Low-density Lipoprotein Cholesterol Levels Research Articles

Efficacy of combination therapy with statin and ezetimibe versus high dose statin monotherapy in secondary prevention in high-risk patients

Abstract Background Secondary prevention in patients with acute coronary syndrome focuses on lowering low-density lipoprotein (LDL) cholesterol below 55 mg/dL. In all statin-naïve patients at high risk (LDL-cholesterol target <55 mg/dL), initiation of high-intensity statin monotherapy is recommended by ESC guidelines. Nonetheless, at one month, a significant proportion of patients do not reach their LDL-cholesterol target. Purpose The aim of this study was to compare lipid-lowering therapy with statin monotherapy versus statin with ezetimibe in secondary prevention in patients at high risk. Methods The current prospective study included 264 consecutive patients admitted with acute ST elevation myocardial infarction who underwent percutaneous coronary intervention. None of the patients had taken lipid-lowering drugs in the previous 12 months. Patients were randomly assigned to one of two treatment groups: Group 1 - rosuvastatin 40 mg (n= 144) and Group 2 - rosuvastatin 40 mg and ezetimibe 10 mg (n= 120). All patients' lipid profiles were assessed upon admission and after one month of lipid-lowering treatment. Results At baseline, no patient had LDL cholesterol level lower than 55 mg/dL. There was no significant difference in lipid profile at baseline between the two groups (all p > 0.05). No differences were observed between the two groups in terms of baseline LDL-cholesterol deviation from the target (103.4% versus 99.70%; p= 0.66). As expected, the combination therapy reduced LDL-cholesterol at one month significantly higher compared to high-dose statin monotherapy (-59.65% versus -37.54%; p< 0.0001). After one month of treatment, only 47.92% of patients in Group 1 reached the LDL-cholesterol target (<55 mg/dL) compared to 90.00% of the patients in Group 2 (p<0.0001; R.R.= 0.53). Conclusion(s) Our findings show that statin and ezetimibe combination therapy is more effective in reduction in LDL-cholesterol levels and reaching targets compared to statin monotherapy alone. In statin-naïve patients at high risk, early initiation of the statin and ezetimibe combination instead of statin monotherapy should be taken into account in secondary prevention, for an earlier reach of the LDL-cholesterol target and to reduce the overall cardiovascular risk.

The impact of discontinuing proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors on clinical outcomes

Abstract Background/Introduction Proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitors have demonstrated efficacy in lowering low-density lipoprotein cholesterol (LDL-C) levels and reducing the risk of cardiovascular events. Despite these advantages, some patients are unable to continue the use of PCSK9 inhibitors due to financial or other reasons. Limited clinical studies have been conducted to investigate the clinical outcomes of patients discontinuing PCSK9 inhibitors for various reasons. Purpose This study aims to specifically investigate patients who were unable to continue PCSK9 inhibitors, with a particular focus on those discontinuing due to financial or other reasons. The primary objective is to assess the impact of discontinuation on major adverse cardiovascular events (MACE). Methods This study focused on 205 Japanese patients who received PCSK9 inhibitors between July 2016 and December 2023. The clinical outcomes of patients who continued or discontinued PCSK9 inhibitors were comprehensively compared. The primary endpoint was major adverse cardiovascular events (MACE), encompassing cardiovascular death, coronary revascularization, target lesion revascularization (TLR), and fatal or non-fatal myocardial infarction (MI). Results Among 205 patients (median age: 69 years; interquartile range [IQR]: 60-76 years 68% male), the median follow-up was 413 days (IQR, 49-1148 days). At one year, the median LDL-C was 43mg/dL, and 158 patients (77%) achieved LDL-C <70 mg/dL. During the follow-up, 64% (131 patients) continued PCSK9 inhibitors, while 36% (74 patients) discontinued. Of the discontinuation group, 30% (22 patients) cited financial problems, 24% (18 patients) clinical stability, and 12% (9 patients) patient preference. Multivariate Cox regression analysis revealed that the group discontinuing PCSK9 inhibitors had a higher incidence of MACE than the group that continued (hazard ratio: 1.84; 95% confidence interval: 1.02 to 3.55; p=0.05). Conclusions This study suggests an increased risk of MACE when PCSK9 inhibitors are discontinued for financial or other reasons. This insight is vital for healthcare management and decision-making among medical practitioners.PCSK9: continuation vs discontinuation

Lipid lowering therapy and the unmet targets in Indian patients with angiographically proven coronary artery disease: results from the OLS registry

Abstract Introduction The Lipid Association of India (LAI) 2020 guidelines classify patients with established atherosclerotic cardiovascular disease in either very high-risk or extreme-risk groups and recommend that intensive lipid-lowering therapy (LLT) should be administered to such patients to achieve a target low-density lipoprotein cholesterol (LDL-C) level below 50 mg/dl at least (preferably < 30 mg/dl in extreme risk groups). Purpose This study aimed to assess the achievement of the LAI-recommended LDL-C goals in patients with angiographically proven coronary artery disease (CAD). Methods The Optimization of LDL-C in the Stable CAD (OLS) registry started in August 2023 in 10 interventional cardiology centers across Northern India. Interventional cardiologists (ICs) were treating all enrolled patients with angiographically proven stable CAD, and data were collected at a single visit, including the most recent LDL-C and the LLT in the preceding three months of that LDL-C reading. The primary outcome was achieving the LAI-recommended LDL-C goal of <50 mg/dl. The achievement of the American College of Cardiology (ACC) recommended goal of <70 mg/dl was also assessed. Results A total of 1860 patients with angiographically proven CAD were enrolled in this ongoing registry over four months (August 2023- November 2023). The mean age of the study population was 60.2 + 9.2 years, and 79% were males. 30.3% of patients had Diabetes mellitus (DM), 36.1% had hypertension (HTN), 42.3% were obese (body mass index > 25kg/m2), and 17.8% of patients were current smokers. 74.2% of patients had a history of myocardial infarction, while 76.7% had undergone prior percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG). Rosuvastatin was the statin prescribed in 59.4% of patients, while atorvastatin was prescribed in 37.2%. 1270 (68.3%) of patients were taking high-intensity statin (HIS) therapy (either 20-40 mg rosuvastatin or 40-80 mg atorvastatin). Only 22 (1.2%) patients took other lipid-lowering agents, including ezetimibe, bempedoic acid, and fibrates. None of the patients were using PCSK9 Inhibitors. Only 482(25.9%) patients achieved their LAI recommended goal of LDL-C <50 mg/dl, 113(6.1%) achieved LDL-C < 30 mg/dl, while 863(46.4%) achieved ACC goal of <70 mg/dl. Notably, only 62(3.3%) patients were not taking any lipid-lowering treatment. Conclusion Results of the OLS study demonstrate the high-risk status of CAD in Indian patients with a high prevalence of DM, HTN, and obesity. Most patients were post-PCI/CABG, mainly because ICs did enrolments. More than two-thirds of patients were taking HIS and very few were not taking any treatment. Despite this, only one-fourth of patients achieved the target LDL-C goals. Greater and early utilization of combination LLT, including HIS and non-statin LLT, is likely needed to reduce these gaps for patients at the highest risk.

Long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive intracerebral hemorrhage in mice

Abstract Background Intracerebral hemorrhage (ICH) is a catastrophic disease with limited treatment options. Statins and low low-density lipoprotein cholesterol (LDL-C) levels have been reported to be associated with increased risk of ICH. Safety concerns of statins were raised as statins become the cornerstone of anti-atherosclerosis therapy. To date, the effect of statins on the incidence of ICH still remains a controversial topic. Purpose The aim of this study was to investigate the effect of atorvastatin on the occurrence and progression of hypertensive ICH in mice. Methods Male wild-type C57BL/6J mice, 13 months old, were randomly divided into atorvastatin (Ato, n=20) group and vehicle (Veh, n=20) group. The atorvastatin group and vehicle group were given atorvastatin (20 mg/kg) and same volume of 0.5% sodium carboxymethylcellulose by oral gavage for 8 weeks, separately. Angiotensin II (Ang II) and L-NAME were then used to induce hypertensive ICH. The time of stroke symptom onset was documented. Hemorrhage volumes were measured by spectrophotometric hemoglobin assay. Results After 8 weeks of atorvastatin or vehicle administration, serum LDL-C levels were significantly lower in the mice treated with atorvastatin than vehicle controls (0.705 vs. 1.008 mmol/L, P<0.001). The administration of atorvastatin did not show significant effects on the systolic blood pressure (SBP) levels when compared with the vehicle group (164 vs. 166 mmHg, P=0.497) after the induction of Ang II and L-NAME. Hemorrhage was observed in brain morphology, and was further verified by hematoxylin and eosin staining or MRI scans in mice that showed signs of stroke. During the 28-day experimental period, 75% (15/20) of mice in the atorvastatin group developed signs of ICH, and 70% (14/20) of mice in the vehicle group developed in the similar time window. The incidence of hypertensive ICH had no significant difference between atorvastatin and vehicle groups (Log-rank P=0.761). Hemorrhage volumes were also comparable between the two groups (1.462 vs. 1.392 uL, P=0.788). Conclusion Reducing serum LDL-C levels by long-term administration of atorvastatin had no effect on the occurrence and progression of spontaneous hypertensive ICH in middle-aged mice.

Remnant cholesterol lowering in cardiovascular disease risk reduction in statin trials: meta-regression analyses

Abstract Background Remnant cholesterol is a causal risk factor for cardiovascular disease. Purpose We tested the hypothesis that remnant cholesterol reduction explains part of the cardiovascular disease risk reduction in statin trials. Methods We included statin trials with >1,000 participants and available data on lipid levels. Baseline and follow-up low-density lipoprotein (LDL) and remnant cholesterol levels were extracted. LDL and remnant cholesterol reductions were differences between intervention and reference groups at year one. Risk ratios for any statin use and per 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were estimated using meta-regressions. Results We included 29 statin trials with 191,202 participants and 26,639 major cardiovascular events. On an absolute scale when LDL cholesterol was reduced 1 mmol/L (39 mg/dL), remnant cholesterol was reduced 0.17 mmol/L (7 mg/dL) (Figure 1). On a relative scale when LDL cholesterol was reduced 20%, remnant cholesterol was reduced 12%. The risk ratio for statin use versus reference was 0.82 (95% confidence interval: 0.81-0.84) for major cardiovascular events (Figure 2). Risk ratios per 1 mmol/L (39 mg/dL) reductions were 0.82 (0.80-0.83) for LDL cholesterol and 0.37 (0.33-0.41) for remnant cholesterol for major cardiovascular events. Corresponding risk ratios for 1 mmol/L (39 mg/dL) LDL and remnant cholesterol reductions were 0.78 (0.75-0.80) and 0.30 (0.25-0.35) for coronary events, 0.86 (0.82 -0.90) and 0.48 (0.38-0.61) for stroke, and 0.93 (0.91-0.95) and 0.71 (0.62-0.80) for any death, respectively. Conclusions Remnant cholesterol lowering likely explain part of the cardiovascular disease risk reduction in statin trials. Figure 1. Remnant cholesterol reduction as a function of LDL cholesterol reduction. Regressions were calculated using inverse-variance weighted unadjusted linear regressions. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. R-C = Remnant cholesterol. ∆ = change from baseline to 1 year follow-up. Figure 2. RR for MACE for statin use and cholesterol reductions. Risk ratios were calculated using fixed and random effects inverse-variance weighted meta-regressions. CI = confidence interval. LDL = low-density lipoprotein. LDL-C = LDL cholesterol. MACE = major cardiovascular events. R-C = remnant cholesterol. RR = risk ratio.Figure 1Figure 2

Gender differences in the treatment with PCSK9 monoclonal antibodies real world experience from a dedicated prevention clinic

Abstract Background Proprotein convertase subtilisin/kexin type 9 monoclonal antibodies (PCSK9 mAb) lower low-density lipoprotein cholesterol (LDL-C) levels and reduce atherosclerotic cardiovascular disease (ASCVD). There are gender differences in PCSK9 biological characteristics, which are not properly addressed in current data. Purpose Examining gender differences in treatment with PCSK9 mAb. Methods A retrospective study based on data from the Prevention Cardiology Clinic in Rabin Medical Center. Included were patients prescribed with PCSK9 mAb (evolocumab or alirocumab), for primary or secondary prevention. Data included medical background and treatment variables. Response to treatment was evaluated by changes in LDL-C at 3 and 12 months. Data was analyzed by gender. Results Study included 246 patients (mean age 67y, ASCVD 78.8%, mean baseline LDL-C 128.2 mg/dL). Women (42% of cohort) prescribed with PCSK9 mAb were older than men (69 vs. 65 years, respectively; p<0.001). The dominant indication for PCSK9 mAb for both genders was secondary prevention, while primary prevention indication was more prevalent in women vs. men (39.4% vs. 16.3%, respectively; p<0.001). Statin intolerance was observed in 82.4% and 58.6% were treated with combination therapy with PCSK9 mAb, without significant gender differences. Baseline mean LDL-C was higher among women vs. men (138.9 vs. 117.3 mg/dL; p<0.001). Overall, high adherence was observed (91.8% and 79.7% at 3 and 12 months, respectively). After 1-year, adherent men had lower LDL-C levels than women (46.8 mg/d and 61.9 mg/dL, respectively; P=0.001), and were more likely to reach their LDL-C therapy goals; below 70 mg/dL (76.1% vs. 62.2%, respectively; P=0.032) and below 55 mg/dL (60.1% vs. 39.8% respectively; P=0.003). Conclusions In patients treated with PCSK9 mAb, gender differences exist in prescription age, indications, baseline LDL-C and achieved LDL-C goals. In this study adherence to PCSK9 mAb was higher than reported before, possibly due to surveillance in a dedicated prevention clinic.LDL-C & Non-HDL-C levels under PCSK9 mABSex Differences in acheived LDL-C goals

Impact of neutrophil-to-lymphocyte ratio on clinical outcomes in patients with acute or chronic coronary syndrome undergoing percutaneous coronary intervention

Abstract Background Neutrophil-to-lymphocyte ratio (NLR) has recently emerged as an inflammatory biomarker associated with atherosclerosis and cardiovascular events. However, its role in patients with coronary artery disease (CAD) undergoing percutaneous coronary intervention (PCI) remains unclear. Purpose We aimed to evaluate the clinical impact of baseline NLR in patients undergoing PCI for acute coronary syndrome (ACS) and chronic coronary syndrome (CCS). Methods We retrospectively evaluated all consecutive patients undergoing PCI between 2012-2022 in a large tertiary US hospital. We excluded patients for whom NLR was not available and those who were deemed to have active hematological or infective diseases, including patients presenting with extremely low or high lymphocyte and neutrophil counts or with hs-CRP above 10 mg/L. Quartiles of NLR were derived in the overall population and patients were stratified according to clinical presentation. Within each group, we estimated the risk of 12-month adverse events using the lowest NLR quartile as reference. The primary endpoint was major adverse cardiovascular events (MACE), defined as the composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACE individual components and any periprocedural or post-discharge clinically relevant bleeding. Results A total of 7,201 patients were included in the analysis; of these 3,975 (55.2%) had ACS and 3,226 (44.8%) CCS. Patients in the 4th quartile (NLR > 5.0) were more frequently male, older, and presented more often with chronic kidney disease and complex coronary artery disease. Smoking, diabetes and history of CAD, as well as triglycerides, LDL, non-HDL and total cholesterol levels were lower in the 4th NLR quartile. In patients presenting with CCS, the risk of MACE, all-cause death, MI was similar across NLR quartiles, while the risk of bleeding increased stepwise (Figure 1). In patients presenting with ACS, the 4th NLR quartile had the highest adjusted risk of MACE (HRadj 1.82, 95% CI 1.25-2.67; P=0.002), all cause death (HRadj 2.56, 95% CI 1.41-4.66; P<0.001), and bleeding (HRadj 1.82 95% CI 1.25-2.63, P<0.001) at 1 year, as compared to the lowest quartile (Table 1). Conclusions Among patients undergoing PCI, elevated NLR is strongly associated with risk of MACE and all-cause mortality in patients presenting with ACS but not in those with CCS. Conversely, the risk of bleeding was augmented with higher NLR in both ACS and CCS patients undergoing PCI. In this setting, NLR may inform risk stratification at the time of PCI.

Lipid-lowering therapy with Inclisiran in the real-world setting: initial data from a national health care service

Abstract Introduction Inclisiran, a first-in-class siRNA enabling long-term inhibition of PCSK9 synthesis, demonstrates good safety and efficacy profile in randomized clinical trials. Challenges for real-life use of inclisiran include limited access to therapy, injections by medical staff, lack of cardiovascular outcome data, and concern from adverse effects considering the novel mechanism and long-term activity. Real-life data on the potential to attain lipid-goals and reduce treatment gaps is lacking. We investigated the implementation of inclisiran in real-world clinical setting in Israel. Methods Data from a nationwide healthcare organization on patients initiating inclisiran therapy during the period of 3/2022-11/2023. Patients’ characteristics, efficacy, use of combination lipid-lowering therapies, and attainment of low-density lipoprotein cholesterol (LDL-C) goals, were evaluated. Results Inclisiran was initiated by 503 patients (57% women; mean age 66±11 years). Atherosclerotic cardiovascular disease was present in 54%, and peak historical LDL-C levels >190 mg/dL documented in 64%. Prior exposure to PCSK9 monoclonal antibodies was evident in 28%. Follow-up lipid profile >2 months after filling first prescription, was available in 397 patients (347 with ≥2 injections). In patients treated by inclisiran only (n=254), median LDL-C reduction from peak historical levels was 57% (IQR, 48%-67%), and from pre-injection levels 40% (19%-54%). In those with concomitant oral lipid-lowering therapies (n=143), median LDL-C reduction from peak levels was 66% (IQR, 55%-73%), and from pre-injection levels 46% (23%-59%) (Figure). LDL-C <70 mg/dL was attained by 39% and LDL-C <55 mg/dL by 21.9%. Of those treated with concomitant statin therapy, 38% attained LDL-C <55 mg/dL. Overall, 6.5% did not persist with inclisiran therapy after initial injection. Conclusions In real-life practice, inclisiran showed good efficacy with positive short-term adherence. However, attainment rates of lipid-goals were suboptimal due to limited use of combination lipid-lowering therapy and high-rates of severe hypercholesterolemia in our patient population cohort.Waterfall Plot of LDL-C (%) Reduction

Risk of recurrent ischaemic events in ACS patients with baseline LDL-C below guideline-recommended thresholds: insights from the prospective SPUM-ACS study

Abstract Introduction The 2023 European Society of Cardiology (ESC) guidelines recommend intensive low-density lipoprotein cholesterol (LDL-C) reduction for patients with acute coronary syndromes (ACS), adding ezetimibe and/or proprotein convertase subtilisin/kexin type 9 inhibitor (PCSK9i) to achieve recommended target goals (LDL-C<55 mg/dL). Purpose This population-based, real-world study aimed to examine cardiovascular (CV) events in ACS patients with baseline LDL-C levels below current guideline thresholds. Methods ACS patients admitted to four Swiss University Hospitals and enrolled in the multicenter SPUM registry (NCT 01000701) between 2009 and 2017 were followed prospectively until 1 year. The composite primary endpoint was major adverse cardiac and cerebrovascular events (MACCE); i.e., non-fatal stroke, myocardial infarction (MI), and death) at 1 year. Multivariable-adjusted Cox proportional hazard regression models were fit to estimate ischaemic risk among those with LDL-C<55 mg/dL. Results Out of 4’787 ACS patients, 226 patients (4.7%) had baseline LDL-C<55 mg/dL. These patients were older (69.7±11.3 vs 63.4±12.4, p<0.001), more frequently male (20.8%vs 15.9%, p<0.001), had more often traditional CV risk factors (all p<0.001) and were more likely to have a complex history of CV disease, such as previous MI (37.2% vs 10.9%, p<0.001), prior percutaneous (47.8% vs 13.2%, p<0.001) or surgical (15.0% vs 3.5%, p<0.001) coronary revascularization. Inflammatory biomarkers were also higher (hs-CRP, 30.1±63.6 vs 10.7±25.8 mg/L), with most patients being on high-dose statin therapy (82.4% vs 38.7%, p<0.001). At 1 year, patients with LDL-C<55 mg/dL had a higher rate of MACCE (16.4% vs 7.0%, p<0.001), with individual components of the primary endpoint occurring more frequently among these patients (all p<0.001), except for a numerical increase in CE (2.7% vs 1.7%, p=n.s.), as shown in the figure (Panel A). The enhanced MACCE risk persisted after adjustment for potential differences in baseline characteristics, with a 51% (adj. HR 1.51, CI95% 1.05-2.17, p=0.026) increase in MACCE (Panel B). Diabetes, low eGFR and high hs-CRP levels remained independent predictors of MACCE in patients with low baseline LDL-C (all p<0.001). Conclusions Our real-world data confirm that even ACS-patients reaching currently recommended LDL-C thresholds have a substantial incidence of recurrent CV events. These findings reinforce the opportunity for lipid-lowering therapy intensification in high-risk patients to levels below guideline-recommended threshold in order to further reduce CV risk.Event-risk according to baseline LDL-C

Relationship of cumulative low-density lipoprotein cholesterol with atherosclerosis

Abstract Background The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. Objective The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). Methods This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg･year/dL, 4000-4999 mg･year/dL, 5000-5999 mg･year/dL, and ≥6000 mg･year/dL. Results The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg･year/dL group was significantly higher than the odds ratios in the other groups (Figure 1A). The odds ratio of the lower quartile of NID in the <4000 mg・year/dL group was significantly higher than the odds ratios in the 5000-5999 mg･year/dL and ≥6000 mg･year/dL groups (Figure 1B). The odds ratio of the prevalence of CCA plaque in the <4000 mg・year/dL group was significantly higher than that in the ≥6000 mg･year/dL group (Figure 1C). Conclusions Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg・year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg･year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg･year/dL.Graphical abstractFigure 1

PCSK9 inhibitors and coronary atherosclerotic plaque modification: a meta-analysis

Abstract Introduction Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have emerged as a promising class of medications, primarily recognized for their potent cholesterol-lowering effects. Beyond their established role in reducing low-density lipoprotein cholesterol levels, recent studies suggest a potential impact of PCSK9 inhibitors on the modification of coronary atherosclerotic plaques. Purpose The purpose of this meta-analysis is to comprehensively synthesize data from relevant clinical studies and trials that have investigated the effects of PCSK9 inhibitors on coronary atherosclerotic plaque characteristics. Methods We performed a literature search for studies assessing the evolution of coronary atherosclerotic plaques after treatment with a PCSK9 inhibitor compared to a control group. We excluded reviews, editorials, case reports/case series, and studies that did not use PCSK9 inhibitors or did not have a control group for comparison. The main outcomes of interest were the changes in percent atheroma volume (PAV), total atheroma volume (TAV), minimal fibrous cap thickness (FCT), lipid arch, as well as the number of patients with improved PAV at follow-up. Effect sizes are presented as standardized mean difference (SMD) or risk ratio (RR) with their corresponding 95% confidence intervals (CIs) and were pooled based on a random-effects model. Publication bias was assessed by funnel plot inspection and egger’s regression test. Results The literature search yielded 189 results. After application of the exclusion criteria, a total of 8 studies were selected for data extraction and inclusion in the meta-analysis. Concerning the intravascular ultrasound findings PCSK9 inhibitors induced greater reductions in PAV (SMD -2.70, 95% CI -5.24 to -0.15, p=0.04) (Figure 1) and TAV (SMD -2.46, 95% CI -4.68 to -0.23, p=0.03) (Figure 2), with a greater proportion of patients exhibiting an improvement in PAV (RR 1.30, 95% CI 1.20 to 1.41, p<0.01). Moving to optical coherence tomography parameters, patients treated with PCSK9 inhibitors had an increase in minimal FCT (SMD 2.09, 95% CI 0.12 to 4.07, p=0.04) and a lower lipid arch (SMD -0.64, 95% CI -0.97 to -0.32, p<0.01). Funnel plot inspection and egger’s regression test did not indicate the presence of publication bias. Conclusion This meta-analysis suggests that PCSK9 inhibitors use is associated with a favorable coronary atherosclerotic plaque remodeling.Figure 1Figure 2

Impact of the severe familial hypercholesterolemia status on atherosclerotic risks

Abstract Backgrounds Risks of atherosclerotic events substantially vary even among patients with familial hypercholesterolemia (FH) with extremely high risk based on life-long exposure to high low-density lipoprotein cholesterol levels. Purpose This study aimed to examine the impact of the severe FH status defined by the International Atherosclerosis Society (IAS). Methods Data of patients with FH (N = 1,050, male = 490) who were admitted to our university hospital between 2000 and 2020 and who were followed up were retrospectively reviewed. The number of major adverse cardiac events (MACEs), including mortality associated with cardiovascular disease, acute coronary syndrome, and ischemic heart disease requiring coronary revascularization per 1,000 person-years, was calculated. Hazard ratio was also calculated using Cox proportional model. Results Overall, 545 (51.9%) patients had severe FH. The median follow-up duration was 12.6 years. In total, 171 MACEs were recorded during the follow-up period. Severe FH was significantly associated with MACE (hazard ratio = 6.48, 95% confidence interval = 2.56–10.40, P < 0.001). The event rates per 1,000 person-years in the primary prevention group of non-severe FH and severe FH, were 0.0 and 15.6, respectively. The event rates per 1,000 person-years in the secondary prevention group of non-severe FH and severe FH, were 2.0 and 32.3, respectively. Conclusions Patients with severe FH exhibited significantly higher risks in primary and secondary prevention settings. This simple criterion provides useful information for identifying patients with even higher risk who may need further management.

Moderate-intensity statin combined with ezetimibe versus high-intensity statin monotherapy for secondary cardiovascular risk reduction: a systematic review and meta-analysis

Abstract Introduction Intensive lowering of LDL cholesterol levels is recommended for patients with atherosclerotic cardiovascular disease (ASCVD) [1]. Statins are the first-line therapy for secondary prevention [1]. Recent studies such as the RACING trial suggest that the combination of moderate-intensity statins and ezetimibe (MIS+EZE) may achieve a greater LDL cholesterol reduction and a lower adverse event rate than high-intensity statins alone (HIS) [2]. Purpose The aim of this systematic review and meta-analysis is to assess cardiovascular outcomes and clinical safety of MIS+EZE versus HIS in patients with ASCVD. Methods We searched PubMed, Cochrane and Embase for studies that compared MIS+EZE to HIS in patients with ASCVD and included studies reporting cardiovascular mortality, all cause mortality, non-fatal stroke, non-fatal myocardial infarction, unstable angina, coronary revascularization, heart failure, and LDL-C ≤ 70mg/dL. Studies with the same statin dose in both treatment groups and studies with overlapping populations were excluded. Treatment effects for binary endpoints were compared using pooled risk-ratios (RR) with 95% confidence intervals. Results Out of 6238 studies, we included 6 RCTs and 2 retrospective cohort studies with 40,236 patients of whom 10,254 were treated with MIS+EZE (25,5%). Mean follow-up ranged from 90 days to 3 years. Cardiovascular mortality (RR 0.83; CI95% 0.73-0.94; p=0.003), all-cause mortality (RR 0.90; CI95% 0.82-0.98; p=0.02) and non-fatal stroke (RR 0.83; CI95% 0.73-0.93; p=0.002) were significantly lower in patients treated with MIS+EZE compared to those treated with HIS. A significantly higher proportion of patients in the MIS+EZE group reached an LDL-C ≤ 70mg/dL (RR 1.26; CI95% 1.19-1.34; p<0.00001). No statistically significant difference was found for non-fatal myocardial infarction (RR 0.87; CI95% 0.64-1.17; p=0.36), coronary revascularization (RR 1.03; CI95% 0.78-1.35; p=0.83), heart failure (RR 0.95; CI95% 0.86-1.06; p=0.38) and unstable angina (RR 1.52; CI95% 0.62-3.75; p=0.36). A RCT sub-analysis was feasible for cardiovascular mortality and showed no statistically significant difference between the two groups (RR 1.01; CI95% 0.42-2.42; p=0.98). Regarding safety endpoints, the risk of adverse events (RR 0.84; CI95% 0.74-0.95; p=0.004) and the risk of muscle-related adverse events (RR 0.67; CI95% 0.49-0.92; p=0.01) were significantly lower in MIS+EZE group. The significant reduction in muscle-related adverse events was maintained in the RCT sub-analysis (RR 0.61; CI95% 0.41-0.91; p=0.02). There was no difference between groups in the risk of liver-related adverse events (RR 0.63; CI95% 0.29-1.41; p=0.26) or new-onset malignancy (RR 0.99; CI95% 0.87-1.12; p=0.85). Conclusion The combination of moderate-intensity statins and ezetimibe may be considered as an alternative therapeutic strategy to reduce secondary cardiovascular risk with lower rates of drug intolerance.

Association between lipoprotein particle concentration and size and progression of coronary plaque: the MACS Longitudinal Coronary CT angiography study

Abstract Background People living with HIV have greater risk of cardiovascular diseases (CVD) than people without HIV and tend to have different risk profiles, including higher serum triglycerides and lower LDL cholesterol levels. Nuclear magnetic resonance (NMR) provides a detailed phenotype of lipoproteins. Purpose To examine the associations between lipoprotein particle concentrations and size and progression of coronary artery plaque among people living with and without HIV, and whether these associations differ by HIV serostatus. Methods Men with no clinical CVD in the Multicenter AIDS Cohort Study (MACS) who underwent a coronary CT angiography at baseline (2010-13) and follow-up (2015-17) were included. NMR spectroscopy was completed on fasting serum samples at baseline. Logistic regression models for the change in total coronary plaque volume (in tertiles) were estimated with NMR-derived lipoproteins as predictors. Levels were log-transformed and standardized to make results comparable. Models were adjusted for demographics, statin use and HIV serostatus (model 1) with addition of CVD risk factors (model 2). Interactions by HIV serostatus were also tested. Results A total of 549 men (314 with HIV; 235 without HIV) were included. Mean age was 53 ±7 years; 58% were White, 30% Black, and 12% Hispanic. Coronary plaque was present in 70% and plaque volume progressed in 79% of the cohort. Among men with HIV, 81% had undetectable HIV RNA and 12% had a diagnosis of AIDS at baseline. Men with HIV had significantly higher levels of small LDL-P, and total, medium and large VLDL-P levels compared to men without HIV, and lower levels of total, small and large HDL-P (Table 1). Men with HIV had significantly greater progression of plaque volume (37 mm3) compared to men without HIV (31 mm3, p<0.05). Levels of total and small LDL-P concentrations were directly associated with plaque progression, whereas large HDL-P was inversely associated with plaque progression in the combined sample (Model 2). Associations between total and small LDL-P with plaque progression were stronger in men with HIV than in men without HIV in models 1 and 2 (interaction p<0.01). While associations in fully adjusted models for total VLDL-P and small VLDL-P were significant in men without HIV, there were no significant associations between these particle concentrations with coronary plaque progression among men without HIV (interaction p< 0.01) (Model 2, Table 2). Conclusion Associations between lipid particle concentrations and coronary plaque progression differed between men with and without HIV, with stronger associations seen in men without HIV for total and small LDL-P. Despite having higher VLDL and lower HDL particle concentrations at baseline, these particle concentrations were only associated with plaque progression in men without HIV. Further research is needed to elucidate HIV specific factors for plaque progression to tailor risk reduction strategies.

Clinical impact of systemic inflammation across the spectrum of different high-sensitivity CRP values in patients undergoing percutaneous coronary intervention

Abstract Background Systemic inflammation enhances atherosclerosis progression and is a well-established determinant of cardiovascular risk. High-sensitivity C-reactive protein (hsCRP), the most widely available biomarker of inflammation, has indeed been associated with the occurrence of major adverse cardiovascular and cerebrovascular events (MACCE) in patients undergoing percutaneous coronary intervention (PCI). However, some heterogeneity exists in the threshold to define high hsCRP associated with increased cardiovascular risk, with the 2 and 3 mg/L cut-offs being used more commonly. Purpose We aimed to evaluate the clinical impact of systemic inflammation in patients undergoing PCI across the spectrum of baseline hsCRP values. Methods We retrospectively evaluated consecutive patients undergoing PCI with drug-eluting stent implantation from 2012 to 2022 at Mount Sinai Hospital (NY, USA). We excluded patients presenting with acute myocardial infarction or active cancer and those for whom baseline hsCRP was not available or was above 10 mg/L. Patients were stratified into three groups according to baseline hsCRP levels: <2.0, 2.0 to 3.0, and >3.0 mg/L. We estimated the risk of 12-month adverse events using the lowest hsCRP group (<2.0 mg/L) as reference. The primary endpoint was MACCE, defined as the composite of all-cause death, myocardial infarction (MI), or stroke. Secondary endpoints were MACCE individual components, target vessel revascularization (TVR), stent thrombosis and bleeding. Results A total of 10,811 patients were included in the analysis. Of these, 6,210 (57.4%) had hsCRP <2.0 mg/L, 1,624 (15.0%) between 2 and 3 mg/L and 2,977 (27.6%) >3.0 mg/L. Incidence of anemia, diabetes mellitus, peripheral and cerebrovascular artery disease, atrial fibrillation and chronic kidney disease increased stepwise across hsCRP groups. Moreover, patients with higher hsCRP tended to present more frequently with unstable angina and higher baseline LDL cholesterol levels. As regards procedural variables, coronary artery disease severity and PCI complexity did not differ significantly across groups. When compared with patients with hsCRP < 2, hsCRP > 3 mg/L was associated with a greater adjusted risk of MACCE (4.9% vs 2.4%; HR 1.75 % CI 1.35 - 2.28), all-cause death (2.5% vs 0.9%, HR 2.34, 95%CI 1.57-3.47) and MI (2.5% vs 1.3%; HR 1.58 95%CI 1.11-2.26) (Figure 1). Risks of stroke, TVR, stent thrombosis and bleeding did not significantly differ across hsCRP groups (Table 1) Conclusions In patients undergoing PCI, elevated hsCRP values exceeding 3 mg/L exhibit a more robust association with the risk of MACCE and all-cause mortality, as compared with both hsCRP < 2.0 and between 2.0 and 3.0 mg/L. In this context, the use of hsCRP might improve the stratification of patients associated with higher inflammatory burden.

Estimated impact of inclisiran treatment on hyperlipidemia prevalence and cardiovascular disease events in NHANES dataset

Abstract Background Inclisiran, administered subcutaneously every 6 months, will result in the reduction of LDL-cholesterol levels of approximately 50%. We estimated the eligibility of the US population for Inclisiran treatment and its impact on blood lipids and CVD events. Methods We applied ORION trial eligibility criteria to US adults aged ≥ 18 years in the US NHANES 1999-2018 to estimate the US eligible population. Blood lipid alterations in ORION 10 were applied to estimate the impact on LDL-C levels and hyperlipidemia prevalence in the ASCVD population sample. We also used the Framingham CVD risk scores to estimate 10-year CVD risks in the ASCVD high-risk population sample based on ORION 11. The difference in estimated risks with and without Inclisiran administration, multiplied by the eligible population from NHANES data, represented the potentially preventable CVD events. Results We identified 651 ASCVD persons (projected to 5.55 million) who fit ORION 10 trial eligibility criteria and 359 ASCVD high-risk persons (projected to 2.53 million) who fit ORION 11 trial eligibility criteria for our analysis. We then analyzed the changes in these populations after Inclisiran treatment. Firstly, we estimated that approximately 3.9 million (72.8%) individuals would experience ≥50% LDL-C reductions. Secondly, we estimated that among the ASCVD patients, 5.07 million (91.3%) with elevated LDL-C, 0.25 million (22.8%) with reduced HDL-C, 1.24 million (95.2%) with elevated TC, and 0.65 million (32.4%) with elevated TG would potentially achieve a more reasonable blood lipid level. Finally, among those without CVD, the estimated 10-year CVD risks were 19% before and 13.8% after Inclisiran treatment, reflecting a 5.2% absolute (and 27.4% relative) reduction in risk translating to potentially 130,000 preventable CVD events over 10 years. Conclusion Inclisiran treatment in eligible US adults may substantially reduce hyperlipidemia prevalence and CVD events.core graphics

Acute hyperlipidemia has transient effects on large-scale bone regeneration in male mice

Excessive dietary fat intake increases plasma lipid levels and has been associated with reduced bone mineral density (BMD) and increased risk of osteoporotic fracture, especially in older postmenopausal women. The objective of this study was to investigate whether there are sex-related differences in lipid metabolism that could have an impact on large-scale bone regeneration. Because ribs provide a unique exception as the only bones capable of completely regenerating large-scale defects, we used a rib resection mouse model in which human features are recapitulated. After 10 days of exposure to a low-fat diet or high-fat diet (HFD), we performed large-scale rib resection surgeries on male and female mice (6–7 weeks old) with deletion of the low-density lipoprotein (LDL) receptor (Ldlr−/−) and age- and sex-matched wild-type (WT) mice were used as controls. Plasma analysis showed that short-term exposure to HFD significantly increases total cholesterol, LDL cholesterol, and triglycerides levels in Ldlr−/− mice but not in WT, with no differences between males and females. However, under HFD, callus bone volume was significantly reduced exclusively in male Ldlr−/− mice when compared to WT, although these differences were no longer apparent by 21 days after resection. Regardless of diet or genotype, BMD of regenerated ribs did not differ significantly between groups, although male mice typically had lower average BMD values. Together, these results suggest that short-term hyperlipidemia has transient effects on large-scale bone regeneration exclusively in male mice.

The Impact of Acute Ammonia Nitrogen Stress on Serum Biochemical Indicators and Spleen Gene Expression in Juvenile Yellowfin Tuna (Thunnus albacares).

The presence of ammonia nitrogen in water has a significant impact on the serum and spleen of fish, potentially leading to changes in substances such as proteins in the serum while also causing damage to the immune function of the spleen. To investigate the effects of ammonia nitrogen (NH3-N) stress on juvenile yellowfin tuna (Thunnus albacares), this study established three NH3-N concentrations, 0, 5, and 10 mg/L, denoted as L0, L1, and L2, respectively. Serum and spleen samples were collected at 6, 24, and 36 h. The effects of different NH3-N concentrations and exposure times on the physiological status of juvenile fish were investigated by analyzing serum biochemical indices and splenic gene expression. The results indicate that in the L1 group, the serum high-density lipoprotein cholesterol (HDL-C), triglycerides (TG), complement 3 (C3) and complement 4 (C4) levels, and acid phosphatase (ACP) activity showed a trend of initially increasing and then decreasing. In the L2 group, the serum low-density lipoprotein cholesterol (LDL-C), HDL-C, and C4 levels and ACP activity also displayed an initially rising and then declining trend, while TG, C3, and creatinine (CRE) levels and alkaline phosphatase (AKP) activity showed an upward trend. In the L1 group, glutathione peroxidase 1b (GPX1b), interleukin 10 (IL-10), interleukin 6 receptor (IL-6r), and tumor necrosis factor alpha (TNF-α) gene expression levels in the spleen exhibited a trend of first increasing and then decreasing. In the L2 group, IL-10, IL-6r, tumor necrosis factor beta (TNF-β), caspase 2 (casp2), and caspase 9 (casp9) gene expression levels in the spleen also showed an initial increase followed by a decrease. When NH3-N levels are below 5 mg/L, it is recommended to limit stress exposure to no more than 36 h for the juvenile fish. For concentrations ranging from 5 to 10 mg/L, stress should be strictly controlled to within 24 h. Exposure to high NH3-N levels may affect biochemical indicators such as serum lipid metabolism, immunity, and metabolism in juvenile fish, and may damage the expression of antioxidant, immune gene, and apoptosis factors in the spleen. This study aims to deepen our understanding of the effects of NH3-N on juvenile tuna, with the goal of establishing effective water quality monitoring and management strategies. This will ensure the quality of aquaculture water, reduce the harm caused by NH3-N to juvenile yellowfin tuna, and enhance aquaculture efficiency and product quality.

Purslane Leaf Extract (Portulaca oleracea) as a Cholesterol Control Herbal Tea Mixture

Cholesterol is one of the essential molecules in humans. An imbalance in cholesterol levels in the body, such as high levels of triglycerides and low-density lipoprotein (LDL) or total cholesterol, can contribute to one of the leading causes of death in Indonesia. Diseases caused by high cholesterol levels include cardiovascular diseases, atherosclerosis, hypercholesterolemia, hyperlipidemia, coronary heart disease, hypertension, and stroke [6,9,14]. As a result, additional intake from sources like omega-3-rich supplements or herbal remedies is recommended. Historically, plant-based treatments have been used as pharmacological therapies. Researchers have explored the use of purslane (Portulaca oleracea) leaves, which contain unsaturated fatty acids and antioxidants, including omega-3 fatty acids, vitamins A and C, and minerals such as magnesium and potassium, offering cardiovascular benefits. The researchers utilized purslane extract as an herbal tea blend, serving as a natural alternative to supplements in capsule form, which may be more expensive. In extract form, purslane leaves are hygienically processed and mixed with herbal tea, creating a convenient health drink for daily consumption. The purslane leaf extract was obtained through method maceration using 96% food-grade ethanol. Proximate tests were conducted to assess total energy, energy from fat, ash content, moisture content, carbohydrates (by difference), total fat, and protein content [5,24]. Sensory evaluation was conducted by semi-trained panelists to assess the color, aroma, and taste of herbal tea blends containing purslane leaf extract. This evaluation aimed to collect subjective feedback from potential consumers regarding the organoleptic characteristics of the product.

Lipid and brain volumetric measures in multiple sclerosis patients: findings from a large observational study.

This study aimed to investigate relationships between cholesterol profile, brain volumetric MRI, and clinical measures in a large observational cohort of multiple sclerosis (MS) patients. We included 1.505 patients with 4.966 time points including complete lipid, clinical, and imaging data. The time among lipid, brain MRI and clinical measures was under 90 days. Cross-sectional statistical analysis at baseline was performed using an adjusted linear regression and analysis of longitudinal lipid and MRI measures data was performed using adjusted linear mixed models. We found associations between higher high-density lipoprotein cholesterol (HDL-C) and lower brain parenchymal fraction (BPF) at cross-sectional analysis at baseline (B = -0.43, CI 95%: -0.73, -0.12, p = 0.005), as well as in longitudinal analysis over follow-up (B = -0.32 ± 0.072, χ2 = 36.6; p = < 0.001). Higher HDL-C was also associated with higher T2-lesion volume in longitudinal analysis (B = 0.11 ± 0.023; χ2 = 23.04; p = < 0.001). We observed a weak negative association between low-density lipoprotein cholesterol (LDL-C) levels and BPF at baseline (B = -0.26, CI 95%: -0.4, -0.11, p = < 0.001) as well as in longitudinal analysis (B = -0.06 ± 0.03, χ2 = 4.46; p = 0.03). T2-LV did not show an association with LDL-C. We did not find any association between lipid measures and disability. The effect of lipid levels on MRI measures and disability was minimal (Cohen f2 < 0.02). Our results contradict the previously described exclusively positive effect of HDL-C on brain atrophy in patients with MS. Higher LDL-C was weakly associated with higher brain atrophy but not with higher lesion burden.