Background: Phenylacetylglutamine (PAGln)—a newly discovered microbial metabolite produced by phenylalanine metabolism—is reportedly associated with cardiovascular events via adrenergic receptors. Nonetheless, its association with cardiovascular outcomes in heart failure (HF) patients remains unknown.Objectives: This study aimed to prospectively investigate the prognostic value of PAGln for HF.Methods: Plasma PAGln levels were quantified by liquid chromatography‐tandem mass spectrometry. We first assessed the association between plasma PAGln levels and the incidence of adverse cardiovascular events in 3152 HF patients (including HF with preserved and reduced ejection fraction) over a median follow‐up period of 2 years. The primary endpoint was the composite of cardiovascular death or heart transplantation. We then assessed the prognostic role of PAGln in addition to the classic biomarker N‐terminal pro‐B‐type natriuretic peptide (NT‐proBNP). The correlation between PAGln levels and β‐blocker use was also investigated.Results: In total, 520 cardiovascular deaths or heart transplantations occurred in the HF cohort. Elevated PAGln levels were independently associated with a higher risk of the primary endpoint in a dose‐response manner, regardless of HF subtype. Concurrent assessment of PAGln and NT‐proBNP levels enhanced risk stratification among HF patients. PAGln further showed prognostic value at low NT‐proBNP levels. Additionally, the interaction effects between PAGln and β‐blocker use were not significant.Conclusions: Plasma PAGln levels are an independent predictor of an increased risk of adverse cardiovascular events in HF. Our work could provide joint and complementary prognostic value to NT‐proBNP levels in HF patients.

Context Carnitine has been associated with cardiac energy metabolism and heart failure, but the association between its precursors—trimethyllysine (TML) and γ-butyrobetaine (GBB)—and heart failure with preserved ejection fraction (HFpEF) remains unclear. Objective To evaluate the relationship between TML-related metabolites and HFpEF in an Asian population. Methods The cross-sectional component of this study examined the association between plasma TML-related metabolites and HFpEF, while a prospective cohort design was applied to examine the association with incident cardiovascular events in HFpEF. Included in the study were 1000 individuals who did not have heart failure (non-HF) and 1413 patients with HFpEF. Liquid chromatography mass spectrometry was used to assess plasma carnitine, GBB, TML and trimethylamine-N-oxide (TMAO) concentrations. Results Plasma GBB and TML were both elevated in patients with HFpEF. After adjusting for traditional risk factors and renal function, TML, but not GBB, was significantly associated with HFpEF. The odds ratio (OR) for the fourth vs first quartile of TML was 1.57 (95% CI 1.09-2.27; P-trend < .01). The OR for each SD increment of log-TML was 1.26 (95% CI 1.08-1.47). Plasma TMAO (P-interaction = 0.024) and estimated glomerular filtration rate (P-interaction = 0.024) modified the TML–HFpEF association. The addition of TML improved the diagnostic value under the multivariable model. In the prospective study of patients with HFpEF, higher plasma TML was associated with increased risk of cardiovascular events. Conclusion Plasma TML concentrations are positively associated with HFpEF, and higher plasma TML indicates increased risk of cardiovascular events.

Background: Brugada syndrome (BrS) is an inheritable arrhythmia syndrome that can lead to sudden cardiac death in patients while the heart structure is normal. However, the genetic background of more than 65% of BrS probands remains unclear. Objectives: The purpose of this study is to report the variant spectrum in a Chinese cohort with suspected BrS and to analyze their distinct clinical and electrocardiographic features. Methods: Patients with suspected BrS from Tongji Hospital between 2008 and 2021 were analyzed retrospectively. Results: A total of 79 probands were included in this study. Patients with type 1 BrS electrocardiogram (ECG) had a prolonged QRS duration compared to patients with type 2/3 BrS ECG. Of them, 59 probands underwent genetic testing. Twenty-five patients (42.37%) showed abnormal genetic testing results, and eight of them (13.56%) carried pathogenic/likely pathogenic (P/LP) mutations. Mutation carriers presented much more prominent depolarization and repolarization abnormalities than non-carriers, including a prolonged P-wave duration, QRS duration, QTc interval, decreased QRS amplitude, and deviation of the electrocardiographic axes (T-wave axis and R-wave axis). Furthermore, our study identified four novel P/LP mutations: Q3508X in TTN, A990G in KCNH2, G1220E, and D372H (in a representative pedigree) in SCN5A. Conclusions: Our study showed the variant spectrum of a suspected Chinese BrS cohort, and we identified four novel P/LP mutations in TTN, KCNH2, and SCN5A.