Genetic Association between the Levels of Plasma Lipids and the Risk of Aortic Aneurysm and Aortic Dissection: A Two-Sample Mendelian Randomization Study

Li, Rui; Zhang, Chao; Du, Xiaona; Chen, Shi

doi:10.3390/jcm12051991

Cited by 3 publications

(3 citation statements)

References 36 publications

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“…To investigate the speci c mechanism of aortic dissection occurrence, we further explored the mechanistic changes in the mouse aorta. Since elevated triglycerides in vivo are positively correlated with the development of aortic aneurysms [34], we rst explored lysosomal acid lipase (LAL), which is associated with TG production.…”

Section: Elevated Triglycerides Increase the Bapn-induced Scorched De...mentioning

confidence: 99%

“…Abnormalities in lipid metabolism are associated with atherosclerosis [30,31], which is one of the risk factors for aortic dissection [32]; therefore, it is reasonable to suspect that the development of aortic dissection may be related to abnormalities in lipid metabolism. There have been articles concerning the association of abnormal lipid metabolism with aortic dissection [33,34], but none of these associations have been studied in depth. In this study, lipid metabolomics and transcriptome sequencing revealed that speci c triglycerides (TGs) were elevated speci cally in TAAD serum and that the differential lipids were associated with an in ammatory response.…”

Section: Introductionmentioning

confidence: 99%

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Supplementary Elevated triglycerides predispose patients to aortic dissection by increasing inflammasome-induced pyroptosis

Chen,

et al. 2024

Preprint

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Aortic dissection (AD) is an acute and life-threatening disease that requires invasive therapy once the aorta has been lacerated. Although several studies have suggested that abnormal lipid metabolism is associated with the development of AD, there are no studies examining the specific mechanisms by which abnormal lipid metabolism contributes to the development of aortic dissection. The aim of this study was to investigate in depth the important role of abnormal lipid metabolism in the development of AD and its possible underlying mechanism. We applied lipid metabolism sequencing and transcriptome sequencing to detect lipid and pathway changes in the blood of AD patients and controls. We applied an AD model via β-aminopropionitrile (BAPN) treatment, and at the same time, we observed the effect of a high-TG environment on AD occurrence in vivo via high-fructose feed. In addition, we applied GSDME knockout mice to reduce GSDME expression. We found that all the upregulated lipids in the serum of AD patients were triglycerides, while the downregulated lipids included mainly sphingomyelin, ceramide, and lysophosphatidylcholine. Lipid metabolism sequencing and transcriptome sequencing revealed differences in serum lipid and proteins related to inflammation. Moreover, in BAPN model mice, elevated triglyceride levels increase the occurrence of aortic dissection, whereas GSDME knockdown inhibits the occurrence of AD but does not inhibit the inflammatory response in the aorta. Elevated triglycerides induce increased pyroptosis in the aortic wall by increasing the inflammatory response in the vasculature, which leads to phenotypic transformation of vascular smooth muscle cells, allowing for an increased incidence of AD.

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Section: Elevated Triglycerides Increase the Bapn-induced Scorched De...mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Supplementary Elevated triglycerides predispose patients to aortic dissection by increasing inflammasome-induced pyroptosis

Chen,

et al. 2024

Preprint

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“…Increased concentrations of non-esterified FAs induce endoplasmic reticulum stress, mitochondrial dysfunction, inflammation and cytokine release, which are causative factors of AD [93]. Observational studies found obvious dyslipidemia in AD patients, and the in-hospital mortality of AD patients was correlated with dyslipidemia [94]. The secretion of arachidonic acid (ARA) and increased synthesis of prostaglandin E2 (PGE2) are associated with endothelial dysfunction and vascular inflammation in patients with MFS [95,96].…”

Section: Lipid Metabolismmentioning

confidence: 99%

Independent and Interactive Roles of Immunity and Metabolism in Aortic Dissection

Li,

Cheng

et al. 2023

IJMS

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Aortic dissection (AD) is a cardiovascular disease that seriously endangers the lives of patients. The mortality rate of this disease is high, and the incidence is increasing annually, but the pathogenesis of AD is complicated. In recent years, an increasing number of studies have shown that immune cell infiltration in the media and adventitia of the aorta is a novel hallmark of AD. These cells contribute to changes in the immune microenvironment, which can affect their own metabolism and that of parenchymal cells in the aortic wall, which are essential factors that induce degeneration and remodeling of the vascular wall and play important roles in the formation and development of AD. Accordingly, this review focuses on the independent and interactive roles of immunity and metabolism in AD to provide further insights into the pathogenesis, novel ideas for diagnosis and new strategies for treatment or early prevention of AD.

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Causal Relationships between Lipid-Lowering Drug Target and Aortic Disease and Calcific Aortic Valve Stenosis: A Two-Sample Mendelian Randomization

Yang,

Xu,

Gao

et al. 2024

Rev. Cardiovasc. Med.

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Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9), 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR), cholesteryl ester transfer protein (CETP) and apolipoprotein C3 (APOC3) are pivotal regulators of lipid metabolism, with licensed drugs targeting these genes. The use of lipid-lowering therapy via the inhibition of these genes has demonstrated a reduction in the risk of cardiovascular disease. However, concerns persist regarding their potential long-term impact on aortic diseases and calcific aortic valve disease (CAVS). This study aims to investigate causal relationships between genetic variants resembling these genes and aortic disease, as well as calcific aortic valve disease using Mendelian randomization (MR). Methods: We conducted drug-target Mendelian randomization employing summary-level statistics of low-density lipoprotein cholesterol (LDL-C) to proxy the loss-of-function of PCSK9, HMGCR, CETP and APOC3. Subsequently, we investigated the association between drug-target genetic variants and calcific aortic valve stenosis and aortic diseases, including thoracic aortic aneurysm (TAA), abdominal aortic aneurysm (AAA), and aortic dissection (AD). Results: The genetically constructed variants mimicking lower LDL-C levels were associated with a decreased risk of coronary artery disease, validating their reliability. Notably, HMGCR inhibition exhibited a robust protective effect against TAA (odds ratio (OR): 0.556, 95% CI: 0.372–0.831, p = 0.004), AAA (OR: 0.202, 95% CI: 0.107–0.315, p = 4.84 × 10-15), and AD (OR: 0.217, 95% CI: 0.098–0.480, p = 0.0002). Similarly, PCSK9, CETP and APOC3 inhibition proxies reduced the risk of AAA (OR: 0.595, 95% CI: 0.485–0.730, p = 6.75 × 10-7, OR: 0.127, 95% CI: 0.066–0.243, p = 4.42 × 10-10, and OR: 0.387, 95% CI: 0.182–0.824, p = 0.014, respectively) while showing a neutral impact on TAA and AD. Inhibition of HMGCR, PCSK9, and APOC3 showed promising potential in preventing CAVS with odds ratios of 0.554 (OR: 0.554, 95% CI: 0.433–0.707, p = 2.27 × 10-6), 0.717 (95% CI: 0.635–0.810, p = 9.28 × 10-8), and 0.540 (95% CI: 0.351–0.829, p = 0.005), respectively. However, CETP inhibition did not demonstrate any significant benefits in preventing CAVS (95% CI: 0.704–1.544, p = 0.836). The consistency of these findings across various Mendelian randomization methods, accounting for different assumptions concerning genetic pleiotropy, enhances the causal inference. Conclusions: Our MR analysis reveals that genetic variants resembling statin administration are associated with a reduced risk of AAA, TAA, AD and CAVS. HMGCR, PCSK9 and APOC3 inhibitors but not CETP inhibitors have positive benefits of reduced CAVS. Notably, PCSK9, CETP and APOC3 inhibitors exhibit a protective impact, primarily against AAA, with no discernible benefits extending to TAA or AD.

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Genetic Association between the Levels of Plasma Lipids and the Risk of Aortic Aneurysm and Aortic Dissection: A Two-Sample Mendelian Randomization Study

Cited by 3 publications

References 36 publications

Supplementary Elevated triglycerides predispose patients to aortic dissection by increasing inflammasome-induced pyroptosis

Supplementary Elevated triglycerides predispose patients to aortic dissection by increasing inflammasome-induced pyroptosis

Independent and Interactive Roles of Immunity and Metabolism in Aortic Dissection

Causal Relationships between Lipid-Lowering Drug Target and Aortic Disease and Calcific Aortic Valve Stenosis: A Two-Sample Mendelian Randomization

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