Impaired Left Atrial Performance Resulting From Age-Related Arial Fibrillation Is Associated With Increased Fibrosis Burden: Insights From a Clinical Study Combining With an in vivo Experiment

Abstract

Background: Atrial fibrillation (AF) is increasingly considered an age-related degenerative disease, whose process is associated with the development of impaired left atrial (LA) performance. However, the subtle dynamic changes of LA performance in AF during aging have yet to be fully elucidated. Atrial fibrosis is a key substrate for the development of AF, but the progression of fibrosis during aging and its relationship with LA dysfunction need to be further explored. Methods: A total of 132 control individuals and 117 persistent AF patients were prospectively studied. Subjects were further stratified into three age groups (age group 1: younger than 65 years, age group 2: between 65 and 79 years old, and age group 3: older than 80 years). The two-dimensional speckle tracking imaging was carried out for analyzing the alterations in LA function underlying LA remodeling, whereas electroanatomic mapping was performed to investigate LA fibrosis burden. In animal study, aged mice and young mice served as research subjects. Echocardiography and histological staining were used to assess LA performance and fibrosis burden, respectively. Results: Echocardiography showed progressive increases in LA dimension and LA stiffness index, and progressive decreases in LA global longitudinal strain and LA strain rates with advancing age in both AF and control cohorts, which was more prominent in AF cohort. Electroanatomic mapping showed progressive decrease in mean LA voltage and progressive increases in LA surface area, low-voltage area %, and LA volume with advancing age, whereas more significant alterations were observed in AF patients. Moreover, left atrial global longitudinal strain was positively correlated with mean LA voltage, whereas LA stiffness index was negatively related to mean LA voltage. In animal experiment, increased LA size and pulmonary artery dimension as well as longer P-wave duration and more prominent LA fibrosis were found in aged mice. Conclusions: This study provides new evidence of subtle changes in structure and performance of left atrium and their association with atrial fibrosis in both AF and non-AF subjects during physiological aging. In addition, our study also provides normal values for LA structure and performance in both AF and non-AF conditions during aging. These measurements may provide an early marker for onset of AF and LA adverse remodeling.

Keywords: age; atrial fibrillation; echocardiography; fibrosis; left atrium performance.

Figure 1

Speckle-tracking echocardiography to quantify LA strain in control and AF patients at three age groups. (A) Representative apical four-chamber view echocardiogram of a control adult. Along the inner contour of the LA wall, we define the target region. (B) The six segments of the LA wall were into strain analysis. (C) The strain curves of six segments and average strain curve (dotted line). The GLAS of control patients were defined Spos minus Sneg. In AF patients, GLAS was identified as the value of Spos. GLAS, left atrial global longitudinal strain; Spos, longitudinal peak early-diastole strain; Sneg, longitudinal peak late-diastole strain.

Figure 2

The LA performance in the control individuals and AF patients during physiological aging. (A) Correlations of LAD and age in control adults and AF patients. (B) The effect of AF on LAD during aging. (C) Correlations of GLAS and age in control adults and AF patients. (D) The worse GLAS was shown in AF patients during aging. (E) A strong positive association between LA stiffness index and age. (F) Changes for LA stiffness index in the absence and presence of AF during aging. LAD, left atrial dimension; GLAS, left atrial global longitudinal strain. *P < 0.05 vs. control in age-match groups; **P < 0.01 vs. control in age-match groups; ***P < 0.001 vs. control in age-match groups.

Figure 3

Examples of LA fibrosis burden in control individuals and AF patients at three age groups. Different values of electrical voltage representing LA fibrosis are color-coded in purple to gray. Purple region, gray region and other color region represent completely healthy myocardial tissue with a voltage ≥0.5 mV, scar with a voltage ≤0.1 mV, and junction area at the voltage of 0.1- to 0.5-mV region, respectively.

Figure 4

The relationship between the LA dysfunction and fibrosis progression under the background of atrial aging. (A,B) In addition to increased LA surface area and LA volume significantly correlating with advanced age, alterations in two measurements were more apparent in AF patients in aging process. (C) Changes for mean LA voltage in the absence and presence of AF during aging. (D,E) Correlations of GLAS and LA stiffness index with mean LA voltage in control adults and AF patients. LA, left atrium; AF, atrial fibrillation; GLAS, left atrial global longitudinal strain. *P < 0.05 vs. control in age-match groups; **P < 0.01 vs. control in age-match groups; ***P < 0.001 vs. control in age-match groups.

Figure 5

Age-related LA remodeling is associated with atrial fibrosis in mice. (A) Representative echocardiographic images of ejection fraction analysis. (B) Representative B-mode echocardiographic recordings of LA area and PA diameter and quantification of LA area and PA diameter (right). (C) Representative electrocardiographic (ECG) recordings (left) in multiple electroconductive physiological recorder and quantification of P-wave duration. (D) Representative results of Masson staining of the left atrium sections obtained from young and old mice, and statistical results of fibrosis area in the left atrium. n = 15 in each group. n.s., no significant difference. *P < 0.05, **P < 0.01, ***P < 0.001.