Low-density Lipoprotein Reduction Research Articles

Anti-Atherosclerosis and Anti-Hypertensive Effects of Flavonoid Isorhamnetin Isolated from the Bark of Cordia dichotoma L

Aims: This study aimed to investigate the anti-atherosclerotic and anti-hypertensive ability of isolated Isorhamnetin from the bark of Cordia dichotoma L.
 Study design: Experimental study
 Place and Duration of Study: The extraction and isolation of bark of Cordia dichotoma L bark (ACDL) was done at Biosapience lab, Bhopal, India. Anti-atherosclerotic activity was done at IFTM University, Moradabad, India. Anti-hypertensive activity was done at BilwalMedchem and Research Laboratory, Pvt. Ltd, Jaipur, India. All the studies was conducted from 2015 to 2021 depending upon the availability of resources.
 Methodology: Column chromatography was done for Ethyl acetate soluble fraction of successive alcoholic extract of Cordia dichotoma L bark (ACDL), followed by successive fractionation using benzene, n-butanol, and acetone. Eluents with similar Rf values were pooled and underwent flavonoid test. Only a single eluents that passed the test was underwent purification. The crystallized powder obtained underwent UV, FTIR, Mass, 1H NMR and 13C NMR analysis for structural identification.
 The evaluation of anti-atherosclerotic activity of isolated Isorhamnetin from bark extract of plant C. dichotoma L was done in high fat induced atherosclerosis rats. The seven groups of Wistar rats were taken and each group containing six rats. To evaluate the anti-hypertensive activity of the plant extract, L-NAME induced hypertension model was used.
 Results: The structural identification and confirmation of flavonoid Isorhamnetin was analyzed by characterizations of isolated product. Lipid, lipoprotein profile and body weight were determined in high fat diet induced atherosclerosis rats. Isorhamnetin isolated from bark of C. dichotoma L produced a significant and dose-dependent anti-atherosclerotic activity in terms of reduction in low density lipoprotein (LDL), very low density lipoprotein (VLDL), Total cholesterol (TC), and Triglyceride (TG) level; and elevation of high density lipoprotein (HDL). Isorhamnetin isolated from the bark of plant C. dichotoma L reduced the elevated arterial pressure of L-NAME induced hypertensive rat significantly to the level of normotensive animal group. The isolated Isorhamnetin have shown its potential as an efficient source for the treatment of hypertension.
 Conclusion: The present study has identified the isolation and characterization of isorhamnetin flavonoid from bark of plant C. dichotoma L. This study also provides evidences of anti-atherosclerotic and antihypertensive effects of C. dichotoma L.

Invention of MK-8262, a Cholesteryl Ester Transfer Protein (CETP) Inhibitor Backup to Anacetrapib with Best-in-Class Properties.

Cholesteryl ester transfer protein (CETP) represents one of the key regulators of the homeostasis of lipid particles, including high-density lipoprotein (HDL) and low-density lipoprotein (LDL) particles. Epidemiological evidence correlates increased HDL and decreased LDL to coronary heart disease (CHD) risk reduction. This relationship is consistent with a clinical outcomes trial of a CETP inhibitor (anacetrapib) combined with standard of care (statin), which led to a 9% additional risk reduction compared to standard of care alone. We discuss here the discovery of MK-8262, a CETP inhibitor with the potential for being the best-in-class molecule. Novel in vitro and in vivo paradigms were integrated to drug discovery to guide optimization informed by a critical understanding of key clinical adverse effect profiles. We present preclinical and clinical evidence of MK-8262 safety and efficacy by means of HDL increase and LDL reduction as biomarkers for reduced CHD risk.

Probiotic Lactobacillus plantarum may reduce cardiovascular risk: An experimental study.

BACKGROUNDReduction of cardiovascular risk (CVR) is based on the correction of risk factors, especially dyslipidemia. Due to the limiting factors of conventional lipid-lowering medications, the investigation of alternative approaches is necessary.METHODSThe present open, comparative, randomized, and parallel investigation was conducted on 77 patients. Participants were of both sexes, 40-74 years-of-age, and had dyslipidemia. The participants were divided into 2 groups; the treatment group (n = 41) received a combination of Lactobacillus plantarum and simvastatin 20 mg once a day, and the control group (n = 36) received simvastatin 20 mg once a day. The trial included 5 visits; screening on the first 2, and treatment on the next 3 (on weeks 4, 8, and 12). On visits 1, 3, 4, and 5, the lipid profile was evaluated and CVR was calculated using 5 tools.RESULTSThe combination treatment led to a more pronounced decrease in total cholesterol (TC) and low-density lipoproteins (LDL) after 8 weeks (P = 0.002 and 0.016, respectively), that persisted after 12 weeks (P < 0.001 and 0.002, respectively). Reduction in TC and LDL by ³ 20% was observed more predominantly in the treatment group. A significant reduction was observed in CVR in the treatment group according to the Prospective Cardiovascular Münster (ýPROCAM) score (P = 0.004). Reduction of CVR by ³ 20% was mostly observed as a result of prescribing combination therapy according to the Framingham Risk Score ý(70.7%; P = 0.003), 2013 ACC/AHA ASCVD Risk Calculator ý(51.2%; P = 0.035), PROCAM (65.9%; P < 0.001), and WHO CVD risk chart (56.1%; P = 0.012).CONCLUSIONAdditional supplementation with Lactobacillus plantarum was more effective in the reduction of TC, LDL, and CVR according to PROCAM and the attainment of treatment goals regarding lipid profile and CVR levels.

Evinacumab Approval Adds a New Option for Homozygous Familial Hypercholesterolemia With a Hefty Price Tag

Evinacumab Approval Adds a New Option for Homozygous Familial Hypercholesterolemia With a Hefty Price Tag

In vivo adenine base editing of PCSK9 in macaques reduces LDL cholesterol levels

Most known pathogenic point mutations in humans are C•G to T•A substitutions, which can be directly repaired by adenine base editors (ABEs). In this study, we investigated the efficacy and safety of ABEs in the livers of mice and cynomolgus macaques for the reduction of blood low-density lipoprotein (LDL) levels. Lipid nanoparticle–based delivery of mRNA encoding an ABE and a single-guide RNA targeting PCSK9, a negative regulator of LDL, induced up to 67% editing (on average, 61%) in mice and up to 34% editing (on average, 26%) in macaques. Plasma PCSK9 and LDL levels were stably reduced by 95% and 58% in mice and by 32% and 14% in macaques, respectively. ABE mRNA was cleared rapidly, and no off-target mutations in genomic DNA were found. Re-dosing in macaques did not increase editing, possibly owing to the detected humoral immune response to ABE upon treatment. These findings support further investigation of ABEs to treat patients with monogenic liver diseases.

What change in BMI is required to improve cardiovascular outcomes in childhood and adolescent obesity lifestyle interventions: a meta-regression

Abstract Funding Acknowledgements Type of funding sources: Public Institution(s). Main funding source(s): This study was supported by the NIHR Biomedical Research Centre at University Hospitals Bristol NHS Foundation Trust and the University of Bristol Background There is minimal evidence regarding the change of body mass index (BMI) needed to improve cardiovascular health in obese children. This paper aims to establish the minimum change in body mass index standard deviation score (BMI-SDS) needed to improve lipid profile and blood pressure (BP) of obese children and adolescents, to aid future trials and guidelines. Methods Studies with participants involved in lifestyle interventions, aged 4–19 years, with a diagnosis of obesity according to defined BMI thresholds, were considered for inclusion in a large systematic review. Interventions had to report pre- and post-intervention (or mean change in) BMI-SDS, plus either systolic blood pressure (SBP), high-density lipoprotein (HDL), low-density lipoprotein (LDL), and/or triglycerides (TG). Random effects meta-regression quantified the relationship between mean change in BMI-SDS and mean change in cardiovascular outcomes. Results Seventy-one papers reported various cardiovascular measurements and mean change in BMI-SDS. Fifty-four, 59, 46, and 54 studies were analysed; reporting change in SBP, HDL, LDL, and TG respectively. Reduction in mean BMI-SDS was significantly related to improvements in SBP, LDL, TG, and HDL (p &amp;lt; 0.05); BMI-SDS reductions of 1, 1.2, and 0.7 ensured a mean reduction of SBP, LDL, and TG respectively although an equivalent value for HDL improvement was indeterminate. Conclusions Reductions in mean BMI-SDS of &amp;gt;1, &amp;gt;1.2, or &amp;gt;0.7 are likely to reduce SBP, LDL, and TG respectively. Further studies are needed to clarify the optimal duration, intensity, and setting for interventions. Consistency is required regarding derived BMI values to facilitate future systematic reviews and meta-analyses.

Effect of natural honey on lowering lipid profile

Objectives:To evaluate the available evidence of natural honey and its effect on improving lipid profiles among the adult population.Methods:The following databases were searched in May 2020 for randomized controlled trials (RCTs) and crossover studies without any restrictions in language, publication year, or status: CENTRAL, Embase Elsevier, ClinicalTrials.gov, MEDLINE, the WHO International Clinical Trials Registry Platform, and Google Scholar. We included all RCTs and crossover studies that studied the effect of natural honey on improving lipid levels in individuals at any age, for any dose and duration. Trials investigated the intake of honey alone or honey dissolved in water. The comparison groups were no intervention or placebo. Two independent reviewers screened and evaluated the included trials. The third reviewer was involved in resolving any disagreement. Our aim was to evaluate the evidence available regarding the effect of natural honey in improving lipid profile.Results:Seven trials with 370 participants fitted the inclusion criteria. Pooled analysis showed, honey was found to reduce total cholesterol levels with statistical significance (mean difference [MD]: -14.97 mg/dl, 95% CI: 19.61 to -10.32). Honey was associated with a statistically significant increase in high-density lipoprotein (HDL) levels (MD: 1.78 mg/dl, 95% CI: 0.68 to 2.88). There was a statistically significant LDL reduction level (MD: 18.99 mg/dl, 95% CI: -22.79 to -15.20). Finally, honey was found to lower triglyceride levels significantly (MD: 9.68 mg/dl, 95% CI: -15.56 to -3.80).Conclusions:Total cholesterol was significantly reduced with the use of natural honey intake, as well as low-density lipoprotein (LDL), and triglycerides. High-density lipoprotein showed significant increment. Small quantity of honey can be recommended for patients with dyslipidemia. The impact on clinical outcomes such as cardiovascular mortality and morbidity needs to be evaluated in large studies.PROSPERO REG. NO. CRD: 42020130741

Inhibitors of Protein Convertase Subtilisin/Kexin 9 (PCSK9) and Acute Coronary Syndrome (ACS): The State-of-the-Art.

Acute Coronary Syndrome (ACS) remains one of the most frequent causes of morbidity and mortality in the world. Although the age- and gender-adjusted incidence of ACS is decreasing, the mortality associated with this condition remains high, especially 1-year after the acute event. Several studies demonstrated that PCSK9 inhibitors therapy determine a significant reduction of major adverse cardiovascular events (MACE) in post-ACS patients, through a process of plaque modification, by intervening in lipid metabolism and platelet aggregation and finally determining an improvement in endothelial function. In the EVACS (Evolocumab in Acute Coronary Syndrome) study, evolocumab allows >90% of patients to achieve LDL-C < 55 mg/dL according to ESC/EAS guidelines compared to 11% of patients who only receive statins. In the EVOPACS (EVOlocumab for Early Reduction of low-density lipoprotein (LDL)-cholesterol Levels in Patients With Acute Coronary Syndromes) study, evolocumab determined LDL levels reduction of 40.7% (95% CI: 45.2 to 36.2; p < 0.001) and allowed 95.7% of patients to achieve LDL levels <55 mg/dL. In ODYSSEY Outcome trial, alirocumab reduced the overall risk of MACE by 15% (HR = 0.85; CI: 0.78–0.93; p = 0.0003), with a reduced risk of all-cause mortality (HR = 0.85; CI: 0.73–0.98: nominal p = 0026), and fewer deaths for coronary heart disease (CHD) compared to the control group (HR = 0.92; CI: 0.76–1.11; p = 0.38). The present review aimed at describing the beneficial effect of PCSK9 inhibitors therapy early after ACS in reducing LDL circulating levels (LDL-C) and the risk of major adverse cardiovascular events, which was very high in the first year and persists higher later after the acute event.

Statin and Its Use in Children: A Review Brief

Atherosclerotic cardiovascular disease (ASCVD) is a disease that occurs causes death among adult patients who previously had a history of familial hypercholesterolemia (FH) in childhood. The main cause of FH is gene mutation in the low-density lipoprotein (LDL) receptor from birth because the mother inherits it. The form of FH consists of two types, namely heterozygous and homozygous. Heterozygous FH is the most usual form of gene abnormalities in children with FH with a prevalence of 1 per 137-250 of the general population. Lipid-lowering drugs are often used adults in hyperlipidemia but rarely used in children. It can be given as a preventative agent so that it does not develop into ASCVD. For FH, statins have been recommended as a first-line treatment for hyperlipidemia, because it has a significant LDL reduction effect. One of the statins that have the most prominent reduction in LDL is with the use of atorvastatin and rosuvastatin. When viewed from various studies on statin use in the long term, pravastatin used for 20 years has a significant reduction in LDL of 32% and is proven to have no side effects. Most statin has mild side effects that commonly report in adults, rhabdomyolysis, but in children is rarely. In other words, statins well tolerated in children.

Lipoprotein apheresis efficacy and challenges: single center experience

IntroductionLipoprotein apheresis (LA) is an extracorporeal therapy which removes apolipoprotein B-containing particles from the circulation. We evaluated techniques and efficiency of lipoprotein apheresis procedures applied to patients with familial and non-familial hypercholesterolemia (FH) at our center. MethodsWe retrospectively evaluated 250 LA procedures applied to 27 patients with dyslipidemia between March 2011 and August 2019. ResultsA total of 27 patients, of whom 19 (70.4%) were male and 8 (29.6%), female, were included. Eighteen (66.7%), 6 (22.2%) and 3 (11.1%) patients were diagnosed with non-FH, homozygous FH (HoFH) and heterozygous FH (HeFH), respectively. Two different apheresis techniques, direct adsorption of lipoproteins (DALI) (48.8%) and double filtration plasmapheresis (DFPP) (51.2%), were used. The change in the serum total cholesterol (TC) level was the median 302 mg/dl (171–604 mg/dl) (60.4%) in HoFH patients, 305 mg/dl (194–393 mg/dl) (60.8%) in HeFH patients and 227 mg/dl (75–749 mg/dl) (65.3%) in non-FH patients. The change in the serum low-density lipoprotein (LDL) level was the median 275 mg/dl (109–519 mg/dl) (64.2%), 232 mg/dl (207–291 mg/dl) (64.5%) and 325 mg/dl (22–735 mg/dl) (70.9%) in patients with HoFH, HeFH and non-FH, respectively. A significantly effective reduction in serum lipid levels, including TC, LDL and triglycerides, was achieved in all patients, regardless of the technique, p < .001. The decrease in the serum TC and LDL levels was significantly higher in the DFPP, compared to the DALI, being 220 mg/dl (−300 to 771) vs 184 mg/dl (64–415), p < .001 and 196 mg/dl (11–712) vs 157 mg/dl (54–340), p < .001, respectively. ConclusionsOur results showed that LA is a highly effective treatment in reducing serum lipid levels and safe, without any major adverse event.

Long-term stable reduction of low-density lipoprotein in nonhuman primates following in vivo genome editing of PCSK9

Gene disruption via programmable, sequence-specific nucleases represents a promising gene therapy strategy in which the reduction of specific protein levels provides a therapeutic benefit. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an antagonist of the low-density lipoprotein (LDL) receptor, is a suitable target for nuclease-mediated gene disruption as an approach to treat hypercholesterolemia. We sought to determine the long-term durability and safety of PCSK9 knockdown in non-human primate (NHP) liver by adeno-associated virus (AAV)-delivered meganuclease following our initial report on the feasibility of this strategy. Six previously treated NHPs and additional NHPs administered AAV-meganuclease in combination with corticosteroid treatment or an alternative AAV serotype were monitored for a period of up to 3 years. The treated NHPs exhibited a sustained reduction in circulating PCSK9 and LDL cholesterol (LDL-c) through the course of the study concomitant with stable gene editing of the PCSK9 locus. Low-frequency off-target editing remained stable, and no obvious adverse changes in histopathology of the liver were detected. We demonstrate similar on-target nuclease activity in primary human hepatocytes using a chimeric liver-humanized mouse model. These studies demonstrate that targeted invivo gene disruption exerts a lasting therapeutic effect and provide pivotal data for safety considerations, which support clinical translation.

LDL Cholesterol Reduction Variability with Different Types and Doses of Statins in Monotherapy or Combined with Ezetimibe. Results from the Spanish Arteriosclerosis Society Dyslipidaemia Registry.

Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10mg (32.5 ± 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40mg (58.7 ± 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10mg combined with ezetimibe (50.6 ± 24.6%) and rosuvastatin 40mg combined with ezetimibe (71.6 ± 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.

Thymoquinone Protects Neurons in the Cerebellum of Rats through Mitigating Oxidative Stress and Inflammation Following High-Fat Diet Supplementation.

High-fat diet (HFD) is a major problem causing neuronal damage. Thymoquinone (TQ) could regulate oxidative stress and the inflammatory process. Hence, the present study elucidated the significant role of TQ on oxidative stress, inflammation, as well as morphological changes in the cerebellum of rats with HFD. Rats were divided into three groups as (1) control, (2) saturated HFD for eight weeks and (3) HFD supplementation (four weeks) followed by TQ 300 mg/kg/day treated (four weeks). After treatment, blood samples were collected to measure oxidative stress markers glutathione (GSH), malondialdehyde (MDA), superoxide dismutase (SOD), and inflammatory cytokines. Furthermore, neuronal morphological changes were also observed in the cerebellum of the rats. HFD rats show higher body weight (286.5 ± 7.4 g) as compared with the control group (224.67 ± 1.78 g). TQ treatment significantly (p < 0.05) lowered the body weight (225.83 ± 13.15 g). TQ produced a significant (p < 0.05) reduction in cholesterol, triglycerides, high-density lipoprotein (HDL), and low-density lipoprotein (LDL). The antioxidative enzymes significantly reduced in HFD rats (GSH, 1.46 ± 0.36 mol/L and SOD, 99.13 ± 5.41 µmol/mL) as compared with the control group (GSH, 6.25 ± 0.36 mol/L and SOD, 159.67 ± 10.67 µmol/mL). MDA was increased significantly in HFD rats (2.05 ± 0.25 nmol/L) compared to the control group (0.695 ± 0.11 nmol/L). Surprisingly, treatment with TQ could improve the level of GSH, MDA, and SOD. TQ treatment significantly (p < 0.05) reduced the inflammatory markers as compared with HFD alone. TQ treatment minimizes neuronal damage as well as reduces inflammation and improves antioxidant enzymes. TQ can be considered as a promising agent in preventing the neuronal morphological changes in the cerebellum of obese populations.

Antidiabetic profiling, cytotoxicity and acute toxicity evaluation of aerial parts of Phragmites karka (Retz.)

Ethnopharmacological relevancePhragmites karka (Retz.) of family Poaceae is a pristine tropical plant that is well known to the local healers for ailments of diabetes, fever, diarrhea and CNS depression but lacks the scientific evidence behind its traditional usage. Hence, we explicated this plant to find the scientific basis of its traditional utilization. Aim of the studyThe current study aims to find out the antidiabetic potential, toxicity after oral administration and in vitro cytotoxic activity of aerial parts of the plant on HeLa cells. MethodsThe plant was extracted with methanol by maceration and the crude extract was then subjected to solvent partitioning with modified Kupchan method for preparing several fractions. Phytochemical screening and total phenolic content of the plant was first determined through established procedures. Acute toxicity of the plant was studied by orally administering a single high dose (5000 mg/kg) of drug. Cytotoxicity of the methanolic plant extract was determined by measuring the percentage of cell viability on human cervical cancer cell lines, HeLa. In vitro antidiabetic activity was determined through iodine starch and DNSA (3,5-dinitrosalicylic acid) method of α-amylase inhibition. Finally, in vivo oral glucose tolerance test and alloxan induced antidiabetic activity test was performed at 150 and 300 mg/kg body weight doses of plant extract to confirm the in vivo antidiabetic activity. ResultsNo mortality was demonstrated by Phragmites karka in the acute toxicity test. However, signs of cellular toxicity was observed and histopathological studies on major organs exhibited necrosis in liver and kidney. In vitro cytotoxicity assay revealed the death of HeLa cells by DCM (dichloromethane) and n-hexane fractions of plant extract at 100 and 10 μg/mL concentrations. The IC50 value of the fractions were later evaluated by MTT assay (316.1 and 96.7 μg/mL for n-hexane and DCM fractions, respectively). In the iodine starch and DNSA method of α-amylase enzyme inhibitory activity test, substantial inhibition of enzyme was observed with the IC50 values of 2.05 and 2.08 mg/mL, respectively. In the in vivo antidiabetic activity test, considerable reduction in blood glucose level of diabetic mice was detected in both oral glucose tolerance test and alloxan induced antidiabetic activity test. In addition, the microscopic examination of pancreas showed noticeable recovery of pancreatic β cells and the blood lipid profile analysis represented a significant (p < 0.05) reduction of total cholesterol, LDL (low density lipoprotein) and triglyceride level in plant extract treated mice. ConclusionResults of this study reveals that the Phragmites karka extract is toxic at cellular level after oral administration and cytotoxic when tested on HeLa cells. The plant also evidenced hypoglycemic property, possibly through the inhibition of α-amylase enzyme and recovered the pancreatic beta cells along with the improvement of lipid profile of diabetic mice. However, robust studies on this plant is required to isolate the bioactive compounds, elucidate structures and evaluate their mechanism of actions in support of our findings. ClassificationToxicology and Safety, Quality Traditional Medicine.

Statins Therapy Improves Acute Ischemic Stroke in Patients with Cardio-metabolic Disorders Measured by Lipoprotein-Associated Phospholipase A2 (Lp-PLA2): New Focal Point.

Acute ischemic stroke (AIS) leads to neuronal and endothelial damage that activate the release of proinflammatory mediators such as lipoprotein-associated phospholipase A2 (Lp-PLA2), which lead to the development of brain edema injury. Most of statins produce differential effects on Lp-PLA2 activity and mass with a comparable reduction in low-density lipoprotein (LDL) serum levels. The aim of this study is to evaluate the differential effect of different statins on the mass of level of Lp-PLA2 in patients with AIS. A total of 69 patients with AIS aged 40-70 years compared with matched 39 healthy controls were involved in this case-control study. The AIS patients were divided according to the statins therapy into 39 patients on statins therapy (statins on), and 30 patients were not on the statins therapy (statins off). Anthropometric variables including weight, height, body mass index (BMI), and blood pressure profile were estimated. Besides, biochemical variables including lipid profile[total cholesterol (TC), triglyceride (TG), LDL, very low-density lipoprotein (VLDL), high-density lipoprotein (HDL)], Lp-PLA2 mass levels, high-sensitive C-reactive protein (Hs-CRP) were estimated. Patients with AIS had high Lp-PLA2 mass levels (P < 0.01) that positively correlated with high Hs-CRP, blood pressure, BMI, TC, TG, VLDL, LDL, and negatively correlated with HDL as compared with healthy controls. As well, statins on patients had lower Lp-PLA2 mass levels (9.82 ± 3.19 IU/mL) compared with statins off patients (16.55 ± 4.72 IU/mL), (P = 0.0001). Regarding the gender differences in the Lp-PLA2 mass level, it was higher in men patients with AIS compared with comparable females (P = 0.03). Lp-PLA2 mass level was higher in patients with AIS and linked with underlying poor cardio-metabolic disorders. Therefore, the Lp-PLA2 mass level is observed to be a surrogate biomarker of AIS mainly in patients with poor cardio-metabolic disorders. Statin therapy improves the Lp-PLA2 mass level and the poor cardio-metabolic profile in patients with AIS.

Lifelong Reduction in LDL (Low-Density Lipoprotein) Cholesterol due to a Gain-of-Function Mutation in LDLR.

Loss-of-function mutations in the LDL (low-density lipoprotein) receptor gene (LDLR) cause elevated levels of LDL cholesterol and premature cardiovascular disease. To date, a gain-of-function mutation in LDLR with a large effect on LDL cholesterol levels has not been described. Here, we searched for sequence variants in LDLR that have a large effect on LDL cholesterol levels. We analyzed whole-genome sequencing data from 43 202 Icelanders. Single-nucleotide polymorphisms and structural variants including deletions, insertions, and duplications were genotyped using whole-genome sequencing-based data. LDL cholesterol associations were carried out in a sample of >100 000 Icelanders with genetic information (imputed or whole-genome sequencing). Molecular analyses were performed using RNA sequencing and protein expression assays in Epstein-Barr virus-transformed lymphocytes. We discovered a 2.5-kb deletion (del2.5) overlapping the 3' untranslated region of LDLR in 7 heterozygous carriers from a single family. Mean level of LDL cholesterol was 74% lower in del2.5 carriers than in 101 851 noncarriers, a difference of 2.48 mmol/L (96 mg/dL; P=8.4×10-8). Del2.5 results in production of an alternative mRNA isoform with a truncated 3' untranslated region. The truncation leads to a loss of target sites for microRNAs known to repress translation of LDLR. In Epstein-Barr virus-transformed lymphocytes derived from del2.5 carriers, expression of alternative mRNA isoform was 1.84-fold higher than the wild-type isoform (P=0.0013), and there was 1.79-fold higher surface expression of the LDL receptor than in noncarriers (P=0.0086). We did not find a highly penetrant detrimental impact of lifelong very low levels of LDL cholesterol due to del2.5 on health of the carriers. Del2.5 is the first reported gain-of-function mutation in LDLR causing a large reduction in LDL cholesterol. These data point to a role for alternative polyadenylation of LDLR mRNA as a potent regulator of LDL receptor expression in humans.

Increasing levels of Parasutterella in the gut microbiome correlate with improving low-density lipoprotein levels in healthy adults consuming resistant potato starch during a randomised trial

BackgroundPrebiotics, defined as a substrate that is selectively utilized by host microorganisms conferring a health benefit, present a potential option to optimize gut microbiome health. Elucidating the relationship between specific intestinal bacteria, prebiotic intake, and the health of the host remains a primary microbiome research goal.ObjectiveTo assess the correlations between gut microbiota, serum health parameters, and prebiotic consumption in healthy adults.MethodsWe performed ad hoc exploratory analysis of changes in abundance of genera in the gut microbiome of 75 participants from a randomized, placebo-controlled clinical trial that evaluated the effects of resistant potato starch (RPS; MSPrebiotic®, N = 38) intervention versus a fully digestible placebo (N = 37) for which primary and secondary outcomes have previously been published. Pearson correlation analysis was used to identify relationships between health parameters (ie. blood glucose and lipids) and populations of gut bacteria.ResultsAbundance of Parasutterella (phylum Proteobacteria) tended to increase in the gut microbiome of individuals consuming RPS and those increases in Parasutterella were correlated with reductions in low-density lipoprotein (LDL) levels in participants consuming RPS but not placebo. Segregating RPS-consuming individuals whose LDL levels decreased (ie “Responders”) from those who did not (ie. “Non-Responders”) revealed that LDL Responders had significantly higher levels of Parasutterella both at baseline and after 12 weeks of consuming RPS.ConclusionOur analyses suggest that RPS may help improve LDL levels depending upon the levels of Parasutterella in an individual’s gut microbiome.Trial registrationThis study protocol was reviewed and approved by Health Canada (Submission #188517; “Notice of Authorization” dated 06/05/13) and registered as NCT01977183 (10/11/13) listed on NIH website: ClinicalTrials.gov. Data generated in this study have been submitted to NCBI (http://www.ncbi.nlm.nih.gov/bioproject/381931).FundingMSP Starch Products Inc.

Liraglutide Reduces Carotid Intima-Media Thickness by Reducing Small Dense Low-Density Lipoproteins in a Real-World Setting of Patients with Type 2 Diabetes: A Novel Anti-Atherogenic Effect.

IntroductionLiraglutide has several non-glycemic effects, including those on plasma lipids and lipoproteins, contributing to its cardiovascular benefit; however, the exact underlying mechanisms remain unclear. We investigated a novel anti-atherogenic effect of liraglutide in a real-world prospective study on patients with type 2 diabetes (T2DM).MethodsSixty-two patients with T2DM (31 men, 31 women; mean age ± standard deviation 61 ± 9 years) naïve to incretin-based therapies were treated with liraglutide (1.2 mg/day) as add-on therapy to metformin (1500–3000 mg/day) for 4 months. Laboratory analyses included the assessment of lipoprotein subclass profile by gel electrophoresis (Lipoprint; Quantimetrix Corp., Redondo Beach, CA, USA). Carotid intima-media thickness (cIMT) was assessed by Doppler ultrasonography. Statistical analyses included the paired t test, Spearman correlation and multiple regression analysis.ResultsThe addition of liraglutide to metformin monotherapy resulted in significant reductions in fasting glycemia, hemoglobin A1c, body mass index, waist circumference, total cholesterol, triglycerides and low-density lipoprotein (LDL)-cholesterol, as well as in cIMT. There was an increase in the large LDL-1 subfraction, with a concomitant reduction in atherogenic small dense LDL-3 and LDL-4 subfractions. Correlation analysis revealed a significant association between changes in cIMT and changes in small dense LDL-3 subfraction (r = 0.501; p < 0.0001). Multivariate analysis, including all of the measured anthropometric and laboratory parameters, revealed that only changes in the small dense LDL-3 subfraction were independent predictors of changes in cIMT (p < 0.0001).ConclusionOur findings are the first to show that the vascular benefit of liraglutide in patients with T2DM is associated with reductions in atherogenic small dense LDL. This effect is independent of glycemic control and body weight reduction and may represent one of the key mechanisms by which liraglutide is able to reduce cardiovascular events.Trial RegistrationClinicalTrials.gov: NCT01715428.

Role of LOX-1 (Lectin-Like Oxidized Low-Density Lipoprotein Receptor 1) as a Cardiovascular Risk Predictor: Mechanistic Insight and Potential Clinical Use.

Atherosclerosis, the underlying cause of cardiovascular disease (CVD), is a worldwide cause of morbidity and mortality. Reducing ApoB-containing lipoproteins-chiefly, LDL (low-density lipoprotein)-has been the main strategy for reducing CVD risk. Although supported by large randomized clinical trials, the persistence of residual cardiovascular risk after effective LDL reduction has sparked an intense search for other novel CVD biomarkers and therapeutic targets. Recently, Lox-1 (lectin-type oxidized LDL receptor 1), an innate immune scavenger receptor, has emerged as a promising target for early diagnosis and cardiovascular risk prediction and is also being considered as a treatment target. Lox-1 was first described as a 50 kDa transmembrane protein in endothelial cells responsible for oxLDL (oxidized LDL) recognition, triggering downstream pathways that intensify atherosclerosis via endothelial dysfunction, oxLDL uptake, and apoptosis. Lox-1 is also expressed in platelets, where it enhances platelet activation, adhesion to endothelial cells, and ADP-mediated aggregation, thereby favoring thrombus formation. Lox-1 was also identified in cardiomyocytes, where it was implicated in the development of cardiac fibrosis and myocyte apoptosis, the main determinants of cardiac recovery following an ischemic insult. Together, these findings have revealed that Lox-1 is implicated in all the main steps of atherosclerosis and has encouraged the development of immunoassays for measurement of sLox-1 (serum levels of soluble Lox-1) to be used as a potential CVD biomarker. Finally, the recent development of synthetic Lox-1 inhibitors and neutralizing antibodies with promising results in animal models has made Lox-1 a target for drug development. In this review, we discuss the main findings regarding the role of Lox-1 in the development, diagnosis, and therapeutic strategies for CVD prevention and treatment.

Evaluation of an intervention to provide brief support and personalized feedback on food shopping to reduce saturated fat intake (PC-SHOP): A randomized controlled trial.

Guidelines recommend reducing saturated fat (SFA) intake to decrease cardiovascular disease (CVD) risk, but there is limited evidence on scalable and effective approaches to change dietary intake, given the large proportion of the population exceeding SFA recommendations. We aimed to develop a system to provide monthly personalized feedback and healthier swaps based on nutritional analysis of loyalty card data from the largest United Kingdom grocery store together with brief advice and support from a healthcare professional (HCP) in the primary care practice. Following a hybrid effectiveness-feasibility design, we tested the effects of the intervention on SFA intake and low-density lipoprotein (LDL) cholesterol as well as the feasibility and acceptability of providing nutritional advice using loyalty card data. The Primary Care Shopping Intervention for Cardiovascular Disease Prevention (PC-SHOP) study is a parallel randomized controlled trial with a 3 month follow-up conducted between 21 March 2018 to 16 January2019. Adults ≥18 years with LDL cholesterol >3 mmol/L (n = 113) were recruited from general practitioner (GP) practices in Oxfordshire and randomly allocated to "Brief Support" (BS, n = 48), "Brief Support + Shopping Feedback" (SF, n = 48) or "Control" (n = 17). BS consisted of a 10-minute consultation with an HCP to motivate participants to reduce their SFA intake. Shopping feedback comprised a personalized report on the SFA content of grocery purchases and suggestions for lower SFA swaps. The primary outcome was the between-group difference in change in SFA intake (% total energy intake) at 3 months adjusted for baseline SFA and GP practice using intention-to-treat analysis. Secondary outcomes included %SFA in purchases, LDL cholesterol, and feasibility outcomes. The trial was powered to detect an absolute reduction in SFA of 3% (SD3). Neither participants nor the study team were blinded to group allocation. A total of 106 (94%) participants completed the study: 68% women, 95% white ethnicity, average age 62.4 years (SD 10.8), body mass index (BMI) 27.1 kg/m2 (SD 4.7). There were small decreases in SFA intake at 3 months: control = -0.1% (95% CI -1.8 to 1.7), BS = -0.7% (95% CI -1.8 to 0.3), SF = -0.9% (95% CI -2.0 to 0.2); but no evidence of a significant effect of either intervention compared with control (difference adjusted for GP practice and baseline: BS versus control = -0.33% [95% CI -2.11 to 1.44], p = 0.709; SF versus control = -0.11% [95% CI -1.92 to 1.69], p = 0.901). There were similar trends in %SFA based on supermarket purchases: control = -0.5% (95% CI -2.3 to 1.2), BS = -1.3% (95% CI -2.3 to -0.3), SF = -1.5% (95% CI -2.5 to -0.5) from baseline to follow-up, but these were not significantly different: BS versus control p = 0.379; SF versus control p = 0.411. There were small reductions in LDL from baseline to follow-up (control = -0.14 mmol/L [95% CI -0.48, 0.19), BS: -0.39 mmol/L [95% CI -0.59, -0.19], SF: -0.14 mmol/L [95% CI -0.34, 0.07]), but these were not significantly different: BS versus control p = 0.338; SF versus control p = 0.790. Limitations of this study include the small sample of participants recruited, which limits the power to detect smaller differences, and the low response rate (3%), which may limit the generalisability of these findings. In this study, we have shown it is feasible to deliver brief advice in primary care to encourage reductions in SFA intake and to provide personalized advice to encourage healthier choices using supermarket loyalty card data. There was no evidence of large reductions in SFA, but we are unable to exclude more modest benefits. The feasibility, acceptability, and scalability of these interventions suggest they have potential to encourage small changes in diet, which could be beneficial at the population level. ISRCTN14279335.