Lower Lp Research Articles

AMG145, a Monoclonal Antibody Against Proprotein Convertase Subtilisin Kexin Type 9, Significantly Reduces Lipoprotein(a) in Hypercholesterolemic Patients Receiving Statin Therapy

Background— Lipoprotein(a) [Lp(a)] is an emerging risk factor for cardiovascular disease. Currently, there are few available therapies to lower Lp(a). We sought to evaluate the impact of AMG145, a monoclonal antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), on Lp(a). Methods and Results— As part of the LDL-C Assessment With PCSK9 Monoclonal Antibody Inhibition Combined With Statin Therapy (LAPLACE)–Thrombolysis in Myocardial Infarction (TIMI) 57 trial, 631 patients with hypercholesterolemia receiving statin therapy were randomized to receive AMG145 at 1 of 3 different doses every 2 weeks or 1 of 3 different doses every 4 weeks versus placebo. Lp(a) and other lipid parameters were measured at baseline and at week 12. Compared with placebo, AMG145 70 mg, 105 mg, and 140 mg every 2 weeks reduced Lp(a) at 12 weeks by 18%, 32%, and 32%, respectively ( P <0.001 for each dose versus placebo). Likewise, AMG145 280 mg, 350 mg, and 420 mg every 4 weeks reduced Lp(a) by 18%, 23%, and 23%, respectively ( P <0.001 for each dose versus placebo). The reduction in Lp(a) correlated with the reduction in low-density lipoprotein cholesterol (ρ=0.33, P <0.001). The effect of AMG145 on Lp(a) was consistent regardless of age, sex, race, history of diabetes mellitus, and background statin regimen. Patients with higher levels of Lp(a) at baseline had larger absolute reductions but comparatively smaller percent reductions in Lp(a) with AMG145 compared with those with lower baseline Lp(a) values. Conclusions— AMG145 significantly reduces Lp(a), by up to 32%, among subjects with hypercholesterolemia receiving statin therapy, offering an additional, complementary benefit beyond robust low-density lipoprotein cholesterol reduction with regard to a patient’s atherogenic lipid profile. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT01380730.

Relationship of Apolipoproteins A-1 and B, and Lipoprotein(a) to Cardiovascular Outcomes: The AIM-HIGH Trial (Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglyceride and Impact on Global Health Outcomes)

This study sought to examine the relationship between baseline and on-study apolipoproteins (apo) A-1 and B and lipoprotein(a) [Lp(a)] levels and the development of subsequent cardiovascular (CV) events in the AIM-HIGH (Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglyceride and Impact on Global Health Outcomes) trial.Niacin has been reported to lower apoB and Lp(a) and to raise apoA-1.Individuals with CV disease and low baseline levels of high-density lipoprotein cholesterol were randomized to simvastatin plus placebo or simvastatin, plus extended-release niacin ([ERN], 1,500 to 2,000 mg/day), with ezetimibe added as needed, in both groups, to maintain an on-treatment low-density lipoprotein cholesterol in the range of 40 to 80 mg/dl. Hazard ratios (HRs) were used to evaluate the relationship between levels of apoA-1, apoB, and Lp(a), and CV events in each treatment group.Baseline apoB and the apoB/apoA-I ratio were significantly predictive of CV events only for the placebo group (HR: 1.17 [p = 0.018] and HR: 1.19 [p = 0.016]). Baseline and on-study Lp(a) were predictive of CV events in both simvastatin plus placebo (baseline HR: 1.24 [p = 0.002] and on-study HR: 1.21 [p = 0.017]) and the simvastatin plus ERN group (baseline HR: 1.25 [p = 0.001] and on-study HR: 1.18 [p = 0.028]). The ERN modestly increased 1-year apoA-1 (7%), decreased apoB (13%), decreased the ApoB/ApoA-1 ratio (19%), and decreased Lp(a) 21%, but did not reduce CV events.Lp(a) was associated with increased CV risk in both treatment groups indicating that it contributes to residual CV risk. However, there was no evidence that ERN reduced CV risk, despite favorable lipoprotein changes.

When should we measure lipoprotein (a)?

Recently published epidemiological and genetic studies strongly suggest a causal relationship of elevated concentrations of lipoprotein (a) [Lp(a)] with cardiovascular disease (CVD), independent of low-density lipoproteins (LDLs), reduced high density lipoproteins (HDL), and other traditional CVD risk factors. The atherogenicity of Lp(a) at a molecular and cellular level is caused by interference with the fibrinolytic system, the affinity to secretory phospholipase A2, the interaction with extracellular matrix glycoproteins, and the binding to scavenger receptors on macrophages. Lipoprotein (a) plasma concentrations correlate significantly with the synthetic rate of apo(a) and recent studies demonstrate that apo(a) expression is inhibited by ligands for farnesoid X receptor. Numerous gaps in our knowledge on Lp(a) function, biosynthesis, and the site of catabolism still exist. Nevertheless, new classes of therapeutic agents that have a significant Lp(a)-lowering effect such as apoB antisense oligonucleotides, microsomal triglyceride transfer protein inhibitors, cholesterol ester transfer protein inhibitors, and PCSK-9 inhibitors are currently in trials. Consensus reports of scientific societies are still prudent in recommending the measurement of Lp(a) routinely for assessing CVD risk. This is mainly caused by the lack of definite intervention studies demonstrating that lowering Lp(a) reduces hard CVD endpoints, a lack of effective medications for lowering Lp(a), the highly variable Lp(a) concentrations among different ethnic groups and the challenges associated with Lp(a) measurement. Here, we present our view on when to measure Lp(a) and how to deal with elevated Lp(a) levels in moderate and high-risk individuals.

The potential of mipomersen, an ApoB synthesis inhibitor, to reduce necessity for LDL-apheresis in patients with heterozygous familial hypercholesterolemia and coronary artery disease

Introduction: LDL-apheresis is a treatment option for familial hypercholesterolemia (FH) with country-specific thresholds for LDL-cholesterol (LDL-C) for initiation. Apheresis also reduces lipoprotein(a) [Lp(a)] and may be used to lower Lp(a) in high-risk patients. Mipomersen, an apolipoproteinB-synthesis-inhibitor, reduces LDL-C and Lp(a). We hypothesized that mipomersen may prevent the necessity for apheresis by reducing the both below thresholds.Methods: Data from a study in 123 patients with heterozygous FH and coronary artery disease on maximally tolerated lipid-lowering therapy were used to evaluate in what percentage adding mipomersen resulted in lipid-levels below apheresis-thresholds. Different thresholds were tested: LDL-C ≥ 2.59 mmol/l, ≥ 3.36 mmol/l, ≥ 4.14 mmol/l, Lp(a) ≥ 60 mg/dl.Results: Mipomersen decreased LDL-C by 28% (baseline 153 mg/dl), Lp(a) by 21% (baseline 45 mg/dl) (placebo no effect). Mipomersen reduced the percentage of patients with LDL-C ≥ 4.14 mmol/l from 39 to 2%, with LDL ≥ 3.36 mmol/l from 62 to 16%, with LDL ≥ 2.59 mmol/l from 98 to 54%, and with Lp(a) ≥ 60 mg/dl from 39 to 23%.Summary: When added to maximally tolerated lipid-lowering therapy, mipomersen may reduce the necessity for apheresis in many of these patients. In Germany, the threshold for apheresis for LDL typically is 2.59 mmol/l, for Lp(a) 60 mg/dl. Almost 50% of the patients could avoid apheresis with the addition of mipomersen. Further studies are warranted to evaluate whether patients who qualify for apheresis could be adequately controlled with mipomersen.

Structure design of refractive index sensor based on LPFG with double-layer coatings

Based on the coupled-mode theory, the mode transition and transmittance of LP modes in an LPFG with double-layer coatings are studied theoretically. As a refractive index sensor, this LPFG structure is designed for high sensitivity by selecting a suitable thickness and refractive index of the double-layer coatings. Date simulation indicates that the effective index of the LP cladding mode increases in steps with the first coating thickness, thus LP mode is guided to the overlay and the mode transition takes place, where the LP modes can be easily affected by the ambient. Thereby, the coated LPFG sensor should be designed to operate at the transition region. In addition, the effective refractive index of LP cladding modes also increases in steps with the refractive index of the second overlay. For the higher order LP modes, the transition regions are broaden and the dynamic responses are greater than the lower LP modes, which means the higher order LP modes can be used for lower index overlay sensing. Further, the transmittance spectrum, sensitivity and measurable dynamic range of this LPFG are analyzed. The sensitivity of the LPFG sensor is available to $$10^{3}$$ with suitable overlay thickness and measurable dynamic range of the sensitive film refractive index is available to $$10^{-2}$$ . So the presented LPFG sensor enhances the design flexibility and enlarges the scope of application, which will likely be developed for high sensitivity LPFG sensors.

Hyperlipoproteinemia(a): Clinical significance and treatment options

Recent epidemiologic and Mendelian randomization studies together have provided evidence that lipoprotein(a) (Lp(a)) plays a causal role in the pathogenesis of atherosclerosis and cardiovascular disease (CVD). The risk association with CVD is weak but seems continuous in shape and without an obvious threshold for Lp(a) levels. A plasma concentration of 60 mg/dl compared to usual levels is associated with an odds ratio for coronary heart disease of about 1.5 after adjustment for other cardiovascular risk factors. Niacin (nicotinic acid) is the pharmacologic means of choice for decreasing elevated Lp(a) levels but the drug is often poorly tolerated due to adverse reactions. Dietary measures, exercise and other lipid-lowering drugs, especially statins, fibrates and ezetimibe, are without effect. In patients with severe progressive cardiovascular disease and very high Lp(a) levels, lipoprotein apheresis may be used to effectively decrease Lp(a) concentrations. The method is expensive and impractical for most patients and its feasibility depends by and large on the healthcare reimbursement system of the respective country. No established treatment, however, selectively reduces Lp(a) without influencing other lipoproteins. Moreover, despite the clear association of hyperlipoproteinemia(a) with cardiovascular risk, no rigorously designed study to date has demonstrated that lowering Lp(a) concentrations has beneficial effects on cardiovascular endpoints. Randomized trials to this effect are urgently needed.

Flexural Rigidity of Actin Bundles Propelled by Heavy Meromyosin

Assembly and reorganization of cytoskeletal networks during cell growth and motility rely on dynamic bundling of actin filaments (F-actin) through actin binding proteins. Fascin is an actin-bundling protein in filopodia that serves as cross-linker for the bundling of F-actin with all filaments having the same polarity. It is possible that actin-binding proteins, such as fascin and myosin, modify the mechanical and structural properties of F-actin per se. In order to test this hypothesis for phalloidin-labeled F-actin and actin bundles, we here measured the persistence length (Lp; proportional to bending stiffness) in solution and from the trajectory of bundles transported by heavy meromyosin in the in vitro motility assay. The numerical value of Lp was obtained from the relationship: =exp(-s/(2∗Lp)), where theta(0) and theta(s) represent the tangent angle for the filament contour-length s in solution or for sliding direction at onset and after distance s along a trajectory in the in vitro motility assay. Measuring the thermal fluctuations in solution, we found Lp values for actin bundles at 2:1 actin:fascin molar ratio (66.0±10.9 μm, N=40; mean ± 95% confidence interval) appreciably larger than for F-actin (8.3±0.8 μm, N=67). Similar to data in solution, Lp for sliding paths of fascin-mediated actin bundles was significantly larger than for F-actin and increased with a reduced actin:fascin ratio. Thus, Lp=28.3±2.3 μm (N=63), 42.4±3.0 μm (N=83) and 77.3±4.7 μm (N=91) at actin:fascin molar ratios of 4:1, 2:1 and 1.2:1, respectively, as compared with F-actin (Lp=7.6±1.0, N=28) in the same set of experiments. The results suggest qualitative similarity of bundles and F-actin with lower Lp in motility assays than measured in solution. The underlying mechanisms are considered in relation to motor induced structural changes in actin filament structure and mechanisms of fascin bundling.

Dimensional Optimization of Nanowire—Complementary Metal Oxide–Semiconductor Inverter

This study is the first to demonstrate dimensional optimization of nanowire-complementary metal-oxide-semiconductor inverter. Noise margins and inflection voltage of transfer characteristics are used as limiting factors in this optimization. Results indicate that optimization depends on both dimensions ratio and digital voltage level (Vdd). Diameter optimization reveals that when Vdd increases, the optimized value of (Dp/Dn) decreases. Channel length optimization results show that when Vdd increases, the optimized value of Ln decreases and that of (Lp/Ln) increases. Dimension ratio optimization reveals that when Vdd increases, the optimized value of Kp/Kn decreases, and silicon nanowire transistor with suitable dimensions (higher Dp and Ln with lower Lp and Dn) can be fabricated.

Emerging therapeutic agents to lower lipoprotein (a) levels

Recent epidemiological and genetic studies have suggested that lipoprotein (a) [Lp(a)] is a causal mediator of cardiovascular disease (CVD). There is now interest in evaluating Lp(a) as a therapeutic target. This review will summarize emerging therapeutic agents to lower Lp(a). Apheresis is the most efficacious method to lower Lp(a). Currently, there are no approved drugs to specifically lower Lp(a). However, recent data has demonstrated that Lp(a) can be significantly lowered, along with reductions in other apolipoprotein B-100 (apoB) containing lipoproteins, with antisense oligonucleotides to apoB, monoclonal antibodies to proprotein convertase subtilisin/kexin type 9, cholesterol ester transfer protein inhibitors, and thyromimetics. The farnesoid X receptor/fibroblast growth factor axis and interleukin-6 also influence Lp(a) levels and may be targets of therapy. Finally, specific apolipoprotein (a) [apo(a)] inhibitors apo(a) have been developed and reduce apo(a) mRNA and protein levels up to 86% without significantly affecting other lipoproteins. Lp(a) remains the last major lipoprotein disorder without any specific therapy. With the strong and accumulating data on its role as a causal risk factor for CVD, a rationale exists to develop novel agents to reduce Lp(a) and test the hypothesis that this will lead to reduced CVD events.

Lipoprotein apheresis in isolated hyperlipoproteinemia(a): a validated treatment or an illusion of validity?

Lipoprotein apheresis in isolated hyperlipoproteinemia(a): a validated treatment or an illusion of validity?

Abstract 18582: Correlation Between Reductions in LDL-cholesterol, Apolipoprotein B, and Lipoprotein(a) with Mipomersen in FH and Other Hypercholesterolemic Patients at High Risk for Coronary Disease

Introduction: Familial hypercholesterolemia (FH) is characterized by markedly elevated LDL-cholesterol (LDL-c) and, if untreated, premature atherosclerosis. Current treatment modalities are directed toward lowering LDL-c, although other atherogenic lipoproteins such as lipoprotein(a) [Lp(a)] are also considered independent causal risk factors for CHD. Lp(a) levels are about 2-fold higher in FH patients. However the LDL receptor is probably not the major route of Lp(a) clearance as statin therapy does not lower Lp(a). As Apo B is an integral component of Lp(a), inhibiting Apo B would be expected to reduce Lp(a) levels. Methods : We evaluated the relationship between the reduction in LDL-c, Apo B, and Lp(a) levels in patients with FH or hypercholesterolemia at high risk for CHD (N=256)and already receiving maximum tolerated lipid-lowering therapy, following treatment with mipomersen, an antisense Apo B synthesis inhibitor. Results: Table shows the absolute and percent changes in lipoprotein parameters pre/post mipomersen 200mg SC weekly for 26 weeks.Percent reductions in LDL-c and Apo B pre/post treatment were tightly correlated (r =0.95, p<0.0001). There was also a positive, but moderate, linear correlation between the percent reductions in Apo B and Lp(a) pre/post treatment (r =0.43, p<0.0001 ). Conclusion: Inhibiting Apo B synthesis with mipomersen reduced not only LDL-c and Apo B, but also Lp(a), and therefore represents a novel potential approach to reducing all three of these atherogenic lipid fractions. *LDL-c and Apo B results are in mean (SD) and Lp(a) in median (CI)

Lipoprotein(a): resurrected by genetics

Plasma lipoprotein(a) [Lp(a)] is a quantitative genetic trait with a very broad and skewed distribution, which is largely controlled by genetic variants at the LPA locus on chromosome 6q27. Based on genetic evidence provided by studies conducted over the last two decades, Lp(a) is currently considered to be the strongest genetic risk factor for coronary heart disease (CHD). The copy number variation of kringle IV in the LPA gene has been strongly associated with both Lp(a) levels in plasma and risk of CHD, thereby fulfilling the main criterion for causality in a Mendelian randomization approach. Alleles with a low kringle IV copy number that together have a population frequency of 25-35% are associated with a doubling of the relative risk for outcomes, which is exceptional in the field of complex genetic phenotypes. The recently identified binding of oxidized phospholipids to Lp(a) is considered as one of the possible mechanisms that may explain the pathogenicity of Lp(a). Drugs that have been shown to lower Lp(a) have pleiotropic effects on other CHD risk factors, and an improvement of cardiovascular endpoints is up to now lacking. However, it has been established in a proof of principle study that lowering of very high Lp(a) by apheresis in high-risk patients with already maximally reduced low-density lipoprotein cholesterol levels can dramatically reduce major coronary events.

Lipoprotein(a) and cardiovascular disease in diabetic patients.

Lipoprotein(a) (Lp[a]) is a LDL-like particle consisting of an ApoA moiety linked to one molecule of ApoB(100). Recent data from large-scale prospective studies and genetic association studies provide highly suggestive evidence for a potentially causal role of Lp(a) in affecting risk of cardiovascular disease (CVD) in general populations. Patients with Type 2 diabetes display clustered metabolic abnormalities and elevated risk of CVD. Lower plasma Lp(a) levels were observed in diabetic patients in several recent studies. Epidemiology studies of Lp(a) and CVD risk in diabetic patients generated inconsistent results. We recently found that Lp(a)-related genetic markers did not predict CVD in two diabetic cohorts. The current data suggest that Lp(a) may differentially affect cardiovascular risk in diabetic patients and in the general population. More prospective studies, Mendelian randomization analysis and functional studies are needed to clarify the causal relationship of Lp(a) and CVD in diabetic patients.

Inhibition of Apolipoprotein(a) Synthesis by Farnesoid X Receptor and Fibroblast Growth Factor 15/19

Lipoprotein(a), or Lp(a), is a plasma lipoprotein that accumulates in concentrations ranging from undetectable to as high as 200 mg/dL, mostly depending on the synthesis rate of its unique protein, apo(a), which consists of multiple repetitions of kringle IV, type 2 of plasminogen.1 Additionally, plasma levels of Lp(a) are inversely proportional to the size of the apo(a) isoform, which is genetically determined.2 Considering that cholesterol represents about one fifth of the particle, Lp(a) can be equivalent to an extra 40 mg/dL of low-density lipoprotein (LDL) cholesterol in some individuals. The complex is the result of a covalent association between apoB100 and the function-free apo(a). The size of this lipoprotein ranges from that of a large high-density lipoprotein (HDL) to that of a small remnant depending on its triglyceride content. It is an apoB-containing lipoprotein and therefore viewed as an atherogenic particle. Because apo(a) does not form Lp(a) in murine plasma, development of a transgenic mouse model has required the concomitant expression of human apo(a) and apoB100.3 Apo(a) binds via a single disulfide bridge to the carboxyl-terminus of apoB100 and thus cannot associate with chylomicrons, which only contain apoB48.4 Also, apo(a) preferentially binds apoB100 of LDL-sized particles, although the linkage between the 2 proteins is likely to take place on the surface of hepatocytes, which produce exclusively VLDL-sized particles.5 On the clearance front, Lp(a) does not bind to the LDL receptor, and only modest increases in Lp(a) levels are seen in patients with familial hypercholesterolemia.6 This means that cholesterol-lowering agents acting more or less directly via upregulation of the LDL receptor (statins, resins, and cholesterol absorption inhibitors) have modest to no effects or may even raise plasma Lp(a) levels.7–9 Other agents, such as fibrates and niacins, share similar lipid-modulating effects (decreasing triglycerides, …

Lipoprotein(a)

Lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease; we highlight the most recent research initiatives that have sought to define Lp(a)-dependent pathogenicity as well as pharmacologic approaches to lowering Lp(a). Recent large-scale meta-analyses have confirmed elevated Lp(a) concentrations to be a moderate but consistent prospective coronary heart disease (CHD) risk factor. The Mendelian randomization approach has also associated LPA variants with Lp(a) concentration and CHD risk. Discoveries linking Lp(a) to oxidized phospholipid burden have implicated a proinflammatory role for Lp(a) hinting at a new mechanism underlying the association with CHD risk, which adds to previous atherogenic and thrombogenic mechanisms. Most existing Lp(a)-lowering drug treatments almost always show simultaneous effects on other lipoproteins, making it difficult to assign any clinical outcome specifically to the effects of Lp(a) lowering. Early experiments with antisense oligonucleotides targeting apolipoprotein(a) mRNA seem to indicate the pleiotropic effects of Lp(a) reduction on LDL and HDL in mice. The mechanism linking Lp(a) concentration with concentrations of other blood lipids remains unknown but may provide an insight into Lp(a) metabolism. Despite the wealth of epidemiologic evidence supporting Lp(a) concentration as a CHD risk factor, the lack of a definitive functional mechanism involving an Lp(a)-dependent pathway in CHD pathogenesis has limited the potential clinical connotation of Lp(a). However, the application of novel technologies to the long-standing mysteries of Lp(a) biology seems to provide the opportunity for expanding our understanding of Lp(a) and its complex role in cardiovascular health.

Polymorphism of the CD36 Gene and Cardiovascular Risk Factors in Patients with Coronary Artery Disease Manifested at a Young Age

This study investigates potential associations between CD36 gene variants and the presence of risk factors in Caucasians with coronary artery disease (CAD) manifested at a young age. The study group consisted of 90 patients; the men were ≤ 50 years old and the women were ≤ 55 years old. Amplicons of exons 4 and 5 including fragments of introns were analyzed by DHPLC. Two polymorphisms were found: IVS3-6 T/C (rs3173798) and IVS4-10 G/A (rs3211892). The C allele of the IVS3-6 T/C polymorphism was associated with higher prevalence of obesity and diabetes, higher hsCRP, lower Lp(a) serum concentrations, and younger age at myocardial infarction. The A allele of the IVS4-10 G/A polymorphism was associated with older age of myocardial infarction and higher white blood cell count. The functional role of CD36 polymorphisms in CAD development needs further research.

Survival Advantage of Normal Weight in Peritoneal Dialysis Patients

Introduction: A high body mass index (BMI) is a positive predictor of outcome in hemodialysis. But reports for peritoneal dialysis (PD) have been less numerous. The aim of the present investigation was to study the association between BMI and survival among PD patients and to discuss the main risk factors affecting survival. Materials and methods: A total of 159 patients who received PD from 1 January 2006 to 31 December 2010 at the Department of Nephrology in the Third Affiliated Hospital of Soochow University were enrolled in the study. Blood samples and baseline characteristics of the study cohort were obtained at the start of PD. Patient survival status was recorded through 31 December 2010. Results: Patients were stratified into two groups as normal weight (BMI, 18.5–24.9) and overweight (BMI, 25.0–29.9). Kaplan–Meier survival curve revealed that the normal weight patients had survival advantage over overweight patients (p < 0.01, by log-rank test). Cox proportional hazard models revealed that BMI, age, diabetes mellitus, coronary vascular disease, congestive heart failure and lipoprotein(a) (Lp(a)) were significant risk factors associated with all-cause mortality (p < 0.05). After adjustment for these covariates, survival was consistently higher for normal weight patients (p < 0.01). Furthermore, the study demonstrated that normal weight patients had lower serum Lp(a) (p < 0.05), C-reactive protein (CRP) (p < 0.05), and peritonitis rate (p < 0.05) compared with overweight patients. Conclusion: The results indicated that normal BMI at the commencement of PD had significant survival advantage in our study. The mechanisms for this might be related to lower cardiovascular risk, less chronic inflammation, and peritonitis prevalence.

Association between the Interleukin-6 Promoter Polymorphism −174G/C and Serum Lipoprotein(a) Concentrations in Humans

BackgroundLipoprotein(a) [Lp(a)] is an independent risk factor for cardiovascular disease. The interleukin-6 (IL-6) receptor antagonist tocilizumab has been shown to lower serum Lp(a) concentrations. We investigated whether the IL-6 single nucleotide polymorphism −174G/C is associated with baseline serum Lp(a) concentrations.Methodology/Principal FindingsWe divided 2321 subjects from the Lipid Analytic Cologne (LIANCO) cohort into 2 groups, the ones with substantially elevated Lp(a), defined as concentrations ≥60 mg/dl (n = 510), and the ones with Lp(a) <60 mg/dl (n = 1811). The association with the genotypes GG (33.7%), GC (50.75%) and CC (15.55%) was investigated. The GC and the CC genotype were associated with a significantly increased odds ratio of having substantially elevated Lp(a) concentrations (OR = 1.3, 95% CI 1.04 to 1.63, P = 0.02 and OR = 1.44, 95% CI 1.06 to 1.93, P = 0.018). These associations remained significant after adjusting for age, sex, smoking behavior, body mass index, serum lipoproteins, hypertension and diabetes. Of these covariates, only LDL cholesterol was significantly and independently associated with elevated Lp(a) concentrations.Conclusions/SignificanceThe IL-6 single nucleotide polymorphism −174G/C is associated with increased odds of having elevated Lp(a). Whether this association plays a role in the Lp(a)-lowering effects of IL-6 receptor antagonists remains to be established.

Increased Intraatrial Conduction Abnormality Assessed by P‐Wave Signal‐Averaged Electrocardiogram in Patients with Brugada Syndrome

Atrial fibrillation (AF) is observed in patients with Brugada syndrome (BS), especially those showing coved-type electrocardiogram (ECG) pattern. Using P-wave signal-averaged ECG (P-SAE), we investigated whether increased intraatrial conduction abnormality contributed to AF generation in BS patients. Twenty BS patients and 20 age- and gender-matched healthy controls were enrolled. At the P-SAE recording, 12 of the 20 BS patients showed coved-type (C-BS) and eight showed saddleback-type (S-BS). The total duration (Ad) and root mean square voltage for the terminal 20 ms (LP(20) ) of the filtered P wave were measured. P-wave dispersion (P-disp) was defined as the difference between the maximum and minimum, measured from 16 precordial recording sites. BS patients had a significantly longer Ad (128.2 ± 7.6 vs 116.3 ± 8.2 ms, P < 0.0001), lower LP(20) (2.6 ± 0.9 vs 3.4 ± 0.8 μV, P < 0.01), and greater P-disp (15.5 ± 7.0 vs 7.4 ± 3.2 ms, P < 0.0001) than the controls. C-BS patients had significantly longer Ad (131.0 ± 7.2 vs 124.1 ± 6.8 ms, P < 0.05) and lower LP(20) (2.2 ± 0.6 vs 3.2 ± 1.0 μV, P < 0.05) than S-BS patients. All C-BS patients and only three S-BS patients had atrial late potential (100% vs 38%, P < 0.01). Intraatrial conduction delay and its heterogeneity may exist in BS patients, especially those showing coved-type ECG patterns. These atrial electrical abnormalities could be a substrate for atrial reentrant tachycardia such as AF.

Correlation between fractional flow reserve and intravascularultrasound lumen area in intermediate coronary artery stenosis

Clinical trials testing proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have demonstrated an unanticipated but significant lipoprotein (a) (Lp(a))-lowering effect, on the order of 25% to 30%. Although the 50% to 60% reduction in low-density lipoprotein (LDL)-cholesterol (LDL-C) achieved by PCSK9i is mediated through its effect on LDL receptor (LDLR) preservation, the mechanism for Lp(a) lowering is unknown.We sought to characterize the degree of concordance between LDL-C and Lp(a) lowering because of PCSK9i in a standard of care patient cohort.Participants were selected from our Center for Preventive Cardiology, an outpatient referral center in a tertiary academic medical center. Subjects were included in this study if they had (1) at least 1 measurement of LDL-C and Lp(a) before and after initiation of the PCSK9i; (2) baseline Lp(a) > 10 mg/dL; and (3) continued adherence to PCSK9i therapy. They were excluded if (1) they were undergoing LDL apheresis; (2) pre- or post-PCSK9i LDL-C or Lp(a) laboratory values were censored; or (3) subjects discontinued other lipid-modifying therapies. In total, 103 subjects were identified as taking a PCSK9i and 26 met all inclusion and exclusion criteria. Concordant response to therapy was defined as an LDL-C reduction >35% and an Lp(a) reduction >10%.The cohort consisted of 26 subjects (15 females, 11 males, mean age 63 ± 12 years). Baseline mean LDL-C and median Lp(a) levels were 167.4 ± 72 mg/dL and 81 mg/dL (interquartile range 38–136 mg/dL), respectively. The average percent reductions in LDL-C and Lp(a) were 52.8% (47.0–58.6) and 20.2% (12.2–28.1). The correlation between %LDL and %Lp(a) reduction was moderate, with a Spearman's correlation of 0.56 (P < .01). All subjects except for 1 had a protocol-appropriate LDL-C response to therapy. However, only 16 of the 26 (62%; 95% confidence interval 41%–82%) subjects had a protocol-concordant Lp(a) response. Although some subjects demonstrated negligible Lp(a) reduction associated with PCSK9i, there were some whose Lp(a) decreased as much as 60%.In this standard-of-care setting, we demonstrate moderate correlation but large discordance (∼40%) in these 2 lipid fractions in response to PCSK9i. The results suggest that pathways beyond the LDLR are responsible for Lp(a) lowering and indicate that PCSK9i have the potential to significantly lower Lp(a) in select patients, although confirmation in larger multicenter studies is required.