Cardiogen peptide: the heart bioregulator with no human studies

Cardiogen is a four-amino-acid synthetic peptide, Ala-Glu-Asp-Arg, from the family of peptide bioregulators developed by Vladimir Khavinson and colleagues at the St Petersburg Institute of Bioregulation and Gerontology. The group’s approach, described in a 2002 monograph-length review, was to extract peptides from an animal organ, analyse their amino-acid composition, and then synthesise a short peptide intended to act on that organ; the review mentions tetrapeptides specific for the heart, liver, brain cortex and pineal gland that stimulate the outgrowth of explants from the corresponding organ in culture ^[9]. The cardiogen bioregulator is the heart-directed member of that set, alongside cortagen for the brain cortex, livagen for the liver and epitalon for the pineal gland.

Cardiogen shares its first three amino acids, Ala-Glu-Asp, with epitalon (Ala-Glu-Asp-Gly), cortagen (Ala-Glu-Asp-Pro), bronchogen (Ala-Glu-Asp-Leu) and cartalax (Ala-Glu-Asp alone). The terminal arginine gives it a positive charge that the others lack, and a 2023 modelling study from the group singled out the AEDR peptide, together with EDR (pinealon) and AEDL, as among the peptides most likely to be carried into cells by the LAT1, LAT2 and PEPT1 transporters ^[7]. Unlike the tripeptides and epitalon, cardiogen has no PubChem record under its sequence, so we do not quote a molecular formula or weight from that source.

Two facts about the evidence should be stated at the outset. The published research on cardiogen is very small: the searchable literature amounts to a handful of papers, most in the Bulletin of Experimental Biology and Medicine or the Russian-language journal Advances in Gerontology, all from the developers or their collaborators. And there are no human studies of any kind, not even the small open reports that exist for pinealon or thymalin. Claims made for cardiogen on supplier sites about heart health, blood pressure or recovery from cardiac disease are not drawn from human data, because there is none.

The Khavinson group’s general hypothesis is that short peptides enter the cell nucleus and change gene expression by binding DNA or histones. For cardiogen specifically, the mechanistic paper is a 2012 study in cultured mouse embryonic fibroblasts, in which H-Ala-Glu-Asp-Arg-OH increased expression of the cytoskeletal proteins actin, tubulin and vimentin by two to five times and of the nuclear matrix proteins lamin A and lamin C by two to three times. The authors concluded that the cardioprotective activity they had previously reported is explained by activation of cytoskeletal and nuclear matrix protein synthesis, which stimulates proliferation and reduces apoptosis ^[1]. This was a fibroblast culture, not heart muscle cells.

In a 2013 biochemical study, AEDR was one of six short peptides shown by fluorescence quenching to bind wheat histones H1, H2B, H3 and H4, apparently through the N-terminal tails of the histones, with binding that depended on the peptide sequence and on whether the DNA in the complex was methylated. The authors proposed that site-specific binding of short peptides to histone tails could act as an epigenetic control on gene activity ^[6]. Wheat histones were used because they are easy to purify; the relevance to human heart cells is inferred, not shown.

The group’s 2021 systematic review of peptide regulation of gene expression sets out the broader case: that peptides of two to seven amino acids can enter nuclei, interact with nucleosomes, histones and DNA, and regulate DNA methylation ^[10]. A 2022 review in the journal Cells applies this to the cardiovascular system, arguing that the senescence-associated secretory phenotype of ageing heart and vessel cells, with its raised p16, p21, p53, IL-6, IL-8, TNF-α and matrix metalloproteinases, is a target for peptides, and lists the KED tripeptide and the AEDR tetrapeptide alongside licensed drugs such as liraglutide and atrial natriuretic peptide as regulators of these molecules ^[5]. The review presents a hypothesis and the group’s own cell data; it does not report a trial.

Searches for cardiogen benefits produce claims about heart muscle repair, healthy ageing of the cardiovascular system and even tumour suppression. Here is what the papers actually contain.

Heart tissue in culture: the first PubMed-indexed cardiogen paper, from 2006, tested cardiogen, bronchogen, prostamax and pancragen on organotypic cultures of heart, lung, prostate and pancreas explants from three-week-old and 18-month-old rats. At an effective concentration of 0.05 ng/mL, each peptide stimulated the culture of its own target tissue compared with control explants, in both young and old animals ^[4]. A 2009 study compared cardiogen with all 20 amino acids in heart explant cultures from three-month-old and 24-month-old rats at a concentration of 10⁻¹² M. Seven amino acids stimulated cell proliferation in young tissue and only two in old tissue, whereas cardiogen strongly stimulated proliferation in both, and immunohistochemistry showed lower expression of the pro-apoptotic protein p53 after cardiogen, which the authors read as inhibition of apoptosis in heart tissue ^[3]. Explant cultures measure cell outgrowth from a piece of tissue in a dish; they do not measure cardiac function.

Other tissues: in ageing cultures of human prostate fibroblasts, cardiogen and the tripeptides T-32 and T-38 all increased the expression of the differentiation markers CXCL12, WEDC1 and ghrelin, which fall as the cultures age, with T-38 the most active ^[8]. This is a reminder that the tissue specificity claimed for these peptides is relative rather than absolute: the heart peptide also acted on prostate cells.

Tumours: a 2009 study transplanted M-1 sarcoma into old rats and injected cardiogen. Tumour cell apoptosis was higher in all treated groups than in controls, and sarcoma growth was inhibited in a dose-dependent way through haemorrhagic necrosis and apoptosis rather than a direct cytostatic effect; the authors concluded that cardiogen acted through the tumour’s blood vessels ^[2]. A peptide that damages the vasculature of a transplanted tumour is an interesting laboratory finding, but it is not evidence of an anti-cancer treatment, and it raises the question, unanswered in the literature, of what the same vascular effect does elsewhere.

What is absent is as important as what is present. We found no study of cardiogen in an animal model of heart attack, heart failure, hypertension or arrhythmia, no study of cardiac function or blood pressure in any species, and no study in humans. The cardioprotective activity referred to in the 2012 paper ^[1] is not described in an accessible primary report.

There are none. We searched PubMed for cardiogen, kardiogen, AEDR and Ala-Glu-Asp-Arg and found no clinical study, case series or case report, and there is no entry on ClinicalTrials.gov. The 2022 Cells review, the most recent English-language discussion of AEDR from the group, cites only laboratory work for the peptide ^[5]. This puts cardiogen in a weaker position than thymalin, which has decades of Russian clinical use, or epitalon and pinealon, which have small open human reports.

Any description of cardiogen as clinically tested, or any quoted improvement in cardiac markers in people, therefore comes from a seller, a forum or an unreferenced review rather than from a published study. If a human study appears, it will need to be assessed on its design; a tetrapeptide from this series has yet to be tested in a randomised controlled trial for any indication.

There is no answer to this question, because there is no controlled study in people or animals with a clinical outcome measured over time. The tissue-culture effects were measured over days in a dish ^{[3] [4]}. Sellers of Khavinson-series peptides in Russia market courses of 10 to 30 days, which is a marketing convention, not a research finding.

The only published doses are laboratory concentrations, and none is a recommendation. In organotypic heart explant cultures, cardiogen was effective at 0.05 ng/mL ^[4] and was tested at 10⁻¹² M ^[3], which are extraordinarily low concentrations; the fibroblast study does not state its concentration in the abstract ^[1]. The sarcoma study describes dose-dependent effects of injected cardiogen in rats without giving the doses in its English abstract ^[2]. No dose has ever been given to a person in a published study, and no pharmacokinetic data exist for any route.

Research suppliers sell cardiogen as a freeze-dried powder, most often in 10 mg or 20 mg vials, and in some markets as capsules. The peptide calculator and its cardiogen page convert vial contents to a concentration for laboratory use. It is worth noting the gap between the picomolar concentrations used in culture and the milligram quantities in a vial: the research offers no basis for choosing any quantity.

In the sarcoma study cardiogen was given by injection ^[2]; in the other studies it was added to culture medium ^{[1] [3] [4] [8]}. In Russia the Khavinson short peptides are sold as oral capsules marketed as food supplements; research suppliers elsewhere sell mainly lyophilised powder for injection. The 2023 transporter modelling study suggests AEDR is a good ligand for intestinal peptide and amino-acid transporters ^[7], but that is a computer model, and there is no measurement of oral absorption of cardiogen in any species.

No cardiogen side effects have been recorded, because cardiogen has never been given to people in a published study. The animal papers do not report toxicity, and a tetrapeptide of common amino acids is unlikely to be acutely toxic. The relevant safety questions are the ones the research raises and does not answer. Cardiogen is reported to reduce p53 expression and apoptosis in heart tissue ^[3] and to stimulate proliferation in fibroblasts ^[1]; lowering p53 and apoptosis is not obviously desirable in every tissue, and no long-term study of cardiogen and cancer incidence exists. Conversely, in a transplanted sarcoma it caused haemorrhagic necrosis through an effect on the tumour vasculature ^[2], and no study has looked at whether it affects normal blood vessels.

For a peptide marketed for the heart, the absence of any measurement of heart rate, blood pressure, rhythm or cardiac function in any animal is a notable gap. There are no data on use in pregnancy, in children, in people with heart disease or with cardiac medicines. None of this shows that cardiogen is harmful; it shows that it has not been studied.

For products bought from research suppliers, the practical risks are identity, purity and sterility. Our guides to third-party testing and how to read a certificate of analysis explain what a test report should show.

Cardiogen is not an approved medicine in the UK, US, EU, Canada or Australia, nor is it a registered medicine in Russia, where it is sold as a supplement. Products sold as cardiogen elsewhere are research chemicals whose sale for human use is not lawful. It is not named on the WADA Prohibited List. See our legal status overview and the pages for the UK, the US and Europe.

Cardiogen is supplied as a freeze-dried powder to be kept cold, dry and away from light; short peptides are relatively stable in this form. Reconstituted solutions are refrigerated and used within a limited period. See how to store peptides and our guide to bacteriostatic water.

A tetrapeptide is inexpensive to synthesise, and cardiogen is usually one of the cheaper listings on a supplier’s site. Compare cardiogen prices, including listings in the UK and the US. Because cardiogen shares three of its four amino acids with epitalon, cortagen and bronchogen, a certificate of analysis should identify the peptide by mass spectrometry as well as HPLC purity, so that a vial of one cannot be passed off as another. Our lists of third-party tested suppliers and suppliers that publish COAs, and our guide to spotting a fake supplier, cover what to check. For the terms used on this page, see what are research peptides.