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Background. The aim of the present study was to evaluate the diagnostic performance of monocyte distribution width (MDW) as a biomarker for sepsis diagnosis in severe patients attended in the Emergency Department for different conditions and not only infections. Methods. We performed an observational study in a consecutive prospective cohort including severe patients attending the Emergency Department with different conditions. MDW and other biomarkers were determined from samples obtained during the first care of patients. The diagnostic performance of the different biomarkers was determined based on the final diagnosis at patient discharge. Results. One hundred two patients, with a mean age of 76.7 (SD 16.5) years were included, 53 being (51.9%) male. Among the patients included, 65 (63.7%) had an infectious disease while the remaining had other different conditions. A MDW cut-off of 20.115 provided the best accuracy to identify infected patients, with a sensitivity of 89.2 (95% CI 79.4-94.7), a specificity of 89.2 (95% CI 75.3-95.7), a positive predictive value of 93.5 (95% CI 84.6-97.5), a negative predictive value of 82.5% (95% CI 68.0-91.3), a positive likelihood ratio of 8.25 (3.26-20.91), and a negative likelihood ratio of 0.12 (0.06-0.24). The area under the receiver operating characteristic curve for infection according to MDW was 0.943 (95% CI 0.897-0.989; p 20.115 may be associated with infection and could help to distinguish between infected and non-infected patients in severe patients. These results must be confirmed in new studies due to the limited patient sample included.

Resumen Introduccion y objetivos La amiloidosis hereditaria por transtirretina (ATTRv) es una enfermedad causada por mutaciones en el gen de la transtirretina que frecuentemente presenta afeccion cardiaca debido al deposito de amiloide en el miocardio. Nuestro objetivo es describir esta afeccion en una cohorte espanola. Metodos Estudio retrospectivo multicentrico de pacientes con ATTRv y afeccion cardiaca provenientes de centros espanoles. Se recogieron datos demograficos, clinicos y geneticos. Resultados En 26 centros se incluyo a 181 pacientes, el 65,2% varones, con una mediana de edad al diagnostico de 62 anos. Las mutaciones mas frecuentes fueron Val50Met (67,7%) y Val142Ile (12,4%). El principal motivo de consulta fue extracardiaco (69%), principalmente neurologico. La media de la fraccion aminoterminal del propeptido natriuretico cerebral (NT-proBNP) fue 2.145 ± 3.586 pg/ml. Lo mas caracteristico del electrocardiograma fueron el patron de seudoinfarto (25,9%) y el bloqueo auriculoventricular (25,3%). El grosor ventricular medio fue 15,4 ± 4,1 mm. El strain longitudinal estaba reducido en segmentos basales en el 29,4%. Se observo realce tardio subendocardico difuso en el 58,8%. En la gammagrafia habia captacion de grados 2-3 en un 75%. En el seguimiento, el 24,9% ingreso por insuficiencia cardiaca, el 34,3% preciso marcapasos y el 31,6%, trasplante hepatico. El 32,5% fallecio, principalmente por insuficiencia cardiaca (28,8%). Las mutaciones diferentes de Val50Met se asociaron en general con un peor pronostico. Conclusiones La ATTRv cardiaca en Espana tiene un espectro genetico y de afeccion heterogeneo. El pronostico es malo principalmente por las complicaciones cardiacas, por lo que son esenciales un diagnostico y un tratamiento precoces.

Introduction and objectives Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. Methods Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. Results A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. Conclusions HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.

Danon disease (DD) is a rare X-linked dominant cardioskeletal myopathy caused by mutations in the lysosome-associated membrane protein-2 (LAMP-2) gene that is usually lethal without cardiac transplantation. The purpose of this study was to characterize post-transplant outcomes in a large cohort of patients with DD who underwent cardiac transplantation.The clinical phenotype and outcome data of patients with DD who underwent cardiac transplantation (n = 38; 19 males and 19 females) were obtained from 8 centers. Study outcomes included graft survival, defined as death or retransplantation, and episodes of acute cellular and antibody-mediated rejection and cardiac allograft vasculopathy at 1 year.Median follow-up time after transplantation for the entire cohort was 4.4 years (IQR: 1.5-12.8 years). The median age at transplant for the cohort was 20.2 years (15.8-27.9 years), with no difference in age between sexes. Median pretransplant left-ventricular ejection fraction for the entire cohort was 30% (range 11%-84%). Males had higher pretransplant aspartate aminotransferase, alanine aminotransferase and creatine phosphokinase levels than females (P0.001). There were 2 deaths in the entire cohort and 2 retransplants. There was no difference in actuarial graft survival between males and females (P = 0.8965); the estimated graft survival was 87.1% (95%CI: 63.6%-95.9%) at 5 years. One episode (2.7%) of antibody-mediated rejection, grade 2, and 7 episodes (19%) of acute cellular rejection, grade 2 or 3, were reported in patients who survived to discharge (6 females and 1 male; P = 0.172).Heart transplantation outcomes are acceptable in DD with high probabilities of 5-year graft survival for males and females suggesting that cardiac transplantation is an effective treatment option for DD patients.

Instituto de Salud Carlos III (ISCIII), European Regional Development Fund/European Social Fund "A way to make Europe"/" Investing in your future" [PI18/0004, PI20/0320, PT17/0015/0043]; ISCIII; MCIN; Pro-CNIC Foundation; Severo Ochoa Centers of Excellence program [CEX2020-001041-S]; ISCIII [CM20/00101], Frutos F. de, Ochoa JP, Navarro-Peñalver M, Baas A, Bjerre JV, Zorio E, Méndez I, Lorca R, Verdonschot JAJ, García-Granja PE, Bilinska Z, Fatkin D, Fuentes-Cañamero ME, García-Pinilla JM, García-Álvarez MI, Girolami F, Barriales-Villa R, Díez-López C, Lopes LR, Wahbi K, García-Álvarez A, Rodríguez-Sánchez I, Rekondo-Olaetxea J, Rodríguez-Palomares JF, Gallego-Delgado M, Meder B, Kubanek M, Hansen FG, Restrepo-Córdoba MA, Palomino-Doza J, Ruiz-Guerrero L, Sarquella-Brugada G, Perez-Perez AJ, Bermúdez-Jiménez FJ, Ripoll-Vera T, Rasmussen TB, Jansen M, Sabater-Molina M, Elliot PM, Garcia-Pavia P; European Genetic Cardiomyopathies Initiative Investigators

Resumen Introduccion y objetivos Investigar si diferentes caracteristicas estructurales/organizativas del hospital y del servicio de urgencias (SU) impactan en los resultados de la insuficiencia cardiaca aguda (ICA). Metodos Analisis secundario del Registro EAHFE. Se recogieron 6 caracteristicas hospitalarias y del SU, y se relacionaron con 7 resultados tras el evento indice y tras el alta, ajustados por ano de inclusion, caracteristicas basales y del episodio de ICA y por dichas caracteristicas estructurales/organizativas. Tambien se relaciono el porcentaje de altas directas desde urgencias (ADU) y resultados, y si habia interaccion segun las caracteristicas hospitalarias o del SU. Resultados Cuarenta SU espanoles incluyeron 17.974 episodios de ICA. Hubo menos estancias prolongadas en hospitales de alta tecnologia, con hospitalizacion a domicilio y con SU con alta frecuentacion, y mas estancias prolongadas en hospitales con unidad de insuficiencia cardiaca y area de observacion en urgencias. Los hospitales de alta tecnologia presentaron menor mortalidad hospitalaria (OR = 0,78; IC95%, 0,65-0,94). Respecto a eventos 30 dias tras el alta, los hospitales con unidad de corta estancia (UCE) tuvieron mas hospitalizaciones (OR = 1,19; IC95%, 1,02-1,38); los SU con alta afluencia, menor mortalidad (OR = 0,73; IC95%, 0,56-0,96) y eventos combinados (OR = 0,87; IC95%, 0,76-0,99), y los hospitales con unidad de insuficiencia cardiaca, menos reconsultas a urgencias (OR = 0,83; IC95%, 0,76-0,91), hospitalizaciones (OR = 0,85; IC95%, 0,75-0,97) y eventos combinados (OR = 0,84; IC95%, 0,77-0,92). A mas ADU, menos estancias prolongadas. Entre otras interacciones, el incremento de ADU se asocio con mas reconsultas, hospitalizaciones y eventos combinados a los 30 dias del alta en hospitales sin UCE, pero no en hospitales con UCE. Conclusiones Las caracteristicas estructurales/organizativas de hospitales y SU y la agresividad en el tratamiento en urgencias influyen significativamente en los resultados en la ICA.

(1) Background and aim: This study aimed to investigate the impact of prehabilitation on the postoperative outcomes of heart transplantation and its cost-effectiveness. (2) Methods: This single-center, ambispective cohort study included forty-six candidates for elective heart transplantation from 2017 to 2021 attending a multimodal prehabilitation program consisting of supervised exercise training, physical activity promotion, nutritional optimization, and psychological support. The postoperative course was compared to a control cohort consisting of patients transplanted from 2014 to 2017 and those contemporaneously not involved in prehabilitation. (3) Results: A significant improvement was observed in preoperative functional capacity (endurance time 281 vs. 728 s, p < 0.001) and quality-of-life (Minnesota score 58 vs. 47, p = 0.046) after the program. No exercise-related events were registered. The prehabilitation cohort showed a lower rate and severity of postoperative complications (comprehensive complication index 37 vs. 31, p = 0.033), lower mechanical ventilation time (37 vs. 20 h, p = 0.032), ICU stay (7 vs. 5 days, p = 0.01), total hospitalization stay (23 vs. 18 days, p = 0.008) and less need for transfer to nursing/rehabilitation facilities after hospital discharge (31% vs. 3%, p = 0.009). A cost-consequence analysis showed that prehabilitation did not increase the total surgical process costs. (4) Conclusions: Multimodal prehabilitation before heart transplantation has benefits on short-term postoperative outcomes potentially attributable to enhancement of physical status, without cost-increasing.

INTRODUCTION AND OBJECTIVES According to the wavefront phenomenon described in the late 1970s, myocardial infarction triggered by acute coronary occlusion progresses with increasing duration of ischemia as a transmural wavefront from the subendocardium toward the subepicardium. However, whether wavefront progression of necrosis also occurs laterally has been disputed. We aimed to assess the transmural and lateral spread of myocardial damage after acute myocardial infarction in humans and to evaluate the impact of metoprolol on these. METHODS We assessed myocardial infarction in the transmural and lateral dimensions in a cohort of 220 acute ST-segment elevation myocardial infarction (STEMI) patients from the METOCARD-CNIC trial (Effect of Metoprolol in Cardioprotection During an Acute Myocardial Infarction). The patients underwent cardiac magnetic resonance imaging at 5 to 7 days and 6 months post-STEMI. RESULTS On day 5 to 7 post-STEMI cardiac magnetic resonance, there was a strong linear correlation between the transmural and lateral extent of infarction (delayed gadolinium enhancement) (r=-0.88; P

Resumen Introduccion y objetivos Esta establecido que la necrosis secundaria a una oclusion coronaria se inicia en el subendocario y progresa hacia el subepicardio. Sin embargo, hay controversia sobre la posibilidad de que la onda de progresion del infarto sea lateral, ademas de transmural, y es el objetivo de este trabajo. Metodos Se estudio la extension del infarto en las dimensiones transmural y lateral en 220 pacientes con infarto agudo de miocardio del ensayo METOCARD-CNIC (Efecto del metoprolol en la cardioproteccion durante un infarto agudo de miocardio). Los pacientes se sometieron a 2 resonancias magneticas. Resultados En la resonancia de los dias 5-7 posinfarto, se encontro una fuerte correlacion lineal entre las extensiones transmural y lateral del infarto (realce tardio de gadolinio) (r = -0,88; p Conclusiones Nuestros hallazgos cuestionan el dogma de que la progresion del infarto solo se produce en sentido transmural. Mostramos que el infarto progresa de forma circunferencial (en sentido tanto transmural como lateral). Esto implica que las terapias cardioprotectoras pueden asociarse con miocardio salvado en los bordes laterales del infarto. Este estudio ha sido registrado en ClinicalTrial.gov (Identificador: NCT01311700).

Pulmonary hypertension (PH) associated with left heart disease is an increasingly prevalent problem, orphan of targeted therapies, and related to a poor prognosis, particularly when pre- and post-capillary PH combine. The current study aimed to determine whether treatment with the selective β3 adrenoreceptor agonist mirabegron improves outcomes in patients with combined pre- and post-capillary PH (CpcPH).The β3 Adrenergic Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure (SPHERE-HF) trial is a multicentre, randomized, parallel, placebo-controlled clinical trial that enrolled stable patients with CpcPH associated with symptomatic heart failure. A total of 80 patients were assigned to receive mirabegron (50 mg daily, titrated till 200 mg daily, n = 39) or placebo (n = 41) for 16 weeks. Of them, 66 patients successfully completed the study protocol and were valid for the main analysis. The primary endpoint was the change in pulmonary vascular resistance (PVR) on right heart catheterization. Secondary outcomes included the change in right ventricular (RV) ejection fraction by cardiac magnetic resonance or computed tomography, other haemodynamic variables, functional class, and quality of life. The trial was negative for the primary outcome (placebo-corrected mean difference of 0.62 Wood units, 95% confidence interval [CI] -0.38, 1.61, p = 0.218). Patients receiving mirabegron presented a significant improvement in RV ejection fraction as compared to placebo (placebo-corrected mean difference of 3.0%, 95% CI 0.4, 5.7%, p = 0.026), without significant differences in other pre-specified secondary outcomes.SPHERE-HF is the first clinical trial to assess the potential benefit of β3 adrenergic agonists in PH. The trial was negative since mirabegron did not reduce PVR, the primary endpoint, in patients with CpcPH. On pre-specified secondary outcomes, a significant improvement in RV ejection fraction assessed by advanced cardiac imaging was found, without differences in functional class or quality of life.

The p.Glu109Lys variant (Glu89Lys) is a rare cause of hereditary transthyretin amyloidosis (ATTRv) for which clinical spectrum remains unresolved. We sought to describe the clinical characteristics and outcomes of ATTR Glu89Lys amyloidosis and assess a potential founder effect in Spain. Patients with the p.Glu109Lys ATTRv variant from 14 families were recruited at 7 centres. Demographics, complementary tests and clinical course were analysed. Haplotype analysis was performed in 7 unrelated individuals. Thirty-eight individuals (13 probands, mean age 40.4 ± 13.1 years) were studied. After median follow-up of 5.1 years (IQR 1.7-9.6), 7 patients died and 7 required heart transplantation (median age at transplantation 50.5 years). Onset of cardiac and neurological manifestations occurred at a mean age of 48.4 and 46.8 years, respectively. Median survival from birth was 61.6 years and no individual survived beyond 65 years. Patients treated with disease-modifying therapies exhibited better prognosis (p

Inhibitors of SGLT2 (SGLT2i) have shown a positive impact in patients with chronic heart failure and reduced ejection fraction (HFrEF). Nonetheless, the direct effects of SGLT2i on cardiac cells and how their association with main drugs used for HFrEF affect the behaviour and signalling pathways of myocardial fibroblasts are still unknown. We aimed to determine the effects of dapagliflozin alone and in combination with sacubitril/valsartan (LCZ696) or spironolactone on the function of myocardial fibroblasts of patients with heart failure and reduced ejection fraction (HFrEF).Myocardial fibroblasts isolated from HFrEF patients (n = 5) were treated with dapagliflozin alone (1 nM-1 μM) or combined with LCZ696 (100 nM) or spironolactone (100 nM). The migratory rate was determined by wound-healing scratch assay. Expression of heart failure (HF) markers and signalling pathways activation were analysed with multiplexed protein array. Commercially available cardiac fibroblasts from healthy donors were used as Control (n = 4). Fibroblasts from HFrEF show higher migratory rate compared with control (P = 0.0036), and increased expression of HF markers [fold-change (Log2): COL1A1-1.3; IL-1b-1.9; IL-6-1.7; FN1-2.9 (P 0.05)]. Dapagliflozin slowed the migration rate of HFrEF fibroblasts in a dose-dependent manner and markedly decreased the expression of IL-1β, IL-6, MMP3, MMP9, GAL3, and FN1. SGLT2i had no effect on control fibroblasts. These effects were associated with decreased phosphorylation of AKT/GSK3 and PYK2 kinases and the signal transducer and activator of transcription (STAT). A combination of dapagliflozin + LCZ696 further decreased fibroblast migration, although it did not have a significant effect on the regulation of signalling pathways and the expression of biomarkers induced by SGLT2 inhibition alone. In contrast, the combination of dapagliflozin + spironolactone did not change the migration rate of fibroblast but significantly altered SGLT2i responses on MMP9, GAL3, and IL-1b expression, in association with increased phosphorylation of the kinases AKT/GSK3 and ERK1/2.SGLT2i, LCZ696, and spironolactone modulate the function of isolated myocardial fibroblasts from HFrEF patients through the activation of different signalling pathways. The combination of SGLT2i + LCZ696 shows an additive effect on migration, while spironolactone modifies the signalling pathways activated by SGLT2i and its beneficial effects of biomarkers of heart failure.

HILIC is a separation technique increasingly used for the study of polar metabolites. However, HILIC suffers of a drawback related to the solvents used for these analyses: acetonitrile as sample solvent leads to the best chromatographic peaks, but it is not capable to extract/dissolve the most polar compounds. In this work we evaluated the use of several strategies for the extraction of polar compounds from plasma samples and, although methanol was the ideal solvent for analyte extraction, distorted peaks were obtained in the chromatography. Different strategies were tested included changing the solvent after extraction or modifying the injection volume and type. Finally, the best solution was using the lowest injection volume possible and to employ a simple sandwich injection including acetonitrile during the injection of the sample. This remarkably improves the peak shape when methanol is used in the sample. We evaluated and applied two HILIC-MS methods, in positive and negative ionization modes, on plasma samples from pigs with pulmonary hypertension produced by aorto-pulmonary shunting to identify metabolic signatures underlying damage to the right heart. Our analyses revealed altered relevant metabolic pathways, suggestive of oxidative stress and reduced energy demands.

Aims: Dilated cardiomyopathy (DCM) associated with dystrophin gene (DMD) mutations in individuals with mild or absent skeletal myopathy is often indistinguishable from other DCM forms. We sought to describe the phenotype and prognosis of DMD associated DCM in DMD mutation carriers without severe skeletal myopathy. Methods and results: At 26 European centres, we retrospectively collected clinical characteristics and outcomes of 223 DMD mutation carriers (83% male, 33 ± 15 years). A total of 112 individuals (52%) had DCM at first evaluation [n = 85; left ventricular ejection fraction (LVEF) 34 ± 11.2%] or developed DCM (n = 27; LVEF 41.3 ± 7.5%) after a median follow-up of 96 months (interquartile range 5–311 months). DCM penetrance was 45% in carriers older than 40 years. DCM appeared earlier in males and was independent of the type of mutation, presence of skeletal myopathy, or elevated serum creatine kinase levels. Major adverse cardiac events (MACE) occurred in 22% individuals with DCM, 18% developed end-stage heart failure and 9% sudden cardiac death or equivalent. Skeletal myopathy was not associated with survival free of MACE in patients with DCM. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Individuals without DCM had favourable prognosis without MACE or death during follow-up. Conclusions: DMD-associated DCM without severe skeletal myopathy is characterized by incomplete penetrance but high risk of MACE, including progression to end-stage heart failure and ventricular arrhythmias. DCM onset is the major determinant of prognosis with similar survival regardless of the presence of skeletal myopathy.

ISO 15189:2012 establishes the requirements for clinical sample management, ensuring quality of process and laboratory information management. The accreditation authority, ENAC in Spain, established the requirements for the authorized use of the label in reports issued by accredited laboratories. These recommendations are applicable to the postanalytical processes and the professionals involved. The Standard requires laboratories to define and document the duration and conditions of sample retention. Laboratories are also required to design an internal quality control scheme to verify whether postanalytical activities attain the expected standards. Information management requirements are also established and laboratories are required to design a contingency plan to ensure the communication of laboratory results. Instructions are finally provided about the correct use of the accreditation label in laboratory reports. A range of nations and scientific societies support that clinical laboratories should be required to obtain accreditation. With ISO 15189 being the most specific standard for demonstrating technical performance, a clear understanding of its requirements is essential for proper implementation.

Resumen La norma ISO 15189:2012 exige una serie de requisitos en cuanto a la gestión de muestras clínicas, el aseguramiento de la calidad del proceso y la gestión de la información del laboratorio. Además, la entidad acreditadora, ENAC en España, tiene establecidas las condiciones para el uso de la marca en el informe de resultados del laboratorio acreditado. Las recomendaciones planteadas aplican a las actividades incluidas en el proceso posanalítico del laboratorio, así como al personal implicado. Se indican los criterios para que el laboratorio defina y documente el tiempo y las condiciones de retención de las muestras, para diseñar un control de calidad interno que verifique si las actividades posanalíticas alcanzan la calidad esperada, los requisitos que debe cumplir la gestión de la información y la necesidad de disponer de un plan de contingencia que asegure la comunicación de los resultados en todo momento. Asimismo, se describe el uso correcto de la marca de acreditación en los informes. Diversos gobiernos y sociedades científicas abogan por la obligatoriedad de la acreditación de los laboratorios clínicos. Siendo la norma ISO 15189 la más específica para demostrar su competencia técnica, es indispensable el conocimiento y la comprensión de sus requisitos para su correcta implantación.

The objective of this paper is to share some considerations about the management of postanalytical processes in relation to the review, reporting and release of test results in accordance with UNE-EN ISO 15189:2013 Standard requirements. The scope of this paper includes postanalytical activities and the personnel involved (laboratory management and staff). We describe the criteria and information required to review and validate analytical results and ensure that clear reports are sent to requesters. These criteria also guarantee that results are transcribed in a reliable way and that all necessary information is provided for the correct interpretation of results. Likewise, the requirements for the correct release of laboratory results are described, with special emphasis on the release of alarming or critical results. In some European countries, clinical laboratories are required to hold partial or full ISO 15189 accreditation, which is a global trend. Therefore, understanding ISO 15189 requirements is imperative for a progressive and more effective implementation of the Standard.

Aims: Genotype and left ventricular scar on cardiac magnetic resonance (CMR) are increasingly recognized as risk markers for adverse outcomes in non-ischaemic dilated cardiomyopathy (DCM). We investigated the combined influence of genotype and late gadolinium enhancement (LGE) in assessing prognosis in a large cohort of patients with DCM. Methods and results: Outcomes of 600 patients with DCM (53.3 ± 14.1 years, 66% male) who underwent clinical CMR and genetic testing were retrospectively analysed. The primary endpoints were end-stage heart failure (ESHF) and malignant ventricular arrhythmias (MVA). During a median follow-up of 2.7 years (interquartile range 1.3–4.9), 24 (4.00%) and 48 (8.00%) patients had ESHF and MVA, respectively. In total, 242 (40.3%) patients had pathogenic/likely pathogenic variants (positive genotype) and 151 (25.2%) had LGE. In survival analysis, positive LGE was associated with MVA and ESHF (both, p < 0.001) while positive genotype was associated with ESHF (p = 0.034) but not with MVA (p = 0.102). Classification of patients according to genotype (G+/G−) and LGE presence (L+/L−) revealed progressively increasing events across L−/G−, L−/G+, L+/G− and L+/G+ groups and resulted in optimized MVA and ESHF prediction (p < 0.001 and p = 0.001, respectively). Hazard ratios for MVA and ESHF in patients with either L+ or G+ compared with those with L−/G− were 4.71 (95% confidence interval: 2.11–10.50, p < 0.001) and 7.92 (95% confidence interval: 1.86–33.78, p < 0.001), respectively. Conclusion: Classification of patients with DCM according to genotype and LGE improves MVA and ESHF prediction. Scar assessment with CMR and genotyping should be considered to select patients for primary prevention implantable cardioverter-defibrillator placement, This work was supported by grants from the Instituto de Salud Carlos III (ISCIII) (PI18/0004, PI19/01283, PI20/0320). (Co-funded by European Regional Development Fund/European Social Fund ‘A way to make Europe’/‘Investing in your future’). The Hospital Universitario Puerta de Hierro Majadahonda, the Hospital Clinic, the Hospital Vall d’Hebron, the Hospital General Universitario Gregorio Marañón and the Hospital Universitario Virgen de la Arrixaca are members of the European Reference Network for rare, low-prevalence, and complex diseases of the heart (ERN GUARD-Heart). The CNIC is supported by the ISCIII, MCIN, the Pro-CNIC Foundation, and the Severo Ochoa Centers of Excellence program (CEX2020-001041-S). Conflict of interest: none declared

Resumen El objeto de este trabajo es establecer unas consideraciones para facilitar la gestión del proceso posanalítico respecto a la revisión, notificación y comunicación de los resultados, de acuerdo con los requisitos de la Norma UNE-EN ISO 15189:2013. El ámbito de aplicación incluye las actividades del proceso posanalítico del laboratorio clínico, así como el personal implicado en él (dirección y personal del laboratorio). Se indican los criterios y la información necesaria para realizar la revisión y validación de los resultados de las pruebas analíticas y así enviar a los destinatarios informes claros, asegurando siempre una transcripción fidedigna de los resultados e incluyendo toda la información necesaria para su correcta interpretación. Asimismo, se describen los requisitos para una correcta comunicación de los resultados del laboratorio, haciendo especial hincapié en la comunicación de aquellos resultados alarmantes o críticos. En algunos países de Europa es obligatoria la acreditación, total o parcial, de los laboratorios clínicos, siguiendo la Norma ISO 15189 y esta parece ser la hoja de ruta marcada en otros muchos países. Por ello, es indispensable la comprensión de sus requisitos para realizar una implementación progresiva y más fácil.

Background Heart transplant (HT) remains the last treatment option for patients with non-obstructive hypertrophic cardiomyopathy (HCM) who develop end-stage heart failure (HF). Early identification of patients who may require a HT in the future is crucial in order to advise them, establish the appropriate follow-up and determine the appropriate time to include them in the waiting list. Objectives Our study sought to find predictive factors related with requiring HT during follow-up in patients with HCM. Methods Consecutive patients with HCM referred to a HCM monographic clinic from 2018 to 2020 (HCM controls) and transplanted patients due to HCM in the same tertiary HT hospital since 2003 (cases) were included. Baseline (on the date of HCM diagnosis) and longitudinal data regarding clinical, genetic, ECG and echocardiographic variables were retrospectively evaluated. Follow-up was registered from HCM diagnosis to HT (in cases) or last medical check up (controls). Results A total of 157 patients (24 HCM-HT cases and 133 HCM controls) were included (45±19 yo; 57% male). At the time of MCH diagnosis (Table), cases were significantly younger than controls, were more frequently symptomatic and showed significantly higher BNP levels and more advanced diastolic dysfunction (larger left atrium, higher E/A ratio and lower e'); also, HCM-HT reported more family history and had higher proportion of pathogenic mutations (being MYH7 the most frequently involved). Left ventricular (LV) systolic function was slightly reduced in HCM-HT cases. In contrast, HCM controls were more frequently diagnosed by casual findings or family screening and had more LV outflow tract obstruction at first medical evaluation. LV maximal wall thickness (MWT) did not differ between groups. During a median follow-up since HCM diagnosis of 6.2 years (median follow-up of 8.9 and 7.1 years in cases and controls, respectively), HCM-HT cases presented a higher incidence of sustained ventricular tachycardia or ICD therapy (HR=4.0; CI95%:1.6–10.0 p=0.03) and HF admissions (HR=3.9; CI95%:1.8–8.1 p Conclusions The presence of symptoms in a young non-obstructive HCM patient, along with family history and a pathogenic mutation, should advice clinicians a closer follow-up and early transfer to a HT referral center, especially if associated with diastolic dysfunction and high BNP values. Funding Acknowledgement Type of funding sources: None. Table 1

Trasplante combinado de corazón e hígado; Cardiomiopatía Trasplantament combinat de fetge i cor; Cardiomiopatia Combined heart-liver transplant; Cardiomyopathy Background Uhl's anomaly is an extremely rare congenital heart defect characterized by absence of the right ventricle myocardium and preserved left ventricular myocardium. Although the disease has a poor prognosis and is generally fatal in the perinatal period, some patients may reach adulthood. Methods We describe a case of Uhl's anomaly complicated with heart failure and decompensated cardiac cirrhosis in a 42-year-old man treated by combined heart-liver transplant. Results The patient underwent heart transplant using the bicaval technique followed by subsequent liver transplant with the piggyback technique without venovenous bypass. Total ischemia time was 108 minutes for the heart and 360 and 25 minutes of cold and warm ischemia, respectively, for the liver. No intraoperative complications occurred. The patient was discharged without severe complications on postoperative day 22. Pathologic examination of the organs reported advanced cirrhosis of the liver and severe dilated myocardiopathy of right ventricle with absence of myocardium and a normal left ventricle. Twenty-seven months after the transplant the patient has been free from hospital admissions, with normal function of both transplanted organs. Conclusions We report the first successful combined heart-liver transplant for Uhl's anomaly indication in an adult patient. Despite of the insufficient knowledge of natural history of this exceptional disease, we successfully apply the management principles of other end-stage right heart disorders complicated with liver failure.

Introduction and objectives: Septal myectomy remains the first septal reduction therapy for hypertrophic obstructive cardiomyopathy in young patients and those requiring concomitant procedures. Its role in advanced ages is questioned due to perceived increased risk. We assess the outcomes of surgical relief of obstruction in patients beyond 65 years old. Methods: A single-center retrospective review of patients ≥ 65 years old undergoing septal myectomy through median sternotomy between April 2015 and February 2020. Results: We identified 52 patients. Mean age was 71.8 ± 4.9 years, 36 (69.2%) were females. All were symptomatic. Mean highest LVOT gradient was 90 ± 39 mmHg. All patients had systolic anterior motion (SAM) of the mitral valve and 36 (69.2%) ≥ moderate mitral regurgitation. Additional LVOT interventions beyond myectomy were performed in 34 (65.4%). At least one other cardiac concomitant procedure was performed 44 (84.6%). No perioperative mortality in elective surgery occurred. One patient (1.9%) developed atrio-ventricular block. Postoperative mean gradient was 4.3 ± 1.9 mmHg, with 46 (88.4%) achieving complete resolution of obstruction. Mitral regurgitation was reduced to grade ≤ I in 46 (88.5%). Mean follow-up time was 2.3 ± 1.2 years and 82% of patients were in NYHA I. Survival at 2 years was 98%. Conclusion: Septal myectomy in the elderly is a safe and effective operation despite the need for concomitant procedures. LVOT interventions beyond septal myectomy to relieve obstruction are common in this advanced cohort of hypertrophic cardiomyopathy patients. This operation carried at experienced centers seems an unmatched therapeutic option.

Heparin-induced thrombocytopaenia (HIT) complicates the management of patients in need for mechanical circulatory support awaiting heart transplantation. The limited available treatment options are fraught with complications and limitations in their applicability. We report on the combined use of therapeutic plasma exchange therapy and intravenous immunoglobulin, used in 3 consecutive heparin-induced thrombocytopaenia-positive patients on temporary mechanical circulatory support awaiting urgent heart transplant. This combined approach allowed us to use heparin safely.

Background The cumulative effects of intensive endurance exercise may induce a broad spectrum of right ventricular remodelling. The mechanisms underlying these variable responses have been scarcely explored, but may involve differential pulmonary vasculature adaptation. Our aim was to evaluate right ventricular and pulmonary circulation in highly trained endurance athletes. Methods Ninety-three highly trained endurance athletes (>12 h training/week at least during the last five years; age: 36 ± 6 years; 52.7% male) and 72 age- and gender-matched controls underwent resting cardiovascular magnetic resonance imaging to assess cardiac dimensions and function, as well as pulmonary artery dimensions and flow. Pulmonary vascular resistance (PVR) was estimated based on left ventricular ejection fraction and pulmonary artery flow mean velocity. Resting and exercise Doppler echocardiography was also performed in athletes to estimate pulmonary artery pressure. Results Athletes showed larger biventricular and biatrial sizes, slightly reduced systolic biventricular function, increased pulmonary artery dimensions and reduced pulmonary artery flow velocity as compared with controls in both genders ( p 4.2 WU) were found in seven of the 93 (9.3%) athletes: those exhibiting an enlarged pulmonary artery (indexed area cm2/m2: 4.8 ± 0.6 vs. 3.9 ± 0.6, p Conclusions Exercise-induced remodelling involves, besides the cardiac chambers, the pulmonary circulation and is associated with an increased estimated PVR. A small subset of athletes exhibited substantial increase of estimated PVR related to pronounced pulmonary circulation remodelling and reduced right ventricular systolic function.

Resumen Introduccion y objetivos La enfermedad de Danon (ED) es una enfermedad producida por mutaciones en el gen LAMP2. Se la considera una enfermedad multisistemica caracterizada por miocardiopatia hipertrofica con preexcitacion e hipertrofia extrema, discapacidad intelectual, miopatia, presentacion infantil y peor pronostico en varones. Hay pocas series que permitan conocer las caracteristicas clinicas y el pronostico de la ED. Metodos Se analizaron los registros clinicos de los pacientes con ED de 10 hospitales espanoles. Resultados Se incluyo a 27 pacientes (edad, 31 ± 19 anos; el 78% mujeres). Los varones mostraron una elevada prevalencia de manifestaciones extracardiacas —miopatia (80%), trastornos del aprendizaje (83%) y alteraciones visuales (60%)— que eran infrecuentes en las mujeres (el 5, el 0 y el 27% respectivamente). Aunque la miocardiopatia hipertrofica era la cardiopatia mas habitual (61%), el grosor ventricular maximo fue 15 ± 7 mm y 12 pacientes (10 mujeres) presentaron miocardiopatia dilatada. Solo 11 pacientes (49%) mostraron preexcitacion y en 16 (65%) la enfermedad se inicio despues de los 20 anos. Tras una mediana de seguimiento de 4 anos [intervalo intercuartilico, 2-9], 4 varones (67%) y 9 mujeres (43%) fallecieron o se sometieron a trasplante. El dano cardiaco y los eventos adversos ocurrieron mas tardiamente en las mujeres (37 ± 9 frente a 23 ± 16 anos y 36 ± 20 frente a 20 ± 11 anos). Conclusiones Las caracteristicas clinicas de la ED difieren sustancialmente de lo considerado tradicionalmente. La edad de presentacion de la ED es mas tardia, no se expresa como una enfermedad multisistemica en las mujeres y la preexcitacion es poco frecuente.

BACKGROUND The clinical relevance of genetic variants in nonischemic dilated cardiomyopathy (DCM) is unsettled. OBJECTIVES The study sought to assess the prognostic impact of disease-causing genetic variants in DCM. METHODS Baseline and longitudinal clinical data from 1,005 genotyped DCM probands were retrospectively collected at 20 centers. A total of 372 (37%) patients had pathogenic or likely pathogenic variants (genotype positive) and 633 (63%) were genotype negative. The primary endpoint was a composite of major adverse cardiovascular events. Secondary endpoints were end-stage heart failure (ESHF), malignant ventricular arrhythmia (MVA), and left ventricular reverse remodeling (LVRR) RESULTS After a median follow-up of 4.04 years (interquartile range: 1.70-7.50 years), the primary endpoint had occurred in 118 (31.7%) patients in the genotype-positive group and in 125 (19.8%) patients in the genotype-negative group (hazard ratio [HR]: 1.51; 95% confidence interval [CI]: 1.17-1.94; P = 0.001). ESHF occurred in 60 (16.1%) genotype-positive patients and in 55 (8.7%) genotype-negative patients (HR: 1.67; 95% CI: 1.16-2.41; P = 0.006). MVA occurred in 73 (19.6%) genotype-positive patients and in 77 (12.2%) genotype-negative patients (HR: 1.50; 95% CI: 1.092.07; P = 0.013). LVRR occurred in 39.6% in the genotype-positive group and in 46.2% in the genotype-negative group (P = 0.047). Among individuals with baseline left ventricular ejection fraction #35%, genotype-positive patients exhibited more major adverse cardiovascular events, ESHF, and MVA than their genotype-negative peers (all P < 0.02). LVRR and clinical outcomes varied depending on the underlying affected gene. CONCLUSIONS In this study, DCM patients with pathogenic or likely pathogenic variants had worse prognosis than genotype-negative individuals. Clinical course differed depending on the underlying affected gene. (J Am Coll Cardiol 2021;78:1682-1699) (c) 2021 by the American College of Cardiology Foundation.

A proper interpretation of the pathogenicity of rare variants is crucial before clinical translation. Ongoing addition of new data may modify previous variant classifications; however, how often a reanalysis is necessary remains undefined. We aimed to extensively reanalyze rare variants associated with inherited channelopathies originally classified 5 years ago and its clinical impact. In 2016, rare variants identified through genetic analysis were classified following the American College of Medical Genetics and Genomics’ recommendations. Five years later, we have reclassified the same variants following the same recommendations but including new available data. Potential clinical implications were discussed. Our cohort included 49 cases of inherited channelopathies diagnosed in 2016. Update show that 18.36% of the variants changed classification mainly due to improved global frequency data. Reclassifications mostly occurred in minority genes associated with channelopathies. Similar percentage of variants remain as deleterious nowadays, located in main known genes (SCN5A, KCNH2 and KCNQ1). In 2016, 69.38% of variants were classified as unknown significance, but now, 53.06% of variants are classified as such, remaining the most common group. No management was modified after translation of genetic data into clinics. After 5 years, nearly 20% of rare variants associated with inherited channelopathies were reclassified. This supports performing periodic reanalyses of no more than 5 years since last classification. Use of newly available data is necessary, especially concerning global frequencies and family segregation. Personalized clinical translation of rare variants can be crucial to management if a significant change in classification is identified.

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 European Commission Project H2020-MSCA-ITN-2016 (764738) and the Clinical Research in Cardiology grant from the Spanish Cardiac Society. Background The aetiology of left ventricular hypertrophy (LVH) is a relevant clinical challenge with consequences for patient management. Phenotypes resulting from hypertensive remodelling and sarcomere mutation often overlap. Synchrotron X-ray phase-contrast imaging (X-PCI) is a technique that can provide 3-dimensional detailed information on myocardial micro-structure non-destructively. The aim is to relate macrostructural/functional, non-invasive, imaging phenotypes of hypertrophic cardiomyopathy (HCM) to the underlying myocardial microstructure assessed with X-PCI. Methods Myocardial tissue samples were obtained from three patients (P1-3) with obstructive myocardial hypertrophy undergoing septal myectomy. Medical history and the 5-year HCM risk scores were evaluated. The patients were imaged with magnetic resonance imaging and echocardiography prior to procedure. Myocardial structure was assessed with wall thickness, late gadolinium enhancement (LGE), whereas function with speckle-tracking deformation (STE) and tissue Doppler imaging (TDI). Myectomy tissue was imaged with X-PCI in the TOMCAT beamline, using a multiscale propagation-based protocol combining a low-resolution (LR) and a high-resolution (HR) setup (5.8 and 0.7 um pixel size, respectively). Results The clinical and imaging data are shown in Fig 1. On initial assessment, wall thickness, LGE distribution, global longitudinal strain and septal TDI demonstrated a similar macrostructural and functional phenotype of P1 and P2, whereas P3 stood out with more severe hypertrophy, scarring and dysfunction. Additional regional deformation analysis with STE revealed reduced deformation in the basal and mid septum in P1, paired with a hypertensive pattern of post-systolic shortening (PSS) (yellow arrows). In comparison, in P2 and P3, deformation was more heterogeneous regionally, with regions of almost complete absence of deformation (orange arrows). Upon further exploration with TDI, areas with abnormal deformation were identified on the transition from basal to mid septum in both P2 and P3, whereas deformation was normal, but reduced in P1, and paired with PSS. LR X-PCI defined regions of interest to scan with HR (yellow frame), where HR revealed extensive interstitial fibrosis (orange arrow) with normal myocyte size and organisation in P1, compatible with severe hypertensive remodelling. However, in P2 and P3, patches of fibrosis (yellow arrow) paired with enlarged myocytes organized in visible disarray, considerably more prominent in P3, were both compatible with sarcomere-mutation HCM. Conclusion The results demonstrate multiscale phenotyping of HCM - relating micro- and macrostructural findings to function, and integrating multimodality data. In-depth regional deformation analysis, validated by synchrotron-based microstructural analysis, showed potential to identify distinct imaging phenotypes in HCM, distinguishing between overlapping presentations in different aetiologies. Abstract Figure 1

Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): Horizon 2020 European Commission Project H2020-MSCA-ITN-2016 (764738) and the Clinical Research in Cardiology grant from the Spanish Cardiac Society Background Exploring phenotypes of left ventricular hypertrophy (LVH) and interpreting the relationship of genotype and phenotype are contemporary clinical challenges. Machine learning (ML) can help by integrating whole-cardiac cycle echo data and separating patients based on subtle differences of cardiac function. The aim is to investigate if an unsupervised ML approach has the potential to explore the LVH spectrum and recognize phenotypes related to distinct disease aetiologies and genotypes. Methods The cohort consisted of 342 participants: patients with hypertrophic cardiomyopathy (HCM)(n = 27), HCM relatives (n = 31), hypertensive patients (HTN) (n = 189), and healthy individuals (n = 95). All had echocardiography performed, whereas magnetic resonance (MR) and genetic testing were performed when clinically indicated. Myocardial deformation of the LV and left atrium, aortic and mitral blood-pool Doppler, as well as the septal mitral annular tissue Doppler velocity profiles were used as input for ML. Clinical data, including echo measurements, were not part of the learning, but used to validate the ML-derived phenotypes. An unsupervised ML algorithm was used to create an output space where participants were positioned based on cardiac function. Regression was used to estimate the echo and clinical characteristics of different regions in the space. Results The ML analysis of HCM and relative data shows grouping of HCM patients in the right-most region of the output space (Fig 1B). This region was related to LV outflow tract obstruction, mitral inflow fusion, systolic impairment with septal involvement, as well as LA and LV strain impairment (Fig 1A). Clinical data concurred - showing reduced global longitudinal strain, elevated LV mass, and a pattern of systolic and diastolic impairment - defining a comprehensive phenotype of LV remodelling related to HCM. Exploration of the genotype/phenotype relationship revealed G + P- relatives grouping on the transition from the healthy to the remodelling region. Projection of the HTN and healthy individuals into the HCM space defined the LVH disease spectrum, with healthy individuals projecting in the existing healthy region and HTNs in the transition from health to extreme remodelling (Fig 1C). MR findings of late gadolinium enhancement correlated with the ML-derived functional remodelling phenotype (Fig 1C). Furthermore, 6 patients with a clinical need for septal myectomy were located in the extreme remodelling part of the output space (Fig 1C, red circles). Conclusion ML can integrate complex, whole-cardiac cycle echo data to group patients based on similarity of cardiac function. Using an interpretable ML approach, we can explore the spectrum of LV remodelling in different aetiologies and interpret the relationship between genotype and phenotype. The methodology can accommodate new patients by projecting them into the existing space to aid in clinical interpretation, risk assessment and patient management. Abstract Figure 1

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine., This work was supported by Obra Social "La Caixa Foundation" (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690) from Instituto Salud Carlos III (ISCIII), and "Fundacio Privada Daniel Bravo Andreu". CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness.

Right ventricle (RV) dysfunction is a main determinant of morbidity and mortality in postcapillary pulmonary hypertension (PH). However, currently there are not available therapies. Since reduced nitric oxide (NO) availability and cyclic guanylate monophosphate (cGMP) levels are central in this disease, therapies targeting the NO pathway might have a beneficial effect on RV performance. In this regard, sildenafil has shown contradictory results. Our objective was to evaluate the effect of sildenafil on RV performance in an experimental pig model of postcapillary PH induced by a fixed banding of the venous pulmonary confluent. Animals were evaluated by right heart catheterization and cardiac magnetic resonance before randomization and after 8 weeks on sildenafil (n = 8) or placebo (n = 8), and myocardial tissues were analyzed with histology and molecular biology. At the end of the study, animals receiving sildenafil showed better RV performance as compared with those on placebo (improvement in RV ejection fraction of 7.3% ± 5.8% versus -0.6% ± 5.0%, P= 0.021) associated with less apoptotic cells and gene expression related with reduced oxidative stress and increased anti-inflammatory activity in the myocardium. No differences were observed in pulmonary hemodynamics. In conclusion, in a translational large animal model of chronic postcapillary PH, sildenafil improved RV systolic function independently of afterload. Further research with pharmacological approaches able to manipulate the NO-cGMP axis are needed to confirm this potential cardioprotective effect. This work was partially funded by the grant Ajut a la Recerca “Josep Font” 2015 (to Dr. Santiago-Vacas) and by Fondo Europeo de Desarrollo Regional (FEDER) Instituto de Salud Carlos III-Fondo de Investigación Sanitaria PI17/00995 (to Dr. García-Álvarez). The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Part of this work was developed at the Centre de Recerca Biomèdica Cellex, IDIBAPS, Barcelona. The IDIBAPS belongs to the CERCA Programme and receives partial funding from the Generalitat de Catalunya Sí

The autonomic nervous system (ANS) and renin-angiotensin-aldosterone system (RAAS) are involved in many cardiovascular disorders, including pulmonary hypertension (PH). The current review focuses on the role of the ANS and RAAS activation in PH and updated evidence of potential therapies targeting both systems in this condition, particularly in Groups 1 and 2. State of the art knowledge in preclinical and clinical use of pharmacologic drugs (beta-blockers, beta-three adrenoceptor agonists, or renin-angiotensin-aldosterone signaling drugs) and invasive procedures, such as pulmonary artery denervation, is provided. This work was partially funded by Fondo Europeo de Desarrollo Regional (FEDER) Instituto de Salud Carlos III-Fondo de Investigación Sanitaria PI17/00995 and Intensificación AES2019 to Dr. García-Álvarez. The CNIC is supported by the Ministerio de Ciencia, Innovación y Universidades and the Pro CNIC Foundation, and is a Severo Ochoa Center of Excellence (SEV-2015-0505). Part of this work was developed at the Centre de Recerca Biomèdica Cellex, IDIBAPS, Barcelona. The IDIBAPS belongs to the CERCA Programme and receives partial funding from the Generalitat de Catalunya. Sí

Background Mutations in dystrophin gene (DMD) can cause skeletal myopathy and dilated cardiomyopathy (DCM) independently or in combination. Natural history of DMD mutation carriers and dystrophin-associated DCM is poorly understood. Objectives This study sought to describe phenotype and prognosis of DMD mutations in a large multicenter cohort of Non-Duchenne DMD mutations carriers. Methods The study cohort comprised 223 individuals with a DMD mutation (83% males, 33±15 years at first evaluation) followed at 26 European centers. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, heart transplant, LVAD implantation, aborted SCD or appropriate ICD shock. Results At initial evaluation, 85 patients (38%) had DCM (52 in combination with muscular disease) and 92 (41%) had isolated muscular disease. After a median follow-up of 96 months, 112 individuals (53%) had DCM and 20% of the individuals who had normal cardiac function at baseline developed DCM. DCM penetrance by age 30 was 56%. DCM onset was associated with male sex and was independent of the type of mutation, the presence of skeletal myopathy or serum creatine kinase levels. MACE occurred in 11% and 22% individuals from the entire cohort and with DCM respectively, and were more frequent in DCM patients without muscular disease than in those with skeletal myopathy (35.5% vs 17.7%; p=0.04). Among patients with DCM, 18% developed end-stage heart failure and 9% a major arrhythmic event (SCD/aborted SCD/ICD shock/VT). There were not differences in survival between patients with isolated DCM and those with DCM and muscular phenotype. Decreased LVEF and increased left ventricular end-diastolic diameter at baseline were associated with MACE. Atrial fibrillation and neurological events were also frequent. Prognosis of individuals who did not develop DCM was good with 96% survival during follow-up. Conclusions DCM caused by mutations in DMD is characterized by moderate penetrance but a high risk of MACE, progression to end-stage heart failure and ventricular arrythmias. DCM onset is the major determinant of prognosis in DMD mutation carriers with similar survival irrespectively of the presence of concomitant muscular disease. Survival free of MACE analysis Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Instituto de Salud Carlos III. Contratos i-PFIS: Doctorados IIS-empresa en Ciencias y Tecnologías de la Salud

Introduction and objectives: To determine whether structural/organizational characteristics of hospitals and emergency departments (EDs) affect acute heart failure (AHF) outcomes. Methods: We performed a secondary analysis of the EAHFE Registry. Six hospital/ED characteristics were collected and were related to 7 postindex events and postdischarge outcomes, adjusted by the period of patient inclusion, baseline patient characteristics, AHF episode features, and hospital and ED characteristics. The relationship between discharge directly from the ED (DDED) and outcomes was assessed, and interaction was analyzed according to the hospital/ED characteristics. Results: We analyzed 17 974 AHF episodes included by 40 Spanish EDs. Prolonged stays were less frequent in high-technology hospitals and those with hospitalization at home and with high-inflow EDs, and were more frequent in hospitals with a heart failure unit (HFU) and an ED observation unit. In-hospital mortality was lower in high-technology hospitals (OR, 0.78; 95%CI, 0.65-0.94). Analysis of 30-day postdischarge outcomes showed that hospitals with a short-stay unit (SSU) had higher hospitalization rates (OR, 1.19; 95%CI, 1.02-1.38), high-inflow EDs had lower mortality (OR, 0.73; 95%CI, 0.56-0.96) and fewer combined events (OR, 0.87; 95%CI, 0.76-0.99), while hospitals with HFU had fewer ED reconsultations (OR, 0.83; 95%CI, 0.76-0.91), hospitalizations (OR, 0.85; 95%CI, 0.75-0.97), and combined events (OR, 0.84; 95%CI, 0.77-0.92). The higher the percentage of DDED, the fewer the prolonged stays. Among other interactions, we found that more frequent DDED was associated with more 30-day postdischarge reconsultations, hospitalizations and combined events in hospitals without SSUs, but not in hospitals with an SSU. Conclusions: AHF outcomes were significantly affected by the structural/organizational characteristics of hospitals and EDs and their aggressiveness in ED management. (C) 2020 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L.U. All rights reserved.

Visual Abstract, Highlights • CpcPH is a relatively common complication of chronic HF, is associated with poor survival, and has no specific pharmacological treatment. • ß3AR stimulation has shown improvement in pulmonary hemodynamics and RV performance in a translational large animal model mimicking this condition. • The SPHERE-HF trial is a Phase II randomized, double-blind clinical trial designed to evaluate the efficacy and safety of mirabegron (oral β3 AR agonist) in patients with CpcPH secondary to HF. • The SPHERE-HF trial will include 80 patients treated with mirabegron or placebo for 16 weeks. • The main outcome is the change in PVR. Secondary outcomes include changes in RV performance, clinical status, NT-proBNP levels, and additional pulmonary hemodynamic parameters., Summary Combined pre-and post-capillary hypertension (CpcPH) is a relatively common complication of heart failure (HF) associated with a poor prognosis. Currently, there is no specific therapy approved for this entity. Recently, treatment with beta-3 adrenergic receptor (β3AR) agonists was able to improve pulmonary hemodynamics and right ventricular (RV) performance in a translational, large animal model of chronic PH. The authors present the design of a phase II randomized clinical trial that tests the benefits of mirabegron (a clinically available β3AR agonist) in patients with CpcPH due to HF. The effect of β3AR treatment will be evaluated on pulmonary hemodynamics, as well as clinical, biochemical, and advanced cardiac imaging parameters. (Beta3 Agonist Treatment in Chronic Pulmonary Hypertension Secondary to Heart Failure [SPHERE-HF]; NCT02775539)