Natural history of exercise-induced left atrial hypertension in patients with heart failure and preserved ejection fraction

Abstract Background Approximately one-third of patients with heart failure and preserved ejection fraction (EF) (HFpEF) have exercise-induced left atrial hypertension (EILAH), characterized by normal pulmonary capillary wedge pressure (PCWP) at rest, but with pathologic PCWP elevation during exercise. It has been proposed that EILAH may represent an early stage of HFpEF that progresses to resting LA hypertension (RELAH) over time, but this has never been shown. Purpose This observational study aimed to investigate the natural history of patients with EILAH, evaluating patients who underwent multiple invasive hemodynamic evaluations over time. Methods Consecutively-evaluated patients with HFpEF and EILAH (PCWP15 mmHg at rest and ≥25 mmHg during exercise) who underwent subsequent invasive hemodynamic testing were identified. Prevalence and characteristics of transition to RELAH (PCWP≥15 mmHg at rest) were evaluated. Results Of 659 patients with EILAH, 84 underwent repeat invasive hemodynamic evaluations over a median follow-up of 1.81 (IQR 0.48-3.40) years (55 female, mean age 66 years). Of this group, 33 (39%) patients changed to RELAH and 51 (61%) remained EILAH. Patients with change to RELAH experienced greater increase in NT-proBNP (+16.6%; 95% CI: 7.1% to 26.0%, P0.001), decreased left ventricular EF (-6.1%, 95% CI: -9.7 to -2.5, P=0.001), right ventricular (RV) global longitudinal strain (-4.5%, 95% CI: -8.8 to -0.3, P=0.037), RV free wall longitudinal strain (-7.3%, 95% CI: -13.1 to -1.6, P=0.013) and worsening tricuspid regurgitation (15% vs 2%, P=0.025) compared to those with no change (Figure 1). Upon invasive hemodynamic at rest, patients with change to RELAH experienced an increase in right atrial pressure (RAP) (+4.4 mmHg, 95% CI: 2.6 to 6.1, P0.001) and mean pulmonary artery (PA) pressure (+6.6 mmHg, 95% CI: 4.2 to 9.0, P0.001) (Figure 1). At the baseline, there were no significant differences in the exercise-induced increases in PCWP, mean PAP, and RAP between the two groups from rest to peak exercise (Figure 2). However, at the final evaluation, patients with change to RELAH displayed a greater increase in PCWP, mean PAP, and RAP during exercise as compared to those who remained EILAH (Figure 2). Of characteristics at the index evaluation, history of atrial fibrillation (OR 3.73; 95% CI 1.09-12.8, P=0.036), and lower resting PA compliance (OR 0.49; 95% CI 0.24-0.99, P=0.048) were independently associated with the transition to RELAH after adjusting the duration from baseline to final examination. Conclusions Approximately 40% of patients with HFpEF that first present with EILAH to RELAH, suggesting that EILAH can be considered an earlier form of HFpEF. History of atrial fibrillation and reduced PA compliance are associated with progression to RELAH, suggesting that interventions to address atrial myopathy and pulmonary vascular disease may be effective to attenuate or prevent this transition.