Different association of atherogenic index of plasma with the risk of high platelet reactivity according to the presentation of acute myocardial infarction.

This study evaluated the association of atherogenic index of plasma (AIP) with platelet reactivity and clinical outcomes according to acute myocardial infarction (AMI). The composite of 3-year adverse outcomes of all-cause death, myocardial infarction, and cerebrovascular accident was evaluated in 10,735 patients after successful percutaneous coronary intervention with drug-eluting stents. AIP was defined as the base 10 logarithm of the ratio of triglyceride to high-density lipoprotein cholesterol concentration. High platelet reactivity (HPR) was defined as ≥ 252 P2Y12 reactivity unit. An increase of AIP (per-0.1 unit) was related to the decreased risk of HPR [odds ratio (OR) 0.97, 95% confidence interval (CI) 0.96-0.99; P = 0.001] in non-AMI patients, not in AMI patients (OR 0.98, 95% CI 0.96-1.01; P = 0.138). The HPR was associated with the increased risk of composite outcomes in both non-AMI and AMI patients (all-P < 0.05). AIP levels were not independently associated with the risk of composite outcomes in both patients with non-AMI and AMI. In conclusion, an inverse association between AIP and the risk of HPR was observed in patients with non-AMI. This suggests that the association between plasma atherogenicity and platelet reactivity may play a substantial role in the development of AMI.Trial registration: NCT04734028.

Expression pattern of the bone morphogenetic protein-4 and its relationship with inflammation, vascular injury in patients suffered the arterial occlusive diseases. / åŠ¨è„‰é˜»å¡žæ€§ç–¾ç— æ‚£è€ è¡€æµ†éª¨å½¢æ€å‘ç”Ÿè›‹ç™½-4çš„è¡¨è¾¾å˜åŒ–åŠå ¶ä¸Žç‚Žç—‡å’Œè¡€ç®¡æŸä¼¤çš„ç›¸å ³æ€§.

OBJECTIVES: Bone morphogenetic protein-4 (BMP4) has been proved to be an important regulatory factor for the pathological process of atherosclerosis (AS). However, there are few related clinical studies. This study aims to investigate the levels of plasma BMP4 in patients suffering from the arterial occlusive diseases (ACD) characterized by AS, and further to test the relationship between BMP4 and inflammation and vascular injury. METHODS: A total of 38 ACD patients (the ACD group) and 38 healthy people for the physical examination (the control group) were enrolled. The plasma in each subject from both groups was obtained to test the levels of BMP4, tumor necrosis factor-α (TNF-α), interleukin-1ß (IL-1ß), IL-10, and vascular endothelial cadherin (VE-cadherin), and the relationship between BMP4 and the detected indicators above were further analyzed. RESULTS: Compared with the control group, the patients in the ACD group displayed significant elevations in the neutrophil to lymphocyte ratio [NLR, 1.63 (1.26, 1.91) vs 3.43 (2.16, 6.61)] and platelet to lymphocyte ratio [PLR, 6.37 (5.26, 7.74) vs 15.79 (7.97, 20.53)], while decrease in the lymphocyte to monocyte ratio [LMR, 5.67 (4.41, 7.14) vs 3.43 (2.07, 3.74)] (all P<0.05). Besides, the ACD patients displayed significant elevations in plasma BMP4 [581.26 (389.85, 735.64) pg/mL vs 653.97(510.95, 890.43) pg/mL], TNF-α [254.16 (182.96, 340.70) pg/mL vs 293.29(238.90, 383.44) pg/mL], and VE-cadherin [1.54 (1.08, 2.13) ng/mL vs 1.85 (1.30, 2.54) ng/mL], and decrease in IL-10 [175.89 (118.39, 219.25) pg/mL vs 135.92 (95.80, 178.04) pg/mL] (all P<0.05). While the levels of IL-1ß remained statistically comparable between the 2 groups (P=0.09). Furthermore, the plasma BMP4 levels were further revealed to be positively correlated with the levels of IL-1ß (r=0.35), TNF-α (r=0.31) and VE-cadherin (r=0.47), while they were negatively correlated with the levels of IL-10 (r=-0.37; all P<0.01). CONCLUSIONS: After ACD occurrence, the patients' plasma concentrations of BMP4 would be upregulated, which may serve as a candidate to indicate the levels of inflammation and vascular injury.

The clinical role of combined circulating complement C1q and AIP for CAD with LDL-C level below 1.8mmol/L.

BACKGROUND: In the past few years, circulating complement C1q involvement in atherosclerosis has garnered growing research interest in addition to the emerging recognition of the novel lipid marker named atherogenic index of plasma (AIP). Nevertheless, among patients experiencing low-density lipoprotein cholesterol (LDL-C) levels less than 1.8mmol/L, the interplay between C1q combined with the AIP for coronary artery disease (CAD) is ambiguous. METHODS: Patients were stratified into a non-CAD and CAD group according to their coronary angiography. The association between C1q in conjunction with the AIP and CAD was explored using restricted cubic spline analyses and logistic regression models. To assess how it predicted, a receiver operating characteristic analysis was undertaken. RESULTS: A total of 7270 patients comprised 1476 non-CAD patients and 5794 patients diagnosed with CAD were analyzed. A comparison of the two groups showed that the C1q levels were notably higher compared to the CAD group, while AIP exhibited an inverse trend. Across quartiles of C1q, the AIP demonstrated a decline with increasing C1q levels, and significant differences were observed between the groups. A correlation analysis underscored a notable negative correlation between the two variables. Univariate and multivariate logistic regression analyses revealed significant associations between CAD and the C1q quartile groups/AIP. Furthermore, compared with the Q4 group, a decrease in the C1q levels corresponded to an escalation in CAD risk, with the odds ratio rising from 1.661 to 2.314. CONCLUSIONS: In conclusion, there appears to be a notable positive correlation between the combination of C1q with the AIP and CAD.

Association of atherogenic indices with myocardial damage and mortality in COVID-19.

BACKGROUND: Lipoproteins in cell membranes are related to membrane stability and play a role against microorganisms. Patients with COVID-19 often experience myocyte membrane damage. OBJECTIVE: This study aimed to search the relationship of atherogenic indices with myocardial damage and mortality in COVID-19. METHODS: This was an observational, single-center, retrospective study. The study population was grouped according to in-hospital mortality. C-reactive protein (CRP), CRP to albumin ratio (CAR), monocyte to high density lipoprotein cholesterol ratio (MHR), levels of total cholesterol (TC), triglycerides, high-density lipoprotein cholesterol (HDLc), and low-density lipoprotein cholesterol (LDLc) and cardiac troponin I (cTnI) were recorded. Atherogenic indices (plasma atherogenic index [AIP], atherogenic coefficient [AC], Castelli's risk indices I and II [CRI I and II], triglyceride to HDLc ratio (THR) were calculated. RESULTS: A total of 783 patients were included. The mortality rate was 15.45% (n = 121). The median age of non-survivor group (NSG) was higher than survivor group (SG) [66.0 years (Q1 -Q3: 55.0-77.5) vs 54.0 years (Q1 -Q3: 43.0-63.0)] (p < 0.001). Study parameters which were measured significantly higher in the NSG were CRP, cTnI, triglyceride, CRI-I, CRI-II, AC, AIP, ferritin, CAR, MHR and THR. LDLc, HDLc, TC and albumin were significantly lower in NSG (p<0.001). CONCLUSION: THR is positively correlated with myocardial damage and strongly predicts in-hospital mortality in COVID-19.

Elevated AIP is associated with the prevalence of MAFLD in the US adults: evidence from NHANES 2017-2018.

Background: Atherogenic Index of plasma (AIP) is closely related to metabolic abnormalities. But as of now, there is no definitive conclusion on the dose-response relationship pattern between AIP and metabolic associated fatty liver disease (MAFLD). Objective: The objective of this study was to provide a fresh insight for understanding the intrinsic link between AIP and the prevalence of MAFLD by exploring the dose-response pattern between AIP and MAFLD. Methods: A total of 9254 participants received the survey and 1090 participants were finally included according to the screening criteria. To evaluate the association between AIP and the prevalence of MAFLD based on weighted multivariate logistic regression. Sensitivity analysis of the association between AIP and MAFLD was performed using propensity score matching (PSM). Restrictive cubic splines (RCS) were used to identify patterns of dose-response relationships between AIP and MAFLD, and receiver operator characteristic (ROC) curves were used to evaluate the predictive ability of AIP and traditional lipid parameters for MAFLD. Results: In this study, a total of 563 participants were found to have MAFLD. The results of weighted multivariate logistic regression analysis demonstrated that, after adjusting for sex and age, participants in the highest quartile (Q4) of AIP had a significantly increased risk of developing MAFLD compared to those in the lowest quartile (Q1) (Model 2: OR = 9.03, 95% CI 4.75-17.17). A similar trend was observed in the fully adjusted model (Model 3: OR = 3.85, 95% CI 1.55-9.52). The RCS analysis revealed a linear dose-response association between AIP and MAFLD(P for crude non-linearity = 0.087). This association remained significant after accounting for potential confounding variables(P for adjusted non-linearity = 0.663). The ROC curve results suggest that AIP performs better than traditional lipid indicators in predicting MAFLD (AUC = 0.732, 95%CI 0.705-0.758). Conclusion: A linear dose-response relationship exists between AIP and MAFLD, suggesting that as AIP increases, so does the risk of developing MAFLD.

Gender differences in the association between changes in the atherogenic index of plasma and cardiometabolic diseases: a cohort study.

OBJECTIVE: The relationship between changes in Atherogenic Index of Plasma (AIP) and cardiometabolic diseases (CMD) in middle-aged and elderly individuals remains unclear. This study aims to explore the association between changes in AIP and CMD. METHODS: This study included 3,791 individuals aged over 45 years from CHARLS. Participants were divided into four groups using the K-Means clustering method. Cumulative AIP was used as a quantitative indicator reflecting changes in AIP. Differences in baseline data and CMD incidence rates among these four groups were compared. Multifactorial logistic regression models were used to assess the relationship between changes in AIP and CMD, and subgroup analysis and interaction tests were conducted to evaluate potential relationships between changes in AIP and CMD across different subgroups. Restricted cubic splines (RCS) were used to assess the dose-response relationship between cumulative AIP and CMD. RESULTS: Changes in AIP were independently and positively associated with CMD. In males, the risk significantly increased in class4 compared to class1 (OR 1.75, 95%CI 1.12-2.73). In females, changes in AIP were not significantly associated with CMD. Cumulative AIP was positively correlated with CMD (OR 1.15, 95%CI 1.01-1.30), with significant gender differences in males (OR 1.29, 95%CI 1.07-1.55) and females (OR 1.03, 95%CI 0.87-1.23) (p for interaction = 0.042). In addition, a linear relationship was observed between cumulative AIP and CMD in male. CONCLUSION: Substantial changes in AIP may increase the risk of CMD in middle-aged and elderly Chinese males. Dynamic monitoring of AIP is of significant importance for the prevention and treatment of CMD.

Resilient Older Subjects with Heterozygous Familial Hypercholesterolemia, Baseline Differences and Associated Factors.

Despite elevated low-density lipoprotein (LDL) cholesterol levels, some older subjects with heterozygous familial hypercholesterolemia (HeFH) do not develop atherosclerotic cardiovascular disease (ACVD) during their lifetime. The factors related to this resilient state have not been fully established. The aim of this study was to evaluate differential characteristics between older HeFH subjects with and without ACVD and factors associated with the presence of ACVD. Subjects were part of the Spanish Atherosclerosis Society Dyslipidemia Registry, and those ≥ 70 years old and with HeFH were included. Baseline characteristics of these subjects with and without ACVD were compared. A multivariate analysis was performed to assess factors associated with the presence of ACVD. A total of 2148 subjects with HeFH were included. Resilient subjects were mostly female, younger and presented fewer comorbidities with respect to the ACVD group. Subjects without ACVD had higher baseline high-density lipoprotein (HDL) cholesterol (55.8 ± 17.1 vs. 47.9 ± 15.4 mg/dL; p < 0.001) and lower lipoprotein(a) [Lp(a)] (53.4 ± 67.9 vs. 66.6 ± 85.6 mg/dL; p < 0.001) levels with respect to those in the ACVD group. Lp(a) and the presence of ≥3 risk factors were associated with the presence of ACVD.

Effects of Recombinant Human Lecithin Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans.

BACKGROUND: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport. METHODS: We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins. RESULTS: As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; P≤0.001), and this was mostly due to the increase in cholesteryl ester content (33.0 mg/dL; P=0.014). This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. There were also no significant changes in the metabolism of APOB100-lipoproteins. CONCLUSIONS: Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.

Association between the atherogenic index of plasma and hearing loss based on a nationwide cross-sectional study.

BACKGROUND: Hearing loss (HL) is a worldwide public health issue for which the role of dyslipidemia has not been fully elucidated. This study aimed to use the atherogenic index of plasma (AIP), a well-established serum lipid marker, to investigate the association of dyslipidemia with HL among the general population. METHODS: Participants (n = 3267) from the National Health and Nutrition Examination Survey database (2005-2012, 2015-2018) were included in the present study. The AIP was calculated based on the following formula: log10 (triglycerides/high-density lipoprotein cholesterol). HL was defined as a pure-tone average of at least 20 dBHL in the better ear. Weighted multivariable logistic regression, subgroup analysis, generalized additive model, and threshold analysis were adopted to reveal the association between the AIP and HL. RESULTS: In this study of US adults, a positive association was found between the AIP and high-frequency HL. However, the association between the AIP and low-frequency HL was not as strong. In addition, a reverse L-shaped curve with an inflection point located at -0.27 was detected between the AIP and high-frequency HL, followed by a significant positive association after the inflection point. CONCLUSIONS: The potential of the AIP as a bioindicator for high-frequency HL is noteworthy, and maintaining an AIP value below a certain threshold might provide beneficial outcomes in the management of high-frequency HL.

Association of the triglyceride-glucose index with early-onset atherosclerotic cardiovascular disease events and all-cause mortality: a prospective cohort study.

BACKGROUND: The association between the triglyceride glucose (TyG) index and the risk of early-onset atherosclerotic cardiovascular disease (ASCVD) events or all-cause mortality in young and middle-aged people is not fully elucidated. METHODS: The present study included 64,489 young and middle-aged people who participated in the 2006 Kailuan Study physical examination. Multivariate Cox proportional hazards models and restricted cubic spline curves were used to assess the association of TyG index with early-onset ASCVD events and all-cause mortality. RESULTS: During a median of 11-year follow-up, 1984 (3.08%) participants experienced at least one ASCVD event and 1,392 (2.16%) participants experienced all-cause death. A higher TyG index was significantly associated with a higher risk of early-onset ASCVD events (HR: 1.61, 95% CI 1.38-1.89) and all-cause mortality (HR: 1.39, 95% CI 1.17-1.65), respectively. For each unit increase in TyG index, the risk of early-onset ASCVD events increased by 20%. In addition, there was a non-linear association between the TyG index and early-onset ASCVD events (P for non-linear < 0.01), and a linear association between TyG index and all-cause mortality (P for non-linear = 0.476). CONCLUSIONS: A higher TyG index is significantly associated with an increased incidence of early-onset ASCVD events and all-cause mortality in a young and middle-aged population from North China.

Assessment of Serum Atherogenic Indices and Insulin Resistance in Retinal Vein Occlusion.

Objectives: This study aimed to investigate serum atherogenic indices as novel cardiovascular risk factors associated with retinal vein occlusion (RVO). Materials and Methods: This retrospective case-control study included 57 patients with newly diagnosed RVO whose plasma lipid profile (low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], total cholesterol [TC], and triglycerides [TG]) and insulin resistance were examined. Serum atherogenic indices (LDL-C/HDL-C, TC/HDL-C, TG/HDL-C, and non-HDL-C/HDL-C ratios) and presence of insulin resistance were compared between the patients and 63 healthy subjects. Cut-off values were determined by receiver operating characteristic curve analysis. Results: The mean age of the RVO patients was 63.7±9.4 years. Plasma levels of LDL-C, HDL-C, TC, and TG showed no significant difference between the patient and control groups (p>0.05). However, LDL-C/HDL-C, non-HDL-C/HDL-C, and TC/HDL-C ratios were higher in the RVO group compared to healthy subjects (p=0.015, p=0.036, and p=0.015, respectively). Fasting insulin concentrations, plasma insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) index were higher in the RVO patients compared to controls (p=0.003, p=0.001, and p=0.001, respectively). Conclusion: LDL-C/HDL-C, TC/HDL-C, and non-HDL-C/HDL-C ratios were found to be increased in RVO. Compared to the traditional plasma lipid profile, serum atherogenic indices were found to be superior predictors of RVO development. Measurement of HOMA-IR index should be taken into consideration in the evaluation of insulin resistance. High serum atherogenic indexes in RVO patients reveal the need to take precautions against the risk of cardiovascular disease and stroke.

Association of the trimethylamine N-oxide with cardiovascular risk and vascular alterations in middle-aged patients with risk factors for cardiovascular diseases.

BACKGROUND: Trimethylamine N-oxide (TMAO) is synthesized by the intestinal microbiota and is an independent predictor of cardiovascular disease (CVD). However, its underlying mechanisms remain unclear. We investigated TMAO levels across different CVD-risk patient groups, and evaluated associations between TMAO and vascular alterations (e.g., arterial stiffness, intima-media thickness [IMT], and the presence and grade of carotid artery plaques [CAPs]). METHODS: We examined 95 patients (58.5 ± 7.3 years): 40 with clinical atherosclerotic cardiovascular disease (ASCVD), 40 with atherosclerosis risk factors (RF), and 15 controls. Arterial stiffness was measured by Carotid-Femoral Pulse Wave Velocity (C-F PWV). B-mode ultrasound was used to evaluate the presence and grade of CAPs and carotid IMT (CIMT). TMAO was measured by high performance liquid chromatography-tandem mass spectrometry (LC-MS/MS) and results were presented as the median (interquartile range). RESULTS: TMAO levels were higher in patients with ASCVD (251.5 [164.5] µg/l) when compared with patients with RFs (194.0 [174] µg/l, P=0.04) and controls (122.0 (77) µg/l, P<0.001). A significant correlation was observed between TMAO and PWV (r = 0.31, P=0.003), which was not confirmed after adjustment for RFs. TMAO levels were significantly correlated with plaque score (r = 0.46, P<0.001) and plaque height (r=0.41, P=0.003), and were independent predictors for grade III plaques (odds ratio [OR] = 1.002, confidence interval (CI) 95%: 1.000047-1.003, P=0.044). CONCLUSIONS: TMAO levels are increased with expanded CVD risk. Across different types of vascular damage, TMAO is associated with atherosclerotic changes.

Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice.

BACKGROUND: Low-dose aspirin is widely used for the secondary prevention of cardiovascular disease. The beneficial effects of low-dose aspirin are attributable to its inhibition of platelet Cox (cyclooxygenase)-1-derived thromboxane A2. Until recently, the use of the Pf4 (platelet factor 4) Cre has been the only genetic approach to generating megakaryocyte/platelet ablation of Cox-1 in mice. However, Pf4-ΔCre displays ectopic expression outside the megakaryocyte/platelet lineage, especially during inflammation. The use of the Gp1ba (glycoprotein 1bα) Cre promises a more specific, targeted approach. METHODS: To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1-/- mice on normolipidemic and hyperlipidemic (Ldlr-/-; low-density lipoprotein receptor) backgrounds. RESULTS: Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in Pf4-ΔCre Cox-1-/-/Ldlr-/- and Gp1ba-ΔCre Cox-1-/-/Ldlr-/- mice. In a mouse model of tail injury, Pf4-ΔCre-mediated and Gp1ba-ΔCre-mediated deletions of Cox-1 were similarly efficient in suppressing platelet prostanoid biosynthesis. Experimental thrombogenesis and attendant blood loss were similar in both models. However, the impact on atherogenesis was divergent, being accelerated in the Pf4-ΔCre mice while restrained in the Gp1ba-ΔCres. In the former, accelerated atherogenesis was associated with greater suppression of PGI2 biosynthesis, a reduction in the lipopolysaccharide-evoked capacity to produce PGE2 (prostaglandin E) and PGD2 (prostanglandin D), activation of the inflammasome, elevated plasma levels of IL-1ß (interleukin), reduced plasma levels of HDL-C (high-density lipoprotein receptor-cholesterol), and a reduction in the capacity for reverse cholesterol transport. By contrast, in the latter, plasma HDL-C and α-tocopherol were elevated, and MIP-1α (macrophage inflammatory protein-1α) and MCP-1 (monocyte chemoattractant protein 1) were reduced. CONCLUSIONS: Both approaches to Cox-1 deletion similarly restrain thrombogenesis, but a differential impact on Cox-1-dependent prostanoid formation by the vasculature may contribute to an inflammatory phenotype and accelerated atherogenesis in Pf4-ΔCre mice.

Association between atherogenic index of plasma and depressive symptoms in US adults: Results from the National Health and Nutrition Examination Survey 2005 to 2018.

OBJECTIVE: This study, utilizing data from the U.S. National Health and Nutrition Examination Survey (NHANES) between 2005 and 2018, investigates the association between the atherogenic index of plasma (AIP), a lipid biomarker, and symptoms of depression in American adults. METHODS: In this cross-sectional study of 12,534 adults aged 20 years and older, depressive symptoms were measured utilizing the Patient Health Questionnaire-9 (PHQ-9) scale. Weighted logistic regression models were employed to scrutinize the independent relationship between AIP levels and the likelihood of developing such symptoms. Moreover, a series of subgroup analyses were conducted to delve deeper into these relationships. RESULTS: Following adjustment for confounders, logistic regression by grouping AIP into quartiles revealed a significant association between AIP and an augmented likelihood of self-reported depression. Participants in the fourth quartile (Q4) exhibited a higher odds ratio (OR = 1.34, 95 % CI: 1.02-1.75, p < 0.05) compared to those in the first quartile (Q1). Notably, subgroup analysis unveiled significant interactions involving the smoking and diabetes subgroups, indicating that smoking status and diabetes may modify the relationship between AIP and depression incidence. CONCLUSION: This study reveals a positive correlation between AIP and the self-reported likelihood of depression among US adults, thereby underscoring AIP's potential clinical utility as a biomarker for depressive disorders. Our findings emphasize the necessity to consider and optimize cardiovascular health factors within depression management strategies and offer fresh insights into the development of risk stratification and intervention methods for psychiatric conditions.

High systemic inflammation as a novel cardiovascular risk factor and target for anti-cytokine therapy: comment regarding the triglyceride glucose index.

In the last century, there has been more than enough research that proved the association of high lipid and glucose levels with cardiovascular disease, thus establishing the current well-known traditional cardiovascular risk factors such as dyslipidemia, diabetes, and metabolic syndrome. Hence, these cardiovascular risk factors are target therapy for glucose and lipid-lowering agents to prevent adverse cardiovascular events. However, despite controlling the lipid and glucose levels, some studies demonstrated the subclinical atherosclerosis suggesting that these cardiovascular risk factors alone cannot account for the entire atherosclerosis burden. In the last years, large-scale clinical trials demonstrated the operation of the inflammatory pathway in atherosclerotic cardiovascular disease (ASCVD) by the immune system, both the innate (neutrophils, macrophages) and adaptive (T cell and other lymphocytes) limbs, contribute to atherosclerosis and atherothrombosis. In this regard, some studies that use antiinflammatory therapy targeting the immune system by modulating or blocking interleukins, also known as anti-cytokine therapy, have been shown to reduce the risk of adverse cardiovascular events in patients with previous coronary artery disease. In this regard, the U.S. Food and Drug Administration (FDA) approved the use of colchicine 0.5 mg once daily for reducing cardiovascular events in patients who have established ASCVD and high residual systemic inflammation. Therefore, measuring the systemic inflammation can improve the cardiovascular risk assessment and identify the subsets of patients that will benefit from anti-cytokine therapy after diagnosis of ASCVD or after myocardial revascularization.

Single Ascending and Multiple-Dose Trial of Zerlasiran, a Short Interfering RNA Targeting Lipoprotein(a): A Randomized Clinical Trial.

Importance: Lipoprotein(a) is a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) and calcific aortic stenosis, with no pharmacological treatments approved by regulatory authorities. Objectives: 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). Design, Setting, and Participants: 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. Interventions: 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. Main Outcomes Measures: The primary outcome was safety and tolerability. Secondary outcomes included serum levels of zerlasiran and effects on lipoprotein(a) serum concentrations. Results: 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. Conclusions: Zerlasiran was well tolerated and reduced lipoprotein(a) concentrations with infrequent administration. Trial Registration: ClinicalTrials.gov Identifier: NCT04606602.

Matrix Gla protein and the long-term incidence and progression of coronary artery and aortic calcification in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Matrix Gla protein (MGP) is an inhibitor of calcification that requires carboxylation by vitamin K for activity. The inactive form of MGP, dephosphorylated-uncarboxylated matrix Gla protein (dp-ucMGP), has been associated with increased calcification. However, it is not known whether there is a longitudinal relationship between dephosphorylated-uncarboxylated matrix Gla protein levels and coronary and aortic calcification in large population cohorts. METHODS: The Multi-Ethnic Study of Atherosclerosis (MESA) followed participants with serial cardiac computed tomography (CT) measures of vascular calcification. Dp-ucMGP was measured at baseline in a subset of participants who completed baseline and follow-up CTs approximately 10 years later and had available plasma specimens (n = 2663). Linear mixed effects models (LMMs) were used to determine the association of dp-ucMGP with the simultaneous incidence and progression of coronary artery, ascending thoracic aortic, or descending thoracic aortic calcification (CAC, ATAC, DTAC)]. RESULTS: For every one standard deviation (SD, 178 pmol/L) increment in dp-ucMGP, CAC increased by 3.44 ([95% CI = 1.68, 5.21], p < 0.001) Agatston units/year (AU/year), ATAC increased by 0.63 ([95% CI = 0.27, 0.98], p = 0.001) AU/year, and DTAC increased by 8.61 ([95% CI = 4.55, 12.67], p < 0.001) AU/year. The association was stronger for DTAC in those ≥65 years and with diabetes. CONCLUSIONS: We found a positive association of the inactive form of matrix Gla protein, dp-ucMGP, and long-term incidence/progression of CAC, ATAC, and DTAC. Future studies should investigate dp-ucMGP as a calcification regulator and MGP as a possible therapeutic target to slow progression of calcification in the vasculature.

The association between atherogenic index of plasma and metabolic dysfunction-associated fatty liver disease as detected by FibroScan.

Introduction: Objectives: this study aimed to explore the potential of the atherogenic index of plasma (AIP) as a predictor of metabolic dysfunction-associated fatty liver disease (MAFLD). Methods: a cross-sectional study, including data from 4473 participants in the National Health and Nutrition Examination Survey (NHANES) 2017-2018, was performed. A control attenuation parameter (CAP) ≥ 285 dB/m was used to confirm hepatic steatosis. Degrees of liver stiffness were confirmed according to liver stiffness measurement (LSM). Weighted multivariate logistic regression models were used to assess the association between AIP and the risk for MAFLD and liver fibrosis. Finally, receiver operating characteristic (ROC) curve analysis was used to test the accuracy of AIP in predicting MAFLD. Results: the association between AIP and the prevalence of MAFLD was positive in all three multivariate logistic regression models (model 1, odds ratio (OR), 18.2 (95 % confidence interval (CI), 14.4-23.1); model 2, OR, 17.0 (95 % CI, 13.3-21.8); model 3, OR, 5.2 (95 % CI, 3.9-7.0)). Moreover, this positive relationship was found to be significant in patients of different sexes and whether they had diabetes. However, no significant differences were observed between AIP and significant fibrosis or cirrhosis as assessed by different liver fibrosis indices. Finally, ROC curve analysis demonstrated that the AIP index also demonstrated positive diagnostic utility (area under the ROC curve, 0.733 (95 % CI, 0.718-0.747); p < 0.001). Conclusion: This study revealed a positive association between AIP and MAFLD among American adults. Furthermore, this association persisted in different sexes and whether they had diabetes.

Introducción: Objetivos: este estudio tuvo como objetivo explorar el potencial del índice aterogénico del plasma (AIP) como predictor de enfermedad hepática grasa asociada a disfunción metabólica (MAFLD). Métodos: se realizó un estudio transversal que incluyó datos de 4473 participantes de la encuesta nacional de exémenes de salud y nutrición (NHANES) 2017-2018. Se utilizó un parámetro de atenuación de control (CAP) ≥ 285 dB/m para confirmar la esteatosis hepática. Los grados de rigidez hepática se confirmaron de acuerdo con la medición de rigidez hepática (LSM). Se utilizaron modelos de regresión logística multivariponderponderados para evaluar la asociación entre AIP y el riesgo de MAFLD y fibrosis hepática. Por último, se utilizó el análisis de la curva ROC para probar la precisión de la AIP en la predicción de la MAFLD. Resultados: la asociación entre AIP y prevalencia de MAFLD fue positiva en los tres modelos de regresión logística multivariable (modelo 1, odds ratio (OR): 18,2 (intervalo de confianza (IC) del 95 %: 14,4-23,1); Modelo 2, OR: 17,0 (IC del 95 %: 13,3-21,8); Modelo 3, OR: 5,2 (IC del 95 %: 3,9-7,0)). Además, esta relación positiva se encontró significativa en pacientes de diferentes sexos ya tuvieran o no diabetes. Sin embargo, no se observaron diferencias significativas entre la AIP y la fibrosis o cirrosis significativa evaluada por diferentes índices de fibrosis hepática. Finalmente, el análisis de la curva ROC demostró que el índice AIP también demostró utilidad diagnóstica positiva (área bajo la curva ROC = 0,733 (IC del 95 %: 0,718-0,747); p < 0,001). Conclusión: este estudio reveló una asociación positiva entre AIP y MAFLD en los adultos estadounidenses. Además, esta asociación persistió en los diferentes sexos ya tuvieran o no diabetes.

Time-domain heart rate dynamics in the prognosis of progressive atherosclerosis.

BACKGROUND AND AIM: The regular uptake of a high-fat diet (HFD) with changing lifestyle causes atherosclerosis leading to cardiovascular diseases and autonomic dysfunction. Therefore, the current study aimed to investigate the correlation of autonomic activity to lipid and atherosclerosis markers. Further, the study proposes a support vector machine (SVM) based model in the prediction of atherosclerosis severity. METHODS AND RESULTS: The Lead-II electrocardiogram and blood markers were measured from both the control and the experiment subjects each week for nine consecutive weeks. The time-domain heart rate variability (HRV) parameters were derived, and the significance level was tested using a one-way Analysis of Variance. The correlation analysis was performed to determine the relation between autonomic parameters and lipid and atherosclerosis markers. The statistically significant time-domain values were used as features of the SVM. The observed results demonstrated the reduced time domain HRV parameters with the increase in lipid and atherosclerosis index markers with the progressive atherosclerosis severity. The correlation analysis revealed a negative association between time-domain HRV parameters with lipid and atherosclerosis parameters. The percentage accuracy increases from 86.58% to 98.71% with the increase in atherosclerosis severity with regular consumption of HFD. CONCLUSIONS: Atherosclerosis causes autonomic dysfunction with reduced HRV. The negative correlation between autonomic parameters and lipid profile and atherosclerosis indexes marker revealed the potential role of vagal activity in the prognosis of atherosclerosis progression. The support vector machine presented a respectable accuracy in the prediction of atherosclerosis severity from the control group.