AtherosclerosisNCT03180775
Effects of Dietary Amino Acids on Serum and Macrophage Atherogenicity
A study testing Glycine, Alanine and Leucine in people with Atherosclerosis and Diet Modification, run by Rambam Health Care Campus.
Trial summary
Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. Read more about this study
- Who is it for?
- Ages 18 to 50 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Atherosclerosis, Diet Modification, Serum; Disease
- What is being tested?
- Glycine, Alanine and Leucine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 110 participants
- Where
- No sites listed yet
- Study dates
- 1 Jul 2017to 1 May 2018
- Phase
- Interventional
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 50 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- healthy adult males between the ages of 18-50 after signing informed consent
Who cannot join
- pregnancy, renal, pulmonary, cardiovascular or endocrinal diseases, diabetes, cancer, morbid obesity (body mass index, BMI > 40 kg/m2), heavy smoking (> 20 cigarettes/day), or consumption of more than two alcoholic drinks per day. Subjects from the same hospital unit or from the laboratory where this study is conducted are also excluded
Trial locations and contacts
No sites are listed yet.
About this study
Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. The findings so far suggest that specific AAs induce selective anti-atherogenic effects (glycine, alanine, leucine and cysteine) or pro-atherogenic effects (glutamate and glutamine) in macrophages. Taking together the above previous reports with the mechanisms behind macrophage foam cell formation and atherogenesis, it is possible that AAs could be anti-atherogenic or pro-atherogenic via their mechanism of action on macrophage foam cell formation. This paradigm may serve as a basis for the development of novel cardio-protective, anti-atherogenic nutritional, or therapeutic approaches, that should be studied in human trials.
Read the detailed description
Atherosclerosis is the underlying cause of cardiovascular diseases (CVD), the major cause of death worldwide. Atherosclerosis is an inflammatory disease of the arteries in which activated macrophages are abundant in the atherosclerotic lesions. Macrophages play key roles during early atherogenesis. After differentiating from peripheral blood monocytes, the formed intimal macrophages take up oxidized/modified lipoproteins and are transformed into lipid-rich foam cells, the hallmark feature of early atherogenesis. In addition to lipoprotein uptake, lipid accumulation in macrophages can also result from alterations in cellular lipid metabolism, e.g. attenuated reverse lipid transport or enhanced rates of lipid biosynthesis. Although much progress has been made in understanding the role of different lipids (fatty acids, cholesterol, phospholipids or triglycerides) in macrophage foam-cell formation and atherosclerosis development, little is known about the potential impact of other nutrients, such as amino acids (AAs).
Previous studies have demonstrated an association between specific AAs and increased CVD risk or higher prevalence of coronary artery disease (CAD). For instance, the role of the branched chain AAs (BCAAs; valine, leucine, and isoleucine) in atherogenesis and CVD has been recently studied. Association studies showed that the plasma levels of BCAAs significantly and independently correlated with dyslipidemia and CAD. However, BCAAs were found to possess cardio-protective effects in a heart failure rat model. Specifically, leucine was reported to attenuate atherosclerosis development in the atherosclerotic apoE-deficient (apoE-/-) mice model, by improving the plasma lipid profile and by reducing systemic inflammation. Other studies have indicated the ability of some AAs to exert anti-atherogenic effects. Glycine, the simplest AA, was inversely associated with the risk of acute myocardial infarction (AMI) in patients with high apolipoprotein B (apoB) and LDL-cholesterol levels. Cysteine is an essential AA in the biosynthesis of glutathione, a key endogenous anti-oxidant known for its anti-atherogenic properties in macrophage lipid metabolism leading to the attenuation of atherosclerosis development. Cysteine analogues such as N-acetyl cysteine (NAC) or ribose cysteine were shown to be anti-atherogenic. Arginine, a basic AA, is the main precursor for nitric oxide production in the vascular endothelium. Arginine was shown to protect endothelial cells from lipid peroxidation, and to delay or reduce atheroma formation. Arginine anti-atherogenicity includes its anti-oxidant properties and its ability to improve endothelial function in CVD or overweight patients.
The aim of the proposed study is to investigate the effects of one month of supplementation with specific AAs on changes in the macrophage atherogenicity and lipid metabolism together with other risk markers of atherosclerosis development, such as serum oxidative status and lipid levels, on healthy subjects. Findings from the current proposed study may shed light on yet unknown mechanisms by which specific AAs affect atherosclerosis development and CVD risk and hence could possibly assist in the future development of anti-atherogenic strategies
- Conditions
- Atherosclerosis, Diet Modification, Serum; Disease
- Being tested
- Cellulose (control), Glycine, Alanine, Leucine, Isoleucine
- Keywords
- Amino acids, Macrophage atherogenicity, Triglycerides, Cholesterol, Lipoproteins
- Medical subject headings
- Atherosclerosis, Disease
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Cellulose (control)Other
Cellulose (a vegetal product, in powder form, used as dietary fiber, that is not digested or absorbed in the intestines), will be supplemented in the form of water soluble powder.
GlycineDietary supplement
Also called Trade name: Glycine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glycine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
AlanineDietary supplement
Also called Trade name: L-Alanine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Alanine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
LeucineDietary supplement
Also called Trade name: L-Leucine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Leucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
IsoleucineDietary supplement
Also called Trade name: L-Isoleucine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Isoleucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
ValineDietary supplement
Also called Trade name: L-Valine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Valine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
CysteineDietary supplement
Also called Trade name: L-Cysteine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Cysteine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
ArginineDietary supplement
Also called Trade name: L-Arginine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Arginine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
MethionineDietary supplement
Also called Trade name: DL-Methionine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Methionine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
GlutamateDietary supplement
Also called Trade name: L-Glutamic acid (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamate will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
GlutamineDietary supplement
Also called Trade name: L-Glutamine (Manufacturer Fagron Inc)
Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490).
| Study group | Role | What they receive |
|---|---|---|
| Control | Sham comparator | Other: Cellulose (control): cellulose, water soluble powder, 2 g in one daily dose, during 30 days Receives: Other: Cellulose (control) |
| Glycine (Trade name: Glycine) | Experimental | Dietary Supplement: Glycine, water soluble powder, 7.8 g daily in one dose, during 30 days. Receives: Dietary Supplement: Glycine |
| Alanine (Trade name: L-Alanine) | Experimental | Dietary Supplement: Alanine, water soluble powder, 8.5 g daily in one dose, during 30 days. Receives: Dietary Supplement: Alanine |
| Leucine (Trade name: L-Leucine) | Experimental | Dietary Supplement: Leucine, water soluble powder, 14 g daily in one dose, during 30 days. Receives: Dietary Supplement: Leucine |
| Isoleucine (Trade name: L-Isoleucine) | Experimental | Dietary Supplement: Isoleucine, water soluble powder, 8.2 g daily in one dose, during 30 days. Receives: Dietary Supplement: Isoleucine |
| Valine (Trade name: L-Valine) | Experimental | Dietary Supplement: Valine, water soluble powder, 9 g daily in one dose, during 30 days. Receives: Dietary Supplement: Valine |
| Cysteine (Trade name: L-Cysteine) | Experimental | Dietary Supplement: Cysteine, water soluble powder, 2.2 g daily in one dose, during 30 days. Receives: Dietary Supplement: Cysteine |
| Arginine (Trade name: L-Arginine) | Experimental | Dietary Supplement: Arginine, water soluble powder, 10 g daily in one dose, during 30 days. Receives: Dietary Supplement: Arginine |
| Methionine (Trade name: DL-Methionine) | Experimental | Dietary Supplement: Methionine, water soluble powder, 4 g daily in one dose, during 30 days. Receives: Dietary Supplement: Methionine |
| Glutamate (Trade name: L-Glutamic acid) | Experimental | Dietary Supplement: Glutamate, water soluble powder, 33 g daily in one dose, during 30 days. Receives: Dietary Supplement: Glutamate |
| Glutamine (Trade name: L-Glutamine) | Experimental | Dietary Supplement: Glutamine, water soluble powder, 30 g daily in one dose, during 30 days. Receives: Dietary Supplement: Glutamine |
What is being measured
The primary outcome is the main question the study is designed to answer.
Serum atherogenicity
Macrophage lipids (triglycerides and cholesterol) content (μg/mg cell protein) following incubation with serum derived from the subjects.
Measured: 1 year
Secondary outcomes (3)
Serum triglyceride concentration
Triglyceride concentration (mg/dL) vs control group
Measured: 1 year
Macrophage cholesterol content
Cholesterol concentration (mg/dL) vs control group
Measured: 1 year
Serum oxidation
Serum levels of thiobarbituric acid reactive substances (TBARS)
Measured: 1 year
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted8 Jun 2017
- Study start1 Jul 2017 (estimated)
- Primary completion15 Dec 2017 (estimated)
- Study completion1 May 2018 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Publications (26)Papers the sponsor has linked to this study.
- Other trials for AtherosclerosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 110 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Rambam Health Care Campus
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Prof. Tony hayek MD, Rambam Health Care Campus
- Investigators
- Tony Hayek, Prof, Principal investigator, Rambam Health Care Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03180775
- Sponsor's protocol ID
- 0566-16-RMB CTIL
- Status last verified
- Jun 2017
- First submitted
- 25 May 2017
- Last updated
- 8 Jun 2017
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Publications
Michas G, Micha R, Zampelas A. Dietary fats and cardiovascular disease: putting together the pieces of a complicated puzzle. Atherosclerosis. 2014 Jun;234(2):320-8. doi: 10.1016/j.atherosclerosis.2014.03.013. Epub 2014 Mar 27.
PubMed 24727233Dickhout JG, Basseri S, Austin RC. Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1413-5. doi: 10.1161/ATVBAHA.108.169144. No abstract available.
PubMed 18650503Rom O, Aviram M. Endogenous or exogenous antioxidants vs. pro-oxidants in macrophage atherogenicity. Curr Opin Lipidol. 2016 Apr;27(2):204-6. doi: 10.1097/MOL.0000000000000287. No abstract available.
PubMed 26959710Afonso Mda S, Castilho G, Lavrador MS, Passarelli M, Nakandakare ER, Lottenberg SA, Lottenberg AM. The impact of dietary fatty acids on macrophage cholesterol homeostasis. J Nutr Biochem. 2014 Feb;25(2):95-103. doi: 10.1016/j.jnutbio.2013.10.001. Epub 2013 Oct 31.
PubMed 24445035Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit? Cardiovasc Res. 2011 May 1;90(2):220-3. doi: 10.1093/cvr/cvr070.
PubMed 21502372Yang RY, Wang SM, Sun L, Liu JM, Li HX, Sui XF, Wang M, Xiu HL, Wang S, He Q, Dong J, Chen WX. Association of branched-chain amino acids with coronary artery disease: A matched-pair case-control study. Nutr Metab Cardiovasc Dis. 2015 Oct;25(10):937-42. doi: 10.1016/j.numecd.2015.06.003. Epub 2015 Jun 14.
PubMed 26231617Shah SH, Bain JR, Muehlbauer MJ, Stevens RD, Crosslin DR, Haynes C, Dungan J, Newby LK, Hauser ER, Ginsburg GS, Newgard CB, Kraus WE. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ Cardiovasc Genet. 2010 Apr;3(2):207-14. doi: 10.1161/CIRCGENETICS.109.852814. Epub 2010 Feb 19.
PubMed 20173117Bhattacharya S, Granger CB, Craig D, Haynes C, Bain J, Stevens RD, Hauser ER, Newgard CB, Kraus WE, Newby LK, Shah SH. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis. 2014 Jan;232(1):191-6. doi: 10.1016/j.atherosclerosis.2013.10.036. Epub 2013 Nov 12.
PubMed 24401236Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci. 2015 Sep 15;137:20-7. doi: 10.1016/j.lfs.2015.06.021. Epub 2015 Jul 2.
PubMed 26141987Zhao Y, Dai XY, Zhou Z, Zhao GX, Wang X, Xu MJ. Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice. Acta Pharmacol Sin. 2016 Feb;37(2):196-203. doi: 10.1038/aps.2015.88. Epub 2015 Dec 21.
PubMed 26687933Wurtz P, Raiko JR, Magnussen CG, Soininen P, Kangas AJ, Tynkkynen T, Thomson R, Laatikainen R, Savolainen MJ, Laurikka J, Kuukasjarvi P, Tarkka M, Karhunen PJ, Jula A, Viikari JS, Kahonen M, Lehtimaki T, Juonala M, Ala-Korpela M, Raitakari OT. High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis. Eur Heart J. 2012 Sep;33(18):2307-16. doi: 10.1093/eurheartj/ehs020. Epub 2012 Mar 26.
PubMed 22450427Selhub J, Troen AM. Sulfur amino acids and atherosclerosis: a role for excess dietary methionine. Ann N Y Acad Sci. 2016 Jan;1363:18-25. doi: 10.1111/nyas.12962. Epub 2015 Dec 8.
PubMed 26647293Toborek M, Kopieczna-Grzebieniak E, Drozdz M, Wieczorek M. Increased lipid peroxidation as a mechanism of methionine-induced atherosclerosis in rabbits. Atherosclerosis. 1995 Jun;115(2):217-24. doi: 10.1016/0021-9150(94)05516-l.
PubMed 7661880Julve J, Escola-Gil JC, Rodriguez-Millan E, Martin-Campos JM, Jauhiainen M, Quesada H, Renteria-Obregon IM, Osada J, Sanchez-Quesada JL, Blanco-Vaca F. Methionine-induced hyperhomocysteinemia impairs the antioxidant ability of high-density lipoproteins without reducing in vivo macrophage-specific reverse cholesterol transport. Mol Nutr Food Res. 2013 Oct;57(10):1814-24. doi: 10.1002/mnfr.201300133. Epub 2013 Jun 10.
PubMed 23754667Yang AN, Zhang HP, Sun Y, Yang XL, Wang N, Zhu G, Zhang H, Xu H, Ma SC, Zhang Y, Li GZ, Jia YX, Cao J, Jiang YD. High-methionine diets accelerate atherosclerosis by HHcy-mediated FABP4 gene demethylation pathway via DNMT1 in ApoE(-/-) mice. FEBS Lett. 2015 Dec 21;589(24 Pt B):3998-4009. doi: 10.1016/j.febslet.2015.11.010. Epub 2015 Nov 26.
PubMed 26606905
Study at a glance
From the registry record, last updated by the sponsor on 8 Jun 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Effects of Dietary Amino Acids on Serum and Macrophage Atherogenicity
- ClinicalTrials.gov ID
- NCT03180775
- Acronym / sponsor ID
- 0566-16-RMB CTIL
- Conditions
- Atherosclerosis, Diet Modification, Serum; Disease
- Keywords
- Amino acids, Macrophage atherogenicity, Triglycerides, Cholesterol, Lipoproteins
- Study type
- Interventional
- Recruitment status
- Unknown status
- Enrolment
- 110 participants (estimated)
- Lead sponsor
- Rambam Health Care CampusUniversity, hospital or other
- Study start
- 1 Jul 2017 (estimated)
- Primary completion
- 15 Dec 2017 (estimated)
- Study completion
- 1 May 2018 (estimated)
- First posted
- 8 Jun 2017 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Recently, the investigators have been screening for anti-atherogenic or pro-atherogenic amino acids (AAs) in the macrophage model system to better understand their role in atherogenesis. The findings so far suggest that specific AAs induce selective anti-atherogenic effects (glycine, alanine, leucine and cysteine) or pro-atherogenic effects (glutamate and glutamine) in macrophages. Taking together the above previous reports with the mechanisms behind macrophage foam cell formation and atherogenesis, it is possible that AAs could be anti-atherogenic or pro-atherogenic via their mechanism of action on macrophage foam cell formation. This paradigm may serve as a basis for the development of novel cardio-protective, anti-atherogenic nutritional, or therapeutic approaches, that should be studied in human trials.
Detailed description
Atherosclerosis is the underlying cause of cardiovascular diseases (CVD), the major cause of death worldwide. Atherosclerosis is an inflammatory disease of the arteries in which activated macrophages are abundant in the atherosclerotic lesions. Macrophages play key roles during early atherogenesis. After differentiating from peripheral blood monocytes, the formed intimal macrophages take up oxidized/modified lipoproteins and are transformed into lipid-rich foam cells, the hallmark feature of early atherogenesis. In addition to lipoprotein uptake, lipid accumulation in macrophages can also result from alterations in cellular lipid metabolism, e.g. attenuated reverse lipid transport or enhanced rates of lipid biosynthesis. Although much progress has been made in understanding the role of different lipids (fatty acids, cholesterol, phospholipids or triglycerides) in macrophage foam-cell formation and atherosclerosis development, little is known about the potential impact of other nutrients, such as amino acids (AAs).
Previous studies have demonstrated an association between specific AAs and increased CVD risk or higher prevalence of coronary artery disease (CAD). For instance, the role of the branched chain AAs (BCAAs; valine, leucine, and isoleucine) in atherogenesis and CVD has been recently studied. Association studies showed that the plasma levels of BCAAs significantly and independently correlated with dyslipidemia and CAD. However, BCAAs were found to possess cardio-protective effects in a heart failure rat model. Specifically, leucine was reported to attenuate atherosclerosis development in the atherosclerotic apoE-deficient (apoE-/-) mice model, by improving the plasma lipid profile and by reducing systemic inflammation. Other studies have indicated the ability of some AAs to exert anti-atherogenic effects. Glycine, the simplest AA, was inversely associated with the risk of acute myocardial infarction (AMI) in patients with high apolipoprotein B (apoB) and LDL-cholesterol levels. Cysteine is an essential AA in the biosynthesis of glutathione, a key endogenous anti-oxidant known for its anti-atherogenic properties in macrophage lipid metabolism leading to the attenuation of atherosclerosis development. Cysteine analogues such as N-acetyl cysteine (NAC) or ribose cysteine were shown to be anti-atherogenic. Arginine, a basic AA, is the main precursor for nitric oxide production in the vascular endothelium. Arginine was shown to protect endothelial cells from lipid peroxidation, and to delay or reduce atheroma formation. Arginine anti-atherogenicity includes its anti-oxidant properties and its ability to improve endothelial function in CVD or overweight patients.
The aim of the proposed study is to investigate the effects of one month of supplementation with specific AAs on changes in the macrophage atherogenicity and lipid metabolism together with other risk markers of atherosclerosis development, such as serum oxidative status and lipid levels, on healthy subjects. Findings from the current proposed study may shed light on yet unknown mechanisms by which specific AAs affect atherosclerosis development and CVD risk and hence could possibly assist in the future development of anti-atherogenic strategies
Study design
- Primary purpose
- Other
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 11
| Arm | Type | Receives |
|---|---|---|
| Control | Sham comparator | Other: Cellulose (control)Other: Cellulose (control): cellulose, water soluble powder, 2 g in one daily dose, during 30 days |
| Glycine (Trade name: Glycine) | Experimental | Dietary Supplement: GlycineDietary Supplement: Glycine, water soluble powder, 7.8 g daily in one dose, during 30 days. |
| Alanine (Trade name: L-Alanine) | Experimental | Dietary Supplement: AlanineDietary Supplement: Alanine, water soluble powder, 8.5 g daily in one dose, during 30 days. |
| Leucine (Trade name: L-Leucine) | Experimental | Dietary Supplement: LeucineDietary Supplement: Leucine, water soluble powder, 14 g daily in one dose, during 30 days. |
| Isoleucine (Trade name: L-Isoleucine) | Experimental | Dietary Supplement: IsoleucineDietary Supplement: Isoleucine, water soluble powder, 8.2 g daily in one dose, during 30 days. |
| Valine (Trade name: L-Valine) | Experimental | Dietary Supplement: ValineDietary Supplement: Valine, water soluble powder, 9 g daily in one dose, during 30 days. |
| Cysteine (Trade name: L-Cysteine) | Experimental | Dietary Supplement: CysteineDietary Supplement: Cysteine, water soluble powder, 2.2 g daily in one dose, during 30 days. |
| Arginine (Trade name: L-Arginine) | Experimental | Dietary Supplement: ArginineDietary Supplement: Arginine, water soluble powder, 10 g daily in one dose, during 30 days. |
| Methionine (Trade name: DL-Methionine) | Experimental | Dietary Supplement: MethionineDietary Supplement: Methionine, water soluble powder, 4 g daily in one dose, during 30 days. |
| Glutamate (Trade name: L-Glutamic acid) | Experimental | Dietary Supplement: GlutamateDietary Supplement: Glutamate, water soluble powder, 33 g daily in one dose, during 30 days. |
| Glutamine (Trade name: L-Glutamine) | Experimental | Dietary Supplement: GlutamineDietary Supplement: Glutamine, water soluble powder, 30 g daily in one dose, during 30 days. |
Who may qualify
- Ages
- 18 to 50 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (1 listed)
- healthy adult males between the ages of 18-50 after signing informed consent
Key exclusion criteria (1 listed)
- pregnancy, renal, pulmonary, cardiovascular or endocrinal diseases, diabetes, cancer, morbid obesity (body mass index, BMI > 40 kg/m2), heavy smoking (> 20 cigarettes/day), or consumption of more than two alcoholic drinks per day. Subjects from the same hospital unit or from the laboratory where this study is conducted are also excluded
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Cellulose (control)Cellulose (a vegetal product, in powder form, used as dietary fiber, that is not digested or absorbed in the intestines), will be supplemented in the form of water soluble powder. | Other | Control |
| GlycineAlso: Trade name: Glycine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glycine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Glycine (Trade name: Glycine) |
| AlanineAlso: Trade name: L-Alanine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Alanine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Alanine (Trade name: L-Alanine) |
| LeucineAlso: Trade name: L-Leucine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Leucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Leucine (Trade name: L-Leucine) |
| IsoleucineAlso: Trade name: L-Isoleucine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Isoleucine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Isoleucine (Trade name: L-Isoleucine) |
| ValineAlso: Trade name: L-Valine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Valine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Valine (Trade name: L-Valine) |
| CysteineAlso: Trade name: L-Cysteine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Cysteine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Cysteine (Trade name: L-Cysteine) |
| ArginineAlso: Trade name: L-Arginine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Arginine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Arginine (Trade name: L-Arginine) |
| MethionineAlso: Trade name: DL-Methionine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Methionine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Methionine (Trade name: DL-Methionine) |
| GlutamateAlso: Trade name: L-Glutamic acid (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamate will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Glutamate (Trade name: L-Glutamic acid) |
| GlutamineAlso: Trade name: L-Glutamine (Manufacturer Fagron Inc)Amino acids are the building blocks of proteins, they are essential organic compounds in the normal diet, and are also individually administered as nutritional supplements. Glutamine will be supplied in the form of water soluble powder (the commercial form), for one daily dose. The corresponding amino acid doses were established based on the highest intakes at the 99th percentile in adult men (Institute of Medicine. 2005. Dietary Reference Intakes for Energy, Carbohydrate, Fiber, Fat, Fatty Acids, Cholesterol, Protein, and Amino Acids. Washington, D.C.: The National Academies Press. doi.org/10.17226/10490). | Dietary supplement | Glutamine (Trade name: L-Glutamine) |
Primary outcome
Serum atherogenicity
Time frame: 1 year
Macrophage lipids (triglycerides and cholesterol) content (μg/mg cell protein) following incubation with serum derived from the subjects.
3 secondary outcomes
Serum triglyceride concentration
Time frame: 1 year
Macrophage cholesterol content
Time frame: 1 year
Serum oxidation
Time frame: 1 year
Results and safety
Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 8 Jun 2017.
- Background: PubMed 24727233Michas G, Micha R, Zampelas A. Dietary fats and cardiovascular disease: putting together the pieces of a complicated puzzle. Atherosclerosis. 2014 Jun;234(2):320-8. doi: 10.1016/j.atherosclerosis.2014.03.013. Epub 2014 Mar 27.
- Background: PubMed 18650503Dickhout JG, Basseri S, Austin RC. Macrophage function and its impact on atherosclerotic lesion composition, progression, and stability: the good, the bad, and the ugly. Arterioscler Thromb Vasc Biol. 2008 Aug;28(8):1413-5. doi: 10.1161/ATVBAHA.108.169144. No abstract available.
- Background: PubMed 26959710Rom O, Aviram M. Endogenous or exogenous antioxidants vs. pro-oxidants in macrophage atherogenicity. Curr Opin Lipidol. 2016 Apr;27(2):204-6. doi: 10.1097/MOL.0000000000000287. No abstract available.
- Background: PubMed 24445035Afonso Mda S, Castilho G, Lavrador MS, Passarelli M, Nakandakare ER, Lottenberg SA, Lottenberg AM. The impact of dietary fatty acids on macrophage cholesterol homeostasis. J Nutr Biochem. 2014 Feb;25(2):95-103. doi: 10.1016/j.jnutbio.2013.10.001. Epub 2013 Oct 31.
- Background: PubMed 21502372Huang Y, Zhou M, Sun H, Wang Y. Branched-chain amino acid metabolism in heart disease: an epiphenomenon or a real culprit? Cardiovasc Res. 2011 May 1;90(2):220-3. doi: 10.1093/cvr/cvr070.
- Background: PubMed 26231617Yang RY, Wang SM, Sun L, Liu JM, Li HX, Sui XF, Wang M, Xiu HL, Wang S, He Q, Dong J, Chen WX. Association of branched-chain amino acids with coronary artery disease: A matched-pair case-control study. Nutr Metab Cardiovasc Dis. 2015 Oct;25(10):937-42. doi: 10.1016/j.numecd.2015.06.003. Epub 2015 Jun 14.
- Background: PubMed 20173117Shah SH, Bain JR, Muehlbauer MJ, Stevens RD, Crosslin DR, Haynes C, Dungan J, Newby LK, Hauser ER, Ginsburg GS, Newgard CB, Kraus WE. Association of a peripheral blood metabolic profile with coronary artery disease and risk of subsequent cardiovascular events. Circ Cardiovasc Genet. 2010 Apr;3(2):207-14. doi: 10.1161/CIRCGENETICS.109.852814. Epub 2010 Feb 19.
- Background: PubMed 24401236Bhattacharya S, Granger CB, Craig D, Haynes C, Bain J, Stevens RD, Hauser ER, Newgard CB, Kraus WE, Newby LK, Shah SH. Validation of the association between a branched chain amino acid metabolite profile and extremes of coronary artery disease in patients referred for cardiac catheterization. Atherosclerosis. 2014 Jan;232(1):191-6. doi: 10.1016/j.atherosclerosis.2013.10.036. Epub 2013 Nov 12.
- Background: PubMed 26141987Tanada Y, Shioi T, Kato T, Kawamoto A, Okuda J, Kimura T. Branched-chain amino acids ameliorate heart failure with cardiac cachexia in rats. Life Sci. 2015 Sep 15;137:20-7. doi: 10.1016/j.lfs.2015.06.021. Epub 2015 Jul 2.
- Background: PubMed 26687933Zhao Y, Dai XY, Zhou Z, Zhao GX, Wang X, Xu MJ. Leucine supplementation via drinking water reduces atherosclerotic lesions in apoE null mice. Acta Pharmacol Sin. 2016 Feb;37(2):196-203. doi: 10.1038/aps.2015.88. Epub 2015 Dec 21.
- Background: PubMed 22450427Wurtz P, Raiko JR, Magnussen CG, Soininen P, Kangas AJ, Tynkkynen T, Thomson R, Laatikainen R, Savolainen MJ, Laurikka J, Kuukasjarvi P, Tarkka M, Karhunen PJ, Jula A, Viikari JS, Kahonen M, Lehtimaki T, Juonala M, Ala-Korpela M, Raitakari OT. High-throughput quantification of circulating metabolites improves prediction of subclinical atherosclerosis. Eur Heart J. 2012 Sep;33(18):2307-16. doi: 10.1093/eurheartj/ehs020. Epub 2012 Mar 26.
- Background: PubMed 26647293Selhub J, Troen AM. Sulfur amino acids and atherosclerosis: a role for excess dietary methionine. Ann N Y Acad Sci. 2016 Jan;1363:18-25. doi: 10.1111/nyas.12962. Epub 2015 Dec 8.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Tony Hayek, Prof principal investigator
Rambam Health Care Center
Questions about this trial
What is this clinical trial studying?
A study testing Glycine, Alanine and Leucine in people with Atherosclerosis and Diet Modification, run by Rambam Health Care Campus.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 1 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: status not confirmed, as of the sponsor's last update on 8 Jun 2017. Status can change between updates, so confirm with the study contact before making plans.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
Contact Claudia Grajeda Iglesias, PhD (972-4-8295278, claugrajeda@technion.ac.il), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Serum atherogenicity (time frame: 1 year). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT03180775, which also lists 26 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 8 Jun 2017.