Caprin-1 binding to the critical stress granule protein G3BP1 is influenced by pH.

G3BP is the central node within stress-induced protein-RNA interaction networks known as stress granules (SGs). The SG-associated proteins Caprin-1 and USP10 bind mutually exclusively to the NTF2 domain of G3BP1, promoting and inhibiting SG formation, respectively. Herein, we present the crystal structure of G3BP1-NTF2 in complex with a Caprin-1-derived short linear motif (SLiM). Caprin-1 interacts with His-31 and His-62 within a third NTF2-binding site outside those covered by USP10, as confirmed using biochemical and biophysical-binding assays. Nano-differential scanning fluorimetry revealed reduced thermal stability of G3BP1-NTF2 at acidic pH. This destabilization was counterbalanced significantly better by bound USP10 than Caprin-1. The G3BP1/USP10 complex immunoprecipated from human U2OS cells was more resistant to acidic buffer washes than G3BP1/Caprin-1. Acidification of cellular condensates by approximately 0.5 units relative to the cytosol was detected by ratiometric fluorescence analysis of pHluorin2 fused to G3BP1. Cells expressing a Caprin-1/FGDF chimera with higher G3BP1-binding affinity had reduced Caprin-1 levels and slightly reduced condensate sizes. This unexpected finding may suggest that binding of the USP10-derived SLiM to NTF2 reduces the propensity of G3BP1 to enter condensates.

Concentration dynamics of polychlorinated biphenyls and organochlorine pesticides in blood of growing Grey heron (Ardea cinerea) chicks in the wild.

Organochlorine contaminants (OCs) - organochlorine pesticides (OCPs) and industrial products and byproducts - are included in different monitoring programmes and surveys, involving various animal species. Fish-eating birds are suitable indicator species for OCs. Adult birds may be difficult to capture, but chicks can be sampled more easily. Blood of birds is a potentially suitable non-destructive matrix for analysis, as OC levels in blood reflect their concentrations in the body. The study was aimed at investigating how age of fast-growing Grey heron (Ardea cinerea) chicks affects contaminant levels in their blood and thus how important is sampling at exact age for biomonitoring purposes. In 1999 on Lake Engure in Latvia whole blood samples of heron chicks were collected at three different time points, with seven and nine days in between the first and second and second and third sampling points, respectively. Twenty-two chicks were sampled at all three times. In total, 102 samples were analysed for 19 polychlorinated biphenyl (PCB) congeners, DDT metabolites - DDE and DDD, hexachlorobenzene (HCB), α-, ß-, γ-hexachlorocyclohexane (HCH), and trans-nonachlor. Total PCB concentrations averaged around 2000 ng/g dry extracted matter (EM). DDE was the dominant individual contaminant (ca. 800 ng/g EM), followed by CB-153, -138, and -118. Most of the other analysed OCs were below 100 ng/g EM. No significant (p > 0.05) differences in OC concentrations were found between the three sampling occasions, except for trans-nonachlor. This means that blood can safely be sampled for biomonitoring purposes during the 17 days' time window. The analysed legacy contaminants may serve as model substances for other persistent organic pollutants.

Surgical repair of diastasis recti abdominis provides long-term improvement of abdominal core function and quality of life: a 3-year follow-up.

BACKGROUND: Diastasis recti abdominis (DRA) is a condition affecting many post-partum women. The aim of this study was to evaluate long-term results of surgical repair of DRA in a cohort of post-partum women. METHODS: Sixty post-partum women with DRA and training-resistant core dysfunctions were included. Surgical repair was performed with suture plication of the linea alba. Abdominal core function was evaluated with the abdominal trunk function protocol (ATFP) including a self-report questionnaire and seven functional tests. Urinary incontinence and quality of life were evaluated with the Urogenital Distress Inventory (UDI-6), the Incontinence Impact Questionnaire (IIQ-7) and the SF-36 questionnaire. Follow-up was performed at 1 and 3 years after surgery. RESULTS: Response rate at the 3-year follow-up was 86.7 per cent for the disability rating index (DRI) questionnaire; and 71.7 per cent for the ATFP, UDI-6, IIQ-7 and SF-36 questionnaires. All DRI parameters were improved (P < 0.001) after 3 years of follow-up compared with preoperative values. The functional tests in the ATFP showed an improvement in core muscle strength and stability (P < 0.001), back muscle strength (P < 0.001) and abdominal muscle strength (P = 0.002) compared to preoperative values as well as an improvement of core muscle strength and stability compared with the 1-year follow-up values (P = 0.003). UDI-6 and IIQ-7 results were improved (P < 0.001 and P = 0.004) compared with preoperative values and showed consistent values compared with the 1-year follow-up (P = 0.09 and P = 1.0). Quality of life measured with SF-36 was improved compared with preoperative values and showed consistent values compared with the 1-year follow-up. CONCLUSION: The functional improvement of surgical reconstruction of the DRA persisted for 3 years in this series of post-partum women with DRA.

Fed-batch production assessment of a tetravalent bispecific antibody: A case study on piggyBac stably transfected HEK293 cells.

The transition from preclinical biological drug development into clinical trials requires an efficient upscaling process. In this context, bispecific antibody drugs are particularly challenging due to their propensity to form aggregates and generally produce low titers. Here, the upscaling process for a tetravalent bispecific antibody expressed by a piggyBac transposon-mediated stable HEK293 cell pool has been evaluated. The project was performed as a case study at Testa Center, a non-GMP facility for scale-up testing of biologics in Sweden, and encompassed media adaptation strategies, fed-batch optimization and a novel antibody purification technology. The cell pool was adapted to different culture media for evaluation in terms of cell viability and titers compared to its original Expi293 Expression Medium. These parameters were assessed in both sequential stepwise adaption and direct media exchanges. By this, a more affordable medium was identified that did not require stepwise adaptation and with similar titers and viability as in the Expi293 Expression Medium. Fed-batch optimizations resulted in culture densities reaching up to 20 × 106 viable cells/mL with over 90 % viability 12 days post-inoculum, and antibody titers three times higher than corresponding batch cultures. By implementing a novel high-speed protein A fiber technology (Fibro PrismA) with a capture residence time of only 7.5 s, 8 L of supernatant could be purified in 4.5 h without compromising the purity, structural integrity and function of the bispecific antibody. Results from this study related to medium adaptation and design of fed-batch protocols will be highly beneficial during the forthcoming scale-up of this therapeutic antibody.

[Are triglyceride rich lipoproteins more dangerous than LDL cholesterol?] / Triglyceridrika lipoproteiner ­ farligare än LDL-kolesterol?

Two prospective epidemiological studies have pointed to the importance of triglyceride rich lipoproteins in causing atherosclerosis. Lipoprotein analyses show that it is the cholesterol content of the lipoproteins that relates to atherosclerotic cardiovascular disease. As high blood levels of these lipoproteins are mostly seen in obese people changes in lifestyle seem to be the most relevant therapeutic measure.

Management of diastasis of the rectus abdominis muscles: recommendations for swedish national guidelines.

BACKGROUND: Diastasis of the rectus abdominis muscle is a common condition. There are no generally accepted criteria for diagnosis or treatment of diastasis of the rectus abdominis muscle, which causes uncertainty for the patient and healthcare providers alike. METHODS: The consensus document was created by a group of Swedish surgeons and based on a structured literature review and practical experience. RESULTS: The proposed criteria for diagnosis and treatment of diastasis of the rectus abdominis muscle are as follows: (1) Diastasis diagnosed at clinical examination using a caliper or ruler for measurement. Diagnostic imaging by ultrasound or other imaging modality, should be performed when concurrent umbilical or epigastric hernia or other cause of the patient's symptoms cannot be excluded. (2) Physiotherapy is the firsthand treatment for diastasis of the rectus abdominis muscle. Surgery should only be considered in diastasis of the rectus abdominis muscle patients with functional impairment, and not until the patient has undergone a standardized 6-month abdominal core training program. (3) The largest width of the diastasis should be at least 5 cm before surgical treatment is considered. In case of pronounced abdominal bulging or concomitant ventral hernia, surgery may be considered in patients with a smaller diastasis. (4) When surgery is undertaken, at least 2 years should have elapsed since last childbirth and future pregnancy should not be planned. (5) Plication of the linea alba is the firsthand surgical technique. Other techniques may be used but have not been found superior. DISCUSSION: The level of evidence behind these statements varies, but they are intended to lay down a standard strategy for treatment of diastasis of the rectus abdominis muscle and to enable uniformity of management.

[Prevention of cardiovascular disease needs longer-term perspective]. / Kardiovaskulär prevention bör ha längre perspektiv.

Non-HDL cholesterol concentrations in blood are strongly associated with long-term risk of atherosclerotic cardiovascular disease. A simple tool has been provided for assessment of individual long-term risk and the potential benefit of early lipid-lowering intervention.

Dalcetrapib Reduces Risk of New-Onset Diabetes in Patients With Coronary Heart Disease.

OBJECTIVE: Incident type 2 diabetes is common among patients with recent acute coronary syndrome and is associated with an adverse prognosis. Some data suggest that cholesteryl ester transfer protein (CETP) inhibitors reduce incident type 2 diabetes. We compared the effect of treatment with the CETP inhibitor dalcetrapib or placebo on incident diabetes in patients with recent acute coronary syndrome. RESEARCH DESIGN AND METHODS: In the dal-OUTCOMES trial, 15,871 patients were randomly assigned to treatment with dalcetrapib 600 mg daily or placebo, beginning 4-12 weeks after an acute coronary syndrome. Absence of diabetes at baseline was based on medical history, no use of antihyperglycemic medication, and hemoglobin A1c and serum glucose levels below diagnostic thresholds. Among these patients, incident diabetes after randomization was defined by any diabetes-related adverse event, new use of antihyperglycemic medication, hemoglobin A1c ≥6.5%, or a combination of at least two measurements of serum glucose ≥7.0 mmol/L (fasting) or ≥11.1 mmol/L (random). RESULTS: At baseline, 10,645 patients (67% of the trial cohort) did not have diabetes. During a median follow-up of 30 months, incident diabetes was identified in 403 of 5,326 patients (7.6%) assigned to dalcetrapib and in 516 of 5,319 (9.7%) assigned to placebo, corresponding to absolute risk reduction of 2.1%, hazard ratio of 0.77 (95% CI 0.68-0.88; P < 0.001), and a need to treat 40 patients for 3 years to prevent 1 incident case of diabetes. Considering only those with prediabetes at baseline, the number needed to treat for 3 years to prevent 1 incident case of diabetes was 25. Dalcetrapib also decreased the number of patients who progressed from normoglycemia to prediabetes and increased the number who regressed from diabetes to no diabetes. CONCLUSIONS: In patients with a recent acute coronary syndrome, incident diabetes is common and is reduced substantially by treatment with dalcetrapib.

Association of high-density lipoprotein particle concentration with cardiovascular risk following acute coronary syndrome: A case-cohort analysis of the dal-Outcomes trial.

BACKGROUND: High-density lipoprotein cholesterol (HDL-C) concentration is inversely related to risk of major adverse cardiovascular events (MACE) in epidemiologic studies but is a poorer predictor of MACE in patients with established coronary heart disease. HDL particle concentration (HDLP) has been proposed as a better predictor of risk. We investigated whether HDLP is associated with risk of MACE after acute coronary syndrome (ACS). METHODS: The dal-Outcomes trial compared the CETP inhibitor dalcetrapib with placebo in patients with recent ACS. In a nested case-cohort analysis, total, large, medium, and small HDLPs were measured by nuclear magnetic resonance spectroscopy at baseline (4-12 weeks after ACS) in 476 cases with MACE and 902 controls. Hazard ratios (HRs; case-control) for 1-SD increment of HDLP or HDL-C at baseline were calculated with and without adjustment for demographic, clinical, laboratory, and treatment variables. Similarly, HRs for MACE were calculated for changes in HDLP or HDL-C from baseline to month 3 of assigned treatment. RESULTS: Over median follow-up of 28 months, the risk of MACE was not associated with baseline HDLP (adjusted HR = 0.98, 95% CI = 0.84-1.15, P = .81), any HDLP subclass, or HDL-C. Dalcetrapib increased HDL-C and total, medium, and large HDLP and decreased small HDLP but had no effect on MACE compared with placebo. There were no association of risk of MACE with change in HDLP or HDL-C and no interaction with assigned study treatment. CONCLUSIONS: Neither baseline HDLP nor the change in HDLP on treatment with dalcetrapib or placebo was associated with risk of MACE after ACS.

Epigenome- and Transcriptome-wide Changes in Muscle Stem Cells from Low Birth Weight Men.

Background: Being born with low birth weight (LBW) is a risk factor for muscle insulin resistance and type 2 diabetes (T2D), which may be mediated by epigenetic mechanisms programmed by the intrauterine environment. Epigenetic mechanisms exert their prime effects in developing cells. We hypothesized that muscle insulin resistance in LBW subjects may be due to early differential epigenomic and transcriptomic alterations in their immature muscle progenitor cells.Results: Muscle progenitor cells were obtained from 23 healthy young adult men born at term with LBW, and 15 BMI-matched normal birth weight (NBW) controls. The cells were subsequently cultured and differentiated into myotubes. DNA and RNA were harvested before and after differentiation for genome-wide DNA methylation and RNA expression measurements.After correcting for multiple comparisons (q ≤ 0.05), 56 CpG sites were found to be significantly, differentially methylated in myoblasts from LBW compared with NBW men, of which the top five gene-annotated CpG sites (SKI, ARMCX3, NR5A2, NEUROG, ESRRG) previously have been associated to regulation of cholesterol, fatty acid and glucose metabolism and muscle development or hypertrophy. LBW men displayed markedly decreased myotube gene expression levels of the AMPK-repressing tyrosine kinase gene FYN and the histone deacetylase gene HDAC7. Silencing of FYN and HDAC7 was associated with impaired myotube formation, which for HDAC7 reduced muscle glucose uptake.Conclusions: The data provides evidence of impaired muscle development predisposing LBW individuals to T2D is linked to and potentially caused by distinct DNA methylation and transcriptional changes including down regulation of HDAC7 and FYN in their immature myoblast stem cells.

Efficacy and Safety of Evolocumab in Chronic Kidney Disease in the FOURIER Trial.

BACKGROUND: Data on PCSK9 inhibition in chronic kidney disease (CKD) is limited. OBJECTIVES: The purpose of this study was to compare outcomes with evolocumab and placebo according to kidney function. METHODS: The FOURIER (Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk) trial randomized individuals with clinically evident atherosclerosis and low-density lipoprotein cholesterol (LDL-C) ≥70 mg/dl or non-high-density lipoprotein cholesterol ≥100 mg/dl to evolocumab or placebo. The primary endpoint (cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization), key secondary endpoint (cardiovascular death, myocardial infarction, or stroke), and safety were analyzed according to chronic kidney disease (CKD) stage estimated from CKD-epidemiology estimated glomerular filtration rate. RESULTS: There were 8,077 patients with preserved kidney function, 15,034 with stage 2 CKD, and 4,443 with ≥stage 3 CKD. LDL-C reduction with evolocumab compared with placebo at 48 weeks was similar across CKD groups at 59%, 59%, and 58%, respectively. Relative risk reduction for the primary endpoint was similar for preserved function (hazard ratio [HR]: 0.82; 95% CI: 0.71 to 0.94), stage 2 (HR: 0.85; 95% CI: 0.77 to 0.94), and stage ≥3 CKD (HR: 0.89; 95% CI: 0.76 to 1.05); pint = 0.77. Relative risk reduction for the secondary endpoint was similar across CKD stages (pint = 0.75)-preserved function (HR: 0.75; 95% CI: 0.62 to 0.90), stage 2 (HR: 0.82; 95% CI: 0.72 to 0.93), stage ≥3 (HR: 0.79; 95% CI: 0.65 to 0.95). Absolute RRs at 30 months for the secondary endpoint were -2.5% (95% CI: -0.4% to -4.7%) for stage ≥3 CKD compared with -1.7% (95% CI: 0.5% to -2.8%) with preserved kidney function. Adverse events, including estimated glomerular filtration rate decline, were infrequent and similar regardless of CKD stage. CONCLUSIONS: LDL-C lowering and relative clinical efficacy and safety of evolocumab versus placebo were consistent across CKD groups. Absolute reduction in the composite of cardiovascular death, MI, or stroke with evolocumab was numerically greater with more advanced CKD. (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]; NCT01764633).

PCSK9-hämmare kan minska total dödlighet - Resultat och konsekvenser av ODYSSEY-studien.

The ODYSSEY outcome study, including subjects with recent acute coronary syndrome on high dose statin therapy, investigated the effect of 75-150 mg alirocumab given subcutaneously every 2 weeks for 2,8 years in comparison with participants on alirocumab placebo Alirocumab decreased the risk of the primary endpoint coronary death, acute myocardial infarction, hospital admittance because of angina pectoris and ischaemic stroke by 15 percent, decreased the risk of total death by 15 percent and was safe and tolerable during the length of the study.

The Short-Form Inguinal Pain Questionnaire (sf-IPQ): An Instrument for Rating Groin Pain After Inguinal Hernia Surgery in Daily Clinical Practice.

BACKGROUND: The Inguinal Pain Questionnaire (IPQ) is a standardised and validated instrument for assessing persisting pain after groin hernia surgery. The IPQ is often perceived as being too extensive for routine use. The aim of this study was to develop and evaluate a condensed version of the IPQ in order to facilitate its use in daily clinical practice. METHODS: The condensed form, i.e. Short-Form Inguinal Pain Questionnaire (sf-IPQ), comprises two main items taken from the IPQ. Four hundred patients were recruited from the Swedish Hernia Register and were sent the IPQ, sf-IPQ and the Short-Form McGill Pain Questionnaire (SF-MPQ) three years after hernia repair. Ratings from the IPQ and the sf-IPQ were converted to a 12-point scale. The reported scores for the two shared items in the IPQ and sf-IPQ were compared using the Intraclass Correlation Coefficient (ICC), Cohen's kappa and McNemar's test. RESULTS: After two reminders, the response rate was 69.8% (n = 279/400). The ICC for the IPQ and sf-IPQ scores was 0.78 (95% confidence interval 0.73-0.82, p < 0.001). Cohen's kappa was 0.66 (95% confidence interval 0.55-0.77, p < 0.001). The sf-IPQ systematically indicated a higher pain score than the IPQ (p = 0.013). CONCLUSIONS: Despite the systematic difference in level of pain scored, correlation, consistency and agreement were seen between the IPQ and sf-IPQ. The forms appear to be interchangeable, though the sf-IPQ may be a more sensitive instrument. The condensed structure of the sf-IPQ is more user-friendly and shows promise as a useful tool in daily clinical practice.

Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.

BACKGROUND: Elevated lipoprotein(a) is a genetic risk factor for cardiovascular disease in general population studies. However, its contribution to risk for cardiovascular events in patients with established cardiovascular disease or on statin therapy is uncertain. METHODS: Patient-level data from seven randomised, placebo-controlled, statin outcomes trials were collated and harmonised to calculate hazard ratios (HRs) for cardiovascular events, defined as fatal or non-fatal coronary heart disease, stroke, or revascularisation procedures. HRs for cardiovascular events were estimated within each trial across predefined lipoprotein(a) groups (15 to <30 mg/dL, 30 to <50 mg/dL, and ≥50 mg/dL, vs <15 mg/dL), before pooling estimates using multivariate random-effects meta-analysis. FINDINGS: Analyses included data for 29 069 patients with repeat lipoprotein(a) measurements (mean age 62 years [SD 8]; 8064 [28%] women; 5751 events during 95 576 person-years at risk). Initiation of statin therapy reduced LDL cholesterol (mean change -39% [95% CI -43 to -35]) without a significant change in lipoprotein(a). Associations of baseline and on-statin treatment lipoprotein(a) with cardiovascular disease risk were approximately linear, with increased risk at lipoprotein(a) values of 30 mg/dL or greater for baseline lipoprotein(a) and 50 mg/dL or greater for on-statin lipoprotein(a). For baseline lipoprotein(a), HRs adjusted for age and sex (vs <15 mg/dL) were 1·04 (95% CI 0·91-1·18) for 15 mg/dL to less than 30 mg/dL, 1·11 (1·00-1·22) for 30 mg/dL to less than 50 mg/dL, and 1·31 (1·08-1·58) for 50 mg/dL or higher; respective HRs for on-statin lipoprotein(a) were 0·94 (0·81-1·10), 1·06 (0·94-1·21), and 1·43 (1·15-1·76). HRs were almost identical after further adjustment for previous cardiovascular disease, diabetes, smoking, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The association of on-statin lipoprotein(a) with cardiovascular disease risk was stronger than for on-placebo lipoprotein(a) (interaction p=0·010) and was more pronounced at younger ages (interaction p=0·008) without effect-modification by any other patient-level or study-level characteristics. INTERPRETATION: In this individual-patient data meta-analysis of statin-treated patients, elevated baseline and on-statin lipoprotein(a) showed an independent approximately linear relation with cardiovascular disease risk. This study provides a rationale for testing the lipoprotein(a) lowering hypothesis in cardiovascular disease outcomes trials. FUNDING: Novartis Pharma AG.

Gestational diabetes and maternal obesity are associated with epigenome-wide methylation changes in children.

Offspring of women with gestational diabetes mellitus (GDM) are at increased risk of developing metabolic disease, potentially mediated by epigenetic mechanisms. We recruited 608 GDM and 626 control offspring from the Danish National Birth Cohort, aged between 9 and 16 years. DNA methylation profiles were measured in peripheral blood of 93 GDM offspring and 95 controls using the Illumina HumanMethylation450 BeadChip. Pyrosequencing was performed for validation/replication of putative GDM-associated, differentially methylated CpGs in additional 905 offspring (462 GDM, 444 control offspring). We identified 76 differentially methylated CpGs in GDM offspring compared with controls in the discovery cohort (FDR, P < 0.05). Adjusting for offspring BMI did not affect the association between methylation levels and GDM status for any of the 76 CpGs. Most of these epigenetic changes were due to confounding by maternal prepregnancy BMI; however, 13 methylation changes were independently associated with maternal GDM. Three prepregnancy BMI-associated CpGs (cg00992687 and cg09452568 of ESM1 and cg14328641 of MS4A3) were validated in the replication cohort, while cg09109411 (PDE6A) was found to be associated with GDM status. The identified methylation changes may reflect developmental programming of organ disease mechanisms and/or may serve as disease biomarkers.

Lipids Shape the Electron Acceptor-Binding Site of the Peripheral Membrane Protein Dihydroorotate Dehydrogenase.

The interactions between proteins and biological membranes are important for drug development, but remain notoriously refractory to structural investigation. We combine non-denaturing mass spectrometry (MS) with molecular dynamics (MD) simulations to unravel the connections among co-factor, lipid, and inhibitor binding in the peripheral membrane protein dihydroorotate dehydrogenase (DHODH), a key anticancer target. Interrogation of intact DHODH complexes by MS reveals that phospholipids bind via their charged head groups at a limited number of sites, while binding of the inhibitor brequinar involves simultaneous association with detergent molecules. MD simulations show that lipids support flexible segments in the membrane-binding domain and position the inhibitor and electron acceptor-binding site away from the membrane surface, similar to the electron acceptor-binding site in respiratory chain complex I. By complementing MS with MD simulations, we demonstrate how a peripheral membrane protein uses lipids to modulate its structure in a similar manner as integral membrane proteins.

Association of Lipoprotein(a) With Risk of Recurrent Ischemic Events Following Acute Coronary Syndrome: Analysis of the dal-Outcomes Randomized Clinical Trial.

Importance: It is uncertain whether lipoprotein(a) [Lp(a)], which is associated with incident cardiovascular disease, is an independent risk factor for recurrent cardiovascular events after acute coronary syndrome (ACS). Objective: To determine the association of Lp(a) concentration measured after ACS with the subsequent risk of ischemic cardiovascular events. Design, Setting, and Participants: This nested case-cohort analysis was performed as an ad hoc analysis of the dal-Outcomes randomized clinical trial. This trial compared dalcetrapib, the cholesteryl ester transfer protein inhibitor, with placebo in patients with recent ACS and was performed between April 2008 and September 2012 at 935 sites in 27 countries. There were 969 case patients who experienced a primary cardiovascular outcome, and there were 3170 control patients who were event free at the time of a case event and had the same type of index ACS (unstable angina or myocardial infarction) as that of the respective case patients. Concentration of Lp(a) was measured by immunoturbidimetric assay. Data analysis for this present study was conducted from June 8, 2016, to April 21, 2017. Interventions: Patients were randomly assigned to receive treatment with dalcetrapib, 600 mg daily, or matching placebo, beginning 4 to 12 weeks after ACS. Main Outcomes and Measures: Death due to coronary heart disease, a major nonfatal coronary event (myocardial infarction, hospitalization for unstable angina, or resuscitated cardiac arrest), or fatal or nonfatal ischemic stroke. Results: The mean (SD) age was 63 (10) years for the 969 case patients and 60 (9) years for the 3170 control patients, and both cohorts were composed of predominantly male (770 case patients [79%] and 2558 control patients [81%]; P = .40) and white patients (858 case patients [89%] and 2825 control patients [89%]; P = .62). At baseline, the median (interquartile range) Lp(a) level was 12.3 (4.7-50.9) mg/dL. There was broad application of evidence-based secondary prevention strategies after ACS, including use of statins in 4030 patients (97%). The cumulative distribution of baseline Lp(a) levels did not differ between cases and controls at P = .16. Case-cohort regression analysis showed no association of baseline Lp(a) level with risk of cardiovascular events. For a doubling of Lp(a) concentration, the hazard ratio (case to control) was 1.01 (95% CI, 0.96-1.06; P = .66) after adjustment for 16 baseline variables, including assigned study treatment. Conclusions and Relevance: For patients with recent ACS who are treated with statins, Lp(a) concentration was not associated with adverse cardiovascular outcomes. These findings call into question whether treatment specifically targeted to reduce Lp(a) levels would thereby lower the risk for ischemic cardiovascular events after ACS. Trial Registration: clinicaltrials.gov Identifier: NCT00658515.

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.