Moon, J.C. (James C.)
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- Sex dimorphism in the myocardial response to aortic stenosis(Elsevier, 2018) Torlasco, C. (Camilla); Espinoza, M. (Maria); Badiani, S. (Sveeta); Hughes, A.D. (Alun D.); Reant, P. (Patricia); Treibel, T.A. (Thomas A.); Moon, J.C. (James C.); Lloyd, G. (Guy); Kozor, R. (Rebecca); Yap, J. (John); Diez, J. (Javier); Fontana, M. (Marianna)Objectives: The goal of this study was to explore sex differences in myocardial remodeling in aortic stenosis (AS) by using echocardiography, cardiac magnetic resonance (CMR), and biomarkers. Background: AS is a disease of both valve and left ventricle (LV). Sex differences in LV remodeling are reported in AS and may play a role in disease phenotyping. Methods: This study was a prospective assessment of patients awaiting surgical valve replacement for severe AS using echocardiography, the 6-min walking test, biomarkers (high-sensitivity troponin T and N-terminal pro-brain natriuretic peptide), and CMR with late gadolinium enhancement and extracellular volume fraction, which dichotomizes the myocardium into matrix and cell volumes. LV remodeling was categorized into normal geometry, concentric remodeling, concentric hypertrophy, and eccentric hypertrophy.
- Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients(European Society of Cardiology, 2018) Menacho, K. (Katia); DiSalvo, C. (Carmelo); Schofield, R.S. (Rebecca S.); White, S.K. (Steven K.); Ravassa, S. (Susana); Ashworth, M.T. (Michael T.); Treibel, T.A. (Thomas A.); Roberts, N. (Neil); Moon, J.C. (James C.); Gonzalez, A. (Arantxa); López, B. (Begoña); Diez, J. (Javier); Fontana, M. (Marianna)Aims To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.
- Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance(2020) Liu, B. (Boyang); Edwards, N.C. (Nicola C.); Steeds, R.P. (Richard P.); Neil, D.A.H. (Desley A.H.); Premchand, M. (Monisha); Nikolaidis, N. (Nicolas); Treibel, T.A. (Thomas A.); Moon, J.C. (James C.); Gonzalez, A. (Arantxa); Billing, J.S. (J. Stephen); Bhabra, M. (Moninder); Hodson, J. (James); Patel, R. (Ramesh); Barker, T. (Thomas)Background: Myocardial fbrosis occurs in end-stage heart failure secondary to mitral regurgitation (MR), but it is not known whether this is present before onset of symptoms or myocardial dysfunction. This study aimed to characterise myocardial fbrosis in chronic severe primary MR on histology, compare this to tissue characterisation on cardiovascular magnetic resonance (CMR) imaging, and investigate associations with symptoms, left ventricular (LV) function, and exercise capacity. Methods: Patients with class I or IIa indications for surgery underwent CMR and cardiopulmonary exercise testing. LV biopsies were taken at surgery and the extent of fbrosis was quantifed on histology using collagen volume fraction (CVFmean) compared to autopsy controls without cardiac pathology. Results: 120 consecutive patients (64±13 years; 71% male) were recruited; 105 patients underwent MV repair while 15 chose conservative management. LV biopsies were obtained in 86 patients (234 biopsy samples in total). MR patients had more fbrosis compared to 8 autopsy controls (median: 14.6% [interquartile range 7.4–20.3] vs. 3.3% [2.6–6.1], P<0.001); this diference persisted in the asymptomatic patients (CVFmean 13.6% [6.3–18.8], P<0.001), but severity of fbrosis was not signifcantly higher in NYHA II-III symptomatic MR (CVFmean 15.7% [9.9–23.1] (P=0.083). Fibrosis was patchy across biopsy sites (intraclass correlation 0.23, 95% CI 0.08–0.39, P=0.001). No signifcant relationships were identifed between CVFmean and CMR tissue characterisation [native T1, extracellular volume (ECV) or late gadolinium enhancement] or measures of LV function [LV ejection fraction (LVEF), global longitudinal strain (GLS)]. Although the range of ECV was small (27.3±3.2%), ECV correlated with multiple measures of LV function (LVEF: Rho=−0.22, P=0.029, GLS: Rho=0.29, P=0.003), as well as NTproBNP (Rho=0.54, P<0.001) and exercise capacity (%PredVO2max: R=−0.22, P=0.030). Conclusions: Patients with chronic primary MR have increased fbrosis before the onset of symptoms. Due to the patchy nature of fbrosis, CMR derived ECV may be a better marker of global myocardial status. Clinical trial registration Mitral FINDER study; Clinical Trials NCT02355418, Registered 4 February 2015, https://clinicaltr ials.gov/ct2/show/NCT02355418
- Reverse myocardial remodeling following valve replacement in patients with aortic stenosis(Elsevier BV, 2018) Manisty, C. (Charlotte); Schofield, R.S. (Rebecca S.); Bhuva, A.N. (Anish N.); Treibel, T.A. (Thomas A.); Sheikh, A. (Amir); Benedetti, G. (Giulia); Moon, J.C. (James C.); Gonzalez, A. (Arantxa); Lloyd, G. (Guy); Kellman, P. (Peter); Kozor, R. (Rebecca); López, B. (Begoña); Diez, J. (Javier); Fontana, M. (Marianna)Background Left ventricular (LV) hypertrophy, a key process in human cardiac disease, results from cellular (hypertrophy) and extracellular matrix expansion (interstitial fibrosis). Objectives This study sought to investigate whether human myocardial interstitial fibrosis in aortic stenosis (AS) is plastic and can regress.
- Myocardial extracellular volume quantification by cardiovascularagn magnetic resonance and computed tomography(Springer, 2018) Bastarrika, G. (Gorka); Treibel, T.A. (Thomas A.); Moon, J.C. (James C.); Scully, P.R. (Paul R.)Purpose of review This review article discusses the evolution of extracellular volume (ECV) quantification using both cardiovascular magnetic resonance (CMR) and computed tomography (CT). Recent findings Visualizing diffuse myocardial fibrosis is challenging and until recently, was restricted to the domain of the pathologist. CMR and CT both use extravascular, extracellular contrast agents, permitting ECV measurement. The evidence base around ECV quantification by CMR is growing rapidly and just starting in CT. In conditions with high ECV (amyloid, oedema and fibrosis), this technique is already being used clinically and as a surrogate endpoint. Non-invasive diffuse fibrosis quantification is also generating new biological insights into key cardiac diseases. Summary CMR and CT can estimate ECV and in turn diffuse myocardial fibrosis, obviating the need for invasive endomyocardial biopsy. CT is an attractive alternative to CMR particularly in those individuals with contraindications to the latter. Further studies are needed, particularly in CT.
- H3K27ac acetylome signatures reveal the epigenomic reorganization in remodeled non-failing human hearts(2020) Vink, A. (Aryan); Pasterkamp, G. (Gerard); El-Azzouzi, H. (Hamid); Boukens, B.J. (Bastiaan J.); Verhaar, M.C. (Marianne C.); Efimov, I.R. (Igor R.); Mokry, M. (Michal); Cheng, C. (Caroline); Nieuwenhuis, E.E.S. (Edward E.S.); Harakalova, M. (Magdalena); Kararigas, G. (Georgios); Treibel, T.A. (Thomas A.); Asselbergs, F.W. (Folkert W.); Duncker, D.J. (Dirk J.); Moon, J.C. (James C.); Gonzalez, A. (Arantxa); Lumbers, R.T. (R. Thomas); Moore, J.H. (Jason H.); van-den-Dungen, N. (Noortje); van-Dijk, C.G.M. (Christian); de-Weger, R. (Roel); Pei, J. (Jiayi); López, B. (Begoña); den-Ruijter, H.M. (Hester M.); Krebber, M.M. (Merle M.); Huibers, M.M. (Manon M.); van-Dinter, J.T. (Jip T.)Background: H3K27ac histone acetylome changes contribute to the phenotypic response in heart diseases, particularly in end-stage heart failure. However, such epigenetic alterations have not been systematically investigated in remodeled non-failing human hearts. Therefore, valuable insight into cardiac dysfunction in early remodeling is lacking. This study aimed to reveal the acetylation changes of chromatin regions in response to myocardial remodeling and their correlations to transcriptional changes of neighboring genes. Results: We detected chromatin regions with differential acetylation activity (DARs; Padj. < 0.05) between remodeled non-failing patient hearts and healthy donor hearts. The acetylation level of the chromatin region correlated with its RNA polymerase II occupancy level and the mRNA expression level of its adjacent gene per sample. Annotated genes from DARs were enriched in disease-related pathways, including fibrosis and cell metabolism regulation. DARs that change in the same direction have a tendency to cluster together, suggesting the well-reorganized chromatin architecture that facilitates the interactions of regulatory domains in response to myocardial remodeling. We further show the differences between the acetylation level and the mRNA expression level of cell-type-specific markers for cardiomyocytes and 11 non-myocyte cell types. Notably, we identified transcriptome factor (TF) binding motifs that were enriched in DARs and defined TFs that were predicted to bind to these motifs. We further showed 64 genes coding for these TFs that were differentially expressed in remodeled myocardium when compared with controls. Conclusions: Our study reveals extensive novel insight on myocardial remodeling at the DNA regulatory level. Differences between the acetylation level and the transcriptional level of cell-type-specific markers suggest additional mechanism(s) between acetylome and transcriptome. By integrating these two layers of epigenetic profiles, we further provide promising TF-encoding genes that could serve as master regulators of myocardial remodeling. Combined, our findings highlight the important role of chromatin regulatory signatures in understanding disease etiology.