Search

Compelling evidence supports a causal role for lipoprotein(a) (Lp(a)) in cardiovascular disease. No pharmacotherapies directly targeting Lp(a) are currently available for clinical use. Here we report the discovery and development of olpasiran, a first-in-class, synthetic, double-stranded, N-acetylgalactosamine-conjugated small interfering RNA (siRNA) designed to directly inhibit LPA messenger RNA translation in hepatocytes and potently reduce plasma Lp(a) concentration. Olpasiran reduced Lp(a) concentrations in transgenic mice and cynomolgus monkeys in a dose-responsive manner, achieving up to over 80% reduction from baseline for 5-8 weeks after administration of a single dose. In a phase 1 dose-escalation trial of olpasiran (ClinicalTrials.gov: NCT03626662 ), the primary outcome was safety and tolerability, and the secondary outcomes were the change in Lp(a) concentrations and olpasiran pharmacokinetic parameters. Participants tolerated single doses of olpasiran well and experienced a 71-97% reduction in Lp(a) concentration with effects persisting for several months after administration of doses of 9 mg or higher. Serum concentrations of olpasiran increased approximately dose proportionally. Collectively, these results validate the approach of using hepatocyte-targeted siRNA to potently lower Lp(a) in individuals with elevated plasma Lp(a) concentration.

BACKGROUND Lipoprotein(a) is a presumed risk factor for atherosclerotic cardiovascular disease. Olpasiran is a small interfering RNA that reduces lipoprotein(a) synthesis in the liver. METHODS We conducted a randomized, double-blind, placebo-controlled, dose-finding trial involving patients with established atherosclerotic cardiovascular disease and a lipoprotein(a) concentration of more than 150 nmol per liter. Patients were randomly assigned to receive one of four doses of olpasiran (10 mg every 12 weeks, 75 mg every 12 weeks, 225 mg every 12 weeks, or 225 mg every 24 weeks) or matching placebo, administered subcutaneously. The primary end point was the percent change in the lipoprotein(a) concentration from baseline to week 36 (reported as the placebo-adjusted mean percent change). Safety was also assessed. RESULTS Among the 281 enrolled patients, the median concentration of lipoprotein(a) at baseline was 260.3 nmol per liter, and the median concentration of low-density lipoprotein cholesterol was 67.5 mg per deciliter. At baseline, 88% of the patients were taking statin therapy, 52% were taking ezetimibe, and 23% were taking a proprotein convertase subtilisin-kexin type 9 (PCSK9) inhibitor. At 36 weeks, the lipoprotein(a) concentration had increased by a mean of 3.6% in the placebo group, whereas olpasiran therapy had significantly and substantially reduced the lipoprotein(a) concentration in a dose-dependent manner, resulting in placebo-adjusted mean percent changes of -70.5% with the 10-mg dose, -97.4% with the 75-mg dose, -101.1% with the 225-mg dose administered every 12 weeks, and -100.5% with the 225-mg dose administered every 24 weeks (P

Objectives:It is uncertain if long-term levels of low-density lipoprotein-cholesterol (LDL-C) affect cognition in middle age. We examined the association of LDL-C levels over 25 years with cognitive function in a prospective cohort of black and white US adults.Methods:Lipids were measured at baseline (1985–1986; age: 18–30 years) and at serial examinations conducted over 25 years. Time-averaged cumulative LDL-C was calculated using the area under the curve for 3,328 participants with ≥3 LDL-C measurements and a cognitive function assessment. Cognitive function was assessed at the Year 25 examination with the Digit Symbol Substitution Test [DSST], Rey Auditory Visual Learning Test [RAVLT], and Stroop Test. A brain magnetic resonance imaging (MRI) sub-study (N = 707) was also completed at Year 25 to assess abnormal white matter tissue volume (AWMV) and gray matter cerebral blood flow volume (GM-CBFV) as secondary outcomes.Results:There were 15.6%, 32.9%, 28.9%, and 22.6% participants with time-averaged cumulative LDL-C SD lower to 0.09 SD higher across time-averaged LDL-C categories in comparison to those with LDL-C < 100 mg/dL. After covariate adjustment, participants with higher versus lower time-averaged LDL-C had a lower RAVLT score (p-trend = 0.02) but no differences were present for DSST, Stroop Test, AWMV, or GM-CBFV.Conclusion:Cumulative LDL-C was associated with small differences in memory, as assessed by RAVLT scores, but not other cognitive or brain MRI measures over 25 years of follow-up.

BACKGROUND Data support lipoprotein(a) (Lp[Lp(a)]) being a risk factor for atherosclerotic cardiovascular disease (ASCVD). Olpasiran is a small interfering RNA molecule that markedly reduces Lp(a) production in hepatocytes. STUDY DESIGN The Olpasiran trials of Cardiovascular Events And lipoproteiN(a) reduction-DOSE finding study is a multicenter, randomized, double-blind, placebo-controlled dose-finding study in 281 subjects with established ASCVD and Lp(a) > 150 nmol/L. Patients were randomly allocated to one of 4 active subcutaneous doses of olpasiran (10 mg q12 weeks, 75 mg q12 weeks, 225 mg q 12 weeks, or 225 mg q24 weeks) or matched placebo. The primary objective is to evaluate the effects of olpasiran dosed every 12 weeks compared with placebo on the percent change in Lp(a) from baseline at 36 weeks. Enrollment is now complete and follow-up is ongoing. CONCLUSIONS OCEAN(a)-DOSE trial is assessing the Lp(a)-lowering efficacy and safety of olpasiran. These data will be used to determine optimal dosing and design for a cardiovascular outcomes trial.

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

On-treatment levels of high sensitivity C-reactive protein (hsCRP) in statin-treated patients predict plaque progression and the prospective risk of atherosclerotic cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produce additional LDL-C lowering, reduce plaque burden and improve cardiovascular outcomes in statin-treated patients. It is unknown whether residual systemic inflammation attenuates their favorable effects on plaque burden.GLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis in statin-treated patients with coronary artery disease.Clinical demographics, biochemistry and changes in both the burden (percentage atheroma volume (PAV), total atheroma volume (TAV), n ​= ​413) and composition (n ​= ​162) of coronary plaque were evaluated in evolocumab-treated patients according to baseline hsCRP strata (1, 1-3,3 ​mg/L).The study cohort comprised 413 evolocumab-treated patients (32% low [1 ​mg/L], 41% intermediate [1-3 ​mg/L] and 27% high [3 ​mg/L] baseline hsCRP levels). Patients in the highest hsCRP stratum were more likely to be female and had a higher prevalence of diabetes, hypertension, and the metabolic syndrome. LDL-C levels were similar across the groups, however participants with higher hsCRP levels had higher triglyceride and lower HDL-C levels at baseline. At follow-up, the change in PAV from baseline (-0.87% [low] vs. -0.84% [intermediate] vs. -1.22% [high], p ​= ​0.46) and the proportion of patients experiencing any degree of regression (65.9% vs. 63.5% vs. 63.1%, p ​= ​0.88) was similar across hsCRP strata and when evaluated by levels of achieved LDL-C. There were no serial differences in plaque composition by hsCRP strata.The ability of evolocumab to induce regression in statin-treated patients is not attenuated by the presence of enhanced systemic inflammation. This underscores the potential benefits of intensive lipid lowering, even in the presence of heightened inflammatory states.

Introduction: Mendelian and epidemiological randomization studies have identified lipoprotein(a) [Lp(a)] as a risk factor for myocardial infarction and other atherosclerotic events. There are currently no approved medicines that selectively target Lp(a) and have demonstrated reduction in CV events. AMG 890 is a siRNA designed to reduce the production of Lp(a) by targeting mRNA transcribed from the LPA gene. Methods: This phase 1 study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of AMG 890. Adults with plasma concentrations of Lp(a) ≥ 70 to ≤ 199 nmol/L (cohorts 1-5), and ≥ 200 nmol/L (cohorts 6-7), were randomized 3:1 to receive a single subcutaneous dose of investigational product (IP; AMG 890 or placebo). The primary endpoints were treatment-emergent adverse events (TEAEs), safety laboratory analytes, vital signs and ECGs. Secondary endpoints included PK parameters and percent reduction from baseline in Lp(a). Results: 64 subjects were administered IP (cohorts 1-5: AMG 890, n=30, doses: 3 mg, 9 mg, 30 mg, 75 mg, 225 mg; placebo, n=10; cohorts 6-7: AMG 890, n=18, doses: 9 mg and 75 mg; placebo, n=6). The most common TEAEs were headache (10% AMG 890; 25% placebo) and upper respiratory tract infection (15% AMG 890; 13% placebo); no safety concerns were identified for AMG 890. In cohorts 1-5, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 71-96% (based on doses) at Day 43, and by 80-94% at Day 113 (cohorts 2-5). In cohorts 6 and 7, single doses of AMG 890 effectively reduced mean Lp(a) levels from baseline by 75% and 89% at Day 43, respectively, and by 61% and 80% at Day 113, respectively. Conclusions: In adults with elevated Lp(a), single-dose treatment of AMG 890 was well-tolerated and significantly reduced Lp(a) with observed maximal percent reductions of > 90% and effects persisting for more than 6 months at doses of 9 mg or higher.

Background: Incremental low-density lipoprotein (LDL) cholesterol lowering with the proprotein convertase subtilisin kexin type 9 inhibitor evolocumab regresses coronary atherosclerosis in statin-treated patients. Objectives: The purpose of this study was to evaluate the effect of adding evolocumab to statin therapy on coronary plaque composition. Methods: A total of 968 statin-treated coronary artery disease patients underwent serial coronary intravascular ultrasound imaging at baseline and following 76 weeks of treatment with placebo or evolocumab 420 mg monthly. Plaque composition changes were determined in 331 patients with evaluable radiofrequency analysis of the ultrasound backscatter signal. Results: Compared with statin monotherapy, evolocumab further reduced LDL cholesterol (33.5 mg/dl vs. 89.9 mg/dl; p < 0.0001) and induced regression of percent atheroma volume (−1.2% vs. +0.17%; p < 0.0001) and total atheroma volume (−3.6 mm3 vs. −0.8 mm3; p = 0.04). No difference was observed between the evolocumab and placebo groups in changes in calcium (1.0 ± 0.3 mm3 vs. 0.6 ± 0.3 mm3; p = 0.49), fibrous (−3.0 ± 0.6 mm3 vs. −2.4 ± 0.6 mm3; p = 0.49), fibrofatty (−5.0 ± 1.0 mm3 vs. −3.0 ± 1.0 mm3; p = 0.49), and necrotic (−0.6 ± 0.5 mm3 vs. −0.1 ± 0.5 mm3; p = 0.49) volumes. An inverse correlation was observed between changes in LDL cholesterol and plaque calcification (r = −0.15; p < 0.001). Conclusions: The addition of evolocumab to a statin did not produce differential changes in plaque composition compared with statin monotherapy. This suggests that evaluation of plaque morphology using virtual histology imaging may provide no incremental information about the plaque effects of evolocumab beyond measurement of plaque burden. (GLobal Assessment of Plaque reGression With a PCSK9 antibOdy as Measured by intraVascular Ultrasound [GLAGOV]; NCT01813422)

Background Beyond their potent LDL (low‐density lipoprotein) cholesterol ( LDL ‐C)–lowering efficacy (50–60%), PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors also reduce Lp(a) (lipoprotein[a]) levels by 25% to 30%, suggesting a 2:1 response ratio. We aimed to characterize the relationship between LDL ‐C and Lp(a) lowering by evolocumab, a PCSK 9 inhibitor, in a large clinical trial population and to determine the prevalence of concordant/discordant LDL ‐C and Lp(a) responses to PCSK 9 inhibition. Methods and Results Data were analyzed from 4 randomized, 12‐week, multicenter, phase 3 evolocumab trials. Patients with familial hypercholesterolemia, nonfamilial hypercholesterolemia, or statin intolerance participated in the trials. The main measure was the degree of concordance or discordance of LDL ‐C and Lp(a) in response to PCSK 9 inhibition; concordant response was defined as LDL ‐C reduction >35% and Lp(a) reduction >10%. The study cohort comprised 895 patients (438 female; median age: 59.0 years [interquartile range: 51–66 years]). Baseline mean level of LDL ‐C was 133.6 mg/dL (SE: 1.7) and median Lp(a) level was 46.4 mg/dL (interquartile range: 18.4–82.4 mg/dL). A discordant response was observed in 165 (19.7%) patients. With these cutoffs, the prevalence of discordance was higher when considering baseline Lp(a) concentrations >30 mg/dL (26.5%) or >50 mg/dL (28.6%). Conclusions We demonstrate high prevalence of discordance in LDL ‐C and Lp(a) reduction in response to evolocumab, particularly when considering higher baseline Lp(a) concentrations, indicating the possibility of alternative pathways beyond LDLR ( LDL receptor)–mediated clearance involved in Lp(a) reduction by evolocumab. Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01763827, NCT 01763866, NCT 01763905, NCT 01763918.

Statin-mediated low-density lipoprotein cholesterol (LDL-C) lowering fails to prevent more than half of cardiovascular events in clinical trials. Serial plaque imaging studies have highlighted the benefits of aggressive LDL-C lowering, with plaque regression evident in up to two-thirds of patients with achieved LDL-C levels

Objective: On-treatment levels of high sensitivity C-reactive protein (hsCRP) in statin-treated patients predict plaque progression and the prospective risk of atherosclerotic cardiovascular events. Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors produce additional LDL-C lowering, reduce plaque burden and improve cardiovascular outcomes in statin-treated patients. It is unknown whether residual systemic inflammation attenuates their favorable effects on plaque burden. Methods: GLAGOV compared the effects of treatment for 78 weeks with evolocumab or placebo on progression of coronary atherosclerosis in statin-treated patients with coronary artery disease.Clinical demographics, biochemistry and changes in both the burden (percentage atheroma volume (PAV), total atheroma volume (TAV), n ​= ​413) and composition (n ​= ​162) of coronary plaque were evaluated in evolocumab-treated patients according to baseline hsCRP strata (3 ​mg/L). Results: The study cohort comprised 413 evolocumab-treated patients (32% low [3 ​mg/L] baseline hsCRP levels). Patients in the highest hsCRP stratum were more likely to be female and had a higher prevalence of diabetes, hypertension, and the metabolic syndrome. LDL-C levels were similar across the groups, however participants with higher hsCRP levels had higher triglyceride and lower HDL-C levels at baseline. At follow-up, the change in PAV from baseline (−0.87% [low] vs. −0.84% [intermediate] vs. −1.22% [high], p ​= ​0.46) and the proportion of patients experiencing any degree of regression (65.9% vs. 63.5% vs. 63.1%, p ​= ​0.88) was similar across hsCRP strata and when evaluated by levels of achieved LDL-C. There were no serial differences in plaque composition by hsCRP strata. Conclusion: The ability of evolocumab to induce regression in statin-treated patients is not attenuated by the presence of enhanced systemic inflammation. This underscores the potential benefits of intensive lipid lowering, even in the presence of heightened inflammatory states.

To review the efficacy, safety, pharmacology, and pharmacokinetics of evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor. PCSK9 inhibitors are a class of lipid-lowering agents that significantly reduce low-density lipoprotein cholesterol (LDL-C) levels in patients with atherosclerotic cardiovascular disease and hyperlipidemia. Evolocumab is a monoclonal antibody that inhibits PCSK9 and has been evaluated in phase II and III studies as monotherapy, in combination with statins and other lipid-lowering therapies, in patients who are statin intolerant, and in patients with heterozygous and homozygous familial hypercholesterolemia. Data from these studies show that evolocumab significantly reduces LDL-C levels. Treatment with evolocumab also significantly improves levels of other lipid parameters (e.g., apolipoproteins A1 and B, lipoprotein(a), non–high-density lipoprotein cholesterol, and triglycerides). Recent results indicate that LDL-C reduction with evolocumab significantly reduces the risk of cardiovascular events and is also associated with atherosclerotic plaque regression. From a safety standpoint, rates of adverse events (AEs), serious AEs, and AEs leading to discontinuation were similar between evolocumab and controls in clinical trials, and no increase in AEs was observed when evolocumab was used in combination with statins. Patients with elevated LDL-C benefit from evolocumab treatment, suggesting that evolocumab could help meet an unmet medical need in high-risk patient populations with atherosclerotic cardiovascular disease and hyperlipidemia that are unable to reduce LDL-C levels sufficiently with statin therapy alone.

Aims Subjects with lipoprotein(a) [Lp(a)] elevation have increased arterial wall inflammation and cardiovascular risk. In patients at increased cardiovascular risk, arterial wall inflammation is reduced following lipid-lowering therapy by statin treatment or lipoprotein apheresis. However, it is unknown whether lipid-lowering treatment in elevated Lp(a) subjects alters arterial wall inflammation. We evaluated whether evolocumab, which lowers both low-density lipoprotein cholesterol (LDL-C) and Lp(a), attenuates arterial wall inflammation in patients with elevated Lp(a). Methods and results In this multicentre, randomized, double-blind, placebo-controlled study, 129 patients {median [interquartile range (IQR)]: age 60.0 [54.0–67.0] years, Lp(a) 200.0 [155.5–301.5] nmol/L [80.0 (62.5–121.0) mg/dL]; mean [standard deviation (SD)] LDL-C 3.7 [1.0] mmol/L [144.0 (39.7) mg/dL]; National Cholesterol Education Program high risk, 25.6%} were randomized to monthly subcutaneous evolocumab 420 mg or placebo. Compared with placebo, evolocumab reduced LDL-C by 60.7% [95% confidence interval (CI) 65.8–55.5] and Lp(a) by 13.9% (95% CI 19.3–8.5). Among evolocumab-treated patients, the Week 16 mean (SD) LDL-C level was 1.6 (0.7) mmol/L [60.1 (28.1) mg/dL], and the median (IQR) Lp(a) level was 188.0 (140.0–268.0) nmol/L [75.2 (56.0–107.2) mg/dL]. Arterial wall inflammation [most diseased segment target-to-background ratio (MDS TBR)] in the index vessel (left carotid, right carotid, or thoracic aorta) was assessed by 18F-fluoro-deoxyglucose positron-emission tomography/computed tomography. Week 16 index vessel MDS TBR was not significantly altered with evolocumab (−8.3%) vs. placebo (−5.3%) [treatment difference −3.0% (95% CI −7.4% to 1.4%); P = 0.18]. Conclusion Evolocumab treatment in patients with median baseline Lp(a) 200.0 nmol/L led to a large reduction in LDL-C and a small reduction in Lp(a), resulting in persistent elevated Lp(a) levels. The latter may have contributed to the unaltered arterial wall inflammation.

Background: Evolocumab significantly lowers low-density lipoprotein cholesterol (LDL-C) when dosed 140 mg every 2 weeks (Q2W) or 420 mg monthly (QM) subcutaneously. Hypothesis: LDL-C changes are comparable among different patient subgroups in a pooled analysis of data from phase 3 trials. Methods: A total of 3146 patients received ≥1 dose of evolocumab or control in four 12-week phase 3 studies. Percent change from baseline in LDL-C for evolocumab 140 mg Q2W or 420 mg QM vs control was reported as the average of week 10 and 12 values. Quantitative and qualitative interactions between treatment group and subgroup by dose regimen were tested. Results: In the pooled analysis, treatment differences vs placebo or ezetimibe were similar for both 140 mg Q2W and 420 mg QM doses across ages (

Background Evolocumab, a fully human monoclonal antibody against PCSK9, significantly reduced low-density lipoprotein-cholesterol (LDL-C) levels in Japanese patients by up to 76% when administered with a statin. We evaluated the efficacy and safety of 1 year of evolocumab in a pooled analysis of patients from the 12-week YUKAWA studies who continued into the open-label extension (OLE) OSLER studies.Methods and Results:YUKAWA-1 and YUKAWA-2 were conducted in hypercholesterolemic, high-cardiovascular-risk Japanese patients who were receiving statin therapy. Patients completing these studies were eligible for an OLE study. At OLE entry, patients were re-randomized 2:1 to evolocumab+standard of care (SOC) or SOC alone (OSLER-1: evolocumab 420 mg monthly; OSLER-2: evolocumab 140 mg biweekly or 420 mg monthly). A 1-year analysis was performed on patients enrolled from the YUKAWA studies into OSLER. At parent-study baseline (YUKAWA-1 or YUKAWA-2 patients continuing into OSLER), mean (SD) age was 61 (10) years; 39% were female; mean (SD) baseline LDL-C (on statin) was 119.7 (33.0) mg/dL. Overall rates of adverse events were comparable between evolocumab+SOC and SOC alone. In YUKAWA patients receiving evolocumab+SOC, mean (SE) reductions in LDL-C from parent-study baseline to OLE 1 year were 69.1% (1.2%; OSLER-1) and 65.1% (2.2%; OSLER-2). Conclusions In a pooled 1-year analysis of Japanese patients in the ongoing OSLER studies, treatment with evolocumab+SOC was well tolerated and resulted in sustained LDL-C reductions at 1 year.

The Open-Label Study of Long-term Evaluation Against LDL-C (OSLER-1) evaluated the durability of long-term efficacy and safety during long-term therapy with evolocumab, a monoclonal antibody against proprotein convertase subtilisin/kexin type 9 (PCSK9).To determine whether LDL-C level reductions with evolocumab persist across different populations. Secondary objectives included assessment of adverse events, antidrug antibodies, and factors contributing to treatment discontinuation.This ongoing, randomized open-label extension trial (OSLER-1) was conducted at 192 sites in 18 countries. A total of 1324 of 1666 patients randomized into 1 of 5 12-week double-blind phase 2 parent studies completed a parent study and chose to participate in OSLER-1; 1255 received 1 or more evolocumab doses. As of August 2016, 812 of 1324 (61%) had 208 weeks of follow-up. This current study was conducted from October 2011 to August 2016, with a data cutoff of August 26, 2016.During year 1, patients were randomized to evolocumab, 420 mg, plus standard of care (SOC) or SOC alone. After year 1, all patients continuing the study received evolocumab, 420 mg, plus SOC.Lipids, safety, and tolerability every 12 weeks. A multivariate model identified factors associated with discontinuation of evolocumab.At parent study baseline, the mean (SD) age of the population was 57.1 (11.6) years, with 52.9% being women. The median LDL-C level was 133 mg/dL (to convert to millimoles per liter, multiply by 0.0259). After 52 weeks, evolocumab plus SOC was associated with a significant reduction in LDL-C level by 61% (95% CI, -63% to -60%) vs 2% (95% CI, -5% to -0.2%) with SOC alone (P .001). At approximately 2, 3, and 4 years of study follow-up, the median LDL-C level was reduced by 59% (95% CI, -60% to -57%), 59% (95% CI, -61% to -58%), and 57% (95% CI, -59% to -55%), respectively, from parent study baseline. For patients receiving statin therapy unchanged from baseline, at week 208, the median LDL-C level reduction was 58%. No neutralizing antibodies to evolocumab were detected. The annualized incidence of new-onset diabetes was 4% in the SOC alone group and, adjusting for duration of evolocumab exposure, 2.8% in the evolocumab plus SOC group. Neurocognitive event rates were 0% (SOC alone) and 0.4% (evolocumab plus SOC). A total of 79% of patients persisted with evolocumab treatment, with a mean exposure duration of 44 months.In the longest clinical trial exposure to a PCSK9 inhibitor to date, evolocumab produced sustained reductions in LDL-C levels. The annual frequency of adverse events did not occur more frequently with cumulative exposure during open-label observation.clinicaltrials.gov Identifier: NCT01439880.

Objective Evidence from coronary imaging studies suggests an association between increased atherosclerotic plaque burden and cardiovascular disease (CVD) outcomes. A systematic review was performed to evaluate the relationship between coronary atherosclerotic plaque burden changes measured by intravascular ultrasound (IVUS) and CVD outcomes. Research design and methods Rigorous systematic review methodology was used to identify prospective studies of any design assessing the relationship between atherosclerotic plaque volume (percentage or total atheroma volume [PAV or TAV]) changes and CVD outcomes, using multivariable analyses. Main outcome measures CVD outcomes including major adverse cardiac events (MACEs) and major adverse cardiac and cerebrovascular events (MACCEs). Results Literature searches from inception to February 2015 retrieved 6958 records after de-duplication. From these four studies (14 papers) were included. One study reported a significantly lower rate of CVD outcomes associated with a greater reduction in PAV (hazard ratio [HR] 0.26, 95% confidence interval [CI] 0.07-0.83). One study reported that large plaque volume was significantly associated with a greater risk of major adverse cardiac events (MACEs) (HR 1.73, 95% CI: 1.02-2.96). Similarly, a third study reported a significant increase in MACE with an increase in baseline PAV (HR 1.51, 95% CI: 1.06-2.51). Only one potentially inadequately powered Japanese study did not find a statistically significant relationship between PAV changes and MACE. Conclusions The current evidence suggests an independent and statistically significant association between increases in coronary atherosclerotic plaque burden measured by IVUS and greater long-term risk of future CVD outcomes. However, this evidence comes from a limited number of studies which mainly focus on Japanese populations and populations after PCI. Further large prospective studies are required to confirm these findings.

Reducing levels of low-density lipoprotein cholesterol (LDL-C) with intensive statin therapy reduces progression of coronary atherosclerosis in proportion to achieved LDL-C levels. Proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitors produce incremental LDL-C lowering in statin-treated patients; however, the effects of these drugs on coronary atherosclerosis have not been evaluated. To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients. The GLAGOV multicenter, double-blind, placebo-controlled, randomized clinical trial (enrollment May 3, 2013, to January 12, 2015) conducted at 197 academic and community hospitals in North America, Europe, South America, Asia, Australia, and South Africa and enrolling 968 patients presenting for coronary angiography. Participants with angiographic coronary disease were randomized to receive monthly evolocumab (420 mg) (n = 484) or placebo (n = 484) via subcutaneous injection for 76 weeks, in addition to statins. The primary efficacy measure was the nominal change in percent atheroma volume (PAV) from baseline to week 78, measured by serial intravascular ultrasonography (IVUS) imaging. Secondary efficacy measures were nominal change in normalized total atheroma volume (TAV) and percentage of patients demonstrating plaque regression. Safety and tolerability were also evaluated. Among the 968 treated patients (mean age, 59.8 years [SD, 9.2]; 269 [27.8%] women; mean LDL-C level, 92.5 mg/dL [SD, 27.2]), 846 had evaluable imaging at follow-up. Compared with placebo, the evolocumab group achieved lower mean, time-weighted LDL-C levels (93.0 vs 36.6 mg/dL; difference, -56.5 mg/dL [95% CI, -59.7 to -53.4]; P

Achieved CRP levels associate with plaque progression and cardiovascular events in statin-treated patients. It is unknown whether CRP levels modulate the ability of the PCSK9 inhibitor, evolocumab, to regress coronary atherosclerosis. GLAGOV compared the effects of treatment for 78 weeks with

There is genetic and epidemiological evidence demonstrating the association between Lp(a) levels and cardiovascular disease. While evolocumab reduces Lp(a) by 25-30%, the impact of PCSK9 inhibition on plaque at different Lp(a) levels is unknown. GLAGOV compared the effects of the PCSK9 inhibitor

The proprotein convertase subtilisin kexin type 9 (PCSK9) inhibitor, evolocumab, promotes regression of coronary atherosclerosis in statin-treated patients. It is unknown whether there are gender related differences in this treatment effect. GLAGOV compared the effects of treatment for 78 weeks

Levels of non-HDL-C reflect the total circulating pool of atherogenic lipid factors and have been associated with ongoing plaque progression on statin treatment. It is unknown whether these levels modulate the degree of regression observed with addition of a proprotein convertase subtilisin kexin

Primary cardiac tumors are far rarer than tumors metastatic to the heart. Angiosarcoma is the primary cardiac neoplasm most frequently detected; lymphomas constitute only 1% of primary cardiac tumors. We present the case of a 55-year-old woman with a recently diagnosed intracardiac mass who was referred to our institution for consideration of urgent orthotopic heart transplantation. Initial images suggested an angiosarcoma; however, a biopsy specimen of the mass was diagnostic for diffuse large B-cell lymphoma. The patient underwent chemotherapy rather than surgery, and she was asymptomatic 34 months later. We use our patient's case to discuss the benefits and limitations of multiple imaging methods in the evaluation of cardiac masses. Certain features revealed by computed tomography, cardiac magnetic resonance, and positron emission tomography can suggest a diagnosis of angiosarcoma rather than lymphoma. Cardiac magnetic resonance and positron emission tomography enable reliable distinction between benign and malignant tumors; however, the characteristics of different malignant tumors can overlap. Despite the great usefulness of multiple imaging methods for timely diagnosis, defining the extent of spread and the hemodynamic impact, and monitoring responses to treatment, we think that biopsy analysis is still warranted in order to obtain a correct histologic diagnosis in cases of suspected malignant cardiac tumors.

GATA transcription factors bind the consensus sequence WGATAR, present in the flanking regions of most erythroid specific genes. GATA-1 and GATA-2, coexpressed in erythroid cells, are important for expression of erythroid genes. To elucidate the role of specific GATA transcription factors on globin gene expression, we examined the human alpha- and beta-globin gene clusters for all GATA sites. Conserved GATA sites were found in each of the hypersensitive sites in both beta-and alpha clusters and in proximal regulatory regions of the zeta-, epsilon- and gamma-globin but not the alpha, delta or beta-globin genes. We then tested the effect of increasing levels of GATA-1 and GATA-2 on the expression of endogenous globin genes in human erythroid cells. Increasing GATA-1 levels in K562 cells decreased the levels of epsilon-globin mRNA but had no effect on the levels of expression of gamma, zeta or alpha-globin genes. Increasing GATA-2 levels increased epsilon-globin and gamma-globin transcripts. Increasing levels of GATA-1 also caused a decrease in the expression of endogenous GATA-2, while increased levels of GATA-2 had no effect on GATA-1 mRNA. Our results indicate a differential role of GATA-1 and -2 transcription factors on globin transcripts and suggest a correlation between the conservation of GATA sites in the regulatory regions and the ability of endogenous globin genes to respond to GATA transcription factors. They also suggest that quantitative changes in the levels of GATA-1 or GATA-2 can result in alterations of globin target gene expression and may participate in the ontogenic control of the globin genes.

Background Cardiac tumors are rare, with estimated prevalence of 0.002-0.3% at autopsy. Symptoms and prognosis of cardiac tumors depend on size, location, and intrinsic aggressiveness. Cardiac magnetic resonance (CMR) imaging is non-invasive and offers unsurpassed soft-tissue characterization. In this study, we sought to examine the CMR imaging of various cardiac tumors and identify radiologic features of clinical relevance for diagnosis, prognosis, and treatment of the patients.

Nickel-dependent recognition and oxidation of guanine have been linked in part through the paramagnetic effects of nickel on the NMR of model oligonucleotide duplexes. Direct interaction between nickel and guanine N7 had originally been postulated from correlations between the efficiency of guanine oxidation and the environment surrounding its N7 position. (1)H and (31)P NMR spectra of DNA containing a single, isolated extrahelical guanine are consistent with selective binding of nickel to the N7 of this unique base over a background of nonspecific association to the phosphate backbone. The presence of a macrocyclic complex or simple salt of nickel did not detectably alter the structure of the duplex or extrahelical residue. Accordingly, nickel appeared to bind the extrahelical guanine N7 within the major groove as indicated by paramagnetic effects on the proton signals of nucleotides on the 5' but not 3' side of the nickel binding site. Similar (1)H NMR analysis of DNA containing a dynamic equilibrium of extrahelical guanine residues also suggested that the nickel complex did not affect the native distribution of structures. Oxidation of these sites by a nickel-mediated pathway consequently reflected their solvent accessibility in a general and metal-independent manner. The close proximity of the extrahelical guanines produced a composite of paramagnetic effects on each adjacent nucleotide resulting from both direct and proximal coordination of nickel.