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Resumen Antecedente y objetivo Los pacientes con insuficiencia cardiaca se caracterizan en 3 fenotipos en funcion de su fraccion de eyeccion ventricular izquierda. El proposito de este estudio fue comparar el perfil clinico, el tratamiento, el pronostico y las causas de muerte de los pacientes con insuficiencia cardiaca y fraccion de eyeccion ventricular izquierda reducida ( Metodologia Analisis de la informacion clinica recogida en un registro prospectivo de pacientes con insuficiencia cardiaca remitidos a una consulta monografica de Cardiologia entre 2010 y 2019. Resultados Se estudiaron 1.404 pacientes con IC-FEr, 239 pacientes con IC-FErm y 266 pacientes con IC-FEp. Se observaron diferencias significativas entre los 3 grupos en relacion con diversas caracteristicas clinicas, y en cuanto a la tasa de prescripcion de farmacos moduladores de la respuesta neurohormonal. La regresion de Cox multivariante revelo un incremento del riesgo de muerte por cualquier causa en los pacientes con IC-FEp (hazard-ratio 1,36; intervalo de confianza al 95% 1,03-1,80; p = 0,028) e IC-FErm (hazard-ratio 1,36; intervalo de confianza al 95% 1,03-1,78; p = 0,029) en comparacion con los pacientes con IC-FEr. La insuficiencia cardiaca fue la causa mas frecuente de muerte en los 3 grupos; se observo un mayor peso relativo de la muerte subita en los pacientes con IC-FEr, mientras que las causas no cardiovasculares de muerte tuvieron un peso relativo mayor en los pacientes con IC-FEp e IC-FErm. Conclusiones El estudio confirma la existencia de diferencias significativas en el perfil clinico, manejo terapeutico, pronostico y causas de muerte de los pacientes con IC-FEr, IC-FErm e IC-FEp.

BackgroundThe Molecular Microscope (MMDx) system classifies heart transplant endomyocardial biopsies as No-rejection (NR), Early-injury, T cell-mediated (TCMR), antibody-mediated (ABMR), mixed, and possible rejection (possible TCMR, possible ABMR). Rejection-like gene expression patterns in NR biopsies have not been described. We extended the MMDx methodology, using a larger data set, to define a new "Minor" category characterized by low-level inflammation in non-rejecting biopsies.MethodsUsing MMDx criteria from a previous study, molecular rejection was assessed in 1,320 biopsies (645 patients) using microarray expression of rejection-associated transcripts (RATs). Of these biopsies, 819 were NR. A new archetypal analysis model in the 1,320 data set split the NRs into NR-Normal (N = 462) and NR-Minor (N = 359).ResultsCompared to NR-Normal, NR-Minor were more often histologic TCMR1R, with a higher prevalence of donor-specific antibody (DSA). DSA positivity increased in a gradient: NR-Normal 24%; NR-Minor 34%; possible ABMR 42%; ABMR 66%. The top 20 transcripts distinguishing NR-Minor from NR-Normal were all ABMR-related and/or IFNG-inducible, and also exhibited a gradient of increasing expression from NR-Normal through ABMR. In random forest analysis, TCMR and Early-injury were associated with reduced LVEF and increased graft loss, but NR-Minor and ABMR scores were not. Surprisingly, hearts with MMDx ABMR showed comparatively little graft loss.ConclusionsMany heart transplants currently diagnosed as NR by histologic or molecular assessment have minor increases in ABMR-related and IFNG-inducible transcripts, associated with DSA positivity and mild histologic inflammation. These results suggest that low-level ABMR-related molecular stress may be operating in many more hearts than previously estimated. (ClinicalTrials.gov #NCT02670408).

The INTERHEART study (ClinicalTrials.gov #NCT02670408) used genome-wide microarrays to detect rejection in endomyocardial biopsies; however, many heart transplants with no rejection have late dysfunction and impaired survival. We used the microarray measurements to develop a molecular classification of parenchymal injury.In 1320 endomyocardial biopsies from 645 patients previously studied for rejection-associated transcripts, we measured the expression of 10 injury-induced transcript sets: 5 induced by recent injury; 2 reflecting macrophage infiltration; 2 normal heart transcript sets; and immunoglobulin transcripts, which correlate with time. We used archetypal clustering to assign injury groups.Injury transcript sets correlated with impaired function. Archetypal clustering based on the expression of injury transcript sets assigned each biopsy to 1 of 5 injury groups: 87 Severe-injury, 221 Late-injury, and 3 with lesser degrees of injury, 376 No-injury, 526 Mild-injury, and 110 Moderate-injury. Severe-injury had extensive loss of normal transcripts (dedifferentiation) and increase in macrophage and injury-induced transcripts. Late-injury was characterized by high immunoglobulin transcript expression. In Severe- and Late-injury, function was depressed, and short-term graft failure was increased, even in hearts with no rejection. T cell-mediated rejection almost always had parenchymal injury, and 85% had Severe- or Late-injury. In contrast, early antibody-mediated rejection (AMR) had little injury, but late AMR often had the Late-injury state.Characterizing heart transplants for their injury state provides new understanding of dysfunction and outcomes and demonstrates the differential impact of T cell-mediated rejection versus AMR on the parenchyma. Slow deterioration from AMR emerges as a major contributor to late dysfunction.

Whereas multiple national, international, and trial registries for heart failure have been created, international standards for clinical assessment and outcome measurement do not currently exist. The working group’s objective was to facilitate international comparison in heart failure care, using standardized parameters and meaningful patient-centered outcomes for research and quality of care assessments. The International Consortium for Health Outcomes Measurement recruited an international working group of clinical heart failure experts, researchers, and patient representatives to define a standard set of outcomes and risk-adjustment variables. This was designed to document, compare, and ultimately improve patient care outcomes in the heart failure population, with a focus on global feasibility and relevance. The working group employed a Delphi process, patient focus groups, online patient surveys, and multiple systematic publications searches. The process occurred over 10 months, employing 7 international teleconferences. A 17-item set has been established, addressing selected functional, psychosocial, burden of care, and survival outcome domains. These measures were designed to include all patients with heart failure, whether entered at first presentation or subsequent decompensation, excluding cardiogenic shock. Sources include clinician report, administrative data, and validated patient-reported outcome measurement tools: the Kansas City Cardiomyopathy Questionnaire; the Patient Health Questionnaire-2; and the Patient-Reported Outcomes Measurement Information System. Recommended data included those to support risk adjustment and benchmarking across providers and regions. The International Consortium for Health Outcomes Measurement developed a dataset designed to capture, compare, and improve care for heart failure, with feasibility and relevance for patients and clinicians worldwide., Central Illustration, Highlights • ICHOM seeks to help standardize and align outcome measurement efforts globally. • Standardization and alignment of this sort does not exist for heart failure. • The heart failure working group developed a standard set of 17 outcomes to be measured. • ICHOM hopes this standardization effort will increase quality and value in heart failure care.

[Abstract] The accepted use of left ventricular assist device (LVAD) technology as a good alternative for the treatment of patients with advanced heart failure together with the improved survival of the LVAD-supported patients on the device and the scarcity of donor hearts has significantly increased the population of LVAD-supported patients. The expected and non-expected device-related and patient-device interaction complications impose a significant burden on the medical system exceeding the capacity of the LVAD implanting centres. The ageing of the LVAD-supported patients, mainly those supported with the 'destination therapy' indication, increases the risk for those patients to experience comorbidities common in the older population. The probability of an LVAD-supported patient presenting with medical emergency to a local emergency department, internal, or surgical ward of a non-LVAD implanting centre is increasing. The purpose of this trilogy is to supply the immediate tools needed by the non-LVAD specialized physician: ambulance clinicians, emergency ward physicians, general cardiologists, internists, anaesthesiologists, and surgeons, to comply with the medical needs of this fast-growing population of LVAD-supported patients. The different issues discussed will follow the patient's pathway from the ambulance to the emergency department and from the emergency department to the internal or surgical wards and eventually to the discharge home from the hospital back to the general practitioner. In this first part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, after the introduction on the assist devices technology in general, definitions and structured approach to the assessment of the LVAD-supported patient in the ambulance and emergency department is presented including cardiopulmonary resuscitation for LVAD-supported patients.

[Abstract] The improvement in left ventricular assist device (LVAD) technology and scarcity of donor hearts have increased dramatically the population of the LVAD-supported patients and the probability of those patients to present to the emergency department with expected and non-expected device-related and patient-device interaction complications. The ageing of the LVAD-supported patients, mainly those supported with the 'destination therapy' indication, increases the risk for those patients to suffer from other co-morbidities common in the older population. In this second part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, definitions and structured approach to the LVAD-supported patient presenting to the emergency department with bleeding, neurological event, pump thrombosis, chest pain, syncope, and other events are presented. The very challenging issue of declaring death in an LVAD-supported patient, as the circulation is artificially preserved by the device despite no other signs of life, is also discussed in detail.

Purpose The INTERHEART study previously used microarray assessment of 889 heart transplant biopsies to develop the Molecular Microscope Diagnostic System (MMDx) based on expression of rejection-associated transcripts (RATs). The present study reclassified the rejection-related states in an expanded set of 1320 prospectively collected biopsies from 645 patients from 13 centers. Methods Biopsies were classified by ensembles of classifiers and analyzed for left ventricular ejection fraction (LVEF) and survival. Results New algorithms identified 853 No rejection (NR), 179 ABMR, 76 TCMR, 13 Mixed, 161 possible ABMR (pABMR), and 38 possible TCMR (pTCMR). No rejection was subclassified as NR-Normal 462, NR-Minor 359, and NR-Early-injury 32 (Figure 1A). Compared to NR-Normal, NR-Minor biopsies had mild elevation of many inflammation transcripts (e.g. IFNG-inducible genes) and to a lesser extent parenchymal injury transcripts. NR-minor biopsies were often designated as TCMR1R by histology. In all NR biopsies, NR-Minor scores and histologic TCMR1R increased through the first year, peaking about one year, suggesting that Minor inflammation is a late response to injury, unrelated to rejection. LVEF was similar in NR-Normal and NR-Minor but depressed in TCMR and Early injury. In a 3-year post-biopsy survival analysis, NR-Minor and NR-Normal had similar survival. TCMR and Early-injury were associated with increased graft loss, but many losses were not related to rejection. Surprisingly, 76 hearts with ABMR (149 biopsies) and follow-up data had only 3 losses within 3 years post-biopsy (Figure 1B). Conclusion Many biopsies with molecular no rejection develop minor increases in rejection-related transcripts in the first year, often called TCMR1R by histology, with no apparent effects on function or survival. An unexpected finding was that molecular ABMR was associated with very few graft losses over three years. (ClinicalTrials.gov #NCT02670408).

[Abstract] The growing population of left ventricular assist device (LVAD)-supported patients increases the probability of an LVAD- supported patient hospitalized in the internal or surgical wards with certain expected device related, and patient-device interaction complication as well as with any other comorbidities requiring hospitalization. In this third part of the trilogy on the management of LVAD-supported patients for the non-LVAD specialist healthcare provider, definitions and structured approach to the hospitalized LVAD-supported patient are presented including blood pressure assessment, medical therapy of the LVAD supported patient, and challenges related to anaesthesia and non-cardiac surgical interventions. Finally, important aspects to consider when discharging an LVAD patient home and palliative and end-of-life approaches are described.

Importance Heart failure with reduced ejection fraction is a progressive clinical syndrome, and many patients’ condition worsen over time despite treatment. Patients with more severe disease are often intolerant of available medical therapies. Objective To evaluate the efficacy and safety of omecamtiv mecarbil for the treatment of patients with severe heart failure (HF) enrolled in the Global Approach to Lowering Adverse Cardiac Outcomes Through Improving Contractility in Heart Failure (GALACTIC-HF) randomized clinical trial. Design, Setting, and Participants The GALACTIC-HF study was a global double-blind, placebo-controlled phase 3 randomized clinical trial that was conducted at multiple centers between January 2017 and August 2020. A total of 8232 patients with symptomatic HF (defined as New York Heart Association symptom class II-IV) and left ventricular ejection fraction of 35% or less were randomized to receive omecamtiv mecarbil or placebo and followed up for a median of 21.8 months (range, 15.4-28.6 months). The current post hoc analysis evaluated the efficacy and safety of omecamtiv mecarbil therapy among patients classified as having severe HF compared with patients without severe HF. Severe HF was defined as the presence of all of the following criteria: New York Heart Association symptom class III to IV, left ventricular ejection fraction of 30% or less, and hospitalization for HF within the previous 6 months. Interventions Participants were randomized at a 1:1 ratio to receive either omecamtiv mecarbil or placebo. Main Outcomes and Measures The primary end point was time to first HF event or cardiovascular (CV) death. Secondary end points included time to CV death and safety and tolerability. Results Among 8232 patients enrolled in the GALACTIC-HF clinical trial, 2258 patients (27.4%; mean [SD] age, 64.5 [11.6] years; 1781 men [78.9%]) met the specified criteria for severe HF. Of those, 1106 patients were randomized to the omecamtiv mecarbil group and 1152 to the placebo group. Patients with severe HF who received omecamtiv mecarbil experienced a significant treatment benefit for the primary end point (hazard ratio [HR], 0.80; 95% CI, 0.71-0.90), whereas patients without severe HF had no significant treatment benefit (HR, 0.99; 95% CI, 0.91-1.08;P = .005 for interaction). For CV death, the results were similar (HR for patients with vs without severe HF: 0.88 [95% CI, 0.75-1.03] vs 1.10 [95% CI, 0.97-1.25];P = .03 for interaction). Omecamtiv mecarbil therapy was well tolerated in patients with severe HF, with no significant changes in blood pressure, kidney function, or potassium level compared with placebo. Conclusions and Relevance In this post hoc analysis of data from the GALACTIC-HF clinical trial, omecamtiv mecarbil therapy may have provided a clinically meaningful reduction in the composite end point of time to first HF event or CV death among patients with severe HF. These data support a potential role of omecamtiv mecarbil therapy among patients for whom current treatment options are limited. Trial Registration ClinicalTrials.gov Identifier:NCT02929329

There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed.

Background Acute Cellular Rejection (ACR) remains a major complication in heart transplantation (HT). Since 1970, endomyocardial biopsy (EMB) has been the gold standard for ACR early detection. However, this invasive procedure has several limitations such as risk of complications, interobserver variability, false negative results and high cost. Therefore, a new non-invasive ACR biomarker is needed. Potential candidates could be microRNAs (miRs), small regulatory RNAs whose serum expression profiling could be modified in ACR patients. The aim of this study is the identification of differentially serum miRs expression patterns in ACR after HT. Methods Among HT performed in our Hospital (2013–2018), we selected patients with following criteria: i) “0R → 2R → 0R” EMB pattern for ACR (0R=no ACR, 2R=moderate ACR); ii) no antibody mediated rejection; iii) serum collected the same day as the EMBs. The 3 serum samples per patient matched in time with EMB were called “0Rs1 → 2Rs2 → 0Rs3”. In each of these serum samples, 179 miRs expression profile according manufacturer's instructions were analysed. Global Mean (GM) method was used to normalize our results expressed as miRs relative expression [2(–ΔCq)]. Expression pattern was defined as a 2 steps process: a significative rise (0Rs1 → 2Rs2) followed by a significative fall (2Rs2 → 0Rs3), or vice versa, in miR expression. Analysis of differences between 3 groups were calculated using one-way ANOVA with matched data and post-hoc Tukey test. ROC curve was generated for selected miRNA. A two-sided p Results 21 patients and their serum “0Rs1 → 2Rs2 → 0Rs3” samples were included in the study. Among 179 miRs analysed, 5 miRs showed significative difference between 0Rs1 and 2Rs2, 3 miRs were over-expressed (miR-181a-5p, miR-339-3p, let-7f-5p) and 2 under-expressed (miR-505-3p, miR-2110). Only miR-181a-5p met significative difference between 2Rs2 and 0Rs3 showing a statistical significative rise/fall pattern. Serum miR-181a-5p ROC analysis demonstrated significant discrimination between biopsy proven ACR from no-ACR biopsy, AUC=0.692 (p=0.0335). Differentially expressed miRs Mean relative expression 2(–ΔCq) (95% CI) Adjusted p-value (ANOVA) AUC (95% CI) 0Rs1 2Rs2 0Rs3 0Rs1 vs 2Rs2 2Rs2 vs 0Rs3 0Rs1 vs 0Rs3 miR-181–5p 0.80 (0.60–1.02) 1.11 (0.90–1.31) 0.86 (0.71–1.01) 0.0194 0.0225 NS 0.692 (0.529–0,855) Relative Expression 2(–ΔCq) and AUC expressed as mean (95% Confident Interval). NS: not significative. Conclusion Our findings suggest miR-181a-5p as a novel serological biomarker for detecting ACR after HT. After this preliminary discovery phase, miR-181a-5p is currently in a new validation phase to demonstrate its diagnostic performance. Acknowledgement/Funding This work was supported by a grant from isciii (PI15/02224) and it is part of the of the “CIBERCV”. Co-financed with FEDER Funds

Background Malignancy is one of the leading causes of mortality in the long term follow up after heart transplantation (HT). Male sex has been described as an independent risk factor for developing cancer in this group of patients. However, the real incidence of all type of neoplasm and its impact prognosis in mortality in both group of sex remains unknown. Purpose The aim of this study was to assess the incidence of malignancy and the disparity in its relative weight as a cause of death between genders. Methods Observational longitudinal study of heart transplant patients from the Spanish post-HT Tumor registry (SPHTTR) who underwent HT in this country from 1984 to 2017. Re-transplant, combined transplant patients and those with survival less than 3 months since HT were excluded. Incidence and mortality rates per 1000 person-year for all tumors, skin cancer (including melanoma), lymphoma and non-skin solid malignancy (NSSM) were calculated for both groups of sex. The main end-point of the study was death for any causes related to cancer following HT. Survival curves since first diagnosis of neoplasia were constructed using Kaplan Meier estimates and comparisons among genders were performed using long-rank test. Results A total of 5865 patients (81.6% male, 18.4% female) were included in the analysis. Incidence and mortality rates in both genders are summarized in Table 1. Total cumulative incidence rate of all tumors, non-skin solid malignancy and lung cancer were higher in men patients (All tumors: 44.8 vs 25.7 per 1000 person-year; female to male RR 0.68, 95% CI 0.60–0.78, p Table 1 Type of tumor Female Male Female to Male Incidence RR Female to male mortality RR Incidence rate* Mortality rate* Incidence rate* Mortality rate* RR p-value RR p-value All tumors 25.7 (22.8–29.0) 94.0 (77.3–114.3) 44.8 (42.9–46.8) 129.6 (120.9–138.9) 0.68 (0.60–0.78) Figure 1 Conclusions Incidence of malignancy post-HT is higher in men than in women specially for skin cancer and de novo solid tumors. The relative weight of cancer as a cause of death was also higher in men than in women, furthermore, this could have impact prognosis in HT survivors.

Purpose End-stage heart failure (HF) is often associated with malnutrition and sarcopenia, both of them are related to adverse HF outcomes. Skeletal muscle mass and attenuation are predictors of mortality after continuous flow left ventricular devices (LVAD) implantation. Our purpose was to assess the prognostic impact of skeletal muscle mass on patients undergoing heart transplantation (HT). Methods Retrospective study of a single-center HT population, between 2009 and 2019. Patients > 18 years-old with a computed chest scan in the previous 6 months before HT were included. Multiorgan transplants were excluded. Unilateral pectoralis muscle mass indexed (PMMi) to body surface area and attenuation (by mean Hounsfield units [PHUm]) were measured in each patient. HT patients were classifiedin tertiles according to PMMi and PHUm and characteristics of patients were compared by Chi-square, t-student and Kruskall-Wallis. Multivariate Cox regression analyses were performed to assess the impact of preoperative PMMi and PHUm on survival after HT. Results 132 patients were included, mean age 58.9, 16.7% female, median follow-up 3.67 years (interquartile range 1.7-5.9 years). 41.7% of patients underwent urgent HT (1.5% INTERMACS 1 situation, 15.2% INTERMACS 2 and 28% INTERMACS 3). Both PMMi and PHUm were lower in females and for lowest weight recipients. Urgent HT frequency was similar between tertiles of PMMi, but recipients in the higher tertile of PHUm were more frequently transplanted in an urgent status (38.2% vs 21.8% in the lowest tertile, p= 0.029). 26 patients (19.7%) died during follow-up, 12 (9.1% of total cohort) during HT admission. In the Cox regression analyses, neither PMMi (HR 1.034, 95% CI 0.891-1.2, p= 0.659) nor PHUm (HR 1.02, 95% CI 0.992-1.050, p=0.160) were associated with an increased mortality. Only the needed of mechanical circulatory support and hemofiltration after HT were associated with a higher risk of death. Conclusion Among this single-center HT recipients population, neither lower PMMi nor lower PHUm were associated with worse outcomes after HT.

Purpose Heart Transplant (HT) patients need complex drug treatment for life: many drugs and several daily doses (usually 5 times a day). This complexity may make it difficult to adhere to the treatment, which is key to therapeutic success. In order to facilitate medication preparation, a Weekly Multi-Dose Pillbox (WMDP-5), 5 doses/day, was designed in our HT program. The aim is to assess the improvement in adherence and satisfaction with the use of the WMDP-5 within a multifactorial intervention. Methods Prospective single-center study started in April 2019. All HT patients were invited to participate. The multilevel intervention included the provision of the WMDP-5 as well as a training session with a specific video and information leaflets. The study was approved by regional ethics committee. To evaluate adherence, the Spanish version of BAASIS (Basel Assessment of Adherence with Immunosuppressive Medication Scale) Patient Questionnaire Interview and the Simplified Medication Adherence Questionnaire (SMAQ) were used at delivery and at the follow-up visit. A Likert Scale (1-5) evaluate satisfaction at the follow-up visit (the next one to the center ≥ 1 months after using the WMDP). Patients with the follow-up visit until October 2019 were analyzed. Results A total of 214 HT patients (mean age 61,8±12,89 years, 79,4% males, with mean time after HT of 9,86±6,9 years) were included in the analysis. The highest level of education was primary school in 45,3%, 67,3% were married and 85% lived with someone. According to the SMAQ, there were 156/214 (72.89%) adherents at baseline and 193/214 (90,2%) at follow-up visit (p=0.006). Of 58 non-adherent patients at the baseline visit, 47 (81%) were adherent (improved) at the follow-up visit; while of 156 adherents at the basal visit, only 10 (6,4%) became non-adherents (worsened). The BAASIS questionnaire documented an overall improvement. Thus, the fist BAASIS question (if any pill was forgotten) at the baseline visit was 8%, while at the follow-up visit was 1,7%. Finally, according to the Likert Scale, 71,5% of the patients responded that the WMDP-5 helped them to take the treatment well. Conclusion The use of a WMDP-5 in the context of a multilevel intervention improves therapeutic adherence in HT patients. It should be noted that this improvement occurs in a cohort of HT patients with already high adherence.

Background: Atrial fibrillation (AF) frequently coexists with heart failure (HF). Aim: To assess clinical characteristics and to identify predictors of one-year outcome of patients hospitalised for HF, depending on whether they were in sinus rhythm (SR) or had AF. Methods: The study included Polish patients hospitalised for HF, participating in the Heart Failure Pilot Survey of the European Society of Cardiology, who were followed for 12 months after discharge. Patients with paced heart rhythm were excluded from the study. The primary endpoint was all-cause death at 12 months. Results: The final analysis included 587 patients. AF occurred in 215 (36.6%) patients. Compared to patients in SR, patients with AF were older, more often had a history of previous HF hospitalisation, were characterised by a higher New York Heart Association (NYHA) class, higher heart rate, and lower diastolic blood pressure at hospital admission, and had higher serum creatinine and lower haemoglobin concentration at admission. In-hospital mortality was higher in AF patients compared to SR patients (5.1% vs. 2.4%, respectively), but the difference did not reach statistical significance (p = 0.1). The primary endpoint occurred in 41 of 215 AF patients (19.1%) and in 40 of 372 SR patients (10.8%; p = 0.006). In a multivariate analysis, predic­tors of the primary endpoint in AF patients were: higher NYHA class at hospital admission (p = 0.02), higher admission heart rate (p = 0.04), lower admission serum sodium concentration (p = 0.0001), and higher heart rate at discharge (p = 0.01). In patients with SR, independent predictors of the primary endpoint included: older age (p = 0.007), lower serum sodium concentration at admission (p = 0.0006), and higher heart rate at discharge (p = 0.008). Conclusions: Patients with HF and concomitant AF differ significantly from HF patients in SR. In the studied group of real-world HF patients, serum sodium concentration at hospital admission and heart rate at hospital discharge were independent prog­nostic factors in patients with AF and in patients in SR. In contrast to SR patients, heart rate at hospital admission in AF patients was also predictive of long-term mortality.

BACKGROUND. Because injury is universal in organ transplantation, heart transplant endomyocardial biopsies present an opportunity to explore response to injury in heart parenchyma. Histology has limited ability to assess injury, potentially confusing it with rejection, whereas molecular changes have potential to distinguish injury from rejection. Building on previous studies of transcripts associated with T cell–mediated rejection (TCMR) and antibody-mediated rejection (ABMR), we explored transcripts reflecting injury. METHODS. Microarray data from 889 prospectively collected endomyocardial biopsies from 454 transplant recipients at 14 centers were subjected to unsupervised principal component analysis and archetypal analysis to detect variation not explained by rejection. The resulting principal component and archetype scores were then examined for their transcript, transcript set, and pathway associations and compared to the histology diagnoses and left ventricular function. RESULTS. Rejection was reflected by principal components PC1 and PC2, and by archetype scores S2TCMR, and S3ABMR, with S1normal indicating normalness. PC3 and a new archetype score, S4injury, identified unexplained variation correlating with expression of transcripts inducible in injury models, many expressed in macrophages and associated with inflammation in pathway analysis. S4injury scores were high in recent transplants, reflecting donation-implantation injury, and both S4injury and S2TCMR were associated with reduced left ventricular ejection fraction. CONCLUSION. Assessment of injury is necessary for accurate estimates of rejection and for understanding heart transplant phenotypes. Biopsies with molecular injury but no molecular rejection were often misdiagnosed rejection by histology. TRAIL REGISTRATION. ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT02670408","term_id":"NCT02670408"}}NCT02670408 FUNDING. Roche Organ Transplant Research Foundation, the University of Alberta Hospital Foundation, and Alberta Health Services.

Background: Metformin is one of the antihyperglycaemic drugs, reducing the risk of major cardiovascular events, including fatal ones. Although it is formally contraindicated in moderate and severe functional stages of heart failure (HF), it is commonly used in patients with concomitant type 2 diabetes mellitus (T2DM). Aim: We sought to evaluate the effect of metformin and T2DM on total mortality and hospitalisation rates in patients with HF. Methods: This retrospective analysis included 1030 adult patients (> 18 years) with HF from the Polish section of the HF Long-Term Registry (enrolled between 2011 and 2014). Patients with T2DM (n = 350) were identified and divided into two groups: those receiving metformin and those not. Both groups were subjected to one-year follow-up. Results: Mean patient age was 65.3 ± 13.5 years, with the predominance of male sex (n = 726) and obesity (mean body mass index 30.3 ± 5.5 kg/m2) and mean left ventricular ejection fraction was 34.3% ± 14.1%. Among patients with T2DM (n = 350) only 135 (38.6%) were treated with metformin. During one-year follow-up, 128 patients with HF died, of whom 53 had T2DM (15.1% vs. 10.9%, hazard ratio [HR] 0.89, 95% confidence interval [CI] 0.87–0.91, p = 0.045). Metformin was associated with a lower mortality rate compared to other antihyperglycaemic agents (9.6% vs. 18.6%, HR 0.85; 95% CI 0.81–0.89, p = 0.023). There were no significant differences in the hospitalisation rate, including that due to HF decompensation, among patients treated with metformin and the remainder (53.5% vs. 40.0%, respectively HR 0.93, 95% CI 0.82–1.04, p = 0.433). Conclusions: Metformin treatment in patients with different degrees of HF and T2DM is associated with a reduction in mortality and does not affect the hospitalisation rate.

There is an unmet need for effective treatment strategies to reduce morbidity and mortality in patients with heart failure with preserved ejection fraction (HFpEF). Until recently, attention in patients with HFpEF was almost exclusively focused on the left side. However, it is now increasingly recognized that right heart dysfunction is common and contributes importantly to poor prognosis in HFpEF. More insights into the development of right heart dysfunction in HFpEF may aid to our knowledge about this complex disease and may eventually lead to better treatments to improve outcomes in these patients. In this position paper from the Heart Failure Association of the European Society of Cardiology, the Committee on Heart Failure with Preserved Ejection Fraction reviews the prevalence, diagnosis, and pathophysiology of right heart dysfunction and failure in patients with HFpEF. Finally, potential treatment strategies, important knowledge gaps and future directions regarding the right side in HFpEF are discussed.

PURPOSE: To assess and compare the prevalence of medication nonadherence (MNA) (implementation and persistence) to immunosuppressants and co-medications in heart transplant recipients. METHODS: MNA prevalence was assessed using the Basel Assessment of Adherence to Immunosuppressive Medications Scale (self-report) and compared using logistic regression in a 4-continent sample of 1397 heart transplant recipients from 36 heart transplant centers in 11 countries. FINDINGS: MNA was significantly (α = 0.05) higher to co-medications than to immunosuppressants (taking nonadherence: 23.9% vs 17.3%; odds ratio [OR] = 1.5; 95% CI, 1.30-1.73; drug holiday: 5.7% vs 1.9%; OR = 3.17; 95% CI, 2.13-4.73; dose alteration: 3.8% vs 1.6%; OR = 2.46; 95% CI, 1.49-4.06; and discontinuation: 2.6% vs 0.5%; OR = 5.15; 95% CI, 2.36-11.20). IMPLICATIONS: The observed MNA necessitates adherence-enhancing interventions encompassing the entire post-heart transplant medication regimen. ClinicalTrials.gov identifier: NCT01608477. ispartof: CLINICAL THERAPEUTICS vol:41 issue:1 pages:130-136 ispartof: location:United States status: published

Purpose In heart and kidney transplants, rejection is a major cause of graft loss. In kidneys, antibody-mediated rejection (ABMR) is more important than T cell-mediated rejection (TCMR), and molecules predict graft loss better than histology (JASN 26 (7):1711-1720, 2015). We examined the relative importance of ABMR vs TCMR in heart transplant endomyocardial biopsies (EMBs), and the molecules predicting graft survival. Methods The INTERHEART population includes 1219 transplant biopsies from 8 centers in Canada, USA, Australia and Europe. Gene expression was studied using microarrays, selecting the most recent biopsy per patient. Random forest classifiers were used to assess predictive accuracy and determine the importance of molecular predictors, including gene sets and scores from analyses in a reference set of 889 EMBs. Results We studied 3-year survival in 484 patients with follow-up times. Graft failure occurred in 60 patients. Median follow-up was 435 days; biopsies were mainly for indications. Surprisingly, TCMR was a greater short-term hazard than ABMR. The molecular archetype clusters for TCMR and injury (Fig. 1) had the highest risk of graft failure. Fig. 2 combines these clusters since they have similar characteristics. Conclusion Unlike kidneys, graft loss (particularly within one year) after EMB is highly associated with TCMR but not ABMR. TCMR may reflect failure of immunosuppression or non-adherence. This difference between the heart and renal transplant populations raises the possibility that TCMR is relatively more destructive, and ABMR less destructive, in heart than in kidney transplants. ClinicalTrials.gov # NCT02670408

We summarize the results of the most important research of the past decade on the post-transplant monitoring of heart transplant patients by gene expression profiling and the quantification of immunoactivity, donor-derived cell-free DNA and rejection-related microRNAs.

Purpose Gene expression profiling testing (GEP; AlloMap) and donor-derived cell free DNA (dd-cfDNA; AlloSure) each provide non-invasive means to detect possible heart allograft rejection, including acute cellular rejection (ACR). This report describes the performance of these two molecular diagnostic methods when used together. Methods A retrospective cohort of 26 heart transplant patients with endomyocardial biopsy-based diagnosis of grade 0 ACR were demographically matched to 27 patients with grade ≥ 2R ACR. The dd-cfDNA (%, AlloSure) and GEP (AlloMap, score 0-39) results were correlated with the biopsy-based diagnosis of ACR. Results Patients with ACR had significantly higher dd-cfDNA (0.48 vs. 0.07; P 0.2% and GEP scores > 34, we calculated a 26% sensitivity and 92% specificity, and an NPV of 98% and a PPV of 6%. When GEP Conclusion In surveillance of heart allograft recipients for rejection, consideration of dd-cfDNA levels together with GEP scores may improve patient management decisions.

This randomized, comparative, multinational phase 3b/4 study of patients 1-8 years postcardiac transplantation (mean 3.9 years) evaluated the effect of conversion from a calcineurin inhibitor (CNI) to sirolimus on renal function in patients with renal insufficiency. In total, 116 patients on CNI therapy with GFR 40-90 mL/min/1.73 m(2) were randomized (1:1) to sirolimus (n = 57) or CNI (n = 59). Intent-to-treat analysis showed the 1-year adjusted mean change from baseline in creatinine clearance (Cockcroft-Gault) was significantly higher with sirolimus versus CNI treatment (+3.0 vs. -1.4 mL/min/1.73 m(2) , respectively; p = 0.004). By on-therapy analysis, values were +4.7 and -2.1, respectively (p < 0.001). Acute rejection (AR) rates were numerically higher in the sirolimus group; 1 AR with hemodynamic compromise occurred in each group. A significantly higher treatment discontinuation rate due to adverse events (AEs; 33.3% vs. 0%; p < 0.001) occurred in the sirolimus group. Most common treatment-emergent AEs significantly higher in the sirolimus group were diarrhea (28.1%), rash (28.1%) and infection (47.4%). Conversion to sirolimus from CNI therapy improved renal function in cardiac transplant recipients with renal impairment, but was associated with an attendant AR risk and higher discontinuation rate attributable to AEs.

Chronic renal failure (CRF) due to calcineurin inhibitor (CNI) nephrotoxicity is a frequent complication among heart transplant (HT) recipients. Small studies have suggested that the introduction of mycophenolate mofetil (MMF) can help to reduce CNI doses thereby to maintaining or improving renal function. We conducted a 4-year, prospective, multicenter study in 89 maintenance HT recipients at 5.6 ± 2.7 years postgrafting who displayed CRF (serum creatinine1.4 mg/dL) and were undergoing treatment with cyclosporine and prednisone ± azathioprine. We introduced MMF and reduced cyclosporine to level below 100 ng/mL. Creatinine clearance (CrCl), acute rejection episodes, and survival were through retrospectively compared with a contemporary cohort of HT recipients who were not treated with MMF (control group; n = 38). After conversion to MMF, a rapid increase was observed in the CrCl, which was maintained over the follow-up: namely, CrCl at month 6 and at 4 years were 51.0 ± 15.6 and 54.1 ± 15.6 mL/min versus 41.9 ± 11.1 mL/min at baseline (P.0001). No renal function changes were observed among the control group. Acute rejection rates were 5.6% and 2.6% in the MMF versus control groups (P = NS) with 4-year survivals85%. In conclusion, the introduction of MMF allowed a safe reduction of cyclosporine and significantly improved renal function after 4 years.

Introduction and objectives: The Kansas City Cardiomyopathy Questionnaire (KCCQ) is specifically designed to evaluate quality of life in patients with chronic heart failure (CHF). The purpose of this study was to assess the reliability, validity, and responsiveness to change of the Spanish version of the KCCQ.

Introduction and objectives: The Kansas City Cardiomyopathy Questionnaire (KCCQ) is specifically designed to evaluate quality of life in patients with chronic heart failure (CHF). The purpose of this study was to assess the reliability, validity, and responsiveness to change of the Spanish version of the KCCQ. Methods: The multicenter study involved 315 patients with CHF. Patients were evaluated at baseline and at weeks 24 and 26. The KCCQ, the Minnesota Living with Heart Failure Questionnaire (MLHFQ), and the Short Form-36 (SF-36) were administered. Reliability was assessed in stable patients (n = 163) by examining test–retest and internal consistency measures between weeks 24 and 26. Validity was evaluated at baseline (n = 315) by determining how KCCQ scores varied with New York Heart Association functional class and by comparing scores with those on similar domains of the MLHFQ and SF-36. Responsiveness to change was assessed in patients who experienced significant clinical improvement between baseline and week 24 (n = 31) by determining the effect size. Results: Reliability coefficients ranged between 0.70 and 0.96 for the different domains. Mean KCCQ scores varied significantly with New York Heart Association functional class (P < .001). Correlations with

J.F. Delgado, N. Manito, L. Almenar, M. Crespo-Leiro, E. Roig, J. Segovia, J.A. Vazquez de Prada, E. Lage, J. Palomo, M. Camprecios, J.M. Arizon, J.L. Rodriguez-Lambert, T. Blasco, L. de la Fuente, D. Pascual, G. Rabago. Risk factors associated with cytomegalovirus infection in heart transplant patients: a prospective, epidemiological study Transpl Infect Dis 2011: 13: 136–144. All rights reserved 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

[Abstract] A multicenter cross-sectional study was conducted to determine the current heart transplant (HTx) outcomes in Spain. Clinical and functional status, health-related quality of life (HRQoL), social support, and caregiver burden were analyzed in 303 adult transplant recipients (77.9% males) living with one functioning graft. Mean age at time of HTx (SD) was 56.4 (11.4) years, and the reason for transplantation in all patients was congestive heart failure. All patients had received a first heart transplant 6 (± 1), 12 (± 2), 36 (± 6), 60 (± 10), or 120 (± 20) months previously. Participants completed the Kansas City Cardiomyopathy Questionnaire (KCCQ), the EQ-5D, the Duke-UNC Functional Social Support Questionnaire, and the Zarit Caregiver Burden Scale. Reasonable HRQoL, social support, and caregiver burden levels were found at all time points, although a slight decrease in HRQoL was recorded at 120 months (p ≤ 0.033). Multivariate regression analyses showed that complications, comorbidities, and hospitalizations were associated with HRQoL (EQ-5D: 48.4% of explained variance, F4,164 = 38.46, p < 0.001; KCCQ overall summary score: 45.0%, F3,198 = 54.073, p < 0.001). Patient functional capabilities and complications affected caregiver burden (p < 0.05). In conclusion, HTx patients reported reasonable levels of HRQoL with low caregiver burden. Clinical variables related to these outcomes included functional status, complications, and number of admissions.

Recent advances in care and management of heart failure have improved outcome, largely as a result of the developing evidence basis for medications, implantable devices and the organization of heart failure follow-up. Such developments have also increased the complexity of delivering and coordinating care. This has led to a change to the way in which heart failure services are organized and to the traditional role of the heart failure nurse. Nurses in many countries now provide a range of services that include providing care for patients with acute and with chronic heart failure, working in and across different sectors of care (inpatient, outpatient, community care, the home and remotely), organising care services around the face-to-face and the remote collection of patient data, and liaising with a wide variety of health-care providers and professionals. To support such advances the nurse requires a skill set that goes beyond that of their initial education and training. The range of nurses' roles across Europe is varied. So too is the nature of their educational preparation. This heart failure nurse curriculum aims to provide a framework for use in countries of the European Society of Cardiology. Its modular approach enables the key knowledge, skills, and behaviours for the nurse working in different care settings to be outlined and so facilitate nursing staff to play a fuller role within the heart failure team.

Barge-Caballero, E., Segovia-Cubero, J., Gonzalez-Vilchez, F., Delgado-Jimenez, J., Perez-Villa, F., Almenar-Bonet, L., Arizon-Del Prado, J.L., Lage-Galle, E., De La Fuente-Galan, L., Manito-Lorite, N., Sanz-Julve, M., Villa-Arranz, A., Lambert Rodriguez, J.L., Brossa-Loidi, V., Pascual-Figal, D., Muniz-Garcia, J., Crespo-Leiro, M.

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

s S113 S. Rao , C. Hayward, P. MacDonald, A. Jabbour, E. Kotlyar, A. Keogh. Heart and Lung Transplantation Unit, St Vincent’s Hospital, Sydney, Australia. Purpose: Since the broadening of age eligibility criteria for orthotropic heart transplantation (OHT) in 2006, there has been an increase in the number of transplants being performed in recipients 60 years and older. Outcomes for older patients have not been reassessed since this guideline change has occurred. Methods: We retrospectively reviewed the UNOS dataset to identify first time OHT recipients from 2006 onwards (n= 18,130). All cause mortality was assessed and modelled using Kaplan-Meier method, and comparison was made between those aged more 60 years vs 18-59 years. Further analysis within the older age group was performed between the 60 to 64 years, 65 to 70 years and ≥ 70 years. Results: Of the 18,130 patients identified, 35% were aged 60 years or more (n= 6,454). Within the older group, 53% were aged 60-64 (n= 3,420), 39% were aged 65-69 (n= 2,505) and 8% were aged 70 or older (n= 529). Survival at 30 days, 1 year and 5 years was 96%, 90% and 79% for the younger group and 96%, 88% and 77% for the older group (p < 0.001). There was no significant difference in survival within the older group (see table, p = 0.18). Conclusion: Recipient age has minimal impact on 5-year survival after heart transplantation in the current era. Broadening the transplant eligibility criteria for OHT has led to an increase in the number of OHT performed in older recipients; however appropriate selection of older patients has led significant improvement in survival in this group such that it now is similar to outcomes for younger patients prior to 2006.

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.

[Abstract] Objectives. We sought to investigate the potential impact of preoperative short-term mechanical circulatory support (MCS) with extracorporeal devices on postoperative outcomes after emergency heart transplantation (HT). Methods. We conducted an observational study of 669 patients who underwent emergency HT in 15 Spanish hospitals between 2000 and 2009. Postoperative outcomes of patients bridged to HT on short-term MCS (n = 101) were compared with those of the rest of the cohort (n = 568). Short-term MCS included veno-arterial extracorporeal membrane oxygenators (VA-ECMOs, n = 23), and both pulsatile-flow (n = 53) and continuous-flow (n = 25) extracorporeal ventricular assist devices (VADs). No patient underwent HT on intracorporeal VADs. Results. Preoperative short-term MCS was independently associated with increased in-hospital postoperative mortality (adjusted odds-ratio 1.75, 95% CI 1.05–2.91) and overall post-transplant mortality (adjusted hazard-ratio 1.60, 95% CI 1.15–2.23). Rates of major surgical bleeding, cardiac reoperation, postoperative infection and primary graft failure were also significantly higher among MCS patients. Causes of death and survival after hospital discharge were similar in MCS and non-MCS candidates. Increased risk of post-transplant mortality affected patients bridged on pulsatile-flow extracorporeal VADs (adjusted hazard-ratio 2.21, 95% CI 1.48–3.30) and continuous-flow extracorporeal VADs (adjusted hazard-ratio 2.24, 95% CI 1.20–4.19), but not those bridged on VA-ECMO (adjusted hazard-ratio 0.51, 95% CI 0.21–1.25). Conclusions. Patients bridged to emergency HT on short-term MCS are exposed to an increased risk of postoperative complications and mortality. In our series, preoperative bridging with VA-ECMO resulted in comparable post-transplant outcomes to those of patients transplanted on conventional support.