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This chapter presents a historical milestone of lung transplantation from the early experimental studies and clinical attempts to the advances of the Toronto Group and Stanford Group to the most recent developments.

Background The use of extracorporeal membrane oxygenation (ECMO) as a bridge to lung transplant (LTX) is still being debated. Methods We performed a retrospective two-center analysis of the relationship between ECMO bridging duration and survival in 25 patients. Further survival analysis was obtained by dividing the patients according to waiting time on ECMO: up to 14 days (Early group) or longer (Late group). We also analyzed the impact of the ventilation strategy during ECMO bridging (ie, spontaneous breathing and noninvasive ventilation [NIV] or intubation and invasive mechanical ventilation [IMV]). Results Seventeen of 25 patients underwent a transplant (with a 76% 1-year survival), whereas eight patients died during bridging. In the 17 patients who underwent a transplant, mortality was positively related to waiting days until LTX (hazard ratio [HR], 1.12 per day; 95% CI, 1.02-1.23; P = .02), and the Early group showed better Kaplan-Meier curves (P = .02), higher 1-year survival rates (100% vs 50%, P = .03), and lower morbidity (days on IMV and length of stay in ICU and hospital). During the bridge to transplant, mortality increased steadily with time. Considering the overall outcome of the bridging program (25 patients), bridge duration adversely affected survival (HR, 1.06 per day; 95% CI, 1.01-1.11; P = .015) and 1-year survival (Early, 82% vs Late, 29%; P = .015). Morbidity indexes were lower in patients treated with NIV during the bridge. Conclusions The duration of the ECMO bridge is a relevant cofactor in the mortality and morbidity of critically ill patients awaiting organ allocation. The NIV strategy was associated with a less complicated clinical course after LTX.

The study investigates Quality of Life (QOL) and correlation with functional status of patients affected by Chronic Thromboembolic Pulmonary Hypertension who undergo Pulmonary Endoarterectomy.We investigated with an observational design (before surgery, three and twelve months afterwards) the hemodynamic data (NYHA class, mean pulmonary arterial pressure, cardiac output and pulmonary vascular resistance), the functional status (using the 6-Minute Walk Test) and the QOL, using three questionnaires: Medical Outcome Study Short Form-36 (SF-36), Minnesota Living with Heart Failure Questionnaire (MLHFQ), Saint George Respiratory Questionnaire (SGRQ). We report the results of forty-nine patients.After surgery there was an improvement on functional and hemodynamic parameters and on QOL. The physical domain (PCS) of SF-36 was weakly but significantly associated with all functional parameters. There was no association between functional parameters and mental domain (MCS) of SF-36 or SGRQ. The improvement in 6-Minute Walk Distance was associated with an increase in MLHFQ.Both QOL and submaximal exercise tolerance improve after surgery. However only the physical domains of SF-36 appear to be significantly associated to the functional data.

Elevated heart rate (HR) has been indicated as risk factor for cardiovascular disease. Experimental data support a role of HR in the progression and severity of atherosclerotic lesions. Sinus tachycardia is common in heart transplant patients due to the lack of autonomic control. This study assessed the role of HR in the development of cardiac allograft vasculopathy (CAV) in heart transplant recipients.Data from 244 allograft recipients were analyzed. Known factors affecting CAV and mean HR obtained from 24-hour recordings at 1 year (dichotomized at ≥90 beats/min) were tested in univariate and multivariable Cox analysis.During a median of 96 months, 60 patients (25%) experienced CAV. Surprisingly, HR90 but not ≥90 beats/min was significantly associated with an increased CAV development. Univariate analysis showed several predictors were associated with the end point; however, at multivariable analysis, only donor's age, chronic renal failure, and left ventricular end-diastolic wall thickness were significant predictors of CAV, with hazard ratios of 1.02 (95% confidence interval, 1.00-1.04), 1.90 (1.13-3.21), and 1.11 (1.00-1.22), respectively. A highly statistically significant difference in donor's age was found among patients with mean heart rate ≥90 or90 beats/min (30 ± 13 vs 40 ± 14 years, p0.0001).In the denervated heart, sinus tachycardia is not a risk factor for coronary atherosclerosis. HR in heart transplant recipients reflects "intrinsic heart rate" and is a simple epiphenomenon of the donor's age.

Background In patients with idiopathic pulmonary hypertension (IPAH) progression of the disease and survival are related to the capability of the right ventricle to adapt to the chronically elevated pulmonary artery pressure. Although several echocardiographic variables have been associated with outcome in previous studies, a comparative evaluation of all right ventricular (RV) function indices obtainable at echocardiography has never been performed. Methods 59 patients consecutively admitted in a tertiary referral centre because of IPAH (22 males, mean age 46.3±16.1 years, 68% in WHO class III/IV at referral) underwent right heart catheterization and echocardiography. During a median follow-up period of 52 months, 21 patients died and 2 underwent lung transplantation in emergency conditions. Results The following parameters were associated with survival: tricuspid annular plane systolic excursion (TAPSE), RV fractional area change, degree of tricuspid regurgitation, inferior vena cava collapsibility, superior vena cava flow velocity pattern, left ventricular diastolic eccentricity index. Patients with TAPSE≤15 mm and left ventricular eccentricity index ≥1.7 had the highest event rate (51.7 per 100 person year); patients with TAPSE>15 mm and mild or no tricuspid regurgitation had the lowest event rate (2.6 per 100 person year). Conclusions A comprehensive echocardiographic assessment of RV systolic and diastolic function based on TAPSE, left ventricular diastolic eccentricity index and degree of tricuspid regurgitation allows an accurate prognostic stratification of patients with IPAH.

Background Although the port-access technique has been shown to be an effective and safe approach for cardiac surgery procedures it has never become routine practice, and it is still limited to few and selected centers. Furthermore, such technique has rarely been applied to treat left ventricle disease. In 1999 we introduced left ventricle aneurysm repair through a left minithoracotomy using the port-access technique. Here we present the results in terms of early and medium-term follow-up using such technique as a routine first choice approach for left ventricle endoplasty. Methods From 1999 to date, out of 38 patients undergoing left ventricle endoplasty (± associate procedures), mini-left thoracotomy and port-access techniques have been used in 32 patients (84%). All patients underwent endoventricular patch-repair with ventricular reshaping and associated procedures were performed in 8 patients. Results All patients survived the operation and were discharged from the hospital (30 days mortality 0%). Two patients (6.2%) experienced prolonged mechanical ventilations and 3 patients (9.3%) prolonged intensive care unit stay. Mean follow-up was 40 ± 34 months (range, 2 to 105). One patient died during follow-up (cumulative mortality 3.3%). Follow-up revealed an improvement of hemodynamic performances (left ventricular ejection fraction 0.44 ± 0.09 compared with 0.34 ± 0.09 preoperatively, p = 0.004) and improved clinical conditions (New York Heart Association class 1.4 ± 0.5 compared with 2.3 ± 1 preoperatively, p = 0.003). Conclusions The port-access technique can be safely applied to perform left ventricle endoplasty through a left minithoracotomy. Such approach allows optimal surgical view and therefore optimal surgical correction. Based on our satisfactory experience we support left minithoracotomy as a valuable alternative approach for left ventricle endoplasty in view of an extended use of minimally invasive techniques.

OBJECTIVES Antiphospholipid (a-PL) antibodies, especially IgG isotype, have been associated with a variety of neurological manifestations related to thrombotic mechanism and reactivity against nervous tissues. Furthermore, high titre of a-PL antibodies has been also correlated to chronic thromboembolic pulmonary hypertension (CTEPH) and, therefore, is frequently reported in patients undergoing pulmonary endarterectomy (PEA). The impact of a-PL antibodies in postoperative outcome following PEA, however, has not been clearly evaluated yet. In this paper, we investigated the impact of a high a-PL IgG titre (HAPT) on postoperative outcome following PEA. METHODS From April 1994 to October 2008, out of 204 patients undergoing PEA at our centre, 184 were prospectively screened for a-PL antibodies. According to the preoperative IgG titre, patients were divided into two groups: Group A (high a-PL antibodies titre - HAPT) with a-PL IgG titre >10 U/ml and Group B (low a-PL antibodies titre - LAPT) with a-PL IgG titre

Background A minimally invasive approach through an upper ministernotomy (UMS) has been used in our Division since 1997. On the basis of favorable outcome we have gradually extended this approach from isolated aortic valve replacement (AVR) to more complex cardiac surgery procedures and it is currently our first choice for a variety of procedures. Here we report our 11 years experience. Methods From 1997 to December 2007, 1,126 procedures were performed at our department, using UMS. Isolated procedures on the aortic valve were performed in 695 patients (61%). Isolated procedures on the aortic valve as redo operation were performed in 77 patients (7%). Complex cardiac surgery procedures (including double valve replacement-repair, ascending aorta-aortic arch replacement, aortic root replacement, aortic dissection, AVR combined with coronary surgery, and complex redo procedures) were performed in 354 patients (32%). Early postoperative outcome was evaluated considering three different groups according to the surgical procedure (first time AVR, redo AVR, and complex procedure). Results Overall conversion to full sternotomy was required in 16 patients (1.4%) with no significant differences between isolated AVR (9 patients, 1.3%) and complex or redo procedures (1 patient [1.2%] and 6 patients [1.6%], respectively). Forty-seven patients died in hospital (cumulative in-hospital mortality of 4.1 %). Mortality according to the procedure was 6.7, 3.8, and 2.8% for complex, redo AVR, or isolated AVR procedures, respectively, with a significant difference only for the complex procedures. Similarly, early postoperative outcome in terms of incidence of prolonged mechanical ventilation and ICU stay was significantly different only in the complex procedure group. Incidence of surgical revision (5.1, 2.9, and 2.7% for complex, redo, or isolated AVR procedures, respectively) showed no statistically significant differences regardless the type of procedures. Conclusions Our experience clearly shows that a minimally invasive approach through upper ministernotomy is feasible and safe not only for isolated AVR but that it can also be utilized for a variety of complex surgical procedures. Minimizing surgical access may be helpful in patients undergoing complex surgical procedures, especially redo procedures, without compromising the surgical result.

Pharmacokinetic modeling supports trough monitoring of everolimus, but prospective data comparing this approach versus mycophenolate mofetil (MMF) in de novo cardiac transplant recipients are currently unavailable.In a 12-month multicenter open-label study, cardiac transplant patients received everolimus (trough level 3-8 ng/mL) with reduced cyclosporine A (CsA) or MMF (3 g/day) with standard CsA, both with corticosteroids+/-induction therapy.In total, 176 patients were randomized (everolimus 92, MMF 84). Mean creatinine clearance was 72.5+/-27.9 and 76.8+/-32.1 mL/min at baseline, 65.4+/-24.7 and 72.2+/-26.2 mL/min at month 6, and 68.7+/-27.7 and 71.8+/-29.8 mL/min at month 12 with everolimus and MMF, respectively. The primary endpoint was not met since calculated CrCl at month 6 posttransplant was 6.9 mL/min lower with everolimus, exceeding the predefined margin of 6 mL/min. However, by month 12 the between-group difference had narrowed versus baseline (3.1 mL/min). All efficacy endpoints were noninferior for everolimus versus MMF. The 12-month incidence of biopsy-proven acute rejection International Heart and Lung Transplantation grade more than or equal to 3A was 21 of 92 (22.8%) with everolimus and 25 of 84 (29.8%) with MMF. Adverse events were consistent with class effects including less-frequent cytomegalovirus infection with everolimus (4 [4.4%]) than MMF (14 [16.9%], P=0.01).Concentration-controlled everolimus with reduced CsA results in similar renal function and equivalent efficacy compared with MMF with standard CsA at 12 months after cardiac transplantation.

Objectives The aim of this study was to analyze the long-term follow-up of dilated cardiolaminopathies. Background Lamin A/C (LMNA) gene mutations cause a variety of phenotypes. In the cardiology setting, patients diagnosed with idiopathic dilated cardiomyopathy (DCM) plus atrioventricular block (AVB) constitute the majority of reported cases. Methods Longitudinal retrospective observational studies were conducted with 27 consecutive families in which LMNA gene defects were identified in the probands, all sharing the DCM phenotype. Results Of the 164 family members, 94 had LMNA gene mutations. Sixty of 94 (64%) were phenotypically affected whereas 34 were only genotypically affected, including 5 with pre-clinical signs. Of the 60 patients, 40 had DCM with AVB, 12 had DCM with ventricular tachycardia/fibrillation, 6 had DCM with AVB and Emery-Dreifuss muscular dystrophy type 2 (EDMD2), and 2 had AVB plus EDMD2. During a median of 57 months (interquartile range 36 to 107 months), we observed 49 events in 43 DCM patients (6 had a later event, excluded from the analysis). The events were related to heart failure (15 heart transplants, 1 death from end-stage heart failure) and ventricular arrhythmias (15 sudden cardiac deaths and 12 appropriate implantable cardioverter-defibrillator interventions). By multivariable analysis, New York Heart Association functional class III to IV and highly dynamic competitive sports for ≥10 years were independent predictors of total events. By a bivariable Cox model, splice site mutations and competitive sport predicted sudden cardiac death. Conclusions Dilated cardiomyopathies caused by LMNA gene defects are highly penetrant, adult onset, malignant diseases characterized by a high rate of heart failure and life-threatening arrhythmias, predicted by New York Heart Association functional class, competitive sport activity, and type of mutation.

Mycophenolic acid (MPA) dose reduction is associated with increased risk of rejection and graft loss in renal transplantation. This analysis investigated the impact of MPA dose changes with enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) in de novo heart transplant recipients. In a 12-month, single-blind trial, 154 patients (EC-MPS, 78; MMF, 76) were randomized to either EC-MPS (1080 mg bid) or MMF (1500 mg bid) in combination with cyclosporine and steroids. The primary efficacy variable was the incidence of treatment failure, comprising a composite of biopsy-proven (BPAR) and treated acute rejection, graft loss or death. Significantly fewer patients receiving EC-MPS required > or =2 dose reductions than patients on MMF (26.9% vs. 42.1% of patients, p = 0.048). Accordingly, the average daily dose of EC-MPS as a percentage of the recommended dose was significantly higher than for MMF (88.4% vs. 79.0%, p = 0.016). Among patients requiring > or =1 dose reduction, the incidence of treated BPAR grade > or =3A was significantly lower with EC-MPS compared with MMF (23.4% vs. 44.0%, p = 0.032). These data suggest that EC-MPS-treated heart transplant patients are less likely to require multiple dose reductions than those on MMF which may be associated with a significantly lower risk of treated BPAR > or =3A.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which results from obstruction of the major pulmonary arteries by incompletely resolved or organized pulmonary emboli which have become incorporated into the pulmonary artery wall, eventually causing an increase in pulmonary vascular resistances. Pulmonary endarterectomy (PEA) is the treatment of choice. Careful pre- and post-operative management is essential for a successful outcome following PEA. In 1994, we started in Pavia a program in which members of a multidisciplinary team work in close interaction with the aim of increase experience in the challenging problems these patients present in the evaluative, surgical, and post-operative phases of their care. So far, 134 PEAs have been performed. Preoperatively, New York Heart Association (NYHA) class distribution was respectively 3-II, 56-III, and 75-IV; mean pulmonary artery pressure and pulmonary vascular resistances were 47 ± 13 mmHg and 1149 ± 535 dynes/sec/cm−5 respectively. The overall operative mortality has been 9.7% (in 2005 mortality rate was 4.5%). At present, 92% of the PEA patients are actively participating in the follow-up study. Follow-up visits are at 3 months after PEA, yearly for the following 5 years, and then at 7, 10, and 15 years postoperatively. Both early and late survivals were excellent. Survival rate at 3 months, 1 year, and 3 years were respectively of 89.5±2.7%, 87.3±3.0%, and 82.7±3.6%. Survival rates had not changed at 5, 7, and 10 years postoperative. Three months after PEA, 29 (58%) subjects were within NYHA class I, 18 (36%) in class II, and 3 (6%) in class III. At 1-year follow-up, 40 (80%) patients were within NYHA class I, 10 (20%) in class II. A statistically significant difference exists not only between the preoperative and the postoperative data (p Hemodynamic data from 35 patients participating to the Pavia Pulmonary Endarterectomy Program with complete 3-year follow-up. CVP mPAP CO CI PVR PVRI CVP (mmHg) central venous pressure; mPAP (mmHg) mean pulmonary artery pressure; CO (L/min) cardiac output; CI (L/min/m2) cardiac index; PVR (dynes/sec/cm-5) pulmonary vascular resistances; PVRI (dynes/sec/cm-5/m2) pulmonary vascular resistances index; RV-EF (%) right ventricle ejection fraction. RV-EF A: Before-PEA 7±6 48±12 3.3±0.9 1.8±0.5 1125±412 2027±731 15±8 B:Before discharge 5±4 25±10 5.2±1.1 2.9±0.5 289±142 505±234 32±8 C: 3 months 2±2 24±11 5.1±1.4 2.8±0.6 231±198 542±271 32±7 D: 1 year 1±2 23±12 5.0±1.1 2.7±0.6 290±191 531±343 35±8 E: 3 years 2±2 24±12 4.9±1.1 2.6±0.5 317±226 579±393 34±8 p value A vs. B: nsA vs. C, D, and E

Everolimus is an immunosuppressive agent that reduces cardiac allograft vasculopathy. This report presents the 24-month results of a multicenter trial of everolimus vs azathioprine in heart transplantation.A total of 634 patients were randomized to receive 1.5 mg everolimus, 3 mg everolimus or azathioprine, with cyclosporine and steroids. A 12-month, double-blind, double-dummy period was followed by a 12-month open-label period.At 24 months, the percentage of patients reaching the composite efficacy end-points was significantly lower with everolimus (1.5 mg: 45.9%, p = 0.016; 3 mg: 36.0%, p0.001) than with azathioprine (57.5%). The change in maximal intimal thickness from baseline to 24 months was significantly smaller with everolimus 1.5 mg (0.07 mm, p = 0.014) and 3 mg (0.06 mm, p = 0.004) compared with azathioprine (0.15 mm). The 24-month incidence of vasculopathy was 33.3% with everolimus 1.5 mg, 45.5% with everolimus 3 mg and 58.3% with azathioprine (p = 0.017 vs everolimus 1.5 mg). Incidence of cytomegalovirus infection was 3-fold lower in patients receiving everolimus compared with azathioprine (7.2% and 7.1% in the 1.5-mg and 3-mg everolimus cohorts, respectively, and 21% in the azathioprine group; p0.0001). Median serum creatinine levels at 24 months were higher with everolimus than with azathioprine, but decreased when cyclosporine exposure was reduced (everolimus 1.5 mg: baseline 167 micromol, after 6 months 157.5 micromol; everolimus 3 mg: baseline 185.6 micromol, after 6 months 160 micromol; azathioprine: baseline 123.3 micromol, after 6 months 127 micromol).Everolimus significantly reduced acute rejection and limited the progression of allograft vasculopathy at 24 months compared with azathioprine. Although graft and patient survival was comparable at 24 months, everolimus therapy may improve longer-term outcomes after heart transplantation.

Background Infection is the leading cause of death for left ventricular assist device (LVAD) patients with end-stage heart failure. Decreased infection may be possible with fully implantable LVADs such as the LionHeart, which lacks percutaneous conduits (PCs), a common source of device-related infection (DRI). This sub-study reports infections with the LionHeart and compares these results with historic data from the REMATCH trial, bridge to recovery (BTR) and bridge-to-transplantation (BTT) studies. Methods Twenty-three patients were implanted with the LionHeart LVAD and followed until death or heart transplant during a non-randomized, multicenter, European trial from October 1999 to April 2004. The nature and incidence of infection were analyzed and adjudicated to definitions similar to, or the same as, the REMATCH definitions. Results The combined number of implant days was 7,980, with a mean of 347 days (median 112, range 17 to 1,259 days). Survival at 1 year was 39%, with 2-year survival at 22%. Seventy-four percent of patients developed one or more infections, with 30% developing sepsis, and 35% developing pump-pocket infections (PSIs). No patients developed pump-housing or inflow- or outflow-tract infections (PI). For comparison, the prevalence rates of sepsis, PSI and PI in REMATCH were 51%, 35% and 19%, respectively. Conclusions The patients in the European LionHeart Clinical Utility Baseline Study (CUBS) trial had less sepsis and less overall DRI compared with the REMATCH LVAD group. Therefore, the fully implanted device may cause less infection than PC devices during destination therapy (DT). Although lower for DT, these rates are still higher than for some BTT experiences. Areas for future improvement include miniaturization of controller/battery components to reduce wound complications related to pocket size, and installation of more modern lithium-ion batteries to decrease the need for re-operations due to battery end-of-life.

Background Neurologic events such as thromboembolic and hemorrhagic strokes are common complications of mechanical circulatory support. We report the neurologic events observed in patients treated for end-stage heart failure with the implantable, pulsatile LionHeart left ventricular assist device (LVAD). This sub-study was part of the LionHeart European Clinical Utility Baseline Study (CUBS). Methods Twenty-three male patients were implanted with the LionHeart LVAD in a non-randomized, observational study. Neurologic events were classified into three categories: (1) transient ischemic attacks (TIAs); (2) strokes, including cerebrovascular accidents (CVAs) and intracranial bleeding (ICB); and (3) "other," including hypoperfusion, coma and brain death. Neurologic injuries were also categorized as transient/reversible or permanent/disabling. Results Thirteen of 23 patients (57%) had a total of 30 neurologic events. Eight patients (35%) had 18 TIAs. Eight patients (35%) also had a stroke, either CVA ( n = 5, 22%) or ICB ( n = 3, 13%), and 5 of these patients (22%) also had 12 TIAs. Three patients (13%) had 4 "other" neurologic events. Ten patients (43%) had transient/reversible neurologic deficits and 10 (43%) had permanent/disabling events. One patient (4%) had intracranial bleeding as a primary cause of death (anti-coagulation–related hemorrhage). The combined incidence of neurologic events was 1.37 events/patient-year. The incidences of transient and permanent events were 0.91 and 0.46 event/patient-year, respectively. Conclusions Neurologic events caused morbidity in the CUBS trial, with infrequent mortality. These results are similar to previous experiences with destination therapy and underscore the need for improvements in LVAD design, patient selection and patient management to reduce the incidence of neurologic events.

Objectives We sought to evaluate the capability of the right ventricle to regain normal morphology and function after pulmonary endarterectomy, to correlate right ventricular reverse remodeling with functional status, and to identify independent predictors of clinical failure after surgical intervention. Methods From December 2000 through August 2003, 45 patients underwent isolated pulmonary endarterectomy. Morphology and function of the right ventricle were studied by using a combination of right heart catheterization, cardiac magnetic resonance, and transthoracic echocardiography. Functional status was evaluated by using New York Heart Association class. Full preoperative data were available for 37 candidates. All patients were evaluated before discharge, at 3 months, and at 1, 2, and 3 years postoperatively using the same modalities. Results Immediately after surgical intervention, right ventricular cavitary dimensions decreased significantly, and tricuspid regurgitation radically improved. Right ventricular ejection fraction and functional status improved and right ventricular hypertrophy reversed over a longer time period. Higher ventricular dimensions and lower ejection fraction of the right ventricle were associated with poorer functional status at any time postoperatively. At discharge, pulmonary vascular resistance of greater than 509 dyne·sec·cm −5 and right ventricular ejection fraction of 24% or less predicted clinical failure at 12 months' follow-up. Conclusions After pulmonary endarterectomy, the right ventricle recovers and maintains normal architecture and function over time, regardless of the severity of preoperative disease. Accurate preoperative evaluation of the hemodynamics and anatomy of the thromboembolic lesions are mandatory. If pulmonary endarterectomy is not expected to decrease pulmonary vascular resistance to less than 509 dyne·sec·cm −5 , indication for surgical intervention needs to be carefully evaluated.

Background The purpose of this study was to advance current understanding of factors that influence long-term quality-of-life (QoL) outcomes after heart transplantation, by addressing the influence of depression on perceived health status. Methods Data were collected from all recipients ( n = 137) still alive at >10 years after transplantation. They completed the Short Form Health Survey (SF-36) inventory and the Beck Depression Inventory (BDI) questionnaire, while objective measures of health status were retrieved from medical records. All instruments used had acceptable reliability and validity. Data were analyzed using descriptive statistics, general linear regression models and survival analysis. Results We assessed 137 patients who received transplants between November 1985 and June 1994 in Pavia and have survived 10 to 18 years after transplantation (mean 13.64 years, SD 2.25). They rated their health as good and only the physical QoL (PCS) was impaired when compared with the general population. Thirty-two percent of patients experienced mood depressive symptoms in the long term after transplantation, indicating a low perceived QoL. Higher educational qualification ( p = 0.049), being unemployed and receiving a disability pension ( p = 0.001), high triglycerides levels ( p = 0.020) and lack of physical activity ( p Conclusions Assessment of depression levels and better understanding of risk factors for psychiatric disorders in the long term after transplantation could be of benefit in predicting negative outcomes and allowing future developments in patient management.

Prolonged or intensive immunosuppressive therapy used after organ transplantation is complicated by an increased incidence of cancer. Striking differences in incidence are observed in heart and heart-lung transplant recipients when compared with renal transplant patients. The most significant increase was in the incidence of lymphomas in cardiac versus renal patients. Moreover, a two-fold greater increase of all neoplasms was found in cardiac recipients, with nearly a six-fold increase in visceral tumors. Several factors may account for these differences. In cardiac allograft recipients, intensive immunosuppression is frequently used to reverse acute rejection and the highest number of cardiac transplants was performed in the era of polypharmacy, usually consisting of triple therapy.

The aim of this study was to compare the short- (< 30 days) and long-term (≥ 30 days) clinical outcomes of left internal mammary artery bypass grafting (LIMA-LAD) and directional coronary atherectomy plus stent implantation (DCA + stent) in the treatment of isolated proximal left anterior descending coronary (LAD) lesions. One hundred and twenty-six patients underwent LIMA-LAD and 132 consecutive patients underwent DCA + stenting. The primary endpoint was the incidence of short- and long-term major adverse cardiac events (MACE); the secondary endpoints included any periprocedural events and long-term target vessel revascularization (TVR). We found no significant between-treatment difference in the occurrence of short-term MACE, and the long-term MACE rate per 100 person-years was 3.0 in the LIMA-LAD group and 4.6 in the DCA + stent group. After 5-year follow-up, 79% of the patients in the DCA + stent group and 89% of those in the LIMA-LAD group were still MACE-free. The risk of any periprocedural events was six times lower in the DCA + stent group, and the risk of TVR was six times higher. We conclude that both procedures lead to good short- and long-term follow-up results in isolated proximal LAD disease. As fewer periprocedural events and more TVRs occur after DCA + stenting than after LIMA-LAD, they can be considered valuable alternatives to each other. Catheter Cardiovasc Interv 2005;64:45–52. © 2004 Wiley-Liss, Inc.

Objective The increasing number of patients awaiting heart transplant and the shortage of donors led to the development of a variety of left ventricular assist devices (LVAD). We analyse our experience in order to evaluate the efficacy of LVAD as bridge to transplant and the feasibility of permanent implantation. Patients The data are drawn from our experience on 50 patients, implanted with the Novacor LVAD and from a limited series of 4 patients implanted with a Lion Heart totally implantable permanent LVAD. Results Seventeen patients died on the device, 32 underwent heart transplant (9 died after transplant) and one is still on device. The causes of death were mostly related to cerebrovascular events or multi-organ failure. Cardiac output, wedge pressure, pulmonary vascular resistance and mean pulmonary pressure improved significantly. Cerebrovascular complications occurred mostly during the first 3 months of assistance, whereas the incidence of infections remained constant during the follow-up period. With a mean time of assistance of 211 days, we had only two cases of device malfunction. The four Lion-Heart patients experienced a clear improvement in hemodynamics but at a price of a significant complication rate. Three of them died after 418, 105 and 380 days of assistance. Device malfunction was observed in two cases. Conclusions LVAD Novacor has shown good hemodynamic improvement and reliable mechanical performance and long-term bridging can be considered fairly safe since most complications seem to occur within the first 90 days. Destination therapy with totally implantable devices seems to need further engineering and technical development.

Background The subset of CD4+CD25+ regulatory T cells, recently identified in humans, may play a central role in the regulation of immune tolerance to graft survival. Methods. This study assesses the frequency and functional profile of CD4+CD25+CD69- cells in the peripheral blood of lung transplant recipients (>3 years from transplantation), 10 of whom were in a stable clinical condition and 11 of whom demonstrated chronic rejection (bronchiolitis obliterans syndrome). We also studied a group of seven healthy subjects. Results. The frequency of CD4+ T cells expressing CD25 (CD4+CD25+) and the highest levels (CD25 high ) were lower in patients with bronchiolitis obliterans syndrome compared with healthy subjects and subjects in a stable clinical condition (P≤0.01). Purified CD4+CD25+ cells exhibited a regulatory functional profile in vitro: they were hyporesponsive, suppressed the proliferation of CD4+CD25- cells, and produced interleukin-10. Conclusion. These results provide in vivo evidence that peripheral CD4+CD25+ T cells may represent an important regulatory subset in lung transplantation.

Endomyocardial biopsy (EMB) is currently the standard method to diagnose acute graft rejection. However, considering the potential complications of this procedure, a noninvasive marker of rejection would be an ideal alternative or at least a helpful adjunct to posttransplant management. We measured myoglobin (Myo), creatine kinase MB mass (CK-MBm), troponin T (cTnT), serum amyloid A (SAA), and C-reactive protein (CRP) in 57 patients (mean age 37.5 years) who underwent orthotopic heart transplantation for end-stage cardiac failure between January and December 2001. Endomyocardial biopsies were performed routinely after surgery and histologically diagnosed rejection was graded according to the criteria of the International Society of Heart and Lung Transplantation. Concomittant with the biopsies, blood samples were drawn from the coronary sinus (central blood samples) and from a peripheral vein (peripheral blood samples) to assay biochemical markers. Among 149 EMB evaluated, 87 were negative (grade 0); 28 showed grade 1a rejection; 26 showed grade 1b; and 8 showed grade > 1b (2 were grade 2, 6 were grade 3a). Grades 0 and 1a were considered to be negative, while grades 1b and >1b were considered positive indicating potential acute graft rejection. cTnT, Myo, CK-MBm, SAA, and CRP levels were measured in 149 central blood samples and 149 peripheral blood samples. Myo and CK-MBm did not show significant changes. cTnT seems to be a potentially useful addition to the EMB results, while SAA and CRP showed variations with respect to EMB grade both in central and peripheral samples.

We evaluated exposure, safety, and efficacy data from an international Phase 3 trial of everolimus in de novo heart transplantation to characterize the longitudinal pharmacokinetics of everolimus and cyclosporine and to identify a therapeutic concentration range for everolimus. We randomized 634 patients to receive either 0.75 mg everolimus twice daily, 1.5 mg everolimus twice daily, or azathioprine in addition to corticosteroids and cyclosporine. At 8 visits during the first 6 months after transplantation, we obtained 2,328 everolimus trough levels (Cmin) and 129 area-under-the-curve (AUC) profiles over the dosing interval in patients treated with everolimus; we collected 3,258 cyclosporine trough concentrations and 174 profiles in all 3 treatment arms. We used median-effect analysis to characterize exposure-response associations between everolimus average Cmin vs freedom from biopsy-confirmed acute rejection; maximum cholesterol, low density lipoprotein, triglyceride, and creatinine levels; and minimum leukocyte and platelet counts. Everolimus Cmins averaged 5.2 +/- 3.8 ng/ml and 9.4 +/- 6.3 ng/ml at the lower and upper dose levels. A 17% underproportionality was noted in Cmins; however, peak exposure and AUC were consistent with dose proportionality. Everolimus exposure was stable during the 6-month period. Interindividual variability was 37% for AUC and 40% for Cmin. The latter parameter was not influenced to a clinically relevant extent by sex, age, or weight. The Cmin was well correlated with AUC (r2 = 0.81). Everolimus Cmin was significantly related to freedom from rejection (p = 0.02) with 3 ng/ml being an informative lower threshold for efficacy. Thrombocytopenia, defined as

Background Cytokines are important mediators of the complex process of extravasation and influx of peripheral mononuclear cells into a site of graft injury, an action that may be affected by the immunosuppressive regimen. The aim of this study was to compare the effect of different immunosuppressive regimens on cytokine expression in the grafted lung. Methods We analyzed the cytokine profiles in broncho-alveolar lavage fluid (BAL-F) from 18 lung transplanted patients undergoing a shift from a cyclosporine- to a tacrolimus-based triple therapy regimen due to refractory acute rejection. Results Three months after the conversion to tacrolimus, BAL-F levels of interleukin 8 (IL8), IL18, IL12 and IL10 were not significantly different than those measured before conversion. In contrast, monocyte chemoattractant protein-1 (MCP-1) levels showed a significant and sustained decrease in BAL-F during tacrolimus therapy. In addition the levels of gamma interferon (IFN-γ) in the BAL-F were decreased albeit not significantly. Conclusion These findings suggest that the clinical and functional stabilization of patients observed after conversion to a tacrolimus based regimen, may be due, at least in part, to the induced down-regulation of MCP-1 production.

Background Preemptive therapy of human cytomegalovirus (HCMV) infections has gained popularity in transplantation centers. However, standardized protocols are not available. In particular, whether a qualitative molecular assay for detection of a late (pp67) HCMV mRNA represents a valuable alternative to quantitative antigenemia remains to be defined. Methods. Overall, 82 heart (HTR) and lung (LTR) transplant recipients were randomized into two arms, where therapy was guided by qualitative pp67 mRNA NASBA (40 patients) or quantitative antigenemia (42 patients). In the NASBA arm, both primary and recurrent infections were treated upon first confirmed positive NASBA result. In the antigenemia arm, primary infections were treated upon first confirmed positive result, while recurrent infections were treated upon cutoff of 100 pp65-positive leukocytes. In both arms, therapy was stopped upon virus disappearance. Primary endpoint was duration of therapy. Results. The number of treated/infected patients was significantly higher in the NASBA arm (25/30 vs. 15/39; P=0.015), as was the number of treated/relapsing patients (5/8 vs. 1/11; P=0.040), whereas the number of HCMV-infected/total number of patients was significantly higher in the antigenemia arm (39/42 vs. 30/40; P=0.026). Thus, in the NASBA arm, although the median duration of therapy was shorter compared to antigenemia (17 vs. 21 days, P>0.05), the overall number of days of therapy was significantly higher. No patient developed HCMV disease. Conclusion. pp67 mRNA NASBA can safely replace antigenemia, with some apparent advantages (semiautomation and objectivity of test results) and disadvantages (overtreatment of patients and greater duration of overall treatment).

Objective Chronic immunosuppressive therapy following solid organ transplantation has been correlated with an increased risk of posttransplantation neoplastic disease (PTND). In this study we evaluated PTND incidence and outcome at our institution over a 17-year period among patients receiving lung transplantation. Materials and Methods Between February 1992 and December 2008, we performed 290 lung transplantations in 280 patients, including 139 single (48% with 5 retransplantations), and 151 double lung transplantations (52% with 5 retransplantations). Among the 280 patients, 2 had undergone previous double lung transplantation in other hospitals. Follow-up of transplant recipients was performed up to December 2009. Results Forty-two patients died in the hospital, producing a cumulative early (30-day) mortality rate of 15%. Among the 238 patients discharged from the hospital who entered our follow-up program, 36 (15%) experienced PTND. The mean time between transplantation and diagnosis was 47 ± 42 months, and patients' mean age at time of diagnosis was 55 ± 14 years. Overall freedom from PTND was 97%, 84%, and 73% at 1, 5, and 10 years, respectively. PTND was considered to be the direct cause of death in 11 patients (30%). Overall survival of patients with PTND at five years (45%) did not differ from the remainder of the transplanted population (46%). However, PTND became a relevant cause of death in the long-term (> 5 years) follow-up. Conclusion Our experience confirms that PTND was frequently diagnosed following lung transplantation. Even if PTND did not seem to significantly affect the survival of patients undergoing lung transplantation, it may become a significant cause of death among those surviving beyond 5 years.

within the chest. For example, patients who have undergone Fontan palliation have only 1 atrioventricular valve, and a capacitance chamber must be constructed to adequately connect the TAH-t. Virtual implantation offers the ability to test several surgical approaches for device placement before the patient even enters the operating room. This study was limited by a single-center experience in a small patient cohort. In addition, the assessment by virtual implantation was retrospective, and no 50cc TAH-t device was actually implanted to confirm the predicted results of the virtual implantation because it was not available during the study. However, two 70cc TAH-t devices were placed successfully as predicted by virtual implantation. In conclusion, virtual compatibility testing allows device consideration for fit to be individualized and represents a movement away from using generalized assumptions about heart size, chest wall anatomy, and spatial relationships of cardiothoracic structures to determine fit. Disclosure statement

The renewed interest in surgical techniques for atrial fibrillation (AF) limited to the left atrium has risen the importance of the original technique of left atrial isolation by means of surgical incision. Transmurality of lesions and cost containment are strong elements to be appreciated in this technique.

Objectives: Mandatory use of prolonged immunosuppression in organ transplantation is complicated by an increased incidence of cancer. The current study represents a retrospective analysis of the incidence of neoplasms in our heart transplantation program. Methods: Fourhundred and seventy-four patients (403 male and 71 female; mean age, 48.6 ^ 12.1 years), with at least 30 days of follow-up, were enrolled in this study. Patients received triple immunosuppression with cyclosporin A, azathioprine and steroids. Moreover, as a prophylactic antilymphocyte therapy, 388 patients (82%) were administered RATG, 67 patients (14%) received ALG and 19 patients (4%) OKT3. The mean follow-up time was 71.1 ^ 43.0 months. Results: Fifty-five patients (11.6%) developed malignant neoplasms. The cancer frequencies were: solid tumors, 55%; non-Hodgkin lymphomas (NHL), 20%; Kaposi’s sarcomas, 11%; skin cancers, 9%; undifferentiated sarcomas and myelomas, 5%. Solid tumors mainly affected the lung (39%), bowel (16%), stomach (6.5%), liver (6.5%), pancreas (6.5%) and oral cavity (6.5%). The times to the onset of cancer from transplantation were: Kaposi’s sarcoma, 12.7 ^ 16.8 months; skin cancers, 34.5 ^ 23.8 months; solid tumors, 54.3 ^ 38.7 months; NHL, 60.1 ^ 36.4 months; undifferentiated sarcomas and myelomas, 90.0 ^ 15.6 months. As determined by univariate and multivariate analyses, sex, number of treated rejections, previous history of tumor, average dose of cyclosporine and prednisone and cyclosporine blood levels did not increase the incidence of malignancies. Univariate analysis suggests a significant correlation between the type of prophylactic immunoglobulins and the average dose of azathioprine with the incidence of neoplasms. Both univariate and multivariate analyses demonstrated a significant correlation between patient’s age at the time of transplantation and risk of cancer occurrence (risk increased by 1.074/year; Pa 0:0056 with multivariate Cox regression). Conclusions: Cancer is a strong limitation for long-term survival after heart transplantation. The only risk factor recognized is the patient’s age at the time of transplant. Furthermore, the type of prophylactic globulins used for induction therapy and some specific immunosuppressant agent (azathioprine) may play a significant role in the development of malignancies after transplantation. q 2001 Elsevier Science B.V. All rights reserved.

The authors performed a comparative analysis of 60 whole blood samples containing cyclosporine (CsA) from heart transplant (HTx) recipients (n = 60) by the two "specific" monoclonal immunoassays, enzyme-multiplied immunoassay technique (EMIT) and fluorescence polarization immunoassay (S-FPIA), using the Altman-Bland approach based on graphical techniques and simple calculations. The CsA blood concentrations measured by S-FPIA [mean (SD): 268.1 (108.8) ng/mL] showed a statistically significant difference (P < 0.001) from the corresponding concentrations measured by EMIT [219.6 (118.7) ng/mL]. The CsA concentrations were 27% (median) higher when determined by monoclonal S-FPIA than by EMIT. The comparison between EMIT and S-FPIA showed a good correlation (S-FPIA conc. (ng/mL) = EMIT conc. (ng/mL) x 0.88 + 76.1, r = 0.96, P < 0.001). However, a high correlation does not mean that the two methods agree, and their use as interchangeable might be misleading. The authors summarized the degree of agreement by calculating the bias estimated by the mean difference (d) and the standard deviation of the difference (SD). For CsA concentration data, the mean difference (S-FPIA minus EMIT) is +49.9 ng/mL and SD is 31.2 ng/mL. Altman-Bland analysis indicates considerable lack of agreement between EMIT and S-FPIA, with discrepancies of more than 100 ng/mL. The present study's data clearly show that there is a considerable and clinically unacceptable lack of agreement between the S-FPIA and the EMIT techniques in HTx recipients for the whole range of concentrations evaluated (25-500 ng/mL), and this is caused by the variation in the overestimation of the CsA parent compound. Even though a similar CsA reference range was reported during maintenance therapy for both methods (150-250 ng/mL), which might encourage their interchangeability in the clinical setting, this approach should be avoided. Laboratory reports should always state both the concentration of CsA and the analytical method.

OBJECTIVES To assess the prevalence of dystrophin defects in dilated cardiomyopathy (DCM) in male patients and to formulate investigation strategies for their identification. BACKGROUND Dystrophin defects presenting with predominant or exclusive cardiac involvement may be clinically indistinguishable from “idiopathic” DCM. Diagnosis may be missed, unless specifically investigated. METHODS Clinical and biochemical evaluation, right ventricular endomyocardial biopsy (EMB), light and electron microscopic and immunohistochemical studies of biopsy samples, six multiplex and two single polymerase chain reactions for 38 exons and automated sequencing of exon 9 and muscle promoter-exon 1 were undertaken in 201 consecutive male patients presenting with DCM, with (n = 14) and without (n = 187) increased serum creatine phosphokinase (sCPK). RESULTS Dystrophin defects were identified in 13 of the 201 patients (6.5%, age 16–50). Family history was positive in four patients. Serum CPK levels were increased in 11 of 13 patients. Light microscopy examination of EMB was uninformative; ultrastructural study showed multiple membrane defects. Dystrophin immunostain was abnormal. Eight patients, all older than 20, had deletions affecting midrod domain, normal or mildly increased CPK and better outcome than the five remaining cases all younger than 20, with more than five-fold increase of sCPK. Two of these latter had proximal and rod-domain deletions. Sisters of two patients were diagnosed as noncarriers with microsatellite analysis. CONCLUSIONS Although the overall prevalence of dystrophin defects in our consecutive DCM male series is low (6.5%), immunohistochemical and molecular studies are essential to identify protein and gene defects; screening studies are justified to define prevalence, clinical profile and genotype-phenotype correlation.

We compared orthotopic heart transplantation (HT) by bicaval technique with the standard technique. Between January 1995 and December 1997, 117 patients underwent 118 HTs; 71 patients (15 women and 56 men) had 72 HTs by standard technique and 46 patients (9 women, 37 men) underwent HT using bicaval procedures. Preoperative parameters were similar in both groups; 5 patients who underwent the standard technique and no patients who underwent bicaval procedures required permanent pacemakers (p = NS). Isoproterenol infusion was significantly longer in the standard technique. Major perioperative arrhythmias (ventricular tachycardia and fibrillation, asystole) appeared in 8.2% and 7.0% of standard and bicaval HTs, respectively; atrial fibrillation appeared in 13.1% and 4.6%, respectively (p = NS). At 1 month, mitral and tricuspid regurgitation rates were higher in the standard group (p = NS); at 1 year only tricuspid regurgitation was still higher (p = NS). Right atrial pressure, Wood units, cardiac output, and cardiac index were examined (p = NS). At multivariate analysis, interaction between preoperative Wood units and transplant type was elicited for Wood units at 1 month and for right atrial pressure at 1, 3, and 6 months. In the high resistance subgroup, the patients who underwent bicaval procedures had higher resistances at 1 month. In the low resistance subgroup, right atrial pressure was higher in patients who underwent standard techniques at 1, 3, and 6 months follow-up. Thus, bicaval HT was found to be safe, without surgically related complications, it provoked significantly less blood loss, and required less isoproterenol use. No significant advantages were observed in conduction disturbances and major arrhythmias or regarding the need for temporary or permanent pacemakers.

Background Coronary thrombosis is a frequent complication of allograft vascular disease (AVD) in cardiac transplant recipients. No data are available on thrombus composition in these hearts. Methods The present study aimed at characterizing thrombus components in coronary arteries from transplanted hearts with AVD, using single and double immunostain with anti-gpIIb-IIIa, anti-fibrin, and anti-endothelial antibodies. The pathologic series consists of 55 grafts survived longer than 2 months, and obtained from 55 patients deceased (n=44) or undergone repeat transplantation (n=11). Results Mural thrombi were found in multiple segments of 75 of 440 total coronary vessels (17%) (recent in 33, organizing in 28, and organized in 14), whereas occlusive thrombi were found in 19 vessels (8 recent and 11 with multichannel pattern of organization). Recent and thin mural thrombi were mostly constituted of CD41a- and CD61-positive platelets; the amount of fibrin progressively increased with the increase of thrombus size. In organizing mural thrombi, gpIIb-IIIa immunostain was still present. Fibrin was the only identifiable thrombus component in old mural thrombi embedded within the intimal lesions. Recent occlusive thrombi immunoreacted both with anti-CD41a and anti-CD61 and with anti-fibrin antibodies, whereas organized occlusive thrombi with multichannel pattern exclusively immunoreacted with anti-fibrin antibodies. Double immunostain showed that mural thrombi were stratified on de-endothelized arterial segments. Conclusions Thrombus composition is related to both type and "age" of thrombus, with platelets as the early and major components of mural microthrombi at one end of the spectrum, and fibrin as the dominant component of occlusive thrombi at the other end.

The minimally invasive Heartport (HP)-assisted technique has become first choice option for mitral valve surgery in many centres.The pool of patients potentially treated using HP techniques, however, is still limited by the presence of peripheral vessel disease, expecially in the elderly population. Alternative approaches to using the HP technique safely in such a subset of patients, therefore, should be evaluated. Here, we present our preliminary experience using the axillary artery as an alternative site of cannulation for HP-assisted redo mitral valve surgery in patients with concomitant peripheral vessel disease.

Preliminary epidemiological and histological studies from Japan suggested that hepatitis C virus (HCV) infection has a role in the development of dilated cardiomyopathy (DCM). This multicenter study was conducted to verify this hypothesis on a large cohort of Italian patients with end-stage heart failure. Antibodies to HCV were determined in the 752 consecutive patients (608 males and 144 females; age, 53 ± 13 years) who entered the waiting list for cardiac transplantation from 1995 to 1997 at the six cardiac surgery centers participating in the North Italy Transplant program. Three hundred and nine patients (41%) had dilated, 9 (1%) restrictive, and 4 (0.5%) hypertrophic cardiomyopathy; 284 patients (38%) had ischemic, 65 (9%) valvular, and 22 (3%) congenital heart disease; 5 patients (0.5%) had primary pulmonary hypertension; 54 patients (7%) had other or nonspecified heart disease. Overall, 41 of 752 patients (5.4%) resulted anti-HCV–reactive. Serological evidence of HCV infection was found in 12 of 309 patients with DCM (3.9%; 95% CI, 1.7–6.0), and in 29 of 443 without DCM (6.5%; 95% CI, 4.2–8.8), without statistical dif- ference (difference of prevalence rate: 2.6%; 95% CI, -4.9 to 5.8). In conclusion, HCV does not seem to have a primary role in the pathogenesis of DCM. However, since our findings are in disagreement with those obtained in smaller series of patients of other ethnicity, large studies from different countries should be conducted. J. Med. Virol. 58:116–120, 1999. © 1999 Wiley-Liss, Inc.

Background: Orthotopic heart transplantation results in cardiac denervation. The presence of cardiac parasympathetic reinnervation in humans has been widely debated based on the application of differing indirect measures of autonomic control. However no attempt has been made to analyse the reflex heart rate response to baroreceptor stimulation whose occurrence is generally considered a reliable marker of the ability to activate cardiac vagal reflexes. This study tested the hypothesis that the presence of donor heart RR interval lengthening following phenylephrine induced blood pressure increase would be an index of parasympathetic reinnervation. Methods Baroreflex sensitivity (BRS) was assessed in 30 patients (mean age 51 ± 12 years) 1–24 months after heart transplantation carried out by the standard Lower-Shumway technique. In 6 patients the recipient atrium rate response (P-P interval) to baroreceptor stimulation by phenylephrine was also simultaneously determined by transesophageal recording. Results None of the 30 patients showed prolongation of RR intervals in the donor heart. The average BRS value was −0.28 ± 0.54 ms/mmHg (range −1.3–0.7 ms/mmHg). In the 6 patients in whom BRS was obtained at both the recipient atrium (P-P) and donor heart (R-R) the changes were 7.6 ± 5.7 ms/mmHg and −0.38 ± 0.58 ms/mmHg respectively ( p = 0.02), thus confirming that the absent RR interval lengthening in the donor heart is the consequence of efferent vagal fiber interruption. Conclusions The absence of any RR interval prolongation following phenylephrine induced baroreceptor stimulation demonstrates that vagal efferent reinnervation of the donor heart does not occur up to 24 months in patients operated via the standard Lower-Shumway procedure. It is also suggested that analysis of baroreceptor reflexes is a more specific method in the examination of cardiac parasympathetic reinnervation.

Background. We analyzed bone marrow changes in heart transplant recipients who develop peripheral cytopenia and underwent bone marrow biopsy (BMB). We correlated the changes in bone marrow with survival, acute and chronic rejection, infections, and malignancy. Methods. The test group was constituted of 64 heart transplant recipients with peripheral cytopenia, in whom 82 BMBs were performed to assess marrow quantitative (cellularity, erythropoiesis, myelopoiesis, megakaryopoiesis, fibrosis, and blast cells) and qualitative (dyserythropoiesis, dysmyelopoiesis, and dysmegakaryopoiesis) changes. The control series was constituted of 217 matchable transplant recipients without cytopenia. Statistical analysis was aimed at assessing whether: (1) cytopenia is an independent risk factor for survival; (2) acute rejection, chronic rejection, infections, and malignancy predict cytopenia ; (3) the degree in BMB change allows further stratification of the risk of death; and (4) characteristics and distribution of BMB lesions vary in patients with and without acute and chronic rejection, infections, and malignancy. Results. In the test group, BMB specimens showed reduced cellularity in 68% of patients and dysplastic changes of a mild degree affecting all three marrow lines (erythropoietic in 88%, myelopoietic in 43%, and megakaryopoietic in 79%). At statistical analysis, peripheral cytopenia was an independent risk factor for survival, and malignancy proved to be a risk factor for cytopenia. Of BMB specimen changes, only dysmegakaryopoiesis showed a trend as a negative risk factor for survival. Acute rejection was associated with a high score of erythropoiesis, infections with a low score of dysmegakaryopoiesis, and malignancy with a high score of cellularity. Conclusions. Peripheral cytopenia is an independent risk factor for survival in heart transplant recipients. Different marrow changes correlate with transplantation-related complications, i.e., acute rejection, infection, and malignancy.

BACKGROUND Our purpose was to establish whether patients on the waiting list for heart-lung or lung transplantation had different survival rates according to diagnosis and to determine the specific variables responsible for early death. METHODS Between 1988 and 1996, 278 patients were placed on the waiting list for organ transplant. Diagnoses were pulmonary vascular disease in 128, parenchymal disease in 141, and retransplantation in 9 patients. Eighty patients received transplants, 100 patients died awaiting transplantation, and 98 patients are still awaiting transplantation. Univariate and multivariate analyses of risk factors for early death on the waiting list were performed. Patients still listed 6 months. RESULTS Patients with primary pulmonary hypertension, pulmonary fibrosis, or cystic fibrosis had statistically significantly lower survival rates at 6, 12, and 24 months (31%, 36% and 26%, respectively, at 24 months) than patients with Eisenmenger's syndrome and chronic obstructive pulmonary disease (76% and 71%). Patients with Eisenmenger's syndrome who died < or =6 months had significantly higher systolic pulmonary artery pressure (134+/-39 vs. 108+/-25 mmHg) and pulmonary vascular resistance (1928+/-1686 vs. 1191+/-730 dyn/sec/cm(-5)) than those who survived longer. Patients with pulmonary fibrosis who died < or =6 months had significantly lower forced vital capacity (36+/-15 vs. 47+/-13% predicted), forced expiratory volume (37+/-14 vs. 48+/-14% predicted), room air PO2 (42+/-11 vs. 50+/-11 mmHg), and room air O2-saturation (78+/-10 vs. 84+/-8%) than those who survived longer. In the multivariate analysis, only the type of pathology was a significant risk factor for death after being on the waiting list < or =6 months. CONCLUSIONS Certain pathologies and variables are risk factors for early death in patients on the waiting list. This information may be used to allocate specific donor organs to patients in greater need.

BACKGROUND Chronic rejection or transplant-associated coronary artery disease (TxCAD) is the most serious complication after human cardiac transplantation. Previous studies, using Western blotting, have shown formation of antibodies against endothelial antigens of 56 and 58 kDa, which are associated with early TxCAD. These antigens were later identified as being vimentin and its breakdown products. The aims of the present study were to devise a robust assay for detection of anti-vimentin antibodies and to compare antibody formation in patients taking different immunosuppressive drugs. METHODS 106 sequential serum samples from 19 patients taking tacrolimus and 68 sera from 12 patients taking cyclosporine were examined by enzyme-linked immunosorbent assay (ELISA) for anti-vimentin antibodies and Western blotting for reactivity against bands at 56/58 kDa. Serum samples were taken before transplantation and at 1, 3, 6, 9, and 12 months. RESULTS The vimentin ELISA produced significantly higher numbers of positive episodes per patient (3.92+/-1.08) compared with use of Western blotting (2.54+/-0.52). Serum from patients taking tacrolimus contained significantly less antibodies measured by ELISA (15.8%) or Western blotting (6.5%) than sera from patients taking cyclosporine (46.8% for ELISA; P=0.001 and 21% by Western blotting, P=0.01). Intravascular ultrasound performed on six patients at 12 months showed a correlation between anti-vimentin antibody formation and detection of early coronary disease. CONCLUSIONS The results demonstrate first, that differences in antibody profiles produced by different immunosuppressive drugs, and second, that detection of anti-vimentin antibodies may be a noninvasive method of detecting disease activity in transplanted vessels.

Objective: To discuss informed consent to heart transplantation in the case of an intensive care unit (ICU) patient: relatives’ informed consent was refused by the patient himself whose cognitive ability appeared to be reasonable for the purpose. Setting: ICU of a university teaching hospital. Patient: a 62-year-old man who underwent myocardial revascularization had in the immediate post-operative hemodynamic instability, continuous serious arrhythmias, ventilatory support, fentanyl infusion. Heart transplantation could be the only chance for his survival. Intervention: heart transplantation. Results: despite patient’s refusal, we decided to hold the relative’s consent as valid, and transplantation was accordingly performed, to the subsequent satisfaction of the patient. Conclusions: Our decision was based on two beliefs: (1) the severity of the patient’s clinical condition may have impaired his cognitive abilities; (2) the very same conditions may mask impairment and certainly make reliable assessment of cognition and judgment impossible. This being so, the preservation of life assumes priority.

We report a successful follow-up after 28 years of a woman with obliterative restrictive endomyocardial fibrosis (EMF) that underwent complete surgical decortication with simultaneous mitral and tricuspid bioprosthetic valve replacement in 1982 and underwent successful reoperation for the structural failure of biological prostheses after 25 years.

The present study aimed to investigate the relationship between acute rejection and human cytomegalovirus (HCMV) infection, as well as the coexpression of HLA-DR and immediate-early (IE) viral antigens, in 143 transbronchial biopsies and bronchoalveolar lavage fluids of 32 lung transplant recipients. We investigated the occurrence of morphologically overt viral infection with conventional histopathology, the expression of IE antigens with single labeling immunohistochemistry, the coexpression of IE antigens and HLA-DR molecules with double labeling techniques, and the presence of viral IE genes with polymerase chain reaction (PCR). Histopathologic study showed overt viral infections (12.6%) in 18 of the 143 biopsies ; 8 were in a context of pneumonia and 10 were localizations without surrounding inflammatory cells ; immunohistochemistry showed IE viral antigen expression in 31 (21.67%) ; PCR detected viral IE genes in 73/143 lavage fluids and biopsies (51%). The double labeling immunohistochemical technique showed that most IE antigen-expressing, noncytopathic cells were either HLA-DR negative in areas without infiltrates, or HLA-DR positive in those areas where inflammatory infiltrates were consistent, in the absence of viral cytopathy, with acute rejection. The results indicate that, in transplanted lung, the frequency of morphologically occult HCMV infection (as detected by immunohistochemistry and/or PCR) is much higher than that of morphologically overt viral infection. The occurrence of inflammatory infiltrates (consistent with acute rejection) around morphologically occult infected cells and the possible lack of inflammation around both early- and late-infected cells suggest that in biopsies with occult infection the infiltrates should be attributed to allograft reaction. This conclusion would be in keeping with the coexpression of HLA-DR and HCMV IE in infiltrate-rich biopsies that are consistent with acute rejection, as well as with the absence of HLA-DR expression in IE antigen-positive cells in infiltrate-free areas.

Objective. The mechanisms of atrial fibrillation arc multiple reentry circuits spinning around the atrial surface, and these baffle any attempt to direct surgical interruption. The purpose of this article is to report the surgical experience in the treatment of isolated and concomitant atrial fibrillation at the Cardiac Surgical Institute of the University of Pavia. Methods. In cases of atrial fibrillation secondary to mitral/valve disease, surgical isolation of the left atrium at the time of mitral valve surgery can prevent atrial fibrillation from involving the right atrium, which can exert its diastolic pump function on the right ventricle. Left atrial isolation was performed on 205 patients at the time of mitral valve surgery. Atrial partitioning (maze operation) creates straight and blind atrial alleys so that non-recentry circuits can take place. Five patients underwent this procedure. In eight-cases of atrial fibrillation secondary to atrial septal defect, the adult patients with atrial septal defect and chronic or paroxysmal atrial fibrillation underwent surgical isolation of the right atrium associated which surgical correction of the defect, in order to let sinus rhythm govern the left atrium and the ventricles. Lone atrial fibrillation occurs in hearts with no detectable organic disease. Bi-atrial isolation with creation of an atrial septal internodal corridor was performed on 14 patients. Results. In cases of atrial fibrillation secondary to mitral valve disease, left atrial isolation was performed on 205 patients at the time of mitral valve surgery with an overall sinus rhythm recovery of 77%. In the same - period, sinus rhythm was recovered and persisted in only 19% of 252 patients who underwent mitral valve replacement along (P

The aim of this study was to evaluate the safety and performance of the Arrow CorAide left ventricular assist system (LVAS) (Arrow International, Reading, PA, USA), a continuous-flow left ventricular assist device, as bridge to transplantation or recovery as well as destination therapy in patients with New York Heart Association (NYHA) class IV heart failure. Twenty-one patients were implanted with the CorAide LVAS between February 2005 and February 2006 in a prospective, multicenter, nonrandomized trial. Seventeen patients (81%) survived to180 days or to transplantation. The cumulative time on device was 16.58 patient years (range 23-796 days, median 192 days). No intraoperative technical issues were observed at the time of implantation. Of the 21 implants, nine patients died on device, two were converted to other devices, and 10 were transplanted. Three patient deaths were attributed to pump polymer coating delamination. Postmortem device inspection determined delamination of the polymer coating on the pump's internal surface to be the cause of the late hemolysis and sudden fatal pump stops. No embolic or driveline infection event was recorded. The automatic flow control algorithm functioned reliably throughout the trial. Primary performance trial endpoint was achieved with 81% survival to 180 days or transplantation. Delamination of the polymer coating on the internal surface of the pump with resultant hemolysis and pump stops was the sole major device event in this trial. Elimination of the polymer coating and replacement with an amorphous carbon coating has resolved this in preclinical testing, prior to initiation of further clinical testing of this device.

Background— The present study was aimed at determining the impact of type 2 diabetes mellitus (DM) on postoperative bioprosthetic structural valve degeneration. Methods and Results— Twelve Italian centers participated in the study. Patient data refer to bioprosthetic implantations performed from November 1988 to December 2009, which resulted in 6184 patients (mean age 71.3±5.4 years, 60.1% male) being enrolled. Of these patients, 1731 (27.9%) had type 2 DM. The propensity score–matching algorithm successfully matched 1113 patients with type 2 DM with the same number of no-DM patients. The postmatching standard differences were less than 0.1 for each of the covariates, and 64.2% of DM patients were matched. The early (30 days) mortality rate was 7.8% (n=87) versus 2.9% (n=33) in patients with or without type 2 DM ( P P Conclusions— Patients with type 2 DM undergoing bioprosthetic valve implantation are at high risk of early and long-term mortality, as well as of structural valve degeneration.

Minimally invasive video-assisted surgery through a right minithoracotomy has become the standard surgical approach for several cardiac diseases at many major centers worldwide. In this article we review the existing literature on the subject and describe different operative techniques, application fields and clinical outcomes.

Purpose: In the case of an acute aortic dissection, a surgical aortic procedure is usually the priority in order to restore the perfusion of vital organs. Afterwards, associated ischemic abdominal visceral lesions can be resected. For particular patients, it could be highly beneficial to perform the abdominal surgery before surgically addressing the aorta. The aim of this paper is to contribute to the therapeutic choice in cases of acute aortic dissection with acute abdomen.Case report: The case is reported of a 38-year-old patient, affected by an acute aortic dissection (Stanford type A) and peritonitis.Suspecting the necessity for a complex combined surgical procedure, the patient underwent emergency diagnostic laparoscopy, which showed an infarctual necrosis of the distal ileum and right colon. Therefore, he immediately underwent a wide right hemicolectomy. Afterwards, an ascending aortic substitution was performed.The patient was discharged on the 15th post-operative day, and he is doing well, 1 year and 3 months after the operation.Conclusion: In the case of an acute aortic dissection with acute abdomen, emergency laparoscopy is a precious surgical technique to identify criteria that can lead to therapeutic decisions, including timing.

We present postoperative and midterm (3 years) angiographic changes after removal of five (of six) occluded stents from the left anterior descending (LAD) coronary artery and its reconstruction with a 9-cm-long on-lay patching done with the left internal mammary artery. # 2011 European Association for Cardio-Thoracic Surgery. Published by Elsevier B.V. All rights reserved.