Left atrial remodeling in mitral regurgitation: A combined experimental-computational study

Abstract

Aims: Progressive changes to left atrial (LA) structure and function following mitral regurgitation (MR) remain incompletely understood. This study aimed to demonstrate potential underlying mechanisms using experimental canine models and computer simulations.

Methods: A canine model of MR was created by cauterization of mitral chordae followed by radiofrequency ablation-induced left bundle-branch block (LBBB) after 4 weeks (MR-LBBB group). Animals with LBBB alone served as control. Echocardiography was performed at baseline, acutely after MR induction, and at 4 and 20 weeks, and correlated with histology and computer simulations.

Results: Acute MR augmented LA reservoir and contractile strain (40±4 to 53±6% and -11±5 to -22±9% respectively, p<0.05). LA fractional area change increased significantly (47±4 to 56±4%, p<0.05) while LA end-systolic area remained unchanged (7.2±1.1 versus 7.9±1.1 cm2 respectively, p = 0.08). LA strain 'pseudonormalized' after 4 weeks and decompensated at 20 weeks with both strains decreasing to 25±6% and -3±2% respectively (p<0.05) together with a progressive increase in LA end-systolic area (7.2±1.1 to 14.0±6.3 cm2, p<0.05). In the LBBB-group, LA remodeling was less pronounced. Histology showed a trend towards increased interstitial fibrosis in the LA of the MR-LBBB group. Computer simulations indicated that the progressive changes in LA structure and function are a combination of progressive eccentric remodeling and fibrosis.

Conclusion: MR augmented LA strain acutely to supranormal values without significant LA dilation. However, over time, LA strain gradually decreases (pseudornormal and decompensated) with LA dilation. Histology and computer simulations indicated a correlation to a varying degree of LA eccentric remodeling and fibrosis.

Fig 1. Timeline schematic of the canine experiments.

MR-LBBB model: Creation of mitral regurgitation after baseline followed by LBBB induction after 4 weeks. LBBB model: LBBB induction after baseline. Circles indicate the time points of echocardiographic and hemodynamic measurements at baseline (blue), acute MR (yellow), 4 weeks (yellow), 16 weeks (white) and 20 weeks (red). The asterisks in the MR-LBBB group indicate death due to heart failure, all within 6 weeks. MR = mitral regurgitation; LBBB = left bundle branch block.

Fig 2. Example of LA strain assessment by 2D speckle-tracking echocardiography at baseline.

Four-chamber longitudinal left atrium strain (LAS). Arrows represent reservoir (r) and contractile (ct) phase (42% and -12%, respectively).

Fig 3. Chronological changes of left atrial strain.

(A-B) Time course of LA reservoir (LAS(r)) and contractile (LAS(ct)) strain for each group (presented as boxplots and lines for individual animals). Statistical significance was assigned at p < 0.05. BL = baseline; LAS(r) = left atrial reservoir strain; LAS(ct) = left atrial contractile strain; LBBB = left bundle branch block, MR = mitral regurgitation; w = weeks.

Fig 4. Histological and gene expression analysis of LA tissue.

Representative examples of 0.1% Sirius Red stained LA tissue sections of the (A) MR-LBBB group and (B) LBBB group at 200x magnification. (C) Comparison of collagen fractional area (CFA) and relative collagen type 1 (Col1a1) expression to Cyclophilin-A for each group (presented as boxplots and scatters for individual animals). A trend towards more interstitial fibrosis and increased Col1a1 expression was found in the MR-LBBB group at 20 weeks, as compared to LBBB group at 16 weeks.

Fig 5. Simulations of LA strain and dilation after acute MR.

Simulated changes in (A) LA strain and (B) LA area (i.e. change in LA end-systolic area relative to baseline simulation) of varying severity of LA passive stiffness (left-to-right) and LA eccentric hypertrophy (top-to-bottom) starting from the simulation of the acute severe MR phase (yellow). Vertical gray areas in the strain panels indicate the period of LV ejection.

Fig 6. Simulations of LA and LV strain with MR after induction of LBBB.

Effect of increasing LV electromechanical activation delay in addition to acute MR. Electromechanical activation delay is characterized by a delayed onset of LV filling, increased LAS(r) and decreased LAS(ct). Vertical gray areas in the strain panels indicate the period of LV ejection. LVfw = left ventricular free wall; Sw = septal wall; ecc. hyp. = eccentric hypertrophy; stiff. = passive stiffness.