Background: Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome requiring invasive and/or exercise stress testing for diagnosis, in contrast with the homogeneous nature of HF with reduced EF (HFrEF). We previously demonstrated that acoustic cardiography (AC), combined with advanced signal analysis, can non-invasively estimate left ventricular (LV) functional indices in an experimental swine model of HFrEF. Objectives: To evaluate whether AC-derived features capture stress-dependent LV functional changes, supporting phenotypic differentiation between porcine models of HFpEF, HFrEF, and Control conditions. Methods: Synchronized invasive LV-pressure and non-invasive ECG, pulse oximetry, and AC signals were collected from 12 anesthetized, closed-chest Göttingen minipigs (Control, n = 3; HFrEF, n = 5; HFpEF, n = 4). Through signal analysis, we derived time and frequency features from the non-invasive signals to predict, using our AI model, the invasively measured LV functional indices. Atrial pacing was performed up to 160 bpm as a controlled heart-rate stress paradigm. Two AI modeling strategies were employed: a standard 80/20 train/test ratio, and a leave-one-animal-out (i.e., 1 animal per health status) to assess generalizability. Results: Standard blind testing achieved >95% accuracy in phenotype classification with <3% relative error for predicted LV indices. The leave-one-animal-out classification performance remained robust (79-95% accuracy), supporting translational potential despite inter-animal variability. Notably, HFpEF animals exhibited greater variability in AC-features across increasing heart rates compared to Control and HFrEF. Conclusions: AC-based modelling offers a rapid, non-invasive approach for assessing LV function. Our methodology may complement existing diagnostic tools, particularly for conditions like HFpEF, but warrants further validation in clinical populations.

BackgroundPreclinical models of heart failure (HF) play a key role in developing new therapeutic strategies. Tachypacing is the gold standard to induce dilated cardiomyopathy (DCM) with reduced ejection fraction (EF) in large animals, but it is not exempted from failures and can induce relevant stress.AimEstablishing a revised porcine model of tachypacing-induced HF to improve reliability and reduce stress on the animals.MethodsEight (n = 8) females Göttingen minipigs were divided in two groups: 4 animals were implanted a right ventricular two-lead pacemaker to induce HF via tachypacing, while 4 animals without implant served as controls. After a recovery period, pigs were paced asynchronously at 180 bpm for 2-weeks and 200 bpm for 4-weeks. Disease progression was assessed by echocardiography, while hemodynamics was measured invasively before sacrifice. Stress was evaluated by jacketed external telemetry (JET), cortisol, body weight, and clinical symptoms.ResultsEchocardiographic assessment showed that all paced animals developed stable DCM as demonstrated by increase of end-systolic and end-diastolic volume at highly depressed ejection fraction. Invasive measurements confirmed these results with stable mAOP despite impaired pump function. JET showed no alterations of respiratory rate and daily activity throughout the protocol. Cortisol and cortisone levels and body weight showed no significant differences between groups or during pacing.ConclusionsWe established a reliable model of tachypacing-induced HF based on slower pacing and milder progression to HF, while reducing the stress and suffering of the animals.

IMPORTANCE:. The effect of left ventricular (LV) mechanical unloading on right ventricular (RV) function in patients with cardiogenic shock (CS) remains poorly understood, yet may have significant implications for device weaning and patient outcomes. OBJECTIVES:. To investigate the short-term effects of LV unloading using a transaortic valve axial flow pump (Impella) on RV function and to assess its predictive value for successful device weaning in patients with CS. DESIGN:. Retrospective analysis of CS patients who received Impella support between 2018 and 2021. SETTING AND PARTICIPANTS:. Single-center study conducted at the German Heart Center, Charité Universitätsmedizin Berlin, Germany. The study included 41 ICU patients with CS due to LV dysfunction who required Impella support for at least 72 hours. MAIN OUTCOMES AND MEASURES:. Biventricular function was evaluated by echocardiography and advanced strain imaging during the weaning process. The primary outcome was successful Impella weaning. Associations between changes in RV free-wall longitudinal strain (RVFWLS) and weaning outcomes were assessed using multiple logistic regression. RESULTS:. Patients received Impella support for a median duration of 216 hours (interquartile range, 144–264 hr). Eighteen patients (43.9%) were successfully weaned, while 23 (56.1%) required LVAD implantation (31.7%) or died (24.4%). LV unloading significantly improved RV systolic function, as demonstrated by increased RV fractional area change, tricuspid annular systolic velocity, and RVFWLS. Notably, patients who failed weaning showed a significantly lower change in RVFWLS (ΔRVFWLS) during the weaning process, which emerged as an independent predictor of weaning outcome. CONCLUSIONS AND RELEVANCE:. Impella-mediated LV unloading enhances both LV and RV function in CS patients. However, inadequate RV longitudinal systolic reserve, as indicated by lower ΔRVFWLS during weaning, is associated with weaning failure and may guide clinical decisions regarding prolonged mechanical circulatory support or transition to durable devices.

Assessment of right ventricular (RV) mechanical performance during open chest surgery is typically based on invasive methods and subjective evaluations. This study developed a porcine model of acute progressive RV pressure overload to evaluate hemodynamic changes and validate the three- dimensional (3-D) video kinematic assessment of the videocardiograph (VCG). Seven healthy Landrace pigs were instrumented under fluoroscopic guidance with Swan-Ganz and RV conductance catheters. Following a median sternotomy, pulmonary artery banding (PB) was performed in two stages to induce minimal (PBmin) and maximal (PBmax) pressure overload. In a proof-of-concept experiment, different PB steps were performed to record both videos for the VCG and invasive pressure-volume assessments (PV loop). In addition, these videos were subjectively evaluated by five consultant surgeons, similar to clinical routine. PBmax significantly increased end-systolic pressure from baseline (21.1 ± 3.3 mmHg vs. 39.8 ± 7.8 mmHg, P = 0.001) and led to RV dilation, reduced ejection fraction (52.8 ± 10.3% vs. 33.9 ± 9.8%, P = 0.012), and decreased myocardial efficiency. In the proof-of-concept experiment, visual evaluations were highly variable among the cardiac surgeons, resulting in only a moderate reliability of their assessments (ICC = 0.59 for RV function; ICC = 0.60 for filling status). VCG-derived epicardial z-axis displacements, systolic timing, diastolic velocity, and volume demonstrated excellent relationships with PV loop data. This study established a porcine model of progressive RV pressure overload with robust PV loop assessment. VCG-derived epicardial kinematics reliably quantified RV mechanical activity and correlated with gold-standard hemodynamic measurements. This noninvasive, cost-effective method shows promise for early detection of acute RV dysfunction in the operating room and warrants further clinical investigation.NEW & NOTEWORTHY This study established a porcine model of acute right ventricular pressure overload using pulmonary artery banding to assess intraoperative RV mechanics. Hemodynamic changes were measured using pressure-volume (PV) loops and compared with 3-D video kinematic analysis from the videocardiograph (VCG). VCG-derived kinematic parameters correlated well with invasive PV loop data, whereas surgeons' visual assessments were highly variable. The findings suggest that VCG offers a reliable, noninvasive method for intraoperative RV function monitoring, warranting further clinical evaluation.

We previously have shown the potential of human endomyocardial biopsy (EMB)-derived cardiac adherent proliferating cells (CardAPs) as a new cell-therapeutic treatment option for virus-induced myocarditis. To overcome the limited cell yield per EMB, CardAPs have been isolated from the human right atrial appendage (RAA) in view of allogeneic application and off-the-shelf use. We aimed to investigate the cardioprotective and immunomodulatory potential of RAA-CardAPs in experimental acute and chronic Coxsackievirus B3 (CVB3)-induced myocarditis upon injection in the viral and inflammatory phase. In the acute model, male C57BL6/J mice were intraperitoneally (i.p.) injected with the CVB3 Nancy strain or phosphate buffered saline (PBS). One day after infection, mice were intravenously (i.v.) injected with RAA-CardAPs, EMB-CardAPs (as reference cells) or PBS. For the chronic model, male Naval Medical Research Institute mice were i.p. injected with the CVB3 31-1-93 strain or PBS. Ten days after infection, mice were i.v. injected with RAA-CardAPs. Cardiac function was characterized, followed by harvest of the left ventricle (LV) and spleen for subsequent analysis, 7 and 28 days after CVB3 infection in the acute and chronic model, respectively. In the acute model, RAA-CardAPs decreased cardiac fibrosis and improved cardiac function in CVB3 mice. RAA-CardAPs mice exerted immunomodulatory effects as evidenced by lower LV chemokines expression (C-C motif ligand [CCL]2 and CCL7), CD68+ cells presence, intercellular adhesion molecule-1, vascular cell adhesion molecule-1, tumor necrosis factor-α, and IL-6 mRNA expression. In the chronic model, RAA-CardAPs reduced cardiac fibrosis and the severity of myocarditis, associated with an improvement in LV function. We conclude that RAA-CardAPs represent a treatment strategy to reduce the development of acute and chronic CVB3-induced myocarditis.

Recombinant proteins, cell, and gene therapies are collectively defined as biological drugs or biologics. These therapies have transformed the lives of millions of patients over the past decades, with the number of FDA-approved biologics increasing exponentially in recent years. However, out of approximately 700 biological therapies approved by the FDA in the last 20 years, less than 1

Abstract Introduction Atrial fibrillation (AF) is one of the most common heart pathologies in daily clinical practice and confers significant mortality and morbidity. However, AF ablation often proves ineffective - even after successful pulmonary vein isolation (PVI). The prediction of PVI failure for the long-term treatment of AF as well as the improved assessment of the underlying substrate appears pivotal. We hypothesize, that ML can be applied to better characterize the substrate and recurrence in AF patients upon PVI. Methods & Results We retrospectively evaluated data from 205 patients that underwent AF ablation between 2019 and 2023, including high-density 3D electroanatomic maps (sinus rhythm), LA rotational angiography, invasive LA hemodynamic measurements (after transseptal passage), echocardiography, 12-lead ECG and laboratory testing. A neuronal net was trained on selected features extracted from those datasets using supervised learning and employed to predict measures of atrial cardiomyopathy and AF recurrence. Patients were 66±1 years old and received first or second pulmonary vein isolation (PVI) for paroxysmal atrial fibrillation with 18% documented recurrences upon a mean follow-up of 23±1months. First, we extensively refined or developed tools for automated P-wave analysis from 12-lead ECGs as well as local LA voltage and volume quantification. Next, LA hemodynamics and volumes were assessed: Mean LA volume as derived from rotational angiography significantly correlated with LA volume index as obtained using echocardiography. Interestingly, LA size showed no correlation with NT-proBNP, LA low voltage or LA hemodynamics. In addition, global (25±2% of total LA area) and local (i.e. anterior, posterior, roof) LA voltage was determined and shown to be an independent predictor of AF recurrence. In our first unselected subset of 136 patients with 2nd PVI for atrial fibrillation, our ML models predicted LA fibrosis (i.e. low voltage regions; Utah stage) from 12-lead ECGs with an accuracy of 90%. Accuracy was 87% for the prediction of AF recurrences from LA pressure and low-voltage regions. In addition, the algorithm predicted AF recurrences from 12-lead SR ECGs obtained before PVI with an accuracy of 91%. Conclusion Artificial neural networks allow to quantitatively and qualitatively predict measures of atrial cardiomyopathy and atrial fibrillation recurrence probability upon complete PVI with high accuracy.Figures

Abstract Background Right ventricular (RV) dysfunction is a known independent factor influencing the outcome of patients in cardiogenic shock (CS). The aim of this monocentric retrospective study was to investigate the impact of left ventricular (LV) unloading on the right heart function and its predictive role regarding weaning following Impella device implantation in patients with profound CS due to LV failure. Methods We performed a retrospective analysis of 41 patients admitted to intensive care unit over a period of 3 years with CS due to LV dysfunction requiring support with Impella. Clinical and echocardiographic data were collected and correlated with weaning success. Finally, a multivariate analysis to identify independent predictors of weaning success was performed. Results After Impella implantation, the following was observed: right ventricular fractional area change (RVFAC) increased from a mean value of 28% to 38% (p=0.01), the tricuspid annular systolic velocity (TASV) increased from 9 cm/s to 10 cm/s (p=0.01), the velocity time integral right ventricular outflow tract (VTI RVOT) increased from 10 to 13 cm3/stroke (p=0.01), the right ventricular free wall longitudinal strain (RVFWLS) increased from -12% to -21% (p< 0.001). However, following LV unloading, a decrease in both RVFAC from 38% to 30% (p 0.01) and in VTI RVOT from 13 to 11 cm3/stroke (p<0.01) was observed. Moreover, there was a significant decrease in RVFWLS from -21% to -14% (p < 0.001). Notably, the percentage of change in RVFWLS between maximum and minimum (Δ%RVFWLSPmax-Pmin) support with Impella during the weaning process was significantly lower in weanable patients (34.5% in weaned vs 86% in non-weaned; p=0.038). Investigating the predicting ability of these parameters, Δ%RVFWLSPmax-Pmin emerged showing an AUC of 0.826 (0.690-0.962) in identifying non-weaned patients with a cut-off value of 38%. According to the multivariate analysis, Δ%RVFWLSPmax-Pmin in non-weaned patients remained the only significant parameter even considering possible confounders. Conclusions LV unloading with Impella in advanced CS patients improved RV function echocardiographic parameters. RVFWLS increased significantly after Impella implantation and its percentage of change between maximum and minimum support was significantly lower in weanable compared to non-weanable patients. Our findings suggest that RVFWLS could be used as a predictor of myocardial recovery allowing to identify weanable patients with adequate accuracy.

BACKGROUND:The lack of disease-modifying drugs is one of the major unmet needs in patients with heart failure (HF). Peptides are highly selective molecules with the potential to act directly on cardiomyocytes. However, a strategy for effective delivery of therapeutics to the heart is lacking. OBJECTIVES:In this study, the authors sought to assess tolerability and efficacy of an inhalable lung-to-heart nano-in-micro technology (LungToHeartNIM) for cardiac-specific targeting of a mimetic peptide (MP), a first-in-class for modulating impaired L-type calcium channel (LTCC) trafficking, in a clinically relevant porcine model of HF. METHODS:Heart failure with reduced ejection fraction (HFrEF) was induced in Göttingen minipigs by means of tachypacing over 6 weeks. In a setting of overt HFrEF (left ventricular ejection fraction [LVEF] 30% ± 8%), animals were randomized and treatment was started after 4 weeks of tachypacing. HFrEF animals inhaled either a dry powder composed of mannitol-based microparticles embedding biocompatible MP-loaded calcium phosphate nanoparticles (dpCaP-MP) or the LungToHeartNIM only (dpCaP without MP). Efficacy was evaluated with the use of echocardiography, invasive hemodynamics, and biomarker assessment. RESULTS:DpCaP-MP inhalation restored systolic function, as shown by an absolute LVEF increase over the treatment period of 17% ± 6%, while reversing cardiac remodeling and reducing pulmonary congestion. The effect was recapitulated ex vivo in cardiac myofibrils from treated HF animals. The treatment was well tolerated, and no adverse events occurred. CONCLUSIONS:The overall tolerability of LungToHeartNIM along with the beneficial effects of the LTCC modulator point toward a game-changing treatment for HFrEF patients, also demonstrating the effective delivery of a therapeutic peptide to the diseased heart.

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. To test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF. 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. Dapagliflozin or placebo for 24 weeks. 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. 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. 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. ClinicalTrials.gov Identifier: NCT04730947

4D-flow MRI is a promising technique for assessing vessel hemodynamics. However, its utilization is currently limited by the lack of reference values, particularly for pulmonary vessels. In this work, we have analysed flow and velocity in the pulmonary trunk (PT), left and right pulmonary arteries (LPA and RPA, respectively) in Landrace pigs at both rest and stress through the software MEVISFlow. Nine healthy Landrace pigs were acutely instrumented closed-chest and transported to the CMR facility for evaluation. After rest measurements, dobutamine was administered to achieve a 25% increase in heart rate compared to rest. 4D-flow MRI images have been analysed through MEVISFlow by two independent observers. Inter- and intra-observer reproducibility was quantified using intraclass correlation coefficient. A significant difference between rest and stress regarding flow and velocity in all the pulmonary vessels was observed. Mean flow increased 55% in PT, 75% in LPA and 40% in RPA. Mean peak velocity increased 55% in PT, 75% in LPA and 66% in RPA. A good-to-excellent reproducibility was observed in rest and stress for flow measurements in all three arteries. An excellent reproducibility for velocity was found in PT at rest and stress, a good one for LPA and RPA at rest, while poor reproducibility was found at stress. The current study showed that pulmonary flow and velocity assessed through 4D-flow MRI follow the physiological alterations during cardiac cycle and after stress induced by dobutamine. A clinical translation to assess pulmonary diseases with 4D-flow MRI under stress conditions needs investigation.

Bioimpedance analysis (BIA) is a validated non-invasive technique already proven to be useful for the diagnosis, prognosis, and management of body fluids in subjects with heart failure (HF) and chronic kidney disease (CKD). Although BIA has been widely employed for research purposes, its clinical application is still not fully widespread. The aim of this review is to provide a comprehensive overview of the state of the art of BIA utilization by analyzing the clinical benefits, limitations, and potential future developments in this clinically unexplored field.

Aims We aimed to clarify the extent to which cardiac and peripheral impairments to oxygen delivery and utilization contribute to exercise intolerance and risk for adverse events, and how this relates to diversity and multiplicity in pathophysiologic traits. Methods and results Individuals with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnoea (controls) underwent invasive cardiopulmonary exercise testing and clinical follow-up. Haemodynamics and oxygen transport responses were compared. HFpEF patients were then categorized a priori into previously-proposed, non-exclusive descriptive clinical trait phenogroups, including cardiometabolic, pulmonary vascular disease, left atrial myopathy, and vascular stiffening phenogroups based on clinical and haemodynamic profiles to contrast pathophysiology and clinical risk. Overall, patients with HFpEF (n = 643) had impaired cardiac output reserve with exercise (2.3 vs. 2.8 L/min, p = 0.025) and greater reliance on peripheral oxygen extraction augmentation (4.5 vs. 3.8 ml/dl, p < 0.001) compared to dyspnoeic controls (n = 219). Most (94%) patients with HFpEF met criteria for at least one clinical phenogroup, and 67% fulfilled criteria for multiple overlapping phenogroups. There was greater impairment in peripheral limitations in the cardiometabolic group and greater cardiac output limitations and higher pulmonary vascular resistance during exertion in the other phenogroups. Increasing trait multiplicity within a given patient was associated with worse exercise haemodynamics, poorer exercise capacity, lower cardiac output reserve, and greater risk for heart failure hospitalization or death (hazard ratio 1.74, 95% confidence interval 1.08-2.79 for 0-1 vs. >= 2 phenogroup traits present). Conclusions Though cardiac output response to exercise is limited in patients with HFpEF compared to those with non-cardiac dyspnoea, the relative contributions of cardiac and peripheral limitations vary with differing numbers and types of clinical phenotypic traits present. Patients fulfilling criteria for greater multiplicity and diversity of HFpEF phenogroup traits have poorer exercise capacity, worsening haemodynamic perturbations, and greater risk for adverse outcome. [GRAPHICS] .

Heart failure (HF) is defined as the inability of the heart to meet body oxygen demand requiring an elevation in left ventricular filling pressures (LVP) to compensate. LVP increase can be assessed in the cardiac catheterization laboratory, but this procedure is invasive and time-consuming to the extent that physicians rather rely on non-invasive diagnostic tools. In this work, we assess the feasibility to develop a novel machine-learning (ML) approach to predict clinically relevant LVP indices. Synchronized invasive (pressure–volume tracings) and non-invasive signals (ECG, pulse oximetry, and cardiac sounds) were collected from anesthetized, closed-chest Göttingen minipigs. Animals were either healthy or had HF with reduced ejection fraction and circa 500 heartbeats were included in the analysis for each animal. The ML algorithm showed excellent prediction of LVP indices estimating, for instance, the end-diastolic pressure with a R2 of 0.955. This novel ML algorithm could assist clinicians in the care of HF patients.

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.