Background: Although the associations between serum lipid levels and aneurysms have been investigated in epidemiological studies, causality remains unknown. Thus, this study aimed to investigate the causal relationships of serum high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglyceride (TG) levels on five types of aneurysms, using genetic variants associated with four lipid traits as instrumental variables in a Mendelian randomization (MR) analysis. Methods: We performed two-sample Mendelian randomization (MR) analyses to evaluate the associations of HDL-C, LDL-C, TC, and TG levels with risks for five types of aneurysms and those of LDL-C- (HMGCR, NPC1L1, PCSK9, CETP, and LDLR) and TG-lowering targets (ANGPTL3 and LPL) with aneurysms. Results: The sample sizes of the included studies ranged from nearly 80,000 to 410,000. We found inverse associations between genetically predicted HDL-C levels and aortic (OR = 0.74, 95% CI = 0.65–0.85) and abdominal aortic aneurysms (0.58, 0.45–0.75). A 1-SD increase in LDL-C and TC levels was associated with increased risks for aortic (1.41, 1.26–1.58 and 1.36, 1.18–1.56, respectively) and abdominal aortic aneurysms (1.82, 1.48–2.22 and 1.55, 1.25–1.93, respectively). TG levels were significantly associated with aortic (1.36, 1.18–1.56) and lower extremity artery aneurysms (2.76, 1.48–5.14), but limited to cerebral aneurysm (1.23, 1.06–1.42). Secondary analyses revealed a relationship between genetically proxied LDL-C-lowering targets and all types of aneurysms; however, the drug targets remained heterogeneous. We found a weak association between TG-lowering therapies and aortic (ANGPTL3, 0.51, 0.29–0.89) and abdominal aortic aneurysms (LPL, 0.64, 0.44–0.94). Conclusion: According to genetic evidence, lipid dysfunction is a causal risk factor for aneurysms. Lipid-lowering drugs may be a potential effective strategy in preventing and managing aneurysms.

Marfan syndrome (MFS) is a life-threatening autosomal dominant genetic disorder of connective tissue caused by the pathogenic mutation of FBN1. Whole exome sequencing and Sanger sequencing were performed to identify the pathogenic mutation. The transcriptional consequence of the splice-altering mutation was analyzed via minigene assays and reverse-transcription PCR. We identified a novel pathogenic mutation (c.8051+1G>C) in the splice site of exon 64 of the FBN1 gene in an MFS-pedigree. This mutation was confirmed to cause two different truncated transcripts (entire exon 64 skipping; partial exon 64 exclusion). We also systematically summarized previously reported transcriptional studies of pathogenic splice-altering mutations in the FBN1 gene to investigate the clinical and transcriptional consequences. In conclusion, we reported for the first time that a splice-altering mutation in the FBN1 gene leads to two abnormal transcripts simultaneously.

Aortic aneurysm and dissection (AAD) represent a life-threatening aortic disorder, for which current treatment strategies rely predominantly on surgical interventions, with limited pharmacological options targeting the underlying pathophysiology. Vascular smooth muscle cell (VSMC) dysfunction constitutes a central pathological mechanism in the development and progression of AAD. This review outlines the association between VSMCs and AAD, covering their physiological functions and pathological alterations, including phenotypic switching, cell death, and VSMC-mediated extracellular matrix remodeling. It further discusses the impact of epigenetic modifications on VSMC core functions. Additionally, this review addresses normal energy metabolism pathways of VSMCs and the mechanisms of metabolic reprogramming, as well as abnormalities in amino acid metabolism, lipid metabolism, and other metabolic pathways. Signaling mechanisms related to AMPK activation and mitochondrial function are also highlighted. Currently, AAD management is dominated by surgical interventions, while pharmacological therapy remains limited to symptomatic control. Looking ahead, future research should focus on VSMC metabolism-related mechanisms to develop early prevention strategies and novel targeted therapeutics, thereby improving the current treatment landscape for AAD.

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.

Aims: The prognosis of heart failure (HF) depends on genetic predisposition, and recent studies have shown that impaired autophagy is involved in HF. This study was aimed to construct a prognostic model combining polygenetic background based on the autophagy pathway and other traditional risk factors (TRF) of HF prognosis. Methods and results: Via re-analysing the transcriptomic data of 50 failing and 14 non-failing donors, differentially expressed autophagy-related genes (ARGs) were chosen for further comparison and analysis with whole exome sequencing and follow-up data of 1000 HF patients. By searching from reported articles, prognosis-related polymorphisms were identified. ARGs and prognosis-related polymorphisms were used to develop genetic risk score (GRS) and genetic risk factor (GRF), respectively. We compared the predictive power of five models [Model 1, GRS; Model 2, composite of TRF and N-terminal B-type natriuretic peptide (NT-proBNP); Model 3, composite of TRF, NT-proBNP, and GRS; Model 4, composite of TRF, NT-proBNP, and GRF; and Model 5, composite of TRF, NT-proBNP, GRF, and GRS] by applying receiver operating characteristic curves. Twenty-four prognosis-related polymorphisms were used to construct GRF and 11 variants among 48 differentially expressed ARGs associated with clinical outcomes of HF patients were applied for GRS. GRS was strongly associated with cardiac mortality of HF patients, independent of TRF and GRF (95% confidence interval 1.273–1.739, P = 5.78 × 10−7). Comparing with patients with lowest GRS tertile, those with highest tertile had higher risks of developing worse clinical outcomes (hazard ratio = 1.866; 95% confidence interval 1.352–2.575, P = 1.47 × 10−4). The discrimination power of the model including GRS, TRF, GRF, and NT-proBNP is most considerable (area under curve = 0.777), especially in men, patients over 60, patients with hypertension, patients without diabetes or hyperlipidaemia. Conclusions: The model combining autophagy-related GRS, TRF, GRF, and NT-proBNP performs well in distinguishing between worse-prognosis and better-prognosis HF patients, leading a promising strategy for HF treatment and HF prevention.

Mutations of LDLR, APOB and PCSK9 have been well-established to cause hypercholesterolemia while the pathogenic effects of LPL has been confirmed by cohort