Luciano Potena

The 2016 International Society for Heart Lung Transplantation listing criteria for heart transplantation: A 10-year update

Mandeep R. Mehra, MD (Chair), Charles E. Canter, MD, Margaret M. Hannan, MD, Marc J. Semigran, MD, Patricia A. Uber, PharmD, David A. Baran, MD, Lara Danziger-Isakov, MD, MPH, James K. Kirklin, MD, Richard Kirk, MD, Sudhir S. Kushwaha, MD, Lars H. Lund, MD, PhD, Luciano Potena, MD, PhD, Heather J. Ross, MD, David O. Taylor, MD, Erik A.M. Verschuuren, MD, PhD, Andreas Zuckermann, MD and on behalf of the International Society for Heart Lung Transplantation (ISHLT) Infectious Diseases, Pediatric and Heart Failure and Transplantation Councils

Acute rejection and cardiac allograft vascular disease is reduced by suppression of subclinical cytomegalovirus infection

Background. Anticytomegalovirus (CMV) prophylaxis prevents the acute disease but its impact on subclinical infection and allograft outcome is unknown. We sought to determine whether CMV prophylaxis administered for three months after heart transplant would improve patient outcomes. Methods. This prospective cohort study of 66 heart transplant recipients compared aggressive CMV prophylaxis (n=21, CMV hyperimmune globulin [CMVIG] plus four weeks of intravenous ganciclovir followed by two months of valganciclovir); with standard prophylaxis (n=45, intravenous ganciclovir for four weeks). Prophylaxis was based on pretransplant donor (D) and recipient (R) CMV serology: R−/D+ received aggressive prophylaxis; R+ received standard prophylaxis. Outcome measures were: CMV infection assessed by DNA-polymerase chain reaction on peripheral blood polymorphonuclear leukocytes, acute rejection, and cardiac allograft vascular disease (CAV) assessed by intravascular ultrasound. All patients completed one year of follow-up. Results. CMV infection was subclinical in all but four patients (two in each group). Aggressively treated patients had a lower incidence of CMV infection (73±10% vs. 94±4%; P=0.038), and an independent reduced relative risk for acute rejection graded ≥3A (relative risk [95% CI]=0.55 [0.26–0.96]; P=0.03), as compared with the standard prophylaxis group. Aggressively prophylaxed patients also showed a slower progression of CAV, in terms of coronary artery lumen loss (lumen volume change=−21±13% vs. −10±14%; P=0.05); and vessel shrinkage (vessel volume change=−15±11% vs. −3±18%; P=0.03). Conclusions. Prolonged (val)ganciclovir plus CMVIG reduces viral levels, acute rejection, and allograft vascular disease, suggesting a role for chronic subclinical infection in the pathophysiology of the most common diseases affecting heart transplant recipients.

Everolimus Versus Mycophenolate Mofetil in Heart Transplantation: A Randomized, Multicenter Trial

In an open‐label, 24‐month trial, 721 de novo heart transplant recipients were randomized to everolimus 1.5 mg or 3.0 mg with reduced‐dose cyclosporine, or mycophenolate mofetil (MMF) 3 g/day with standard‐dose cyclosporine (plus corticosteroids ± induction). Primary efficacy endpoint was the 12‐month composite incidence of biopsy‐proven acute rejection, acute rejection associated with hemodynamic compromise, graft loss/retransplant, death or loss to follow‐up. Everolimus 1.5 mg was noninferior to MMF for this endpoint at month 12 (35.1% vs. 33.6%; difference 1.5% [97.5% CI: –7.5%, 10.6%]) and month 24. Mortality to month 3 was higher with everolimus 1.5 mg versus MMF in patients receiving rabbit antithymocyte globulin (rATG) induction, mainly due to infection, but 24‐month mortality was similar (everolimus 1.5 mg 10.6% [30/282], MMF 9.2% [25/271]). Everolimus 3.0 mg was terminated prematurely due to higher mortality. The mean (SD) 12‐month increase in maximal intimal thickness was 0.03 (0.05) mm with everolimus 1.5 mg versus 0.07 (0.11) mm with MMF (p < 0.001). Everolimus 1.5 mg was inferior to MMF for renal function but comparable in patients achieving predefined reduced cyclosporine trough concentrations. Nonfatal serious adverse events were more frequent with everolimus 1.5 mg versus MMF. Everolimus 1.5 mg with reduced‐dose cyclosporine offers similar efficacy to MMF with standard‐dose cyclosporine and reduces intimal proliferation at 12 months in de novo heart transplant recipients.

Hydroxymethyl-Glutaryl Coenzyme A Reductase Inhibition Limits Cytomegalovirus Infection in Human Endothelial Cells

Background—Statins exert anti-inflammatory effects independently of cholesterol-lowering properties. Cytomegalovirus (CMV) infection appears to be implicated in the pathophysiology of atherosclerosis by inducing inflammatory modifications in endothelial cells, especially in immunosuppressed patients. We investigated whether the activity of statins can inhibit replication of CMV in human endothelial cells. Methods and Results—Human umbilical vein endothelial cells (HUVECs) were infected with CMV and coincubated with fluvastatin at 0.1 and 0.2 &mgr;mol/L. Fluvastatin inhibited (P <0.001) CMV antigen expression, and this effect was dose related (P <0.001). Quantitative polymerase chain reaction showed that CMV DNA concentration was consistently lower in supernatants from fluvastatin-treated cells than in infected controls, and viral particle concentration was up to 30 times lower in 0.2 &mgr;mol/L fluvastatin-treated cells than in infected controls (10.5±0.9 versus 0.34±0.03 per 103 pfu/mL, P <0.001). Addition of mevalonate to treated cultures almost completely abolished fluvastatin inhibition of viral growth. Electrophoretic mobility shift assay showed that fluvastatin reduced nuclear factor-&kgr;B binding activity in CMV-infected cells. Conclusions—HMG-CoA inhibition by fluvastatin restrains CMV replication in HUVECs by inhibiting viral antigen expression, DNA synthesis, and viral particle production, conceivably by involving a reduction of nuclear factor-&kgr;B binding activity.

Prophylaxis Versus Preemptive Anti-cytomegalovirus Approach for Prevention of Allograft Vasculopathy in Heart Transplant Recipients

BACKGROUND Cytomegalovirus (CMV) infection may influence the development of cardiac allograft vasculopathy (CAV). Prophylactic or preemptive administration of anti-CMV agents effectively prevents acute CMV manifestations. However, studies comparing allograft-related outcomes between these anti-CMV approaches are lacking. Herein we report a longitudinal observational study comparing CAV development between prophylactic and preemptive approaches. METHODS The 1-year change in maximal intimal thickening (MIT) assessed by intravascular ultrasound at 1 and 12 months after heart transplantation (the major surrogate for late survival) was compared in groups of patients routinely assigned to a preemptive strategy (from November 2004 to October 2005; n = 21) or receiving valganciclovir prophylaxis (from November 2005 to October 2006; n = 19). CMV infection was monitored with pp65 antigenemia. RESULTS The 1-year increase in MIT was significantly lower in patients receiving prophylaxis compared with those managed preemptively (0.15 +/- 0.17 vs 0.31 +/- 0.20 mm; p = 0.01). Prophylaxed recipients presented less frequently with MIT change > or =0.3 mm (p = 0.03) and > or =0.5 mm (p = 0.10) than those managed preemptively. Prophylaxis was also associated with later onset of CMV infection (p = 0.01), lower peak CMV detection (p < 0.01) and reduced incidence of CMV disease/syndrome (p = 0.04). After adjusting for metabolic risk factors and other possible confounders, prophylaxis remained independently associated with lower risk for MIT change > or =0.3 mm (odds ratio = 0.09, 95% confidence interval 0.01 to 0.93; p = 0.04). CONCLUSIONS Universal prophylaxis was associated with delayed onset of CMV infection, lower viral burden, reduced CMV disease/syndrome and less intimal thickening, as compared with a preemptive anti-CMV approach. Randomized studies are required to confirm the potential benefits of prophylaxis vs a preemptive approach in heart transplant recipients.

Relevance of cytomegalovirus infection and coronary-artery remodeling in the first year after heart transplantation: a prospective three-dimensional intravascular ultrasound study.

Background. Transplant coronary artery disease (TxCAD) is a major cause of long-term mortality after heart transplantation. Although vascular remodeling has been implicated in the pathophysiology of TxCAD, its determinants remain unknown. Methods. Twenty-nine consecutive heart-transplant recipients prospectively received intravascular ultrasound (IVUS) of the left-anterior descending artery 1 and 12 months after transplant, with volumetric reconstruction of the proximal 30 mm. Results. Overall, patients exhibited intimal volume increase (+83%, P <0.001), wheras vessel volume remained largely unchanged (+4%, P =0.270); consequently, overall lumen volume decreased (−6%, P =0.058). Among the clinical and laboratory variables, cytomegalovirus (CMV) infection requiring treatment (occurring in 12 patients), as assessed by pp65 antigenemia, was independently associated with the impaired ability of the vessel wall to enlarge in response to intimal volume increase, ultimately resulting in lumen loss (OR [95% CI]=0.098 [0.010–0.920];P =0.042). However, adequate vessel response to intimal hyperplasia with consequent lumen preservation was observed in the remaining 17 patients who did not present CMV infection requiring treatment. Conclusions. The present study demonstrates that either adequate or inadequate coronary remodeling may occur during the first year after transplantation. Moreover, for the first time, it strongly suggests that remodeling modalities may be negatively influenced by the occurrence of clinically relevant CMV infection. Randomized prospective trials are warranted to investigate whether aggressive treatment of CMV infection may help prevent TxCAD.

Cytomegalovirus-associated allograft rejection in heart transplant patients.

Purpose of review Modern antiviral strategies are effective in controlling the clinical syndromes associated with acute cytomegalovirus infection in heart transplant recipients. Despite this effectiveness, subclinical cytomegalovirus infection is a common finding in these patients and its impact on long-term graft outcome is currently underestimated. Recent findings Recent studies provide evidence implicating subclinical cytomegalovirus infection in the pathogenesis of allograft rejection and cardiac allograft vasculopathy. In this process, cytomegalovirus interacts with local inflammatory pathways, and systemic immune-regulation mechanisms, which may lead to graft damage, even in the absence of cytomegalovirus replication within the graft. Consequently, in addition to pharmacologic strategies that inhibit viral replication, immune-based therapies that abrogate host immune response may provide an effective tool to prevent the indirect impact of cytomegalovirus on graft function. Summary Current evidence suggests that subclinical cytomegalovirus infection plays an important role in the pathogenesis of long-term graft dysfunction in heart transplant recipients and in other solid organ transplant recipients. Pending the availability of definitive data from randomized trials, we propose that the use of pharmacologic and immune-based approaches, directed at complete suppression of cytomegalovirus infection, represents the best strategy for prevention of cytomegalovirus-induced rejection, cardiac allograft vasculopathy and chronic allograft damage.

Heart Transplantation in Hypertrophic Cardiomyopathy

Heart transplantation (HT) is the sole therapeutic option for selected patients with hypertrophic cardiomyopathy (HC) and refractory heart failure. However, the results of HT have not been systematically investigated in HC. We assessed the pathophysiologic profile of HT candidates and the outcome after transplantation in 307 patients with HC consecutively evaluated at our tertiary referral center from 1987 to 2005; follow-up was 9.9+8.2 years. Outcome of recipients with HC was compared with that of 141 patients who underwent transplantation for idiopathic dilated cardiomyopathy at our center over the same period. Of 21 patients with HC who entered the transplantation list, 20 had end-stage evolution with systolic dysfunction and 1 had an extremely small left ventricular cavity with impaired filling and recurrent cardiogenic shock during paroxysmal atrial fibrillation. Of 33 study patients with HC who showed end-stage evolution during follow-up, the 23 who were included on the waiting list or died from refractory heart failure (2 patients) were significantly younger than the 10 patients who remained clinically stable (37+/-14 vs 57+/-17 years, p=0.004). Of the 21 HT candidates, 18 underwent transplantation during follow-up. In heart transplant recipients, 7-year survival rate was 94% and not different from that of the 141 patients who received transplants for idiopathic dilated cardiomyopathy (p=0.66). In conclusion, long-term outcome after HT in patients with HC is favorable and similar to that of patients with idiopathic dilated cardiomyopathy. In patients with end-stage HC, young age is associated with more rapid progression to refractory heart failure.

Accelerated QRS widening as an independent predictor of cardiac death or of the need for heart transplantation in patients with congestive heart failure

We analyzed QRS interval for 6 months or more in 82 patients with dilated cardiomyopathy. At 1 year, the incidence of cardiac death/need for heart transplantation was higher among patients with QRS-interval widening of 0.5 msec/month or greater (p = 0.002). At multivariate analysis, QRS widening independently and unfavorably predicted cardiac death/need for heart transplantation (p = 0.029). Randomized prospective studies are necessary to confirm the prognostic value of accelerated QRS widening in patients with dilated cardiomyopathy and to investigate its significance in selecting candidates for electrical resynchronization and heart transplantation.

The Influence of Immunosuppressive Agents on the Risk of De Novo Donor-Specific HLA Antibody Production in Solid Organ Transplant Recipients

Production of de novo donor-specific antibodies (dnDSA) is a major risk factor for acute and chronic antibody-mediated rejection and graft loss after all solid organ transplantation. In this article, we review the data available on the risk of individual immunosuppressive agents and their ability to prevent dnDSA production. Induction therapy with rabbit antithymocyte globulin may achieve a short-term decrease in dnDSA production in moderately sensitized patients. Rituximab induction may be beneficial in sensitized patients, and in abrogating rebound antibody response in patients undergoing desensitization or treatment for antibody-mediated rejection. Use of bortezomib for induction therapy in at-risk patients is of interest, but the benefits are unproven. In maintenance regimens, nonadherent and previously sensitized patients are not suitable for aggressive weaning protocols, particularly early calcineurin inhibitor withdrawal without lymphocyte-depleting induction. Early conversion to mammalian target of rapamycin inhibitor monotherapy has been reported to increase the risk of dnDSA formation, but a combination of mammalian target of rapamycin inhibitor and reduced-exposure calcineurin inhibitor does not appear to alter the risk. Early steroid therapy withdrawal in standard-risk patients after induction has no known dnDSA penalty. The available data do not demonstrate a consistent effect of mycophenolic acid on dnDSA production. Risk minimization for dnDSA requires monitoring of adherence, appropriate risk stratification, risk-based immunosuppression intensity, and prospective DSA surveillance.