Nowadays, poisoning with metal phosphides, especially aluminum phosphide (ALP), is one of the main health threats in human societies. Patients suffer from significant complications due to this type of poisoning, and the heart is one of the main organs targeted by ALP. Therefore, in this study, we discussed the effect of phosphine on cardiac function. This study is based on data obtained from PubMed, between 2002 and 2020. The key keywords included “Aluminum phosphide,” “Oxidative Stress,” “Mitochondria,” “Cardiovascular disease,” and “Treatment.” The results showed that ALP produced reactive oxygen species (ROS) due to mitochondrial dysfunction. ROS production leads to red blood cell hemolysis, decreased ATP production, and induction of apoptosis in cardiomyocytes, which eventually results in cardiovascular disease. Since ALP has the most significant effect on cardiomyocytes, the use of appropriate treatment strategies to restore cell function can increase patients’ survival.
Hinweise
Communicated by Mitzi C. Glover.
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Introduction
The use of pesticides has led to an increase in the quantity and quality of agricultural products in some developing countries. However, improper use of these chemicals can lead to severe acute and chronic poisoning [1]. Poisoning with pesticides can be intentional, accidental, occupational, or for murder purposes, and it leads to the deaths of about 300,000 people worldwide each year, making it a global health problem [2]. Metal phosphides make a large part of pesticides that are currently used in many countries [3]. These metal phosphides cause a wide range of effects, including electrolyte imbalances, metabolic disorders, cell toxicity, oxidative stress, inhibition of cholinesterase, circulatory failure, and damage to various organs [4]. Aluminum phosphide (ALP) is one of the most widely used metal phosphides and a highly toxic substance with a high mortality rate (40–80%) [5]. The most important causes of death are cardiac shock, severe metabolic acidosis, and hypotension [6]. ALP produces phosphine gas (PH3) after exposure to moisture and acidic stomach conditions, which leads to severe toxicity in poisoned individuals [7]. PH3 is a highly toxic metabolite known as a mitochondrial toxin [8]. However, organs that are mainly dependent on oxidative phosphorylation are quickly affected [9]. So far, the pathophysiological mechanism of ALP poisoning has not been established in humans. However, inhibition of cytochrome C oxidase activity, oxidative stress and Ca2+ and Mg2+ compounds are among the proposed ALP poisoning mechanisms. In addition to inhibiting cytochrome C oxidase, ALP affects other enzymes and consequently it causes severe energy failure. Also, by increasing the production of reactive oxygen species (ROS), it can cause tissue damage synergistically [9‐11]. Cardiomyocytes are one of the main targets for PH3, and cardiac toxicity has been reported as the main cause of death in ALP poisoning cases [12, 13]. Despite supportive care and medical treatment, most patients die after ALP poisoning in the hospital. Therefore, it is necessary to investigate the mechanisms involved in causing tissue damage, especially the heart, as the main organ involved in this poisoning. The diagnosis of ALP poisoning is mainly based on statements from the patients or witnesses, as well as the inspection of remnants or residues. The toxicological analysis of gastric contents and viscera, along with the typical pungent garlicky odor perceptible in many cases upon opening the stomach, may serve as an indication of a potential ALP casualty. Diagnosis of phosphide poisoning can be doubtlessly confirmed by detecting the phosphine gas in samples. Quantitative methods for the detection of phosphine include a simple colorimetric method and gas chromatograph [14]. In this study, we collected scientific data to identify the risk factors for cardiac damage and treatment strategies with the aim of early diagnosis, improvement of therapeutic conditions, and enhanced patient survival.
Mitochondrial Complex as the Main Target of ALP
Mitochondria provide more than 90% of total ATP for eukaryotic cells [15]. Phosphine, by changing in electron transfer chain, reacts with the mitochondrial respiratory chain as the main source of free radical production and interferes with oxidative phosphorylation, leading to high production of ROS and decreased ATP levels. This causes a cell energy crisis. Therefore mitochondria are known to be the main target of phosphine [11, 16].
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By producing ROS including superoxide (O20−) and H2O2, cellular oxidative stress acts the same as reactive nitrogen species (RNS) which mainly include NO and peroxynitrite as by-products of a set of enzymes that participate in electron transfer. ROS/RNS potentially damage biological macromolecules, leading to cell death [16]. Although many studies have so far been performed to identify the mechanism of phosphine toxicity, its exact mechanism is still unclear. However, most studies have estimated an increase in oxidative stress and a decrease in antioxidant capacity as the primary mechanism of toxicity [17, 18]. Phosphine acts at the mitochondrial level, and after systemic absorption, impairs the synthesis of enzymes and proteins [1, 19]. Also, its toxicity mechanism involves formation of highly reactive hydroxyl radicals. Phosphine is a highly reactive radical that penetrates the intracellular space and disrupts mitochondrial function by reacting with the mitochondrial respiratory chain as the primary source of ROS production and creating extensive oxidative stress [7]. Evidence suggests that Complex IV and cytochrome C oxidase are the main sites of interaction between phosphine and the electron transport chain, and phosphine inhibits the potential of mitochondrial membrane (Δψm) by inhibiting this enzyme at the site of Complex IV [20]. Besides, phosphine reduces the activity of complexes I and II, which reduce the activity of mitochondrial complexes and inhibit its aerobic respiration, leading to mass production of ROS, impaired ATP synthesis, and energy failure [17, 18]. ROS production resulted by phosphine toxicity is a fatal cause of energy deficiency, and a decrease in ROS production along with a reduction in energy metabolism can increase tolerance to phosphine [21].
Inhibition of cytochrome oxidase by phosphine, along with decreased catalase and peroxidase activity, leads to hydrogen peroxide (H2O2) accumulation and formation of hydroxyl radicals (⋅OH) [11]. In the meantime, ROS can damage or alter mitochondrial DNA, which can result in inefficient and effective respiration and overcoming genes that encode resistance to phosphine toxicity. Suppression of mitochondrial respiration chain genes leads to increased phosphine resistance, and its persistence may be the result of activation of genes that encode the components of the respiratory chain, including Complexes I (NADH/ubiquinone) and III (cytochrome c reductase) [22, 23]. Resistance is stronger when gene complexes III are suppressed, indicating that this complex plays a more critical role in phosphine resistance [24, 25]. In addition to increasing H2O2 production, phosphine performance is associated with increased lipid peroxidation (LPO) following glutathione (GSH) reduction. Reduced concentration of GSH in various tissues in ALP poisoning can also explain cellular damage because GSH catalyzes H2O2 to O2 and H2O, which is way to protect against oxidation [26, 27]. In general, toxicity of PH3 is closely related to the availability and metabolic absorption of oxygen and is increased in the presence of oxygen while decreased under anoxic conditions [4]. Due to its high oxygen consumption, the heart is the organ most vulnerable to ALP poisoning. Cardiac toxicity has been attributed to the increase in free radicals produced by inhibiting respiratory chain complexes. These free radicals cause LPO, DNA damage, and ultimately oxidative stress, targeting the apoptotic process in cardiomyocytes [12, 20]. Finally, in case of PH3 poisoning, the rate of damage to the heart can be assessed by identifying markers related to cardiac damage such as troponin. The efficiency of cardiomyocytes in patients can be increased using appropriate treatment strategies.
Relevance of Intravascular Hemolysis and ALP
Following the uptake of phosphine through gastric mucosa, vascular wall degeneration, hemolysis, and methemoglobinemia (Met-Hb) occur, leading to organ damage [28]. ALP can directly damage blood vessels and the RBC membrane, or by inducing free radicals, it can cause hemoglobinemia and intravascular hemolysis, in which oxidative stress plays a significant role in the formation of these lesions [29, 30].
Exposure to chemicals that oxidize ferrous hemoglobin to ferric form can lead to the production of Met-Hb [31]. Decreased Met-Hb capacity to deliver enough oxygen to tissues could be another reason for multiple organ failure following ALP poisoning [29]. Clinical manifestations of Met-Hb are due to a decrease in oxygen transport capacity, and consequently tissue hypoxia, which helps to worsen the patient's condition [32]. These manifestations depend on the blood concentration, and according to recent studies there is a clear and significant relationship between blood levels of Met-Hb and mortality in poisoned individuals. Intravascular hemolysis can have a more significant impact on the transmission of oxygen to the target tissues [29]. ALP oxidizing properties can oxidize hemoglobin protein and precipitate it as Heinz bodies, leading to intravascular hemolysis [33]. Intravascular hemolysis usually occurs in patients with G6PD deficiency, and when G6PD levels are low, the ability of erythrocytes to produce NADPH is impaired, and cells are prone to hemolysis [34, 35]. Hemolysis is also possibly due to metabolic acidosis, which is a common feature of ALP poisoning. However, hemolysis is rarely reported despite the common G6PD deficiency following this poisoning, which is due to cardiogenic shock and death before hemolysis [36]. Decreased G6PD also impairs NO production and increases vascular oxidative stress, leading to cardiovascular disease (CVD) progression [35, 37]. However, although hemolysis is a rare symptom of ALP poisoning, it is essential to diagnose it because of its serious consequences.
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Effect of ALP on Cardiomyocyte
The heart is the main organ affected by ALP poisoning. Cardiovascular disorders due to ALP poisoning, which include refractory hypotension, dysrhythmia, and congestive heart failure, occur within 12 to 24 h of exposure [38]. In general, cardiac toxicity, cardiac dysfunction, and circulatory collapse that lead to cardiomyocyte death have been identified as the leading causes of death in ALP poisoning [39]. Cardiomyocytes make 75% of cardiac tissue and play a vital role in cardiac circulation. Mitochondria, as critical organelles, are abundant in cardiomyocytes, and by producing ATP through the process of oxidative phosphorylation, contribute to the contractile function of cardiomyocytes and provide 90% of the energy of these cells [15].
One of the most important and prominent features of ALP poisoning is impaired hemostasis of cardiac energy [19], with ALP directly affecting cardiac myocytes. ALP also disrupts the electron transport chain, which in turn disrupts cell energy demand, inhibits cytochrome c oxidase activity as one of the enzymes in the electron transport chain (ETC), reduces ATP levels, and ultimately reduces myocardial energy. In addition to reducing energy, the production of free radicals, especially ROS, and oxidative stress, which lead to LPO, contributes to ALP-induced cardiac toxicity [15, 40]. In general, the heart is very sensitive to oxidative damage due to its high O2 intake, limited antioxidant system, and high metabolic activity [41]. In addition, inhibiting antioxidant enzymes and producing superoxide radicals, reduce NO bioavailability, which increases the adhesion of neutrophils to coronary arteries and leads to vasoconstriction [42]. Excess radical superoxide reacts with NO, leading to increased LPO, which in turn causes cell damage and activation of the apoptotic process in cardiomyocytes (Fig. 1) [43]. ALP-induced myocardial damage is also associated with changes in biochemical biomarkers such as creatine phosphokinase (CPK), creatine kinase myocardial band (CK-MB), and Troponin-T in some cases [44]. However, some reports suggest a change in these biomarkers following ALP poisoning, but according to studies performed by Soltaninejad and her colleagues, these markers are unreliable, and despite ECG changes in acute poisoning, there are conflicting reports of normal and abnormal levels of CPK-MB [45]. In this regard, Karami and Mohajeri state that the average level of these enzymes could not rule out cardiac toxicity, while its high level can confirm myocardial damage [46]. Therefore, it can be said that in the future, with further studies determining the role of CPK and CK-MB markers as diagnostic markers, it is possible to predict ALP damage to cardiomyocytes and to prevent disease progression using appropriate treatment strategies.
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Therapeutic Approaches and Their Challenges
Due to the increasing prevalence of ALP poisoning in recent years, many studies have been conducted on this topic, especially to find effective treatment (Table 1). Given that ALP intoxication has no particular counteractant, the foundation of treatment is supportive care. To manage ALP poisoning, gastric lavage with potassium permanganate or a mix with coconut oil and sodium bicarbonate, and injection of charcoal, along with alleviative treatment are used. Besides, acidosis can be treated with early intravenous injection of sodium bicarbonate, cardiogenic shock with liquid vasopressor, and refractory cardiogenic shock with intra-aortic balloon pump or digoxin [47, 48]. However, some disagree with the utilization of sodium bicarbonate for metabolic acidosis treatment in ALP intoxication. They justify their claim by experiments in which no beneficial hemodynamic effects of sodium bicarbonate was found in patients with lactic acidosis. Alternatives for therapy modalities mentioned are intravenous methylene blue for methemoglobinemia, N-acetylcysteine, digoxin, hyperbaric oxygen, trimetazidine, and boric acid [13]. The administration of exogenous drugs has not been a compelling factor in ALP poisoning. The main reason for this is the low efficiency of these drugs, their symptomatic interventions, and the absence of any change in the pathogenic mechanisms following the use of these drugs [12]. Of course, this is not true with drugs that have antioxidant properties. However, the lack of specific antidote and effective supportive care results in high mortality of this type of poisoning.
Table 1
Summary of some studies for the treatment of ALP poison patients
Conducted by
Type of study
Number of patients
Type of sample
Clinical finding
Refs.
Taghaddosinejad et al
Case–control
63
Human
N-Acetyl-cysteine (NAC) cause inhibition cardiotoxicity induced by ALP poison
Melatonin is a powerful antioxidant that can easily cross all cellular parts with the highest concentration in mitochondria and protect cells against oxidative stress [49]. Studies show that melatonin affects mitochondrial energy homeostasis and can neutralize the reduced activity of complexes I and IV in toxicity and increase ATP production by increasing activity and expression of ETC complexes [50, 51]. Melatonin and its metabolites (C3OHM and AMK) have also been known as a strong lipid peroxyl radical (LOO) scavenger [52, 53]. Melatonin stimulates the expression of genes and the activity of antioxidant enzymes such as glutathione peroxidase (GPx), superoxide dismutase (SOD), glutathione reductase (GR) and catalase (CAT), reducing LPO and ROS levels [38]. Besides, melatonin inhibits selective inhibition of iNOS/i-mt NO, which prevents high NO production in cardiac mitochondria [54]. On the other hand, activation of melatonin receptors reduces cAMP levels and induces PI4,5 biphosphate, which leads to vasocontraction. In general, it regulates blood pressure through an adjustment mechanism [55]. Melatonin also has antiapoptotic effects and prevents apoptosis by preventing the release of cytochrome C and direct inhibition of mitochondrial transition pore opening (MPTP) opening [56].
Another useful substance that has antioxidant properties is Triiodothyramin (T3) [57]. The use of thyroid hormones in the control and treatment of ALP poisoning is mainly due to their antioxidant effect, which plays a significant role in their cytoprotective effects. This antioxidant effect is due to the increased activity of uncoupling proteins in mitochondria, which is accompanied by decreased ROS production with no reduction in ATP synthesis and an increase in activity and expression of mitochondrial ATP-sensitive potassium (mitoK ATP). Studies also show the effect of T3 on improving and increasing serum levels of Total Thiol Molecule (TTM), which plays an essential role against ROS [40, 57, 58].
Minocycline also has a protective effect on the heart due to its radical scavenger activity as well as its crucial role in apoptosis and inflammation pathways [59, 60]. Minocycline improves mitochondrial function by acting on MPTP and inhibiting mitochondrial diffusion in the apoptosis and inflammation processes. These events lead to an increase in ST height, which indicates myocardial and pericardial damage that is significantly associated with mortality following poisoning. The prolonged QTC interval is observed following ALP poisoning that indicates left ventricular dysfunction, arrhythmia, and cardiac cell death. Also, the proliferation of QRS complex occurs as a change in the potential of right and left ventricular depolarization [61, 62]. Haghi-Aminjan and colleagues reported that minocycline had a significant effect on improving these cardiac parameters. This effect is due to its accumulation in cardiomyocytes several times more than the level of plasma and its ability to be chelated into bivalent cations such as Ca2+ cardiomyocytes [61].
In addition to oxidative changes, acidosis and hypoxia also occur after ALP poisoning, which reduces pH and intracellular energy, affects contraction, and causes arrhythmias. Also, following hypoxia, there will be a decrease in cellular Mg2+ but an increase in mitochondrial Ca2+ consumption, leading to inhibition of ATP synthesis [63, 64]. Recent studies have shown that 25Mg PMC16 increases ATP in the heart by activating the transfer of Mg2+ into cardiac cells. It is interesting to know note that sodium bicarbonate (NaHCO3) as standard treatment was not able to improve ALP poisoning in terms of QRS, HR, and BP changes. However, concomitant treatment with 25mg PMC16 was very successful [65]. In general, the effects of Mg2+ are attributed to three main mechanisms, namely rapid distribution to the myocardium, strong antioxidant potential, and the ability to increase intracellular energy [66, 67].
l-carnitine is an essential cofactor in the metabolism of fatty acids, which is the primary source of energy for the cardiac muscle. Decreased oxidation of fatty acids after myocardial ischemia leads to the accumulation of long-chain Acyl-CoA esters, which leads to a decrease in the energy of cardiomyocytes and affects muscle contraction and electrical conduction of the heart [68]. ALP poisoning leads to myocardial necrosis similar to the one that occurs during ischemia and is associated with the accumulation of long-chain Acyl-CoA metabolites. According to previous studies, reducing the effects of these metabolites on cardiac metabolism leads to good results [69].
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However, the primary therapeutic challenge for ALP poisoning is the effective management of resistant blood pressure and shock due to reduced cardiac contraction which has a high priority. Vasopressors and phosphodiesterase inhibitors can support this hemodynamic condition, but they are not harmless [70, 71]. Jafari et al. found that vasopressin had beneficial effects on severe hypotension and shock. Milrinone, as a phosphodiesterase III inhibitor, was able to improve acute heart failure by increasing intracellular cAMP in myocytes and strong inotropic effects [72]. This inotropic compound increased the contractile force of the myocardium by reducing the O2 cardiac demand of catecholamines [73]. Also, evidence indicates that it causes corrective effects on ST, QRS complex, and QTC changes as electrical conductivity indicators that occur after ALP poisoning [72]. Adding digoxin and glucagon can be helpful for poisoned patients who still have refractory shock despite the use of conventional vasopressors and inotropic drugs. Digoxin is a Na–K ATPase inhibitor that increases myocardial contraction and inotropy without significantly affecting peripheral arteries [74, 75]. Early detection and intervention at the onset of cardiac damage appear to be effective in delaying their progression. In recent years, many studies have shown that changes in red cell distribution width (RDW) levels as a predictor marker are associated with prognosis and assessment of the severity and progression of CVD [76]. Increased causative stress in RBCs worsens their mechanical properties and leads to tissue perfusion disorders, which are reflected in increased RDW levels [77]. Therefore, RDW may be considered a predictor of cardiovascular complications from ALP poisoning.
Conclusion and Future Perspective
Nowadays, poisoning with metal phosphides, especially aluminum phosphide (ALP), is one of the main health threats in human societies. So far, many studies have been performed on ALP pathogenesis in patients, and the results of most studies emphasize that ALP causes mitochondrial dysfunction. Mitochondrial dysfunction leads to decreased ATP production and increased intravascular hemolysis of RBCs. These disorders result in decreased myocytes function and CVD. Since cardiac disorders, especially cardiac shock, are the leading causes of death in ALP patients, it can be argued that identifying markers associated with cardiac diseases in the early stages of poisoning can lead to the best choices of treatment strategies.
Acknowledgements
We wish to thank all our colleagues in legal medicine organization, Ahvaz, Iran.
Compliance with Ethical Standards
Conflict of interest
Authors declare that they have no conflict of interest.
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