Technical considerations for isolated limb perfusion: A consensus paper.

BACKGROUND: Isolated limb perfusion (ILP) is a well-established surgical procedure for the administration of high dose chemotherapy to a limb for the treatment of advanced extremity malignancy. Although the technique of ILP was first described over 60 years ago, ILP is utilised in relatively few specialist centres, co-located with tertiary or quaternary cancer centres. The combination of high dose cytotoxic chemotherapy and the cytokine tumour necrosis factor alpha (TNFα), mandates leakage monitoring to prevent potentially serious systemic toxicity. Since the procedure is performed at relatively few specialist centres, an ILP working group was formed with the aim of producing technical consensus guidelines for the procedure to streamline practice and to provide guidance for new centres commencing the technique. METHODS: Between October 2021 and October 2023 a series of face to face online and hybrid meetings were held in which a modified Delphi process was used to develop a unified consensus document. After each meeting the document was modified and recirculated and then rediscussed at subsequent meeting until a greater than 90% consensus was achieved in all recommendations. RESULTS: The completed consensus document comprised 23 topics in which greater than 90% consensus was achieved, with 83% of recommendations having 100% consensus across all members of the working group. The consensus recommendations covered all areas of the surgical procedure including pre-operative assessment, drug dosing and administration, perfusion parameters, hyperthermia, leakage monitoring and theatre logistics, practical surgical strategies and also post-operative care, response evaluation and staff training. CONCLUSION: We present the first joint expert-based consensus statement with respect to the technical aspects of ILP that can serve as a reference point for both existing and new centres in providing ILP.

Generation of Self-Induced Myocardial Ischemia in Large-Sized Cardiac Spheroids without Alteration of Environmental Conditions Recreates Fibrotic Remodeling and Tissue Stiffening Revealed by Constriction Assays.

A combination of human-induced pluripotent stem cells (hiPSCs) and 3D microtissue culture techniques allows the generation of models that recapitulate the cardiac microenvironment for preclinical research of new treatments. In particular, spheroids represent the simplest approach to culture cells in 3D and generate gradients of cellular access to the media, mimicking the effects of an ischemic event. However, previous models required incubation under low oxygen conditions or deprived nutrient media to recreate ischemia. Here, we describe the generation of large spheroids (i.e., larger than 500 µm diameter) that self-induce an ischemic core. Spheroids were generated by coculture of cardiomyocytes derived from hiPSCs (hiPSC-CMs) and primary human cardiac fibroblast (hCF). In the proper medium, cells formed aggregates that generated an ischemic core 2 days after seeding. Spheroids also showed spontaneous cellular reorganization after 10 days, with hiPSC-CMs located at the center and surrounded by hCFs. This led to an increase in microtissue stiffness, characterized by the implementation of a constriction assay. All in all, these phenomena are hints of the fibrotic tissue remodeling secondary to a cardiac ischemic event, thus demonstrating the suitability of these spheroids for the modeling of human cardiac ischemia and its potential application for new treatments and drug research.

Prognosis after heart transplant in patients with hypertrophic and restrictive cardiomyopathy. A nationwide registry analysis.

INTRODUCTION AND OBJECTIVES: Posttransplant outcomes among recipients with a diagnosis of hypertrophic cardiomyopathy (HCM) or restrictive cardiomyopathy (RCM) remain controversial. METHODS: Retrospective analysis of a nationwide registry of first-time recipients undergoing isolated heart transplant between 1984 and 2021. One-year and 5-year mortality in recipients with HCM and RCM were compared with those with dilated cardiomyopathy (DCM). RESULTS: We included 3703 patients (3112 DCM; 331 HCM; 260 RCM) with a median follow-up of 5.0 [3.1-5.0] years. Compared with DCM, the adjusted 1-year mortality risk was: HCM: HR, 1.38; 95%CI, 1.07-1.78; P=.01, RCM: HR, 1.48; 95%CI, 1.14-1.93; P=.003. The adjusted 5-year mortality risk was: HCM: HR, 1.17; 95%CI, 0.93-1.47; P=.18; RCM: HR, 1.52; 95%CI, 1.22-1.89; P<.001. Over the last 20 years, the RCM group showed significant improvement in 1-year survival (adjusted R2=0.95) and 5-year survival (R2=0.88); the HCM group showed enhanced the 5-year survival (R2=0.59), but the 1-year survival remained stable (R2=0.16). CONCLUSIONS: Both RCM and HCM were linked to a less favorable early posttransplant prognosis compared with DCM. However, at the 5-year mark, this unfavorable difference was evident only for RCM. Notably, a substantial temporal enhancement in both early and late mortality was observed for RCM, while for HCM, this improvement was mainly evident in late mortality.

Obesity and outcomes after left ventricular assist device implantation: insights from the EUROMACS Registry.

OBJECTIVES: The objective was to analyse associations between obesity and outcomes after left ventricular assist device (LVAD) implantation. METHODS: A retrospective analysis of the EUROMACS Registry was performed. Adult patients undergoing primary implantation of a continuous-flow LVAD between 2006 and 2019 were included (Medtronic HeartWare® HVAD®, Abbott HeartMate II®, Abbott HeartMate 3™). Patients were classified into 4 different groups according to body mass index at the time of surgery (body mass index <20 kg/m2: n = 254; 20-24.9 kg/m2: n = 1281; 25-29.9 kg/m2: n = 1238; ≥ 30 kg/m2: n = 691). RESULTS: The study cohort was comprised of 3464 patients. Multivariable Cox proportional cause-specific hazards regression analysis demonstrated that obesity (body mass index ≥30 kg/m2) was independently associated with significantly increased risk of mortality (body mass index ≥30 vs 20-24.9 kg/m2: hazard ratio 1.36, 95% confidence interval 1.18-1.57, overall P < 0.001). Moreover, obesity was associated with significantly increased risk of infection and driveline infection. The probability to undergo heart transplantation was significantly decreased in obese patients (body mass index ≥30 vs 20-24.9 kg/m2: hazard ratio 0.59, 95% confidence interval 0.48-0.74, overall P < 0.001). CONCLUSIONS: Obesity at the time of LVAD implantation is associated with significantly higher mortality and increased risk of infection as well as driveline infection. The probability to undergo heart transplantation is significantly decreased. These aspects should be considered when devising a treatment strategy before surgery.

A Fibrosis Biomarker Early Predicts Cardiotoxicity Due to Anthracycline-Based Breast Cancer Chemotherapy.

Anthracycline-based cancer chemotherapy (ACC) causes myocardial fibrosis, a lesion contributing to left ventricular dysfunction (LVD). We investigated whether the procollagen-derived type-I C-terminal-propeptide (PICP): (1) associates with subclinical LVD (sLVD) at 3-months after ACC (3m-post-ACC); (2) predicts cardiotoxicity 1-year after ACC (12m-post-ACC) in breast cancer patients (BC-patients); and (3) associates with LVD in ACC-induced heart failure patients (ACC-HF-patients). Echocardiography, serum PICP and biomarkers of cardiomyocyte damage were assessed in two independent cohorts of BC-patients: CUN (n = 87) at baseline, post-ACC, and 3m and 12m (n = 65)-post-ACC; and HULAFE (n = 70) at baseline, 3m and 12m-post-ACC. Thirty-seven ACC-HF-patients were also studied. Global longitudinal strain (GLS)-based sLVD (3m-post-ACC) and LV ejection fraction (LVEF)-based cardiotoxicity (12m-post-ACC) were defined according to guidelines. BC-patients: all biomarkers increased at 3m-post-ACC versus baseline. PICP was particularly increased in patients with sLVD (interaction-p < 0.001) and was associated with GLS (p < 0.001). PICP increase at 3m-post-ACC predicted cardiotoxicity at 12m-post-ACC (odds-ratio ≥ 2.95 per doubling PICP, p ≤ 0.025) in both BC-cohorts, adding prognostic value to the early assessment of GLS and LVEF. ACC-HF-patients: PICP was inversely associated with LVEF (p = 0.004). In ACC-treated BC-patients, an early increase in PICP is associated with early sLVD and predicts cardiotoxicity 1 year after ACC. PICP is also associated with LVD in ACC-HF-patients.

Profilaxis primaria estándar versus prolongada de la infección por citomegalovirus en el trasplante de órgano sólido / Standard versus extended primary cytomegalovirus prophylaxis in solid organ transplantation

Antecedentes y objetivo:Se han comparado la eficacia y seguridad de la profilaxis primaria estándar o prolongada de la infección por citomegalovirus (CMV) en el trasplante de órgano sólido.Materiales y métodos:Estudio retrospectivo de los receptores CMV seronegativos de donante seropositivo (D+/R−) que recibieron profilaxis frente a CMV tras un trasplante de órgano sólido (2007-2017). Se comparó la frecuencia de infección por CMV en los 2 primeros años postrasplante en los receptores que recibieron profilaxis durante más o menos de 100 días. Se evaluó asimismo la mielotoxicidad durante la profilaxis.Resultados:Se analizaron 66 pacientes. De ellos el 43,9% (n=29) presentaron infección por CMV. El 68,2% (n=45) recibieron profilaxis prolongada, sin asociarse su uso con una menor tasa de infección (42,2 vs. 47,6%, p=0,44) ni de enfermedad posprofilaxis (15,6 vs. 19%, p=0,72). La profilaxis prolongada se asoció con una mayor frecuencia de mielotoxicidad (68,9 vs. 42,9%, p<0,05).Conclusiones:La prolongación de la profilaxis primaria más de 100 días no aumenta su efectividad pero sí la toxicidad hematológica. (AU)

Background and objective:We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation.Materials and methods:Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R−) (2007–2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared.Results:CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05).Conclusions:Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity. (AU)

The European Registry for Patients with Mechanical Circulatory Support of the European Association for Cardio-Thoracic Surgery: third report.

OBJECTIVES: In the third report of the European Registry for Patients with Mechanical Circulatory Support of the European Association for Cardio-Thoracic Surgery, outcomes of patients receiving mechanical circulatory support are reviewed in relation to implant era. METHODS: Procedures in adult patients (January 2011-June 2020) were included. Patients from centres with <60% follow-ups completed were excluded. Outcomes were stratified into 3 eras (2011-2013, 2014-2017 and 2018-2020). Adverse event rates (AERs) were calculated and stratified into early phase (<3 months) and late phase (>3 months). Risk factors for death were explored using univariable Cox regression with a stepwise time-varying hazard ratio (<3 vs >3 months). RESULTS: In total, 4834 procedures in 4486 individual patients (72 hospitals) were included, with a median follow-up of 1.1 (interquartile range: 0.3-2.6) years. The annual number of implants (range: 346-600) did not significantly change (P = 0.41). Both Interagency Registry for Mechanically Assisted Circulatory Support class (classes 4-7: 23, 25 and 33%; P < 0.001) and in-hospital deaths (18.5, 17.2 and 11.2; P < 0.001) decreased significantly between eras. Overall, mortality, transplants and the probability of weaning were 55, 25 and 2% at 5 years after the implant, respectively. Major infections were mainly noted early after the implant occurred (AER<3 months: 1.44 vs AER>3 months: 0.45). Bilirubin and creatinine levels were significant risk factors in the early phase but not in the late phase after the implant. CONCLUSIONS: In its 10 years of existence, EUROMACS has become a point of reference enabling benchmarking and outcome monitoring. Patient characteristics and outcomes changed between implant eras. In addition, both occurrence of outcomes and risk factor weights are time dependent.

[Standard versus extended primary cytomegalovirus prophylaxis in solid organ transplantation]. / Profilaxis primaria estándar versus prolongada de la infección por citomegalovirus en el trasplante de órgano sólido.

BACKGROUND AND OBJECTIVE: We compared the efficacy and safety of standard vs. extended primary cytomegalovirus (CMV) prophylaxis in solid organ transplantation. MATERIALS AND METHODS: Retrospective cohort study of CMV seronegative recipients who received CMV prophylaxis after solid organ transplantation from seropositive donor (D+/R-) (2007-2017). CMV infection in the first two years after transplantation in recipients with prophylaxis longer or shorter than 100 days were compared. RESULTS: CMV infection occurred in 29 of 66 patients (43.9%) with prophylaxis. Forty-five patients (68.2%) received extended prophylaxis. CMV infection and disease rates were not different between patients with extended and standard prophylaxis. However, extended prophylaxis was associated with a higher rate of myelotoxicity (68.9% vs. 42.9%, p<0.05). CONCLUSIONS: Extending primary CMV prophylaxis over 100 days did not prevent late-onset infection but it was associated with hematological toxicity.

Impact of intrapatient blood level variability of calcineurin inhibitors on heart transplant outcomes.

INTRODUCTION AND OBJECTIVES: Intrapatient blood level variability (IPV) of calcineurin inhibitors has been associated with poor outcomes in solid-organ transplant, but data for heart transplant are scarce. Our purpose was to ascertain the clinical impact of IPV in a multi-institutional cohort of heart transplant recipients. METHODS: We retrospectively studied patients aged ≥18 years, with a first heart transplant performed between 2000 and 2014 and surviving≥ 1 year. IPV was assessed by the coefficient of variation of trough levels from posttransplant months 4 to 12. A composite of rejection or mortality/graft loss or rejection and all-cause mortality/graft loss between years 1 to 5 posttransplant were analyzed by Cox regression analysis. RESULTS: The study group consisted of 1581 recipients (median age, 56 years; women, 21%). Cyclosporine immediate-release tacrolimus and prolonged-release tacrolimus were used in 790, 527 and 264 patients, respectively. On multivariable analysis, coefficient of variation> 27.8% showed a nonsignificant trend to association with 5-year rejection-free survival (HR, 1.298; 95%CI, 0.993-1.695; P=.056) and with 5-year mortality (HR, 1.387; 95%CI, 0.979-1.963; P=.065). Association with rejection became significant on analysis of only those patients without rejection episodes during the first year posttransplant (HR, 1.609; 95%CI, 1.129-2.295; P=.011). The tacrolimus-based formulation had less IPV than cyclosporine and better results with less influence of IPV. CONCLUSIONS: IPV of calcineurin inhibitors is only marginally associated with mid-term outcomes after heart transplant, particularly with the tacrolimus-based immunosuppression, although it could play a role in the most stable recipients.

Influence of Gender in Advanced Heart Failure Therapies and Outcome Following Transplantation.

Biological differences between males and females change the course of different diseases and affect therapeutic measures' responses. Heart failure is not an exception to these differences. Women account for a minority of patients on the waiting list for heart transplantation or other advanced heart failure therapies. The reason for this under-representation is unknown. Men have a worse cardiovascular risk profile and suffer more often from ischemic heart disease. Conversely, transplanted women are younger and more frequently have non-ischemic cardiac disorders. Women's poorer survival on the waiting list for heart transplantation has been previously described, but this trend has been corrected in recent years. The use of ventricular assist devices in women is progressively increasing, with comparable results than in men. The indication rate for a heart transplant in women (number of women on the waiting list for millions of habitants) has remained unchanged over the past 25 years. Long-term results of heart transplants are equal for both men and women. We have analyzed the data of a national registry of heart transplant patients to look for possible future directions for a more in-depth study of sex differences in this area. We have analyzed 1-year outcomes of heart transplant recipients. We found similar results in men and women and no sex-related interactions with any of the factors related to survival or differences in death causes between men and women. We should keep trying to approach sex differences in prospective studies to confirm if they deserve a different approach, which is not supported by current evidence.

Long-Term Prognostic Value of Coronary CTA in Orthotopic Heart Transplant Recipients.

OBJECTIVE. This study aimed to evaluate the long-term prognostic value of coronary CTA (CCTA) in heart transplant recipients. MATERIALS AND METHODS. The records of 114 patients who had undergone a heart transplant (mean age, 61.7 ± 11.1 [SD] years; 83.3% men) and who underwent CCTA for the surveillance of coronary allograft vasculopathy (CAV) from June 2007 to December 2017 were retrospectively evaluated for the occurrence of major adverse cardiovascular events (MACEs) (cardiac death, nonfatal myocardial infarction, unstable angina requiring hospitalization, coronary revascularization, cardiac arrhythmias, stroke, and retransplant). Patients were classified according to the presence of nonobstructive CAV (lumen reduction < 50%) or obstructive disease (lumen reduction ≥ 50%) and using a coronary segment involvement score (SIS). Differences in MACE rate between groups were compared. RESULTS. Obstructive CAV was observed in 12 heart transplant recipients (10.5%). During a mean follow-up of 67.5 ± 41.4 months the overall rates of MACE were 50% and 14.7% in patients with obstructive and nonobstructive CAV, respectively (p < .05), resulting in an odds ratio for MACE of 6 (95% CI, 1.7-21.2). Comparison of event-free survival showed a hazard ratio (HR) of 5 (95% CI, 1.95-13; p =. 004) for patients with obstructive disease. The presence of four or more stenotic coronary segments (SIS ≥ 4) was associated with a higher rate of events (HR, 3.46; 95% CI, 1.46-8.23). CONCLUSION. In patients who have undergone a heart transplant, CCTA offers a significant long-term prognostic impact on the prediction of MACEs.

Gender differences in heart transplantation: Twenty-five year trends in the nationwide Spanish heart transplant registry.

The study of gender differences may lead into improvement in patient care. We have aimed to identify the gender differences in heart transplantation (HT) of adult HT recipients in Spain and their evolution in a study covering the years 1993-2017 in which 6740 HT (20.6% in women) were performed. HT indication rate per million inhabitants was lower in women, remaining basically unchanged during the 25-year study period. HT rate was higher in men, although this decreased over the 25-year study period. Type of heart disease differed in men versus women (p < .001): ischemic heart disease 47.6% versus 22.5%, dilated cardiomyopathy 41.3% versus 34.6%, or other 36% versus 17.8%, respectively. Men were more frequently diabetics (18% vs. 13.1% p < .001), hypertensives (33.1% vs. 24% p < .001), and smokers (21.7% vs. 12.9% p < .001), respectively. Women had more pre-HT malignancies (7.1% vs. 2.8% p < .001), and their clinical status was worse at HT due to renal function and mechanical ventilation. Adjusted survival (p = .198) and most of the mortality-related variables were similar in men and women. Death occurred more frequently in women due to rejection (7.9% vs. 5.1% p < .001) and primary failure (18.2% vs. 12.5% p < .001) and in men due to malignancies (15.1% vs. 6.6% p < .001).

Systolic High-Pitch Coronary CT Angiography for Evaluation of the Coronary Arteries in Heart Transplant Recipients.

OBJECTIVE. The purpose of this study was to evaluate the feasibility, image quality, and radiation dose of high-pitch coronary CT angiography (CCTA) in orthotopic heart transplant (OHT) recipients. SUBJECTS AND METHODS. Twenty-two consecutive OHT recipients (16 men, six women; median age, 66.5 years [interquartile range, 51.3-70.3 years]; median heart rate, 91 beats/min [interquartile range, 79.3-97.3 beats/min]) underwent CCTA with a third-generation dual-source CT scanner in high-pitch mode to rule out coronary allograft vasculopathy. Data acquisition was triggered at 30% of the R-R interval. Two independent observers blindly assessed image quality on a per-segment, per-vessel, and per-patient basis using a 4-point scale (4, excellent; 1, not evaluative). Scores 2-4 indicated diagnostic quality. Studies were compared with previously performed retrospective ECG-gated examinations, when available. Interobserver agreement on the image quality was assessed with kappa statistics. Radiation dose was recorded. RESULTS. A total of 322 coronary segments were evaluated. Diagnostic image quality was observed in 97.5% of the segments. Interobserver agreement for image quality assessment was very good on a per-patient (κ = 0.82), per-vessel (κ = 0.83), and per-segment basis (κ = 0.89). The median per-patient image quality score was 4.0 (3.0-4.0) for the entire coronary tree. A comparison of image quality scores between high-pitch and retrospective ECG-gated CCTA examinations showed no significant differences, but the estimated mean radiation dose was significantly lower for the high-pitch mode (median dose-length product, 31.6 mGy × cm [interquartile range, 23.1-38.8 mGy × cm] vs 736.5 mGy × cm [interquartile range, 655.5-845.7 mGy × cm], p < 0.001). CONCLUSION. Performing single-heartbeat high-pitch CCTA during the systolic phase of the cardiac cycle in OHT recipients results in diagnostic image quality in coronary angiograms at very low radiation dose.

CT-1 (Cardiotrophin-1)-Gal-3 (Galectin-3) Axis in Cardiac Fibrosis and Inflammation.

Myocardial fibrosis is a main contributor to the development of heart failure (HF). CT-1 (cardiotrophin-1) and Gal-3 (galectin-3) are increased in HF and associated with myocardial fibrosis. The aim of this study is to analyze whether CT-1 regulates Gal-3. Proteomic analysis revealed that Gal-3 was upregulated by CT-1 in human cardiac fibroblasts in parallel with other profibrotic and proinflammatory markers. CT-1 upregulation of Gal-3 was mediated by ERK (extracellular signal-regulated kinase) 1/2 and Stat-3 (signal transducer and activator of transcription 3) pathways. Male Wistar rats and B6CBAF1 mice treated with CT-1 (20 µg/kg per day) presented higher cardiac Gal-3 levels and myocardial fibrosis. In CT-1-treated rats, direct correlations were found between cardiac CT-1 and Gal-3 levels, as well as between Gal-3 and perivascular fibrosis. Gal-3 genetic disruption in human cardiac fibroblasts and pharmacological Gal-3 inhibition in mice prevented the profibrotic and proinflammatory effects of CT-1. Dahl salt-sensitive hypertensive rats with diastolic dysfunction showed increased cardiac CT-1 and Gal-3 expression together with cardiac fibrosis and inflammation. CT-1 and Gal-3 directly correlated with myocardial fibrosis. In HF patients, myocardial and plasma CT-1 and Gal-3 were increased and directly correlated. In addition, HF patients with high CT-1 and Gal-3 plasma levels presented an increased risk of cardiovascular death. Our data suggest that CT-1 upregulates Gal-3 which, in turn, mediates the proinflammatory and profibrotic myocardial effects of CT-1. The elevation of both molecules in HF patients identifies a subgroup of patients with a higher risk of cardiovascular mortality. The CT-1/Gal-3 axis emerges as a candidate therapeutic target and a potential prognostic biomarker in HF.

Quantitative assessment of left ventricular size and function in cardiac transplant recipients: Side-by-side comparison of real time two-dimensional echocardiography, contrast-enhanced two-dimensional echocardiography, three-dimensional echocardiography, and contrast-enhanced three-dimensional echocardiography as compared to magnetic resonance imaging.

INTRODUCTION: We evaluate the ability of 2D non-contrast-enhanced echocardiography (CE-echo), 2DCE-echo, 3D-echo, 3D non-CE-echo, and 3DCE-echo to evaluate allograft function and dimensions in orthotropic heart transplantation (OHT). Cardiac resonance (CMR) was used as reference. METHODS: Twenty six consecutive OHT-recipients were prospectively recruited. Bland-Altman, Spearman rank, and concordance-correlation coefficients (CCC) were determined. RESULTS: Good CCCs were found between the four modalities and CMR for ejection fraction (r ≥ 0.72/P < 0.001; r ≥ 0.77/ P < 0.001; r ≥ 0.51/ P < 0.23; r ≥ 0.75/ P < 0.001, respectively). Highest intraclass correlation coefficient (ICC) was for 2D CE-echo(CCC = 0.77). End-diastolic volume(EDV) measurements statistically differed when 2D non-CE-echo, 2DCE-echo, and 3D non-CE-echo were compared with the cross-sectional imaging modalities, but they did not differ significantly from 3DCE-echo. End-systolic volume (ESV) and stroke volume (SV) differed statistically between the four modalities; however, SV measured by CMR and 3DCE-echo were comparable. Overall, 2D non-CE-echo, 2DCE-echo, and 3D non-CE-echo showed lower mean EDV, ESV, and SV than CMR. ICC was that of the ESV variable in the 4 techniques, with the values of the ICC of the 3DCE-echo technique superior to the rest. Overall, the best CCC were found for 3DCE(r = 0.88, 0.92 and 0.76 for EDV, ESV and SV, respectively). CONCLUSION: Routine use of 3DCE-echo may allow more comprehensive cardiac assessment in cardiac transplant recipients.

Innovative Strategies in Heart Failure: Present and Future.

Heart failure (HF) is a progressively debilitating disease that considerably decreases the life expectancy and quality of life. It has become an important area of focus since it remains one of the most common reasons for admission in patients over the age of 65. Importantly, the incidence of HF has not declined within the past 20 years, but the survival after onset has increased in younger patients and men. This has been in part due to the growing interest in therapies that may decrease morbidity, mortality, along with the substantial health care expenditures associated with the disease. It can be said that over the past 50 years, there have been three distinct eras relating to HF management; a) the non-pharmacologic era, focused its treatments on fluid restriction; b) the pharmacologic era, marked by the increased use of inotropes and diuretics and the discovery of vasodilators, and the posterior discovery of medications relating to neurohormonal pathways; c) the device era, with the discovery, acceptance, and increased use of implantable cardioverter defibrillators, cardiac resynchronization therapy (CRT), and left ventricular assist devices (LVADs) among others. A new forth era could be about to arrive, with the advent of regenerative therapies. In this review article will discuss new therapeutic discoveries as well as provide insight into future therapies.

Perioperative hemoglobin area under the curve is an independent predictor of renal failure after cardiac surgery. Results from a Spanish multicenter retrospective cohort study.

Perioperative anemia is an important risk factor for cardiac surgery-associated acute kidney injury (CSA-AKI). Nonetheless, the severity of the anemia and the time in the perioperative period in which the hemoglobin level should be considered as a risk factor is conflicting. The present study introduces the concept of perioperative hemoglobin area under the curve (pHb-AUC) as a surrogate marker of the evolution of perioperative hemoglobin concentration. Through a retrospective analysis of prospectively collected data, we assessed this new variable as a risk factor for the development of acute kidney injury after cardiac surgery in 966 adult patients who underwent cardiac surgery with cardiopulmonary bypass, at twenty-three academic hospitals in Spain. Exclusion criteria were patients on renal replacement therapy, who needed a reoperation because of bleeding and/or with missing perioperative hemoglobin or creatinine values. Using a multivariate regression analysis, we found that a pHb-AUC <19 g/dL was an independent risk factor for CSA-AKI even after adjustment for intraoperative red blood cell transfusion (OR 1.41, p <0.05). It was also associated with mortality (OR 2.48, p <0.01) and prolonged hospital length of stay (4.67 ± 0.99 days, p <0.001).

First-line use of rituximab correlates with increased overall survival in late post-transplant lymphoproliferative disorders: retrospective, single-centre study.

This retrospective study evaluates the impact of rituximab on PTLD response and survival in a single-centre cohort. PTLD cases between 1984 and 2009, including heart, kidney, liver and lung transplant recipients, were included. Survival was analysed taking into account the type of PTLD (monomorphic vs. polymorphic), EBV infection status, IPI score, Ann Arbor stage and use of rituximab. Among 1335 transplanted patients, 24 developed PTLD. Median age was 54 yr (range 29-69), median time to diagnosis 50 months (range 0-100). PTLD type was predominantly late/monomorphic (79% and 75%), mostly diffuse large B-cell type. Overall response rate (ORR) was 62% (66% rituximab vs. 50% non-rituximab; P = 0.5). R-CHOP-like regimens were used most frequently (72% of patients treated with rituximab). Median overall survival was 64 months (CI 95% 31-96). OS was significantly increased in patients treated with rituximab (P = 0.01; CI 95% rituximab 58-79 months; non-rituximab 1-30 months). Post-transplant immunosuppression regimen had no effect on survival or time to PTLD, except for cyclosporine A (CyA), which associated with increased time to PTLD (P = 0.02). Rituximab was associated with increased survival in our single-centre series, and it should be considered as first-line therapy for PTLD patients. The possible protective effect of CyA for development of PTLD should be prospectively evaluated.

Evaluation of humoral immunity profiles to identify heart recipients at risk for development of severe infections: A multicenter prospective study.

BACKGROUND: New biomarkers are necessary to improve detection of the risk of infection in heart transplantation. We performed a multicenter study to evaluate humoral immunity profiles that could better enable us to identify heart recipients at risk of severe infections. METHODS: We prospectively analyzed 170 adult heart recipients at 8 centers in Spain. Study points were before transplantation and 7 and 30 days after transplantation. Immune parameters included IgG, IgM, IgA and complement factors C3 and C4, and titers of specific antibody to pneumococcal polysaccharide antigens (anti-PPS) and to cytomegalovirus (CMV). To evaluate potential immunologic mechanisms leading to IgG hypogammaglobulinemia, before heart transplantation we assessed serum B-cell activating factor (BAFF) levels using enzyme-linked immunoassay. The clinical follow-up period lasted 6 months. Clinical outcome was need for intravenous anti-microbials for therapy of infection. RESULTS: During follow-up, 53 patients (31.2%) developed at least 1 severe infection. We confirmed that IgG hypogammaglobulinemia at Day 7 (defined as IgG <600 mg/dl) is a risk factor for infection in general, bacterial infections in particular, and CMV disease. At Day 7 after transplantation, the combination of IgG <600 mg/dl + C3 <80 mg/dl was more strongly associated with the outcome (adjusted odds ratio 7.40; 95% confidence interval 1.48 to 37.03; p = 0.014). We found that quantification of anti-CMV antibody titers and lower anti-PPS antibody concentrations were independent predictors of CMV disease and bacterial infections, respectively. Higher pre-transplant BAFF levels were a risk factor of acute cellular rejection. CONCLUSION: Early immunologic monitoring of humoral immunity profiles proved useful for the identification of heart recipients who are at risk of severe infection.

Association of cystatin C with heart failure with preserved ejection fraction in elderly hypertensive patients: potential role of altered collagen metabolism.

OBJECTIVES: Cystatin C has been shown to be associated with heart failure with preserved ejection fraction (HFPEF). In addition, myocardial fibrosis has been involved in diastolic dysfunction in HFPEF. Therefore, we hypothesized that increased cystatin C levels may be associated with altered collagen metabolism, contributing to diastolic dysfunction in patients with HFPEF. METHODS: One hundred and forty-one elderly hypertensive patients with HFPEF were included. Cardiac morphology and function was assessed by echocardiography. Circulating levels of cystatin C, biomarkers of collagen type I synthesis (carboxy-terminal propeptide of procollagen type I) and degradation [matrix metalloproteinase-1 (MMP-1) and its inhibitor TIMP-1] and osteopontin were analyzed by ELISA. Twenty elderly sex-matched patients with no identifiable cardiac disease were used as controls. In-vitro studies were performed in human cardiac fibroblasts. RESULTS: Compared with controls, cystatin C was increased (P < 0.001) in patients with HFPEF, even in those with a normal estimated glomerular filtration rate (eGFR; P < 0.05). Cystatin C was directly correlated with the estimated pulmonary capillary wedge pressure (P < 0.01), TIMP-1 and osteopontin (P < 0.001) and inversely correlated with MMP-1:TIMP-1 (P < 0.01), but not with carboxy-terminal propeptide of procollagen type I or MMP-1 in all patients with HFPEF. These associations were independent of eGFR. In vitro, osteopontin (P < 0.01) and TIMP-1 (P < 0.001) increased in the supernatant of cardiac fibroblasts exposed to cystatin C. CONCLUSION: In patients with HFPEF of hypertensive origin, cystatin C is increased and associated with diastolic dysfunction and alterations in collagen metabolism independently of eGFR. An excess of cystatin C might contribute to diastolic dysfunction in HFPEF by facilitating myocardial fibrosis via accumulation of osteopontin and TIMP-1.