Editing Proton-pump inhibitor (section)

=== Cardiovascular ===
Associations of PPI use and cardiovascular events have also been widely studied but clear conclusions have not been made as these relative risks are confounded by other factors.<ref name="pmid23425521">{{cite journal | vauthors = Agewall S, Cattaneo M, Collet JP, Andreotti F, Lip GY, Verheugt FW, Huber K, Grove EL, Morais J, Husted S, Wassmann S, Rosano G, Atar D, Pathak A, Kjeldsen K, Storey RF | title = Expert position paper on the use of proton pump inhibitors in patients with cardiovascular disease and antithrombotic therapy | journal = European Heart Journal | volume = 34 | issue = 23 | pages = 1708–13, 1713a-1713b | date = June 2013 | pmid = 23425521 | doi = 10.1093/eurheartj/eht042 | doi-access = free }}</ref><ref name="pmid25587094">{{cite journal | vauthors = Melloni C, Washam JB, Jones WS, Halim SA, Hasselblad V, Mayer SB, Heidenfelder BL, Dolor RJ | title = Conflicting results between randomized trials and observational studies on the impact of proton pump inhibitors on cardiovascular events when coadministered with dual antiplatelet therapy: systematic review | journal = Circulation: Cardiovascular Quality and Outcomes | volume = 8 | issue = 1 | pages = 47–55 | date = January 2015 | pmid = 25587094 | pmc = 6143138 | doi = 10.1161/CIRCOUTCOMES.114.001177 }}</ref> PPIs are commonly used in people with cardiovascular disease for gastric protection when [[aspirin]] is given for its antiplatelet actions.<ref name="pmid23425521" /><ref name="pmid21047145">{{cite journal | vauthors = Kwok CS, Nijjar RS, Loke YK | title = Effects of proton pump inhibitors on adverse gastrointestinal events in patients receiving clopidogrel: systematic review and meta-analysis | journal = Drug Safety | volume = 34 | issue = 1 | pages = 47–57 | date = January 2011 | pmid = 21047145 | doi = 10.2165/11584750-000000000-00000 | s2cid = 21231797 }}</ref> An interaction between PPIs and the metabolism of the platelet inhibitor [[clopidogrel]] is known and this drug is also often used in people with cardiac disease.<ref name="pmid22851683">{{cite journal | vauthors = Focks JJ, Brouwer MA, van Oijen MG, Lanas A, Bhatt DL, Verheugt FW | title = Concomitant use of clopidogrel and proton pump inhibitors: impact on platelet function and clinical outcome- a systematic review | journal = Heart | volume = 99 | issue = 8 | pages = 520–7 | date = April 2013 | pmid = 22851683 | doi = 10.1136/heartjnl-2012-302371 | s2cid = 23689175 }}</ref><ref name="pmid26196021">{{cite journal | vauthors = Cardoso RN, Benjo AM, DiNicolantonio JJ, Garcia DC, Macedo FY, El-Hayek G, Nadkarni GN, Gili S, Iannaccone M, Konstantinidis I, Reilly JP | title = Incidence of cardiovascular events and gastrointestinal bleeding in patients receiving clopidogrel with and without proton pump inhibitors: an updated meta-analysis | journal = Open Heart | volume = 2 | issue = 1 | pages = e000248 | year = 2015 | pmid = 26196021 | pmc = 4488889 | doi = 10.1136/openhrt-2015-000248 }}</ref><ref name="doi/10.1136/bmj.l1580">{{cite journal | vauthors = Xie Y, Bowe B, Yan Y, Xian H, Li T, [[Ziyad Al-Aly|Al-Aly Z]] | title = Estimates of all cause mortality and cause specific mortality associated with proton pump inhibitors among US veterans: cohort study | journal = BMJ | volume = 365 | pages = l1580 | date = May 2019 | pmid = 31147311 | pmc = 6538974 | doi = 10.1136/bmj.l1580 | url = https://medicine.wustl.edu/news/popular-heartburn-drugs-linked-to-fatal-heart-disease-chronic-kidney-disease-stomach-cancer/ | quote = Taking PPIs is associated with a small excess of cause specific mortality including death due to cardiovascular disease, chronic kidney disease, and upper gastrointestinal cancer. The burden was also observed in patients without an indication for PPI use.  | publisher = Washington University School of Medicine }}</ref> There are associations with an increased risk of stroke, but this appears to be more likely to occur in people who already have an elevated risk.<ref>{{cite journal | vauthors = Yang M, He Q, Gao F, Nirantharakumar K, Veenith T, Qin X, Page AT, Wong MC, Huang J, Kuo ZC, Xia B, Zhang C, He Y, Meng W, Yuan J, Pan Y | title = Regular use of proton-pump inhibitors and risk of stroke: a population-based cohort study and meta-analysis of randomized-controlled trials | journal = BMC Medicine | volume = 19 | issue = 1 | pages = 316 | date = December 2021 | pmid = 34856983 | doi = 10.1186/s12916-021-02180-5 | publisher = Springer Science and Business Media LLC | pmc = 8641218 | s2cid = 244803096 | doi-access = free }}</ref>

One suggested mechanism for cardiovascular effects is because PPIs bind and inhibit [[dimethylargininase]], the enzyme that degrades [[asymmetric dimethylarginine]] (ADMA), resulting in higher ADMA levels and a decrease in bioavailable [[nitric oxide]].<ref name="pmid24780466">{{cite journal | vauthors = Schepers E, Speer T, Bode-Böger SM, Fliser D, Kielstein JT | title = Dimethylarginines ADMA and SDMA: the real water-soluble small toxins? | journal = Seminars in Nephrology | volume = 34 | issue = 2 | pages = 97–105 | date = March 2014 | pmid = 24780466 | doi = 10.1016/j.semnephrol.2014.02.003 | url = https://biblio.ugent.be/publication/5866529/file/5866574 | quote = It also seems to be the pathophysiological link between the use of proton pump inhibitors and increased cardiovascular event rate because these medications bind and inhibit DDAH, the enzyme that degrades ADMA, which results in higher ADMA levels and a decrease in bioavailable NO. }}</ref>