Myocardial fibrosis in asymptomatic and symptomatic chronic severe primary mitral regurgitation and relationship to tissue characterisation and left ventricular function on cardiovascular magnetic resonance

Boyang Liu, Desley A H Neil, Monisha Premchand, Moninder Bhabra, Ramesh Patel, Thomas Barker, Nicolas Nikolaidis, J Stephen Billing, Thomas A Treibel, James C Moon, Arantxa González, James Hodson, Nicola C Edwards, Richard P Steeds, Boyang Liu, Desley A H Neil, Monisha Premchand, Moninder Bhabra, Ramesh Patel, Thomas Barker, Nicolas Nikolaidis, J Stephen Billing, Thomas A Treibel, James C Moon, Arantxa González, James Hodson, Nicola C Edwards, Richard P Steeds

Abstract

Background: Myocardial fibrosis 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 fibrosis 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 fibrosis was quantified 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 fibrosis 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 difference persisted in the asymptomatic patients (CVFmean 13.6% [6.3-18.8], P < 0.001), but severity of fibrosis was not significantly 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 significant relationships were identified 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 fibrosis before the onset of symptoms. Due to the patchy nature of fibrosis, 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://ichgcp.net/clinical-trials-registry/NCT02355418.

Keywords: Exercise capacity; Extracellular volume; Histological fibrosis; Late gadolinium enhancement; Mitral regurgitation; Myocardial strain; Symptom status.

Conflict of interest statement

The authors declare no competing interest or relationship with industry.

Figures

Fig. 1
Fig. 1
Boxplots illustrating the distribution of mean collagen volume fraction (CVFmean) (top) and cardiomyocyte cross sectional area (CSA) (bottom) in autopsy controls vs. asymptomatic and symptomatic mitral regurgitation (MR) patients. P values are derived from Mann–Whitney U tests for non-parametric variables (collagen volume fraction) and independent T-test for parametric variables (cardiomyocyte cross sectional area, extracellular volume). MR mitral regurgitation
Fig. 2
Fig. 2
Histological specimens from mitral regurgitation patients and controls. Sections are stained with Masson Trichrome highlighting fibrous tissue as blue and myocytes as purple-red. Histological fibrosis is patchy with little congruence in fibrosis burden across different biopsy sites. Extracellular volume fraction (ECV) can provide an overall estimation of myocardial status, but fails to account for endocardial fibrosis
Fig. 3
Fig. 3
Relationship between ECV and histological evidence of interstitial fibrosis on biopsy (CVFmean) for a all biopsies, and b biopsies containing only myocardium. The trendlines are based on regression models, with ECV as the independent variable, and Log2CVFmean as the independent variable. This relationship was not found to be statistically significant when all biopsies were included within analyses (a, Rho = 0.18, P = 0.101, N = 83), but became statistically significant when limiting analyses to biopsies that contained only myocardium (b, Rho = 0.33, P = 0.015, N = 56)

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