Comparison of in vivo and in situ detection of hippocampal metabolites in mouse brain using 1 H-MRS.

The study of cerebral metabolites relies heavily on detection methods and sample preparation. Animal experiments in vivo require anesthetic agents that can alter brain metabolism, whereas ex vivo experiments demand appropriate fixation methods to preserve the tissue from rapid postmortem degradation. In this study, the metabolic profiles of mouse hippocampi using proton magnetic resonance spectroscopy (1 H-MRS) were compared in vivo and in situ with or without focused beam microwave irradiation (FBMI) fixation. Ten major brain metabolites, including lactate (Lac), N-acetylaspartate (NAA), total choline (tCho), myo-inositol (mIns), glutamine (Gln), glutamate (Glu), aminobutyric acid (GABA), glutathione (GSH), total creatine (tCr) and taurine (Tau), were analyzed using LCModel. After FBMI fixation, the concentrations of Lac, tCho and mIns were comparable with those obtained in vivo under isoflurane, whereas other metabolites were significantly lower. Except for a decrease in NAA and an increase in Tau, all the other metabolites remained stable over 41 hours in FBMI-fixed brains. Without FBMI, the concentrations of mIns (before 2 hours), tCho and GABA were close to those measured in vivo. However, higher Lac (P < .01) and lower NAA, Gln, Glu, GSH, tCr and Tau were observed (P < .01). NAA, Gln, Glu, GSH, tCr and Tau exhibited good temporal stability for at least 20 hours in the unfixed brain, whereas a linear increase of tCho, mIns and GABA was observed. Possible mechanisms of postmortem degradation are discussed. Our results indicate that a proper fixation method is required for in situ detection depending on the targeted metabolites of specific interests in the brain.

Phase 1B, Randomized, Double-Blinded, Dose Escalation, Single-Center, Repeat Dose Safety and Pharmacodynamics Study of the Oral NLRP3 Inhibitor Dapansutrile in Subjects With NYHA II-III Systolic Heart Failure.

ABSTRACT: The NLRP3 inflammasome has been implicated in the development and progression of heart failure. The aim of this study was to determine the safety of an oral inhibitor of the NLRP3 inflammasome, dapansutrile (OLT1177), in patients with heart failure and reduced ejection fraction (HFrEF). This was a phase 1B, randomized, double-blind, dose escalation, single-center, repeat dose safety and pharmacodynamics study of dapansutrile in stable patients with HFrEF (New York Heart Association Class II-III). Subjects were randomized to treatment with dapansutrile for up to 14 days at a ratio of 4:1 into 1 of 3 sequential ascending dose cohorts (500, 1000, or 2000 mg) each including 10 patients. Subjects underwent clinical assessment, biomarker determination, transthoracic echocardiogram, and maximal cardiopulmonary exercise testing at baseline, day 14, and day 28 to ascertain changes in clinical status. Placebo cases (N = 2 per cohort) were used as a decoy to reduce bias and not for statistical comparisons. Thirty participants (20 men) were treated for 13 (12-14) days. No serious adverse events during the study were recorded. All clinical or laboratory parameters at day 14 compared with baseline suggested clinical stability without significant within-group differences in the dapansutrile-pooled group or the 3 dapansutrile cohorts. Improvements in left ventricular EF [from 31.5% (27.5-39) to 36.5% (27.5-45), P = 0.039] and in exercise time [from 570 (399.5-627) to 616 (446.5-688) seconds, P = 0.039] were seen in the dapansutrile 2000 mg cohort. Treatment with dapansutrile for 14 days was safe and well tolerated in patients with stable HFrEF.

Change in Eosinophil Count in Patients with Heart Failure Treated with Anakinra.

BACKGROUND: Interleukin-1 blockade with anakinra leads to a transient increase in eosinophil blood count (eosinophils) in patients with acute myocardial infarction. We aimed to investigate the effect of anakinra on changes in eosinophils in patients with heart failure (HF) and their correlation with cardiorespiratory fitness (CRF). METHODS: We measured eosinophils in 64 patients with HF (50% females), 55 (51-63) years of age, before and after treatment, and, in a subset of 41 patients, also after treatment cessation. We also evaluated CRF, measuring peak oxygen consumption (VO2) with a treadmill test. RESULTS: Treatment with anakinra significantly and transiently increased eosinophils, from 0.2 [0.1-0.3] to 0.3 [0.1-0.4] × 103 cells/µL (p < 0.001) and from 0.3 [0.2-0.5] to 0.2 [0.1-0.3] × 103 cells/µL, with suspension (p < 0.001). Changes in eosinophils correlated with the changes in peak VO2 (Spearman's Rho = +0.228, p = 0.020). Eosinophils were higher in patients with injection site reactions (ISR) (n = 8, 13%; 0.5 [0.4-0.6] vs. 0.2 [0.1-0.4] × 103 cells/µL, p = 0.023), who also showed a greater increase in peak VO2 (3.0 [0.9-4.3] vs. 0.3 [-0.6-1.8] mLO2·kg-1·min-1, p = 0.015). CONCLUSION: Patients with HF treated with anakinra experience a transient increase in eosinophils, which is associated with ISR and a greater improvement in peak VO2.

Patient Perceptions of Exertion and Dyspnea With Interleukin-1 Blockade in Patients With Recently Decompensated Systolic Heart Failure.

Interleukin-1 (IL-1) blockade is an anti-inflammatory treatment that may affect exercise capacity in heart failure (HF). We evaluated patient-reported perceptions of exertion and dyspnea at submaximal exercise during cardiopulmonary exercise testing (CPET) in a double-blind, placebo-controlled, randomized clinical trial of IL-1 blockade in patients with systolic HF (REDHART [Recently Decompensated Heart Failure Anakinra Response Trial]). Patients underwent maximal CPET at baseline, 2, 4, and 12 weeks and rated their perceived level of exertion (RPE, on a scale from 6 to 20) and dyspnea on exertion (DOE, on a scale from 0 to 10) every 3 minutes throughout exercise. Patients also answered 2 questionnaires to assess HF-related quality of life: the Duke Activity Status Index and the Minnesota Living with Heart Failure Questionnaire. From baseline to the 12-week follow-up, IL-1 blockade significantly reduced RPE and DOE at 3- and 6-minutes during CPET without changing values for heart rate, oxygen consumption, and cardiac workload at 3- and 6-minutes. Linear regression identified 6-minute RPE to be a strong independent predictor of both physical symptoms (Minnesota Living with Heart Failure Questionnaire; ß = 0.474, p = 0.002) and perceived exercise capacity (Duke Activity Status Index; ß = -0.443, p = 0.008). In conclusion, patient perceptions of exertion and dyspnea at submaximal exercise may be valuable surrogates for quality of life and markers of response to IL-1 blockade in patients with HF.

Recurrent pericarditis: an update on diagnosis and management.

Acute pericarditis is a disease of the pericardium characterized by inflammation. Around 16-38% of patients develop recurrent events after the first episode. Recurrent pericarditis (RP) seems to be caused by a pathological immune response. An inadequate treatment in terms of drug choice, dose, duration of therapy or tapering, has been shown to increase the risk of recurrences. Symptoms, physical and electrocardiographic signs are usually less severe during a recurrent event as compared to the first episode, thus favoring imaging as a tool to confirm the diagnosis of RP. Cardiac magnetic resonance is becoming the technique of choice because of its ability to detect active pericardial inflammation. Inflammatory biomarkers can be used to assess the risk of recurrences and to guide the tapering of treatments. First-line treatment is based on non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine. NSAIDs are useful for pain control, and colchicine has shown to reduce the risk of further recurrences. Glucocorticoids are often used as second-line drugs, but they are associated with a high rate of recurrent events. Interleukin-1 inhibitors, such as anakinra and rilonacept, significantly reduce the risk of recurrences in patients with RP while on treatment.

Meta-analysis of clinical outcomes of PCSK9 modulators in patients with established ASCVD.

The advent of monoclonal antibodies targeting proprotein convertase subtilisin/kexin type 9 (PCSK9) ushered in a new era of dyslipidemia pharmacotherapy. The first two antibodies targeting PCSK9 (evolocumab, alirocumab) approved by the United States Food and Drug Administration (FDA) provided significant and sustained reductions in atherogenic lipids and a reduced risk of atherosclerotic cardiovascular disease (ASCVD) events. More recently, phase 3 trials of inclisiran-a small interfering RNA-based agent targeting PCSK9-reported similar lipid-lowering effects and preliminary evidence of ASCVD risk reduction, although significant questions remain regarding the extent of benefits across cardiovascular outcomes. We conducted a systematic review and meta-analysis (random-effects model) of the available data on lipid lowering, incidence of atherosclerotic cardiovascular disease (ASCVD) events, and safety of pharmacologic agents targeting PCSK9. A significant and consistent reduction in low-density lipoprotein cholesterol (LDL-C) was observed across all agents (-51% [95% confidence interval {CI}: -61%, -41%]). Despite the impressive reduction in LDL-C, the individual effects on mortality, cardiovascular death, myocardial infarction (MI), and stroke remained nonsignificant. However, a consistent reduction was observed in the composite outcomes of MI, stroke, and cardiovascular death [relative risk {RR} (95% CI): 0.80 (0.73-0.87)] and MI, stroke, unstable angina (requiring revascularization), and cardiovascular death [RR (95% CI): 0.85 (0.74-0.97)]. In terms of safety outcomes, there was no significant difference in severe adverse events, new onset diabetes, neurocognitive disorders, or myalgia. Meanwhile, injection site reaction was more frequent in patients receiving these agents compared to placebo [RR 2.11 (95% CI): 1.26-3.54]. These findings suggest a class effect for favorable lipid changes and a low risk of serious adverse events among pharmacologic agents targeting PCSK9. Although there is compelling evidence that PCSK9-targeting agents reduce the risk of some cardiovascular outcomes, adequately powered studies with longer follow-up may be needed to fully characterize the magnitude of benefits across the cardiovascular spectrum.

Preservation of Cardiac Reserve and Cardiorespiratory Fitness in Patients With Acute De Novo Versus Acute on Chronic Heart Failure With Reduced Ejection Fraction.

There is limited understanding on the potential differences in the pathophysiology between de novo heart failure with reduced ejection fraction (HFrEF) and acute on chronic HFrEF. The aim of this study was to assess differences in cardiorespiratory fitness (CRF) parameters between de novo heart failure and acute on chronic HFrEF using cardiopulmonary exercise testing (CPX). We retrospectively analyzed CPX data measured within 2 weeks of discharge following acute hospitalization for HFrEF. Data are reported as median and interquartile range or frequency and percentage (%). We included 102 patients: 32 (31%) women, 81 (79%) black, 57 (51 to 64) years of age, BMI of 34 (29 to 39) Kg/m2. Of these, 26 (25%) had de novo HFrEF and 76 (75%) had acute on chronic HFrEF. When compared with acute on chronic, patients with de novo HFrEF had a significantly higher peak oxygen consumption (VO2) (16.5 [12.2 to 19.4] vs 12.8 [10.1 to 15.3] ml·kg-1·min-1, p <0.001), %-predicted peak VO2 (58% [51 to 75] vs 49% [42 to 59]) p = 0.012), peak heart rate (134 [117 to 147] vs 117 [104 to 136] beats/min, p = 0.004), peak oxygen pulse (12.2 [10.5 to 15.5] vs 9.9 [8.0 to 13.1] ml/beat, p = 0.022) and circulatory power (2,823 [1,973 to 3,299] vs 1,902 [1,372 to 2,512] mm Hg·ml·kg-1·min-1, p = 0.002). No significant difference in resting left ventricular ejection fraction was found between groups. In conclusion, patients with de novo HFrEF have better CRF parameters than those with acute on chronic HFrEF. These differences are not explained by resting left ventricular systolic function but may be related to greater preservation in cardiac reserve during exercise in de novo HFrEF patients.

Clinical trial enrollment at a rural satellite hospital during COVID-19 pandemic.

INTRODUCTION: Controlled clinical trials (CCTs) have traditionally been limited to urban academic clinical centers. Implementation of CCTs in rural setting is challenged by lack of resources, the inexperience of patient care team members in CCT conductance and workflow interruption, and global inexperience with remote data monitoring. METHODS: We report our experience during the coronavirus disease 2019 (COVID-19) pandemic in activating through remote monitoring a multicenter clinical trial (the Study of Efficacy and Safety of Canakinumab Treatment for cytokine release syndrome (CRS) in Participants with COVID-19-induced Pneumonia [CAN-COVID] trial, ClinicalTrials.gov Identifier: NCT04362813) at a rural satellite hospital, the VCU Health Community Memorial Hospital (VCU-CMH) in South Hill, VA, that is part of the larger VCU Health network, with the lead institution being VCU Health Medical College of Virginia Hospital (VCU-MCV), Richmond, VA. We used the local resources at the facility and remote guidance and oversight from the VCU-MCV resources using a closed-loop communication network. Investigational pharmacy, pathology, and nursing were essential to operate the work in coordination with the lead institution. RESULTS: Fifty-one patients with COVID-19 were enrolled from May to August 2020, 35 (69%) at VCU-MCV, and 16 (31%) at VCU-CMH. Among the patients enrolled at VCU-CMH, 37.5% were female, 62.5% Black, and had a median age of 60 (interquartile range 56-68) years. CONCLUSION: Local decentralization of this trial in our experience gave rural patients access to a novel treatment and also accelerated enrollment and more diverse participants' representative of the target population.

P2Y12 Inhibitor Monotherapy After a Short Dual Antiplatelet Therapy Versus Standard-Term Dual Antiplatelet Therapy in Patients Undergoing Percutaneous Coronary Intervention: A Contemporary Meta-Analysis.

BACKGROUND AND OBJECTIVES: Dual antiplatelet therapy (DAPT) after percutaneous coronary intervention (PCI) reduces the incidence of thrombotic events but increases the risk of bleeding, which is associated with a substantial and durable risk of death and could offset the benefits of a reduction in thrombotic events. P2Y12 inhibitor monotherapy after short-term DAPT could be an option to reduce the risk of bleeding. We carried out a meta-analysis comparing P2Y12 inhibitor monotherapy after short-term DAPT with standard-term DAPT in patients undergoing PCI. METHODS: We searched the PubMed and EMBASE databases through 11 April 2020. Two authors independently reviewed and selected eligible trials. The DerSimonian-Laird method with the binary random-effects model was used to calculate the relative risk (RR) with 95% confidence interval (CI). RESULTS: Five trials involving 23,762 patients were included in the final analyses; four were open-label trials, while the TWILIGHT trial was double-blinded. Ticagrelor was used in three trials, and the other two trials included several P2Y12 inhibitors. P2Y12 inhibitor monotherapy after short-term DAPT significantly reduced the bleeding events, defined as Bleeding Academic Research Consortium (BARC) type 3 or 5 bleeding and Thrombolysis in Myocardial Infarction (TIMI) major or minor bleeding, by 39% (RR 0.61, 95% CI 0.38-0.99; p = 0.045) and 46% (RR 0.56, 95% CI 0.42-0.73; p < 0.001), respectively. A significant reduction in cardiovascular death was associated with P2Y12 inhibitor monotherapy after short-term DAPT (RR 0.75, 95% CI 0.58-0.98; p = 0.037; I2 = 0). No significant difference in all-cause mortality, myocardial infarction, stroke, or definite or probable stent thrombosis was observed. CONCLUSIONS: This meta-analysis showed a significantly lowered risk of major bleeding and similar benefits of P2Y12 inhibitor monotherapy after short-term DAPT compared with standard-term DAPT in patients undergoing PCI.