Diagnóstico no invasivo de la enfermedad vascular del injerto en receptores de un trasplante cardiaco

Premi Extraordinari de Doctorat concedit pels programes de doctorat de la UAB per curs acadèmic 2017-2018La enfermedad vascular del injerto (EVI) es junto con las neoplasias uno de los principales factores limitantes de supervivencia a partir del primer año del trasplante cardíaco. Consiste en la afectación de los vasos de los corazones implantados, incluyendo arterias, venas y microcirculación. Se caracteriza desde el punto de vista histológico por una hiperplasia de la íntima con proliferación de células musculares lisas, depósito de proteoglicanos, matriz extracelular y fibrosis, que lleva a la obliteración progresiva de la luz vascular. Aunque la etiologia de la EVI no es del todo bien conocida, se cree que la base de la enfermedad está en la disfunción endotelial causada por diferentes mecanismos inmunológicos y no inmunológicos. La denervación de los corazones implantados condiciona que la EVI sea un fenómeno habitualmente silente y que las manifestacions clínicas aparezcan en estadios avanzados de la enfermedad. El diagnóstico se realiza habitualmente con coronariografia y últimamente disponemos del TAC de arterias coronarias. Ambos procedimientos no pueden realizarse de forma repetitiva debido a la morbilidad asociada. Las opciones de tratamiento son limitadas. Si bien algunos inmunosupresores han demostrado ser eficaces en retrasar la aparición de EVI si se administran en los primeros meses tras el trasplante, el tratamiento farmacológico no ha mostrado ser útil en evitar la progresión de la EVI establecida; la revascularización quirúrgica a menudo no es técnicamente factible y los procedimientos de revascularización percutáneos no han demostrado hasta la actualidad impacto sobre la supervivencia. La única opción terapéutica definitiva es el retrasplante, cuya indicación se lleva a cabo de manera excepcional y en casos muy seleccionados. Teniendo en cuenta las limitaciones terapéuticas cuando la enfermedad está evolucionada sería fundamental prevenir su aparición y realizar un diagnóstico precoz. El objetivo de este estudio fue evaluar la utilidad de los biomarcadores sAXl, GAS6, Lp-PLA2, GDF-15, c-TnT-hs y del cociente Th1/Treg en el diagnóstico de la EVI y en la predicción de eventos clínicos en un grupo de 96 pacientes trasplantados de corazón. La determinación de los biomarcadores se realizó en un margen de 6 meses respecto la coronariografía o TAC de coronarias programado de acuerdo con el protocolo asistencial de nuestro centro. Los resultados muestran que la determinación de cTnT-hs y sAXL es útil en la detección de vasculopatía del injerto, siendo cTnT-hs el biomarcador con mayor poder predictivo independiente. El cociente Th1/Treg es el marcador que presenta mayor sensibilidad en el diagnóstico de EVI. Los niveles de cTnT-hs y sAXL se han asociado de manera independiente a mayor riesgo de eventos clínicos en pacientes receptores de trasplante cardiaco y las concentraciones de cTnT-hs son además predictoras de eventos clínicos en pacientes con EVI moderada-severa. Los biomarcadores GAS6, Lp-PLA2 y GDF-15 no han mostrado ser de utilidad en la detección de la EVI. En consecuencia la determinación de las concentraciones de cTnT-hs y del cociente de poblaciones linfocitarias Th1/Treg en el seguimiento de los receptores de trasplante cardíaco podría plantearse como alternativa no invasiva en el diagnóstico de la vasculopatía del injertoCardiac allograft vasculopathy (CAV) and neoplasms are the main limiting factors for long term survival after heart transplantation. CAV is characterized by intimal hyperplasia with proliferation of smooth muscle cells, deposition of proteoglycans, extracellular matrix and fibrosis which leads to progressive obliteration of the lumen. It involves all the vessels of the implanted hearts, including arteries, veins and microcirculation. It has been proposed that endothelial damage is a primary precipitating event in the pathogenesis of CAV. Different immunological and non-immunological mechanisms are responsable of the endothelial dysfunction. CAV is usually a silent phenomenon due to the denervation of the implanted heart. Clinical symptoms appear in advanced stages of the disease. The diagnosis is usually made with coronary angiography. In the last years coronary CT scan has also been used for the diagnosis. Both procedures can not be performed repeatedly because of the morbidity. Treatment options are limited. Although some immunosuppressive drugs have proven effective in delaying the onset of CAV given in the first months after transplantation, drug therapy has not shown to be useful in preventing the progression of established CAV. Surgical revascularization is often not technically feasible and percutaneous revascularization procedures have not demonstrated impact on survival. The definitive treatment is re-transplantation. However this option is available only for selected cases. Given the relatively poor prognosis of CAV, prevention and early diagnosis remain an important strategy. The aim of this study was to evaluate the usefulness of sAXL, GAS6, Lp-PLA2, GDF-15, c-TnT-hs biomarkers and Th1 / Treg lymphocyte populations ratio in the diagnosis of CAV and in predicting clinical events in a group of 96 heart transplanted patients. The results show that the determination of hs-cTnT and sAXL is useful in detecting cardíac allograft vasculopathy. The biomarker hs-cTnT has the more independent predictive power. The Th1 / Treg ratio is the marker that has higher sensitivity in the diagnosis of CAV. Levels of hs-cTnT and sAXL were independently associated with increased risk of clinical events in patients receiving heart transplants. hs-cTnT concentrations are also predictors of clinical events in patients with moderate to severe CAV. The GAS6, Lp-PLA2 and GDF-15 biomarkers have not been useful in the detection of CAV. The evaluation of hs-cTnT concentrations and the Th1 / Treg ratio could be a non-invasive method to identify heart transplant patients at high risk of develop cardiac allograft vasculopathy

Growth differentiation factor 15 as mortality predictor in heart failure patients with non-reduced ejection fraction

Altres ajuts: This study was supported by Fundació d'Investigació Sant Pau (G-60136934).The prognostic value of biomarkers in patients with heart failure (HF) and mid-range (HFmrEF) or preserved ejection fraction (HFpEF) has not been widely addressed. The aim of this study was to assess whether the prognostic value of growth differentiation factor 15 (GDF-15) is superior to that of N-terminal pro-brain natriuretic peptide (NT-proBNP) in patients with HFmrEF or HFpEF. Heart failure patients with either HFpEF or HFmrEF were included in the study. During their first visit to the HF unit, serum samples were obtained and stored for later assessment of GDF-15 and NT-proBNP concentrations. Patients were followed up by the HF unit. The main endpoint was all-cause mortality. A total of 311 patients, 90 (29%) HFmrEF and 221 (71%) HFpEF, were included. Mean age was 72 ± 13 years, and 136 (44%) were women. No differences were found in GDF-15 or NT-proBNP concentrations between both HF groups. During a median follow-up of 15 months (Q1-Q3: 9-30 months), 98 patients (32%) died, most (71%) of cardiovascular causes. Patients who died had higher median concentrations of GDF-15 (4085 vs. 2270 ng/L, P 65 years (P 4330 ng/L), and survival curves were evaluated using the Kaplan-Meier technique. Patients in the highest tertile had the poorest 5 year survival, at 16%, whereas the lowest tertile had the best survival, of 78% (P < 0.001). Growth differentiation factor 15 was superior to NT-proBNP for assessing prognosis in patients with HFpEF and HFmrEF. GDF-15 emerges as a strong, independent biomarker for identifying HFmrEF and HFpEF patients with worse prognosis

Mobile health to improve adherence and patient experience in heart transplantation recipients : The mheart trial

Altres ajuts: Amgen SL, General Pharmaceutical Council of Barcelona i Astellas Pharma USBackground:Non-adherence after heart transplantation (HTx) is a significant problem. The main objective of this study was to evaluate if a mHealth strategy is more effective than standard care in improving adherence and patients' experience in heart transplant recipients. Methods: This was a single-center, randomized controlled trial (RCT) in adult recipients >1.5 years post-HTx. Participants were randomized to standard care (control group) or to the mHeart Strategy (intervention group). For patients randomized to the mHeart strategy, multifaceted theory-based interventions were provided during the study period to optimize therapy management using the mHeart mobile application. Patient experience regarding their medication regimens were evaluated in a face-to-face interview. Medication adherence was assessed by performing self-reported questionnaires. A composite adherence score that included the SMAQ questionnaire, the coefficient of variation of drug levels and missing visits was also reported. Results: A total of 134 HTx recipients were randomized (intervention N = 71; control N = 63). Mean follow-up was 1.6 (SD 0.6) years. Improvement in adherence from baseline was significantly higher in the intervention group versus the control group according to the SMAQ questionnaire (85% vs. 46%, OR = 6.7 (2.9; 15.8), p-value < 0.001) and the composite score (51% vs. 23%, OR = 0.3 (0.1; 0.6), p-value = 0.001). Patients' experiences with their drug therapy including knowledge of their medication timing intakes (p-value = 0.019) and the drug indications or uses that they remembered (p-value = 0.003) significantly improved in the intervention versus the control group. Conclusions: In our study, the mHealth-based strategy significantly improved adherence and patient beliefs regarding their medication regimens among the HTx population. The mHeart mobile application was used as a feasible tool for providing long-term, tailor-made interventions to HTx recipients to improve the goals assessed

Heart transplantation using allografts from older donors: multicenter study results

33rd Annual Meeting and Scientific Session of the International Society for Heart and Lung Transplantation, April 24–27, 2013, Montreal, Canada.[Abstract] Background. The lengthy waiting time for heart transplantation is associated with high mortality. To increase the number of donors, new strategies have emerged, including the use of hearts from donors ≥50 years old. However, this practice remains controversial. The aim of this study was to evaluate outcomes of patients receiving heart transplants from older donors. Methods. We retrospectively analyzed 2,102 consecutive heart transplants in 8 Spanish hospitals from 1998 to 2010. Acute and overall mortality were compared in patients with grafts from donors ≥50 years old versus grafts from younger donors. Results. There were 1,758 (84%) transplanted grafts from donors < 50 years old (Group I) and 344 (16%) from donors ≥50 years old (Group II). Group I had more male donors than Group II (71% vs 57%, p = 0.0001). The incidence of cardiovascular risk factors was higher in older donors. There were no differences in acute mortality or acute rejection episodes between the 2 groups. Global mortality was higher in Group II (rate ratio, 1.40; 95% confidence interval, 1.18–1.67; p = 0.001) than in Group I. After adjusting for donor cause of death, donor smoking history, recipient age, induction therapy, and cyclosporine therapy, the differences lost significance. Group II had a higher incidence of coronary allograft vasculopathy at 5 years (rate ratio, 1.67; 95% confidence interval, 1.22–2.27; p = 0.001). Conclusions. There were no differences in acute and overall mortality after adjusting for confounding factors. However, there was a midterm increased risk of coronary allograft vasculopathy with the use of older donors. Careful selection of recipients and close monitoring of coronary allograft vasculopathy are warranted in these patients.Instituto de Salud Carlos III; RD12/0042/00

Incremental prognostic value of lung ultrasound on contemporary heart failure risk scores

Introduction: Over the last decades, several scores have been developed to aid clinicians in assessing prognosis in patients with heart failure (HF) based on clinical data, medications and, ultimately, biomarkers. Lung ultrasound (LUS) has emerged as a promising prognostic tool for patients when assessed at discharge after a HF hospitalization. We hypothesized that contemporary HF risk scores can be improved upon by the inclusion of the number of B-lines detected by LUS at discharge to predict death, urgent visit, or HF readmission at 6- month follow-up. Methods: We evaluated the discrimination improvement of adding the number of B-lines to 4 contemporary HF risk scores (Get with the Guidelines -GWTG-, MAGGIC, Redin-SCORE, and BCN Bio-HF) by comparing the change in the area under the receiver operating curve (AUC), the net reclassification index (NRI), and the integrated discrimination improvement (IDI). The population of the study was constituted by the 123 patients enrolled in the LUS-HF trial, adjusting the analyses by the intervention. Results: The AUC of the GWTG score increased from 0.682 to 0.789 (p = 0.02), resulting in a NRI of 0.608 and an IDI of 0.136 (p < 0.05). Similar results were observed when adding the number of B-lines to the MAGGIC score, with an AUC that increased from 0.705 to 0.787 (p < 0.05). This increase translated into a NRI of 0.608 and an IDI of 0.038 (p < 0.05). Regarding Redin-SCORE at 1-month and 1-year, the AUC increased from 0.714 to 0.773 and from 0.681 to 0.757, although it did not reach statistical significance (p = 0.08 and p = 0.06 respectively). Both IDI and NRI were significantly improved (0.093 and 0.509 in the 1-month score, p < 0.05; 0.056 and 0.111 in the 1-year score, p < 0.05). Lastly, the AUC for the BCN Bio-HF score increased from 0.733 to 0.772, which was statistically non-significant, with a NRI value of 0.363 (p = 0.06) and an IDI of 0.092 (p < 0.05). Conclusion: Adding the results of LUS evaluated at discharge improved the predictive value of most of the contemporary HF risk scores. As it is a simple, fast, and non-invasive test it may be recommended to assess prognosis at discharge in HF patients

A Mobile App (mHeart) to Detect Medication Nonadherence in the Heart Transplant Population : Validation Study

Medication nonadherence in heart transplant recipients (HTxR) is related to graft loss and death. mHeart is a mobile app that uses electronic patient-reported outcome measures (ePROMs) to identify and manage medication nonadherence in the outpatient heart transplant (HTx) population. The study primarily aimed to validate mHeart to measure medication nonadherence in early stage HTxR by assessing the psychometric properties of ePROMs. The secondary aims were to (1) measure patient satisfaction with the mHeart tool and its usability and (2) explore the impact of a theory-based treatment on medication nonadherence rates to determine its scalability to larger research. A prospective study was conducted in the outpatient clinic of a tertiary hospital. All consecutive early stage HTxR (0.7, P <.001). Reproducibility was moderate (Haynes-Sackett κ=0.6, P <.002) or poor (Morisky-Green-Levine κ=0.3, P =.11) because of unexpected improved medication adherence rates during the test-retest period. According to responsiveness, the theory-based multifaceted intervention program improved medication nonadherence by 16% to 26% (P <.05). A burden analysis showed that ePROMs could potentially overcome traditional on-site limitations (eg, automatic recording of ePROM responses in the hospital information system). The mean score for overall patient satisfaction with the mHeart approach was 9 (SD 2; score range: 0-10). All 100% (29/29) of patients surveyed reported that they would recommend the mHeart platform to other HTxR. ePROMs adhered to the quality standards and successfully identified medication nonadherence in the HTx population, supporting their widespread use. The theory-based intervention program showed a promising improvement in medication adherence rates and produced excellent patient satisfaction and usability scores in HTxR

Chronic renal dysfunction in maintenance heart transplant patients: the ICEBERG study

[Abstract] Chronic renal dysfunction (CRD) is a major complication after heart transplantation. We sought to describe the renal function over time, to assess the risk factors associated with CRD development, and to evaluate the clinical attitudes on diagnosis and treatment of CRD. A retrospective, cross-sectional, multicenter study was conducted in 13 outpatient clinics in Spain. A total of 244 heart recipients who survived more than 2 years after transplantation were included. Post-transplantation follow-up was 7.7 years (range: 2-22 years). CRD was diagnosed in 32.4% of patients at a mean of 3.3 years after transplantation. Serum creatinine increased 0.1 ± 0.2 mg/dL per year in CRD group compared with 0.0 ± 0.2 mg/dL per year in non-CRD group (P = .003) and glomerular filtration rate decreased −1.5 ± 4.3 mL/min/1.73 m2 per year in CRD group versus −0.1 ± 4.8 mL/min/1.73 m2 per year in non-CRD group (P = .027). After CRD diagnosis, major changes in immunosuppression based on calcineurin inhibitors reduction were instituted in 46.8% of patients. Multivariate model identified recipient age (P < .0001), female sex (P = .0398), and time since transplant (P < .0001) as predictors of CRD. In conclusion, the prevalence of CRD in long-term heart recipient survivors was quite high. CRD was associated with nonmodifiable factors (age, gender, and time since transplant)

Conversion from immediate-release tacrolimus to prolonged-release tacrolimus in stable heart transplant patients: a retrospective study

[Abstract] Background Lifelong adherence with post-transplant immunosuppression is challenging, with nonadherence associated with greater acute rejection (AR) risk. Methods This retrospective study evaluated conversion from immediate-release tacrolimus (IRT) to prolonged-release tacrolimus (PRT), between January 2008 and December 2012 in stable adult heart transplant recipients. Cumulative incidence rate (IR) of AR and infection pre- and postconversion, safety, tacrolimus dose and trough levels, concomitant immunosuppression, and PRT discontinuation were analyzed (intention-to-treat population). Results Overall, 467 patients (mean age, 59.3 [SD, 13.3] years) converted to PRT at 5.1 (SD, 4.9) years post transplant and were followed for 3.4 (SD, 1.5) years. During the 6 months post conversion, 5 patients (1.1%; 95% CI, 0.35%–2.48%) had an AR episode and IR was 2.2/100 patient-years (95% CI, 0.91–5.26). Incidence of rejection preconversion varied by time from transplant to conversion. Infection IR was similar post- and preconversion (9.2/100 patient-years [95% CI, 7.4–11.3] vs 10.6/100 patient-years [95% CI, 8.8–12.3], respectively; P = .20). Safety variables remained similar post conversion. The IR of mortality/graft loss was 2.3/100 patient-years (95% CI, 1.7–3.1). Conclusions Conversion from IRT to PRT in heart transplant recipients in Spain was associated with no new safety concerns and appropriate immunosuppressive effectiveness

Impacto de la variabilidad intrapaciente en la concentración sanguínea de anticalcineurínicos en los resultados del trasplante cardiaco

[Abstract] 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.[Resumen] Introducción y objetivos. El objetivo es estudiar el impacto clínico de la variabilidad intrapaciente (VIP) de la concentración sanguínea de los anticalcineurínicos en el trasplante cardiaco, pues la información actual es escasa. Métodos. Se analizó retrospectivamente a pacientes de edad ≥ 18 años con un trasplante cardiaco realizado entre 2000 y 2014 y con supervivencia ≥ 1 año. La VIP se valoró mediante el coeficiente de variación de concentraciones entre los meses 4 a 12 postrasplante. El compuesto de rechazo, mortalidad o pérdida del injerto y la mortalidad o pérdida del injerto 1-5 años tras el trasplante se analizaron mediante regresión de Cox. Resultados. Se estudió a 1.581 receptores (edad, 56 años; mujeres, 21%), tratados con ciclosporina (790 pacientes) o tacrolimus (791 pacientes). En el análisis multivariable, un coeficiente de variación > 27,8% tendió a asociarse con el compuesto de rechazo/mortalidad (HR = 1,298; IC95%, 0,993-1,695; p = 0,056) y con la mortalidad (HR = 1,387; IC95%, 0,979-1,963; p = 0,065) a los 5 años. La asociación con el rechazo fue significativa al analizar a la población sin rechazos durante el primer año del trasplante (HR = 1,609; IC95%, 1,129-2,295; p = 0,011). El tacrolimus tuvo menos VIP que la ciclosporina, junto con unos mejores resultados por la menor influencia de la VIP. Conclusiones. La VIP de los anticalcineurínicos, especialmente con la inmunosupresión basada en el tacrolimus, se asocia solo marginalmente con los resultados a medio plazo del trasplante cardiaco, aunque puede tener influencia en los pacientes más estables durante el primer año tras el trasplante

Prevalence, Incidence, and Outcomes of Hyperkalaemia in Patients with Chronic Heart Failure and Reduced Ejection Fraction from a Spanish Multicentre Study: SPANIK-HF Design and Baseline Characteristics

[Abstract] Hyperkalaemia is a growing concern in the treatment of patients with heart failure and reduced ejection fraction (HFrEF) as it limits the use of some prognostic-modifying drugs and has a negative impact on prognosis. The objective of the present study was to estimate the prevalence of hyperkalaemia in outpatients with HFrEF and its impact on achieving optimal medical treatment. For this purpose, a multicentre, prospective, and observational study was carried out on consecutive HFrEF patients who were monitored as outpatients in heart failure (HF) units and who, in the opinion of their doctor, received optimal medical treatment. A total of 565 HFrEF patients were included from 16 specialised HF units. The mean age was 66 ± 12 years, 78% were male, 45% had an ischemic cause, 39% had atrial fibrillation, 43% were diabetic, 42% had a glomerular filtration rate < 60 mL/min/1.7 m2, and the mean left ventricular ejection fraction was 31 ± 7%. Treatment at the study entry included: 76% on diuretics, 13% on ivabradine, 7% on digoxin, 18.9% on angiotensin-conversing enzyme inhibitors (ACEi), 11.3% on angiotensin receptors blockers (ARBs), 63.8% on angiotensin-neprilysin inhibitors (ARNi), 78.5% on mineralocorticoid receptor antagonists (MRAs), and 92.9% on beta-blockers. Potassium levels in the baseline analysis were: ≤5 mEq/L = 80.5%, 5.1–5.4 mEq/L = 13.8%, 5.5–5.9 mEq/L = 4.6%, and ≥6 mEq/L = 1.06%. Hyperkalaemia was the reason for not prescribing or reaching the target dose of an MRAs in 34.8% and 12.5% of patients, respectively. The impact of hyperkalaemia on not prescribing or dropping below the target dose in relation to ACEi, ARBs, and ARNi was significantly less. In conclusion, hyperkalaemia is a frequent problem in the management of patients with HFrEF and a limiting factor in the optimisation of medical treatment.AstraZeneca Farmacéutica; ESR-17-1324