Abstract
Background:
Early, non-invasive identification of heart failure with preserved ejection fraction (HFpEF) patients with congestion may allow for timely tailoring of decongestive therapies. The 2016 American Society of Echocardiography / European Association of Cardiovascular Imaging guidelines provide an algorithm to assess for elevated left atrial pressure (LAP); the associations of echocardiographic LAP (echo-LAP) with clinical status and disease progression in HFpEF are unclear.
Methods:
We categorized participants in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in HFpEF (RELAX) trial into 1 of 4 pre-specified guideline-based echo-LAP categories: 1) normal, 2) elevated, 3) atrial fibrillation (AF) at the time of echocardiography, or 4) indeterminate. We evaluated the associations of echo-LAP categories with baseline exercise capacity, change in exercise capacity, and change in NT-proBNP over 24 weeks.
Results:
Of 216 participants, 199 had mitral inflow Doppler echocardiography for LAP categorization. Participants with elevated echo-LAP (n=81) or AF (n=57) were older and had higher prevalence of kidney dysfunction. Compared with the normal echo-LAP group (n=28), elevated echo-LAP and AF were each independently associated with a greater reduction in peak oxygen consumption over 24 weeks after adjusting for baseline values and clinical covariates (β-coefficient for elevated echo-LAP: −1.55 [95% CI: −2.59, −0.51], p=0.004; β-coefficient for AF: −1.33 [95% CI: −2.49, −0.17], p=0.03). Indeterminate echo-LAP (n=33) was also independently associated with a reduction in exercise capacity at 24 weeks compared with normal echo-LAP (β-coefficient: −1.35 [95% CI: −2.51, −0.19], p=0.02). Finally, elevated echo-LAP and AF were significantly associated with increases in NT-proBNP over 24 weeks compared with normal echo-LAP.
Conclusions:
In chronic HFpEF, elevated echo-LAP and indeterminate echo-LAP, as defined by contemporary guidelines, and AF were each independently associated with a reduction in exercise capacity compared with normal echo-LAP. These findings suggest potential utility of non-invasive LAP assessment in HFpEF for tailoring treatments that decrease congestion.
Keywords: heart failure with preserved ejection fraction, echocardiography, hemodynamics, atrial fibrillation, exercise capacity
INTRODUCTION
Heart failure (HF) with preserved ejection fraction (HFpEF) accounts for approximately half of the cases of HF in the United States, carries a poor prognosis, and therapeutic options are limited.1, 2 Some patients with HFpEF develop elevated filling pressures exclusively during exercise, whereas others display high pressures at rest, which can be considered as a congested phenotype. Simple methods to identify HFpEF patients at risk for clinical deterioration in the latter category remain elusive.3 Although invasively determined filling pressures remain the gold standard, echocardiography is a readily available and non-invasive alternative for filling pressure assessment.4, 5 Early identification of HFpEF patients with a congested phenotype at rest is particularly important to tailor pharmacologic and device therapies (e.g. inter-atrial shunt device, wireless pulmonary artery monitoring) aimed to decongest this high-risk cohort with elevated left atrial pressure (LAP).2, 6–10
The 2016 American Society of Echocardiography/European Association of Cardiovascular Imaging (ASE/EACVI) guidelines for the assessment of diastolic function provide a straight-forward algorithm for assessing LAP in individuals with a left ventricular ejection fraction (LVEF) ≥50% and myocardial disease.11 While these guidelines were based on expert consensus, subsequent analyses have demonstrated that LAP classification based on this algorithm provides a more accurate estimation of invasively-determined filling pressures than the corresponding 2009 guidelines.11–16 However, the clinical and biomarker correlates of LAP categories defined by the 2016 guidelines as well as the prognostic implications of LAP categories among individuals with HFpEF remain unclear. Additionally, given the frequent co-occurrence of atrial fibrillation (AF) and HFpEF, the exclusion of individuals in AF at the time of echocardiography from the basic algorithm may complicate its application to HFpEF patients.15 As such, we aimed to evaluate the associations of LAP categories as defined by the 2016 ASE/EACVI guidelines, and AF at echocardiogram with 1) baseline biomarkers of cardiovascular stress and their changes over time and 2) exercise capacity at baseline and over time in the Phosphodiesterase-5 Inhibition to Improve Clinical Status and Exercise Capacity in Heart Failure with Preserved Ejection Fraction (RELAX) trial. We hypothesized that elevated LAP would be associated with a more advanced HFpEF phenotype and a greater reduction in exercise capacity at 24 weeks. Additionally, we hypothesized that patients with indeterminate LAP due to the presence of atrial fibrillation (AF) would have similar biomarker and exercise profiles as those with elevated LAP.
MATERIALS AND METHODS
Study Population
The design and rationale of the RELAX trial have been previously reported.17, 18 Briefly, RELAX sought to determine the effect of sildenafil on exercise capacity in patients with chronic HFpEF. The study was conducted with support from the National Heart, Lung and Blood Institute (NHLBI) and data for this analysis was obtained from the NHLBI Biological Specimen and Data Repository Information Coordinating Center (BioLINCC, Calverton, MA). All participants provided written informed consent prior to randomization and this analysis was approved by the Institutional Review Board of Northwestern University and by BioLINCC.
RELAX enrolled 216 patients with preserved EF (≥50%) and New York Heart Association (NYHA) functional class II or III symptoms from 26 sites across the United States and Canada. In the 12 months prior to enrollment, patients were required to have had (1) a hospitalization for HF, (2) treatment with intravenous diuretics, (3) chronic loop diuretic therapy with left atrial enlargement, or (4) invasively documented elevated LV filling pressures at rest or with exercise. Additionally, all enrolled participants without documented elevated filling pressures were required to have elevated N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels (≥400pg/mL). On screening cardiopulmonary exercise testing (CPET), all patients were required to have a peak volume of oxygen (VO2) ≤60% of age-and sex-specific normal values and achieve a respiratory exchange ratio ≥1.00. Participants with significant valve disease (> mild aortic or mitral stenosis; > moderate aortic or mitral regurgitation) were excluded from the RELAX trial.
Trial Protocol
After enrollment, participants underwent CPET and biomarker assessment at baseline. CPET was performed using coordinated bicycle and treadmill protocols. Participants underwent 3-minutes of low-level exercise followed by 10 watt/minute incremental ramp. Peak VO2 was determined by the highest 30 second median VO2 value during the final minute of exercise. CPET data was analyzed by the core CPET testing lab (Massachusetts General Hospital, Boston, MA).17 Pre-specified cardiovascular biomarkers were obtained at baseline as part of the RELAX trial and were analyzed at the core laboratory (University of Vermont, Burlington, VT). The pre-specified biomarkers and their categories were: neurohormonal activation (N-terminal pro-B-type natriuretic peptide [NT-proBNP], aldosterone, and endothelin-1), myocardial necrosis (high-sensitivity troponin I), fibrosis (galectin-3, NT-procollagen III peptide, and carboxy-terminal telopeptide of collagen type I [CITP]), inflammation (high-sensitivity C-reactive protein [hs-CRP], uric acid), and renal dysfunction (cystatin-C). Participants were randomly assigned sildenafil or placebo. Sildenafil was titrated to goal dose of 60 mg three times daily. Both CPET and biomarkers were repeated at the final study visit (24 weeks from baseline) in enrolled participants.
Cardiovascular Imaging
Comprehensive 2-dimensional, M-mode, and Doppler echocardiography and cardiac magnetic resonance (CMR) were performed at enrollment as part of the trial protocol. Echocardiographic measurements were conducted by the core lab (Mayo Clinic, Rochester, MN) in accordance to published guidelines.19 Left ventricular EF (LVEF) was calculated using the biplane Simpson method. LV mass and left atrial volume were indexed to body surface area and calculated based on ASE guidelines.20 Stroke volume was calculated using the velocity time integral based on Doppler measurements of flow across the LV outflow tract (LVOT) and the LVOT area. Among participants in AF at echocardiogram, measurements were averaged over 3–5 beats. Simpson’s rule was used to calculate chamber volumes by the CMR core lab (Duke University Medical Center, Durham, NC).
Early transmitral flow velocity (E), early diastolic medial and lateral mitral annular tissue velocity (medial e’; lateral e’), and the ratio of E/e’(average e’) were used to estimate LV relaxation and LV filling pressures, respectively. Pulmonary artery systolic pressure (PASP) was calculated through a modified version of the Bernoulli equation using the measured peak tricuspid regurgitant (TR) velocity and right atrial pressure was assessed by inferior vena cava measurements.
Assessment of Left Atrial Pressure
We categorized trial participants with available mitral inflow Doppler patterns at baseline by LAP into the 4 following pre-specified groups: (1) normal LAP, (2) elevated LAP, (3) AF at the time of echocardiography, and (4) indeterminate LAP. LAP was classified according to the 2016 societal recommendations for patients with an EF ≥50% and myocardial disease, as RELAX participants were required to have clinical HF and documentation of elevated cardiac filling pressures through invasive testing or biomarker (NT-proBNP) assessment (Figure 1).11
Figure 1. Flowchart for study inclusion and LAP categorization.
This flowchart describes the stepwise exclusion and categorization of HFpEF patients according to the 2016 ASE/EACVI guidelines. LAP= left atrial pressure. HFpEF = heart failure with preserved ejection fraction TR= tricuspid regurgitant. LAVI = left atrial volume index.
The presence of elevated LAP was determined by assessing the mitral E/A ratio and E velocity followed by an assessment of 3 indices: left atrial volume index (LAVI), tricuspid regurgitant (TR) peak velocity and average mitral E/e’. Individuals were categorized as having elevated LAP if (1) mitral E/A ratio ≥2.0 or (2) E/A ratio >0.8 and <2.0 or E/A ≤0.8 and peak E velocity >50 cm/s and at least 2 of the following: LAVI >34 mL/m2, TR peak velocity >2.8 m/sec, or mitral E/e’ >14. Those with an (1) E/A ratio ≤0.8 and a peak E velocity <50 cm/s or (2) E/A ratio >0.8 and <2.0 or E/A ≤0.8 and peak E velocity >50 cm/s with ≤1 parameter (LAVI >34 mL/m2, TR peak velocity >2.8 m/sec, or mitral E/e’ >14) were classified as having normal LAP. Those with AF at the time of echocardiogram were categorized as a distinct group for this analysis. Finally, those with an E/A ratio >0.8 and <2.0 or E/A ≤0.8 and peak E velocity >50 cm/s who were missing 2 of the 3 additional indices (LAVI, TR peak velocity or mitral E/e’), or who had discrepant indices were classified as having indeterminate LAP. Among participants with left bundle branch block or ventricular pacing who had E/A ≤ 0.8 + E >50 cm/s or E/A > 0.8 – <2, only 2 parameters were examined (TR velocity and LAVI) given challenges in interpreting E/e’ in the context of left bundle branch block or ventricular pacing.11
Statistical Analysis
Categorical variables were presented as numbers and percentages; normally distributed continuous variables were presented as means with standard deviations; and non-normal continuous data were presented as medians with 25th-75th percentiles. Comparison of baseline characteristics by LAP category was assessed by χ2 or Fisher’s exact tests for categorical variables and one-way analysis of variance (ANOVA) or Kruskal Wallis tests for continuous variables. Multivariable linear regression models were used to evaluate the association of LAP category (independent variable) with baseline peak VO2 (dependent variable). For all regression models, model covariates were chosen a priori. Model 1 adjusted for exercise modality of CPET (bicycle vs. treadmill). Model 2 further adjusted for age, sex, LVEF, diabetes mellitus (DM), chronotropic index, hypertension, and hemoglobin level. In linear regression models evaluating LAP categories (independent variable) and change in peak VO2 at 24 weeks (dependent variable, change in peak VO2 = peak VO2 (24 weeks) - peak VO2 (baseline)), regression models further adjusted for baseline peak VO2 and treatment arm. Multivariable linear regression models were also used to evaluate the association between LAP category (independent variable) and change in NT-proBNP at 24 weeks (dependent variable, change in NT-proBNP = NT-proBNP (24 weeks) - NT-proBNP (baseline)). Model 1 adjusted for baseline NT-proBNP, Model 2 further adjusted for age, sex, LVEF, DM, hypertension, body mass index, treatment arm, and glomerular filtration rate (GFR).
In exploratory analyses, we evaluated the associations of LAP categories with the remaining biomarkers of neurohormonal activation, myocardial injury, inflammation/oxidative stress, fibrosis, and renal dysfunction using similar covariates for adjustment. In sensitivity analyses, we categorized participants in AF at echocardiogram into 3 categories: 1) septal E/e’ ratio> 11 and peak TR velocity >2.8 m/s (“Two LAP parameters”) 2) E/e’ ratio> 11 or peak TR velocity >2.8 m/s (“One LAP parameter”) and 3) E/e’ ratio ≤11 and peak TR velocity ≤2.8 m/s (“Referent”) to determine the independent association of LAP parameters with change in peak VO2 and with change in NT-proBNP among participants with AF. Two-sided P-values <0.05 were considered statistically significant. All analyses were performed using R version 3.5.0 (R Foundation for Statistical Computing, Vienna, Austria).
RESULTS
Study Population and Baseline Clinical Characteristics
Among the 216 participants in the RELAX trial, 17 were excluded due to lack of mitral inflow Doppler echocardiography. Of the 199 participants who represented the final analytic cohort, 28 (14%) had normal LAP, 81 (41%) had elevated LAP, 57 (29%) were in AF at echocardiogram, and 33 (17%) had indeterminate LAP (Figure 1, Supplemental Table 1).
Baseline clinical characteristics stratified by LAP category are shown in Table 1. No significant differences in NYHA class, history of ischemic heart disease, hypertension, DM, peripheral artery disease, or stroke were noted by LAP group. Individuals with elevated LAP had the highest proportion of women and had the highest systolic blood pressure while individuals with normal LAP were the least likely to have an elevated jugular venous pressure or be treated with a loop diuretic. Individuals classified as having elevated LAP or AF at the time of echocardiography were older and had higher rates of chronic kidney disease (CKD). Laboratory assessment at baseline showed no differences in sodium, potassium, or hemoglobin among the LAP categories; GFR was lowest in those with elevated LAP or AF.
Table 1.
Baseline Clinical Characteristics by LAP Category.
| Normal LAP (n=28) |
Elevated LAP (n=81) |
AF at echocardiogram (n=57) |
Indeterminate LAP (n=33) |
p-value | |
|---|---|---|---|---|---|
| Demographics | |||||
| Age, years, mean±SD | 61.9 ±10.6 | 70.4 ±9.8 | 71.7 ±9.2 | 63.0 ±10.0 | <0.001 |
| Female, n (%) | 14 (50.0) | 44 (54.3) | 24 (42.1) | 15 (45.5) | 0.54 |
| White, n (%) | 26 (92.9) | 70 (86.4) | 56 (98.2) | 29 (87.9) | 0.10 |
| Medical History | |||||
| NYHA functional class III, n (%) | 14 (50.0) | 43 (53.1) | 29 (50.9) | 18 (54.5) | 0.98 |
| Ischemic heart disease, n (%) | 12 (42.9) | 31 (38.3) | 23 (40.4) | 11 (33.3) | 0.88 |
| Hypertension, n (%) | 23 (82.1) | 73 (90.1) | 45 (78.9) | 29 (87.9) | 0.29 |
| Stroke, n (%) | 4 (14.3) | 8 (9.9) | 2 (3.5) | 0 (0.0) | 0.08 |
| Pacemaker, n (%) | 0 (0.0) | 16 (19.8) | 14 (24.6) | 1 (3.0) | 0.003 |
| COPD, n (%) | 7 (25.0) | 13 (16.0) | 11 (19.3) | 7 (21.2) | 0.75 |
| Diabetes mellitus, n (%) | 17 (60.7) | 34 (42.0) | 21 (36.8) | 13 (39.4) | 0.20 |
| Chronic kidney disease, n (%) | 7 (25.0) | 49 (62.8) | 33 (58.9) | 16 (48.5) | 0.005 |
| Depression, n (%) | 12 (42.9) | 22 (27.2) | 15 (26.3) | 11 (33.3) | 0.38 |
| Current smoker, n (%) | 1 (3.6) | 10 (12.3) | 9 (15.8) | 11 (33.3) | 0.008 |
| Peripheral arterial disease, n (%) | 2 (7.1) | 8 (9.9) | 9 (15.8) | 7 (21.2) | 0.27 |
| Hyperlipidemia, n (%) | 22 (78.6) | 60 (74.1) | 40 (70.2) | 27 (81.8) | 0.63 |
| Medications | |||||
| ACE-I, n (%) | 11 (39.3) | 36 (44.4) | 25 (43.9) | 14 (42.4) | 0.97 |
| ARB, n (%) | 10 (35.7) | 26 (32.1) | 11 (19.3) | 6 (18.2) | 0.16 |
| Beta-blocker, n (%) | 20 (71.4) | 65 (80.2) | 46 (80.7) | 21 (63.6) | 0.20 |
| MRA, n (%) | 4 (14.3) | 5 (6.2) | 8 (14.0) | 5 (15.2) | 0.34 |
| Loop diuretic, n (%) | 14 (50.0) | 61 (75.3) | 55 (96.5) | 20 (60.6) | <0.001 |
| Thiazide diuretic, n (%) | 3 (10.7) | 12 (14.8) | 14 (24.6) | 7 (21.2) | 0.33 |
| Physical Examination | |||||
| Heart rate, bpm, mean±SD | 71.7 ±9.2 | 65.7 ±10.1 | 72.3 ±12.9 | 70.8 ±12.3 | 0.004 |
| Systolic blood pressure, mmHg, mean±SD | 123.0 ±11.7 | 135.2 ±18.6 | 122.0 ±13.0 | 127.1 ±17.2 | <0.001 |
| Diastolic blood pressure, mmHg, mean±SD | 71.4 ±10.0 | 69.7 ±10.3 | 70.3 ±10.7 | 68.7 ±11.3 | 0.77 |
| BMI, kg/m2, mean±SD | 36.5 ±7.5 | 33.0 ±6.3 | 33.0 ±6.3 | 35.9 ±8.1 | 0.03 |
| JVP >8cm, n (%) | 4 (14.8) | 38 (47.5) | 36 (65.5) | 11 (34.4) | <0.001 |
| Edema, n (%) | 0.23 | ||||
| None | 15 (53.6) | 29 (35.8) | 21 (36.8) | 17 (51.5) | |
| Trace | 9 (32.1) | 37 (45.7) | 19 (33.3) | 10 (30.3) | |
| Moderate | 4 (14.3) | 15 (18.5) | 17 (29.8) | 6 (18.2) | |
| Laboratory | |||||
| Sodium mEq/L, mean±SD | 139.8 ±2.4 | 139.6 ±3.7 | 139.3 ±2.8 | 140.2 ±2.6 | 0.68 |
| Potassium, mEq/L, mean±SD | 4.4 ±0.5 | 4.3 ±0.5 | 4.3 ±0.5 | 4.3 ±0.5 | 0.92 |
| Hemoglobin, mg/dL, mean±SD | 13.4 ±1.9 | 12.8 ±1.4 | 12.8 ±1.4 | 13.3 ±1.4 | 0.14 |
| Creatinine, mg/dL, median [IQR] | 0.88 [0.70–1.16] | 1.14 [0.86–1.54] | 1.15 [0.87–1.31] | 1.08 [0.84, 1.37] | 0.04 |
| GFR, mL/min/1.73m2, median [IQR] | 72.2 [58.8–88.5] | 52.3 [33.3, 66.2] | 50.5 [41.2–66.3] | 60.5 [40.0–80.9] | 0.001 |
AF: atrial fibrillation; BMI: body mass index; COPD: chronic obstructive lung disease; GFR: glomerular filtration rate; IQR = interquartile range; JVP: jugular venous pressure; LAP: left atrial pressure; NYHA: New York Heart Association
Biomarker Profile by LAP Category
There were significant differences in biomarker profiles across the spectrum of LAP categories (Figure 2). Biomarkers associated with (1) neurohormonal activation/myocardial necrosis (aldosterone, endothelin-1, NT-proBNP, troponin-I), (2) fibrosis (CITP, galectin 3), and (3) inflammation/renal dysfunction (cystatin-C, uric acid) differed significantly by LAP categories, in which levels were lowest in those with normal LAP (Figure 2). The AF and elevated LAP groups had the highest levels NT-proBNP, endothelin-1, troponin I, galectin-3, cystatin-C, and uric acid.
Figure 2. Baseline biomarker profiles of RELAX participants by LAP category.
Biomarkers of (A) neurohormonal activation/myocardial necrosis, (B) myocardial fibrosis, and (C) inflammation/renal dysfunction are depicted. Bars signify median and error bars indicate interquartile range; P-values reflect trend across all LAP categories. *indicates a significant (p<0.05) difference compared with normal LAP. AF: atrial fibrillation; CITP: carboxy-terminal telopeptide of type I collagen; hs-CRP: high-sensitivity C-reactive protein; LAP = left atrial pressure.
Baseline Cardiac Imaging Parameters
Echocardiographic diastolic parameters differed between groups (medial e’, lateral e’, LAVI, medial E/e’, PASP), as did stroke volume (Table 2). No differences in LVEF or LV end diastolic diameter were noted by LAP group. Conversely, indexed LV end diastolic and systolic volumes by CMR differed between groups, as those with normal LAP had the smallest LV volumes.
Table 2.
Baseline Cardiac Structure and Function by LAP Category.
| Normal LAP (n=28) |
Elevated LAP (n=81) |
AF at echocardiogram (n=57) |
Indeterminate LAP (n=33) |
p-value | |
|---|---|---|---|---|---|
| Echocardiogram (n=199) | |||||
| Ejection fraction, %, mean±SD | 62.8 ±6.0 | 61.1 ±7.5 | 61.0 ±6.2 | 62.6 ±7.1 | 0.49 |
| Left-ventricular end-diastolic diameter, cm, mean±SD | 4.73 ±0.47 | 4.65 ±0.63 | 4.59 ±0.64 | 4.81 ±0.79 | 0.52 |
| Stroke volume, mL, median (IQR) | 82.5 [66.0–96.4] | 81.6 [65.8–90.1] | 64.6 [54.0–84.0] | 84.2 [68.7, 105.8] | 0.001 |
| Medial e’, m/s, mean±SD | 0.07 ±0.02 | 0.06 ±0.02 | 0.07 ±0.02 | 0.06 ±0.02 | <0.001 |
| Lateral e’, m/s, mean±SD | 0.09 ±0.03 | 0.07 ±0.03 | 0.10 ±0.03 | 0.08 ±0.03 | <0.001 |
| Left atrial volume index, mL/m2, median [IQR] | 30.3 [25.6–33.1] | 44.7 [40.0–55.3] | 59.4 [44.1–70.8] | 40.5 [34.6–52.6] | <0.001 |
| Medial E/e’, median [IQR] | 10.6 [9.8–14.0] | 21.7 [15.7–27.5] | 14.3 [11.8–20.0] | 14.0 [10.6–18.3] | <0.001 |
| Pulmonary artery systolic pressure, mmHg, mean±SD | 38.8 ±16.5 | 53.4 ±13.8 | 53.2 ±15.6 | 51.4 ±23.9 | 0.008 |
| CMR (n= 110) | |||||
| Left ventricular end-systolic volume index, mL/m2, mean±SD | 17.9 ±6.6 | 21.0 ±8.8 | 31.9 ±13.5 | 22.3 ±9.9 | 0.008 |
| Left ventricular end-diastolic volume index, mL/m2, median [IQR] | 46.3 [41.1–56.9] | 57.4 [48.8–66.8] | 66.2 [54.2–87.2] | 57.9 [50.4–68.8] | 0.007 |
CMR: cardiac magnetic resonance; IQR: interquartile range
Associations of LAP Categories with Peak VO2 and Changes in NT-proBNP
Baseline CPET parameters stratified by LAP category are displayed in Table 3. On unadjusted analysis, peak VO2 varied significantly by LAP group, in which levels were lowest among those with elevated LAP and AF at the time of echocardiography. There were no differences in chronotropic index and duration of exercise by LAP category.
Table 3.
Baseline Cardiopulmonary Exercise Test Parameters by LAP Category.
| Normal LAP (n=28) |
Elevated LAP (n=81) |
AF at echocardiogram (n=57) |
Indeterminate LAP (n=33) |
p-value | |
|---|---|---|---|---|---|
| Rest | |||||
| Heart rate, bpm, mean±SD | 73.1 ±11.7 | 66.0 ±11.2 | 74.0 ±13.9 | 68.4 ±13.6 | 0.002 |
| Oxygen saturation, %, mean±SD | 96.4 ±2.5 | 96.9 ±2.3 | 96.8 ±2.9 | 96.0 ±3.1 | 0.36 |
| Systolic blood pressure, mmHg, mean±SD | 124.2 ±22.1 | 134.0 ±21.2 | 118.1 ±17.1 | 121.4 ±20.7 | <0.001 |
| Diastolic blood pressure, mmHg, mean±SD | 69.6 ±10.5 | 71.3±11.9 | 70.5 ±10.7 | 70.8±10.1 | 0.92 |
| VO2, mL/kg/min, mean±SD | 3.0 ±1.2 | 2.9 ±0.6 | 3.2 ±0.6 | 2.9 ±0.7 | 0.17 |
| Pulse pressure, mmHg, mean±SD | 54.6 ±16.1 | 62.7 ±19.2 | 47.6 ±13.6 | 50.6 ±15.2 | <0.001 |
| Peak Exercise | |||||
| Heart rate, bpm, mean±SD | 117.9 ±21.3 | 105.1 ±23.5 | 112.5 ±28.8 | 113.0 ±19.2 | 0.07 |
| Oxygen saturation, %, mean±SD | 95.8 ±4.1 | 95.5 ±3.2 | 95.0 ±4.1 | 94.6 ±3.5 | 0.54 |
| Systolic blood pressure, mmHg, mean±SD | 168.8 ±37.5 | 161.4±25.8 | 134.8±29.7 | 158.1±28.4 | <0.001 |
| Diastolic blood pressure, mmHg, mean±SD | 77.0 ±14.9 | 73.3 ±14.8 | 68.8 ±14.2 | 75.1 ±15.8 | 0.08 |
| Peak VO2, mL/kg/min, mean±SD | 14.0 ±3.3 | 11.9 ±2.6 | 11.8 ±3.1 | 13.5 ±3.3 | 0.001 |
| Peak pulse pressure, mmHg, mean±SD | 91.7 ±28.3 | 88.1 ±23.4 | 66.1 ±27.7 | 83.0 ±21.4 | <0.001 |
| Exercise duration, min, mean±SD | 10.5 ±3.4 | 9.5 ±2.6 | 9.6 ±3.1 | 10.6 ±3.2 | 0.19 |
| Chronotropic index, mean±SD | 0.54 ±0.24 | 0.47 ±0.25 | 0.54 ±0.37 | 0.49 ±0.18 | 0.46 |
VO2: oxygen consumption
The multivariable-adjusted associations of LAP groups with peak VO2 are shown in Table 4. Compared with normal LAP, both elevated LAP and AF groups were associated with a lower baseline peak VO2 in crude models. After full covariate adjustment, both elevated LAP and AF were independently associated with lower baseline peak VO2 compared with normal LAP. Furthermore, both elevated LAP and AF were independently associated with a greater reduction in peak VO2 at from baseline to 24 weeks compared with the normal LAP group after full covariate adjustment, including baseline peak VO2 levels. There was no significant association of indeterminate LAP with baseline peak VO2, but there was a significant association with reduction in peak VO2 from baseline to 24 weeks compared with the normal LAP group (Table 4).
Table 4.
Association of LAP Categories with Peak VO2 at Baseline and after 24 Weeks.
| Baseline Peak VO2 | Change in Peak VO2* | |||||
|---|---|---|---|---|---|---|
| N | β-coefficient (95% CI) | p-value | N | β-coefficient (95% CI) | p-value | |
| Model 1† | 198 | 173 | ||||
| Normal LAP | [Referent] | -- | [Referent] | -- | ||
| Elevated LAP | −2.14 (−3.42, −0.86) | 0.001 | −1.47 (−2.46, −0.48) | 0.001 | ||
| AF | −2.49 (−3.85, −1.13) | <0.001 | −1.19 (−2.26, −0.12) | 0.03 | ||
| Indeterminate LAP | −0.66 (−2.16, 0.84) | 0.39 | −1.12 (−2.23, −0.004) | 0.049 | ||
| Model 2‡ | 196 | 171 | ||||
| Normal LAP | [Referent] | -- | [Referent] | -- | ||
| Elevated LAP | −1.18 (−2.22, −0.14) | 0.03 | −1.55 (−2.59, −0.51) | 0.004 | ||
| AF | −1.81 (−2.94, −0.68) | 0.002 | −1.33 (−2.49, −0.17) | 0.03 | ||
| Indeterminate LAP | −0.84 (−2.02, 0.34) | 0.16 | −1.35 (−2.51, −0.19) | 0.02 | ||
The dependent variable is change in peak VO2 over 24 weeks (peak VO2 (24 weeks) - peak VO2 (baseline))
Adjusted for mode of exercise (for both models). Additionally adjusted for baseline peak VO2 in change in peak VO2 models.
Adjusted for Model 1 covariates + age, sex, LV ejection fraction, diabetes mellitus, chronotropic index, hypertension, and hemoglobin. Additionally adjusted for treatment arm in change in peak VO2 models.
AF: atrial fibrillation; LAP: left atrial pressure; peak VO2: maximum rate of oxygen consumption
The association of LAP category with change in NT-proBNP from baseline to 24 weeks is shown in Table 5. After full covariate adjustment, both elevated LAP and AF were independently associated with increase in NT-proBNP at 24 weeks compared with normal LAP. There was no significant association between indeterminate LAP and change in NT-proBNP compared with the normal LAP group (Table 5). Compared with normal LAP, elevated LAP was associated with increase in endothelin-1 and AF was associated with increase in cystatin-C at 24 weeks (Supplemental Table 2).
Table 5.
Association of LAP Categories with Change in NT-proBNP
| N | β-coefficient (95% CI)* | p-value | |
|---|---|---|---|
| Model 1† | 175 | ||
| Normal LAP [Referent] | -- | -- | |
| Elevated LAP | 443.0 (147.1, 738.8) | 0.004 | |
| AF | 364.7 (40.6, 688.8) | 0.03 | |
| Indeterminate LAP | 251.6 (−81.6, 584.7) | 0.14 | |
| Model 2‡ | 174 | ||
| Normal LAP [Referent] | -- | -- | |
| Elevated LAP | 489.1 (185.8, 792.4) | 0.002 | |
| AF | 396.6 (66.7, 726.6) | 0.02 | |
| Indeterminate LAP | 329.9 (−0.54, 660.2) | 0.051 |
The dependent variable is change in NT-proBNP over 24 weeks (NT-proBNP(24 weeks) - NT-proBNP(baseline))
Adjusted for baseline NT-proBNP
Adjusted for Model 1 covariates + age, sex, diabetes, ejection fraction, treatment arm, hypertension, body mass index, and glomerular filtration rate.
AF: atrial fibrillation; LAP: left atrial pressure; NT-proBNP: N-terminal prohormone of brain natriuretic peptide
In a sensitivity analysis among participants in AF, meeting 1 or 2 elevated LAP parameters (E/e’ >11, TR velocity >2.8m/s; compared with meeting neither parameter) was not independently associated with baseline peak VO2, change in peak VO2, or change in NT-proBNP after covariate adjustment (Supplemental Tables 3 and 4).
DISCUSSION
In this analysis of a chronic HFpEF cohort, we determined non-invasive LAP categories in accordance with the 2016 ASE/EACVI guidelines and described the associations of baseline LAP categories with cardiovascular biomarkers, cardiorespiratory fitness, and their changes over time. In the RELAX trial, individuals with elevated LAP or AF at echocardiogram shared similar baseline clinical profiles, highlighted by renal dysfunction and poor exercise capacity, which were distinct from those with normal or indeterminate LAP. Additionally, elevated LAP and AF groups had severe derangements in biomarkers of neurohormonal activation, myocardial injury, and renal impairment. Finally, we demonstrated that elevated LAP, indeterminate LAP, and AF at echocardiogram were independently associated with reduction in exercise capacity over time. In aggregate, our findings suggest that (1) the 2016 societal guidelines appropriately identify a high-risk congested HFpEF population, and (2) the presence of concomitant AF additionally represents an advanced and clinically distinct HFpEF phenotype.
Our analysis adds to the evolving body of evidence that supports the use of clinical echocardiography to stratify risk among individuals with HFpEF.14, 21 Indeed, echocardiography is commonly performed among patients with HFpEF for a variety of clinical reasons, and current guidelines recommend reporting of LAP among patients with myocardial disease. However, while prior analyses in HFpEF cohorts have demonstrated an association between invasively determined left-sided filling pressures and poor outcomes, the association of non-invasively derived filling pressures with change in exercise capacity over time in HFpEF is less clear. In our study that utilized the most recent ASE/EACVI guideline definitions, elevated LAP was independently associated with both baseline peak VO2 and reduction in peak VO2 over time. These findings add to previous investigations which have demonstrated that E/e’ is associated with lower baseline exercise capacity and that LA dysfunction is associated with worse HF symptoms.22, 23 Echocardiographic LAP assessment incorporates multiple hemodynamic measurements and may be sensitive to acute changes, thus providing real-time congestion status. It may be a useful adjunct to LAVI alone, as LAVI reflects anatomic remodeling and may be a sign of more chronic elevation of LAP.
While LAP was assessed on resting echocardiograms, our findings are consistent with invasive studies that have shown an association between exercise pulmonary capillary wedge pressure and peak VO2.24 Poor exercise capacity represents a key clinical and pathophysiological characteristic of HFpEF that has been strongly associated with worse quality of life and adverse long-term clinical outcomes.24–26 The ability to simply identify those at risk for significant reductions in exercise capacity through standardized, guideline-recommended echocardiographic protocols could meaningfully inform clinical decision making and patient education.27, 28
We note that the presence of AF is ultimately associated with a high-risk clinical and biomarker profile that is similar to those patients with elevated LAP adding to prior observations from RELAX showing an association between AF and worse baseline exercise capacity.29 Indeed, the presence of AF at echocardiogram was independently associated with reduction of exercise capacity and increase in NT-proBNP over time, similar to those with guideline definition-based elevated LAP. Notably, sensitivity analyses grouping patients with AF by the presence of additional echocardiographic markers of elevated LAP (E/e’>11, TR velocity >2.8m/s), did not identify AF subgroups at particularly increased risk, which may be driven by the small sample size.
Due to technical challenges and inherent limitations, it is often difficult to estimate LAP in accordance with current guidelines. The relevance of indeterminate LV filling pressures is not clear because a variety of clinical reasons may account for its presence. Our findings ultimately reveal the heterogeneous risk-profile among the substantial group of individuals who may have indeterminate filling pressures on echocardiogram.30, 31 In fact, indeterminate LAP carried a similar clinical/biomarker profile as normal LAP but was associated with a significant decline in exercise capacity at 24 weeks. This finding is consistent with other studies which have demonstrated that indeterminate LAP by the 2016 ASE/EACVI guidelines is associated with poor outcomes. As such, the 2016 ASE/EACVI algorithm for LAP assessment has prognostic utility even in the setting of indeterminate LA pressures. Those patients with discrepant indices should not be viewed as prognostically similar to those who have available indices that are subsequently categorized as normal LAP. Given the diversity of individuals with indeterminate LAP, further investigations are required to understand the mechanisms that may underlie this association.15, 32, 33
The clinical similarity among individuals with AF or elevated-LAP may be driven by similar degree of LA mechanical failure among these 2 groups. Given poor LA reservoir and contractile function in the setting of AF, such patients may particularly benefit from LA-specific decongestion (i.e., inter-atrial shunt device therapy). Patients with elevated LAP or AF had higher baseline levels of aldosterone, endothelin-1, NT-proBNP, and troponin-I, indicating a more advanced HF phenotype characterized by more severe neurohormonal dysregulation. We also note that HFpEF patients with elevated LAP or AF at echocardiogram had not only higher baseline NT-proBNP levels, but also greater increases in NT-proBNP levels after 24 weeks compared with those with normal LAP. Indeed, observational studies of HFpEF cohorts have shown that increasing NT-proBNP levels are associated with poor clinical outcomes and increased congestion.34–36 Our findings suggest a cycle of worsening congestion among those with either elevated filling pressures at baseline or AF, which may be due to impaired LA mechanical function.
Taken together, these results demonstrate the ability of the 2016 guidelines to identify a congested HFpEF phenotype at particular risk for deterioration. The simple categorization offered by the guidelines provides a clinically useful tool by which HFpEF patients with a congested phenotype may be readily identified and offered placement of wireless pulmonary artery pressure monitoring or targeted therapies aimed at decongestion (e.g. sodium-glucose cotransporter-2 inhibitors or angiotensin receptor-neprilysin inhibitors), and/or reduction in LAP (e.g. interatrial shunt device). Future clinical trials may also be able to take advantage of guideline-directed categorization of HFpEF patients to enrich their cohorts and test for the efficacy of novel treatments among patients with a shared phenotype.
Our study has limitations. This study was a secondary analysis of the RELAX trial and was limited by the inclusion criteria applied to participants. Thus, our findings may not be generalizable to other populations of HFpEF, as RELAX represented a particularly sick cohort with high comorbidity burden and poor exercise capacity at baseline. While the RELAX study population was relatively small, it represents a well-phenotyped cohort with comprehensive biomarker assessment, cardiac imaging, and exercise data. The trial protocol did not include invasive hemodynamic testing and we were thus unable to compare non-invasively derived LAP categories by 2016 guidelines with invasive LAP. However, the primary aim of this study was to understand the clinical value of this contemporary non-invasive algorithm in HFpEF. While Doppler measurements were not available for all RELAX participants, we were able to characterize >90% of participants into 1 of the 4 pre-specified categories. Indices of LV mass and right ventricular size and function were not available in the current dataset. Valsalva maneuver was not part of the RELAX echocardiography protocol and pulmonary venous Doppler patterns were not readily available in the majority of the final analytic cohort (n=104, 52%), and were thus not included as part of the LAP assessment. It is possible that participants in the indeterminate category may have been reclassified using these additional measures, which are recommended in the ASE guidelines. While moderate to severe mitral annular calcification (MAC) was not a strict exclusion criteria of the RELAX trial, exclusion of individuals with >mild mitral stenosis and >moderate mitral regurgitation likely limited the prevalence of moderate to severe MAC in the RELAX cohort. Our analysis showed that those with AF and those with elevated LAP had increased NT-proBNP levels at baseline as well as after 24 weeks (adjusting for baseline levels). While it has been shown that there is a relationship between higher NT-proBNP levels and poor clinical outcomes among HFpEF patients without AF, this relationship is somewhat less straightforward in those with AF.37 Furthermore, few studies have analyzed the clinical significance of NT-proBNP trajectories in HFpEF patients with or without AF, and trials which have used NT-proBNP levels to guide therapy in HF have included few HFpEF patients.38, 39 Future studies are needed to investigate whether increases in NT-proBNP levels among HFpEF patients with elevated LAP or AF relate to poor clinical outcomes and whether therapeutics aimed at decongestion are able to improve these patients’ overall trajectories.
CONCLUSION
In a cohort of chronic HFpEF patients, elevated LAP as defined by the 2016 ASE/EACVI guidelines and AF were associated with clinical and biochemical signs of advanced HFpEF. In contrast to those with normal LAP, individuals in AF at echocardiogram shared many high-risk characteristics as those with elevated LAP. Elevated LAP, indeterminate LAP, and AF were also independently associated with worse exercise capacity over time. The 2016 ASE/EACVI guidelines for LAP assessment, in conjunction with identification of comorbid AF, offer clinical utility in identifying a congested HFpEF phenotype within the vulnerable HFpEF population.
Supplementary Material
Highlights.
The 2016 ASE/EACVI guidelines allow a simple evaluation of LAP in HFpEF patients
HFpEF patients with a high-risk congested phenotype can be identified using the 2016 guidelines
In HFpEF, elevated LAP is independently associated with impaired exercise capacity, elevations in key cardiac biomarkers and clinical decline
HFpEF patients in atrial fibrillation have similar characteristics and prognosis as those with elevated LAP
Acknowledgements
Funding:
Research reported in this manuscript was supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health under award number U10 HL084904 and award numbers U10 HL110297, U10 HL110342, U10 HL110309, U10 HL110262, U10 HL110338, U10 HL110312, U10 HL110302, U10 HL110336, and U10 HL110337. Dr. Ravi Patel is supported by the National Institutes of Health’s National Center for Advancing Translational Sciences (KL2TR001424). Dr. Leah Rethy received funding from the Sarnoff Cardiovascular Research Foundation (2018–2019).
The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Disclosures
Dr. Sanjiv J. Shah was supported by National Institutes of Health grants R01 HL105755, HL127028, R01 HL140731; and American Heart Association grants #16SFRN28780016 and #15CVGPSD27260148; and has received research grants from Actelion, AstraZeneca, Corvia, and Novartis; and consulting fees from Actelion, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Cardiora, Eisai, Ironwood, Merck, Novartis, Sanofi, Tenax, and United Therapeutics. All remaining authors have nothing to disclose.
Footnotes
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