Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes.

BACKGROUND: Obesity and type 2 diabetes are prevalent in patients with heart failure with preserved ejection fraction and are characterized by a high symptom burden. No approved therapies specifically target obesity-related heart failure with preserved ejection fraction in persons with type 2 diabetes. METHODS: We randomly assigned patients who had heart failure with preserved ejection fraction, a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or more, and type 2 diabetes to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: A total of 616 participants underwent randomization. The mean change in the KCCQ-CSS was 13.7 points with semaglutide and 6.4 points with placebo (estimated difference, 7.3 points; 95% confidence interval [CI], 4.1 to 10.4; P<0.001), and the mean percentage change in body weight was -9.8% with semaglutide and -3.4% with placebo (estimated difference, -6.4 percentage points; 95% CI, -7.6 to -5.2; P<0.001). The results for the confirmatory secondary end points favored semaglutide over placebo (estimated between-group difference in change in 6-minute walk distance, 14.3 m [95% CI, 3.7 to 24.9; P = 0.008]; win ratio for hierarchical composite end point, 1.58 [95% CI, 1.29 to 1.94; P<0.001]; and estimated treatment ratio for change in CRP level, 0.67 [95% CI, 0.55 to 0.80; P<0.001]). Serious adverse events were reported in 55 participants (17.7%) in the semaglutide group and 88 (28.8%) in the placebo group. CONCLUSIONS: Among patients with obesity-related heart failure with preserved ejection fraction and type 2 diabetes, semaglutide led to larger reductions in heart failure-related symptoms and physical limitations and greater weight loss than placebo at 1 year. (Funded by Novo Nordisk; STEP-HFpEF DM ClinicalTrials.gov number, NCT04916470.).

Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity.

BACKGROUND: Heart failure with preserved ejection fraction is increasing in prevalence and is associated with a high symptom burden and functional impairment, especially in persons with obesity. No therapies have been approved to target obesity-related heart failure with preserved ejection fraction. METHODS: We randomly assigned 529 patients who had heart failure with preserved ejection fraction and a body-mass index (the weight in kilograms divided by the square of the height in meters) of 30 or higher to receive once-weekly semaglutide (2.4 mg) or placebo for 52 weeks. The dual primary end points were the change from baseline in the Kansas City Cardiomyopathy Questionnaire clinical summary score (KCCQ-CSS; scores range from 0 to 100, with higher scores indicating fewer symptoms and physical limitations) and the change in body weight. Confirmatory secondary end points included the change in the 6-minute walk distance; a hierarchical composite end point that included death, heart failure events, and differences in the change in the KCCQ-CSS and 6-minute walk distance; and the change in the C-reactive protein (CRP) level. RESULTS: The mean change in the KCCQ-CSS was 16.6 points with semaglutide and 8.7 points with placebo (estimated difference, 7.8 points; 95% confidence interval [CI], 4.8 to 10.9; P<0.001), and the mean percentage change in body weight was -13.3% with semaglutide and -2.6% with placebo (estimated difference, -10.7 percentage points; 95% CI, -11.9 to -9.4; P<0.001). The mean change in the 6-minute walk distance was 21.5 m with semaglutide and 1.2 m with placebo (estimated difference, 20.3 m; 95% CI, 8.6 to 32.1; P<0.001). In the analysis of the hierarchical composite end point, semaglutide produced more wins than placebo (win ratio, 1.72; 95% CI, 1.37 to 2.15; P<0.001). The mean percentage change in the CRP level was -43.5% with semaglutide and -7.3% with placebo (estimated treatment ratio, 0.61; 95% CI, 0.51 to 0.72; P<0.001). Serious adverse events were reported in 35 participants (13.3%) in the semaglutide group and 71 (26.7%) in the placebo group. CONCLUSIONS: In patients with heart failure with preserved ejection fraction and obesity, treatment with semaglutide (2.4 mg) led to larger reductions in symptoms and physical limitations, greater improvements in exercise function, and greater weight loss than placebo. (Funded by Novo Nordisk; STEP-HFpEF ClinicalTrials.gov number, NCT04788511.).

Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: a pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials.

BACKGROUND: In the STEP-HFpEF (NCT04788511) and STEP-HFpEF DM (NCT04916470) trials, the GLP-1 receptor agonist semaglutide improved symptoms, physical limitations, bodyweight, and exercise function in people with obesity-related heart failure with preserved ejection fraction. In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, we aimed to provide a more definitive assessment of the effects of semaglutide across a range of outcomes and to test whether these effects were consistent across key patient subgroups. METHODS: We conducted a prespecified pooled analysis of individual patient data from STEP-HFpEF and STEP-HFpEF DM, randomised, double-blind, placebo-controlled trials at 129 clinical research sites in 18 countries. In both trials, eligible participants were aged 18 years or older, had heart failure with a left ventricular ejection fraction of at least 45%, a BMI of at least 30 kg/m2, New York Heart Association class II-IV symptoms, and a Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (KCCQ-CSS; a measure of heart failure-related symptoms and physical limitations) of less than 90 points. In STEP-HFpEF, people with diabetes or glycated haemoglobin A1c concentrations of at least 6·5% were excluded, whereas for inclusion in STEP-HFpEF DM participants had to have been diagnosed with type 2 diabetes at least 90 days before screening and to have an HbA1c of 10% or lower. In both trials, participants were randomly assigned to either 2·4 mg semaglutide once weekly or matched placebo for 52 weeks. The dual primary endpoints were change from baseline to week 52 in KCCQ-CSS and bodyweight in all randomly assigned participants. Confirmatory secondary endpoints included change from baseline to week 52 in 6-min walk distance, a hierarchical composite endpoint (all-cause death, heart failure events, and differences in changes in KCCQ-CSS and 6-min walk distance); and C-reactive protein (CRP) concentrations. Heterogeneity in treatment effects was assessed across subgroups of interest. We assessed safety in all participants who received at least one dose of study drug. FINDINGS: Between March 19, 2021 and March 9, 2022, 529 people were randomly assigned in STEP-HFpEF, and between June 27, 2021 and Sept 2, 2022, 616 were randomly assigned in STEP-HFpEF DM. Overall, 1145 were included in our pooled analysis, 573 in the semaglutide group and 572 in the placebo group. Improvements in KCCQ-CSS and reductions in bodyweight between baseline and week 52 were significantly greater in the semaglutide group than in the placebo group (mean between-group difference for the change from baseline to week 52 in KCCQ-CSS 7·5 points [95% CI 5·3 to 9·8]; p<0·0001; mean between-group difference in bodyweight at week 52 -8·4% [-9·2 to -7·5]; p<0·0001). For the confirmatory secondary endpoints, 6-min walk distance (mean between-group difference at week 52 17·1 metres [9·2 to 25·0]) and the hierarchical composite endpoint (win ratio 1·65 [1·42 to 1·91]) were significantly improved, and CRP concentrations (treatment ratio 0·64 [0·56 to 0·72]) were significantly reduced, in the semaglutide group compared with the placebo group (p<0·0001 for all comparisons). For the dual primary endpoints, the efficacy of semaglutide was largely consistent across multiple subgroups, including those defined by age, race, sex, BMI, systolic blood pressure, baseline CRP, and left ventricular ejection fraction. 161 serious adverse events were reported in the semaglutide group compared with 301 in the placebo group. INTERPRETATION: In this prespecified pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials, semaglutide was superior to placebo in improving heart failure-related symptoms and physical limitations, and reducing bodyweight in participants with obesity-related heart failure with preserved ejection fraction. These effects were largely consistent across patient demographic and clinical characteristics. Semaglutide was well tolerated. FUNDING: Novo Nordisk.

Arrhythmia and Death Following Percutaneous Revascularization in Ischemic Left Ventricular Dysfunction: Prespecified Analyses From the REVIVED-BCIS2 Trial.

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82-1.30]; P=0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01920048.

Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): an investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial.

BACKGROUND: For patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric carboxymaltose administration improves quality of life and exercise capacity in the short-term and reduces hospital admissions for heart failure up to 1 year. We aimed to evaluate the longer-term effects of intravenous ferric derisomaltose on cardiovascular events in patients with heart failure. METHODS: IRONMAN was a prospective, randomised, open-label, blinded-endpoint trial done at 70 hospitals in the UK. Patients aged 18 years or older with heart failure (left ventricular ejection fraction ≤45%) and transferrin saturation less than 20% or serum ferritin less than 100 µg/L were eligible. Participants were randomly assigned (1:1) using a web-based system to intravenous ferric derisomaltose or usual care, stratified by recruitment context and trial site. The trial was open label, with masked adjudication of the outcomes. Intravenous ferric derisomaltose dose was determined by patient bodyweight and haemoglobin concentration. The primary outcome was recurrent hospital admissions for heart failure and cardiovascular death, assessed in all validly randomly assigned patients. Safety was assessed in all patients assigned to ferric derisomaltose who received at least one infusion and all patients assigned to usual care. A COVID-19 sensitivity analysis censoring follow-up on Sept 30, 2020, was prespecified. IRONMAN is registered with ClinicalTrials.gov, NCT02642562. FINDINGS: Between Aug 25, 2016, and Oct 15, 2021, 1869 patients were screened for eligibility, of whom 1137 were randomly assigned to receive intravenous ferric derisomaltose (n=569) or usual care (n=568). Median follow-up was 2·7 years (IQR 1·8-3·6). 336 primary endpoints (22·4 per 100 patient-years) occurred in the ferric derisomaltose group and 411 (27·5 per 100 patient-years) occurred in the usual care group (rate ratio [RR] 0·82 [95% CI 0·66 to 1·02]; p=0·070). In the COVID-19 analysis, 210 primary endpoints (22·3 per 100 patient-years) occurred in the ferric derisomaltose group compared with 280 (29·3 per 100 patient-years) in the usual care group (RR 0·76 [95% CI 0·58 to 1·00]; p=0·047). No between-group differences in deaths or hospitalisations due to infections were observed. Fewer patients in the ferric derisomaltose group had cardiac serious adverse events (200 [36%]) than in the usual care group (243 [43%]; difference -7·00% [95% CI -12·69 to -1·32]; p=0·016). INTERPRETATION: For a broad range of patients with heart failure, reduced left ventricular ejection fraction and iron deficiency, intravenous ferric derisomaltose administration was associated with a lower risk of hospital admissions for heart failure and cardiovascular death, further supporting the benefit of iron repletion in this population. FUNDING: British Heart Foundation and Pharmacosmos.

The Impact of Ferric Derisomaltose on Cardiovascular and Noncardiovascular Events in Patients With Anemia, Iron Deficiency, and Heart Failure With Reduced Ejection Fraction.

BACKGROUND: In some countries, intravenous ferric derisomaltose (FDI) is only licensed for treating iron deficiency with anemia. Accordingly, we investigated the effects of intravenous FDI in a subgroup of patients with anemia in the IRONMAN (Effectiveness of Intravenous (IV) Iron Treatment Versus Standard Care in Patients With Heart Failure and Iron Deficiency) trial. METHOD AND RESULTS: IRONMAN enrolled patients with heart failure, a left ventricular ejection fraction of ≤45%, and iron deficiency (ferritin <100 µg/L or transferrin saturation of <20%), 771 (68%) of whom had anemia (hemoglobin <12 g/dL for women and <13 g/dL for men). Patients were randomized, open label, to FDI (n = 397) or usual care (n = 374) and followed for a median of 2.6 years. The primary end point, recurrent hospitalization for heart failure and cardiovascular death, occurred less frequently for those assigned to FDI (rate ratio 0.78, 95% confidence interval 0.61-1.01; P = .063). First event analysis for cardiovascular death or hospitalization for heart failure, less affected by the coronavirus disease 2019 pandemic, gave similar results (hazard ratio 0.77, 95% confidence interval 0.62-0.96; P = .022). Patients randomized to FDI reported a better Minnesota Living with Heart Failure quality of life, for overall (P = .013) and physical domain (P = .00093) scores at 4 months. CONCLUSIONS: In patients with iron deficiency anemia and heart failure with reduced left ventricular ejection fraction, intravenous FDI improves quality of life and may decrease cardiovascular events.

Interaction between the transmembrane domains of neurotrophin receptors p75 and TrkA mediates their reciprocal activation.

The neurotrophin receptors p75 and tyrosine protein kinase receptor A (TrkA) play important roles in the development and survival of the nervous system. Biochemical data suggest that p75 and TrkA reciprocally regulate the activities of each other. For instance, p75 is able to regulate the response of TrkA to lower concentrations of nerve growth factor (NGF), and TrkA promotes shedding of the extracellular domain of p75 by α-secretases in a ligand-dependent manner. The current model suggests that p75 and TrkA are regulated by means of a direct physical interaction; however, the nature of such interaction has been elusive thus far. Here, using NMR in micelles, multiscale molecular dynamics, FRET, and functional studies, we identified and characterized the direct interaction between TrkA and p75 through their respective transmembrane domains (TMDs). Molecular dynamics of p75-TMD mutants suggests that although the interaction between TrkA and p75 TMDs is maintained upon mutation, a specific protein interface is required to facilitate TrkA active homodimerization in the presence of NGF. The same mutations in the TMD protein interface of p75 reduced the activation of TrkA by NGF as well as reducing cell differentiation. In summary, we provide a structural model of the p75-TrkA receptor complex necessary for neuronal development stabilized by TMD interactions.

Remote monitoring data from cardiac implantable electronic devices predicts all-cause mortality.

AIMS: To determine if remotely monitored physiological data from cardiac implantable electronic devices (CIEDs) can be used to identify patients at high risk of mortality. METHODS AND RESULTS: This study evaluated whether a risk score based on CIED physiological data (Triage-Heart Failure Risk Status, 'Triage-HFRS', previously validated to predict heart failure (HF) events) can identify patients at high risk of death. Four hundred and thirty-nine adults with CIEDs were prospectively enrolled. Primary observed outcome was all-cause mortality (median follow-up: 702 days). Several physiological parameters [including heart rate profile, atrial fibrillation/tachycardia (AF/AT) burden, ventricular rate during AT/AF, physical activity, thoracic impedance, therapies for ventricular tachycardia/fibrillation] were continuously monitored by CIEDs and dynamically combined to produce a Triage-HFRS every 24 h. According to transmissions patients were categorized into 'high-risk' or 'never high-risk' groups. During follow-up, 285 patients (65%) had a high-risk episode and 60 patients (14%) died (50 in high-risk group; 10 in never high-risk group). Significantly more cardiovascular deaths were observed in the high-risk group, with mortality rates across groups of high vs. never-high 10.3% vs. <4.0%; P = 0.03. Experiencing any high-risk episode was associated with a substantially increased risk of death [odds ratio (OR): 3.07, 95% confidence interval (CI): 1.57-6.58, P = 0.002]. Furthermore, each high-risk episode ≥14 consecutive days was associated with increased odds of death (OR: 1.26, 95% CI: 1.06-1.48; P = 0.006). CONCLUSION: Remote monitoring data from CIEDs can be used to identify patients at higher risk of all-cause mortality as well as HF events. Distinct from other prognostic scores, this approach is automated and continuously updated.

The effect of spironolactone on cardiovascular function and markers of fibrosis in people at increased risk of developing heart failure: the heart 'OMics' in AGEing (HOMAGE) randomized clinical trial.

AIMS: To investigate the effects of spironolactone on fibrosis and cardiac function in people at increased risk of developing heart failure. METHODS AND RESULTS: Randomized, open-label, blinded-endpoint trial comparing spironolactone (50 mg/day) or control for up to 9 months in people with, or at high risk of, coronary disease and raised plasma B-type natriuretic peptides. The primary endpoint was the interaction between baseline serum galectin-3 and changes in serum procollagen type-III N-terminal pro-peptide (PIIINP) in participants assigned to spironolactone or control. Procollagen type-I C-terminal pro-peptide (PICP) and collagen type-1 C-terminal telopeptide (CITP), reflecting synthesis and degradation of type-I collagen, were also measured. In 527 participants (median age 73 years, 26% women), changes in PIIINP were similar for spironolactone and control [mean difference (mdiff): -0.15; 95% confidence interval (CI) -0.44 to 0.15 µg/L; P = 0.32] but those receiving spironolactone had greater reductions in PICP (mdiff: -8.1; 95% CI -11.9 to -4.3 µg/L; P < 0.0001) and PICP/CITP ratio (mdiff: -2.9; 95% CI -4.3 to -1.5; <0.0001). No interactions with serum galectin were observed. Systolic blood pressure (mdiff: -10; 95% CI -13 to -7 mmHg; P < 0.0001), left atrial volume (mdiff: -1; 95% CI -2 to 0 mL/m2; P = 0.010), and NT-proBNP (mdiff: -57; 95% CI -81 to -33 ng/L; P < 0.0001) were reduced in those assigned spironolactone. CONCLUSIONS: Galectin-3 did not identify greater reductions in serum concentrations of collagen biomarkers in response to spironolactone. However, spironolactone may influence type-I collagen metabolism. Whether spironolactone can delay or prevent progression to symptomatic heart failure should be investigated.

The Biased Ligands NGF and NT-3 Differentially Stabilize Trk-A Dimers.

Trk-A is a receptor tyrosine kinase (RTK) that plays an essential role in the development and functioning of the nervous system. Trk-A is expressed in neurons and signals in response to two ligands, NGF and neurotrophin-3 (NT-3), with very different functional consequences. Thus, NGF and NT-3 are "biased" ligands for Trk-A. Because it has been hypothesized that biased RTK ligands induce differential stabilization of RTK dimers, here, we seek to test this hypothesis for NGF and NT-3. In particular, we use Förster resonance energy transfer (FRET) and fluorescence intensity fluctuation spectroscopy to assess the strength of Trk-A interactions and Trk-A oligomer size in the presence of the two ligands. Although the difference in Trk-A behavior in response to the two ligands has been previously attributed to differences in their binding to Trk-A in the endosomes at low pH, here, we further show differences in the stabilities of the NGF- and NT-3-bound Trk-A dimers in the plasma membrane and at neutral pH. We discuss the biological significance of these new findings and their implications for the design of Trk-A ligands with novel functionalities.

Misdiagnosis of Heart Failure: A Systematic Review of the Literature.

BACKGROUND: Heart failure (HF) is a chronic disease associated with a significant burden to patients, families, and health services. The diagnosis of HF can be easily missed owing to similar symptoms with other conditions especially respiratory diseases. METHODS AND RESULTS: We conducted a systematic review to determine the rates of HF and cardiomyopathy misdiagnosis and explored the potential causes. The included studies were narratively synthesized. Ten studies were identified including a total of 223,859 patients. There was a lack of definition of HF misdiagnosis in the studies and inconsistent diagnostic criteria were used. The rates of HF misdiagnosis ranged from 16.1% in hospital setting to 68.5% when general practitioner referred patients to specialist setting. The most common cause for misdiagnosis was chronic obstructive pulmonary disease (COPD). One study using a COPD cohort showed that HF was unrecognized in 20.5% of patients and 8.1% had misdiagnosis of HF as COPD. Another study suggests that anemia and chronic kidney disease are associated with an increase in the odds of unrecognized left ventricular systolic dysfunction. Other comorbidities such as obesity, old age, atrial fibrillation, and ischemic heart disease are prevalent in patients with a misdiagnosis of HF. CONCLUSIONS: The misdiagnosis of HF is an unfortunate part of everyday clinical practice that occurs with a variable rate depending on the population studied. HF is frequently misdiagnosed as COPD. More research is needed to better understand the missed opportunities to correctly diagnose HF so that harm to patients can be avoided and effective treatments can be implemented.

Cost-Effectiveness Analyses of an Absorbable Antibacterial Envelope for Use in Patients at Increased Risk of Cardiac Implantable Electronic Device Infection in Germany, Italy, and England.

OBJECTIVES: To model the cost-effectiveness of the TYRX Absorbable Antibacterial Envelope when used in patients at increased risk of cardiac implantable electronic device (CIED) infection in the context of 3 European healthcare systems: Germany, Italy, and England. METHODS: A decision tree model with a lifetime horizon was populated using data from the Worldwide Randomized Antibiotic Envelope Infection Prevention Trial, a large multicenter randomized controlled trial. Use of the antibacterial envelope adjunctive to standard of care was compared to standard of care infection prevention alone. Patients in the model were divided into subgroups based on presence of factors known to increase infection risk. RESULTS: The antibacterial envelope had the most favorable cost-effectiveness profile when patients had previously experienced CIED infection, had a history of immunosuppressive therapy, or had a Prevention of Arrhythmia Device Infection Trial (PADIT) score indicating high risk of infection (scores ≥6) at cost-effectiveness thresholds of €50 000 in Germany (assumed in the absence of an official threshold), €40 000 in Italy, and £30 000 in England. Probabilistic sensitivity analysis indicated that the antibacterial envelope was likely to be cost-effective in patients with other risk factors (including replacement of high power CIEDs, generator replacement with lead modification, and PADIT scores indicating intermediate risk of infection) when used with some device types and in some countries. CONCLUSIONS: The absorbable antibacterial envelope was associated with cost-effectiveness ratios below European benchmarks in selected patients at increased risk of infection, suggesting the envelope provides value for European healthcare systems by reducing CIED infections.

Use of healthcare claims to validate the Prevention of Arrhythmia Device Infection Trial cardiac implantable electronic device infection risk score.

AIM: The Prevention of Arrhythmia Device Infection Trial (PADIT) infection risk score, developed based on a large prospectively collected data set, identified five independent predictors of cardiac implantable electronic device (CIED) infection. We performed an independent validation of the risk score in a data set extracted from U.S. healthcare claims. METHODS AND RESULTS: Retrospective identification of index CIED procedures among patients aged ≥18 years with at least one record of a CIED procedure between January 2011 and September 2014 in a U.S health claims database. PADIT risk factors and major CIED infections (with system removal, invasive procedure without system removal, or infection-attributable death) were identified through diagnosis and procedure codes. The data set was randomized by PADIT score into Data Set A (60%) and Data Set B (40%). A frailty model allowing multiple procedures per patient was fit using Data Set A, with PADIT score as the only predictor, excluding patients with prior CIED infection. A data set of 54 042 index procedures among 51 623 patients with 574 infections was extracted. Among patients with no history of prior CIED infection, a 1 unit increase in the PADIT score was associated with a relative 28% increase in infection risk. Prior CIED infection was associated with significant incremental predictive value (HR 5.66, P < 0.0001) after adjusting for PADIT score. A Harrell's C-statistic for the PADIT score and history of prior CIED infection was 0.76. CONCLUSION: The PADIT risk score predicts increased CIED infection risk, identifying higher risk patients that could potentially benefit from targeted interventions to reduce the risk of CIED infection. Prior CIED infection confers incremental predictive value to the PADIT score.

The biophysical basis of receptor tyrosine kinase ligand functional selectivity: Trk-B case study.

Tropomyosin receptor kinase B (Trk-B) belongs to the second largest family of membrane receptors, Receptor Tyrosine Kinases (RTKs). Trk-B is known to interact with three different neurotrophins: Brain-Derived Neurotrophic Factor (BDNF), Neurotrophin-4 (NT-4), and Neurotrophin-3 (NT-3). All three neurotrophins are involved in survival and proliferation of neuronal cells, but each induces distinct signaling through Trk-B. We hypothesize that the different biological effects correlate with differences in the interactions between the Trk-B receptors, when bound to different ligands, in the plasma membrane. To test this hypothesis, we use quantitative FRET to characterize Trk-B dimerization in response to NT-3 and NT-4 in live cells, and compare it to the previously published data for Trk-B in the absence and presence of BDNF. Our study reveals that the distinct Trk-B signaling outcomes are underpinned by both different configurations and different stabilities of the three ligand-bound Trk-B dimers in the plasma membrane.

Do all patients with implantable cardioverter defibrillator need a generator change? A health service evaluation of patients who underwent generator changes from a single tertiary center.

BACKGROUND: The patient characteristics, therapy received and outcomes after one or more implantable cardioverter defibrillator (ICD) generator changes from contemporary practice is not well known. METHODS: We conducted a health service evaluation of patients who underwent ICD implantation and generator change. Patients who had generator changes from February 2016 to October 2019 were identified from our database and electronic records were reviewed for patient characteristics, number of generator changes, receipt of therapy and death. RESULTS: Our database included 88 patients with a generator change. A total of 22 patients (25.0%) received dual chamber ICD, 10 patients (11.4%) received single chamber ICD, 54 patients (61.3%) received cardiac resynchronization therapy defibrillator and 2 patients (2.3%) received subcutaneous ICD. A second generator change occurred in 18 patients and a third generator changes was performed in 6 patients. There were 29 deaths and a follow up period of 9.4 ± 2.9 years. From implant to initial generator change 39 patients had appropriate antitachycardia pacing (ATP), 6 patient had inappropriate ATP, 29 patients had appropriate shocks and 5 patients had an inappropriate shock. Between the 1st and 2nd generator change and the 2nd and 3rd there were no cases of inappropriate ATP or shock. Overall, 42 patients out of the 88 had appropriate therapy (47.7%) and 7 patients had inappropriate therapy (8.0%). CONCLUSIONS: Most patients with ICDs do not receive therapy and a minority have inappropriate therapy which typically occur before the first generator change as we observed no inappropriate therapy beyond the first generator change.

Pirfenidone in Heart Failure with Preserved Ejection Fraction-Rationale and Design of the PIROUETTE Trial.

BACKGROUND: The PIROUETTE (PIRfenidOne in patients with heart failUre and preserved lEfT venTricular Ejection fraction) trial is designed to evaluate the efficacy and safety of the anti-fibrotic pirfenidone in patients with chronic heart failure and preserved ejection fraction (HFpEF) and myocardial fibrosis. HFpEF is a diverse syndrome associated with substantial morbidity and mortality. Myocardial fibrosis is a key pathophysiological mechanism of HFpEF and myocardial fibrotic burden is strongly and independently associated with adverse outcome. Pirfenidone is an oral anti-fibrotic agent, without haemodynamic effect, that leads to regression of myocardial fibrosis in preclinical models. It has proven clinical effectiveness in pulmonary fibrosis. METHODS: The PIROUETTE trial is a randomised, double-blind, placebo-controlled phase II trial evaluating the efficacy and safety of 52 weeks of treatment with pirfenidone in patients with chronic HFpEF (symptoms and signs of heart failure, left ventricular ejection fraction ≥ 45%, elevated natriuretic peptides [BNP ≥ 100 pg/ml or NT-proBNP ≥ 300 pg/ml; or BNP ≥ 300 pg/ml or NT-proBNP ≥ 900 pg/ml if in atrial fibrillation]) and myocardial fibrosis (extracellular matrix (ECM) volume ≥ 27% measured using cardiovascular magnetic resonance). The primary outcome measure is change in myocardial ECM volume. A sub-study will investigate the relationship between myocardial fibrosis and myocardial energetics, and the impact of pirfenidone, using 31phosphorus magnetic resonance spectroscopy. DISCUSSION: PIROUETTE will determine whether pirfenidone is superior to placebo in relation to regression of myocardial fibrosis and improvement in myocardial energetics in patients with HFpEF and myocardial fibrosis (NCT02932566). CLINICAL TRIAL REGISTRATION: clinicaltrials.gov (NCT02932566) https://clinicaltrials.gov/ct2/show/NCT02932566.

Dimerization of the Trk receptors in the plasma membrane: effects of their cognate ligands.

Receptor tyrosine kinases (RTKs) are cell surface receptors which control cell growth and differentiation, and play important roles in tumorigenesis. Despite decades of RTK research, the mechanism of RTK activation in response to their ligands is still under debate. Here, we investigate the interactions that control the activation of the tropomyosin receptor kinase (Trk) family of RTKs in the plasma membrane, using a FRET-based methodology. The Trk receptors are expressed in neuronal tissues, and guide the development of the central and peripheral nervous systems during development. We quantify the dimerization of human Trk-A, Trk-B, and Trk-C in the absence and presence of their cognate ligands: human ß-nerve growth factor, human brain-derived neurotrophic factor, and human neurotrophin-3, respectively. We also assess conformational changes in the Trk dimers upon ligand binding. Our data support a model of Trk activation in which (1) Trks have a propensity to interact laterally and to form dimers even in the absence of ligand, (2) different Trk unliganded dimers have different stabilities, (3) ligand binding leads to Trk dimer stabilization, and (4) ligand binding induces structural changes in the Trk dimers which propagate to their transmembrane and intracellular domains. This model, which we call the 'transition model of RTK activation,' may hold true for many other RTKs.

The SAM domain inhibits EphA2 interactions in the plasma membrane.

All members of the Eph receptor family of tyrosine kinases contain a SAM domain near the C terminus, which has been proposed to play a role in receptor homotypic interactions and/or interactions with binding partners. The SAM domain of EphA2 is known to be important for receptor function, but its contribution to EphA2 lateral interactions in the plasma membrane has not been determined. Here we use a FRET-based approach to directly measure the effect of the SAM domain on the stability of EphA2 dimers on the cell surface in the absence of ligand binding. We also investigate the functional consequences of EphA2 SAM domain deletion. Surprisingly, we find that the EphA2 SAM domain inhibits receptor dimerization and decreases EphA2 tyrosine phosphorylation. This role is dramatically different from the role of the SAM domain of the related EphA3 receptor, which we previously found to stabilize EphA3 dimers and increase EphA3 tyrosine phosphorylation in cells in the absence of ligand. Thus, the EphA2 SAM domain likely contributes to a unique mode of EphA2 interaction that leads to distinct signaling outputs.

EphA2 Receptor Unliganded Dimers Suppress EphA2 Pro-tumorigenic Signaling.

The EphA2 receptor tyrosine kinase promotes cell migration and cancer malignancy through a ligand- and kinase-independent distinctive mechanism that has been linked to high Ser-897 phosphorylation and low tyrosine phosphorylation. Here, we demonstrate that EphA2 forms dimers in the plasma membrane of HEK293T cells in the absence of ephrin ligand binding, suggesting that the current seeding mechanism model of EphA2 activation is incomplete. We also characterize a dimerization-deficient EphA2 mutant that shows enhanced ability to promote cell migration, concomitant with increased Ser-897 phosphorylation and decreased tyrosine phosphorylation compared with EphA2 wild type. Our data reveal a correlation between unliganded dimerization and tumorigenic signaling and suggest that EphA2 pro-tumorigenic activity is mediated by the EphA2 monomer. Thus, a therapeutic strategy that aims at the stabilization of EphA2 dimers may be beneficial for the treatment of cancers linked to EphA2 overexpression.

The performance of quantitation methods in the evaluation of cardiac implantable electronic device (CIED) infection: A technical review.

BACKGROUND: Quantitative assessment of [18F]-FDG PET/CT images has been shown to be useful in the diagnosis of cardiac implantable electronic device (CIED) infection. This study aimed to compare the accuracy of various quantitative methods, using the same patient cohort and to assess the utility of dual time point imaging. METHODS: The study comprised a retrospective review of 80 [18F]-FDG PET/CT studies. Of these, 41 were oncological patients with an asymptomatic CIED in situ (Group 1), and 39 were studies performed in patients with symptomatic devices. Of these, 14 were subsequently deemed on follow-up to be non-infected (Group 2), and 25 confirmed as infected post-device extraction (Group 3). Ratios of maximal uptake around the CIED in both the attenuation corrected and non-attenuation corrected images were calculated to regions of normal physiological uptake, along with the maximal standardized uptake value (SUVmax) alone. Receiver operating characteristic analysis was performed for all methods at both time points. Measurement reliability was assessed using the intraclass correlation coefficient (ICC). RESULTS: Using Group 1 as a reference, all methods gave an area under the curve (AUC) greater than 0.93. Using Group 2 as reference, the accuracy varied greatly, with AUC values ranging from 0.71 to 0.97. The hepatic blood pool (HBP) ratio gave the highest AUC values. The calculated ICC values for each method showed the SUVmax and HBP measurement to have the greatest reliability, with values of 1.0 and 0.97, respectively. CONCLUSIONS: Quantitation of [18F] FDG uptake was found to have a high degree of accuracy in confirming the diagnosis of CIED infection. Normalization to HBP uptake was found to give the greatest AUC and demonstrated excellent reliability. Inconsistencies from published data indicate that individual imaging centers should only use published data for guidance.