Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: practical clinical management questions.

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.

[Side effects of proliferation signal inhibitors and their management]. / Effets secondaires des inhibiteurs du signal de prolifération et leur gestion.

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.

Safety and efficacy of a new transpulmonary echo contrast agent in echocardiographic studies in patients.

OBJECTIVES: This study was designed to investigate in patients the effect of a new transpulmonary echo contrast agent, made from 5% human serum albumin (Albunex), on systemic and pulmonary hemodynamics and the influence of the contrast doses on left ventricular opacification. BACKGROUND: New intravenous transpulmonary echo contrast agents are promising, allowing contrast stress echocardiography and myocardial contrast echocardiography. Nevertheless, some shortcomings still remain. Thus, the pulmonary hypertension observed in pigs after Albunex injection should be investigated in humans, and the optimal dose of contrast agent remains to be determined because previous experiments indicated that the left ventricular opacification and attenuation are dose dependent. METHODS: Albunex in doses of 0.08 and 0.22 ml/kg was successively injected intravenously in 20 catheterized patients; in 11 of them, anti-inflammatory drugs were withdrawn to avoid the blocking of an eventual thromboxane-mediated pulmonary artery hypertension. Systemic blood pressure and pulmonary artery, capillary wedge and right atrial pressures were continuously monitored. Cardiac output, left ventricular fractional shortening and blood gases were determined 5 min before and 5 and 10 min after each injection. The left ventricular opacification was qualitatively assessed by three independent observers using a grading scale from 0 to 3, with 0 indicating an absence of contrast effect and 3 indicating full opacification. RESULTS: No clinical, hemodynamic or respiratory adverse reactions were observed in any patient. Irrespective of doses, a left ventricular opacification grade > or = 2 was observed in 74% of the 35 injections that could be evaluated. This percentage increased to 94% when the higher dose group was considered alone. CONCLUSIONS: This first report of the effect of Albunex injected intravenously on pulmonary artery pressures in humans demonstrates that this contrast agent appears to be safe. The significant left ventricular opacification obtained in a majority of patients without an important increase in attenuation supports the use of the higher dose of the contrast agent.

Oxidative capacity of skeletal muscle in heart failure patients versus sedentary or active control subjects.

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.

Exercise-induced increase in circulating adrenomedullin is related to mean blood pressure in heart transplant recipients.

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.

Lung membrane diffusing capacity, heart failure, and heart transplantation.

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.

Endothelin participates in increased circulating atrial natriuretic peptide early after human heart transplantation.

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.

VO(2) kinetics reveal a central limitation at the onset of subthreshold exercise in heart transplant recipients.

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.

Contrast echocardiography in coronary artery diseased patients: effect of systemic and pulmonary artery pressures on left heart opacification after intravenous injection of Albunex.

BACKGROUND: Contrast echocardiography is a useful tool for assessing repeatedly patients with coronary artery disease. Nevertheless, elevated pulmonary artery and systemic blood pressures likely to be associated with cardiac ischemia may limit the left ventricular opacification (LVO) because of the microspheres' sensitivity to pressure. OBJECTIVE: To determine the effects of systemic and pulmonary artery blood pressures on LVO. METHODS: We performed 55 intravenous injections (0.08 and 0.22 ml/kg) of a new transpulmonary contrast agent (Albunex), during two separated exposures, into 20 cardiac ischemic patients while monitoring invasively their cardiac indexes, and intracardiac, systemic, and pulmonary artery blood pressures. LVO was graded qualitatively from faint to full. RESULTS: A logistic model with the grade of LVO as the dependent variable and a selection from among the dose, exposure, right and left atrial blood pressures, systolic systemic and pulmonary artery blood pressures (ranges 94-208 and 14-45 mmHg, respectively), cardiac index, stroke index, and pulmonary and systemic vascular resistances as the explanatory variables demonstrated that increasing the dose gives an increasing probability of LVO (P = 0.02) and that increasing the pulmonary artery pressure reduces that probability (P = 0.006). A decreased cardiac index tended also to be associated with decreased LVO. The systemic blood pressure and the pulmonary and systemic vascular resistances had no statistically significant effect on the grade of LVO. CONCLUSIONS: LVO after intravenous administration of Albunex is dose-dependent and limited by an elevated pulmonary artery pressure. These data suggest that one should use higher doses for cardiac ischemic patients with elevated pulmonary artery pressures and that use of Albunex has the potential to detect pulmonary hypertension in patients.

Exercise training with a heart device: a hemodynamic, metabolic, and hormonal study.

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.

Is a prosthetic ring required for mitral repair of mitral insufficiency due to posterior leaflet prolapse? Long-term results in 96 patients submitted to repair with no ring.

OBJECTIVE: It is a common statement that every mitral repair should be stabilized by some type of prosthetic mitral ring. In the very specific situation of isolated prolapse of the posterior leaflet (PPL), this statement may be enhanced by the possible anatomically discontinuity of the mitral annulus. This article concerns 96 patients with 'isolated' PPL (IPPL) who were operated upon without ring insertion. Long-term follow-up was obtained in order to ascertain the survival, stability of the repair and the need for reoperation, thus justifying or not the lack of use of a ring. METHODS: A total of 96 patients, 70 male and 26 female, underwent mitral repair for mitral insufficiency (MI) almost exclusively caused by PPL. Age ranged from 33 to 81 years (mean 60.7+/-11.3). All underwent quadrangular resection of the prolapsed portion and plication of the annulus. In 69 cases local stabilization was achieved by four U stitches, two on each side of the plication, passed through and sutured on some flexible material, 2-3 cm in length. Twenty seven patients had no such local reinforcement. RESULTS: There was one case of early death (1%) caused by refractory hypoxemia in a patient with long lasting pre-operative pulmonary edema. Two patients were lost for follow-up after 2 months. Follow-up was from 0.2 to 14.7 years (mean 4.5), for a total of 422.7 patient-years. There were four late deaths at a mean of 6-year follow-up (0.9-10 years). Actuarial survival was 95.5 and 90.5% at 5 and 8 years, respectively. Event-free for recurrence of significant mitral insufficiency (MI) was 96 and 92% at 5 and 8 years. Event-free of thromboembolic or hemorrhagic events was 84.3 and 72.3% at 5 and 8 years. Event-free from reoperation was 97.8 and 94% at 5 and 8 years. CONCLUSION: One can conclude that (a) IPPL repair without insertion of a ring is safe and long-lasting (b) the incidence of late death, recurrence of MI, thromboembolic/hemorrhagic events, need for reoperation, is not higher in this subset of patients than in conventional repair (c) such repair might work better and for a longer time, as reaction and sclerosis resulting from ring insertion are avoided (d) minor advantages could be due to an easier surgical procedure, especially through a minimally invasive approach.

Safety of a new transpulmonary echocontrast agent (Albunex) in repeated echocardiographic studies in patients.

BACKGROUND AND HYPOTHESIS: Multiple contrast-enhanced echocardiographic studies are to be expected in patients with cardiac ischemic disease, but the sonication process used to produce the echocontrast agent Albunex may result in new epitopes that could cause an immunogenic response. METHODS: Repeated exposures to intravenous Albunex over a period of time long enough to allow development of an eventual immune reaction were performed in 12 patients while monitoring for lymphocyte transformation, microsphere specific IgE and IgG antibodies, and systemic, pulmonary artery, capillary wedge, and right atrial pressures, as well as cardiac output, left ventricular fractional shortening, and blood gases. RESULTS: No significant 3H-thymidine incorporation and thus no specific blastic transformation of the patients' lymphocytes were observed either for high or low Albunex concentrations, corresponding to the expected hepatic and plasma concentrations of microspheres. No formation of microsphere-specific IgE and IgG antibodies was observed after the first or second Albunex exposure. Furthermore, no clinically significant hemodynamic or respiratory adverse reactions were observed in any patient. CONCLUSION: These results suggest that repeated exposures to intravenous Albunex induce no adverse effect on the cellular and humoral immune systems and on left and right heart hemodynamics in patients.