Phosphodiesterase 5 and its inhibitors with ischemic heart disease: a Mendelian randomization analysis and a real-world study.

IF 5.3 1区医学 Q1 CARDIAC & CARDIOVASCULAR SYSTEMS

European Heart Journal - Cardiovascular Pharmacotherapy Pub Date : 2024-10-18 DOI:10.1093/ehjcvp/pvae081

Jun Xiao, Naiqi Zhang, Ziting Gao, Yajing Wei, Hongye Wei, Ziyi Qiu, Kristina Sundquist, Jan Sundquist, Jianguang Ji, Wuqing Huang

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引用次数: 0

Abstract

Background: Accumulating studies reported that several phosphodiesterases (PDEs) inhibitors might have cardiovascular benefits.

Objectives: This study aimed to explore the relationship between genetically-predicted PDEs and ischemia heart disease via drug target Mendelian randomization (MR) approach, and then examine the effect of inhibitors of identified target on the outcomes by using real-world data.

Methods: In the two-sample MR study, the expression of genes encoding PDEs was used to proxy the level of PDEs and available expression quantitative trait loci (eQTLs) for each target gene were identified as the genetic instruments. The outcomes included coronary heart disease (CHD) and myocardial infarction (MI). In the real-world study, a retrospective cohort was conducted to compare the incidence of outcomes between PDE5 inhibitors and alprostadil use by linking Swedish nationwide registers.

Results: MR analyses identified two types of PDEs, PDE5 and PDE8, genetically-predicted expression in blood of the encoded genes was significantly associated with the risk of CHD (ORPDE5A = 1.22,95% CI = 1.06-1.40; ORPDE8A = 1.26,95% CI = 1.07-1.49) and MI (ORPDE5A = 1.27,95% CI = 1.09-1.48; ORPDE8A = 1.24,95% CI = 1.04-1.48). Notably, the highest expression of PDE5A was observed in artery aorta, which was also positively related to CHD (OR = 1.17,95% CI = 1.05-1.32) and MI (OR = 1.15,95% CI = 1.02-1.30). Real-world study provided supportive evidence that as compared to alprostadil use, PDE5 inhibitors use significantly reduced the incidence of CHD (adjusted HR = 0.70,95% CI = 0.66-0.73) and MI (adjusted HR = 0.79,95% CI = 0.73-0.84).

Conclusion: This study provided observational and genetic evidence about the protective role of PDE5 inhibition against ischemic heart disease, indicating the potential of these drugs to be repurposed for ischemia heart disease prevention and treatment.

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磷酸二酯酶 5 及其抑制剂与缺血性心脏病：孟德尔随机分析和真实世界研究。

背景：越来越多的研究表明，几种磷酸二酯酶（PDEs）抑制剂可能对心血管有益：本研究旨在通过药物靶点孟德尔随机化（MR）方法探讨基因预测的磷酸二酯酶与缺血性心脏病之间的关系，然后利用真实世界的数据研究确定靶点的抑制剂对结果的影响：在双样本 MR 研究中，使用编码 PDEs 的基因的表达来替代 PDEs 的水平，并为每个靶基因确定可用的表达定量性状位点（eQTLs）作为遗传工具。研究结果包括冠心病（CHD）和心肌梗死（MI）。在真实世界研究中，通过链接瑞典全国范围内的登记册，进行了一项回顾性队列研究，以比较 PDE5 抑制剂和阿普斯地尔使用之间的结果发生率：MR分析确定了两种类型的PDE，即PDE5和PDE8，编码基因在血液中的遗传预测表达与冠心病（ORPDE5A = 1.22，95% CI = 1.06-1.40；ORPDE8A = 1.26，95% CI = 1.07-1.49）和心肌梗死（ORPDE5A = 1.27，95% CI = 1.09-1.48；ORPDE8A = 1.24，95% CI = 1.04-1.48）的风险显著相关。值得注意的是，PDE5A 在动脉主动脉中的表达量最高，这也与冠心病（OR = 1.17,95% CI = 1.05-1.32）和心肌梗死（OR = 1.15,95% CI = 1.02-1.30）呈正相关。真实世界研究提供的支持性证据表明，与使用阿普斯地尔相比，使用PDE5抑制剂可显著降低冠心病（调整后HR = 0.70，95% CI = 0.66-0.73）和心肌梗死（调整后HR = 0.79，95% CI = 0.73-0.84）的发病率：这项研究为PDE5抑制剂对缺血性心脏病的保护作用提供了观察和遗传学证据，表明这些药物有可能被重新用于缺血性心脏病的预防和治疗。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

European Heart Journal - Cardiovascular Pharmacotherapy Medicine-Cardiology and Cardiovascular Medicine

CiteScore

10.10

自引率

14.10%

发文量

期刊介绍： The European Heart Journal - Cardiovascular Pharmacotherapy (EHJ-CVP) is an international, peer-reviewed journal published in English, specifically dedicated to clinical cardiovascular pharmacology. EHJ-CVP publishes original articles focusing on clinical research involving both new and established drugs and methods, along with meta-analyses and topical reviews. The journal's primary aim is to enhance the pharmacological treatment of patients with cardiovascular disease by interpreting and integrating new scientific developments in this field. While the emphasis is on clinical topics, EHJ-CVP also considers basic research articles from fields such as physiology and molecular biology that contribute to the understanding of cardiovascular drug therapy. These may include articles related to new drug development and evaluation, the physiological and pharmacological basis of drug action, metabolism, drug interactions, and side effects.