Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

AIMS: Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. METHODS AND RESULTS: TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. CONCLUSION: Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.

In this randomized controlled trial of 286 participants with elevated triglycerides, treatment with vupanorsen, an ANGPTL3 inhibitor, lowered remnant cholesterol by up to 59% and VLDL cholesterol by up to 67% over placebo. The effect of the treatment was sustained throughout 24 weeks and consistent across key patient subgroups. ANGPTL3 inhibition may be a promising approach to treat patients with elevated triglycerides.

Long-Term Efficacy of Evolocumab in Patients With or Without Multivessel Coronary Disease.

BACKGROUND: In FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk), during a median follow-up of 2.2 years, risk reduction for major adverse cardiovascular event with evolocumab was greater in patients with multivessel disease (MVD). The FOURIER Open-Label Extension (FOURIER-OLE) provides an additional median follow-up of 5 years. OBJECTIVES: The purpose of this study was to assess the long-term benefit of evolocumab in patients with and without MVD. METHODS: FOURIER randomized 27,564 patients to evolocumab vs placebo; 6,635 entered FOURIER-OLE. Patients with coronary artery disease were categorized based on the presence of MVD (≥40% stenosis in ≥2 large vessels). The primary endpoint was cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; the key secondary endpoint was cardiovascular death, myocardial infarction, or stroke. RESULTS: Of 23,656 patients in FOURIER with coronary artery disease, 25.4% had MVD; 5,887 patients continued into FOURIER-OLE. The risk reduction with initial allocation to evolocumab tended to be greater in patients with MVD than in those without: 23% (HR: 0.77 [95% CI: 0.68-0.87]) vs 11% (HR: 0.89 [95% CI: 0.82-0.96]) for the primary and 31% (HR: 0.69 [95% CI: 0.59-0.81]) vs 15% (HR: 0.85 [95% CI: 0.77-0.94]) for the key secondary endpoints (Pinteraction = 0.062 and Pinteraction = 0.031, respectively). The magnitude of benefit tended to grow during the first several years, reaching 37% to 38% reductions in risk in patients with MVD and 23% to 28% reductions in risk in patients without MVD. CONCLUSIONS: Evolocumab reduced the rate of major adverse cardiovascular event in patients with and without MVD. The benefit tended to occur earlier and was larger in patients with MVD. However, the magnitude grew over time in both groups. These data support early initiation of intensive low-density lipoprotein cholesterol lowering both in patients with and without MVD.

Benzodiazepine use and risk of incident MCI and dementia in a community sample.

OBJECTIVES: Older adults commonly take benzodiazepines (BZDs) that may have long-term adverse cognitive effects. We investigated whether BZD use was related to developing mild cognitive impairment (MCI) or dementia in cognitively normal older adults in the community. SETTING/PARTICIPANTS: A population-based cohort (n = 1959) of adults aged 65 and over, recruited from communities of low socioeconomic status. MEASUREMENTS: BZD use, Clinical Dementia Rating (CDR), anxiety symptoms, depression symptoms, sleep difficulties, and APOE genotype. DESIGN: We examined time from study entry to MCI (CDR = 0.5) and time from study entry to dementia (CDR ≥ 1) in participants who were cognitively normal at baseline (CDR = 0). We used survival analysis (Cox model), adjusted for age, sex, education, sleep, anxiety, and depression. For all the models, we included an interaction term between BZD use and APOE*4. RESULTS: Taking BZDs was significantly associated with higher risk of developing MCI, but not of developing dementia. The effect was not affected by APOE genotype. CONCLUSIONS: In a population-based sample of cognitively normal older adults, BZD use is associated with developing MCI, but not dementia. BZD use may be a potentially modifiable risk factor for MCI.

Hepatic fat changes with antisense oligonucleotide therapy targeting ANGPTL3.

BACKGROUND: Angiopoietin-like protein 3 (ANGPTL3) is a novel therapeutic target for hyperlipidemia. Vupanorsen, an antisense oligonucleotide targeting ANGPTL3, reduced triglycerides up to 57% in a phase 2b trial, but caused dose-dependent increases in hepatic fat fraction (HFF). OBJECTIVE: To determine the degree of HFF progression with escalating doses of vupanorsen, differential HFF increases in key patient subgroups, and the correlation between changes in HFF and liver enzymes. METHODS: TRANSLATE-TIMI 70 was a randomized, placebo-controlled trial testing 7 dosing regimens of vupanorsen in 286 adults with hyperlipidemia. A total of 227 patients had HFF measured at baseline and 24 weeks and were included in this analysis. RESULTS: The median HFF at baseline was 8.5%. Vupanorsen led to dose-dependent relative increases in HFF of up to 76% at 24 weeks (p < 0.001), corresponding to an absolute increase of up to 7.0% at the highest dose (p < 0.001). Increases in HFF were numerically greater in patients who had elevated baseline HFF, body mass index, triglycerides, or diabetes. Vupanorsen also increased liver enzymes in a dose-dependent manner, and changes in HFF were moderately positively correlated with changes in aspartate transaminase (AST) (rho = 0.49, p < 0.001) and alanine transaminase (ALT) (rho = 0.50, p < 0.001). CONCLUSION: Vupanorsen, an inhibitor of ANGPTL3 protein synthesis, caused dose-dependent increases in HFF. Increases in HFF were only moderately correlated with elevations in AST and ALT, suggesting that liver enzymes are an imperfect indicator to detect increases in hepatic fat. These results highlight the need to monitor HFF in clinical trials of therapies targeting intracellular ANGPTL3 inhibition, especially those that are targeted to the liver.

Anticholinergic Drug Burden and Risk of Incident MCI and Dementia: A Population-based Study.

OBJECTIVE: We investigated whether anticholinergic drug use was related to developing mild cognitive impairment (MCI) or dementia in older adults at the population level. METHODS: We used an Anticholinergic Rating (ACR) scale, Clinical Dementia Rating, APOE genotype, and number of prescription medications. We examined time to incident MCI and incident dementia in a population-based cohort (n=1959). We assessed whether developing MCI or dementia was associated with (1) any anticholinergic drug use, (2) total ACR score, or (3) number of anticholinergic drugs taken. RESULTS: Taking any anticholinergic drug was significantly associated with higher risk of developing MCI; however, higher ACR score or higher number of anticholinergic drugs, compared with lower, were not associated with greater risk of developing MCI. We found no significant relationship between anticholinergic use and developing dementia. The relationship between anticholinergic use and cognitive outcome was not affected by APOE genotype. CONCLUSIONS: Among cognitively normal older adults in a population-based sample, anticholinergic drug use is independently associated with subsequently developing MCI, but not dementia. Thus, anticholinergic drug use may influence risk of MCI that is nonprogressive to dementia and potentially be a modifiable risk factor for MCI.

Psychosocial implications of early COVID-19 restrictions on older adults in a small-town region in Southwestern, Pennsylvania (USA).

OBJECTIVES: The restrictions put in place in 2020 to mitigate the spread of the coronavirus disease 2019 limited or eliminated social connections that are vital for psychosocial well-being. The objectives of this research were to examine the impact of early pandemic-related restrictions on feelings of loneliness, depression, and anxiety as well as social activity disruption and their concomitant associations in a sample of community-dwelling older adults residing in a small-town region in the USA. DESIGN AND SETTING: Cross-sectional data collected from an ongoing population-based cohort study in Southwestern, Pennsylvania. PARTICIPANTS: Analyses included 360 adults aged 65 years and older whose annual study assessment occurred during the first 120 days of pandemic-related restrictions. MEASUREMENTS: Self-reported feelings of loneliness, depression, and anxiety due to the pandemic-related restrictions were each measured using a single question. Depressive symptoms and anxiety were also assessed with the modified Center for Epidemiologic Studies-Depression and Generalized Anxiety Disorder-7 item tools. Disruption in a variety of common social activities was also assessed. RESULTS: Feeling lonely affected 36% of participants who were more likely to be female, not currently married, and living alone. Giving up in-person visits with family was associated with significantly higher odds of feeling lonely, and feeling lonely was associated with significantly higher odds of feelings of anxiety and depression. CONCLUSIONS: Loneliness is a serious outcome of pandemic-related restrictions among older adults, potentially linked to loss of connection with family, and may be associated with increased feelings of depression and anxiety.

Small Interfering RNA to Reduce Lipoprotein(a) in Cardiovascular Disease.

BACKGROUND: Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS: We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS: Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P<0.001 for all comparisons with baseline). The overall incidence of adverse events was similar across the trial groups. The most common olpasiran-related adverse events were injection-site reactions, primarily pain. CONCLUSIONS: Olpasiran therapy significantly reduced lipoprotein(a) concentrations in patients with established atherosclerotic cardiovascular disease. Longer and larger trials will be necessary to determine the effect of olpasiran therapy on cardiovascular disease. (Funded by Amgen; OCEAN[a]-DOSE ClinicalTrials.gov number, NCT04270760.).

Ambient fine particulate matter exposure and incident mild cognitive impairment and dementia.

BACKGROUND/OBJECTIVE: Poor air quality is implicated as a risk factor for cognitive impairment and dementia. Few studies have examined these associations longitudinally in well-characterized population-based cohorts with standardized annual assessment of both mild cognitive impairment (MCI) and dementia. We investigated the association between estimated ambient fine particulate matter (PM2.5 ) and risk of incident MCI and dementia in a post-industrial region known for historically poor air quality. SETTING/PARTICIPANTS: Adults aged 65+ years in a population-based cohort (n = 1572). MEASUREMENTS: Census tract level PM2.5 from Environmental Protection Agency (EPA) air quality monitors; Clinical Dementia Rating (CDR)®. DESIGN: We estimated ambient PM2.5 exposure (µg/m3 , single-year and 5-year averages) by geocoding participants' residential addresses to census tracts with daily EPA PM2.5 measurements from 2002 to 2014. Using Bayesian spatial regression modeling adjusted for age, sex, education, smoking history, and household income, we examined the association between estimated PM2.5 exposure and risk of incident MCI (CDR = 0.5) and incident dementia (CDR ≥ 1.0). RESULTS: Modeling estimated single-year exposure, each 1 µg/m3 higher ambient PM2.5 was associated with 67% higher adjusted risk of incident dementia (hazard ratio [HR] = 1.669, 95% credible interval [CI]: 1.298, 2.136) and 75% higher adjusted risk of incident MCI (HR = 1.746, 95% CI: 1.518, 2.032). Estimates were higher when modeling 5-year ambient PM2.5 exposure for incident dementia (HR = 2.082, 95% CI: 1.528, 3.015) and incident MCI (HR = 3.419, 95% CI: 2.806, 4.164). CONCLUSIONS: Higher estimated ambient PM2.5 was associated with higher risk of incident MCI and dementia, particularly when considering longer-term exposure, and independent of demographic characteristics and smoking history. Targeting poor air quality may be a reasonable population-wide intervention to reduce the risk of cognitive impairment in older adults, particularly in regions exceeding current recommendations for safe exposure to PM2.5 .

Predictors of attrition in a longitudinal population-based study of aging.

BACKGROUND: Longitudinal studies predictably experience non-random attrition over time. Among older adults, risk factors for attrition may be similar to risk factors for outcomes such as cognitive decline and dementia, potentially biasing study results. OBJECTIVE: To characterize participants lost to follow-up which can be useful in the study design and interpretation of results. METHODS: In a longitudinal aging population study with 10 years of annual follow-up, we characterized the attrited participants (77%) compared to those who remained in the study. We used multivariable logistic regression models to identify attrition predictors. We then implemented four machine learning approaches to predict attrition status from one wave to the next and compared the results of all five approaches. RESULTS: Multivariable logistic regression identified those more likely to drop out as older, male, not living with another study participant, having lower cognitive test scores and higher clinical dementia ratings, lower functional ability, fewer subjective memory complaints, no physical activity, reported hobbies, or engagement in social activities, worse self-rated health, and leaving the house less often. The four machine learning approaches using areas under the receiver operating characteristic curves produced similar discrimination results to the multivariable logistic regression model. CONCLUSIONS: Attrition was most likely to occur in participants who were older, male, inactive, socially isolated, and cognitively impaired. Ignoring attrition would bias study results especially when the missing data might be related to the outcome (e.g. cognitive impairment or dementia). We discuss possible solutions including oversampling and other statistical modeling approaches.

Association of Sleep Apnea with Mortality in Patients with Advanced Kidney Disease.

BACKGROUND AND OBJECTIVES: In the general population, sleep disorders are associated with mortality. However, such evidence in patients with CKD and ESKD is limited and shows conflicting results. Our aim was to examine the association of sleep apnea with mortality among patients with CKD and ESKD. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: In this prospective cohort study, 180 patients (88 with CKD stage 4 or 5, 92 with ESKD) underwent in-home polysomnography, and sleep apnea measures such as apnea hypopnea index (AHI) and nocturnal hypoxemia were obtained. Mortality data were obtained from the National Death Index. Cox proportional hazard models were used for survival analysis. RESULTS: Among the 180 patients (mean age 54 years, 37% women, 39% with diabetes, 49% CKD with mean eGFR 18±7 ml/min per 1.73 m2), 71% had sleep apnea (AHI>5) and 23% had severe sleep apnea (AHI>30). Median AHI was 13 (range, 4-29) and was not significantly different in patients with advanced CKD or ESKD. Over a median follow-up of 9 years, there were 84 (47%) deaths. AHI was not significantly associated with mortality after adjusting for age, sex, race, diabetes, body mass index, CKD/ESKD status, and kidney transplant status (AHI>30: hazard ratio [HR], 1.5; 95% confidence interval [95% CI], 0.6 to 4.0; AHI >15 to 30: HR, 2.3; 95% CI, 0.9 to 5.9; AHI >5 to 15: HR, 2.1; 95% CI, 0.8 to 5.4, compared with AHI≤5). Higher proportion of sleep time with oxygen saturation <90% and lower mean oxygen saturation were significantly associated with higher mortality in adjusted analysis (HR, 1.4; 95% CI, 1.1 to 1.7; P=0.007 for every 15% higher proportion, and HR, 1.6; 95% CI, 1.2 to 2.1; P=0.003 for every 2% lower saturation, respectively). Sleep duration, sleep efficiency, or periodic limb movement index were not associated with mortality. CONCLUSIONS: Hypoxemia-based measures of sleep apnea are significantly associated with increased risk of death among advanced CKD and ESKD.

Does Kidney Transplantation Affect Sleep and Fatigue in Patients With Kidney Disease?

BACKGROUND: Sleep disorders and fatigue are highly prevalent in chronic kidney disease (CKD) and end-stage kidney disease (ESKD) patients but there is limited evidence on the effect of kidney transplant (KTx) on these. METHODS: In a prospective cohort study of patients with advanced CKD (estimated glomerular filtration rate<30 mL/min/1.73 m2) or ESKD, polysomnography and patient-reported symptom assessments were conducted. Pre- and post-KTx changes in sleep apnea (SA) severity (measured by apnea hypopnea index [AHI]) were analyzed and compared with patients who did not receive KTx. Regression models were used to examine predictors of SA severity. RESULTS: Among 77 patients (mean age 51 y, BMI 29 kg/m2, 66% males, 23% ESKD), 61% had SA at baseline. Among 39 KTx recipients, 56% had SA, with 39% having moderate-severe SA after 10 ± 5.6 months post-KTx. There was no difference in AHI in either the KTx (median 6 versus 8; P = 0.37) or no-KTx (median 15 versus 16; P = 0.61) groups after an average of 19.9 ± 8.9 months. KTx led to significant clinically meaningful improvements in fatigue and health-related quality of life (adjusted effect size 0.3-0.6). In multivariable regression, baseline AHI was the only significant predictor of SA severity (adjusted ß = 3.6/5 units, 95% confidence interval 2.1, 5.2) after adjusting for KTx status, age, sex, and body mass index. CONCLUSIONS: More than half of the KTx recipients had SA. There was no significant change in SA severity with KTx. Clinically meaningful moderate size improvements in patient-reported fatigue and health-related quality of life may be seen with KTx.

Volvalerine A, an unprecedented N-containing sesquiterpenoid dimer derivative from Valeriana officinalis var. latifolia.

Volvalerine A (1), a novel N-containing bisesquiterpenoid derivative with a dihydroisoxazole ring, and its possible biosynthetic precursor, 1-hydroxy-1,11,11-trimethyldecahydrocyclopropane azulene-10-one (2), were isolated from the roots of Valeriana officinalis var. latifolia. Their structures and relative configurations were identified using spectroscopic data and X-ray crystallography. A plausible biosynthetic pathway for 1 is also presented.

Volvalerenol A, a new triterpenoid with a 12-membered ring from Valeriana hardwickii.

Volvalerenol A (1), an unprecedented type of triterpenoid with a 7/12/7 tricyclic ring system, was obtained from the ethanol extracts of the roots of Valeriana hardwickii. The structure and relative configurations were established by comprehensive analysis of MS and NMR spectroscopic data. The possible biogenetic pathway of 1 was also deduced.

Sesquiterpenoids from Chloranthus multistachys.

An 8,9-seco-lindenane disesquiterpenoid, chloramultiol G, four eudesmane sesquiterpenoids, ent-(3R)-3-hydroxyatractylenolide III and multistalactones A-C, and four guaiane sesquiterpenoids, (1R,4S,5R,8S,10S)-zedoalactone A and multistalactones D-F, along with 14 known compounds, were isolated from whole plant tissues of Chloranthus multistachys. Their structures were established by extensive NMR experiments in conjunction with mass spectrometry. Except for chloramultiol G, the absolute stereochemistries of the other eight were confirmed by single-crystal X-ray crystallography and CD spectra. Nine compounds were tested for cytotoxicity against five human tumor cell lines and for antifungal activity against four microorganisms in vitro, but all were inactive.

Sesquiterpenoids and lignans from the roots of Valeriana officinalis L.

Two new guaiane-type sesquiterpenoids, valerol A (1) and kessyl 3-acetate (2), together with nine known compounds, valeracetate (3), anismol A (4), orientalol C (5), spatulenol (6), 4α,10α-epoxyaromadendrane (7), (+)-8-hydroxypinoresinol (8), pinorespiol (9), pinoresinol 4-O-ß-D-glucopyranoside (10), and 8-hydroxypinoresinol 4'-O-ß-D-glucopyranoside (11) were isolated from the roots of Valeriana officinalis. The structures and relative configurations of 1 and 2 were elucidated on the basis of spectroscopic methods (1D- and 2D-NMR, MS, UV, and IR). These compounds were evaluated for inhibitory activity on acetylcholinesterase (AChE) and enhancing activity on nerve growth factor (NGF)-mediated neurite outgrowth in PC12 cells.

Volvalerelactones A and B, two new sesquiterpenoid lactones with an unprecedented skeleton from Valeriana officinalis var. latifolia.

Volvalerelactones A and B (1 and 2), two new sesquiterpenoid lactones with an unprecedented 3/7/6 tricyclic ring system, were isolated from the roots of Valeriana officinalis var. latifolia. Their structures and relative configurations were elucidated by spectroscopic data and single-crystal X-ray diffraction crystallography, and the absolute configuration was assigned by computational methods. The possible biosynthetic pathways of 1 and 2 were also proposed.

Germacrane-type sesquiterpenoids from the roots of Valeriana officinalis var. latifolia.

Eight new germacrane-type sesquiterpenoids, volvalerenals A-E (2-6) and volvalerenic acids A-C (7-9), along with four known compounds, were isolated from a chloroform extract of the roots of Valeriana officinalis var. latifolia. The structures and relative configurations of 2-9 were elucidated on the basis of spectroscopic data interpretation. The effects of all compounds isolated on acetylcholinesterase were evaluated.

Chloramultiols A-F, lindenane-type sesquiterpenoid dimers from Chloranthus multistachys.

Six new highly complex lindenane-type sesquiterpenoid dimers, chloramultiols A-F (1-6), along with six known analogues, were isolated from the whole plant of Chloranthus multistachys. The structures of 1-6 were elucidated on the basis of mass spectrometry (MS) and 1D and 2D NMR spectroscopic analysis. Among them, compounds 1 and 6 contain a unique 18-membered macrocyclic triester ring. All compounds isolated were evaluated for the inhibition of the growth of five tumor cell lines.

Iridoids and sesquiterpenoids from the roots of Valeriana officinalis.

Two new iridoids, volvaltrates A and B (1 and 2), and three new sesquiterpenoids, E-(-)-3beta,4beta-epoxyvalerenal (3), E-(-)-3beta,4beta-epoxyvalerenyl acetate (4), and mononorvalerenone (5), together with five known iridoids and two known sesquiterpenoids were isolated from the roots of Valeriana officinalis. The structures and relative configurations of 1-5 were elucidated by spectroscopic evidence. Compound 1 was an unusual iridoid with an oxygen bridge connecting C-3 and C-10, forming a cage-like structure, and compound 5 was a mononorsesquiterpenoid.