Abstract
BACKGROUND:
Approximately one-third of patients with heart failure and preserved ejection fraction (HFpEF) have normal pulmonary capillary wedge pressure (PCWP) at rest, with left atrial hypertension that is induced only during exercise (EILAH). EILAH may represent a discrete HFpEF phenotype, or an earlier stage of HFpEF that progresses to resting LA hypertension (RELAH) over time.
OBJECTIVES:
We investigated the clinical course of HFpEF patients with EILAH who underwent repeat invasive hemodynamic evaluation.
METHODS:
This observational study investigates the natural history of EILAH, evaluating patients who underwent multiple invasive hemodynamic studies to evaluate for progression from EILAH to RELAH, and then identify pathophysiologic correlates of progression. Consecutively evaluated patients with HFpEF and EILAH (PCWP<15 mmHg at rest and ≥25 mmHg during exercise) who underwent repeat invasive hemodynamic testing were identified.
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. Of this group, 33 (39%) patients changed to RELAH (PCWP≥15 mmHg at rest) and 51 (61%) did not. Patients with change to RELAH had greater duration between index and repeat catheterizations (median 2.68 (1.74–3.97) vs 0.99 (0.44–2.16) years, P=0.001), experienced greater increases in NT-proBNP (Interaction P value =0.036), more severe worsening in left ventricular EF (P<0.001), RV free wall longitudinal strain (P=0.003) and more worsening tricuspid regurgitation (+15% vs +2%, P=0.025) compared to those who did not transition to RELAH. Of characteristics at the index evaluation, history of atrial fibrillation (OR 4.57; 95% CI 1.63–12.8), lower LA compliance (OR 0.47; 95% CI 0.22–0.99), and lower PA compliance (OR 0.48; 95% CI 0.25–0.93) were independently associated with the transition to RELAH after adjusting follow-up duration.
CONCLUSIONS:
Many patients with HFpEF first presenting with EILAH transition to RELAH, suggesting that EILAH may represent an earlier stage of HFpEF. History of atrial fibrillation, impaired LA compliance, and reduced PA compliance are associated with progression to RELAH, calling for further studies of interventions enhancing atriopulmonary compliance in early-stage HFpEF.
Keywords: Heart failure, PCWP, HFpEF, EILAH, RELAH
Central illustration:
Progression from EILAH to RELAH in HFpEF.
This illustration summarizes the longitudinal progression from exercise-induced left atrial hypertension (EILAH) to resting left atrial hypertension (RELAH) in heart failure with preserved ejection fraction (HFpEF). Approximately 40% of patients with EILAH developed RELAH during a median follow-up of 1.8 years, demonstrating that EILAH represents an early, transitional form of HFpEF. Patients who transitioned to RELAH exhibited pathophysiological characteristics including increased N-terminal pro B-type natriuretic peptide (NT-proBNP) levels, reduced right ventricular (RV) function, and worsening tricuspid regurgitation (TR) severity. The predictors of transition were lower left atrial (LA) and pulmonary arterial (PA) compliance, as well as a history of atrial fibrillation, reflecting the interplay between atrial myopathy and pulmonary vascular disease.
EILAH, exercise-induced left atrial hypertension; LA, left atrial; HFpEF, heart failure with preserved ejection fraction; NT-proBNP, N-terminal pro B-type natriuretic peptide; PA, pulmonary arterial; PCWP, pulmonary capillary wedge pressure; RELAH, resting left atrial hypertension; RV, right ventricular; TR, tricuspid regurgitation.
INTRODUCTION
Heart failure (HF) with preserved ejection fraction (HFpEF) is characterized by an inability of the heart to perfuse the body without requiring pathological increases in cardiac filling pressure.1–3 Most patients with HFpEF fulfill this definition at rest, with elevated resting pulmonary capillary wedge pressure (PCWP), but approximately one-third display elevation in PCWP only during exercise.4,5 These patients with exercise-induced left atrial (LA) hypertension (EILAH) have increased risk for adverse outcome compared with patients without HF,5–7 However, compared with patients with HFpEF and resting LA hypertension (RELAH), those with EILAH have fewer physical findings associated with congestion, lower natriuretic peptide levels, less severe cardiac remodeling and dysfunction, and lower risk for worsening HF or death.4,8 These observations suggests that EILAH may represent an earlier form of HFpEF that progresses to RELAH, but this theoretical progression has not been systematically evaluated.
In longitudinal noninvasive studies, patients with HFpEF on average display worsening right-sided HF over time that is tied to the presence of atrial fibrillation,9 a marker of underlying atrial myopathy and risk factor for worsening pulmonary vascular disease (PVD).10 In health, compliance properties of the LA and pulmonary vessels allow for increases in volume during the cardiac cycle without untoward increases in pressure. In HFpEF, atriopulmonary compliance becomes progressively more impaired, increasing pulmonary venous and arterial pressures out of proportion to elevation in left ventricular diastolic pressure.
We hypothesized that a significant proportion of patients with EILAH progress to RELAH over time, and that this progression is accentuated among patients with more impaired left atrial and pulmonary artery compliance, including patients with atrial fibrillation, who are known to display the greatest reductions in atriopulmonary compliance.10 To test these hypotheses, we investigated the clinical course of patients with HFpEF and EILAH who underwent repeat invasive hemodynamic evaluation.
METHODS
Study population and design
Consecutive patients undergoing invasive hemodynamic testing with concurrent expiratory gas analysis to evaluate dyspnea of unknown cause at the Mayo Clinic in Rochester, MN, between 2006 and 2024 were identified. From this cohort, patients with HFpEF were defined by New York Heart Association functional Class II–III dyspnea with activity, left ventricular (LV) ejection fraction (LVEF) ≥50%, and PCWP ≥15 mmHg at rest or ≥25 mmHg during exercise. Among patients with HFpEF, EILAH was defined as PCWP <15 mmHg at rest and PCWP ≥25 mmHg during exercise, and RELAH was defined as PCWP ≥15 mmHg at rest. Patients with RELAH at the baseline evaluation, EF<50%, primary cardiomyopathies, valvular heart disease (moderately-severe or greater left-sided regurgitation, mild or greater stenosis), pericardial disease, severe coronary artery disease, congenital heart disease, and high output HF were excluded. We then identified patients with EILAH who underwent repeat invasive hemodynamic exercise testing, who were then divided into those who changed from EILAH to RELAH at the final hemodynamic evaluation and those who did not transition to RELAH. The study complies with the Declaration of Helsinki and was approved by the institutional review board of the Mayo Clinic. All participants provided consent for data use by completing a research authorization form, and all authors had full access to the data and were responsible for its integrity.
Echocardiography
Echocardiography was performed concurrently with invasive hemodynamic exercise testing. Two-dimensional, Doppler, and tissue Doppler echocardiography was performed in all patients according to the guidelines of the American Society of Echocardiography.11 LV global longitudinal strain (LV GLS) was measured using 2D speckle tracking and determined as the average of the two apical views (4- and 2-chamber views). The myocardial reservoir function of the LA was evaluated by the LA strain peak during LA relaxation.10,12 Right ventricular (RV) GLS and RV free wall longitudinal strain (RV FWLS) were obtained by the average values of peak longitudinal systolic strain from the free wall and septal wall of the right ventricle.9,13 With the use of 2D echocardiographic speckle tracking, RA endocardial contours were traced and RA reservoir strain was subsequently measured.14,15 All Doppler measurements were the average of ≥3 beats. Myocardial deformation analyses were conducted offline (TomTec Imaging Systems, Unterschleissheim, Germany), with results presented as absolute values.
Catheterization protocol
Patients underwent invasive hemodynamic exercise testing with simultaneous expiratory gas analysis to volitional exhaustion by supine cycle ergometry, using methods we have previously described.16,17 Right atrial pressure (RAP), PA pressures (PAP), and PCWP were measured at end-expiration (average of ≥3 beats) using a 2 Fr high-fidelity micromanometer-tipped catheter advanced through the lumen of a 7 Fr fluid-filled catheter at rest. During exercise, PAP and PCWP were measured using a micromanometer, and RAP was measured from the side arm of the 9 Fr sheath at the junction of the superior vena cava and right atrium. The position of PCWP was confirmed by standard criteria, such as appearance on fluoroscopy, characteristic pressure waveforms, and evidence of oxyhemoglobin saturation ≥94%. A 4–6 Fr radial arterial cannula was used to measure arterial blood pressure and obtain arterial blood gas samples throughout the test. Pressure tracings from the entire study were digitized (240 Hz) and stored for offline analysis.
After baseline hemodynamic assessment, subjects underwent a supine cycle exercise testing, with the first stage at 20 W for 3–5 minutes, followed by increasing workload in 20 W increments until volitional exhaustion (2-minute stages, with hemodynamics assessed in the last minute of each stage). As with rest, pressures were measured at end-expiration by one observer as an average of 3 cardiac cycles (or 5 cardiac cycles in the case of atrial fibrillation). Arterial and mixed venous (PA) oxygen samples were taken at baseline, 20 W, and peak exercise. Oxygen uptake (VO2) was calculated by expiratory gas analysis (MedGraphics, St. Louis, MN, USA). Arterial-venous oxygen content difference (Ca-vO2) was directly measured as the difference between systemic arterial and PA oxygen contents (= saturation × hemoglobin ×1.34). CO was determined by the direct Fick method (CO=VO2/Ca-vO2). Pulmonary vascular resistance (PVR) was calculated by (mean PAP-PCWP)/CO. Pulmonary artery compliance was calculated by stroke volume (SV)/PA pulse pressure. Left atrial compliance was calculated as the quotient of LA reservoir strain and the difference between the V wave peak and X descent nadir.10 Systemic vascular resistance was calculated by (mean arterial pressure-RAP)/CO.
Statistical analysis
Continuous variables are presented as means ± standard deviations when normally distributed and as medians and interquartile ranges (IQRs) when non-normally distributed. Parameters were compared between groups that changed from EILAH to RELAH and those who did not transition to RELAH using unpaired t-tests or Mann-Whitney U tests for continuous variables and by Chi-squared tests or Fisher’s exact test for dichotomous variables, when appropriate. Within group differences at individual time points between the baseline and final examination were compared using a paired t-test. Within-group differences were assessed by 1-way repeated measures analysis of variance (ANOVA) to account for the rest, 20W exercise and peak exercise. To account for unequal follow-up duration and missing data, longitudinal changes between baseline and follow-up examinations were evaluated using linear mixed-effects models. Participant was included as a random effect to account for within-subject correlation. Fixed effects included group (transition to RELAH vs no transition), visit (baseline vs follow-up), time between assessments, and the group-by-visit interaction. Absolute changes in characteristics, laboratories, echocardiography and hemodynamics were calculated by subtracting the final visit values from the baseline visit values to define the dependent variables for the analysis. Multivariable logistic regression analysis was performed to assess determinants of transition from EILAH to RELAH. Candidate predictors were selected a priori based on clinical plausibility and pathophysiologic relevance, with univariable analyses used to inform but not dictate model inclusion. To minimize overfitting given the limited number of events, a maximum of three non-colinear covariates were included in each model. A two-sided P value of <0.05 was considered statistically significant. The predictive ability for transition from EILAH to RELAH was evaluated by area under the curve (AUC). All data were analyzed using Stata MP64 version 16 (StataCorp, College Station, TX, USA).
RESULTS
Patient characteristics at baseline exam
Of 1,535 consecutively evaluated patients undergoing hemodynamic exercise testing with resting PCWP <15 mmHg, 789 (51%) had exercise PCWP <25 mmHg, and 87 (6%) had EF <50%, leaving 659 (43%) patients with EILAH. Of this group, 84 (13%) underwent repeat invasive exercise testing a median of 1.81 (IQR 0.48–3.40) years following index study. The most common indication for repeat catheterization was participation in a research study that included cardiac catheterization as part of its protocol (46%), followed by worsening symptoms (40%), and other clinical follow-up not further specified (14%) (Table 1). Compared with patients with EILAH who did not undergo repeat invasive testing, those who underwent follow-up evaluation were more likely to have a history of atrial fibrillation and diabetes, to be prescribed diuretics, and to have slightly poorer kidney function (Table S1). In contrast, key markers of left atrial structure and diastolic function, including LA volume index, E/e’, TR velocity, and NT-proBNP, were similar between groups (Table S1).
Table 1:
Patients Characteristics at Baseline Examination
| Total (n = 84) |
No Change to RELAH (n = 51) |
Change to RELAH (n = 33) |
P Value | |
|---|---|---|---|---|
| Age, years | 66 ± 10 | 65 ± 10 | 67 ± 11 | 0.43 |
| Women, n (%) | 55 (65%) | 30 (59%) | 25 (76%) | 0.11 |
| Body weight, kg | 93.0 ± 22.2 | 95.6 ± 22.3 | 89.0 ± 21.7 | 0.18 |
| Body mass index, kg/m2 | 33.1 ± 6.8 | 33.7 ± 6.9 | 32.3 ± 6.5 | 0.37 |
| H2FPEF score | 4 (3–6) | 4 (3–6) | 5 (3–6) | 0.48 |
| Indications for repeated testing, % | ||||
| Symptom/ Clinical Follow-up/ Study visit | 40/13/46 | 33/12/55 | 52/15/33 | 0.15 |
| Comorbidities | ||||
| Obesity (BMI ≥30 kg/m2), n (%) | 57 (68%) | 36 (71%) | 21 (64%) | 0.51 |
| Hypertension, n (%) | 60 (71%) | 36 (71%) | 24 (73%) | 0.83 |
| Diabetes, n (%) | 27 (32%) | 19 (37%) | 8 (24%) | 0.21 |
| Any Atrial fibrillation, n (%) | 29 (35%) | 11 (22%) | 18 (55%) | 0.002 |
| Paroxysmal/Persistent AF, n (%) | 22/7 (76/24%) | 10/1 (91/9%) | 12/6 (67/33%) | 0.14 |
| Stage 3 or greater CKD, n (%) | 28 (33%) | 14 (27%) | 14 (42%) | 0.16 |
| Coronary artery disease, n (%) | 48 (57%) | 31 (61%) | 17 (52%) | 0.40 |
| COPD, n (%) | 7 (8%) | 3 (6%) | 4 (12%) | 0.31 |
| Sleep apnea syndrome, n (%) | 41 (49%) | 24 (47%) | 17 (52%) | 0.69 |
| CIED, n (%) | 13 (15%) | 5 (10%) | 8 (24%) | 0.074 |
| Pulmonary vein isolation, n (%) | 11 (13%) | 5 (10%) | 6 (18%) | 0.27 |
| Medications | ||||
| Diuretic, n (%) | 38 (45%) | 21 (41%) | 17 (52%) | 0.35 |
| RAAS Inhibitor, n (%) | 37 (44%) | 22 (43%) | 15 (45%) | 0.83 |
| Beta-blocker, n (%) | 41 (49%) | 25 (49%) | 16 (48%) | 0.96 |
| Mineralocorticoid antagonist, n (%) | 25 (30%) | 18 (35%) | 7 (21%) | 0.17 |
| SGLT-2 inhibitor, n (%) | 5 (6%) | 4 (8%) | 1 (3%) | 0.36 |
| Laboratories | ||||
| Hemoglobin, g/dL | 12.8 ± 1.6 | 13.0 ± 1.6 | 12.5 ± 1.7 | 0.21 |
| Estimated GFR, mL/min/1.73 m2 | 67.2 (55.7–77.9) | 71.8 (59.5–81.7) | 60.9 (49.2–71.9) | 0.023 |
| NTproBNP, pg/mL | 173 (77–387) | 119 (57–297) | 289 (99–781) | 0.010 |
| Echocardiography | ||||
| Left ventricular ejection fraction, % | 60 ± 7 | 60 ± 7 | 61 ± 7 | 0.50 |
| LV diastolic dimension, mm | 48.9 ± 5.3 | 49.5 ± 5.4 | 48.0 ± 5.0 | 0.21 |
| LV systolic dimension, mm | 31.3 ± 4.8 | 31.7 ± 4.7 | 30.7 ± 4.9 | 0.36 |
| LA volume index, mL/m2 | 32.5 (24.5–44.0) | 28.8 (23.0–40.5) | 37.0 (29.5–54.0) | 0.009 |
| LV mass index, g/m2 | 89.9 ± 29.5 | 87.4 ± 24.8 | 94.1 ± 36.0 | 0.33 |
| E-wave velocity, m/s | 0.7 (0.6–0.9) | 0.7 (0.6–0.9) | 0.7 (0.6–1.0) | 0.077 |
| E/A ratio | 0.88 (0.71–1.21) | 0.87 (0.71–1.19) | 0.98 (0.79–1.42) | 0.53 |
| Septal e’ velocity, m/s | 0.07 ± 0.02 | 0.07 ± 0.02 | 0.07 ± 0.02 | 0.64 |
| Lateral e’ velocity, m/s | 0.09 ± 0.02 | 0.09 ± 0.02 | 0.09 ± 0.02 | 0.77 |
| Average E/e’ | 10.0 (8.0–11.7) | 10.0 (7.8–11.4) | 10.0 (8.3–13.3) | 0.29 |
| TR velocity, m/s | 2.59 (2.40–2.80) | 2.52 (2.40–2.70) | 2.69 (2.37–3.07) | 0.11 |
| LV GLS (%) | 15.4 ± 4.3 | 15.9 ± 4.2 | 14.6 ± 4.4 | 0.20 |
| LA reservoir strain (%) | 24.6 ± 9.6 | 26.7 ± 8.5 | 21.1 ± 10.3 | 0.013 |
| LA booster strain (%) | 12.4 ± 6.2 | 12.8 ± 5.9 | 11.6 ± 7.0 | 0.50 |
| RV GLS (%) | 16.6 ± 6.1 | 16.8 ± 5.8 | 16.2 ± 6.6 | 0.64 |
| RV FWLS (%) | 18.6 ± 7.3 | 18.3 ± 7.0 | 19.1 ± 7.8 | 0.63 |
| RA reservoir strain (%) | 22.4 ± 10.6 | 22.4 ± 9.2 | 22.5 ± 12.6 | 0.96 |
| RA booster strain (%) | 11.0 ± 6.1 | 10.8 ± 4.7 | 11.2 ± 8.6 | 0.87 |
| Any MR, n (%) | 14 (17%) | 7 (14%) | 7 (21%) | 0.37 |
| Any TR, n (%) | 38 (45%) | 20 (39%) | 18 (55%) | 0.17 |
| Mild atrial MR, n (%) | 12 (14%) | 6 (12%) | 6 (18%) | 0.41 |
| Mild TR, n (%) | 31 (37%) | 18 (35%) | 13 (39%) | 0.70 |
| Moderate or severe MR, n (%) | 2 (2%) | 1 (2%) | 1 (3%) | 0.75 |
| Moderate or severe TR, n (%) | 7 (8%) | 2 (4%) | 5 (15%) | 0.069 |
Values represent mean ± standard deviation, median (25th, 75th), or n (%).
Abbreviations: BMI, body mass index; CIED, Cardiovascular implantable electronic device; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; EILAH, exercise-induced left atrial hypertension; FWLS, free wall longitudinal strain; GFR, glomerular filtration rate; GLS, global longitudinal strain; LA, left atrial; LV, left ventricular; MR, mitral regurgitation; NTproBNP, N terminal pro brain natriuretic peptide; RA, right atrial; RAAS, renin-angiotensin-aldosterone system; RV, right ventricular; RELAH, resting left atrial hypertension; SGLT, sodium-glucose co-transporters; TR, tricuspid regurgitation.
Of the 84 patients who underwent repeat testing, 33 (39%) transitioned to RELAH at repeat evaluation, while 51 (61%) did not (Figure 1). The interval from the first to final hemodynamic evaluation was significantly longer in patients with a change to RELAH [median 2.68 (1.74–3.97) vs 0.99 (0.44–2.16) years, P=0.001]. There was no significant difference between the two groups in the indication for repeat catheterization due to worsening symptoms (52% vs 33%, P=0.15). Patients with subsequent change to RELAH had a higher prevalence of atrial fibrillation at baseline, but there were no differences in age, sex, body weight, body mass index, prevalence of obesity, hypertension, diabetes, coronary artery disease, or medication use. Patients with change to RELAH had lower estimated glomerular filtration rate (eGFR) and higher N-terminal pro–B-type natriuretic peptide (NT-proBNP) levels at baseline (Table 1). At the baseline echocardiogram, patients with subsequent change to RELAH displayed higher LA volume index, lower LA reservoir strain, and higher prevalence of TR, but there were no differences in LVEF, LV mass index, average E/e’, TR velocity, and prevalence of MR when compared to those with no change to RELAH (Table 1).
Figure 1:
Study population.
EILAH, exercise-induced left atrial hypertension; LVEF, left ventricular ejection fraction; PCWP, pulmonary capillary wedge pressure; RELAH, resting left atrial hypertension.
On baseline hemodynamic evaluation, patients displayed typical findings of HFpEF with EILAH, including normal resting biventricular filling pressures and normal resting cardiac output (CO) (Table 2). Pulmonary hypertension at rest (mean PAP>20 mmHg) was present at the index evaluation in 27 (53%) of patients who did not progress to RELAH, and 23 (70%) of patients that did progress to RELAH (P=0.13 between groups). Compared with patients who did not transition to RELAH at follow-up, those with a change to RELAH displayed higher resting heart rate and systolic PAP, and lower PA and LA compliance (Figure 2), but there were no differences in resting RAP, PCWP, or CO between groups (Table 2). At peak exercise during the baseline hemodynamic evaluation, patients with transition to RELAH displayed higher systolic PAP, mean PAP, higher PCWP/CO slope and mean PAP/CO slope, and lower peak workload, peak VO2, PA compliance, CO, and SV (Table 2 and Figure 2). The invasive hemodynamics at final examination are shown in Table S2.
Table 2:
Invasive Hemodynamic Assessment at Baseline Examination
| Total (n = 84) |
No Change to RELAH (n = 51) |
Change to RELAH (n = 33) |
P Value | |
|---|---|---|---|---|
| Rest | ||||
| Heart rate, bpm | 71 ± 12 | 68 ± 11 | 75 ± 13 | 0.006 |
| Systolic BP, mmHg | 141 ± 22 | 140 ± 19 | 143 ± 26 | 0.58 |
| Central pressures | ||||
| RAP, mmHg | 7 ± 3 | 7 ± 3 | 7 ± 3 | 0.88 |
| PCWP, mmHg | 11 ± 2 | 11 ± 2 | 12 ± 2 | 0.69 |
| PCWP v wave, mmHg | 17 ± 5 | 16 ± 4 | 18 ± 6 | 0.10 |
| PCWP v wave height, mmHg | 6 ± 4 | 5 ± 4 | 7 ± 4 | 0.064 |
| LA compliance, %/mmHg | 4.34 (2.40–8.00) | 5.12 (3.20–8.07) | 2.60 (1.67–7.40) | 0.004 |
| Systolic PAP, mmHg | 34 ± 7 | 32 ± 6 | 35 ± 7 | 0.049 |
| Mean PAP, mmHg | 21 ± 4 | 20 ± 4 | 22 ± 5 | 0.11 |
| Mean PAP >20 mmHg, n (%) | 50 (60%) | 27 (53%) | 23 (70%) | 0.13 |
| Vascular function | ||||
| PVR, WU | 1.84 (1.20–2.45) | 1.79 (0.98–2.26) | 1.89 (1.31–2.87) | 0.12 |
| PVR >2.0 WU, n (%) | 35 (42%) | 20 (39%) | 15 (45%) | 0.57 |
| PA compliance, mL/mmHg | 4.1 ± 1.5 | 4.4 ± 1.5 | 3.5 ± 1.3 | 0.006 |
| Oxygen transport | ||||
| VO2, mL/min/kg | 229 ± 48 | 231 ± 49 | 227 ± 48 | 0.70 |
| Ca-vO2, mL/dL | 4.6 ± 1.1 | 4.5 ± 1.2 | 4.7 ± 1.0 | 0.66 |
| CO, L/min | 5.16 ± 1.34 | 5.25 ± 1.43 | 5.02 ± 1.19 | 0.43 |
| Stroke volume, mL | 74.1 ± 20.0 | 78.4 ± 20.9 | 67.5 ± 17.0 | 0.014 |
| Exercise | ||||
| Heart rate, bpm | 110 ± 21 | 109 ± 21 | 112 ± 22 | 0.49 |
| Systolic BP, mmHg | 188 ± 33 | 189 ± 33 | 187 ± 33 | 0.85 |
| Peak workload, Watt | 60 (40–80) | 60 (60–80) | 40 (20–80) | 0.006 |
| RER | 1.04 (0.97–1.10) | 1.06 (0.96–1.12) | 1.03 (0.97–1.09) | 0.59 |
| Central pressures | ||||
| RAP, mmHg | 16 ± 5 | 15 ± 5 | 16 ± 5 | 0.37 |
| PCWP, mmHg | 31 ± 6 | 30 ± 5 | 33 ± 8 | 0.085 |
| Systolic PAP, mmHg | 61 ± 13 | 58 ± 12 | 65 ± 15 | 0.016 |
| Mean PAP, mmHg | 40 ± 9 | 39 ± 8 | 43 ± 9 | 0.031 |
| PCWP/CO slope | 4.4 (2.9–6.9) | 3.7 (2.8–5.8) | 5.9 (4.2–10.2) | 0.004 |
| Mean PAP/CO slope | 4.5 (2.6–7.4) | 4.1 (2.5–5.6) | 6.0 (3.8–12.2) | 0.003 |
| Vascular function | ||||
| PVR, WU | 0.76 (0.32–1.44) | 0.67 (0.13–1.18) | 0.90 (0.47–2.00) | 0.053 |
| PA compliance, mL/mmHg | 3.1 ± 1.4 | 3.5 ± 1.5 | 2.6 ± 1.1 | <0.001 |
| Oxygen transport | ||||
| VO2, mL/min/kg | 1031 ± 335 | 1089 ± 324 | 931 ± 335 | 0.043 |
| Ca-vO2, mL/dL | 10.8 ± 2.2 | 10.8 ± 2.4 | 10.8 ± 2.0 | 1.00 |
| CO, L/min | 9.70 ± 2.74 | 10.27 ± 2.57 | 8.74 ± 2.80 | 0.016 |
| Stroke volume, mL | 90.3 ± 29.6 | 97.7 ± 31.9 | 77.8 ± 20.0 | 0.003 |
Values represent mean ± standard deviation or median (25th, 75th).
Abbreviations: BP, blood pressure; Ca-vO2, arterial-venous oxygen content difference; CO, cardiac output; EILAH, exercise-induced left atrial hypertension; LA, left atrial; PA, pulmonary artery; PAP, pulmonary artery pressure; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RAP, right atrial pressure; RELAH, resting left atrial hypertension; RER, respiratory exchange ratio; SVR, systemic vascular resistance; VO2, oxygen consumption; WU, wood unit.
Figure 2:
Differences in LA compliance and PA compliance at baseline.
LA compliance at rest (A) and PA compliance at rest and during exercise (B) in patients with change to RELAH or who did not transition to RELAH.
LA; left atrial; PA, pulmonary artery; RELAH, resting left atrial hypertension. Error bars in the panel reflect standard deviation.
In a sensitivity analysis limited to patients who underwent repeat catheterization as part of a research protocol (n = 39), the rate of transition to RELAH was similar (28%) and the direction of associations for key predictors were consistent with the main analysis (Tables S3–S4).
Longitudinal changes in hemodynamics and clinical measures
At the final examination, there were significant decreases in both eGFR and body weight observed among all patients (both P<0.01 for within-group changes), but no differences in these changes between those that transitioned to RELAH and those that did not (Table 3, Figure 3). Patients with change to RELAH had more frequently been started on beta-blockers (27% vs 4%, P=0.002), but there were no differences between the groups in other medication use, including diuretics (Table S5). Compared with patients who did not change to RELAH, those with transition to RELAH had greater increase in NT-proBNP level (Interaction P value =0.036), greater decrease in LVEF (P<0.001; even as LVEF remained normal), were more likely to experience worsening TR severity (15% vs 2%, P=0.025), had greater decreases in RV GLS (P=0.010), and RV FWLS (P =0.003) (Table 3 and Figure 3).
Table 3:
Longitudinal Changes from Baseline to Final Examination
| Change from baseline | No Change to RELAH | P value | Change to RELAH | P value | Interaction P value |
|---|---|---|---|---|---|
| Characteristics | |||||
| Change in Body weight, kg | −2.8 [−5.0 to −0.6] | 0.013 | −5.7 [−8.5 to −3.0] | <0.001 | 0.10 |
| Diuretic initiation or dose increase | 16 (31%) | 12 (36%) | - | ||
| Mineralocorticoid antagonist initiation | 13 (25%) | 9 (27%) | - | ||
| Beta-blocker initiation | 2 (4%) | 9 (27%) | - | ||
| SGLT-2 inhibitor initiation | 13 (25%) | 6 (18%) | - | ||
| New onset of Atrial Fibrillation | 5 (10%) | 2 (6%) | - | ||
| New Intervention for coronary artery | 0 | - | 0 | - | - |
| Laboratories | |||||
| Change in Hemoglobin, g/dL | +0.1 [−0.2 to +0.5] | 0.51 | −0.1 [−0.5 to +0.3] | 0.65 | 0.45 |
| Change in eGFR, mL/min/1.73 m2 | −6.2 [−11.0 to −1.4] | 0.01 | −11.1 [−17.1 to −5.1] | <0.001 | 0.21 |
| Change in NT-proBNP, pg/mL | +121 [−1879 to +2121] | 0.90 | +3575 [+1053 to +6097] | 0.006 | 0.036 |
| Echocardiography | |||||
| Change in Left ventricular EF, % | +1.0 [−1.2 to +3.2] | 0.38 | −5.3 [−8.1 to −2.6] | <0.001 | <0.001 |
| Change in LA volume index, mL/m2 | −1.8 [−5.8 to +2.2] | 0.37 | +3.2 [−2.5 to +8.9] | 0.27 | 0.16 |
| Change in LV mass index, g/m2 | −4.2 [−12.2 to +3.7] | 0.29 | −7.6 [−17.5 to +2.3] | 0.13 | 0.60 |
| Change in TR velocity, m/s | −0.03 [−0.17 to +0.11] | 0.68 | +0.03 [−0.15 to +0.21] | 0.75 | 0.61 |
| Worsening TR severity | 1 (2%) | 5 (15%) | - | ||
| Change in LV GLS (%) | +1.0 [−0.3 to +2.4] | 0.15 | −0.9 [−2.6 to +0.8] | 0.28 | 0.08 |
| Change in LA reservoir strain (%) | −2.30 [−5.1 to +0.5] | 0.11 | −2.4 [−6.1 to +13] | 0.19 | 0.96 |
| Change in RV GLS (%) | +2.1 [−0.4 to +4.5] | 0.10 | −3.2 [−6.4 to −0.10] | 0.043 | 0.010 |
| Change in RV FWLS (%) | +2.6 [−0.7 to +5.9] | 0.13 | −5.7 [−9.9 to −1.5] | 0.009 | 0.003 |
| Change in RA reservoir strain (%) | +0.9 [−4.3 to +6.1] | 0.73 | −7.2 [−12.9 to −1.4] | 0.015 | 0.04 |
| Hemodynamics at rest | |||||
| Change in Systolic BP, mmHg | +0.8 [−5.6 to +7.2] | 0.80 | −7.2 [−15.2 to +0.7] | 0.07 | 0.12 |
| Change in Heart rate, bpm | +4.2 [−0.8 to +7.6] | 0.016 | −5.0 [−9.2 to −0.8] | 0.022 | <0.001 |
| Change in PCWP, mmHg | −1.2 [−2.2 to −0.1] | 0.028 | +6.7 [+5.4 to +8.0] | <0.001 | <0.001 |
| Change in RAP, mmHg | −1.5 [−2.6 to −0.4] | 0.052 | +2.9 [+1.5 to +4.3] | <0.001 | <0.001 |
| Change in Mean PAP, mmHg | −2.4 [−3.9 to −0.9] | 0.002 | +4.2 [+2.3 to +6.0] | <0.001 | <0.001 |
| Change in PVR, WU | −0.25 [−0.59 to +0.06] | 0.11 | −0.34 [−0.73 to +0.03] | 0.07 | 0.69 |
| Change in PA compliance, mL/mmHg | +0.09 [−0.43 to +0.62] | 0.73 | −0.32 [−0.97 to +0.34] | 0.34 | 0.34 |
| Change in CO, L/min | −0.15 [−0.54 to +0.24] | 0.44 | −0.53 [−1.02 to −0.05] | 0.03 | 0.22 |
| Hemodynamics during peak exercise | |||||
| Change in Systolic BP, mmHg | −8.9 [−21.3 to +3.4] | 0.15 | −6.5 [−23.6 to +10.5] | 0.45 | 0.82 |
| Change in Heart rate, bpm | +2.0 [−3.8 to +7.7] | 0.50 | −2.7 [−10.8 to +5.4] | 0.51 | 0.35 |
| Change in PCWP, mmHg | −7.6 [−10.0 to −5.3] | <0.001 | −4.5 [−7.8 to −1.3] | 0.007 | 0.13 |
| Change in RAP, mmHg | −1.5 [−3.7 to +0.6] | 0.15 | +1.9 [−1.1 to +4.9] | 0.21 | 0.07 |
| Change in Mean PAP, mmHg | −4.4 [−7.1 to −1.8] | 0.002 | −0.4 [−4.2 to +3.3] | 0.82 | 0.09 |
| Change in PVR, WU | +0.33 [+0.07 to +0.60] | 0.013 | +0.65 [0.28 to +1.03] | 0.001 | 0.18 |
| Change in PA compliance, mL/mmHg | +0.62 [+0.17 to +1.08] | 0.008 | −1.07 [−1.90 to −0.25] | 0.011 | 0.36 |
| Change in CO, L/min | +0.17 [−0.69 to +1.03] | 0.70 | −0.15 [−1.39 to +1.09] | 0.81 | 0.68 |
Figure 3:
Longitudinal change of patients characteristics.
Body weight (A), NTproBNP (B), eGFR (C), RV FWLS (D), and prevalence of TR (E) in patients with change to resting left atrial hypertension (RELAH, red) or who did not transition to RELAH (orange).
eGFR, estimated glomerular filtration rate; NTproBNP, N terminal pro brain natriuretic peptide; RELAH, resting left atrial hypertension; RV FWLS, right ventricular free wall longitudinal strain; TR, tricuspid regurgitation. Error bars in the panel reflect standard error. *Mean single time point between group comparisons; *P<0.05, **P<0.01. †Means paired t-test for within-group comparisons from baseline to final examinations, †P<0.05, ††P<0.01.
Upon final invasive hemodynamic evaluation at rest, patients with change to RELAH displayed lower resting heart rate (Interaction P value <0.001), increased RAP (P<0.001), and increased mean PAP (P <0.001) compared to those with no change (Table 3 and Figure 4). At peak exercise, there were no differences in PCWP, RAP, mean PAP, or CO (Table 3 and Figure 4).
Figure 4:
Longitudinal change of invasive hemodynamics.
At resting hemodynamics, pulmonary capillary wedge pressure (PCWP) (A), right atrial pressure (RAP) (B), mean pulmonary artery (PA) pressure (C), and PA compliance (D); at peak exercise, PCWP (E), RAP (F), mean PA pressure (G), and PA compliance (H) in patients with change to resting left atrial hypertension (RELAH, red) or who did not transition to RELAH (orange).
EILAH, exercise-induced left atrial hypertension; PA, pulmonary artery; PCWP, pulmonary capillary wedge pressure; RAP, right atrial pressure; RELAH, resting left atrial hypertension. Error bars in the panel reflect standard error. * Mean single time point between group comparisons; *P<0.05, **P<0.01. †Means paired t-test for within-group comparisons from baseline to final examinations, †P<0.05, ††P<0.01.
Correlates of the change from EILAH to RELAH in baseline parameters
Transition from EILAH to RELAH was most strongly predicted by lower resting LA compliance and lower exercise PA compliance [AUC C-statistics 0.71 (0.57–0.85) and 0.72 (0.60–0.84), respectively]. (Table S6). In univariable logistic regression, history of atrial fibrillation, longer duration of follow-up, higher resting heart rate, NT-proBNP, LA volume index, and lower LA reservoir strain, LA compliance, PA compliance, peak workload, and peak VO2 were associated with change from EILAH to RELAH (Table 4). In multivariable logistic regression of baseline parameters, history of atrial fibrillation (OR 4.57; 95% CI 1.63–12.8, P=0.004), lower resting LA compliance (OR 0.47; 95% CI 0.22–0.99, P=0.049), and lower resting PA compliance (OR 0.48; 95% CI 0.25–0.93, P=0.030) were independently associated with change from EILAH to RELAH even after adjusting the duration from baseline to final examination (Table 4).
Table 4:
Predictors of the Transition to RELAH from Baseline Examination
| Univariable Analysis | Multivariable Analysis | |||||
|---|---|---|---|---|---|---|
| Model 1 | Model 2 | |||||
| Odds ratio (95%CI) | P Value | Odds ratio (95%CI) | P Value | Odds ratio (95%CI) | P Value | |
| Follow-up duration, years (SD) | 1.71 (1.07 – 2.73) | 0.025 | 1.49 (0.88 – 2.51) | 0.14 | 1.21 (0.72 – 2.05) | 0.48 |
| Age, year (SD) | 1.19 (0.77 – 1.85) | 0.43 | Not selected | - | Not selected | - |
| Gender, female | 2.18 (0.83 – 5.78) | 0.11 | Not selected | - | Not selected | - |
| Body weight, kg (SD) | 0.73 (0.46 – 1.16) | 0.18 | Not selected | - | Not selected | - |
| Systolic BP, mmHg (SD) | 1.13 (0.73 – 1.75) | 0.57 | Not selected | - | Not selected | - |
| History of obesity | 0.73 (0.29 – 1.85) | 0.51 | Not selected | - | Not selected | - |
| Hemoglobin, mg/dL (SD) | 0.74 (0.46 – 1.19) | 0.21 | Not selected | - | Not selected | - |
| Rest mean PAP, mmHg (SD) | 1.59 (0.89 – 2.82) | 0.12 | Not selected | - | Not selected | - |
| Log rest PVR, WU (SD) | 1.68 (0.93 – 3.00) | 0.088 | Not selected | - | Not selected | - |
| Heart rate, bpm (SD) | 1.91 (1.17 – 3.11) | 0.009 | Not selected | - | Not selected | - |
| History of atrial fibrillation | 4.36 (1.68 – 11.4) | 0.003 | 4.57 (1.63 – 12.8) | 0.004 | Not selected | - |
| Log NTproBNP, pg/mL (SD) | 1.83 (1.12 – 2.98) | 0.016 | Not selected | - | Not selected | - |
| LA volume index, mL/m2 (SD) | 1.96 (1.28 – 3.41) | 0.017 | Not selected | - | Not selected | - |
| LA reservoir strain, % (SD) | 0.54 (0.33 – 0.91) | 0.020 | Not selected | - | Not selected | - |
| Log LA compliance, %/mmHg (SD) | 0.55 (0.18 – 0.75) | 0.006 | Not selected | - | 0.47 (0.22 – 0.99) | 0.049 |
| Log rest PA compliance, mL/mmHg (SD) | 0.46 (0.26 – 0.82) | 0.009 | 0.48 (0.25 – 0.93) | 0.030 | 0.55 (0.27 – 1.13) | 0.10 |
| Peak mean PAP, mmHg (SD) | 1.74 (1.03 – 2.93) | 0.039 | Not selected | - | Not selected | - |
| Log peak PA compliance, mL/mmHg (SD) | 0.41 (0.23 – 0.74) | 0.003 | Not selected | - | Not selected | - |
| PCWP/CO slope (SD) | 2.68 (0.996 – 7.18) | 0.051 | Not selected | - | Not selected | - |
| Mean PAP/CO slope (SD) | 2.56 (1.30 – 5.04) | 0.007 | Not selected | - | Not selected | - |
| Rest stroke volume, mL (SD) | 0.54 (0.33 – 0.90) | 0.018 | Not selected | - | Not selected | - |
| Peak stroke volume, mL (SD) | 0.39 (0.20 – 0.76) | 0.005 | Not selected | - | Not selected | - |
| Peak workload, 10 Watt | 0.80 (0.67 – 0.95) | 0.012 | Not selected | - | Not selected | - |
| Peak VO2, mL/min/kg (SD) | 0.61 (0.37 – 0.99) | 0.048 | Not selected | - | Not selected | - |
DISCUSSION
Approximately one-third of patients with HFpEF have elevation in PCWP only during exercise (EILAH), and it has remained unclear whether such patients represent a distinct form of heart failure, or potentially, and earlier stage that may progress to HFpEF that is apparent at rest (RELAH). Using serial invasive hemodynamic evaluations, we show here for the first time many patients that first present with EILAH transitioned to RELAH at repeat assessment. Patients with change to RELAH had lower eGFR, higher NT-proBNP, more TR, higher LA volume index, and lower LA reservoir strain, but the strongest predictors of transition to RELAH were impairments in LA and PA compliance at baseline, along with prevalent atrial fibrillation, which is intimately related to atrial myopathy and PVD in HFpEF. Patients who transitioned to RELAH had a greater increase in NT-proBNP level and were more likely to experience worsening TR severity and a greater decrease in biventricular systolic function. The present findings support the idea that EILAH may represent an earlier stage of HFpEF, and call for testing whether interventions that enhance atriopulmonary compliance could mitigate HFpEF progression.
Characteristics of patients with EILAH who progress to RELAH
NT-proBNP levels, prevalence of atrial fibrillation, and prevalence of CKD were relatively low in the patients with EILAH at index evaluation, consistent with previous cross sectional studies.5,8 Patients displayed typical findings of HFpEF with EILAH,5,8 including normal resting biventricular filling pressures and cardiac output. Most patients displayed pulmonary hypertension at baseline, which in the absence of exercise testing, would have been considered as precapillary PH rather than HFpEF, as the resting PCWP was normal, and potentially treated in at least some individuals with pulmonary vasodilators rather than treatments for HFpEF.
The most significant finding of this study is that a substantial proportion of patients initially presenting with EILAH transitioned to RELAH over time, suggesting that EILAH represents an earlier stage of HFpEF. Interestingly, the patients with a change to RELAH displayed markers of greater atrial myopathy, myocardial stress, and cardiorenal abnormalities, identifying a subgroup within EILAH with a higher risk of progression. These patients had greater LA enlargement, reduced LA reservoir strain, and lower LA compliance at baseline, as well as higher prevalence of functional TR, an important clue to the presence of underlying HFpEF.18,19 In a smaller study of 45 patients with EILAH, 5 were found to have RELAH at subsequent hemodynamic evaluations (11%), though it was not reported how many of the 45 patients underwent repeat catheterization.6 The present findings align with previous studies indicating that atrial remodeling plays a pivotal role in the pathophysiology of HFpEF and may contribute to the eventual development of PVD.10 Longitudinal changes further highlight the progressive natural history of this condition. Patients with a transition to RELAH exhibited a greater increase in NT-proBNP levels over time, alongside worsening TR severity and significant declines in RV GLS and RV FWLS. These findings suggest that worsening RV function and increased filling pressures may be key contributors to or consequences of transition from EILAH to RELAH. Although our main analysis focused on parameters of baseline examination, it is noteworthy that patients who progressed to RELAH displayed higher exercise PVR at follow-up (median 1.65 WU, Table S2), a value approaching the 1.74 WU threshold that identified responders in the REDUCE-LAP II trial.20 This observation further supports the notion that pulmonary vascular involvement becomes manifest as the disease advances from EILAH to RELAH.
Identifying Risk and Preventing Transition to RELAH
Compared to patients with noncardiac dyspnea, patients with HFpEF and EILAH have an increased risk for HF hospitalization or death, but patients with elevated resting PAWP (RELAH) have an even higher risk than those with EILAH.5 Therefore, while both EILAH and RELAH are part of the HFpEF spectrum, it may be important to identify patients with EILAH at higher risk for transition to RELAH to initiate treatment. The present results relating worsening atrial and pulmonary vascular compliance, as well as markers of right heart failure as predictors of this transition are consistent with prior noninvasive longitudinal studies from Obokata et al.9 and Sorimachi et al.21 that showed deterioration in RV function, increasing TR, and greater impairment in LA reservoir strain over time in HFpEF.
Arterial, pulmonary arterial and atrial compliances reflect the abilities of the systemic and pulmonary circulations and left atrium (respectively) to accept the stroke volume and venous return during the cardiac cycle without untoward increases in pressure. In the present study, PA compliance was lower in those who later developed RELAH, suggesting that loss of this buffering capacity of the lung vessels could contribute to progression to resting LA hypertension. The SGLT-2 inhibitor dapagliflozin has been shown to improve PA compliance at rest and during exercise in HFpEF,22 along with improvements in total arterial compliance.23 SGLT-2 inhibitors may also favorably affect atrial myopathy, as secondary analyses from the DECLARE trial showed that dapagliflozin reduced new onset of atrial fibrillation in patients with and without HF (another biomarker of atrial myopathy).24 These studies suggest that SGLT2 inhibitors may help prevent transition from EILAH to RELAH through favorable effects on atrial, systemic, and pulmonary vascular compliance, pointing to potential roles for other cardiometabolic interventions in this setting.
Atrial fibrillation was an independent predictor of transition to RELAH, begging the question whether its treatment could mitigate this transition. There is limited evidence on the effectiveness of ablation for atrial fibrillation in patients with HFpEF,25,26 but one small mechanistic trial in HFpEF with atrial fibrillation showed improvement in exercise hemodynamics and aerobic capacity following catheter ablation, to the point where some of the participants no longer fulfilled the diagnostic criteria for EILAH following catheter ablation.27 An ongoing randomized trial (CABA-HFPEF, NCT05508256) is evaluating the effect of catheter ablation on hemodynamic and clinical outcomes in HFpEF with atrial fibrillation.28 Conversely, atrial fibrosis from catheter ablation could worsen LA compliance. Further study in randomized trials is indicated.
Limitations
The cross sectional nature of the data precludes drawing inferences toward causality in the associations between atriopulmonary compliance and transition to RELAH. The sample size is modest owing to the requirement for multiple invasive studies, reducing power, but such data are singular in the literature exploring longitudinal changes over time in invasive exercise hemodynamics. Since patient enrollment began in 2006, the use of contemporary HFpEF therapies such as SGLT-2 inhibitors and GLP-1 receptor agonists has been very limited. Wider adoption of these medications in current practice may alter disease trajectories and hemodynamic responses observed in this study. The most significant limitation relates to the observational design and potential selection bias, as analyses were restricted to patients who underwent repeat invasive cardiopulmonary exercise testing. Only 13% of patients with EILAH underwent subsequent testing, and this subgroup represented a higher-risk population with poorer kidney function, greater diuretic use, and higher prevalence of diabetes and atrial fibrillation, and the observed transition rate should be interpreted within the context of the greater comorbidity burden of those with repeat evaluation. Follow-up duration was not uniform and was longer among patients who progressed to RELAH. However, multivariable logistic regression analysis examining the predictors of patients with change from EILAH to RELAH adjusted the observation duration as a covariate, and the fact that follow-up duration was greater in those developing RELAH is consistent with the fact that cardiac mechanics and arterial compliance worsen over time, so a greater duration of time thus allowed for greater exposure to cause RELAH. In addition, although we intentionally avoided including closely related variables within the same multivariable models, residual collinearity among physiologically related measures cannot be fully excluded and may influence the estimated magnitude of individual associations. Some patients who did not transition to RELAH no longer met exercise hemodynamic criteria for HFpEF at follow-up, potentially reflecting lifestyle modification, optimization of volume status, or initiation of guideline-directed medical therapies such as SGLT2 inhibitors and MRA.22 Our study focused on forward transition from EILAH to RELAH, and future bidirectional analyses, including patients with RELAH at baseline, may better characterize the dynamic hemodynamic continuum in HFpEF. Finally, we did not attempt to determine specific cut-off values for LA or PA compliance to avoid potential overfitting in this relatively small cohort. Future larger studies are warranted to validate clinically meaningful thresholds for these parameters and to determine their predictive utility in broader HFpEF populations, but this first report supports the concept hypothesis that impairments in LA and PA compliance are associated with progression to RELAH.
Conclusions
A significant number of patients with HFpEF that first present with exercise-induced LA hypertension transition to develop resting LA hypertension over time, suggesting that EILAH may represent an earlier form of HFpEF. History of atrial fibrillation and reductions in LA and PA compliance are independently associated with progression to RELAH, suggesting a potential role for interventions that enhance atriopulmonary compliance as promising treatment to mitigate disease progression in HFpEF.
Supplementary Material
CLINICAL PERSPECTIVES:
COMPETENCY IN MEDICAL KNOWLEDGE:
Progression from exercise-induced to resting left atrial hypertension represents a key transition in the natural history of HFpEF. Impaired left atrial and pulmonary vascular compliance identifies patients at higher risk, underscoring the pathophysiologic continuum linking atrial myopathy and pulmonary vascular disease in HFpEF.
TRANSLATIONAL OUTLOOK:
Future studies should evaluate interventions that enhance atrial and pulmonary vascular compliance to mitigate or even reverse disease progression in HFpEF.
Acknowledgements
The authors thank the staff of the Mayo Clinic Earl Wood Catheterization Laboratory and the patients who agreed to participate in research, allowing for this study to be completed.
Sources of Funding
Dr Borlaug is supported by R01 HL128526 and U01 HL160226, from the NIH and W81XWH2210245, from the US Department of Defense. Dr Tada is supported by a research fellowship from the Uehara Memorial Foundation, Japan.
Disclosures
Dr. Borlaug receives research support from the National Institutes of Health (NIH), the United States Department of Defense, and the Schoen Foundation, as well as research grant funding from AstraZeneca, Axon, GlaxoSmithKline, Medtronic, Mesoblast, Novo Nordisk, Rivus, and Tenax Therapeutics. Dr. Borlaug has served as a consultant for Actelion, Amgen, Aria, Axon Therapies, BD, Boehringer Ingelheim, Cytokinetics, Edwards Lifesciences, Eli Lilly, Imbria, Janssen, Merck, Novo Nordisk, NGM, NXT, and VADovations, and is named inventor (US Patent no. 10,307,179) for the tools and approach for a minimally invasive pericardial modification procedure to treat heart failure.
List of abbreviations:
- EILAH
exercise-induced left atrial hypertension
- LA
left atrial
- HFpEF
heart failure with preserved ejection fraction
- LVEF
left ventricular ejection fraction
- NT-proBNP
N-terminal pro B-type natriuretic peptide
- PCWP
pulmonary capillary wedge pressure
- PAP
pulmonary arterial pressure
- PVR
pulmonary vascular resistance
- RELAH
resting left atrial hypertension
- RV
right ventricular
Footnotes
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