Pulmonary artery pressure monitoring in chronic heart failure: effects across clinically relevant subgroups in the MONITOR-HF trial.

BACKGROUND AND AIMS: In patients with chronic heart failure (HF), the MONITOR-HF trial demonstrated the efficacy of pulmonary artery (PA)-guided HF therapy over standard of care in improving quality of life and reducing HF hospitalizations and mean PA pressure. This study aimed to evaluate the consistency of these benefits in relation to clinically relevant subgroups. METHODS: The effect of PA-guided HF therapy was evaluated in the MONITOR-HF trial among predefined subgroups based on age, sex, atrial fibrillation, diabetes mellitus, left ventricular ejection fraction, HF aetiology, cardiac resynchronisation therapy, and implantable cardioverter defibrillator. Outcome measures were based upon significance in the main trial and included quality of life, clinical, and PA pressure endpoints, and were assessed for each subgroup. Differential effects in relation to the subgroups were assessed with interaction terms. Both unadjusted and multiple testing adjusted interaction terms were presented. RESULTS: The effects of PA monitoring on quality of life, clinical events, and PA pressure were consistent in the predefined subgroups, without any clinically relevant heterogeneity within or across all endpoint categories (all adjusted interaction P-values were nonsignificant). In the unadjusted analysis of the primary endpoint quality-of-life change, weak trends towards a less pronounced effect in older patients (Pinteraction = 0.03; adjusted Pinteraction = 0.33) and diabetics (Pinteraction = 0.01; adjusted Pinteraction = 0.06) were observed. However, these interaction effects did not persist after adjusting for multiple testing. CONCLUSIONS: This subgroup analysis confirmed the consistent benefits of PA-guided HF therapy observed in the MONITOR-HF trial across clinically relevant subgroups, highlighting its efficacy in improving quality of life, clinical, and PA pressure endpoints in chronic HF patients.

The plasma proteome is linked with left ventricular and left atrial function parameters in patients with chronic heart failure.

BACKGROUND: Examining the systemic biological processes in the heterogeneous syndrome of heart failure with reduced ejection fraction (HFrEF), as reflected by circulating proteins, in relation to echocardiographic characteristics, may provide insights into HF pathophysiology. OBJECTIVE: We investigated the link of 4210 repeatedly measured circulating proteins with repeatedly measured echocardiographic parameters, as well as with elevated left atrial pressure (LAP), in HFrEF patients, to provide insights into underlying mechanisms. METHODS: In 173 HFrEF patients, we performed six-monthly echocardiography and trimonthly blood sampling during a median follow-up of 2.7(IQR:2.5-2.8) years. We investigated circulating proteins in relation to echocardiographic parameters of left ventricular (left ventricular ejection fraction[LVEF], global longitudinal strain[GLS]), and left atrial function (left atrial reservoir strain[LASr]) and elevated LAP(E/e' ratio >15), and used gene enrichment analyses to identify underlying pathophysiological processes. RESULTS: We found 723, 249, 792 and 427 repeatedly measured proteins, with significant associations with LVEF, GLS, LASr and E/e' ratio, respectively. Proteins associated with LASr reflected pathophysiological mechanisms mostly related to the extracellular matrix (ECM). Proteins associated with GLS reflected cardiovascular biological processes and diseases, whereas those associated with LVEF reflected processes involved in the sympathetic nervous system. Moreover, 49 proteins were associated with elevated LAP; after correction for LVEF, three proteins remained: Cystatin-D, Fibulin-5 and HSP40. CONCLUSION: Circulating proteins show varying associations with different echocardiographic parameters in HFrEF patients. These findings suggest that pathways involved in atrial and ventricular dysfunction, as reflected by the plasma proteome, are distinct.

Benefits of remote hemodynamic monitoring in heart failure.

Despite treatment advancements, HF mortality remains high, prompting interest in reducing HF-related hospitalizations through remote monitoring. These advances are necessary considering the rapidly rising prevalence and incidence of HF worldwide, presenting a burden on hospital resources. While traditional approaches have failed in predicting impending HF-related hospitalizations, remote hemodynamic monitoring can detect changes in intracardiac filling pressure weeks prior to HF-related hospitalizations which makes timely pharmacological interventions possible. To ensure successful implementation, structural integration, optimal patient selection, and efficient data management are essential. This review aims to provide an overview of the rationale, the available devices, current evidence, and the implementation of remote hemodynamic monitoring.

Search for Λ[over ¯]-Λ Baryon-Number-Violating Oscillations in the Decay J/ψ→pK

We report on the first search for Λ[over ¯]-Λ oscillations in the decay J/ψ→pK^{-}Λ[over ¯]+c.c. by analyzing 1.31×10^{9} J/ψ events accumulated with the BESIII detector at the BEPCII collider. The J/ψ events are produced using e^{+}e^{-} collisions at a center of mass energy sqrt[s]=3.097 GeV. No evidence for hyperon oscillations is observed. The upper limit for the oscillation rate of Λ[over ¯] to Λ hyperons is determined to be P(Λ)=[B(J/ψ→pK^{-}Λ+c.c.)/B(J/ψ→pK^{-}Λ[over ¯]+c.c.)]<4.4×10^{-6} corresponding to an oscillation parameter δm_{ΛΛ[over ¯]} of less than 3.8×10^{-18} GeV at the 90% confidence level.

Circulating Acylcarnitines Associated with Hypertrophic Cardiomyopathy Severity: an Exploratory Cross-Sectional Study in MYBPC3 Founder Variant Carriers.

Hypertrophic cardiomyopathy (HCM) is a relatively common genetic heart disease characterised by myocardial hypertrophy. HCM can cause outflow tract obstruction, sudden cardiac death and heart failure, but severity is highly variable. In this exploratory cross-sectional study, circulating acylcarnitines were assessed as potential biomarkers in 124 MYBPC3 founder variant carriers (59 with severe HCM, 26 with mild HCM and 39 phenotype-negative [G + P-]). Elastic net logistic regression identified eight acylcarnitines associated with HCM severity. C3, C4, C6-DC, C8:1, C16, C18 and C18:2 were significantly increased in severe HCM compared to G + P-, and C3, C6-DC, C8:1 and C18 in mild HCM compared to G + P-. In multivariable linear regression, C6-DC and C8:1 correlated to log-transformed maximum wall thickness (coefficient 5.01, p = 0.005 and coefficient 0.803, p = 0.007, respectively), and C6-DC to log-transformed ejection fraction (coefficient -2.50, p = 0.004). Acylcarnitines seem promising biomarkers for HCM severity, however prospective studies are required to determine their prognostic value.

Prognostic value of temporal patterns of left atrial reservoir strain in patients with heart failure with reduced ejection fraction.

BACKGROUND: We investigated whether repeatedly measured left atrial reservoir strain (LASr) in heart failure with reduced ejection fraction (HFrEF) patients provides incremental prognostic value over a single baseline LASr value, and whether temporal patterns of LASr provide incremental prognostic value over temporal patterns of other echocardiographic markers and NT-proBNP. METHODS: In this prospective observational study, 153 patients underwent 6-monthly echocardiography, during a median follow-up of 2.5 years. Speckle tracking echocardiography was used to measure LASr. Hazard ratios (HRs) were calculated for LASr from Cox models (baseline) and joint models (repeated measurements). The primary endpoint (PEP) comprised HF hospitalization, left ventricular assist device, heart transplantation, and cardiovascular death. RESULTS: Mean age was 58 ± 11 years, 76% were men, 82% were in NYHA class I/II, mean LASr was 20.9% ± 11.3%, and mean LVEF was 29% ± 10%. PEP was reached by 50 patients. Baseline and repeated measurements of LASr (HR per SD change (95% CI) 0.20 (0.10-0.41) and (0.13 (0.10-0.29), respectively) were both significantly associated with the PEP, independent of both baseline and repeated measurements of other echo-parameters and NT-proBNP. Although LASr was persistently lower over time in patients with PEP, temporal trajectories did not diverge in patients with versus without the PEP as the PEP approached. CONCLUSION: LASr was associated with adverse events in HFrEF patients, independent of baseline and repeated other echo-parameters and NT-proBNP. Temporal trajectories of LASr showed decreased but stable values in patients with the PEP, and do not provide incremental prognostic value for clinical practice compared to single measurements of LASr.

Longitudinal Changes in Circulating Ketone Body Levels in Patients With Acute Heart Failure: A Post Hoc Analysis of the EMPA-Response-AHF Trial.

BACKGROUND: Ketone bodies are endogenous fuels produced by the liver under conditions of metabolic or neurohormonal stress. Circulating ketone bodies are increased in patients with chronic heart failure (HF), yet little is known about the effect of acute HF on ketosis. We tested the hypothesis that ketogenesis is increased in patients with acute decompensated HF. METHODS AND RESULTS: This was a post hoc analysis of 79 patients with acute HF included in the EMPA-RESPONSE-AHF trial, which compared sodium-dependent glucose-cotransporter protein 2 inhibitor treatment with empagliflozin for 30 days with placebo in patients with acute HF [NCT03200860]. Plasma concentrations of ketone bodies acetone, ß-hydroxybutyrate, and acetoacetate were measured at baseline and 5 different timepoints. Changes in ketone bodies over time were monitored using repeated measures analysis of variance. In the total cohort, median total ketone body concentration was 251 µmol/L (interquartile range, 178-377 µmol/L) at baseline, which gradually decreased to 202 µmol/L (interquartile range, 156-240 µmol/L) at day 30 (P = .041). Acetone decreased from 60 µmol/L (interquartile range, 34-94 µmol/L) at baseline to 30 µmol/L (interquartile range, 21-42 µmol/L) ( P < .001), whereas ß-hydroxybutyrate and acetoacetate remained stable over time. Higher acetone concentrations were correlated with higher N-terminal pro brain natriuretic peptide levels (r = 0.234; P = .039). Circulating ketone bodies did not differ between patients treated with empagliflozin or placebo throughout the study period. A higher acetone concentration at baseline was univariately associated with a greater risk of the composite end point, including in-hospital worsening HF, HF rehospitalizations, and all-cause mortality after 30 days. However, after adjustment for age and sex, acetone did not remain an independent predictor for the combined end point. CONCLUSIONS: Circulating ketone body concentrations, and acetone in particular, were significantly higher during an episode of acute decompensated HF compared with after stabilization. Treatment with empagliflozin did not affect ketone body concentrations in patients with acute HF.

MART-1 TCR gene-modified peripheral blood T cells for the treatment of metastatic melanoma: a phase I/IIa clinical trial.

Background: Adoptive cell therapy with peripheral blood T cells expressing transgenic T-cell receptors (TCRs) is an innovative therapeutic approach for solid malignancies. We investigated the safety and feasibility of adoptive transfer of autologous T cells expressing melanoma antigen recognized by T cells 1 (MART-1)-specific TCR, cultured to have less differentiated phenotypes, in patients with metastatic melanoma. Materials and methods: In this phase I/IIa trial, peripheral blood T cells from HLA-A2∗02:01-positive patients with unresectable stage IIIC/IV melanoma expressing MART-1 were selected and stimulated with anti-CD3/CD28 beads, transduced with a modified MART-1(26-35)-specific 1D3 TCR (1D3HMCys) and expanded in interleukin (IL)-7 and IL-15. Patients received a single infusion of transgenic T cells in a dose-escalating manner. Feasibility, safety and objective response rate were assessed. Results: Twelve pretreated metastatic cutaneous (n = 7) and uveal (n = 5) melanoma patients were included. Patient 1 received 4.6 × 109 1D3HMCys T cells and experienced grade 5 toxicity after 9 days. Subsequent patients received 5.0 × 107 [n = 3; cohort (c) 2], 2.5 × 108 (n = 2; c3) and 1.0 × 108 (n = 6; c4) 1D3HMCys T cells. The study was prematurely terminated because of dose-dependent toxicity, concerning skin (10/12), eyes (3/12), ears (4/12) and cytokine release syndrome (5/12), with 7 patients experiencing grade 3-5 toxicity. Partial responses were seen in 2/11 (18%) assessable patients and persistence of 1D3HMCys T cells corresponded to infused cell dose. Conclusions: Production of TCR-modified cells as described leads to highly potent T cells. Partial responses were seen in 18% of patients with dose-dependent 'on-target, off-tumor' toxicity and a maximum tolerated dose of 1.0 × 108 cells.

Observation of J/ψ Electromagnetic Dalitz Decays to X(1835), X(2120), and X(2370).

Using a sample of about 10^{10} J/ψ events collected at a center-of-mass energy sqrt[s]=3.097 GeV with the BESIII detector, the electromagnetic Dalitz decays J/ψ→e^{+}e^{-}π^{+}π^{-}η^{'}, with η^{'}→γπ^{+}π^{-} and η^{'}→π^{+}π^{-}η, have been studied. The decay J/ψ→e^{+}e^{-}X(1835) is observed with a significance of 15σ, and also an e^{+}e^{-} invariant-mass dependent transition form factor of J/ψ→e^{+}e^{-}X(1835) is presented for the first time. The intermediate states X(2120) and X(2370) are also observed in the π^{+}π^{-}η^{'} invariant-mass spectrum with significances of 5.3σ and 7.3σ. The corresponding product branching fractions for J/ψ→e^{+}e^{-}X, X→π^{+}π^{-}η^{'} [X=X(1835), X(2120), and X(2370)] are reported.

Diagnostic role of echocardiography for patients with heart failure symptoms and preserved left ventricular ejection fraction.

The syndrome heart failure with preserved ejection fraction (HFpEF) represents patients with different comorbidities and specific etiologies, but with a key and common alteration: an elevation in left ventricular (LV) filling pressure or pulmonary capillary wedge pressure (PCWP). Expert consensuses, society guidelines, and diagnostic scores have been stated to diagnose HFpEF syndrome based mainly on the determination of elevated LV filling pressure or PCWP by transthoracic echocardiography (TTE). Echocardiographic parameters such as early (E) and late diastolic mitral inflow velocity (mitral E/A ratio), septal and lateral mitral annular early diastolic velocity (E'), ratio of the early diastolic mitral inflow and annular velocity (E/E'-ratio), maximal left atrial volume index (LAVImax), and tricuspid regurgitation peak velocity (VTR) constitute the pivotal parameters for determining elevated LV filling pressure or PCWP in patients with suspected HFpEF symptoms. Notwithstanding this, taking into consideration the heterogeneity of patients with HFpEF symptoms, the term "HFpEF" should be considered as a syndrome rather than an entity since HFpEF results from different pathological entities that should and can be characterized by echocardiography and multimodality imaging. Comprehensive TTE might help diagnose specific diseases and etiologies by characterization of specific cardiac phenotypes.

Observation of the Singly Cabibbo Suppressed Decay Λ_{c}

The singly Cabibbo-suppressed decay Λ_{c}^{+}→nπ^{+} is observed for the first time with a statistical significance of 7.3σ by using 3.9 fb^{-1} of e^{+}e^{-} collision data collected at center-of-mass energies between 4.612 and 4.699 GeV with the BESIII detector at BEPCII. The branching fraction of Λ_{c}^{+}→nπ^{+} is measured to be (6.6±1.2_{stat}±0.4_{syst})×10^{-4}. By taking the upper limit of branching fractions of Λ_{c}^{+}→pπ^{0} from the Belle experiment, the ratio of branching fractions between Λ_{c}^{+}→nπ^{+} and Λ_{c}^{+}→pπ^{0} is calculated to be larger than 7.2 at the 90% confidence level, which disagrees with most predictions of the available phenomenological models. In addition, the branching fractions of the Cabibbo-favored decays Λ_{c}^{+}→Λπ^{+} and Λ_{c}^{+}→Σ^{0}π^{+} are measured to be (1.31±0.08_{stat}±0.05_{syst})×10^{-2} and (1.22±0.08_{stat}±0.07_{syst})×10^{-2}, respectively, which are consistent with previous results.

Measurement of the Cross Section for e

Based on electron-positron collision data collected with the BESIII detector operating at the Beijing Electron-Positron Collider II storage rings, the value of R≡σ(e^{+}e^{-}→hadrons)/σ(e^{+}e^{-}→µ^{+}µ^{-}) is measured at 14 center-of-mass energies from 2.2324 to 3.6710 GeV. The resulting uncertainties are less than 3.0% and are dominated by systematic uncertainties.

Immune checkpoint inhibitor-associated myocarditis : Case reports and a review of the literature.

Immune checkpoint inhibitors (ICIs) are increasingly recognised to effectuate long-lasting therapeutic responses in solid tumours. However, ICI therapy can also result in various immune-related adverse events, such as ICI-associated myocarditis, a rare but serious complication. The clinical spectrum is wide and includes asymptomatic patients and patients with fulminant heart failure, making it challenging to diagnose this condition. Furthermore, the optimal diagnostic algorithm and treatment of ICI-associated myocarditis is unknown. In this review, we describe two cases on both ends of the spectrum and discuss the challenges in recognising, diagnosing and treating ICI-associated myocarditis.

First Measurement of Polarizations in the Decay D

Using a data sample corresponding to an integrated luminosity of 2.93 fb^{-1} collected at a center-of-mass energy sqrt[s]=3.773 GeV by the BESIII detector, the decay D^{0}→ωϕ is observed for the first time. The branching fraction is measured to be (6.48±0.96±0.40)×10^{-4} with a significance of 6.3σ, where the first and second uncertainties are statistical and systematic, respectively. An angular analysis reveals that the ϕ and ω mesons from the D^{0}→ωϕ decay are transversely polarized. The 95% confidence level upper limit on longitudinal polarization fraction is set to be less than 0.24, which is inconsistent with current theoretical expectations and challenges our understanding of the underlying dynamics in charm meson decays.

Rationale and design of the PHOspholamban RElated CArdiomyopathy intervention STudy (i-PHORECAST).

BACKGROUND: The p.Arg14del (c.40_42delAGA) phospholamban (PLN) pathogenic variant is a founder mutation that causes dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM). Carriers are at increased risk of malignant ventricular arrhythmias and heart failure, which has been ascribed to cardiac fibrosis. Importantly, cardiac fibrosis appears to be an early feature of the disease, occurring in many presymptomatic carriers before the onset of overt disease. As with most monogenic cardiomyopathies, no evidence-based treatment is available for presymptomatic carriers. AIMS: The PHOspholamban RElated CArdiomyopathy intervention STudy (iPHORECAST) is designed to demonstrate that pre-emptive treatment of presymptomatic PLN p.Arg14del carriers using eplerenone, a mineralocorticoid receptor antagonist with established antifibrotic effects, can reduce disease progression and postpone the onset of overt disease. METHODS: iPHORECAST has a multicentre, prospective, randomised, open-label, blinded endpoint (PROBE) design. Presymptomatic PLN p.Arg14del carriers are randomised to receive either 50 mg eplerenone once daily or no treatment. The primary endpoint of the study is a multiparametric assessment of disease progression including cardiac magnetic resonance parameters (left and right ventricular volumes, systolic function and fibrosis), electrocardiographic parameters (QRS voltage, ventricular ectopy), signs and/or symptoms related to DCM and ACM, and cardiovascular death. The follow-up duration is set at 3 years. BASELINE RESULTS: A total of 84 presymptomatic PLN p.Arg14del carriers (n = 42 per group) were included. By design, at baseline, all participants were in New York Heart Association (NHYA) class I and had a left ventricular ejection fraction > 45% and < 2500 ventricular premature contractions during 24-hour Holter monitoring. There were no statistically significant differences between the two groups in any of the baseline characteristics. The study is currently well underway, with the last participants expected to finish in 2021. CONCLUSION: iPHORECAST is a multicentre, prospective randomised controlled trial designed to address whether pre-emptive treatment of PLN p.Arg14del carriers with eplerenone can prevent or delay the onset of cardiomyopathy. iPHORECAST has been registered in the clinicaltrials.gov-register (number: NCT01857856).

Measurement of the Absolute Branching Fraction of D_{s}

Using a dataset of 6.32 fb^{-1} of e^{+}e^{-} annihilation data collected with the BESIII detector at center-of-mass energies between 4178 and 4226 MeV, we have measured the absolute branching fraction of the leptonic decay D_{s}^{+}→τ^{+}ν_{τ} via τ^{+}→e^{+}ν_{e}ν[over ¯]_{τ}, and find B_{D_{s}^{+}→τ^{+}ν_{τ}}=(5.27±0.10±0.12)×10^{-2}, where the first uncertainty is statistical and the second is systematic. The precision is improved by a factor of 2 compared to the previous best measurement. Combining with f_{D_{s}^{+}} from lattice quantum chromodynamics calculations or the |V_{cs}| from the CKMfitter group, we extract |V_{cs}|=0.978±0.009±0.012 and f_{D_{s}^{+}}=(251.1±2.4±3.0) MeV, respectively. Combining our result with the world averages of B_{D_{s}^{+}→τ^{+}ν_{τ}} and B_{D_{s}^{+}→µ^{+}ν_{µ}}, we obtain the ratio of the branching fractions B_{D_{s}^{+}→τ^{+}ν_{τ}}/B_{D_{s}^{+}→µ^{+}ν_{µ}}=9.72±0.37, which is consistent with the standard model prediction of lepton flavor universality.

First Measurement of the Absolute Branching Fraction of Λ→pµ

The absolute branching fraction of Λ→pµ^{-}ν[over ¯]_{µ} is reported for the first time based on an e^{+}e^{-} annihilation sample of 10×10^{9} J/ψ events collected with the BESIII detector at sqrt[s]=3.097 GeV. The branching fraction is determined to be B(Λ→pµ^{-}ν[over ¯]_{µ})=[1.48±0.21(stat)±0.08(syst)]×10^{-4}, which is improved by about 30% in precision over the previous indirect measurements. Combining this result with the world average of B(Λ→pe^{-}ν[over ¯]_{e}), we obtain the ratio {[Γ(Λ→pµ^{-}ν[over ¯]_{µ})]/[Γ(Λ→pe^{-}ν[over ¯]_{e})]} to be 0.178±0.028, which agrees with the standard model prediction assuming lepton flavor universality. The asymmetry of the branching fractions of Λ→pµ^{-}ν[over ¯]_{µ} and Λ[over ¯]→p[over ¯]µ^{+}ν_{µ} is also determined, and no evidence for CP violation is found.

Observation of D

Using 2.93 fb^{-1} of e^{+}e^{-} collision data taken with the BESIII detector at a center-of-mass energy of 3.773 GeV, the observation of the D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} semileptonic decay is presented. The statistical significance of the decay D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is greater than 10σ. The branching fraction of D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is measured to be (1.09±0.13_{-0.16}^{+0.09}±0.12)×10^{-3}. Here, the first uncertainty is statistical, the second is systematic, and the third originates from the assumed branching fraction of K_{1}(1270)^{-}→K^{-}π^{+}π^{-}. The fraction of longitudinal polarization in D^{0}→K_{1}(1270)^{-}e^{+}ν_{e} is determined for the first time to be 0.50±0.19_{stat}±0.08_{syst}.

Direct Measurement of the Branching Fractions B(ψ(3686)→J/ψX) and B(ψ(3770)→J/ψX), and Observation of the State R(3760) in e

We report a measurement of the observed cross sections of e^{+}e^{-}→J/ψX based on 3.21 fb^{-1} of data accumulated at energies from 3.645 to 3.891 GeV with the BESIII detector operated at the BEPCII collider. In analysis of the cross sections, we measured the decay branching fractions of B(ψ(3686)→J/ψX)=(64.4±0.6±1.6)% and B(ψ(3770)→J/ψX)=(0.5±0.2±0.1)% for the first time. The energy-dependent line shape of these cross sections cannot be well described by two Breit-Wigner (BW) amplitudes of the expected decays ψ(3686)→J/ψX and ψ(3770)→J/ψX. Instead, it can be better described with one more BW amplitude of the decay R(3760)→J/ψX. Under this assumption, we extracted the R(3760) mass M_{R(3760)}=3766.2±3.8±0.4 MeV/c^{2} , total width Γ_{R(3760)}^{tot}=22.2±5.9±1.4 MeV, and product of leptonic width and decay branching fraction Γ_{R(3760)}^{ee}B[R(3760)→J/ψX]=(79.4±85.5±11.7) eV. The significance of the R(3760) is 5.3σ. The first uncertainties of these measured quantities are from fits to the cross sections and second systematic.