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Arterial wall inflammation has been consistently suggested to serve a causal role in promoting atherosclerosis and predisposing to hard cardiovascular outcomes. Therefore, there is a global trend in the pharmaceutical industry to develop safe and effective anti-inflammatory agents that could lessen arterial wall inflammation and prevent its detrimental impact on atheroma growth and instability. To this end, autophagy has emerged as a key regulator of inflammation and dysfunctional autophagy machinery has been consistently reported as a contributing factor to atherosclerosis and inflammation. Trehalose, a natural disaccharide sugar found extensively among miscellaneous organisms, by preventing protein denaturation plays various protective roles against stress conditions. Numerous studies indicated trehalose's ability to induce macrophage autophagy-lysosomal biogenesis and reduce inflammation. Also, intravenous (IV) administration of trehalose showed beneficial effects in the reversal of atherosclerosis in atherosclerotic animals. Therefore, in this study, the investigators will explore the potential efficacy of IV trehalose administration on arterial inflammation by employing an positron emission tomography (PET) with 18F-labeled fluoro-2-deoxyglucose (18F-FDG) and computed tomography (18F-FDG PET/CT) technique which noninvasively characterizes vascular inflammation and atherosclerosis.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Trehalose | Experimental | Participants will be received intravenous trehalose infusion weekly (15 g/week) for a period of 12 weeks |
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| Placebo | Placebo Comparator | Participants will be received equal volume of normal saline weekly for a period of 12 weeks |
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| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Trehalose | Drug | Trehalose is a natural disaccharide sugar found extensively among miscellaneous organisms including bacteria, plants, insects, yeast, fungi, and invertebrates. By preventing protein denaturation, it plays various protective roles against stress conditions such as heat, freeze, oxidation, desiccation and dehydration. Owing to this capacity, trehalose is an FDA-approved pharmaceutical excipient that is used as a stabilizer in numerous medicines including parenteral products. In this study, all injections will be conducted by a trained nurse in the presence of a specialist physician at a duration of 45-90 minutes. |
| Measure | Description | Time Frame |
|---|---|---|
| Arterial wall inflammation in the aorta and carotid arteries | This will be assessed using the 18F-FDG PET/CT imaging technique | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measure | Description | Time Frame |
|---|---|---|
| Carotid intima-media thickness (cIMT) | This will be assessed using doppler sonography | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring beclin-1 to assess autophagy activation |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Amirhossien Sahebkar, PharmD, PhD | Contact | +985138002299 | SahebkarA@mums.ac.ir |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Ghaem Educational, Research and Treatment Center | Recruiting | Mashhad | Razavi Khorasan Province | 9919991766 | Iran |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 22895665 | Background | Libby P. Inflammation in atherosclerosis. Arterioscler Thromb Vasc Biol. 2012 Sep;32(9):2045-51. doi: 10.1161/ATVBAHA.108.179705. | |
| 29325641 | Background | Libby P, Hansson GK. Taming Immune and Inflammatory Responses to Treat Atherosclerosis. J Am Coll Cardiol. 2018 Jan 16;71(2):173-176. doi: 10.1016/j.jacc.2017.10.081. No abstract available. |
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| ID | Term |
|---|---|
| D054058 | Acute Coronary Syndrome |
| D001167 | Arteritis |
| ID | Term |
|---|---|
| D017202 | Myocardial Ischemia |
| D006331 | Heart Diseases |
| D002318 | Cardiovascular Diseases |
| D014652 | Vascular Diseases |
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| ID | Term |
|---|---|
| D014199 | Trehalose |
| D000077330 | Saline Solution |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D005936 | Glucans |
| D011134 | Polysaccharides |
| D002241 | Carbohydrates |
| D004187 | Disaccharides |
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This study will be performed double-blind
|
|
| Normal saline | Drug | A solution of 0.90% w/v of sodium chloride (NaCl) in water |
|
|
| At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring high-sensitivity C-reactive protein (hs-CRP) to assess systemic inflammation | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring complete blood count (CBC) (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Assessing lipid profile (Safety) | Including triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Assessing glucose (Safety) | Fasting blood glucose (FBS) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring thyroid-stimulating hormone (TSH) to assess thyroid function (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring alanine aminotransferase (ALT), aspartate aminotransferase (AST) and bilirubin (Bil) to assess liver function (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring creatinine (Cr), urine (Ur) and blood urea nitrogen (BUN) to assess renal function (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Evaluating electrocardiogram (ECG) and heart rhythm to assess heart function (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| Measuring creatinine phosphokinase (CPK) to detect muscle damage (Safety) | At the beginning and end of the intervention trial (Day 0 and week 12) |
| 22445600 | Background | Liao X, Sluimer JC, Wang Y, Subramanian M, Brown K, Pattison JS, Robbins J, Martinez J, Tabas I. Macrophage autophagy plays a protective role in advanced atherosclerosis. Cell Metab. 2012 Apr 4;15(4):545-53. doi: 10.1016/j.cmet.2012.01.022. Epub 2012 Mar 22. |
| 23401644 | Background | Maiuri MC, Grassia G, Platt AM, Carnuccio R, Ialenti A, Maffia P. Macrophage autophagy in atherosclerosis. Mediators Inflamm. 2013;2013:584715. doi: 10.1155/2013/584715. Epub 2013 Jan 21. |
| 26750103 | Background | Shao BZ, Han BZ, Zeng YX, Su DF, Liu C. The roles of macrophage autophagy in atherosclerosis. Acta Pharmacol Sin. 2016 Feb;37(2):150-6. doi: 10.1038/aps.2015.87. Epub 2016 Jan 11. |
| 29175654 | Background | Iwatsuka R, Matsue Y, Yonetsu T, O'uchi T, Matsumura A, Hashimoto Y, Hirao K. Arterial inflammation measured by 18F-FDG-PET-CT to predict coronary events in older subjects. Atherosclerosis. 2018 Jan;268:49-54. doi: 10.1016/j.atherosclerosis.2017.11.016. Epub 2017 Nov 21. |
| 26841377 | Background | Chrapko BE, Chrapko M, Nocun A, Stefaniak B, Zubilewicz T, Drop A. Role of 18F-FDG PET/CT in the diagnosis of inflammatory and infectious vascular disease. Nucl Med Rev Cent East Eur. 2016;19(1):28-36. doi: 10.5603/NMR.2016.0006. |
| 19443587 | Background | Menezes LJ, Kotze CW, Hutton BF, Endozo R, Dickson JC, Cullum I, Yusuf SW, Ell PJ, Groves AM. Vascular inflammation imaging with 18F-FDG PET/CT: when to image? J Nucl Med. 2009 Jun;50(6):854-7. doi: 10.2967/jnumed.108.061432. Epub 2009 May 14. |
| 15299033 | Background | Chen Q, Haddad GG. Role of trehalose phosphate synthase and trehalose during hypoxia: from flies to mammals. J Exp Biol. 2004 Aug;207(Pt 18):3125-9. doi: 10.1242/jeb.01133. |
| 23851366 | Background | Castillo K, Nassif M, Valenzuela V, Rojas F, Matus S, Mercado G, Court FA, van Zundert B, Hetz C. Trehalose delays the progression of amyotrophic lateral sclerosis by enhancing autophagy in motoneurons. Autophagy. 2013 Sep;9(9):1308-20. doi: 10.4161/auto.25188. Epub 2013 Jun 6. |
| 26905424 | Background | Mardones P, Rubinsztein DC, Hetz C. Mystery solved: Trehalose kickstarts autophagy by blocking glucose transport. Sci Signal. 2016 Feb 23;9(416):fs2. doi: 10.1126/scisignal.aaf1937. |
| 28589926 | Background | Sergin I, Evans TD, Zhang X, Bhattacharya S, Stokes CJ, Song E, Ali S, Dehestani B, Holloway KB, Micevych PS, Javaheri A, Crowley JR, Ballabio A, Schilling JD, Epelman S, Weihl CC, Diwan A, Fan D, Zayed MA, Razani B. Exploiting macrophage autophagy-lysosomal biogenesis as a therapy for atherosclerosis. Nat Commun. 2017 Jun 7;8:15750. doi: 10.1038/ncomms15750. |
| 27496857 | Background | van der Valk FM, Bekkering S, Kroon J, Yeang C, Van den Bossche J, van Buul JD, Ravandi A, Nederveen AJ, Verberne HJ, Scipione C, Nieuwdorp M, Joosten LA, Netea MG, Koschinsky ML, Witztum JL, Tsimikas S, Riksen NP, Stroes ES. Oxidized Phospholipids on Lipoprotein(a) Elicit Arterial Wall Inflammation and an Inflammatory Monocyte Response in Humans. Circulation. 2016 Aug 23;134(8):611-24. doi: 10.1161/CIRCULATIONAHA.116.020838. Epub 2016 Aug 5. |
| 27639759 | Background | van der Valk FM, Verweij SL, Zwinderman KA, Strang AC, Kaiser Y, Marquering HA, Nederveen AJ, Stroes ES, Verberne HJ, Rudd JH. Thresholds for Arterial Wall Inflammation Quantified by 18F-FDG PET Imaging: Implications for Vascular Interventional Studies. JACC Cardiovasc Imaging. 2016 Oct;9(10):1198-1207. doi: 10.1016/j.jcmg.2016.04.007. Epub 2016 Sep 14. |
| D014657 |
| Vasculitis |
| D009844 |
| Oligosaccharides |
| D000073893 | Sugars |
| D000077324 | Crystalloid Solutions |
| D007552 | Isotonic Solutions |
| D012996 | Solutions |
| D004364 | Pharmaceutical Preparations |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |