Björn Kornhall

Altered serum miRNA profiles during acute rejection after heart transplantation: Potential for non-invasive allograft surveillance

interstitial edema were more frequent in the TBI and PE groups than in the hanging group. In the LV, hypereosinophilia and interstitial edema were more frequent in the TBI and PE groups compared with the hanging group. The other signs were similarly observed in the three groups (Table 1). In the RV, positive reaction against fibronectin was more frequent in the TBI (80.9%) and PE (100%) groups compared with the hanging group (47.6%, p o 0.05 and p o 0.01) and was more frequent in the PT than in the TBI group (p o 0.05). A positive reaction against C5b-9 was more frequent in the TBI (28.6%) and PT (36.9%) groups than in the hanging group, in which no positive cases were observed (p o 0.05 and p o 0.01). The difference between the TBI and PE groups did not reach statistical significance. In the LV, positive reaction against fibronectin was more frequent in the PE group (73.7%) than in the TBI and hanging groups (33.3% and 42.9%), but this difference was not statistically significant. Overall, C5b-9 was positive in only 1 case from the TBI group. The IHC findings are summarized in Figure 1. Figure 2 shows the IHC expression of the antibodies used. To our knowledge, this is the first study to demonstrate an increased expression of fibronectin and C5b-9 in the RV after fatal TBI, indicating fresh cardiac ischemic lesions, similar to those observed after fatal PE. We may postulate that, after a severe TBI, the RV undergoes ischemic stress resulting from a sudden pressure overload due to catecholamine-mediated, acutely raised PAP. We propose that such a mechanism may play (beside direct catecholamine toxicity) an important role in damage of the RV myocardium. This may partly explain the RV dysfunction often observed in heart transplant recipients when donors were victims of TBI. Our findings suggest that invasive monitoring of PAP and PH-targeted therapies may improve the number and the quality of donor hearts, thereby improving transplantation rates and outcomes. Similar to most of the morphologic studies on autopsy material, we have presented a snapshot of the investigated pathologies, but have not presented clinical ‘‘dynamic’’ evidence. Another potential limitation is that the differences in baseline characteristics of the victims may partly explain the results.

Heart transplantation across the antibodies against HLA and ABO.

We have intentionally performed heart transplantation in a 5‐year‐old child, despite the most unfavourable risk factors for patient survival; the presence of high level of antibodies against donors human leucocyte antigen (HLA) class I/II and blood group antigens. Pretransplant treatment by mycophenolate mofetil, prednisolone, tacrolimus, intravenous immunoglobulin, rituximab, protein‐A immunoadsorption (IA) and plasma exchange reduced antibody titres against the donors lymphocytes from 128 to 16 and against the donors blood group antigen from 256 to 0. The patient was urgently transplanted with a heart from an ABO incompatible donor (A1 to O). A standard triple‐drug immunosuppressive protocol was used. No hyperacute rejection was seen. Antibodies against the donors HLA antigens remained at a low level despite three acute rejections. Rising anti‐A1 blood group antibodies preceded the second rejection and were reduced by two blood group‐specific IAs and remained at a low level. The patient is doing well despite the persistence of donor‐reactive antibodies.

Acute cellular rejection the first year after heart transplantation and its impact on survival: a single‐centre retrospective study at Skåne University Hospital in Lund 1988–2010

Acute cellular rejection (ACR) the first year after heart transplantation (HT) and its impact on survival was investigated. All 215 HT patients at our centre 1988–2010, including 219 HTs and 2990 first‐year endomyocardial biopsies (EMBs), were studied. ‘Routine’ EMBs obtained 1, 2, 3, 4, 6, 8, 10, 12, 16, 20, 24, 32, 40 and 52 weeks after HT, and ‘additional clinically indicated’ (ACI) EMBs, were graded according to the 1990‐ISHLT‐WF. The frequency and severity of first‐year ACRs was low, with 6.5% of routine EMBs and 14.1% of ACI EMBs showing ACR ≥ grade 2. Proportionally more (P < 0.05) first‐year ACRs ≥ grade 2 were found among EMBs in HTs performed during 1988–1999 (9.6%) than 2000–2010 (5.5%), EMBs performed during 16–52 weeks (8.8%) than 1–12 weeks (6.3%) after HT, EMBs in HTs with paediatric (11.3%) than adult (7.1%) donors, and EMBs in sex‐mismatched (10.4%) than sex‐matched (6.3%) HTs. Five‐ and ten‐year survival was furthermore lower (P < 0.05) among HTs with ≥1 compared with 0 first‐year ACRs ≥ grade 3A/3B (82% vs. 92% and 69% vs. 82%, respectively). Ten‐year survival was 74% compared with 53% in the ISHLT registry. In conclusion, our results indicate that first‐year ACRs ≥ grade 3A/3B affect long‐term survival. We believe frequent first‐year EMBs may allow early ACR detection and continuous immunosuppressive adjustments, preventing low‐grade ACRs from progressing to ACRs ≥ grade 3A/3B, thereby improving survival.

Characteristics and survival of adult Swedish PAH and CTEPH patients 2000-2014

Abstract Objectives: The Swedish Pulmonary Arterial Hypertension Register (SPAHR) is an open continuous register, including pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) patients from 2000 and onwards. We hereby launch the first data from SPAHR, defining baseline characteristics and survival of Swedish PAH and CTEPH patients. Design: Incident PAH and CTEPH patients 2008–2014 from all seven Swedish PAH-centres were specifically reviewed. Results: There were 457 PAH (median age: 67 years, 64% female) and 183 CTEPH (median age: 70 years, 50% female) patients, whereof 77 and 81%, respectively, were in functional class III–IV at diagnosis. Systemic hypertension, diabetes, ischaemic heart disease and atrial fibrillation were common comorbidities, particularly in those >65 years. One-, 3- and 5-year survival was 85%, 71% and 59% for PAH patients. Corresponding numbers for CTEPH patients with versus without pulmonary endarterectomy were 96%, 89% and 86% versus 91%, 75% and 69%, respectively. In 2014, the incidence of IPAH/HPAH, associated PAH and CTEPH was 5, 3 and 2 per million inhabitants and year, and the prevalence was 25, 24 and 19 per million inhabitants. Conclusion: The majority of the PAH and CTEPH patients were diagnosed at age >65 years, in functional class III–IV, and exhibiting several comorbidities. PAH survival in SPAHR was similar to other registers.

Desensitization and Heart Transplantation of a Patient With High Levels of Donor-Reactive Anti-Human Leukocyte Antigen Antibodies.

Background. To prepare a highly immunized recipient for heart transplantation, reduction of high levels of cytotoxic antibodies against human leukocyte antigen (HLA) was deemed essential to prevent antibody-mediated graft failure. Methods. Antibodies were analyzed by lymphocytotoxic and solid-phase assays. The pretransplant desensitization treatment protocol included daily tacrolimus and mycophenolate mofetil, weekly protein-A immunoadsorption (IA), intravenous immunoglobulin, and daclizumab. Posttransplant treatment consisted of tacrolimus, mycophenolate mofetil, prednisolone, IA, and daclizumab. Results. During pretransplant desensitization, each of the weekly immunoadsorption treatments reduced anti-HLA antibody levels by 50% to 70%, but they returned to the pretreatment level within 1 week as measured by flow cytometry. Cytotoxic antibodies remained reduced. After perioperative immunoadsorption, the donor-reactive antibodies (DRAs) were reduced to low levels. The patient underwent successful heart transplantation after 6 weeks on a waiting list. During the first week posttransplant, DRAs remained low. However, after the first week, anti-HLA DRAs reappeared and increased slightly over a 3-week period and then decreased slowly. Cytotoxic crossmatches were negative before and 3 week after transplantation. No clinical rejection was encountered. The patient was doing well 3 years after transplantation, and yearly clinical cardiac investigations were all normal. Three hyperimmunized patients have now undergone successful heart transplantation at our center using this desensitization protocol. Conclusions. IA in combination with pretransplant immunosuppressive drug treatment temporarily reduces antibody levels. The therapeutic levels of drug treatment at the time of transplantation may be of crucial importance. The treatment protocol resulted in freedom from rejection and other clinical adverse events.

Preoperative pulmonary hypertension and its impact on survival after heart transplantation.

Abstract Objectives. Pulmonary hypertension (PH) due to left heart disease may impair outcome after heart transplantation (HT). To evaluate to what extent previous, and present, haemodynamic criteria discriminate the impact of pre-operative-PH on survival, we characterized the PH in our HT-patients according to ESCs guidelines, ISHLTs summary statement and ISHLTs relative contraindications and criteria for early risk of death after HT. Design. Records from the 215 HT-patients in Lund during 1988–2010 were reviewed. Subsequent analysis included adults (n = 94) evaluated with right-heart-catheterization at our lab, at rest before HT. End of follow-up was 30th of June 2012. Results. Survival (mean, n) did not differ (p = ns) for the 94 HT-patients; without (13.0 years, n = 28) or with (13.9 years, n = 66) PH, passive (13.8 years, n = 50) or reactive (12.2 years, n = 13) post-capillary-PH, “modified” passive (13.1 years, n = 40), mixed (16.6 years, n = 23), “modified” reactive (12.6 years, n = 7) or non-reactive (12.2 years, n = 8) post-capillary-PH; or for ISHLTs relative contraindications (12.0 years, n = 22) or increased risk of right-heart-failure and early death (16.5 years, n = 23) after HT. Conclusions. As previous and present haemodynamic criteria did not sufficiently discriminate the impact of pre-operative-PH for survival after HT at our centre, larger multi-centre studies are encouraged to redefine criteria that may influence outcome.