Alexandre Loupy1,2, Guillaume Coutance1,3, Guillaume Bonnet1,4, Jan Van Keer5, Marc Raynaud1, Olivier Aubert1,2, Marie-Cécile Bories4, Maud Racapé1, Daniel Yoo1, Jean-Paul Duong Van Huyen6, Patrick Bruneval7, Jean-Luc Taupin8, Carmen Lefaucheur1, Shaida Varnous3,9, Pascal Leprince3,9, Romain Guillemain4, Jean-Philippe Empana1,4, Ryan Levine10, Maarten Naesens11,12, Jigneh K Patel10, Xavier Jouven1,4, Jon Kobashigawa10. 1. Université de Paris, INSERM, Paris Translational Research Centre for Organ Transplantation, France (A.L., G.C., G.B., M. Raynaud, O.A., M. Racapé, D.Y., C.L., J.-P.E., X.J.). 2. Kidney Transplant Department (A.L., O.A.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France. 3. Department of Cardiac and Thoracic Surgery, Cardiology Institute, Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris (AP-HP), Sorbonne University Medical School, France (G.C., S.V., P.L.). 4. Cardiology and Heart Transplant Department (G.B., M.-C.B., R.G., J.-P.E., X.J.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France. 5. Departments of Cardiology (J.V.K.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium. 6. Pathology Department (J.P.D.V.H.), Necker Hospital, Assistance Publique-Hôpitaux de Paris, France. 7. Pathology Department (P.B.), Georges Pompidou Hospital, Assistance Publique-Hôpitaux de Paris, France. 8. Laboratory of Immunology and Histocompatibility, AP-HP, Saint Louis Hospital, Paris, France (J.-L.T.). 9. INSERM, UMRS 1166-ICAN, Institute of Cardiometabolism and Nutrition, Paris, France (S.V., P.L.). 10. Department of Cardiology, Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA (R.L., J.K.P., J.K.). 11. Microbiology, Immunology, and Transplantation and of Nephrology(M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium. 12. Renal Transplantation (M.N.), University Hospitals Leuven, Katholieke Universiteit Leuven, Belgium.
Abstract
BACKGROUND: Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development. METHODS: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality. RESULTS: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (P<0.001), donor male sex (P<0.001), donor tobacco consumption (P=0.001), recipient dyslipidemia (P=0.009), class II anti-human leukocyte antigen donor-specific antibodies (P=0.004), and acute cellular rejection ≥2R (P=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (P<0.001). CONCLUSIONS: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
BACKGROUND:Cardiac allograft vasculopathy (CAV) is a major contributor of heart transplant recipient mortality. Little is known about the prototypes of CAV trajectories at the population level. We aimed to identify the different evolutionary profiles of CAV and to determine the respective contribution of immune and nonimmune factors in CAV development. METHODS: Heart transplant recipients were from 4 academic centers (Pitié-Salpêtrière and Georges Pompidou Hospital, Paris, Katholieke Universiteit Leuven, and Cedars-Sinai, Los Angeles; 2004-2016). Patients underwent prospective, protocol-based monitoring consisting of repeated coronary angiographies together with systematic assessments of clinical, histological, and immunologic parameters. The main outcome was a prediction for CAV trajectory. We identified CAV trajectories by using unsupervised latent class mixed models. We then identified the independent predictive variables of the CAV trajectories and their association with mortality. RESULTS: A total of 1301 patients were included (815 and 486 in the European and US cohorts, respectively). The median follow-up after transplantation was 6.6 (interquartile range, 4-9.1) years with 4710 coronary angiographies analyzed. We identified 4 distinct profiles of CAV trajectories over 10 years. The 4 trajectories were characterized by (1) patients without CAV at 1 year and nonprogression over time (56.3%), (2) patients without CAV at 1 year and late-onset slow CAV progression (7.6%), (3) patients with mild CAV at 1 year and mild progression over time (23.1%), and (4) patients with mild CAV at 1 year and accelerated progression (13.0%). This model showed good discrimination (0.92). Among candidate predictors assessed, 6 early independent predictors of these trajectories were identified: donor age (P<0.001), donor male sex (P<0.001), donor tobacco consumption (P=0.001), recipient dyslipidemia (P=0.009), class II anti-human leukocyte antigen donor-specific antibodies (P=0.004), and acute cellular rejection ≥2R (P=0.028). The 4 CAV trajectories manifested consistently in the US independent cohort with similar discrimination (0.97) and in different clinical scenarios, and showed gradients for overall-cause mortality (P<0.001). CONCLUSIONS: In a large multicenter and highly phenotyped prospective cohort of heart transplant recipients, we identified 4 CAV trajectories and their respective independent predictive variables. Our results provide the basis for a trajectory-based assessment of patients undergoing heart transplantation for early risk stratification, patient monitoring, and clinical trials. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04117152.
Authors: Eliot G Peyster; Andrew Janowczyk; Abigail Swamidoss; Samhith Kethireddy; Michael D Feldman; Kenneth B Margulies Journal: Circulation Date: 2022-04-11 Impact factor: 39.918
Authors: Hidetoshi Tsuda; Nina Dvorina; Karen S Keslar; Jessica Nevarez-Mejia; Nicole M Valenzuela; Elaine F Reed; Robert L Fairchild; William M Baldwin Journal: Am J Pathol Date: 2022-04-29 Impact factor: 5.770
Authors: Michal Pazdernik; Helena Bedanova; Zhi Chen; Josef Kautzner; Vojtech Melenovsky; Ivan Malek; Antonij Slavcev; Michaela Bartonova; Vladimir Karmazin; Tomas Eckhardt; Ales Tomasek; Eva Ozabalova; Tomas Kovarnik; Peter Wohlfahrt; Milan Sonka Journal: Transpl Immunol Date: 2020-10-15 Impact factor: 2.032
Authors: Kyu-Yong Ko; Iksung Cho; Subin Kim; Yeonchan Seong; Dae-Young Kim; Ji Won Seo; Seng Chan You; Chi Young Shim; Geu-Ru Hong; Jong-Won Ha Journal: J Am Heart Assoc Date: 2022-07-29 Impact factor: 6.106