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Review
. 2023 Jan-Dec:17:17539447231215213.
doi: 10.1177/17539447231215213.

Methotrexate and cardiovascular prevention: an appraisal of the current evidence

Arduino A Mangoni  1   2 , Salvatore Sotgia  3 , Angelo Zinellu  3 , Ciriaco Carru  4   5 , Gianfranco Pintus  3 , Giovanni Damiani  6   7 , Gian Luca Erre  8 , Sara Tommasi  9   10
Affiliations
Review

Methotrexate and cardiovascular prevention: an appraisal of the current evidence

Arduino A Mangoni et al. Ther Adv Cardiovasc Dis. 2023 Jan-Dec.

Abstract

New evidence continues to accumulate regarding a significant association between excessive inflammation and dysregulated immunity (local and systemic) and the risk of cardiovascular events in different patient cohorts. Whilst research has sought to identify novel atheroprotective therapies targeting inflammation and immunity, several marketed drugs for rheumatological conditions may serve a similar purpose. One such drug, methotrexate, has been used since 1948 for treating cancer and, more recently, for a wide range of dysimmune conditions. Over the last 30 years, epidemiological and experimental studies have shown that methotrexate is independently associated with a reduced risk of cardiovascular disease, particularly in rheumatological patients, and exerts several beneficial effects on vascular homeostasis and blood pressure control. This review article discusses the current challenges with managing cardiovascular risk and the new frontiers offered by drug discovery and drug repurposing targeting inflammation and immunity with a focus on methotrexate. Specifically, the article critically appraises the results of observational, cross-sectional and intervention studies investigating the effects of methotrexate on overall cardiovascular risk and individual risk factors. It also discusses the putative molecular mechanisms underpinning the atheroprotective effects of methotrexate and the practical advantages of using methotrexate in cardiovascular prevention, and highlights future research directions in this area.

Keywords: atherosclerosis; heart disease risk factors; immunity; inflammation; methotrexate.

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Conflict of interest statement

A.A.M. received funding from medac GmbH (Germany) to conduct an investigator-initiated trial on the effects of methotrexate on blood pressure and arterial function in patients with rheumatoid arthritis.

Figures

Figure 1.
Figure 1.
The pharmacology of methotrexate. AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMP, adenosine monophosphate; ATIC, aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase; DHF, dihydrofolate; DHFR, dihydrofolate reductase; dTMP, deoxythymidine monophosphate; dUMP, deoxyuridine monophosphate; FAICAR, 5-formamidoimidazole-4-carboxamide ribotide; FPGS, folylpolyglutamate synthetase; IMP, inosine monophosphate; MTX-PGs, methotrexate polyglutamates; SLC19A1, solute carrier family 19 member 1; THF, tetrahydrofolate; TYMS, thymidylate synthase.
Figure 2.
Figure 2.
The effects of methotrexate on adenosine, AICAR and AMPK. AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMP, adenosine monophosphate; AMPK, 5′ adenosine monophosphate-activated protein kinase; ATIC, aminoimidazole carboxamide ribonucleotide transformylase/inosine monophosphate cyclohydrolase; FAICAR, 5-formamidoimidazole-4-carboxamide ribotide; IMP, inosine monophosphate; MTX-PGs, methotrexate polyglutamates; 5′-NT, 5′-Nucleotidase.
Figure 3.
Figure 3.
Effects of methotrexate on cardiovascular risk factors (orange) and putative atheroprotective mechanisms (cyan) according to experimental and clinical studies. AICAR, 5-aminoimidazole-4-carboxamide ribonucleoside; AMPK, 5′ adenosine monophosphate-activated protein kinase.
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