Abstract Elevated lipoprotein(a) (Lpa) is a causal genetic risk factor for cardiovascular disease. To determine if current evidence supports both screening and treatment for elevated Lp(a) in ...high-risk patients, an English-language search of PubMed and MEDLINE was conducted. In population studies, there is a continuous association between Lp(a) concentrations and cardiovascular risk, with synergistic effects when low-density lipoprotein (LDL) is also elevated. Candidates for Lp(a) screening include patients with a personal or family history of premature cardiovascular disease, familial hypercholesterolemia, recurrent cardiovascular events, or inadequate LDL cholesterol (LDL-C) responses to statins. Given the comparative strength of clinical evidence, reducing LDL-C to the lowest attainable value with a high-potency statin should be the primary focus of lipid-modifying therapies. If the Lp(a) level is 30 mg/dL or higher in a patient who has the aforementioned characteristics plus residual LDL-C elevations (≥70-100 mg/dL) despite maximum-potency statins or combination statin therapy, the clinician may consider adding niacin (up to 2 g/d). If, after these interventions, the patient has progressive coronary heart disease (CHD) or LDL-C levels of 160-200 mg/dL or higher, LDL apheresis should be contemplated. Although Lp(a) is a major causal risk factor for CHD, no currently available controlled studies have suggested that lowering it through either pharmacotherapy or LDL apheresis specifically and significantly reduces coronary risk. Further research is needed to (1) optimize management in order to reduce CHD risk associated with elevated Lp(a) and (2) determine what other intermediate- or high-risk groups might benefit from Lp(a) screening.
Myalgia, which often manifests as pain or soreness in skeletal muscles, is among the most salient adverse events associated with 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins). ...Clinical issues related to statin-associated myotoxicity include (1) incidence in randomized controlled trials and occurrence in postmarketing surveillance databases; (2) potential differences between statins in their associations with such adverse events; and (3) diagnostic and treatment strategies to prevent, recognize, and manage these events. Data from systematic reviews, meta-analyses, clinical and observational trials, and postmarketing surveillance indicate that statin-associated myalgia typically affects approximately 5.0% of patients, as myopathy in 0.1% and as rhabdomyolysis in 0.01%. However, studies also suggest that myalgia is among the leading reasons patients discontinue statins (particularly high-dose statin monotherapy) and that treatment with certain statins (eg, fluvastatin) is unlikely to result in such adverse events. This review presents a clinical algorithm for monitoring and managing statin-associated myotoxicity. The algorithm highlights risk factors for muscle toxicity and provides recommendations for (1) creatine kinase measurements and monitoring; (2) statin dosage reduction, discontinuation, and rechallenge; and (3) treatment alternatives, such as extended-release fluvastatin with or without ezetimibe, low-dose or alternate-day rosuvastatin, or ezetimibe with or without colesevelam. The algorithm should help to inform and enhance patient care and reduce the risk of myalgia and other potentially treatment-limiting muscle effects that might undermine patient adherence and compromise the overall cardioprotective benefits of statins.
Objectives To determine the relationship between non–high-density lipoprotein cholesterol (HDL-C) lowering and coronary heart disease (CHD) risk reduction for various lipid-modifying therapies. ...Background Non–HDL-C is the second lipid target of therapy after low-density lipoprotein cholesterol (LDL-C). Methods Randomized placebo or active-controlled trials were evaluated. The effect of mean non–HDL-C reduction on the relative risk of nonfatal myocardial infarction and CHD death was estimated using Bayesian random-effects meta-analysis models adjusted for study duration. Cochrane's Q was used to test for heterogeneity. Results Inclusion criteria were met by 14 statin (n = 100,827), 7 fibrate (n = 21,647), and 6 niacin (n = 4,445) trials, and 1 trial each of a bile acid sequestrant (n = 3,806), diet (n = 458), and ileal bypass surgery (n = 838). For statins, each 1% decrease in non–HDL-C resulted in an estimated 4.5-year CHD relative risk of 0.99 (95% Bayesian confidence interval: 0.98 to 1.00). The fibrate model did not differ from the statin model (Bayes factor K = 0.49) with no evidence of heterogeneity. The niacin model was moderately different from the statin model (K = 7.43), with heterogeneity among the trials (Q = 11.8, 5 df; p = 0.038). The only niacin monotherapy trial (n = 3,908) had a 1:1 relationship between non–HDL-C and risk reduction. No consistent relationships were apparent for the 5 small trials of niacin in combination. The 95% confidence intervals for the single trials of diet, bile acid sequestrants, and surgery also included the 1:1 relationship. Conclusions Non–HDL-C is an important target of therapy for CHD prevention. Most lipid-modifying drugs used as monotherapy have an ≈1:1 relationship between percent non–HDL-C lowering and CHD reduction.
Background Statins substantially reduce the risk of cardiovascular disease and are generally well-tolerated. Despite this, many patients discontinue therapy. A better understanding of the ...characteristics of current and former statin users may be helpful for formulating strategies to improve long-term adherence. Objective The Understanding Statin Use in America and Gaps in Education (USAGE) survey assessed the attitudes, beliefs, practices, and behavior of current and former statin users. Methods Individuals 18 years or older who reported a history of high cholesterol and current or former statin use were identified within a registered consumer panel cohort in the United States and invited to participate in an Internet survey. Results Of the 10,138 respondents, 8918 (88%) were current statin users and 1220 (12%) were former users. Participants (mean age 61 years) were predominantly white (92%), female (61%), of middle income (median $44,504/yr), and had health insurance (93%). Among current users, 95% took a statin alone, and 70% had not missed a dose in the past month. Although ∼70% reported that their physicians had explained the importance of cholesterol levels for their heart health former users were less satisfied with the discussions (65% vs. 83%, P < .05). Muscle-related side effects were reported by 60% and 25% of former and current users, respectively ( P < .05). Nearly half of all respondents switched statins at least once. The primary reason for switching by current users was cost (32%) and the primary reason for discontinuation was side effects (62%). Conclusions This survey provides important insights into behavior and attitudes among current and former statin users and the results suggest that more effective dialogue between healthcare providers and patients may increase persistence of statin use, particularly when the patient has concerns about side effects and drug costs.
This study evaluated the relation between apolipoprotein B (apoB) decrease and coronary heart disease, stroke, and cardiovascular disease risk. Bayesian random-effects meta-analysis was used to ...evaluate the association of mean absolute apoB decrease (milligrams per deciliter) with relative risk of coronary heart disease (nonfatal myocardial infarction and coronary heart disease death), stroke (nonfatal stroke and fatal stroke), or cardiovascular disease (coronary heart disease, stroke, and coronary revascularization). Analysis included 25 trials (n = 131,134): 12 on statin, 4 on fibrate, 5 on niacin, 2 on simvastatin–ezetimibe, 1 on ileal bypass surgery, and 1 on aggressive versus standard low-density lipoprotein (LDL) cholesterol and blood pressure targets. Combining the 25 trials, each 10-mg/dl decrease in apoB was associated with a 9% decrease in coronary heart disease, no decrease in stroke, and a 6% decrease in major cardiovascular disease risk. Non-high-density lipoprotein (non-HDL) cholesterol decrease modestly outperformed apoB decrease for prediction of coronary heart disease (Bayes factor BF 1.45) and cardiovascular disease (BF 2.07) risk decrease; apoB decrease added to non-HDL cholesterol plus LDL cholesterol decrease slightly improved cardiovascular disease risk prediction (1.13) but did not improve coronary heart disease risk prediction (BF 1.03) and worsened stroke risk prediction (BF 0.83). In the 12 statin trials, apoB and non-HDL cholesterol decreases similarly predicted cardiovascular disease risk; apoB improved coronary heart disease prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 3.33) but did not improve stroke risk prediction when added to non-HDL cholesterol/LDL cholesterol decrease (BF 1.06). In conclusion, across all drug classes, apoB decreases did not consistently improve risk prediction over LDL cholesterol and non-HDL cholesterol decreases. For statins, apoB decreases added information to LDL cholesterol and non-HDL cholesterol decreases for predicting coronary heart disease but not stroke or overall cardiovascular disease risk decrease.
AbstractObjectiveTo evaluate whether early initiation of prophylactic anticoagulation compared with no anticoagulation was associated with decreased risk of death among patients admitted to hospital ...with coronavirus disease 2019 (covid-19) in the United States.DesignObservational cohort study.SettingNationwide cohort of patients receiving care in the Department of Veterans Affairs, a large integrated national healthcare system.ParticipantsAll 4297 patients admitted to hospital from 1 March to 31 July 2020 with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and without a history of anticoagulation.Main outcome measuresThe main outcome was 30 day mortality. Secondary outcomes were inpatient mortality, initiating therapeutic anticoagulation (a proxy for clinical deterioration, including thromboembolic events), and bleeding that required transfusion.ResultsOf 4297 patients admitted to hospital with covid-19, 3627 (84.4%) received prophylactic anticoagulation within 24 hours of admission. More than 99% (n=3600) of treated patients received subcutaneous heparin or enoxaparin. 622 deaths occurred within 30 days of hospital admission, 513 among those who received prophylactic anticoagulation. Most deaths (510/622, 82%) occurred during hospital stay. Using inverse probability of treatment weighted analyses, the cumulative incidence of mortality at 30 days was 14.3% (95% confidence interval 13.1% to 15.5%) among those who received prophylactic anticoagulation and 18.7% (15.1% to 22.9%) among those who did not. Compared with patients who did not receive prophylactic anticoagulation, those who did had a 27% decreased risk for 30 day mortality (hazard ratio 0.73, 95% confidence interval 0.66 to 0.81). Similar associations were found for inpatient mortality and initiation of therapeutic anticoagulation. Receipt of prophylactic anticoagulation was not associated with increased risk of bleeding that required transfusion (hazard ratio 0.87, 0.71 to 1.05). Quantitative bias analysis showed that results were robust to unmeasured confounding (e-value lower 95% confidence interval 1.77 for 30 day mortality). Results persisted in several sensitivity analyses.ConclusionsEarly initiation of prophylactic anticoagulation compared with no anticoagulation among patients admitted to hospital with covid-19 was associated with a decreased risk of 30 day mortality and no increased risk of serious bleeding events. These findings provide strong real world evidence to support guidelines recommending the use of prophylactic anticoagulation as initial treatment for patients with covid-19 on hospital admission.
According to the generally accepted scenario, the last giant impact on Earth formed the Moon and initiated the final phase of core formation by melting Earth's mantle. A key goal of geochemistry is ...to date this event, but different ages have been proposed. Some argue for an early Moon-forming event, approximately 30 million years (Myr) after the condensation of the first solids in the Solar System, whereas others claim a date later than 50 Myr (and possibly as late as around 100 Myr) after condensation. Here we show that a Moon-forming event at 40 Myr after condensation, or earlier, is ruled out at a 99.9 per cent confidence level. We use a large number of N-body simulations to demonstrate a relationship between the time of the last giant impact on an Earth-like planet and the amount of mass subsequently added during the era known as Late Accretion. As the last giant impact is delayed, the late-accreted mass decreases in a predictable fashion. This relationship exists within both the classical scenario and the Grand Tack scenario of terrestrial planet formation, and holds across a wide range of disk conditions. The concentration of highly siderophile elements (HSEs) in Earth's mantle constrains the mass of chondritic material added to Earth during Late Accretion. Using HSE abundance measurements, we determine a Moon-formation age of 95 ± 32 Myr after condensation. The possibility exists that some late projectiles were differentiated and left an incomplete HSE record in Earth's mantle. Even in this case, various isotopic constraints strongly suggest that the late-accreted mass did not exceed 1 per cent of Earth's mass, and so the HSE clock still robustly limits the timing of the Moon-forming event to significantly later than 40 Myr after condensation.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Signaling across cellular membranes, the 826 human G protein-coupled receptors (GPCRs) govern a wide range of vital physiological processes, making GPCRs prominent drug targets. X-ray crystallography ...provided GPCR molecular architectures, which also revealed the need for additional structural dynamics data to support drug development. Here, nuclear magnetic resonance (NMR) spectroscopy with the wild-type-like A2A adenosine receptor (A2AAR) in solution provides a comprehensive characterization of signaling-related structural dynamics. All six tryptophan indole and eight glycine backbone 15N–1H NMR signals in A2AAR were individually assigned. These NMR probes provided insight into the role of Asp522.50 as an allosteric link between the orthosteric drug binding site and the intracellular signaling surface, revealing strong interactions with the toggle switch Trp 2466.48, and delineated the structural response to variable efficacy of bound drugs across A2AAR. The present data support GPCR signaling based on dynamic interactions between two semi-independent subdomains connected by an allosteric switch at Asp522.50.
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•Comprehensive view of GPCR signaling pathways using NMR probes•Allosteric signaling monitored by NMR probes distributed throughout A2AAR•Function-related conformational polymorphisms at intracellular A2AAR surface•Strong coupling between allosteric switch and signaling-activation motif
Monitoring dynamics of GPCR signaling using stable isotope NMR reveals the path of communication enabling an allosteric response to ligand binding.
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Prof. Geoffrey Burnstock originated the concept of purinergic signaling. He demonstrated the interactions and biological roles of ionotropic P2X and metabotropic P2Y receptors. This ...review paper traces the historical origins of many currently used antagonists and agonists for P2 receptors, as well as adenosine receptors, in early attempts to identify ligands for these receptors – prior to the use of chemical libraries for screening. Rather than presenting a general review of current purinergic ligands, we focus on common chemical scaffolds (privileged scaffolds) that can be adapted for multiple receptor targets. By carefully analyzing the structure activity relationships, one can direct the selectivity of these scaffolds toward different receptor subtypes. For example, the weak and non-selective P2 antagonist reactive blue 2 (RB-2) was derivatized using combinatorial synthetic approaches, leading to the identification of selective P2Y2, P2Y4, P2Y12 or P2X2 receptor antagonists.
A P2X4 antagonist NC-2600 is in a clinical trial, and A3 adenosine agonists show promise, for chronic pain. P2X7 antagonists have been in clinical trials for depression (JNJ-54175446), inflammatory bowel disease (IBD), Crohn’s disease, rheumatoid arthritis, inflammatory pain and chronic obstructive pulmonary disease (COPD). P2X3 antagonists are in clinical trials for chronic cough, and an antagonist named after Burnstock, gefapixant, is expected to be the first P2X3 antagonist filed for approval. We are seeing that the vision of Prof. Burnstock to use purinergic signaling modulators, most recently at P2XRs, for treating disease is coming to fruition.
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