Use of serum levels of high sensitivity troponin T, galectin-3 and C-terminal propeptide of type I procollagen at long term follow-up in heart failure patients with reduced ejection fraction: Comparison with soluble AXL and BNP.

BACKGROUND: Prognostic biomarkers are needed to improve the management of the heart failure (HF) epidemic, being the brain natriuretic peptides the most valuable. Here we evaluate 3 biomarkers, high sensitivity troponin T (hs-TnT), galectin-3 (Gal-3) and C-terminal propeptide of type I procollagen (CICP), compare them with a recently described new candidate (sAXL), and analyze their relationship with BNP. METHODS: HF patients with reduced ejection fraction (n=192) were included in this prospective observational study, with measurements of candidate biomarkers, functional, clinical and echocardiographic variables. A Cox regression model was used to determine predictors for clinical events, i.e. all-cause mortality and heart transplantation. RESULTS: Hs-TnT circulating values were correlated to clinical characteristics indicative of more advanced HF. When analyzing the event-free survival at a mean follow-up of 3.6years, patients in the higher quartile of either BNP, hs-TnT, CICP and sAXL had increased risk of suffering a clinical event, but not Gal-3. Combination of high sAXL and BNP values had greater predictive value (HR 6.8) than high BNP alone (HR 4.9). In a multivariate Cox regression analysis, BNP, sAXL and NYHA class were independent risk factors for clinical events. CONCLUSIONS: In this HF cohort, hs-TnT is a good HF marker and has a very significant prognostic value. The prognostic value of CICP and sAXL was of less significance. However, hs-TnT did not add predictive value to BNP, while sAXL did. This suggests that elevated troponin has a common origin with BNP, while sAXL could represent an independent pathological mechanism.

A New Quantitative Approach to Assessing Noncompliance With Medical Recommendations in Heart Transplant Recipients.

BACKGROUND: Failure of compliance with medical regimen is one of the major risk factors associated with morbidity and mortality in heart transplant (HT) recipients. Nevertheless, to date, there is no specific, gold-standard, comprehensive set of tools for assessing compliance in these patients. OBJECTIVE: The objective of the present study was to develop a specific instrument for the assessment of noncompliance with medical recommendations in HT recipients. METHODS: This prospective observational study used a nonprobability sampling method, which was performed from January 2006 to December 2012. All of the patients met clinical criteria for being included on the waiting list for a HT. We designed a scale for measuring the compliance degree at 12 months after heart transplantation. This scale included the most important aspects of the medical regimen, using nine discrete quantitative variables. The total score was described as the patient's Noncompliance Factor (NCF). The results were analysed by mean, ranks, and percentages. RESULTS: The sample was constituted of 61 participants who underwent surgical HT intervention and completed the 12-month follow-up assessment. The overall incidence of noncompliance was around 30% and only 43.1% of the recipients had an acceptable degree of compliance. CONCLUSIONS: The overall incidence of noncompliance in HT recipients is high and this can generate worse clinical outcomes. Evaluation by specific screening instruments like the one proposed in the present study can be useful for a systematic detection of this phenomenon.

Cost-Effectiveness of Highly Sensitive Cardiac Troponin T to Rule Out Acute Rejection After Heart Transplantation.

BACKGROUND: Endomyocardial biopsy (EMB) remains the gold standard for detecting acute rejection (AR) after heart transplantation (HTx). Non-invasive detection of AR thus far remains a challenge. Several studies have demonstrated that highly sensitive cardiac troponin T (hs-cTnT) concentrations have a low positive predictive value for diagnosing AR. Nevertheless, hs-cTnT proved to be useful for ruling out AR after HTx. An hs-cTnT concentration <17 ng/L, a value close to that used for rule-in or rule-out myocardial infarction, was associated with a 100% negative predictive value of AR. However, the cost-effectiveness of a strategy with the use of hs-cTnT for ruling out AR in HTx patients remains to be proven. METHODS: The cost-effectiveness of hs-cTnT determination for ruling out AR was assessed, comparing the costs of hs-cTnT measurements in 305 blood samples obtained at the time of EMB. Eighteen samples were excluded because the EMB was not assessable. RESULTS: Hs-cTnT determination cost 16.00€ per sample, whereas EMB cost 1752.00€ per biopsy; cost estimations included direct and indirect (30%) charges. Thirty-nine (13.6%) of the 287 blood samples presented hs-cTnT concentrations <17 ng/L; in none of them was an AR >2R degree found in the EMB. The cost of the assessment in the 287 blood samples and biopsies was of 4592.00€ for hs-cTnT and 502,824.00€ for EMB. Hs-cTnT systematic measurement would have avoided 39 EMB, with a saving of 68,328.00€, which represents the 13.5% of the total budget expended in these cases. CONCLUSIONS: The use of hs-cTnT values to rule out the need of EMB for AR diagnosis after HTx appears to be a cost-effective procedure.

Clinical features and outcomes of tuberculosis in transplant recipients as compared with the general population: a retrospective matched cohort study.

There are no previous studies comparing tuberculosis in transplant recipients (TRs) with other hosts. We compared the characteristics and outcomes of tuberculosis in TRs and patients from the general population. Twenty-two TRs who developed tuberculosis from 1996 through 2010 at a tertiary hospital were included. Each TR was matched by age, gender and year of diagnosis with four controls selected from among non-TR non-human immunodeficiency virus patients with tuberculosis. TRs (21 patients, 96%) had more factors predisposing to tuberculosis than non-TRs (33, 38%) (p <0.001). Pulmonary tuberculosis was more common in non-TRs (77 (88%) vs. 12 TRs (55%); p 0.001); disseminated tuberculosis was more frequent in TRs (five (23%) vs. four non-TRs (5%); p 0.005). Time from clinical suspicion of tuberculosis to definitive diagnosis was longer in TRs (median of 14 days) than in non-TRs (median of 0 days) (p <0.001), and invasive procedures were more often required (12 (55%) TRs and 15 (17%) non-TRs, respectively; p 0.001). Tuberculosis was diagnosed post-mortem in three TRs (14%) and in no non-TRs (p <0.001). Rates of toxicity associated with antituberculous therapy were 38% in TRs (six patients) and 10% (seven patients) in non-TRs (p 0.014). Tuberculosis-related mortality rates in TRs and non-TRs were 18% and 6%, respectively (p 0.057). The adjusted Cox regression analysis showed that the only predictor of tuberculosis-related mortality was a higher number of organs with tuberculosis involvement (adjusted hazard ratio 8.6; 95% CI 1.2-63). In conclusion, manifestations of tuberculosis in TRs differ from those in normal hosts. Post-transplant tuberculosis resists timely diagnosis, and is associated with a higher risk of death before a diagnosis can be made.

The falling incidence of hematologic cancer after heart transplantation.

BACKGROUND: A number of changes in the management of heart transplantation (HT) patients have each tended to reduce the risk of post-HT hematologic cancer, but little information is available concerning the overall effect on incidence in the HT population. METHODS: Comparison of data from the Spanish Post-Heart-Transplantation Tumour Registry for the periods 1991-2000 and 2001-2010. RESULTS: The incidence among patients who underwent HT in the latter period was about half that observed in the former, with a particularly marked improvement in regard to incidence more than five yr post-HT. CONCLUSIONS: Changes in HT patient management have jointly reduced the risk of hematologic cancer in the Spanish HT population. Long-term risk appears to have benefited more than short-term risk.

Toxoplasmic encephalitis associated with meningitis in a heart transplant recipient.

Toxoplasma gondii is an opportunistic pathogen that causes neurologic and extraneurologic manifestations in immunosuppressed patients. Encephalitis and intracranial mass lesions are easily recognized as typical manifestations of toxoplasmosis. However, meningitis caused by T. gondii is a rare condition with very few cases described in the literature. We present the case of a heart transplant recipient who developed toxoplasmic encephalitis associated with meningitis. After an extensive review of the medical literature, we found only 1 case of meningitis in solid organ transplant recipients and <25 cases in immunosuppressed patients, such as patients infected with human immunodeficiency virus or those with Hodgkin's disease. In this report, we consider toxoplasmosis in the differential diagnosis of meningitis in immunocompromised individuals.

AXL receptor tyrosine kinase is increased in patients with heart failure.

BACKGROUND: AXL is a membrane receptor tyrosine kinase highly expressed in the heart and has a conspicuous role in cardiovascular physiology. The role of AXL in heart failure (HF) has not been previously addressed. METHODS AND RESULTS: AXL protein was enhanced 6-fold in myocardial biopsies of end-stage HF patients undergoing heart transplantation compared to controls from heart donors (P<0.0001). Next, we performed a transversal study of patients with chronic HF (n=192) and a group of controls with no HF (n=67). sAXL and BNP circulating levels were quantified and clinical and demographic data were collected. sAXL levels in serum were higher in HF (86.3 ± 2.0 ng/mL) than in controls (67.8 ± 2.0 ng/mL; P<0.0001). Also, sAXL correlated with several parameters associated with worse prognosis in HF. Linear regression analysis indicated that serum creatinine, systolic blood pressure and atrial fibrillation, but not BNP levels, were predictive of sAXL levels. Cox regression analysis indicated that high sAXL values at enrollment time were related to the major HF events (all-cause mortality, heart transplantation and HF hospitalizations) at one year follow-up (P<0.001), adding predictive value to high BNP levels. CONCLUSIONS: Myocardial expression and serum concentration of AXL is elevated in HF patients compared to controls. Furthermore, peripheral sAXL correlates with parameters associated with the progression of HF and with HF events at short term follow-up. All together these results suggest that sAXL could belong to a new molecular pathway involved in myocardial damage in HF, independent from BNP.

Epidemiology and risk factors for late infection in solid organ transplant recipients.

BACKGROUND: Information concerning the risk factors and outcome of late infection (LI) after solid organ transplantation (SOT) still remains scarce. METHODS: We prospectively analyzed all patients undergoing SOT from July 2003 to March 2008, who survived the first 6 months after surgery and with a minimum 1-year follow-up. Risk factors associated with the development of bacterial and cytomegalovirus (CMV) LI and survival were identified. RESULTS: Overall, 942 SOT recipients (491 kidney, 280 liver, 65 heart, and 106 double transplants) were included. During the study period 147 patients (15.6%) developed 276 episodes of LI (incidence rate, 0.43 per 1000 transplantation-days). Bacteria were the most prevalent etiology (88.0%). Primary sources of infection included urinary tract (36.9%), intra-abdominal (16.7%), and sepsis without source (13.4%). Independent risk factors for late bacterial infection were: age (hazard ratio [HR] [per year] 1.0; 95% confidence interval [CI]: 1.0-1,0), female gender (HR 1.7; 95%CI: 1.1-2.6), anti-hepatitis C virus (HCV) positive serostatus (HR 1.8; 95%CI: 1.1-3.0), chronic allograft dysfunction (HR 3.2; 95%CI: 1.7-6.1), early CMV disease (HR 2.2; 95%CI 1.2-4.1), and early bacterial infection (HR 2.5; 95%CI 1.6-3.8). The occurrence of chronic allograft dysfunction was an independent risk factor for late CMV disease (HR 6.5; 95%CI: 1.7-24.6), whereas immunosuppression based on mammalian target of rapamycin inhibitors protected against the development of late CMV disease (HR 0.3; 95%CI: 0.1-1.0). Cox model selected anti-HCV positive serostatus (adjusted HR [aHR] 2.67; 95%CI: 1.27-5.59), age (aHR [per year] 1.06; 95%CI: 1.02-1.10), and the occurrence of LI (aHR 9.12; 95%CI: 3.90-21.33) as independent factors for mortality. CONCLUSIONS: LI did not constitute an uncommon complication in our cohort, and patients at risk may benefit from close clinical monitoring.

Temporal trends in the use of proliferation signal inhibitors in maintenance heart transplantation: a Spanish multicenter study.

Proliferation signal inhibitors (PSI; sirolimus, everolimus) are being increasingly used in heart transplantation. We performed an observational, retrospective, multicenter study in 9 Spanish centers seeking to describe the clinical context in which a PSI was used among maintenance heart recipients and its evolution over time. We collected a cohort of 548 patients in whom a PSI was prescribed from October 2001 to March 2009. The group was divided into 3 time periods. The use of PSI steeply increased in the 2005-2006 period, remaining stable thereafter. There were no significant differences over time with regard to age, gender, or time from transplantation to the introduction of the PSI. Everolimus usage overtook sirolimus from 2005 on; currently, >90% of the subjects with PSI indications are prescribed everolimus. Compared with earlier periods, patients in the more recent period (October 2006-March 2009) showed less vascular graft disease and better basal renal function, irrespective of the primary indication for the PSI prescription. Also, skin cancer overtook solid cancer as the main type of neoplasm in patients for whom malignancy was the primary indication for the use of the PSI. The actuarial incidence of PSI withdrawal owing to adverse effects did not change significantly over time.

Outcome after steroid withdrawal in heart transplantation.

BACKGROUND: There is a lack of consensus and insufficient data to assess the impact of late steroid withdrawal after heart transplantation (HTx). The aim of the study was to investigate the security and feasibility of corticosteroid withdrawal at 1 year after transplantation. METHODS AND RESULTS: Steroid withdrawal was attempted after at least 12 months of treatment in 86 HTx patients who fulfilled the criteria. At 1 and 3 months after drug discontinuation, patients underwent 2 endomyocardial biopsies (EMB). After a mean follow-up of 25 +/- 13 months, 63% of the patients remained steroid free. In 30 patients (35%) corticosteroids were reinitiated, in 15 cases because of acute rejection (7%), 5 (6%) because of worsening renal function, 5 (6%) because of malignancy, 3 (4%) because of adverse effects of immunosuppressive drugs, and 2 because of severe allograft coronary artery disease. Four patients (5%) died after drug discontinuation. There was a significant decrease in total cholesterol (198 +/- 35 to 181 +/- 38 mg/dL; P < .001) and low-density lipoprotain (LDL) cholesterol levels (113 +/- 30 to 105 +/- 30 mg/dL; P < .001). There were no differences in mortality between patients with and without corticosteroids. CONCLUSION: Steroid withdrawal is feasible and safe in HTx patients. In our study, it was successfully maintained in 63% of the patients. EMB is helpful to identify patients with acute rejection at 1 and 3 months after withdrawal. Short- to mid-term metabolic benefits are significant reductions in serum total and LDL cholesterol.

Tuberculosis in solid organ transplant recipients at a tertiary hospital in the last 20 years in Barcelona, Spain.

OBJECTIVE: Mycobacterium tuberculosis (TB) is a serious opportunistic infection in solid organ transplant recipients. The TB incidence is 20 to 74 times greater than that among the general population. Our aim was to determine the incidence as well as the clinical, radiological, and microbiological features and outcomes of TB in these patients. MATERIALS AND METHODS: We reviewed the clinical records of subjects with posttransplant TB from January 1988 to December 2007. A definite TB case was defined by a positive culture; probable TB by a positive smear or histological finding; and disseminated TB when 2 organs were involved. We noted an early diagnosis as ones in the first year posttransplantation. Outcomes were classified following the WHO recommendation and mortality related defined by death during treatment. RESULTS: Among 4634 recipients (2757 kidney, 1334 liver, 361 double kidney-pancreas, and 182 heart), 21 (0.45%) developed posttransplant TB: namely, 0.47%, 0.22%, 1.1%, and 0.54%, respectively. In 2 cases M. tuberculosis did not grow upon culture; the diagnosis was established by positive acid-fast bacilli on a sputum smear or by histological findings on biopsy. The mean posttransplantation time to TB diagnosis was 21 months (48% early TB). Two patients had a previous history of TB. Fever was the most common symptom (71%). Pulmonary tuberculosis represented 47.6% of cases; extrapulmonary, 28.6%; and disseminated, 23.8%. Among the cases of pulmonary TB, 60% had unilateral infiltrates and 10% cavitations on X ray. Eighteen patients completed treatment. Five patients displayed adverse events, 3 of which were liver toxicity. Four patients died, with 3 deaths related to TB. CONCLUSIONS: The incidence of TB in this cohort was higher than that among the general population (450 cases/100,000 recipients). TB was associated with adverse effects of treatment and significant mortality.

Decreased expression of thrombospondin-1 in failing hearts may favor ventricular remodeling.

BACKGROUND: Thrombospondin-1 (TSP-1) is a potent inhibitor of angiogenesis and an activator of tissue transforming growth factor-beta1 (TGF-beta1). Analyses using genetically modified mice suggested that TSP-1 may play a protective role to prevent infiltration and tissue remodeling responses after myocardial infarction. The expression levels of TSP-1 and their putative role in ventricular remodeling have not been determined in patients with heart failure (HF). MATERIALS AND METHODS: We analyzed the expression of TSP-1 and TGF-beta1 mRNA in myocardial biopsies from 34 subjects with end-stage HF undergoing heart transplantation and 13 healthy controls from heart donors. Among total RNA extracted from the left ventricle, 1 microg was retrotranscribed and mRNA expression levels were quantified by real-time polymerase chain reaction (PCR). RESULTS: The mean age of subjects was 54 +/- 2 years; mean ejection fraction, 21 +/- 5%; end-diastolic diameter and end-systolic diameter, 73 +/- 10 and 61 +/- 11 mm, respectively. TSP-1 mRNA expression in ventricular tissue from HF patients was lower (159.04 +/- 14.55 ng-equivalents [ng-equiv]) than in controls (234 +/- 30.66 ng-equiv; P < .05). Tissue from HF subjects also showed lower levels of TGF-beta1 (68.42 +/- 4.36 vs 80.58 +/- 5.26 ng-equiv; P < .05). TSP-1 mRNA levels correlated positively with TGF-beta1 (P = .001; R(2) = .2), and lower TSP-1 mRNA levels were observed with increasing left ventricular diameters. CONCLUSIONS: Patients with end-stage HF show decreased TSP-1 mRNA levels, which agrees with published results showing lower circulating TSP-1. Ventricular dilatation observed in these patients may be related to lower expression of TSP-1. Surprisingly, TGF-beta1 mRNA levels were lower in failing hearts, which suggested that fibrogenesis takes place in earlier phases of HF.

Steroid use in heart transplant patients in Spain in the current era: a multicenter survey.

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

TH1/TH2 cytokine release pattern during in vivo cytomegalovirus disease in solid organ transplantation.

BACKGROUND: Cytomegalovirus (CMV) disease is associated with an increased net immunosuppressive state in solid organ transplant recipients, leading to more bacterial and fungal infections. The release of pro- and anti-inflammatory cytokines could be one of the responsible factors. METHODS: We prospectively included all patients undergoing solid organ transplantation between April and November 2004. During follow-up, plasma samples were collected in the immediate postsurgical period, at the first and second months, at the time of maximum antigenemia during CMV disease, and at 6 months posttransplantation. We determine the levels of tumor necrosis factor (TNF)-alpha, interleukin (IL)-6, and IL-10. Log-transformed data were compared by a nonparametric Wilcoxon test for related variables. RESULTS: During the study period, we monitored 146 recipients of solid organ transplantation: 77 kidneys, 8 kidney-pancreas, 46 liver, 11 heart, 2 liver-kidney, and 2 heart-kidney. No differences were observed between the TNF-alpha and IL-10 levels in the immediate postsurgical period or during CMV disease. TNF-alpha and IL-10 levels during CMV disease were higher than levels during the first month (mean TNF-alpha first month = 12.71 pg/mL vs CMV disease = 22.71 pg/mL, P = .028; mean IL-10 first month = 3.47 pg/mL vs CMV disease = 19.2 pg/mL, P = .018). Th1/Th2 ratio (measured as TNF-alpha/IL-10) was 1.75 in the immediate postsurgical period, 7.5 during the first month, 1.86 at the time of CMV disease, and 4.61 at the sixth month. The difference in Th1/Th2 ratio during CMV disease and in the first month was statistically significant (P = .043). CONCLUSION: During CMV disease, we observed an increase in TNF-alpha and IL-10 release, which was similar to that during the postsurgical period. An imbalance toward an anti-inflammatory pattern was noted in these two periods. This could reflect a cooperative factor increasing the net state of immunosuppression during CMV disease.

Clinical implications of late mitral valve regurgitation appearance in the follow-up of heart transplantation.

BACKGROUND: Tricuspid regurgitation is frequently observed after orthotopic heart transplantation (OHT), in association with severe pulmonary hypertension. However, the incidence of left-sided valvular disease has not been addressed. AIM: We analyzed the incidence and prognostic implications of left-sided valve disease in 141 patients after OHT. METHODS: Echocardiography was performed with every endomyocardial biopsy during the first year after OHT and every 6 months thereafter. Mitral regurgitation (MR) grade II or III was considered significant. Graft vasculopathy was assessed using coronary angiography. RESULTS: Eight patients (6%) developed significant left-sided valvular disease, namely, MR in 6 (4%) and aortic regurgitation (AR) in 2 (1.4%). The 2 cases with AR were diagnosed the first week after OHT, whereas significant MR was diagnosed at mean follow- up of 34 +/- 6 months. Mean regurgitant orifice and volume were 34 +/- 14 mm2 and 41 +/- 15 mL/beat, respectively. Patients with significant MR had experienced a greater number of acute rejection episodes >or=3A, (1.8 +/- 1.7 vs 0.8 +/- 1.05; P = .02) and were associated with allograft vasculopathy in 83% vs 6% among unaffected patients (P = .0001). Four of 6 patients with significant MR died during follow-up (67%) and 1 of the living patients underwent reparative mitral valve surgery. The probability of survival using Kaplan-Meier curves was significantly lower when patients developed late significant MR (54% vs 76%; P = .0001). CONCLUSIONS: The incidence of significant left-sided valvular disease after OHT was low. MR was associated with a higher degree of previous acute rejection, of graft vasculopathy, and mortality. The presence of moderate or severe MR of late appearance identified a group of OHT patients with poor outcomes.

Elevated levels of serum interleukin-6 are associated with low grade cellular rejection in patients with heart transplantation.

UNLABELLED: Endomyocardial biopsy is the gold-standard procedure to diagnose acute cellular rejection after heart transplantation. This study assessed whether the blood levels of cytokines involved in inflammation and immune activation are useful to detect the presence of acute cellular rejection. METHODS: Blood specimens collected before 275 endomyocardial biopsies in 66 patients were assayed for levels of TNFalpha, IL6, IL1beta, and IL2 receptor. The biopsies were grouped according to the presence (n = 41) or absence (n = 234) of acute cellular rejection grade > or = 3A of the International Society for Heart and Lung Transplantation. We compared the levels of cytokines in the two groups. RESULTS: Circulating IL6 levels were significantly higher when there was a low grade (0-2) cellular rejection in the biopsy versus the group of biopsies grade > or = 3A (19.8 +/- 27 versus 12.9 +/- 10 pg/mL; P = .001). An IL6 level higher than 30 pg/mL showed a negative predictive value of 95% for the presence of acute rejection grade > or = 3A. CONCLUSION: In heart transplant patients, high levels of serum IL6 were associated with low grade cellular rejection. Determination of IL6 levels may be useful to reduce the number of endomyocardial biopsies during follow-up in these patients.

Value of NT-proBNP determinations in the follow-up of heart transplantation.

BACKGROUND: The N-terminal pro-brain natriuretic peptide (NT-proBNP) has been useful in the diagnosis and follow-up of heart failure. Whether it can be useful in the detection of acute rejection (AR) after heart transplantation (HT) has not been addressed. Our aim was to assess the prognostic value of NT-proBNP determinations after HT. METHODS: We analyzed 137 endomyocardial biopsies (EMB) performed in 51 patients as assessment of AR and correlated them with NT-proBNP determinations. The value of NT-proBNP in the early follow-up of the novo HT was also assessed. RESULTS: AR grade > or =3A was diagnosed in 10 of the 137 performed biopsies. There were no significant differences in NT-proBNP values between patients with or without AR (1047 +/- 629 versus 1886 +/- 3026 pg/mL, P = NS). There were 24 de novo HT, in these patients increased NT-proBNP levels showed an inverse significant correlation with time since HT (r = -0.40, P = .0001). During follow-up, 15 of the novo HT had a descending NT-proBNP curve over time, and in the remaining 9 (37%) a late increase of NT-proBNP values were observed. Those 9 patients had the following complications: AR > or =3A in 5 cases, 1 death, 2 required a permanent pacemaker, and in the last patient a significant EMB could not be obtained. CONCLUSIONS: NT-proBNP values follow a descending curve early after HT. During the first months, a late increase of NT-proBNP value was associated with HT complications, with AR being the most frequent. Isolated increased NT-proBNP levels were not useful for the detection of AR. More studies are needed to establish the prognostic value of NT-proBNP after HT.

Invasive pulmonary aspergillosis in solid organ and bone marrow transplant recipients.

BACKGROUND: Invasive pulmonary aspergillosis (IPA) remains a major cause of mortality in transplant recipients. New strategies in therapy are needed. METHODS: We prospectively followed all solid organ and bone marrow transplant recipients from January 1998 to January 2003 who showed pulmonary infiltrates. We retrospectively analyzed all of the patients diagnosed as having IPA. Clinical and epidemiological data were collected. Influence of new treatment strategies on survival was also analyzed. RESULTS: Thirty-one cases of API were found: 8 definite, 18 probable, 5 possible among recipients of liver (11), bone marrow (9), kidney (7), kidney-pancreas (3), and heart (1) transplants. Five patients (16%) were previously receiving antifungal prophylaxis. The most common symptoms were fever (74%) and dyspnea and dry cough (48%). Six cases (19%) showed dissemination to extrapulmonary sites: central nervous system (CNS) in five and bone in one. The most common radiographic patterns were alveolar infiltrates (58%); the lesions were usually diffuse and bilateral (58%). The most common Aspergillus species identified was A. fumigatus (74%). The test to detect Aspergillus antigen (galactomannan) in serum performed in 13 cases, was positive in eight (61%). The crude mortality rate was 61% (19 of 31), but in patients on mechanical ventilation, it was 94% (OR 88, IC 95%: 7.1-1094), and in patients with CNS involvement, it was 100%. The influence of the different treatment regimens on survival was analyzed in definite and probable cases: Group 1 (12) included patients who received conventional monotherapy and group 2 (12) patients received combination antifungal therapy or liposomal amphotericin B (1-AMB) at high doses. The mortality in group 1 was 83% (10 of 12), and in group 2 it was 42% (5 of 12) (P < 0.05). CONCLUSIONS: The mortality rate of IPA remains high, especially among patients with CNS involvement or those under mechanical ventilation. Combined antifungal therapy or monotherapy with 1-AMB at high doses significantly reduced mortality compared with conventional monotherapy.

Cryopreservation alters antigenicity of allografts in a porcine model of transplant vasculopathy.

UNLABELLED: The need for arterial grafts in coronary surgery to complement autologous vessels has generated interest in cryopreservation of small diameter allografts. We evaluated functional and histologic changes occurring in cryopreserved allografts 3 months after porcine femoral artery transplants. METHODS: Twenty recipient and 15 donor pigs included a control group of 16 fresh and 12 cryopreserved nonimplant arteries were used. Fresh (n=5) and cryopreserved (n=5) autografts were implanted to assess cryopreservation effects in the absence of rejection. Fresh allografts with or without treatment with cyclosporine (CsA) (n=6 of 8) and cryopreserved allografts with or without treatment with CsA (n=6 of 10) were performed to study the antigenicity of cryopreserved allografts. Arteries were stained with hematoxylin and eosin, Masson's trichrome, and orcein for morphometric analyses and immunostained to identify endothelial cells, smooth muscle cells, T lymphocytes, and macrophages. RESULTS: Among nonimplant arteries, cryopreservation reduced alpha-actin expression and increased the luminal area. All implanted autografts were patent. Cryopreserved autografts showed reduced alpha-actin expression and developed intimal hyperplasia compared to fresh autografts. Treatment with CsA improved the patency of fresh allografts from 0% to 83% (P <.01) and of cryopreserved allografts from 40% to 100% (P <.05). Cryopreserved allografts showed substantial intimal hyperplasia, and fresh allografts had more T lymphocyte infiltration in the intimal layer with aneurysmal dilatation. CONCLUSIONS: Cryopreservation reduces the deposition of inflammatory cells and prevents the thrombosis or aneurysmal lesions observed in fresh allografts. Therefore, cryopreservation modifies the antigenicity of vascular allografts.

Prognostic value of serum cytokines in patients with congestive heart failure.

BACKGROUND: Increased levels of circulating cytokines have been previously reported in patients with congestive heart failure; however, whether they have prognostic implications is still unknown. The aim of this study was to assess the prognostic implications of elevated serum cytokines in patients with heart failure and to identify the predictors of cytokine activation. METHODS AND RESULTS: We assessed neurohormonal determinations, circulating cytokines, ejection fraction (EF) and end-diastolic and end-systolic left ventricular lengths in 87 patients (aged 57 +/- 9 years) with left ventricular dysfunction (EF 24% +/- 6%). In 48 patients, we also assessed cytokine receptors. During follow-up (mean, 14 +/- 9 months), 8 patients died and 12 had new heart failure episodes that required hospital admission, 5 of whom underwent heart transplantation. The univariate predictors of these events were serum interleukin-6 (IL-6) (p = 0.00001), New York Heart Association (NYHA) functional class (p = 0.0004), tumor necrosis factor-soluble receptor I (p = 0. 001), atrial natriuretic peptide (p = 0.002), tumor necrosis factor-soluble receptor II (p = 0.004), angiotensin II (p = 0.006), serum interleukin-1 beta (p = 0.01), and plasma renin activity (p = 0.02). Increased serum interleukin-6 (>10 pg/ml) was a significant predictor of death or new heart failure episodes according to the Kaplan-Meier survival method by log-rank test (p = 0.004). By Cox regression analysis, serum IL-6 (p = 0.0005) and the NYHA functional class (p = 0.005) were identified as independent predictors of prognosis. CONCLUSIONS: In patients with congestive heart failure, increased serum IL-6 was identified as a powerful independent predictor of the combined end point: death, new heart failure episodes, and need for heart transplantation.