Daniel Hoefer

Concordance Among Pathologists in the Second Cardiac Allograft Rejection Gene Expression Observational Study (CARGO II)

Background There has been no large evaluation of the ISHLT 2004 acute cellular rejection grading scheme for heart graft endomyocardial biopsy specimens (EMBs). Methods We evaluated agreement within the CARGO II pathology panel and between the panel (acting by majority) and the collaborating centers (treated as a single entity), regarding the ISHLT grades of 937 EMBs (with all grades ≥2R merged because of small numbers). Results Overall all-grade agreement was almost 71% both within the panel and between the panel and the collaborating centers but, in both cases, was largely because of agreement on grade 0: for the average pair of pathologists, fewer than a third of the EMBs assigned grade ≥2R by at least one were assigned this grade by both. Conclusion The 2004 revision has done little to improve agreement on the higher ISHLT grades. An EMB grade ≥2R is not by itself sufficient as a basis for clinical decisions or as a research criterion. Steps should be taken toward greater uniformity in EMB grading, and efforts should be made to replace the ISHLT classification with diagnostic criteria—EMB based or otherwise—that correspond better with the pathophysiology of the transplanted heart.

Clinical usefulness of gene-expression profile to rule out acute rejection after heart transplantation: CARGO II

Abstract Aims A non-invasive gene-expression profiling (GEP) test for rejection surveillance of heart transplant recipients originated in the USA. A European-based study, Cardiac Allograft Rejection Gene Expression Observational II Study (CARGO II), was conducted to further clinically validate the GEP test performance. Methods and results Blood samples for GEP testing (AlloMap®, CareDx, Brisbane, CA, USA) were collected during post-transplant surveillance. The reference standard for rejection status was based on histopathology grading of tissue from endomyocardial biopsy. The area under the receiver operating characteristic curve (AUC-ROC), negative (NPVs), and positive predictive values (PPVs) for the GEP scores (range 0–39) were computed. Considering the GEP score of 34 as a cut-off (>6 months post-transplantation), 95.5% (381/399) of GEP tests were true negatives, 4.5% (18/399) were false negatives, 10.2% (6/59) were true positives, and 89.8% (53/59) were false positives. Based on 938 paired biopsies, the GEP test score AUC-ROC for distinguishing ≥3A rejection was 0.70 and 0.69 for ≥2–6 and >6 months post-transplantation, respectively. Depending on the chosen threshold score, the NPV and PPV range from 98.1 to 100% and 2.0 to 4.7%, respectively. Conclusion For ≥2–6 and >6 months post-transplantation, CARGO II GEP score performance (AUC-ROC = 0.70 and 0.69) is similar to the CARGO study results (AUC-ROC = 0.71 and 0.67). The low prevalence of ACR contributes to the high NPV and limited PPV of GEP testing. The choice of threshold score for practical use of GEP testing should consider overall clinical assessment of the patients baseline risk for rejection.

Caspofungin‐resistant Aspergillus flavus after heart transplantation and mechanical circulatory support: a case report

Abstract: Invasive aspergillosis (IA) is a severe complication in the post‐transplant period in recipients of solid organs. Therefore, early diagnosis and specific therapy of fungal infections in these patients are indispensable. We report the case of a 49‐year‐old patient, who suffered from IA after cardiac transplantation, which was complicated by post‐transplant right heart failure requiring mechanical circulatory support using veno‐arterial extracorporeal membrane oxygenation and a right ventricular assist device. Despite antifungal treatment, the patient died 3 weeks after transplantation because of multi‐organ failure secondary to IA. The isolated Aspergillus strains exhibited in vitro resistance to caspofungin.

Efficacy and Safety of Low-Dose Cyclosporine with Everolimus and Steroids in de novo Heart Transplant Patients: A Multicentre, Randomized Trial

A six-month, multicenter, randomized, open-label study was undertaken to determine whether renal function is improved using reduced-exposure cyclosporine (CsA) versus standard-exposure CsA in 199 de novo heart transplant patients receiving everolimus and steroids ± induction therapy. Mean C2 levels were at the low end of the target range in standard-exposure patients (n = 100) and exceeded target range in reduced-exposure patients (n = 99) throughout the study. Mean serum creatinine at Month 6 (the primary endpoint) was 141.0 ± 53.1 μmol/L in standard-exposure patients versus 130.1 ± 53.7 μmol/L in reduced-exposure patients (P = 0.093). The incidence of biopsy-proven acute rejection ≥3A at Month 6 was 21.0% (21/100) in the standard-exposure group and 16.2% (16/99) in the reduced-exposure group (n.s.). Adverse events and infections were similar between treatment groups. Thus, everolimus with reduced-exposure CsA resulted in comparable efficacy compared to standard-exposure CsA. No renal function benefits were demonstrated; that is possibly related to poor adherence to reduced CsA exposure.

Donor hypo- and hypernatremia are predictors for increased 1-year mortality after cardiac transplantation

Donor hypernatremia is known to be associated with initial graft dysfunction in liver transplantation. Controversial data exist regarding the impact of sodium dysregulation on patient survival after heart transplantation (HTX). The aim of this study was to investigate the influence of donor sodium levels on survival in a large cohort of heart transplant recipients from the Eurotransplant registry. From 1997 to 2005, all consecutive adult HTX performed in the Eurotransplant region were included into this study (n = 4641 patients). Multivariate analysis was applied to investigate possible clinical predictors for 1‐year post‐transplant survival after cardiac transplantation (donor sodium levels, donor age, donor cause of death, recipient age, primary disease, urgency status, cold ischemia time). In multivariate analysis, recipients receiving a donor heart with serum sodium level lower than 130 mmol/l or higher than 170 mmol/l had a 1.25‐fold higher risk for 1‐year post‐transplant mortality than patients with normal donor sodium ranges (P = 0.007). Other independent risk factors for impaired 1‐year survival were recipient age, the indication for transplantation and the urgency status of the recipient. Our study demonstrates that hyponatremia as well as hypernatremia show a strong U‐shaped correlation with poor survival after cardiac transplantation. Accurate donor management to avoid electrolyte disorder seems to be crucial for ensuring good quality of donor hearts.

Successful administration of levosimendan in a patient with low-gradient low-output aortic stenosis

SummaryAortic valve replacement in patients suffering from low-gradient aortic stenosis and congestive heart failure is associated with high operative mortality, and the perioperative use of inotropes is common. Levosimendan is a calcium sensitizer with positive inotropic and vasodilatory effects and has been developed for treatment of decompensated heart failure. Although its use in patients with low-gradient aortic stenosis is not established, we hypothesized that it might have beneficial effects on outcome after aortic valve replacement. We report on a high-risk operation in a 73-year-old man with low-gradient aortic stenosis, congestive heart failure and coronary artery disease. Levosimendan was administered perioperatively (0.1 mg/kg/min 16 hours prior to the operation without a loading dose) and allowed rapid recovery of the patient, who required only brief treatment in the intensive care unit. No levosimendan-specific adverse events were observed, in particular no hypotension. The excellent postoperative result was maintained after the patient was discharged from hospital.ZusammenfassungEin Aortenklappenersatz bei Patienten mit einer Aortenklappenstenose mit niedrigem Druckgradienten und hochgradig eingeschränkter Linksventrikelfunktion ist mit einer hohen Mortalität assoziiert und der perioperative Einsatz von positiv inotropen Substanzen ist häufig erforderlich. Levosimendan ist ein Kalzium-Sensitizer, der für die Therapie der akuten Herzinsuffizienz entwickelt wurde. Der Einsatz bei Patienten mit Aortenklappenstenose mit niedrigem Druckgradienten ist nicht etabliert, wir erwarteten jedoch vom perioperativen Einsatz dieses Medikaments einen positiven Einfluss auf das Überleben. Wir berichten über eine Hochrisiko-Operation bei einem 73-jährigen Mann mit einer Aortenklappenstenose mit niedrigem Druckgradienten, einer hochgradig eingeschränkten Linksventrikelfunktion und koronarer Herzkrankheit. Levosimendan wurde perioperativ verabreicht (0,1 mg/kg/min ohne Bolusgabe, Beginn 16 Stunden präoperativ), was die schnelle Erholung des Patienten und damit eine kurze Intensivtherapie begünstigte. Es traten keine Levosimendan-assoziierten Komplikationen, insbesondere keine Hypotonie, auf. Das exzellente postoperative Ergebnis ist auch im Langzeitverlauf stabil.

The pediatric mechanical circulatory support program in Innsbruck, Austria, and the impact of such programs on lack of donor hearts in Europe.

Strategy and results of the Innsbruck Mechanical Circulatory Support Program are presented, and the impact of such programs on pediatric heart transplantation (HTX) in Europe is discussed. Venoarterial extracorporeal membrane oxygenation (vaECMO) and ventricular assist devices (VADs) were used in 21 pediatric patients (median age 3.3 years, 2 days to 17 years) for acute heart failure (AHF) following a bridge or bridge-to-bridge strategy. Twelve patients were treated with vaECMO: eight were weaned after 2–10 days, two died, and two were switched to a VAD. Of the last, one was weaned 47 days later and the other underwent HTX 168 days later. In nine patients, VAD was implanted without preceding vaECMO. One such patient died (cerebral hemorrhage) after 236 days; of the remaining eight patients three were weaned and five underwent HTX. Waiting time for HTX (high-urgency status) varied from 4 to 372 days. Fifteen patients were discharged (follow up: 2–74 months); 14 are doing very well (New York Heart Association (NYHA) Functional Classification Class I, neurologically normal), whereas one suffers from severe neurologic damage, presumably from resuscitation before vaECMO. Data from Eurotransplant on pediatric HTX in 2004, 2005, and 2006 (33, 49, and 34 transplanted hearts, respectively; recipients <16 years of age) are discussed. Mechanical circulatory support (MCS) substantially improves survival with AHF in pediatric patients. Medium-term support (up to 400 days in our patients) is possible and outcome of survivors is excellent. Wide spread use of MCS might slightly aggravate the lack of donor organs, which could result in longer support times.

Interventional and medical treatment of acute heart failure due to inflammation: four cases.

Four patients (aged 15–41 years, mean age 26.7 years) with fulminant myocarditis undergoing mechanical circulatory support are reported. All patients suffered from acute low-output syndrome refractory to inotropic support. Diagnosis was confirmed by histology and immunohistochemistry. RT-PCR (reverse transcription-polymerase chain reaction) from endomyocardial biopsy specimens revealed parvovirus B19 in two patients and a coinfection with Chlamydia pneumoniae and parvovirus B19 in one patient. Midterm support with the biventricular Thoratec® system was preceded by implantation of an extracorporeal membrane oxygenation (ECMO) device in two patients. Two patients regained full cardiac function and were successfully weaned from the ventricular assist device (VAD) after 12 and 40 days. Heart transplantation was performed in another patient without evidence of myocardial recovery after 53 days. One patient died of cerebral hemorrhage on day 12 after VAD implantation. In summary, patients with life-threatening fulminant myocarditis can be successfully bridged to recovery or transplantation with mechanical circulatory support.ZusammenfassungDie fulminante Myokarditis ist eine seltene Manifestation der inflammatorischen Kardiomyopathie. Die rasche Entwicklung eines kardiogenen Schocks bzw. ei ner schweren kardialen Dysfunktion kennzeichnet diese Erkrankung. Die Langzeitprognose ist günstig, sofern der Patient die akute Erkrankungsphase überlebt. Berichtet wird über eigene Erfahrungen mit der Implantation mechanischer Unterstützungssysteme bei vier Patienten mit fulminanter Myokarditis.Die Diagnose wurde jeweils histologisch und immunhistochemisch gesichert. Mittels RT-PCR (reverse Transkription-Polymerase-Kettenreaktion) konnte im Myokard von Patientin A (24 Jahre) eine Koinfektion mit Chlamydia pneumoniae und Parvovirus B19, bei zwei Patienten (Patient B männlich, 41 Jahre; Patient C weiblich, 27 Jahre) eine isolierte Infektion mit Parvovirus B19 nachgewiesen werden. Bei Patient D (15 Jahre) fand sich kein Erreger. Patienten A und B erhielten Immunglobuline (2 ×10 g), Patientin A in Kombination mit einem Makrolidantibiotikum.Alle Patienten wiesen eine kurze Erkrankungsdauer mit rascher Entwicklung eines akuten Low-Output-Syndroms auf. Die Implantation des mechani schen Unterstützungssystems erfolgte wegen unzureichender Wirkung der medikamentösen inotropen Unterstützung. Bei zwei Patienten (A, B) wurde zunächst eine extrakorporale Membranoxygenie rung (ECMO) implantiert, welche nach 2 bzw. 4 Tagen durch ein biventrikuläres Unterstützungssystem (BVAD) ersetzt wurde. Zwei Patienten wurden primär mit diesem System versorgt.Bei zwei Patienten (A, D) zeigte sich eine sukzessive Erholung der kardialen Funktion, so dass das Unterstützungssystem nach 12 bzw. 40 Tagen entfernt werden konnte. Beide Patienten wiesen bei der Entlassung eine normale Ventrikelfunktion auf. Patient B wurde nach 53 Tagen wegen fehlender Verbesserung der Pumpfunktion erfolgreich einer Herztransplantation unterzogen. Patientin C verstarb am 12. Tag am Kunstherz an einer Hirnblutung. Als Ursache ist neben der notwendigen Antikoagulanzientherapie ein erworbenes Von-Willebrand-Syndrom anzunehmen.Insgesamt zeigte sich in dieser Serie, dass bei Patienten mit fulminanter Myokarditis mit Hilfe eines mechanischen Unterstützungssystems eine erfolgreiche Überbrückung bis zur Erholung des Myokards bzw. zur Herztransplantation möglich ist.

Interventional and Medical Treatment of Acute Heart Failure Due to Inflammation

Four patients (aged 15–41 years, mean age 26.7 years) with fulminant myocarditis undergoing mechanical circulatory support are reported. All patients suffered from acute low-output syndrome refractory to inotropic support. Diagnosis was confirmed by histology and immunohistochemistry. RT-PCR (reverse transcription-polymerase chain reaction) from endomyocardial biopsy specimens revealed parvovirus B19 in two patients and a coinfection with Chlamydia pneumoniae and parvovirus B19 in one patient. Midterm support with the biventricular Thoratec® system was preceded by implantation of an extracorporeal membrane oxygenation (ECMO) device in two patients. Two patients regained full cardiac function and were successfully weaned from the ventricular assist device (VAD) after 12 and 40 days. Heart transplantation was performed in another patient without evidence of myocardial recovery after 53 days. One patient died of cerebral hemorrhage on day 12 after VAD implantation. In summary, patients with life-threatening fulminant myocarditis can be successfully bridged to recovery or transplantation with mechanical circulatory support.ZusammenfassungDie fulminante Myokarditis ist eine seltene Manifestation der inflammatorischen Kardiomyopathie. Die rasche Entwicklung eines kardiogenen Schocks bzw. ei ner schweren kardialen Dysfunktion kennzeichnet diese Erkrankung. Die Langzeitprognose ist günstig, sofern der Patient die akute Erkrankungsphase überlebt. Berichtet wird über eigene Erfahrungen mit der Implantation mechanischer Unterstützungssysteme bei vier Patienten mit fulminanter Myokarditis.Die Diagnose wurde jeweils histologisch und immunhistochemisch gesichert. Mittels RT-PCR (reverse Transkription-Polymerase-Kettenreaktion) konnte im Myokard von Patientin A (24 Jahre) eine Koinfektion mit Chlamydia pneumoniae und Parvovirus B19, bei zwei Patienten (Patient B männlich, 41 Jahre; Patient C weiblich, 27 Jahre) eine isolierte Infektion mit Parvovirus B19 nachgewiesen werden. Bei Patient D (15 Jahre) fand sich kein Erreger. Patienten A und B erhielten Immunglobuline (2 ×10 g), Patientin A in Kombination mit einem Makrolidantibiotikum.Alle Patienten wiesen eine kurze Erkrankungsdauer mit rascher Entwicklung eines akuten Low-Output-Syndroms auf. Die Implantation des mechani schen Unterstützungssystems erfolgte wegen unzureichender Wirkung der medikamentösen inotropen Unterstützung. Bei zwei Patienten (A, B) wurde zunächst eine extrakorporale Membranoxygenie rung (ECMO) implantiert, welche nach 2 bzw. 4 Tagen durch ein biventrikuläres Unterstützungssystem (BVAD) ersetzt wurde. Zwei Patienten wurden primär mit diesem System versorgt.Bei zwei Patienten (A, D) zeigte sich eine sukzessive Erholung der kardialen Funktion, so dass das Unterstützungssystem nach 12 bzw. 40 Tagen entfernt werden konnte. Beide Patienten wiesen bei der Entlassung eine normale Ventrikelfunktion auf. Patient B wurde nach 53 Tagen wegen fehlender Verbesserung der Pumpfunktion erfolgreich einer Herztransplantation unterzogen. Patientin C verstarb am 12. Tag am Kunstherz an einer Hirnblutung. Als Ursache ist neben der notwendigen Antikoagulanzientherapie ein erworbenes Von-Willebrand-Syndrom anzunehmen.Insgesamt zeigte sich in dieser Serie, dass bei Patienten mit fulminanter Myokarditis mit Hilfe eines mechanischen Unterstützungssystems eine erfolgreiche Überbrückung bis zur Erholung des Myokards bzw. zur Herztransplantation möglich ist.

THERMAL PRECONDITIONING PROTECTS THE HUMAN INTERNAL MAMMARY ARTERY FROM HYPOXIA/RE-OXYGENATION-INDUCED DAMAGE

1 Preconditioning has been demonstrated to ameliorate ischaemia/reperfusion injury in several cells and tissues. Therefore, in the present study we investigated whether preconditioning of human bypass grafts, internal mammary artery (IMA) and saphenous vein (SV) induces heat shock protein (Hsp) expression and reduces apoptosis in response to subsequent hypoxia/re‐oxygenation damage in both vessels. 2 Internal mammary artery and SV rings, obtained from 30 patients (median age 66.5 years) undergoing coronary artery bypass grafting, were either incubated for 30 min at 42°C (preconditioned) or kept in a standard incubator at 37°C (not preconditioned). Six hours later, graft segments were exposed to 90 min hypoxia followed by a 30 min re‐oxygenation period. Western blot, real‐time quantative polymerase chain reaction analysis and apoptosis detection by the Terminal deoxyribonucleotidyl transferase‐mediated dUTP–digoxigenin nick end‐labelling method were performed. 3 Heat‐preconditioned IMA showed significantly increased protein expression of Hsp72 after hypoxia/re‐oxygenation treatment compared with controls (median 9.1 vs 5.0 µg/mg total protein; P = 0.048). Expression of Hsp73 was weak and Hsp60 was not detectable in the IMA. 4 In the SV, neither protein nor mRNA expression of Hsp were significantly different between preconditioned and not preconditioned veins. 5 There were significantly fewer apoptotic cells in the intima of the preconditioned compared with not preconditioned IMA (P = 0.041) after hypoxia/re‐oxygenation injury, whereas in the SV apoptosis was not significantly prevented by preconditioning. 6 Mild heat preconditioning before hypoxia/re‐oxygenation injury is a stimulus for Hsp72 protein expression and a reduction in apoptosis in the human IMA.