Antibody-mediated rejection in heart transplantation: new developments and old uncertainties.

PURPOSE OF REVIEW: Antibody-mediated rejection (AMR) currently represents one of the main problems for clinical management of heart transplant because of its diagnostic complexity and poor evidences supporting treatments. RECENT FINDINGS: Disorder-based diagnosis is a cornerstone in defining AMR. The limitations of the current classification have been partially overcome by novel studies improving the description of the immune-pathological graft abnormalities, and by new molecular approaches allowing a better understanding of the mechanisms behind AMR and of its relationship with cellular rejection and chronic vasculopathy. In-depth characterization of donor-specific antibodies showed to provide additional prognostic information and guide for treatment. Clinical relevance of AMR is bound to appropriate detection of graft dysfunction. In addition to traditional longitudinal evaluation by echocardiogram, cardiac magnetic resonance and detection of cell-free DNA may represent novel sensitive markers for graft injury that could prompt treatment before dysfunction becomes clinically manifest. SUMMARY: Despite improvements in the diagnostic process, therapeutic strategies made little progress in addition to the consolidation of practices supported by limited evidences. Novel complement inhibitors appear promising in changing this scenario. Nevertheless, collaborative multicenter studies are needed to develop standardized approaches tailored to the highly variable clinical and laboratory features of AMR.

Decrease in work rate in order to keep a constant heart rate: biomarker of exercise intolerance following a 10-day bed rest.

Aerobic exercise prescription is often set at specific heart rate (HR) values. Previous studies demonstrated that during exercise carried out at a HR slightly above that corresponding to the gas exchange threshold (GET), work rate (WR) has to decrease in order to maintain HR constant. We hypothesized a greater WR decrease at a fixed HR after simulated microgravity/inactivity (bed rest, BR). Ten male volunteers (23 ± 5 yr) were tested before (PRE) and after (POST) a 10-day horizontal BR and performed on a cycle ergometer 1) incremental exercise; b) 15-min HRCLAMPED exercise, in which WR was continuously adjusted to maintain a constant HR, corresponding to that at 120% of GET determined in PRE; 3) two moderate-intensity constant WR (MOD) exercises. Breath-by-breath O2 uptake (V̇o2), HR, and other variables were determined. After BR, peak V̇o2 (V̇o2peak) and GET significantly decreased, by ∼10%. During HRCLAMPED (145 ± 11 beats·min-1), the decrease in WR needed to maintain a constant HR was greater in POST versus PRE (-39 ± 10% vs. -29 ± 14%, P < 0.01). In six subjects the decreased WR switched from the heavy- to the moderate-intensity domain. The decrease in WR during HRCLAMPED, in PRE versus POST, was significantly correlated with the V̇o2peak decrease (R2 = 0.52; P = 0.02). A greater amplitude of the slow component of the HR kinetics was observed during MOD following BR. Exercise at a fixed HR is not associated with a specific WR or WR domain; the problem, affecting exercise evaluation and prescription, is greater after BR. The WR decrease during HRCLAMPED is a biomarker of exercise intolerance after BR.NEW & NOTEWORTHY During a 15-min exercise carried out at a heart rate (HR) slightly above that corresponding to the gas exchange threshold, to keep HR constant work rate significantly decreased; the decrease was more pronounced after a 10-day horizontal bed rest. The work rate decrease at a fixed HR can be considered a systemic biomarker of exercise intolerance during microgravity/inactivity and could also be easily and reliably determined during spaceflights or in patients.

Clinical relevance of the International Society for Heart and Lung Transplantation consensus classification of primary graft dysfunction after heart transplantation: Epidemiology, risk factors, and outcomes.

BACKGROUND: Primary graft dysfunction (P-GD) is the leading cause of early mortality after heart transplantation (HT). In this 2-center study we analyze outcomes and risk factors of P-GD according to the recent consensus conference classification endorsed by International Society for Heart and Lung Transplantation. METHODS: We included all adult HTs performed between 1999 and 2013. P-GD was graded as mild, moderate, and severe, according to International Society for Heart and Lung Transplantation recommendations, and analyzed separately from secondary GD. The primary end point was the combined occurrence of in-hospital death or emergency retransplantation. RESULTS: Early GD was found in 118 of 518 patients (23%), and 72 (13.9%) met the criteria for P-GD. Of these, 4 (5%) were mild, 33 (46%) moderate, and 35 (49%) severe and mostly characterized by biventricular involvement (78%). The end point occurred in 53 patients (10.2%). Overall, GD was a strong predictor of death-graft loss (odds ratio, 15.9; 95% confidence interval, 7.9-33.5; p < 0.01), with non-significant worse outcomes in P-GD (37%) vs secondary GD (27%) patients (p = 0.2). The study end point was more frequent in severe P-GD patients (65%) than in moderate (12%) or mild (0%; p < 0.01). Several known risk factors influenced the risk for P-GD, and the combination of specific donor and recipient risk factors accounted for approximately 22-times increased odds for P-GD. Donor age, recipient diabetes, ischemic time, and post-operative dialysis predicted non-recovery from P-GD. CONCLUSIONS: Consensus-defined P-GD identifies patients at major risk for early death and graft loss after HT, although the "mild" grade appeared under-represented and clinically irrelevant. The amplified negative effect of donor and recipient factors on P-GD risk underscores the need for appropriate donor-recipient match.

Occurrence of Fatal and Nonfatal Adverse Outcomes after Heart Transplantation in Patients with Pretransplant Noncytotoxic HLA Antibodies.

HLA antibodies (HLA ab) in transplant candidates have been associated with poor outcome. However, clinical relevance of noncytotoxic antibodies after heart transplant (HT) is controversial. By using a Luminex-based HLA screening, we retested pretransplant sera from HT recipients testing negative for cytotoxic HLA ab and for prospective crossmatch. Out of the 173 consecutive patients assayed (52 ± 13y; 16% females; 47% ischemic etiology), 32 (18%) showed pretransplant HLA ab, and 12 (7%) tested positive against both class I and class II HLA. Recipients with any HLA ab had poorer survival than those without (65 ± 9 versus 82 ± 3%; P = 0.02), accounting for a doubled independent mortality risk (P = 0.04). In addition, HLA-ab detection was associated with increased prevalence of early graft failure (35 versus 15%; P = 0.05) and late cellular rejection (29 versus 11%; P = 0.03). Of the subgroup of 37 patients suspected for antibody mediated rejection (AMR), the 9 with pretransplant HLA ab were more likely to display pathological AMR grade 2 (P = 0.04). By an inexpensive, luminex-based, HLA-screening assay, we were able to detect non-cytotoxic HLA ab predicting fatal and nonfatal adverse outcomes after heart transplant. Allocation strategies and desensitization protocols need to be developed and prospectively tested in these patients.