This randomized clinical trial investigates the effect of dapagliflozin on right ventricular performance and vascular load during exertion in heart failure with preserved ejection fraction (HFpEF).
Key Points
Question
What is the effect of dapagliflozin on right ventricular performance and vascular load during exertion in heart failure with preserved ejection fraction (HFpEF)?
Findings
In this randomized clinical trial including 37 participants, dapagliflozin improved pulsatile pulmonary vascular load and right ventricular function during exercise with significant improvement in pulmonary artery (PA) compliance, PA elastance, PA pulsatility index, and right ventricular–PA coupling. These changes were correlated with pulmonary capillary wedge pressure reduction, demonstrating the benefit of PCWP reduction on pulsatile right ventricular afterload in HFpEF.
Meaning
Dapagliflozin improves right ventricular pulsatile afterload and myocardial performance during exercise, findings that are related to PCWP reduction.
Abstract
Importance
Increases in pulmonary capillary wedge pressure (PCWP) during exercise reduce pulmonary artery (PA) compliance, increase pulsatile right ventricular (RV) afterload, and impair RV-PA coupling in patients with heart failure with preserved ejection fraction (HFpEF). The effects of the sodium-glucose cotransporter 2 (SGLT2) inhibitor dapagliflozin on pulmonary vascular properties and RV-PA coupling are unknown.
Objective
To test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.
Design, Setting, and Participants
Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) randomized clinical trial demonstrated improvement in PCWP at rest and exercise over 24 weeks with dapagliflozin compared with placebo with participants recruited between February 2021 and May 2022. This secondary analysis evaluates the effects of dapagliflozin on pulsatile pulmonary vascular load and RV-PA coupling using simultaneous echocardiography and high-fidelity invasive hemodynamic testing with exercise. This was a single-center study including patients with hemodynamically confirmed HFpEF with exercise PCWP of 25 mm Hg or greater.
Interventions
Dapagliflozin or placebo for 24 weeks.
Main Outcomes and Measures
Pulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s′]/PA mean) during rest and exercise.
Results
Among 37 randomized participants (mean [SD] age, 67.4 [8.5] years; 25 female [65%]; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), there was no effect of dapagliflozin on PA loading or RV-PA interaction at rest. However, with exercise, dapagliflozin improved PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; −0.17 mm Hg/mL; 95% CI, −0.28 to −0.07 mm Hg/mL; P = .001). RV function during exercise improved, with increase in PA pulsatility index (0.33; 95% CI, 0.08-0.59; P = .01) and increase in exercise RV s′ indexed to PA pressure (0.09 cm·s−1/mm Hg; 95% CI, 0.02-0.16 cm·s−1/mm Hg; P = .01). Improvements in pulsatile RV load and RV-PA coupling were correlated with reduction in right atrial (RA) pressure (PA elastance Pearson r = 0.55; P =.008; RV s′/PA elastance Pearson r = −0.60; P =.002) and PCWP (PA elastance Pearson r = 0.58; P <.001; RV s′/PA elastance Pearson r = −0.47; P = .02). Dapagliflozin increased resistance-compliance time (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [−0.02 to 0.05] seconds; P =.046), resulting in higher PA compliance for any exercise pulmonary vascular resistance.
Conclusions and Relevance
Results of this randomized clinical trial reveal that treatment with dapagliflozin for 24 weeks reduced pulsatile pulmonary vascular load and enhanced dynamic RV-PA interaction during exercise in patients with HFpEF, findings that are related to the magnitude of PCWP reduction. Benefits on dynamic right ventricular–pulmonary vascular coupling may partially explain the benefits of SGLT2 inhibitors in HFpEF.
Trial Registration
ClinicalTrials.gov Identifier: NCT04730947
Introduction
Sodium-glucose cotransporter-2 (SGLT2) inhibitors improve clinical outcomes and health status in patients with heart failure (HF) with preserved ejection fraction (HFpEF).1,2,3 The mechanisms of benefit are protean and widespread but remain incompletely understood. Dapagliflozin reduces rest and exercise pulmonary capillary wedge pressure (PCWP),4 a key determinant of symptoms5,6,7 that is associated with increased risk of hospitalization.8 Elevation in PCWP causes pulmonary hypertension and lung vascular remodeling,9 ultimately driving progression to right ventricular (RV) failure10 and its attendant increases in mortality.11,12 However, even among patients with HFpEF and no overt RV failure at rest, limitations in RV and pulmonary artery (PA) vascular interactions are present during exercise (dynamic RV-PA uncoupling),13,14 which are important targets to prevent disease progression.
The chronic effects of PCWP reduction on the pulmonary vasculature and RV-PA coupling in HFpEF are unknown. Increases in PCWP during exercise functionally stiffen the pulmonary circulation, such that the capacity of the lungs to accept each stroke volume is diminished, leading to greater increase in systolic pressure and greater pulsatile loading on the RV.15 PCWP is universally abnormal during exercise in HFpEF, suggesting that therapies improving exercise PCWP (such as dapagliflozin) may have greater effects on pulsatile load and RV-PA coupling.8 There may also be direct vascular effects. In animal models, SGLT2 inhibitors reduce mitochondrial oxidative stress in vascular smooth muscle, mitigating exercise pulmonary hypertension.16 These data led us to hypothesize that dapagliflozin could improve pulsatile pulmonary vascular load and RV-PA coupling during exercise in patients with HFpEF.
Methods
Study Overview
The Evaluation of the Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction (CAMEO-DAPA) trial was an investigator-initiated, prospective, randomized clinical trial of dapagliflozin, 10 mg, once daily compared with placebo for 24 weeks in patients with HFpEF. The primary results have been published (trial protocol and statistical analysis plan are available in Supplement 1 and Supplement 2, respectively).4 The Mayo Clinic institutional review board approved the study, and all participants provided written informed consent. Investigators, patients, treating physicians, and outcome assessors were blinded to treatment assignment. The current analysis was a planned secondary analysis of the trial data evaluating RV-PA coupling relationships. The Consolidated Standards of Reporting Trials (CONSORT) reporting guidelines were followed.
Study Patients
Ambulatory patients with a diagnosis of HFpEF were eligible if they were 18 years or older, with symptoms of exertional dyspnea (New York Heart Association [NYHA] class II-III) and left ventricular EF of 50% or greater. Patients were required to display elevated PCWP during exercise (≥25 mm Hg) at the baseline invasive exercise test after consent. Patients not meeting this criterion were considered screen failures. Other exclusion criteria included type 1 diabetes or type 2 diabetes with poor control (hemoglobin A1c ≥10%), primary cardiomyopathy or pericardial disease, significant left-sided valvular heart disease, dyspnea primarily due to lung disease or ischemic heart disease, and severe anemia, liver, or kidney disease (estimated glomerular filtration rate <30). This study was inclusive of all racial participation with information on race collected based on self-report. Participants self-identified with the following races: American Indian and White. Information on race was collected to describe baseline characteristics of the study population.
Study Design
Following consent, participants underwent right-sided heart catheterization at rest and with exercise to volitional exhaustion.4 Echocardiography was performed simultaneously with catheterization at rest and during exercise by a cardiologist. Patients fulfilling the hemodynamic eligibility criteria were randomized to treatment with dapagliflozin, 10 mg, once daily or matching placebo. Video or telephone visits (based upon patient preference) were conducted at 2 days, 1 week, 2 weeks, and then every 4 weeks for the 24-week study duration to assess for adverse events and encourage adherence with study medication. At 24 weeks, participants again underwent rest/exercise right-sided heart catheterization with simultaneous rest/exercise echocardiography. A final follow-up telephone/video visit was carried out 1 week after the 24-week visit.
Outcome Measures
Pulmonary vascular hemodynamics were measured using a high-fidelity, solid-state 2F micromanometer advanced through a 7F balloon-tipped catheter as we have previously described.17,18,19 Pressures were taken at end expiration and represent the mean of 3 replicate measurements during rest and exercise. This allowed precise measurement of phasic PA pressures in systole and diastole during rest and exercise without whip and ringing artifact that is often present using fluid-filled catheters (eFigure 1 in Supplement 3). Oxygen consumption (VO2) was measured (MGC Diagnostics) using expired gas analysis at rest and during exercise. Arterial and mixed venous (PA) blood samples were obtained at rest and during each stage of exercise to measure O2 content. Cardiac output was determined using the direct Fick method as the quotient of VO2 and the difference of arterial and mixed venous O2 content.
Pulmonary Vascular Load and RV-PA Coupling Indices
Pulmonary vascular load was calculated using well-established physiological modeling approaches to estimate both steady-state and pulsatile pulmonary vascular load (eFigures 2 and 3 in Supplement 3). Estimation of nonpulsatile load in the pulmonary circulation assumes steady continuous flow of cardiac output, without accounting for the pulsatile nature induced by ejection of each stroke volume into the PA. The opposition to flow in this context is defined as the pulmonary vascular resistance (PVR), calculated as the pressure drop across the lungs (mean PA pressure – PCWP) divided by cardiac output. A PVR of 2 Wood units or greater is considered abnormal.20 Application of PVR oversimplifies RV afterload because ejection into the PA is not continuous but rather occurs in a pulsatile manner. Pulsatile pulmonary vascular load was measured by PA compliance (stroke volume/[PA systolic – PA diastolic pressure]). This can be conceptualized as the ability of the lung vasculature to accept the phasic inflow of stroke volume without excessive rise in pressure (eFigure 3 in Supplement 3). PA elastance (effective stiffness) is a lumped measure of net load (pulsatile and steady), estimated by PA systolic pressure/stroke volume, as previously described.7,17 To account for the nonlinear relationship between PVR and PA compliance, we created PVR-PA resistance-compliance curves (R-C) curves and computed R-C time as the product of PVR and PA compliance expressed in seconds. The R-C time reflects the time constant for monoexponential decay in PA pressure during diastole. With increased PA pulsatile load (such as with PCWP elevation), there is more rapid PA pressure decay during diastole with a shorter R-C time.15 Due to the inverse hyperbolic relationship between PVR and PA compliance, therapeutic effects in those with HFpEF and early pulmonary vascular disease (only mild PVR elevation) are best captured by changes in PA compliance as opposed to PVR (eFigure 4 in Supplement 3).21
RV function at rest was assessed by RV fractional area change (FAC), tricuspid annular plane systolic excursion (TAPSE), and systolic tricuspid annular velocities by tissue Doppler echocardiography (s′). RV function during exercise was assessed using only RV s′, which is most feasible to obtain during supine invasive exercise studies during the short interval available for dynamic imaging in our experience.13,17 RV s′ is similar to TAPSE in that it reflects the maximal velocity of annular motion rather than the maximal displacement of the annulus (as with TAPSE). RV systolic function was independently assessed by the PA pulsatility index (PAPI), calculated as (PA systolic − PA diastolic pressure)/RA pressure, which has recently been shown to directly reflect RV sarcomere contractile function by Hsu and colleauges.22 To account for the well-known afterload sensitivity of right ventricular systolic performance,11,13,17,22,23,24 measures of RV-PA coupling were calculated during rest and exercise using echocardiographic measures of RV function (RV s′) indexed to invasive mean PA pressure or PA elastance as measures of steady and total pulmonary vascular load, respectively. This is directly analogous to prior studies using TAPSE indexed to pressure, taking RV s′ velocity in place of systolic excursion.24,25 The resultant measures of RV-PA coupling allowed estimation of load-independent RV myocardial performance after adjusting for change in RV afterload during rest and exercise. An improvement in RV-PA coupling is reflected by increased RV contractile performance for a given PA afterload (higher RV s′/mean PA pressure), whereas RV-PA uncoupling is associated with worse RV contractile performance for a given PA afterload (lower RVs′/mean PA pressure).
Statistical Analysis
To account for the paired nature of comparisons, the difference between corresponding rest and exercise hemodynamics and cardiac function indices before and at end of study were calculated by subtracting 6-month (end of study) values from baseline values, and these differences were compared by unpaired t test between dapagliflozin and placebo groups. Linear regression analyses were used to assess relationships between changes in variables of interest. All P values are 2-sided. P < .05 was taken as statistically significant, and no corrections for multiple testing have been added to any reported P values or CIs. Analyses were performed using JMP, version 14.1.0 (JMP Statistical Discovery).
Results
Study Participants
As previously described,4 a total of 43 patients consented between February 2021 and May 2022, with 38 patients receiving treatment with the study drug, and 37 participants (mean [SD] age, 67.4 (8.5) years; 25 female [65%]; 12 male [35%]; 2 American Indian [5%]; 35 White [95%]) completing the study, who were included in the present analysis (eFigure 5 in Supplement 3). Patients had demographics consistent with HFpEF in the community being, on average, older and obese (27 of 38 patients [71%] having obesity; mean [SD] body mass index, 34.9 [6.7]; calculated as weight in kilograms divided by height in meters squared), with a third having atrial fibrillation (Table 1).
Table 1. Baseline Characteristics.
| Characteristic | Placebo (n = 17) | Dapagliflozin (n = 21) |
|---|---|---|
| Age, mean (SD), y | 67 (9) | 67 (9) |
| Sex, No. (%) | ||
| Female | 11 (65) | 14 (67) |
| Male | 6 (35) | 7 (33) |
| BMI, mean (SD)a | 34.5 (5.7) | 35.0 (7.2) |
| Obesity (BMI ≥30), No. (%) | 12 (71) | 15 (71) |
| Atrial fibrillation, No. (%) | 6 (35) | 7 (33) |
| NYHA functional class, No. (%)b | ||
| Class II | 5 (29) | 7 (33) |
| Class III | 12 (71) | 14 (67) |
| Left ventricular ejection fraction, mean (SD), % | 63 (6) | 61 (6) |
| NT-proBNP, median (IQR), pg/mL | 118 (76-226) | 235 (102-394) |
| Diuretic, No. (%) | 12 (71) | 12 (57) |
| Diuretic dose furosemide equivalent, mean (SD), mg | 69 (62) | 41 (57) |
| ACEi/ARB/ARNI, No. (%) | 4 (24) | 6 (29) |
| β-Blocker, No. (%) | 9 (53) | 6 (29) |
| Mineralocorticoid antagonist, No. (%) | 6 (35) | 7 (33) |
Abbreviations: ACEi, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; ARNI, angiotensin receptor blocker/neprilysin antagonist; BMI, body mass index; NT-proBNP, N-terminal pro–brain natriuretic peptide; NYHA, New York Heart Association.
SI conversion factor: To convert NT-proBNP to nanograms per liter, multiply by 1.
Calculated as weight in kilograms divided by height in meters squared.
Higher class indicates more severe heart failure severity.
Baseline Hemodynamics and Pulmonary Vascular Function
Rest and exercise hemodynamics along with echocardiography measures of RV function and RV-PA coupling for both groups before randomization are presented in Table 2. Pulmonary hypertension was common, with 31 participants (84%) having a mean PA pressure of 20 mm Hg or greater and 15 participants (43%) having at least mild pulmonary vascular disease evidenced by PVR of 2 or more Wood units (Table 2). PA compliance and elastance worsened in both groups from rest to exercise, with evidence of RV-PA uncoupling during exertion with a decrease in RV systolic function for any PA load during exercise.
Table 2. Right Ventricular (RV) Function, Pulmonary Vascular Load, and RV–Pulmonary Artery (PA) Coupling at Baseline.
| Heart function parameter | Rest | Exercise | ||
|---|---|---|---|---|
| Placebo (n = 16) | Dapagliflozin (n = 21) | Placebo (n = 16) | Dapagliflozin (n = 21) | |
| Pressure/flow, No. (%) | ||||
| PA systolic, mm Hg (n = 37) | 36.8 (10.7) | 36.4 (8.6) | 65.5 (15.0) | 65.6 (14.9) |
| PA mean, mm Hg (n = 37) | 26.1 (7.9) | 26.5 (6.9) | 48.7 (10.6) | 49.9 (10.2) |
| PCWP mean, mm Hg (n = 37) | 15.7 (4.7) | 16.0 (3.9) | 31.3 (5.0) | 33.5 (7.5) |
| RA mean, mm Hg (n = 37) | 9.4 (3.3) | 10.4 (2.4) | 17.9 (6.3) | 19.9 (7.0) |
| CO, L/min (n = 35) | 5.6 (1.1) | 5.3 (1.9) | 10.3 (1.9) | 10.2 (3.1) |
| SV, mL (n = 35) | 79.4 (18.7) | 74.9 (26.0) | 93.7 (20.1) | 84.4 (24.4) |
| Pulmonary vascular load, mean (SD) | ||||
| PVR, Wood units (n = 35) | 1.9 (0.9) | 2.3 (1.0) | 1.8 (1.1) | 1.7 (0.7) |
| PAC, mL/mm Hg (n = 35) | 4.7 (1.6) | 4.5 (1.7) | 3.4 (1.3) | 3.3 (1.3) |
| PA Ea, mm Hg/mL (n = 35) | 0.5 (0.2) | 0.6 (0.2) | 0.7 (0.3) | 0.9 (0.4) |
| Pulmonary vascular disease severity (rest), No. (%) | ||||
| Mean PA ≥20 mm Hg | 13 (81) | 18 (86) | NA | NA |
| Mean PA ≥25 mm Hg | 8 (50) | 11 (52) | NA | NA |
| PVR ≥2 Wood units | 6 (38) | 9 (47) | NA | NA |
| PVR ≥3 Wood units | 3 (19) | 3 (16) | NA | NA |
| IpC PH HFpEF | 4 (25) | 4 (20) | NA | NA |
| Cpc PH HFpEF | 6 (38) | 8 (40) | NA | NA |
| Right ventricular function, mean (SD) | ||||
| RV s′, cm·s−1 (n = 37) | 10.6 (2.8) | 11.1 (2.3) | 14.0 (2.6) | 15.1 (3.8) |
| TAPSE, mm (n = 37) | 18.9 (4.0) | 20.2 (5.4) | NA | NA |
| FAC, % (n = 36) | 43.4 (9.6) | 41.1 (5.9) | NA | NA |
| PAPI (n = 37) | 2.1 (0.7) | 1.7 (0.5) | 1.8 (0.4) | 1.5 (0.5) |
| RV dysfunction, TAPSE <17 mm, No. (%) | 3 (19) | 5 (24) | NA | NA |
| RV dysfunction, RV s′ <9.5 cm/s, No. (%) | 7 (44) | 5 (24) | NA | NA |
| RV-PA coupling, mean (SD) | ||||
| RVs′/PA mean, cm·s−1/mm Hg (n = 37) | 0.4 (0.2) | 0.5 (0.2) | 0.3 (0.1) | 0.3 (0.1) |
| RV s′/ PA Ea, cm·s−1/mm Hg·mL−1 (n = 33) | 25.6 (13.6) | 24.1 (10.3) | 21.1 (9.8) | 21.6 (12.2) |
Abbreviations: CO, cardiac output; Cpc PH, combined pre- and postcapillary pulmonary hypertension; FAC, fractional area change; HFpEF, heart failure with preserved ejection fraction; IpC PH, isolated postcapillary pulmonary hypertension; NA, not applicable; PA, pulmonary artery; PAC, PA compliance; PA Ea, PA elastance; PAPI, pulmonary artery pulsatility index; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RA, right atrial; RV, right ventricular; s′, RV systolic velocity; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion.
Effect of Dapagliflozin on Resting PA Vascular Indices and RV-PA Coupling
As previously reported, treatment with dapagliflozin reduced resting PCWP compared with placebo (Table 3). Dapagliflozin had no effect on resting RV function as assessed by traditional load-dependent measures (RV s′, FAC, or TAPSE). There was no improvement in resting measures of steady or pulsatile pulmonary vascular load. There was also no improvement in PAPI or load-independent measures of RV function adjusting for steady-state or pulsatile afterload with no observed improvement in resting RV-PA coupling. There was no difference in diuretic titration between groups expressed in furosemide milligram equivalents over the study period (mean [SD], 20 [64] mg with placebo and 5 [42] mg with dapagliflozin; mean difference. −15 mg; 95% CI, −50 to 20 mg; P = .39).
Table 3. Effect of Dapagliflozin on Resting and Exercise Measures of Right Ventricular Performance.
| Effect | Change at 24 wk, placebo | Change at 24 wk, dapagliflozin | Difference (95% CI)a | P value |
|---|---|---|---|---|
| Resting hemodynamics | ||||
| Pressure/flow, mean (SD) | ||||
| PA systolic, mm Hg (n = 37) | 0.3 (8.5) | −2.2 (5.4) | −2.6 (−7.2 to 2.3) | .27 |
| PA mean, mm Hg (n = 37) | 1.1 (7.4) | −1.8 (4.0) | −2.8 (−6.7 to 1.0) | .15 |
| PCWP mean, mm Hg (n = 37) | 1.1 (6.0) | −2.5 (3.7) | −3.5 (−6.8 to −0.3) | .03 |
| RA mean, mm Hg (n = 37) | 0.3 (4.0) | −1.6 (2.6) | −1.9 (−4.1 to 0.3) | .08 |
| CO, L/min (n = 33) | −0.3 (1.0) | −0.6 (1.2) | −0.3 (−1.1 to 0.6) | .52 |
| SV, mL (n = 33) | −6.3 (14.9) | −5.6 (16.1) | 0.6 (−10.5 to 11.8) | .91 |
| Pulmonary vascular load, mean (SD) | ||||
| PVR, Wood units (n = 33) | 0.3 (0.6) | 0.3 (0.6) | 0.1 (−0.3 to 0.6) | .58 |
| PAC, mL/mm Hg (n = 33) | −0.36 (0.95) | −0.13 (1.16) | −0.23 (−0.53 to 0.99) | .54 |
| Pa Ea, mm Hg/mL (n = 33) | 0.05 (0.11) | −0 (0.12) | −0.05 (−0.14 to 0.03) | .20 |
| Right ventricular function, mean (SD) | ||||
| RV s′, cm·s−1 (n = 37) | 1.0 (2.6) | −0.8 (3.6) | −1.7 (−3.9 to 0.4) | .11 |
| TAPSE, mm (n = 36) | 0.5 (3.6) | 0.3 (5.0) | −0.2 (−3.3 to 2.8) | .89 |
| FAC, % (n = 34) | 0.7 (11.6) | 0.2 (7.9) | −0.4 (−7.3 to 6.4) | .90 |
| PAPI (n = 37) | −0 (0.8) | 0.2 (0.6) | 0.2 (−0.2 to 0.7) | .30 |
| RV-PA coupling, mean (SD) | ||||
| RVs′/PA mean, cm·s−1/mm Hg (n = 37) | 0.01 (0.16) | 0 (0.21) | −0.01 (−0.13 to 0.12) | .90 |
| RV s′/ PA Ea, cm·s−1/mm Hg·mL−1 (n = 33) | −1.5 (7.4) | −2.6 (10.1) | −1.1 (−7.5 to 5.4) | .74 |
| Exercise hemodynamics | ||||
| Pressure/flow, mean (SD) | ||||
| PA systolic, mm Hg (n = 37) | −0.1 (10.3) | −5.4 (8.0) | −5.3 (−11.4 to 0.8) | .08 |
| PA mean, mm Hg (n = 37) | 0.7 (8.7) | −5.2 (7.0) | −5.9 (−11.0 to −0.8) | .02 |
| PCWP mean, mm Hg (n = 37) | −0.4 (8.4) | −6.6 (7.2) | −6.1 (−11.3 to −0.9) | .02 |
| RA mean, mm Hg (n = 37) | 0.8 (5.7) | −3.4 (4.0) | −4.2 (−7.4 to −1.0) | .01 |
| CO, L/min (n = 34) | −0.4 (1.7) | −0.2 (1.7) | 0.2 (−1.0 to 1.4) | .75 |
| SV, mL (n = 34) | −4.6 (11.4) | 4.3 (11.7) | 8.9 (0.8 to 17.0) | .03 |
| Peak watts (n = 37) | 0 | 0 | NA | .74 |
| Peak respiratory exchange ratio (n = 36) | −0.03 (0.08) | −0.03 (0.08) | −0 (−0.06 to 0.05) | .87 |
| Pulmonary vascular load, mean (SD) | ||||
| PVR, Wood units (n = 33) | 0.2 (0.6) | 0.3 (0.6) | 0.1 (−0.3 to 0.6) | .58 |
| PAC, mL/mm Hg (n = 33) | −0.17 (0.53) | 0.41 (0.74) | 0.57 (0.11 to 1.03) | .02 |
| PA Ea, mm Hg/mL (n = 34) | 0.04 (0.14) | −0.13 (0.15) | −0.17 (−0.28 to −0.07) | .001 |
| Right ventricular function, mean (SD) | ||||
| RV s′, cm·s−1 (n = 24) | −1.3 (1.6) | 0.1 (4.0) | 1.5 (−1.4 to 4.4) | .31 |
| PAPI (n = 37) | −0.1 (0.4) | 0.2 (0.3) | 0.3 (0.1 to 0.6) | .01 |
| RV-PA coupling | ||||
| RVs′/PA mean, cm·s−1/mm Hg (n = 24) | −0.05 (0.06) | 0.04 (0.09) | 0.09 (0.02 to 0.26) | .01 |
| RV s′/PA Ea, cm·s−1/mm Hg·mL−1 (n = 23) | −4.0 (4.5) | 2.4 (8.1) | 6.3 (0.2 to 12.5) | .04 |
Abbreviations: CO, cardiac output; Cpc PH, combined pre- and postcapillary pulmonary hypertension; FAC, fractional area change; HFpEF, heart failure with preserved ejection fraction; IpC PH, isolated postcapillary pulmonary hypertension; NA, not applicable; PA, pulmonary artery; PAC, PA compliance; PA Ea, PA elastance; PAPI, pulmonary artery pulsatility index; PCWP, pulmonary capillary wedge pressure; PVR, pulmonary vascular resistance; RA, right atrial pressure; RV, right ventricular; s′, RV systolic velocity; SV, stroke volume; TAPSE, tricuspid annular plane systolic excursion.
The estimated treatment difference is the difference in the delta values between groups.
Effect of Dapagliflozin on Exercise Pulmonary Vascular Load and RV-PA Coupling
With exercise to peak exhaustion, treatment with dapagliflozin reduced PCWP along with reductions in mean PA pressure and RA pressure compared with placebo, as previously reported (Table 3). There was no change in peak cardiac output, but treatment with dapagliflozin led to a statistically significant increase in exercise stroke volume (8.9 mL; 95% CI, 0.8-17.0 mL; P = .03) (Table 3).
Treatment with dapagliflozin significantly improved pulsatile pulmonary vascular load as assessed by PA compliance (placebo-corrected mean difference, 0.57 mL/mm Hg; 95% CI, 0.11-1.03 mL/mm Hg; P = .02) and decreased PA elastance (stiffness; −0.17 mm Hg/mL; 95% CI, −0.28 to −0.07 mm Hg/mL; P = .001) as compared with placebo (Figure 1 and Table 3). There was no effect on exercise PVR. RV function during exercise also improved with dapagliflozin as compared with placebo, assessed by RV s′ indexed to PA mean (steady-state load; 0.09 cm·s−1/mm Hg; 95% CI, 0.02-0.16 cm·s−1/mm Hg; P = .01) or PA elastance (incorporating pulsatile afterload) as well as PAPI (0.33; 95% CI, 0.08-0.59; P = .01) (Figure 1 and eTable 1 in Supplement 3). Decreases in central venous (right atrial) pressure during exercise were significantly associated with reductions in pulsatile RV load (PA elastance Pearson r = 0.55; P = .008; PA compliance Pearson r = −0.35; P = .009) and RV-PA coupling (RV s′/PA mean Pearson r = −0.65; P <.001; RV s′/PA elastance Pearson r = −0.60; P = .002) (eFigures 6 and 7 in Supplement 3).
Figure 1. Effect of Dapagliflozin on Pulsatile Pulmonary Artery (PA) Load and Right Ventricular (RV)–PA Coupling During Exercise.
Dapagliflozin was associated with improved pulsatile pulmonary vascular load during exercise as assessed by PA elastance (Ea) and PA compliance (PAC) with improved load-independent RV function (RV s′/PA mean and PA pulsatility index). Data are shown as mean with SE bars. PAPI indicates PA pulsatility index; s′, RV systolic velocity.
To account for the nonlinear relationship between PVR and PA compliance, pulmonary vascular R-C curves were constructed, with calculation of R-C time. There was rightward shift of the R-C curve, with an increase in the R-C time during exercise with dapagliflozin (dapagliflozin, median [IQR] change, 0.06 [0.03-0.15] seconds; placebo, median [IQR] change, 0.01 [−0.02 to 0.05] seconds; P = .046), reflecting an increase in PA compliance for any PVR (Figure 2). The increase in exercise RC time after treatment was correlated with the reduction in exercise PCWP (Pearson r = −0.53; P = .001).
Figure 2. Change in Pulmonary Vascular Resistance–Pulmonary Artery (PA) Compliance Relationship During Peak Exercise Before and After Dapagliflozin.
Treatment with dapagliflozin was associated with a rightward shift in the exercise PA compliance–pulmonary vascular resistance (PVR) relationship with a significant increase in resistance-compliance (R-C) time (A and B). Reduction in exercise pulmonary capillary wedge pressure (PCWP) was associated with the increase in exercise R-C time (C) and improved right ventricular (RV)–PA coupling (D).
Effect of Dapagliflozin on Pulmonary Hypertension Phenotype
After dapagliflozin therapy, there was a reduction in the prevalence of isolated postcapillary pulmonary hypertension HFpEF from 20% (n = 4) to 10% (n = 2), a reduction in the prevalence of overall pulmonary hypertension from 86% (n = 18) to 71% (n = 15), and a reduction in resting elevation in PCWP (≥15 mm Hg) from 62% (n = 13) to 43% (n = 9). Although all patients were required by study design to display exercise PCWP value of 25 mm Hg or greater before treatment, one-third of patients (7 [33%]) no longer met HFpEF criteria after treatment with dapagliflozin, with an exercise PCWP value less than 25 mm Hg at final study visit.
Correlations Between RV Functional Reserve, PA Vascular Load, and PCWP
As expected, reduction in resting PCWP was strongly correlated with the reduction in mean PA pressure (R2 = 0.80; P <.001) and moderately correlated with improvement in resting RV-PA coupling and PA elastance (eTable 2 in Supplement 3). Similarly, reduction in exercise PCWP was strongly correlated with reduction in mean PA pressure (R2 = 0.78; P <.001), and moderately correlated with changes in PA elastance, PA compliance, PAPI, and RV-PA coupling (Figure 2 and eFigure 8 in Supplement 3).
Discussion
Although SGLT2 inhibitors in HFpEF unequivocally reduce risk of HF hospitalization and improve quality of life,1,2,3 the mechanisms of benefit remain incompletely understood. We present the first study, to our knowledge, that evaluated the effects of SGLT2 inhibitors on the right ventricle and pulmonary vasculature during rest and exercise in patients with HFpEF. The use of simultaneous echocardiography and high fidelity micromanometer pressures during exercise enabled precise measurement of pulsatile load and RV-PA coupling over the dynamic range of loading conditions that the heart is exposed to during activities of daily living. Despite resting PCWP reduction, dapagliflozin had no detectable effect on resting right ventricular function or pulmonary vascular load. However, during exercise, dapagliflozin lowered PA and PCWP for similar cardiac output, with improvements in PA compliance, RV-PA coupling, RV function, and stroke volume reserve. The improvement in pulsatile PA load and RV-PA coupling was associated with lower exercise RA pressure, with an improvement in load-independent RV functional reserve. Each of these effects was strongly associated with the reduction in exercise PCWP, emphasizing the critical role of left heart unloading to enhance RV-PA coupling and RV function during exertion in HFpEF. These data extend our understanding of the mechanisms of benefit with SGLT2 inhibitors beyond the left heart to also include favorable secondary effects on the right ventricle and pulmonary vasculature.
Right Ventricular Dysfunction in HFpEF
Although HFpEF was initially considered as an isolated disorder of left heart diastolic dysfunction, it is now established that pulmonary vascular disease and RV failure importantly contribute.13,26,27 Right-sided heart abnormalities are detectable even in early-stage HFpEF where PCWP and PA pressures are normal at rest,7,13 due in part to abnormalities in exertional pulmonary vascular reserve.7,13,14,17 The degree of right-sided heart dysfunction is associated with an increase in pulmonary edema formation with exercise, likely through elevation in central venous pressure that impedes pulmonary lymphatic drainage via the thoracic duct, in tandem with increases in fluid filtration due to elevation in capillary pressures.7,23,28 Even subtle increases in PA load during exercise are associated with impairments in cardiac output, reductions in exercise capacity, increased risk for adverse events, and differential response to novel treatments such as atrial shunt devices.13,14,29 Treatments that enhance pulmonary vascular reserve and improve RV-PA coupling with exercise in HFpEF have been shown to enhance cardiac output relative to workload,17 which is often impaired in HFpEF.13,30
Clinical Implications
The present study provides the first, to our knowledge, randomized trial-based evaluation of the effect of SGLT2 inhibitors on the right ventricle–pulmonary vascular dyad and showed that treatment with dapagliflozin for 24 weeks improves exercise right-sided heart function associated with reductions in pulsatile pulmonary vascular load with exertion. These findings were coupled to the reduction in exercise PCWP, and remarkably, one-third of patients treated with dapagliflozin no longer met HFpEF diagnostic criteria during exercise after treatment, even as they clearly had been shown to have HFpEF at enrollment. Health status and symptom severity are impaired in HFpEF related to limitations in exercise performance with abnormal exercise hemodynamics.5,6,31 The ability of SGLT2 inhibitors to improve dynamic right ventricular myocardial performance at lower filling pressures may partly explain the improved quality of life and 6-minute walk distance observed in trials3,32,33,34,35 but not others enrolling less symptomatic patients.36,37,38
There are currently no approved direct therapies for pulmonary vascular disease in HFpEF. Although pulmonary vasodilation may improve cardiac output,17,39 no clear clinical benefit has been demonstrated, with some signals of harm potentially related to pulmonary edema due to left atrial overfilling with isolated pulmonary vasodilation.39,40 The ability of SGLT2 inhibitors to lower PCWP and increase exertional PA compliance without changing PVR is notable in this regard. This suggests a new hypothesis: that pulmonary vasodilators may be safer and more effective in patients with HFpEF when administered in combination with SGLT2 inhibitors that can better unload the left heart. This question merits further study.
The mechanisms of improvement in dynamic RV function and pulsatile pulmonary vascular load with dapagliflozin in this study appear to be at least partially related to the magnitude of PCWP reduction (eTable 2 in Supplement 3). Elevation in PCWP is known to worsen pulsatile RV afterload,15 and rightward shift in the R-C curves with increase in R-C time with dapagliflozin were consistent with the reduction in PCWP observed during exercise. There is also emerging evidence that systemic changes in autophagy, mitochondrial health, and oxidative stress occur in response to SGLT2 inhibition that may contribute to the multiorgan benefits in HFpEF.41 In an animal model, increased PA smooth muscle mitochondrial oxidative stress was associated with upregulation of microRNA-193b and decreased transcription of soluble guanylate cyclase—the primary mediator of nitric oxide dependent pulmonary vasodilation. These molecular changes were coupled with exercise-induced pulmonary hypertension and RV dysfunction. Treatment with empagliflozin in this animal model was associated with decreased PA smooth muscle mitochondrial oxidative stress, lower microRNA-193b, and improved soluble guanylate cyclase levels, resulting in attenuation of exercise pulmonary hypertension.16 Thus, although the decrease in exercise PCWP with dapagliflozin is likely a key mediator of improved pulsatile pulmonary vascular load and RV-PA coupling during exertion, direct effects of SGLT2 inhibitors on the PA smooth muscle cell with restoration of soluble guanylate cyclase signaling and large vessel PA vascular capacitance may also potentially contribute, requiring further study.
Strengths and Limitations
Although the sample size is modest, this size was selected to balance cost and participant burden given the invasive nature of the protocol that required 2 exercise catheterizations over 24 weeks while still providing adequate power. Participants with HFpEF in this study had high prevalence of obesity, relatively low natriuretic peptide levels, and many had normal resting PCWP. Although these findings mirror current estimates in the US,8,42,43,44 the present results may be less applicable to those with more severe congestion at rest and lower body mass. The use of high-fidelity micromanometer catheters allowed precise measurement of phasic pressures in the PA during exercise that are more difficult to detect with traditional fluid-filled catheter systems, thereby decreasing measurement variability (eFigure 1 in Supplement 3). The estimated treatment difference for PCWP in this study during exercise is slightly higher than that reported in our original study (6.1 mm Hg vs 5.7 mm Hg). This is due to different statistical methodologic approaches, as the present study compared group differences only in patients completing the trial, whereas the original analysis included 1 additional patient who completed the baseline study but withdrew before the final visit. Measures of echocardiographic RV function were not available in all patients during exercise due to reduction in image quality during stress, but this would only be expected to bias results to the null by decreasing power. Measures of RV sarcomere function independent of echocardiography such as PAPI22 were also consistent with improved RV function with dapagliflozin supporting internal validity.
Conclusions
Results of this randomized clinical trial show that treatment with dapagliflozin for 24 weeks favorably improved pulsatile pulmonary vascular load and RV-PA coupling during exertion in patients with HFpEF, associated with salutary reductions in central venous pressure and PCWP. These data suggest that improvement in ability of the right ventricle and pulmonary vasculature to respond to dynamic changes in loading conditions with exercise may represent one of the mechanisms of benefit of dapagliflozin in HFpEF.
Trial Protocol.
Statistical Analysis Plan.
eTable 1. Effect on Dapagliflozin on Right Ventricular Performance During Peak Exercise Expressed as Percentage Change
eTable 2. Correlation Between Treatment Effect on Pulmonary Capillary Wedge Pressure With Measures of Right Ventricular Performance
eFigure 1. Difference in Precision in Estimation of Pulsatile PA Load With Micromanometers Compared With Standard Fluid Filled Catheters
eFigure 2. Modeling Approach for Measuring Nonpulsatile Pulmonary Artery Load
eFigure 3. Modeling Approach for Measuring Pulsatile Pulmonary Artery Load
eFigure 4. Resistance Compliance Curve and Shift With Change in PCWP
eFigure 5. CONSORT Diagram
eFigure 6. Relationship Between Change in Exercise Pulmonary Artery Elastance and Exercise RA pressure
eFigure 7. Relationship Between Change in Exercise RV-PA Coupling and Exercise RA Pressure
eFigure 8. Relationship Between Change in Exercise PCWP With Pulsatile PA Load and RV Function
Data Sharing Statement.
References
- 1.Solomon SD, McMurray JJV, Claggett B, et al. ; DELIVER Trial Committees and Investigators . Dapagliflozin in Heart failure with mildly reduced or preserved ejection fraction. N Engl J Med. 2022;387(12):1089-1098. doi: 10.1056/NEJMoa2206286 [DOI] [PubMed] [Google Scholar]
- 2.Anker SD, Butler J, Filippatos G, et al. ; EMPEROR-Preserved Trial Investigators . Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med. 2021;385(16):1451-1461. doi: 10.1056/NEJMoa2107038 [DOI] [PubMed] [Google Scholar]
- 3.Nassif ME, Windsor SL, Borlaug BA, et al. The SGLT2 inhibitor dapagliflozin in heart failure with preserved ejection fraction: a multicenter randomized trial. Nat Med. 2021;27(11):1954-1960. doi: 10.1038/s41591-021-01536-x [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Borlaug BA, Reddy YNV, Braun A, et al. Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction: the CAMEO-DAPA trial. Circulation. 2023;148(10):834-844. doi: 10.1161/CIRCULATIONAHA.123.065134 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5.Obokata M, Olson TP, Reddy YNV, Melenovsky V, Kane GC, Borlaug BA. Hemodynamics, dyspnea, and pulmonary reserve in heart failure with preserved ejection fraction. Eur Heart J. 2018;39(30):2810-2821. doi: 10.1093/eurheartj/ehy268 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Reddy YNV, Olson TP, Obokata M, Melenovsky V, Borlaug BA. Hemodynamic correlates and diagnostic role of cardiopulmonary exercise testing in heart failure with preserved ejection fraction. JACC Heart Fail. 2018;6(8):665-675. doi: 10.1016/j.jchf.2018.03.003 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Reddy YNV, Obokata M, Wiley B, et al. The hemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction. Eur Heart J. 2019;40(45):3721-3730. doi: 10.1093/eurheartj/ehz713 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Omote K, Verbrugge FH, Sorimachi H, et al. Central hemodynamic abnormalities and outcome in patients with unexplained dyspnea. Eur J Heart Fail. 2023;25(2):185-196. doi: 10.1002/ejhf.2747 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9.Lam CSP, Roger VL, Rodeheffer RJ, Borlaug BA, Enders FT, Redfield MM. Pulmonary hypertension in heart failure with preserved ejection fraction: a community-based study. J Am Coll Cardiol. 2009;53(13):1119-1126. doi: 10.1016/j.jacc.2008.11.051 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10.Obokata M, Reddy YNV, Melenovsky V, Pislaru S, Borlaug BA. Deterioration in right ventricular structure and function over time in patients with heart failure and preserved ejection fraction. Eur Heart J. 2019;40(8):689-697. doi: 10.1093/eurheartj/ehy809 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11.Melenovsky V, Hwang SJ, Lin G, Redfield MM, Borlaug BA. Right heart dysfunction in heart failure with preserved ejection fraction. Eur Heart J. 2014;35(48):3452-3462. doi: 10.1093/eurheartj/ehu193 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12.Inciardi RM, Abanda M, Shah AM, et al. ; PARAGON-HF Investigators . Right ventricular function and pulmonary coupling in patients with heart failure and preserved ejection fraction. J Am Coll Cardiol. 2023;82(6):489-499. doi: 10.1016/j.jacc.2023.05.010 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13.Borlaug BA, Kane GC, Melenovsky V, Olson TP. Abnormal right ventricular-pulmonary artery coupling with exercise in heart failure with preserved ejection fraction. Eur Heart J. 2016;37(43):3293-3302. doi: 10.1093/eurheartj/ehw241 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14.Huang W, Oliveira RKF, Lei H, Systrom DM, Waxman AB. Pulmonary vascular resistance during exercise predicts long-term outcomes in heart failure with preserved ejection fraction. J Card Fail. 2018;24(3):169-176. doi: 10.1016/j.cardfail.2017.11.003 [DOI] [PubMed] [Google Scholar]
- 15.Tedford RJ, Hassoun PM, Mathai SC, et al. Pulmonary capillary wedge pressure augments right ventricular pulsatile loading. Circulation. 2012;125(2):289-297. doi: 10.1161/CIRCULATIONAHA.111.051540 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Satoh T, Wang L, Espinosa-Diez C, et al. Metabolic syndrome mediates ROS-miR-193b-NFYA-dependent downregulation of soluble guanylate cyclase and contributes to exercise-induced pulmonary hypertension in heart failure with preserved ejection fraction. Circulation. 2021;144(8):615-637. doi: 10.1161/CIRCULATIONAHA.121.053889 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Reddy YNV, Obokata M, Koepp KE, Egbe AC, Wiley B, Borlaug BA. The β-adrenergic agonist albuterol improves pulmonary vascular reserve in heart failure with preserved ejection fraction. Circ Res. 2019;124(2):306-314. doi: 10.1161/CIRCRESAHA.118.313832 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18.Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol. 2015;66(15):1672-1682. doi: 10.1016/j.jacc.2015.07.067 [DOI] [PubMed] [Google Scholar]
- 19.Borlaug BA, Melenovsky V, Koepp KE. Inhaled sodium nitrite improves rest and exercise hemodynamics in heart failure with preserved ejection fraction. Circ Res. 2016;119(7):880-886. doi: 10.1161/CIRCRESAHA.116.309184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.Humbert M, Kovacs G, Hoeper MM, et al. ; ESC/ERS Scientific Document Group . 2022 ESC/ERS guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237 [DOI] [PubMed] [Google Scholar]
- 21.Lankhaar JW, Westerhof N, Faes TJC, et al. Pulmonary vascular resistance and compliance stay inversely related during treatment of pulmonary hypertension. Eur Heart J. 2008;29(13):1688-1695. doi: 10.1093/eurheartj/ehn103 [DOI] [PubMed] [Google Scholar]
- 22.Aslam MI, Jani V, Lin BL, et al. Pulmonary artery pulsatility index predicts right ventricular myofilament dysfunction in advanced human heart failure. Eur J Heart Fail. 2021;23(2):339-341. doi: 10.1002/ejhf.2084 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Omote K, Sorimachi H, Obokata M, et al. Pulmonary vascular disease in pulmonary hypertension due to left heart disease: pathophysiologic implications. Eur Heart J. 2022;43(36):3417-3431. doi: 10.1093/eurheartj/ehac184 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Guazzi M, Dixon D, Labate V, et al. RV contractile function and its coupling to pulmonary circulation in heart failure with preserved ejection fraction: stratification of clinical phenotypes and outcomes. JACC Cardiovasc Imaging. 2017;10(10 Pt B):1211-1221. doi: 10.1016/j.jcmg.2016.12.024 [DOI] [PubMed] [Google Scholar]
- 25.Tello K, Wan J, Dalmer A, et al. Validation of the tricuspid annular plane systolic excursion/systolic pulmonary artery pressure ratio for the assessment of right ventricular-arterial coupling in severe pulmonary hypertension. Circ Cardiovasc Imaging. 2019;12(9):e009047. doi: 10.1161/CIRCIMAGING.119.009047 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 26.Rommel KP, von Roeder M, Oberueck C, et al. Load-independent systolic and diastolic right ventricular function in heart failure with preserved ejection fraction as assessed by resting and handgrip exercise pressure-volume loops. Circ Heart Fail. 2018;11(2):e004121. doi: 10.1161/CIRCHEARTFAILURE.117.004121 [DOI] [PubMed] [Google Scholar]
- 27.Aslam MI, Hahn VS, Jani V, Hsu S, Sharma K, Kass DA. Reduced right ventricular sarcomere contractility in heart failure with preserved ejection fraction and severe obesity. Circulation. 2021;143(9):965-967. doi: 10.1161/CIRCULATIONAHA.120.052414 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28.Burrage MK, Hundertmark M, Valkovič L, et al. Energetic basis for exercise-induced pulmonary congestion in heart failure with preserved ejection fraction. Circulation. 2021;144(21):1664-1678. doi: 10.1161/CIRCULATIONAHA.121.054858 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29.Borlaug BA, Blair J, Bergmann MW, et al. ; REDUCE LAP-HF-II Investigators . Latent pulmonary vascular disease may alter the response to therapeutic atrial shunt device in heart failure. Circulation. 2022;145(21):1592-1604. doi: 10.1161/CIRCULATIONAHA.122.059486 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 30.Abudiab MM, Redfield MM, Melenovsky V, et al. Cardiac output response to exercise in relation to metabolic demand in heart failure with preserved ejection fraction. Eur J Heart Fail. 2013;15(7):776-785. doi: 10.1093/eurjhf/hft026 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 31.Reddy YNV, Rikhi A, Obokata M, et al. Quality of life in heart failure with preserved ejection fraction: importance of obesity, functional capacity, and physical inactivity. Eur J Heart Fail. 2020;22(6):1009-1018. doi: 10.1002/ejhf.1788 [DOI] [PubMed] [Google Scholar]
- 32.Spertus JA, Birmingham MC, Nassif M, et al. The SGLT2 inhibitor canagliflozin in heart failure: the CHIEF-HF remote, patient-centered randomized trial. Nat Med. 2022;28(4):809-813. doi: 10.1038/s41591-022-01703-8 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 33.Kosiborod MN, Bhatt AS, Claggett BL, et al. Effect of dapagliflozin on health status in patients with preserved or mildly reduced ejection fraction. J Am Coll Cardiol. 2023;81(5):460-473. doi: 10.1016/j.jacc.2022.11.006 [DOI] [PubMed] [Google Scholar]
- 34.Kosiborod MN, Angermann CE, Collins SP, et al. Effects of empagliflozin on symptoms, physical limitations, and quality of life in patients hospitalized for acute heart failure: results from the EMPULSE trial. Circulation. 2022;146(4):279-288. doi: 10.1161/CIRCULATIONAHA.122.059725 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35.Butler J, Filippatos G, Jamal Siddiqi T, et al. Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: the EMPEROR preserved trial. Circulation. 2022;145(3):184-193. doi: 10.1161/CIRCULATIONAHA.121.057812 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36.Abraham WT, Lindenfeld J, Ponikowski P, et al. Effect of empagliflozin on exercise ability and symptoms in heart failure patients with reduced and preserved ejection fraction, with and without type 2 diabetes. Eur Heart J. 2021;42(6):700-710. doi: 10.1093/eurheartj/ehaa943 [DOI] [PubMed] [Google Scholar]
- 37.McMurray JJV, Docherty KF, de Boer RA, et al. Effect of dapagliflozin vs placebo on symptoms and 6-minute walk distance in patients with heart failure: the DETERMINE randomized clinical trials. Circulation. 2024;149(11):825-838. doi: 10.1161/CIRCULATIONAHA.123.065061 [DOI] [PubMed] [Google Scholar]
- 38.Cleland JGF. Nature and magnitude of the benefits of dapagliflozin and empagliflozin for heart failure. Circulation. 2024;149(11):839-842. doi: 10.1161/CIRCULATIONAHA.123.068089 [DOI] [PubMed] [Google Scholar]
- 39.Dachs TM, Duca F, Rettl R, et al. Riociguat in pulmonary hypertension and heart failure with preserved ejection fraction: the haemoDYNAMIC trial. Eur Heart J. 2022;43(36):3402-3413. doi: 10.1093/eurheartj/ehac389 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 40.Bermejo J, Yotti R, García-Orta R, et al. ; Sildenafil for Improving Outcomes after VAlvular Correction (SIOVAC) investigators . Sildenafil for improving outcomes in patients with corrected valvular heart disease and persistent pulmonary hypertension: a multicenter, double-blind, randomized clinical trial. Eur Heart J. 2018;39(15):1255-1264. doi: 10.1093/eurheartj/ehx700 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 41.Zannad F, Ferreira JP, Butler J, et al. Effect of empagliflozin on circulating proteomics in heart failure: mechanistic insights into the EMPEROR program. Eur Heart J. 2022;43(48):4991-5002. doi: 10.1093/eurheartj/ehac495 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 42.Litwin SE, Komtebedde J, Hu M, et al. ; REDUCE LAP-HF Investigators and Research Staff . Exercise-induced left atrial hypertension in heart failure with preserved ejection fraction. JACC Heart Fail. 2023;11(8 Pt 2):1103-1117. doi: 10.1016/j.jchf.2023.01.030 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 43.Verbrugge FH, Omote K, Reddy YNV, Sorimachi H, Obokata M, Borlaug BA. Heart failure with preserved ejection fraction in patients with normal natriuretic peptide levels is associated with increased morbidity and mortality. Eur Heart J. 2022;43(20):1941-1951. doi: 10.1093/eurheartj/ehab911 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 44.Morgen CS, Haase CL, Oral TK, Schnecke V, Varbo A, Borlaug BA. Obesity, cardiorenal comorbidities, and risk of hospitalization in patients with heart failure with preserved ejection fraction. Mayo Clin Proc. 2023;98(10):1458-1468. doi: 10.1016/j.mayocp.2023.07.008 [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Trial Protocol.
Statistical Analysis Plan.
eTable 1. Effect on Dapagliflozin on Right Ventricular Performance During Peak Exercise Expressed as Percentage Change
eTable 2. Correlation Between Treatment Effect on Pulmonary Capillary Wedge Pressure With Measures of Right Ventricular Performance
eFigure 1. Difference in Precision in Estimation of Pulsatile PA Load With Micromanometers Compared With Standard Fluid Filled Catheters
eFigure 2. Modeling Approach for Measuring Nonpulsatile Pulmonary Artery Load
eFigure 3. Modeling Approach for Measuring Pulsatile Pulmonary Artery Load
eFigure 4. Resistance Compliance Curve and Shift With Change in PCWP
eFigure 5. CONSORT Diagram
eFigure 6. Relationship Between Change in Exercise Pulmonary Artery Elastance and Exercise RA pressure
eFigure 7. Relationship Between Change in Exercise RV-PA Coupling and Exercise RA Pressure
eFigure 8. Relationship Between Change in Exercise PCWP With Pulsatile PA Load and RV Function
Data Sharing Statement.