Risk Factor For Atherosclerotic Disease Research Articles

PCSK9 inhibitors as safer therapeutics for atherosclerotic cardiovascular disease (ASCVD): Pharmacophore design and molecular dynamics analysis.

Cardiovascular disorders are still challenging and are among the deadly diseases. As a major risk factor for atherosclerotic cardiovascular disease, dyslipidemia, and high low-density lipoprotein cholesterol in particular, can be prevented primary and secondary by lipid-lowering medications. Therefore, insights are still needed into designing new drugs with minimal side effects. Proprotein convertase subtilisin/kexin 9 (PCSK9) enzyme catalyses protein-protein interactions with low-density lipoprotein, making it a critical target for designing promising inhibitors compared to statins. Therefore, we screened for potential compounds using a redesigned PCSK9 conformational behaviour to search for a significantly extensive chemical library and investigated the inhibitory mechanisms of the final compounds using integrated computational methods, from ligand essential functional group screening to all-atoms MD simulations and MMGBSA-based binding free energy. The inhibitory mechanisms of the screened compounds compared with the standard inhibitor. K31 and K34 molecules showed stronger interactions for PCSK9, having binding energy (kcal/mol) of -33.39 and -63.51, respectively, against -27.97 of control. The final molecules showed suitable drug-likeness, non-mutagenesis, permeability, and high solubility values. The C-α atoms root mean square deviation and root mean square fluctuation of the bound-PCSK9 complexes showed stable and lower fluctuations compared to apo PCSK9. The findings present a model that unravels the mechanism by which the final molecules proposedly inhibit the PCSK9 function and could further improve the design of novel drugs against cardiovascular diseases.

Comparison of the pleiotropic effect of atorvastatin and rosuvastatin on postmenopausal changes in bone turnover: A randomized comparative study.

Statins are the first-line treatment for dyslipidemia, which is a major modifiable risk factor for atherosclerotic cardiovascular disease. Studies have shown that in addition to the beneficial lipid-lowering effect, statins also exhibit a number of pleiotropic effects that may find application in other diseases, including osteoporosis. This study aimed to assess the effect of statins on bone turnover, as measured by the concentration of bone turnover markers, and to compare the effect of atorvastatin as a lipophilic statin and rosuvastatin as a hydrophilic statin. This study included 34 postmenopausal women aged < 65 years with newly diagnosed dyslipidemia requiring statin therapy. Patients were randomly assigned to receive a statin drug. Statins were initiated at standard doses of 5 to 10 mg of rosuvastatin and 20 mg of atorvastatin. The levels of C-terminal telopeptide of type I collagen as a bone resorption marker and N-terminal propeptide of procollagen type I as a marker of bone formation, lipid concentrations and other biochemical parameters were assessed at baseline and after 6 and twelve months of treatment. There were no statistically significant differences between the levels of bone turnover markers before and 6 months after statin implementation (P > .05) - for all patients or subgroups according to statin use. Analysis of the results showed that after 12 months, there was a statistically significant decrease in N-terminal propeptide of procollagen type I concentration in all subjects (P = .004). By statin subgroup, a statistically significant decrease in N-terminal propeptide of procollagen type I was observed only in patients receiving rosuvastatin (P = .012) and not in those receiving atorvastatin (P = .25). Moreover, changes in bone turnover markers did not correlate with changes in lipid concentrations. These results may indicate the superiority of atorvastatin over rosuvastatin in inhibiting adverse changes in bone turnover in postmenopausal women. Confirmed by studies involving a larger population, the observed differences might find particular applications in clinical practice, and the choice of atorvastatin over rosuvastatin for women could be considered in the early postmenopausal period to reduce the risk of osteoporosis and subsequent osteoporotic fractures.

Management of Cardiovascular Risk in the Non‑alcoholic Fatty Liver Disease Setting

Non-alcoholic fatty liver disease (NAFLD) is an overlooked and undetected pathology, which affects more than 32% of adults worldwide. NAFLD is becoming more common in Western industrialised countries, particularly in patients with central obesity, type 2 diabetes, dyslipidaemia and metabolic syndrome. Although NAFLD has traditionally been interpreted as a liver disease with a high risk of liver-related complications, NAFLD is an underappreciated and independent risk factor for atherosclerotic cardiovascular disease, which is the principal cause of death in patients with NAFLD. Treatment options to counteract both the progression and development of cardiovascular disease and NAFLD include lifestyle interventions, such as weight loss, increased physical activity and dietary modification, and optimal medical therapy of comorbid conditions; nevertheless, further studies are needed to define optimal treatment strategies for the prevention of both hepatic and cardiovascular complications of NAFLD.

The effect of lipid-lowering therapy on lipid-related residual risk factors: a prospective study

BackgroundRemnant cholesterol (RC) and nonhigh-density lipoprotein cholesterol (nonHDL-C) are key risk factors for atherosclerotic cardiovascular disease (ASCVD), with apolipoprotein B (apoB) and lipoprotein(a) [Lp(a)] also contributing to its residual risk. However, real-world population-based evidence regarding the impact of current clinical LDL-C-centric lipid-lowering therapy (LLT) on achieving RC and nonHDL-C goals, as well as on modifying residual CVD risk factors is limited.MethodsThis prospective observational study enrolled 897 CVD patients from September, 2020 to July, 2021. All participants had previously received low-/moderate-intensity LLT and were discharged with either low-/moderate-intensity LLT or high-intensity LLT. After a median follow-up of 3 months, changes in RC, nonHDL-C, and other biomarkers were assessed. Multivariate logistic regression was performed to analyze the impact of the LLT on goal attainment.ResultsAmong all patients, 83.50% transitioned to high-intensity LLT from low or moderate. After follow-up, the high-intensity group saw significantly greater reductions in RC (-20.51% vs. -3.90%, P = 0.025), nonHDL-C (-25.12% vs. 0.00%, P < 0.001), apoB (-19.35% vs. -3.17%, P < 0.001), triglycerides (-17.82% vs. -6.62%, P < 0.001), and LDL-C and total cholesterol. Spearman correlation analysis revealed that LDL-C reduction from current LLT was strongly correlated with nonHDL-C reduction (r = 0.87, P < 0.001). Patients who received high-intensity LLT had significant improvements in attainment of RC (from 44.2% to 60.7%, χ² = 39.23, P < 0.001) and nonHDL-C (from 19.4% to 56.9%, χ² = 226.06, P < 0.001) goals. Furthermore, multivariate logistic regression showed that high-intensity LLT was a protective factor for RC [odds ratio (OR) = 0.66; 95% confidence intervals (CI), 0.45–0.97; P = 0.033] and nonHDL-C goal attainment (OR = 0.51; 95% CI, 0.34–0.75; P < 0.001), without a significant increase of adverse reactions.ConclusionCurrent levels of clinically prescribed LDL-C-centric treatment can reduce RC and other lipid-related residual risk factors, but high-intensity LLT is better at achieving nonHDL-C and RC goals than low-/moderate-intensity LLT, with a good safety profile. More targeted RC treatments are still needed to reduce residual lipid risk further.

Independent Relationship of Lipoprotein(a) and Carotid Atherosclerosis With Long-Term Risk of Cardiovascular Disease.

Lipoprotein(a) (Lp(a)) is considered to be a causal risk factor of atherosclerotic cardiovascular disease (ASCVD), but whether there is an independent or joint association of Lp(a) and atherosclerotic plaque with ASCVD risk remains uncertain. This study aims to assess ASCVD risk independently or jointly conferred by Lp(a) and carotid atherosclerotic plaque. A total of 5471 participants with no history of cardiovascular disease at baseline were recruited and followed up for ASCVD events (all fatal and nonfatal acute coronary and ischemic stroke events) over a median of 11.5 years. Independent association of Lp(a), or the joint association of Lp(a) and carotid plaque with ASCVD risk, was explored using Cox proportional hazards models. Overall, 7.6% of the participants (60.0±7.9 years of age; 2649 [48.4%] men) had Lp(a) ≥50 mg/dL, and 539 (8.4/1000 person-years) incident ASCVD events occurred. Lp(a) concentrations were independently associated with long-term risk of total ASCVD events, as well as coronary events and ischemic stroke events. Participants with Lp(a) ≥50 mg/dL had a 62% higher risk of ASCVD incidence (95% CI, 1.19-2.21) than those with Lp(a) <10 mg/dL, and they exhibited a 10-year ASCVD incidence of 11.7%. This association exists even after adjusting for prevalent plaque. Moreover, participants with Lp(a) ≥30 mg/dL and prevalent plaque had a significant 4.18 times higher ASCVD risk than those with Lp(a) <30 mg/dL and no plaque. Higher Lp(a) concentrations are independently associated with long-term ASCVD risk and may exaggerate cardiovascular risk when concomitant with atherosclerotic plaque.

Evaluating the Impact of Smoking and Hyperlipidemia in Patients with Atherosclerotic Cardiovascular Disease

Hyperlipidemia and Smoking are risk factors of atherosclerotic cardiovascular disease in Pakistani community. Objectives: To determine whether smoking and hyperlipidemia were associated with atherosclerotic cardiovascular disease. Methods: A comparative, cross-sectional study was conducted upon a sample of 200 male and female participants with different cardiac complications were selected and divided them into different groups like Group A and Group B. The individuals with medical complications such as severe chest pain, unexpected numbness or weakness in arms or legs and loss of vision were placed in Group A. While in Group-B 70 male and 30 female individuals with mild chest pain were include. BMI, Cholesterol, Triglyceride, LDL and HDL levels and other demographics such as age, smoking habits were measured respectively. Results: In Group A (severe disease group) there were 75 males and 25 females while in Group B (mild disease group) 70 male and 30 female individuals were listed. The mean age in Group A (59.09 ± 0.01) and Group B (59.09 ± 0.01). The results showed significant difference in Group A and B mean cholesterol (279.9 ± 0.04 vs. 239.09 ± 0.04), Triglycerides (187.02 ± 0.01 vs. 127.02 ± 0.01), LDL (153.01 ± 0.02 vs. 123.01 ± 0.02), HDL (49.04 ± 0.01 vs. 40.01 ± 0.01) and (p value&lt;0.05). Conclusions: It was concluded that hyperlipidemia and smoking were significant (p≤0.05) risk factors for atherosclerotic cardiovascular disease, as seen by increasing levels of cholesterol, Triglycerides and LDL in cardiovascular patients.

Association between lipoprotein(a) and premature atherosclerotic cardiovascular disease: a systematic review and meta-analysis.

High lipoprotein(a) [Lp(a)] level has been demonstrated as an important risk factor for atherosclerotic cardiovascular diseases (ASCVD) amongst the older populations, whereas its effects in the younger population remain unclear. This study evaluated the associations between Lp(a) and the risk of premature ASCVD. PubMed and Embase were searched for related studies until 12 November 2023. Fifty-one studies including 100 540 participants were included. Mean age of patients ranged from 35.3 to 62.3 years. The proportion of male participants ranged from 0% to 100%. The mean follow-up was provided in five studies ranging from 1 year to 40 years. The definition of elevated Lp(a) varied among studies, such as >30 mg/dL, >50 mg/dL, the top tertiles, the top quartiles, the top quintiles, and so on. Higher Lp(a) was significantly associated with the composite ASCVD [odds ratio (OR): 2.15, 95% confidence interval (95% CI): 1.53-3.02, P < 0.001], especially for coronary artery disease (OR: 2.44, 95% CI: 2.06-2.90, P < 0.001) and peripheral arterial disease (OR: 2.56, 95% CI: 1.56-4.21, P < 0.001). This association remained significant in familial hypercholesterolaemia (FH) (OR: 3.11, 95% CI: 1.63-5.96, P < 0.001) and type 2 diabetes mellitus (T2DM) patients (OR: 2.23; 95% CI: 1.54-3.23, P < 0.001).Significant results were observed in South Asians (OR: 3.71, 95% CI: 2.31-5.96, P < 0.001), Caucasians (OR: 3.17, 95% CI: 2.22-4.52, P < 0.001), and patients with baseline low-density lipoprotein cholesterol (LDL-c) level ≥ 2.6 mmol/L. Elevated Lp(a) predicts the risk of the composite or individual ASCVD in young, regardless of study design, gender, population characteristics (community or hospitalized), different premature definitions, and various Lp(a) measurement approaches. This association was important in South Asians, Caucasians, FH patients, T2DM patients, and patients with baseline LDL-c level ≥ 2.6 mmol/L.

Impact of LDLR polymorphisms on lipid levels and atorvastatin’s efficacy in a northern Chinese adult Han cohort with dyslipidemia

BackgroundDyslipidemia, a significant risk factor for atherosclerotic cardiovascular disease (ASCVD), is influenced by genetic variations, particularly those in the low-density lipoprotein receptor (LDLR) gene. This study aimed to elucidate the effects of LDLR polymorphisms on baseline serum lipid levels and the therapeutic efficacy of atorvastatin in an adult Han population in northern China with dyslipidemia.MethodsIn this study, 255 Han Chinese adults receiving atorvastatin therapy were examined and followed up. The 3’ untranslated region (UTR) of the LDLR gene was sequenced to identify polymorphisms. The associations between gene polymorphisms and serum lipid levels, as well as changes in lipid levels after intervention, were evaluated using the Wilcoxon rank sum test, with a P < 0.05 indicating statistical significance. Assessment of linkage disequilibrium patterns and haplotype structures was conducted utilizing Haploview.ResultsEleven distinct polymorphisms at LDLR 3’ UTR were identified. Seven polymorphisms (rs1433099, rs14158, rs2738466, rs5742911, rs17249057, rs55971831, and rs568219285) were correlated with the baseline serum lipid levels (P < 0.05). In particular, four polymorphisms (rs14158, rs2738466, rs5742911, and rs17249057) were in strong linkage disequilibrium (r2 = 1), and patients with the AGGC haplotype had higher TC and LDL-C levels at baseline. Three polymorphisms (rs1433099, rs2738467, and rs7254521) were correlated with the therapeutic efficacy of atorvastatin (P < 0.05). Furthermore, carriers of the rs2738467 T allele demonstrated a significantly greater reduction in low-density lipoprotein cholesterol (LDL-C) levels post-atorvastatin treatment (P = 0.03), indicating a potentially crucial genetic influence on therapeutic outcomes. Two polymorphisms (rs751672818 and rs566918949) were neither correlated with the baseline serum lipid levels nor atorvastatin’s efficacy.ConclusionsThis research outlined the complex genetic architecture surrounding LDLR 3’ UTR polymorphisms and their role in lipid metabolism and the response to atorvastatin treatment in adult Han Chinese patients with dyslipidemia, highlighting the importance of genetic profiling in enhancing tailored therapeutic strategies. Furthermore, this investigation advocates for the integration of genetic testing into the management of dyslipidemia, paving the way for customized therapeutic approaches that could significantly improve patient care.Trial registrationThis multicenter study was approved by the Ethics Committee of Xiangya Hospital Central South University (ethics number K22144). It was a general ethic. In addition, this study was approved by The First Hospital of Hebei Medical University (ethics number 20220418).

Remnant cholesterol and the risk of carotid plaque in hypertension: results from a community-based screening among old adults in Hangzhou, China

Elevated remnant cholesterol (RC) is considered a risk factor for atherosclerotic cardiovascular disease, but the evidence on this association applies to the Chinese population with hypertension is limited. We aimed to explore the association between RC levels and carotid plaque in old adults with hypertension. 8523 hypertensive patients aged ≥ 60 years with serum lipids and carotid ultrasonography data were included in this community-based screening. Fasting RC was calculated as total cholesterol minus high-density lipoprotein cholesterol minus low-density lipoprotein cholesterol (LDLC). The associations of RC levels with carotid plaque risk were evaluated using Logistic regression and restricted cubic spline models. Carotid plaque was screened in 4821 (56.56%) subjects. After multivariable-adjusted, RC was significantly related to carotid plaque [Odd ratio (OR)] = 1.043 per 0.1 mmol/L increase, 95% confidence interval (CI): 1.030–1.056). The highest versus the lowest quartile of RC was 1.928 (1.673–2.223) for carotid plaque. A nonlinear association was found between serum RC levels and the risk of carotid plaque (P for nonlinearity < 0.001). Moreover, an RC > 0.78 mmol/L differentiated patients at a higher risk of carotid plaque compared to those at lower concentrations, regardless of whether LDLC was on target at 2.59 mmol/L. In old adults with hypertension, elevated RC was positively associated with carotid plaque, independent of LDLC and other conventional risk factors.

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a)

Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities. To assess the safety and tolerability of zerlasiran, a short interfering RNA targeting hepatic synthesis of apolipoprotein(a), and effects on serum concentrations of lipoprotein(a). Single- and multiple-dose study in healthy participants and patients with stable ASCVD, respectively, with lipoprotein(a) serum concentrations greater than 150 nmol/L, conducted at 7 research sites in the US, the Netherlands, UK, and Australia between November 18, 2020, and February 8, 2023, with last follow-up on August 23, 2023. Participants were randomized to receive (1) a single subcutaneous dose of placebo (n = 8), zerlasiran 300 mg (n = 6) or 600 mg (n = 6); or (2) 2 doses of placebo (n = 9), zerlasiran 200 mg (n = 9) at a 4-week interval or 300 mg (n = 9) or 450 mg (n = 9) at an 8-week interval. The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations. Among 37 patients in the multiple-dose group (mean age, 56 [SD, 10.4] years; 15 [42%] women), 36 completed the trial. Among 14 participants with extended follow-up after single doses, 13 completed the trial. There were no serious adverse events. Median baseline lipoprotein(a) concentrations in the multiple-dose group were 288 (IQR, 199-352) nmol/L. Median changes in lipoprotein(a) concentration at 365 days after single doses were 14% (IQR, 13% to 15%) for the placebo group, -30% (IQR, -51% to -18%) for the 300 mg of zerlasiran group, and -29% (IQR, -39% to -7%) for the 600-mg dose group. After 2 doses, maximal median changes in lipoprotein(a) concentration were 19 (IQR, -17 to 28) nmol/L for the placebo group, -258 (IQR, -289 to -188) nmol/L for the 200 mg of zerlasiran group, -310 (IQR, -368 to -274) nmol/L for the 300-mg dose group, and -242 (IQR, -343 to -182) nmol/L for the 450-mg dose group, with maximal median percent change of 7% (IQR, -4% to 21%), -97% (IQR, -98% to -95%), -98% (IQR, -99% to -97%), and -99% (IQR, -99% to -98%), respectively, attenuating to 0.3% (IQR, -2% to 21%), -60% (IQR, -71% to -40%), -90% (IQR, -91% to -74%), and -89% (IQR, -91% to -76%) 201 days after administration. Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration. ClinicalTrials.gov Identifier: NCT04606602.

Elevated Lp(a): Guidance for Identifying and Managing Patients.

Lipoprotein(a) (Lp(a)) is a unique low-density lipoprotein-like lipoprotein that is considered an independent and causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic valve stenosis. The Lp(a) molecule also contains apolipoprotein A and apolipoprotein B, which collectively promote atherosclerosis, thrombosis, and inflammation. Lp(a) is highly genetic and minimally responsive to nonpharmacological measures. Lp(a) serum levels ≥125 nmol/L are associated with increased ASCVD risk, but this threshold has not been accepted universally. Elevated Lp(a) is the most common genetic dyslipidemia affecting approximately 20% of the general population. Certain currently available lipid-lowering drugs, including the proprotein convertase subtilisin/kexin type 9 therapies, produce moderate reductions in Lp(a); however, none are indicated for the treatment of elevated Lp(a). There are currently four investigational RNA-based therapeutic agents that reduce Lp(a) by 70% to 100%. Two of these agents are being evaluated for ASCVD risk reduction in adequately powered outcomes trials, with results expected in 2 to 3 years. Until such therapies become available and demonstrate favorable clinical outcomes, strategies for elevated Lp(a) primarily involve early and intensive ASCVD risk factor management.

Discrimination and net-reclassification of cardiovascular disease risk with Lipoprotein(a) levels: the ATTICA study (2002-2022)

BackgroundLipoprotein(a) [Lp(a)] is a recognized as risk factor for atherosclerotic cardiovascular disease (ASCVD). However, its influence on clinical risk evaluations remains unclear. ObjectiveThis study aimed to determine whether Lp(a) improves CVD risk prediction among apparently healthy adults from the general population. MethodsIn 2002, n=3,042 adults free of CVD, residing in Athens metropolitan area, in Greece, were recruited. A 20-year follow-up was conducted in 2022, comprising n=2,169 participants, of which n=1,988 had complete data for CVD incidence. ResultsLp(a) levels were significantly associated with 20-year ASCVD incidence in the crude model (Hazard Ratio per 1 mg/dL: 1.004, p=0.048), but not in multi-adjusted models considering demographic, lifestyle, and clinical factors. Adding Lp(a) to the Reynolds Risk Score (RRS) and Framingham Risk Score (FRS) models resulted in positive Net Reclassification Improvement (NRI) values (0.329 and 0.365 respectively), indicating improved risk classification. Mediation analysis suggested that C-reactive protein, Interleukin-6, and Fibrinogen mediate the relationship between Lp(a) and ASCVD. No significant interaction was observed between Lp(a) and potential moderators. ConclusionLp(a) levels can predict 20-year CVD outcomes and improve CVD risk prediction within the general population, possibly via the intricate relationship between Lp(a), systemic inflammation, atherothrombosis.

Fixed-dose combination therapy for the prevention of atherosclerotic cardiovascular disease.

Fixed-dose combination (FDC) therapy, also known as polypill therapy, targets risk factors for atherosclerotic cardiovascular disease (ASCVD) and has been proposed as a strategy to reduce global ASCVD burden. Here we conducted a systematic search for relevant studies from 2016-2022 to assess the effects of FDC therapy for prevention of ASCVD. The studies selected include randomized trials evaluating FDC therapy with at least one blood pressure-lowering drug and one lipid-lowering drug. The study data were independently extracted, the quality of evidence was appraised by multiple reviewers and effect estimates were pooled using a fixed-effect meta-analysis when statistical heterogeneity was low to moderate. The main outcomes of the analysis were all-cause mortality, fatal and nonfatal ASCVD events, adverse events, systolic blood pressure, low-density lipoprotein cholesterol and adherence. Among 26 trials (n = 27,317 participants, 43.2% female and mean age range 52.9-76.0), FDC therapy was associated with lower low-density lipoprotein cholesterol and systolic blood pressure, with higher rates of adherence and adverse events in both primary and mixed secondary prevention populations. For studies with a mostly primary prevention population, FDC therapy was associated with lower risk of all-cause mortality by 11% (5.6% versus 6.3%; relative risk (risk ratio) of 0.89; 95% confidence interval 0.78 to 1.00; I2 = 0%; four trials and 16,278 participants) and risk of fatal and nonfatal ASCVD events by 29% (6.1% versus 8.4%; relative risk (risk ratio) of 0.71; 95% confidence interval 0.63 to 0.79; I2 = 0%; five trials and 15,503 participants). One adequately powered trial in an exclusively secondary prevention population showed that FDC therapy reduced the risk of major adverse cardiovascular events by 24%. These findings support adoption and implementation of polypills to lower risk for all-cause mortality and ASCVD.

Costs attributable to hypercholesterolemia in a single period and over the life cycle.

Hypercholesterolemia is a major risk factor for atherosclerotic cardiovascular disease leading to reduced (healthy) life years. The aim of this study is to quantify the societal costs associated with hypercholesterolemia. We use epidemiologic data on the distribution of cholesterol levels as well as data on relative risks regarding ischemic heart disease, stroke, and other cardiovascular diseases. The analytical approach is based on the use of population-attributable fractions applied to direct medical, direct non-medical and indirect costs using data of Austria. Within a life-cycle analysis we sum up the costs of hypercholesterolemia for the population of 2019 and, thus, consider future morbidity and mortality effects on this population. Epidemiologic data suggest that approximately half of Austria's population have low-density lipoprotein cholesterol (LDL-C) levels above the target levels (i.e., are exposed to increased risk). We estimate that 8.2% of deaths are attributable to hypercholesterolemia. Total costs amount to about 0.33% of GDP in the single-period view. In the life-cycle perspective, total costs amount to €806.06 million, €312.1 million of which are medical costs, and about €494 million arise due to production loss associated with hypercholesterolemia. The study points out that significant shares of deaths, entries into disability pension and care allowance, full-time equivalents lost to the labor market as well as monetary costs for the health system and the society could be avoided if LDL-C-levels of the population were reduced.

Remnant Cholesterol, Not LDL Cholesterol, Explains Peripheral Artery Disease Risk Conferred by apoB: A Cohort Study.

Elevated apoB-containing lipoproteins (=remnants+LDLs [low-density lipoproteins]) are a major risk factor for atherosclerotic cardiovascular disease, including peripheral artery disease (PAD) and myocardial infarction. We tested the hypothesis that remnants and LDL both explain part of the increased risk of PAD conferred by elevated apoB-containing lipoproteins. For comparison, we also studied the risk of chronic limb-threatening ischemia and myocardial infarction. apoB, remnant cholesterol, and LDL cholesterol were measured in 93 461 individuals without statin use at baseline from the Copenhagen General Population Study (2003-2015). During up to 15 years of follow-up, 1207 had PAD, 552 had chronic limb-threatening ischemia, and 2022 had myocardial infarction in the Danish National Patient Registry. Remnant and LDL cholesterol were calculated from a standard lipid profile. Remnant and LDL particle counts were additionally measured with nuclear magnetic resonance spectroscopy in 25 347 of the individuals. Results were replicated in 302 167 individuals without statin use from the UK Biobank (2004-2010). In the Copenhagen General Population Study, multivariable adjusted hazard ratios for risk of PAD per 1 mmol/L (39 mg/dL) increment in remnant and LDL cholesterol were 1.9 (95% CI, 1.5-2.4) and 1.1 (95% CI, 1.0-1.2), respectively; corresponding results in the UK Biobank were 1.7 (95% CI, 1.4-2.1) and 0.9 (95% CI, 0.9-1.0), respectively. In the association from elevated apoB to increased risk of PAD, remnant and LDL cholesterol explained 73% (32%-100%) and 8% (0%-46%), respectively; corresponding results were 63% (30%-100%) and 0% (0%-33%) for risk of chronic limb-threatening ischemia and 41% (27%-55%) and 54% (38%-70%) for risk of myocardial infarction; results for remnant and LDL particle counts corroborated these findings. PAD risk conferred by elevated apoB-containing lipoproteins was explained mainly by elevated remnants, while myocardial infarction risk was explained by both elevated remnants and LDL.

Lipoprotein(a) and Atherosclerotic Cardiovascular Disease: Where Do We Stand?

Lipoprotein(a) [Lp(a)] consists of a low-density lipoprotein-like molecule and an apolipoprotein(a) [apo(a)] particle. Lp(a) has been suggested to be an independent risk factor of atherosclerotic cardiovascular disease (ASCVD). Lp(a) plasma levels are considered to be 70-90% genetically determined through the codominant expression of the LPA gene. Therefore, Lp(a) levels are almost stable during an individual's lifetime. This lifelong stability, together with the difficulties in measuring Lp(a) levels in a standardized manner, may account for the scarcity of available drugs targeting Lp(a). In this review, we synopsize the latest data regarding the structure, metabolism, and factors affecting circulating levels of Lp(a), as well as the laboratory determination measurement of Lp(a), its role in the pathogenesis of ASCVD and thrombosis, and the potential use of various therapeutic agents targeting Lp(a). In particular, we discuss novel agents, such as antisense oligonucleotides (ASOs) and small interfering RNAs (siRNAs) that are currently being developed and target Lp(a). The promising role of muvalaplin, an oral inhibitor of Lp(a) formation, is then further analyzed.

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

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. 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. 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.

Clonal hematopoiesis is associated with cardiovascular events in patients with stable coronary artery disease

Clonal hematopoiesis (CH) is a risk factor for atherosclerotic cardiovascular disease, but the impact of smaller clones and the effect on inflammatory parameters is largely unknown. Using ultrasensitive single-molecule molecular inversion probe sequencing, we evaluated the association between CH and a first major adverse cardiovascular event (MACE) in patients with angiographically documented stable coronary artery disease (CAD) and no history of acute ischemic events. CH was associated with an increased rate of MACE at four years follow-up. The size of the clone predicted MACE at an optimal cut-off value of 1.07% variant allele frequency (VAF). Mutation carriers had no change in monocytes subsets or cytokine production capacity but had higher levels of circulating tissue factor, matrilysin, and proteinase-activated receptor-1. Our study identified CH driver mutations with a VAF as small as 1.07% as a residual cardiovascular risk factor and identified potential biomarkers and therapeutic targets for patients with stable CAD.

Lipoprotein(a) as a risk factor for atherosclerotic cardiovascular disease in patients in non-metropolitan areas of Brandenburg, Germany.

In the non-metropolitan region of Brandenburg (Germany), which is characterized by high rates of cardiovascular diseases and underserved medical care, there is a lack of awareness regarding lipoprotein(a) [Lp(a)] as a risk factor. In addition, data from patients with atherosclerotic cardiovascular disease (ASCVD) in diverse regional backgrounds, including the understudied Brandenburg cohort, and various healthcare statuses remain insufficient. In this WalkByLab study, Lp(a) levels were monitored in a non-metropolitan cohort (n = 850) in Brandenburg, Germany, comprising 533 patients at high cardiovascular risk and 317 healthy controls. Patients underwent a comprehensive angiological screening, which included blood serum analysis, assessment of medical and family history, cardiovascular risk, and disease status, and evaluation of lifestyle and quality of life. All parameters were evaluated with regard to two groups based on Lp(a) levels: low (<50 mg/dl) and high (≥50 mg/dl). Brandenburg patients with cardiovascular diseases showed higher Lp(a) levels than healthy controls (24.2% vs. 14.8%, p = 0.001). Logistic regression analysis with different characteristics revealed that Lp(a) was an independent risk factor significantly associated with ASCVD (OR 2.26, 95% CI 1.32-3.95, p = 0.003). The high-Lp(a) group showed a higher proportion of patients with coronary artery disease, peripheral artery disease, or cerebrovascular disease compared to the low-Lp(a) group (50% vs. 36.8%; 57.7% vs. 45.8%; 17.6% vs. 9.2%; p = 0.004); also, a higher percentage of patients in the high-Lp(a) group had heart failure (72.8% vs. 53.2%, p = 0.014) and myocardial infarction (24.7% vs. 13.9%, p = 0.001). The high-Lp(a) group exhibited higher rates of statins (63.1% vs. 50.4%, p = 0.003), ezetimibe (14.8% vs. 5.5.%, p = 0.001), and beta-blockers (55.7% vs. 40.7%, p = 0.001) use. Lp(a) levels were found to be independent of physical activity or smoking behavior and did not change over time (12 months). Our study highlights the significance of elevated Lp(a) levels in Brandenburg cardiovascular patients and identifies them as an independent risk factor for ASCVD, which has implications for addressing cardiovascular health of non-metropolitan populations.

Lipoprotein(a) serum concentrations in children in relation to body mass index, age and sex.

Lipoprotein(a) (Lp(a)) is an inherited risk factor for atherosclerotic cardiovascular disease (ASCVD). Limited data exist on Lp(a) values in children. We aimed to evaluate whether Lp(a) concentrations in youth are influenced by BMI. 756 blood samples of 248 children with obesity and 264 matched healthy children aged 5 and 18 years, enrolled in the population-based LIFE Child (German civilization diseases cohort) study, were analyzed. Repeat measurements were available in 154 children (1-4 follow ups, ~1 year apart). The median Lp(a) concentration in the total cohort (n = 512) at first visit was 9.7 mg/dL (IQR 4.0-28.3). Lp(a) concentrations between 30-50 mg/dL were observed in 11.5%, while 12.5% exhibited Lp(a) ≧50 mg/dL. There was no association of Lp(a) with body mass index (BMI) (ß = 0.004, P = 0.49). Lp(a) levels did not correlate with age or sex, while Lp(a) was associated positively with low-density lipoprotein cholesterol (ß = 0.05, P < 0.0001). The Lp(a) risk category remained stable in 94% of all children in repeated measurements. The data showed no association of Lp(a) levels in children with BMI, age or sex. Measurement of Lp(a) in youth may be useful to identify children at increased lifetime risk for ASCVD. In youth, Lp(a) levels are not affected by age, sex and BMI. Lp(a) risk categories remain stable over time in repeated measurements in children. Measurement of Lp(a) in children may be useful as an additional factor to identify children at increased lifetime risk for ASCVD and for reverse family screening.