[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: Introduction and objectivesRed 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.MethodsA 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 %). 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].ResultsA 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
Revista Espa de Cardiologia 07/2012; 65(7):606–612. · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
The American journal of cardiology 05/2012; 110(5):655-61. · 3.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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 %). 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].
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).
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.
Revista Espanola de Cardiologia 03/2012; 65(7):606-12. · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Introduction and objectivesDetection 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.
Revista Espa de Cardiologia 12/2011; · 3.34 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
sST2 concentrations are modulated by the presence of acute rejection and provide complementary predictive ability to NT-proBNP for the biochemical identification of rejection.
The Annals of thoracic surgery 12/2011; 92(6):2118-24. · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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).
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%]).
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.
Revista Espa de Cardiologia 09/2011; 64(12):1109-13. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
Human immunology 06/2011; 72(10):841-8. · 2.55 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
268 consecutive non-anemic patients with acutely decompensated HF (ADHF) were enrolled at hospital discharge and RDW was measured. At 6month follow-up, change in hemoglobin as well as new-onset anemia was studied as a function of RDW at discharge.
RDW at discharge correlated negatively with hemoglobin values at 6months (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 6months, 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).
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.
International journal of cardiology 05/2011; 160(3):196-200. · 6.18 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To investigate the use of biomarkers providing independent information regarding physiology in acutely decompensated heart failure (ADHF) for assessment of risk.
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.
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.
European Journal of Heart Failure 05/2011; 13(7):718-25. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The longer survival of patients with heart transplantation (HT) favors calcineurin inhibitor-related chronic kidney disease (CKD). It behoves to identify risk factors. At 14 Spanish centers, data on 1062 adult patients with HT (age 59.2 ± 12.3 yr, 82.5% men) were collected at routine follow-up examinations. Glomerular filtration rate, GFR, was estimated using the four-variable MDRD equation, and moderate-or-severe renal dysfunction (MSRD) was defined as K/DOQI stage 3 CKD or worse. Time since transplant ranged from one month to 22 yr (mean 6.7 yr). At assessment, 26.6% of patients were diabetic and 63.9% hypertensive; 53.9% were taking cyclosporine and 33.1% tacrolimus; and 61.4% had MSRD. Among patients on cyclosporine or tacrolimus at assessment, multivariate logistic regression identified male sex (OR 0.44), pre- and post-HT creatinine (2.73 and 3.13 per mg/dL), age at transplant (1.06 per yr), time since transplant (1.05 per yr), and tacrolimus (0.65) as independent positive or negative predictors of MSRD. It is concluded that female sex, pre- and one-month post-HT serum creatinine, age at transplant, time since transplant, and immunosuppression with cyclosporine rather than tacrolimus may all be risk factors for development of CKD ≥ stage 3 by patients with HT.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
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).
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.
Revista Espa de Cardiologia 12/2009; 62(12):1381-7. · 3.20 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
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.
Higher RDW levels at discharge were associated with a worse long-term outcome, regardless of haemoglobin levels and anaemia status.
European Journal of Heart Failure 09/2009; 11(9):840-6. · 6.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 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.
We sent an 11-item questionnaire to the clinical director in charge of each unit. The questionnaire was completed and returned by 14 units.
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 <or=5 mg/d. More than 80% used the following selection criteria for SW: no acute rejection episodes (ARE) in the first 3 to 6 months, low immunological risk, and concomitant immunosuppression. The main expected benefits were: a decrease in the incidence of diabetes, bone problems, and obesity, and improved dyslipidemia, hypertension, and overweight. Twenty-eight percent of units performed an endomyocardial biopsy (EMB) before SW, while 3 units also repeated it after SW. In most cases (72%), an EMB was always performed at 1 month after withdrawal. In a low percentage of cases (<30%), all units had to reintroduce steroids in the maintenance regimen due to an ARE (73%).
Most heart transplant units (78.5%) performed SW at 1 year after transplantation in selected patients: those without an ARE in the first 3 to 6 months and those with low immunological risk. The main benefits were to avoid or reduce diabetes and bone problems, and to a lesser extent, overweight, hypertension, and hypercholesterolemia. In <30% of patients steroids had to be reintroduced due to an ARE.