuation of statin therapy, which results in inadequate control of hyperlipidemia and increased cardiovascular risk. However, most patients who experience adverse symptoms during statin use are able to tolerate at least some degree of statin therapy. Given the profound cardiovascular benefits derived from statins, an adequate practical approach to statin intolerance is, therefore, of great clinical importance. Statin intolerance can be defined as the occurrence of myalgia or other adverse symptoms that are attributed to statin therapy and that lead to its discontinuation. In reality, these symptoms are actually unrelated to statin use in many patients, especially in those with atypical presentations following long periods of treatment. Thus, the first step in approaching patients with adverse symptoms during the course of statin therapy is identification of those patients for whom true statin intolerance is unlikely, since most of these patients would probably be capable of tolerating adequate statin therapy. In patients with statin intolerance, an altered dosing regimen of very low doses of statins should be attempted and, if tolerated, should gradually be increased to achieve the highest tolerable doses. In addition, other lipid-lowering drugs may be needed, either in combination with statins, or alone, if statins are not tolerated at all. Stringent control of other risk factors can aid in reducing cardiovascular risk if attaining lipid treatment goals proves difficult.

Levels and changes of HDL cholesterol and apolipoprotein A-I in relation to risk of cardiovascular events among statin-treated patients: a meta-analysis.

BACKGROUND: It is unclear whether levels of high-density lipoprotein cholesterol (HDL-C) or apolipoprotein A-I (apoA-I) remain inversely associated with cardiovascular risk among patients who achieve very low levels of low-density lipoprotein cholesterol on statin therapy. It is also unknown whether a rise in HDL-C or apoA-I after initiation of statin therapy is associated with a reduced cardiovascular risk. METHODS AND RESULTS: We performed a meta-analysis of 8 statin trials in which lipids and apolipoproteins were determined in all study participants at baseline and at 1-year follow-up. Individual patient data were obtained for 38,153 trial participants allocated to statin therapy, of whom 5387 suffered a major cardiovascular event. HDL-C levels were associated with a reduced risk of major cardiovascular events (adjusted hazard ratio [HR], 0.83; 95% confidence interval [CI], 0.81-0.86 per 1 standard deviation increment), as were apoA-I levels (HR, 0.79; 95% CI, 0.72-0.82). This association was also observed among patients achieving on-statin low-density lipoprotein cholesterol levels <50 mg/dL. An increase of HDL-C was not associated with reduced cardiovascular risk (HR, 0.98; 95% CI, 0.94-1.01 per 1 standard deviation increment), whereas a rise in apoA-I was (HR, 0.93; 95% CI, 0.90-0.97). CONCLUSIONS: Among patients treated with statin therapy, HDL-C and apoA-I levels were strongly associated with a reduced cardiovascular risk, even among those achieving very low low-density lipoprotein cholesterol. An apoA-I increase was associated with a reduced risk of major cardiovascular events, whereas for HDL-C this was not the case. These findings suggest that therapies that increase apoA-I concentration require further exploration with regard to cardiovascular risk reduction.

Biological relevance of inflammation and oxidative stress in the pathogenesis of arterial diseases.

Over the past three decades, age-adjusted rates of cardiovascular morbidity and mortality have fallen in the United States, but the prevalence of obesity and associated metabolic disorders has risen dramatically. Recent studies have begun to unravel the complex linkages between adipose and vascular tissues that may accelerate the development of atherosclerosis in the context of obesity. Experimental models indicate that inflammation and oxidative stress, which mutually amplify each other within the vasculature and in visceral fat, are key processes that drive the initiation, progression, and subsequent rupture of the atherosclerotic lesion. Emerging research is further elucidating the contributions made by chemokines and their receptors, adipokines, and miRNAs to arterial disease. Translation of these basic science findings to clinical applications represents a tantalizing possibility for reducing the global burden of obesity-associated atherosclerosis and other cardiovascular diseases.