Left atrial (LA) alterations are an important component of the overall subclinical substrate determining cardiovascular disease, yet the influence of risk factor exposure on LA remodeling remains incompletely understood (1). This longitudinal study aims to define the determinants of aging-related LA remodeling in the MESA (Multi-Ethnic Study of Atherosclerosis) trial, a population free of clinical cardiovascular disease at baseline (2).
We examined 2,361 participants who underwent magnetic resonance imaging (MRI) at both the baseline and 10-year follow-up examinations. Participants who (n = 65) had an intermediate cardiovascular event and were excluded from this analysis; thus, 2,296 participants were included. The MESA CMR protocol used fast gradient echo sequences to obtain cine images of the heart at baseline and steady-state free precession at year 10, both using 1.5-T MRI scanners. Fifty cases acquired with both sequences during the same examination were used for calibration of values from the different pulse sequences. LA volumes (modified biplane Simpson) and strain throughout the cardiac cycle were obtained using semi-automated tissue tracking software (multimodality tissue tracking [MTT], Toshiba [Otawara, Japan]) on 2- and 4-chamber long-axis images (3). LA maximum and minimum volumes were indexed by body surface area (Vmax and Vmin), and LA reservoir/total (LATEF), conduit/passive (LAPEF), and booster-pump/active (LAAEF) emptying fractions were calculated. All research was approved by institutional ethics committees.
At baseline, participants were 59 ± 9 years of age, with 53% women; 43% Caucasian, 12% Chinese-American, 24% African-American, and 22% Hispanic. Over 10 years of follow-up, the number of current smokers decreased (11.5% to 7.5%), whereas the number of diabetics (8.8% to 17.9%), and participants receiving antihypertensive (31.5% to 52.7%) and lipid-lowering (15.0% to 38.0%) therapy increased. The average body mass index of the population increased from 27.8 ± 4.9 to 28.1 ± 5.2 kg/m2. Over 10 years of follow-up, mean volumes (ml/m2) increased (Vmax: 29.9 ± 9.1 to 35.3 ± 11.5; Vmin: 12.1 ± 6.0 to 16.5 ± 8.7), whereas LA function decreased (LATEF: 62 ± 12% to 55 ± 11%; LAPEF: 27 ± 9% to 23 ± 8%; LAAEF: 48 ± 13% to 42 ± 12%; maximum strain: 37 ± 11 to 31 ± 14).
Multivariable linear regression models assessed the association of changes in LA parameters with demographics and change in cardiovascular risk factors over 10 years of follow-up (Table 1). Our results confirmed that aging was an important modifier of LA structure and function. Age was associated with greater increases in LA volumes (Vmin: 0.11 ml/m2/year) and a greater decrease in LA reservoir (LATEF: −0.22%/year) and passive (LAPEF: −0.31%/year) function. However, active function change was not associated with age as a result of compensation for reduced passive function. Men had a significant worsening of LA function (LATEF: −2.18%/year) but not volumes compared with women. Compared with Chinese-Americans, increases in LA volume were higher (Vmax: 2.12 ml/m2) and decreases in LA function (LATEF: −6.44%) were greater in Whites.
TABLE 1.
Longitudinal Associations of Demographics and Changes in Risk Factors Over 10 Years of Follow-Up With Changes in LA Structure and Function
| ΔLA Volume Max (ml/m2) | ΔLA Volume Min (ml/m2) | ΔLA Total Emptying Fraction (%) | ΔLA Passive Emptying Fraction (%) | ΔLA Active Emptying Fraction (%) | ΔLA Strain Max (%) | |
|---|---|---|---|---|---|---|
| Age (per yr) | 0.06 (0.01) | 0.11 (<0.001) | −0.22 (<0.001) | −0.31 (<0.001) | −0.04 (0.16) | −0.22 (<0.01) |
| Male | −0.35 (0.41) | 0.16 (0.61) | −2.18 (<0.001) | −3.08 (<0.001) | −1.31 (<0.01) | −4.37 (0.01) |
| Race | ||||||
| Ref: Chinese | ||||||
| Caucasian | 2.12 (<0.01) | 2.66 (<0.001) | −6.44 (<0.001) | −3.86 (<0.001) | −6.42 (<0.001) | −10.94 (<0.01) |
| African-American | 1.60 (0.04) | 2.49 (<0.001) | −7.57 (<0.001) | −3.55 (<0.001) | −8.67 (<0.001) | −11.61 (<0.01) |
| Hispanic | 1.87 (0.02) | 2.54 (<0.001) | −6.59 (<0.001) | −3.59 (<0.001) | −6.54 (<0.001) | −10.91 (<0.01) |
| Change (Δ) | ||||||
| Obesity | ||||||
| Ref: Never obese | ||||||
| Weight loss | 0.32 (0.75) | 0.30 (0.68) | −0.61 (0.53) | −0.83 (0.24) | 0.11 (0.92) | −1.49 (0.22) |
| Weight gain | −0.95 (0.27) | −0.55 (0.38) | 0.58 (0.50) | −2.23 (<0.001) | 1.88 (0.05) | −0.86 (0.42) |
| Long-term obese | −0.03 (0.95) | 0.11 (0.78) | −0.90 (0.10) | −2.31 (<0.001) | 0.58 (0.36) | −2.75 (<0.01) |
| ΔSystolic blood pressure (10 mm Hg) | 0.15 (0.17) | 0.12 (0.11) | −0.16 (0.13) | −0.10 (0.17) | −0.17 (0.17) | −0.06 (0.67) |
| Hypertension med use | ||||||
| Ref: No Med Use | ||||||
| Stop | 1.94 (0.15) | 1.75 (0.09) | 0.37 (0.79) | 0.96 (0.33) | 0.41 (0.79) | 2.29 (0.18) |
| New | 0.26 (0.65) | 0.72 (0.09) | −1.33 (0.02) | −0.89 (0.31) | −1.06 (0.11) | 0.09 (0.90) |
| Long-standing use | 1.53 (<0.01) | 1.51 (<0.001) | −1.70 (<0.01) | −1.48 (<0.001) | −1.41 (0.03) | −1.48 (0.04) |
| Diabetes status | ||||||
| Ref: No diabetes | ||||||
| Improvement | −3.96 (0.20) | −3.40 (0.14) | 2.11 (0.49) | 2.19 (0.33) | 3.06 (0.40) | 2.68 (0.48) |
| New | −0.65 (0.41) | −0.33 (0.57) | −0.78 (0.31) | −0.49 (0.38) | −0.25 (0.78) | −2.56 (<0.01) |
| Long-standing | 0.71 (0.36) | 0.62 (0.29) | −1.04 (0.18) | −1.06 (0.06) | −1.05 (0.25) | −1.71 (0.07) |
| Smoking status | ||||||
| Ref: Never smokers | ||||||
| Stop | −2.53 (<0.01) | −1.01 (0.16) | −1.17 (0.22) | −1.13 (0.10) | −1.51 (0.17) | −1.60 (0.18) |
| New | −0.72 (0.71) | −1.97 (0.18) | 2.99 (0.13) | −0.54 (0.70) | 2.52 (0.26) | −0.05 (0.99) |
| Long-standing use | −0.88 (0.31) | 0.12 (0.86) | −2.08 (0.02) | −2.15 (<0.001) | −1.50 (0.12) | −3.07 (<0.01) |
| ΔTotal cholesterol (per 10 mg/dl) | −0.06 (0.38) | −0.04 (0.43) | −0.001 (0.99) | 0.02 (0.94) | −0.07 (0.38) | −0.06 (0.44) |
| ΔHDL cholesterol (per 10 mg/dl) | −0.09 (0.65) | −0.08 (0.60) | 0.30 (0.14) | 0.29 (0.05) | −0.03 (0.91) | 0.3 (0.20) |
| Lipid MedX Use | ||||||
| Ref: No MedX Use | ||||||
| Stop | −0.06 (0.96) | −0.86 (0.38) | 1.42 (0.28) | 0.74 (0.44) | 1.32 (0.39) | 0.69 (0.67) |
| New | −0.64 (0.30) | −0.71 (0.12) | 0.71 (0.24) | 0.46 (0.29) | 0.84 (0.23) | 0.18 (0.82) |
| Long-standing use | −0.80 (0.25) | −1.36 (<0.01) | 2.05 (<0.01) | 0.75 (0.13) | 2.11 (<0.01) | 1.52 (0.08) |
| Baseline LA parameter | −0.43 (<0.001) | −0.34 (<0.001) | −0.69 (<0.001) | −0.82 (<0.001) | −0.77 (<0.001) | −0.80 (<0.01) |
| r2 of multivariable regression model | 0.14 | 0.10 | 0.39 | 0.57 | 0.47 | 0.37 |
Each column represents a single multivariable model. Bold values are the r-squared value for each model with all the variables.
HDL = high-density lipoprotein; LA = left atrial.
Long-standing diabetes and long-term smoking were both associated with reduced conduit and reservoir function as characterized by LAPEF (diabetes: −1.06%; smoking: −2.15%) and maximum strain (diabetes: −1.71%; smoking: −3.07%), respectively. Long-term antihypertensive therapy was also associated with greater increase in LA volumes (~1.5 ml/m2) and greater decreases in LA reservoir (~1.7%) and conduit (~1.5%) function. Longitudinally, weight gain as assessed by change in body mass index category was associated with greater reduction in conduit function (~2.3%) and a compensatory increase in booster pump function (~1.9%). Long-standing obesity was associated with greater reduction in conduit function (~2.3%) without an improvement in booster pump function, perhaps because of a result of over-utilization of the compensation mechanism. Lipid-lowering therapy was associated with smaller increases in volume (Vmin: 1.4 ml/m2) and smaller decreases in LA function (LATEF: ~2%), indicative of the beneficial effect of statins on LA remodeling. To put the effect sizes in perspective, a 1-SD decrease in LATEF or LA strain or 1-SD increase in Vmin predicted incident atrial fibrillation in MESA with hazard ratios of 0.62, 0.70, and 1.64, respectively (1).
Increases in left ventricular (LV) mass were associated with increases in LA volumes (Vmax: 0.16; p < 0.001) but with decreased reservoir and conduit function (LATEF: −0.05; p = 0.029; LAAEF: 22120.07; p = 0.005). A decrease in LV ejection fraction over 10 years was associated with an increase in LA minimum volume (coefficient: −0.13; p < 0.001) and a concomitant decrease in LA function (LATEF: 0.26; p < 0.001; strain: 0.24; p < 0.001). LV concentric remodeling (increased mass-to-volume-ratio) over 10 years was associated with greater reduction in both LA volumes (Vmax: −14.9; p < 0.001) and function (LATEF: −6.3; p < 0.001; strain: −10.7; p < 0.001).
This longitudinal study demonstrated the influences of diverse risk factor exposures on aging-related LA remodeling. In addition, we demonstrated that aging-related LV concentric remodeling was associated with reduction of both LA volumes and function.
Acknowledgments
This research was supported by contracts 75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N92020D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95162, 75N92020D00006, N01-HC-95163, 75N92020D00004, N01-HC-95164, 75N92020D00007, N01-HC-95165, N01-HC-95166, N01-HC-95167, N01-HC-95168, and N01-HC-95169 from the National Heart, Lung, and Blood Institute, and by grants UL1-TR-000040, UL1-TR-001079, and UL1-TR-001420 from the National Center for Advancing Translational Sciences (NCATS). The authors have reported that they have no relationships relevant to the contents of this paper to disclose. The authors thank the other investigators, the staff, and the participants of the MESA study for their valuable contributions. A full list of participating MESA investigators and institutions can be found at http://www.mesa-nhlbi.org.
Footnotes
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’ institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information, visit the Author Center.
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