Ugolino Livi

Photopheresis for the Prevention of Rejection in Cardiac Transplantation

BACKGROUND Photopheresis is an immunoregulatory technique in which lymphocytes are reinfused after exposure to a photoactive compound (methoxsalen) and ultraviolet A light. We performed a preliminary study to assess the safety and efficacy of photopheresis in the prevention of acute rejection of cardiac allografts. METHODS A total of 60 consecutive eligible recipients of primary cardiac transplants were randomly assigned to standard triple-drug immunosuppressive therapy (cyclosporine, azathioprine, and prednisone) alone or in conjunction with photopheresis. The photopheresis group received a total of 24 photopheresis treatments, each pair of treatments given on two consecutive days, during the first six months after transplantation. The regimen for maintenance immunosuppression, the definition and treatment of rejection episodes, the use of prophylactic antibiotics, and the schedule for cardiac biopsies were standardized among all 12 study centers. All the cardiac-biopsy samples were graded in a blinded manner at a central pathology laboratory. Plasma from the subgroup of 34 patients (57 percent) who were enrolled at the nine U.S. centers was analyzed by polymerase-chain-reaction amplification for cytomegalovirus DNA. RESULTS After six months of follow-up, the mean (+/-SD) number of episodes of acute rejection per patient was 1.44+/-1.0 in the standard-therapy group, as compared with 0.91+/-1.0 in the photopheresis group (P=0.04). Significantly more patients in the photopheresis group had one rejection episode or none (27 of 33) than in the standard-therapy group (14 of 27), and significantly fewer patients in the photopheresis group had two or more rejection episodes (6 of 33) than in the standard-therapy group (13 of 27, P=0.02). There was no significant difference in the time to a first episode of rejection, the incidence of rejection associated with hemodynamic compromise, or survival at 6 and 12 months. Although there were no significant differences in the rates or types of infection, cytomegalovirus DNA was detected significantly less frequently in the photopheresis group than in the standard-therapy group (P=0.04). CONCLUSIONS In this pilot study, the addition of photopheresis to triple-drug immunosuppressive therapy significantly decreased the risk of cardiac rejection without increasing the incidence of infection.

Effects of Age and Heart Failure on Human Cardiac Stem Cell Function

Currently, it is unknown whether defects in stem cell growth and differentiation contribute to myocardial aging and chronic heart failure (CHF), and whether a compartment of functional human cardiac stem cells (hCSCs) persists in the decompensated heart. To determine whether aging and CHF are critical determinants of the loss in growth reserve of the heart, the properties of hCSCs were evaluated in 18 control and 23 explanted hearts. Age and CHF showed a progressive decrease in functionally competent hCSCs. Chronological age was a major predictor of five biomarkers of hCSC senescence: telomeric shortening, attenuated telomerase activity, telomere dysfunction-induced foci, and p21(Cip1) and p16(INK4a) expression. CHF had similar consequences for hCSCs, suggesting that defects in the balance between cardiomyocyte mass and the pool of nonsenescent hCSCs may condition the evolution of the decompensated myopathy. A correlation was found previously between telomere length in circulating bone marrow cells and cardiovascular diseases, but that analysis was restricted to average telomere length in a cell population, neglecting the fact that telomere attrition does not occur uniformly in all cells. The present study provides the first demonstration that dysfunctional telomeres in hCSCs are biomarkers of aging and heart failure. The biomarkers of cellular senescence identified here can be used to define the birth date of hCSCs and to sort young cells with potential therapeutic efficacy.

Severe ischemic left ventricular failure: Coronary operation or heart transplantation?☆

Severe left ventricular failure in ischemic heart disease may contraindicate conservative surgical procedures. To redefine therapeutic indications, the clinical and angiographic data of 143 patients (137 men and 6 women) with ischemic heart disease and a left ventricular ejection fraction less than 0.30 who were seen by us between June 1985 and December 1990 were retrospectively analyzed. Patients were divided into three groups according to therapy: medical only, 72 (group 1); myocardial revascularization, 20 (group 2); and heart transplantation, 51 (group 3). Clinical status was poorer in group 3, with congestive heart failure as predominant symptom; angina was more frequent in group 2. No difference was noted in hemodynamic variables. Four early deaths (20.0%) occurred in group 2 and 7 (13.7%) in group 3. Follow-up ranged from 1 to 64 months (mean, 22 +/- 19 months), with an actuarial survival of 28% +/- 9%, 80% +/- 8% and 82% +/- 5% at 5 years in groups 1, 2, and 3, respectively. Even though postoperative New York Heart Association class was better in group 3 (1.0 versus 2.3 in group 2; p < 0.01), the difference in survival was not significant. Although in patients with ischemic heart disease and low left ventricular ejection fraction heart transplantation offers the best clinical results, considering the donor shortage, we conclude that myocardial revascularization may still be performed with good midterm results.

Skin cancer in heart transplant recipients: frequency and risk factor analysis

BACKGROUND The frequency of skin cancer is increased among organ transplant recipients, but the predisposing risk factors are controversial. It is also unclear whether heart transplant patients face an increased risk compared to recipients of other organs, e.g. kidney transplants. METHODS We performed univariate and multivariate analysis of risk factors for skin cancer in 252 heart transplants and in a control series of 228 kidney transplants followed up at a single center. An extensive dermatologic examination was carried out; baseline features, type of immunosuppression, number of 3A rejection episodes, extent of sunlight exposure and skin type were recorded. Multivariate analysis (Cox regression) included: age at transplantation, sex, skin type (Fitzpatricks criteria), presence of solar keratosis, presence of warts, type of organ, sunlight exposure. RESULTS During follow up skin cancer was more common among heart transplants (40, 16 %) than in kidney transplants (16, 7%, p = 0.004). The cumulative incidence of skin cancer by life table analysis increased from 16% after 5 years to 33% after 10 years in heart transplant patients and from 6% to 17% in kidney transplants (p 10000 hours (relative risk = 2.8), but not organ type were significant risk factors. CONCLUSION Age at transplant, skin type and sunlight exposure, but not type of organ and type of immunosuppressive regimen, are associated with increased risk of skin cancer in heart transplantation.

Mechanisms of symptomatic spinal cord ischemia after TEVAR: insights from the European Registry of Endovascular Aortic Repair Complications (EuREC).

Purpose To test the hypothesis that simultaneous closure of at least 2 independent vascular territories supplying the spinal cord and/or prolonged hypotension may be associated with symptomatic spinal cord ischemia (SCI) after thoracic endovascular aortic repair (TEVAR). Methods A pattern matching algorithm was used to develop a risk model for symptomatic SCI using a prospective 63-patient single-center cohort to test the positive predictive value (PPV) of prolonged intraoperative hypotension and/or simultaneous closure of at least 2 of 4 the vascular territories supplying the spinal cord (left subclavian, intercostal, lumbar, and hypogastric arteries). This risk model was then applied to data extracted from the multicenter European Registry on Endovascular Aortic Repair Complications (EuREC). Between 2002 and 2010, the 19 centers participating in EuREC reported 38 (1.7%) cases of symptomatic spinal cord ischemia among the 2235 patients in the database. Results In the single-center cohort, direct correlations were seen between the occurrence of symptomatic SCI and both prolonged intraoperative hypotension (PPV 1.00, 95% CI 0.22 to 1.00, p=0.04) and simultaneous closure of at least 2 independent spinal cord vascular territories (PPV 0.67, 95% CI 0.24 to 0.91, p=0.005). Previous closure of a single vascular territory was not associated with an increased risk of symptomatic spinal cord ischemia (PPV 0.07, 95% CI 0.01 to 0.16, p=0.56). The combination of prolonged hypotension and simultaneous closure of at least 2 territories exhibited the strongest association (PPV 0.75, 95% CI 0.38 to 0.75, p<0.0001). Applying the model to the entire EuREC cohort found an almost perfect agreement between the predicted and observed risk factors (kappa 0.77, 95% CI 0.65 to 0.90). Conclusion Extensive coverage of intercostal arteries alone by a thoracic stent-graft is not associated with symptomatic SCI; however, simultaneous closure of at least 2 vascular territories supplying the spinal cord is highly relevant, especially in combination with prolonged intraoperative hypotension. As such, these results further emphasize the need to preserve the left subclavian artery during TEVAR.

Surgical excision of intracardiac myxomas: A 20-year follow-up

Since November 1968, 54 patients have undergone excision of an intracardiac myxoma, which was located in the left atrium in 46 (85%), in the right atrium in 6 (11%), and in the right ventricle in 2 (4%). There were 35 female and 19 male patients with a mean age of 48 +/- 14 years (range, 7 to 68 years). Four patients were asymptomatic; the others were seen mostly with exertional dyspnea, palpitation, signs of systemic illness, and syncopal episodes. Before operation, embolic episodes occurred in 13 patients with a left atrial myxoma. There were two early (3.7%) and two late deaths (3.8). Actuarial survival at 20 years is 91% +/- 4%, and most of the current survivors are asymptomatic at a mean follow-up of 6.5 +/- 5 years (range, 0.2 year to 20 years). Noninvasive reevaluation was performed with echocardiographic studies in 44 patients and 24-hour electrocardiographic monitoring in 34. No instances of tumor recurrence were observed, and there was a low incidence of major supraventricular arrhythmias late postoperatively. We conclude that excision of intracardiac myxomas is curative and long-term survival is excellent. The transseptal approach provides adequate exposure and allows complete removal of the tumor regardless of its location.

Everolimus with reduced cyclosporine versus MMF with standard cyclosporine in de novo heart transplant recipients.

Background. 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. Methods. 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. Results. 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). Conclusion. 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.

Combined Intramyocardial Delivery of Human Pericytes and Cardiac Stem Cells Additively Improves the Healing of Mouse Infarcted Hearts Through Stimulation of Vascular and Muscular Repair

RATIONALE Optimization of cell therapy for cardiac repair may require the association of different cell populations with complementary activities. OBJECTIVE Compare the reparative potential of saphenous vein-derived pericytes (SVPs) with that of cardiac stem cells (CSCs) in a model of myocardial infarction, and investigate whether combined cell transplantation provides further improvements. METHODS AND RESULTS SVPs and CSCs were isolated from vein leftovers of coronary artery bypass graft surgery and discarded atrial specimens of transplanted hearts, respectively. Single or dual cell therapy (300 000 cells of each type per heart) was tested in infarcted SCID (severe combined immunodeficiency)-Beige mice. SVPs and CSCs alone improved cardiac contractility as assessed by echocardiography at 14 days post myocardial infarction. The effect was maintained, although attenuated at 42 days. At histological level, SVPs and CSCs similarly inhibited infarct size and interstitial fibrosis, SVPs were superior in inducing angiogenesis and CSCs in promoting cardiomyocyte proliferation and recruitment of endogenous stem cells. The combination of cells additively reduced the infarct size and promoted vascular proliferation and arteriogenesis, but did not surpass single therapies with regard to contractility indexes. SVPs and CSCs secrete similar amounts of hepatocyte growth factor, vascular endothelial growth factor, fibroblast growth factor, stem cell factor, and stromal cell-derived factor-1, whereas SVPs release higher quantities of angiopoietins and microRNA-132. Coculture of the 2 cell populations results in competitive as well as enhancing paracrine activities. In particular, the release of stromal cell-derived factor-1 was synergistically augmented along with downregulation of stromal cell-derived factor-1-degrading enzyme dipeptidyl peptidase 4. CONCLUSIONS Combinatory therapy with SVPs and CSCs may complementarily help the repair of infarcted hearts.

Morphologic spectrum of primary restrictive cardiomyopathy

A restrictive hemodynamic profile with left ventricular (LV) end-diastolic volume < 100 ml/m2 and LV end-diastolic pressure > 18 mm Hg, in the absence of endomyocardial, pericardial, and specific cardiomyopathy, is a peculiar feature of primary restrictive cardiomyopathy. From 1985 to 1994, 7 hearts of patients who met the above hemodynamic criteria and underwent endomyocardial biopsy because of heart failure, were studied through gross (5 cardiectomies and 2 autopsies), histologic, and electron microscopic investigations. Ages ranged from 9 to 48 years (mean age 29 +/- 13). Four patients (57%) had a positive family history: 2 for hypertrophic and 2 for restrictive cardiomyopathy. Three patterns were identified in the 7 hearts: (1) pure restrictive form in 4 cases with mass/volume ratio 1.2 +/- 0.5 g/ml, ejection fraction 58 +/- 5%, LV end-diastolic volume 67.5 +/- 12.6 ml/m2, LV end-diastolic pressure 26.7 +/- 3.5 mm Hg; (2) hypertrophic-restrictive form in 2 cases with mass/volume ratio 1.5 +/- 0.07 g/ml, ejection fraction 62 +/- 1%, LV end-diastolic volume 69 +/- 10 ml/m2, LV end-diastolic pressure 30 +/- 7 mm Hg; and (3) mildly dilated restrictive form in 1 case with mass/volume ratio 0.9 g/ml, ejection fraction 25%, LV end-diastolic volume 98 ml/m2, LV end-diastolic pressure 40 mm Hg. Histology and electron microscopy disclosed myocardial and myofibrillar disarray and endoperimysial interstitial fibrosis in each pattern. The familial forms suggest the presence of a genetic abnormality. Primary restrictive cardiomyopathy may present with or without hypertrophy and shares similar microscopic pictures with hypertrophic cardiomyopathy. The 2 entities may represent a different phenotypic expression of the same genetic disease.

Extracorporeal photochemotherapy as adjuvant treatment of heart transplant recipients with recurrent rejection

Recurrent rejection is an uncommon, severe complication after heart transplantation that is associated with a poor long-term prognosis. Photopheresis (ECP), a new form of extracorporeal photo-chemotherapy used for the treatment of cutaneous T cell lymphoma and several autoimmune diseases, has also been used for prevention and treatment of acute rejection in heart transplant recipients. It seems to induce specific suppression of both cellular and humoral rejection. In this study, we evaluated whether ECP added to standard therapies allowed better control of rejection and reduction of conventional immunosuppressive drugs in patients with repeated rejection episodes. Eight heart transplant recipients (6 men and 2 women, mean age 48 yr), with recurrent rejection were treated with ECP for 6 months. Endomyocardial biopsies (EMB) were performed monthly. As a result of treatment, 7 patients on ECP experienced a reduction of the number and severity of rejection episodes. The fraction of EMB negative for rejection increased from 13 to 41%, whereas the fraction of specimens with multifocal and/or diffuse moderate lymphocytes infiltration (grades 3A and 3B) decreased from 41 to 21%. ECP allowed reductions of daily immunosuppressive therapy: prednisone by 44% (16.9 vs. 9.4 mg), cyclosporine by 21% (366 vs. 291 mg), and azathioprine by 29% (137 vs. 97 mg). No major side effects were observed. We conclude that, although the number of patients is small, the use of ECP was safe and associated with improved control of recurrent rejection. This allowed tapering of immunosuppressive drugs, which was particularly useful in two patients with insulin-dependent diabetes and one with sternal wound osteomyelitis.