RESUMEN
BACKGROUND: Despite improvements in the care of patients who have received cardiac transplants, coronary allograft vasculopathy (CAV) remains the most prevalent cause of late allograft failure and cardiac mortality. Few proven therapies are available for this important disease. The presence of coronary collaterals imparts a favorable prognosis in patients with native ischemic heart disease; however, the impact of collaterals in CAV is unknown. METHODS AND RESULTS: To determine whether the development of coronary collaterals is associated with improved outcomes in patients with CAV, we performed a retrospective analysis of patients followed in the heart transplant program at Barnes Jewish Hospital from 1994 to 2008. The primary end points included all cause mortality and the composite of all cause mortality, retransplantation, and inotrope dependence. We screened 485 patients and identified 59 (12%) subjects with moderate-to-severe CAV. Angiographically visible coronary collaterals were present in 34 (57%) subjects. Kaplan-Meier and Cox multivariable analyses revealed that patients with collaterals had reduced incidence of all cause mortality (hazard ratio, 0.20; P<0.001) and the composite end point (hazard ratio, 0.17; P<0.001). In addition, patients with collaterals had less severe heart failure symptoms as measured by New York Heart Association class. Immunostaining of biopsy specimens revealed that among patients with CAV, the presence of coronary collaterals correlated with increased microvascular density, reduced fibrosis, and decreased left ventricular end-diastolic pressure. CONCLUSIONS: Together, these data demonstrate that the presence of coronary collaterals predicts a favorable prognosis in patients with CAV and suggests that interventions aimed at promoting collateral and microvascular growth may serve as effective therapies for this disease.
Asunto(s)
Circulación Colateral/fisiología , Circulación Coronaria/fisiología , Enfermedad Coronaria/cirugía , Rechazo de Injerto/mortalidad , Rechazo de Injerto/fisiopatología , Trasplante de Corazón/mortalidad , Trasplante de Corazón/fisiología , Adulto , Enfermedad Coronaria/mortalidad , Enfermedad Coronaria/fisiopatología , Femenino , Fibrosis , Rechazo de Injerto/diagnóstico , Insuficiencia Cardíaca , Trasplante de Corazón/inmunología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Miocardio/patología , Pronóstico , Estudios Retrospectivos , Trasplante HomólogoRESUMEN
BACKGROUND: Mitochondria are key players in the development and progression of heart failure (HF). Mitochondrial (mt) dysfunction leads to diminished energy production and increased cell death contributing to the progression of left ventricular failure. The fundamental mechanisms that underlie mt dysfunction in HF have not been fully elucidated. METHODS AND RESULTS: To characterize mt morphology, biogenesis, and genomic integrity in human HF, we investigated left ventricular tissue from nonfailing hearts and end-stage ischemic (ICM) or dilated (DCM) cardiomyopathic hearts. Although mt dysfunction was present in both types of cardiomyopathy, mt were smaller and increased in number in DCM compared with ICM or nonfailing hearts. mt volume density and mtDNA copy number was increased by ≈2-fold (P<0.001) in DCM hearts in comparison with ICM hearts. These changes were accompanied by an increase in the expression of mtDNA-encoded genes in DCM versus no change in ICM. mtDNA repair and antioxidant genes were reduced in failing hearts, suggestive of a defective repair and protection system, which may account for the 4.1-fold increase in mtDNA deletion mutations in DCM (P<0.05 versus nonfailing hearts, P<0.05 versus ICM). CONCLUSIONS: In DCM, mt dysfunction is associated with mtDNA damage and deletions, which could be a consequence of mutating stress coupled with a peroxisome proliferator-activated receptor γ coactivator 1α-dependent stimulus for mt biogenesis. However, this maladaptive compensatory response contributes to additional oxidative damage. Thus, our findings support further investigations into novel mechanisms and therapeutic strategies for mt dysfunction in DCM.
Asunto(s)
Cardiomiopatías/metabolismo , Cardiomiopatías/patología , Recambio Mitocondrial/fisiología , Adulto , Anciano , Anciano de 80 o más Años , Cardiomiopatías/genética , ADN Mitocondrial/genética , ADN Mitocondrial/metabolismo , Femenino , Trasplante de Corazón/patología , Trasplante de Corazón/fisiología , Humanos , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Brain death (BD) can immunologically prime the donor organ and is thought to lead to exacerbated ischemia/reperfusion injury after transplantation. Using a newly developed mouse model of BD, we investigated the effect of donor BD on posttransplantation cardiac ischemia/reperfusion injury. We further investigated the therapeutic effect of a targeted complement inhibitor in recipients of BD donor hearts and addressed the clinical relevance of these studies by analyzing human heart biopsies from BD and domino (living) donors. METHODS AND RESULTS: Hearts from living or BD donor C57BL/6 mice were transplanted into C57BL/6 or BALB/c recipients. Recipient mice were treated with the complement inhibitor CR2-Crry or vehicle control (n=6). Isografts were analyzed 48 hours after transplantation for injury, inflammation, and complement deposition, and allografts were monitored for graft survival. Human cardiac biopsies were analyzed for complement deposition and inflammatory cell infiltration. In the murine model, donor BD exacerbated ischemia/reperfusion injury and graft rejection, as demonstrated by increased myocardial injury, serum cardiac troponin, cellular infiltration, complement deposition, inflammatory chemokine and cytokine levels, and by decreased graft survival. CR2-Crry treatment of recipients significantly reduced all measured outcomes in grafts from both BD and living donors compared with controls. Analysis of human samples documented the relevance of our experimental findings and revealed exacerbated complement deposition and inflammation in grafts from BD donors compared with grafts from living donors. CONCLUSIONS: BD exacerbates posttransplantation cardiac ischemia/reperfusion injury in mice and humans and decreases survival of mouse allografts. Furthermore, targeted complement inhibition in recipient mice ameliorates BD-exacerbated ischemia/reperfusion injury.
Asunto(s)
Muerte Encefálica/fisiopatología , Proteínas del Sistema Complemento/fisiología , Trasplante de Corazón/fisiología , Daño por Reperfusión/fisiopatología , Donantes de Tejidos , Adolescente , Adulto , Animales , Biopsia , Citocinas/metabolismo , Femenino , Corazón/efectos de los fármacos , Trasplante de Corazón/mortalidad , Humanos , Masculino , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , Persona de Mediana Edad , Modelos Animales , Miocardio/metabolismo , Miocardio/patología , Proteínas Recombinantes de Fusión/farmacología , Estudios Retrospectivos , Tasa de Supervivencia , Adulto JovenRESUMEN
Exercise capacity remains lower in heart transplant recipients (HTRs) following transplant compared with normal subjects, despite improved cardiac function. Moreover, metaboreceptor activity in the muscle has been reported to increase. The aim of the present investigation was to assess exercise capacity together with metaboreflex activity in HTR patients for 1 yr following heart transplant, to test the hypothesis that recovery in exercise capacity was paralleled by improvements in response to metaboreflex. A cardiopulmonary test for exercise capacity and Vo(2max) and hemodynamic response to metaboreflex activation obtained by postexercise ischemia were gathered in six HTRs and nine healthy controls (CTL) four times: at the beginning of the study (T0, 42 ± 6 days after transplant), at the 3rd, 6th, and 12th month after TO (T1, T2, and T3). The main results were: 1) exercise capacity and Vo(2max) were seen to progressively increase in HTRs; 2) at T0 and T1, HTRs achieved a higher blood pressure response in response to metaboreflex compared with CTL, and this difference disappeared at T2 and T3; and 3) this exaggerated blood pressure response was the result of a systemic vascular resistance increment. This study demonstrates that exercise capacity progressively improves in HTRs after transplant and that this phenomenon is accompanied by a progressive reduction of the metaboreflex-induced increase in blood pressure and systemic vascular resistance. These facts indicate that, despite improved cardiac function, resetting of cardiovascular regulation in HTRs requires months.
Asunto(s)
Ejercicio Físico/fisiología , Trasplante de Corazón/fisiología , Corazón/fisiología , Hemodinámica/fisiología , Músculo Esquelético/fisiología , Reflejo/fisiología , Presión Sanguínea/fisiología , Humanos , Isquemia/fisiopatología , Masculino , Persona de Mediana Edad , Consumo de Oxígeno/fisiologíaAsunto(s)
Rechazo de Injerto/genética , Trasplante de Corazón/fisiología , Tolerancia al Trasplante/genética , Factor B de Crecimiento Endotelial Vascular/biosíntesis , Animales , Regulación hacia Abajo/genética , Regulación de la Expresión Génica , Rechazo de Injerto/metabolismo , Miocitos Cardíacos/metabolismo , Miocitos Cardíacos/patología , ARN Mensajero/antagonistas & inhibidores , ARN Mensajero/biosíntesis , Ratas , Factor B de Crecimiento Endotelial Vascular/antagonistas & inhibidores , Factor B de Crecimiento Endotelial Vascular/genéticaRESUMEN
Smoking, both by donors and by recipients, has a major impact on outcomes after organ transplantation. Recipients of smokers' organs are at greater risk of death (lungs hazard ratio [HR], 1.36; heart HR, 1.8; and liver HR, 1.25), extended intensive care stays, and greater need for ventilation. Kidney function is significantly worse at 1 year after transplantation in recipients of grafts from smokers compared with nonsmokers. Clinicians must balance the use of such higher-risk organs with the consequences on waiting list mortality if the donor pool is reduced further by exclusion of such donors. Smoking by kidney transplant recipients significantly increases the risk of cardiovascular events (29.2% vs. 15.4%), renal fibrosis, rejection, and malignancy (HR, 2.56). Furthermore, liver recipients who smoke have higher rates of hepatic artery thrombosis, biliary complications, and malignancy (13% vs. 2%). Heart recipients with a smoking history have increased risk of developing coronary atherosclerosis (21.2% vs. 12.3%), graft dysfunction, and loss after transplantation. Self-reporting of smoking is commonplace but unreliable, which limits its use as a tool for selection of transplant candidates. Despite effective counseling and pharmacotherapy, recidivism rates after transplantation remain high (10-40%). Transplant services need to be more proactive in educating and implementing effective smoking cessation strategies to reduce rates of recidivism and the posttransplantation complications associated with smoking. The adverse impact of smoking by the recipient supports the requirement for a 6-month period of abstinence in lung recipients and cessation before other solid organs.
Asunto(s)
Trasplante de Corazón/fisiología , Trasplante de Riñón/fisiología , Trasplante de Hígado/fisiología , Trasplante de Pulmón/fisiología , Fumar/efectos adversos , Consejo , Medicina Basada en la Evidencia , Trasplante de Corazón/ética , Humanos , Trasplante de Riñón/ética , Trasplante de Hígado/ética , Trasplante de Pulmón/ética , Cese del Hábito de Fumar , Donantes de Tejidos , TrasplanteRESUMEN
BACKGROUND: A key determinant of long-term survival in heart transplant recipients is the development of coronary vasculopathy. Both coronary macrovascular and microvascular disease are prognostically important. However, the relationship between these in transplant patients and the determinants of microvascular disease are not known. METHODS: We reviewed the simultaneously obtained endomyocardial biopsies and intravascular ultrasound (IVUS) images of coronary arteries in 33 heart transplant recipients. Coronary microvascular disease was classified by light microscopy into four grades based on thickening of endothelial cell layer and stenotic versus nonstenotic medial wall thickening. Macrovascular disease was evaluated from IVUS studies and assigned into one of five grades based on the Stanford classification. Coronary microvascular and macrovascular diseases were compared. RESULTS: Age at transplantation was 26 (18) years; 67% were men, and the average time to posttransplantation study was 4 years. Endomyocardial biopsy revealed more advanced grade C and D microvascular disease in 45% and 36% of the patients, respectively. However, IVUS analysis for macrovascular disease revealed mostly lesser changes with grade 1 in 12%, grade 2 in 61%, and grade 3 in 21%. There was no significant correlation between grades of microvascular and macrovascular disease (P=0.10). Microvascular disease correlated positively with donor age (P=0.06) and treatment with tacrolimus (0=0.02) and statins (P=0.05). CONCLUSIONS: There is a poor relationship between coronary microvascular and macrovascular disease in patients with cardiac transplants, likely indicating divergent pathogenetic mechanisms. Microvascular disease increases with donor age. There is an intriguing positive relationship between microvascular disease and treatment with statins and tacrolimus.
Asunto(s)
Enfermedad de la Arteria Coronaria/etiología , Enfermedad de la Arteria Coronaria/fisiopatología , Trasplante de Corazón/patología , Trasplante de Corazón/fisiología , Microvasos/patología , Enfermedades Vasculares/etiología , Enfermedades Vasculares/fisiopatología , Adolescente , Adulto , Factores de Edad , Biopsia , Niño , Preescolar , Enfermedad de la Arteria Coronaria/epidemiología , Endocardio/patología , Endotelio Vascular/patología , Femenino , Rechazo de Injerto/prevención & control , Humanos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/efectos adversos , Inhibidores de Hidroximetilglutaril-CoA Reductasas/uso terapéutico , Lactante , Masculino , Microvasos/diagnóstico por imagen , Microvasos/fisiopatología , Persona de Mediana Edad , Prevalencia , Estudios Retrospectivos , Factores de Riesgo , Tacrolimus/efectos adversos , Tacrolimus/uso terapéutico , Túnica Media/diagnóstico por imagen , Ultrasonografía Intervencional , Enfermedades Vasculares/epidemiología , Adulto JovenRESUMEN
BACKGROUND: The main cause of early death after heart transplantation (HTx) is so-called early primary or secondary graft failure (GF). The risk of profound GF has not declined in the past decade, as the consequence of the liberalisation of donor acceptance criteria because of the scarcity of donors. It is therefore important to try to diagnose graft failure and recognise the mechanisms of early graft dysfunction. AIM: To establish haemodynamic and echocardiographic criteria of early GF to define patients who should be considered for assist device support or re-transplantation. METHODS: Between January 2000 and March 2009, 116 HTx patients were studied. On the basis of echocardiography and continuous invasive monitoring, three groups were identified: (1) The true graft failure group (GF) consisted of 46 patients; (2) The latent right ventricular (RV) dysfunction group (RV-D) consisted of 25 patients with small left ventricular (LV) chamber (ã 39 mm) and RV ejection fraction (RVEF) ã 50%; (3) The control group consisted of 45 consecutive HTx patients without any haemodynamic complications. RESULTS: Postoperatively, only the GF group required large doses of norepinephrine (ã 0.3 µmg/kg/min) and inhalative NO (40 ppm). Nevertheless, right and left filling pressures were significantly higher than in the controls (right 12 ± 3.6 vs. 9.0 ± 2 and left atrial pressure 13.0 ± 3.2 vs. 9.6 ± 2 mm Hg, both p ã 0.001). Cardiac index was significantly smaller (2.9 ± 0.7 vs. 3.7 ± 0.9, p ã 0.001) but neither pulmonary artery pressure (29.5 ± 6 vs. 29.7 ± 7 mm Hg) nor transpulmonary gradient (6 ± 5 vs. 5.1 ± 5 mm Hg) nor pulmonary vascular resistance (273 ± 97 vs. 287 ± 144 dyn × s × cm-5) differed significantly from those of the control group. In the GF group, LV end diastolic dimension (LVEDD) was significantly smaller and function poorer than in controls (39.8 ± 5 vs. 44.4 ± 5 mm, respectively, p = 0.001). RV function was also significantly worse (RVEF 42.2 ± 14% vs. 56.0 ± 9%), respectively, p = 0.001), whereas RV dimension did not differ significantly. Mechanical support after failure of the initial medical treatment was necessary in 37% of patients; 29 (63.0%) patients from the GF group died, the cause of death being sepsis with multi-organ failure. In the RV-D group, remodelling was quite similar but LVEF was excellent and maximal systolic velocity from the posterior wall was significantly higher than in GF. No death occurred. CONCLUSIONS: True early GF represents a grave haemodynamic situation with high mortality. Bedside echocardiography helps to distinguish between latent RV dysfunction and true GF.
Asunto(s)
Rechazo de Injerto/diagnóstico , Rechazo de Injerto/fisiopatología , Trasplante de Corazón/diagnóstico por imagen , Disfunción Ventricular Izquierda/fisiopatología , Disfunción Ventricular Derecha/fisiopatología , Causalidad , Comorbilidad , Diagnóstico Precoz , Ecocardiografía , Femenino , Rechazo de Injerto/epidemiología , Trasplante de Corazón/fisiología , Hemodinámica , Humanos , Masculino , Persona de Mediana Edad , Insuficiencia Multiorgánica/etiología , Insuficiencia Multiorgánica/mortalidad , Disfunción Ventricular Izquierda/diagnóstico por imagen , Disfunción Ventricular Izquierda/epidemiología , Disfunción Ventricular Derecha/diagnóstico por imagen , Disfunción Ventricular Derecha/epidemiologíaRESUMEN
BACKGROUND: Allograft dysfunction is a common finding early after heart transplant (HT). We sought to assess the recovery of left (LV) and right ventricular (RV) function during the first year after HT in children and young adults using pulsed-wave tissue Doppler imaging. METHODS AND RESULTS: We analyzed serially performed echocardiography in 44 pediatric HT recipients (median age: 7.3 years at HT) who remained rejection-free during the first year post-transplant. Age-based normative values for systolic (S'), early-diastolic (E'), and late-diastolic (A') velocities obtained using pulsed-wave tissue Doppler imaging in 380 healthy children were used to transform patient data into z scores. Pulsed-wave tissue Doppler imaging studies ≤10 days post-HT demonstrated biventricular systolic and diastolic dysfunction with most prominent impairment in RV systolic function (S' z score -2.7±0.8), RV early-diastolic filling (E' z score -2.3±1.1), and LV early-diastolic filling (E' z score -2.3±1.1). LV systolic function (S' z score) and late-diastolic filling (A' z score) improved to normal in 11 to 30 days, LV early-diastolic filling (E' z score) in 4 to 6 months, and RV early-diastolic filling in 6 to 9 months (P<0.001 for all on longitudinal analysis). However, RV systolic function (RV S' z score -1.2±1.1) remained impaired 1-year post-transplant. Analysis of serial cardiac catheterization studies showed that RV and LV filling pressures were elevated early post-HT and declined gradually during the first year post-transplant. CONCLUSIONS: Pediatric HT recipients have biventricular dysfunction using pulsed-wave tissue Doppler imaging early after HT with most significant impairment in RV systolic function and RV and LV early-diastolic filling. Although other aspects of LV and RV function normalize in 6 to 9 months, RV systolic function remains abnormal 1 year-post-transplant.
Asunto(s)
Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Función Ventricular/fisiología , Adolescente , Niño , Preescolar , Ecocardiografía Doppler en Color , Femenino , Estudios de Seguimiento , Rechazo de Injerto , Humanos , Lactante , Masculino , Estudios Retrospectivos , Factores de Tiempo , Trasplante Homólogo , Resultado del Tratamiento , Adulto JovenRESUMEN
BACKGROUND: For over 40 years now orthotopic heart transplantation (OHT) has been the treatment of choice in patients with advanced heart failure. For many years patients undergoing OHT have been treated with the classical approach involving anastomosis of the donor atria with the recipient atria resulting in a heart in which the atria are enlarged. An alternative method for OHT is the bicaval anastomosis technique, which involves connecting both of the donor's venae cavae with the recipient's venae cavae. AIM: To assess left ventricular (LV) filling in patients undergoing OHT using the classical (biatrial) versus bicaval approach. METHODS: We analysed 60 patients who had undergone OHT between 1 and 36 months before. Myocardial biopsy at echocardiography revealed grade 0 or 1A rejection in all the patients. All the patients were also in NYHA functional class I. The patients were divided in two groups: patients who had undergone biatrial anastomosis (Group 1, n = 40) and patients who had undergone bicaval OHT (Group 2, n = 20). In order to render the results independent of pre-OHT blood pressure values in the pulmonary circulation we assessed the values of right ventricular systolic pressure (RVSP), mean pulmonary artery pressure (PAP) and transpulmonary gradient (TPG) in all the patients before OHT. We assessed the following echocardiographic parameters: peak early filling velocity (E-wave), peak atrial filling velocity (A-wave), E-wave deceleration time, early diastolic mitral valve ring motion velocity (E'), E/E', isovolumetric relaxation time of the LV, duration of the A-wave, right atrial area and left atrial area, LV mass, LV mass index, LV end-diastolic and end-systolic dimension, and the severity of tricuspid regurgitation (TR). RESULTS: The values of RVSP, PAP and TPG in the study groups before OHT did not differ significantly. The values of E (86.5 ± 12.5 vs. 67.3 ± 8.5; p < 0.001), E' (11.9 ± 1.1 vs. 10.9 ± 0.9; p = 0.003) and E/E' (7.4 ± 1.5 vs. 6.1 ± 0.85; p = 0.006) differed between the groups and were significantly higher in the group undergoing surgery using the biatrial approach. The duration of the A-wave was significantly longer in the group undergoing surgery using the bicaval approach (129.0 ± 5.1 vs. 136.7 ± 10.0; p = 0.001). There were no significant differences in the other parameters of LV filling. Right atrial area was significantly lower in the group undergoing surgery using the bicaval approach (19.2 ± 3.0 vs. 14.0 ± 2.0; p < 0.001). LV size, LV mass and LV mass index did not differ significantly between the groups. The lack of TR was more commonly observed in the group undergoing surgery using the bicaval approach at the limit of p = 0.05. Pacemaker implantation was required in 12 (30%) patients from the group undergoing surgery using the classical method and 2 (10%) patients from the group undergoing OHT using the bicaval approach (p = 0.04). CONCLUSIONS: Certain echocardiographic parameters suggest a better LV filling in patients undergoing OHT using the bicaval approach. Preservation of the right atrial geometry in patients undergoing OHT using the bicaval approach plays an important role in LV filling.
Asunto(s)
Atrios Cardíacos/diagnóstico por imagen , Trasplante de Corazón/métodos , Trasplante de Corazón/fisiología , Ventrículos Cardíacos/diagnóstico por imagen , Miocardio/patología , Función Ventricular Izquierda/fisiología , Anastomosis Quirúrgica/métodos , Ecocardiografía , Rechazo de Injerto , Trasplante de Corazón/patología , Humanos , Arteria Pulmonar/fisiopatología , Circulación Pulmonar , Sístole/fisiología , Venas Cavas/cirugíaRESUMEN
BACKGROUND: Microvascular dysfunction is emerging as a strong predictor of outcome in heart transplant recipients. At this time, the determinants and consequences of early microvascular dysfunction are not well established. The objective of the study was to determine the risk factors and functional correlates associated with early microvascular dysfunction in heart transplant recipients. METHODS AND RESULTS: Sixty-three heart transplant recipients who had coronary physiology assessment, right heart catheterization, and echocardiography performed at the time of their first annual evaluation were included in the study. Microvascular dysfunction was assessed using the recently described index of microcirculatory resistance. The presence of microvascular dysfunction, predefined by an index of microcirculatory resistance >20, was observed in 46% of patients at 1 year. A history of acute rejection and undersized donor hearts were associated with microvascular dysfunction at 1 year, with odds ratio of 4.0 (1.3-12.8) and 3.6 (1.2-11.1), respectively. Patients with microvascular dysfunction had lower cardiac index (3.1±0.7 versus 3.5±0.7 L/min per m(2); P=0.02) and mild graft dysfunction measured by echocardiography-derived left and right myocardial performance indices ([0.54±0.09 versus 0.43±0.09; P<0.01] and [0.47±0.14 versus 0.32±0.05; P<0.01], respectively). Microvascular dysfunction was also associated with a higher likelihood of death, graft failure, or allograft vasculopathy at 5 years after transplant (hazard ratio, 2.52 [95% CI, 1.04-5.91]). CONCLUSIONS: A history of acute rejection during the first year and smaller donor hearts were identified as risk factors for early microvascular dysfunction. Microvascular dysfunction assessed using index of microcirculatory resistances at 1 year was also associated with worse graft function and possibly worse clinical outcomes.
Asunto(s)
Rechazo de Injerto/epidemiología , Trasplante de Corazón/fisiología , Microcirculación/fisiología , Microvasos/fisiopatología , Adulto , Estudios de Cohortes , Ecocardiografía , Femenino , Rechazo de Injerto/fisiopatología , Ventrículos Cardíacos/diagnóstico por imagen , Ventrículos Cardíacos/fisiopatología , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Pronóstico , Estudios Retrospectivos , Factores de RiesgoAsunto(s)
Cardiopatías/cirugía , Trasplante de Corazón/historia , Corazón/fisiología , Factores de Edad , Cardiopatías/epidemiología , Cardiopatías/psicología , Trasplante de Corazón/métodos , Trasplante de Corazón/fisiología , Trasplante de Corazón/estadística & datos numéricos , Historia del Siglo XX , Historia del Siglo XXI , Humanos , Pinturas , Procedimientos Quirúrgicos Torácicos/historia , Procedimientos Quirúrgicos Torácicos/métodos , Procedimientos Quirúrgicos Torácicos/psicología , Procedimientos Quirúrgicos Torácicos/estadística & datos numéricos , Donantes de TejidosRESUMEN
BACKGROUND: Engineered heart tissue (EHT) is being developed for clinical implantation in heart failure or congenital heart disease and therefore requires a comprehensive functional characterization and scale-up of EHT. Here we explored the effects of scale-up of self-organizing EHT and present detailed electrophysiologic and contractile functional characterization. METHODS: Fibers from EHT were generated from self-organizing neonatal rat cardiac cells (0.5×10(6) to 3×10(6)/fiber) on fibrin. We characterized contractile patterns and measured contractile function using a force transducer, and assessed force-length relationship, maximal force generation, and rate of force generation. Action potential and conduction velocity of EHT were measured with optical mapping, and transcript levels of myosin heavy chain beta were measured by reverse transcriptase-polymerase chain reaction. RESULTS: Increasing the cell number per construct resulted in an increase in fiber volume. The force-length relationship was negatively impacted by increasing cell number. Maximal force generation and rate of force generation were also abrogated with increasing cell number. This decrease was not likely attributable to a selective expansion of noncontractile cells as myosin heavy chain beta levels were stable. Irregular contractile behavior was more prevalent in constructs with more cells. Engineered heart tissue (1×10(6)/construct) had an action potential duration of 140.2 milliseconds and a conduction velocity of 23.2 cm/s. CONCLUSIONS: Engineered heart tissue displays physiologically relevant features shared with native myocardium. Engineered heart tissue scale-up by increasing cell number abrogates contractile function, possibly as a result of suboptimal cardiomyocyte performance in the absence of vasculature. Finally, conduction velocity approaches that of native myocardium without any electrical or mechanical conditioning, suggesting that the self-organizing method may be superior to other rigid scaffold-based EHT.
Asunto(s)
Mapeo Epicárdico/métodos , Insuficiencia Cardíaca/cirugía , Trasplante de Corazón/fisiología , Contracción Miocárdica/fisiología , Miocardio/citología , Ingeniería de Tejidos , Animales , Animales Recién Nacidos , Células Cultivadas , Modelos Animales de Enfermedad , Insuficiencia Cardíaca/patología , Insuficiencia Cardíaca/fisiopatología , Ratas , Ratas Sprague-DawleyRESUMEN
OBJECTIVES: Maintenance of endothelial homeostasis may prevent the development of cardiac allograft vasculopathy (CAV). This study investigated whether biomarkers related to endothelial injury and endothelial repair discriminate between CAV-negative and CAV-positive heart transplant recipients. BACKGROUND: CAV is the most important determinant of cardiac allograft survival and a major cause of death after heart transplantation. METHODS: Fifty-two patients undergoing coronary angiography between 5 and 15 years after heart transplantation were recruited in this study. Flow cytometry was applied to quantify endothelial progenitor cells (EPCs), circulating endothelial cells (CECs), and endothelial microparticles. Cell culture was used for quantification of circulating EPC number and hematopoietic progenitor cell number and for analysis of EPC function. RESULTS: The EPC number and function did not differ between CAV-negative and CAV-positive patients. In univariable models, age, creatinine, steroid dose, granulocyte colony-forming units, apoptotic CECs, and apoptotic endothelial microparticles discriminated between CAV-positive and CAV-negative patients. The logistic regression model containing apoptotic CECs and apoptotic endothelial microparticles as independent predictors provided high discrimination between CAV-positive and CAV-negative patients (C-statistic 0.812; 95% confidence interval: 0.692 to 0.932). In a logistic regression model with age and creatinine as covariates, apoptotic CECs (p = 0.0112) and apoptotic endothelial microparticles (p = 0.0141) were independent predictors (C-statistic 0.855; 95% confidence interval: 0.756 to 0.953). These 2 biomarkers remained independent predictors when steroid dose was introduced in the model. CONCLUSIONS: The high discriminative ability of apoptotic CECs and apoptotic endothelial microparticles is a solid foundation for the development of clinical prediction models of CAV.
Asunto(s)
Apoptosis/fisiología , Micropartículas Derivadas de Células/fisiología , Enfermedad de la Arteria Coronaria/diagnóstico , Enfermedad de la Arteria Coronaria/fisiopatología , Células Endoteliales/fisiología , Displasia Fibromuscular/diagnóstico , Displasia Fibromuscular/fisiopatología , Rechazo de Injerto/diagnóstico , Rechazo de Injerto/fisiopatología , Trasplante de Corazón/fisiología , Complicaciones Posoperatorias/diagnóstico , Complicaciones Posoperatorias/fisiopatología , Adulto , Angiografía Coronaria , Femenino , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Valores de ReferenciaRESUMEN
BACKGROUND: Heart transplantation is limited by a severe donor organ shortage. Potential donors with brain death (BD) and left ventricular dysfunction due to neurogenic stunning are currently excluded from donation--although such abnormalities can be reversible with aggressive treatment including Hormonal Treatment (HT) and deferred organ retrieval. AIM: To assess the recovery of left ventricular dysfunction in potential brain-dead donors with hemodynamic instability treated by aggressive treatment and HT. METHODS: In a single-center, observational study design, we evaluated 15 consecutive brain-dead potential donors (DBD) (8 males, age = 48 ± 15 years) with hemodynamic instability. All underwent standard hemodynamic monitoring and transthoracic 2-dimensional echo (2-DE) with assessment of Ejection Fraction (EF). Measurements were obtained before BD and after BD within 6 h, at 24 h and within 48 h. HT (with insulin, methylprednisolone, vasopressin and T3) was started as soon as possible to treat hemodynamic instability and avoid administration of norepinephrine (NE). Eligible potential heart donors underwent coronary angiography. RESULTS: After HT, we observed a normalization of hemodynamic conditions with improvement of mean arterial pressure (pre = 68 ± 8 mmHg vs post = 83 ± 13 mmHg, p < .01), cardiac index (pre = 2.4 ± 0.6 L/min/m2 vs post 3.7 ± 1.2 L/min/m2, p < .05), EF (pre = 48 ± 15 vs post = 59 ± 3%, p < .01) without administration of norepinephrine (NE) in 67% of cases. Five potential donors were excluded from donation (opposition, n = 3, tubercolosis n = 1, malignancy n = 1). At pre-harvesting angiography, coronary artery stenosis was present in 2 of the 10 consented donors. Eight hearts were uneventfully transplanted. No early graft failure occurred and all eight recipients were alive at 6-month follow-up. CONCLUSION: In BD donors, intensive treatment including HT is associated with improvement of regional and global LV function and reverse remodeling detectable by transthoracic 2DE. Donor hearts with recovered LV function may be eligible for uneventful heart transplant. The wait (in brain death), treat (with HT) and see (with 2D echo) strategy can help rescue organs suitable for heart donation.
Asunto(s)
Muerte Encefálica , Ecocardiografía/métodos , Trasplante de Corazón/fisiología , Recuperación de la Función , Donantes de Tejidos/provisión & distribución , Recolección de Tejidos y Órganos/métodos , Disfunción Ventricular Izquierda/diagnóstico por imagen , Femenino , Humanos , Masculino , Persona de Mediana Edad , Estudios Retrospectivos , Factores de TiempoRESUMEN
Two-photon intravital microscopy has substantially broadened our understanding of tissue- and organ-specific differences in the regulation of inflammatory responses. However, little is known about the dynamic regulation of leukocyte recruitment into inflamed heart tissue, largely due to technical difficulties inherent in imaging moving tissue. Here, we report a method for imaging beating murine hearts using intravital 2-photon microscopy. Using this method, we visualized neutrophil trafficking at baseline and during inflammation. Ischemia reperfusion injury induced by transplantation or transient coronary artery ligation led to recruitment of neutrophils to the heart, their extravasation from coronary veins, and infiltration of the myocardium where they formed large clusters. Grafting hearts containing mutant ICAM-1, a ligand important for neutrophil recruitment, reduced the crawling velocities of neutrophils within vessels, and markedly inhibited their extravasation. Similar impairment was seen with the inhibition of Mac-1, a receptor for ICAM-1. Blockade of LFA-1, another ICAM-1 receptor, prevented neutrophil adherence to endothelium and extravasation in heart grafts. As inflammatory responses in the heart are of great relevance to public health, this imaging approach holds promise for studying cardiac-specific mechanisms of leukocyte recruitment and identifying novel therapeutic targets for treating heart disease.
Asunto(s)
Miocardio/citología , Infiltración Neutrófila , Animales , Técnicas de Imagen Cardíaca/métodos , Vasos Coronarios/citología , Proteínas Fluorescentes Verdes/biosíntesis , Trasplante de Corazón/inmunología , Trasplante de Corazón/fisiología , Rodamiento de Leucocito , Ratones , Ratones Endogámicos C57BL , Microscopía de Fluorescencia por Excitación Multifotónica/métodos , Contracción Miocárdica , Miocardio/inmunología , Puntos Cuánticos , Proteínas Recombinantes/biosíntesis , Imagen de Lapso de TiempoRESUMEN
We describe the case of a serological reactivation in a Toxoplasma-seropositive subject, following a cardiac transplantation transmitting cysts contained in the myocardial tissue. In a context of acute graft rejection, primary chemoprophylaxis enables to avoid onset of opportunistic toxoplasmosis, emerging with immunodepletion performed by high-dose steroids. Then, we draw up a brief review of the bibliographical literature about pathophysiological mechanisms of toxoplasmic reactivation in heart transplants.
Asunto(s)
Anticuerpos Antiprotozoarios/inmunología , Rechazo de Injerto/etiología , Trasplante de Corazón/efectos adversos , Trasplante de Corazón/inmunología , Toxoplasmosis/diagnóstico , Toxoplasmosis/etiología , Enfermedad Aguda , Anticuerpos Antiprotozoarios/sangre , Rechazo de Injerto/inmunología , Rechazo de Injerto/parasitología , Trasplante de Corazón/fisiología , Humanos , Activación de Linfocitos/inmunología , Activación de Linfocitos/fisiología , Masculino , Persona de Mediana Edad , Serología , Donantes de Tejidos , Toxoplasma/inmunología , Toxoplasma/aislamiento & purificación , Toxoplasma/fisiología , Toxoplasmosis/sangre , Toxoplasmosis/inmunologíaRESUMEN
BACKGROUND: Mycophenolate mofetil is a commonly used immunosuppressant in heart transplantation but pharmacokinetic monitoring is not routinely done. We performed a prospective pilot multi-center trial in de-novo heart transplant recipients to evaluate the pharmacokinetics (PK) of mycophenolic acid (MPA) at multiple time points in the first year following transplant.
MATERIAL/METHODS: MPA trough and estimated area-under-the-curve (AUC) values were obtained at multiple visits from 21 enrolled patients. We attempted to correlate the side-effects and rejections with PK parameters.
RESULTS: MPA AUC and trough levels increased modestly over 12 months with substantial inter and intra patient variability. Cardiac rejection was associated with low MPA AUC values with a threshold of <36.2 mg×h/L during the first two post-transplant weeks. A threshold of 2-weeks average MPA trough level of 1.43 mg/L provided a sensitivity 82% and a specificity of 60%.
CONCLUSIONS: Adequate MPA levels are associated with decreased risk of allograft rejection. For patients with Cyclosporine co-immunosuppression, we propose an MPA trough of 1.4 mg/L and an MPA AUC of 36 mg × h/L as threshold values for dose adjustments. We recommend monitoring MPA levels at 1, 2 and 4 weeks, 6 months, 1 year and whenever an unexplained side-effect or allograft rejection occurs. Additional MPA AUC measurements are recommended when trough levels do not explain the clinical picture.