Cardiac and peripheral gene expresison profiles of acute cardiac allograft rejection

La greffe cardiaque est le traitement ultime de l’insuffisance cardiaque. Le rejet aigu pose plusieurs problématiques, en particulier sa survenue imprévisible même sous traitement immunosuppresseur, et un diagnostic histologique qui nécessite des biopsies endomyocardiques (BEM) invasives répétées, et qui souffre de nombreuses limites. Le besoin de critères diagnostiques et prédictifs, idéalement non invasifs, nous a conduits à étudier le rejet aigu de greffe cardiaque sur le plan moléculaire. Nous avons caractérisé les profils d’expression génique (PEG) myocardiques et sanguins lors de différentes phases du rejet cellulaire (RC) et du rejet médié par les anticorps (RMA), par analyse sans a priori des transcriptomes sur puce à ADN. Par une première étude des PEG myocardiques menée sur une collection historique de BEM, nous avons montré la modification des PEG tissulaires lors du RC. Pour le même grade histologique, deux profils de RC aux degrés d’activation immunitaire différents ont été identifiés. De plus, les PEG myocardiques étaient modifiés dès un mois avant la survenue d’un RC, quand l’analyse histologique ne montrait encore aucune anomalie. Par une seconde étude conduite sur une collection prospective de BEM et échantillons sanguins, nous avons confirmé les résultats de la première étude, et de plus montré l’existence de modulations des PEG également dans le sang périphérique, aussi bien pendant un épisode de RC qu’un mois avant. Enfin pour la première fois la modulation tissulaire et périphérique des PEG a été montrée dans le RMA en transplantation cardiaque. L’existence de voies modulées dans les deux types de rejet devrait conduire à la recherche de biomarqueurs.Heart transplantation is the last treatment in case of terminal heart failure. Acute rejection after heart transplantation raises several issues due to its occurrence despite immunosuppressive therapies and the requirement of invasive and repeated endomyocardial biopsies (EMB) that have several histological grading limitations. The need of non-invasive diagnostic and predictive criteria led us to study the acute rejection of cardiac allograft using a molecular approach. We characterized myocardial and peripheral blood gene expression profiles (GEP) during acute cellular rejection (CR) and antibody-mediated rejection (AMR) by mean of microarray analyses. By a retrospective study conducted on a historical EMB collection, we first showed a strong immunologic modulation during CR. For the same CR histological grading, two transcriptional profiles were identified according to the inflammation level. Moreover, myocardial GEP modifications were observed one month before the occurrence of CR, while histological characteristics showed no abnormality. A second study conducted on a prospective collection of both EMB and peripheral blood samples confirmed the results obtained on EMB and showed peripheral blood GEP modulations during both CR and even one month earlier. Finally, we have also shown for the first time in heart transplantation, myocardial and peripheral GEP modulations in AMR. Identification of modulated pathways in both types of rejection should allow for the determination of rejection biomarkers

Recherche des marqueurs prédictifs de rejet de greffe cardiaque par analyse transcriptomique

PARIS7-Xavier Bichat (751182101) / SudocSudocFranceF

Myocardial native T2 measurement to differentiate light-chain and transthyretin cardiac amyloidosis and assess prognosis

Abstract Background To assess the diagnostic and prognosis value of myocardial native T2 measurement in the distinction between Light-chain (AL) and Transthyretin (ATTR) cardiac amyloidosis (CA). Methods Forty-four patients with CA (24 AL; 20 ATTR) and 40 healthy subjects underwent 1.5 T cardiovascular magnetic resonance (CMR). They all underwent T1 and T2 mapping (modified Look-Locker inversion recovery), cine and late gadolinium enhancement (LGE) imaging. The Query Amyloid Late Enhancement (QALE) score, myocardial native T2, T1 and extra cellular volume fraction (ECV) were calculated for all patients. Results Of the 44 patients, 36 (82%) exhibited enhancement on LGE images. Mean QALE score of AL (7.9 ± 6) and ATTR (10.5 ± 5) patients were similar (p = 0.6). Myocardial native T2 was significantly (p < 0.0001) higher in AL (63.2 ± 4.7 ms) than in ATTR (56.2 ± 3.1 ms) patients, and both higher (p < 0.001) than healthy subjects (51.1 ± 3.1 ms). Myocardial native T2 was highly correlated with myocardial native T1 (Spearman’s rho = 0.79; p < 0.001) and exhibited higher diagnostic performance than T1 to separate AL and ATTR patients: the area under curve (AUC) of T2 was 0.94 (95% CI: 0.86–1, p < 0.001) and the AUC of T1 was 0.77 (95% CI: 0.62–0.91, p = 0.03). Myocardial native T2 did not impact overall survival in patients (HR 1.03 (0.94–1.12); p = 0.53) in contrast to ECV that was the best predictor of outcome (HR 1.66 per 0.1 increase in ECV (1.24–2.22); p = 0.0006). Conclusions Myocardial native T2 significantly is increased in CA, especially in AL patients in comparison to ATTR patients. Myocardial native T2 does not impact survival in CA patients in contrast to ECV that was the best predictor of outcome. Trial registration Trial Registration and unique number: CNIL cardio 1778041. Date of registration: 20 December 2012

Echocardiographic Patterns of Left Ventricular Diastolic Function in Cardiac Amyloidosis: An Updated Evaluation

Aims: Multimodal imaging has allowed cardiac amyloidosis (CA) to be increasingly recognised as a treatable cause of heart failure with preserved ejection fraction, but its prognosis remains poor due to late diagnosis. To assess the left ventricular diastolic function (LVDF) patterns in a large contemporary CA cohort according to the current recommendations and to identify their determinants. Methods and Results: We conducted a monocentric, observational study on a cohort of CA patients from a tertiary CA referral centre. Diastolic function was analysed using standard echocardiography and clinical, laboratory and survival parameters were collected. Four hundred and sixty-four patients with one of the three main type of CA were included: 41% had grade III diastolic dysfunction (restrictive mitral pattern), 25% had grade II diastolic dysfunction, and 25% had grade I diastolic dysfunction; 9% were unclassified. No difference was found between the main CA types. After multivariate analyses, grades II and III were independently associated with dyspnoea, elevated NT-proBNP, cardiac infiltration and systolic dysfunction (global longitudinal strain). Grade I patients had a better prognosis. Conclusions: All LVDF patterns can be observed in CA. One quarter of CA patients have grade I LVDF, reflecting the emergence of earlier stage-related phenotypes with a better prognosis