Two-Dimensional Speckle Tracking Echocardiography in Heart Transplant Patients: Two-Year Follow-Up of Right and Left Ventricular Function.

BACKGROUND: Evolution of left and right ventricular (LV and RV) function after heart transplantation (HT) has not been well described. Our objective was to evaluate the evolution of echocardiographic parameters of both ventricles along the first 2 years after HT. METHODS: We followed 31 HT recipients with serial echocardiograms for up to 2 years. Echocardiograms with AR ≥2R were excluded. We analyzed LV global longitudinal strain (LV GLS) by speckle tracking in 12 segments in four- and two-chamber views and RV global longitudinal strain (RV GLS) in four-chamber view. Control group included 25 healthy volunteers. RESULTS: Even though LVEF was preserved, LV GLS was reduced early post-HT (-17.7 ± 3.0 in HT vs. -20.7 ± 2.8 in controls, P = 0.02), improving progressively until its complete normalization 2 years after HT (-20.0 ± 3.7 vs. -20.7 ± 2.8, P = 0.60). TAPSE was impaired in the early post-HT period and increased progressively (11.9 ± 2.9 mm at baseline vs. 19.0 ± 3.6 mm at 2 years, P < 0.001). RV GLS rose during follow-up as well (-17.4 ± 3.5 at baseline vs. -22.6 ± 3.3 at 2 years, P = 0.001), reaching normal values 1 year after HT. CONCLUSION: In this series of HT recipients with uneventful postoperative course, LV and RV GLS values were significantly reduced early after HT and improved progressively until their complete normalization two and 1 year after HT, respectively. This is the first study to show a full recovery of LV and RV deformation parameters and offers "normal" strain values that, if confirmed in larger studies, could be useful for monitoring the evolution of HT recipients.

The impact of the prevention strategies on the indirect effects of CMV infection in solid organ transplant recipients.

Transplant recipients receiving immunosuppressive therapy are at increased risk of active cytomegalovirus (CMV) infection and disease. Without appropriate prophylaxis, as many as 80% of solid organ transplant recipients may experience CMV infection. In addition to the direct effects of CMV, infection may be associated with a range of indirect effects, including an increase in risk of other infections, as well as a higher incidence of rejection, graft loss and death. The indirect effects of CMV infection can vary depending on the transplanted organ. For example, CMV-infected kidney transplant recipients may be at increased risk of cardiovascular disease and diabetes, while CMV infection in liver transplant recipients may potentiate hepatitis C infection and increase the risk of post-transplant lymphoproliferative disease. Indirect effects result from a number of pathological processes, including immune modulation and immunosuppression, generation of cytotoxic, pro-inflammatory responses, and smooth muscle proliferation. Prophylactic treatment with antiviral medication can reduce the risk of CMV disease, thereby improving graft survival and overall outcomes, particularly in kidney and heart transplant recipients. Antiviral prophylaxis should be considered for all patients at risk of CMV infection after solid organ transplantation. In this paper we review the main indirect effects of CMV infection in solid organ transplant recipients, and the impact of CMV prophylaxis on these effects.

Primary graft failure after heart transplantation: characteristics in a contemporary cohort and performance of the RADIAL risk score.

BACKGROUND: Primary graft failure (PGF) is the leading cause of early heart transplantation (HT) mortality. Our aim was to analyze PGF currently and explore the ability of a dedicated score for PGF risk stratification. METHODS: After applying a dedicated PGF definition, we analyzed its incidence, mortality, and associated factors in a multicenter cohort of 857 HTs performed in 2006 to 2009. We used the following criteria: recipient right (R) atrial pressure ≥ 10 mm Hg; age (A) ≥ 60 years; diabetes (D) mellitus, and inotrope (I) dependence; donor age (A) ≥ 30 years, and length (L) of ischemia ≥ 240 minutes to calculate the RADIAL score for PGF risk prediction. RESULTS: PGF incidence was 22%. The right ventricle was almost always affected, alone (45%) or as part of biventricular failure (47%). Mechanical circulatory support was used in 55%. Mortality attributable to PGF was 53% and extended through the third month after HT, but thereafter, PGF had little influence in long-term outcome. The RADIAL score was higher in PGF patients (2.78 ± 1.1 vs. 2.42 ± 1.1, p = 0.001) and stratified 3 groups with incremental PGF incidence: low risk (12.1%), intermediate risk (19.4%), and high risk (27.5%, p = 0.001). CONCLUSIONS: PGF had a strong impact, with an incidence of 22% and a mortality exceeding 50% that extends through the third post-HT month. The RADIAL score classified patients into 3 groups with incremental risk for PGF and may be useful for its prevention and early therapy.

New concepts and best practices for management of pre- and post-transplantation cancer.

Solid-organ transplant recipients are at increased risk of developing cancer compared with the general population. Tumours can arise de novo, as a recurrence of a preexisting malignancy, or from the donated organ. The ATOS (Aula sobre Trasplantes de Órganos Sólidos; the Solid-Organ Transplantation Working Group) group, integrated by Spanish transplant experts, meets annually to discuss current advances in the field. In 2011, the 11th edition covered a range of new topics on cancer and transplantation. In this review we have highlighted the new concepts and best practices for managing cancer in the pre-transplant and post-transplant settings that were presented at the ATOS meeting. Immunosuppression plays a major role in oncogenesis in the transplant recipient, both through impaired immunosurveillance and through direct oncogenic activity. It is possible to transplant organs obtained from donors with a history of cancer as long as an effective minimization of malignancy transmission strategy is followed. Tumour-specific wait-periods have been proposed for the increased number of transplantation candidates with a history of malignancy; however, the patient's individual risk of death from organ failure must be taken into consideration. It is important to actively prevent tumour recurrence, especially the recurrence of hepatocellular carcinoma in liver transplant recipients. To effectively manage post-transplant malignancies, it is essential to proactively monitor patients, with long-term intensive screening programs showing a reduced incidence of cancer post-transplantation. Proposed management strategies for post-transplantation malignancies include viral monitoring and prophylaxis to decrease infection-related cancer, immunosuppression modulation with lower doses of calcineurin inhibitors, and addition of or conversion to inhibitors of the mammalian target of rapamycin.

Abordaje familiar en la amiloidosis cardiaca hereditaria por transtiretina / Familial approach in hereditary transthyretin cardiac amyloidosis

La amiloidosis cardiaca es una enfermedad de difícil diagnóstico y tratamiento. Entre los subtipos de amiloidosis cardiacas figuran las formas hereditarias, de las que la causada por mutaciones en el gen de la transtiretina es la más frecuente. La correcta identificación de los pacientes cuya amiloidosis se debe a un defecto genético tiene gran importancia, ya que modifica la actitud diagnóstica y terapéutica que adoptar con el enfermo y sus familiares. En este trabajo describimos nuestra experiencia en la evaluación de dos familias con amiloidosis cardiaca hereditaria por transtiretina. Discutimos diversos aspectos relacionados con el abordaje diagnóstico de los pacientes, así como la actitud diagnóstica y terapéutica que adoptar con los familiares (AU)

Cardiac amyloidosis is a disease of complex diagnosis and treatment. Some subtypes of cardiac amyloidosis are inherited. Among these, the most common variant is caused by mutations in the transthyretin gene. Correct identification of amyloidosis produced by a genetic defect is of great importance because it modifies the diagnostic and therapeutic approach in patients and their families. We describe our experience in the evaluation of two families with hereditary transthyretin cardiac amyloidosis. We discuss a number of considerations related to the evaluation of these patients and the diagnostic and therapeutic approach to perform in relatives (AU)

[Familial approach in hereditary transthyretin cardiac amyloidosis]. / Abordaje familiar en la amiloidosis cardiaca hereditaria por transtiretina.

Cardiac amyloidosis is a disease of complex diagnosis and treatment. Some subtypes of cardiac amyloidosis are inherited. Among these, the most common variant is caused by mutations in the transthyretin gene. Correct identification of amyloidosis produced by a genetic defect is of great importance because it modifies the diagnostic and therapeutic approach in patients and their families. We describe our experience in the evaluation of two families with hereditary transthyretin cardiac amyloidosis. We discuss a number of considerations related to the evaluation of these patients and the diagnostic and therapeutic approach to perform in relatives.

Apoptosis and acute cellular rejection in human heart transplants.

INTRODUCTION AND OBJECTIVES: Apoptosis has been implicated in the pathophysiology of various forms of heart disease. Acute cellular rejection leads to morbidity after heart transplantation and invasive techniques are needed for its diagnosis. We investigated the presence of cardiomyocyte apoptosis in transplanted hearts, its progression, its relationship with rejection, and the possibility that serological markers of apoptosis can be used to detect rejection noninvasively. METHODS: Overall, 130 endomyocardial biopsies obtained sequentially from 14 consecutive patients during the first 6 months following heart transplantation underwent histochemical analysis. The degree of acute rejection was determined, myocyte apoptosis was assessed using the TUNEL method, and caspase-3 activity was measured. In the first 10 patients, soluble Fas, tumor necrosis factor-alpha (TNFα) and interleukin 6 levels were determined in serum collected at biopsy. RESULTS: Apoptotic cells were detected in 81.5% of biopsies. No significant correlation was found between the apoptotic index and either the degree of rejection or the time from transplantation; there was only a trend to higher values during prolonged episodes of rejection, which did not reach statistical significance. An inverse correlation was observed between the degree of rejection and the TNFα level (rs=-0.33; P=.003). There was no correlation with any other variable. CONCLUSIONS: Cardiomyocyte loss due to apoptosis was observed in transplanted hearts, but no correlation was observed with either acute rejection or the time from transplantation. Our findings suggest there could be an inverse correlation between rejection and the serum TNFα level. No serum parameter evaluated was regarded as suitable for the noninvasive diagnosis of acute rejection.

Apoptosis y rechazo agudo celular en el trasplante cardiaco humano / Apoptosis and acute cellular rejection in human heart transplants

Introducción y objetivos. La apoptosis se ha implicado en la fisiopatología de diversas cardiopatías. El rechazo agudo celular causa morbilidad tras el trasplante cardiaco y su diagnóstico requiere técnicas invasivas. Hemos investigado la existencia de apoptosis de cardiomiocitos en el corazón trasplantado, su evolución temporal, su relación con el rechazo y la posibilidad de diagnosticar de forma no invasiva el rechazo mediante detección de marcadores séricos de apoptosis. Métodos. Análisis histoquímico de 130 biopsias endomiocárdicas obtenidas secuencialmente de 14 pacientes consecutivos en los primeros 6 meses tras el trasplante. Se determinaron: grado de rechazo agudo, apoptosis de cardiomiocitos mediante TUNEL y actividad de caspasa 3. En los primeros 10 pacientes, se analizaron en sueros extraídos simultáneamente a las biopsias: Fas soluble, factor de necrosis tumoral alfa e interleucina 6. Resultados. Se detectaron células apoptósicas en el 81,5% de las biopsias. No encontramos correlación del índice apoptósico con el grado de rechazo ni con el tiempo desde el trasplante, sólo una tendencia a valores mayores en casos de rechazo prolongado que no alcanza la significación estadística. Observamos correlación inversa entre grado de rechazo y factor de necrosis tumoral alfa (rs = -0,33; p = 0,003). No encontramos correlación del rechazo con el resto de las variables. Conclusiones. Detectamos en el corazón trasplantado pérdida de cardiomiocitos por apoptosis. No hallamos correlación con el rechazo agudo ni con el tiempo desde el trasplante. Nuestros datos indican que podría haber correlación inversa entre rechazo y factor de necrosis tumoral alfa en suero. Consideramos que ninguno de los parámetros séricos valorados es óptimo para diagnóstico no invasivo de rechazo (AU)

Introduction and objectives. Apoptosis has been implicated in the pathophysiology of various forms of heart disease. Acute cellular rejection leads to morbidity after heart transplantation and invasive techniques are needed for its diagnosis. We investigated the presence of cardiomyocyte apoptosis in transplanted hearts, its progression, its relationship with rejection, and the possibility that serological markers of apoptosis can be used to detect rejection noninvasively. Methods. Overall, 130 endomyocardial biopsies obtained sequentially from 14 consecutive patients during the first 6 months following heart transplantation underwent histochemical analysis. The degree of acute rejection was determined, myocyte apoptosis was assessed using the TUNEL method, and caspase-3 activity was measured. In the first 10 patients, soluble Fas, tumor necrosis factor-alpha (TNFα) and interleukin 6 levels were determined in serum collected at biopsy. Results. Apoptotic cells were detected in 81.5% of biopsies. No significant correlation was found between the apoptotic index and either the degree of rejection or the time from transplantation; there was only a trend to higher values during prolonged episodes of rejection, which did not reach statistical significance. An inverse correlation was observed between the degree of rejection and the TNFα level (rs=-0.33; P=.003). There was no correlation with any other variable. Conclusions. Cardiomyocyte loss due to apoptosis was observed in transplanted hearts, but no correlation was observed with either acute rejection or the time from transplantation. Our findings suggest there could be an inverse correlation between rejection and the serum TNFα level. No serum parameter evaluated was regarded as suitable for the noninvasive diagnosis of acute rejection (AU)

[Ischemia-reperfusion injury during experimental heart transplantation. Evaluation of trimetazidine's cytoprotective effect]. / Daño por isquemia-reperfusión durante el trasplante cardíaco experimental. Evaluación del papel citoprotector de la trimetazidina.

INTRODUCTION AND OBJECTIVES: The objectives of this study were to analyze the ischemia-reperfusion injury due to free radicals that occurs during heart transplantation and to determine the potential cytoprotective effect of trimetazidine. MATERIAL AND METHOD: A total of 21 orthotopic heart transplantations were performed in pigs. We divided the experimental animals into 2 groups: in group A (n=11),standard myocardial protection was used; in group B (n=10), trimetazidine was added to the cardioplegic solution used to protect the donor heart and to the solution administered to the recipient prior to release of the aortic clamp (trimetazidine, 10(-5) mol/L), and recipients were pretreated with trimetazidine, 2.5 mg/kg. Blood samples were taken from the recipients coronary sinus at three times: at baseline, during ischemia, and during reperfusion. We measured the levels of malondialdehyde, a marker of lipid peroxidation, and of several antioxidants: glutathione peroxidase, glutathione reductase, superoxide dismutase, alpha-tocopherol, and retinol. The total antioxidant status was also determined. RESULTS: Malondialdehyde production and enzymatic antioxidant activity rose during ischemia and reperfusion, while the retinol level decreased. The increases in malondialdehyde level and glutathione peroxidase activity that occurred between baseline and reperfusion were significantly higher in group A. CONCLUSIONS. The degree of lipid peroxidation and the level of activity of intracellular antioxidant mechanisms increased progressively throughout transplantation. Trimetazidine had a cytoprotective effect. It ameliorated free radical-induced reperfusion injury and modified the response pattern of several defense mechanisms.

Daño por isquemia-reperfusión durante el trasplante cardíaco experimental. Evaluación del papel citoprotector de la trimetazidina / Ischemia-reperfusion injury during experimental heart transplantation. Evaluation of trimetazidine’s cytoprotective effect

Introducción y objetivos. El objetivo de este trabajo fueanalizar el daño por isquemia-reperfusión mediado por radicales libres que se produce durante el trasplante cardíaco y eva-luar el posible efecto citoprotector de la trimetazidina (TMZ). Material y método. Se realizaron 21 trasplantes cardíacos ortotópicos en cerdos. Dividimos los experimentos en 2 grupos: A (n = 11), en el que se realizó una protección miocárdica estándar, y B (n = 10), en el que se administró TMZ en la cardioplejía empleada para parar el corazón donante (TMZ, 10–5 mol/l), como pretratamiento intravenosodel receptor (TMZ, 2,5 mg/kg) y como parte de la cardio-plejía infundida en el receptor antes de despinzar la aorta(TMZ, 10–5 mol/l). Se tomaron muestras de sangre del senocoronario del receptor en 3 momentos: basal, isquemia y reperfusión. Se determinó la concentración de malonildial-dehído como marcador de peroxidación lipídica y de variosantioxidantes: glutatión peroxidasa, glutatión reductasa,superóxido dismutasa, α-tocoferol, retinol y estado de antioxidantes totales. Resultados. Durante la isquemia-reperfusión aumentóla producción de malonildialdehído y la actividad de losantioxidantes enzimáticos, mientras que el retinol disminuyó. El incremento de malonildialdehído y de la actividad de la glutatión peroxidasa entre el momento basal y la reperfusión fue significativamente mayor en el grupo A. Conclusiones. Durante el trasplante se incrementó progresivamente el nivel de peroxidación lipídica y se activaronlos sistemas antioxidantes intracelulares. La TMZ ejerció un efecto citoprotector y limitó el daño por isquemia-reperfusión generado por los radicales libres, además de modificar el patrón de reacción de parte de los sistemas de defensa

Introduction and objectives. The objectives of thisstudy were to analyze the ischemia-reperfusion injury dueto free radicals that occurs during heart transplantationand to determine the potential cytoprotective effect of trimetazidine. Material and method. A total of 21 orthotopic heart transplantations were performed in pigs. We divided the experimental animals into 2 groups: in group A (n=11),standard myocardial protection was used; in group B(n=10), trimetazidine was added to the cardioplegic solution used to protect the donor heart and to the solution administered to the recipient prior to release of the aortic clamp (trimetazidine, 10–5mol/L), and recipients were pretreated with trimetazidine, 2.5 mg/kg. Blood samples weretaken from the recipient’s coronary sinus at three times: at baseline, during ischemia, and during reperfusion. We measured the levels of malondialdehyde, a marker of lipid peroxidation, and of several antioxidants: glutathione peroxidase, glutathione reductase, superoxide dismutase, α-tocopherol, and retinol. The total antioxidant status wasalso determined. Results. Malondialdehyde production and enzymaticanti oxidant activity rose during ischemia and reperfusion, while the retinol level decreased. The increases in malondialdehyde level and glutathione peroxidase activity that occurred between baseline and reperfusion were significantly higher in group A. Conclusions. The degree of lipid peroxidation and the level of activity of intracellular antioxidant mechanisms increased progressively throughout transplantation. Trimetazidine had a cytoprotective effect. It ameliorated free radical-induced reperfusion injury and modified the response pattern of several defense mechanisms

Comparison of low and high initial tacrolimus dosing in primary heart transplant recipients: a prospective European multicenter study.

BACKGROUND: The purpose of this prospective, randomized, open-label, phase II, multicenter study was to optimize the initial oral dose of tacrolimus. METHODS: A total of 113 patients were randomly assigned to initial low-dose (0.075 mg/kg/day, n=55) or high-dose (0.15 mg/kg/day, n=58) oral tacrolimus and followed for 3 months. Target whole-blood trough levels were 10 to 20 ng/mL. Prophylactic use of corticosteroids and azathioprine was identical in both groups, and antibody induction was mandatory. The primary endpoint was the time to and incidence of the initial oral tacrolimus dose adjustment because of toxicity or rejection, or withdrawal before initial dose change. Efficacy was assessed by the occurrence of biopsy-proven rejection (International Society for Heart and Lung Transplantation grade > or =1B). RESULTS: In the primary endpoint, no significant difference was observed between the low- and high-dose groups. After 3 months, there was no difference in freedom from initial oral tacrolimus dose change because of rejection, toxicity, or withdrawal (89.0% vs. 87.6%; not significant [NS]). In both groups, dose adjustments were mainly required to achieve and maintain target blood levels (80.0% vs. 82.8%; NS). Patient survival was 92.7% and 98.3% (NS). There was no significant difference between groups regarding freedom from biopsy-proven acute rejection (57.1% vs. 66.3%; NS). The overall safety profiles indicated a tendency toward better tolerability in the low-dose group. CONCLUSIONS: Although low-dose and high-dose tacrolimus had similar efficacy, low-dose tacrolimus was associated with a more favorable safety profile. Therefore we recommend starting tacrolimus therapy after antibody induction at 0.075 mg/kg and adjust dose according to whole-blood trough levels.

Resincronización cardíaca: punto de vista del cardiólogo clínico / Cardiac resynchronization therapy: a clinical perspective

La terapia de resincronización cardíaca produce mejoría sintomática y hemodinámica en pacientes con insuficiencia cardíaca avanzada y asincronía ventricular. Los resultados de diferentes estudios han demostrado de forma consistente que la resincronización produce mejoría significativa de la calidad de vida, capacidad de ejercicio y de la función cardíaca, objetivándose una reducción significativa de la mortalidad total y del número de hospitalizaciones en pacientes tratados con insuficiencia cardíaca avanzada, en clase funcional de la New York Heart Association (NYHA) III o IV a pesar de tratamiento médico óptimo y de un complejo QRS ancho. Claramente, el tratamiento de la insuficiencia cardíaca requiere, en el momento actual, una colaboración multidisciplinaria entre los clínicos especialistas en insuficiencia cardíaca, electrofisiólogos y cirujanos. Sin embargo, hasta el 30% de los pacientes puede no beneficiarse de esta terapia. Se están investigando nuevos marcadores de asincronía, como la determinación de asincronía guiada por ecocardiografía, en un intento de mejorar la identificación de los respondedores. Actualmente se está investigando el beneficio de la terapia de resincronización en otros grupos de pacientes que potencialmente se podrían beneficiar de ella, como aquellos en fibrilación auricular (aproximadamente el 20-30% de los pacientes con insuficiencia cardíaca severa), asincronía secundaria a estimulación convencional derecha, o en clase II de la NYHA. En pacientes con insuficiencia cardíaca avanzada y complejo QRS ancho que permanecen sintomáticos a pesar de recibir tratamiento médico óptimo, la terapia de resincronización ha demostrado una reducción de la morbimortalidad. Por tanto, actualmente debería considerarse de forma sistemática en estos pacientes (AU)

Cardiac resynchronization therapy improves hemodynamics and symptoms in patients with advanced heart failure and ventricular dyssynchrony. The results of numerous studies of cardiac resynchronization in patients with advanced heart failure (i.e., New York Heart Association class III or IV) who have a wide QRS complex and who are receiving optimal medical therapy have consistently demonstrated significant improvements in quality of life, exercise capacity and cardiac function and a significant reduction in the number reaching the combined endpoint of mortality or hospitalization due to all causes. Clearly, the management of heart failure requires multidisciplinary collaboration between heart failure specialists, electrophysiologists and surgeons. However, up to 30% of patients may not benefit from this type of therapy. New markers of dyssynchrony, such as echocardiographically guided measurement of ventricular asynchrony, are currently being investigated with the aim of identifying responders more accurately. At present, the efficacy of cardiac resynchronization therapy is undergoing further study in other groups of patients who may benefit: those with atrial fibrillation (potentially 20% to 30% of patients with severe heart failure), those with dyssynchrony secondary to conventional right ventricular pacing, and those in NYHA class II. Cardiac resynchronization therapy has been shown to reduce morbidity and mortality in patients with advanced heart failure and a wide QRS complex who remain symptomatic despite optimal medical therapy. It should, therefore, be offered routinely to eligible patients with heart failure (AU)