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Medicament de teràpia avançada; Medicament en investigació; Translacional (regulació) Medicamento de terapia avanzada; Medicamento en investigación; Traslacional (regulación) Advanced therapy medicinal product; Investigational medicinal product; Translational (regulation) A systematic and ordered product development program, in compliance with current quality and regulatory standards, increases the likelihood of yielding a successful advanced therapy medicinal product (ATMP) for clinical use as safe and effective therapy. As this is a novel field, little accurate information is available regarding the steps to be followed, and the information to be produced to support the development and use of an ATMP. Notably, successful clinical translation can be somewhat cumbersome for academic researchers. In this article, we have provided a summary of the available information, supported by our experience in Spain throughout the development of an ATMP for myocardial infarction, from the pre-clinical stage to phase I clinical trial approval. This work was supported by the Spanish Cell Therapy Network (TerCel) [RD16/0011/0006 and RD16/0011/0028]; and CIBER Cardiovascular [CB16/11/00403] projects, as a part of the National R&D&I Plan, and was co-funded by the ISCIII-Sub-Directorate General for Research Assessment and Promotion and the European Regional Development Fund (ERDF); the Government of Catalonia: Agency for Management of University and Research Grants (AGAUR) [2017-SGR-483 and 2017-SGR-719], PERIS Program (Health Department) [SLT002/16/00234 and SLT002/16/00209] and CERCA Program; La Caixa Banking Foundation; grants from the Spanish Ministry of Science, Innovation and Universities (MICINN) [SAF2017-84324-C2-1-R]; Institute of Health Carlos III (ISCIII) [PI18/00256, PIC18/00014, ICI19/00039, and PI19/01788], and cofunded by European Union (ERDF/ESF) - A way to build Europe. This work has also been funded by the Sociedad Española de Cardiología and by the Call for Expression of Interest (EoI) for Collaborative Projects on Regenerative Medicine 2019 of Center for Regenerative Medicine of Barcelona (CMR[B]). The funders of the study had no role in the study design, data collection, data analysis, data interpretation, or writing of the report.

Specific proteins and processes have been identified in post-myocardial infarction (MI) pathological remodeling, but a comprehensive understanding of the complete molecular evolution is lacking. We generated microarray data from swine heart biopsies at baseline and 6, 30, and 45 days after infarction to feed machine-learning algorithms. We cross-validated the results using available clinical and experimental information. MI progression was accompanied by the regulation of adipogenesis, fatty acid metabolism, and epithelial–mesenchymal transition. The infarct core region was enriched in processes related to muscle contraction and membrane depolarization. Angiogenesis was among the first morphogenic responses detected as being sustained over time, but other processes suggesting post-ischemic recapitulation of embryogenic processes were also observed. Finally, protein-triggering analysis established the key genes mediating each process at each time point, as well as the complete adverse remodeling response. We modeled the behaviors of these genes, generating a description of the integrative mechanism of action for MI progression. This mechanistic analysis overlapped at different time points; the common pathways between the source proteins and cardiac remodeling involved IGF1R, RAF1, KPCA, JUN, and PTN11 as modulators. Thus, our data delineate a structured and comprehensive picture of the molecular remodeling process, identify new potential biomarkers or therapeutic targets, and establish therapeutic windows during disease progression.

The administration of extracellular vesicles (EV) from mesenchymal stromal cells (MSC) is a promising cell-free nanotherapy for tissue repair after myocardial infarction (MI). However, the optimal EV delivery strategy remains undetermined. Here, we designed a novel MSC-EV delivery, using 3D scaffolds engineered from decellularised cardiac tissue as a cell-free product for cardiac repair. EV from porcine cardiac adipose tissue-derived MSC (cATMSC) were purified by size exclusion chromatography (SEC), functionally analysed and loaded to scaffolds. cATMSC-EV markedly reduced polyclonal proliferation and pro-inflammatory cytokines production (IFNγ, TNFα, IL12p40) of allogeneic PBMC. Moreover, cATMSC-EV recruited outgrowth endothelial cells (OEC) and allogeneic MSC, and promoted angiogenesis. Fluorescently labelled cATMSC-EV were mixed with peptide hydrogel, and were successfully retained in decellularised scaffolds. Then, cATMSC-EV-embedded pericardial scaffolds were administered in vivo over the ischemic myocardium in a pig model of MI. Six days from implantation, the engineered scaffold efficiently integrated into the post-infarcted myocardium. cATMSC-EV were detected within the construct and MI core, and promoted an increase in vascular density and reduction in macrophage and T cell infiltration within the damaged myocardium. The confined administration of multifunctional MSC-EV within an engineered pericardial scaffold ensures local EV dosage and release, and generates a vascularised bioactive niche for cell recruitment, engraftment and modulation of short-term post-ischemic inflammation., Graphical abstract Image 1, Highlights • A bioactive engineered scaffold can locally deliver EV to the infarcted myocardium. • Porcine cATMSC-EV promote endothelial cell recruitment and in vivo vascularization. • Porcine cATMSC-EV reduce inflammation, and macrophage and T cell infiltration.

Altres ajuts: This work was supported in part by Fundació La Marató de TV3 (201516-10, 201502-30), Societat Catalana de Cardiologia, "la Caixa" Banking Foundation. Altres ajuts: PERIS/SLT002-16-00234 Sacubitril/valsartan is a first-in-class angiotensin receptor-neprilysin inhibitor developed for the treatment of heart failure with reduced ejection fraction. Its benefits are achieved through the inhibition of neprilysin (NEP) and the specific blockade of the angiotensin receptor AT1. The many peptides metabolized by NEP suggest multifaceted potential consequences of its inhibition. We sought to evaluate the short-term changes in serum endorphin (EP) values and their relation with patients' physical functioning after initiation of sacubitril/valsartan treatment. A total of 105 patients with heart failure with reduced ejection fraction, who were candidates for sacubitril/valsartan treatment, were included in this prospective, observational, multicentre, and international study. In a first visit, and in agreement with current guidelines, treatment with angiotensin-converting enzyme inhibitors or angiotensin receptor blocker was replaced by sacubitril/valsartan because of clinical indication by the responsible physician. By protocol, patients were reevaluated at 30 days after the start of sacubitril/valsartan. Serum levels of α- (α-EP), γ-Endorphin (γ-EP), and soluble NEP (sNEP) were measured using enzyme-linked immunoassays. New York Heart Association (NYHA) functional class was used as an indicator of patient's functional status. Baseline median levels of circulating α-EP, γ-EP, and sNEP were 582 (160-772), 101 (37-287), and 222 pg/mL (124-820), respectively. There was not a significant increase in α-EP nor γ-EP serum values after sacubitril/valsartan treatment (P value = 0.194 and 0.102, respectively). There were no significant differences in sNEP values between 30 days and baseline (P value = 0.103). Medians (IQR) of Δα-EP, Δγ-EP, and ΔsNEP between 30 days and baseline were 9.3 (−34 − 44), −3.0 (−46.0 − 18.9), and 0 units (−16.4 − 157.0), respectively. In a pre-post sacubitril/valsartan treatment comparison, there was a significant improvement in NYHA class, with 36 (34.3%) patients experiencing improvement by at least one NYHA class category. Δα-EP and ΔsNEP showed to be significantly associated with NYHA class after 30 days of treatment (P = 0.014 and P < 0.001, respectively). Δα-EP was linear and significantly associated with NYHA class improvement after 30 days of sacubitril/valsartan treatment. These preliminary data suggest that beyond the haemodynamic benefits achieved with sacubitril/valsartan, the altered cleavage of endorphin peptides by NEP inhibition may participate in patients' symptoms improvement.

Resumen Introduccion y objetivos A nivel cerebral, el amiloide-beta participa en la fisiopatologia de trastornos cognitivos; en la circulacion, el papel del amiloide-beta es incierto pero podria estar relacionado con procesos de inflamacion esteril y senescencia. Se ha analizado la relacion entre concentraciones circulantes de amiloide-beta 1-40 (Aβ40), cognicion y mortalidad (global, cardiovascular y por insuficiencia cardiaca [IC]) en pacientes ambulatorios con IC. Metodos El Aβ40 circulante se midio en 939 pacientes consecutivos con IC. El estado cognitivo se evaluo con el cuestionario de Pfeiffer (ajustado al nivel educacional) en condiciones basales y durante el seguimiento. Se utilizaron analisis de regresion multiple de Cox y medidas de funcion (discriminacion, calibracion y reclasificacion), ajustando por riesgos competitivos para causas de muerte especificas. Resultados Durante 5.1 ± 2.9 anos, 471 pacientes murieron: 250 de causa cardiovascular y 131 por IC. La mediana de Aβ40 circulante fue de 519,1 pg/ml [Q1-Q3: 361,8-749,9 pg/ml]. La concentracion de Aβ40 correlaciono con la edad, indice de masa corporal, insuficiencia renal y clase funcional de la New York Heart Association (todas p Conclusiones Las concentraciones circulantes de Aβ40 no se asocian a trastorno cognitivo en la IC. Aβ40 fue predictor de mortalidad y podria indicar envejecimiento sistemico.

Allogeneic cell therapy; Haplotype frequency; Heart failure Teràpia cel·lular al·logènica; Freqüència haplotípica; Insuficiència cardíaca Terapia celular alogénica; Frecuencia haplotípica; Insuficiencia cardíaca AIMS: Cell therapy can be used to repair functionally impaired organs and tissues in humans. Although autologous cells have an immunological advantage, it is difficult to obtain high cell numbers for therapy. Well-characterized banks of cells with human leukocyte antigens (HLA) that are representative of a given population are thus needed. The present study investigates the HLA allele and haplotype frequencies in a cohort of heart failure (HF) patients. METHODS AND RESULTS: We carried out the HLA typing and the allele and haplotype frequency analysis in 247 ambulatory HF patients. We determined HLA class I (A, B, and C) and class II (DRB1 and DQB1) using next-generation sequencing technology. The allele frequencies were obtained using Python for Population Genomics (PyPop) software, and HLA haplotypes were estimated using HaploStats. A total of 30 HLA-A, 56 HLA-B, 23 HLA-C, 36 HLA-DRB1, and 15 HLA-DQB1 distinct alleles were identified within the studied cohort. The genotype frequencies of all five HLA loci were in Hardy-Weinberg equilibrium. We detected differences in HLA allele frequencies among patients when the etiological cause of HF was considered. There were a total of 494 five-loci haplotypes, five of which were present six or more times. Moreover, the most common estimated HLA haplotype was HLA-A*01:01, HLA-B*08:01, HLA-C*07:01, HLA-DRB1*03:01, and HLA-DQB1*02:01 (6.07% haplotype frequency per patient). Remarkably, the 11 most frequent haplotypes would cover 31.17% of the patients of the cohort in need of allogeneic cell therapy. CONCLUSIONS: Our findings could be useful for improving allogeneic cell administration outcomes without concomitant immunosuppression.

Aims: There is a need for alternative strategies that might avoid recurrent admissions in patients with heart failure. home telemonitoring (HTM) to monitor patient's symptoms from a distance may be useful. This study attempts to assess changes in HTM vital signs in response to daily life activities (variations in medication, salt intake, exercise, and stress) and to establish which variations affect weight, blood pressure, and heart rate. Methods and results: We assessed 76 patients with heart failure (mean age 76 ± 10.8 years, 75% male, mainly in NYHA class II/III and from ischaemic aetiology cause). Patients were given a calendar of interventions scheduling activities approximately twice a week before measuring their vital signs. Eating salty food or a large meal were the activities that had a significant impact on weight gain (+0.3 kg; P

Background Although frailty has been associated with increased risks for hospitalization and mortality in chronic heart failure, the precise average effect remains uncertain. We performed a systematic review and meta‐analysis to summarize the hazards for mortality and incident hospitalization in patients with heart failure and frailty compared with those without frailty and explored the heterogeneity underlying the effect size estimates. Methods and Results MEDLINE , EMBASE, and Cochrane databases were queried for articles published between January 1966 and March 2018. Predefined selection criteria were used. Hazard ratios ( HRs ) were pooled for meta‐analyses, and where odds ratios were used previously, original data were recalculated for HR . Overlapping data were consolidated, and only unique data points were used. Study quality and bias were assessed. Eight studies were included for mortality (2645 patients), and 6 studies were included for incident hospitalization (2541 patients) during a median follow‐up of 1.82 and 1.12 years, respectively. Frailty was significantly associated with an increased hazard for mortality ( HR , 1.54; 95% confidence interval, 1.34–1.75; P HR , 1.56; 95% confidence interval, 1.36–1.78; P HR , 1.80; 95% confidence interval, 1.41–2.28; P HR , 1.57; 95% confidence interval, 1.30–1.89; P 2 =0%), and high quality of studies was verified by the Newcastle‐Ottawa scale. Conclusions Overall, the presence of frailty in chronic heart failure is associated with an increased hazard for death and hospitalization by ≈1.5‐fold.

Objective: To assess the effects of comorbidities, fragility, and quality of life (QOL) on long-term prognosis in ambulatory patients with heart failure (HF) with midrange left ventricular ejection fraction (HFmrEF), an unexplored area. Patients and Methods: Consecutive patients prospectively evaluated at an HF clinic between August 1, 2001, and December 31, 2015, were retrospectively analyzed on the basis of left ventricular ejection fraction category. We compared patients with HFmrEF (n=185) to those with reduced (HFrEF; n=1058) and preserved (HFpEF; n=162) ejection fraction. Fragility was defined as 1 or more abnormal evaluations on 4 standardized geriatric scales (Barthel Index, Older Americans Resources and Services scale, Pfeiffer Test, and abbreviated-Geriatric Depression Scale). The QOL was assessed with the Minnesota Living with Heart Failure Questionnaire. A comorbidity score (0-7) was constructed. All-cause death, HF-related hospitalization, and the composite end point of both were assessed. Results: Comorbidities and QOL scores were similar in HFmrEF (2.41±1.5 and 30.1±18.3, respectively) and HFrEF (2.30±1.4 and 30.8±18.5, respectively) and were higher in HFpEF (3.02±1.5, P

Summary Background & aims There is no consensus on the best method for nutritional screening and assessment in patients with heart failure (HF). This study aimed to determine which nutritional assessment method had the highest prognostic significance for patients with HF treated in outpatient clinics. We also aimed to identify a fast, reliable screening method for detecting malnutrition in these patients. Methods This prospective study included 151 subjects that attended an outpatient HF clinic at a university hospital. All patients completed three nutritional screening tools: the Malnutrition Universal Screening Tool (MUST), the MNA-short form (MNA-SF), and the Malnutrition Screening Tool (MST), and then, two nutritional assessment questionnaires: the Subjective Global Assessment (SGA) and the Mini Nutritional Assessment®(MNA). Patients were followed-up for 2 years. The primary endpoint was all-cause mortality. Results Malnutrition or nutritional risk was identified in 15.9% of patients with the SGA and in 25.1% of patients with the MNA. Age, New York Heart Association (NYHA) functional class, and MNA were the only independent all-cause death predictors after adjusting for age, gender, NYHA functional class, body mass index, Barthel index, 25-hydroxyvitamin D concentrations, treatment with angiotensin converting enzyme inhibitors or angiotensin II receptor blockers, and treatment with beta-blockers. The SGA could not independently predict all-cause mortality in a multivariate analysis that included the same covariates. The MNA-SF had the best sensitivity, specificity, and kappa coefficient for screening malnutrition, based on the MNA and the SGA as references, compared to the other screening methods. Conclusions In our cohort, malnutrition assessed by MNA, but not by SGA, was an independent predictor of mortality. MNA-SF showed remarkable sensitivity and specificity; thus, it might be a valuable tool for rapidly identifying malnutrition risk in outpatients with HF.

INTRODUCTION AND OBJECTIVES: Neprilysin breaks down numerous vasoactive peptides. The soluble form of neprilysin, which was recently identified in heart failure, is associated with cardiovascular outcomes. Within a multibiomarker strategy, we directly compared soluble neprilysin and N-terminal pro-B-type natriuretic peptide as risk stratifiers in a real-life cohort of heart failure patients. METHODS: Soluble neprilysin, N-terminal pro-B-type natriuretic peptide, ST2, and high-sensitivity troponin T levels were measured in 797 consecutive ambulatory heart failure patients followed up for 4.7 years. Comprehensive multivariable analyses and soluble neprilysin vs N-terminal pro-B-type natriuretic peptide head-to-head assessments of performance were performed. A primary composite endpoint included cardiovascular death or heart failure hospitalization. A secondary endpoint explored cardiovascular death alone. RESULTS: Median soluble neprilysin and N-terminal pro-B-type natriuretic peptide concentrations were 0.64ng/mL and 1187 ng/L, respectively. Both biomarkers significantly correlated with age (P

Resumen Introduccion y objetivos La neprilisina degrada numerosos peptidos vasoactivos. La forma soluble de neprilisina, que se ha identificado recientemente en la insuficiencia cardiaca, se asocia con eventos cardiovasculares. Se compararon de manera directa la neprilisina soluble y la fraccion aminoterminal del propeptido natriuretico cerebral como estratificadores de riesgo, dentro de una estrategia multimarcadores, en una cohorte de pacientes con insuficiencia cardiaca de la practica clinica real. Metodos Se determinaron las concentraciones de neprilisina soluble, la fraccion aminoterminal del propeptido natriuretico cerebral, ST2 y troponina T de alta sensibilidad en 797 pacientes ambulatorios consecutivos con insuficiencia cardiaca seguidos durante 4,7 anos. Se llevaron a cabo analisis multivariables exhaustivos y se realizaron comparaciones directas de neprilisina soluble frente a la fraccion aminoterminal del propeptido natriuretico cerebral mediante estadisticas de rendimiento. El objetivo final principal fue el compuesto por muerte cardiovascular u hospitalizacion por insuficiencia cardiaca. Un objetivo secundario exploro la muerte cardiovascular sola. Resultados Las medianas de concentracion de neprilisina soluble y la fraccion aminoterminal del propeptido natriuretico cerebral fueron de 0,64 ng/ml y 1.187 ng/l respectivamente. Ambos biomarcadores presentaron una correlacion significativa con la edad (p hazard ratio = 1,14; intervalo de confianza del 95%, 1,02-1,27; p = 0,03) y la muerte cardiovascular ( hazard ratio = 1,15; intervalo de confianza del 95%, 1,01-1,31; p = 0,04), pero no asi la fraccion aminoterminal del propeptido natriuretico cerebral. La comparacion directa de la neprilisina soluble con la fraccion aminoterminal del propeptido natriuretico cerebral puso de manifiesto buena calibracion y discriminacion y reclasificacion similares con ambos biomarcadores neurohormonales, pero solo la neprilisina soluble mejoro la bondad de ajuste global. Conclusiones La neprilisina soluble mantuvo el valor pronostico independiente al incluirlo en una estrategia multimarcadores, mientras que la fraccion aminoterminal del propeptido natriuretico cerebral perdio la significacion en la estratificacion del riesgo en los pacientes ambulatorios con insuficiencia cardiaca. Ambos biomarcadores obtuvieron medidas de rendimiento similares en los analisis de comparacion directa.

Given the epidemic of readmissionsfor heart failure (HF) in western countries, new tools for congestion tracking are needed in the management of patients with HF. We previously presented a novel, wearable textile vest that could track decongestion during therapy for acutely decompensated HF (ADHF) in a cardiac ward. The vest wraps around the chest and has textile electrodes placed on the lateral sides so that multi-frequency measurements of bio-impedance can be taken of the whole chest. The vest data showed strong agreement with fluid loss as determined by weight changes and good correlation with changes in signs and symptom (HF severity score) [1]. Here,weassessedtheabilityofthisvesttoprovideadditionalinsight

Idiopathic dilated cardiomyopathy (IDCM) is a frequent cause of heart transplantation. Potentially valuable blood markers are being sought, andlow-density lipoprotein receptor-related protein 1 (LRP1) has been linked to the underlying molecular basis of the disease. This study comparedcirculating levels of soluble LRP1 (sLRP1) in IDCM patients and healthy controls and elucidated whether sLRP1 is exported out of the myocardiumthrough extracellular vesicles (EVs) to gain a better understanding of the pathogenesis of the disease. LRP1achain expression was analysed insamples collected from the left ventricles of explanted hearts using immunohistochemistry. sLRP1 concentrations were determined in platelet-freeplasma by enzyme-linked immunosorbent assay. Plasma-derived EVs were extracted by size-exclusion chromatography (SEC) and characterizedby nanoparticle tracking analysis and cryo-transmission electron microscopy. The distributions of vesicular (CD9, CD81) and myocardial (caveolin-3) proteins and LRP1achain were assessed in SEC fractions by flow cytometry. LRP1achain was preferably localized to blood vessels in IDCMcompared to control myocardium. Circulating sLRP1 was increased in IDCM patients. CD9- and CD81-positive fractions enriched with membranevesicles with the expected size and morphology were isolated from both groups. The LRP1achain was not present in these SEC fractions, whichwere also positive for caveolin-3. The increase in circulating sLRP1 in IDCM patients may be clinically valuable. Although EVs do not contribute tohigher sLRP1 levels in IDCM, a comprehensive analysis of EV content would provide further insights into the search for novel blood markers, This work was supported by grants from the Ministerio de Educación y Ciencia (SAF2014-59892-R), the Ministerio de Econom ıa yCompetitividad (Juan de la Cierva, JCI-2012-14025), Fundacio La MARATO de TV3 (201502, 201516, 201521_10), the Fundaci o Daniel Bravo Andreu, the Sociedad Española de Cardiología, the Societat Catalana de Cardiologia, the Generalitat de Catalunya (SGR 2014,CERCA Programme), and the Fundacio Bancaria La Caixa. This workwas also funded by the Red de Terapia Celular–TerCel (RD16/0011/0006), the CIBER Cardiovascular–(CB16/11/00403) and Fondo deInvestigaci on Sanitaria, Instituto de Salud Carlos III (FIS PI14/01682,FIS PI14/01729 and CD14/00109) as part of the Plan Nacional deI+D+I cofounded by ISCIII-Sudirecci on General de Evaluaci on y elFondo Europeo de Desarrollo Regional (FEDER)

IntroductionCardiac adipose tissue is a source of progenitor cells with regenerative capacity. Studies in rodents demonstrated that the intramyocardial delivery of cells derived from this tissue improves cardiac function after myocardial infarction (MI). We developed a new reparative approach for damaged myocardium that integrates the regenerative properties of cardiac adipose tissue with tissue engineering. In the adipose graft transposition procedure (AGTP), we dissect a vascularised flap of autologous pericardial adipose tissue and position it over the myocardial scarred area. Following encouraging results in acute and chronic MI porcine models, we performed the clinical trial (NCT01473433, AdiFLAP trial) to evaluate safety in patients with chronic MI undergoing coronary artery bypass graft. The good safety profile and trends in efficacy warranted a larger trial.Study designThe AGTP II trial (NCT02798276) is an investigator initiated, prospective, randomised, controlled, multicentre study to assess the efficacy of the AGTP in 108 patients with non-revascularisable MI. Patients will be assigned to standard clinical practice or the AGTP. The primary endpoint is change in necrotic mass ratio by gadolinium enhancement at 91 and 365 days. Secondary endpoints include improvement in regional contractibility by MRI at 91 and 365 days; changes in functional MRI parameters (left ventricular ejection fraction, left and right ventricular geometric remodelling) at 91 and 365 days; levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) at 7, 91 and 365 days; appearance of arrhythmias from 24 hour Holter monitoring at 24 hours, and at 91 and 365 days; all cause death or re-hospitalisation at 365 days; and cardiovascular death or re-hospitalisation at 365 days.Ethics and disseminationThe institutional review board approved the trial which will comply with the Declaration of Helsinki. All patients will provide informed consent. It may offer a novel, effective and technically simple technique for patients with no other therapeutic options. The results will be submitted to indexed medical journals and national and international meetings.Trial registration numberClinicalTrials.gov:NCT02798276, pre-results.

Background Heart failure (HF) is a chronic condition with poor prognosis, and has a high prevalence among older adults. Due to older age, fragility is often present among HF patients. However, even young HF patients show a high degree of fragility. The effect of fragility on long-term prognosis in HF patients, irrespective of age, remains unexplored. The aim of this study was to assess the influence of fragility on long-term prognosis in outpatients with HF. Methods and results At least one abnormal evaluation among four standardized geriatric scales was used to identify fragility. Predefined criteria for such scales were: Barthel Index, 3 (±1, depending on educational grade); and ≥1 positive response for depression on the abbreviated Geriatric Depression Scale (GDS). We assessed 1314 consecutive HF outpatients (27.8% women, mean age years 66.7±12.4years with different etiologies. Fragility was detected in 581 (44.2%) patients. 626 deaths occurred during follow-up; the median follow-up was 3.6years [P 25 –P 75 : 1.8–6.7] for the total cohort, and 4.9years [P 25 –P 75 : 2.5–8.4] for living patients. Fragility and its components were significantly associated with decreased survival by univariate analysis. In a comprehensive multivariable Cox regression analysis, fragility remained independently associated with survival in the entire cohort, and in age and left ventricular ejection fraction subgroups. Conclusion Fragility is a key determinant of survival in ambulatory patients with HF across all age strata.

Heart failure (HF) is a chronic disease that frequently causes quality of life (QoL) impairment. We aimed to evaluate whether fragility affects QoL perception in outpatients with HF across age strata. The Minnesota Living with Heart Failure Questionnaire (MLWHFQ) was used to assess QoL, and fragility was defined according to basic standardized geriatric scales. Predefined criteria for such scales were scores of Barthel index90, Older Americans' Resources and Services scale10 in women and6 in men, and Pfeiffer test3 (±1 depending on educational grade) and ≥1 positive depression response on the abbreviated Geriatric Depression Scale. We evaluated 1,405 consecutive outpatients with HF (27.8% women, median age 69 years [twenty-fifth to seventy-fifth percentiles: 59 to 76 years]). Fragility, defined as at least 1 abnormal evaluation, was detected in 621 patients (44.2%). A positive depression response on the abbreviated Geriatric Depression Scale was the most prevalent (31.2%) component of fragility. We found a strong correlation between MLWHFQ score and the presence of fragility and all fragility components (all p0.001). These associations prevailed in both younger (75 years) and older patients (≥75 years; all p values0.001 except for Pfeiffer test in younger patients [p = 0.007]). In multivariate regression analysis, QoL remained significantly associated with fragility after adjustment for age, gender, etiology of HF, left ventricular ejection fraction, New York Heart Association functional class, co-morbidities, and HF treatment, in both younger and older patients (p 0.001). In conclusion, MLWHFQ, a specific HF QoL questionnaire, is significantly influenced by fragility regardless of age.

Objective: Idiopathic dilated cardiomyopathy (IDCM) affects myocardial vascularization. Whether a lack of demand for increased myocardial vascularization and/or an impaired response of circulating angiogenic-supportive cells are responsible for the vascular derangements found in IDCM is unknown. Methods and results: Left ventricle (LV) samples obtained at transplant from IDCM hearts were compared to control hearts from non-cardiac decedents. Peripheral colony-forming myeloid cells were extracted from age- and sex-matched IDCM patients and healthy volunteers. At the tissue level, no differences were detected in stromal cell-derived factor (SDF)-1 alpha expression, but integrin-linked kinase (ILK) levels and activity were increased in IDCM. A marked co-localization of SDF-1 alpha and the specific marker of cholesterol-enriched lipid rafts Flotillin (Flot)-1 was found in IDCM. SDF-1 alpha was also highly distributed into IDCM lipid rafts. Non-adherent pro-angiogenic cells from both groups, which were found increased in patients but showed similar surface levels of CXCR-4, equally supported Matrigel-mediated cell network formation. However, SDF-1-mediated migration was reduced in IDCM-derived cells, which also exhibited decreased ILK activity and downstream ERK activation. Conclusions: Taken together, our results point out that myocardial competency to increase vascularization is not altered in IDCM, but dysfunctional SDF-1-mediated migration by peripheral pro-angiogenic cells through ILK and downstream ERK signaling may compromise endothelial recovery in patients. We provide new insights into lipid raft function in human IDCM and envision more effective treatments. (C) 2013 Elsevier Ireland Ltd. All rights reserved.

Aims Heart failure (HF) is a chronic condition that typically affects a patient's quality of life (QoL). Little is known about long-term QoL monitoring in HF. This study aimed to evaluate the temporal changes and prognostic value of QoL assessment in a real-life cohort of HF patients. Methods and results The Minnesota Living with Heart Failure Questionnaire was used to monitor QoL at baseline and at 1, 3, and 5 years for 1151 consecutive patients {71.7% men, median age 69 years [25th–75th percentiles (P25–P75) 59–76]} in an HF unit. Follow-up for prognosis assessment was extended to 6 years. The number of answered questionnaires was 1151 at baseline, 746 at 1 year, 268 at 3 years, and 240 at 5 years. QoL scores showed a steep decrease (indicating QoL improvement) during the first year [29 (P25–P75 16–43) at baseline vs. 15 (P25–P75 8–27) at 1 year, P < 0.001], which was tempered, yet significant up to 5 years [12 (P25–P75 7–23) at 3 years vs. 10 (P25–P75 5–21) at 5 years, P = 0.012]. We recorded 457 deaths during follow-up. In a comprehensive multivariable Cox regression analysis, baseline QoL remained a significant prognosticator during follow-up [hazard ratio (HR)Cox for death 1.012, 95% confidence interval 1.006–1.018, P < 0.001]. QoL monitoring showed that a score increase ≥10% between consecutive assessments stratified high-risk patients within the next 12 months (P = 0.008). Conclusion Both baseline and follow-up QoL monitoring were useful for patient risk stratification in a real-life HF cohort. Worse QoL may warn of a worse prognosis. Widespread QoL monitoring in routine clinical practice is recommended.

In the brain, amyloid-beta generation participates in the pathophysiology of cognitive disorders; in the bloodstream, the role of amyloid-beta is uncertain but may be linked to sterile inflammation and senescence. We explored the relationship between blood levels of amyloid-beta 1-40 peptide (Aβ40), cognition, and mortality (all-cause, cardiovascular, and heart failure [HF]-related) in ambulatory patients with HF.Bloodstream Aβ40 was measured in 939 consecutive patients with HF. Cognition was evaluated with the Pfeiffer questionnaire (adjusted for educational level) at baseline and during follow-up. Multivariate Cox regression analyses and measurements of performance (discrimination, calibration, and reclassification) were used, with competing risk for specific causes of death.Over 5.1 ± 2.9 years, 471 patients died (all-cause): 250 from cardiovascular causes and 131 HF-related. The median Aβ40 concentration was 519.1 pg/mL [Q1-Q3: 361.8-749.9 pg/mL]. The Aβ40 concentration correlated with age, body mass index, renal dysfunction, and New York Heart Association functional class (all P.001). There were no differences in Aβ40 in patients with and without cognitive impairment at baseline (P = .97) or during follow-up (P = .20). In multivariable analysis, including relevant clinical predictors and N-terminal pro-B-type natriuretic peptide, Aβ40 remained significantly associated with all-cause death (HR, 1.22; 95%CI, 1.10-1.35; P.001) and cardiovascular death (HR, 1.18; 95%CI, 1.03-1.36; P = .02), but not with HF-related death (HR, 1.13; 95%CI, 0.93-1.37; P = .22). Circulating Aβ40 improved calibration and patient reclassification.Blood levels of Aβ40 are not associated with cognitive decline in HF. Circulating Aβ40 was predictive of mortality and may indicate systemic aging.

Recently, a new surgical technique to rescue infarcted myocardium (AGTP) has already tested (NCT01473433, AdiFLAP Trial). Here, we present the new minimally invasive AGTP (mi-AGTP) by thoracoscopy.

Multi-frequency trans-thoracic bioimpedance (TTI) could be used to track fluid changes and congestion of the lungs, however, patient specific characteristics may impact the measurements. We investigated the effects of thoracic geometry and composition on measurements of TTI and developed an equation to calculate a personalized fluid index. Simulations of TTI measurements for varying levels of chest circumference, fat and muscle proportion were used to derive parameters for a model predicting expected values of TTI. This model was then adapted to measurements from a control group of 36 healthy volunteers to predict TTI and lung fluids (fluid index). Twenty heart failure (HF) patients treated for acute HF were then used to compare the changes in the personalized fluid index to symptoms of HF and predicted TTI to measurements at hospital discharge. All the derived body characteristics affected the TTI measurements in healthy volunteers and together the model predicted the measured TTI with 8.9% mean absolute error. In HF patients the estimated TTI correlated well with the discharged TTI (r = 0.73, p

The present study evaluates the safety and efficacy of the Adipose Graft Transposition Procedure (AGTP) as a biological regenerative innovation for patients with a chronic myocardial scar. This prospective, randomized single-center controlled study included 10 patients with established chronic transmural myocardial scars. Candidates for myocardial revascularization were randomly allocated into two treatment groups. In the control arm (n = 5), the revascularizable area was treated with CABG and the non-revascularizable area was left untouched. Patients in the AGTP-treated arm (n = 5) were treated with CABG and the non-revascularizable area was covered by a biological adipose graft. The primary endpoint was the appearance of adverse effects derived from the procedure including hospital admissions and death, and 24-hour Holter monitoring arrhythmias at baseline, 1 week, and 3 and 12 months. Secondary endpoints of efficacy were assessed by cardiac MRI. No differences in safety were observed between groups in terms of clinical or arrhythmic events. On follow-up MRI testing, participants in the AGTP-treated arm showed a borderline smaller left ventricular end systolic volume (LVESV; p = 0.09) and necrosis ratio (p = 0.06) at 3 months but not at 12 months. The AGTP-treated patient with the largest necrotic area and most dilated chambers experienced a noted improvement in necrotic mass size (− 10.8%), and ventricular volumes (LVEDV: − 55.2 mL and LVESV: − 37.8 mL at one year follow-up) after inferior AGTP. Our results indicate that AGTP is safe and may be efficacious in selected patients. Further studies are needed to assess its clinical value. (ClinicalTrials.org , AdiFlap Trial). The Adipose Graft Transposition Procedure (AGTP) is a new surgical technique for reducing the scar after a heart attack. It has been evaluated in 10 patients for the first time and has been proved to be safe. This technique consists on the use of the existing fat surrounding the heart that has beneficial properties. The procedure is easy for the surgeons to perform. The next step will be to test the efficacy in a larger population.

Background Among patients with heart failure (HF), body mass index (BMI) has been inversely associated with mortality, giving rise to the so-called obesity paradox. The aim of this study was to examine the relationship between BMI and two modes of cardiac death: pump failure death and sudden death. Methods Nine hundred seventy-nine patients with mild to moderate chronic symptomatic HF from the MUSIC (MUerte Subita en Insuficiencia Cardiaca) Study, a prospective, multicenter, and longitudinal study designed to assess risk predictors of cardiac mortality, were followed up during a median of 44 months. Independent predictors of death were identified by a multivariable Cox proportional hazards model. Results Higher BMI emerged as an independent predictor of all-cause mortality (hazard ratio [HR] = 0.94, 95% confidence interval [CI] = 0.91-0.97, P = .0003) and pump failure death (HR = 0.93, 95% CI=0.88-0.98, P = .004). Sudden death accounted for 45% of deaths in obese patients, 53% in overweight patients, and 37% in lean patients. No significant relationship between BMI and sudden death was observed (HR = 0.97, 95% CI=0.92-1.02, P = .28). The only independent predictors of sudden death were prior history of myocardial infarction (HR = 1.89, 95% CI=1.23-2.90, P = .004), hypertension (HR = 1.66, 95% CI=1.05-2.63, P = .03), left ventricular ejection fraction (HR = 0.88, 95% CI=0.79-0.96, P = .006), and N-terminal pro–B-type natriuretic peptide (HR = 1.01, 95% CI=1.00-1.02, P = .048). Conclusions The obesity paradox in HF affects all-cause mortality and pump failure death but not sudden death. The risk of dying suddenly was similar across BMI categories in this cohort of ambulatory patients with HF.

a ICREC Research Group, Health Research Institute Germans Trias i Pujol, Badalona, Spain b Department of Electronic Engineering, Technical University of Catalonia, Barcelona, Spain c Cardiology Service, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain d Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain e Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain

a Signal Processing Systems, Eindhoven University of Technology, The Netherlands b Philips Research, Eindhoven, The Netherlands c ICREC Research Program, Fundacio Institut d'Investigacio en Ciencies de la Salut Germans Trias i Pujol (IGTP), Badalona, Spain d Cardiology Service, Hospital Clinico Universitario de Valencia, Spain e Cardiology Service, Hospital Universitari Germans Trias i Pujol, Badalona, Spain f Department of Medicine, Universitat Autonoma de Barcelona, Barcelona, Spain

Summary Background & aims Nutritional assessment may help to explain the incompletely understood obesity paradox in patients with heart failure (HF). Currently, obesity is usually identified by body mass index (BMI). Our objective was to assess the prognostic influence of undernourishment in HF outpatients. Methods Two published definitions of undernourishment were used to assess 214 ambulatory HF patients. Definition 1 included albumin, total lymphocyte count, tricipital skinfold (TS), subscapular skinfold, and arm muscle circumference (AMC) measurements (≥2 below normal considered undernourishment). Definition 2 included TS, AMC, and albumin (≥1 below normal considered undernourishment). Patients were also stratified by BMI and body fat percentage and followed for 2 years. All-cause death or HF hospitalization was the primary endpoint. Results Based on BMI strata, among underweight patients, 60% and 100% were undernourished by Definitions 1 and 2, respectively (31% and 44% among normal-weight, 4% and 11% among overweight, and 0% and 3% among obese patients, respectively, according to the two definitions). The most prevalent undernourishment type was marasmus-like (18% of the total cohort). Undernourishment by both definitions was significantly associated with lower event-free survival. Following multivariable analysis, age, NYHA functional class, NTproBNP, and undernourishment (hazard ratio [HR] 2.25 [1.11–4.56] and 2.24 [1.19–4.21] for Definitions 1 and 2, respectively) remained in the model. In this cohort, BMI and percentage of body fat did not independently predict 2-year event-free survival. Conclusions Nutritional status is a key prognostic factor in HF above and beyond BMI and percentage of body fat. Patients in normal BMI range and even in overweight and obese groups showed undernourishment. The high mortality observed in undernourishment, infrequent in high BMI patients, may help to partly explain the obesity paradox. Proper undernourishment assessment should become routine in patients with HF.

Lipoprotein receptor expression plays a crucial role in the pathophysiology of adipose tissue in in vivo models of diabetes. However, there are no studies in diabetic patients. The aims of this study were to analyze (a) low-density lipoprotein receptor-related protein 1 (LRP1) and very low-density lipoprotein receptor (VLDLR) expression in epicardial and subcutaneous fat from type 2 diabetes mellitus compared with nondiabetic patients and (b) the possible correlation between the expression of these receptors and plasmatic parameters. Adipose tissue biopsy samples were obtained from diabetic (n = 54) and nondiabetic patients (n = 22) undergoing cardiac surgery before the initiation of cardiopulmonary bypass. Adipose LRP1 and VLDLR expression was analyzed at mRNA level by real-time PCR and at protein level by Western blot analysis. Adipose samples were also subjected to lipid extraction, and fat cholesterol ester, triglyceride, and free cholesterol contents were analyzed by thin-layer chromatography. LRP1 expression was higher in epicardial fat from diabetic compared with nondiabetic patients (mRNA 17.63 +/- A 11.37 versus 7.01 +/- A 4.86; P = 0.02; protein 11.23 +/- A 7.23 versus 6.75 +/- A 5.02, P = 0.04). VLDLR expression was also higher in epicardial fat from diabetic patients but only at mRNA level (231.25 +/- A 207.57 versus 56.64 +/- A 45.64, P = 0.02). No differences were found in the expression of LRP1 or VLDLR in the subcutaneous fat from diabetic compared with nondiabetic patients. Epicardial LRP1 and VLDLR mRNA overexpression positively correlated with plasma triglyceride levels (R (2) = 0.50, P = 0.01 and R (2) = 0.44, P = 0.03, respectively) and epicardial LRP1 also correlated with plasma glucose levels (R (2) = 0.33, P = 0.03). These results suggest that epicardial overexpression of certain lipoprotein receptors such as LRP1 and VLDLR expression may play a key role in the alterations of lipid metabolism associated with type 2 diabetes mellitus.

Introduction and objectives: In the general population, heart events occur more often during early morning, on Mondays, and during winter. However, the chronobiology of death in heart failure has not been analyzed. The aim of this study was to determine the circadian, day of the week, and seasonal variability of all-cause mortality in chronic heart failure. Methods: This was an analysis of all consecutive heart failure patients followed in a heart failure unit from January 2003 to December 2008. The circadian moment of death was analyzed at 6-h intervals and was determined by reviewing medical records and by information provided by the relatives. Results: Of 1196 patients (mean [standard deviation] age, 69 [13] years; 62% male), 418 (34.9%) died during a mean (standard deviation) follow-up of 29 (21) months. Survivors were younger, had higher body mass index, left ventricular ejection fraction, glomerular filtration rate, hemoglobin and sodium levels, and lower Framingham risk scores, amino-terminal pro-B type natriuretic peptide, troponin T, and urate values. They were more frequently treated with angiotensin receptor blockers, beta-blockers, mineralocorticoids receptor antagonists, digoxin, nitrates, hydralazine, statins, loop diuretics, and thiazides. The analysis of the circadian and weekly variability did not reveal significant differences between the four 6-h intervals or the days of the week. Mortality occurred more frequently during the winter (30.6%) compared with the other seasons (P=.024). Conclusions: All cause mortality does not follow a circadian pattern, but a seasonal rhythm in patients with heart failure. This finding is in contrast to the circadian rhythmicity of cardiovascular events reported in the general population. (C) 2013 Sociedad Espanola de Cardiologia. Published by Elsevier Espana, S.L. All rights reserved.

To assess the relationship between statins and prognosis in ischemic and nonischemic patients with heart failure (HF) in a real-life cohort followed up for a long period.This prospective study included 960 patients with HF with preserved or depressed left ventricular ejection fraction (LVEF), irrespective of HF etiology, who were referred to the HF clinic of a university hospital between August 1, 2001, and December 31, 2008. The patients were followed up for a maximum of 9.1 years (median, 3.7 years), and survival in ischemic and nonischemic patients was determined.Median age was 69 years, and median LVEF was 31%. Of the 960 patients, 532 (55.4%) had ischemic HF etiology, and most received angiotensin-converting enzyme inhibitors or angiotensin receptor blockers (846; 88.1%) and β-blockers (776; 80.8%). Patients with HF of ischemic origin were more often treated with statins (P.001). During follow-up, 440 patients (45.8%) died. Statin therapy was associated with significantly improved survival (hazard ratio, 0.45 [95% confidence interval, 0.37-0.54]; P.001). After adjustment for HF prognostic factors (age, sex, cholesterol level, New York Heart Association class, HF etiology, LVEF, body mass index, HF duration, atrial fibrillation, implantable cardioverter-defibrillator therapy, and medicines), statins remained significantly associated with lower mortality risk in both ischemic (P=.007) and nonischemic (P=.002) patients.In contrast to results of large randomized trials, statins were independently and significantly associated with lower mortality risk in our real-life HF cohort, including patients with nonischemic HF etiology.

The obesity paradox in heart failure (HF) is criticized because of the limitations of body mass index (BMI) in correctly characterizing overweight and obese patients, necessitating a better evaluation of nutritional status. The aim of this study was to assess nutritional status, BMI, and significance in terms of HF survival. Anthropometry and biochemical nutritional markers were assessed in 55 HF patients. Undernourishment was defined as the presence of >= 2 of the following indexes below the normal range: triceps skinfold, subscapular skinfold, arm muscle circumference, albumin, and total lymphocyte count. Patients were also stratified by BMI and followed for a median of 26.7 months. Across BMI strata, no patient was underweight, 31% were normal weight, 42% were overweight, and 27% were obese. Undernourishment was present in 53% of normal-weight patients, 22% of overweight patients, and none of the obese patients (p = 0.001). Undernourished patients had significantly higher mortality (p = 0.009) compared to well-nourished patients. In multivariate analysis, only undernutrition (hazard ratio 3.149, 95% confidence interval 1.367 to 7.253), New York Heart Association functional class (hazard ratio 3.374, 95% confidence interval 1.486 to 7.659), and age (hazard ratio 1.115, 95% confidence interval 1.045 to 1.189) remained in the model. Among nutritional indicators, subscapular skinfold was the best predictor of mortality; patients with subscapular skinfold in the fifth percentile had higher mortality (p = 0.0001). In conclusion, BMI does not indicate true nutritional status in HF. Classifying patients as well nourished or undernourished may improve risk stratification. (C) 2011 Elsevier Inc. All rights reserved. (Am J Cardiol 2011;108: 1166-1170)

Introduction: Heart failure (HF) is one of the most important chronic diseases that cause quality of life (QOL) impairment. The Minnesota Living with Heart Failure Questionnaire (MLWHFQ) is probably the most comprehensively used tool for studying QoL in HF patients. It is a disease-specific questionnaire, but it can be related to frailty, as we previously observed in elderly patients. Geriatric evaluations have been applied successfully to general population regardless the age. Objective and methods: To assess the relationship between the MLWHFQ score and the results obtained in a basic geriatric evaluation with standardised geriatric scales such as Barthel Index, OARS Scale, Pfeiffer Test, and abbreviate Geriatric Depression Scale (GDS), in a general population admitted to a HF Unit. The MLWHFQ and the basic geriatric evaluation were performed at the first visit to the Unit. Predefined criteria (Barthel 3 (±1 depending on educational grade) and 1 positive depression response in abbreviate GDS), were considered abnormal. Every patient having at least one abnormal evaluation was considered frail. Results: 1405 patients were evaluated (1015 men and 390 women). Median age was 69 years (P25-75 59-76). 44.2% of patients (621) fulfilled frailty criteria. Two hundred and eighty six patients (20.4%) had a Barthel Index