Better Respiratory Function in Heart Failure Patients With Use of Central-Acting Therapeutics.

Background: Diaphragm atrophy can contribute to dyspnea in patients with heart failure (HF) with its link to central neurohormonal overactivation. HF medications that cross the blood-brain barrier could act centrally and improve respiratory function, potentially alleviating diaphragmatic atrophy. Therefore, we compared the benefit of central- vs peripheral-acting HF drugs on respiratory function, as assessed by a single cardiopulmonary exercise test (CPET) and outcomes in HF patients. Methods: A retrospective study was conducted of 624 ambulatory adult HF patients (80% male) with reduced left ventricular ejection fraction ≤ 40% and a complete CPET, followed at a single institution between 2001 and 2017. CPET parameters, and the outcomes all-cause death, a composite endpoint (all-cause death, need for left ventricular assist device, heart transplantation), and all-cause and/or HF hospitalizations, were compared in patients receiving central-acting (n = 550) vs peripheral-acting (n = 74) drugs. Results: Compared to patients who receive peripheral-acting drugs, patients who receive central-acting drugs had better respiratory function (peak breath-by breath oxygen uptake [VO2], P = 0.020; forced expiratory volume in 1 second [FEV1], P = 0.007), and ventilatory efficiency (minute ventilation / carbon dioxide production [VE/VCO2], P < 0.001; end-tidal carbon dioxide tension [PETCO2], P = 0.015; and trend for forced vital capacity [FVC], P = 0.056). Many of the associations between the CPET parameters and drug type remained significant after multivariate adjustment. Moreover, patients receiving central-acting drugs had fewer composite events (P = 0.023), and HF hospitalizations (P = 0.044), although significance after multivariant correction was not achieved, despite the hazard ratio being 0.664 and 0.757, respectively. Conclusions: Central-acting drugs were associated with better respiratory function as measured by CPET parameters in HF patients. This could extend to clinically meaningful composite outcomes and hospitalizations but required more power to be definitive in linking to drug effect. Central-acting HF drugs show a role in mitigating diaphragm weakness.

Contexte: L'atrophie du diaphragme peut contribuer à la dyspnée chez les personnes atteintes d'insuffisance cardiaque (IC), compte tenu de son lien avec la suractivation neuro-hormonale centrale. Or, les médicaments contre l'IC qui franchissent la barrière hématoencéphalique pourraient exercer une action centrale, améliorer la respiration et ainsi éventuellement atténuer l'atrophie du diaphragme. C'est pourquoi nous avons voulu comparer, au moyen d'une seule épreuve d'effort cardiopulmonaire (EECP), les effets bénéfiques exercés par des médicaments à action périphérique et des médicaments à action centrale sur la fonction respiratoire, de même que l'issue des patients atteints d'IC auxquels ils ont été administrés. Méthodologie: Nous avons réalisé une étude rétrospective auprès de 624 adultes ambulatoires atteints d'IC (80 % d'hommes) dont la fraction d'éjection ventriculaire gauche était réduite (≤ 40 %), qui se sont prêtés à une EECP complète et qui ont été suivis dans le même établissement entre 2001 et 2017. Les paramètres de l'EECP et la mortalité toutes causes confondues, un critère d'évaluation composé (décès toutes causes confondues, nécessité de recourir à un dispositif d'assistance ventriculaire gauche, transplantation cardiaque), et les hospitalisations toutes causes confondues et/ou liées à l'IC ont été comparés entre les patients qui recevaient des médicaments à action centrale (n = 550) et ceux qui recevaient des médicaments à action périphérique (n = 74). Résultats: Comparativement aux patients ayant reçu des médicaments à action périphérique, ceux qui ont reçu des médicaments à action centrale ont bénéficié d'une meilleure fonction respiratoire (consommation maximale d'oxygène [VO2], p = 0,020; volume expiratoire maximal par seconde [VEMS], p = 0,007) et d'une meilleure efficacité ventilatoire (ventilation minute/production de dioxyde de carbone [VE/VCO2], p < 0,001; pression partielle de dioxyde de carbone en fin d'expiration [PETCO2], p = 0,015; et tendance de la capacité vitale forcée [CVF], p = 0,056). De plus, bon nombre des associations entre les paramètres de l'EECP et le type de médicament sont demeurées significatives après ajustement multivarié. Les patients qui ont reçu des médicaments à action centrale ont également présenté moins d'événements faisant partie du critère d'évaluation composé (p = 0,023) et moins d'hospitalisations liées à l'IC (p = 0,044), même si la différence après correction multivariée n'a pas été significative et que les rapports de risques étaient respectivement de 0,664 et de 0,757. Conclusions: Les médicaments à action centrale ont été associés à une meilleure fonction respiratoire, mesurée à l'aide des paramètres d'une EECP, chez les patients atteints d'IC. Ce résultat pourrait également s'appliquer au critère d'évaluation composé et aux hospitalisations, mais une étude plus puissante est nécessaire pour établir un lien cliniquement significatif avec l'effet des médicaments. Les médicaments à action centrale contre l'IC ont donc un rôle à jouer dans la correction de la faiblesse du diaphragme.

Predicting heart failure outcomes by integrating breath-by-breath measurements from cardiopulmonary exercise testing and clinical data through a deep learning survival neural network.

Aims: Mathematical models previously developed to predict outcomes in patients with heart failure (HF) generally have limited performance and have yet to integrate complex data derived from cardiopulmonary exercise testing (CPET), including breath-by-breath data. We aimed to develop and validate a time-to-event prediction model using a deep learning framework using the DeepSurv algorithm to predict outcomes of HF. Methods and results: Inception cohort of 2490 adult patients with high-risk cardiac conditions or HF underwent CPET with breath-by-breath measurements. Potential predictive features included known clinical indicators, standard summary statistics from CPETs, and mathematical features extracted from the breath-by-breath time series of 13 measurements. The primary outcome was a composite of death, heart transplant, or mechanical circulatory support treated as a time-to-event outcomes. Predictive features ranked as most important included many of the features engineered from the breath-by-breath data in addition to traditional clinical risk factors. The prediction model showed excellent performance in predicting the composite outcome with an area under the curve of 0.93 in the training and 0.87 in the validation data sets. Both the predicted vs. actual freedom from the composite outcome and the calibration of the prediction model were excellent. Model performance remained stable in multiple subgroups of patients. Conclusion: Using a combined deep learning and survival algorithm, integrating breath-by-breath data from CPETs resulted in improved predictive accuracy for long-term (up to 10 years) outcomes in HF. DeepSurv opens the door for future prediction models that are both highly performing and can more fully use the large and complex quantity of data generated during the care of patients with HF.

Optimization of Postprocessing parameters for abdominal Forensic CT scans.

Aim: Postmortem Computed Tomography (PMCT) is gradually introduced at forensic institutes. Image reconstruction software can increase diagnostic potential in CT by increasing distinction between structures and reduction of artifacts. The aim of this study was to develop and evaluate novel image reconstruction parameters for postmortem conditions, to increase image quality and diagnostic potential of CT scans. Method: Twenty PMCT scans of deceased hereof two in severe decay were subjected to four reconstruction techniques: a standard reconstruction algorithm, the detail reconstruction algorithm and two novel algorithms based on the standard algorithm, but with different Hounsfield settings. Image quality was evaluated by visual grading analysis (VGA) by four forensic radiologist observers. Results: The VGA did not prove that any of the reconstruction techniques were superior to the others. For standard and detail, the two pre-defined reconstruction algorithms, VGA scores were indiscernible and were superior to the equally indiscernible Hounsfield reconstructions on parameters translated into Sharpness and Low Contrast Resolution. The two alternative Hounsfield settings were superior with respect to Noise and Artifacts/Beam Hardening. Conclusion: The study elucidates the possiblity for multiple reconstructions specialized for PMCT conditions, to accommodate the special conditions when working with the deceased. Despite the lack of clear improvements in the tested reconstructions, this study provides an insight into some of the possibilities of improving PMCT quality using reconstruction techniques.

Discovery and preclinical development of a therapeutically active nanobody-based chimeric antigen receptor targeting human CD22.

Chimeric antigen receptor (CAR) T cell therapies targeting B cell-restricted antigens CD19, CD20, or CD22 can produce potent clinical responses for some B cell malignancies, but relapse remains common. Camelid single-domain antibodies (sdAbs or nanobodies) are smaller, simpler, and easier to recombine than single-chain variable fragments (scFvs) used in most CARs, but fewer sdAb-CARs have been reported. Thus, we sought to identify a therapeutically active sdAb-CAR targeting human CD22. Immunization of an adult Llama glama with CD22 protein, sdAb-cDNA library construction, and phage panning yielded >20 sdAbs with diverse epitope and binding properties. Expressing CD22-sdAb-CAR in Jurkat cells drove varying CD22-specific reactivity not correlated with antibody affinity. Changing CD28- to CD8-transmembrane design increased CAR persistence and expression in vitro. CD22-sdAb-CAR candidates showed similar CD22-dependent CAR-T expansion in vitro, although only membrane-proximal epitope targeting CD22-sdAb-CARs activated direct cytolytic killing and extended survival in a lymphoma xenograft model. Based on enhanced survival in blinded xenograft studies, a lead CD22sdCAR-T was selected, achieving comparable complete responses to a benchmark short linker m971-scFv CAR-T in high-dose experiments. Finally, immunohistochemistry and flow cytometry confirm tissue and cellular-level specificity of the lead CD22-sdAb. This presents a complete report on preclinical development of a novel CD22sdCAR therapeutic.

N-Terminal Pro-Brain Type Natriuretic Peptide Predicts Cardiovascular Events Independently of Arterial Stiffness, Assessed By Carotid-to-Femoral Pulse Wave Velocity, in Apparently Healthy Subjects.

AIM: This study aimed to evaluate whether N-terminal pro-brain natriuretic peptide (NT-proBNP) and carotid-to-femoral pulse wave velocity (PWV) carried independent prognostic value in predicting cardiovascular events in apparently healthy individuals beyond traditional risk factors. METHODS: A total of 1,872 participants aged 41, 51, 61, or 71 years from the MONItoring of trends and determinants in CArdiovascular disease (MONICA) study were included. Traditional risk factors were assessed, including: smoking status; mean systolic and diastolic blood pressure; body mass index; fasting plasma glucose; serum triglycerides; total, high-density, and low-density lipoprotein cholesterol; NT-proBNP; and PWV. The principal endpoint that was assessed during 16 years of follow-up was a composite of major adverse cardiovascular events (MACE). The secondary endpoints were cardiovascular mortality (CVM), hospitalisation for coronary artery disease (CAD), and a composite of hospitalisation for heart failure (HF) or atrial fibrillation (AF). RESULTS: At baseline, NT-proBNP was associated with PWV (ß=0.14; p<0.001), but not after adjustment for traditional risk factors (ß=-0.01; p=0.67). In models including traditional risk factors and PWV, NT-proBNP was associated with all four outcomes (HRMACE=1.33, 95% CI 1.16-1.52; HRCVM=2.02, 95% CI 1.65-2.48; HRCAD=1.29, 95% CI 1.07-1.55; and HRHF or AF=1.79, 95% CI 1.40-2.28). In the same model, PWV was only associated with CVM (HRCVM=1.20, 95% CI 1.01-1.41). No interactions between NT-proBNP and PWV were found. N-terminal pro-brain natriuretic peptide significantly improved net reclassification (NRI) for MACE (NRI=0.12; p=0.03), CVM (NRI=0.33; p<0.001), and HF or AF (NRI=0.33; p<0.001) beyond traditional risk factors, while PWV did not aid in net reclassification improvement for any endpoint. CONCLUSIONS: In apparently healthy individuals, NT-proBNP and PWV predicted cardiovascular events independently. N-terminal pro-brain natriuretic peptide improved reclassification for the prediction of MACE, CVM, and hospitalisation for HF or AF beyond traditional risk factors, while PWV did not.

An analysis of national media coverage of a parental leave reform investigating sentiment, semantics and contributors.

While paid leave for fathers after the birth of a child has become increasingly available, mothers still take most of the parental leave. A recent European Union (EU) reform addresses the unequal sharing of leave between parents via earmarking of paid, non-shareable leave to each parent. Given that the reform's success will depend on uptake by families, we analysed Danish national media coverage to understand how journalists were writing about the reform. We assessed the sentiment and semantics of leave reform coverage compared to general news from the same period, also considering the inferred journalist gender and newspaper political orientation. Parental leave reform articles were slightly more emotional than general news, independent of who authored the article, or the newspaper where it was published. We found a robust difference in the semantics of how female journalists wrote about the reform, relative to male journalists, and that female journalists contributed to media coverage at a higher-than-expected rate. The tendency for media coverage to be written with a non-neutral sentiment can be understood in terms of the enduring political tensions over gender equality, the role of the EU and families' rights to self-organization. That female journalists over-contributed to media coverage is interesting in understanding topic assignments or interest in parental leave.

Pulmonary Artery Catheter Usage and Impact on Mortality in Patients With Cardiogenic Shock: Results From a Canadian Single-Centre Registry.

BACKGROUND: Hemodynamic assessment for cardiogenic shock (CS) phenotyping in patients has led to renewed interest in the use of pulmonary artery catheters (PACs). METHODS: We included patients admitted with CS from January 2014 to December 2020 and compared clinical outcomes among patients who received PACs and those who did not. The primary outcome was the rate of in-hospital mortality. Secondary outcomes included use of advanced heart failure therapies and coronary intensive care unit (CICU) and hospital lengths of stay. RESULTS: A total of 1043 patients were analysed and 47% received PACs. Patients selected for PAC-guided management were younger and had lower left ventricular function. They also had higher use of vasopressor and inotropes, and 15.2% of them were already supported with temporary mechanical circulatory support (MCS). In-hospital mortality was lower in patients who received PACs (29.3% vs 36.2%; P = 0.02), mainly driven by a reduction in mortality among those in Society for Cardiovascular Angiography and Interventions (SCAI) stages D and E CS. Patients who received PACs were more likely to receive temporary MCS with Impella, durable ventricular assist devices (VADs), or orthotopic heart transplantation (OHT) (P < 0.001 for all analyses). CICU and hospital lengths of stay were longer in patients who used PACs. CONCLUSIONS: Among patients with CS, the use of PACs was associated with lower in-hospital mortality, especially among those in SCAI stages D and E. Patients who received PACs were also more frequently rescued with temporary MCS or received advanced heart failure therapies, such as durable VADs or OHT.

Sexual function improves as depressive symptoms decrease during treatment with escitalopram: results of a naturalistic study of patients with major depressive disorder.

BACKGROUND: Major depressive disorder (MDD) is closely associated with sexual dysfunction, which may worsen during treatment with selective serotonin reuptake inhibitors (SSRIs) due to the side effects of pharmacologic treatment. AIM: To examine the association between sexual function and severity of MDD in drug-naïve patients as compared with healthy controls and how treatment with SSRIs affects sexual function over time in individuals with MDD. Interaction with gender and treatment response was examined. METHODS: In 92 patients with MDD, we measured MDD severity with 6- and 17-item versions of the Hamilton Depression Rating Scale (HDRS6 and HDRS17) and the level of sexual function with the Changes in Sexual Functioning Questionnaire at baseline and 4, 8, and 12 weeks after initiating treatment with escitalopram. Baseline sexual function was compared with the sexual function of 73 healthy controls. Linear regression models were used to assess differences in sexual function between healthy controls and patients and change in sexual function from baseline to week 12. Linear mixed models were used to assess differences in change in sexual function between treatment response groups. OUTCOMES: Outcomes included total scores on the HDRS6, HDRS17, and Changes in Sexual Functioning Questionnaire and changes in total scores from baseline to week 12. RESULTS: Unmedicated patients with MDD reported impaired sexual function as compared with healthy controls. Level of sexual function was not associated with severity of MDD at baseline. Patients' sexual function improved significantly during treatment, which was coupled with amelioration of depressive symptoms. Treatment response groups (remitters, intermediate responders, nonresponders) did not predict change in sexual function. Gender had no effect on sexual dysfunction symptoms during treatment. CLINICAL IMPLICATIONS: Major depression is a risk factor for sexual problems, and improvement in sexual function was coupled with amelioration of depressive symptoms. STRENGTHS AND LIMITATIONS: Among its strengths, this was a naturalistic study reflecting real-world settings in clinical practice. It additionally included a baseline measurement of sexual function and MDD severity on drug-naïve patients prior to the initiation of treatment. Finally, the follow-up of 12 weeks extends beyond the acute phase of treatment in which previous research has observed a peak in sexual side effects. In terms of limitations, there was no placebo arm; thus, the study cannot attribute the effects on sexual function to treatment with antidepressants per se. Also, the patients were young, which may have served as a protective factor against sexual side effects. CONCLUSION: Sexual dysfunction was strongly associated with MDD and improved in parallel with overall symptoms of depression across a standard 12-week treatment with SSRI antidepressants. CLINICAL TRIAL REGISTRATION: NCT02869035 (https://clinicaltrials.gov/ct2/show/NCT02869035).

The influence of age and sex on the prognostic importance of traditional cardiovascular risk factors, selected circulating biomarkers and other markers of subclinical cardiovascular damage.

PURPOSE OF REVIEW: There is an increasing need for improved risk stratification to better individualize cardiovascular preventive measures. Although age and sex are strong and easily obtained cardiovascular risk factors (CVRFs), their influence on the prognostic importance of other CVRF, circulating biomarkers and other markers of subclinical cardiovascular damage has not previously been systematically and critically appraised. Therefore, we have revisited the European MORGAM and the Danish MONI10 cohorts. RECENT FINDINGS: Theoretically, the relative risk of many CVRF is expected to be lower in older healthy individuals due to a combination of selection bias by disease, higher absolute risk primarily due to older age, and the fact that the CVRF and markers may primarily influence or reflect early parts of the cardiovascular disease process. This influence of age may vary between sexes, as the cardiovascular disease process is delayed and possibly different in women compared with men. SUMMARY: Adjusted for the remaining Systematic COronary Risk Evaluation (SCORE) CVRF, higher SBP, serum cholesterol, soluble urokinase-type plasminogen activator receptor, left ventricular mass index and atherosclerotic plaques were more closely associated with outcomes in individuals younger than 52 years with some sex-specific differences, whereas higher N-terminal pro-brain natriuretic peptide and urine albumin/creatine ratio were more closely associated with outcomes in subjects aged 61 or 71 years.

Risk prediction of atrial fibrillation and its complications in the community using hs troponin I.

AIMS: Atrial fibrillation (AF) is becoming increasingly common. Traditional cardiovascular risk factors (CVRF) do not explain all AF cases. Blood-based biomarkers reflecting cardiac injury such as high-sensitivity troponin I (hsTnI) may help close this gap. METHODS: We investigated the predictive ability of hsTnI for incident AF in 45,298 participants (median age 51.4 years, 45.0% men) across European community cohorts in comparison to CVRF and established biomarkers (C-reactive protein, N-terminal pro B-type natriuretic peptide). RESULTS: During a median follow-up of 7.7 years, 1734 (3.8%) participants developed AF. Those in the highest hsTnI quarter (≥4.2 ng/L) had a 3.91-fold (95% confidence interval (CI) 3.30, 4.63; p < .01) risk for developing AF compared to the lowest quarter (<1.4 ng/L). In multivariable-adjusted Cox proportional hazards models a statistically significant association was seen between hsTnI and AF (hazard ratio (HR) per 1 standard deviation (SD) increase in log10(hsTnI) 1.08; 95% CI 1.01, 1.16; p = .03). Inclusion of hsTnI did improve model discrimination (C-index CVRF 0.811 vs. C-index CVRF and hsTnI 0.813; p < .01). Higher hsTnI concentrations were associated with heart failure (HR per SD 1.37; 95% CI 1.12, 1.68; p < .01) and overall mortality (HR per SD 1.24; 95% CI 1.09, 1.41; p < .01). CONCLUSION: hsTnI as a biomarker of myocardial injury does not improve prediction of AF incidence beyond classical CVRF and NT-proBNP. However, it is associated with the AF-related disease heart failure and mortality likely reflecting underlying subclinical cardiovascular impairment.

Exploring the incremental utility of circulating biomarkers for robust risk prediction of incident atrial fibrillation in European cohorts using regressions and modern machine learning methods.

AIMS: To identify robust circulating predictors for incident atrial fibrillation (AF) using classical regressions and machine learning (ML) techniques within a broad spectrum of candidate variables. METHODS AND RESULTS: In pooled European community cohorts (n = 42 280 individuals), 14 routinely available biomarkers mirroring distinct pathophysiological pathways including lipids, inflammation, renal, and myocardium-specific markers (N-terminal pro B-type natriuretic peptide [NT-proBNP], high-sensitivity troponin I [hsTnI]) were examined in relation to incident AF using Cox regressions and distinct ML methods. Of 42 280 individuals (21 843 women [51.7%]; median [interquartile range, IQR] age, 52.2 [42.7, 62.0] years), 1496 (3.5%) developed AF during a median follow-up time of 5.7 years. In multivariable-adjusted Cox-regression analysis, NT-proBNP was the strongest circulating predictor of incident AF [hazard ratio (HR) per standard deviation (SD), 1.93 (95% CI, 1.82-2.04); P < 0.001]. Further, hsTnI [HR per SD, 1.18 (95% CI, 1.13-1.22); P < 0.001], cystatin C [HR per SD, 1.16 (95% CI, 1.10-1.23); P < 0.001], and C-reactive protein [HR per SD, 1.08 (95% CI, 1.02-1.14); P = 0.012] correlated positively with incident AF. Applying various ML techniques, a high inter-method consistency of selected candidate variables was observed. NT-proBNP was identified as the blood-based marker with the highest predictive value for incident AF. Relevant clinical predictors were age, the use of antihypertensive medication, and body mass index. CONCLUSION: Using different variable selection procedures including ML methods, NT-proBNP consistently remained the strongest blood-based predictor of incident AF and ranked before classical cardiovascular risk factors. The clinical benefit of these findings for identifying at-risk individuals for targeted AF screening needs to be elucidated and tested prospectively.

Patients with fulminant myocarditis supported with veno-arterial extracorporeal membrane oxygenation: a systematic review and meta-analysis of short-term mortality and impact of risk factors.

Fulminant myocarditis (FM) may lead to cardiogenic shock requiring veno-arterial extracorporeal membrane oxygenation (VA-ECMO). Results of effectiveness studies of VA-ECMO have been contradictory. We evaluated the aggregate short-term mortality after VA-ECMO and predictive factors in patients with FM. We systematically searched in electronic databases (February 2022) to identify studies evaluating short-term mortality (defined as mortality at 30 days or in-hospital) after VA-ECMO support for FM. We included studies with 5 or more patients published after 2009. We assessed the quality of the evidence using the QUIPS and GRADE tools. Mortality was pooled using random effect models. We performed meta-regression to explore heterogeneity based on a priori defined factors. We included 54 observational studies encompassing 2388 FM patients supported with VA-ECMO. Median age was 41 years (25th to 75th percentile 37-47), and 50% were female. The pooled short-term mortality was 35% (95% CI 29-40%, I2 = 69%; moderate certainty). By meta-regression, studies with younger populations showed lower mortality. Female sex, receiving a biopsy, cardiac arrest, left ventricular unloading, and earlier recruitment time frame, did not explain heterogeneity. These results remained consistent regardless of continent and the risk of bias category. In individual studies, low pH value, high lactate, absence of functional cardiac recovery on ECMO, increased burden of malignant arrhythmia, high peak coronary markers, and IVIG use were identified as independent predictors of mortality. When conventional therapies have failed, especially in younger patients, cardiopulmonary support with VA-ECMO should be considered in the treatment of severe FM.

Association Between the Incidence of Hospitalizations for Acute Cardiovascular Events, Weather, and Air Pollution.

Background: The incidence of hospitalizations for cardiovascular events has been associated with specific weather conditions and air pollution. A comprehensive model including the interactions between various environmental factors remains to be developed. Objectives: The purpose of this study was to develop a comprehensive model of the association between weather patterns and the incidence of cardiovascular events and use this model to forecast near-term spatiotemporal risk. Methods: We present a spatiotemporal analysis of the association between atmospheric data and the incidence rate of hospital admissions related to heart failure (922,132 episodes), myocardial infarction (521,988 episodes), and ischemic stroke (263,529 episodes) in ∼24 million people in Canada between 2007 and 2017. Our hierarchical Bayesian model captured the spatiotemporal distribution of hospitalizations and identified weather and air pollution-related factors that could partially explain fluctuations in incidence. Results: Models that included weather and air pollution variables outperformed models without those covariates for most event types. Our results suggest that environmental factors may interact in complex ways on human physiology. The impact of environmental factors was magnified with increasing age. The weather and air pollution variables included in our models were predictive of the future incidence of heart failure, myocardial infarction, and ischemic strokes. Conclusions: The increasing importance of environmental factors on cardiovascular events with increasing age raises the need for the development of educational materials for older patients to recognize environmental conditions where exacerbations are more likely. This model could be the basis of a forecasting system used for local, short-term clinical resource planning based on the anticipated incidence of events.

Hemodynamic reserve predicts early right heart failure after LVAD implantation.

BACKGROUND: Early right heart failure (RHF) remains a major source of morbidity and mortality after left ventricular assist device (LVAD) implantation, yet efforts to predict early RHF have proven only modestly successful. Pharmacologic unloading of the left ventricle may be a risk stratification approach allowing for assessment of right ventricular and hemodynamic reserve. METHODS: We performed a multicenter, retrospective analysis of patients who had undergone continuous-flow LVAD implantation from October 2011 to April 2020. Only those who underwent vasodilator testing with nitroprusside during their preimplant right heart catheterization were included (n = 70). Multivariable logistic regression was used to determine independent predictors of early RHF as defined by Mechanical Circulatory Support-Academic Research Consortium. RESULTS: Twenty-seven patients experienced post-LVAD early RHF (39%). Baseline clinical characteristics were similar between patients with and without RHF. Patients without RHF, however, achieved higher peak stroke volume index (SVI) (30.1 ± 8.8 vs 21.7 ± 7.4 mL/m2; p < 0.001; AUC: 0.78; optimal cut-point: 22.1 mL/m2) during nitroprusside administration. Multivariable analysis revealed that peak SVI was significantly associated with early RHF, demonstrating a 16% increase in risk of early RHF per 1 ml/m2 decrease in SVI. A follow up cohort of 10 consecutive patients from July 2020 to October 2021 resulted in all patients being categorized appropriately in regards to early RHF versus no RHF according to peak SVI. CONCLUSION: Peak SVI with nitroprusside administration was independently associated with post-LVAD early RHF while resting hemodynamics were not. Vasodilator testing may prove to be a strong risk stratification tool when assessing LVAD candidacy though additional prospective validation is needed.

Identification of the Biosynthetic Gene Cluster for Pyracrimycin A, an Antibiotic Produced by Streptomyces sp.

Actinomycetes make a wealth of complex, structurally diverse natural products, and a key challenge is to link them to their biosynthetic gene clusters and delineate the reactions catalyzed by each of the enzymes. Here, we report the biosynthetic gene cluster for pyracrimycin A, a set of nine genes that includes a core nonribosomal peptide synthase (pymB) that utilizes serine and proline as precursors and a monooxygenase (pymC) that catalyzes Baeyer-Villiger oxidation. The cluster is similar to the one for brabantamide A; however, pyracrimycin A biosynthesis differs in that feeding experiments with isotope-labeled serine and proline suggest that a ring opening reaction takes place and a carbon is lost from serine downstream of the oxidation reaction. Based on these data, we propose a full biosynthesis pathway for pyracrimycin A.

Impact of serial measurements of tricuspid annular plane systolic excursion on mortality and morbidity after heart transplantation.

The impact of right ventricular (RV) dysfunction on long-term post-HTx outcomes remains uncertain. We assessed the impact of serial measurements of Tricuspid Annular Plane Systolic Excursion (TAPSE) on post-HTx mortality and morbidity. This two-center retrospective cohort study included consecutive adult HTx recipients (2000-2017). We used multivariable extended hazard regression models to evaluate the association between TAPSE and left ventricular ejection fraction (LVEF), entered as time-dependent variables, and all-cause mortality, cardiac allograft vasculopathy (CAV), acute cellular rejection (ACR), and chronic kidney disease (CKD). TAPSE was modelled using cubic splines. We included 485 HTx recipients (9461 TAPSE measurements), median (25th- 75th percentile) 19 (10-27) mm; median age was 52 (41-59) years, and 71.3% were male. During a follow-up of 6.7 (3.0-10.8) years, 92 patients died, 225 had ACR >2R, 234 CAV, and 91 CKD. By multivariable analysis, for each 1-mm decrease in patients with a TAPSE value <15mm, mortality increased by 22% (P<.001). For the average HTx recipient with a TAPSE of 15mm, 10mm, and 6mm, 1-year mortality was 3%, 7%, and 17%, and 5-year mortality was 8%, 20%, and 43%, respectively. Reduced TAPSE was significantly associated with increased CAV but notACR and CKD. A decrease in TAPSE below 15mm represents clinically significant graft dysfunction, warranting close monitoring.

Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma.

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell-mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

Risk Factors, Subsequent Disease Onset, and Prognostic Impact of Myocardial Infarction and Atrial Fibrillation.

Background Although myocardial infarction (MI) and atrial fibrillation (AF) are frequent comorbidities and share common cardiovascular risk factors, the direction and strength of the association of the risk factors with disease onset, subsequent disease incidence, and mortality are not completely understood. Methods and Results In pooled multivariable Cox regression analyses, we examined temporal relations of disease onset and identified predictors of MI, AF, and all-cause mortality in 108 363 individuals (median age, 46.0 years; 48.2% men) free of MI and AF at baseline from 6 European population-based cohorts. During a maximum follow-up of 10.0 years, 3558 (3.3%) individuals were diagnosed exclusively with MI, 1922 (1.8%) with AF but no MI, and 491 (0.5%) individuals developed both MI and AF. Association of sex, systolic blood pressure, antihypertensive treatment, and diabetes appeared to be stronger with incident MI than with AF, whereas increasing age and body mass index showed a higher risk for incident AF. Total cholesterol and daily smoking were significantly related to incident MI but not AF. Combined population attributable fraction of cardiovascular risk factors was >70% for incident MI, whereas it was only 27% for AF. Subsequent MI after AF (hazard ratio [HR], 1.68; 95% CI, 1.03-2.74) and subsequent AF after MI (HR, 1.75; 95% CI, 1.31-2.34) both significantly increased overall mortality risk. Conclusions We observed different associations of cardiovascular risk factors with both diseases indicating distinct pathophysiological pathways. Subsequent diagnoses of MI and AF significantly increased mortality risk.

Advanced heart failure: guideline-directed medical therapy, diuretics, inotropes, and palliative care.

Heart failure (HF) is a major cause of mortality, hospitalizations, and reduced quality of life and a major burden for the healthcare system. The number of patients that progress to an advanced stage of HF is growing. Only a limited proportion of these patients can undergo heart transplantation or mechanical circulatory support. The purpose of this review is to summarize medical management of patients with advanced HF. First, evidence-based oral treatment must be implemented although it is often not tolerated. New therapeutic options may soon become possible for these patients. The second goal is to lessen the symptomatic burden through both decongestion and haemodynamic improvement. Some new treatments acting on cardiac function may fulfil both these needs. Inotropic agents acting through an increase in intracellular calcium have often increased risk of death. However, in the recent Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) trial, omecamtiv mecarbil was safe and effective in the reduction of the primary outcome of cardiovascular death or HF event compared with placebo (hazard ratio, 0.92; 95% confidence interval, 0.86-0.99; P = 0.03) and its effects were larger in those patients with more severe left ventricular dysfunction. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit, whereas patients without severe HF did not (P = 0.005 for interaction). Lastly, clinicians should take care of the end of life with an appropriate multidisciplinary approach. Medical treatment of advanced HF therefore remains a major challenge and a wide open area for further research.