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Background: In June, 2021, WHO published the most complete catalogue to date of resistance-conferring mutations in Mycobacterium tuberculosis. Here, we aimed to assess the performance of genome-based antimicrobial resistance prediction using the catalogue and its potential for improving diagnostics in a real low-burden setting., Methods: In this retrospective population-based genomic study M tuberculosis isolates were collected from 25 clinical laboratories in the low-burden setting of the Valencia Region, Spain. Culture-positive tuberculosis cases reported by regional public health authorities between Jan 1, 2014, and Dec 31, 2016, were included. The drug resistance profiles of these isolates were predicted by the genomic identification, via whole-genome sequencing (WGS), of the high-confidence resistance-causing variants included in the catalogue and compared with the phenotype. We determined the minimum inhibitory concentration (MIC) of the isolates with discordant resistance profiles using the resazurin microtitre assay., Findings: WGS was performed on 785 M tuberculosis complex culture-positive isolates, and the WGS resistance prediction sensitivities were: 85·4% (95% CI 70·8-94·4) for isoniazid, 73·3% (44·9-92·2) for rifampicin, 50·0% (21·1-78·9) for ethambutol, and 57·1% (34·0-78·2) for pyrazinamide; all specificities were more than 99·6%. Sensitivity values were lower than previously reported, but the overall pan-susceptibility accuracy was 96·4%. Genotypic analysis revealed that four phenotypically susceptible isolates carried mutations (rpoB Leu430Pro and rpoB Ile491Phe for rifampicin and fabG1 Leu203Leu for isoniazid) known to give borderline resistance in standard phenotypic tests. Additionally, we identified three putative resistance-associated mutations (inhA Ser94Ala, katG Leu48Pro, and katG Gly273Arg for isoniazid) in samples with substantially higher MICs than those of susceptible isolates. Combining both genomic and phenotypic data, in accordance with the WHO diagnostic guidelines, we could detect two new multidrug-resistant cases. Additionally, we detected 11 (1·6%) of 706 isolates to be monoresistant to fluoroquinolone, which had been previously undetected., Interpretation: We showed that the WHO catalogue enables the detection of resistant cases missed in phenotypic testing in a low-burden region, thus allowing for better patient-tailored treatment. We also identified mutations not included in the catalogue, relevant at the local level. Evidence from this study, together with future updates of the catalogue, will probably lead in the future to the partial replacement of culture testing with WGS-based drug susceptibility testing in our setting., Funding: European Research Council and the Spanish Ministerio de Ciencia., Competing Interests: Declaration of interests IC received consultancy fees from the Foundation for Innovative New Diagnostics. IC and VF have participated in the elaboration of the WHO catalogue used in this study. All other authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

In the tourism and hospitality industry, ensuring the well-being of visitors is essential to achieving a competitive tourist destination. This objective is even more pressing in the gastronomy sector. Surprisingly, the scientific literature on this topic is scarce and relies on questionnaire surveys and interviews as a data source. After scrutinizing the 13 articles on gastronomy tourism and well-being indexed in the Web of Science or in Scopus, this study proposes two new lines of research interrelated by the concept of gastronomic image. These exploit the content shared online by consumers in order to assess subjective well-being derived from quality gastronomic experiences. The first is a framework for the customer-perceived image based on Grönroos's service quality model, and the second is a conceptual model based on Morris's semiotics to measure gastronomic image. Through mixed methodologies, i.e., qualitative in the first research line and quantitative in the second, the study applies the theoretical framework to Michelin-starred restaurants in two tourist regions with similar features but with different gastronomic cultures-Taiwan (Asia) and Catalonia (Europe)-using as a data source all the online travel reviews (OTRs) written in English about these restaurants shared on the TripAdvisor portal. Comparing the three categories of restaurants in both regions, the results show branding and marketing problems and significant differences in the popularity of restaurants and the satisfaction and well-being of diners. There is a positive relationship between the category of restaurants according to the number of Michelin stars and their popularity according to the number of OTRs, as well as with the satisfaction and well-being of diners, except for a 3-star restaurant that is the worst-rated. These outcomes from the demand side can be useful to stakeholders to design or improve gastronomic products and services.

Culinary or gastronomic tourism has become one of the main exponents of cultural tourism and a key element of a destination's image identity. Since travellers consult and produce online travel reviews (OTR) before and during a trip, this research aims to provide and implement a framework for analysing OTRs of dining establishments to measure their contribution to destination image formation in their designative (cognitive) and appraisive (affective and evaluative) aspects. To do this, a website was selected from which to download OTRs, extract useful information from the textual and paratextual elements, build a keyword frequency matrix, and perform a quantitative and thematic content analysis. This method was applied to a random sample of 500,000 OTRs from the TripAdvisor restaurants section, written in English, between 2013 and 2017, by tourists visiting the Canary Islands. Results show that, although the gastronomic image of the destination is positive in general, the local and regional gastronomy representative of the community's sociocultural identity is not the most popular nor the best valued in tourists' comments. This research shows a method to measure the main aspects that make up the gastronomic image of a destination and that allow for extracting insights and business intelligence through big data from user-generated content.

Background: Whole genome sequencing provides better delineation of transmission clusters in Mycobacterium tuberculosis than traditional methods. However, its ability to reveal individual transmission links within clusters is limited. Here, we used a 2-step approach based on Bayesian transmission reconstruction to (1) identify likely index and missing cases, (2) determine risk factors associated with transmitters, and (3) estimate when transmission happened., Methods and Findings: We developed our transmission reconstruction method using genomic and epidemiological data from a population-based study from Valencia Region, Spain. Tuberculosis (TB) incidence during the study period was 8.4 cases per 100,000 people. While the study is ongoing, the sampling frame for this work includes notified TB cases between 1 January 2014 and 31 December 2016. We identified a total of 21 transmission clusters that fulfilled the criteria for analysis. These contained a total of 117 individuals diagnosed with active TB (109 with epidemiological data). Demographic characteristics of the study population were as follows: 80/109 (73%) individuals were Spanish-born, 76/109 (70%) individuals were men, and the mean age was 42.51 years (SD 18.46). We found that 66/109 (61%) TB patients were sputum positive at diagnosis, and 10/109 (9%) were HIV positive. We used the data to reveal individual transmission links, and to identify index cases, missing cases, likely transmitters, and associated transmission risk factors. Our Bayesian inference approach suggests that at least 60% of index cases are likely misidentified by local public health. Our data also suggest that factors associated with likely transmitters are different to those of simply being in a transmission cluster, highlighting the importance of differentiating between these 2 phenomena. Our data suggest that type 2 diabetes mellitus is a risk factor associated with being a transmitter (odds ratio 0.19 [95% CI 0.02-1.10], p < 0.003). Finally, we used the most likely timing for transmission events to study when TB transmission occurred; we identified that 5/14 (35.7%) cases likely transmitted TB well before symptom onset, and these were largely sputum negative at diagnosis. Limited within-cluster diversity does not allow us to extrapolate our findings to the whole TB population in Valencia Region., Conclusions: In this study, we found that index cases are often misidentified, with downstream consequences for epidemiological investigations because likely transmitters can be missed. Our findings regarding inferred transmission timing suggest that TB transmission can occur before patient symptom onset, suggesting also that TB transmits during sub-clinical disease. This result has direct implications for diagnosing TB and reducing transmission. Overall, we show that a transition to individual-based genomic epidemiology will likely close some of the knowledge gaps in TB transmission and may redirect efforts towards cost-effective contact investigations for improved TB control., Competing Interests: The authors have declared that no competing interests exist.

Introduction and Objectives: Abnormal electrocardiographic findings are highly common. The aim of this study was to analyze the prevalence of abnormal electrocardiographic patterns in the general Spanish population aged 40 years or older., Methods: This subanalysis of the OFRECE study selected a representative sample of the Spanish population aged 40 years or older. Clinical data and electrocardiograms were available in all participants. The electrocardiograms were read centrally. Each electrocardiogram was independently assessed by 2 trained cardiologists and, if there was disagreement, a third was consulted to reach a consensus-based diagnosis. Prior to reading the electrocardiograms, diagnostic criteria were strictly defined for each of the abnormalities analyzed. We analyzed the prevalence and clinical factors associated with cavity enlargement, conduction disorders, repolarization abnormalities, pathological Q waves, atrial and ventricular premature beats, and pre-excitation., Results: A total of 8343 individuals were evaluated, (mean age, 59.2 years; 52.4% women). Only 4074 (51.2%) participants had a completely normal electrocardiogram. The most frequent abnormalities were nonspecific repolarization abnormalities (16%) associated with coronary heart disease and atrial fibrillation; right bundle-branch block (8.1%) associated with chronic pulmonary obstructive disease; left anterior hemiblock (6.5%) related to hypertension and congestive heart failure; and long PR interval (3.7%), which was associated with coronary heart disease., Conclusions: Electrocardiographic abnormalities are very common in the general population aged 40 years or older. Only about half of the population had a completely normal electrocardiogram., (Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Introduction and Objectives: To analyze differences between sexes in the clinical management of patients presenting with symptoms of chest pain and/or palpitations within a population-based study., Methods: The OFRECE study included a random sample of 8400 individuals from the Spanish population aged 40 years and older; 1132 (13.5%) had previously consulted for chest pain and 1267 (15.1%) had consulted for palpitations and were included in the present study. We calculated both the crude and adjusted odds ratios (OR) of undergoing certain tests and the results of consultations by sex. Adjustment was performed by classic cardiovascular risk factors, a personal history of cardiovascular disease, and a diagnosis of stable angina or atrial fibrillation confirmed in the OFRECE study in each case., Results: No differences were observed in history of consultation for chest pain between women and men (13% vs 14.1%; P=.159) but differences were found in palpitations (19% vs 10.4%, respectively; P <.001). Women who had previously consulted for chest pain underwent fewer echocardiograms (32.5% vs 45.3%, respectively; P <.001), were less frequently referred to a cardiologist (49.1% vs 60.1%; P <.001), were less often admitted to hospital (20.1% vs 39.4%; P <.001), and less frequently received a confirmed diagnosis (60.9 vs 71, 9; P <.001). After full adjustment, all differences decreased and become nonsignificant echocardiograms: adjusted OR, 0.81; 95%CI, 0.60-1.09; referral to a cardiologist: adjusted OR, 0.86; 95%CI, 0.63-1.16; hospital admission: adjusted OR, 0.76; 95%CI, 0.54-1.09). For palpitations, crude differences were smaller and all became nonsignificant after adjustment., Conclusions: This study does not confirm the existence of sex-related bias in the management of chest pain and palpitations. However, such bias cannot be completely ruled out in diagnoses confirmed within the OFRECE study, which might limit its ability to detect sex-related differences in health care., (Copyright © 2018 Sociedad Española de Cardiología. Published by Elsevier España, S.L.U. All rights reserved.)

Background: The lengthy waiting time for heart transplantation is associated with high mortality. To increase the number of donors, new strategies have emerged, including the use of hearts from donors ≥50 years old. However, this practice remains controversial. The aim of this study was to evaluate outcomes of patients receiving heart transplants from older donors., Methods: We retrospectively analyzed 2,102 consecutive heart transplants in 8 Spanish hospitals from 1998 to 2010. Acute and overall mortality were compared in patients with grafts from donors ≥50 years old versus grafts from younger donors., Results: There were 1,758 (84%) transplanted grafts from donors < 50 years old (Group I) and 344 (16%) from donors ≥50 years old (Group II). Group I had more male donors than Group II (71% vs. 57%, p = 0.0001). The incidence of cardiovascular risk factors was higher in older donors. There were no differences in acute mortality or acute rejection episodes between the 2 groups. Global mortality was higher in Group II (rate ratio, 1.40; 95% confidence interval, 1.18-1.67; p = 0.001) than in Group I. After adjusting for donor cause of death, donor smoking history, recipient age, induction therapy, and cyclosporine therapy, the differences lost significance. Group II had a higher incidence of coronary allograft vasculopathy at 5 years (rate ratio, 1.67; 95% confidence interval, 1.22-2.27; p = 0.001)., Conclusions: There were no differences in acute and overall mortality after adjusting for confounding factors. However, there was a midterm increased risk of coronary allograft vasculopathy with the use of older donors. Careful selection of recipients and close monitoring of coronary allograft vasculopathy are warranted in these patients., (Copyright © 2015 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: The present article reports the characteristics and outcome of heart transplantation in Spain since it was first performed in May 1984., Methods: We provide a descriptive analysis of the characteristics of the recipients, the donors, the surgical procedure, and results of the heart transplantations performed in Spain until 31 December 2013., Results: During 2013, a total of 248 transplantation procedures were carried out, bringing the time series to a total of 7023 transplantations. The temporal analysis confirms a significant deterioration in the clinical profile of the recipients (higher percentage of older patients, severe renal failure, insulin-dependent diabetes mellitus, previous heart surgery, mechanical ventilation), of the donors (higher proportion of older donors and greater weight mismatch), and of the procedure (higher percentage of emergency transplantations which, in 2013, reached 49%, and with ischemia times > 240min). There was a marked increase in the use of circulatory assist devices prior to transplantation which, in 2013, were employed in 25.2% of all the patients. The survivals at 1, 5, 10, and 15 years were 76%, 65%, 52%, and 37%, respectively, and have remained stable since 1995., Conclusions: Heart transplantation activity in Spain remains stable in recent years, with around 250 procedures a year. Despite the clear deterioration in the clinical characteristics of the donors and recipients, and lengthening of the operative times, the results in terms of mortality continue to be comparable to those reported in our neighboring countries, and a growing use of circulatory assist devices prior to transplantation is confirmed., (Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: Symptomatic mitral regurgitation has an unfavorable prognosis unless treated by surgery. However, the European registry of valvular heart disease reports that 49% of patients with this condition do not undergo surgery. Percutaneous treatment of mitral regurgitation with MitraClip® has been proved a safe, efficient adjunct to medical treatment in patients with this profile. The objective of the present study is to describe initial experience of MitraClip® therapy in Spain., Methods: Retrospective observational study including all patients treated between November 2011 and July 2013 at the 4 Spanish hospitals recording the highest numbers of implantations., Results: A total of 62 patients (77.4% men) were treated, mainly for restrictive functional mitral regurgitation (85.4%) of grade III (37%) or grade IV (63%), mean (standard deviation) ejection fraction 36% (14%), and New York Heart Association functional class III (37%) or IV (63%). Device implantation was successful in 98% of the patients. At 1 year, 81.2% had mitral regurgitation ≤ 2 and 90.9% were in New York Heart Association functional class ≤ II. One periprocedural death occurred (sepsis at 20 days post-implantation) and another 3 patients died during follow-up (mean, 9.1 months). Two patients needed a second implantation due to partial dehiscence of the first device and 2 others underwent heart transplantation., Conclusions: In Spain, MitraClip® therapy has principally been aimed at patients with functional mitral regurgitation, significant systolic ventricular dysfunction, and high surgical risk. It is considered a safe alternative treatment, which can reduce mitral regurgitation and improve functional capacity., (Copyright © 2014 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: Atrial fibrillation is associated with substantial morbidity and mortality and both its incidence and prevalence are high. Nevertheless, comprehensive data on this condition in Spain are lacking. The aim of this study was to estimate the prevalence of atrial fibrillation in Spain., Methods: A cross-sectional study was conducted in the general Spanish population older than 40 years. Two-stage random sampling was used, in which first-stage units were primary care physicians randomly selected in every Spanish province and second-stage units were 20 randomly selected persons drawn from each participating physician's assigned population. The reported prevalence was standardized for the age and sex distribution of the Spanish population. The electrocardiogram recordings were read centrally., Results: Overall, 8343 individuals were evaluated. The mean age was 59.2 years (95% confidence interval, 58.6-59.8 years), and 52.4% of the participants were female. The overall age-adjusted prevalence of atrial fibrillation was 4.4% (95% confidence interval, 3.8-5.1). Prevalence was similar in both sexes, men 4.4% (3.6-5.2) and women 4.5% (3.6-5.3), rising with increasing age older than 60 years. In patients older than 80 years, the prevalence was 17.7% (14.1-21.3). In 10% of patients an unknown atrial fibrillation was diagnosed., Conclusions: The prevalence of atrial fibrillation in the general Spanish population older than 40 years is high, at 4.4%. The prevalence is similar in both sexes and rises steeply above 60 years of age. It is estimated that there are over 1 million patients with atrial fibrillation in the Spanish population, of whom over 90,000 are undiagnosed., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: To analyze the association between higher body mass index and waist circumference, and the prognostic values of both indicators in total and cardiac mortality in patients with chronic heart failure., Methods: The study included 2254 patients who were followed up for 4 years. Obesity was classified as a body mass index ≥30 and overweight as a body mass index of 25.0-29.9. Central obesity was defined as waist circumference ≥88 cm for women and ≥102cm for men. Independent predictors of total and cardiac mortality were assessed in a multivariate Cox model adjusted for confounding variables., Results: Obesity was present in 35% of patients, overweight in 43%, and central obesity in 60%. Body mass index and waist circumference were independent predictors of lower total mortality: hazard ratio=0.84 (P<.001) and hazard ratio=0.97 (P=.01), respectively, and lower cardiac death (body mass index, hazard ratio=0.84, P<.001; waist circumference, hazard ratio=0.97, P=.01). The interaction between body mass index and waist circumference (hazard ratio=1.001, P<.01) showed that the protective effect of body mass index was lost in patients with a waist circumference >120cm., Conclusions: Mortality was significantly lower in patients with a high body mass index and waist circumference. The results also showed that this protection was lost when these indicators over a certain limit., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Introduction and Objectives: The present article reports the characteristics and results of heart transplantation in Spain since this therapeutic modality was first used in May 1984., Methods: We summarize the main features of recipients, donors, and surgical procedures, as well as the results of all heart transplantations performed in Spain until December 31, 2012., Results: A total of 247 heart transplantations were performed in 2012. The whole series consisted of 6775 procedures. Recent years have seen a progressive worsening in the clinical characteristics of recipients (34% aged over 60 years, 22% with severe kidney failure, 17% with insulin-dependent diabetes, 29% with previous heart surgery, 16% under mechanical ventilation) and donors (38% aged over 45 years, 26% with recipient: donor weight mismatch>20%), and in surgical conditions (29% of procedures at >4 h ischemia and 36% as emergency transplantations). The probability of survival at 1, 5, 10, and 15 years of follow-up was 78%, 67%, 53%, and 38%, respectively. These results have remained stable since 1995., Conclusions: In recent years, the number of heart transplantations/year in Spain has remained stable at around 250. Despite the worsening of recipient and donor clinical characteristics and of time-to-surgery, the results in terms of mortality have remained stable and compare favorably with those of other countries., (Copyright © 2013 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

We sought to determine the incidence, risk factors, and consequences of acute rejection (AR) after conversion from a calcineurin inhibitor (CNI) to a proliferation signal inhibitor (PSI) in maintenance heart transplantation. Relevant clinical data were retrospectively obtained for 284 long-term heart transplant recipients from nine centers in whom CNIs were replaced with a PSI (sirolimus or everolimus) between October 2001 and March 2009. The rejection rate at one yr was 8.3%, stabilizing to 2% per year thereafter. The incidence rate after conversion (4.9 per 100 patient-years) was significantly higher than that observed on CNI therapy in the pre-conversion period (2.2 per 100 patient-years). By multivariate analysis, rejection risk was associated with a history of late AR prior to PSI conversion, early conversion (<5 yr) after transplantation and age <50 yr at the time of conversion. Use of mycophenolate mofetil was a protective factor. Post-conversion rejection did not significantly influence the evolution of left ventricular ejection fraction, renal function, or mortality during further follow-up. Conversion to a CNI-free immunosuppression based on a PSI results in an increased risk of AR. Awareness of the clinical determinants of post-conversion rejection could help to refine the current PSI conversion strategies., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Elevated heart rate (HR) is associated with adverse cardiovascular outcome in the general population and in patients with cardiovascular disease. Elevated HR due to graft denervation is often found in heart transplantation (HTx) patients; the effect on graft survival and vasculopathy is unclear. Thus, the aim of this study was to evaluate the role of elevated HR at 12 months post-HTx and its power to predict HTx long-term outcome., Methods: We evaluated retrospectively a prospective database of 312 patients undergoing HTx at two centers. HR was registered at 12 months post-HTx. The median HR was used as a cutoff point. Cox regression analysis was performed with variables known to be clinically relevant to mortality and those selected from the univariate analysis., Results: During a mean follow-up of 5.5 ± 2.8 years there were 58 deaths (19%). Patients with a HR ≥ 90 bpm (median HR) at 12 months had an increased risk for all-cause mortality (Hazard Ratio=2.4, 95% CI 1.2 to 4.5, p=0.009) and mortality related to coronary allograft vasculopathy (CAV) (Hazard Ratio=3.0, 95% CI 1.25-7.14, p=0.01). Multivariate analysis showed that a HR ≥ 90 bpm independently predicted mortality (HR 3.2, 95% CI 1.4-7.1, p=0.004)., Conclusions: Elevated HR measured at 12 months after HTx is an independent predictor of all-cause mortality in HTx recipients. A HR ≥ 90 bpm identifies a group of patients at high risk of death and CAV-related mortality at mid- to long-term., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: The increasing use of proliferation signal inhibitors (PSIs) has raised the issue of their risk profile. We sought to determine the causes, incidence, risk factors, and consequences of withdrawal due to adverse events of PSIs in maintenance heart transplantation., Methods: This was a retrospective study from 9 centers of the Spanish Registry for Heart Transplantation. Demographic, clinical, analytic, and evolution data were obtained for patients in whom a PSI (sirolimus or everolimus) was used between October 2001 and March 2009., Results: In the first year, 16% of 548 patients could not tolerate PSIs. This incidence rate stabilized to 3% to 4% per year thereafter. The most frequent causes for discontinuation were edema (4.7%), gastrointestinal toxicity (3.8%), pneumonitis (3.3%), and hematologic toxicity (2.0%). In multivariate analysis, withdrawal of PSI was related to the absence of statin therapy (p = 0.006), concomitant treatment with anti-metabolites (p = 0.006), a poor baseline renal function (p = 0.026), and multiple indications for PSI use (p = 0.04). Drug discontinuation was associated with a decline in renal function (p = 0.045) but not with an excess in mortality (p = 0.42)., Conclusions: In this large cohort of maintenance heart transplant recipients taking a PSI, 16% withdrew treatment in the first year, and 25% had stopped PSI due to severe adverse events by the fourth year. This high rate of toxicity-related PSI withdrawal could limit the clinical utility of this otherwise novel class of immunosuppressive agents., (Copyright © 2012 International Society for Heart and Lung Transplantation. Published by Elsevier Inc. All rights reserved.)

Introduction and Objectives: Most studies have shown that prognosis of heart failure with preserved systolic function is as poor as that of heart failure with depressed systolic function, although these results may be biased by the fact that these types of heart failure have different characteristics (age, comorbidity, treatment), which can influence prognosis. Our aim was to determine whether short-term morbidity and mortality differed in these 2 subgroups of heart failure patients when they were comparable in terms of age, associated comorbidity, and therapy., Methods: We analyzed 2 groups of patients aged >70 years who were candidates to receive beta blockers (preserved systolic function, 245; depressed systolic function, 374), consecutively discharged from 53 participating Spanish hospitals with a diagnosis of heart failure, and compared cardiovascular morbidity and mortality 3 months after discharge., Results: Mean age was similar (77.5±4.8 vs 78.2±5.5 years). Left ventricular ejection fraction was 56.2%±8.1% vs 33%±6.9% (P<.001). The combined event rate (death, hospitalization for heart failure, acute coronary syndrome, or stroke) at 3 months after discharge was lower in patients with heart failure and preserved systolic function (13.4% vs 20.6%; P=.026). Depressed systolic function was an independent predictor of greater incidence of events (odds ratio=1.732; P=.048)., Conclusions: In patients of similar age and receiving similar treatment, short-term prognosis is better in patients with heart failure and preserved systolic function than in those with depressed systolic function., (Copyright © 2011 Sociedad Española de Cardiología. Published by Elsevier Espana. All rights reserved.)

Heart transplantation (HT) remains the treatment of choice for patients with end-stage heart failure. Cardiac allograft vasculopathy (CAV), a diffuse form of coronary atherosclerosis, is the major cause of death after the first year of HT. CAV is thought to be multifactorial in origin. Although nonimmune factors may play a role in CAV development, it is primarily an immune-mediated disease. CAV is diagnosed by routine annual coronary angiography, and usually when diagnosed, the disease is advanced. There is a need to develop noninvasive surrogate markers for early detection. For this purpose, careful immune monitoring and graft histologic assessment are mandatory. The main objective of this study was the assessment of immunologic markers as mediators of CAV development in HT. Flow cytometry was performed to assess peripheral blood mononuclear cell populations forming CD3, CD4, CD8, CD19, CD56, Th1 (CD3+IFNγ+) or Treg (CD4+CD25(high)FoxP3+) markers among 20 de novo HT recipients. The control group included 13 patients who were more than 2 years post-HT (four with and nine without CAV) as well as 20 healthy subjects. CAV-related events over 2 years' follow-up correlated with the Th1/Treg ratio. An increased Th1 lymphocyte percentage was detected over the follow-up. Patients with medium and high Th1/Treg ratios showed higher acute rejection scores as well as greater incidences of CAV. These results indicated that the Th1/Treg ratio may represent a valuable marker to monitor allospecific T-cell responses in peripheral blood. Changes in the Th1/Treg ratio may help in the early detection of patients at risk for CAV. More studies with longer follow-up are needed to confirm these preliminary results., (Copyright © 2011 Elsevier Inc. All rights reserved.)

In this study we analyzed Spanish Post-Heart-Transplant Tumour Registry data for adult heart transplantation (HT) patients since 1984. Median post-HT follow-up of 4357 patients was 6.7 years. Lung cancer (mainly squamous cell or adenocarcinoma) was diagnosed in 102 (14.0% of patients developing cancers) a mean 6.4 years post-HT. Incidence increased with age at HT from 149 per 100 000 person-years among under-45s to 542 among over-64s; was 4.6 times greater among men than women; and was four times greater among pre-HT smokers (2169 patients) than nonsmokers (2188). The incidence rates in age-at-diagnosis groups with more than one case were significantly greater than GLOBOCAN 2002 estimates for the general Spanish population, and comparison with published data on smoking and lung cancer in the general population suggests that this increase was not due to a greater prevalence of smokers or former smokers among HT patients. Curative surgery, performed in 21 of the 28 operable cases, increased Kaplan-Meier 2-year survival to 70% versus 16% among inoperable patients., (©2011 The Authors Journal compilation©2011 The American Society of Transplantation and the American Society of Transplant Surgeons.)

Background: The objectives of this epidemiological, prospective study were to describe the characteristics of cytomegalovirus (CMV) infection in heart transplant (HT) recipients and to identify the variables that may influence the development of CMV viremia and CMV disease in these patients., Methods: HT recipients ≥18 years of age (n=199) were included in the study. Variables studied included CMV serostatus, immunosuppressive treatment, and administration of anti-CMV prophylaxis., Results: The mean age of the population was 52 years, and 84% were males. Immunosuppressive regimens were administered as induction therapy to 92.5% of patients; 88.5% of patients received calcineurin inhibitors as maintenance therapy. Anti-CMV treatment was given to 59% of 199 patients as prophylaxis (70%), preemptive therapy (10%), or to treat CMV infection (20%). Overall, 43% of patients had at least 1 positive viremia test. No patient with a high-risk serostatus (donor+/recipient-) receiving prophylaxis developed CMV syndrome, and only 2.5% of 199 patients developed CMV invasive disease. Multivariate analysis showed that having a positive donor CMV serostatus was associated with an increased risk of developing CMV viremia (P<0.012), while use of mammalian target of rapamycin (mTOR) inhibitors was associated with a decreased risk (P=0.005)., Conclusions: In a population of HT recipients, the CMV infection rate was similar to that seen in previous studies, but the progression to overt CMV disease was very low. Having a CMV-positive donor was identified as an independent risk factor for developing CMV viremia, while the use of mTOR inhibitors was protective against viremia., (© 2010 John Wiley & Sons A/S.)

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., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Introduction: The incidence of skin cancer in heart transplant (HT) patients is higher than in the general population, reversing the proportion of cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) with a predominance of the former. The etiologic role of new immunosuppressants is not well known. We sought to ascertain the incidence of SCC and BCC in HT patients and the risk factors for its occurrence., Patients and Methods: We report the incidence of all types of post-HT skin cancer, SCC, and BCC among adult HT patients in Spain (4089 subjects) as well as the influence of gender, age at heart transplant, immunosuppression, and sunlight exposure., Results: The incidence rates of SCC and BCC, per 1000 persons/year, were 8.5 and 5.2, respectively. Males had a higher risk of SCC but not BCC. Induction therapy increased the risk of SCC and BCC. The relative risk of mycophenolate mofetil (MMF) was 0.3 (0.2-0.6; P<.0005) and azathioprine (AZA) 1.8 (1.2-2.7; P<.0032) for SCC, whereas tacrolimus and cyclosporine showed no difference. The relative risk of BCC was not affected by any immunosuppressant., Conclusion: Age at transplantation>45 years, induction therapy use, and high sunshine zone were risk factors for both SCC and BCC. Different immunosuppressive agents have different risks of nonmelanoma skin cancer, as AZA increases the risk of SCC and MMF is a protective factor. The relative risk of BCC was not affected by any immunosuppressor., (Copyright © 2010 Elsevier Inc. All rights reserved.)

Background: Chronic renal failure is a common complication of heart transplantation. Sirolimus (SRL) is an immunosuppressive drug that, unlike calcineurin inhibitors (CNIs), is not associated with nephrotoxicity., Methods: We collected efficacy and safety data from a Spanish registry of heart transplant recipients who were switched from a CNI to SRL due to renal failure. Patients were included if the serum creatinine level before switching was >1.5 mg/dL and/or the estimated creatinine clearance level was below 50 mL/min., Results: Ninety-seven patients started SRL due to renal impairment. When SRL was started, CNIs were progressively tapered and in some cases withdrawn. Mean baseline creatinine level was 2.5 mg/dL and mean creatinine clearance level was 39 mL/min. Only 1 episode of acute rejection was observed in a patient receiving SRL plus cyclosporine (CsA) but the eventual allograft function remained stable. Compared with baseline, a significant improvement in renal function was observed at 6 months among patients who stopped CNIs before the third month after SRL was started, although not among those who continued taking CNIs. Upon multivariate analysis, no predictors of response were observed. SRL was withdrawn in 18% of patients due to adverse events., Conclusions: Switching to SRL was safe in heart allograft recipients, improving renal function among those previously receiving a CNI. Renal function improves if CNIs are withdrawn soon after starting SRL.

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

Amyloidosis (Am), a systemic disease, has poor prognosis because of organ damage produced by protein deposition in the extracellular space. Although heart transplantation (HTx) is possible, donor availability concerns and high mortality make this approach controversial. The Spanish Registry for Heart Transplantation includes 25 Am patients (54 +/- 9 years): 13 with AL type, 2 with AA and 10 with TTR mutation. Fifteen patients (60%) died during follow-up (4.9 +/- 1.3 years): 9 AL-Am patients, both AA-Am patients and 4 with TTR-Am. HTx survival for Am patients was similar to patients without Am at 1 month but significantly worse at 5 years: 46% versus 78% (p < 0.02). Of 10 AL-Am patients undergoing successful HTx, 4 died of systemic Am. Stem cell transplantation was performed in 3 (1 died of acute rejection). Five of 10 patients with TTR-Am underwent liver transplant; 4 remained alive at the last follow-up. Findings include poor outcome for AL-Am patients despite HTx and better survival for TTR-Am patients if HTx is associated with liver transplantation. Given the shortage of donors and poor outcome for Am patients, we would recommend that HTx be reserved for patients without or with mild systemic Am and be supplemented by additional therapies as indicated.

Aims: Cardiac resynchronization therapy (CRT) has been proven to be effective in patients suffering from chronic heart failure (CHF) associated with electrical dyssynchrony. However, long-term predictors of mortality in that subset have not been extensively investigated. The aim of this study was to establish baseline long-term predictors of cardiovascular mortality in CHF patients treated with CRT., Methods and Results: A total of 188 consecutive patients with moderate to severe CHF who had undergone a successful CRT implant were evaluated. Baseline measurements included clinical history, a 6-min walking test (6MWT), and echocardiographic parameters. Patients with cardiac or non-cardiac diseases limiting their ability to perform a 6MWT were excluded, with the final count totalling 155 patients [82% men, mean age 69 +/- 8 years, New York Heart Association (NYHA) functional class: II 22%, III 73.5%, IV 4.5%]. A total of 24 patients (15.5%) died of cardiovascular causes and one patient underwent heart transplantation during a mean follow-up of 24.4 +/- 18.1 months. Univariate analysis showed that NYHA class, distance walked in the 6MWT, left atrial diameter, digoxine and left ventricle (LV) ejection fraction were all significantly related to rates of mortality. Multivariate Cox regression after adjustment for the presence of a defibrillator showed that the LV ejection fraction [HR 0.91 (95% CI: 0.84-0.98) P = 0.008] and 6MWT distance <225 m [HR 5.6 (95% CI: 1.2-25.3) P = 0.026] were independent predictors of cardiovascular mortality., Conclusion: Baseline functional capacity, measured by the 6MWT distance, and LV ejection fraction are independent predictors of mortality in moderate to severe CHF patients, despite CRT. A 6MWT distance walked of <225 m identifies patients at high risk of cardiovascular death at mid-long term.

The Spanish Post-Heart-Transplant Tumour Registry comprises data on neoplasia following heart transplantation (HT) for all Spanish HT patients (1984-2003). This retrospective analysis of 3393 patients investigated the incidence and prognosis of neoplasia, and the influence of antiviral prophylaxis. About 50% of post-HT neoplasias were cutaneous, and 10% lymphomas. The cumulative incidence of skin cancers and other nonlymphoma cancers increased with age at HT and with time post-HT (from respectively 5.2 and 8.9 per 1000 person-years in the first year to 14.8 and 12.6 after 10 years), and was greater among men than women. None of these trends held for lymphomas. Induction therapy other than with IL2R-blockers generally increased the risk of neoplasia except when acyclovir was administered prophylactically during the first 3 months post-HT; prophylactic acyclovir halved the risk of lymphoma, regardless of other therapies. Institution of MMF during the first 3 months post-HT reduced the incidence of skin cancer independently of the effects of sex, age group, pre-HT smoking, use of tacrolimus in the first 3 months, induction treatment and antiviral treatment. Five-year survival rates after first tumor diagnosis were 74% for skin cancer, 20% for lymphoma and 32% for other tumors.

Background: Lymphoma after heart transplantation (HT) has been associated with induction therapy and herpesvirus infection. It is not known whether anti-viral agents administered immediately after HT can reduce the incidence of lymphoma., Methods: This study was a retrospective review of 3,393 patients who underwent HT in Spain between 1984 and December 2003. Variables examined included development of lymphoma and, as possible risk factors, recipient gender and age, induction therapies (anti-thymocyte globulin, OKT3 and anti-interleukin-2 receptor antibodies) and anti-viral prophylaxis (acyclovir or ganciclovir). To study the effect of evolving treatment strategy, three HT eras were considered: 1984 to 1995; 1996 to 2000; and 2001 to 2003., Results: Induction therapy was employed in >60% of HTs, and anti-viral prophylaxis in >50%. There were 62 cases of lymphoma (3.1 per 1,000 person-years, 95% confidence interval: 2.4 to 4.0). Univariate analyses showed no influence of gender, age at transplant, HT era, pre-HT smoking or the immunosuppressive maintenance drugs used in the first 3 months post-HT. The induction agent anti-thymocyte globulin (ATG) was associated with increased risk of lymphoma, and prophylaxis with acyclovir with decreased risk of lymphoma. Multivariate analyses (controlling for age group, gender, pre-HT smoking and immunosuppression in the first 3 months with mycophenolate mofetil and/or tacrolimus) showed that induction increased the risk of lymphoma if anti-viral prophylaxis was not used (regardless of induction agent and anti-viral agent), but did not increase the risk if anti-viral prophylaxis was used., Conclusions: Induction therapies with ATG or OKT3 do or do not increase the risk of lymphoma depending on whether anti-viral prophylaxis with acyclovir or ganciclovir is or is not employed, respectively.

Human herpesvirus 6 (HHV-6) infection is potentially life-threatening to immunosuppressed patients. There is a lack of information regarding the risk and the clinical manifestations of primary HHV-6 infection in solid-organ transplant recipients. We prospectively evaluated patients undergoing solid organ transplantation with negative immunoglobulin (Ig) G antibodies against HHV-6 by means of HHV-6 quantitative polymerase chain reaction. Among 193 recipients, seven were HHV-6 seronegative (prevalence 3.6%). We detected a positive HHV-6 viral load in only one patient, and four patients seroconverted after one year posttransplantation. The patient with a positive HHV-6 viral load developed cholestatic hepatitis without fever and did not experience severe end-organ disease. In conclusion, our findings show a low incidence of symptomatic primary HHV-6 infection among seronegative solid-organ transplant recipients.

Introduction and Objectives: Recent studies have shown that brain natriuretic peptide (BNP) and N-terminal proBNP (NT-proBNP) are useful in the diagnosis of heart failure in patients presenting with dyspnea. However, the cutoff values used with these markers vary according to patient characteristics and dyspnea severity. The aim of this study was to investigate the diagnostic accuracy of using the plasma NT-proBNP level for identifying heart failure in a heterogeneous population of patients with dyspnea., Methods: A multicentre study involving 247 consecutive patients with recent-onset dyspnea was carried out at 12 Spanish hospitals. Patients previously diagnosed with heart failure or any other condition known to cause dyspnea were excluded., Results: Of the 247 patients, 161 (65%) had heart failure. The remaining 86 (35%) presented with dyspnea of non-cardiac origin. Plasma NT-proBNP levels were higher in patients with heart failure (5600 [7988] pg/mL vs 1182 [4406] pg/mL; P=.0001), and increased as functional status deteriorated (P=.036). The area under the receiver operating characteristic curve was 0.87 (0.02) (95% CI, 0.81-0.91) for the optimum cutoff value of 1335 pg/mL. The sensitivity of this cutoff value for diagnosing heart failure was 77% (95% CI, 70%-83%), the specificity was 92% (95% CI, 84%-97%), the positive predictive value was 94%, and the negative predictive value was 68%., Conclusions: The plasma NT-proBNP concentration provides an accurate means of diagnosing heart failure. However, the negative predictive value found in this study was somewhat lower than the values found in previous studies involving more homogeneous patient populations.

Background and Objective: Heart transplant requires a heavy use of high cost resources. Economic data related to this procedure had not been specifically addressed and there are very few publications which analyze this topic. The aim of this study was to analyze the costs related to heart transplant in a series of patients from a single institution., Patients and Method: Data from all patients included in the Hospital Clínic heart transplant programme in which a cardiac transplant was effectively performed between 1999 and 2000 were analyzed, including one year of follow-up. Patients who died within this first year were also included. Organ procurement costs were excluded. Cost analysis was performed by micro-costing techniques., Results: A total of 21 patients undergoing a heart transplant were included. One year survival rate was 76%. Mean (standard deviation) of total cost (procedure costs + one year follow-up cost) was 59,349 (18,881) euros (range: 29,380-113,470 euros). Procedure mean cost was 41,724 (17,584) euros (70% of total costs) and one year follow up mean cost was 17,625 (10,096) euros (30% of total costs) per patient. When the initial episode (heart transplant procedure) was analyzed, main cost drivers were personnel costs euros 59% of all costs; mean: 24,795 (7,633) euros and treatment costs -20% of all costs; mean: 8,386 (7,250) euros., Conclusions: Costs of heart transplant in Barcelona (Spain) are similar to those published for other European Union countries, and well below the costs related to the procedure in the United States.

Prevalence, prognosis, and coronary anatomy associated with nontransmural myocardial infarction (MI) were prospectively assessed in 458 consecutive men admitted to our coronary care unit with a first MI. Cardiac catheterization was performed in 402 of the 436 survivors within 1 month of the acute event. Mean follow-up was 33 months (range 5 to 72). Nontransmural MI was diagnosed in 28 patients (6%). These patients were younger (46 +/- 10 versus 51 +/- 7 years, p less than 0.001) and had lower peak creatine kinase values (601 +/- 319 versus 1,141 +/- 923 U, p less than 0.01) and better ejection fraction (63 +/- 8 versus 46 +/- 14, p less than 0.001) than did their counterparts. Survivors of nontransmural MI also had fewer affected arteries (p less than 0.001) and a lower prevalence of total or subtotal occlusion (greater than 90%) in the involved artery (p less than 0.01). Mortality in the acute phase and long-term survival at 4 years (Kaplan-Meier) in patients with nontransmural MI (94%) were similar to those in patients with transmural MI (90%). The occurrence of new nonfatal coronary events was also similar in both groups of MI survivors. Thus, in the absence of symptoms, more aggressive management to improve survival does not seem warranted after nontransmural MI.

Prevalence of three-vessel disease was prospectively analyzed in a series of 462 consecutive infarct survivors aged 60 years or less. Eighty-seven percent (403) of the patients were catheterized within one month of the acute event, and were followed for a mean of 43 months (range 21 to 69). Three-vessel disease was present in 96 cases (24%) and these patients form the study population. The primary goals of this study were to determine the prevalence of three-vessel disease and to identify predictors of survival and new coronary events among this subset of infarct survivors. During follow-up, 15 patients died, 17 had a recurrent nonfatal infarction, and 54 developed angina (4-year probability of each cardiac event being 0.20, 0.22, and 0.59, respectively). Cox's stepwise multivariate analysis identified the ejection fraction (EF) as the only predictor of survival (p less than 0.001). No predictors for nonfatal ischemic events were found among the independent variables considered. Patients were stratified in risk categories according to the EF. Four-year probability of survival was 1.0 in participants with EF = greater than 50% (n = 23), 0.77 for those with EF = 21% to 49% (n = 66), and 0.22 in patients with more severe left ventricular dysfunction, EF = less than 20% (n = 7). Probability of occurrence of nonfatal reinfarction or angina was similar in the three risk categories. Thus, our results indicate that a normal ejection fraction is found in 25% of infarct survivors with three-vessel disease, and that this subset of patients has a low incidence of early and intermediate range coronary events.