Reddy, Y

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 (PCWP<15 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%, P<0.001), 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, P<0.001) and mean pulmonary artery (PA) pressure (+6.6 mmHg, 95% CI: 4.2 to 9.0, P<0.001) (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.

Abstract Background Left atrial pressure (LAP) is clinically estimated by the occluded pulmonary artery (PA) pressure (PA wedge pressure, PAWP), which should equalize with downstream LAP. Early studies reported the potential for PAWP to exceed LAP, but the frequency and clinical significance of this finding is unclear. Purpose This study aimed to investigate the hemodynamic characteristics, physiologic determinants, and prognostic impact of patients with PAWP exceeding LAP. Method Patients who underwent right heart catheterization (RHC) for diagnosis or treatment with PAWP and simultaneous measurement of LAP were identified. Patients were divided into two groups based on differences in PAWP and LAP. Pulmonary capillary pressure (Pc) was measured using the PA occlusion technique. Pulmonary vascular resistance (PVR) was then partitioned into upstream PVRa ([mean PA pressure (PAP)-Pc]/cardiac output [CO]) and downstream PVRv ([Pc-PAWP]/CO), with each expressed as a percentage of PVR. Results 675 patients underwent RHC with transseptal puncture allowing measurement of both PAWP and LAP simultaneously. A strong correlation and agreement between PAWP and LAP were demonstrated (r=0.92, P<0.001; bias +0.5 mmHg), but 310 patients (46%) displayed PAWP exceeding LAP by at least 1 mmHg (mean difference 3±2 mmHg). Patients with PAWP exceeding LAP displayed higher mean PAP (Figure 1A) and PVR calculated using LAP as the downstream pressure (PVR-LA: 2.10 [1.13-3.53] vs 3.38 [2.19-5.66] WU, P<0.001). PAWP was significantly higher in patients with PAWP exceeding LAP, although there was no significant difference in LAP between the groups (Figure 1B-C). PA compliance, which does not rely on either PAWP or LAP for calculation, was significantly lower in patients with PAWP exceeding LAP (2.7 [1.8-4.0] vs 2.1 [1.5-3.0] mL/mmHg, P<0.001, Figure 1D). The difference between PAWP and LAP was significantly correlated with mean PAP (r=0.32, P<0.001, Figure 1E). In 63 patients where Pc could be measured, those with PAWP exceeding LAP showed a higher Pc and greater pulmonary venous (vs arterial) distribution of PVR (Figure 1F-H). Over 5.4 (IQR 1.7-10.2) years, the composite outcome of all-cause death or heart failure hospitalization occurred in 326 patients (48%). Patients with PAWP exceeding LAP had a higher risk of the composite outcome than those without (log-rank P<0.001, Figure 2). Patients with PAWP exceeding LAP had 37% greater risk of composite outcome than those without (hazard ratio 1.37, 95% CI 1.09-1.73; P=0.008) after adjusting for age, sex, hemoglobin, moderate or greater mitral regurgitation, and tricuspid regurgitation, LAP, and mean PAP. Conclusions While PAWP is a robust surrogate for LAP, the former commonly exceeds the latter, and patients with PAWP exceeding LAP have more severe pulmonary vascular disease, greater capillary hypertension and venous involvement, and a higher risk for adverse outcomes.