Registro Español de Trasplante Cardiaco: XXXI Informe Oficial de la Asociación de Insuficiencia Cardiaca de la Sociedad Española de Cardiología

[Abstract] Introduction and objectives. The present report describes the clinical characteristics and outcomes of heart transplants in Spain and updates the data to 2019. Methods. We describe the clinical characteristics and outcomes of heart transplants performed in Spain in 2019, as well as trends in this procedure from 2010 to 2018. Results. In 2019, 300 transplants were performed (8794 since 1984; 2745 between 2010 and 2019). Compared with previous years, the most notable findings were the decreasing rate of urgent transplants (38%), and the consolidation of the type of circulatory support prior to transplant, with an almost complete disappearance of counterpulsation balloon (0.7%), stabilization in the use of extracorporeal membrane oxygenation (9.6%), and an increase in the use of ventricular assist devices (29.0%). Survival from 2016 to 2018 was similar to that from 2013 to 2015 (P=.34). Survival in both these periods was better than that from 2010 to 2012 (P=.002 and P=.01, respectively). Conclusions. Heart transplant activity has remained stable during the last few years, as have outcomes (in terms of survival). There has been a trend to a lower rate of urgent transplants and to a higher use of ventricular assist devices prior to transplant.[Resumen] Introducción y objetivos. Se presentan las características clínicas y los resultados de los trasplantes cardiacos realizados en España con la actualización correspondiente a 2019. Métodos. Se describen las características clínicas y los resultados de los trasplantes cardiacos realizados en 2019, así como las tendencias de estos en el periodo 2010-2018. Resultados. En 2019 se realizaron 300 trasplantes (8.794 desde 1984; 2.745 entre 2010 y 2019). Respecto a años previos, los cambios más llamativos son el descenso hasta el 38% de los trasplantes realizados en código urgente, y la consolidación en el cambio de asistencia circulatoria pretrasplante, con la práctica desaparición del balón de contrapulsación (0,7%), la estabilización del uso del oxigenador extracorpóreo de membrana (9,6%) y el aumento de los dispositivos de asistencia ventricular (29%). La supervivencia en el trienio 2016-2018 es similar a la del trienio 2013-2015 (p=0,34), y ambas mejores que la del trienio 2010-2012 (p=0,002 y p=0,01 respectivamente). Conclusiones. Se mantienen estables tanto la actividad del trasplante cardiaco en España como los resultados en supervivencia en los últimos 2 trienios. Hay una tendencia a realizar menos trasplantes urgentes, la mayoría con dispositivos de asistencia ventricular

Registro Español de Trasplante Cardiaco: XXIX Informe Oficial de la Sección de Insuficiencia Cardiaca de la Sociedad Española de Cardiología (1984-2017)

[Resumen] Introducción y objetivos. Se actualizan las características clínicas y los resultados de los trasplantes cardiacos realizados en España en el periodo 2008-2017. Métodos. Se describen las características de los receptores, los donantes, los procedimientos quirúrgicos y los resultados de los trasplantes realizados en 2017 y se ponen en contexto respecto a los del periodo 2008-2016. Resultados. En 2017 se realizaron 304 trasplantes. Desde 1984, se han realizado 8.173 trasplantes, 2.689 de ellos desde 2008. Para el periodo 2008-2017, se observan tendencias temporales significativas en las características del receptor (menores resistencias vasculares pulmonares, menos ventilación mecánica previa al trasplante, mayor tasa de diabéticos y cirugía cardiaca previa), el donante (de más edad, más donantes mujeres y más donantes con parada cardiaca) y el procedimiento (menos tiempo de isquemia). En 2017, el 27% de los trasplantes se realizaron previa asistencia ventricular mecánica (p < 0,001 para la tendencia). En la última década, se observa una tendencia a una mejor supervivencia. Conclusiones. La actividad de trasplante cardiaco se estabiliza en alrededor de 300 procedimientos al año. Se extiende el uso de dispositivos de asistencia ventricular antes del trasplante, con tendencia a la mejora de la supervivencia

Impacto de la edad del donante-receptor en la supervivencia al trasplante cardiaco. Subanálisis del Registro Español de Trasplante Cardiaco

[Abstract] Introduction and objectives. The age of heart transplant recipients and donors is progressively increasing. It is likely that not all donor-recipient age combinations have the same impact on mortality. The objective of this work was to compare survival in transplant recipients according to donor-recipient age combinations. Methods. We performed a retrospective analysis of transplants performed between 1 January 1993 and 31 December 2017 in the Spanish Heart Transplant Registry. Pediatric transplants, retransplants and combined transplants were excluded (6505 transplants included). Four groups were considered: a) donor < 50 years for recipient < 65 years; b) donor < 50 years for recipient ≥ 65 years; c) donor ≥ 50 years for recipient ≥ 65 years, and d) donor ≥ 50 years for recipient < 65 years. Results. The most frequent group was young donor for young recipient (73%). There were differences in the median survival between the groups (P < .001): a) younger-younger: 12.1 years, 95%CI, 11.5-12.6; b) younger-older: 9.1 years, 95%CI, 8.0-10.5; c) older-older: 7.5 years, 95%CI, 2.8-11.0; d) older-younger: 10.5 years, 95%CI, 9.6-12.1. On multivariate analysis, independent predictors of mortality were the age of the donor and the recipient (0.008 and 0.001, respectively). The worst combinations were older-older vs younger-younger (HR, 1.57; 95%CI, 1.22-2.01; P < .001) and younger-older vs younger-younger (HR, 1.33; 95%CI, 1.12-1.58; P = .001). Conclusions. Age (of the donor and recipient) is a relevant prognostic factor in heart transplant. The donor-recipient age combination has prognostic implications that should be identified when accepting an organ for transplant.[Resumen] Introducción y objetivos. La edad de receptores y donantes cardiacos se está incrementando progresivamente. Es probable que no todas las combinaciones tengan el mismo impacto en la mortalidad. El objetivo de este trabajo es comparar la supervivencia de los pacientes trasplantados según la combinación de edades de donante y receptor. Métodos. Análisis retrospectivo del Registro Español de Trasplante Cardiaco de los trasplantes realizados entre el 1 de enero de 1993 y el 31 de diciembre de 2017. Se excluyeron los pediátricos, los retrasplantes y los trasplantes combinados (se incluyeron 6.505 trasplantes). Se consideraron 4 grupos: a) donante menor de 50 años para receptor menor de 65 años; b) donante menor de 50 años para receptor de edad ≥ 65 años; c) donante de edad ≥ 50 años para receptor de 65 o más, y d) donante de edad ≥ 50 años para receptor menor de 65. Resultados. El grupo más frecuente fue el de donante joven para receptor joven (73%). Hubo diferencias en la mediana de supervivencia entre los grupos (p < 0,001): a) joven-joven: 12,1 años (IC95%, 11,5-12,6); b) joven-mayor: 9,1 años (IC95%, 8,0-10,5); c) mayor-mayor: 7,5 años (IC95%, 2,8-11,0), y d) mayor-joven: 10,5 años (IC95%, 9,6-12,1). En el análisis multivariante, las edades del donante y del receptor resultaron predictoras independientes de la mortalidad (0,008 y 0,001 respectivamente). Las peores combinaciones fueron mayor-mayor frente a joven-joven (HR = 1,57; IC95%, 1,22-2,01; p < 0,001) y joven-mayor frente a joven-joven (HR = 1,33; IC95%, 1,12-1,58; p = 0,001). Conclusiones. La edad (del donante y del receptor) es un factor pronóstico relevante en el trasplante cardiaco. La combinación de edades de donante y receptor posee implicaciones pronósticas que se debe conocer a la hora de aceptar un órgano para trasplante

Cold ischemia >4 hours increases heart transplantation mortality. An analysis of the Spanish heart transplantation registry

[Abstract] Background. Cold ischemia time (CIT) has been associated to heart transplantation (HT) prognosis. However, there is still uncertainty regarding the CIT cutoff value that might have relevant clinical implications. Methods. We analyzed all adults that received a first HT during the period 2008–2018. CIT was defined as the time between the cross-clamp of the donor aorta and the reperfusion of the heart. Primary outcome was 1-month mortality. Results. We included 2629 patients, mean age was 53.3 ± 12.1 years and 655 (24.9%) were female. Mean CIT was 202 ± 67 min (minimum 20 min, maximum 600 min). One-month mortality per CIT quartile was 9, 12, 13, and 19%. One-year mortality per CIT quartile was 16, 19, 21, and 28%. CIT was an independent predictor of 1-month mortality, but only in the last quartile of CIT >246 min (odds ratio 2.1, 95% confidence interval 1.49–3.08, p < .001). We found no relevant differences in CIT during the study period. However, the impact of CIT in 1-month and 1-year mortality decreased with time (p value for the distribution of ischemic time by year 0.01), particularly during the last 5 years. Conclusions. Although the impact of CIT in HT prognosis seems to be decreasing in the last years, CIT in the last quartile (>246 min) is associated with 1-month and 1-year mortality. Our findings suggest the need to limit HT with CIT > 246 min or to use different myocardial preservation systems if the expected CIT is >4 h

Malignancy following heart transplantation: differences in incidence and prognosis between sexes – a multicenter cohort study

[Abstract] Male patients are at increased risk for developing malignancy postheart transplantation (HT); however, real incidence and prognosis in both genders remain unknown. The aim of this study was to assess differences in incidence and mortality related to malignancy between genders in a large cohort of HT patients. Incidence and mortality rates were calculated for all tumors, skin cancers (SCs), lymphoma, and nonskin solid cancers (NSSCs) as well as survival since first diagnosis of neoplasia. 5865 patients (81.6% male) were included. Total incidence rates for all tumors, SCs, and NSSCs were lower in females [all tumors: 25.7 vs. 44.8 per 1000 person‐years; rate ratio (RR) 0.68, (0.60–0.78), P < 0.001]. Mortality rates were also lower in females for all tumors [94.0 (77.3–114.3) vs. 129.6 (120.9–138.9) per 1000 person‐years; RR 0.76, (0.62–0.94), P = 0.01] and for NSSCs [125.0 (95.2–164.0) vs 234.7 (214.0–257.5) per 1000 person‐years; RR 0.60 (0.44–0.80), P = 0.001], albeit not for SCs or lymphoma. Female sex was associated with a better survival after diagnosis of malignancy [log‐rank p test = 0.0037; HR 0.74 (0.60–0.91), P = 0.004]. In conclusion, incidence of malignancies post‐HT is higher in males than in females, especially for SCs and NSSCs. Prognosis after cancer diagnosis is also worse in males

Autoantibody screening in Guillain-Barré syndrome

Background: Guillain?Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. Methods: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factor

Autoantibody screening in Guillain-Barré syndrome

Background: Guillain-Barré syndrome (GBS) is an acute inflammatory neuropathy with a heterogeneous presentation. Although some evidences support the role of autoantibodies in its pathogenesis, the target antigens remain unknown in a substantial proportion of GBS patients. The objective of this study is to screen for autoantibodies targeting peripheral nerve components in Guillain-Barré syndrome. Methods: Autoantibody screening was performed in serum samples from all GBS patients included in the International GBS Outcome study by 11 different Spanish centres. The screening included testing for anti-ganglioside antibodies, anti-nodo/paranodal antibodies, immunocytochemistry on neuroblastoma-derived human motor neurons and murine dorsal root ganglia (DRG) neurons, and immunohistochemistry on monkey peripheral nerve sections. We analysed the staining patterns of patients and controls. The prognostic value of anti-ganglioside antibodies was also analysed. Results: None of the GBS patients (n = 100) reacted against the nodo/paranodal proteins tested, and 61 (61%) were positive for, at least, one anti-ganglioside antibody. GBS sera reacted strongly against DRG neurons more frequently than controls both with IgG (6% vs 0%; p = 0.03) and IgM (11% vs 2.2%; p = 0.02) immunodetection. No differences were observed in the proportion of patients reacting against neuroblastoma-derived human motor neurons. Reactivity against monkey nerve tissue was frequently detected both in patients and controls, but specific patterns were only detected in GBS patients: IgG from 13 (13%) patients reacted strongly against Schwann cells. Finally, we confirmed that IgG anti-GM1 antibodies are associated with poorer outcomes independently of other known prognostic factors. Conclusion: Our study confirms that (1) GBS patients display a heterogeneous repertoire of autoantibodies targeting nerve cells and structures; (2) gangliosides are the most frequent antigens in GBS patients and have a prognostic value; (3) further antigen-discovery experiments may elucidate other potential antigens in GBS

A Multitrait Genetic Study of Hemostatic Factors and Hemorrhagic Transformation after Stroke Treatment

BACKGROUND: Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient\u27s prognosis. OBJECTIVES: to investigate the association between genetically determined natural hemostatic factors\u27 levels and increased risk of HT after r-tPA treatment. METHODS: Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT. RESULTS: Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10 CONCLUSION: We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed

Single nucleotide variations in ZBTB46 are associated with post-thrombolytic parenchymal haematoma

Haemorrhagic transformation is a complication of recombinant tissue-plasminogen activator treatment. The most severe form, parenchymal haematoma, can result in neurological deterioration, disability, and death. Our objective was to identify single nucleotide variations associated with a risk of parenchymal haematoma following thrombolytic therapy in patients with acute ischaemic stroke. A fixed-effect genome-wide meta-analysis was performed combining two-stage genome-wide association studies (n = 1904). The discovery stage (three cohorts) comprised 1324 ischaemic stroke individuals, 5.4% of whom had a parenchymal haematoma. Genetic variants yielding a P-value < 0.05 1 x 10(-5) were analysed in the validation stage (six cohorts), formed by 580 ischaemic stroke patients with 12.1% haemorrhagic events. All participants received recombinant tissue-plasminogen activator; cases were parenchymal haematoma type 1 or 2 as defined by the European Cooperative Acute Stroke Study (ECASS) criteria. Genome-wide significant findings (P < 5 x 10(-8)) were characterized by in silica functional annotation, gene expression, and DNA regulatory elements. We analysed 7 989 272 single nucleotide polymorphisms and identified a genome-wide association locus on chromosome 20 in the discovery cohort; functional annotation indicated that the ZBTB46 gene was driving the association for chromosome 20. The top single nucleotide polymorphism was rs76484331 in the ZBTB46 gene [P = 2.49 x 10(-8); odds ratio (OR): 11.21; 95% confidence interval (CI): 4.82-26.55]. In the replication cohort (n = 580), the rs76484331 polymorphism was associated with parenchymal haematoma (P = 0.01), and the overall association after meta-analysis increased (P = 1.61 x 10(-8), OR: 5.84; 95% CI: 3.16-10.76). ZBTB46 codes the zinc finger and BTB domain-containing protein 46 that acts as a transcription factor. In silica studies indicated that ZBTB46 is expressed in brain tissue by neurons and endothelial cells. Moreover, rs76484331 interacts with the promoter sites located at 20q13. In conclusion, we identified single nucleotide variants in the ZBTB46 gene associated with a higher risk of parenchymal haematoma following recombinant tissue-plasminogen activator treatment.Peer reviewe

A multitrait genetic study of hemostatic factors and hemorrhagic transformation after stroke treatment

[Background] Thrombolytic recombinant tissue plasminogen activator (r-tPA) treatment is the only pharmacologic intervention available in the ischemic stroke acute phase. This treatment is associated with an increased risk of intracerebral hemorrhages, known as hemorrhagic transformations (HTs), which worsen the patient’s prognosis.[Objectives] To investigate the association between genetically determined natural hemostatic factors’ levels and increased risk of HT after r-tPA treatment.[Methods] Using data from genome-wide association studies on the risk of HT after r-tPA treatment and data on 7 hemostatic factors (factor [F]VII, FVIII, von Willebrand factor [VWF], FXI, fibrinogen, plasminogen activator inhibitor-1, and tissue plasminogen activator), we performed local and global genetic correlation estimation multitrait analyses and colocalization and 2-sample Mendelian randomization analyses between hemostatic factors and HT.[Results] Local correlations identified a genomic region on chromosome 16 with shared covariance: fibrinogen-HT, P = 2.45 × 10−11. Multitrait analysis between fibrinogen-HT revealed 3 loci that simultaneously regulate circulating levels of fibrinogen and risk of HT: rs56026866 (PLXND1), P = 8.80 × 10−10; rs1421067 (CHD9), P = 1.81 × 10−14; and rs34780449, near ROBO1 gene, P = 1.64 × 10−8. Multitrait analysis between VWF-HT showed a novel common association regulating VWF and risk of HT after r-tPA at rs10942300 (ZNF366), P = 1.81 × 10−14. Mendelian randomization analysis did not find significant causal associations, although a nominal association was observed for FXI-HT (inverse-variance weighted estimate [SE], 0.07 [−0.29 to 0.00]; odds ratio, 0.87; 95% CI, 0.75-1.00; raw P = .05).[Conclusion] We identified 4 shared loci between hemostatic factors and HT after r-tPA treatment, suggesting common regulatory mechanisms between fibrinogen and VWF levels and HT. Further research to determine a possible mediating effect of fibrinogen on HT risk is needed.This study is supported in part by the National Heart, Lung, and Blood Institute grants HL134894, HL139553, and HL141291. G.T.-S. is supported by the Pla Estratègic de Recerca i Innovació en Salut grant from the Catalan Department of Health for junior research personnel (SLT017/20/000100). M.S.-L. is supported by a Miguel Servet contract from the Instituto de Salud Carlos III (ISCIII) Spanish Health Institute (CPII22/00007) and cofinanced by the European Social Fund. E.M. is supported by a Río Hortega Contract (CM18/00198) from the ISCIII. J.C.-M. is supported by an Agència de Gestió d’Ajuts Universitaris i de Recerca Contract (FI_DGR 2020, grant number 2020FI_B1 00157) cofinanced by the European Social Fund. C.G.-F. is supported by a Sara Borrell Contract (CD20/00043) from ISCIII and Fondo Europeo de Desarrollo Regional (ISCIII- FEDER). M.L. is supported by a Contratos Predoctorales de Formación en Investigación en Salud Contract from the ISCIII (FI19/00309).Peer reviewe