During a median follow-up of 7.9 (interquartile range: 4.8–8.1) years, 106 subjects (12.4%) were hospitalized for HF, of whom 71 (67.0%) had no prior history of heart failure. Baseline characteristics of participants across quartiles of LAFI are displayed in . LAFI was also strongly associated with each of the other prognostic biomarkers and echocardiographic parameters ().
Baseline Characteristics of 855 Participants with Stable Coronary Heart Disease and EF≥50%, by Quartile of Left Atrial Functional Index
Baseline Measures of Other Known Prognostic Markers by Quartile of Left Atrial Functional Index among 855 Participants with Coronary Heart Disease and EF≥50%
Event rates increased from 5.3 per 1000 person years in the highest quartile of LAFI to 47.0 per 1000 person years in the lowest quartile (). Kaplan-Meier survival estimates () revealed early separation of the event-free survival curves (within the first few months), which continued to diverge throughout follow-up. After adjustment for demographics (age, sex, white race), clinical risk factors (tobacco use, prior revascularization, history of heart failure, AF, low density lipoprotein, estimated glomerular filtration rate) medication use (angiotensin inhibitors, loop diuretics), and heart rate, every SD decrease in LAFI increased the adjusted hazard of HF two-fold (HR 2.0, 95% CI, 1.5–2.7; p<0.001). The association also remained independent after further adjustment for log NT-proBNP and a wide range of other echocardiographic measures (per SD decrease in LAFI: HR 1.5, 95% CI, 1.0–2.1; p=0.05) Even after further adjustment for pulmonary artery systolic pressure, point estimates revealed little attenuation (per SD decrease in LAFI: HR 1.4, 95% CI 0.9–2.1, p=0.10) (). Notably, when PASP was entered into the model as a categorical predictor with missing data treated as a fifth category, data from the missing category was non-informative with respect to the association between LAFI and HF (HR 0.88, 95% CI 0.4–1.9, p=0.88).
Unadjusted Association of Quartiles of Left Atrial Functional Index with Heart Failure Hospitalization
Proportion Without Heart Failure Hospitalization, Stratified by Quartiles of Left Atrial Functional Index
Association of Left Atrial Functional Index with Heart Failure Hospitalization, With Multivariate Adjustment
To determine whether the association was independent of interval cardiac events, we also performed a sensitivity analysis in which we added interim cardiac events (myocardial infarction and AF) to the adjusted model 2 covariates, and found demonstrated no attenuation of the association (per SD decrease in LAFI: HR 2.2, 95% CI 1.7–2.9; p<0.001).
The association did not vary by age, sex, or the presence of obesity, prior history of HF, or AF (p for interaction > 0.10 for all). We found significant interactions between LAFI and the presence of hypertension (p=0.01) and diabetes (p<0.001). However, stratified analyses revealed the association was present among all subsets, and point estimates were similar in both strata (Hypertension present: n=185, HR 3.0 per SD decrease in LAFI, 95% CI 1.1–8.3 vs. Hypertension absent: n=670, HR 2.0 per SD decrease in LAFI, 95% CI 1.5–2.7; Diabetes present: n=239, HR 1.7 per SD decrease in LAFI, 95% CI 1.2–2.4, Diabetes absent: n=616, HR 2.3 per SD decrease in LAFI, 95% CI 1.6–3.4).
To better characterize the predictive ability of LAFI for incident HF, we also performed a subgroup analysis restricted to subjects with no prior history of HF (n=724) and found results were similar to those of the entire cohort: subjects with LAFI in the lowest quartile had nearly 6 times the rate of incident HF hospitalization compared with those in the highest quartile (adjusted for model 1 covariates: HR 5.8, 95% CI 2.3–14.3; p<0.001), and the rate of HF hospitalization was 80% greater per SD decrease in LAFI (HR 1.8, 95% CI 1.3–2.5, p<0.001). Given the marked preponderance of AF in the lowest quartile of LAFI, we also performed a subgroup analysis limited to only subjects without AF (n=818), which demonstrated no difference compared with the entire cohort (adjusted for model 2 covariates: HR 6.8, 95% CI 3.0–15.0, p<0.001), and the rate of HF hospitalization was 2-fold greater for every 1 SD decrease in LAFI (HR 2.0, 95%CI 1.5–2.7, p<0.001).
The discrimination of LAFI for HF hospitalization was also superior to each of its individual components (unadjusted c-statistics: LAFI 0.73 vs. LVOT-VTI 0.60 (p for comparison < 0.001), LA emptying fraction 0.65 (p<0.001), LAVI 0.69 (p = 0.07)). Cox models also revealed that LAFI provides prognostic value incremental to its component measures (chi-square likelihood ratio testing: p<0.001 for all).
We also compared c-statistics to determine the incremental prognostic value of LAFI when used in conjunction with clinical risk factors and log NT-proBNP. The addition of LAFI to clinical risk factors was significantly more predictive of HF hospitalization than clinical risk factors alone (0.81 for clinical risk factors plus LAFI vs. 0.77 for clinical risk factors alone; p<0.001), or clinical risk factors plus log NT-proBNP (0.85 for clinical risk factors plus log NT-proBNP plus LAFI vs. 0.81 for clinical risk factors plus log NT-proBNP alone; p<0.001).