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ImportanceGreater splanchnic nerve ablation may improve hemodynamics in patients with heart failure and preserved ejection fraction (HFpEF).ObjectiveTo explore the feasibility and safety of endovascular right-sided splanchnic nerve ablation for volume management (SAVM).Design, Setting, and ParticipantsThis was a phase 2, double-blind, 1:1, sham-controlled, multicenter, randomized clinical trial conducted at 14 centers in the US and 1 center in the Republic of Georgia. Patients with HFpEF, left ventricular ejection fraction of 40% or greater, and invasively measured peak exercise pulmonary capillary wedge pressure (PCWP) of 25 mm Hg or greater were included. Study data were analyzed from May 2023 to June 2024.InterventionSAVM vs sham control procedure.Main Outcomes and MeasuresThe primary efficacy end point was a reduction in legs-up and exercise PCWP at 1 month. The primary safety end point was serious device- or procedure-related adverse events at 1 month. Secondary efficacy end points included HF hospitalizations, changes in exercise function and health status through 12 months, and baseline to 1-month change in resting, legs-up, and 20-W exercise PCWP.ResultsA total of 90 patients (median [range] age, 71 [47-90] years; 58 female [64.4%]) were randomized at 15 centers (44 SAVM vs 46 sham). There were no differences in adverse events between groups. The primary efficacy end point did not differ between SAVM or sham (mean between-group difference in PCWP, −0.03 mm Hg; 95% CI, −2.5 to 2.5 mm Hg; P = .95). There were also no differences in the secondary efficacy end points. There was no difference in the primary safety end point between the treatment (6.8% [3 of 44]) and sham (2.2% [1 of 46]) groups (difference, 4.6%; 95% CI, −6.1% to 15.4%; P = .36). There was no difference in the incidence of orthostatic hypotension between the treatment (11.4% [5 of 44]) and sham (6.5% [3 of 46]) groups (difference, 4.9%; 95% CI, −9.2% to 18.8%; P = .48).Conclusions and RelevanceResults show that SAVM was safe and technically feasible, but it did not reduce exercise PCWP at 1 month or improve clinical outcomes at 12 months in a broad population of patients with HFpEF.Trial RegistrationClinicalTrials.gov Identifier: NCT04592445

Abstract Aims The effects of obesity on Fontan haemodynamics are poorly understood. Accordingly, we assessed its impact on exercise invasive haemodynamics and exercise capacity. Methods and results Seventy-seven adults post-Fontan undergoing exercise cardiac catheterization (supine cycle protocol) were retrospectively identified using an institutional database and categorized according to the presence of obesity [body mass index (BMI) > 30 kg/m2] and overweight/normal BMI (BMI ≤ 30 kg/m2). There were 18 individuals with obesity (BMI 36.4 ± 3 kg/m2) and 59 with overweight/normal BMI (BMI 24.1 ± 3.6 kg/m2). Peak oxygen consumption (VO2) on non-invasive cardiopulmonary exercise testing was lower in patients with obesity (15.6 ± 3.5 vs. 19.6 ± 5.8 mL/kg/min, P = 0.04). At rest, systemic flow (Qs) [7.0 (4.8; 8.3) vs. 4.8 (3.9; 5.8) L/min, P = 0.001], pulmonary artery (PA) pressure (16.3 ± 3.5 vs. 13.1 ± 3.5 mmHg, P = 0.002), and PA wedge pressure (PAWP) (11.7 ± 4.4 vs. 8.9 ± 3.1 mmHg, P = 0.01) were higher, while arterial O2 saturation was lower [89.5% (86.5; 92.3) vs. 93% (90; 95)] in obesity compared with overweight/normal BMI. Similarly, patients with obesity had higher exercise PA pressure (29.7 ± 6.5 vs. 24.7 ± 6.8 mmHg, P = 0.01) and PAWP (23.0 ± 6.5 vs. 19.8 ± 7.3 mmHg, P = 0.047), but lower arterial O2 saturation [82.4 ± 7.0% vs. 89% (85; 92), P = 0.003]. Conclusion Adults post-Fontan with obesity have worse aerobic capacity, increased Qs, higher filling pressures, and decreased arterial O2 saturation compared with those with overweight/normal BMI, both at rest and during exercise, mirroring the findings observed in the obesity phenotype of heart failure with preserved ejection fraction. Whether treating obesity and its cardiometabolic sequelae in Fontan patients will improve haemodynamics and outcomes requires further study.

This randomized trial tested the effect of metformin on glycemic control and cardiac function in patients with heart failure (HF) and type 2 diabetes while evaluating intestinal effects on selected gut microbiome products reflected by trimethylamine-N-oxide (TMAO) and gut-derived incretins. Metformin treatment improved glycemic control and postprandial metabolism and enhanced postprandial glucagon-like peptide 1 (GLP-1) secretion but did not influence cardiac function or the TMAO levels. Metabolic effects of metformin in HF may be mediated by an improvement in intestinal endocrine function and enhanced secretion of the gut-derived incretin GLP-1.

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a major cause of morbidity and mortality in patients with type 2 diabetes (T2D). Acute increases in circulating levels of ketone body 3-hydroxybutyrate have beneficial acute hemodynamic effects in patients without T2D with chronic heart failure with reduced ejection fraction. However, the cardiovascular effects of prolonged oral ketone ester (KE) treatment in patients with T2D and HFpEF remain unknown. METHODS: A total of 24 patients with T2D and HFpEF completed a 6-week randomized, double-blind crossover study. All patients received 2 weeks of KE treatment (25 g D-ß-hydroxybutyrate-(R)-1,3-butanediol × 4 daily) and isocaloric and isovolumic placebo, separated by a 2-week washout period. At the end of each treatment period, patients underwent right heart catheterization, echocardiography, and blood samples at trough levels of intervention, and then during a 4-hour resting period after a single dose. A subsequent second dose was administered, followed by an exercise test. The primary end point was cardiac output during the 4-hour rest period. RESULTS: During the 4-hour resting period, circulating 3-hydroxybutyrate levels were 10-fold higher after KE treatment (1010±56 µmol/L; P <0.001) compared with placebo (91±55 µmol/L). Compared with placebo, KE treatment increased cardiac output by 0.2 L/min (95% CI, 0.1 to 0.3) during the 4-hour period and decreased pulmonary capillary wedge pressure at rest by 1 mm Hg (95% CI, –2 to 0) and at peak exercise by 5 mm Hg (95% CI, –9 to –1). KE treatment decreased the pressure-flow relationship (∆ pulmonary capillary wedge pressure/∆ cardiac output) significantly during exercise ( P <0.001) and increased stroke volume by 10 mL (95% CI, 0 to 20) at peak exercise. KE right-shifted the left ventricular end-diastolic pressure-volume relationship, suggestive of reduced left ventricular stiffness and improved compliance. Favorable hemodynamic responses of KE treatment were also observed in patients treated with sodium-glucose transporter-2 inhibitors and glucagon-like peptide-1 analogs. CONCLUSIONS: In patients with T2D and HFpEF, a 2-week oral KE treatment increased cardiac output and reduced cardiac filling pressures and ventricular stiffness. At peak exercise, KE treatment markedly decreased pulmonary capillary wedge pressure and improved pressure-flow relationship. Modulation of circulating ketone levels is a potential new treatment modality for patients with T2D and HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05236335.

BACKGROUND: Systemic arterial compliance and venous capacitance are typically impaired in patients with heart failure with preserved ejection fraction (HFpEF), contributing to hemodynamic congestion with stress. Sodium-glucose cotransporter-2 inhibitors reduce hemodynamic congestion and improve clinical outcomes in patients with HFpEF, but the mechanisms remain unclear. This study tested the hypothesis that Dapagliflozin would improve systemic arterial compliance and venous capacitance during exercise in patients with HFpEF. METHODS: In this secondary analysis from the CAMEO-DAPA trial (Cardiac and Metabolic Effects of Dapagliflozin in Heart Failure With Preserved Ejection Fraction Trial), 37 patients with HFpEF (mean age 68 ± 9 years, women 65%) underwent invasive hemodynamic exercise testing with simultaneous echocardiography at baseline and following treatment for 24 weeks with Dapagliflozin or placebo. Radial artery pressure (BP) was measured continuously using a fluid-filled catheter with transformation to aortic pressure, central hemodynamics were measured using high-fidelity micromanometers, and stressed blood volume was estimated from hemodynamic indices fit to a comprehensive cardiovascular model. RESULTS: There was no statistically significant effect of Dapagliflozin on resting BP, but Dapagliflozin reduced systolic BP during peak exercise (estimated treatment difference [ETD], −18.8 mm Hg [95% CI, −33.9 to −3.7] P =0.016). Reduction in BP was related to improved exertional total arterial compliance (ETD, 0.06 mL/mm Hg/m 2 [95% CI, 0.003–0.11] P =0.039) and aortic root characteristic impedance (ETD, −2.6 mm Hg/mL*sec [95% CI: −5.1 to −0.03] P =0.048), with no significant effect on systemic vascular resistance. Dapagliflozin reduced estimated stressed blood volume at rest and during peak exercise (ETD, −292 mm Hg [95% CI, −530 to −53] P =0.018), and improved venous capacitance evidenced by a decline in ratio of estimated stressed blood volume to total blood volume (ETD, −7.3% [95% CI, −13.3 to −1.3] P =0.020). Each of these effects of Dapagliflozin at peak exercise were also observed during matched 20W exercise intensity. Improvements in total arterial compliance and estimated stressed blood volume were correlated with decreases in body weight, and reduction in systolic BP with treatment was correlated with the change in estimated stressed blood volume during exercise (r=0.40, P =0.019). Decreases in BP were correlated with reduction in pulmonary capillary wedge pressure during exercise (r=0.56, P <0.001). CONCLUSIONS: In patients with HFpEF, treatment with Dapagliflozin improved systemic arterial compliance and venous capacitance during exercise, while reducing aortic characteristic impedance, suggesting a reduction in arterial wall stiffness. These vascular effects may partially explain the clinical benefits with sodium-glucose cotransporter-2 inhibitors in HFpEF. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04730947.

Abstract Aims The clinical utility of pulmonary hypertension (PH) risk scores in non-group 1 PH with pulmonary vascular disease (PVD) remains unresolved. Methods and results We utilized the prospective multicenter PVDOMICS cohort with group 2, 3, 4 or 5 PH-related PVD and calculated group 1 PH risk scores (REVEAL 2.0, REVEAL Lite 2, French registry score and COMPERA 2). The c-statistic to predict death was compared separately in (i) pre-capillary PH groups 3/4/5, and (ii) combined post- and pre-capillary PH group 2. Exercise right heart catheterization reserve, ventricular interdependence and right ventricular–pulmonary artery (RV-PA) coupling were compared across risk categories. Among 449 individuals with group 3/4/5 PH, the REVEAL 2.0 risk score had the highest c-statistic for predicting death (0.699, 95% confidence interval [CI] 0.660–0.737, p &lt; 0.0001) with comparable performance using the simpler REVEAL Lite 2 score (0.695, 95% CI 0.656–0.734, p &lt; 0.0001). The French and COMPERA 2 risk scores were also predictive of mortality, but performance of both was statistically inferior to REVEAL 2.0 (c-statistic difference −0.072, 95% CI −0.123 to −0.020, p = 0.006, and −0.043, 95% CI −0.067 to −0.018, p = 0.0007, respectively). RV function and RV-PA coupling measures were prognostic in isolation, but did not add incremental value to REVEAL (p &gt; 0.50 for all). Findings were similar in patients with group 2 PH (n = 239). Stratification by the REVEAL Lite 2 score non-invasively identified non-group 1 PH with more advanced PVD with worse exercise capacity, RV-PA uncoupling, ventricular interdependence and impaired cardiac output reserve (p &lt; 0.05 for all). Conclusions Non-invasive REVEAL risk predicts mortality in non-group 1 PH without incremental prognostic value from detailed RV function or RV-PA coupling assessment. Baseline REVEAL Lite 2 risk stratification non-invasively identifies greater pulmonary vascular dysfunction and right heart-related exercise limitation, which may help guide patient selection for targeted pulmonary vascular therapies in non-group 1 PH.

ImportanceIncreases 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.ObjectiveTo test the effect of dapagliflozin on right ventricular performance and pulmonary vascular load during exertion in HFpEF.Design, Setting, and ParticipantsEvaluation 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.InterventionsDapagliflozin or placebo for 24 weeks.Main Outcomes and MeasuresPulsatile pulmonary vascular load (PA compliance and elastance) and right ventricular performance (PA pulsatility index, RV systolic velocity [s′]/PA mean) during rest and exercise.ResultsAmong 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 &amp;lt;.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 RelevanceResults 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 RegistrationClinicalTrials.gov Identifier: NCT04730947