Ezetimibe and Improving Cardiovascular Outcomes: Current Evidence and Perspectives

Pradhan, Akshyaya; Bhandari, Monika; Sethi, Rishi

doi:10.1155/2020/9815016

Cited by 21 publications

(17 citation statements)

References 52 publications

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“…In addition, cholesterol homeostasis was shown to be regulated by substrate as well. Absorption of cholesterol by the intestine is a major determinant of cholesterol homeostasis and the target of an important cholesterol-lowering drug, ezetimibe (93,94). Furthermore, the cholesterol biosynthesis pathway is essential for homeostasis of the intestinal epithelium (95,96).…”

Section: Discussionmentioning

confidence: 99%

Drivers of transcriptional variance in human intestinal epithelial organoids

Criss

Bhasin

Rienzi

et al. 2021

Physiological Genomics

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Human intestinal epithelial organoids (enteroids and colonoids) are tissue cultures used for understanding the physiology of the intestinal epithelium. Here, we explored the effect on the transcriptome of common variations in culture methods, including extracellular matrix substrate, format, tissue segment, differentiation status, and patient heterogeneity. RNA-sequencing datasets from 276 experiments performed on 37 human enteroid and colonoid lines from several groups in the Texas Medical Center. DESeq2 and Gene Set Enrichment Analysis (GSEA) was used to identify differentially expressed genes and enriched of pathways. PERMANOVA, Pearson's correlation, and dendrogram analysis of the data originally indicated three tiers of influence of culture methods on transcriptomic variation: substrate (collagen vs. Matrigel) and format (3D, transwell, and monolayer) had the largest effect; segment of origin (duodenum, jejunum, ileum, colon) and differentiation status had a moderate effect, and patient heterogeneity and specific experimental manipulations (e.g., pathogen infection) had the smallest effect. GSEA identified hundreds of pathways that varied between culture methods, such as IL1 cytokine signaling enriched in transwell vs. monolayer cultures, and E2F target genes enriched in collagen vs. Matrigel cultures. The transcriptional influence of the format was furthermore validated in a synchronized experiment performed with various format-substrate combinations. Additionally, experimental manipulations such as infection had modest effects. These results show that common variations in culture conditions can have large effects on intestinal organoids and should be accounted for when designing experiments and comparing results between laboratories. Our data constitute the largest RNA-seq dataset interrogating human intestinal organoids.

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Section: Discussionmentioning

confidence: 99%

Drivers of transcriptional variance in human intestinal epithelial organoids

Criss

Bhasin

Rienzi

et al. 2021

Physiological Genomics

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show abstract

“…Here we highlighted one example of a pathway that is influenced by substrate with showing the enrichment of cholesterol homeostats in monolayers on Matrigel in comparison to monolayers on collagen. Absorption of cholesterol by the intestine is a major determinant of cholesterol homeostasis and the target of an important cholesterol-lowering drug, ezetimibe (Malhotra, Gill, Saksena, & Alrefai, 2020;Pradhan, Bhandari, & Sethi, 2020). Furthermore, the cholesterol biosynthesis pathway is essential for homeostasis of the intestinal epithelium (McFarlane et al, 2015;Rong, McDonald, & Engelking, 2017).…”

Section: Discussionmentioning

confidence: 99%

Drivers of Transcriptional Variance in Human Intestinal Epithelial Organoids

Criss

Bhasin

Rienzi

et al. 2021

Preprint

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Background & Aims: Human intestinal epithelial organoids (enteroids and colonoids) are tissue cultures used for understanding the physiology of the intestinal epithelium. Here, we explored the effect on the transcriptome of common variations in culture methods, including extracellular matrix substrate, format, tissue segment, differentiation status, and patient heterogeneity. Methods: RNA-sequencing datasets from 251 experiments performed on 35 human enteroid and colonoid lines from 28 patients were aggregated from several groups in the Texas Medical Center. DESeq2 and Gene Set Enrichment Analysis (GSEA) was used to identify differentially expressed genes and enriched of pathways. Results: PERMANOVA, Pearson correlations, and dendrogram analysis of all data indicated three tiers of influence of culture methods on transcriptomic variation: substrate (collagen vs. Matrigel) and format (3D, transwell, and monolayer) had the largest effect (7,271-1,305 differentially expressed genes-DEGs); segment of origin (duodenum, jejunum, ileum, colon) and differentiation status had a moderate effect (5,977-420 DEGs), and patient heterogeneity and specific experimental manipulations (e.g., pathogen infection) had the smallest effect. GSEA identified hundreds of pathways that varied between culture methods, such as IL1 cytokine signaling enriched in transwell vs. monolayer cultures, and cholesterol biosynthesis genes enriched in Matrigel vs. collagen cultures. Conclusions: Surprisingly large differences in organoid transcriptome were driven by variations in culture methods such as format and substrate, whereas experimental manipulations such as infection had modest effects. These results show that common variations in culture conditions can have large effects on intestinal organoids and should be accounted for when designing experiments and comparing results between laboratories. Our data constitute the largest RNA-seq dataset interrogating human intestinal organoids.

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“…It is worth mentioning that our study analysed the effects of LLT escalation mostly by adding ezetimibe to high-intensity statins. Although the benefit of ezetimibe has remained uncertain for several years 19 , recent clinical trials have shown that adding ezetimibe to statin therapy elicited a reduction in cardiovascular events and greater coronary plaque regression 16 , 20 , 21 . In this regard, the latest European guidelines raised the recommendation level of ezetimibe in patients who do not achieve LDL-C goal with maximal tolerable dose statins 3 .…”

Section: Discussionmentioning

confidence: 99%

Escalation of liPid-lOwering therapy in patientS wiTh vascular disease receiving HIGH-intensity statins: the retrospective POST-HIGH study

Lee

Kang

et al. 2021

Sci Rep

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In this retrospective study, we investigated whether lipid-lowering therapy (LLT) escalation has clinical benefits in patients with atherosclerotic cardiovascular disease (ASCVD) and low-density lipoprotein cholesterol (LDL-C) levels of 55–99 mg/dL (1.4–2.6 mmol/L), post high-intensity. Out of 6317 Korean patients screened in 2005–2018, 1159 individuals with ASCVD and LDL-C levels of 55–99 mg/dL after statin use equivalent to 40 mg atorvastatin were included. After 1:2 propensity score matching, 492 patients (164 with LLT escalation, 328 controls without LLT escalation) were finally analysed. Primary outcome variables were major adverse cardiovascular and cerebrovascular events (MACCE) and all-cause death. At median follow-up (1.93 years), the escalation group had a lower MACCE rate (1.72 vs. 3.38 events/100 person-years; hazard ratio [HR] 0.34, 95% confidence interval [CI] 0.14–0.83; p = 0.018) than the control group. The incidence of all-cause death (0.86 vs. 1.02 events/100 person-years; HR 0.58, 95% CI 0.15–2.19; p = 0.42) and each MACCE component did not differ between groups. Kaplan–Meier curves exhibited lower risk of MACCE in the escalation group (HR 0.36, 95% CI 0.12–0.97; p = 0.040) but a difference not statistically significant in all-cause death (HR 0.30, 95% CI 0.04–2.48; p = 0.26). LLT escalation was associated with reduced cardiovascular risk, supporting more aggressive LLT in this population.

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Ezetimibe and Improving Cardiovascular Outcomes: Current Evidence and Perspectives

Cited by 21 publications

References 52 publications

Drivers of transcriptional variance in human intestinal epithelial organoids

Drivers of transcriptional variance in human intestinal epithelial organoids

Drivers of Transcriptional Variance in Human Intestinal Epithelial Organoids

Escalation of liPid-lOwering therapy in patientS wiTh vascular disease receiving HIGH-intensity statins: the retrospective POST-HIGH study

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