mPAP/CO Slope and Oxygen Uptake Add Prognostic Value in Aortic Stenosis.

BACKGROUND: Recent guidelines redefined exercise pulmonary hypertension as a mean pulmonary artery pressure/cardiac output (mPAP/CO) slope >3 mm Hg·L-1·min-1. A peak systolic pulmonary artery pressure >60 mm Hg during exercise has been associated with an increased risk of cardiovascular death, heart failure rehospitalization, and aortic valve replacement in aortic valve stenosis. The prognostic value of the mPAP/CO slope in aortic valve stenosis remains unknown. METHODS: In this prospective cohort study, consecutive patients (n=143; age, 73±11 years) with an aortic valve area ≤1.5 cm2 underwent cardiopulmonary exercise testing with echocardiography. They were subsequently evaluated for the occurrence of cardiovascular events (ie, cardiovascular death, heart failure hospitalization, new-onset atrial fibrillation, and aortic valve replacement) during a follow-up period of 1 year. Findings were externally validated (validation cohort, n=141). RESULTS: One cardiovascular death, 32 aortic valve replacements, 9 new-onset atrial fibrillation episodes, and 4 heart failure hospitalizations occurred in the derivation cohort, whereas 5 cardiovascular deaths, 32 aortic valve replacements, 1 new-onset atrial fibrillation episode, and 10 heart failure hospitalizations were observed in the validation cohort. Peak aortic velocity (odds ratio [OR] per SD, 1.48; P=0.036), indexed left atrial volume (OR per SD, 2.15; P=0.001), E/e' at rest (OR per SD, 1.61; P=0.012), mPAP/CO slope (OR per SD, 2.01; P=0.002), and age-, sex-, and height-based predicted peak exercise oxygen uptake (OR per SD, 0.59; P=0.007) were independently associated with cardiovascular events at 1 year, whereas peak systolic pulmonary artery pressure was not (OR per SD, 1.28; P=0.219). Peak Vo2 (percent) and mPAP/CO slope provided incremental prognostic value in addition to indexed left atrial volume and aortic valve area (P<0.001). These results were confirmed in the validation cohort. CONCLUSIONS: In moderate and severe aortic valve stenosis, mPAP/CO slope and percent-predicted peak Vo2 were independent predictors of cardiovascular events, whereas peak systolic pulmonary artery pressure was not. In addition to aortic valve area and indexed left atrial volume, percent-predicted peak Vo2 and mPAP/CO slope cumulatively improved risk stratification.

Evolution of the use of intraosseous vascular access in prehospital advanced cardiopulmonary resuscitation: The IOVA-CPR study.

INTRODUCTION: Obtaining vascular access is crucial in critically ill patients. The EZ-IO® device is easy to use and has a high insertion success rate. Therefore, the use of intraosseous vascular access (IOVA) has gradually increased. AIM: We aim to determine how IOVA was integrated into management of vascular access during out-of-hospital cardiac arrest (OHCA) resuscitation. METHODS: Analysing the data from the OHCA French registry for events occurring between 1 January 2013 and 15 March 2021, we studied: demography, circumstances of occurrence and management including vascular access, delays and evolution. The primary outcome was the rate of IOVA implantation. RESULTS: Among the 7156 OHCA included in the registry, we analysed the 3964 (55%) who received cardiopulmonary resuscitation. The vascular access was peripheral in 3122 (79%) cases, intraosseous in 775 (20%) cases and central in 12 (<1%) cases. The use of IOVA has increased linearly (R2 = 0.61) during the 33 successive trimesters studied representing 7% of all vascular access in 2013 and 33% in 2021 (p = 0.001). It was significantly more frequent in traumatic cardiac arrest: 12% versus 5%; p < 0.0001. The first epinephrine bolus occurred significantly later in the IOVA group, at 6 (4-10) versus 5 (3-8) min; p < 0.0001. Survival rate in the IOVA group was significantly lower, at 1% versus 7%; p < 0.0001. CONCLUSION: The insertion rate of IOVA significantly increased over the studied period, to reach 30% of all vascular access in the management OHCA patients. The place of the intraosseous route in the strategy of venous access during the management of prehospital cardiac arrest has yet to be determined.

Digit preference and biased conclusions in cardiac arrest studies.

BACKGROUND: In cardiac arrest (CA), time is directly predictive of patients' prognosis. The increase in mortality resulting from delayed cardiopulmonary resuscitation has been quantified minute by minute. Times reported in CA management studies could reflect a timestamping bias referred to as "digit preference". This phenomenon leads to a preference for certain numerical values (such as 2, 5, or 10) over others (such as 13). Our objective was to investigate whether or not digit preference phenomenon could be observed in reported times of the day related to CA management, as noted in a national registry. METHODS: We analyzed data from the French National Electronic Registry of Cardiac Arrests. We analyzed twelve times-of-the-day corresponding to each of the main steps of CA management reported by the emergency physicians who managed the patients in prehospital settings. We postulated that if CA occurred at random times throughout the day, then we could expect to see events related to CA management occurring at a similar rate each minute of each hour of the day, at a fraction of 1/60. We compared the fraction of times reported as multiples of 15 (0, 15, 30, and 45 - on the hour, quarters, half hour) with the expected fraction of 4/60 (i.e. 4 × 1/60). MAIN RESULTS: A total of 47,211 times-of-the-day in relation to 6131 CA were analyzed. The most overrepresented numbers were: 0, with 3737 occurrences (8% vs 2% expected, p < 0.0001) and 30, with 2807 occurrences (6% vs 2% expected, p < 0.0001). Times-of-the-day as multiples of 15 were overrepresented (22% vs 7% expected, p < 0.0001). CONCLUSION: Prospectively collected times were considerably influenced by digit preference phenomenon. Studies that are not based on automatic time recordings and that have not evaluated and considered this bias should be interpretated with caution.

Arrythmia-Mediated Valvular Heart Disease.

The aging population is rising at record pace worldwide. Along with it, a steep increase in the prevalence of atrial fibrillation and heart failure with preserved ejection fraction is to be expected. Similarly, both atrial functional mitral and tricuspid regurgitation (AFMR and AFTR) are increasingly observed in daily clinical practice. This article summarizes all current evidence regarding the epidemiology, prognosis, pathophysiology, and therapeutic options. Specific attention is addressed to discern AFMR and AFTR from their ventricular counterparts, given their different pathophysiology and therapeutic needs.

Prognostic importance of the transmitral pressure gradient in mitral annular calcification with associated mitral valve dysfunction.

AIMS: The aim of this study was to define the natural history of patients with mitral annular calcification (MAC)-related mitral valve dysfunction and to assess the prognostic importance of mean transmitral pressure gradient (MG) and impact of concomitant mitral regurgitation (MR). METHODS AND RESULTS: The institutional echocardiography database was examined from 2001 to 2019 for all patients with MAC and MG ≥3 mmHg. A total of 5754 patients were stratified by MG in low (3-5 mmHg, n = 3927), mid (5-10 mmHg, n = 1476), and high (≥10 mmHg, n = 351) gradient. The mean age was 78 ± 11 years, and 67% were female. MR was none/trace in 32%, mild in 42%, moderate in 23%, and severe in 3%. Primary outcome was all-cause mortality, and outcome models were adjusted for age, sex, and MAC-related risk factors (hypertension, diabetes, coronary artery disease, chronic kidney disease). Survival at 1, 5, and 10 years was 77%, 42%, and 18% in the low-gradient group; 73%, 38%, and 17% in the mid-gradient group; and 67%, 25%, and 11% in the high-gradient group, respectively (log-rank P < 0.001 between groups). MG was independently associated with mortality (adjusted HR 1.064 per 1 mmHg increase, 95% CI 1.049-1.080). MR severity was associated with mortality at low gradients (P < 0.001) but not at higher gradients (P = 0.166 and 0.372 in the mid- and high-gradient groups, respectively). CONCLUSION: In MAC-related mitral valve dysfunction, mean transmitral gradient is associated with increased mortality after adjustment for age, sex, and MAC-related risk factors. Concomitant MR is associated with excess mortality in low-gradient ranges (3-5 mmHg) but gradually loses prognostic importance at higher gradients, indicating prognostic utility of transmitral gradient in MAC regardless of MR severity.

[Prevalence of advance directives and impact on the progress of cardiac arrest resuscitation in EHPAD]. / Prévalence des directives anticipées et impact sur le déroulement de la réanimation d'arrêts cardiaques en Ehpad.

Anticipated directives are of great value among patients living in residential care facilities for the elderly. Their prevalence in cases of cardiac arrest was studied. It was found that this issue is not systematically addressed. This results in the inappropriate use of resuscitation manoeuvres that could be avoided. This is an area that needs to be addressed in depth.

Can We Reduce Frame Rate to 15 Images per Second in Pediatric Videofluoroscopic Swallow Studies?

Videofluoroscopic Swallow studies (VFSS) are useful radiological examinations to explore swallowing disorders but which require ionizing radiation. The aim of our study was to evaluate the comparability of pediatric VFSS at 15 frames per second (fps) with 30 fps. Fifty-five loops including 190 swallowings of VFSS at 30 fps performed on 32 consecutive pediatric patients in a University Hospital Center were retrospectively modified by a software to delete one image out of two to obtain secondary loops with a frame rate of 15 fps. An otorhinolaryngologist-phonatrician and a radiologist reviewed all swallowings blindly and randomly using the penetration and aspiration scale (PAS). In case of discordance, they concluded a consensual interpretation. Fifteen girls and seventeen boys were included. The median age was 4 years and 8 months (range = 4 months-16 yr.). 144 swallowings were normal. Swallowing disorder was confirmed in 46 swallowings, (23 supraglottic penetrations and 23 aspirations). Considering each swallowing at 15 fps, sensitivity and specificity were, respectively, 93% (CI 0.82-0.98) and 98% (CI 0.94-0.99). The Cohen'Kappa coefficient between each interpretation at 15 and 30 fps was "almost perfect" (κ = 0.95; CI 0.88-0.99). Considering each loop, conclusion was identical. Reducing frame rate at 15 fps during pediatric VFSS seemed to be acceptable with comparable diagnostic performances without clinical impact compared to 30 fps, while being an efficient way to reduce the ionizing radiation exposition in children. We would suggest reconsidering the possibility of using VFSS with a 15 fps in a pediatric population.

Biocompatible Spherical Gold Nanoparticles Synthesis in Aqueous Tetraethylene Oxide Solution and Their Cellular Uptake.

Small well-defined spherical gold nanoparticles were synthesized by a simple non-physical method based on a mixture of gold salt, tetraethylene oxide and water, free of any additional reducing chemical agent or physical method. The ratio of tetraethylene oxide to water was optimized to achieve a fast synthesis within 30 min. Transmission electron microscopy images showed well dispersed gold nanospheres with a size ranging from 10 to 15 nm. XPS was used to confirm the oxidation state of gold nanoparticles and the oxidation products from tetraethylene oxide after the reaction. This new protocol performed in sustainable and biocompatible conditions is complementary to the current methods used to synthesize gold nanospheres. In order to use these particles in biological samples, we correlated the atomic absorption with the colorimetric concentration of nanospheres in solution. After 24 h of incubation of cancer or neuronal cell lines with these nanoparticles, transmission electron microscopy images showed similar cellular uptake in both cell lines, especially in cytoplasmic vesicular structures.

Dual antiplatelet therapy after percutaneous left atrial appendage occlusion: single center experience with the Amplatzer Cardiac Plug.

BACKGROUND: Percutaneous left atrial appendage occlusion (LAAO) is an alternative to anticoagulation in atrial fibrillation patients at high bleeding risk. Dual antiplatelet therapy (DAPT) is generally recommended in the months following the procedure to prevent thrombotic complications. The aim of this study was to evaluate the safety and efficacy of DAPT after LAAO in a single-centre population of high bleeding risk patients. METHODS: All patients who received DAPT after LAAO using the Amplatzer Cardiac Plug at Jessa Hospital (Hasselt, BE) between February 2011 and October 2016 were included. Patient characteristics, procedural outcome and clinical events (bleeding, stroke and adverse events) were prospectively followed. Changes in antithrombotic and/or anticoagulant regimens were assessed. RESULTS: Thirty-nine patients (77 ± 7 years, 51% male, CHA2DS2-VASc 5(3-6), Hypertension, Abnormal Renal/Liver Function, Stroke, Bleeding History or Predisposition, Labile INR, Elderly, Drugs/Alcohol Concomitantly (HAS-BLED) 3(3-4)) were included. An initial strategy of one month DAPT (n = 2) was changed to six months DAPT (n = 37) after one thrombotic complication (device thrombosis) at 4.5 months. Post-procedural DAPT duration was 6.1 ± 3.7 months, after which aspirin monotherapy (62%), no antiplatelet/anticoagulant therapy (15%) or a tailored antithrombotic regimen was maintained. At mean follow-up of 21 ± 13 months, seven patients had died (18%), no strokes had occurred (0%) and nine bleedings of which four were major (10%). All major bleedings occurred within the first six months after the procedure during DAPT. CONCLUSION: Antithrombotic therapy after percutaneous LAAO is needed to prevent thrombotic complications, yet these impose bleeding complications in this high-risk population. Further efforts are needed to define the optimal duration of DAPT, aimed at reducing bleeding complications while maintaining a low thrombosis rate.

Exercise Dynamics in Secondary Mitral Regurgitation: Pathophysiology and Therapeutic Implications.

Secondary mitral valve regurgitation (MR) remains a challenging problem in the diagnostic workup and treatment of patients with heart failure. Although secondary MR is characteristically dynamic in nature and sensitive to changes in ventricular geometry and loading, current therapy is mainly focused on resting conditions. An exercise-induced increase in secondary MR, however, is associated with impaired exercise capacity and increased mortality. In an era where a multitude of percutaneous solutions are emerging for the treatment of patients with heart failure, it becomes important to address the dynamic component of secondary MR during exercise as well. A critical reappraisal of the underlying disease mechanisms, in particular the dynamic component during exercise, is of timely importance. This review summarizes the pathophysiological mechanisms involved in the dynamic deterioration of secondary MR during exercise, its functional and prognostic impact, and the way current treatment options affect the dynamic lesion and exercise hemodynamics in general.

Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-ß burden in several amyloid transgenic mouse models.

Chronic inflammation represents a central component in the pathogenesis of Alzheimer's disease (AD). Recent work suggests that breaking immune tolerance by Programmed cell Death-1 (PD1) checkpoint inhibition produces an IFN-γ-dependent systemic immune response, with infiltration of the brain by peripheral myeloid cells and neuropathological as well as functional improvements even in mice with advanced amyloid pathology (Baruch et al., (): Nature Medicine, 22:135-137). Immune checkpoint inhibition was therefore suggested as potential treatment for neurodegenerative disorders when activation of the immune system is appropriate. Because a xenogeneic rat antibody (mAb) was used in the study, whether the effect was specific to PD1 target engagement was uncertain. In the present study we examined whether PD1 immunotherapy can lower amyloid-ß pathology in a range of different amyloid transgenic models performed at three pharmaceutical companies with the exact same anti-PD1 isotype and two mouse chimeric variants. Although PD1 immunotherapy stimulated systemic activation of the peripheral immune system, monocyte-derived macrophage infiltration into the brain was not detected, and progression of brain amyloid pathology was not altered. Similar negative results of the effect of PD1 immunotherapy on amyloid brain pathology were obtained in two additional models in two separate institutions. These results show that inhibition of PD1 checkpoint signaling by itself is not sufficient to reduce amyloid pathology and that additional factors might have contributed to previously published results (Baruch et al., (): Nature Medicine, 22:135-137). Until such factors are elucidated, animal model data do not support further evaluation of PD1 checkpoint inhibition as a therapeutic modality for Alzheimer's disease.

Application of the cghRA framework to the genomic characterization of Diffuse Large B-Cell Lymphoma.

MOTIVATION: Although sequencing-based technologies are becoming the new reference in genome analysis, comparative genomic hybridization arrays (aCGH) still constitute a simple and reliable approach for copy number analysis. The most powerful algorithms to analyze such data have been freely provided by the scientific community for many years, but combining them is a complex scripting task. RESULTS: The cghRA framework combines a user-friendly graphical interface and a powerful object-oriented command-line interface to handle a full aCGH analysis, as is illustrated in an original series of 107 Diffuse Large B-Cell Lymphomas. New algorithms for copy-number calling, polymorphism detection and minimal common region prioritization were also developed and validated. While their performances will only be demonstrated with aCGH, these algorithms could actually prove useful to any copy-number analysis, whatever the technique used. AVAILABILITY AND IMPLEMENTATION: R package and source for Linux, MS Windows and MacOS are freely available at http://bioinformatics.ovsa.fr/cghRA. CONTACT: mareschal@ovsa.fr or fabrice.jardin@chb.unicancer.fr. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Haploinsufficiency for NR3C1, the gene encoding the glucocorticoid receptor, in blastic plasmacytoid dendritic cell neoplasms.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and highly aggressive leukemia for which knowledge on disease mechanisms and effective therapies are currently lacking. Only a handful of recurring genetic mutations have been identified and none is specific to BPDCN. In this study, through molecular cloning in an index case that presented a balanced t(3;5)(q21;q31) and molecular cytogenetic analyses in a further 46 cases, we identify monoallelic deletion of NR3C1 (5q31), encoding the glucocorticoid receptor (GCR), in 13 of 47 (28%) BPDCN patients. Targeted deep sequencing in 36 BPDCN cases, including 10 with NR3C1 deletion, did not reveal NR3C1 point mutations or indels. Haploinsufficiency for NR3C1 defined a subset of BPDCN with lowered GCR expression and extremely poor overall survival (P = .0006). Consistent with a role for GCR in tumor suppression, functional analyses coupled with gene expression profiling identified corticoresistance and loss-of-EZH2 function as major downstream consequences of NR3C1 deletion in BPDCN. Subsequently, more detailed analyses of the t(3;5)(q21;q31) revealed fusion of NR3C1 to a long noncoding RNA (lncRNA) gene (lincRNA-3q) that encodes a novel, nuclear, noncoding RNA involved in the regulation of leukemia stem cell programs and G1/S transition, via E2F. Overexpression of lincRNA-3q was a consistent feature of malignant cells and could be abrogated by bromodomain and extraterminal domain (BET) protein inhibition. Taken together, this work points to NR3C1 as a haploinsufficient tumor suppressor in a subset of BPDCN and identifies BET inhibition, acting at least partially via lncRNA blockade, as a novel treatment option in BPDCN.

Specialist Advice Support for Management of Severe Hereditary Angioedema Attacks: A Multicenter Cluster-Randomized Controlled Trial.

STUDY OBJECTIVE: Hereditary angioedema is a rare disease associated with unpredictable, recurrent attacks of potentially life-threatening edema. Management of severe attacks is currently suboptimal because emergency medical teams are often unaware of new specific treatments. The objective of this trial is to test whether a dedicated national telephone care-management strategy would reduce resource use during severe hereditary angioedema attacks. METHODS: We conducted a cluster-randomized multicenter prospective trial of patients with a documented diagnosis of hereditary angioedema (type I, II or FXII hereditary angioedema). Participants were enrolled between March 2013 and June 2014 at 8 participating reference centers. The randomized units were the reference centers (clusters). Patients in the intervention arm were given a national free telephone number to call in the event of a severe attack. Emergency physicians in the SOS-hereditary angiœdema (SOS-HAE) call center were trained to advise or prescribe specific treatments. The primary outcome was number of admissions for angioedema attacks. Economic evaluation was also performed. RESULTS: We included 100 patients in the SOS-HAE group and 100 in the control group. During the 2 years, there were 2,368 hereditary angioedema attacks among 169 patients (85%). Mean number of hospital admissions per patient in the 2-year period was significantly greater in the usual-practice group (mean 0.16 [range 0 to 2] versus 0.03 [range 0 to 1]); patient risk difference was significant: -0.13 (95% confidence interval -0.22 to -0.04; P=.02). Probabilistic sensitivity graphic analysis indicated a trend toward increased quality-adjusted life-years in the SOS-HAE group. CONCLUSION: A national dedicated call center for management of severe hereditary angioedema attacks is associated with a decrease in hospital admissions and may be cost-effective if facilities and staff are available to deliver the intervention alongside existing services.

NF-L in cerebrospinal fluid and serum is a biomarker of neuronal damage in an inducible mouse model of neurodegeneration.

Accumulation of neurofilaments (NFs), the major constituents of the neuronal cytoskeleton, is a distinctive feature of neurological diseases and several studies have shown that soluble NFs can be detected in the cerebrospinal fluid (CSF) of patients with neurological diseases, such as multiple sclerosis and frontotemporal dementia. Here we have used an inducible transgenic mouse model of neurodegeneration, CamKII-TetOp25 mice, to evaluate whether NF-L levels in CSF or blood can be used as a biochemical biomarker of neurodegeneration. Induction of p25 transgene brain expression led to increase in CSF and serum NF-L levels that correlated with ongoing neurodegeneration. Switching off p25 prevented further increases in both CSF and serum NF-L levels and concomitantly stopped the progression of neurodegeneration. The levels of CSF NF-L detected in p25 mice are about 4-fold higher than the CSF levels detected in patients with chronic neurodegenerative diseases, such as symptomatic FTD (bvFTD). In addition, our data indicate that the NF-L detected in CSF is most likely a cleaved form of NF-L. These results suggest that CSF and serum NF-L are of interest to be further explored as potential translational dynamic biomarkers of neurodegeneration or as pharmacodynamics biomarkers at least in preclinical animal studies.

Role of the microtubule-associated TPPP/p25 in Parkinson's and related diseases and its therapeutic potential.

INTRODUCTION: The discovery and development of therapeutic strategies for the treatments of Parkinson's disease (PD) and other synucleinopathies are limited by a lack of understanding of the pathomechanisms and their connection with different diseases such as cancers. Areas covered: The hallmarks of these diseases are frequently multifunctional disordered proteins displaying moonlighting and/or chameleon features, which are challenging drug targets. A representative of these proteins is the disordered Tubulin Polymerization Promoting Protein (TPPP/p25) expressed specifically in oligodendrocytes (OLGs) in normal brain. Its non-physiological level is tightly related to the etiology of PD and Multiple System Atrophy (TPPP/p25 enrichment in inclusions of neurons and OLGs, respectively), multiple sclerosis (TPPP/p25-positive OLG destruction), as well as glioma (loss of TPPP/p25 expression). The established anti-proliferative potency of TPPP/p25 may raise its influence in cancer development. The recognition that whereas too much TPPP/p25 could kill neurons in PD, but its loss keeps cells alive in cancer could contribute to our understanding of the interrelationship of 'TPPP/p25 diseases'. Expert commentary: The knowledge accumulated so far underlines the key roles of the multifunctional TPPP/p25 in both physiological and diverse pathological processes, consequently its validation as drug target sorely needs a new innovative strategy that is briefly reviewed here.

Feasibility and Association of Neurohumoral Blocker Up-titration After Cardiac Resynchronization Therapy.

BACKGROUND: Cardiac resynchronization therapy (CRT) improves mortality and morbidity on top of optimal medical therapy in heart failure with reduced ejection fraction (HFrEF). This study aimed to elucidate the association between neurohumoral blocker up-titration after CRT implantation and clinical outcomes. METHODS AND RESULTS: Doses of angiotensin-converting enzyme inhibitors (ACE-Is), angiotensin receptor blockers (ARBs), and beta-blockers were retrospectively evaluated in 650 consecutive CRT patients implanted from October 2008 to August 2015 and followed in a tertiary multidisciplinary CRT clinic. All 650 CRT patients were on a maximal tolerable dose of ACE-I/ARB and beta-blocker at the time of CRT implantation. However, further up-titration was successful in 45.4% for ACE-I/ARB and in 56.8% for beta-blocker after CRT-implantation. During a mean follow-up of 37 ± 22 months, a total of 139 events occurred for the combined end point of heart failure admission and all-cause mortality. Successful, versus unsuccessful, up-titration was associated with adjusted hazard ratios of 0.537 (95% confidence interval 0.316-0.913; P = .022) for ACE-I/ARB and 0.633 (0.406-0.988; P = .044) for beta-blocker on the combined end point heart failure admission and all-cause mortality. Patients in the up-titration group exhibited a similar risk for death or heart failure admission as patients treated with the maximal dose (ACE-I/ARB: P = .133; beta-blockers: P = .709). CONCLUSIONS: After CRT, a majority of patients are capable of tolerating higher dosages of neurohumoral blockers. Up-titration of neurohumoral blockers after CRT implantation is associated with improved clinical outcomes, similarly to patients treated with the guideline-recommended target dose at the time of CRT implantation.

Plasma Volume Is Normal but Heterogeneously Distributed, and True Anemia Is Highly Prevalent in Patients With Stable Heart Failure.

BACKGROUND: Intravascular volume overload and depletion as well as anemia are associated with increased hospital admissions and mortality in patients with heart failure. This study aimed to accurately measure plasma volume and red cell mass (RCM) in stable patients with chronic heart failure with reduced ejection fraction (HFrEF) and gain more insight into plasma volume regulation and anemia in stable conditions of HFrEF. METHODS AND RESULTS: Plasma volume and RCM measurement based on 99Tc-labeled red blood cells, venous blood sample,s and clinical parameters were obtained in 24 stable HFrEF patients under optimal medical therapy. Measured plasma volume values were compared with predicted values based on body surface area. Plasma volume was on average normal (99.98% of predicted) but heterogeneously distributed (variations of 81%-133%). Neurohumoral activation and medication use were not associated with plasma volume status. Furthermore, anemia based on actual measurement of RCM was present in up to 75% of subjects, but rarely hemodilutional. CONCLUSIONS: In stable chronic HFrEF patients under optimal medical therapy, plasma volume is overall normal but heterogeneously distributed. Anticipated factors such as neurohumoral activation and heart failure medication were not associated with plasma volume. Furthermore, anemia is more common than as assessed by hemoglobin.

Oncogenic events rather than antigen selection pressure may be the main driving forces for relapse in diffuse large B-cell lymphomas.

Little is known on the phylogenetic relationship between diagnostic and relapse clones of diffuse large B-cell lymphoma (DLBCL). We applied high throughput sequencing (HTS) of the VDJ locus of Immunoglobulin heavy chain (IGHV) on 14 DLBCL patients with serial samples, including tumor biopsies and/or peripheral blood mononuclear cells (PBMC). Phylogenetic data were consolidated with targeted sequencing and cytogenetics. Phylogeny clearly showed that DLBCL relapse could occur according either an early or a late divergent mode. These two modes of divergence were independent from the elapsed time between diagnosis and relapse. We found no significant features for antigen selection pressure in complementary determining region both at diagnosis and relapse for 9/12 pairs and a conserved negative selection pressure for the three remaining cases. Targeted HTS and conventional cytogenetics revealed a branched vs. linear evolution for 5/5 IGHV early divergent cases, but unexpected such "oncogenetic" branched evolution could be found in at least 2/7 IGHV late divergent cases. Thus, if BCR signaling is mandatory for DLBCL emergence, oncogenetic events under chemotherapy selection pressure may be the main driving forces at relapse. Finally, circulating subclones with divergent IGHV somatic hypermutations patterns from initial biopsy could be detected in PBMC at diagnosis for 4/6 patients and, for two of them, at least one was similar to the ones found at relapse. This study highlights that oncogenetic intraclonal diversity of DLBCL should be evaluated beyond the scope a single biopsy and represents a rationale for future investigations using peripheral blood for lymphoid malignancies genotyping. Am. J. Hematol. 92:68-76, 2017. © 2016 Wiley Periodicals, Inc.