Haemodynamic effects of istaroxime in SCAI stage B HF‐related cardiogenic shock: Insights from the SEISMiC trial

Abstract Aims The haemodynamic effects of istaroxime in SCAI stage B cardiogenic shock (CS) due to acute decompensated heart failure (ADHF) have not been evaluated. We assessed the impact of istaroxime on specific invasively‐obtained haemodynamic measures. Methods and results In the SEISMiC extension study, 30 patients with ADHF‐related SCAI stage B CS were randomized to 60‐h intravenous infusion of either placebo ( n  = 11) or istaroxime at maximum 0.5–1.0 μg/kg/min ( n  = 19). In this post hoc analysis, invasively‐obtained haemodynamic measures, simulated group‐averaged pressure‐volume (PV) loops, and end‐systolic elastance (Ees), derived from individual‐patient PV relationships, were compared between istaroxime‐ and placebo‐treated patients. Compared with placebo, patients randomized to istaroxime for 48–60 h had greater increases in aortic pulsatility index (API) and left ventricular (LV) stroke work index (LVSWI) at 6, 12, 24, and 48 h; and greater increase in pulmonary artery (PA) compliance and reduction in PA elastance at 48 h. At group‐averaged PV loop analysis, LV contractility remained stable and right ventricular (RV) contractility tended to deteriorate over time with placebo, whereas LV contractility improved and RV contractility tended to be stabilized with istaroxime. Greater increases in both LV Ees and RV Ees were observed with istaroxime versus placebo from baseline to 48 h. Conclusions In patients with ADHF‐pre‐CS, istaroxime at doses up to 1.0 μg/kg/min for up to 60 h was associated with sustained improvements in measures of LV performance (API and LVSWI), in parallel with increase in PA compliance and reduction in PA elastance at 48 h. As compared with placebo, istaroxime improved LV contractility and preserved RV contractility, which deteriorated on placebo, over time.

The role of kidney disease progression in heart failure prognosis: Bridging the evidence gap for optimal management

A multicentre, randomized, double‐blind, active and placebo‐controlled study of pecavaptan, a dual V1a/ V2 vasopressin receptor antagonist, in patients with acute heart failure: The AVANTI trial

Abstract Aims Balanced dual V1a/ V2 vasopressin receptor antagonism may offer potential advantages as an adjunctive and/or a replacement therapy to loop diuretic therapy. Methods and results AVANTI was a double‐blind, randomized trial in patients hospitalized with heart failure and residual congestion. In Part A, patients received pecavaptan or placebo as adjunctive therapy to standard of care for 30 days. In Part B, patients were randomized to continuation of furosemide or replacement by pecavaptan, as single diuretic therapies for 30 days. Co‐primary endpoints were for Part A changes in weight and serum creatinine and for Part B, changes in weight and blood urea nitrogen/creatinine ratio. Among 483 patients randomized into Part A, there was no difference in weight reduction between pecavaptan and placebo (between‐group difference: −0.27 kg, upper one‐sided 95% confidence interval [CI] –0.29, p  = 0.21) and no effect on serum creatinine (between‐group difference: 0.05 mg/dl, upper one‐sided 95% CI 0.12, p  = 0.87). Subsequently, 286 patients were randomized into Part B. The difference in weight change between the pecavaptan and furosemide monotherapy groups over 30 days was 0.69 kg (upper one‐sided 80% CI 0.95, p  = 0.16), satisfying non‐inferiority criteria of 1 kg. The between‐group difference in log‐transformed change in blood urea nitrogen/creatinine ratio was −0.22 (upper one‐sided 80% CI –0.19, p  < 0.0001) favouring pecavaptan. Adverse events and serious adverse events related to congestion including heart failure hospitalizations were numerically higher in the pecavaptan groups in both parts of the trial. Conclusions Adjunctive pecavaptan for 30 days in patients with residual congestion had no impact on weight loss nor on renal function. Post‐discharge pecavaptan monotherapy was non‐inferior to furosemide monotherapy for weight change over 30 days, but was associated with improved renal function. The increase in congestion events suggests that future trials will need optimized background diuretic dosing. Clinical Trial Registration: ClinicalTrials.gov NCT03901729.

Impact of genotype–phenotype associations on prognosis in dilated cardiomyopathy

Aims Dilated cardiomyopathy (DCM) has a monogenic aetiology in up to 40% of patients. Understanding the spectrum of genotype–phenotype associations in DCM is crucial for risk stratification and personalized treatment. We aimed to (i) characterize genotype‐specific features, (ii) evaluate whether phenotype‐based clustering reflects underlying genotype, and (iii) compare the prognostic value of genotype‐ versus phenotype‐based approaches. Methods and results A multicentre cohort of 534 DCM patients with a (likely) pathogenic variant were grouped by genotype (genotype‐first approach) and clustered by clinical phenotype (phenotype‐first approach). We compared clinical characteristics, identified genotype–phenotype associations, and evaluated outcomes, including all‐cause mortality, heart failure hospitalization, heart transplantation, and malignant ventricular arrhythmias. Using the genotype‐first approach, significant genotype–phenotype associations were found for 10 genes. FLNC, LMNA, DSP , and PLN variants were linked to arrhythmias. BAG3, TNNT2, DMD , and TTN were associated with increased cardiac volumes and decreased left ventricular ejection fraction (LVEF). Clustering identified four phenotypic clusters: (1) young, moderately reduced LVEF; (2) arrhythmias, moderate reduced LVEF; (3) low LVEF; (4) arrhythmias, low LVEF. There were no clear correlations between phenotypic clusters and genotype. The genotype‐first approach showed that LMNA, FLNC, and BAG3 variants had the highest risk for heart failure and arrhythmogenic adverse outcomes. The phenotype‐first approach indicated that clusters 3 and 4 were associated with the worst prognosis. Overall, genotype was the strongest predictor of outcome. Conclusions Patients with a genetic form of DCM exhibit clinical and genetic heterogeneity. Genotype‐based risk stratification is more accurate compared to a phenotype‐first approach, highlighting the importance of broad genetic screening among patients with DCM. Additionally, gene‐specific risk prediction should become more prominent in current guidelines on management of genetic DCM patients.

Inborn Errors of Nucleic Acid Sensing and Type I Interferon Signaling Determine Viral Susceptibility in Humans

ABSTRACT The innate immune system relies on nucleic acid (NA) sensors to detect viral infections and trigger type I interferon (IFN‐I) responses, which are crucial for antiviral defense. NA pattern recognition receptors detect viral RNA or DNA within various cellular compartments, initiating antiviral signaling pathways. However, inherited deficiencies in these NA sensing mechanisms can result in increased susceptibility to severe viral infections. This review explores key genetic mutations affecting NA sensing and IFN‐I pathways that predispose individuals to life‐threatening viral diseases, including herpesviruses, respiratory viruses, enteroviruses, arboviruses, and vaccine‐strain disseminated viral diseases. The identification of these monogenic defects in individuals afflicted by severe viral infections, along with the observed incomplete penetrance of these mutations, highlight the intricate interplay of the host's intrinsic, innate, and adaptive immune response with invading viral pathogens. These insights into the molecular basis of antiviral immunity not only underscore the clinical challenges associated with viral susceptibility but also offers the opportunity for personalized treatment strategies, including genetic screening, tailored vaccination protocols, and targeted antiviral therapies.

Hyperinflammation by Human Macrophages Induced by SARS‐CoV‐2 Anti‐Spike IgG Is Dependent on Glucose and Fatty Acid Metabolism

ABSTRACT Severe COVID‐19 is an immunological disorder characterized by excessive immune activation following infection with SARS‐CoV‐2, which typically occurs around the time of seroconversion. Anti‐spike IgG of critically ill COVID‐19 patients induces excessive inflammation by activation of Fc gamma receptors (FcγRs) on human alveolar macrophages, leading to tissue damage, pulmonary edema, and coagulopathy. While metabolic reprogramming of immune cells is critical for the induction of inflammatory responses, still little is known about the metabolic pathways that are involved in COVID‐19‐specific hyperinflammation. In this study, we identified that anti‐spike IgG immune complexes (ICs) induce rapid metabolic reprogramming of alveolar macrophages, which is essential for the induction of inflammation. Through functional inhibition, we identified that glycolysis, fatty acid synthesis, and pentose phosphate pathway (PPP) activation are critical for anti‐spike IgG‐induced hyperinflammation. Remarkably, while excessive proinflammatory cytokine production by macrophages is critically dependent on simultaneous stimulation with viral stimuli and anti‐spike IgG complexes, we show that the required metabolic reprogramming is specifically driven by anti‐spike IgG complexes. These findings provide new insights into the metabolic pathways driving hyperinflammation by macrophages in the context of severe COVID‐19. Targeting of these pathways may reveal new possibilities to counteract pathological inflammatory responses in severe COVID‐19 and related diseases.

Facile Synthesis of Versatile and Air‐stable Cuprous Synthons of Type [Cu(NHC)(OC(H)(CF 3 ) 2 )] (NHC=N‐Heterocyclic Carbene)

Abstract A new family of Cu‐NHC complexes having general formula [Cu(NHC)(OC(H)(CF 3 ) 2 )] (NHC=N‐Heterocyclic Carbene; OC(H)(CF 3 ) 2 =1,1,1,3,3,3‐hexafluoroisopropanol (HFIP)) is reported. The operational simple protocol of the weak base route allows the formation of a series of new fluorinated cuprous synthons, opening the doors to new possible synthetic and catalytic pathways, as demonstrated by the hexafluoroisopropoxylation of 9‐chloroacridine using [Cu(IPr)(OC(H)(CF 3 ) 2 )] ( 2 ).

Expanding the Chemical Space of Allyl Palladates with Anticancer Properties

Allyl palladates are emerging as promising anticancer agents due to their unique mechanisms of action, including thioredoxin reductase inhibition and immunogenic cell death activation. However, their lack of selectivity toward cancer cells has hindered their therapeutic potential. Herein, a library of ten novel allyl palladates featuring diverse azolium ligands is synthesized via a solvent‐free approach, including 1) ring‐expanded azolium salts; 2) azolium salts functionalized with phosphonium, thioether, selenoether, or sulfoxide groups; 3) 12‐membered cyclic alkyl groups; or 4) bulky or methoxy‐functionalized aryl groups. The newly synthesized compounds are tested against A2780, A2780cis, and U87 cancer cell lines, as well as MRC‐5 non‐cancerous cells. Results reveal a general excellent cytotoxicity (in the micromolar or submicromolar range), with allyl palladates 2c–d showing the greatest activity but limited selectivity. Compounds 2f and 2h , however, demonstrate improved selectivity toward cancer cells, highlighting the influence of thioether and selenoether functional groups.

A New Paradigm for the Supramolecular Structure of Laterally Offset Diarenes: Polymorphs II of Para ‐Substituted Acetophenone Azines, Y p Ph(Me)CNNC(Me)PhY p (Y = Cl, Br, CH 3 )

The crystal structures of polymorphs II of acetophenone azines Y p PhRCNNCRPhY p with R = CH 3 and Y = Cl ( 1M ), Br ( 2M ), and CH 3 ( 8M ) are discussed. The azine molecules in polymorphs II are C i ‐symmetric with trans ‐azine moieties and conrotatory phenyl twists. Polymorphs 1M‐I and 2M‐I contain C 2 ‐symmetric enantiomers with pronounced azine twists and disrotatory phenyl twists and allow for strong lateral double T‐contacts. The three polymorphs II exemplify the new Paradigm IV for the supramolecular architectures of “laterally offset diarenes” and result in “shiplap/flat” idioteloamphiphile monolayers. Intralayer lateral attraction is provided by edge‐to‐face arene‐arene contacts between molecules with substantial longitudinal offset and involves arene edges bridging one azine‐N and one phenyl center (EAzArB synthon) or one phenyl center and substituent Y (EYArB synthon) of different neighbors. These bridging synthons are characterized by a survey of pertinent structure parameters and their structural significance is corroborated by analysis of distance mapped Hirshfeld surfaces and the computation of 2D‐fingerprint plots. The edge‐to‐face contacts are the most attractive intermolecular interactions, and these interactions are quantified via the computed pair interaction energies and the results of aromatic analyzer analysis. Synthon binding energies and lattice energies are determined to assess polymorph preference energies.

Fluorescent β‐Sheet‐Based Peptide Hydrogels with Aggregation‐Enhanced Emission Properties

Novel fluorescent peptide hydrogels are reported by combining 1,8‐naphthalimide‐derived amino acids with a previously developed peptide‐based controlled drug release matrix. Aggregation‐enhanced emission is achieved by inserting the fluorescent naphthalimide moieties in a peptide sequence with self‐assembling properties. The formation of β‐sheets directs the orientation of the luminescent side chains, leading to the avoidance of aggregation‐caused quenching. The relation between the β‐sheet‐underpinned fiber formation and the emission characteristics is further elucidated by spectroscopic and microscopic techniques, including correlative fluorescence and atomic force microscopy imaging. Owing to the incorporation of the naphthalimide moiety, the gelation concentration is lowered and the gel strength improved. The resulting hydrogels does not contain any organic solvent (in contrast to ample literature examples), present thixotropic behavior, and the fluorescent properties are sensitive to environmental conditions such as temperature and medium. These features make the soft biomaterials interesting for applications such as biosensing, real‐time bioimaging, and 3D printing. The high tunability of the peptide sequence composition and configuration, as well as the chemical structure of the 1,8‐naphthalimide moiety, allows for modulating the material toward desired properties.