Marco Ribezzo

The Use of CO2 Removal Devices in Patients Awaiting Lung Transplantation: An Initial Experience

BACKGROUND Lung transplantation is the treatment of choice for patients with end-stage lung failure. Limitations are presented by the shortage of donors and the long waiting list periods. New techniques, such as extracorporeal membrane ventilator devices with or without pump support, have been developed as bridges to transplantation for patients with severe, unresponsive respiratory insufficiency. METHODS Between November 2005 and September 2009, 12 patients (7 males and 5 females), of overall mean age of 43.3 +/- 15.5 years underwent decapneization with extracorporeal devices. In 6 cases, a NovaLung system was used; in the remaining 6 patients, it was a Decap device. Causes of respiratory failure that led to implantation of such devices were cystic fibrosis (n = 6), pulmonary emphysema (n = 5), and chronic rejection of a previous double lung transplant (n = 1). RESULTS Mean time on extracorporeal decapneization was 13.5 +/- 14.2 days. Eight patients died on the device. Three patients were bridged to lung transplantation; 1 recovered and was weaned from the device after 11 days. Mean PaCO(2) on the extracorporeal gas exchanger was significantly lower for both the devices at 24, 48, and 72 hours after implantation (P < .05). No significant difference was observed for the 2 systems. CONCLUSION In our initial experience, decapneization devices have been simple, efficient methods to support patients with mild hypoxia and severe hypercapnia that is refractory to mechanical ventilation. This could represent a valid bridge to lung transplantation in these patients.

Human cardiac progenitor cell grafts as unrestricted source of supernumerary cardiac cells in healthy murine hearts.

Human heart harbors a population of resident progenitor cells that can be isolated by stem cell antigen‐1 antibody and expanded in culture. These cells can differentiate into cardiomyocytes in vitro and contribute to cardiac regeneration in vivo. However, when directly injected as single cell suspension, less than 1%‐5% survive and differentiate. Among the major causes of this failure are the distressing protocols used to culture in vitro and implant progenitor cells into damaged hearts. Human cardiac progenitors obtained from the auricles of patients were cultured as scaffoldless engineered tissues fabricated using temperature‐responsive surfaces. In the engineered tissue, progenitor cells established proper three‐dimensional intercellular relationships and were embedded in self‐produced extracellular matrix preserving their phenotype and multipotency in the absence of significant apoptosis. After engineered tissues were leant on visceral pericardium, a number of cells migrated into the murine myocardium and in the vascular walls, where they integrated in the respective textures.

Incidence and severity of primary graft dysfunction after lung transplantation using rejected grafts reconditioned with ex vivo lung perfusion

OBJECTIVES Ex vivo lung perfusion (EVLP) is a novel technique used to evaluate and recondition marginal or rejected grafts. Primary graft dysfunction (PGD) is a major early complication after lung transplantation (LTx). The use of marginal or initially rejected grafts may increase its incidence and severity. The aim of this study is to evaluate the incidence of PGD after LTx using rejected grafts reconditioned with EVLP. METHODS PGD has been evaluated immediately after LTx (t0) and after 72 h (t72) in patients receiving standard (Group A) or reconditioned (Group B) grafts. EVLP was performed using a controlled acellular perfusion according to the Toronto technique. RESULTS From July 2011 to February 2013, 36 LTxs have been performed: 28 patients (21 M/7 F, mean age 51.7 ± 14.7 years) in Group A and 8 (6 M/2 F, mean age 46.6 ± 9.8 years) in Group B (successful recondition rate of 73%, 8 of 11 cases). Incidence rate of PGD 3 at t0 and at t72 (Group A versus Group B) was 50 vs 37% (P = NS) and 25 vs 0% (P = NS), respectively. Post-transplant extracorporeal membrane oxygenation was required in 5 and 2 patients in Groups A and B, respectively (P = NS). CONCLUSIONS The use of initially rejected grafts treated with EVLP does not increase the incidence and severity of PGD after LTx. Although comparison of PGD 3 incidence in the two groups did not reach a statistical difference, all EVLP patients suffering from severe PGD early after transplant recovered normal lung function at 72 h, suggesting a protective role of EVLP against PGD occurrence and severity.

Role of Oral Sildenafil in the Treatment of Right Ventricular Dysfunction After Heart Transplantation

OBJECTIVE Right ventricular dysfunction (RVD) after heart transplantation is a major complication, especially in patients with pulmonary hypertension (PH). Herein we have presented our initial experience with oral sildenafil for RVD following heart transplantation. MATERIALS AND METHODS From February 2006 to February 2008, 10 patients (7 males and 3 females) of overall mean age of 56.7 +/- 9.5 years suffered from acute RVD immediately after heart transplantation. Preoperative hemodynamic data before and after a vasodilatation test (sodium nitroprusside; NTP) showed: systolic pulmonary arterial pressure (SPAP) 59.5 +/- 12.9 and 44.2 +/- 12.4 mm Hg; cardiac output (CO) 3.3 +/- 0.9 and 3.7 +/- 0.8 L/min; transpulmonary gradient (TPG) 11.7 +/- 3.9 and 8.7 +/- 3.6 mm Hg; and pulmonary vascular resistance (PVR) 3.9 +/- 2.1 and 2.4 +/- 1.3 wood units (WU), respectively. All patients required inotropes and inhaled nitric oxide (iNO) to be weaned from cardiopulmonary bypass (CPB). RESULTS Intravenous (IV) or inhaled vasodilators could be weaned using oral sildenafil in all patients. The hemodynamic data obtained during IV or inhaled drugs (between postoperative days 5 and 10) compared with those obtained on sildenafil therapy alone (about 1 month after transplantation) showed a significant decrease in SPAP (39.0 +/- 8.2 vs 32.0 +/- 6.5 mm Hg; P = .049). CONCLUSION These data suggested that oral sildenafil may have a role in the treatment of RVD after heart transplantation.

Regional mapping of myocardial hibernation phenotype in idiopathic end-stage dilated cardiomyopathy

Myocardial hibernation (MH) is a well‐known feature of human ischaemic cardiomyopathy (ICM), whereas its presence in human idiopathic dilated cardiomyopathy (DCM) is still controversial. We investigated the histological and molecular features of MH in left ventricle (LV) regions of failing DCM or ICM hearts. We examined failing hearts from DCM (n = 11; 41.9 ± 5.45 years; left ventricle‐ejection fraction (LV‐EF), 18 ± 3.16%) and ICM patients (n = 12; 58.08 ± 1.7 years; LVEF, 21.5 ± 6.08%) undergoing cardiac transplantation, and normal donor hearts (N, n = 8). LV inter‐ventricular septum (IVS) and antero‐lateral free wall (FW) were transmurally (i.e. sub‐epicardial, mesocardial and sub‐endocardial layers) analysed. LV glycogen content was shown to be increased in both DCM and ICM as compared with N hearts (P < 0.001), with a U‐shaped transmural distribution (lower values in mesocardium). Capillary density was homogenously reduced in both DCM and ICM as compared with N (P < 0.05 versus N), with a lower decrease independent of the extent of fibrosis in sub‐endocardial and sub‐epicardial layers of DCM as compared with ICM. HIF1‐α and nestin, recognized ischaemic molecular hallmarks, were similarly expressed in DCM‐LV and ICM‐LV myocardium. The proteomic profile was overlapping by ~50% in DCM and ICM groups. Morphological and molecular features of MH were detected in end‐stage ICM as well as in end‐stage DCM LV, despite epicardial coronary artery patency and lower fibrosis in DCM hearts. Unravelling the presence of MH in the absence of coronary stenosis may be helpful to design a novel approach in the clinical management of DCM.

PPARγ in coronary atherosclerosis: In vivo expression pattern and correlations with hyperlipidemic status and statin treatment

OBJECTIVE Peroxisome proliferator-activated receptor-γ (PPARγ) is involved in regulation of macrophage inflammation and in atherosclerosis. Herein we investigate the influence of statin treatment on PPARγ expression in coronary artery disease. METHOD PPARγ expression was investigated in coronary atherosclerotic atherectomies (N=48) and arteries (N=12) from patients with stable or unstable coronary syndromes or undergoing cardiac transplantation for end-stage ischemic cardiomyopathy, respectively, by immunohistochemistry. Plaque components and tissue factor immunoreactivity were also investigated. Atherectomies were obtained from de novo culprit lesions of hypercholesterolemic (16 statin-treated and 16 untreated) and normolipidemic (N=16) patients. Furthermore, PPARγ expression was evaluated in patients peripheral blood monocytes and in monocytic U937 cells after atorvastatin incubation, by Western blot analysis. RESULT PPARγ expression was higher in coronary plaques and peripheral blood monocytes of statin-treated patients, and it significantly increased in monocytes after 24h atorvastatin incubation (p<0.05). Intra-plaque macrophage content, atheroma, neoangiogenesis and hemorrhage, and circulating CRP levels were lower in statin-treated than untreated hypercholesterolemic patients and comparable with normolipidemic subjects. PPARγ immunoreactivity was localized to neointima and media, its distribution pattern being different from that of tissue factor. CONCLUSION PPARγ expression was enhanced in statin-treated patients with different distribution and behavior as compared to atheroma, macrophage content, tissue factor immunoreactivity and serum CRP. In vitro studies showed increased PPARγ expression in monocytes after atorvastatin incubation. These findings provide further evidence as to the protective role of statins in coronary artery disease and their influence on PPARγ expression in coronary plaques and on the inflammatory status of patients.

Does Everolimus Associated With a Low Dose of Cyclosporine in Long-Term Cardiac Transplant Recipients Improve Renal Function? Initial Experience

BACKGROUND Cyclosporine (CsA) renal toxicity is a well-known side effect. Various immunosuppressive strategies have been developed to minimize renal insufficiency. The use of everolimus associated with low levels of CsA can be an alternative strategy. METHODS From October 2007 to April 2008, everolimus was started with a lower dose of cyclosporine (trough levels from 109.3 +/- 27.5 to 93.7 +/- 30.1 ng/mL after 45 days) in 21 cardiac transplant recipients (18 male and 3 female patients, mean age 56.4 +/- 10.7 years). Pre-everolimus therapy creatinine levels, creatinine clearances, and glomerular filtration rates were 1.9 +/- 0.9 mg/dL, 54.2 +/- 18.1 mL/mins and 44.3 +/- 16.5 mL/min/m(2), respectively. RESULTS We observed a significant reduction in creatinine levels (from 1.9 +/- 0.9 to 1.4 +/- 0.3 mg/dL, P = .022) as well as a significant improvement in creatinine clearances (from 54.2 +/- 18.1 to 69.0 +/- 19.0 mL/min, P = .020) and glomerular filtration rates (from 44.3 +/- 16.5 to 57.1 +/- 16.3 mL/min/m(2), P = .010) after 7 days of everolimus therapy. Upon univariate analysis patient age, pretransplantation creatinine clearance, creatinine clearance after everolimus introduction, glomerular filtration rate at 45 days, and time from transplantation were associated with renal improvement. Upon multivariate analysis, only creatinine clearance at 7 days was related to the renal improvement. CONCLUSIONS These preliminary data suggested that everolimus with a low dose of CsA may be safe and effective to reduce CsA-related renal insufficiency among selected, heart transplant patients.

Prognostic Role of Myocardial Performance Index on Long-Term Survival after Heart Transplantation: A Prospective Study

The survival rate of heart transplant patients is increasing, underlying the need for accurate predictors of adverse events during clinical follow‐up. Myocardial performance index (MPI) is a Doppler‐derived index of combined systolic and diastolic function: we assessed the prognostic role of MPI in survival of patients >1 year after heart transplantation (HT). A total of 152 consecutive HT patients referred to our institution were enrolled in this prospective study. Primary endpoints were cardiac death and a composite of major adverse cardiac events (MACE). During follow‐up (69 ± 22 months), 68 (44.7%) patients had an adverse event and 20 (13.15%) patients died. Patients with MACE during follow‐up showed lower EF (57.3 ± 9.3 vs. 63 ± 6.1; P < 0.001) and higher MPI (0.45 ± 0.19 vs. 0.31 ± 0.13; P < 0.001) at enrolment. MPI and EF were independently related to MACE (OR = 2.2; 95% confidence interval [CI] = 1.01–5.1; and OR = 6.6; 95% CI = 3.5–11.2, respectively) and showed strong diagnostic power (MPI: receiver operating characteristic [ROC] area = 79%, with 79% sensitivity and 81% specificity; EF: ROC area = 77%, with 54% sensitivity and 91% specificity) in the subsequent year. Patients with EF > 50% and MPI < 0.45 at enrolment showed 75% event‐free survival 5 years after HT. In HT patients, MPI combined with EF was an accurate means of predicting long‐term adverse events.

C4d Analysis in Endomyocardial Biopsies of Heart Transplant Patients: Is There a Correlation with Hemodynamic Data?

BACKGROUND Endomyocardial biopsy (EMB) is the gold standard for immunologic follow-up to detect acute cellular rejection after cardiac transplantation. Conversely, protocols for the diagnosis and treatment of antibody-mediated rejection (AMR) are not well defined. Histologically, AMR is diagnosed by the presence of capillary damage associated with complement activation. The aim of this study was to correlate C4d expression of activated complement in EMB with hemodynamic compromise upon right heart catheterization. METHODS Heart transplant patients underwent hemodynamic and histologic follow-up with EMB and right heart catheterization between January 2008 and December 2009 for a total of 491 procedures. The cardiac biopsy was evaluated for acute cellular and AMR by means of the presence of the C4d complement fraction. The histologic results were compared with hemodynamic data registered during right heart catheterization. RESULTS Comparison of the hemodynamic data of subjects with versus without C4d positivity showed no significant difference. Furthermore, there was no significant difference comparing patients with versus without C4d positivity in the absence of significant acute cellular rejection episodes. (C4d-/ACR- vs C4d+/ACR-). The variation of each single hemodynamic parameter from its basal value (defined as the mean value in case of C4d-/ACR-) seemed to not be influenced by the presence of C4d+. CONCLUSIONS In our experience, C4d has been routinely evaluated in the majority of EMBs. We could not demonstrate a significant correlation of C4d positivity with hemodynamic compromise. These findings suggest that significant allograft dysfunction is not related to C4d positivity. Therefore, the diagnosis of AMR is difficult to establish, because allograft dysfunction is 1 of the 3 fundamental criteria.

Emergent coronary artery bypass grafting for cardiogenic shock caused by very late drug-eluting stent thrombosis.

We describe a case of cardiogenic shock caused by a very late drug-eluting stent (DES) thrombosis. The patient underwent emergent coronary artery bypass grafting (CABG) and was discharged home 15 days after the operation. The incidence of stent restenosis had been reduced by the use of DES, but the Achilles’ heel of DES is represented by a higher rate of stent thrombosis. In our case, the DES thrombosis occurred 5 years after its implantation, underlining the importance of prolonged dual antiplatelet therapy. Even though rare, this complication may be life-threatening. We believe that CABG provides better event-free survival than percutaneous coronary intervention in patients with multivessel coronary disease despite the use of DES.