Best practices during COVID-19 pandemic in solid organ transplant programs in Spain.

Clinical management of transplant patients abruptly changed during the first months of COVID-19 pandemic (March to May 2020). The new situation led to very significant challenges, such as new forms of relationship between healthcare providers and patients and other professionals, design of protocols to prevent disease transmission and treatment of infected patients, management of waiting lists and of transplant programs during state/city lockdown, relevant reduction of medical training and educational activities, halt or delays of ongoing research, etc. The two main objectives of the current report are: 1) to promote a project of best practices in transplantation taking advantage of the knowledge and experience acquired by professionals during the evolving situation of the COVID-19 pandemic, both in performing their usual care activity, as well as in the adjustments taken to adapt to the clinical context, and 2) to create a document that collects these best practices, thus allowing the creation of a useful compendium for the exchange of knowledge between different Transplant Units. The scientific committee and expert panel finally standardized 30 best practices, including for the pretransplant period (n = 9), peritransplant period (n = 7), postransplant period (n = 8) and training and communication (n = 6). Many aspects of hospitals and units networking, telematic approaches, patient care, value-based medicine, hospitalization, and outpatient visit strategies, training for novelties and communication skills were covered. Massive vaccination has greatly improved the outcomes of the pandemic, with a decrease in severe cases requiring intensive care and a reduction in mortality. However, suboptimal responses to vaccines have been observed in transplant recipients, and health care strategic plans are necessary in these vulnerable populations. The best practices contained in this expert panel report may aid to their broader implementation.

Spanish experience with heart transplants from controlled donation after the circulatory determination of death using thoraco-abdominal normothermic regional perfusion and cold storage.

Heart transplantation from controlled donation after the circulatory determination of death (cDCDD) may help to increase the availability of hearts for transplantation. During 2020, four heart transplants were performed at three different Spanish hospitals based on the use of thoraco-abdominal normothermic regional perfusion (TA-NRP) followed by cold storage (CS). All donors were young adults <45 years. The functional warms ischemic time ranged from 8 to 16 minutes. In all cases, the heart recovered sinus rhythm within 1 minute of TA-NRP. TA-NRP was weaned off or decreased <1L within 25 minutes. No recipient required mechanical support after transplantation and all were immediately extubated and discharged home (median hospital stay: 21 days) with an excellent outcome. Four livers, eight kidneys, and two pancreata were also recovered and transplanted. All abdominal grafts recipients experienced an excellent outcome. The use of TA-NRP makes heart transplantation feasible and allows assessing heart function before organ procurement without any negative impact on the preservation of abdominal organs. The use of TA-NRP in cDCDD heart donors in conjunction with cold storage following retrieval can eliminate the need to use ex situ machine perfusion devices, making cDCDD heart transplantation economically possible in other countries.

Conversion From Immediate-Release Tacrolimus to Prolonged-Release Tacrolimus in Stable Heart Transplant Patients: A Retrospective Study.

BACKGROUND: Lifelong adherence with post-transplant immunosuppression is challenging, with nonadherence associated with greater acute rejection (AR) risk. METHODS: This retrospective study evaluated conversion from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT), between January 2008 and December 2012 in stable adult heart transplant recipients. Cumulative incidence rate (IR) of AR and infection pre- and postconversion, safety, tacrolimus dose and trough levels, concomitant immunosuppression, and PRT discontinuation were analyzed (intention-to-treat population). RESULTS: Overall, 467 patients (mean age, 59.3 [SD, 13.3] years) converted to PRT at 5.1 (SD, 4.9) years post transplant and were followed for 3.4 (SD, 1.5) years. During the 6 months post conversion, 5 patients (1.1%; 95% CI, 0.35%-2.48%) had an AR episode and IR was 2.2/100 patient-years (95% CI, 0.91-5.26). Incidence of rejection preconversion varied by time from transplant to conversion. Infection IR was similar post- and preconversion (9.2/100 patient-years [95% CI, 7.4-11.3] vs 10.6/100 patient-years [95% CI, 8.8-12.3], respectively; P = .20). Safety variables remained similar post conversion. The IR of mortality/graft loss was 2.3/100 patient-years (95% CI, 1.7-3.1). CONCLUSIONS: Conversion from IRT to PRT in heart transplant recipients in Spain was associated with no new safety concerns and appropriate immunosuppressive effectiveness.

Mineralocorticoid receptor antagonists modulate galectin-3 and interleukin-33/ST2 signaling in left ventricular systolic dysfunction after acute myocardial infarction.

OBJECTIVES: This study aimed to evaluate the specific role of the 2 available mineralocorticoid receptor antagonists (MRAs), eplerenone and spironolactone, on the modulation of galectin-3 (Gal-3) and interleukin (IL)-33/ST2 signaling in an experimental model of left ventricular systolic dysfunction after acute myocardial infarction (MI). BACKGROUND: The molecular mechanisms of benefits of MRAs in patients with left ventricular systolic dysfunction after MI not well understood. METHODS: MI and left ventricular systolic dysfunction were induced by permanent ligation of the anterior coronary artery in 45 male Wistar rats, randomly assigned to no therapy (MI group, n = 15) or to receive MRAs (100 mg/kg/day) for 4 weeks; either eplerenone (n = 15) or spironolactone (n = 15) was used. A sham group was used as a control (n = 8). Elements of the pathway for Gal-3 including transforming growth factor (TGF)-ß and SMAD3, as well as that for IL-33/ST2 (including IL-33 and soluble ST2 [sST2]) were analyzed in the infarcted and noninfarcted myocardium by quantitative real-time reverse transcription polymerase chain reaction. Expression of markers of fibrosis (collagen types I and III, tissue inhibitor of metalloproteinase-1) and inflammation (IL-6, tumor necrosis factor-α, monocyte chemotactic protein-1) was also examined. RESULTS: In the infarcted myocardium, compared with sham animals, the MI group had higher concentrations of Gal-3, TGF-ß, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-ß, and SMAD3 and enhanced IL-33/ST2 signaling with lower expression of sST2; protective IL-33 up-regulation was unaffected by MRAs. Modulation of Gal-3 and IL-33/ST2 signaling induced by MRAs correlated with lower expression levels of fibrosis and inflammatory markers. No differences were found between eplerenone and spironolactone. In the noninfarcted myocardium, compared with sham animals, the MI group exhibited a higher expression of Gal-3 and IL-33, but no signs of inflammation or fibrosis were observed; in the presence of MRAs, IL-33 expression was significantly up-regulated, but Gal-3 was unaffected. CONCLUSIONS: MRAs play a pivotal role in the Gal-3 and IL-33/ST2 modulation in post-MI cardiac remodeling.

Optical coherence tomography and highly sensitivity troponin T for evaluating cardiac allograft vasculopathy.

Cardiac allograft vasculopathy (CAV) is a major impediment to long-term graft survival after heart transplantation. Intravascular ultrasound (IVUS) is more sensitive than coronary angiography for diagnosis, but the identification of specific plaque components or plaque composition is limited. In addition, there is an evident need for other noninvasive tools for diagnosing CAV. The aim of this study was to assess the utility of 2 new techniques for evaluating CAV: optical coherence tomography (OCT), and new high-sensitivity troponin T (hsTnT) assays. In 21 heart transplantation patients, coronary arteriography with IVUS and OCT were performed. Maximal intimal thickness (MIT) and luminal area at the most severe site were measured using the 2 techniques. Immediately before cardiac catheterization, blood samples were obtained and hsTnT levels measured. The evaluation of CAV by OCT showed a good correlation with IVUS measurements, with a mean difference in MIT of 0.0033 (95% confidence interval -0.049 to 0.043), taking advantage of lower interobserver variability (r = 0.94 for OCT vs r = 0.78 for IVUS) and better plaque characterization. When independent predictors of MIT were assessed in a multiple linear regression model, time after transplantation (ß = 0.488, p = 0.004) and hsTnT (ß = 0.392, p = 0.011) were the only independent predictors of MIT (R(2) = 0.591). In conclusion, this study is the first to evaluate 2 new techniques, OCT and hsTnT, in the challenging setting of CAV. The findings suggest that OCT provides lower interobserver variability and better plaque characterization than IVUS. Also, hsTnT could become a useful tool for ruling out CAV.

Red blood cell distribution width adds prognostic value for outpatients with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Red blood cell distribution width has emerged as a new prognostic biomarker in cardiovascular diseases. Its additional value in risk stratification of patients with chronic heart failure has not yet been established. METHODS: A total of 698 consecutive outpatients with chronic heart failure were studied (median age 71 years [interquartile range, 62-77], 63% male, left ventricular ejection fraction 40 [14]%). On inclusion, the red cell distribution width was measured and clinical, biochemical, and echocardiographic variables were recorded. The median follow-up period was 2.5 years [interquartile range 1.2-3.7]. RESULTS: A total of 211 patients died and 206 required hospitalization for decompensated heart failure. Kaplan-Meier analysis showed an increase in the probability of death and hospitalization for heart failure with red cell distribution width quartiles (log rank, P<.001). A ROC analysis identified a red cell distribution width of 15.4% as the optimal cut-off point for a significantly higher risk of death (P<.001; hazard ratio=2.63; 95% confidence interval, 2.01-3.45) and hospitalization for heart failure (P<.001; hazard ratio=2.37; 95% confidence interval, 1.80-3.13). This predictive value was independent of other covariates, and regardless of the presence or not of anaemia. Importantly, the addition of red cell distribution width to the clinical risk model for the prediction of death or hospitalization for heart failure at 1 year had a significant integrated discrimination improvement of 33% (P<.001) and a net reclassification improvement of 10.3% (P=.001). CONCLUSIONS: Red cell distribution width is an independent risk marker and adds prognostic information in outpatients with chronic heart failure. These findings suggest that this biological measurement should be included in the management of these patients. Full English text available from:www.revespcardiol.org.

Red blood cell distribution width predicts new-onset anemia in heart failure patients.

BACKGROUND: Hematologic abnormalities such as elevated red blood cell distribution width (RDW) as well as anemia are prognostically meaningful among heart failure (HF) patients. The inter-relationship between these hematologic abnormalities in HF is unclear, however. We therefore aimed to assess whether RDW is predicting changes in hemoglobin concentrations as well as onset of anemia. METHODS: 268 consecutive non-anemic patients with acutely decompensated HF (ADHF) were enrolled at hospital discharge and RDW was measured. At 6 month follow-up, change in hemoglobin as well as new-onset anemia was studied as a function of RDW at discharge. RESULTS: RDW at discharge correlated negatively with hemoglobin values at 6 months (r=-0.220; p<0.001); a greater decrease in hemoglobin concentration occurred in those with higher values of RDW at discharge (p=0.004), independently of baseline hemoglobin concentration and other risk factors. At 6 months, 54 patients (20%) developed new-onset anemia. RDW values at discharge were significantly higher among patients who developed new-onset anemia (15.1 ± 2.2 vs. 14.2 ± 1.4, p=0.005). In integrated discrimination improvement analyses, the addition of RDW measurement improved the ability to predict new-onset anemia (IDI 0.0531, p<0.001), beyond known risk factors as hemoglobin, renal function, age, diabetes mellitus, sex and HF symptom severity. In adjusted analyses, patients with RDW>15% (derived from receiver operating characteristic analysis) had a tripling of the risk of new-onset anemia (OR=3.1, 95% CI 1.5-5.1, p=0.002). CONCLUSION: Among non-anemic patients with ADHF, RDW measurement at the time of hospital discharge independently predicts lower hemoglobin concentrations and new-onset anemia over a 6-month follow up period.

Utilidad de la prueba de troponina T de alta sensibilidad en la detección de rechazo agudo en trasplante cardiaco / Usefulness of high sensitivity troponin T assay in detecting acute allograft rejection after heart transplantation

Introducción y objetivos. La detección del rechazo agudo en pacientes trasplantados cardiacos mediante métodos no invasivos representa un reto. La disponibilidad de un nuevo método de alta sensibilidad para la determinación de troponina T podría ayudar a su detección. Métodos. Estudio case-crossover, en el que cada paciente sirvió como control de sí mismo, mediante la selección de muestras obtenidas en episodios de rechazo agudo tratados (29 casos) y muestras sin rechazo obtenidas inmediatamente antes y/o después (38 controles). La determinación de alta sensibilidad de troponina T se realizó mediante un nuevo test precomercial (Elecsys Troponina T HS). Resultados. La troponina T fue detectable en todas las muestras: mediana, 0,068 [intervalo intercuartílico, 0,030-0,300] ng/l. Sus concentraciones se correlacionaron con la presión auricular derecha (r=0,37; p=0,002), la fracción aminoterminal del propéptido natriurético cerebral (r=0,67; p<0,001) y el tiempo transcurrido desde el trasplante (r=–0,81; p<0,001). Las concentraciones de troponina T fueron mayores en presencia de rechazo (0,155 frente a 0,047 ng/l; p=0,006). En el análisis operador-receptor, el área bajo la curva fue 0,67 (intervalo de confianza del 95%, 0,53-0,77) y el mejor punto de corte, 0,035 ng/l, que se asoció con mayor riesgo de rechazo (odds ratio=3,7; intervalo de confianza del 95%, 1,2-11,9; p=0,02). Durante los primeros 2 meses, el área bajo la curva aumentó hasta 0,86 (intervalo de confianza del 95%, 0,66-0,97), con un punto de corte óptimo de 1,1 ng/l (sensibilidad, 58% [28-85%]; especificidad, 100% [74-100%]). Conclusiones. El análisis de alta sensibilidad detectó troponina T en todas las muestras tras el trasplante, en mayor concentración en caso de rechazo agudo, si bien su utilidad en la monitorización se limitaría a servir como apoyo ante la sospecha clínica o histológica, especialmente en los primeros meses (AU)

Introduction and objectives. Detection of acute allograft rejection in heart transplant recipients by noninvasive methods is a challenge in the management of these patients. In this study, the usefulness of a new highly sensitive method for the measurement of troponin T is evaluated. Methods. We designed a case-crossover study, in which each patient served as his or her own control, by selecting samples from treated acute rejection episodes (29 cases) and samples obtained immediately before and/or after rejection (38 controls). The highly sensitive troponin T was measured by a new pre-commercial test (Elecsys Troponin T HS). Results. In all samples, highly sensitive troponin was detectable, with a median of 0.068 ng/mL (IQR, 0.030-0.300 ng/mL). The levels correlated with right atrial pressure (r=0.37; P=.002), N-terminal pro-brain natriuretic peptide concentration (r=0.67; P<.001), and time since transplantation (r=–0.81; P<.001). The highly sensitive troponin concentrations were higher in patients with rejection (0.155 ng/mL vs 0.047 ng/mL; P=.006). In the receiver operating characteristic analysis, the area under the curve was 0.67 (95% confidence interval, 0.53-0.77) and the best cutoff was 0.035 ng/mL, which was associated with rejection (odds ratio=3.7; 95% confidence interval, 1.2-11.9; P=.02). By restricting the analysis to the first 2 months, the area under the curve increased to 0.86 (95% confidence interval 0.66-0.97), with an optimal cutoff of 1.10 ng/mL (S=58% [28%-85%]; E=100% [74%-100%]). Conclusions. Troponin T was detectable in all samples when a new highly sensitive assay was used, and at higher concentrations in the presence of acute rejection; however, the usefulness of this test in patient management is limited to support for clinical or histological suspicion of rejection, especially in the early post-transplant period (AU)

Soluble ST2 is a marker for acute cardiac allograft rejection.

BACKGROUND: Soluble ST2 (sST2), an interleukin (IL)-1 receptor family member, has a role in immunologic tolerance and has also emerged as a biomarker of cardiac stretch and remodeling. The sST2 role in heart transplantation is still unknown. METHODS: From the heart transplantation population at our institution (n = 74), we selected a subset of 26 patients who had an acute rejection episode in the first year after transplantation (35%; 52 ± 14 years; 76% men). Endomyocardial biopsy (EMB) results obtained at the time of the first rejection episode represented the rejection cohort (n = 26). Each patient served as a control to himself or herself, with EMB without rejection obtained before and after the rejection episode (n = 52). All laboratory measurements and blood samples were obtained at the time of EMB. RESULTS: sST2 concentrations rose significantly in the context of acute rejection (130 [60 to 238] versus 51 ng/mL [28 to 80]; p = 0.002). Tertile analyses of sST2 concentrations revealed a graded association with rejection (p = 0.002) and repeated measurement analyses showed that sST2 concentrations were significantly modulated by the presence of rejection (p = 0.001). In receiver operator characteristic (ROC) analysis, sST2 had an area under the curve (AUC) of 0.72; the optimal cutoff point was 68 ng/mL (positive predictive value of 53%, negative predictive value of 83%), which predicted acute cellular rejection (odds ratio [OR] 4.9; 95% confidence interval [CI], 1.7 to 14.5; p = 0.004). The addition of sST2 values to those for the N-terminal pro B-type natriuretic peptide (NT-proBNP) resulted in a significant improvement on the integrated discrimination index (IDI) for rejection (relative improvement of 24%; p = 0.021). CONCLUSIONS: sST2 concentrations are modulated by the presence of acute rejection and provide complementary predictive ability to NT-proBNP for the biochemical identification of rejection.

[Usefulness of high sensitivity troponin T assay in detecting acute allograft rejection after heart transplantation]. / Utilidad de la prueba de troponina T de alta sensibilidad en la detección de rechazo agudo en trasplante cardiaco.

INTRODUCTION AND OBJECTIVES: Detection of acute allograft rejection in heart transplant recipients by noninvasive methods is a challenge in the management of these patients. In this study, the usefulness of a new highly sensitive method for the measurement of troponin T is evaluated. METHODS: We designed a case-crossover study, in which each patient served as his or her own control, by selecting samples from treated acute rejection episodes (29 cases) and samples obtained immediately before and/or after rejection (38 controls). The highly sensitive troponin T was measured by a new pre-commercial test (Elecsys Troponin T HS). RESULTS: In all samples, highly sensitive troponin T was detectable, with a median of 0.068 ng/L (IQR, 0.030-0.300 ng/L). The levels correlated with right atrial pressure (r=0.37; P=.002), N-terminal pro-brain natriuretic peptide concentration (r=0.67; P<.001), and time since transplantation (r=-0.81; P<.001). The highly sensitive troponin T concentrations were higher in patients with rejection (0.155 ng/mL vs 0.047 ng/mL; P=.006). In the receiver operating characteristic analysis, the area under the curve was 0.67 (95% confidence interval, 0.53-0.77) and the best cutoff was 0.035 ng/mL, which was associated with rejection (odds ratio=3.7; 95% confidence interval, 1.2-11.9; P=.02). By restricting the analysis to the first 2 months, the area under the curve increased to 0.86 (95% confidence interval 0.66-0.97), with an optimal cutoff of 1.10 ng/mL (S=58% [28%-85%]; E=100% [74%-100%]). CONCLUSIONS: Troponin T was detectable in all samples when a new highly sensitive assay was used, and at higher concentrations in the presence of acute rejection; however, the usefulness of this test in patient management is limited to support for clinical or histological suspicion of rejection, especially in the early post-transplant period.

Soluble ST2, high-sensitivity troponin T- and N-terminal pro-B-type natriuretic peptide: complementary role for risk stratification in acutely decompensated heart failure.

AIM: To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk. METHODS AND RESULTS: This was a prospective study of 107 patients hospitalized with ADHF (mean age 72 ± 13 years, 44% male, left ventricular ejection fraction 47 ± 15%). Blood samples were collected on presentation to measure soluble (s)ST2, high-sensitivity troponin T (hsTnT), and amino-terminal pro-B type natriuretic peptide (NT-proBNP) levels. Clinical follow-up was obtained for all patients over a median period of 739 days, and all-cause mortality was registered. Concentrations of sST2 [per 10 ng/mL, hazard ratio (HR) 1.09, 95% confidence interval (CI) 1.04-1.13; P< 0.001], hsTnT (per 0.1 ng/mL, HR 1.16, 95% CI 1.09-1.24; P< 0.001), and NT-proBNP (per 100 pg/mL, HR 1.01, 95% CI 1.003-1.01; P< 0.001) were each predictive of a higher risk of death. In bootstrapped models, each biomarker retained independent predictive value for mortality. Patients with all three biomarkers below their optimal cut-off at presentation were free of death (0%) during follow-up, whereas 53% of those with elevations of all three biomarkers had died. For each elevated marker (from 0 to 3) adjusted analysis suggested a tripling of the risk of death (for each elevated marker, HR 2.64, 95% CI 1.63-4.28, P< 0.001). Integrated discrimination analyses indicated that the use of these three markers in a multimarker approach uniquely improved prediction of death. CONCLUSIONS: Biomarkers reflecting remodelling (sST2), myonecrosis (hsTnT), and myocardial stretch (NT-proBNP) provide complementary prognostic information in patients with ADHF. When used together, these novel markers provide superior risk stratification.

Impact of kidney dysfunction on plasma and urinary N-terminal pro-B-type natriuretic peptide in patients with acute heart failure.

The precise mechanism explaining the increased N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentrations among patients with concomitant acute heart failure (AHF) and kidney dysfunction is not fully understood. The aim of this study was to assess the impact of kidney dysfunction on simultaneous measures of plasma and urinary NT-proBNP in an unselected cohort of patients with AHF. One hundred thirty-eight consecutive hospitalized patients (median age: 74 years; interquartile range: 67-80 years; 54% male) with a diagnosis of AHF were prospectively studied. Blood and urine samples were collected on hospital arrival to determine NT-proBNP concentrations. Both plasma and urinary NT-proBNP concentrations increased with declining estimated glomerular filtration rate (eGFR; P<.001 for both). However, after multivariate adjustment, eGFR was found to be an independent predictor of plasma (but not urinary) NT-proBNP concentration (eGFR: ß=-0.19; P=.016). Indeed, plasma NT-proBNP was the main independent determinant of its urinary concentration (ß=0.42; P<.001), and the ratio of urine/plasma NT-proBNP was independent of kidney function and similar across the range of eGFR examined (P=.368). In patients with AHF and concomitant kidney dysfunction, the increased circulating NT-proBNP may be mainly related to increased cardiac secretion and not decreased renal clearance.

Prevalence and severity of renal dysfunction among 1062 heart transplant patients according to criteria based on serum creatinine and estimated glomerular filtration rate: results from the CAPRI study.

Chronic kidney disease (CKD) is staged on the basis of glomerular filtration rate; generally, the MDRD study estimate, eGFR, is used. Renal dysfunction (RD) in heart transplant (HT) patients is often evaluated solely in terms of serum creatinine (SCr). In a cross-sectional, 14-center study of 1062 stable adult HT patients aged 59.1±12.5 yr (82.3% men), RD was graded as absent-or-mild (AoM), moderate, or severe (this last including dialysis and kidney graft) by two classifications: SCr-RD (SCr cutoffs 1.6 and 2.5 mg/dL) and eGFR-RD (eGFR cutoffs 60 and 30 mL/min/1.73 m2). SCr-RD was AoM in 68.5% of patients, moderate in 24.9%, and severe in 6.7%; eGFR-RD, AoM in 38.6%, moderate in 52.2%, severe in 9.2%. Among patients evaluated <2.7, 2.7-6.2, 6.2-9.5 and >9.5 yr post-HT (the periods defined by time-since-transplant quartiles), AoM/moderate/severe RD prevalences were <2.7, SCr-RD 74/21/5%, eGFR-RD 47/47/6%; 2.7-6.2, SCr-RD 73/22/5%, eGFR-RD 37/56/7%; 6.2-9.5, SCr-RD 69/24/7%, eGFR-RD 37/54/9%; >9.5, SCr-RD 58/32/10%, eGFR-RD 32/52/16%. The prevalence of severe RD increases with time since transplant. If the usual CKD stages are appropriate for HT patients, the need for less nephrotoxic immunosuppressants and other renoprotective measures is greater than is suggested by direct SCr-based grading, which should be abandoned as excessively insensitive.

Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Sex hormone-binding globulin (SHBG) is a key regulator of the actions of anabolic steroids. Chronic heart failure (HF) has been associated with anabolic steroid deficiency, but its relationship with SHBG is not known. METHODS: The study involved 104 men (53+/-11 years) with HF (i.e. left ventricular ejection fraction [LVEF] <40%) attending a specialist clinic on optimum treatment and in a stable condition. At enrolment, the median and interquartile range (IQR) SHBG level was determined, associated hormone levels were measured, and known risk factors were recorded. The study end-point was cardiac death within 3 years. RESULTS: At enrolment, the SHBG level (median 34.5 nmol/L, IQR 27-50 nmol/L) was correlated with the N-terminal probrain natriuretic peptide level (r=0.271, P=.005), LVEF (r=-0.263, P=.007), body mass index (r=-0.199, P=.020) and total testosterone level (r=0.332, P=.001). The median SHBG level was higher in the 16 patients (15.4%) who died, at 48.5 nmol/L (IQR 36-69.5 nmol/L) vs. 33 nmol/L (IQR 25.3-48.7 nmol/L; P=.001), and a high level was associated with an increased risk of death (hazard ratio [HR]=1.045, 95% confidence interval [CI] 1.021-1.069; P< .001). The association remained significant after adjustment in Cox multivariate regression modeling, at HR=1.049 (95% CI 1.020-1.079; P=.001). Analysis by SHBG tertiles showed mortality was 30% in the third tertile, 14% in the second, and 4% in the first (log rank 0.007; HR=3.25, 95% CI 1.43-7.34; P=.004). CONCLUSIONS: The SHBG level correlated with measures of HF severity and was associated with a higher risk of cardiac death. Further studies are needed to clarify whether SHBG plays a role in HF pathophysiology.

Globulina transportadora de hormonas sexuales: nuevo marcador de severidad y pronóstico en varones con insuficiencia cardiaca crónica / Sex hormone-binding globulin: a new marker of disease severity and prognosis in men with chronic heart failure

Introducción y objetivos. La globulina transportadora de hormonas sexuales (SHBG) es una molécula clave en la regulación del efecto de los esteroides anabolizantes. En la insuficiencia cardiaca crónica se ha descrito un deterioro anabólico, pero se desconoce el valor de la SHBG. Métodos. Se incluyeron 104 varones (53 ± 11 años) con insuficiencia cardiaca (FEVI < 40%) atendidos en una consulta especializada, con tratamiento optimizado y situación clínica estable. A la inclusión, se midieron los niveles de SHBG (mediana [rango intercuartil]), otras hormonas relacionadas y factores de riesgo conocidos. Se estudió la aparición de muerte cardiaca a los 3 años. Resultados. A la inclusión, los niveles de SHBG (34,5 [27-50] nmol/l) se correlacionaron con los de NT-proBNP (r = 0,271; p = 0,005), la FEVI (r = -0,263; p = 0,007), el ín-dice de masa corporal (r = -0,199; p = 0,020) y la testosterona total (r = 0,332; p = 0,001). Los niveles de SHBG fueron mayores (48,5 [36-69,5] frente a 33 [25,3-48,7] nmol/l; p = 0,001) en pacientes que fallecieron (n = 16 [15,4%]) y se asociaron a un mayor riesgo de muerte (HR = 1,045; IC del 95%, 1,021-1,069; p < 0,001), que fue significativo tras el ajuste en un modelo multivariable de Cox (HR = 1,049; IC del 95%, 1,020-1,079; p = 0,001). El análisis por terciles mostró una mortalidad del 30% en el tercer tercil; el 14% en el segundo y el 4% en el primer tercil (log rank test, 0,007; HR = 3,25; IC del 95%, 1,43-7,34; p = 0,004). Conclusiones. Los niveles de SHBG se correlacionan con medidas de severidad de la insuficiencia cardiaca y se asocian a un mayor riesgo de muerte cardiaca. Nuevos estudios deben aclarar si la SHBG tiene un papel en la fisiopatología de la insuficiencia cardiaca (AU)

Introduction and objectives. Sex hormone-binding globulin (SHBG) is a key regulator of the actions of anabolic steroids. Chronic heart failure (HF) has been associated with anabolic steroid deficiency, but its relationship with SHBG is not known. Methods. The study involved 104 men (53±11 years) with HF (i.e. left ventricular ejection fraction [LVEF] <40 attending a specialist clinic on optimum treatment and in stable condition at enrolment the median interquartile range iqr shbg level was determined associated hormone levels were measured known risk factors recorded study end-point cardiac death within 3 years results 34 5 nmol l 27-50 correlated with n-terminal probrain natriuretic peptide r="0.332," p lvef body mass index total testosterone higher 16 patients 15 4 who died 48 36-69 vs 33 25 3-48 7 high an increased of hazard ratio hr 95 confidence interval ci 1 021-1 069 <.001). The association remained significant after adjustment in Cox multivariate regression modeling, at HR=1.049 (95% CI 1.020-1.079; P=.001). Analysis by SHBG tertiles showed mortality was 30% in the third tertile, 14% in the second, and 4% in the first (log rank 0.007; HR=3.25, 95% CI 1.43-7.34; P=.004). Conclusions. The SHBG level correlated with measures of HF severity and was associated with a higher risk of cardiac death. Further studies are needed to clarify whether SHBG plays a role in HF pathophysiology (AU)

Red blood cell distribution width predicts long-term outcome regardless of anaemia status in acute heart failure patients.

AIMS: To study the long-term prognostic value of red blood cell distribution width (RDW) in patients hospitalized with acute heart failure (AHF) and to compare the value of this measurement with haemoglobin levels and anaemia status. METHODS AND RESULTS: During a 2-year period, we studied 628 consecutive patients (aged 71 years [interquartile range, IQR: 61-77], 68% male) hospitalized with AHF. Demographic, clinical, echocardiographic, and laboratory characteristics were registered at discharge and patients were closely followed-up for 38.1 months [16.5-49.1]. Median RDW was 14.4% [13.5-15.5] and was higher among decedents (15.0% [13.8-16.1] vs. 14.2 [13.3-15.3], P < 0.001). After adjustment for other prognostic factors in a multivariable Cox proportional-hazards model, RDW remained a significant predictor (P = 0.004, HR 1.072, 95% CI 1.023-1.124); whereas, haemoglobin or anaemia status did not add prognostic information. RDW levels above the median were associated with a significantly lower survival rate on long-term follow-up (log rank <0.001). These levels were predictive of death in anaemic patients (n = 263, P = 0.029) and especially in non-anaemic patients (n = 365) (P < 0.001, HR 1.287, 95% CI 1.147-1.445), even after adjustment in the multivariable model. CONCLUSION: Higher RDW levels at discharge were associated with a worse long-term outcome, regardless of haemoglobin levels and anaemia status.

Usefulness of serial monitoring of B-type natriuretic peptide for the detection of acute rejection after heart transplantation.

Serum B-type natriuretic peptide (BNP) is increased after heart transplantation (HT), but it has not been well established whether BNP could be used to detect acute rejection in asymptomatic patients after HT. A total of 259 routine endomyocardial biopsy specimens from 50 consecutive patients after HT (83% men; age 50 +/- 15 years) were studied. Serial BNP measurements were performed at the time of each biopsy. BNP was evaluated as an absolute level (picograms per milliliter) and percentage of change from the previous biopsy (BNP - BNP at previous biopsy)/BNP at previous biopsy] x 100). Rejection was defined as grade > or =2R International Society of Heart and Lung Transplantation grading system. BNP correlated independently with time after HT (p <0.001), pulmonary artery systolic pressure (p <0.001), creatinine (p = 0.001), and age (p = 0.0012). Asymptomatic rejection was found in 15 biopsy specimens (6%), for which absolute BNP (106 pg/ml; interquartile range [IQR] 67 to 495) did not differ from nonrejection biopsy specimens (92 pg/ml; IQR 49 to 230; p = 0.286). BNP percentage of change showed a median of +60% (IQR -29 to +154%) in rejection versus -17% (IQR -47 to +19%) in nonrejection biopsy specimens (p = 0.009). After multivariable adjustment, BNP percentage of change was a consistent predictor of rejection (+10%; odds ratio 1.05, 95% confidence interval 1.01 to 1.09, p = 0.021). Receiver-operator characteristic analysis showed an area under the curve of 0.71 (95% confidence interval 0.643 to 0.768) and identified percentage of change <+38% as an optimal cut-off point, with a negative predictive value of 97%. In conclusion, serial monitoring of BNP, evaluated as a percentage of change, may be a useful noninvasive tool in the clinical management of rejection.

Pulmonary surfactant protein B in the peripheral circulation and functional impairment in patients with chronic heart failure.

INTRODUCTION AND OBJECTIVES: Surfactant protein B (SP-B) is a marker of damage to the alveolar-capillary barrier that could be useful for monitoring functional impairment in patients with chronic heart failure (HF). METHODS: Dyspnea-limited cardiopulmonary exercise testing was carried out in 43 outpatients with chronic HF (age 51+/-10 years, 77% male, left ventricular ejection fraction [LVEF] 33+/-11%). Peripheral blood serum samples were obtained at rest and during the first minute of peak exercise. The presence and concentration of SP-B in the serum samples were determined by Western blot analysis. RESULTS: At rest, SP-B was detected in 35 (82%) patients compared with only six (23%) healthy volunteers in a control group (n=26, age 51+/-10 years, 77% male). The median circulating SP-B level was higher in HF patients, at 174 [interquartile range, 70-283] vs. 77 [41-152] (P< .001) in the control group. In HF patients, the presence of circulating SP-B was associated with a lower LVEF (31.4+/-9.6% vs. 41.8+/-15%; P=.01). Multivariate analysis showed that the resting SP-B level correlated with a greater VE/VCO2 slope (beta=1.45; P=.02). The peak-exercise SP-B level correlated almost perfectly with the resting level (r=0.980; P< .001), but there was no significant increase with exercise (P=.164). Nor was there a correlation with any other exercise parameter. CONCLUSIONS: In patients with chronic HF, the level of pulmonary surfactant protein B in the peripheral circulation is increased and is correlated with ventilatory inefficiency during exercise, as indicated by the VE/VCO2 slope.

Proteína surfactante pulmonar tipo B en circulación periférica y deterioro funcional en pacientes con insuficiencia cardiaca crónica / Pulmonary Surfactant Protein B in the Peripheral Circulation and Functional Impairment in Patients With Chronic Heart Failure

Introducción y objetivos. La proteína surfactante tipo B (PS-B) es un marcador de daño en la barrera alveolocapilar y podría ser útil en la monitorización del deterioro pulmonar asociado a la insuficiencia cardiaca crónica (ICC). Métodos. Se estudió a 43 pacientes ambulatorios con ICC (edad, 51 ± 10 años; el 77% varones; fracción de eyección del ventrículo izquierdo [FEVI], 33% ± 11%) a los que se realizó una prueba de esfuerzo cardiopulmonar limitada por disnea. Se obtuvieron muestras de sangre periférica en reposo y en el primer minuto tras el máximo esfuerzo. La presencia y la cantidad de PS-B en suero sanguíneo se analizaron mediante análisis Western blot. Resultados. En reposo, se detectó PS-B circulante en 35 (82%) pacientes, frente a sólo 6 (23%) voluntarios sanos de una muestra control (n = 26; edad, 51 ± 10 años; el 77% varones), con mayores concentraciones circulantes en pacientes con ICC (mediana [intervalo intercuartílico], 174 [70-283]) frente al grupo control (77 [41-152]; p < 0,001). En pacientes con ICC, la presencia de PS-B circulante se asoció a una menor FEVI (31,4% ± 9,6% frente a 41,8% ± 15%; p = 0,01). Tras el ajuste multivariable, la cantidad de PS-B en reposo se correlacionó con una mayor pendiente VE/VCO2 (β = 1,45; p = 0,02). Los valores de PS-B en el esfuerzo máximo se correlacionaron casi perfectamente con las cifras en reposo (r = 0,980; p < 0,001), pero no se incrementaron significativamente con el esfuerzo (p = 0,164) ni se correlacionaron con los parámetros de ejercicio. Conclusiones. En pacientes con ICC, la proteína surfactante pulmonar tipo B está incrementada en la circulación periférica y se correlaciona con la ineficiencia ventilatoria en el ejercicio expresada como pendiente VE/VCO2

Introduction and objectives. Surfactant protein B (SP-B) is a marker of damage to the alveolar-capillary barrier that could be useful for monitoring functional impairment in patients with chronic heart failure (HF). Methods. Dyspnea-limited cardiopulmonary exercise testing was carried out in 43 outpatients with chronic HF (age 51±10 years, 77% male, left ventricular ejection fraction [LVEF] 33±11%). Peripheral blood serum samples were obtained at rest and during the first minute of peak exercise. The presence and concentration of SP-B in the serum samples were determined by Western blot analysis. Results. At rest, SP-B was detected in 35 (82%) patients compared with only six (23%) healthy volunteers in a control group (n=26, age 51±10 years, 77% male). The median circulating SP-B level was higher in HF patients, at 174 [interquartile range, 70-283] vs. 77 [41-152] (P<.001) in the control group. In HF patients, the presence of circulating SP-B was associated with a lower LVEF (31.4±9.6% vs. 41.8±15%; P=.01). Multivariate analysis showed that the resting SP-B level correlated with a greater VE/VCO2 slope (β=1.45; P=.02). The peak-exercise SP-B level correlated almost perfectly with the resting level (r=0.980; P<.001), but there was no significant increase with exercise (P=.164). Nor was there a correlation with any other exercise parameter. Conclusions. In patients with chronic HF, the level of pulmonary surfactant protein B in the peripheral circulation is increased and is correlated with ventilatory inefficiency during exercise, as indicated by the VE/VCO2 slope

Comparison of late mortality in hospitalized patients >70 years of age with systolic heart failure receiving beta blockers versus those not receiving beta blockers.

Beta blockers are underprescribed to elderly patients with systolic heart failure (HF). We studied whether the prescription of a beta blocker is associated with a survival benefit in a nonselected population of patients >70 years of age hospitalized with acute HF and systolic dysfunction. We studied 272 consecutive patients >70 years (median 77.0, interquartile range 73.4 to 81.1) hospitalized with acute HF (left ventricular ejection fraction 34 +/- 8%) during a 2-year period. At discharge, beta-blocker therapy was prescribed in 139 patients (51.1%). A propensity score for the likelihood of receiving beta-blocker therapy was developed and showed a good performance (c-statistic = 0.825 and Hosmer-Lemeshow p = 0.820). After discharge, 120 patients (44.1%) died during the follow-up (median 31 months, interquartile range 12 to 46). Cox regression analysis showed a lower risk of death associated with beta-blocker prescription (p <0.001, hazard ratio [HR] 0.450, 95% confidence interval [CI] 0.310 to 0.655), which persisted after risk adjusting for the propensity score (HR 0.521, 95% CI 0.325 to 0.836, p = 0.007). In a propensity-matched cohort of 130 patients, there was a significantly lower mortality in patients receiving beta blockers (log rank 0.009, HR 0.415, 95% CI 0.234 to 0.734, p = 0.003). Risk reduction associated with beta blockade was observed with both high doses (HR 0.472, 95% CI 0.300 to 0.742, p = 0.001) and low doses (HR 0.425, 95% CI 0.254 to 0.711, p = 0.001). In conclusion, beta-blocker prescription at discharge in a nonselected population >70 years of age hospitalized with systolic HF is associated with a significantly lower risk of death even at low doses. This benefit remains consistent after adjustment for potential confounders.