Tedford, Ryan J.

BACKGROUND: Among accepted US heart organs, listing centers accept organ offers earliest for White women, followed by Black women, White men, and Black men. Understanding the relationships of center- and geographic-level decisions is necessary to understand waitlist disparities. We sought to determine whether listing center and geography are associated with the first heart organ acceptance by candidate race, since race demographics vary regionally across the United States. METHODS: Using the United Network for Organ Sharing data sets, we identified first organ offers for Black and White candidates listed for heart transplant (October 18, 2018 to September 30, 2024) and compared models with and without listing center effects adjusted for candidate-, donor-, and offer-level variables. RESULTS: Among 20 668 candidates (31.6% Black, 68.4% White, 26.5% women), the adjusted odds of first offer acceptance were lower for Black candidates compared with White candidates (odds ratio, 0.84 [95% CI, 0.76–0.94]; P =0.001) when listing center was not included in the model; but after adjusting for listing center effects, odds were similar by race (odds ratio, 0.98 [95% CI, 0.88–1.10]; P =0.78). There were no clear geographic patterns by center, but centers with lower proportions of Black candidates had higher acceptance rates. CONCLUSIONS: Variability in overall acceptance rate among listing centers explains the lower first offer acceptance for Black compared with White heart candidates. Baseline acceptance rates were linked to the center-level proportion of Black candidates but not geography. Investigation of strategies to systemically improve early acceptance of good heart organs may reduce Black and White disparities in wait time duration.

Abstract Background and Aims Whether hemodynamic and symptomatic benefits of the APTURE left atrial-to-coronary sinus shunt translate into clinical outcome benefit in heart failure with left ventricular ejection fraction >40% remains unknown. Methods In this post hoc analysis of ALT-FLOW EFS patients undergoing APTURE implantation, Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score-predicted 1-year all-cause mortality was compared with observed mortality by Kaplan-Meier analysis of adjudicated events. Heart failure hospitalization (HFH) rates were compared for the 12 months before vs after implantation. Additional analyses included stratification by baseline sodium-glucose cotransporter 2 inhibitor (SGLT2i) use and N-terminal pro-B-type natriuretic peptide (NT-proBNP), recurrent HFH cumulative hazard estimation (Nelson-Aalen), and H2FPEF score calculation. Results Among 95 patients (mean age 70.9 ± 8.5 years; 50% women; 93% New York Heart Association Class III; 85.9% with H2FPEF score >3), MAGGIC-predicted 1-year mortality was 13.0%. Observed 1-year survival was significantly higher than predicted (94.7% vs 87.0%; P=0.04), consistent across SGLT2i subgroups (log-rank P=0.59). The proportion of patients with HFH declined from 37.9% pre implantation to 9.6% post implantation (P<0.0001), with event rates falling from 0.61 to 0.21 per patient-year (P<0.001) and a 1-year cumulative hazard of recurrent HFH of 0.19 (95% confidence interval, 0.12-0.31). HFHs were evenly distributed across NT-proBNP strata. Conclusions In ALT-FLOW EFS, observed 1-year mortality was lower than MAGGIC-predicted mortality, and post implantation HFH rates were lower than pre implantation rates. These hypothesis-generating findings will require confirmation in the randomized, sham-controlled ALT-FLOW II trial.

Abstract Introduction Left atrial-to-coronary sinus (LA-to-CS) shunting through the APTURE transcatheter shunt system aims to unload the LA while preserving the interatrial septum. This article aims to examine the 3-year health status, functional capacity, and clinical outcomes of the ALT-FLOW Early Feasibility Study (EFS). Methods Device safety, patency, and echocardiographic parameters, but also symptoms, health status, and exercise capacity were assessed in patients with left ventricular ejection fraction (LVEF) > 40% (n & 95). Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) score predicted 3-year all-cause mortality was compared with observed mortality assessed by Kaplan–Meier analysis using adjudicated events. Predicted and observed HF hospitalization (HFH)-free survival rates were also compared. Results At 3 years, the safety profile remained stable with no new safety signals, and all implanted shunts remained patent. 76.3% of patients improved by at least one NYHA class, and mean KCCQ Overall Summary Scores increased by 25 points from baseline (P < .0001). The 6-min walk distance improved by an average of 39 m (P & .002). These benefits were consistent regardless of baseline pulmonary vascular resistance (PVR). Right heart echocardiographic parameters after 3 years were stable, though a reduction in TAPSE was observed, primarily in the high PVR subgroup. The observed 3-year survival was significantly higher than the MAGGIC-predicted survival (84.4% vs 70.2, respectively; P & .009), as well as the HFH-free survival (68.0% vs 24.0%, respectively; P < 0001). Conclusion In patients with HF and LVEF >40%, the APTURE LA-to-CS shunting confirmed an acceptable safety profile with stable right heart parameters and sustained improvements in symptoms, quality of life, and functional capacity at 3 years. Observed survival and HFH were superior to MAGGIC predictions.

Abstract Aims Heart failure (HF) with preserved (HFpEF) and mildly reduced (HFmrEF) ejection fraction are prevalent, yet frequently underdiagnosed syndromes associated with high morbidity and mortality, impaired quality of life, and escalating healthcare expenditures. Although guideline-directed medications like SGLT2 inhibitors have been shown to reduce the risk of hospitalization and cardiovascular death, their use remains limited and substantial residual risk persists. This trial aims to evaluate the safety and performance of a novel left-atrium-to-coronary-sinus shunt (Edwards APTURE transcatheter shunt system) in HFpEF and HFmrEF patients. Methods ALT-FLOW II is a prospective multi-centre, randomized, sham-controlled, double-blinded (patient and assessor) trial. Approximately 100 symptomatic HF patients aged ≥18 years with left ventricular ejection fraction >40% and exercise pulmonary capillary wedge pressure (PCWP) ≥25 mm Hg with a PCWP to right atrial pressure gradient ≥8 mm Hg will be randomized 1:1 to the APTURE shunt vs sham control. Key exclusion criteria include severe HF, significant valvular disease, and more than mild right ventricular dysfunction. The primary endpoints are the safety of the APTURE device at 30 days and change in workload-corrected PCWP normalized to bodyweight at 6 months. Secondary endpoints include changes in patient-reported outcomes, and hemodynamic and echocardiographic parameters through 5 years. The trial will also explore the impact of the device on short-term cardiac remodelling and intra-cardiac flow patterns using multi-modality imaging. Conclusions The ALT-FLOW II trial will evaluate the safety and performance of the APTURE system in symptomatic HFpEF and HFmrEF patients with elevated left atrial pressure.

Achieving optimal unloading in patients with left ventricular assist devices (LVADs) is associated with improved outcomes but remains unattainable in some cases. We retrospectively reviewed 33 patients with a HeartMate 3 LVAD who underwent speed optimization with concomitant echocardiography and right heart catheterization for inadequate left ventricular (LV) unloading between January 2016 and December 2023. Patients were stratified based on left ventricular transmural pressure (LVTMP) into two groups: LVTMP ⩽7 mmHg and LVTMP >7 mmHg using a median split approach. Pulmonary capillary wedge pressure (PCWP) decreased in both groups with increased LVAD speed; however, the mean PCWP change per 100 rpm was significantly smaller in patients with LVTMP ⩽7 mmHg (−0.50 vs −0.99 mmHg per 100 rpm, p = 0.003). Comparative analysis demonstrated LVTMP’s superiority over established RV markers, with the strongest interaction effect for predicting speed optimization response. Changes in cardiac output were similar between the two groups. In univariate analysis, multiple hemodynamic parameters were significantly associated with reduced LVTMP, including right atrial pressure (OR = 1.27, p = 0.036), TPG (OR = 1.25, p = 0.037), DPG (OR = 1.69, p = 0.012), and PAPi (OR = 0.35, p = 0.019).LVTMP, as a surrogate for true LV preload, particularly in the context of RV failure, may offer predictive value for the success or failure of LV unloading with LVAD speed optimization.

ABSTRACT Cardiogenic shock (CS) remains a high morbidity and mortality condition worldwide frequently complicating acute myocardial infarction (AMI) and decompensated heart failure (HF). Within the management of CS, mechanical circulatory support (MCS) devices play a critical role in maintaining hemodynamic stability, preserving end‐organ perfusion and bridging patients through to recovery, implantation of durable support or transplantation. Despite their use, optimal timing of initiation, as well as patient and device selection remain unclear. This review explores the current landscape of MCS devices, surrounding evidence and key distinctions between devices. With increasing acknowledgment for the heterogeneity of CS, understanding the strengths and limitations of each device remains crucial to improving outcomes in this high‐risk population.

Background Right ventricular (RV) maladaptation to elevated pulmonary afterload is the primary determinant of outcomes in pulmonary artery (PA) hypertension; however, the pathobiological mechanisms underlying RV decompensation remain poorly understood. Methods We performed global untargeted metabolomics on plasma from 55 patients who underwent gold‐standard RV‐PA coupling measurements using multibeat pressure volume loop assessment in a single‐center cohort and from 1027 patients with coupling surrogate measurements in a larger multicenter cohort, the PVDOMICS (Pulmonary Vascular Disease Phenomics) study. Age and sex‐adjusted linear regression was performed to identify associations between metabolites and coupling metrics. Additionally, we performed a metabolic flux analysis using gene expression data from RV tissue in an independent cohort of 32 patients. Partial least squares–discriminant analysis was used to identify metabolites and reactions characteristic of the decompensated RV. Results RV‐PA coupling was negatively associated with tricarboxylic acid (TCA) cycle intermediate levels. Specifically, plasma α‐ketoglutarate and fumarate were significantly associated with all coupling metrics in both cohorts. Metabolic flux analysis indicated that decompensated RVs exhibited aberrant TCA cycle activity, including reduced acetyl coenzyme A entry and increased lactate elimination, suggesting a shift from the TCA cycle toward glycolysis at the RV tissue level. Conclusions We identify an association between circulating TCA cycle intermediate levels and RV‐PA uncoupling in 2 independent cohorts, and dysregulated TCA cycle metabolism in decompensated PA hypertension RVs, suggesting that aberrant TCA cycle metabolism could represent a hallmark of RV maladaptation in PA hypertension. Further study of this pathway is warranted to develop novel biomarkers of RV function or RV‐targeted therapies.

Abstract Aims Inter-atrial shunt device therapy has shown mixed results in clinical trials, with clinical ‘non-responders’ typically showing features of more advanced heart failure. We aimed to analyse the haemodynamic and clinical response of a novel left atrial to coronary sinus (LA-CS) shunt device in patients with higher natriuretic peptide (NP) levels, a marker of disease severity. Methods and results An analysis population (n = 95) of patients from the ALT-FLOW early feasibility study with left ventricular ejection fraction >40% and 1-year follow up was analysed. The cohort was divided into low and high subgroups based on NP levels [b-type natriuretic peptide (BNP) and n-terminal pro BNP (NT-proBNP)]. The mean BNP and NT-proBNP levels for low versus high subgroups were 64.2 ± 34.3 versus 261 ± 103 and 322 ± 269 versus 2050 ± 1070 pg/mL, respectively. Patients in the high NP subgroup had evidence of more advanced disease including worse haemodynamic profiles, lower estimated glomerular filtration rate, and higher percentages of atrial fibrillation. The high NP subgroup experienced significant improvements in KCCQ-OSS and NYHA functional class (P < 0.0001 and P < 0.001, respectively) and to a similar magnitude compared with the low NP subgroup. Compared with pre-implant baseline, workload adjusted pulmonary artery wedge pressure at peak exercise declined in the high NP subgroup (PCWL, 164.1 vs. 96.0 mmHg/W/kg at 6 months, P < 0.003) as well as the low NP subgroup (115.9 vs. 65.9 mmHg/W/keg at 6 months, P < 0.001). Importantly, in both NP subgroups, there was preservation of cardiac index through 6 months as well as right ventricular structure (right ventricular diastolic dimension) and function (tricuspid annular systolic plane excursion) through 1 year. Conclusions The quality-of-life, haemodynamic, and functional class improvements along with stable right heart function seen in ALT-FLOW study of LA-CS shunt remain consistent in the subgroup with highest NP levels. This suggests that shunting location could influence outcomes in symptomatic heart failure patients.

ImportanceThe advanced ambulatory heart failure (HF) population comprises patients who have progressed beyond the pillars of recommended stage C HF therapies but can still find meaningful life-years ahead. Although these patients are commonly encountered in practice, national databases selectively capture the small groups accepted for heart transplant listing or left ventricular assist devices. The epidemiology, trajectories, and therapies for other ambulatory patients with advanced HF are poorly understood.ObservationsIn December 2022, the National Heart, Lung and Blood Institute convened a team of experts to identify knowledge gaps and research priorities for the ambulatory population with limiting daily symptoms and transition toward refractory end-stage D HF, designated as stage C2D. This article summarizes the findings from that 3-day workshop. Workshop participants surveyed the initial challenges and knowledge gaps for (1) recognition of ambulatory C2D HF, (2) estimation of the magnitude of the affected population and identifiable subpopulations, and (3) physiologic phenotypes, such as low cardiac output, right HF, cardiorenal syndromes, congestive hepatopathy and frailty, which offer distinct targets for existing and emerging therapies. Social drivers of HF and patient preferences for quality/length of survival were highlighted as essential modifiers for personalization of therapies.Conclusions and RelevanceTen key points summarized workshop findings, with target cohorts for study proposed as a crucial next step. This workshop summary is intended as a call for action to address knowledge gaps and develop new strategies to improve outcomes in the large ambulatory population with C2D HF.

BACKGROUND: Plasma NT-proBNP (N-terminal pro-B-type natriuretic peptide) is commonly used to diagnose heart failure with preserved ejection fraction (HFpEF), but its diagnostic performance in the ambulatory/outpatient setting is unknown because previous studies lacked objective reference standards. METHODS: Among patients with chronic dyspnea, diagnosis of HFpEF or noncardiac dyspnea was determined conclusively by exercise catheterization in a derivation cohort (n=414), multicenter validation cohort 1 (n=560), validation cohort 2 (n=207), and a nonobese Japanese validation cohort 3 (n=77). Optimal NT-proBNP cut points for HFpEF rule out (optimizing sensitivity) and rule in (optimizing specificity) were derived and tested, stratified by obesity and atrial fibrillation. Derived cut points were tested in 3 additional validation cohorts (cohorts 4–6) in whom HFpEF was diagnosed by resting catheterization only (n=260), previous hospitalization for heart failure (n=447), or exercise echocardiography (n=517), respectively. RESULTS: Current recommended rule-out NT-proBNP threshold <125 pg/mL had 82% sensitivity (95% CI, 77%–88%) with a body mass index (BMI) <35 kg/m 2 , decreasing to 67% (95% CI, 58%–77%) with a BMI ≥35 kg/m 2 . A lower rule-out NT-proBNP threshold <50 pg/mL displayed good sensitivity with a BMI <35 kg/m 2 (97% [95% CI, 95%–99%]), with a modest decline in sensitivity with a BMI ≥35 kg/m 2 (86% [95% CI, 79%–93%]); diagnostic thresholds were confirmed in validation cohorts 1 and 2 (91% [95% CI, 88%–95%] and 86% [95% CI, 80%–93%] with a BMI <35 kg/m 2 ; 80% [95% CI, 74%–87%] and 84% [95% CI, 74%–93%] with a BMI ≥35 kg/m 2 ). Current consensus age- and BMI-stratified rule-in thresholds demonstrated only 65% specificity (95% CI, 57%–72%). Rule-in NT-proBNP threshold ≥500 pg/mL had 85% specificity (95% CI, 78%–91%) with a BMI <35 kg/m 2 (87% [95% CI, 80%–94%] and 90% [95% CI, 81%–99%] in validation cohorts), with 100% specificity at a BMI ≥35 kg/m 2 (93% [95% CI, 81%–100%] and 100% in validation cohorts). With a BMI ≥35 kg/m 2 , lower rule-in thresholds (≥220 pg/mL) provided good specificity (88% [95% CI, 73%–100%]; 93% [95% CI, 81%–100%] and 100% in validation cohorts). Findings were consistent in validation cohorts 3 through 6 (sensitivity of <50 pg/mL, 93%–98%; specificity of ≥500 pg/mL, 82%–89%). NT-proBNP provided no incremental discrimination among patients with history of AF; ≥98% of patients with AF and dyspnea were found to have HFpEF in our cohorts. CONCLUSIONS: In patients with chronic unexplained dyspnea, current rule-in and rule-out NT-proBNP diagnostic thresholds lead to unacceptably high error rates, with important interactions by obesity and AF status. In our study, NT-proBNP provided little value in those with AF and dyspnea because the presence of AF is by itself a robust biomarker of HFpEF. Use of separate rule-in and rule-out diagnostic thresholds stratified by BMI reduces miscategorization and can guide more appropriate use of exercise testing for possible HFpEF.