Statin-associated muscle symptoms (SAMS) are one of the principal reasons for statin non-adherence and/or discontinuation, contributing to adverse cardiovascular outcomes. This European ...Atherosclerosis Society (EAS) Consensus Panel overviews current understanding of the pathophysiology of statin-associated myopathy, and provides guidance for diagnosis and management of SAMS. Statin-associated myopathy, with significant elevation of serum creatine kinase (CK), is a rare but serious side effect of statins, affecting 1 per 1000 to 1 per 10 000 people on standard statin doses. Statin-associated muscle symptoms cover a broader range of clinical presentations, usually with normal or minimally elevated CK levels, with a prevalence of 7-29% in registries and observational studies. Preclinical studies show that statins decrease mitochondrial function, attenuate energy production, and alter muscle protein degradation, thereby providing a potential link between statins and muscle symptoms; controlled mechanistic and genetic studies in humans are necessary to further understanding. The Panel proposes to identify SAMS by symptoms typical of statin myalgia (i.e. muscle pain or aching) and their temporal association with discontinuation and response to repetitive statin re-challenge. In people with SAMS, the Panel recommends the use of a maximally tolerated statin dose combined with non-statin lipid-lowering therapies to attain recommended low-density lipoprotein cholesterol targets. The Panel recommends a structured work-up to identify individuals with clinically relevant SAMS generally to at least three different statins, so that they can be offered therapeutic regimens to satisfactorily address their cardiovascular risk. Further research into the underlying pathophysiological mechanisms may offer future therapeutic potential.
Hemiptera, the largest non-holometabolous order of insects, represents approximately 7% of metazoan diversity. With extraordinary life histories and highly specialized morphological adaptations, ...hemipterans have exploited diverse habitats and food sources through approximately 300 Myr of evolution. To elucidate the phylogeny and evolutionary history of Hemiptera, we carried out the most comprehensive mitogenomics analysis on the richest taxon sampling to date covering all the suborders and infraorders, including 34 newly sequenced and 94 published mitogenomes. With optimized branch length and sequence heterogeneity, Bayesian analyses using a site-heterogeneous mixture model resolved the higher-level hemipteran phylogeny as (Sternorrhyncha, (Auchenorrhyncha, (Coleorrhyncha, Heteroptera))). Ancestral character state reconstruction and divergence time estimation suggest that the success of true bugs (Heteroptera) is probably due to angiosperm coevolution, but key adaptive innovations (e.g. prognathous mouthpart, predatory behaviour, and haemelytron) facilitated multiple independent shifts among diverse feeding habits and multiple independent colonizations of aquatic habitats.
In this trial, intravascular ultrasonography was used to compare the effects of atorvastatin versus rosuvastatin on regression of coronary atherosclerosis. Both statins led to regression in two ...thirds of patients, with no significant difference between their effects.
Randomized clinical trials have consistently shown that inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (statins) reduce cardiovascular event rates.
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The favorable effects of statins extend across a range of levels of low-density lipoprotein (LDL) cholesterol, with no apparent lower threshold for a benefit.
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In parallel, imaging trials have shown that intensive statin regimens slow the progression of coronary atherosclerosis and may even result in disease regression in some patients.
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Accordingly, guidelines for cardiovascular disease prevention have increasingly emphasized that lowering LDL cholesterol levels with statins is the primary goal of lipid-modulating therapy.
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Available statins differ considerably . . .
The concept of raising high-density lipoprotein (HDL) has been the focus of increasing attention as a strategy to reduce cardiovascular disease. HDL particles are, however, highly heterogeneous in ...structure, intravascular metabolism and biological activity. In this review, we describe major HDL subpopulations and discuss new findings on the antiatherogenic properties of HDL particles. Across the HDL subpopulation spectrum, small, dense, protein-rich HDLs display potent atheroprotective properties, which can be attributed to specific clusters of proteins and lipids; such activities can be compromised under conditions of atherogenic dyslipidemia. Comprehensive structural and compositional analyses of HDL may provide key information to identify subpopulations displaying specific biological functions and acquiring deficient functionality, with the potential to reveal novel biomarkers of cardiovascular risk and new pharmacological targets.
To critically appraise new insights into HDL structure and function in type 1 diabetes (T1DM) and type 2 diabetes (T2DM).
In young T1DM patients with early renal impairment and a high inflammatory ...score, both HDL antioxidative activity and endothelial vasodilatory function were impaired, revealing a critical link between HDL dysfunction, subclinical vascular damage, systemic inflammation and end organ damage. HDL may inhibit development of T2DM by attenuating endoplasmic reticulum (ER) stress and apoptotic loss of pancreatic β-cells, an effect due in part to ABC transporter-mediated efflux of specific oxysterols with downstream activation of the hedghehog signalling receptor, Smoothened. The apoM-sphingosine-1-phosphate complex is critical to HDL antidiabetic activity, encompassing protection against insulin resistance, promotion of insulin secretion, enhanced β-cell survival and inhibition of hepatic glucose production. Structure-function studies of HDL in hyperglycemic, dyslipidemic T2DM patients revealed both gain and loss of lipidomic and proteomic components. Such changes attenuated both the optimal protective effects of HDL on mitochondrial function and its capacity to inhibit endothelial cell apoptosis. Distinct structural components associated with individual HDL functions.
Extensive evidence indicates that both the proteome and lipidome of HDL are altered in T1DM and T2DM, with impairment of multiple functions.
IMPORTANCE: Triglycerides and cholesterol are both carried in plasma by apolipoprotein B (ApoB)–containing lipoprotein particles. It is unknown whether lowering plasma triglyceride levels reduces the ...risk of cardiovascular events to the same extent as lowering low-density lipoprotein cholesterol (LDL-C) levels. OBJECTIVE: To compare the association of triglyceride-lowering variants in the lipoprotein lipase (LPL) gene and LDL-C–lowering variants in the LDL receptor gene (LDLR) with the risk of cardiovascular disease per unit change in ApoB. DESIGN, SETTING, AND PARTICIPANTS: Mendelian randomization analyses evaluating the associations of genetic scores composed of triglyceride-lowering variants in the LPL gene and LDL-C–lowering variants in the LDLR gene, respectively, with the risk of cardiovascular events among participants enrolled in 63 cohort or case-control studies conducted in North America or Europe between 1948 and 2017. EXPOSURES: Differences in plasma triglyceride, LDL-C, and ApoB levels associated with the LPL and LDLR genetic scores. MAIN OUTCOMES AND MEASURES: Odds ratio (OR) for coronary heart disease (CHD)—defined as coronary death, myocardial infarction, or coronary revascularization—per 10-mg/dL lower concentration of ApoB-containing lipoproteins. RESULTS: A total of 654 783 participants, including 91 129 cases of CHD, were included (mean age, 62.7 years; 51.4% women). For each 10-mg/dL lower level of ApoB-containing lipoproteins, the LPL score was associated with 69.9-mg/dL (95% CI, 68.1-71.6; P = 7.1 × 10−1363) lower triglyceride levels and 0.7-mg/dL (95% CI, 0.03-1.4; P = .04) higher LDL-C levels; while the LDLR score was associated with 14.2-mg/dL (95% CI, 13.6-14.8; P = 1.4 × 10−465) lower LDL-C and 1.9-mg/dL (95% CI, 0.1-3.9; P = .04) lower triglyceride levels. Despite these differences in associated lipid levels, the LPL and LDLR scores were associated with similar lower risk of CHD per 10-mg/dL lower level of ApoB-containing lipoproteins (OR, 0.771 95% CI, 0.741-0.802, P = 3.9 × 10−38 and OR, 0.773 95% CI, 0.747-0.801, P = 1.1 × 10−46, respectively). In multivariable mendelian randomization analyses, the associations between triglyceride and LDL-C levels with the risk of CHD became null after adjusting for differences in ApoB (triglycerides: OR, 1.014 95% CI, 0.965-1.065, P = .19; LDL-C: OR, 1.010 95% CI, 0.967-1.055, P = .19; ApoB: OR, 0.761 95% CI, 0.723-0.798, P = 7.51 × 10−20). CONCLUSIONS AND RELEVANCE: Triglyceride-lowering LPL variants and LDL-C–lowering LDLR variants were associated with similar lower risk of CHD per unit difference in ApoB. Therefore, the clinical benefit of lowering triglyceride and LDL-C levels may be proportional to the absolute change in ApoB.
Statins are known to lower levels of LDL cholesterol, protect against cardiovascular disease, and slightly increase the risk of type 2 diabetes. This analysis of genetic variants in 112,772 ...participants from 14 studies suggests that PCSK9 inhibitors may do the same.
Monoclonal antibodies and other therapies that inhibit proprotein convertase subtilisin–kexin type 9 (PCSK9) have been shown to reduce low-density lipoprotein (LDL) cholesterol levels by approximately 50 to 60% in several randomized trials.
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Whether lowering LDL cholesterol levels by inhibiting PCSK9 will reduce the risk of cardiovascular events and, like statins, also increase the risk of new-onset diabetes is unknown.
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Exploratory and post hoc analyses of randomized trials have suggested that lowering LDL cholesterol levels by approximately 70 mg per deciliter (1.81 mmol per liter) with a PCSK9 inhibitor may reduce the risk of major cardiovascular events by up to . . .
High-density lipoproteins (HDL) possess key atheroprotective biological properties, including cellular cholesterol efflux capacity, and anti-oxidative and anti-inflammatory activities. Plasma HDL ...particles are highly heterogeneous in physicochemical properties, metabolism, and biological activity. Within the circulating HDL particle population, small, dense HDL particles display elevated cellular cholesterol efflux capacity, afford potent protection of atherogenic low-density lipoprotein against oxidative stress and attenuate inflammation. The antiatherogenic properties of HDL can, however be compromised in metabolic diseases associated with accelerated atherosclerosis. Indeed, metabolic syndrome and type 2 diabetes are characterized not only by elevated cardiovascular risk and by low HDL-cholesterol (HDL-C) levels but also by defective HDL function. Functional HDL deficiency is intimately associated with alterations in intravascular HDL metabolism and structure. Indeed, formation of HDL particles with attenuated antiatherogenic activity is mechanistically related to core lipid enrichment in triglycerides and cholesteryl ester depletion, altered apolipoprotein A-I (apoA-I) conformation, replacement of apoA-I by serum amyloid A, and covalent modification of HDL protein components by oxidation and glycation. Deficient HDL function and subnormal HDL-C levels may act synergistically to accelerate atherosclerosis in metabolic disease. Therapeutic normalization of attenuated antiatherogenic HDL function in terms of both particle number and quality of HDL particles is the target of innovative pharmacological approaches to HDL raising, including inhibition of cholesteryl ester transfer protein, enhanced lipidation of apoA-I with nicotinic acid and infusion of reconstituted HDL or apoA-I mimetics. A preferential increase in circulating concentrations of HDL particles possessing normalized antiatherogenic activity is therefore a promising therapeutic strategy for the treatment of common metabolic diseases featuring dyslipidemia, inflammation, and premature atherosclerosis.
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