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Lung ultrasound (LUS) is an effective tool for diagnosing acute heart failure (AHF). However, several imaging protocols currently exist and how to best use LUS remains undefined. We aimed at developing a lung ultrasound-based model for AHF diagnosis using machine learning. Random forest and decision trees were generated using the LUS data (via an 8-zone scanning protocol) in patients with acute dyspnea admitted to the Emergency Department (PLUME study, N = 117) and subsequently validated in an external dataset (80 controls from the REMI study, 50 cases from the Nancy AHF cohort). Using the random forest model, total B-line sum (i.e., in both hemithoraces) was the most significant variable for identifying AHF, followed by the difference in B-line sum between the superior and inferior lung areas. The decision tree algorithm had a good diagnostic accuracy [area under the curve (AUC) = 0.865] and identified three risk groups (i.e., low 24%, high 70%, and very high-risk 96%) for AHF. The very high-risk group was defined by the presence of 14 or more B-lines in both hemithoraces while the high-risk group was described as having either B-lines mostly localized in superior points or in the right hemithorax. Accuracy in the validation cohort was excellent (AUC = 0.906). Importantly, adding the algorithm on top of a validated clinical score and classical definition of positive LUS scanning for AHF resulted in a significant improvement in diagnostic accuracy (continuous net reclassification improvement = 1.21, P < 0.001). Our simple lung ultrasound-based machine learning algorithm features an excellent performance and may constitute a validated strategy to diagnose AHF.
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Dystrophin Dp71 is the major product of the Duchenne muscular dystrophy (DMD) gene in the brain, and its loss in DMD patients and mouse models leads to cognitive impairments. Dp71 is expressed as a range of proteins generated by alternative splicing of exons 71 to 74 and 78, classified in the main Dp71d and Dp71f groups that contain specific C-terminal ends. However, it is unknown whether each isoform has a specific role in distinct cell types, brain regions, and/or stages of brain development. In the present study, we characterized the expression of Dp71 isoforms during fetal (E10.5, E15.5) and postnatal (P1, P7, P14, P21 and P60) mouse and rat brain development. We finely quantified the expression of several Dp71 transcripts by RT-PCR and cloning assays in samples from whole-brain and distinct brain structures. The following Dp71 transcripts were detected: Dp71d, Dp71d∆71, Dp71d∆74, Dp71d∆71,74, Dp71d∆71-74, Dp71f, Dp71f∆71, Dp71f∆74, Dp71f∆71,74, and Dp71fΔ71-74. We found that the Dp71f isoform is the main transcript expressed at E10.5 (> 80%), while its expression is then progressively reduced and replaced by the expression of isoforms of the Dp71d group from E15.5 to postnatal and adult ages. This major finding was confirmed by third-generation nanopore sequencing. In addition, we found that the level of expression of specific Dp71 isoforms varies as a function of postnatal stages and brain structure. Our results suggest that Dp71 isoforms have different and complementary roles during embryonic and postnatal brain development, likely taking part in a variety of maturation processes in distinct cell types.
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In the central nervous system, the formation of myelin by oligodendrocytes (OLs) relies on the switch from the polymerization of the actin cytoskeleton to its depolymerization. The molecular mechanisms that trigger this switch have yet to be elucidated. Here, we identified P21-activated kinase 1 (PAK1) as a major regulator of actin depolymerization in OLs. Our results demonstrate that PAK1 accumulates in OLs in a kinase-inhibited form, triggering actin disassembly and, consequently, myelin membrane expansion. Remarkably, proteomic analysis of PAK1 binding partners enabled the identification of NF2/Merlin as its endogenous inhibitor. Our findings indicate that Nf2 knockdown in OLs results in PAK1 activation, actin polymerization, and a reduction in OL myelin membrane expansion. This effect is rescued by treatment with a PAK1 inhibitor. We also provide evidence that the specific Pak1 loss-of-function in oligodendroglia stimulates the thickening of myelin sheaths in vivo. Overall, our data indicate that the antagonistic actions of PAK1 and NF2/Merlin on the actin cytoskeleton of the OLs are critical for proper myelin formation. These findings have broad mechanistic and therapeutic implications in demyelinating diseases and neurodevelopmental disorders.
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Vaina de Mielina , Oligodendroglía , Quinasas p21 Activadas , Quinasas p21 Activadas/metabolismo , Oligodendroglía/metabolismo , Animales , Vaina de Mielina/metabolismo , Neurofibromina 2/metabolismo , Neurofibromina 2/genética , Ratas , Actinas/metabolismo , Células Cultivadas , Ratones , Ratones Endogámicos C57BL , Citoesqueleto de Actina/metabolismoRESUMEN
AIM: Venoarterial extracorporeal membrane oxygenation (VA-ECMO) has become a common intervention for patients with cardiogenic shock (CS), often complicated by cardiac arrest (CA). Moderate hypothermia (MH) has shown promise in mitigating ischemia-reperfusion injury following CA. The HYPO-ECMO trial aimed to compare the effect of MH versus normothermia in refractory CS rescued by VA-ECMO. The primary aim of this non-predefined post hoc study was to assess the treatment effect of MH in the subgroup of patients with cardiac arrest (CA) within the HYPO-ECMO trial. Additionally, we will evaluate the prognostic significance of CA in these patients. METHODS: This post hoc analysis utilized data from the randomized HYPO-ECMO trial conducted across 20 French cardiac shock care centers between October 2016 and July 2019. Participants included intubated patients receiving VA-ECMO for CS for less than 6 h, with 334 patients completing the trial. Patients were randomized to early MH (33-34 °C) or normothermia (36-37 °C) for 24 h. RESULTS: Of the 334 patients, 159 (48%) experienced preceding CA. Mortality in the CA group was 50.9% at 30 days and 59.1% at 180 days, compared to 42.3% and 51.4% in the no-CA group, respectively (adjusted risk difference [RD] at 30 days, 8.1% [-0.8 to 17.1%], p = 0.074 and RD at 180 days 7.0% [-3.0 to 16.9%], p = 0.17). MH was associated with a significant reduction in primary (RD -13.3% [-16.3 to -0.3%], p = 0.031) and secondary outcomes in the CA group only (p < 0.025 for all), with a significant interaction between MH and CA status for 180-day mortality [p = 0.03]. CONCLUSIONS: This post hoc analysis suggests that MH shows potential for reducing mortality and composite endpoints in patients with cardiac arrest and refractory CS treated with VA-ECMO without an increased risk of severe bleeding or infection. Further research is needed to validate these findings and elucidate underlying mechanisms.
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Oxigenación por Membrana Extracorpórea , Paro Cardíaco , Hipotermia Inducida , Choque Cardiogénico , Humanos , Oxigenación por Membrana Extracorpórea/métodos , Masculino , Femenino , Hipotermia Inducida/métodos , Persona de Mediana Edad , Paro Cardíaco/terapia , Paro Cardíaco/mortalidad , Paro Cardíaco/complicaciones , Choque Cardiogénico/terapia , Choque Cardiogénico/etiología , Choque Cardiogénico/mortalidad , AncianoRESUMEN
BACKGROUND AND AIMS: Chronic inflammation plays a key role in arterial stiffness pathogenesis. Dietary components can display anti- or pro-inflammatory properties. Nonetheless, the association between the diet's overall inflammatory potential and arterial stiffness is unclear. This study aimed to assess the association between the diet's overall inflammatory potential and arterial stiffness assessed by carotid-femoral pulse wave velocity (cfPWV). METHODS AND RESULTS: This cross-sectional study included 1307 participants from the STANISLAS family cohort study. Dietary data were collected using a validated food frequency questionnaire. The adapted dietary inflammatory index (ADII) score was calculated to assess the inflammatory potential of the participants' diet. The association of ADII score quartile with cfPWV was assessed using IPW-weighted linear mixed models with random family effect. The median (Q1-Q3) ADII score was 0.45 (-1.57, 2.04). Participants exhibiting higher ADII scores demonstrated elevated energy intake, dietary saturated fat, and ultra-processed foods. Conversely, individuals with lower ADII scores exhibited higher vitamins and omega intakes, and a higher diet quality, as assessed by the DASH score. Despite these observations from the descriptive analyses, ADII score quartiles were not significantly associated with cfPWV (ß(95% CI) were 0.01 (-0.02,0.04) for Q2, 0.02 (-0.01,0.05) for Q3, and 0.02 (-0.01,0.05) for Q4 compared to Q1). CONCLUSION: In this cross-sectional study, participants had a relatively modest consumption of pro-inflammatory foods, no substantial associations were observed between the diet inflammatory potential and arterial stiffness. Further longitudinal studies in larger cohorts are needed to better understand the link between inflammatory diet and arterial stiffness.
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Velocidad de la Onda del Pulso Carotídeo-Femoral , Dieta , Inflamación , Rigidez Vascular , Humanos , Estudios Transversales , Masculino , Femenino , Persona de Mediana Edad , Francia/epidemiología , Inflamación/diagnóstico , Inflamación/fisiopatología , Inflamación/epidemiología , Adulto , Factores de Riesgo , Dieta/efectos adversos , Mediadores de Inflamación/sangre , Medición de Riesgo , Dieta Saludable , Valor Nutritivo , Anciano , Análisis de la Onda del PulsoRESUMEN
BACKGROUND: The cardio-ankle vascular index (CAVI) measure of arterial stiffness is associated with prevalent cardiovascular risk factors, while its predictive value for cardiovascular events remains to be established. The aim was to determine associations of CAVI with cardiovascular morbimortality (primary outcome) and all-cause mortality (secondary outcome), and to establish the determinants of CAVI progression. METHODS: TRIPLE-A-Stiffness, an international multicentre prospective longitudinal study, enrolled >2000 subjects ≥40 years old at 32 centres from 18 European countries. Of these, 1250 subjects (55% women) were followed for a median of 3.82 (2.81-4.69) years. FINDINGS: Unadjusted cumulative incidence rates of outcomes according to CAVI stratification were higher in highest stratum (CAVI > 9). Cox regression with adjustment for age, sex, and cardiovascular risk factors revealed that CAVI was associated with increased cardiovascular morbimortality (HR 1.25 per 1 increase; 95% confidence interval, CI: 1.03-1.51) and all-cause mortality (HR 1.37 per 1 increase; 95% CI: 1.10-1.70) risk in subjects ≥60 years. In ROC analyses, CAVI optimal threshold was 9.25 (c-index 0.598; 0.542-0.654) and 8.30 (c-index 0.565; 0.512-0.618) in subjects ≥ or <60 years, respectively, to predict increased CV morbimortality. Finally, age, mean arterial blood pressure, anti-diabetic and lipid-lowering treatment were independent predictors of yearly CAVI progression adjusted for baseline CAVI. INTERPRETATION: The present study identified additional value for CAVI to predict outcomes after adjustment for CV risk factors, in particular for subjects ≥60 years. CAVI progression may represent a modifiable risk factor by treatments. FUNDING: International Society of Vascular Health (ISVH) and Fukuda Denshi, Japan.
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Índice Vascular Cardio-Tobillo , Enfermedades Cardiovasculares , Rigidez Vascular , Humanos , Femenino , Masculino , Persona de Mediana Edad , Anciano , Enfermedades Cardiovasculares/mortalidad , Enfermedades Cardiovasculares/diagnóstico , Enfermedades Cardiovasculares/etiología , Estudios Prospectivos , Progresión de la Enfermedad , Factores de Riesgo , Curva ROC , Adulto , Estudios Longitudinales , Pronóstico , Factores de Riesgo de Enfermedad CardiacaRESUMEN
BACKGROUND: Lung ultrasound (LUS) is often used to assess congestion in heart failure (HF). In this study, we assessed the prognostic role of LUS in HF patients at admission and hospital discharge, and in an out-patient setting and explored whether clinical factors (age, sex, left ventricular ejection fraction (LVEF) and atrial fibrillation) impact the prognostic value of LUS findings. Further, we assessed the incremental prognostic value of LUS on top of AHEAD and MAGGIC clinical risk scores. METHODS AND RESULTS: We pooled data of patients hospitalized for HF or followed-up in out-patient clinics from international cohorts. We enrolled 1,947 patients, at admission (n=578), discharge (n=389) and in out-patient clinic (n=980). Total LUS B-line count was calculated for the 8-zone scanning protocol. The primary outcome was a composite of re-hospitalization for HF and all-cause death. Compared to those in the lower tertiles of B-lines, patients in the highest tertile were older, more likely to have signs of HF and higher NT-proBNP levels. A higher number of B-lines was associated with increased risk of primary outcome at discharge (Tertile3 vs Tertile1: adjustedHR= 5.74 (3.26- 10.12), p<0.0001) and in out-patients (Tertile3 vs Tertile1: adjustedHR= 2.66 (1.08- 6.54), p=0.033). Age and LVEF did not influence the prognostic capacity of LUS in different clinical settings. Adding B-line count to MAGGIC and AHEAD scores improved net reclassification significantly in all three clinical settings. CONCLUSION: A higher number of B-lines in patients with HF was associated with increased risk of morbidity and mortality, regardless of the clinical setting.
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Introduction: Epinephrine has been the main drug recommended for decades during cardiopulmonary resuscitation (CPR). But epinephrine's ß-adrenergic effects might increase myocardial oxygen consumption and may cause arrythmias after ROSC. Norepinephrine has a weaker ß-adrenergic effect and could be useful during CPR. Studies on norepinephrine's effect on hemodynamic parameters and cerebral perfusion are scarce. This study aimed to assess norepinephrine's hemodynamic impact in an experimental model of cardiac arrest. Methods: After an initial dose study to determine the optimal dose, we conducted a prospective randomized study with 19 pigs. After 3 minutes of untreated ventricular fibrillation, animals received boluses of 0.5 mg Epinephrine (EPI) or 1 mg Norepinephrine (NE) every 5 minutes during CPR. Coronary perfusion pressure (CPP), carotid blood flow (CBF) and cerebral perfusion pressure (CePP) were evaluated. Results: At baseline, hemodynamic parameters did not differ between the two groups. During CPR, CPP and CBF were similar: 17.3 (12.8; 31.8) in the EPI group vs 16.0 (11.1; 37.7) in the NE group, p = 0.9 and 28.4 (22.0; 54.8) vs 30.8 (12.2; 56.3) respectively, p = 0.9. CePP was not significantly lower during resuscitation in the NE group compared to the EPI group: 12.2 (-8.2; 42.2) vs 7.8 (-2.0; 32.0) p = 0.4. Survival rate was low with only one animal in the EPI group and 2 in the NE group. Conclusion: Cerebral perfusion pressure, coronary perfusion pressure and carotid blood flow during CPR did not significantly differ between the norepinephrine group and the epinephrine group. Further investigations should evaluate different options such as a continuous NE infusion.
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AIMS: High left ventricular filling pressure increases left atrial volume and causes myocardial fibrosis, which may decrease with spironolactone. We studied clinical and proteomic characteristics associated with left atrial volume indexed by body surface area (LAVi), and whether LAVi influences the response to spironolactone on biomarker expression and clinical variables. METHODS AND RESULTS: In the HOMAGE trial, where people at risk of heart failure were randomized to spironolactone or control, we analysed 421 participants with available LAVi and 276 proteomic measurements (Olink) at baseline, month 1 and 9 (mean age 73 ± 6 years; women 26%; LAVi 32 ± 9 ml/m2). Circulating proteins associated with LAVi were also assessed in asymptomatic individuals from a population-based cohort (STANISLAS; n = 1640; mean age 49 ± 14 years; women 51%; LAVi 23 ± 7 ml/m2). In both studies, greater LAVi was significantly associated with greater left ventricular masses and volumes. In HOMAGE, after adjustment and correction for multiple testing, greater LAVi was associated with higher concentrations of matrix metallopeptidase-2 (MMP-2), insulin-like growth factor binding protein-2 (IGFBP-2) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) (false discovery rates [FDR] <0.05). These associations were externally replicated in STANISLAS (all FDR <0.05). Among these biomarkers, spironolactone decreased concentrations of MMP-2 and NT-proBNP, regardless of baseline LAVi (pinteraction > 0.10). Spironolactone also significantly reduced LAVi, improved left ventricular ejection fraction, lowered E/e', blood pressure and serum procollagen type I C-terminal propeptide (PICP) concentration, a collagen synthesis marker, regardless of baseline LAVi (pinteraction > 0.10). CONCLUSION: In individuals without heart failure, LAVi was associated with MMP-2, IGFBP-2 and NT-proBNP. Spironolactone reduced these biomarker concentrations as well as LAVi and PICP, irrespective of left atrial size.
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Atrios Cardíacos , Insuficiencia Cardíaca , Antagonistas de Receptores de Mineralocorticoides , Proteómica , Espironolactona , Humanos , Espironolactona/uso terapéutico , Femenino , Masculino , Atrios Cardíacos/fisiopatología , Atrios Cardíacos/patología , Atrios Cardíacos/diagnóstico por imagen , Atrios Cardíacos/metabolismo , Atrios Cardíacos/efectos de los fármacos , Anciano , Proteómica/métodos , Persona de Mediana Edad , Insuficiencia Cardíaca/tratamiento farmacológico , Insuficiencia Cardíaca/fisiopatología , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/farmacología , Biomarcadores/sangre , Péptido Natriurético Encefálico/sangre , Metaloproteinasa 2 de la Matriz/sangre , Metaloproteinasa 2 de la Matriz/metabolismo , Fragmentos de Péptidos/sangre , Volumen Sistólico/fisiologíaRESUMEN
BACKGROUND: Reliable predictors of outcomes in venoarterial extracorporeal membrane oxygenation (VA-ECMO) therapy are limited. While elevated lactate levels over time have been linked to outcomes in cardiogenic shock (CS), their significance in VA-ECMO-treated patients remains inconclusive. METHODS: We conducted a post hoc analysis of data from the HYPO-ECMO trial, which compared normothermia to moderate hypothermia in CS patients supported by VA-ECMO. We examined daily lactate levels collected over a week to assess their correlation with 30-day mortality. RESULTS: Among the 318 out of 334 patients (95%) with baseline lactate measurements, 66 had normal levels (< 2.2 mmol/l, 21%). No difference was found in lactate course between moderate hypothermia and normothermia groups. Lactate levels were consistently higher in non-survivors at each time point (p = 0.0002). Baseline hyperlactatemia was associated with an increased risk of death (Hazard Ratio [HR]: 1.85 (1.12-3.05), p = 0.016). When considering all time points, lactate levels during the ICU stay were significantly and gradually associated with a higher risk of death (p < 0.0001). In the overall population, a decrease in lactate levels was not linked to 30-day mortality. However, patients with baseline hyperlactatemia exhibited a more significant decrease in lactate levels from day one to seven (p < 0.0001). In this group, survivors had a significantly greater decrease in lactate levels at day 1 compared to non-survivors (63% (48-77) versus 57% (21-75), p = 0.026). Patients experiencing a secondary increase in lactate (24%) had a worse prognosis (Hazard Ratio: 1.78 (1.21-2.61), p = 0.004), regardless of both baseline lactate levels and the occurrence of severe ischemic adverse events (intestinal and/or limb ischemia). CONCLUSIONS: The consistent and significant association between lactate levels, whether assessed at baseline or during ICU treatment, and the risk of mortality underscores the pivotal prognostic relevance of lactate levels in patients with CS undergoing VA-ECMO therapy. The study findings provide some novel insights, regarding the trend profile and the relevance of a second peak during the 7 day period after ECMO start. Trial Registration identifier NCT02754193 registered on 2016-04-12.
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Composite outcomes are commonly used in critical care trials to estimate the treatment effect of an intervention. A significant limitation of classical analytic approaches is that they assign equal statistical importance to each component in a composite, even if these do not have the same clinical importance (i.e., in a composite of death and organ failure, death is clearly more important). The win ratio (WR) method has been proposed as an alternative for trial outcomes evaluation, as it effectively assesses events based on their clinical relevance (i.e., hierarchical order) by comparing each patient in the intervention group with their counterparts in the control group. This statistical approach is increasingly used in cardiovascular outcome trials. However, WR may be useful to unveil treatment effects also in the critical care setting, because these trials are typically moderately sized, thus limiting the statistical power to detect small differences between groups, and often rely on composite outcomes that include several components of different clinical importance. Notably, the advantages of this approach may be offset by several drawbacks (such as ignoring ties and difficulties in selecting and ranking endpoints) and challenges in appropriate clinical interpretation (i.e., establishing clinical meaningfulness of the observed effect size). In this perspective article, we present some key elements to implementing WR statistics in critical care trials, providing an overview of strengths, drawbacks, and potential applications of this method. To illustrate, we conduct a reevaluation of the HYPO-ECMO (Hypothermia during Venoarterial Extracorporeal Membrane Oxygenation) trial using the WR framework as a case example.
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Cuidados Críticos , Evaluación de Resultado en la Atención de Salud , HumanosRESUMEN
AIMS: Patients who experience hospitalizations due to heart failure (HF) face a significant risk of readmission and mortality. Our objective was to evaluate whether the risk of hospitalization and mortality following discharge from HF hospitalization differed based on adherence to the outpatient follow-up (FU) protocol comprising an appointment with a general practitioner (GP) within 15 days, a cardiologist within 2 months or both (termed combined FU). METHODS AND RESULTS: We studied all adults admitted for a first HF hospitalization from 2016 to 2020 in France's Grand Est region. Association between adherence to outpatient FU and outcomes were assessed with time-dependent survival analysis model. Among 67 476 admitted patients (mean age 80.3 ± 11.3 years, 53% women), 62 156 patients (92.2%) were discharged alive and followed for 723 (317-1276) days. Combined FU within 2 months was used in 21.1% of patients, with lower rates among >85 years, women, and those with higher comorbidity levels (p < 0.0001 for all). Combined FU was associated with a lower 1-year death or rehospitalization (adjusted hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.88-0.94, p < 0.0001) mostly related to lower mortality (adjusted HR 0.65, 95% CI 0.62-0.68, p < 0.0001) whereas HF readmission was higher (adjusted HR 1.19, 95% CI 1.15-1.24, p < 0.0001). When analysing components of combined FU separately, 1-year mortality was more related to cardiologist FU (HR 0.65, 95% CI 0.62-0.67, p < 0.0001), than GP FU (HR 0.87, 95% CI 0.85-0.90, p < 0.0001). CONCLUSION: Combined FU is carried out in a minority of patients following HF hospitalization, yet it is linked to a substantial reduction in 1-year mortality, albeit at the expense of an increase in HF hospitalizations.
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Insuficiencia Cardíaca , Readmisión del Paciente , Adulto , Humanos , Femenino , Anciano , Anciano de 80 o más Años , Masculino , Alta del Paciente , Insuficiencia Cardíaca/epidemiología , Insuficiencia Cardíaca/terapia , Estudios de Seguimiento , Cuidados Posteriores , HospitalizaciónRESUMEN
BACKGROUND: While exercise impairments are central to symptoms and diagnosis of heart failure with preserved ejection fraction (HFpEF), prior studies of HFpEF biomarkers have mostly focused on resting phenotypes. We combined precise exercise phenotypes with cardiovascular proteomics to identify protein signatures of HFpEF exercise responses and new potential therapeutic targets. METHODS AND RESULTS: We analyzed 277 proteins (Olink) in 151 individuals (N=103 HFpEF, 48 controls; 62±11 years; 56% women) with cardiopulmonary exercise testing with invasive monitoring. Using ridge regression adjusted for age/sex, we defined proteomic signatures of 5 physiological variables involved in HFpEF: peak oxygen uptake, peak cardiac output, pulmonary capillary wedge pressure/cardiac output slope, peak pulmonary vascular resistance, and peak peripheral O2 extraction. Multiprotein signatures of each of the exercise phenotypes captured a significant proportion of variance in respective exercise phenotypes. Interrogating the importance (ridge coefficient magnitude) of specific proteins in each signature highlighted proteins with putative links to HFpEF pathophysiology (eg, inflammatory, profibrotic proteins), and novel proteins linked to distinct physiologies (eg, proteins involved in multiorgan [kidney, liver, muscle, adipose] health) were implicated in impaired O2 extraction. In a separate sample (N=522, 261 HF events), proteomic signatures of peak oxygen uptake and pulmonary capillary wedge pressure/cardiac output slope were associated with incident HFpEF (odds ratios, 0.67 [95% CI, 0.50-0.90] and 1.43 [95% CI, 1.11-1.85], respectively) with adjustment for clinical factors and B-type natriuretic peptides. CONCLUSIONS: The cardiovascular proteome is associated with precision exercise phenotypes in HFpEF, suggesting novel mechanistic targets and potential methods for risk stratification to prevent HFpEF early in its pathogenesis.
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Insuficiencia Cardíaca , Humanos , Femenino , Masculino , Volumen Sistólico/fisiología , Proyectos Piloto , Proteómica , Fenotipo , Oxígeno/metabolismo , Prueba de Esfuerzo/métodos , Tolerancia al Ejercicio/fisiologíaRESUMEN
BACKGROUND: Patients with heart failure with reduced ejection fraction (HFrEF) and central sleep apnea (CSA) are at a very high risk of fatal outcomes. OBJECTIVE: To test whether the circulating miRNome provides additional information for risk stratification on top of clinical predictors in patients with HFrEF and CSA. METHODS: The study included patients with HFrEF and CSA from the SERVE-HF trial. A three-step protocol was applied: microRNA (miRNA) screening (n = 20), technical validation (n = 60), and biological validation (n = 587). The primary outcome was either death from any cause, lifesaving cardiovascular intervention, or unplanned hospitalization for worsening of heart failure, whatever occurred first. MiRNA quantification was performed in plasma samples using miRNA sequencing and RT-qPCR. RESULTS: Circulating miR-133a-3p levels were inversely associated with the primary study outcome. Nonetheless, miR-133a-3p did not improve a previously established clinical prognostic model in terms of discrimination or reclassification. A customized regression tree model constructed using the Classification and Regression Tree (CART) algorithm identified eight patient subphenotypes with specific risk patterns based on clinical and molecular characteristics. MiR-133a-3p entered the regression tree defining the group at the lowest risk; patients with log(NT-proBNP) ≤ 6 pg/mL (miR-133a-3p levels above 1.5 arbitrary units). The overall predictive capacity of suffering the event was highly stable over the follow-up (from 0.735 to 0.767). CONCLUSIONS: The combination of clinical information, circulating miRNAs, and decision tree learning allows the identification of specific risk subphenotypes in patients with HFrEF and CSA.
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Insuficiencia Cardíaca , MicroARNs , Apnea Central del Sueño , Disfunción Ventricular Izquierda , Humanos , Apnea Central del Sueño/complicaciones , Biomarcadores , Volumen Sistólico , MicroARNs/genética , Árboles de DecisiónRESUMEN
INTRODUCTION: Ischaemia/reperfusion injuries (IRIs) are associated with poorer survival of kidney grafts from expanded criteria donors. Preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) prevent acute and chronic post-ischaemic renal dysfunction by limiting IRI. However, data concerning the safety of MRAs in brain-dead donor patients are scarce. We seek to investigate the tolerance of MRAs on the haemodynamics in this population. METHODS AND ANALYSIS: CANREO-PMO is a randomised, controlled, single-centre, double-blind study. Brain-dead organ donors hospitalised in intensive care are randomised 1:1 after consent to receive 200 mg potassium canrenoate or its matching placebo every 6 hours until organ procurement. The primary outcome is a hierarchical composite endpoint that includes: (1) cardiocirculatory arrest, (2) the impossibility of kidney procurement, (3) the average hourly dose of norepinephrine/epinephrine between randomisation and departure to the operating room, and (4) the average hourly volume of crystalloids and/or colloids received. Thirty-six patients will be included. The secondary endpoints evaluated among the graft recipients are the: (1) vital status of the kidney graft recipients and serum creatinine level with estimated glomerular filtration rate (GFR) according to Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) at 3 months after renal transplantation, (2) percentage of patients dependent on dialysis and/or with an estimated GFR <20 mL/min/1.73 m2 at 3 months, (3) vital status of the kidney graft recipients at 3 months, and (4) vital status of the kidney graft recipients and creatinine levels (in µmol/L), with the estimated GFR according to CKD-EPI (in mL/min/1.73 m2), at 1 year, 3 years and 10 years after transplantation. ETHICS AND DISSEMINATION: This trial has full ethical approval (Comité de Protection des Personnes: CPP Ouest II-ANGERS, France), and the written consent of relatives will be obtained. Results will be reported at conferences, peer-reviewed publications and using social media channels. TRIAL REGISTRATION NUMBER: NCT04714710.
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Ácido Canrenoico , Trasplante de Riñón , Antagonistas de Receptores de Mineralocorticoides , Humanos , Encéfalo , Muerte Encefálica , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto , Diálisis Renal , Insuficiencia Renal Crónica/tratamiento farmacológico , Insuficiencia Renal Crónica/cirugía , Donantes de Tejidos , Método Doble Ciego , Daño por Reperfusión Miocárdica/prevención & controlRESUMEN
AIMS: The prognostic value of 'high dose' loop diuretics in advanced heart failure outpatients is unclear. We aimed to assess the prognosis associated with loop diuretic dose in ambulatory patients awaiting heart transplantation (HT). METHODS AND RESULTS: All ambulatory patients (n = 700, median age 55 years and 70% men) registered on the French national HT waiting list between 1 January 2013 and 31 December 2019 were included. Patients were divided into 'low dose', 'intermediate dose', and 'high dose' loop diuretics corresponding to furosemide equivalent doses of ≤40, 40-250, and >250 mg, respectively. The primary outcome was a combined criterion of waitlist death and urgent HT. N-terminal pro-B-type natriuretic peptide, creatinine levels, pulmonary capillary wedge pressure, and pulmonary pressures gradually increased with higher diuretic dose. At 12 months, the risk of waitlist death/urgent HT was 7.4%, 19.2%, and 25.6% (P = 0.001) for 'low dose', 'intermediate dose', and 'high dose' patients, respectively. When adjusting for confounders, including natriuretic peptides, hepatic, and renal function, the 'high dose' group was associated with increased waitlist mortality or urgent HT [adjusted hazard ratio (HR) 2.23, 1.33 to 3.73; P = 0.002] and a six-fold higher risk of waitlist death (adjusted HR 6.18, 2.16 to 17.72; P < 0.001) when compared with the 'low dose' group. 'Intermediate doses' were not significantly associated with these two outcomes in adjusted models (P > 0.05). CONCLUSIONS: A 'high dose' of loop diuretics is strongly associated with residual congestion and is a predictor of outcome in patients awaiting HT despite adjustment for classical cardiorenal risk factors. This routine variable may be helpful for risk stratification of pre-HT patients.
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Diuréticos , Trasplante de Corazón , Masculino , Humanos , Persona de Mediana Edad , Femenino , Inhibidores del Simportador de Cloruro Sódico y Cloruro Potásico , Pronóstico , FurosemidaRESUMEN
AIM: Eplerenone reduces the risk of cardiovascular death or first hospitalization for heart failure (HF) in patients with HF and a reduced ejection fraction (HFrEF), but it is still frequently underused in routine practice. We evaluated the time course of benefits of eplerenone after its initiation in HFrEF patients from the EMPHASIS-HF trial. METHODS AND RESULTS: The EMPHASIS-HF trial was a double-blind randomized clinical trial assessing the effect of eplerenone in patients (n = 2737, mean age 68.6 ± 7.6 years, 22.3% women) with HFrEF and mild symptoms. The time trajectories for the effect of eplerenone versus placebo on the primary composite endpoint (cardiovascular death or first hospitalization for HF) were investigated using Cox proportional hazards models with truncated data at each day post-randomization. A significant reduction in the primary composite endpoint was observed 26 days after randomization (hazard ratio 0.58; 95% confidence interval, 0.34-1.00, p = 0.049). Eplerenone was first associated with a significant reduction in the primary endpoint in 35 days or less in most subgroups, including patients with HF history ≥18 months (day 24), estimated glomerular filtration rate <60 ml/min (day 12), ischaemic HF aetiology (day 28), age ≥65 years (day 28), narrow QRS (day 30), higher MAGGIC score (day 35), lower potassium (day 30), left ventricular ejection fraction ≥30% (day 28) or already treated with beta-blockers (day 25). CONCLUSIONS: Eplerenone provides statistically significant and clinically meaningful benefits shortly after treatment initiation in most patients, irrespective of clinical profile. This result reinforces the need for an early initiation of eplerenone in HFrEF, as part of rapidly instituting guideline-directed medical therapy.
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Insuficiencia Cardíaca , Humanos , Femenino , Persona de Mediana Edad , Anciano , Masculino , Eplerenona/uso terapéutico , Espironolactona/uso terapéutico , Antagonistas de Receptores de Mineralocorticoides/uso terapéutico , Volumen Sistólico , Función Ventricular Izquierda , HospitalizaciónRESUMEN
BACKGROUND: COVID-19-associated acute respiratory distress syndrome (ARDS) supported by veno-venous extra-corporal membrane oxygenation (vv-ECMO) results in a high in-hospital mortality rate of more than 35%. However, after cannulation, no prognostic factor has been described to guide the management of these patients. The objective was to assess the association between static respiratory compliance over the first 10 days post-vv-ECMO implantation on 180-day mortality. RESULTS: In this multicentric retrospective study in three ECMO referral centers, all patients with COVID-19-associated ARDS supported by vv-ECMO were included from 03/01/2020 to 12/31/2021. Patients were ventilated with ultra-protective settings targeting a driving pressure lower than 15 cmH2O. 122 patients were included. Median age was 59 IQR (52-64), 83 (68%) were male, with a median body mass index of 33 (28-37) kg/m2. Delay between first symptoms to vv-ECMO implantation was 16 (10-21) days. Six-month death was 48%. Over the first ten days, compliance increased in 180 day survivors [from 18 (12-25) to 20 (15-27) mL/cmH2O] compared to non-survivors [from 12 (9-20) to 10 (8-14) mL/cmH2O, p interaction < 0.0001]. A time varying multivariable Cox model found age, history of chronic lung disease, compliance from day one to day ten and sweep gas flow from day one to day ten as independent factors associated with 180-day mortality. CONCLUSIONS: In COVID-19-associated ARDS, static respiratory compliance course over the first ten days post-vv-ECMO implantation is associated with 180-day mortality. This new information may provide crucial information on the patient's prognosis for intensivists.
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BACKGROUND: Diagnosis of heart failure with preserved ejection fraction (HFpEF) remains challenging despite the use of scores/algorithms. This study intended to assess the diagnostic value of exercise lung ultrasound (LUS) for HFpEF diagnosis. METHODS: We studied two independent case-control studies of HFpEF patients and control subjects undergoing different exercise protocols: (i) submaximal exercise stress echocardiography (ESE) with LUS performed by expert cardiologists (N = 116, HFpEF = 65.5%), and (ii) maximal cycle ergometer test (CET) (N = 54, HFpEF = 50%) with LUS performed by unexperienced physicians shortly trained for the study. B-line kinetics (i.e. peak values and their changes from rest) were assessed. RESULTS: In the ESE cohort, the C-index (95% CI) of peak B-lines for HFpEF diagnosis was 0.985 (0.968-1.000), whereas the C-index of rest and exercise HFA-PEFF scores (i.e. including stress echo findings) were < 0.90 (CI 0.823-0.949), and that of H2FPEF score was < 0.70 (CI 0.558-0.764). The C-index increase of peak B-lines on top of the above-mentioned scores was significant (C-index increase > 0.090 and P-value < 0.001 for all). Similar results were observed for change B-lines. Peak B-lines > 5 (sensitivity = 93.4%, specificity = 97.5%) and change B-lines > 3 (sensitivity = 94.7%, specificity = 87.5%) were the best cutoffs for HFpEF diagnosis. Adding peak or change B-lines on top of HFpEF scores and BNP significantly improved diagnostic accuracy. Peak B-lines showed a good diagnostic accuracy in the LUS beginner-led CET cohort (C-index = 0.713, 0.588-0.838). CONCLUSIONS: Exercise LUS showed excellent diagnostic value for HFpEF diagnosis regardless of different exercise protocols/level of expertise, with additive diagnostic accuracy on top of available scores and natriuretic peptides.
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Insuficiencia Cardíaca , Humanos , Ecocardiografía de Estrés/métodos , Prueba de Esfuerzo , Insuficiencia Cardíaca/diagnóstico , Pulmón/diagnóstico por imagen , Volumen Sistólico , Función Ventricular IzquierdaRESUMEN
BACKGROUND: We sought to identify protein biomarkers of new-onset heart failure (HF) in 3 independent cohorts (HOMAGE cohort [Heart Omics and Ageing], ARIC study [Atherosclerosis Risk in Communities], and FHS [Framingham Heart Study]) and assess if and to what extent they improve HF risk prediction compared to clinical risk factors alone. METHODS: A nested case-control design was used with cases (incident HF) and controls (without HF) matched on age and sex within each cohort. Plasma concentrations of 276 proteins were measured at baseline in ARIC (250 cases/250 controls), FHS (191/191), and HOMAGE cohort (562/871). RESULTS: In single protein analysis, after adjusting for matching variables and clinical risk factors (and correcting for multiple testing), 62 proteins were associated with incident HF in ARIC, 16 in FHS, and 116 in HOMAGE cohort. Proteins associated with incident HF in all cohorts were BNP (brain natriuretic peptide), NT-proBNP (N-terminal pro-B-type natriuretic peptide), eukaryotic translation initiation factor 4E-BP1 (4E-binding protein 1), hepatocyte growth factor (HGF), Gal-9 (galectin-9), TGF-alpha (transforming growth factor alpha), THBS2 (thrombospondin-2), and U-PAR (urokinase plasminogen activator surface receptor). The increment in C-index for incident HF based on a multiprotein biomarker approach, in addition to clinical risk factors and NT-proBNP, was 11.1% (7.5%-14.7%) in ARIC, 5.9% (2.6%-9.2%) in FHS, and 7.5% (5.4%-9.5%) in HOMAGE cohort, all P<0.001), each of which was a larger increase than that for NT-proBNP on top of clinical risk factors. Complex network analysis revealed a number of overrepresented pathways related to inflammation (eg, tumor necrosis factor and interleukin) and remodeling (eg, extracellular matrix and apoptosis). CONCLUSIONS: A multiprotein biomarker approach improves prediction of incident HF when added to natriuretic peptides and clinical risk factors.