Goyal, Parag

Abstract Ferritin, consisting of ferritin heavy chain (FTH1) and light chain (FTL) subunits, is an essential intracellular iron storage protein fundamental for cellular function. However, the source and the biological role of extracellular ferritin (ex-ferritin) are less understood. Recent studies have linked elevated serum ex-ferritin with adverse outcomes in individuals with acute respiratory distress syndrome (ARDS). In this study, we demonstrate that both FTH1 and FTL are significantly enriched in the serum, blood monocytes, and alveolar macrophages (AMs) of individuals with ARDS, a phenomenon we successfully replicate in a murine hyperoxia-induced acute lung injury (HALI) model. We show that FTH1 is consistently upregulated in macrophages during lung injury development, and mice with a targeted deletion of FTH1 in myeloid (LysMcre) or resident lung macrophage (Cd11ccre) populations exhibit attenuated HALI. This reduced injury is linked to macrophage resistance to ferroptotic cell death, ferritinophagy, altered airway inflammatory responses, and lower lung extracellular iron and higher levels of FTL-ex-ferritin. Transplantation of FTL-ex-ferritin-enriched bronchoalveolar lavage fluid to wild-type mice protected against HALI. The ratio of FTL-ex-ferritin to FTH1 in the serum of individuals with ARDS who died was higher than that of those that survived, suggesting that the balance between FTH1 and FTL may play a role in injury modulation. Our findings highlight macrophage ferritin as a key regulator of macrophage survival and the response of the lung to injury, presenting a potentially targetable pathway for ARDS treatment.

Importance Transthyretin amyloid cardiomyopathy (ATTR-CM) is underdiagnosed despite expanding treatment options. Objective To develop and evaluate an artificial intelligence (AI)–augmented clinical program for ATTR-CM detection. Design, Setting, and Participants This nonrandomized clinical trial involved constructing an AI model, ATTRACTnet, using electrocardiogram waveforms, echocardiographic measurements, demographics, and diagnosis codes for orthopedic manifestations of amyloidosis. A single-system, multisite, single-arm, open-label trial was conducted to evaluate its real-world performance. The model was trained and validated at a large academic referral site for ATTR-CM with external validation at an academic site. The trial was conducted as a single-system, multisite trial. Patients with left ventricular (LV) wall thickness 12 mm or more and an ATTRACTnet score 0.5 or higher were eligible. Exclusions included prior ATTR-CM testing, hypertrophic cardiomyopathy, expected life span less than 1 year, nursing home residence, advanced dementia, or LV wall thickness less than 14 mm explained by uncontrolled hypertension or moderate/severe aortic stenosis. Intervention Eligible patients were notified and offered nuclear scintigraphy testing, monoclonal protein testing, and follow-up care on agreement from the treating physician. Main Outcomes and Measure The primary outcome was a diagnosis of ATTR-CM by consensus criteria. ATTR-CM testing positivity was compared with historical and contemporary controls. Results ATTRACTnet was developed in an internal test set of 799 patients (mean [SD] age, 75.1 [11.1] years; 516 [64.7%] male and 283 [35.3%] female) using 5-fold cross-validation with an additional external test set of 422 patients. It had good discrimination for ATTR-CM detection with an area under the receiver operator characteristic curve of 0.85 (5-fold cross-validation, 0.77-0.85) in the internal set and 0.82 (95% CI, .81-0.83) in the external test set with similar performance in Hispanic, non-Hispanic Black, and non-Hispanic White patients. A total of 1471 patients were identified with positive AI model scores 0.5 or more during the study period, with 256 eligible patients who met study criteria. Of these patients, 50 underwent amyloidosis testing after physician and patient approval; 24 (48%) were diagnosed with ATTR-CM, and 21 (88%) initiated treatment within 3 months. The positivity rate was more than 2.8 times higher than historical controls (15.3%; 95% CI, 13.1%-17.9%; P < .001), with an 18% relative increase in new diagnoses vs the prior year. Conclusions and Relevance AI-augmented screening may improve ATTR-CM detection and identify patients who are missed by usual care. Prospective randomized trials are needed to determine if outcomes are improved. Trial Registration ClinicalTrials.gov Identifier: NCT06469372

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 Post-operative atrial fibrillation (POAF) is associated with stroke and mortality. It is unknown if POAF is associated with subsequent heart failure (HF) hospitalization. This study aims to examine the association between POAF and incident HF hospitalization among patients undergoing cardiac and non-cardiac surgeries. Methods and results A retrospective cohort study was conducted using all-payer administrative claims data that included all non-federal emergency department visits and acute care hospitalizations across 11 states in the USA. The study population included adults aged at least 18 years hospitalized for surgery without a prior diagnosis of HF. Cox proportional hazards regression models were used to examine the association between POAF and incident HF hospitalization after making adjustment for socio-demographics and comorbid conditions. Among 76 536 patients who underwent cardiac surgery, 14 365 (18.8%) developed incident POAF. In an adjusted Cox model, POAF was associated with incident HF hospitalization [hazard ratio (HR) 1.33; 95% confidence interval (CI) 1.25–1.41]. In a sensitivity analysis excluding HF within 1 year of surgery, POAF remained associated with incident HF hospitalization (HR 1.15; 95% CI 1.01–1.31). Among 2 929 854 patients who underwent non-cardiac surgery, 23 763 (0.8%) developed incident POAF. In an adjusted Cox model, POAF was again associated with incident HF hospitalization (HR 2.02; 95% CI 1.94–2.10), including in a sensitivity analysis excluding HF within 1 year of surgery (HR 1.49; 95% CI 1.38–1.61). Conclusions Post-operative atrial fibrillation is associated with incident HF hospitalization among patients without prior history of HF undergoing both cardiac and non-cardiac surgeries. These findings reinforce the adverse prognostic impact of POAF and suggest that POAF may be a marker for identifying patients with subclinical HF and those at elevated risk for HF.

Aims In 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 results The 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). Conclusion The 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.

Abstract Objective Evaluate the association between prefrailty and the risk of heart failure (HF) among older adults. Design, setting, and participants This prospective, community‐based cohort study included participants from the Atherosclerotic Risk in Communities study who underwent detailed frailty assessment using Fried Criteria and physical function assessment using the Short Performance Physical Battery (SPPB) score. Individuals with prevalent HF and frailty were excluded. Main outcomes and measures Adjusted association between prefrailty (vs robust), physical function measures (SPPB score, grip strength, and gait speed), and incident HF (overall and HF subtypes, HF with reduced [HFrEF, EF < 50%] and preserved ejection fraction [HFpEF]) were assessed using Cox proportional hazards models. Results Among 5210 participants (mean age 75 years, 58% women), 2565 (49.2%) were identified as prefrail. In cross‐sectional analysis, prefrail individuals had a higher burden of chronic myocardial injury (troponin, Std β = 0.08 [0.05–0.10]) and neurohormonal stress (NT‐ProBNP, Std β = 0.03 [0.02–0.05]) after adjustment for potential confounders. Over a median follow‐up of 4.6 years, there were 232 (4.5%) HF events (HFrEF: 102; HFpEF: 97). Prefrailty was associated with an increased risk of HF after adjusting for potential clinical confounders and cardiac biomarkers (aHR [95% CI] = 1.65 [1.24–2.20]). Among HF subtypes, prefrailty was associated with an increased risk of HFpEF but not HFrEF (aHR [95% CI] = 1.73 [1.11–2.70] and 1.38 [0.90–2.10], respectively). A lower SPPB score was also associated with an increased risk of overall HF and HFpEF, but not HFrEF. Among individual components, increased gait speed were associated with a lower risk of HFpEF, but not HFrEF. Conclusions and relevance Subtle abnormalities in physiological reserve (prefrailty) and impairment in physical function (SPPB) were both significantly associated with a higher risk of incident HF, particularly HFpEF. These findings highlight the potential role of routine assessment of geriatric syndromes for early identification of HF risk.