Introduction

Cyanobacteria (blue-green algae) are ubiquitous prokaryotes which developed the aerobic atmosphere of the Earth through oxygenic photosynthesis (Yadav et al. 2011; Cardona et al. 2018). They are commonly found throughout the world in eutrophicated freshwater lakes, rivers and reservoirs, and in brackish and marine environments. They also colonize surfaces of rocks and buildings and the top layers of soils. Cyanobacterial populations can form mass occurrences known as cyanobacterial blooms in waterbodies under favorable environmental conditions. Visible scums on water surfaces, and mats in shallow waters and along waterbody margins, may be formed by certain genera of cyanobacteria (Chorus and Bartram 1999; Whitton and Potts 2012; Huisman et al. 2018). Anthropogenic eutrophication is one of the major factors contributing to cyanobacterial dominance in many aquatic ecosystems (Bláha et al. 2009). Global climate change is expected to favor cyanobacterial populations, i.e. to increase their magnitude and promote their geographical spread, and to extend their growth periods (Codd et al. 2005; Bláhová et al. 2008; Huisman et al. 2018).

Some cyanobacterial secondary metabolites have been identified as potent toxins (cyanotoxins), which have significant adverse bioactivities at environmentally encountered concentrations. Cyanotoxins can cause illness and mortality of humans and terrestrial animals, with further toxicities to aquatic vertebrates and invertebrates, and consequent negative impacts on ecosystems (Codd et al. 1999, 2005; Sivonen and Jones 1999; Metcalf and Codd 2012; Janssen 2019; Chorus and Welker 2021).

Acutely lethal cyanotoxins can be divided into groups depending on their main targets in (mammalian) organisms (Meriluoto et al. 2017). These include hepatotoxins (microcystins–MCs and nodularins–NODs), cytotoxins (cylindrospermopsin and analogues–CYNs), and neurotoxins (anatoxin-a and analogues–ATXs, anatoxin-a(S)–ATX-a(S), and saxitoxin and analogues–STXs). Nota bene, the new name guanitoxin–GNTX has been introduced for ATX-a(S) by Fiore et al. (2020). There are also irritants of various potency (lyngbyatoxin and analogues–LTXs and lipopolysaccharides–LPSs). In addition, cyanobacteria contain neurotoxic di-amino acids (e.g. β-N-methylamino-L-alanine–BMAA and 2,4-diaminobutyric acid–DAB). The long-term effects of BMAA and DAB are under investigation (Dunlop et al. 2021). The general characteristics of common cyanotoxins are summarised in Table 1.

Table 1 General information on cyanotoxins
Full size table

The toxicity of MCs is mainly mediated via the inhibition of serine/threonine protein phosphatases PP1 and PP2A activities, with PP4 and PP5 also being susceptible to inhibition (Mackintosh et al. 1990; Hastie et al. 2005; Metcalf and Codd 2012) and modulation of PP2A expression (Chen and **), blood pressure (MCs increasing vascular permeability due to endothelial injuries) and effects on the heart muscles. Upon prolonged exposure, MCs can cause significant cytoskeletal alterations including enlargement of cardiomyocytes, loss of cell cross-striations, fibrosis and abnormal nuclei. Taken together, these results suggest that long-term exposure to relatively low doses of MCs can induce myocardial atrophy and fibrosis. The changes in heart rate are basically caused by mitochondrial dysfunction, whereas the changes in blood pressure are caused by increased protein content in blood capillaries (because of increased vascular permeability) and the damage to heart muscles is caused by ROS production and oxidative stress. All of these cellular and subcellular changes, together with damage to the endoplasmic reticulum caused by MCs, can lead to cardiomyopathy and heart failure.

Although less frequently detected and investigated, further cyanotoxins are present and can be harmful (Tables 2, 3, 4, 5, 6). Other cyanotoxins are far less studied than MCs (especially MC-LR) and it is necessary to study them more intensively in future research.

Purified cyanotoxins, cyanobacterial cell extracts and cyanobacterial biomass

Purified cyanotoxins are frequently used in toxicological research (Table 7) but this type of approach presents a limitation in toxicity studies, since it does not correspond to a natural exposure scenario where a mixture of toxic metabolites (and other compounds of various characteristics) are typically present. On the other hand, the use of cyanobacterial cell extracts may lead to confusing results as the attribution of toxicity among the mixture of diverse and potentially bioactive compounds cannot be unambiguous. Combinations can exert e.g. additive, synergistic and antagonistic toxicities and a certain concentration of a known toxin may have a different potency in a matrix. For these reasons it is encouraged to conduct studies with both pure toxins and cyanobacterial cell extracts.

Localization methods for cyanotoxins in cardiovascular systems

Recognition and understanding of the involvement of cyanotoxins in cardiotoxicity and -pathology could be aided by the application of more modern cyanotoxin-related analytical and localization methods to cardiac cells and tissues. For example, by analysis for cardiac protein phosphatase-MC covalent associations, and the subcellular localization of cyanotoxins by immunogold-electron microscopy (Young et al. 2005).

Exposure route

The most frequently involved natural and hitherto recognized exposure route is the oral route, with cyanotoxins occurring in environmental untreated- and ineffectively treated drinking waters, or recreational waters, or in food items. For this reason, further studies examining cyanobacterial toxicity should pay more attention to cyanotoxin exposure via the oral route. However, based on the collected data (Table 9), only 8 of 67 studies (12%) have employed oral exposure. The bulk of research is thus not directly comparable to the typical human exposure scenario which would typically involve repeated oral exposure through ingestion of drinking water and foodstuffs instead of e.g. a single i.p. injection.

Exposure to environmentally relevant cyanotoxin concentrations and chronic exposure

Tables 2, 3, 4, 5, 6 and 9 also show that research approaches vary greatly in the type of cyanotoxin, dose, manner and duration of exposure and the organisms used (i.e. inter-species variation should also be taken into account). Many of the concentrations used are much above any realistic concentration found in a natural setting. There is thus a need to conduct the exposure studies at environmentally relevant cyanotoxin concentrations if the goal is to assess the real risks of cardiovascular and other health problems caused by cyanotoxins. There is also no real consensus about which durations of exposure should be understood as chronic and subchronic.

Human epidemiological research

The majority of the tested organisms have been rodents and fish (Table 10), while further species which are phylogenetically and physiologically closer to humans should also be included. Such an approach is needed to obtain a relevant picture of cardiovascular toxicity to humans. There are only a few case studies of human health problems known to have been associated with-, or caused by contact with cyanobacteria and their toxins. Medical professionals have not been employed in most cases to an optimal extent. Some cases have been described by non-medical professionals and postmortem and other pathological examinations are mostly missing. As there are plenty of populations which are naturally exposed to cyanotoxins in their drinking water one way forward in understanding the cardiovascular toxicity of cyanotoxins is to conduct epidemiological research.

Gaps in knowledge

Whilst this review has focused on the impacts of cyanotoxins on cardiovascular structure and function, it is recognised that these toxins can cause damage to multiple structural and physiological systems in the vertebrate body (causing hepatotoxicity, nephrotoxicity, neurotoxicity, genotoxicity, etc.). The degree to which these multiple outcomes are interlinked, with cardiovascular toxicity being a direct consequence of cyanotoxin exposure, or as part of a cascade of damage to the body’s physiological systems requires investigation.

Whether the adverse effects of MCs, and potentially of NOD, on vertebrate cardiovascular structure and function arise only from an initial inhibition of protein phosphatases in vivo by these cyanotoxins also requires investigation. Indeed, understanding of whether such actions do include mechanisms without involving protein phosphatase inhibition is needed: in vitro studies have shown that purified MC-LR and NOD cause pore formation, weakening and electrical conductivity changes in synthetic lipid bilayer membranes (Petrov et al. 1991; Mellor et al. 1993), with no protein phosphatases in the assay systems.

Organic anion transporter polypeptides (OATPs) are expressed in several tissues including kidney, liver and brain (Nigam et al. 2015). They have a crucial role in the uptake and excretion of many xenobiotics and endogenous substances. It has been shown that the isoforms OATP1B1 and OATP1B3 mediate the uptake of MCs in hepatocytes (Fischer et al. 2010). As OATP1B1 and OATP1B3 are selectively expressed in the liver (Roth et al. 2012) and other OATP isoforms appear to have no or less affinity for MCs, the effects of these toxins are more pronounced in the liver tissue. As there are tissues where OATPs with high affinity for MCs are not present, but effects still can be seen, it is plausible to assume that either other transporters or other (passive) uptake mechanisms for MCs are in place in these tissues. MCs are relatively polar molecules while the more hydrophobic amino acid residues in some of them could be expected to have an influence on their toxicokinetics and possibly also on their toxicity (Ward and Codd 1999). Indeed, MC-LW and MC-LF showed a higher surface activity than MC-LR on a phosphatidylcholine-cholesterol monolayer when tested by biophysical methods (Vesterkvist and Meriluoto 2003). A follow-up study showed that MC-LW and MC-LF induced stronger cytotoxic effects on Caco-2 cells than MC-LR (Vesterkvist et al. 2012). By analogy, it could be hypothesized that the more hydrophobic MCs could have a higher cardiovascular toxicity than the more hydrophilic congeners.

It is likely that there are additional toxic substances and medical conditions which might potentiate the adverse (cardiovascular) effects of cyanotoxins but the data on this topic are scarce. One interesting aspect is whether the COVID-19 disease known to have cardiovascular effects (Salabei et al. 2022; **e et al. 2022) may have any interactions with cyanobacterial toxicity.

Overall conclusions

In the light of the presented evidence, it is likely that cyanotoxins do not constitute a major risk to cardiovascular health under ordinary conditions met in everyday life. The risk of illnesses in other organs, in particular the liver, is higher under the same exposure conditions. However, cardiovascular effects could be expected due to indirect effects arising from damage in other organs. In addition to risks related to extraordinary concentrations of the cyanotoxins and atypical exposure routes, chronic exposure and co-existing diseases could make some of the cyanotoxins more hazardous to cardiovascular health.

It is generally concluded that the emphasis in future research should thus be on oral, chronic exposure of mammalian species, including at environmentally relevant concentrations. It is also necessary that in vivo experiments are conducted in parallel with studies on cells and tissues. It would be extremely beneficial to attract more medical professionals to cyanotoxin research ranging from molecular level studies to epidemiology. The efforts should finally lead to environmental health guidelines aiming at human health protection.