Left ventricular mass regression, all-cause and cardiovascular mortality in chronic kidney disease: a meta-analysis.

BACKGROUND: Cardiovascular disease is an important driver of the increased mortality associated with chronic kidney disease (CKD). Higher left ventricular mass (LVM) predicts increased risk of adverse cardiovascular outcomes and total mortality, but previous reviews have shown no clear association between intervention-induced LVM change and all-cause or cardiovascular mortality in CKD. METHODS: The primary objective of this meta-analysis was to investigate whether treatment-induced reductions in LVM over periods ≥12 months were associated with all-cause mortality in patients with CKD. Cardiovascular mortality was investigated as a secondary outcome. Measures of association in the form of relative risks (RRs) with associated variability and precision (95% confidence intervals [CIs]) were extracted directly from each study, when reported, or were calculated based on the published data, if possible, and pooled RR estimates were determined. RESULTS: The meta-analysis included 42 trials with duration ≥12 months: 6 of erythropoietin stimulating agents treating to higher vs. lower hemoglobin targets, 10 of renin-angiotensin-aldosterone system inhibitors vs. placebo or another blood pressure lowering agent, 14 of modified hemodialysis regimens, and 12 of other types of interventions. All-cause mortality was reported in 121/2584 (4.86%) subjects in intervention groups and 168/2606 (6.45%) subjects in control groups. The pooled RR estimate of the 27 trials ≥12 months with ≥1 event in ≥1 group was 0.72 (95% CI 0.57 to 0.90, p = 0.005), with little heterogeneity across studies. Directionalities of the associations in intervention subgroups were the same. Sensitivity analyses of ≥6 months (34 trials), ≥9 months (29 trials), and >12 months (10 trials), and including studies with no events in either group, demonstrated similar risk reductions to the primary analysis. The point estimate for cardiovascular mortality was similar to all-cause mortality, but not statistically significant: RR 0.67, 95% CI 0.39 to 1.16. CONCLUSIONS: These results suggest that LVM regression may be a useful surrogate marker for benefits of interventions intended to reduce mortality risk in patients with CKD.

Ziltivekimab for Treatment of Anemia of Inflammation in Patients on Hemodialysis: Results from a Phase 1/2 Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Patients with CKD who are on hemodialysis are hyporesponsive to erythropoiesis-stimulating agents (ESAs) because of anemia of inflammation. Interleukin-6 (IL-6) induced hepcidin expression is a key mediator of such inflammation. METHODS: This phase 1/2, placebo-controlled trial assessed effects of ziltivekimab, a novel anti-IL-6 ligand antibody, in patients on hemodialysis with rs855791, a single nucleotide polymorphism of the TMPRSS6 gene that is hypothesized to heighten susceptibility to IL-6-mediated inflammatory effects. After a screening period documenting stable ESA and iron dosing, we randomized 61 patients with elevated IL-6 (≥4 pg/ml) to receive placebo or ziltivekimab (doses of 2, 6, or 20 mg), administered intravenously every 2 weeks for 12 weeks during hemodialysis. ESA dose adjustments were allowed after 4 weeks. We analyzed safety and effects on inflammation, iron metabolism, serum albumin, and anti-drug antibodies. RESULTS: No patient experienced dose-limiting toxicity. Four patients (two each in the 6- and 20-mg cohorts) died of a treatment-emergent adverse event. Compared with patients receiving placebo, those receiving ziltivekimab experienced significantly greater reductions of high-sensitivity C-reactive protein, serum amyloid A, and fibrinogen from baseline to end of treatment. Median ESA usage decreased by 15,000, 15,000, or 33,000 IU/wk per patient in the 2-, 6-, and 20-mg ziltivekimab cohorts, respectively, compared with no change in the placebo group. We also noted significant dose responses for decreased ESA resistance index and increased serum iron, total iron binding capacity, transferrin saturation, and serum albumin. CONCLUSIONS: Ziltivekimab significantly improved markers of inflammation, reduced ESA requirements, and increased serum albumin in patients on hemodialysis with inflammation and hyporesponsiveness to ESA therapy. CLINICAL TRIAL REGISTRY NAME AND REGISTRATION NUMBER: Study to Assess the Safety, Pharmacokinetics, and Pharmacodynamics of Multiple Doses of COR-001, NCT02868229.

Watching for Disease: the Changing Paradigm of Disease Screening in the Age of Consumer Health Devices.

There has been a recent proliferation of consumer health devices (CHDs) that enable user-initiated screening for a variety of diseases. These devices represent a paradigm shift in the deployment of disease screening, a process that has historically been led by clinicians following the guidance of professional bodies. The detection of AF via CHDs is a contemporary example of this phenomenon and highlights several important implications of the shift of disease screening from clinicians to CHD users. These include responsibility for patient data and outcomes, healthcare costs and access, and an evolution of the patient-provider relationship. However, as CHD technologies mature and become more affordable, they have the potential to detect actionable subclinical disease and improve health. Rather than allow CHDs to enter the marketplace organically with the potential for unintended negative consequences, it is critical that clinical, research, and industry communities proactively collaborate and establish best practices for their use.

Narcolepsy, Anesthesia, and Sedation: A Survey of the Perioperative Experience of Patients With Narcolepsy.

BACKGROUND: Patients with narcolepsy may be at increased perioperative risk due to the interactions among anesthesia, narcolepsy, and narcolepsy medications. This study sought to determine the perioperative experience of narcoleptic patients undergoing anesthesia or sedation, the frequency of perioperative counseling, and self-reported surgical complications. METHODS: A 22-question survey was developed by expert consensus and distributed by the Narcolepsy Network. Recruitment was via the Narcolepsy Network's list-serve and a Facebook link to the survey. One thousand and twenty respondents reported a diagnosis of narcolepsy and 1 or more procedures under anesthesia or sedation. Descriptive, comparative statistics and logistic regression were utilized. RESULTS: Respondents were mostly women (79.5%) and Caucasian (84.9%), with a mean age of 45 ± 16 years. Most respondents did not receive counseling regarding the possibility of increased sleepiness (70%), cataplexy (90%), or drowsy driving (59%) postanesthesia. More than half of respondents reported adverse events (medication withdrawal symptoms, inadequate pain relief, increased cataplexy). Subjects with cataplexy more frequently reported surgical complications (70% vs 31%; P = .03) and medication withdrawal symptoms (stimulant medications: odds ratio, 3.0 [95% CI, 1.9, 3.06]; P > .001 and antidepressant medications: odds ratio, 6.5 [95% CI, 2.1-19.5]; P = .001). Of the total sample, 18% indicated surgical complications. Undergoing 5 or more separate surgeries or procedures was associated with a 2-fold increase in self-reported complications (odds ratio, 2.2 [95% CI, 1.3-3.4]; P = .001), difficulty waking (odds ratio, 2.1 [95% CI, 1.45-3.06]; P = .001), and inadequate pain relief (odds ratio, 1.77 [95% CI, 1.01-3.13]; P < .05). CONCLUSIONS: Most narcoleptic patients report not receiving counseling regarding potential worsening of narcolepsy symptoms postanesthesia or an increased risk of drowsy driving. Enhanced education of perioperative providers about potential narcolepsy-related issues is essential. Respondents frequently self-report adverse events in the perioperative period. Future studies should clarify the perioperative risk associated with narcolepsy to optimize the care and safety of narcoleptic patients.

Knowledge Gaps in the Perioperative Management of Adults With Narcolepsy: A Call for Further Research.

There is increasing awareness that sleep disorders may be associated with increased perioperative risk. The Society of Anesthesia and Sleep Medicine created the Narcolepsy Perioperative Task Force: (1) to investigate the current state of knowledge of the perioperative risk for patients with narcolepsy, (2) to determine the viability of developing perioperative guidelines for the management of patients with narcolepsy, and (3) to delineate future research goals and clinically relevant outcomes. The Narcolepsy Perioperative Task Force established that there is evidence for increased perioperative risk in patients with narcolepsy; however, this evidence is sparse and based on case reviews, case series, and retrospective reviews. Mechanistically, there are a number of potential mechanisms by which patients with narcolepsy could be at increased risk for perioperative complications. These include aggravation of the disease itself, dysautonomia, narcolepsy-related medications, anesthesia interactions, and withdrawal of narcolepsy-related medications. At this time, there is inadequate research to develop an expert consensus or guidelines for the perioperative management of patients with narcolepsy. The paucity of available literature highlights the critical need to determine if patients with narcolepsy are at an increased perioperative risk and to establish appropriate research protocols and clearly delineated patient-centered outcomes. There is a real need for collaborative research among sleep medicine specialists, surgeons, anesthesiologists, and perioperative providers. This future research will become the foundation for the development of guidelines, or at a minimum, a better understanding how to optimize the perioperative care of patients with narcolepsy.

Anesthetic Management of Narcolepsy Patients During Surgery: A Systematic Review.

BACKGROUND: Narcolepsy is a rare sleep disorder characterized by excessive daytime sleepiness, sleep paralysis, and/or hypnagogic/hypnopompic hallucinations, and in some cases cataplexy. The response to anesthetic medications and possible interactions in narcolepsy patients is unclear in the perioperative period. In this systematic review, we aim to evaluate the current evidence on the perioperative outcomes and anesthetic considerations in narcolepsy patients. METHODS: Electronic literature search of Medline, Medline in-process, Embase, Cochrane Database of Systematic Reviews databases, international conference proceedings, and abstracts was conducted in November 2015 according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Protocols guideline. A total of 3757 articles were screened using a 2-stage strategy (title-abstract followed by full text). We included case studies/series, cohort studies, and randomized controlled trials of narcolepsy patients undergoing surgical procedures under anesthesia or sedation. Preoperative narcolepsy symptoms and sleep study data, anesthetic technique, and perioperative complications were extracted. Screening of articles, data extraction, and compilation were conducted by 2 independent reviewers and any conflict was resolved by the senior author. RESULTS: A total of 19 studies including 16 case reports and 3 case series were included and evaluated. The majority of these patients received general anesthesia, whereas a small percentage of patients received regional anesthesia. Reported complications of narcolepsy patients undergoing surgeries were mainly related to autonomic dysregulation, or worsening of narcolepsy symptoms intra/postoperatively. Narcolepsy symptoms worsened only in those patient populations where the preoperative medications were either discontinued or reduced (mainly in obstetric patients). In narcolepsy patients, use of depth of anesthesia monitoring and total intravenous technique may have some advantage in terms of safety profile. Several patients undergoing neurosurgery involving the hypothalamus or third or four ventricles developed new-onset narcolepsy. CONCLUSIONS: We found a paucity of prospective clinical trials in this patient population, as most of the studies were case reports or observational studies. Continuation of preoperative medications, depth of anesthesia monitoring, use of multimodal analgesia with short-acting agents and regional anesthesia techniques were associated with favorable outcomes. Obstetric patients may be at greater risk for worsening narcolepsy symptoms, possibly related to a reduction or discontinuation of medications. For neurosurgical procedures involving the hypothalamus or third and fourth ventricle, postoperative considerations should include monitoring for symptoms of narcolepsy. Future studies are needed to better define perioperative risks associated with anesthesia and surgery in this population of patients.

Myocardial pressure overload induces systemic inflammation through endothelial cell IL-33.

Hypertension increases the pressure load on the heart and is associated with a poorly understood chronic systemic inflammatory state. Interleukin 33 (IL-33) binds to membrane-bound ST2 (ST2L) and has antihypertrophic and antifibrotic effects in the myocardium. In contrast, soluble ST2 appears to act as a decoy receptor for IL-33, blocking myocardial and vascular benefits, and is a prognostic biomarker in patients with cardiovascular diseases. Here we report that a highly local intramyocardial IL-33/ST2 conversation regulates the heart's response to pressure overload. Either endothelial-specific deletion of IL33 or cardiomyocyte-specific deletion of ST2 exacerbated cardiac hypertrophy with pressure overload. Furthermore, pressure overload induced systemic circulating IL-33 as well as systemic circulating IL-13 and TGF-beta1; this was abolished by endothelial-specific deletion of IL33 but not by cardiomyocyte-specific deletion of IL33. Our study reveals that endothelial cell secretion of IL-33 is crucial for translating myocardial pressure overload into a selective systemic inflammatory response.

Correlation of D-Dimer Level with the Presence and Severity of Pulmonary Embolism on Computed Tomography Pulmonary Angiography.

INTRODUCTION: Early diagnosis of pulmonary embolism can reduce morbidity and motility. D-dimer is well known parameter having high negative prediction value. This study focused on role of D-dimer in early prediction of presence and severity of pulmonary embolism. MATERIAL AND METHODS: Thirty patients with clinical suspicion of pulmonary embolism along with high D-dimer value were included in this study. All selected patients underwent computed tomography pulmonary angiography assessment. D- dimer value was correlated with presence and proximity of pulmonary embolism. RESULTS: Out of thirty selected patients 50% had pulmonary embolism on computed tomography pulmonary angiography assessment. D-dimer value correlated well with presence and proximity of pulmonary embolism. CONCLUSION: D-dimer value more than 4000 ng/ml had high positive prediction value (79%) in suspected clinical cases. Value more than 8000 ng/ml further improve value to nearly 100% in suspected cases.

Prospective Study of Posterior Lumbar Interbody Fusion With Either Interbody Graft or Interbody Cage in the Treatment of Degenerative Spondylolisthesis.

STUDY DESIGN: A prospective study of 2 different fusion techniques for the treatment of single-level degenerative spondylolisthesis. OBJECTIVE: To determine whether the addition of an intervertebral cage improves the clinical outcome and fusion rate of patients undergoing posterior lumbar interbody fusion (PLIF) after decompression for degenerative spondylolisthesis. SUMMARY OF BACKGROUND DATA: The surgical approach that should be used for degenerative spondylolisthesis is a controversial issue. Decompression and PLIF with an interbody cage is widely used. Theoretical advantages in favor of PLIF include anterior column support, indirect foraminal decompression, restoration of lordosis, and reduction of the slip via ligamentotaxis. Despite numerous publications, the scientific support for the PLIF method is, however, weak. MATERIALS AND METHODS: A prospective study was carried out including 59 patients with degenerative spondylolisthesis. Average age of patients was 66 years: 34 males and 25 females. Patients were divided into 2 treatment groups: group 1-32 patients with PLIF with interbody graft and group 2-27 patients with PLIF with cage. Minimum 2-year follow-up. Outcomes were assessed by measuring preoperative and postoperative lordotic angles. SF-12 physical and mental health scores were recorded along with visual analogue scores for pain. Complications were also recorded. RESULTS: No significant difference in the postoperative lordotic angles was achieved between the 2 techniques. Nonsignificant difference in the clinical outcomes between both the techniques. CONCLUSIONS: We have found the use of a cage to achieve lumbar interbody fusion in the treatment of degenerative lumbar spondylolisthesis does not confer any significant advantages in terms of restoration of lumbar lordosis, improvement in clinical symptoms, or relief of pain postoperatively.

Interleukin 33 as a mechanically responsive cytokine secreted by living cells.

Interleukin 33 (IL-33), a member of the Interleukin 1 cytokine family, is implicated in numerous human inflammatory diseases such as asthma, atherosclerosis, and rheumatoid arthritis. Despite its pathophysiologic importance, fundamental questions regarding the basic biology of IL-33 remain. Nuclear localization and lack of an export signal sequence are consistent with the view of IL-33 as a nuclear factor with the ability to repress RNA transcription. However, signaling via the transmembrane receptor ST2 and documented caspase-dependent inactivation have suggested IL-33 is liberated during cellular necrosis to effect paracrine signaling. We determined the subcellular localization of IL-33 and tracked its intracellular mobility and extracellular release. In contrast to published data, IL-33 localized simultaneously to nuclear euchromatin and membrane-bound cytoplasmic vesicles. Fluorescent pulse-chase fate-tracking documented dynamic nucleo-cytoplasmic flux, which was dependent on nuclear pore complex function. In murine fibroblasts in vitro and in vivo, mechanical strain induced IL-33 secretion in the absence of cellular necrosis. These data document IL-33 dynamic inter-organelle trafficking and release during biomechanical overload. As such we recharacterize IL-33 as both an inflammatory as well as mechanically responsive cytokine secreted by living cells.

The use of the three-point index in the management of extra-articular distal radius fractures.

Conservative management has been the mainstay of treatment for simple extra-articular distal radius fractures. Several factors, such as quality of definitive casting, have been implicated in the risk of fracture re-displacement during follow-up. Objective assessments of the quality of casting using various indices have been documented in literature, although overall evidence remains scant, and only one study in the literature discusses the use of the three-point index (3-PI) in adults. Currently, no independent study assessing the 3-PI in adults has been documented. This retrospective study aimed to assess the 3-PI in terms of (1) predicting fracture re-displacement and (2) evaluating its practicality in everyday clinical use. We had 54 patients (47 female, 7 female), out of which 35 patients had a 3-PI greater than the suggested cutoff value of 0.8; of these, 22 went on to re-displace. The remaining 19 patients had a 3-PI below the cutoff and 14 went on to re-displace. No statistical significance was found for the 3-PI as a predictor for fracture re-displacement, although inter-observer reliability was high; its impact on clinic times (in calculating the 3-PI) remained low.

Role of ST2 in non-ST-elevation acute coronary syndrome in the MERLIN-TIMI 36 trial.

OBJECTIVE: We investigated the prognostic performance of ST2 with respect to cardiovascular death (CVD) and heart failure (HF) in patients with non-ST-elevation acute coronary syndrome (NSTE-ACS) in a large multinational trial. BACKGROUND: Myocytes that are subjected to mechanical stress secrete ST2, a soluble interleukin-1 receptor family member that is associated with HF after STE-ACS. METHODS: We measured ST2 with a high-sensitivity assay in all available baseline samples (N=4426) in patients enrolled in the Metabolic Efficiency With Ranolazine for Less Ischemia in the Non-ST-Elevation Acute Coronary Syndrome Thrombolysis in Myocardial Infarction 36 (MERLIN-TIMI 36), a placebo-controlled trial of ranolazine in NSTE-ACS. All events, including cardiovascular death and new or worsening HF, were adjudicated by an independent events committee. RESULTS: Patients with ST2 concentrations in the top quartile (>35 µg/L) were more likely to be older and male and have diabetes and renal dysfunction. ST2 was only weakly correlated with troponin and B-type natriuretic peptide. High ST2 was associated with increased risk for CVD/HF at 30 days (6.6% vs 1.6%, P<0.0001) and 1 year (12.2% vs 5.2%, P<0.0001). The risk associated with ST2 was significant after adjustment for clinical covariates and biomarkers (adjusted hazard ratio CVD/HF 1.90, 95% CI 1.15-3.13 at 30 days, P=0.012; 1.51, 95% CI 1.15-1.98 at 1 year, P=0.003), with a significant integrated discrimination improvement (P<0.0001). No significant interaction was found between ST2 and ranolazine (Pinteraction=0.15). CONCLUSIONS: ST2 correlates weakly with biomarkers of acute injury and hemodynamic stress but is strongly associated with the risk of HF after NSTE-ACS. This biomarker and related pathway merit further investigation as potential therapeutic targets for patients with ACS at risk for cardiac remodeling.

Intramyocardial fibroblast myocyte communication.

Cardiac fibroblasts are emerging as key components of normal cardiac function, as well as the response to stressors and injury. These most numerous cells of the heart interact with myocytes via paracrine mechanisms, alterations in extracellular matrix homeostasis, and direct cell-cell interactions. It is possible that they are a contributor to the inability of adult myocytes to proliferate and may influence cardiac progenitor biology. Furthering our understanding of how cardiac fibroblasts and myocytes interact may provide an avenue to novel treatments for heart failure prevention. This review discusses the most recent concepts in cardiac fibroblast-myocyte communication and areas of potential future research.

Residual deformity versus recurrence following Dupuytren's palmar fasciectomy-a long term follow-up of 142 cases.

INTRODUCTION: and background: Surgical options for Dupuytren's disease (DD) are multiple, and Dupuytren's palmar fasciectomy (PF) is a common surgical procedure performed for contractures that cause functional and cosmetic disability. The recurrence rate for PF has been reported to be very variable, ranging from 12 to 73%, according to various studies. One of the reasons for the varied range is the inconsistency in the method followed to define recurrence. Subsequently, a consensus-based definition was formulated in 2016, and we analysed the outcome in our series of patients treated with PF based on this standard definition. We also analysed the residual deformity associated in these cases. METHOD: ology: Our study is a retrospective analysis of 142 consecutive cases of primary Dupuytren's palmar fasciectomy by a single surgeon in three different centres. We followed the international consensus definition for analysing recurrence in these cases, and we also analysed residual cases as a separate entity. RESULTS: The mean age of the cases was 67.13 years and the mean follow-up period was 3.95 years. Alcoholism, smoking, diabetes and hypercholesterolemia were the commonest associated risk factors. The commonest affected finger and the finger with the maximum deformity were the little finger. The overall rate of recurrence of deformity was 3.5% and the rate of residual deformity was 30.3%. The overall complication rate was 11.9%. CONCLUSION: Recurrence and residual deformity can be considered as separate entities. The term 'residual deformity' can be used to denote patients with persisting deformity or those who incur deformity within one year of the primary surgery.

Race, Interleukin-6, TMPRSS6 Genotype, and Cardiovascular Disease in Patients With Chronic Kidney Disease.

Background Differences in death rate and cardiovascular disease (CVD) between Black and White patients with chronic kidney disease is attributed to sociocultural factors, comorbidities, genetics, and inflammation. Methods and Results We examined the interaction of race, plasma IL-6 (interleukin-6), and TMPRSS6 genotype as determinants of CVD and mortality in 3031 Chronic Renal Insufficiency Cohort study participants. The primary outcomes were all-cause mortality and a composite of incident myocardial infarction, peripheral artery disease, stroke, and heart failure. During the median follow-up of 10 years, Black patients with chronic kidney disease experienced a significantly higher mortality (34% versus 26%) and CVD composite (41% versus 28%) compared with White patients. After adjustment, TMPRSS6 genotype did not associate with the outcomes. The adjusted hazard ratio for mortality (4.11 [2.48-6.80], P<0.001) and CVD composite (2.52 [1.96-3.24], P<0.001) were higher for the highest versus lowest IL-6 quintile. The adjusted hazards for death per 1-quintile increase in IL-6 in White and Black individuals were 1.53 (1.42-1.64) versus 1.29 (1.20-1.38) (P<0.001), respectively. For CVD composite they were 1.61 (1.50-1.74) versus 1.30 (1.22-1.39) (P<0.001), respectively. In Cox proportional hazard models that included IL-6, there was no longer a racial disparity for death (1.01 [0.87-1.16], P=0.92), but significant unexplained mediation remained for CVD (1.24 [1.07-1.43]; P=0.004). Path models that included IL-6, diabetes, and urine albumin to creatinine ratio were able to identify variables responsible for racial disparity in mortality and CVD. Conclusions Racial differences in mortality and CVD among patients with chronic kidney disease could be explained by good-fitting path models that include selected mediator variables including diabetes and plasma IL-6.

Stresses in the ankle joint and total ankle replacement design.

The ankle is a highly congruent joint with a surface area of 11-13 cm(2). Total ankle replacements have been attempted since the early 1970s and design has continually evolved as the early designs were a failure. This was because the stresses involved and the mutiaxial motion of the ankle has not been understood until recently. It has been shown that the talus slides as well as rolls during the ankle arc of motion from plantarflexion to dorsiflexion. Furthermore, the articular surfaces and the calcaneofibular and tibiocalcaneal ligaments have been shown to form a four bar linkage dictating ankle motion. A new design ankle replacement has been suggested recently which allows multiaxial motion at the ankle while maintaining congruency throughout the arc of motion. The early results of this ankle replacement have been encouraging without any reported failures due to mechanical loosening.

Pisiform dislocation.

A pisiform dislocation is an uncommon injury which can lead to significant morbidity if missed. The literature regarding pisiform dislocation is limited and largely from case reports. In this case, we present a 51-year-old right-hand dominant male who sustained the injury after a fall. He attended the emergency department on the same day and a closed reduction was able to be performed under a haematoma block. On review in follow-up clinic the patient's symptoms had completely resolved.

A Phase 1 Randomized Dose-Escalation Study of a Human Monoclonal Antibody to IL-6 in CKD.

Background: Chronic systemic inflammation is highly prevalent in patients with CKD (measured as an elevated high-sensitivity C-reactive protein, hsCRP) and independently associated with cardiovascular events and all-cause mortality. An IL-6 blocker to suppress inflammation represents a potential novel paradigm to reduce cardiovascular risk in CKD. Methods: A phase 1 trial of ziltivekimab, a fully human mAb against IL-6, was conducted in patients with moderate-to-severe nondialysis-dependent CKD (eGFR of 20-60 ml/min per 1.73 m2) and evidence of chronic inflammation (hsCRP level >2 mg/L over two consecutive measurements). Three cohorts of n=4 (3:1 active:placebo) were blindly randomized to a single dose of ziltivekimab (5 mg, 15 mg, and 50 mg subcutaneous injection), and followed for 12 weeks for safety and pharmacokinetic/pharmacodynamic assessments, with an additional 20 weeks for safety and antidrug antibody assessments. Results: Participants were 67±11 years old; baseline eGFR: 40±13 ml/min per 1.73 m2; baseline hsCRP: 5.0±2.5 mg/L. Dose escalation was approved, and all adverse events were within the expected range for a CKD population with chronic inflammation. No serious adverse events were reported in any active cohort. hsCRP levels were substantially reduced with ziltivekimab. Of participants, 100% achieved suppression of hsCRP to <2 mg/L with the 15 mg and 50 mg dose, and several patients had undetectable levels of hsCRP with the 50 mg dose. The mean t1/2 ranged from of 45 to 65 days. Conclusions: In adults with moderate-to-severe CKD and evidence of chronic inflammation, a single-injection of the IL-6 inhibitor ziltivekimab was safe and highly effective at suppressing hsCRP over 12 weeks.

Inflammation in Heart Failure: JACC State-of-the-Art Review.

It has long been observed that heart failure (HF) is associated with measures of systemic inflammation. In recent years, there have been significant advancements in our understanding of how inflammation contributes to the pathogenesis and progression of HF. However, although numerous studies have validated the association between measures of inflammation and HF severity and prognosis, clinical trials of anti-inflammatory therapies have proven mostly unsuccessful. On this backdrop emerges the yet unmet goal of targeting precise phenotypes within the syndrome of HF; if such precise definitions can be realized, and with better understanding of the roles played by specific inflammatory mediators, the expectation is that targeted anti-inflammatory therapies may improve prognosis in patients whose HF is driven by inflammatory pathobiology. Here, the authors describe mechanistic links between inflammation and HF, discuss traditional and novel inflammatory biomarkers, and summarize the latest evidence from clinical trials of anti-inflammatory therapies.

A dual apolipoprotein C-II mimetic-apolipoprotein C-III antagonist peptide lowers plasma triglycerides.

Recent genetic studies have established that hypertriglyceridemia (HTG) is causally related to cardiovascular disease, making it an active area for drug development. We describe a strategy for lowering triglycerides (TGs) with an apolipoprotein C-II (apoC-II) mimetic peptide called D6PV that activates lipoprotein lipase (LPL), the main plasma TG-hydrolyzing enzyme, and antagonizes the TG-raising effect of apoC-III. The design of D6PV was motivated by a combination of all-atom molecular dynamics simulation of apoC-II on the Anton 2 supercomputer, structural prediction programs, and biophysical techniques. Efficacy of D6PV was assessed ex vivo in human HTG plasma and was found to be more potent than full-length apoC-II in activating LPL. D6PV markedly lowered TG by more than 80% within a few hours in both apoC-II-deficient mice and hAPOC3-transgenic (Tg) mice. In hAPOC3-Tg mice, D6PV treatment reduced plasma apoC-III by 80% and apoB by 65%. Furthermore, low-density lipoprotein (LDL) cholesterol did not accumulate but rather was decreased by 10% when hAPOC3-Tg mice lacking the LDL-receptor (hAPOC3-Tg × Ldlr-/- ) were treated with the peptide. D6PV lowered TG by 50% in whole-body inducible Lpl knockout (iLpl-/- ) mice, confirming that it can also act independently of LPL. D6PV displayed good subcutaneous bioavailability of about 80% in nonhuman primates. Because it binds to high-density lipoproteins, which serve as a long-term reservoir, it also has an extended terminal half-life (42 to 50 hours) in nonhuman primates. In summary, D6PV decreases plasma TG by acting as a dual apoC-II mimetic and apoC-III antagonist, thereby demonstrating its potential as a treatment for HTG.