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Domingo A Pascual-Figal, Francisco Pastor-Perez, Luis Caballero, Iris P Garrido, Maria Teresa Perez-MartinezCardiology Department, Virgen de la Arrixaca University Hospital, School of Medicine, University of Murcia, Murcia, SpainAbstract: Acute heart failure (AHF) represents a major burden in developed countries. However, pharmacological approaches have remained almost the same for 30 years and are still based on consensus rather than evidence, given that no medical therapy has been shown to positively affect clinical outcomes. Current pharmacological approaches are still based on decongestion by using diuretics in almost all patients, plus either vasodilators or inotropic agents to improve hemodynamics according to perfusion status. The role of loop diuretics (furosemide) and nitrates (nitroglycerin and nitroprusside) is well established, but new agents such as vasopressin and adenosine antagonists, as well as nesiritide, have failed to show any additional value. In the presence of hypoperfusion, the use of inotropics must be considered despite the lack of benefit in terms of survival, and the use of phosphodiesterase inhibitors and levosimendan has not shown any significant advantages over catecholamines (dobutamine). AHF involves a wide spectrum of patients and syndromes, and this probably accounts for the failure of trials set up to evaluate new therapeutic approaches for improving outcomes: therapies need to be tailored to specific patients. At this time, serelaxin represents a promising new agent which has a multifaceted effect, including organ protection, and has shown encouraging results when tailored for a well defined population. In addition, the role of ularitide, a synthetic form of the natriuretic peptide urodilatin, and the new cardiac myosin activators, as a new class of inotropic agents, will be established in the near future by ongoing trials. Therefore, AHF continues to be an unsolved problem and, in light of the lessons learned, new pharmacological approaches should be tailored to well defined AHF populations, incorporating concepts such as “the sooner the better”, “improve and stabilize”, and “prevent organ damage”, in order to be able to improve clinical outcomes, including both mortality and readmission rates.Keywords: heart failure, acute, therapy, pharmacology

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Inc.)

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., (© 2020 The American Society of Transplantation and the American Society of Transplant Surgeons.)

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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)

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)-β 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-β, SMAD3, IL-33, and sST2, as well as higher concentrations of markers of fibrosis and inflammation. Treatment with MRAs down-regulated Gal-3, TGF-β, 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., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Cardiac allograft vasculopathy (CAV) is the single most important long-term limitation to heart transplantation. This study aimed to assess the value of monitoring soluble human leukocyte antigen-G (sHLA-G) during the first year post-transplantation to predict the severity of CAV, in 21 out of 77 heart recipients assessed by intravascular ultrasound (IVUS). Serum sHLA-G concentration increased after transplant in recipients free of severe CAV, but decreased in recipients suffering from severe CAV, significant differences between these two groups were found 6 to 12 months post-transplantation. The optimal value of the change in post-transplant sHLA-G for identifying severe CAV was ≥0.062%, which maximized sensitivity (80%) and specificity (100%). Importantly, increases in post-transplant sHLA-G were inversely associated with severe CAV, but directly associated with human cytomegalovirus reactivation. In addition, recipients presenting non-severe CAV or an increased sHLA-G post-transplantation, showed higher numbers of CD8(+)CD28(-) T cells and a down-modulation of CD28 on CD4(+) lymphocytes, which typically identifies CD8(+) regulatory T cells and anergic/tolerogenic T helper cells, respectively. In conclusion, quantification of sHLA-G might offer a complementary non-invasive method for identifying recipients at risk of more severe CAV and who might benefit from earlier preventive therapies, although these results need to be confirmed in larger series., (Copyright © 2012 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

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 (β = 0.488, p = 0.004) and hsTnT (β = 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., (Copyright © 2012 Elsevier Inc. All rights reserved.)

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., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

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., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

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., (Copyright © 2011 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Viral infections and cellular acute rejection (AR) condition immunosuppressive therapy and compromise the evolution of allografts. Immune monitoring can be useful for ascertaining rejection and for differentiating allo-reaction from activation induced by infections. This work analyzes the usefulness of monitoring the expression of CD28 and KIR2D receptors in peripheral blood T lymphocytes by flow cytometry, to ascertain the immune response in heart and liver transplant recipients. In both types of transplant, the up-regulation of CD28 in CD4(+) lymphocytes in the periods of greatest AR frequency indicates an effective allo-response, whereas the post-transplantation emergence of circulating CD8(+)CD28(-) and CD8(+)CD28(-)KIR2D(+) T cells correlates with better early clinical results. Cytomegalovirus (CMV) infection, but not hepatitis C virus (HCV) or other infections, abrogated both CD28 up-regulation and CD8(+)CD28(-)KIR2D(+) T-cell expansion. Our results show that monitoring the expression of CD28 and KIR2D receptors on T lymphocytes might be considered as sensors of the immune status of heart and liver recipients., (Copyright © 2011 American Society for Histocompatibility and Immunogenetics. Published by Elsevier Inc. All rights reserved.)

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: β=-0.19; P=.016). Indeed, plasma NT-proBNP was the main independent determinant of its urinary concentration (β=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., (© 2010 Wiley Periodicals, Inc.)

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., (© 2009 John Wiley & Sons A/S.)

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.

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.

Objective: Steroid withdrawal (SW) from maintenance therapy in heart transplant patients is still a controversial subject. We designed a questionnaire to ascertain the attitudes and procedures of a number of Spanish heart transplant units (16) regarding the use/withdrawal of steroids as part of the immunosuppressive maintenance therapy., Materials and Methods: We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units., Results: In 21.5% of the centers SW was performed in all patients, while 78.5% of the centers only performed SW in selected patients. In 57% of units SW was performed at 12 months posttransplantation and between 6 and 12 months in the rest. Fewer than 20% of patients were steroid-free in 46% of units while in 23% of units this proportion was >50%. In 11 units, the minimum prednisone dose administered was

The aims of this study were to compare the prognostic value of cystatin C over creatinine and the Modification of Diet in Renal Disease (MDRD) equation and to evaluate whether it provides complementary information to cardiac biomarkers in the risk stratification of an unselected cohort of patients with acute heart failure. Consecutive hospitalized patients with established diagnoses of acute heart failure were prospectively studied. Blood samples were collected on hospital arrival to determine cystatin C, cardiac troponin T, and N-terminal-pro-brain natriuretic peptide. Clinical follow-up was obtained, and the occurrence of mortality and/or heart failure readmission was registered. One hundred thirty-eight patients (median age 74 years, interquartile range 67 to 80; 54% men) were studied. During a median follow-up period of 261 days (interquartile range 161 to 449), 60 patients (43.5%) presented with adverse events. After multivariate adjustment, cystatin C, N-terminal-pro-brain natriuretic peptide, cardiac troponin T, New York Heart Association functional class III or IV, and diabetes mellitus were identified as independent predictors of mortality and/or heart failure readmission. In contrast to creatinine and the MDRD equation, the highest cystatin C tertile (>1.50 mg/L) was a significant independent risk factor for adverse events (hazard ratio 3.08, 95% confidence interval 1.54 to 6.14, p = 0.004). A multimarker approach combining cardiac troponin T, N-terminal-pro-brain natriuretic peptide, and cystatin C improved risk stratification further, showing that patients with 2 (hazard ratio 2.37, 95% confidence interval 1.10 to 5.71) or 3 (hazard ratio 3.64, 95% confidence interval 1.55 to 8.56) elevated biomarkers had a higher risk for adverse events than patients with no elevated biomarkers (p for trend = 0.015). In conclusion, in this unselected cohort, cystatin C was a stronger predictor of adverse events than conventional measures of kidney function. In addition, cystatin C offered complementary prognostic information to cardiac biomarkers and could help clinicians perform more accurate risk stratification of patients with acute heart failure.

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.

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.

Background: The optimal antithrombotic therapy strategy for atrial fibrillation (AF) patients who undergo percutaneous coronary intervention with stent implantation (PCI-S) is unknown. We assessed the safety of antithrombotic therapy strategies in AF patients with indication for oral anticoagulation (OAC) undergoing PCI-S., Methods: We studied consecutive AF patients with indication for OAC who underwent PCI-S. We compared patients that received triple antithrombotic therapy (TT) [aspirin, clopidogrel, and coumadin] against other regimes (non-TT) after PCI-S. The primary end point was defined as the occurrence of major bleeding complications that were termed as early major bleeding (EMB) [< or = 48 h] or late major bleeding (LMB) [> 48 h]. Clinical follow-up was performed, and complications were recorded., Results: We studied 104 patients (mean age +/- SD, 72 +/- 8 years; 70% men); TT was used in 51 patients (49%). TT was associated with a higher incidence of LMB (21.6% vs non-TT, 3.8%; p = 0.006) but not of EMB (5.8% vs non-TT, 11.3%; p = 0.33). In multivariate analyses, glycoprotein (GP) IIb/IIIa inhibitor use (hazard ratio [HR], 13.5; 95% confidence interval [CI], 1.7 to 108.3; p = 0.014) and PCI-S of three vessels or left main artery disease (HR, 7.9; 95% CI, 1.6 to 39.2; p = 0.01) were independent predictors for EMB. TT use (HR, 7.1; 95% CI, 1.5 to 32.4; p = 0.012), the occurrence of EMB (HR, 6.7; 95% CI, 1.8 to 25.3; p = 0.005), and baseline anemia (HR, 3.8; 95% CI, 1.2 to 12.5; p = 0.027) were independent predictors for LMB. No differences in major cardiovascular events were observed in patients treated with TT vs non-TT (25.5% vs 21.0%; p = 0.53)., Conclusion: A high rate of major bleeding is observed in AF patients with indication for OAC undergoing PCI-S who receive TT. GP IIb/IIIa inhibitor use and multivessel/left main artery disease during PCI-S were independent predictors for EMB, while TT use, occurrence of EMB, and baseline anemia were independent predictors for LMB.

Although aortic regurgitation is a diastolic phenomenon, it has been observed during systole in a few cases. Our aims were to determine the incidence of systolic aortic regurgitation in routine clinical practice and to investigate the clinical profiles of patients with the condition. An exhaustive prospective study of all investigations performed by a hospital echocardiographic unit over one month was carried out. Systolic aortic regurgitation was detected in five out of a total of 216 investigations (2.3%). In all cases, the patient had some degree of heart failure. Overall, the condition was present in 5.9% of patients with heart failure. In one patient with atrial fibrillation, systolic aortic regurgitation disappeared and the patient's clinical status improved after atrioventricular node modulation using a cryoablation catheter. Systolic aortic regurgitation was not an exceptional occurrence in hospitalized patients. Moreover, it tended to be specifically associated with heart failure.

Introduction and Objective: The usefulness of prolonged troponin-T (TnT) monitoring in outpatients with nonischemic heart failure (HF) is not clear. The aim of this study was to investigate the incidence, prognostic value and determinants of a raised TnT level., Methods: The study involved 80 outpatients (age 56+/-14 years, 69% male) with chronic stable HF (mean left ventricular ejection fraction 24+/-9%; 51 in New York Heart Association class II and 29 in class III) of non-ischemic origin, as confirmed with coronary angiography. The TnT level was measured at study entry and at every outpatient visit (median interval, 3.1 months; interquartile range [IQR], 1.8-5.0 months) in a follow-up period of 22.2+/-10.6 months. Patients were TnT+ if the level was measurable (i.e., >0.01 ng/mL)., Results: At study entry, 7 (9%) patients were TnT+. By 5 years, the cumulative incidence had reached 53%, and the median TnT level was 0.059 ng/mL (IQR, 0.023-0.100 ng/mL; range, 0.013-0.500 ng/mL). Beta-blocker therapy was associated with a reduction in incidence (hazard ratio [HR]=0.220; 95% confidence interval [CI], 0.089-0.540; P=.001) while the incidence increased with the N-terminal probrain natriuretic peptide (NT-proBNP) level (HR=1.005; 95% CI, 1.001-1.010; P=0.021). During follow-up, 14 (17.5%) patients had a cardiac event (i.e., 9 cardiac deaths and 5 urgent transplants); these occurred in 12 (50%) of the 24 TnT+ patients vs. 2 (3.6%) of the 56 TnT- patients (P< .001). After adjustment, Cox multivariate analysis showed that being TnT+ was a predictor of an adverse event (HR per 0.01 ng/mL=1.359; 95% CI, 1.037-1.782; P=.026), independently of the NT-proBNP level (HR per 500 pg/mL=1.057; 95% CI, 1.023-1.092; P=.001)., Conclusions: A measurable TnT level was frequently observed during clinical monitoring of outpatients with non-ischemic HF and indicated a poor prognosis, even when the level was low.

Background: Renal dysfunction (RD) is a common complication after heart transplantation (HT), but predictors of post-HT RD have not been clearly identified., Methods: We studied 262 HT patients (mean age 54 years, 221 men) with normal baseline renal function. Potential risk factors examined were age, sex, pre-HT ischemic cardiomyopathy, pre- and post-HT diabetes mellitus, pre- and post-HT arterial hypertension, initial immunosuppressive protocol (before 1998 [high cyclosporine, azathioprine, and prednisone] vs after 1998 [low cyclosporine, mycophenolate mofetil, and prednisone]), occurrence of rejection episodes > or =ISHLT Grade 3A, and creatinine level 1 month after HT. RD was considered mild if creatinine level was 1.5 to 2.5 mg/dl, moderate if creatinine level was >2.5 mg/dl, and severe if dialysis or kidney transplant was required., Results: The cumulative incidence of RD (creatinine >1.5 mg/dl) was 35% at 12 months, 42% at 24 months, and 47% at 60 months (mean follow-up 59 +/- 31 months). Only 1% of patients had severe RD 60 months after HT. Independent predictors of RD 24 months after HT were older age (odds ratio [OR] 1.1 [95% confidence interval (95% CI) 1.0-1.1]; p = 0.001), male sex (OR 3.3 [95% CI 1.3-8.1]; p = 0.008), pre-1998 immunosuppressive protocol (OR 2.8 [95% CI 1.4-5.4]; p = 0.003), and creatinine level 1 month after HT (OR 3.2 [95% CI 1.0-5.4]; p < 0.0001)., Conclusions: The cumulative incidence of RD in HT patients treated with calcineurin inhibitors increased with time after HT. Age, male sex, an immunosuppressive protocol with relatively high cyclosporine levels and creatinine level 1 month after HT were independent predictors of the presence of RD 24 months after HT.

To assess the prognostic value of exercise echocardiography in subjects who had diabetes, we studied 214 patients who had 28 hard cardiac events (cardiac death in 15, myocardial infarction in 13) during a follow-up of 44 +/- 16 months. Independent risk factors for predicting cardiac events were insulin therapy (odds ratio 2.313), peak left ventricular ejection fraction (odds ratio 0.973), and ischemia detected by exercise echocardiography (odds ratio 2.513).

This study compared ischemia-modified albumin levels, a marker of ischemia in patients undergoing percutaneous coronary intervention. Ischemia-modified albumin levels were significantly lower in patients with collateral circulation compared with those without collateral circulation.

Background: HAV syndrome, the combination of hypotension, acidosis and vasodilation (HAV), is a serious postoperative complication after heart transplantation (HT). Its etiology and prognosis are poorly understood., Aim: To determine the incidence and prognosis of post-HT HAV syndrome and examine possible risk factors., Methods: Retrospective examination of the records of 85 consecutive patients who underwent HT between December 1999 and June 2002 sought the HAV criteria: systolic BP <85 mm Hg plus HCO3 <19 mEq/l whole excluding cardiogenic, hypovolemic and septic shock. Donor variables included sex, age, weight, height, cause of death, time in ICU, and ischemic time; while recipient variables, sex, age, weight, height, etiology of cardiopathy, previous cardiopulmonary bypass surgery, preoperative amiodarone, beta-blockers, catecholamines, mechanical ventilation or intra aortic balloon pump (IABP), RVP, time on waiting list, pump time, reoperations, polytransfusion, preoperative creatinine, GOT, GPT and GGT, induction with OKT3 or anti-CD25, bypass-to-HAV time, duration of catecholamine treatment, and 1 month survival after HT., Results: The 11 HAV cases (13%) appeared between 1 and 72 h after HT (75% in the first hour). Catecholamines were used for 1 to 6 days; control was achieved within 48 h in 58% of cases. Two HAV patients (18%) died within the first month versus six non-HAV patients (8.1%) (P=.275). Only polytransfusion showed more than a borderline value to predict HAV syndrome., Conclusions: HAV syndrome has an incidence of 13% and a mortality of 18% within 1 month post-HT. The only likely risk factor is polytransfusion.

The results in this study confirm and expand previous reports that ischemia-modified albumin (IMA) is an early marker of ischemia in the setting of percutaneous coronary intervention (PCI). We observed that IMA levels are related to the number of inflations, inflation pressure, and duration of inflations. It is therefore likely that IMA reflects the magnitude and duration of ischemia induced during PCI.

Background: Renal dysfunction is a common complication after orthotopic heart transplantation (HT). The importance of factors other than exposure to immunosuppressive drugs is unclear. The purpose of this study was to determine the incidence and natural history of renal dysfunction following heart transplantation, and to evaluate a number of variables as risk factors for this condition., Methods: We examined the creatinine levels at 1, 6, 12, 24, and 60 months in 262 consecutive heart transplant patients who survived at least 1 year. The potential risk factors included pre- and posttransplantation diabetes mellitus, arterial hypertension, and drugs used to control arterial hypertension., Results: 17.2% of patients showed mild renal dysfunction (creatinine 1.5-2.5 mg/dL) and 1.9% moderate dysfunction (creatinine >2.5 mg/dL) at 1 month; 29.8% showed mild and 1.1% moderate dysfunction at 6 months; 33.2% showed mild and 1.9% moderate dysfunction at 1 year; 40% showed mild, 0.9% moderate and 0.4% severe dysfunction (requiring dialysis or renal transplantation) at 2 years; and 43.6% showed mild, 1.7% moderate and 0.9% severe dysfunction at 5 years. None of the conditions analyzed as possible risk factors showed a significant association with renal dysfunction except the use of diuretics., Conclusion: The incidence of renal dysfunction after orthotopic heart transplantation was 33.6% within the first year after transplant and 44% within the first five years, although more than 95% of cases were mild. The incidence increased with time after transplantation. Renal dysfunction seems likely to be multifactorial in origin, but no individual risk factors were identified.