Exercise Pulmonary Capillary Wedge Pressure Research Articles

Left atrial to coronary sinus shunting for treatment of heart failure with mildly reduced or preserved ejection fraction: The ALT FLOW Early Feasibility Study 1-year results.

Patients with heart failure and mildly reduced or preserved ejection fraction have limited therapeutic options. The ALT-FLOW Early Feasibility Study evaluated safety, haemodynamics and outcomes for the APTURE transcatheter shunt system, a novel left atrium to coronary sinus shunt in these patients. Safety and shunt implantation success was evaluated for all 116 enrolled patients. An analysis population of implanted patients with a left ventricular ejection fraction (LVEF) >40% (n = 95) was chosen to assess efficacy via paired comparison between baseline and follow-up haemodynamic (3 and 6 months), and echocardiographic, clinical and functional outcomes (6 months and 1 year). Health status and quality of life outcomes were assessed using the Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS). The primary safety endpoint, major adverse cardiac, cerebral, and renal events, and reintervention through 30 days, occurred in 3/116 patients (2.6%). All implanted shunts were patent at 1 year. In patients with LVEF >40%, the mean (95% confidence interval) reduction in exercise pulmonary capillary wedge pressure (PCWP) at 20 W was -5.7 (-8.6, -2.9) mmHg at 6 months (p < 0.001). At baseline, 8% had New York Heart Association class I-II status and improved to 68% at 1 year (p < 0.001). KCCQ-OSS at baseline was 39 (35, 43) and improved at 6 months and 1 year by 25 (20-30) and 27 (22-32) points, respectively (both p < 0.0001). No adverse changes in haemodynamic and echocardiographic indices of right heart function were observed at 1 year. Overall, the reduction in PCWP at 20 W and improvement in KCCQ-OSS in multiple subgroups were consistent with those observed for the entire population. In patients with heart failure and LVEF >40%, the APTURE shunt demonstrated an acceptable safety profile with significant sustained improvements in haemodynamic and patient-centred outcomes, underscoring the need for further evaluation of the APTURE shunt in a randomized trial.

Cardiovascular Effects of Oral Ketone Ester Treatment in Patients With Heart Failure With Reduced Ejection Fraction: A Randomized, Controlled, Double-Blind Trial.

Heart failure triggers a shift in myocardial metabolic substrate utilization, favoring the ketone body 3-hydroxybutyrate as energy source. We hypothesized that 14-day treatment with ketone ester (KE) would improve resting and exercise hemodynamics and exercise capacity in patients with heart failure with reduced ejection fraction. In a randomized, double-blind cross-over study, nondiabetic patients with heart failure with reduced ejection fraction received 14-day KE and 14-day isocaloric non-KE comparator regimens of 4 daily doses separated by a 14-day washout period. After each treatment period, participants underwent right-sided heart catheterization, echocardiography, and blood sampling at plasma trough levels and after dosing. Participants underwent an exercise hemodynamic assessment after a second dosing. The primary end point was resting cardiac output (CO). Secondary end points included resting and exercise pulmonary capillary wedge pressure and peak exercise CO and metabolic equivalents. We included 24 patients with heart failure with reduced ejection fraction (17 men; 65±9 years of age; all White). Resting CO at trough levels was higher after KE compared with isocaloric comparator (5.2±1.1 L/min versus 5.0±1.1 L/min; difference, 0.3 L/min [95% CI, 0.1-0.5), and pulmonary capillary wedge pressure was lower (8±3 mm Hg versus 11±3 mm Hg; difference, -2 mm Hg [95% CI, -4 to -1]). These changes were amplified after KE dosing. Across all exercise intensities, KE treatment was associated with lower mean exercise pulmonary capillary wedge pressure (-3 mm Hg [95% CI, -5 to -1] ) and higher mean CO (0.5 L/min [95% CI, 0.1-0.8]), significantly different at low to moderate steady-state exercise but not at peak. Metabolic equivalents remained similar between treatments. In exploratory analyses, KE treatment was associated with 18% lower NT-proBNP (N-terminal pro-B-type natriuretic peptide; difference, -98 ng/L [95% CI, -185 to -23]), higher left ventricular ejection fraction (37±5 versus 34±5%; P=0.01), and lower left atrial and ventricular volumes. KE treatment for 14 days was associated with higher CO at rest and lower filling pressures, cardiac volumes, and NT-proBNP levels compared with isocaloric comparator. These changes persisted during exercise and were achieved on top of optimal medical therapy. Sustained modulation of circulating ketone bodies is a potential treatment principle in patients with heart failure with reduced ejection fraction. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05161650.

Endovascular Ablation of the Right Greater Splanchnic Nerve in Heart Failure With Preserved Ejection Fraction: Rationale, Design and Lead-in Phase Results of the REBALANCE-HF Trial

IntroductionSplanchnic vasoconstriction augments transfer of blood volume from the abdomen into the thorax, which may increase filling pressures and hemodynamic congestion in patients with noncompliant hearts. Therapeutic interruption of splanchnic nerve activity holds promise to reduce hemodynamic congestion in patients with heart failure with preserved ejection fraction (HFpEF). Here we describe (1) the rationale and design of the first sham-controlled randomized clinical trial (RCT) of splanchnic nerve ablation for HFpEF; and (2) the 12-month results of the lead-in (open-label) trial participants. MethodsREBALANCE-HF is a prospective, multicenter, randomized, double-blinded, sham-controlled clinical trial of endovascular, transcatheter right-sided greater splanchnic nerve ablation for volume management (SAVM) in patients with HFpEF. The primary objectives are to evaluate the safety and efficacy of SAVM and identify responder characteristics to inform future studies. The trial consists of an open-label lead-in phase followed by the randomized, sham-controlled phase. The primary efficacy endpoint is the reduction in pulmonary capillary wedge pressure (PCWP) at 1-month follow-up compared to baseline during passive leg raise and 20W exercise. Secondary and exploratory endpoints include health status (Kansas City Cardiomyopathy Questionnaire), 6-minute walk test distance, New York Heart Association, and NTproBNP at 3, 6, and 12 months. The primary safety endpoint is device- or procedure-related serious adverse events at 1-month follow-up. ResultsThe lead-in phase of the study, which enrolled 26 HFpEF patients who underwent SAVM, demonstrated favorable safety outcomes and reduction in exercise PCWP at 1-month post-procedure; and improvements in all secondary endpoints at 6 and 12 months of follow-up. The randomized phase of the trial (n=44 SAVM, n=46 sham) has completed enrollment, and follow-up is ongoing. ConclusionREBALANCE-HF is the first sham-controlled RCT of greater splanchnic nerve ablation in HFpEF. Initial 12-month open-label results are promising, and the results of the randomized portion of the trial will inform the design of a future pivotal clinical trial. SAVM may offer a promising therapeutic option for patients with HFpEF. Trial RegistrationNCT04592445

Right Ventricular-Vascular Uncoupling Predicts Pulmonary Hypertension in Clinically Diagnosed Heart Failure With Preserved Ejection Fraction.

Pulmonary hypertension (PH) is highly prevalent in patients with heart failure with preserved ejection fraction (HFpEF), and it is a strong predictor of adverse outcomes. We aimed to determine possible echocardiographic parameters to predict the presence of PH in patients with HFpEF. A total of 113 patients with HFpEF were prospectively enrolled from November 2017 to July 2022. The patients underwent invasive cardiac catheterization and simultaneous echocardiography at rest and during exercise. The parameters indicating right ventricle-pulmonary artery uncoupling, including tricuspid annular plane systolic excursion (TAPSE)/pulmonary artery systolic pressure (PASP) and tricuspid annular systolic velocity (TAS')/PASP were calculated. Receiver operating characteristic curve analysis was used to determine the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH. Sixty-eight patients with HFpEF with PH and 45 without PH were included. Those with PH had lower TAPSE/PASP and TAS'/PASP at rest and during exercise compared with those without PH. Both resting/stress TAPSE/PASP and TAS'/PASP were correlated with rest/exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In multivariable regression analysis, TAPSE/PASP remained a significant predictor of exercise pulmonary capillary wedge pressure and mean pulmonary artery pressure. In receiver operating characteristic curve analysis, the optimal cut-off points of TAPSE/PASP and TAS'/PASP to differentiate patients with HFpEF with PH from those without PH were ≤0.62 and ≤0.47, respectively. Right ventricle-pulmonary artery uncoupling is closely correlated with abnormal rest/exercise hemodynamics (pulmonary capillary wedge pressure and mean pulmonary artery pressure) in patients with HFpEF. TAPSE/PASP and TAS'/PASP can be useful parameters to detect PH in patients with HFpEF.

Obesity in heart failure with preserved ejection fraction: Insights from the REDUCE LAP-HF II trial.

Obesity is causally related to the development of heart failure with preserved ejection fraction (HFpEF) but complicates the diagnosis and treatment of this disorder. We aimed to determine the relationship between severity of obesity and clinical, echocardiographic and haemodynamic parameters in a large cohort of patients with documented HFpEF. The REDUCE LAP-HF II trial randomized 626 patients with ejection fraction ≥40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg to atrial shunt or sham procedure. We tested for associations between body mass index (BMI), clinical characteristics, cardiac structural and functional abnormalities, physical limitations, quality of life and outcomes with atrial shunt therapy. Overall, 60.9% of patients had BMI ≥30 kg/m2 . As the severity of obesity increased, symptoms (Kansas City Cardiomyopathy Questionnaire score) and 6-min walk distance worsened. More severe obesity was associated with lower natriuretic peptide levels despite more cardiac remodelling, higher cardiac filling pressures, and higher cardiac output. Lower cut points for E/e' were needed to identify elevated PCWP in more obese patients. Strain measurements in all four chambers were maintained as BMI increased. Pulmonary vascular resistance at rest and exercise decreased with higher BMI. Obesity was associated with more first and recurrent heart failure events. However, there was no significant interaction between obesity and treatment effects of the atrial shunt. Increasing severity of obesity was associated with greater cardiac remodelling, higher right and left ventricular filling pressures, higher cardiac output and increased subsequent heart failure events. Despite significant obesity, many HFpEF patients have preserved right heart and pulmonary vascular function and thus, may be appropriate candidates for atrial shunt therapy.

Post-exercise left atrial conduit strain predicted hemodynamic change in heart failure with preserved ejection fraction.

Left ventricle function directly impacts left atrial (LA) conduit function, and LA conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction (HFpEF). Pulmonary capillary wedge pressure (PCWP) before and during exercise is the current gold standard for diagnosing HFpEF. Post-exercise ΔPCWP can lead to worse long-term outcomes. This study examined the correlation between LA strain and post-exercise ΔPCWP in patients with HFpEF. We enrolled 100 subjects, including 74 with HFpEF and 26 with non-cardiac dyspnea, from November 2017 to December 2020. Subjects underwent echocardiography, invasive cardiac catheterization, and expired gas analysis at rest and during exercise. Arterial blood pressure, right atrial pressure, pulmonary artery pressure, and PCWP were recorded during cardiac catheterization. Cardiac output, stroke volume, pulmonary vascular resistance, pulmonary artery compliance, systemic vascular resistance, and LV stroke work were calculated using standard formulas. Exercise LA conduit strain significantly correlated with both post-exercise ΔPCWP (r =  - 0.707, p < 0.001) and exercise PCWP (r =  - 0.659; p < 0.001). Exercise LA conduit strain differentiated patients who did and did not meet the 2016 European Society of Cardiology HFpEF criteria with an area under the curve of 0.69 (95% confidence interval, 0.548-0.831) using a cutoff value of 14.25, with a sensitivity of 0.64 and a specificity of 0.68. Exercise LA conduit strain significantly correlates with post-exercise ΔPCWP and has a comparable power to identify patients with HFpEF. Additional studies are warranted to confirm the ability of LA conduit strain to predict long-term outcomes among patients with HFpEF. Exercise left atrial conduit strain was highly associated with the difference of post-exercise pulmonary capillary wedge pressure and may indicate increased mortality risk in patients with heart failure with preserved ejection fraction, and also has comparable diagnostic ability. • Left atrial conduit strain is associated with exercise intolerance in patients with heart failure with preserved ejection fraction. • Left atrial conduit strain during exercise can identify patients with heart failure with preserved ejection fraction. • Exercise left atrial conduit strain significantly correlates with the difference of pulmonary capillary wedge pressure during and before exercise which might predict the long-term outcomes of heart failure with preserved ejection fraction patients.

Diastolic exercise stress testing in heart failure with preserved ejection fraction: The DEST-HF study.

Pulmonary capillary wedge pressure (PAWP) ≥25 mmHg during bicycle ergometry is recommended to uncover occult heart failure with preserved ejection fraction. We hypothesized that PAWP increase would differ in available diastolic stress tests and that the margin of PAWP ≥25 mmHg would only be reliably achieved through ergometry. We conducted a prospective, single-arm study in patients with an intermediate risk for heart failure with preserved ejection fraction according to the ESC HFA-PEFF score. A total of 19 patients underwent four stress test modalities in randomized order: leg raise, fluid challenge, handgrip, and bicycle ergometry. The primary outcome was the difference (Δ) between resting and exercise PAWP in each modality. Secondary outcomes were differences (Δ) in mean pulmonary artery pressure (mPAP), cardiac output (CO), as well as the ratios between mPAP and PAWP to CO. Compared to resting values, passive leg raise (Δ7.7 ± 8.0 mmHg, p = 0.030), fluid challenge (Δ9.2 ± 6.4 mmHg, p = 0.003), dynamic handgrip (Δ9.6 ± 7.5 mmHg, p = 0.002), and bicycle ergometry (Δ22.3 ± 5.0 mmHg, p < 0.001) uncovered increased PAWP during exercise. Amongst these, bicycle ergometry also demonstrated the highest ΔmPAP (27.2 ± 7.1 mmHg, p < 0.001), ΔCO (3.3 ± 2.6 L/min, p < 0.001), ΔmPAP/CO ratio (2.3 ± 2.0 mmHg/L/min, p < 0.001), and ΔPAWP/CO ratio (2.2 ± 1.4 mmHg/L/min, p < 0.001) compared to other modalities. PAWP ≥25 mmHg was only reliably achieved in bicycle ergometry (31.1 ± 3.9 mmHg). In all other modalities only 10.5% of patients achieved PAWP ≥25 mmHg (handgrip 18.4 ± 6.6 mmHg, fluid 18.1 ± 5.6 mmHg, leg raise 16.5 ± 7.0 mmHg). We demonstrate that bicycle ergometry exhibits a distinct haemodynamic response with higher increase of PAWP compared to other modalities. This finding needs to be considered for valid detection of exercise PAWP ≥25 mmHg when non-bicycle tests remain inconclusive.

No-Implant Interatrial Shunt for HFpEF: 6-Month Outcomes From Multicenter Pilot Feasibility Studies

BackgroundMost approaches to the creation of an interatrial shunt require placement of a permanent implant to maintain patency. ObjectivesThe goal of this study was to investigate the safety and efficacy of a no-implant interatrial shunt for patients with heart failure with preserved ejection fraction (HFpEF) and heart failure with mildly reduced ejection fraction (HFmrEF). MethodsThis was a multicenter, uncontrolled study of patients with HFpEF/HFmrEF and NYHA functional class ≥II, ejection fraction >40%, and pulmonary capillary wedge pressure (PCWP) during supine exercise ≥25 mm Hg with PCWP-to–right atrial gradient ≥5 mm Hg. Follow-up was through 6 months with imaging to assess shunt durability. ResultsA total of 28 patients were enrolled: mean age was 68 ± 9 years, and 68% were female. Baseline resting and peak exercise PCWP were 19 ± 7 mm Hg and 40 ± 11 mm Hg, respectively. All procedures displayed technical success with confirmation of left-to-right flow (shunt diameter 7.1 ± 0.9 mm). At 1 month, peak exercise PCWP decreased 5.4 ± 9.6 mm Hg (P = 0.011) with no change in right atrial pressure. There were no serious device or procedure-related adverse events through 6 months. Mean 6-minute walk distance increased 101 ± 71 meters (P < 0.001); Kansas City Cardiomyopathy Questionnaire Overall Summary Score increased 26 ± 19 points (P < 0.001); N-terminal pro–B-type natriuretic peptide decreased 372 ± 857 pg/mL (P = 0.018); and shunt patency was confirmed with unchanged diameter. ConclusionsIn these feasibility studies of a no-implant interatrial shunt, HFpEF/HFmrEF shunts exhibited stability with favorable safety and early efficacy signals. The results show promise toward this new approach for treating patients with HFpEF/HFmrEF and an appropriate hemodynamic profile. (Evaluation of the Safety and Feasibility of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-1]; NCT04583527; Evaluation of the Safety and Effectiveness of a Percutaneously Created Interatrial Shunt to Alleviate Heart Failure Symptoms in Patients With Chronic Heart Failure and Preserved or Mid-Range Left Ventricular Ejection Fraction [ALLEVIATE-HF-2]; NCT04838353)

SERCA2a Agonist Effects on Cardiac Performance During Exercise in Heart Failure With Preserved Ejection Fraction

BackgroundImpaired ventricular relaxation influences left ventricular pressures during exercise in heart failure with preserved ejection fraction (HFpEF). Sarco/endoplasmic reticulum calcium-adenosine triphosphatase (SERCA2a) facilitates myocardial relaxation by increasing calcium reuptake and is impaired in HFpEF. ObjectivesThis study sought to investigate the effects of istaroxime, a SERCA2 agonist, on lusitropic and hemodynamic function during exercise in patients with HFpEF and control subjects. MethodsEleven control subjects (7 male, 4 female) and 15 patients with HFpEF (8 male, 7 female) performed upright cycle exercise with right-sided heart catheterization. Participants received istaroxime (0.5 μg/kg/min) or saline placebo (single-blind, crossover design). Cardiac output, pulmonary capillary wedge pressure (PCWP), and diastolic function were measured at rest and during submaximal exercise. In an exploratory analysis (Hedge's g), 7 patients with HFpEF received higher-dose istaroxime (1.0 μg/kg/min). End-systolic elastance (Ees) was calculated by dividing systolic blood pressure (SBP) × 0.9 by end-systolic volume (ESV) (on 3-dimensional echocardiography). ResultsPatients with HFpEF had higher PCWP (25 ± 10 mm Hg vs 12 ± 5 mm Hg; P < 0.001) and lower tissue Doppler velocities during exercise. Istaroxime (0.5 μg/kg/min) had no effect on resting or exercise measures in patients with HFpEF or control subjects. Control subjects had a larger increase in Ees (Δ 1.55 ± 0.99 mm Hg/mL vs Δ 0.86 ± 1.31 mm Hg/mL; P = 0.03), driven by lower ESV. Comparing placebo and istaroxime 1.0 μg/kg/min during exercise, PCWP during the 1.0 μg/kg/min istaroxime dose was slightly lower (Δ 2.2 mm Hg; Hedge's g = 0.30). There were no effects on diastolic function, but there were increases in SBP and s′, suggesting a mild inotropic effect. ConclusionsLow-dose istaroxime had no effect on cardiac filling pressure or parameters of relaxation in patients with HFpEF during exercise. Higher doses of istaroxime may have been more effective in reducing exercise PCWP in patients with HFpEF. (Hemodynamic Response to Exercise in HFpEF Patients After Upregulation of SERCA2a; NCT02772068)

Left Atrial to Coronary Sinus Shunting for Treatment of Symptomatic Heart Failure

BackgroundHeart failure (HF) is associated with both mortality and a significant decline in health status. Interatrial shunting is increasingly being investigated as a novel therapeutic option. ObjectivesThe ALT FLOW Early Feasibility Study was designed to evaluate the safety of the Edwards left atrial to coronary sinus APTURE Transcatheter Shunt System in patients with symptomatic HF. MethodsA total of 18 centers enrolled patients with symptomatic HF with a pulmonary capillary wedge pressure >15 mm Hg at rest or 25 mm Hg during exercise. ResultsBetween May 2018 and September 2022, 87 patients underwent attempted APTURE shunt implantation. Mean age was 71 years, and 53% were male. At baseline, mean left ventricular ejection fraction was 59% with 90% of the patients being in NYHA functional class III. Device success was achieved in 78 patients (90%), with no device occlusions or associated adverse events identified after implantation. The primary safety outcome occurred in only 2 patients (2.3%) at 30 days. At 6 months, health status improved: 67% of participants achieved NYHA functional class I to II status, with a 23-point improvement (P < 0.0001; 95% CI: 17-29 points) in the Kansas City Cardiomyopathy Questionnaire overall summary score. Also at 6 months, 20-W exercise pulmonary capillary wedge pressure was 7 mm Hg lower (P < 0.0001; 95% CI: −11 to −4 mm Hg) without change in right atrial pressure or other right heart function indices. ConclusionsIn this single-arm experience, the APTURE Transcatheter Shunt System in patients with symptomatic HF was observed to be safe and resulted in reduction in pulmonary capillary wedge pressure and clinically meaningful improvements in HF symptoms and quality of life indices.

Atrial Fibrillation Ablation for Heart Failure With Preserved Ejection Fraction: A Randomized Controlled Trial

BackgroundPatients with heart failure with preserved ejection fraction (HFpEF) frequently develop atrial fibrillation (AF). There are no randomized trials examining the effects of AF ablation on HFpEF outcomes. ObjectivesThe aim of this study is to compare the effects of AF ablation vs usual medical therapy on markers of HFpEF severity, including exercise hemodynamics, natriuretic peptide levels, and patient symptoms. MethodsPatients with concomitant AF and HFpEF underwent exercise right heart catheterization and cardiopulmonary exercise testing. HFpEF was confirmed with pulmonary capillary wedge pressure (PCWP) of 15 mm Hg at rest or ≥25 mm Hg on exercise. Patients were randomized to AF ablation vs medical therapy, with investigations repeated at 6 months. The primary outcome was change in peak exercise PCWP on follow-up. ResultsA total of 31 patients (mean age: 66.1 years; 51.6% females, 80.6% persistent AF) were randomized to AF ablation (n = 16) vs medical therapy (n = 15). Baseline characteristics were comparable across both groups. At 6 months, ablation reduced the primary outcome of peak PCWP from baseline (30.4 ± 4.2 to 25.4 ± 4.5 mm Hg; P < 0.01). Improvements were also seen in peak relative VO2 (20.2 ± 5.9 to 23.1 ± 7.2 mL/kg/min; P < 0.01), N-terminal pro–B-type natriuretic peptide levels (794 ± 698 to 141 ± 60 ng/L; P = 0.04), and MLHF (Minnesota Living with Heart Failure) score (51 ± −21.9 to 16.6 ± 17.5; P < 0.01). No differences were detected in the medical arm. Following ablation, 50% no longer met exercise right heart catheterization–based criteria for HFpEF vs 7% in the medical arm (P = 0.02). ConclusionsAF ablation improves invasive exercise hemodynamic parameters, exercise capacity, and quality of life in patients with concomitant AF and HFpEF.

Abstract 12714: Impact of Reduced Left Ventricular Filling Pressure on Diastolic Function During Exercise in Patients With HFpEF

Background: During exercise, patients with heart failure with preserved ejection fraction (HFpEF) have an exaggerated increase in pulmonary capillary wedge pressure (PCWP) and left atrial-left ventricular pressure gradient (E wave velocity), as well as a blunted increase in early diastolic recoil (e’ velocity). It is unknown if non-invasive markers of diastolic function improve when exercise PCWP is acutely ameliorated. Methods: Patients with invasively proven HFpEF (n = 34, 71±6 years, 59% female, PCWP &gt; 25 or Δ15 mm hg at peak exercise) underwent 2 seated cycle exercise tests with sublingual nitroglycerin (NTG) and placebo (PLB) in a cross-over design. PCWP (right heart catheter), tissue Doppler velocities of the mitral annulus (e’) and mitral inflow velocities (E) were measured at rest and during 20-watt submaximal steady state exercise. Differences between placebo and GTN conditions were assessed by repeated measures mixed model. Results: PCWP was 7.6±3.9 mmHg at rest and 21.1±7.8 mmHg with sub-maximal exercise and was decreased by 14% and 24% respectively by NTG (Drug effect p &lt; 0.001, Figure ). Mean E’ was 6.2±1.5 cm/sec at rest and 8.8±1.7 cm/sec during exercise and was decreased by 6% and 8% respectively by NTG (p = 0.003), but augmentation during exercise was unchanged (NTG +36%, PLB +41%, p = 0.211). The E wave velocity was 69.6±21.2 cm/sec rest and 101.9±31.3 cm/sec during exercise and was decreased by 12% and 11% with NTG respectively (p &lt;0.001), but augmentation during exercise was unchanged (NTG +48%, PLB +46%, p = 0.507). Conclusions: NTG significantly and acutely lowered exercise PCWP in patients with HFpEF but did not improve diastolic function as assessed by echocardiography. The symmetrical slowing of E wave velocity and e’ with reduced PCWP demonstrate that higher preload helps maintain diastolic recoil and early diastolic filling for patients with HFpEF. Therapies that reduce preload in HFpEF may result in apparently worsened markers of diastolic function.

Catheter ablation in atrial fibrillation and heart failure with preserved ejection fraction improves peak pulmonary capillary wedge pressure, exercise capacity and quality of life: RCT STALL HFpEF

Abstract Introduction Atrial fibrillation (AF) frequently accompanies heart failure with preserved ejection fraction (HFpEF). AF exacerbates HFpEF through adverse haemodynamic effects. In turn, HFpEF promotes AF through adverse left atrial remodelling. Observational data suggest sinus rhythm restoration improves outcomes in patients with AF and HFpEF. However, there are no randomised data examining the effects of rhythm control with catheter-based AF ablation on HFpEF outcomes. Purpose To compare the effects of AF ablation versus usual medical therapy on markers of HFpEF severity, including exercise haemodynamics, natriuretic peptide levels and patient symptoms. Methods Patients with symptomatic AF and HFpEF underwent exercise right heart catheterization (RHC) and cardiopulmonary exercise testing (CPET). HFpEF diagnosis was based on left ventricular ejection fraction (LVEF) ≥50%, elevated natriuretic peptide and echocardiographic diastolic impairment. HFpEF was confirmed on exercise RHC based on peak exercise pulmonary capillary wedge pressure (PCWP) of ≥25mmHg. Patients were randomised to AF ablation versus medical therapy, with investigations repeated at 6 months. The primary outcome was change in PCWP on follow-up. Results 31 patients aged 66.1±7.5 years were randomized to AF ablation (16) versus medical therapy (15), with 51.6% female and 80.6% persistent AF. Baseline characteristics were comparable across groups. Paired analyses of ablation cohort showed significant reductions in peak PCWP (29.6±3.7 vs 25.9±4.6 mmHg, p&amp;lt;0.01), PCWP indexed for workload (39.0±57.9 vs 33.0±50.5 mmHg/W/kg, p&amp;lt;0.01), and BNP (146.2±80.5 vs 82.2±75.4 pg/mL, p=0.01); and increased resting cardiac output (4.6±0.9 vs 5.6±1.2 L/min, p=0.01), peak cardiac output (9.6±4.2 vs 10.4±3.7 L/min, p=0.02), peak (30s averaged) VO2 (1875.1±759.2 vs 2193.7±878.1 mL/min, p&amp;lt;0.01), peak absolute VO2 (1937.3±739.3 vs 2216.3±861.9 mL/min, p&amp;lt;0.01), peak (30s averaged) relative VO2 (19.4±5.9 vs 22.9±7.4 ml/kg/min) and peak workload (162.0±81.1 vs 184.4±83.4 W, p&amp;lt;0.01). Quality of life scores improved: AFEQT (45.3±20.9 vs 75±20.7, p&amp;lt;0.01) and MLHF (53±23.3 vs 17.5±22.8, p&amp;lt;0.01). Reversal of HFpEF by PCWP criteria occurred in 31.2% following AF ablation, and 50% among those free from arrhythmia recurrence. In the medical arm, there were no significant differences in RHC, CPET, and natriuretic peptide outcomes on follow-up versus baseline. Repeated measures mixed ANOVA testing showed significant time-randomisation interaction on peak VO2, absolute peak VO2, peak relative VO2, AFEQT/ MLHF scores, suggesting that significant improvements in these parameters were related to AF ablation. Conclusion In patients with concomitant AF and HFpEF, AF ablation improves invasive exercise haemodynamic parameters, increases exercise capacity, and enhances quality of life. Successful AF ablation may reverse the clinical syndrome of HFpEF in a subset of cases. Funding Acknowledgement Type of funding sources: None.

Trimetazidine in heart failure with preserved ejection fracton: a randomized, double-blind cross-over trial

Abstract Introduction Impaired myocardial mitochondrial function plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and there is evidence indicative of a causal relationship between observed impaired energy homeostasis and diastolic dysfunction. Improvement of mitochondrial function with metabolism-modulating drugs may be a promising novel therapeutic approach in HFpEF. Trimetazidine – a fatty acid oxidation inhibitor – shifts mitochondrial metabolism towards glucose oxidation, which results in higher mitochondrial oxygen efficiency. In this study we investigated whether trimetazidine improves diastolic function during exercise in HFpEF by improving the myocardial energy homeostasis. Methods The DoPING-HFpEF trial was a phase II single-center, double-blind, placebo-controlled, randomized cross-over trial. The study consisted of two treatment periods of three months separated by a 2-week wash-out period (Figure 1). Patients were treated with placebo or trimetazidine three times a day (or twice daily in case of an impaired kidney function). The primary endpoint was change in pulmonary capillary wedge pressure (PCWP) measured with right heart catheterization at multiple stages of exercise. Secondary endpoint was change in phosphocreatine (PCr)/adenosine triphosphate (ATP) ratio, an index of the myocardial energy status, measured with phosphorus-31 magnetic resonance (MR) spectroscopy. Additional exploratory endpoints were 6-minute-walking-distance, diastolic and systolic parameters measured with echocardiography or cardiac MR, NT-proBNP levels, and quality of life. Results Twenty-five HFpEF patients were included and completed the trial, 80% of which were included based on previously established elevated (exercise) PCWP, and 20% were included based on diastolic dysfunction grade ≥II on echocardiography and elevated NT-proBNP levels. There was no effect on the primary outcome PCWP at multiple levels of exercise, with an average change in PCWP of 0±4 (SD) mmHg (Figure 2A, P=0.97). Myocardial PCr/ATP in the trimetazidine arm was similar to placebo (Figure 2B, P=0.08). There was no change by trimetazidine in the exploratory parameters 6-minute walking distance, NT-proBNP, overall quality of life, or other parameters for diastolic function measured with echocardiography and cardiac MR. There was no indication of period or cross over effect. Conclusion Trimetazidine did not improve diastolic function or myocardial energy homeostasis in patients with HFpEF. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): Dutch Heart Foundation (DHF) and “Out-of-the-Box” grant from the Amsterdam Cardiovascular Sciences (ACS) Institute, Amsterdam, The Netherlands.

Diagnosis of Heart Failure With Preserved Ejection Fraction Among Patients With Unexplained Dyspnea

Diagnosis of heart failure with preserved ejection fraction (HFpEF) among dyspneic patients without overt congestion is challenging. Multiple diagnostic approaches have been proposed but are not well validated against the independent gold standard for HFpEF diagnosis of an elevated pulmonary capillary wedge pressure (PCWP) during exercise. To evaluate H2FPEF and HFA-PEFF scores and a PCWP/cardiac output (CO) slope of more than 2 mm Hg/L/min to diagnose HFpEF. This retrospective case-control study included patients with unexplained dyspnea from 6 centers in the US, the Netherlands, Denmark, and Australia from March 2016 to October 2020. Diagnosis of HFpEF (cases) was definitively ascertained by the presence of elevated PCWP during exertion; control individuals were those with normal rest and exercise hemodynamics. Logistic regression was used to evaluate the accuracy of HFA-PEFF and H2FPEF scores to discriminate patients with HFpEF from controls. Among 736 patients, 563 (76%) were diagnosed with HFpEF (mean [SD] age, 69 [11] years; 334 [59%] female) and 173 (24%) represented controls (mean [SD] age, 60 [15] years; 109 [63%] female). H2FPEF and HFA-PEFF scores discriminated patients with HFpEF from controls, but the H2FPEF score had greater area under the curve (0.845; 95% CI, 0.810-0.875) compared with the HFA-PEFF score (0.710; 95% CI, 0.659-0.756) (difference, -0.134; 95% CI, -0.177 to -0.094; P < .001). Specificity was robust for both scores, but sensitivity was poorer for HFA-PEFF, with a false-negative rate of 55% for low-probability scores compared with 25% using the H2FPEF score. Use of the PCWP/CO slope to redefine HFpEF rather than exercise PCWP reclassified 20% (117 of 583) of patients, but patients reclassified from HFpEF to control by this metric had clinical, echocardiographic, and hemodynamic features typical of HFpEF, including elevated resting PCWP in 66% (46 of 70) of reclassified patients. In this case-control study, despite requiring fewer data, the H2FPEF score had superior diagnostic performance compared with the HFA-PEFF score and PCWP/CO slope in the evaluation of unexplained dyspnea and HFpEF in the outpatient setting.

Endovascular ablation of the right greater splanchnic nerve in heart failure with preserved ejection fraction: early results of the REBALANCE-HF trial roll-in cohort.

AimsIn heart failure (HF) with preserved ejection fraction (HFpEF), excessive redistribution of blood volume into the central circulation leads to elevations of intracardiac pressures with exercise limitations. Splanchnic ablation for volume management (SAVM) has been proposed as a therapeutic intervention. Here we present preliminary safety and efficacy data from the initial roll‐in cohort of the REBALANCE‐HF trial.Methods and resultsThe open‐label (roll‐in) arm of REBALANCE‐HF will enrol up to 30 patients, followed by the randomized, sham‐controlled portion of the trial (up to 80 additional patients). Patients with HF, left ventricular ejection fraction (LVEF) ≥50%, and invasive peak exercise pulmonary capillary wedge pressure (PCWP) ≥25 mmHg underwent SAVM. Baseline and follow‐up assessments included resting and exercise PCWP, New York Heart Association (NYHA) class, Kansas City Cardiomyopathy Questionnaire (KCCQ), 6‐min walk test, and N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). Efficacy and safety were assessed at 1 and 3 months. Here we report on the first 18 patients with HFpEF that have been enrolled into the roll‐in, open‐label arm of the study across nine centres; 14 (78%) female; 16 (89%) in NYHA class III; and median (interquartile range) age 75.2 (68.4–81) years, LVEF 61.0 (56.0–63.2)%, and average (standard deviation) 20 W exercise PCWP 36.4 (±8.6) mmHg. All 18 patients were successfully treated. Three non‐serious moderate device/procedure‐related adverse events were reported. At 1‐month, the mean PCWP at 20 W exercise decreased from 36.4 (±8.6) to 28.9 (±7.8) mmHg (p < 0.01), NYHA class improved by at least one class in 33% of patients (p = 0.02) and KCCQ score improved by 22.1 points (95% confidence interval 9.4–34.2) (p < 0.01).ConclusionThe preliminary open‐label results from the multicentre REBALANCE‐HF roll‐in cohort support the safety and efficacy of SAVM in HFpEF. The findings require confirmation in the ongoing randomized, sham‐controlled portion of the trial.

Latent Pulmonary Vascular Disease May Alter the Response to Therapeutic Atrial Shunt Device in Heart Failure.

In REDUCE LAP-HF II (A Study to Evaluate the Corvia Medical, Inc IASD System II to Reduce Elevated Left Atrial Pressure in Patients With Heart Failure), implantation of an atrial shunt device did not provide overall clinical benefit for patients with heart failure with preserved or mildly reduced ejection fraction. However, prespecified analyses identified differences in response in subgroups defined by pulmonary artery systolic pressure during submaximal exercise, right atrial volume, and sex. Shunt implantation reduces left atrial pressures but increases pulmonary blood flow, which may be poorly tolerated in patients with pulmonary vascular disease (PVD). On the basis of these results, we hypothesized that patients with latent PVD, defined as elevated pulmonary vascular resistance during exercise, might be harmed by shunt implantation, and conversely that patients without PVD might benefit. REDUCE LAP-HF II enrolled 626 patients with heart failure, ejection fraction ≥40%, exercise pulmonary capillary wedge pressure ≥25 mm Hg, and resting pulmonary vascular resistance <3.5 Wood units who were randomized 1:1 to atrial shunt device or sham control. The primary outcome-a hierarchical composite of cardiovascular death, nonfatal ischemic stroke, recurrent HF events, and change in health status-was analyzed using the win ratio. Latent PVD was defined as pulmonary vascular resistance ≥1.74 Wood units (highest tertile) at peak exercise, measured before randomization. Compared with patients without PVD (n=382), those with latent PVD (n=188) were older, had more atrial fibrillation and right heart dysfunction, and were more likely to have elevated left atrial pressure at rest. Shunt treatment was associated with worse outcomes in patients with PVD (win ratio, 0.60 [95% CI, 0.42, 0.86]; P=0.005) and signal of clinical benefit in patients without PVD (win ratio, 1.31 [95% CI, 1.02, 1.68]; P=0.038). Patients with larger right atrial volumes and men had worse outcomes with the device and both groups were more likely to have pacemakers, heart failure with mildly reduced ejection fraction, and increased left atrial volume. For patients without latent PVD or pacemaker (n=313; 50% of randomized patients), shunt treatment resulted in more robust signal of clinical benefit (win ratio, 1.51 [95% CI, 1.14, 2.00]; P=0.004). In patients with heart failure with preserved or mildly reduced ejection fraction, the presence of latent PVD uncovered by invasive hemodynamic exercise testing identifies patients who may worsen with atrial shunt therapy, whereas those without latent PVD may benefit.

Abstract 11279: Coronary Microvascular Dysfunction in Patients with Elevated Filling Pressures During Exercise

Introduction: Ischemia due to coronary microvascular dysfunction (CMD) may cause a loss of lusitropy and resultant elevated filling pressures which can worsen with exercise. CMD is prevalent in patients with heart failure with preserved ejection fraction (HFpEF) and exercise studies are useful in diagnosing early HFpEF. The relationship between CMD and early HFpEF is not well characterized. Hypothesis: CMD is prevalent in patients with elevated pulmonary capillary wedge pressure (PCWP) at rest and those with normal resting PCWP but elevated post-exercise PCWP. Methods: All patients without obstructive CAD who underwent cardiac catheterization with coronary physiology and exercise bicycle studies at the University of Chicago Medical Center between 2015-2021 were included. Elevated resting PCWP was defined as &gt; 15 and elevated post-exercise PCWP was defined as &gt; 25. Patients were separated into three groups: elevated resting PCWP (group 1), normal resting &amp; elevated exercise PCWP (group 2), and normal resting and exercise PCWP (group 3). Results: A total of 22 patients (mean age 56 + 10 years, 77% female) were studied. There were 9 patients in group 1, 8 patients in group 2, and 5 patients in group 3. A diagnosis of HFpEF was present in all patients in groups 1 and 2 and no patients in group 3. There was a nonsignificant trend towards lower median CFR in groups 1 (2.1 IQR 1.6-2.8) and 2 (2.3 IQR 1.75-3.65) compared to group 3 (3.8 IQR 1.8-5.5; Figure 1). Similarly, there was a nonsignificant trend towards higher median IMR in groups 1 (23.2 IQR 16.9-41.3) and 2 (25.9 IQR 19.0-35.2) compared to group 3 (14.4 IQR 11-25; Figure 1). Conclusion: Like patients with elevated resting PCWP, patients with normal resting and elevated post-exercise PCWP tend to have lower CFR and higher IMR than those patients with normal pre and post-exercise PCWP. This may indicate that CMD plays a role in the development of early HFpEF though more patients are needed to further characterize this relationship.

Assessment of diastolic function in aortic stenosis: A comparison between 2009 and 2016 guidelines.

New diastolic dysfunction (DD) guidelines were introduced in 2016 to replace the 2009 guidelines, but have not yet been evaluated in aortic stenosis (AS). We aimed to compare the 2009 and 2016 DD guidelines in severe AS patients in terms of association with left ventricular (LV) and left atrial (LA) remodeling, with pulmonary capillary wedge pressure (PCWP) at rest and exercise, and with prognosis. We included 212 patients with severe AS (112 undergoing AVR, 100 asymptomatic). Echocardiography, magnetic resonance imaging, and brain natriuretic peptides (BNP) were performed/measured. Thirty-nine asymptomatic patients had PCWP measured during rest and maximal exertion. Asymptomatic patients were followed for 3.1 years for the combined endpoint of death, AVR or admission with heart failure. The 2009 and 2016 DD guidelines agreed poorly with each other (Cohens' κ=.15). 2009 guidelines showed many ambiguous DD findings. With the 2016 guidelines, 20% of patients had indeterminate DD. DD grade 2 according to 2016 guidelines showed stronger association with symptom status, BNP, global longitudinal strain (GLS) and peak exercise PCWP than 2009 guidelines. For indeterminate DD patients according to 2009 guidelines, GLS above the median was associated with event-free survival (HR .11 (95% CI .02-.53)). For neither guideline was DD associated with the combined endpoint in asymptomatic patients. The 2016 guidelines show a stronger association with BNP, GLS, and exercise PCWP than the 2009 guidelines. The 2016 guidelines result in 20% of patients with indeterminate DD; however, these patients may possibly be stratified according to GLS.

July 2021 at a glance: focus on blood volume distribution, haemodynamics and adherence to therapy.

Treatment with loop diuretics has a pivotal role in heart failure (HF) and may have an impact on outcome.1, 2 The association between loop diuretics, HF and outcome was investigated in patients with type 2 diabetes at high risk for cardiovascular (CV) events enrolled in EMPA-REG OUTCOME. Patients with both a diagnosis of HF and on loop diuretics had the highest rates of all-cause and CV mortality and HF hospitalizations. The subgroups of patients with HF and those on loop diuretics but without an investigator-reported diagnosis of HF had a similar, greater risk of all outcomes, compared with those with neither HF nor on diuretics, suggesting a possible under-diagnosis of HF and the usefulness of diuretic prescription as a surrogate for a diagnosis of HF.3 Miller et al.4 studied the relation between total blood volume (TBV), measured by radiolabel indicator-dilution methodology and haemodynamic parameters assessed by echocardiography and right heart catheterization, in 66 patients with chronic HF. Patients were divided into hypervolaemic (n = 39) or euvolaemic (n = 27), according to their TBV. Hypervolaemic patients showed higher central venous pressure (CVP) and pulmonary capillary wedge pressure (PCWP) compared to the euvolaemic ones. However, 15% of hypervolaemic patients had normal right and left ventricular (LV) pressures and 70% and 63% of the euvolaemic patients had elevated CVP and PCWP, respectively. TBV, LV e', and left atrial strain were independently associated with PCWP, thus showing the major role cardiac function as determinant on filling pressure in HF.4 Congestion is a major determinant of the significance of changes in serum creatinine levels.5 Wettersten et al.6 examined the relation between improved renal function, defined by ≥20% increase in estimated glomerular filtration rate from admission, and congestion, assessed through B-type natriuretic peptide (BNP) levels, in 760 patients with acute HF. Patients with improved renal function had more severe HF with a 25% 1-year mortality, compared with a 15% in the others. However, differently from BNP, improved renal function was not an independent predictor of outcome with a similar high mortality in patients without a decrease in BNP, with or without improved renal function.6 Dauw et al.7 studied the effects of one day diuretic omission in 40 ambulatory patients with chronic HF on 40–80 mg furosemide daily. After diuretic omission, patients had a 50% drop in natriuresis and a 31% reduction in urine output, compared with the day before. The rationale for the development of a novel nytroxyl donor has been previously described.8 In a randomized, multicentre, double-blind, crossover trial, the effects of nitroxyl donor cimlanod on cardiac function were compared with those of nitroglycerin or placebo in patients with HF and reduced ejection fraction (HFrEF). Both drugs had similar effects, namely venodilatation and preload reduction, without additional inotropic or lusitropic effects.9 Cardiac contractility modulation (CCM) may improve functional capacity and reduce CV and HF hospitalizations.10, 11 Long-term effects of CCM were evaluated in a European prospective registry including 503 patients. Quality of life and LV ejection fraction (LVEF) improved, while HF hospitalizations were reduced compared to before treatment.12 Approximately 60–70% of blood volume resides in the venous circulation and up to 20–50% is in the high capacitance, highly innervated, veins of the splanchnic compartment. Sympathetic stimulation causes their constriction or shifting blood to the heart with a rise in intracardiac pressure. Splanchnic nerve modulation is proposed to inhibit such effect. It is reviewed here, and its favourable effects in a first series of patients with heart failure and preserved ejection fraction (HFpEF) on exercise PCWP and improved quality of life are reported.13, 14 Strategies to improve adherence to guideline-directed medical therapy (GDMT) are needed for patients with HFrEF.15-17 In 2345 patients with worsening HF from the BIOSTAT-CHF study, up-titration of renin–angiotensin inhibitors (RASi) and beta-blockers had beneficial effects in patients with LVEF ≤49% and ≤40%, respectively. Up-titration of beta-blockers in those with LVEF ≥50% was associated with a greater risk of HF hospitalizations.18 Gupta et al.19 used liquid chromatography-mass spectrometry in a single spot urine sample to assess non-adherence to medications in 1296 patients with worsening HF enrolled in BIOSTAT-CHF. Non-adherence to at least one prescribed medication was observed in 45.9% of patients and was associated with a 38% increased risk of all-cause death or HF hospitalization. Bhatt et al.20 showed the usefulness of a pharmacist–physician GDMT team, compared to no team, to optimize treatment during a non-CV hospitalization of patients with HFrEF. Cognitive impairment is frequent in patients with HF and may be an obstacle for adherence to therapy.21, 22 It was a major determinant of the benefits of a disease management programme on 30-day and 90-day readmission or death in 1152 consecutive patients with a recent hospitalization for HF.23 The beneficial effects of sodium–glucose co-transporter 2 inhibitors in HFrEF patients at risk for CV events are now well established.16, 24-26 Their efficacy in patients with HFpEF will be shown by the EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction (EMPEROR-Preserved), whose rationale, design and baseline characteristics of the included patients were recently published,27-29 and the Dapagliflozin Evaluation to Improve the LIVEs of Patients With PReserved Ejection Fraction Heart Failure (DELIVER) trial, whose design is published in the current issue.30 Mehra et al.31 present the design of the Antiplatelet Removal and Hemocompatibility Events with the HeartMate 3 Pump (ARIES HM3) trial, a study assessing the safety and efficacy for the reduction of bleeding events of withdrawal of antiplatelet therapy in patients with a HeartMate 3 LV assist device.