RESUMO
Although malignancy is a major threat to long-term survival of heart transplant (HT) recipients, clear strategies to manage immunosuppression in these patients are lacking. Several lines of evidences support the hypothesis of an anticancer effect of proliferation signal inhibitors (PSIs: mammalian target of rapamycin [mTOR] inhibitors) in HT recipients. This property may arise from PSI's ability to replace immunosuppressive therapies that promote cancer progression, such as calcineurin inhibitors or azathioprine, and/or through their direct biological actions in preventing tumor development and progression. Given the lack of randomized studies specifically exploring these issues in the transplant setting, a collaborative group reviewed current literature and personal clinical experience to reach a consensus aimed to provide practical guidance for the clinical conduct in HT recipients with malignancy, or at high risk of malignancy, with a special focus on advice relevant to potential role of PSIs.
Assuntos
Proliferação de Células/efeitos dos fármacos , Cardiopatias/complicações , Transplante de Coração/efeitos adversos , Imunossupressores/uso terapêutico , Neoplasias/tratamento farmacológico , Neoplasias/etiologia , Complicações Pós-Operatórias , Cardiopatias/cirurgia , HumanosRESUMO
Proliferation signal inhibitors (PSI) could help to lower the calcineurine inhibitors level to minimize their toxicity and improve long-term graft survival. Side effects of this drugs are specific and must been known. Hyperlipidemia and cutaneous side-effects are the most frequent, angioedema and interstital pneumonitis the most serious. In majority of cases, early and adapted management could limit the impact of these side effects.
Assuntos
Rejeição de Enxerto/prevenção & controle , Imunossupressores/efeitos adversos , Peptídeos e Proteínas de Sinalização Intracelular/antagonistas & inibidores , Proteínas Serina-Treonina Quinases/antagonistas & inibidores , Angioedema/induzido quimicamente , Angioedema/prevenção & controle , Inibidores de Calcineurina , Cicatriz/prevenção & controle , Ciclosporina/efeitos adversos , Sobrevivência de Enxerto , Doenças Hematológicas/induzido quimicamente , Doenças Hematológicas/prevenção & controle , Humanos , Hiperlipidemias/induzido quimicamente , Hiperlipidemias/prevenção & controle , Nefropatias/induzido quimicamente , Nefropatias/prevenção & controle , Linfocele/induzido quimicamente , Linfocele/prevenção & controle , Pneumonia/induzido quimicamente , Pneumonia/prevenção & controle , Sirolimo/efeitos adversos , Sirolimo/uso terapêutico , Dermatopatias/induzido quimicamente , Dermatopatias/prevenção & controle , Serina-Treonina Quinases TORAssuntos
Tolerância ao Exercício , Transplante de Coração , Taurina/fisiologia , Humanos , Taurina/sangueAssuntos
Transplante de Coração/efeitos adversos , Falência Renal Crônica/epidemiologia , Adolescente , Adulto , Idoso , Feminino , Seguimentos , Transplante de Coração/mortalidade , Humanos , Falência Renal Crônica/etiologia , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias/epidemiologia , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida , Fatores de TempoAssuntos
Ciclosporina/toxicidade , Dedos/irrigação sanguínea , Transplante de Coração/imunologia , Imunossupressores/toxicidade , Temperatura Cutânea , Monitoramento de Medicamentos/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fluxo Sanguíneo Regional , Sensibilidade e Especificidade , Termografia/métodosAssuntos
Transplante de Coração/fisiologia , Transplante de Rim/fisiologia , Transplante de Pâncreas/fisiologia , Adulto , Cardiomiopatia Dilatada/cirurgia , Diabetes Mellitus Tipo 1/cirurgia , Nefropatias Diabéticas/cirurgia , Seguimentos , Insuficiência Cardíaca , Humanos , Masculino , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Insuficiência Cardíaca/fisiopatologia , Transplante de Coração/fisiologia , Coração/fisiologia , Hemodinâmica/fisiologia , Consumo de Oxigênio , Função Ventricular Esquerda/fisiologia , Adulto , Anaerobiose , Teste de Esforço , Coração/fisiopatologia , Frequência Cardíaca , Humanos , Cinética , Pessoa de Meia-Idade , Valores de Referência , Fatores de TempoRESUMO
OBJECTIVES: We investigated the in situ properties of muscle mitochondria using the skinned fiber technique in patients with chronic heart failure (CHF) and sedentary (SED) and more active (ACT) controls to determine: 1) whether respiration of muscle tissue in the SED and ACT groups correlates with peak oxygen consumption (pVO(2)), 2) whether it is altered in CHF, and 3) whether this results from deconditioning or CHF-specific myopathy. BACKGROUND: Skeletal muscle oxidative capacity is thought to partly determine the exercise capacity in humans and its decrease to participate in exercise limitation in CHF. METHODS: M. Vastus lateralis biopsies were obtained from 11 SED group members, 10 ACT group members and 15 patients with CHF at the time of transplantation, saponine-skinned and placed in an oxygraphic chamber to measure basal and maximal adenosine diphosphate (ADP)-stimulated (V(max)) respiration rates and to assess mitochondrial regulation by ADP. All patients received angiotensin-converting enzyme (ACE) inhibitors. RESULTS: The pVO(2) differed in the order CHF < SED < ACT. Compared with SED, muscle alterations in CHF appeared as decreased citrate synthase, creatine kinase and lactate dehydrogenase, whereas the myosin heavy chain profile remained unchanged. However, muscle oxidative capacity (V(max), CHF: 3.53 +/- 0.38; SED: 3.17 +/- 0.48; ACT: 7.47 +/- 0.73, micromol O(2).min(-1).g(-1)dw, p < 0.001 vs. CHF and SED) and regulation were identical in patients in the CHF and SED groups, differing in the ACT group only. In patients with CHF, the correlation between pVO(2) and muscle oxidative capacity observed in controls was displaced toward lower pVO(2) values. CONCLUSIONS: In these patients, the disease-specific muscle metabolic impairments derive mostly from extramitochondrial mechanisms that disrupt the normal symmorphosis relations. The possible roles of ACE inhibitors and level of activity are discussed.
Assuntos
Exercício Físico/fisiologia , Insuficiência Cardíaca/metabolismo , Mitocôndrias Musculares/metabolismo , Músculo Esquelético/metabolismo , Consumo de Oxigênio , Citrato (si)-Sintase/metabolismo , Creatina Quinase/metabolismo , Feminino , Humanos , L-Lactato Desidrogenase/metabolismo , Masculino , Pessoa de Meia-Idade , Cadeias Pesadas de Miosina/metabolismoRESUMO
PURPOSE: The mechanisms of the training-induced improvements in left ventricular assist (LVAD) patients are unknown. METHODS: We measured the hemodynamic, gas exchange, and metabolic and hormonal effects of 6-wk exercise training in a cardiogenic shock patient who was assisted by an LVAD. RESULTS: After training, the peak power and VO2 increased by 166% and 56%, respectively (80 W and 16.1 mL x min(-1) x kg(-1)), whereas the ventilatory drive decreased. Although the LVAD output increased little with exercise, the systemic cardiac output rose (adequately for the VO2) from 5.91 and 4.90 L x min(-1) at rest to 9.75 and 9.47 L x min(-1) at peak work rate, before and after training, respectively. Thus, the left ventricle ejected again through the aortic valve. Unloading and/or retraining resulted in a left ventricular filling pressure decrease. Although the right ventricular ejection fraction increased with exercise, it decreased again at the maximal load after training. For a given work rate the arterial lactate, the norepinephrine (NE) and epinephrine (E) concentrations fell after training, but the enhanced maximal work rate elicited higher NE and E concentrations (4396 and 1848 pg x mL(-1), respectively). The lack of right ventricular unloading might have kept the atrial natriuretic peptide higher after training, but the blood cyclic GMP and endothelin were lower after training. CONCLUSION: In an LVAD patient, retraining returns the exercise capacity to the class III level by peripheral and left ventricular hemodynamic improvements, but the safety of maximal exercise remains to be proven in terms of right ventricular function and orthosympathetic drive.
Assuntos
Cardiomiopatias/terapia , Exercício Físico/fisiologia , Coração Auxiliar , Hemodinâmica/fisiologia , Hormônios/fisiologia , Cardiomiopatias/metabolismo , Cardiomiopatias/fisiopatologia , Hormônios/metabolismo , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Adrenomedullin (ADM) is a newly discovered potent vasorelaxing and natriuretic peptide that recently has been shown to be increased after heart transplantation. To investigate the hemodynamic factors modulating its release and the eventual role of ADM in blood pressure regulation after heart transplantation, seven matched heart-transplant recipients (Htx) and seven normal subjects performed a maximal bicycle exercise test while monitoring for heart rate, blood pressure, and circulating ADM. Baseline heart rate and systemic blood pressure were higher in Htx; left ventricular mass index and ADM tended to be higher after heart transplantation and correlated positively in Htx (r = 0.79, P = 0.03). As expected, exercise-induced increase in heart rate was lower in Htx than in controls (60 +/- 11 % vs. 121 +/- 14 %, respectively) and blood pressure increase was similar in both groups. Maximal exercise increased significantly plasma ADM in both groups (from 25.3 +/- 3.1 to 30.7 +/- 3.5 pmol/L, P < 0.05 and from 15.2 +/- 1.4 to 29.1 +/- 4.4 pmol/L, P = 0.02 in Htx and controls, respectively), the hypotensive peptide level remaining elevated until the 30th min of recovery. A significant inverse relationship was observed between peak mean blood pressure and circulating ADM in Htx (r = -0.86, P < 0.02). Besides showing that circulating ADM is increased after heart transplantation, the present study demonstrates a positive relationship between baseline ADM and left ventricular mass index. Furthermore, maximal exercise-induced increase in ADM is inversely related to mean blood pressure in Htx, suggesting that ADM might participate in blood pressure regulation during exercise after heart transplantation.
Assuntos
Pressão Sanguínea , Transplante de Coração/fisiologia , Hemodinâmica , Peptídeos/sangue , Esforço Físico/fisiologia , Adrenomedulina , Adulto , Frequência Cardíaca , Humanos , Masculino , Consumo de Oxigênio , Peptídeos/metabolismo , Valores de Referência , Análise de Regressão , Função Ventricular EsquerdaRESUMO
Because the cardiocirculatory response of heart transplant recipients (HTR) to exercise is delayed, we hypothesized that their O(2) uptake (VO(2)) kinetics at the onset of subthreshold exercise are slowed because of an impaired early "cardiodynamic" phase 1, rather than an abnormal subsequent "metabolic" phase 2. Thus we compared the VO(2) kinetics in 10 HTR submitted to six identical 10-min square-wave exercises set at 75% (36 +/- 5 W) of the load at their ventilatory threshold (VT) to those of 10 controls (C) similarly exercising at the same absolute (40 W; C40W group) and relative load (67 +/- 14 W; C67W group). Time-averaged heart rate, breath-by-breath VO(2), and O(2) pulse (O(2)p) data yielded monoexponential time constants of the VO(2) (s) and O(2)p increase. Separating phase 1 and 2 data permitted assessment of the phase 1 duration and phase 2 VO(2) time constant (). The VO(2) time constant was higher in HTR (38.4 +/- 7.5) than in C40W (22.9 +/- 9.6; P < or = 0. 002) or C67W (30.8 +/- 8.2; P < or = 0.05), as was the O(2)p time constant, resulting from a lower phase 1 VO(2) increase (287 +/- 59 vs. 349 +/- 66 ml/min; P < or = 0.05), O(2)p increase (2.8 +/- 0.6 vs. 3.6 +/- 1.0 ml/beat; P < or = 0.0001), and a longer phase 1 duration (36.7 +/- 12.3 vs. 26.8 +/- 6.0 s; P < or = 0.05), whereas the was similar in HTR and C (31.4 +/- 9.6 vs. 29.9 +/- 5.6 s; P = 0.85). Thus the HTR have slower subthreshold VO(2) kinetics due to an abnormal phase 1, suggesting that the heart is unable to increase its output abruptly when exercise begins. We expected a faster in HTR because of their prolonged phase 1 duration. Because this was not the case, their muscular metabolism may also be impaired at the onset of subthreshold exercise.
Assuntos
Exercício Físico/fisiologia , Transplante de Coração/fisiologia , Consumo de Oxigênio , Adulto , Teste de Esforço , Frequência Cardíaca , Transplante de Coração/reabilitação , Humanos , Masculino , Esforço Físico/fisiologia , Valores de Referência , RespiraçãoRESUMO
The pulmonary diffusing capacity for carbon monoxide (DLCO) is reduced in chronic heart failure and remains decreased after heart transplantation. This decrease in DLCO may depend on a permanent alteration after transplantation of one or the other of its components: diffusion of the alveolar capillary membrane or the pulmonary capillary blood volume (Vc). Therefore, we measured DLCO, the membrane conductance, and Vc before and after heart transplantation. At the time of hemodynamic measurements, the Roughton and Forster method of measuring DLCO at varying alveolar oxygen concentrations was used to determine the membrane conductance, Vc, DLCO/alveolar volume (VA), the membrane conductance/VA and thetaVc/VA (theta = carbon monoxide conductance of blood, VA = alveolar volume) in 21 patients with class III to IV heart failure before and after transplantation, and in 21 healthy controls. Transplantation normalized pulmonary capillary pressure and increased cardiac index. DLCO was decreased before transplantation (7.11 vs 10.0 mmol/min/kPa in controls), but DLCO/VA was normal (1.67+/-0.44 vs 1.71+/-0.26 mmol/min/kPa/L in controls). DLCO/VA remained unchanged after transplantation, because the decrease in Vc (82+/-30 vs 65+/-18 ml before and after transplantation) and thetaVc/VA was not compensated by the changes in membrane conductance (11+/-4 vs 12+/-5 mmol/min/kPa before and after transplantation, respectively) and membrane conductance/VA. We conclude that the decrease in DLCO in patients with chronic heart failure is due to a restrictive ventilatory pattern because their DLCO/VA remains normal; the decrease in the membrane conductance is compensated by the increase in Vc. After transplantation, the decrease in Vc due to normalization of pulmonary hemodynamics is not completely compensated for by an increase in membrane conductance. Because the membrane conductances, measured before and after transplantation, are negatively correlated with duration of heart failure, its abnormal pulmonary hemodynamics may have irreversibly altered the alveolar capillary membrane.
Assuntos
Monóxido de Carbono/metabolismo , Insuficiência Cardíaca/metabolismo , Transplante de Coração , Capacidade de Difusão Pulmonar , Adulto , Amiodarona/farmacologia , Antiarrítmicos/farmacologia , Estudos de Casos e Controles , Infecções por Citomegalovirus/metabolismo , Diuréticos/farmacologia , Feminino , Furosemida/farmacologia , Insuficiência Cardíaca/fisiopatologia , Insuficiência Cardíaca/cirurgia , Hemodinâmica , Humanos , Modelos Lineares , Masculino , Pessoa de Meia-Idade , Capacidade de Difusão Pulmonar/efeitos dos fármacos , Testes de Função Respiratória , Fumar/metabolismo , Fatores de TempoAssuntos
Transplante de Coração/fisiologia , Terapia de Imunossupressão , Transplante de Rim/fisiologia , Transplante de Fígado/fisiologia , Sistemas Neurossecretores/efeitos dos fármacos , Adulto , Fator Natriurético Atrial/sangue , Azatioprina/uso terapêutico , Pressão Sanguínea , Creatinina/sangue , Ciclosporina/uso terapêutico , Quimioterapia Combinada , Endotelinas/sangue , Frequência Cardíaca , Transplante de Coração/imunologia , Humanos , Imunossupressores/uso terapêutico , Transplante de Rim/imunologia , Transplante de Fígado/imunologia , Pessoa de Meia-Idade , Peptídeo Natriurético Encefálico , Proteínas do Tecido Nervoso/sangue , Norepinefrina/sangue , Prednisona/uso terapêutico , Valores de ReferênciaRESUMO
BACKGROUND: Hemodynamic improvement after heart transplantation is expected to normalize the neuroendocrine balance, but circulating atrial natriuretic peptide (ANP) remains elevated. Endothelin stimulates ANP secretion and its concentration increases after heart transplantation, suggesting a role for this peptide in the cardiovascular adaptative response to heart transplantation. METHODS: To investigate whether endothelin may induce ANP increase in heart transplant recipients, we monitored daily ANP, endothelin, and related hormonal, biologic, and hemodynamic parameters before and during the first week after either heart transplantation (n = 15) or coronary artery bypass grafting (n = 10). RESULTS: Surgery induced a transient secretory peak of arginine vasopressin and endothelin in both groups at day 1. Bypass grafting did not modify normal ANP (11.8 +/- 2.1 pmol/L), endothelin (2.4 +/- 0.3 pmol/L), renin activity (0.11 +/- 0.04 pmol/L/sec), or aldosterone (492 +/- 122 pmol/L) values. Heart transplantation normalized the renin-aldosterone axis, but the early decrease observed for ANP (from 27.2 +/- 4.8 to 21.14 +/- 1.4 pmol/L) was only partial and transient. Endothelin further increased (from 4.4 +/- 0.8 to 9.14 +/- 1.8 pmol/L; p < 0.01) after transplantation. Positive correlations were observed between endothelin, isoproterenol dose, creatinine, right atrial pressure, and ANP, but multiple correlation analysis showed the important role of endothelin (r = 0.69, p < 0.001). Cyclic guanosine monophosphate correlated with ANP (r = 0.65, p < 0.001). CONCLUSIONS: Elevated endothelin, suggesting vascular dysfunction, likely contributes to the ANP increase observed early after heart transplantation. Furthermore, ANP, through a cardiac endothelium feedback, may act in the maintenance of circulatory homeostasis in heart transplant recipients.