Chair of Epidemiology, Ludwig-Maximilians-Universität München, UNIKA-T Augsburg, Augsburg, Germany.
Independent Research Group Clinical Epidemiology, Helmholtz Zentrum München, German Research Center for Environmental Health, Neuherberg, Germany.
Pharmacotherapy. 2021 Feb;41(2):198-204. doi: 10.1002/phar.2504. Epub 2021 Feb 4.
Long-term intake of proton pump inhibitors (PPIs) might increase the risk of cardiovascular events. One suggested mechanism is that PPIs inhibit the enzyme dimethylarginine dimethylaminohydrolase (DDAH) and thereby block the degradation of endothelial asymmetrical dimethylarginine (ADMA). Excess ADMA in turn leads to impaired endothelial nitric oxide (NO) generation. So far, this mechanism has only been established in human cell cultures. Previous studies that examined this pathway in human populations measured circulating ADMA and found no association with PPI use and excess plasma ADMA. But in a recent study, plasma ADMA was not correlated with intracellular ADMA. We therefore focused on changes in plasma citrulline as an indicator for potential DDAH inhibition.
We analyzed the association between regular daily PPI intake and flow-mediated dilation (FMD) of the brachial artery as well as plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine using inverse probability weighting to adjust for confounding and censoring.
Data of 1298 participants from two independent cohorts of the population-based Study of Health in Pomerania were used.
Participants of the population-based Study of Health in Pomerania are a stratified random sample of the study region.
Regular daily intake of PPIs.
FMD of the brachial artery and plasma concentrations of citrulline, arginine, ADMA, and symmetric dimethylarginine.
Eighty-seven participants (57.5% female) were regular daily users of PPIs. In the fully adjusted models, associations were identified for FMD and plasma citrulline concentrations. PPI users revealed a 0.99% (95% CI: -1.96 to -0.02) lower FMD and 3.03 µmol/L (95% CI: -4.96 to -1.10) lower plasma citrulline levels as compared to non-users.
Our data provide evidence that long-term intake of PPIs might inhibit human DDAH activity, resulting in impaired endothelial NO production and reduced vascular function. In the long run, this might explain an increased risk for cardiovascular diseases associated with long-term PPI use.
长期服用质子泵抑制剂（PPIs）可能会增加心血管事件的风险。一种推测的机制是，PPIs 抑制酶二甲基精氨酸二甲氨基水解酶（DDAH），从而阻止内皮不对称二甲基精氨酸（ADMA）的降解。过量的 ADMA 反过来又导致内皮一氧化氮（NO）生成受损。到目前为止，这种机制仅在人体细胞培养中得到证实。以前在人群中研究该途径的研究测量了循环 ADMA，并未发现与 PPI 使用和血浆 ADMA 过量有关。但在最近的一项研究中，血浆 ADMA 与细胞内 ADMA 无关。因此，我们专注于血浆瓜氨酸的变化作为潜在 DDAH 抑制的指标。
我们使用逆概率加权法来调整混杂因素和删失，分析了常规每日 PPI 摄入与肱动脉血流介导的扩张（FMD）以及血浆瓜氨酸、精氨酸、ADMA 和对称二甲基精氨酸浓度之间的关系。
使用基于人群的波罗的海健康研究的两个独立队列中的 1298 名参与者的数据。
波罗的海健康研究的参与者是研究区域的分层随机样本。
常规每日服用 PPIs。
肱动脉 FMD 和血浆瓜氨酸、精氨酸、ADMA 和对称二甲基精氨酸浓度。
87 名参与者（57.5%为女性）为常规每日 PPI 使用者。在完全调整的模型中，FMD 和血浆瓜氨酸浓度之间存在关联。与非使用者相比，PPI 使用者的 FMD 降低了 0.99%（95%CI：-1.96 至 -0.02），血浆瓜氨酸水平降低了 3.03µmol/L（95%CI：-4.96 至 -1.10）。
我们的数据提供了证据表明，长期服用 PPIs 可能会抑制人体 DDAH 活性，导致内皮一氧化氮生成受损和血管功能降低。从长远来看，这可能解释了与长期 PPI 使用相关的心血管疾病风险增加的原因。
