Sabine Pattier

Early Structural Valve Deterioration of Mitroflow Aortic Bioprosthesis Mode, Incidence, and Impact on Outcome in a Large Cohort of Patients

Background— Structural valve deterioration (SVD) is a major flaw of bioprostheses. Early SVD has been suspected in the last models of Mitroflow bioprosthesis. We sought to assess the incidence, mode, and impact of SVD on outcome in a large series of Mitroflow aortic valve replacement. Methods and Results— Six hundred seventeen consecutive patients (aged 76.1±6.3 years) underwent aortic valve replacement with a Mitroflow prosthesis (models 12A/LX) between 2002 and 2007. By echocardiography, 39 patients developed early SVD (1.66% per patient-year), with stenosis as the main mode (n=36). Mean delay to SVD was only 3.8±1.4 years, and 5-year SVD-free survival was 91.6% (95% confidence interval [CI], 88.7–94.7) for the whole cohort and 79.8% (95% CI, 71.2–89.4) and 94.0% (95% CI, 90.3–97.8) for 19- and 21-mm sizes, respectively. Among the 39 patients with SVD, 13 patients (33%) had an accelerated SVD once the mean gradient exceeded 30 mm Hg. Valve-related death was 46.2% in this SVD subgroup. Five-year overall survival was 69.6% (95% CI, 65.7–73.9). In multivariable analysis, SVD was the strongest correlate of overall mortality (hazard ratio=7.7; 95% CI, 4.4–13.6). Conclusions— Early SVD is frequent in Mitroflow bioprosthesis (models 12A/LX), especially for small sizes (19 and 21 mm), and reduces overall survival. An unpredictable accelerated pattern of SVD constitutes a life-threatening condition. In view of the large number of Mitroflow valves implanted worldwide, one can expect an epidemic of SVD and valve-related deaths, which represents a major public health issue, especially in the elderly. Hence, a close follow-up with yearly echocardiography after Mitroflow implantation is advisable. An urgent reoperation should be discussed in patients with severe SVD even though they are still asymptomatic.Background— Structural valve deterioration (SVD) is a major flaw of bioprostheses. Early SVD has been suspected in the last models of Mitroflow bioprosthesis. We sought to assess the incidence, mode, and impact of SVD on outcome in a large series of Mitroflow aortic valve replacement. Methods and Results— Six hundred seventeen consecutive patients (aged 76.1±6.3 years) underwent aortic valve replacement with a Mitroflow prosthesis (models 12A/LX) between 2002 and 2007. By echocardiography, 39 patients developed early SVD (1.66% per patient-year), with stenosis as the main mode (n=36). Mean delay to SVD was only 3.8±1.4 years, and 5-year SVD-free survival was 91.6% (95% confidence interval [CI], 88.7–94.7) for the whole cohort and 79.8% (95% CI, 71.2–89.4) and 94.0% (95% CI, 90.3–97.8) for 19- and 21-mm sizes, respectively. Among the 39 patients with SVD, 13 patients (33%) had an accelerated SVD once the mean gradient exceeded 30 mm Hg. Valve-related death was 46.2% in this SVD subgroup. Five-year overall survival was 69.6% (95% CI, 65.7–73.9). In multivariable analysis, SVD was the strongest correlate of overall mortality (hazard ratio=7.7; 95% CI, 4.4–13.6). Conclusions— Early SVD is frequent in Mitroflow bioprosthesis (models 12A/LX), especially for small sizes (19 and 21 mm), and reduces overall survival. An unpredictable accelerated pattern of SVD constitutes a life-threatening condition. In view of the large number of Mitroflow valves implanted worldwide, one can expect an epidemic of SVD and valve-related deaths, which represents a major public health issue, especially in the elderly. Hence, a close follow-up with yearly echocardiography after Mitroflow implantation is advisable. An urgent reoperation should be discussed in patients with severe SVD even though they are still asymptomatic. # CLINICAL PERSPECTIVE {#article-title-37}

Disseminated Scedosporium/Pseudallescheria Infection after Double-Lung Transplantation in Patients with Cystic Fibrosis

ABSTRACT We report a case of disseminated Scedosporium/Pseudallescheria infection due to Pseudallescheria boydii sensu stricto after lung transplantation in a patient with cystic fibrosis. Dissemination occurred under voriconazole. Despite surgery and combination therapy with voriconazole, caspofungin, and terbinafine, the patient died 8 months after transplantation. Previously reported cases are reviewed.

Outcome of Heart Transplants 15 to 20 Years Ago : Graft Survival, Post-transplant Morbidity, and Risk Factors for Mortality

OBJECTIVES The study was conducted to determine the long-term outcome of patients who underwent heart transplantation 15 to 20 years ago, in the cyclosporine era, and identify risk factors for death. METHODS A retrospective analysis was done of 148 patients who had undergone heart transplantation between 1985 and 1991 at a single center. Operative technique and immunosuppressive treatment were comparable in all patients. RESULTS Actuarial survival rates were 75% (n = 111), 58% (n = 86), and 42% (n = 62) at 5, 10, and 15 years, respectively. The mean follow-up period was 12.1 +/- 5.6 years for patients who survived more than 3 months after transplantation (n = 131). The major causes of death were malignancy (35.8%) and cardiac allograft vasculopathy (24.7%). No death related to acute rejection was reported after the first month of transplantation. Graft coronary artery disease was detected on angiography in 66 (50.3%), and 7 (5.3%) had retransplantation. Malignancies developed in 131 patients (48.1%), including skin cancers in 31 (23.6%), solid tumors in 26 (19.8%), and hematologic malignancies in 14 (10.6%). Severe renal function requiring dialysis or renal transplantation developed in 27 patients (20.6%). By multivariable analysis, the only pre-transplant risk factor found to affect long-term survival was a history of cigarette use (p < 0.0004). CONCLUSIONS Long-term survival at 15 years after cardiac transplantation remains excellent in the cyclosporine era. Controlling acute allograft rejection can be achieved but seems to carry a high rate of cancers and renal dysfunction. History of cigarette use affects significantly long-term survival in our study.

Late Failing Heart Allografts: Pathology of Cardiac Allograft Vasculopathy and Association With Antibody-Mediated Rejection

In heart transplantation, there is a lack of robust evidence of the specific causes of late allograft failure. We hypothesized that a substantial fraction of failing heart allografts may be associated with antibody‐mediated injury and immune‐mediated coronary arteriosclerosis. We included all patients undergoing a retransplantation for late terminal heart allograft failure in three referral centers. We performed an integrative strategy of heart allograft phenotyping by assessing the heart vascular tree including histopathology and immunohistochemistry together with circulating donor‐specific antibodies. The main analysis included 40 explanted heart allografts patients and 402 endomyocardial biopsies performed before allograft loss. Overall, antibody‐mediated rejection was observed in 19 (47.5%) failing heart allografts including 16 patients (40%) in whom unrecognized previous episodes of subclinical antibody‐mediated rejection occurred 4.5 ± 3.5 years before allograft loss. Explanted allografts with evidence of antibody‐mediated rejection demonstrated higher endothelitis and microvascular inflammation scores (0.89 ± 0.26 and 2.25 ± 0.28, respectively) compared with explanted allografts without antibody‐mediated rejection (0.42 ± 0.11 and 0.36 ± 0.09, p = 0.046 and p < 0.0001, respectively). Antibody‐mediated injury was observed in 62.1% of failing allografts with pure coronary arteriosclerosis and mixed (arteriosclerosis and atherosclerosis) pattern, while it was not observed in patients with pure coronary atherosclerosis (p = 0.0076). We demonstrate that antibody‐mediated rejection is operating in a substantial fraction of failing heart allografts and is associated with severe coronary arteriosclerosis. Unrecognized subclinical antibody‐mediated rejection episodes may be observed years before allograft failure.

Gene Expression Profiling for the Identification and Classification of Antibody-Mediated Heart Rejection

Background: Antibody-mediated rejection (AMR) contributes to heart allograft loss. However, an important knowledge gap remains in terms of the pathophysiology of AMR and how detection of immune activity, injury degree, and stage could be improved by intragraft gene expression profiling. Methods: We prospectively monitored 617 heart transplant recipients referred from 4 French transplant centers (January 1, 2006–January 1, 2011) for AMR. We compared patients with AMR (n=55) with a matched control group of 55 patients without AMR. We characterized all patients using histopathology (ISHLT [International Society for Heart and Lung Transplantation] 2013 grades), immunostaining, and circulating anti-HLA donor-specific antibodies at the time of biopsy, together with systematic gene expression assessments of the allograft tissue, using microarrays. Effector cells were evaluated with in vitro human cell cultures. We studied a validation cohort of 98 heart recipients transplanted in Edmonton, AB, Canada, including 27 cases of AMR and 71 controls. Results: A total of 240 heart transplant endomyocardial biopsies were assessed. AMR showed a distinct pattern of injury characterized by endothelial activation with microcirculatory inflammation by monocytes/macrophages and natural killer (NK) cells. We also observed selective changes in endothelial/angiogenesis and NK cell transcripts, including CD16A signaling and interferon-&ggr;–inducible genes. The AMR-selective gene sets accurately discriminated patients with AMR from those without and included NK transcripts (area under the curve=0.87), endothelial activation transcripts (area under the curve=0.80), macrophage transcripts (area under the curve=0.86), and interferon-&ggr; transcripts (area under the curve=0.84; P<0.0001 for all comparisons). These 4 gene sets showed increased expression with increasing pathological AMR (pAMR) International Society for Heart and Lung Transplantation grade (P<0.001) and association with donor-specific antibody levels. The unsupervised principal components analysis demonstrated a high proportion of molecularly inactive pAMR1(I+), and there was significant molecular overlap between pAMR1(H+) and full-blown pAMR2/3 cases. Endothelial activation transcripts, interferon-&ggr;, and NK transcripts showed association with chronic allograft vasculopathy. The molecular architecture and selective AMR transcripts, together with gene set discrimination capacity for AMR identified in the discovery set, were reproduced in the validation cohort. Conclusions: Tissue-based measurements of specific pathogenesis-based transcripts reflecting NK burden, endothelial activation, macrophage burden, and interferon-&ggr; effects accurately classify AMR and correlate with degree of injury and disease activity. This study illustrates the clinical potential of a tissue-based analysis of gene transcripts to refine diagnosis of heart transplant rejection.

Inflammatory cell burden and phenotype in endomyocardial biopsies with antibody-mediated rejection (AMR): a multicenter pilot study from the AECVP.

This multicenter case‐controlled pilot study evaluated myocardial inflammatory burden (IB) and phenotype in endomyocardial biopsies (EMBs) with and without pathologic antibody‐mediated rejection (pAMR). Sixty‐five EMBs from five European heart transplant centers were centrally reviewed as positive (grade 2, n = 28), suspicious (grade 1, n = 7) or negative (n = 30) for pAMR. Absolute counts of total, intravascular (IV) and extravascular (EV) immunophenotyped mononuclear cells were correlated with pAMR grade, capillary C4d deposition, donor specific antibody (DSA) status and acute cellular rejection (ACR). In pAMR+ biopsies, equivalent number of IV CD3+ T lymphocytes (23 ± 4/0.225 mm2) and CD68+ macrophages (21 ± 4/0.225 mm2) were seen. IB and cell phenotype correlated with pAMR grade, C4d positivity and DSA positivity (p < 0.0001). High numbers of IV T lymphocytes were associated with low grade ACR (p = 0.002). In late‐occurring AMR EV plasma cells occurring in 34% of pAMR+ EMBs were associated with higher IB. The IB in AMR correlated with pAMR+, C4d positivity and DSA positivity. In pAMR+ equivalent numbers of IV T lymphocytes and macrophages were found. The presence of plasma cells was associated with a higher IB and occurrence of pAMR late after transplantation.

A case of aortic and mitral valve involvement in granulomatosis with polyangiitis

Granulomatosis with polyangiitis (GPA) (Wegeners) is a necrotizing systemic vasculitis of the small-sized blood vessels, affecting kidneys, lungs, upper respiratory tract and skin. Cardiac valvular involvement is an uncommon manifestation of GPA. We report the case of a 60-year-old woman with arthritis and lung nodules due to GPA without antineutrophil cytoplasmic antibodies (ANCA) at time of diagnosis. Remission was obtained with cyclophosphamide and corticosteroid. Azathioprine was then prescribed for 2years. Four years later, she developed severe inflammatory aortic and mitral valvular involvement characterized by GPA typical histopathological valvular lesions. Search for ANCA was positive at this time (anti-myeloperoxidase). Cardiac valvular involvement is a rare and potentially fatal complication of GPA and may misleadingly suggest infectious endocarditis. A review of literature revealed few cases of histologically well-documented cardiac valvular involvement in GPA. Pathologists should be aware of valvular heart diseases in GPA, which usually comprise valvular necrotic lesions without any microbial agents.

Two cases of atypical Whipple's disease associated with cytoplasmic ANCA of undefined specificity

complement component. On a longitudinal analysis of SSc duration, as measured by the interval from the onset of the first nonRaynaud’s symptom, the proportion of patients with hypocomplementaemia remained unchanged. Similarly, there was no significant difference between hypocomplementaemic and normocomplementaemic patients with the changes in mRSS, pulmonary arterial pressures, diffusing capacity of the lung for carbon monoxide (DLCO), and forced vital capacity (FVC) at follow-up (data not shown). The prevalence of hypocomplementaemia in our multicentre analysis was lower than that registered by others (14–17%) (9, 10). Cuomo et al reported an association between hypocomplementaemia and skin, vascular, heart, and lung involvement (10). These discrepancies cannot be explained by a higher proportion of SSc overlap syndromes, as they had been excluded in the study of Cuomo et al, but their analysis might have included patients with autoantibodies other than anti-Scl70 and anti-centromere. Our study is limited by the lack of a centralized assessment of the labile analyte. Measuring degradation products could have been a more sensitive measure of complement activation. On the contrary, complement activation may occur in vitro during blood processing and increase the prevalence of hypocomplementaemia. This artefact, however, cannot account for the relatively low prevalence of hypocomplementaemia encountered in our study. Finally, overlap syndromes patients are not specifically excluded in EUSTAR, but they are more likely to be hypocomplementaemic than those with pure SSc (9). In summary, our results do not support a role of C3 and C4 measurements in the assessment of pure SSc. Acknowledgements

Renal insufficiency, mortality, and drug management in heart transplant. Results of the CARIN study.

Renal insufficiency (RI) is a frequent complication in heart transplant (HT) patients. The main objectives of the Cardiac trAnsplantation and Renal INsufficiency (CARIN) study were to follow the evolution of renal function after heart transplantation (HTx), to identify the factors associated with the decline of renal function, to describe the impact of RI on mortality during 3 years after the HT, and to observe the renal profile of the prescriptions. CARIN was a French retrospective, multicentric, study. Data were collected for patients who received a HT between 2000 and 2005. Data collection was performed at five time points: before HTx (T0), 1(T1), 6(T6), 12 (T12), and 36 (T36) months after HTx. Glomerular filtration rate (GFR) was estimated with aMDRD formula. RI was defined as GFR < 60 ml/min/1.73 m². Four hundred and forty‐one patients from five HT centers were included. The prevalences of RI were 28.8% (T0), 54.0% (T1), 50.4% (T6), 51.6% (T12), and 59.6% (T36). Age and cyclosporine were independently linked to the decline of renal function. Hypertension and GFR < 60 at T0 were independent risk factors of mortality. 48.7–64.7% of the nonimmunosuppressive prescriptions were drugs that required dosage adjustment in RI patients or for which no data were available concerning administration in RI patients. RI is highly frequent after HTx. Because RI is a risk factor of mortality, any sparing renal strategies have to be undertaken.

Heart transplantation in selected patients aged 60 years and older: a two-decade retrospective and multicentre analysis

OBJECTIVES This study analysed survival and long-term outcomes of heart transplantation in patients aged 60 years and older. We also analysed the impact of a national graft allocation priority [Super Emergency (SE)] and compared survival with younger patients in our centres and in France. METHODS We performed a multicentre (University Hospitals in Nantes, Rennes and Tours), 2-decade retrospective study between 1 January 1994 and 31 December 2013. Elderly recipients were placed on the same list as younger patients; the use of marginal donors remained occasional. RESULTS A total of 212 patients aged between 60 and 68 years were included. The 1-, 5-, and 10-year survival rates were 83.2%, 77.4% and 63.8%, respectively, which were significantly worse than those of recipients aged <60 years (1-, 5-, and 10-year survival rates of 87.3%, 80.4% and 68.0%, respectively). The postoperative course was acceptable. The main cause of death was malignancy (29.8% in our cohort). Survival was similar between the first and second decades and among the SE group. Our population exhibited better survival than patients <60 years transplanted in France during the same period with 1-, 5-, and 10-year survival rates of 76.8%, 68.0% and 56.3%, respectively. Predictors of survival in the multivariate analysis included ischaemic cardiomyopathy [hazard ratio (HR) 4.1] and postoperative complications, such as dialysis (HR 9.5) and mechanical circulatory support (HR 4.2). CONCLUSIONS We report positive postoperative course and long-term outcomes after heart transplantation in older recipients using conventional donors. Our satisfactory outcomes may be explained by the stringent selection of recipients combined with regular follow-up.