Frontiers in lipid research lipoprotein(a), apolipoprotein C-III and E, and PCSK9 haloperidol mechanism of action and inflammation – HCP Feed

The new 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk 1 have redefined target haloperidol mechanism of action levels of LDL cholesterol (LDL-C). Besides LDL-C, raised lipoprotein(a) is a genetically determined lipid disorder that has been associated haloperidol mechanism of action with an increased cardiovascular (CV) risk. 2 , 3 several lipoprotein(a)-lowering therapies are currently being developed with the long-term goal of reducing CV morbidity and mortality as statins haloperidol mechanism of action actually increase lipoprotein(a) levels. 4 furthermore, the relationship between lipoprotein(a) and mortality independent of LDL-C levels has not been fully established. 5 in their article ‘ high lipoprotein(a) and high risk of mortality’ børge grønne nordestgaard and colleagues from the herlev university hospital haloperidol mechanism of action in denmark 6 tested the hypothesis that lipoprotein(a) levels are associated with mortality in individuals of the danish haloperidol mechanism of action population, of which 69 764 had information on lipoprotein(a) concentrations, 98 810 on LPA KIV-2 number of repeats, and 119 094 on LPA rs10455872 genotype. Lipoprotein(a) levels >93 mg/dl compared with 93 mg/dl or ≤93 mg/dl was 83.9 and 85.1 years, respectively. For CV mortality, a 50 mg/dl increase in lipoprotein(a) levels was associated with a hazard ratio of 1.16 and genetically with risk ratios of 1.23 based on LPA KIV-2 and of 0.98 based on LPA rs10455872. For all-cause mortality, corresponding values were 1.05, 1.10, and 0.97, respectively ( figure 1). Finally, for a similar cholesterol content increase, lipoprotein(a) was more strongly associated with CV and all-cause mortality than LDL-C, implying that the mortality effect of lipoprotein(a) is above that explained by its cholesterol content. Thus, lipoprotein(a) through low LPA KIV-2 number of repeats rather than high cholesterol content is haloperidol mechanism of action associated with high mortality risk. These truly novel findings are put into context in a haloperidol mechanism of action thought-provoking editorial by kausik ray from the imperial college london haloperidol mechanism of action in the UK. 7

Observational analyses of plasma lipoprotein(a) and genetic, causal analyses of LPA kringle-IV type 2 number of repeats and rs10455872 genotype on haloperidol mechanism of action risk of all-cause mortality. Based on studies from the copenhagen general population study (from langsted A, kamstrup PR, nordestgaard BG. High lipoprotein(a) and high risk of mortality. See pages 2760–2770).

Of note, patients with high lipoprotein(a) levels have increased arterial inflammation, which can be markedly reduced by lipoprotein apheresis 8 and haloperidol mechanism of action also to some degree by statins. 9 indeed, lipid apheresis may even reduce angina in those with refractory haloperidol mechanism of action symptoms. 10 proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors reduce LDL-C by 60% and lipoprotein(a) by 20–30% in those without elevated levels. In their FAST TRACK contribution entitled ‘ persistent arterial wall inflammation in patients with elevated lipoprotein(a) despite strong low-density lipoprotein cholesterol reduction by proprotein convertase subtilisin/kexin type 9 antibody treatment’, erik S.G. Stroes and colleagues from the academic medical center in amsterdam, the netherlands evaluated whether PCSK9 inhibition reduces inflammation in a haloperidol mechanism of action multicentre, randomized, double-blind, placebo-controlled study of 129 patients. 11 compared with placebo, evolocumab reduced LDL-C by 61% and lipoprotein(a) by 14%, resulting in LDL-C levels of 1.6 mmol/L and lipoprotein(a) levels of 188.0 nmol/L. Arterial inflammation as assessed by [ 18 F]fluoro-deoxyglucose positron emission tomography and computed tomography did not lead haloperidol mechanism of action to a reduced inflammation with evolocumab compared with placebo. Thus, evolocumab reduces LDL-C impressively, but lipoprotein(a) only does so modestly and does not lead to a haloperidol mechanism of action further reduction in arterial inflammation. The implications of these findings are further discussed in an haloperidol mechanism of action editorial by jean-claude tardif from the montreal heart institute in quebec, canada. 12

Elevated apolipoprotein C-III (apoc-III) levels are associated with hypertriglyceridaemia and coronary heart disease. 13 apoc-III is considered a potential therapeutic target in this context. 14 antisense technology may offer a particularly effective treatment option. In another FAST TRACK contribution entitled ‘ N-acetyl galactosamine-conjugated antisense drug to APOC3 mrna, triglycerides, and atherogenic lipoprotein levels’ sotirios tsimikas and colleagues from the university of california at haloperidol mechanism of action san diego in la jolla, USA investigated whether AKCEA-APOCIII-lrx, an N-acetyl galactosamine-conjugated antisense oligonucleotide targeted to the liver, would reduce apoc-III in a double-blind, placebo-controlled phase I/iia study in healthy volunteers with elevated triglycerides. 15 A single dose of 10, 30, 60, 90 or 120 mg of AKCEA-APOCIII-lrx reduced apoc-III by 4, 32, 65, 78, and 91%, and triglycerides by 12, 11, 43, 68, and 77%, respectively ( figure 2). Multiple dosages of 15 and 30 mg weekly and 60 haloperidol mechanism of action mg every 4 weeks reduced apoc-III by 65, 84, and 83%, and triglycerides by 61, 71, and 65%, respectively. AKCEA-APOCIII-lrx was well tolerated. Thus, treatment of hypertriglyceridaemia with AKCEA-APOCIII-lrx results in an impressive improvement in lipid profiles with haloperidol mechanism of action a favourable safety and tolerability, a finding that is put into clinical context in an haloperidol mechanism of action editorial by deepak L. Bhatt from the harvard medical school in boston, USA. 16

Panel ( A) represents the size and density patterns of HDL, LDL, and VLDL particles. Each of the particles is shown containing variable amounts of haloperidol mechanism of action apoc-III. The relative proportion and locations of total cholesterol, HDL-C, LDL-C, and VLDL-C, and apob are shown in a stylized tube of ultracentrifugally haloperidol mechanism of action prepared lipoproteins ( B). The effect of APOCIII-L rx on these lipoproteins are shown on the right haloperidol mechanism of action ( C) with significant reductions in triglycerides, VLDL-C, LDL-C, and increases in HDL-C. IDL and chylomicrons are not shown in this figure as haloperidol mechanism of action the subjects were fasting. The numbers in the illustration are derived from the 30 haloperidol mechanism of action mg/weekly dose measured at 1 week after the last dose haloperidol mechanism of action (from alexander VJ, xia S, hurh E, hughes SG, O’dea L, geary RS, witztum JL, tsimikas S. N-acetyl galactosamine-conjugated antisense drug to APOC3 mrna, triglycerides and atherogenic lipoprotein levels. See pages 2785–2796).

PCSK9 inhibitors impressively lower LDL-C beyond statins 17 and further reduce the risk of haloperidol mechanism of action myocardial infarction and mortality. 18 , 19 however, less is known about which types of myocardial infarction according haloperidol mechanism of action to the third universal definition 20 are primarily affected. In a FAST TRACK contribution entitled ‘ effects of alirocumab on types of myocardial infarction: insights from the ODYSSEY OUTCOMES trial’, harvey D. White et al. Address this issue. 21 of 1860 infarctions, 65.8% were of type 1, 20.8% of type 2, 0.1% of type 3, 13.1% of type 4, and 0.3% of type 5. Alirocumab reduced first myocardial infarctions by 15%, with reductions in both type 1 (13%) and type 2 (23%), but not of type 4. Treatment benefit on type 1 infarction increased with time, particularly after 2 years. Thus, this analysis for the first time shows that after acute haloperidol mechanism of action coronary syndromes, alirocumab added to statin therapy reduces both type 1 and haloperidol mechanism of action 2 myocardial infarctions, a finding that kristian thygesen from the aarhus university hospital haloperidol mechanism of action in denmark further elaborates on in his editorial. 22

Another lipoprotein is apolipoprotein E (apoe). In their article ‘ plasma levels of apolipoprotein E, APOE genotype, and all-cause and cause-specific mortality in 105 949 individuals from a white general haloperidol mechanism of action population cohort’ ruth frikke-schmidt and colleagues from the rigshospitalet in copenhagen, denmark investigated in 105 949 individuals from the general population haloperidol mechanism of action whether plasma apoe levels and APOE genotype are associated with haloperidol mechanism of action all-cause and cause-specific mortality. 23 they confirmed the well-known association between APOE genotypes and mortality. For all-cause, CV, and cancer mortality, high levels of apoe were associated with increased risk, while for dementia-associated mortality low levels were associated with increased risk. For the highest vs. The fifth septile of plasma apoe, hazard ratios were 1.20 for all-cause, 1.28 for CV, and 1.18 for cancer mortality. Conversely, for the lowest vs. The fifth septile, the hazard ratio was 1.44 for dementia-associated mortality. Examining genetically determined plasma apoe, a 1 mg/dl increase conferred risk ratios of 0.97 for CV and 1.01 for cancer mortality, while a 1 mg/dl decrease conferred a risk ratio of 1.70 for dementia-associated mortality. Thus, high plasma levels of apoe are associated with increased all-cause, CV, and cancer mortality, while low levels were causally associated with increased dementia-associated mortality.

Finally, we should wonder why humans are the only species in haloperidol mechanism of action nature with extremely high LDL-C levels. Are we all hyperlipidaemic? Indeed, in evolution, only humans have such high LDL-C levels and atherosclerosis. 24 in a current opinion entitled ‘ why is hypercholesterolaemia so prevalent? A view from evolutionary medicine’ ulrich laufs and colleagues from the universität leipzig in germany haloperidol mechanism of action address this issue. 25 this phenomenon must have evolutionary roots. Indeed, prehistoric lifestyles involved substantially more energy expenditure and frequent food haloperidol mechanism of action shortages (i.E. Intermittent fasting), which may have led to the selection of genotypes that haloperidol mechanism of action efficiently transport and store energy-rich triglycerides. VLDL is an important triglyceride-providing vehicle, and traits favouring VLDL triglyceride delivery to peripheral tissues, including skeletal muscle, adipose tissue, and lactating breasts, are possible adaptations that promote survival and reproductive fitness during haloperidol mechanism of action periods of food scarcity. As VLDL particles deliver triglycerides to peripheral cells, they are converted into triglyceride-depleted LDL particles that become enriched in cholesterol due to haloperidol mechanism of action the action of cholesterylester transfer protein. LDL-C appears to have little adaptive value because cholesterol is haloperidol mechanism of action not an energy source for mammals, and virtually all mammalian cell types can synthesize sufficient cholesterol haloperidol mechanism of action endogenously or secure it from non-LDL sources. However, with the recent adoption of westernized lifestyles, i.E. Overabundant food supply and low physical activity, LDL-C accumulates, leading to hypercholesterolaemia and atherosclerosis. Westernized lifestyles would negate the energetic benefits of VLDL-favouring traits, but the legacy of those traits as possible contributors to haloperidol mechanism of action hypercholesterolaemia and atherosclerosis may persist, because their maladaptive consequences such as CV events manifest in haloperidol mechanism of action older individuals that are beyond the influence of natural selection.