Atherosclerotic Cardiovascular 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.

Prognostic Value of Cardiovascular Biomarkers in the Population.

Identification of individuals at high risk for atherosclerotic cardiovascular disease within the population is important to inform primary prevention strategies. To evaluate the prognostic value of routinely available cardiovascular biomarkers when added to established risk factors. Individual-level analysis including data on cardiovascular biomarkers from 28 general population-based cohorts from 12 countries and 4 continents with assessments by participant age. The median follow-up was 11.8 years. Measurement of high-sensitivity cardiac troponin I, high-sensitivity cardiac troponin T, N-terminal pro-B-type natriuretic peptide, B-type natriuretic peptide, or high-sensitivity C-reactive protein. The primary outcome was incident atherosclerotic cardiovascular disease, which included all fatal and nonfatal events. The secondary outcomes were all-cause mortality, heart failure, ischemic stroke, and myocardial infarction. Subdistribution hazard ratios (HRs) for the association of biomarkers and outcomes were calculated after adjustment for established risk factors. The additional predictive value of the biomarkers was assessed using the C statistic and reclassification analyses. The analyses included 164 054 individuals (median age, 53.1 years [IQR, 42.7-62.9 years] and 52.4% were women). There were 17 211 incident atherosclerotic cardiovascular disease events. All biomarkers were significantly associated with incident atherosclerotic cardiovascular disease (subdistribution HR per 1-SD change, 1.13 [95% CI, 1.11-1.16] for high-sensitivity cardiac troponin I; 1.18 [95% CI, 1.12-1.23] for high-sensitivity cardiac troponin T; 1.21 [95% CI, 1.18-1.24] for N-terminal pro-B-type natriuretic peptide; 1.14 [95% CI, 1.08-1.22] for B-type natriuretic peptide; and 1.14 [95% CI, 1.12-1.16] for high-sensitivity C-reactive protein) and all secondary outcomes. The addition of each single biomarker to a model that included established risk factors improved the C statistic. For 10-year incident atherosclerotic cardiovascular disease in younger people (aged <65 years), the combination of high-sensitivity cardiac troponin I, N-terminal pro-B-type natriuretic peptide, and high-sensitivity C-reactive protein resulted in a C statistic improvement from 0.812 (95% CI, 0.8021-0.8208) to 0.8194 (95% CI, 0.8089-0.8277). The combination of these biomarkers also improved reclassification compared with the conventional model. Improvements in risk prediction were most pronounced for the secondary outcomes of heart failure and all-cause mortality. The incremental value of biomarkers was greater in people aged 65 years or older vs younger people. Cardiovascular biomarkers were strongly associated with fatal and nonfatal cardiovascular events and mortality. The addition of biomarkers to established risk factors led to only a small improvement in risk prediction metrics for atherosclerotic cardiovascular disease, but was more favorable for heart failure and mortality.

A comparative study of the hypolipidemic effects and mechanisms of action of Laminaria japonica- and Ascophyllum nodosum-derived fucoidans in apolipoprotein E-deficient mice.

The structural characteristics of fucoidans exhibit species and regional diversity. Previous studies have demonstrated that Laminaria japonica- and Ascophyllum nodosum-derived fucoidans have type I and type II fucosyl chains, respectively. These chemical differences may contribute to distinct hypolipidemic effects and mechanisms of action. Chemical analysis demonstrated that the percentage contents of sulfate, glucuronic acid, and galactose were higher in L. japonica-derived fucoidans than those of A. nodosum-derived fucoidans. In hyperlipidemic apolipoprotein E-deficient mice, both A. nodosum- and L. japonica-derived fucoidans significantly decreased the plasma and hepatic levels of total cholesterol and triglyceride, leading to the reduction of atherosclerotic plaques. Western blotting experiments demonstrated that these fucoidans significantly enhanced the expression and levels of scavenger receptor B type 1, cholesterol 7 alpha-hydroxylase A1, and peroxisome proliferator-activated receptor (PPAR)-α, contributing to circulating lipoprotein clearance and fatty acid degradation, respectively. Differentially, L. japonica-derived fucoidan significantly increased the LXR/ATP-binding cassette G8 signaling pathway in the small intestine, as revealed by real-time quantitative PCR, which may lead to further cholesterol and other lipid excretion. Collectively, these data are useful for understanding the hypolipidemic mechanisms of action of seaweed-derived fucoidans, and their potential application for the prevention and/or treatment of atherosclerotic cardiovascular diseases.

The natural polyphenol fisetin in atherosclerosis prevention: a mechanistic review.

The incidence and mortality rate of atherosclerotic cardiovascular disease (ASCVD) is increasing yearly worldwide. Recently, a growing body of evidence has unveiled the anti-atherosclerotic properties of fisetin, a natural polyphenol compound. In this article, we reviewed the pharmacologic actions of fisetin on experimental atherosclerosis and its protective effects on disease-relevant cell types such as endothelial cells, macrophages, vascular smooth muscle cells, and platelets. Based on its profound cardiovascular actions, fisetin holds potential for clinical translation and could be developed as a potential therapeutic option for atherosclerosis and its related complications. Large-scale randomized clinical trials are warranted to ascertain the safety and efficacy of fisetin in patients with or high risk for ASCVD.

Sodium-Glucose Cotransporter-2 Inhibitors and Cardiovascular Protection Among Patients With Type 2 Diabetes Mellitus: A Systematic Review

Background: Accumulating evidence has demonstrated the positive effects of sodium-glucose cotransporter-2 (SGLT2) inhibitors in managing patients with type 2 diabetes mellitus (T2DM). SGLT2 inhibitors protect patients with T2DM from cardiovascular complications and are generally safe.Aim: The aim of this study is to assess the cardiovascular effects of SGLT2 inhibitors in patients with T2DM.Methods: A systematic review was conducted using published English literature in PubMed and Google Scholar databases.Results: Most of the studies showed significant positive cardiovascular effects of SGLT2 inhibitors in patients with and without established cardiovascular disease (CVD). Empagliflozin reduced the risk of cardiovascular death, hospitalization for heart failure (HHF), cardiovascular death or heart failure, and major adverse cardiovascular events (MACE) such as nonfatal stroke, nonfatal myocardial infarction, and cardiovascular death regardless of the number of cardiovascular risk factors. The effects of empagliflozin on cardiovascular events and mortality in patients with coronary artery bypass graft (CABG) were assessed. Further, the efficacy of empagliflozin in three different phenotypic groups, namely, younger patients with shorter duration of T2DM and highest glomerular filtration rate, women without coronary artery disease, and older adults with advanced coronary artery disease plus several comorbidities, was also assessed. The effects of canagliflozin were evaluated in patients with and without a history of CVD and with different body weights, and in those with and without prior heart failure. Treatment with canagliflozin based on multivariable-predicted cardiovascular risk factors prevented heart failure events more than treatment based on glycated hemoglobin and albuminuria alone. The efficacy of dapagliflozin was evaluated in patients with or at risk of atherosclerotic cardiovascular disease (ASCVD), heart failure status, and left ventricular ejection fraction (LVEF), as well as the elderly population. A reduction in HHF or cardiovascular death and insignificant reduction in MACE were noted. Furthermore, significant reduction in the risk of cardiovascular death and all-cause mortality in patients with heart failure with reduced ejection fraction (HFrEF) was also observed. Sotagliflozin was studied for its cardiovascular outcomes in patients with chronic kidney disease with or without albuminuria and resulted in a reduction in cardiovascular-related deaths and HHF.Conclusion: SGLT2 inhibitors have beneficial cardiovascular effects in patients with T2DM and should be incorporated into their management.

Relationship between atherosclerotic cardiovascular disease and diabetic retinopathy in patients with type 2 diabetes mellitus.

This study aimed to explore the potential correlation between atherosclerotic cardiovascular disease (ASCVD) and diabetic retinopathy (DR) in patients with type 2 diabetes mellitus (T2DM). We enrolled 6540 patients with T2DM who were receiving chronic disease management for hypertension, hyperglycemia, and hyperlipidemia in Chengyang District of Qingdao. Among them, 730 had ASCVD (ASCVD group), which 5810 did not (N-ASCVD group). The results showed significantly higher levels of age, blood glucose, glycosylated hemoglobin (HbA1c), systolic blood pressure, ASCVD family history, female proportion, and DR incidence in the N-ASCVD group. Additionally, the glomerular filtration rate was significantly lower in the ASCVD group. Logistic regression analysis revealed a positive correlation between DR and ASCVD risk. DR was further categorized into 2 subtypes, nonproliferative DR (NPDR) and proliferative DR (PDR), based on e lesion severity. Interestingly, only the PDR was associated with ASCVD. Even after accounting for traditional ASCVD risk factors such as age, sex, and family history, PDR remained associated with ASCVD, with a staggering 718% increase in the risk for patients with PDR. Therefore, there is a strong association between ASCVD and DR in individuals with T2DM, with PDR particularly exhibiting an independent and positive correlation with increased ASCVD risk.

Diagnosis and treatment of dyslipidemia in children and adolescents

Background: Atherosclerotic cardiovascular disease is a major cause of morbidity and mortality worldwide, including in South Korea. Dyslipidemia is an independent risk factor for the development of atherosclerotic cardiovascular diseases. There is strong evidence that atherosclerosis begins early in life and that elevated lipid levels in childhood predict elevated lipid levels into adulthood.Current Concepts: A universal approach for cholesterol screening in all children is recommended. Lipid profiles should be studied for all children aged 9 to 11 years and then for those aged 17 to 21 years, as cholesterol levels may vary after puberty. The non-fasting lipid profile can be as useful in detecting severe genetic dyslipidemias as the fasting lipid profile and thus can be used as a first-line screening in children. The initial treatment for dyslipidemia in a child always begins with a 6-month trial of lifestyle modifications, such as improvements in dietary and physical activity patterns. Statins are as effective in children as in adults and can lower low-density lipoprotein cholesterol levels by up to 50%. Therefore, they are considered first-line therapy for children who meet the criteria for pharmacological therapy.Discussion and Conclusion: Statins and non-statin lipid-lowering agents can lower cholesterol levels with minimal adverse effects in children and adolescents with hypercholesterolemia. However, limited data is currently available on the long-term safety and efficacy of lipid-lowering agents in the pediatric population. Furthermore, non-statin lipid-lowering agents are used far less frequently in children. Therefore, further long-term safety and efficacy studies on lipid-lowering agents in pediatric populations and clinical trials with non-statin lipid-lowering agents are required.

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.

Inclisiran (Leqvio)

CADTH recommends that Leqvio not be reimbursed by public drug plans as an adjunct to lifestyle changes, including diet, to further reduce low-density lipoprotein cholesterol (LDL-C) levels in adults who are on a maximally tolerated dose (MTD) of a statin, with or without other LDL-C–lowering therapies, and who have nonfamilial hypercholesterolemia (nFH) with atherosclerotic cardiovascular disease (ASCVD). Evidence from 2 clinical trials showed that treatment with Leqvio lowered bad cholesterol (LDL-C) in adults with nFH with ASCVD who were already being treated with the highest possible dose of statins and in those who cannot tolerate treatment with statins. A post hoc pooled analysis of major adverse cardiovascular events (MACEs) from the ORION-10 and ORION-11 trials precluded the Canadian Drug Expert Committee (CDEC) from determining whether inclisiran reduces the risk of cardiovascular morbidity and death in adults with nFH with ASCVD. Patients identified a need for treatments that are less burdensome, can reduce bad cholesterol (LDL-C) and cardiovascular morbidity and death, and improve health-related quality of life (HRQoL); however, there was not enough evidence to show that Leqvio would reduce cardiovascular morbidity and death or improve HRQoL.

Predictors of cardiovascular risk in familial hypercholesterolemia.

Familial Hypercholesterolemia is associated with an increased risk of cardiovascular disease. The current international guidelines of the main scientific societies consider that all people with familial hypercholesterolemia have a high or very high cardiovascular risk. However, the occurrence of atherosclerotic cardiovascular disease is very heterogeneous in this population. Stratifying risk within people with familial hypercholesterolemia is essential to identify individuals who require intensive cholesterol-lowering therapies. In the last year, several studies have been published focusing on the contribution of diabetes to familial hypercholesterolemia, the role of stroke, as a manifestation of atherosclerotic disease, and the external validation of the SAFEHEART risk equation in the English population diagnosed with Familial Hypercholesterolemia. It is necessary the development of a tool that allows us to identify, in a simple, reproducible, and universal way, patients who may have a high risk of suffering a cardiovascular event and who are susceptible to more intensive treatments to reduce cholesterol levels.

Sex-based utilization of guideline recommended statin therapy and cardiovascular disease outcomes: Data from a multisite healthcare network primary prevention cohort

BackgroundIn the US, women have similar cardiovascular death rates as men. However, less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes. MethodsStatin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013 and 2019. Guideline-directed statin intensity (GDSI) at index (at least moderate intensity, defined per pooled-cohort equation) and follow-up visits were compared between sexes across ASCVD risk groups, defined by the pooled-cohort equation. Cox regression hazard ratios were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied. ResultsAmong 282,298 patients, (mean age ∼ 50 years) 17.1 % women and 19.5 % men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-up were lower compared to high-risk men (2-years: 27.7 vs 32.0 %, and 5-years: 47.2 vs 55.2 %, p < 0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA among both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22–1.59]) vs. men (HR=1.67 [1.50–1.86]) of similar risk (p value interaction=0.004). ConclusionIn a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to remain on GDSI compared to high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.

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.

Heart groups in South Africa advocate for tighter LDL-C control and lipoprotein(a) testing to curb atherosclerotic cardiovascular disease

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The prognostic value of remnant cholesterol in patients with ST segment elevation myocardial infarction

Abstract Funding Acknowledgements None. Background Remnant cholesterol (RC) is the cholesterol content within triglyceride rich lipoproteins. It promotes atherosclerotic cardiovascular disease beyond low density lipoprotein cholesterol (LDL-C). Purpose The prognostic role of RC in patients with ST-segment elevation myocardial infarction (STEMI) is unknown. We aimed to estimate RC-related risk beyond LDL-C in patients with STEMI. Methods A total of 6602 consecutive patients with STEMI treated with primary percutaneous coronary intervention (PCI) from 1999 to 2016 were included. RC was calculated as total cholesterol minus LDL-C minus high-density lipoprotein cholesterol. Adjusted Cox models were used to estimate the association between continuous RC levels and all-cause mortality, cardiovascular death, ischemic stroke, and recurrent myocardial infarction (MI) at long-term (median follow-up of 6.0 years). Besides, discordance analyses were applied to examine the risk of the discordantly high RC (RC percentile rank minus LDL-C percentile rank&amp;gt; 10 units) compared to the discordantly low RC (LDL-C percentile rank minus RC percentile rank&amp;gt; 10 units). The concordance was defined as the percentile rank difference between RC and LDL-C ≤ 10 units. Results The median age of patients was 63 years old [interquartile range (IQR) 54–72] and 74.8% of them were men. There were 2441, 1651 and 2510 people in the discordantly low RC group, concordant group and discordantly high RC group. All outcomes in the discordantly high RC group were higher than the other groups and its event rate of all-cause mortality was 31.87 (event number/patient number in the group*100). In the unadjusted analysis, the discordantly high RC was associated with increased all-cause mortality [hazard ratio (HR) 1.82, 95% confidence interval (CI) 1.63–2.04] and increased cardiovascular death (HR 1.79, 95% CI 1.55–2.06) compared to the discordantly low RC. In an adjusted model RC was associated with higher all-cause mortality (HR 1.14, 95% CI 1.07–1.22). The discordantly high RC was associated with increased all-cause mortality (HR 1.55, 95% CI 1.37–1.75) and increased cardiovascular death (HR 1.47, 95% CI 1.25–1.72) compared to the discordantly low RC. There were no associations between RC and ischemic stroke or recurrent MI. Conclusions In patients with STEMI treated with primary PCI, elevated RC levels beyond LDL-C were independently associated with increased all-cause mortality.Graphical summaryLong-term survival probability

Association of Triglyceride Glucose-Derived Indexes with Recurrent Events Following Atherosclerotic Cardiovascular Disease.

Triglyceride glucose (TyG) and TyG-body mass index (TyG-BMI) are reliable surrogate indexes of insulin resistance and used for risk stratification and outcome prediction in patients with atherosclerotic cardiovascular disease (ASCVD). Here, we inserted estimated average glucose (eAG) into the TyG (TyAG) and TyG-BMI (TyAG-BMI) as derived parameters and explored their clinical significance in cardiovascular risk prediction. This was a population-based cohort study of 9,944 Chinese patients with ASCVD. The baseline admission fasting glucose and A1C-derived eAG values were recorded. Cardiovascular events (CVEs) that occurred during an average of 38.5 months of follow-up were recorded. We stratified the patients into four groups by quartiles of the parameters. Baseline data and outcomes were analyzed. Distribution of the TyAG and TyAG-BMI indexes shifted slightly toward higher values (the right side) compared with TyG and TyG-BMI, respectively. The baseline levels of cardiovascular risk factors and coronary severity increased with quartile of TyG, TyAG, TyG-BMI, and TyAG-BMI (all P<0.001). The multivariate-adjusted hazard ratios for CVEs when the highest and lowest quartiles were compared from low to high were 1.02 (95% confidence interval [CI], 0.77 to 1.36; TyG), 1.29 (95% CI, 0.97 to 1.73; TyAG), 1.59 (95% CI, 1.01 to 2.58; TyG-BMI), and 1.91 (95% CI, 1.16 to 3.15; TyAG-BMI). The latter two showed statistical significance. This study suggests that TyAG and TyAG-BMI exhibit more information than TyG and TyG-BMI in disease progression among patients with ASCVD. The TyAG-BMI index provided better predictive performance for CVEs than other parameters.

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.

Trends and Disparities in Treatment and Control of Atherosclerotic Cardiovascular Disease in US Adults, 1999 to 2018.

Although cardiovascular mortality continued declining from 2000 to 2019, the rate of this decrease decelerated. We aimed to assess the trends and disparities in risk factor control and treatment among US adults with atherosclerotic cardiovascular disease to find potential causes of the deceleration. A total of 55 ,021 participants, aged ≥20 years, from the 1999 to 2018 National Health and Nutrition Examination Survey were included, of which 5717 were with atherosclerotic cardiovascular disease. Risk factor control was defined as hemoglobin A1c <7%, blood pressure <140/90 mm Hg, and non-high-density lipoprotein cholesterol <100 mg/dL. The prevalence of atherosclerotic cardiovascular disease oscillated between 7.3% and 8.9% from 1999 to 2018. A significant increasing trend was observed in the prevalence of diabetes, obesity, heavy alcohol consumption, and self-reported hypertension within the population with atherosclerotic cardiovascular disease (Ptrend≤0.001). Non-high-density lipoprotein cholesterol <100 mg/dL increased from 7.1% in 1999 to 2002 to 15.7% in 2003 to 2006, before plateauing. Blood pressure control (<140/90 mm Hg) increased until 2011 to 2014, but declined to 70.1% in 2015 to 2018 (Ptrend<0.001, Pjoinpoint=0.14). Similarly, the proportion of participants achieving hemoglobin A1c control began to decrease after 2006 (Pjoinpoint=0.05, Ptrend=0.001). The percentage of participants achieving all 3 targets increased significantly from 4.5% to 18.6% across 1999 to 2018 (Ptrend=0.02), but the increasing trend decelerated after 2005 to 2006 (Pjoinpoint<0.001). Striking disparities in risk factor control and medication use persisted between sexes, and between different racial and ethnic populations. Worsened control of glycemia, blood pressure, obesity, and alcohol consumption, leveled lipid control, and persistent socioeconomic disparities may be contributing factors to the observed deceleration in decreasing cardiovascular mortality trends.

European and US Guideline-Based Statin Eligibility, Genetically Predicted Coronary Artery Disease, and the Risk of Major Coronary Events.

A study was designed to investigate whether the coronary artery disease polygenic risk score (CAD-PRS) may guide lipid-lowering treatment initiation as well as deferral in primary prevention beyond established clinical risk scores. Participants were 311 799 individuals from the UK Biobank free of atherosclerotic cardiovascular disease, diabetes, chronic kidney disease, and lipid-lowering treatment at baseline. Participants were categorized as statin indicated, statin indication unclear, or statin not indicated as defined by the European and US guidelines on statin use. For a median of 11.9 (11.2-12.6) years, 8196 major coronary events developed. CAD-PRS added to European-Systematic Coronary Risk Evaluation 2 (European-SCORE2) and US-Pooled Cohort Equation (US-PCE) identified 18% and 12% of statin-indication-unclear individuals whose risk of major coronary events were the same as or higher than the average risk of statin-indicated individuals and 16% and 12% of statin-indicated individuals whose major coronary event risks were the same as or lower than the average risk of statin-indication-unclear individuals. For major coronary and atherosclerotic cardiovascular disease events, CAD-PRS improved C-statistics greater among statin-indicated or statin-indication-unclear than statin-not-indicated individuals. For atherosclerotic cardiovascular disease events, CAD-PRS added to the European evaluation and US equation resulted in a net reclassification improvement of 13.6% (95% CI, 11.8-15.5) and 14.7% (95% CI, 13.1-16.3) among statin-indicated, 10.8% (95% CI, 9.6-12.0) and 15.3% (95% CI, 13.2-17.5) among statin-indication-unclear, and 0.9% (95% CI, 0.6-1.3) and 3.6% (95% CI, 3.0-4.2) among statin-not-indicated individuals. CAD-PRS may guide statin initiation as well as deferral among statin-indication-unclear or statin-indicated individuals as defined by the European and US guidelines. CAD-PRS had little clinical utility among statin-not-indicated individuals.

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.

Patients With Coronary Microvascular Dysfunction Have Less Circulating α-Klotho.

Coronary microvascular dysfunction (CMD) represents an early functional characteristic of coronary vascular aging. Klotho (α-klotho) is a circulating protein inversely linked to physiological aging. We examined low klotho as a potential marker for vascular aging in patients with CMD and no coronary artery disease. Patients undergoing nonurgent angiogram for chest pain who had no coronary artery disease underwent invasive coronary microvascular and endothelial function testing. CMD was defined by ≤50% increase in coronary blood flow (percentage change in coronary blood flow) in response to intracoronary acetylcholine or coronary flow reserve ≤2. Fresh arterial whole blood was used to analyze circulating endothelial progenitor cells with flow cytometry. Stored arterial plasma was used for klotho analysis by ELISA. Participants with CMD (n=62) were compared with those without CMD (n=36). Those with CMD were age 55±10 years (versus 51±11 years; P=0.07) and 73% women (versus 81%; P=0.38). Traditional risk factors for coronary artery disease were similar between groups. Patients with CMD had less klotho (0.88±1.50 versus 1.75±2.38 ng/mL; P=0.03), and the odds of low klotho in CMD were significant in a logistic regression model after adjusting for traditional cardiovascular risk factors (odds ratio [OR], 0.80 [95% CI, 0.636-0.996]; P=0.05). Higher klotho was associated with higher numbers of endothelial progenitor cells with vascular regenerative potential (CD34+ and CD34+CD133+KDR+). Among a subgroup of patients with atherosclerotic cardiovascular disease risk <5% (n=58), CMD remained associated with lower klotho (OR, 0.80 [95% CI, 0.636-0.996]; P=0.047). Klotho may be a biomarker for CMD and may be a therapeutic target for groups of patients without significant traditional cardiovascular risk.