Aggressive Cholesterol Lowering Research Articles

Abstract 1049: Long Noncoding RNA Regulation Of Inflammation In Atherosclerosis

Atherosclerosis is a chronic inflammatory disease driven by cholesterol deposition in the artery wall. Resolution of atherosclerotic inflammation and plaque regression are important clinical goals. As long noncoding RNAs (lncRNAs) are key regulators of gene expression, there is an intense interest in understanding their roles in atherosclerosis and their potential as therapeutic targets. To identify lncRNAs regulated during plaque progression and regression, we performed single cell RNA-sequencing of CD45 + immune cells isolated from aortic arch plaques of Ldlr –/– mice under conditions of plaque progression (16 wks Western diet; WD) or regression (16 wks WD + 4 wks apoB ASO). We screened for lncRNAs acting in cis to modify the expression of proximal protein-coding genes and identified Caslr ( C tsc a nti s ense l nc R NA) , a novel lncRNA transcribed from the opposite strand of Cathepsin C gene ( Ctsc ) encoding a pro-atherosclerotic lysosomal protease. Caslr–Ctsc pair is upregulated in macrophages of progressing plaques and in response to pro-inflammatory stimuli ( i.e . LPS, IL-6) in vitro , and conversely downregulated during atherosclerosis regression and in response to anti-inflammatory stimulus ( i.e. IL-4). LncRNA knockdown approaches combined with transcriptomic analyses and functional assays showed that Caslr regulates Ctsc expression and associated inflammatory responses, including NF-κB signaling and inflammasome-dependent IL-1β release. RNA purification strategies combined with mass-spectrometry revealed that Caslr interacts with spliceosome-associated proteins to coordinate splicing of Ctsc mRNA. Notably, Caslr shares functional homology with a human lncRNA, CASLR, proximal to the CTSC gene, which regulates CTSC expression and protease activity. Human CASLR and CTSC are highly expressed in the blood of hyperlipidemic patients and their expression is coordinately decreased upon aggressive cholesterol lowering by anti-PCSK9 treatment. Collectively, our data identify Caslr as an evolutionary conserved lncRNA acting in cis to drive the expression of cathepsin C with downstream consequences on inflammatory signaling in plaque macrophages, and suggest that targeting this lncRNA may be beneficial in treating atherosclerosis.

Eliminate LDL cholesterol after heart attack … but only for a while.

There is a clear demonstration of the inverse linear correlation between LDL cholesterol levels and clinical benefit. However, the timing of the action of lipid-lowering drugs is not clear. According to animal studies with recombinant lipoprotein A-1, the composition of atherosclerosis changes within 40 h (with variations in lipid and inflammatory contents). Progression-regression studies of atherosclerosis in humans confirm the data, highlighting a rapid change in the plaque over 5 weeks. The data are also in line with what emerges from the survival curves of the old study comparing atorvastatin 80 mg vs. placebo (Myocardial Ischaemia Reduction with Aggressive Cholesterol Lowering). The spacing of the curves occurs after only 4 weeks, indicating the precociousness of the favourable effects of powerful statins. Finally, a recent Odyssey post hoc analysis compared the risk of cardiac death and coronary revascularization between a group in which alirocumab lowered LDL cholesterol to below 15 mg (Group 1 and in which the drug was therefore stopped) against the subjects in the placebo group (Group 2), applying a propensity score matching. The primary endpoint occurred in a lower percentage of patients in Group 1 (6.4 vs. 8.4%). Furthermore, patients in Group 1 had a significantly lower hazard ratio (HR) for major adverse cardiovascular events [0.72; 95% confidence interval (CI) 0.51-0.997; P = 0.047] compared with the entire alirocumab group vs. placebo (HR 0.85; 95% CI 0.78-0.93; P < 0.001). According to these preliminary observations, aggressive and early treatment of hypercholesterolaemia in subjects with acute coronary syndrome translates into improved clinical results compared with a strategy that provides for more gradual control. These data will need to be confirmed through further prospective clinical studies and ideally with early conducted atherosclerosis regression studies.

Abstract 11456: Elevated Lipoprotein(a) is Associated with Statin Resistance

Introduction: LDL-C reduction by statins is the mainstay pharmacologic strategy for ASCVD risk reduction. Despite adherence, some patients fail to achieve LDL-C goals, a phenomenon known as statin resistance. Current LDL-C assays include cholesterol content on both lipoprotein(a) [Lp(a)] and LDL particles. Because statins do not lower Lp(a), Lp(a)-cholesterol may represent a statin insensitive pool within LDL-C. Hypothesis: Elevated Lp(a) contributes to statin resistance in patients treated with high-intensity statin therapy. Methods: A secondary analysis was performed on 2338 patients from the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, randomized to receive atorvastatin 80mg or placebo; baseline and week 16 lipid parameters were analyzed. Results: In the atorvastatin group (n = 1092), mean (SD) baseline LDL-C, absolute LDL-C reduction, median percent LDL-C change from baseline (IQR), and Lp(a) were 123.8 (33.5) mg/dL, 52.2 (36.7) mg/dL, -47.6% (-59.1- -29.9%), and 10.6 (5.1-29.1) mg/dL, respectively. Median (IQR) baseline Lp(a) was higher [12.1 (5.9-38.1) vs 9.2 (4.4-22.4) mg/dL, p &lt; 0.001] in patients with attenuated percent LDL-C reduction compared to group median. The median percent LDL-C reduction on atorvastatin was 42.3% (24.3-52.5%) in patients with baseline Lp(a) between 50 - 99 mg/dL, and 32.6% (11.5-43.7%) with Lp(a) &gt; 100 mg/dL prevalent in ~10% of the population, both significantly attenuated compared to patients with Lp(a) &lt;30 mg/dL (50.4% [33.3-61.1%]), p &lt; 0.001. An LDL-C target of 70 mg/dL or less was achieved in 62.3% of patients with baseline Lp(a) &lt;30 mg/dL, compared to 55.2%, 43.3%, and 24.1% of those with Lp(a) 30 - 49 mg/dL, 50 - 99 mg/dL, and &gt; 100 mg/dL (p &lt; 0.001), respectively [Figure 1]. Conclusions: Elevated Lp(a) is associated with statin resistance and may identify patients who require additional or more potent lipid lowering therapies to achieve LDL-C goals.

Persistent inflammatory residual risk despite aggressive cholesterol-lowering therapy: what is next?

To briefly summarize recently published evidence on the possible therapeutic modulation of inflammatory processes in atherosclerotic cardiovascular disease (ASCVD), focusing on the rationale for an additional randomized clinical trial, targeting both persistently elevated cholesterol and inflammatory residual risk and critically discuss still open issues and future perspectives with regard to treatment allocation. Several large-scale clinical trials over the past few years have advanced our understanding of the role of inflammation in atherosclerosis, demonstrating that targeting the NLRP3 inflammasome and the IL-1β pathway indeed represent a new avenue to reduce residual risk in patients with ASCVD. However, despite optimal lipid-lowering therapy and novel options to modulate residual inflammatory risk, there are still a large number of individuals, being at high risk for recurrent ASCVD events. The integration of a dual target strategy aimed at lowering the inflammatory burden in combination with aggressive lipid-modifying for those at high/very high ASCVD risk may hold potential to significantly improve patient care. However, a number of questions related to the design of such 2 × 2 factorial trial still needs to be answered.

The Prevalence of Heterozygous Familial Hypercholesterolemia in Selected Regions of the Russian Federation: The FH-ESSE-RF Study.

Heterozygous familial hypercholesterolemia (HeFH) is one of the most common genetic conditions but remains substantially underdiagnosed. The aim of our study was to investigate the prevalence of HeFH in the population of 11 different regions of Russia. Individuals were selected from the Epidemiology of Cardiovascular Risk Factors and Diseases in Regions of the Russian Federation Study. All participants who had low-density lipoprotein cholesterol (LDL-C) higher than 4.9 mmol/L, or LDL-C lower than 4.9 mmol/L, but had statin therapy, were additionally examined by FH experts. FH was diagnosed using the Dutch Lipid Clinic Network criteria, incorporating genetic testing. HeFH prevalence was assessed for 18,142 participants. The prevalence of patients with definite or probable HeFH combined was 0.58% (1 in 173). A total of 16.1% of patients with definite or probable HeFH had tendon xanthomas; 36.2% had mutations in one of the three genes; 45.6% of FH patients had coronary artery disease; 63% of HeFH patients received statins; one patient received an additional PCSK9 inhibitor; no patients received ezetimibe. Only 3% of patients reached the LDL-C goal based on 2019 ESC/EAS guidelines. Underdiagnosis and undertreatment of FH in Russia underline the need for the intensification of FH detection with early and aggressive cholesterol-lowering treatment.

BEMPEDOIC ACID 180 MG + EZETIMIBE 10 MG FIXED-DOSE COMBINATION VS EZETIMIBE ALONE OR PLACEBO IN PATIENTS WITH TYPE 2 DIABETES AND HYPERCHOLESTEROLEMIA

Patients with type 2 diabetes mellitus (T2DM) are at high cardiovascular risk. National and international guidelines recommend aggressive low-density lipoprotein cholesterol (LDL-C) lowering with statin therapy; however, statins may increase glucose levels. This phase 2 study was the first to

High sdLDL Cholesterol can be Used to Reclassify Individuals with Low Cardiovascular Risk for Early Intervention: Findings from the Chinese Multi-Provincial Cohort Study.

Aim: A high-risk strategy has been implemented for lipid-lowering therapy in the primary prevention of cardiovascular disease. However, atherosclerosis and cardiovascular events are common among individuals with low cardiovascular risk. This study aimed to determine whether the small dense low-density lipoprotein cholesterol (sdLDLC) level can predict carotid atherosclerosis progression and identify high-risk individuals.Methods: Baseline sdLDLC and low-density lipoprotein cholesterol (LDLC) were measured in 808 particip ants from the Chinese Multi-provincial Cohort Study, aged 45–74 years. Adjusted relative risk was calculated using a modified Poisson regression model to assess the relationship between sdLDLC and 5-year atherosclerosis progression, as indicated by the progression, incidence, and multi-territorial extent of carotid plaque.Results: The 5-year atherosclerosis progression increased significantly with increased sdLDLC. Baseline sdLDLC was significantly associated with the short-term risk of plaque progression after multivariable adjustment, even in participants with low LDLC or a 10-year estimated cardiovascular risk. sdLDLC predicted plaque progression (relative risk 2.05; 95% confidence interval 1.43–2.93) in participants with LDLC < 130 mg/dL. Furthermore, participants with the highest sdLDLC but intermediate or low cardiovascular risk (accounting for 16% of the cohort) had double the risk of plaque progression, which was comparable to those with the same sdLDLC and high cardiovascular risk, relative to those with the lowest sdLDLC levels and low cardiovascular risk.Conclusions: sdLDLC is independently associated with the progression of carotid atherosclerosis, which may provide a basis for clinicians to reclassify individuals believed to be at low cardiovascular risk into the high-risk category, and those with high sdLDLC may benefit from more aggressive cholesterol-lowering treatment.

Coronary heart disease mortality in severe vs. non-severe familial hypercholesterolaemia in the Simon Broome Register

Background and aimsThe International Atherosclerosis Society (IAS) has proposed that patients with “severe” FH (SFH) would warrant early and more aggressive cholesterol-lowering treatment such as with PCSK9 inhibitors. SFH is diagnosed if LDL-cholesterol (LDLC) > 10 mmol/L, or LDLC >8.0 mmol/L plus one high-risk feature, or LDLC >5 mmol/L plus two high-risk features. Here we compare CHD mortality in SFH and non-SFH (NSFH) patients in the UK prospective Simon Broome Register since 1991, when statin use became routine. Methods2929 definite or possible PFH patients (51% women) aged 20–79 years were recruited from 21 UK lipid clinics and followed prospectively between 1992 and 2016. The excess CHD standardised mortality ratio (SMR) compared to the England and Wales population was calculated (with 95% confidence intervals). Results1982 (67.7%) patients met the SFH definition. Compared to the non-SFH, significantly (p < 0.001) more SFH patients had diagnosed CHD at baseline (24.6% vs. 17.5%), were current smokers (21.9% vs 10.2%) and had a BMI > 30 kg/m2 (14.9% vs. 7.8%). The SMR for CHD mortality was significantly (p = 0.007) higher for SFH (220 (184–261) (34,134 person years, 129 deaths observed, vs. 59 expected) compared to NSFH of 144 (98–203) (15,432 person years, 32 observed vs. 22 expected). After adjustment for traditional risk factors, the Hazard Ratio for CHD mortality in SFH vs. NSFH was 1.22 (0.80–1.87) p = 0.36, indicating that the excess risk was largely accounted for by these factors. ConclusionsCHD mortality remains elevated in treated FH, especially for SFH, emphasising the importance of optimal lipid-lowering and management of other risk factors.

Modelling total coronary heart disease burden and long-term benefit of cholesterol lowering in middle aged men with and without a history of cardiovascular disease.

Cumulative coronary heart disease (CHD) events over 20 years were examined in men screened for, and in those randomized to, the West of Scotland Coronary Prevention Study. Record linkage provided CHD-related events and days in hospital for the 80 230 screenees, including the randomized cohort of 6595 men. Risk factors were determined at baseline, and disease burden assessed for groups defined by cholesterol. Effects of cholesterol lowering were modelled from differences between groups, and from the treatment arms of the trial. Over 20 years, those without a history of CHD (n = 61 211) had 23.0 events per 100 subjects in the lowest cholesterol group (mean 4.0 mmol/L) and 65.1 per 100 in the highest (8.8 mmol/L). Corresponding days in hospital were 167.2-435.4 per 100 subjects. Analogous figures for men with a CHD history (n = 8570) were 77.3-141.7 events per 100 and 526.1-936.7 hospital days per 100. Lowering cholesterol by about 1.0 mmol/L in men with average cholesterol and no CHD was predicted to be associated with 8.9 fewer events and a saving of 56.0 hospital days per 100. In those with CHD this difference gave, depending on starting level, 26.8-36.5 fewer events and savings of 158.2-247.3 hospital days per 100 subjects. Comparison of cumulative events in 45-54 vs. 55-64 year olds in the trial revealed greater benefit from intervention in the younger decade. Long-term, longitudinal data reveal the considerable CHD burden in middle-aged men and indicate substantial clinical benefits from both moderate and aggressive cholesterol lowering.

Early, intensive statin treatment reduces 'hard' cardiovascular outcomes after acute coronary syndrome.

Background Early, intensive statin treatment is the standard of care after acute coronary syndrome (ACS). However, the benefit of this approach to prevent major adverse cardiovascular events has been demonstrated in only one randomised, placebo controlled trial. The Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial demonstrated that atorvastatin 80 mg daily, compared with placebo, reduced time to first occurrence of death, non-fatal myocardial infarction, resuscitated cardiac arrest, or hospitalisation for unstable angina (stroke not included) during the 16 week period following ACS. However, there were no significant effects on individual components of the composite endpoint except unstable angina. This led some to question whether early, intensive statin treatment reduces 'hard' events after ACS. Aim The burden of coronary heart disease after ACS, and therefore the efficacy of its treatment, depends not only on the occurrence of one ischaemic event, but rather on cumulative events experienced by patients. Accordingly, we conducted a post-hoc analysis of the MIRACL trial to examine the effect of atorvastatin on first as well as recurrent (i.e. total) hard cardiovascular events after ACS (death, myocardial infarction, stroke, and resuscitated cardiac arrest). Methods and Results In the 3086 patients who comprised the MIRACL trial, atorvastatin 80 mg did not reduce time to first hard event compared with placebo (hazard ratio 0.89, 95% confidence interval 0.72-1.10, P = 0.27). However, atorvastatin significantly reduced total hard events (hazard ratio 0.80, 95% confidence interval 0.66-0.97, P = 0.03). To prevent one hard event during the 16 weeks following ACS, only 11 patient-years of treatment with atorvastatin were required. Conclusion Early, intensive treatment with atorvastatin is an efficient intervention to reduce hard cardiovascular events after ACS.

Abstract 036: LDL-Cholesterol Lowering Among Young Adults Who Experience a First Myocardial Infarction

Background: Current data suggest patients who have a myocardial infarction (MI) benefit from aggressive LDL cholesterol (LDL-C) lowering. Consequently, initiation of lipid lowering therapy is a class I recommendation post-MI to reduce the risk of future adverse events. We sought to evaluate LDL-C lowering among patients who experience a first MI at a young age. Methods: Clinical &amp; billing data were used to identify women &lt; 50 years and men &lt; 45 years who had a first MI from two large medical centers. Type of MI was adjudicated by review of medical records, and only patients with a Type 1 MI were included. The magnitude of LDL-C reduction was calculated by comparing the LDL-C pre-MI to the LDL-C one year later. Results: 280 patients (age 42 years ± 5; 35% women) with a complete lipid panel prior to MI and 1 year post-MI were included in this analysis. The mean LDL-C was 123 mg/dL pre-MI, and 82 mg/dL post-MI (p&lt;0.0001). In the entire population, the mean reduction in LDL-C post MI was 27% (95% CI, -32% to -23%), although men had a greater reduction than women (32% vs. 16%, p&lt;0.001). When examining the post-MI LDL-C levels, 214 (76%) reached an LDL-C of &lt;100 mg/dL and 115 (41%) reached an LDL-C of &lt;70 mg/dL. Out of patients who had LDL-C&gt;130mg/dL pre-MI (n=114), 82 (71%) reached an LDL-C of &lt;100 mg/dL, and 35 (30%) reached an LDL-C of &lt;70 mg/dL. Notably, 54 (19%) patients had an LDL-C increase at one year. Conclusions: Among patients experiencing MI at a young age, LDL-C reduction was only modest (27% reduction). Women had a significantly smaller reduction in LDL-C compared with men. Further research is needed to determine the underlying reasons for the sub-optimal reduction in LDL-C, as well as sex specific differences that may account for these disparities.

Abstract 11806: Early, Intensive Atorvastatin Treatment Reduces First and Recurrent Hard Cardiovascular Events After Acute Coronary Syndrome

Background: Early, intensive statin treatment is standard of care after acute coronary syndrome (ACS), but only one placebo (PBO)-controlled trial has demonstrated an early benefit of such treatment. In the Myocardial Ischemia Reduction with Aggressive Cholesterol Lowering (MIRACL) trial, the primary outcome of time to first occurrence of death, MI, resuscitated cardiac arrest, or hospitalization for unstable angina (UA) was reduced with atorvastatin (ATV) 80 mg/day, compared with PBO. However, this result was borderline significant (HR 0.84, 95% CI 0.70-1.00, p=0.048) and driven largely by reduced UA, leading some to argue that early intensive statin treatment does not modify early “hard” events after ACS. On the other hand, the efficacy of an intervention after ACS is only partially accounted for by time to first event because patients may experience multiple events of similar importance, especially when competing risk for death is relatively low. Objective: In a post-hoc analysis of MIRACL, we evaluated the efficacy of ATV to reduce total (first and recurrent) hard cardiovascular events after ACS. Hard events were defined as death, MI, stroke, and resuscitated cardiac arrest. Methods: 3086 patients were randomly assigned to treatment with ATV or PBO, beginning 1-4 days after ACS and continuing for 16 weeks. Time to first event was assessed by Cox regression. Total events were analyzed by Cox regression with model-based variance estimation to determine correlation between events within a subject. Results: ATV did not significantly reduce time to first hard event (HR 0.89, 95% CI 0.72-1.11, P=0.27), but did significantly reduce total hard events ( Table ). To prevent 1 hard event, only 10.6 patient-years of treatment with ATV were required. The HR for total events was minimally affected by inclusion or exclusion of UA. Conclusion: Intensive treatment with ATV reduces total hard events over 16 weeks following ACS, and is an efficient secondary prevention intervention.

The Promise of Proprotein Convertase Subtilisin/Kexin 9 Inhibitors for the Treatment of Familial Hypercholesterolemia

Familial hypercholesterolemia comprises a constellation of genetic disorders resulting in very high cholesterol levels since childhood. If untreated, it is associated with accelerated atherosclerosis and premature cardiovascular disease. It has been shown that if aggressive cholesterol lowering is achieved in familial hypercholesterolemia, the incidence of cardiovascular disease can be lowered. However, currently approved pharmacological therapies are not able to lower cholesterol to optimal levels in a large number of these patients. Proprotein convertase subtilisin/kexin 9 inhibitors are a new class of cholesterol-lowering medications that can significantly reduce cholesterol levels in these patients especially those with at least some functioning low-density lipoprotein receptors. In this article, we will briefly review familial hypercholesterolemia and the role of proprotein convertase subtilisin/kexin 9 inhibitors in this condition.

MiR33 inhibition overcomes deleterious effects of diabetes mellitus on atherosclerosis plaque regression in mice.

Diabetes mellitus increases cardiovascular disease risk in humans and remains elevated despite cholesterol-lowering therapy with statins. Consistent with this, in mouse models, diabetes mellitus impairs atherosclerosis plaque regression after aggressive cholesterol lowering. MicroRNA 33 (miR33) is a key negative regulator of the reverse cholesterol transport factors, ATP-binding cassette transporter A1 and high-density lipoprotein, which suggested that its inhibition may overcome this impairment. To assess the effects of miR33 inhibition on atherosclerosis regression in diabetic mice. Reversa mice, which are deficient in the low-density lipoprotein receptor and in which hypercholesterolemia is reversed by conditional inactivation of the microsomal triglyceride transfer protein gene, were placed on an atherogenic diet for 16 weeks, then either made diabetic by streptozotocin injection or kept normoglycemic. Lipid-lowering was induced by microsomal triglyceride transfer protein gene inactivation, and mice were treated with anti-miR33 or control oligonucleotides. Although regression was impaired in diabetic mice treated with control oligonucleotides, anti-miR33 treatment decreased plaque macrophage content and inflammatory gene expression in these mice. The decreased macrophage content in anti-miR33 treated diabetic mice was associated with a blunting of hyperglycemia-induced monocytosis and reduced monocyte recruitment to the plaque, which was traced to an inhibition of the proliferation of bone marrow monocyte precursors associated with the upregulation of their Abca1. miR33 inhibition overcomes deleterious effects of diabetes mellitus in atherosclerosis regression in mice, which suggests a therapeutic strategy in diabetic patients, who remain at elevated cardiovascular disease risk, despite plasma cholesterol lowering.

The Gap between the Current Dyslipidemia Guidelines and the Physicians’ Treatment Targets in Patients with Type 2 Diabetes

OP-091 Lipid-lowering therapy (LLT) is a key factor in the prevention of cardiovascular mortality and morbidity in diabetic patients. Current guidelines have expanded the population of patients with diabetes for whom aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy should be

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Cholesterol efflux mediators in homozygous familial hypercholesterolemia patients on low-density lipoprotein apheresis

Homozygous familial hypercholesterolemia (FH) is a rare disorder that may affect 1 person per million. Early initiation of aggressive cholesterol-lowering therapy is essential to prevent premature coronary heart disease. Selective removal of low-density lipoprotein (LDL) by LDL apheresis is a reliable method of treatment. Cholesterol efflux mediators of homozygous FH patients on weekly LDL apheresis were compared with those of age- and sex-matched heterozygous FH patients receiving oral medication only and with healthy control subjects. The data show that (1) compared with healthy controls, homozygous FH patients have significantly lower plasma levels of high-density lipoprotein cholesterol and apoA-I and significantly lower cholesterol-acceptor capacity of serum to promote cholesterol efflux from cholesterol-loaded THP-1 cells, combined with significantly lower peripheral blood mononuclear cell gene expression levels of ATP-binding cassette (ABC) transporter G1 and borderline-significantly lower levels of ABCA1 and scavenger receptor class B type I (SR-BI); and (2) compared with pre-LDL apheresis (a day before treatment), postapheresis (15 days later; on the day after the weekly treatment) levels of HDL cholesterol and apoA-I were significantly reduced, with no significant effect on cholesterol-acceptor capacity of serum or on peripheral blood mononuclear cell gene expression levels of the cellular transporters, except for a borderline-significant reduction in ABCA1 mRNA levels. The data showing decreased levels of cholesterol efflux mediators in plasma and cells may suggest that the overall cholesterol efflux capacity is impaired in homozygous FH patients. However, LDL apheresis may maintain cholesterol efflux capacity, despite a lowering levels of high-density lipoprotein cholesterol and apoA-I.

Acute impact of apheresis on oxidized phospholipids in patients with familial hypercholesterolemia

We measured oxidized phospholipids (OxPL), lipoprotein (a) [Lp(a)], and lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) pre- and postapheresis in 18 patients with familial hypercholesterolemia (FH) and with low(∼10 mg/dl; range 10-11 mg/dl), intermediate (∼50 mg/dl; range 30-61 mg/dl), or high (>100 mg/dl; range 78-128 mg/dl) Lp(a) levels. By using enzymatic and immunoassays, the content of OxPL and Lp-PLA(2) mass and activity were quantitated in lipoprotein density fractions plated in microtiter wells, as well as directly on apoB-100, Lp(a), and apoA-I immunocaptured within each fraction (i.e., OxPL/apoB and Lp-PLA(2)/apoB). In whole fractions, OxPL was primarily detected in the Lp(a)-containing fractions, whereas Lp-PLA(2) was primarily detected in the small, dense LDL and light Lp(a) range. In lipoprotein capture assays, OxPL/apoB and OxPL/apo(a) increased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apoB and Lp-PLA(2)/apoA-I levels were highest in the low Lp(a) group but decreased proportionally with increasing Lp(a) levels. Lp-PLA(2)/apo(a) was lowest in patients with low Lp(a) levels and increased proportionally with increasing Lp(a) levels. Apheresis significantly reduced levels of OxPL and Lp-PLA(2) on apoB and Lp(a) (50-75%), particularly in patients with intermediate and high Lp(a) levels. In contrast, apheresis increased Lp-PLA(2)-specific activity (activity/mass ratio) in buoyant LDL fractions. The impact of apheresis on Lp(a), OxPL, and Lp-PLA(2) provides insights into its therapeutic benefits beyond lowering apoB-containing lipoproteins.

Circulation: Clinical Summaries

Circulation: Clinical Summaries

Two-dimensional speckle tracking echocardiography: A novel approach to evaluate left atrial mechanical function

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