Despite significant progress in combating malaria, it remains the world’s deadliest parasitic disease. The disease is caused by the protozoan plasmodium, which infects a human host with a female Anopheles mosquito bite [9]. In the exo-erythrocytic cycle, sporophores multiply into merozoites, which enter the circulation and then mature to the schizont stage, bursting red blood cells [9]. Direct destruction of red blood cells by plasmodium and autoimmunity is the cause of anemia and splenomegaly [10]. Clinically, severe malaria is characterized by several common symptoms: severe anemia, cerebral malaria, and acute respiratory distress syndrome [10].

Schistosomiasis is widespread worldwide and infects at least 250 million people [11]. Granuloma and fibrosis caused by egg deposition can lead to blockage or structural destruction of blood vessels, especially in the portal vein [12]. The eggs of Schistosoma aegypti are associated with bladder squamous carcinoma, and their deposit in the reproductive system can cause genital inflammation, bleeding, and HIV infection [12] [13]. The clinical manifestations of schistosomiasis occurring in the genitourinary system are frequent urination, painful urination and hematuria, and often proteinuria in cases of the severe immune response. There is a risk of acute schistosomiasis within a few weeks or months in people who are first exposed to schistosome antigens. Acute schistosomiasis has typical clinical manifestations of sudden onset of fever, muscle pain, headache, eosinophilia, malaise, and abdominal pain lasting 2 - 10 weeks [14].

Lymphatic filariasis and onchocerciasis are common parasitic diseases. Lymphatic filariasis mainly manifests as hydrocele testis and celiac disease, while onchocerciasis can cause skin disease and blindness [15]. In the 21st century, the prevalence of lymphatic filariasis has declined significantly worldwide, except in Africa and Southeast Asia [16]. However, the impact of epidemiological differences on the effectiveness of parasitic interventions has led to a severe challenge in the control of onchocerciasis. In addition, onchocerciasis may be associated with nodding syndrome, but further studies are needed to prove this. It is worth noting that the possibility of parasitic filarial worms on pets entering the human body should also be a concern, as rare cases of parasitic filarial worms on pets resulting in ocular involvement and even microfilaraemia have been reported in the past [17] [18]. One of the cases showed that an immunocompetent 70-year-old woman living in rural France developed puffy left upper eyelid and conjunctivitis of the right eye. During a skin biopsy of one of the subcutaneous nodules, a 6 cm long immature worm was found and extracted, and cytologic testing of the blood showed 4 microfilariae per milliliter. She had had a dog for many years, but interestingly, to her knowledge, the dog had never had evidence of filarial disease [17].

Trichinella can infect humans through raw or semi-raw meat consumption containing Trichinella larvae cysts [19]. Trichinella is widely distributed, and the toxic metabolites released by the newborn larvae during the redevelopment into cysts can cause muscle pain, fever, edema, and increased eosinophilia. The most prominent symptom of trichinosis is generalized myalgia. However, it also shows different degrees of damage to the heart, lungs, and brain. For example, myocarditis complicated by heart failure is a common cause of death from trichinosis. Trichinella infection can also manifest psychiatric symptoms, most commonly headache (24.69%), confusion (14.2%), disorientation (11.73%), etc. [20].

Leishmaniasis, caused by Leishmania protozoa infection, has been reported in more than 90 countries with an estimated population of 700,000 to 1 million infected, mostly in tropical and subtropical, and southern European regions [21]. The disease is transmitted by sandflies and presents clinically with skin and mucous membrane damage and visceral infections [22]. However, the treatment of leishmaniasis is currently unsatisfactory.

African trypanosomiasis, whose causative agent is the tsetse flies, threatens 70 million people in 36 countries, mainly in Africa [23]. Despite a significant decrease in the number of reported disease cases in 2016, complete clearance of the pathogen remains extremely difficult [23]. The disease first presents as a generalized fever that progresses with the spread of the parasite, followed by neurological symptoms [24].

American trypanosomiasis (Chagas disease) pathogen is Trypanosoma cruzi (T cruzi), mainly transmitted by triatomine. The acute phase of Chagas disease symptoms include fever, inflammation, lymphadenopathy, and occasionally severe manifestations such as acute myocarditis, pericardial effusion, and meningoencephalitis; the chronic phase is characterized by cardiac involvement, followed by damage to the gastrointestinal tract [25].

Chagas cardiomyopathy was defined in patients who tested serologically positive for Trypanosoma and had at least typical symptoms of heart disease such as electrocardiogram abnormalities. Chronic Chagas cardiomyopathy is characterized by early left anterior bundle branch block or right bundle branch block

[26]. It progresses to severe ventricular arrhythmias, which can lead to heart failure [26]. Some patients have a poor prognosis and are at higher risk of fatal arrhythmias and heart failure, so there is a need to evaluate this disease’s prognosis effectively. Experts recommended risk stratification for all patients with chronic Chagas. The study found impaired left ventricular function and the New York Heart Association (NYHA) cardiac function rating of Grade 3 or 4 were the manifestations of poor prognosis Chagas cardiomyopathy [27].

The distinctive myocardial fibrosis exhibited pathologically in Chagas cardiomyopathy is a feature that distinguishes it from other cardiomyopathies [28]. However, the disease still presents some complicated problems, as below. Current conventional serologic testing is challenging to be effective in patients with low parasitemia levels, antiparasitic therapy is not indicated for patients in the nonacute phase, and patients cannot tolerate angiotensin-converting enzyme inhibitors and β-blockers [25]. The lack of early replacement markers prevents effective follow-up of chronic Chagas disease. And the difficulty of effectively implementing implantable cardioverter-defibrillators and cardiac transplantation therapy.

Studies have shown that 21.4% of patients with trichinosis died with a histological diagnosis of myocarditis [29]. In addition, in a review of 19 autopsy cases of acute Chagas disease, myocarditis was the main cardiac damage [30]. However, clinical symptoms of the acute phase of Chagas disease are not obvious, so the cardiac manifestations of the acute phase of T cruzi infection should be treated with caution and emphasis.

Notably, cardiac involvement was detected in 8 (13%) of 62 patients with trichinosis infection, of which 6 (10%) had pericardial effusion by echocardiography (ECG) [31]. This result indicates that pericarditis is a widespread manifestation of trichinosis cardiac involvement. In addition, toxoplasmosis, cysticercosis, and amoebiasis also occasionally cause pericarditis [3]. The above observations suggest that parasitic infections strongly correlate with the development of myocarditis and pericarditis. However, they are not the main contributors to these symptoms.

Of the 33 case reports of malaria with cardiovascular complications, 4 were diagnosed with ACS [32]. In addition, in a study of 10 patients with trichinosis, 2 of them had cardiac complications in the form of ST-segment elevation myocardial infarction [33]. Notably, patients with the parasitic disease with ACS may not have significant coronary artery obstruction. More researches still need to confirm whether it could be a neglected pathogenetic factor. In addition, compression of internal cardiac structures by the encapsulated cyst, or immediate opening of the encapsulated cyst located in the heart chambers may exhibit symptoms similar to ACS.

Localization of encapsulated cysts in the heart is rare, occurring in less than 2% of cases [34]. However, the current method of eradicating these worm cysts is primarily surgical. The damage that surgery can cause to patients cannot be ignored. Eosinophilic myocarditis may lead to ACS too. It is also worth considering when parasitic diseases are found to coexist with ACS [35]. However, parasite-induced ACS is difficult to identify in some cases, such as noncardiogenic pulmonary edema due to severe malaria, which may interfere with the diagnosis of ACS by inducing acute heart failure or acute myocardial infarction. Accordingly, the clinical management of some cardiovascular symptoms associated with parasitemia should be carefully managed. And the mechanisms behind them deserve further exploration.

The presence of parasitic infections is likely to increase the incidence or exacerbate the onset of arrhythmias. However, the clinical manifestations of arrhythmias vary widely among different types of parasitic infections. In a prospective study of severe malaria, ECG showed sinus bradycardia in 7% of cases, sinus tachycardia in 3.7%, and atrial tachycardia in 3.7% of patients [1]. Although the fever and hypoxemia caused by the parasite can be a reasonable background for tachycardia, the decrease in blood volume and cardiac reserve caused by its direct damage to the heart is also a significant cause of death. Therefore, it is of value to estimate the proportion of influence of plasmodium infection in patients with severe cardiovascular disease and malaria comorbidities.

In a systematic review of 49 population-based studies, patients with Chagas had a higher incidence of overall ECG abnormalities compared to those without Chagas (OR = 2.78; 95% CIs = 2.37 - 3.26), including complete right bundle branch block (OR = 4.60; 95% CIs = 2.97 - 7.11), left anterior bundle block (OR = 1.60; 95% CIs = 1.21 - 2.13), atrial fibrillation OR flutter (OR = 2.11; 95% CIs = 1.40 - 3.19) and premature ventricular contraction (OR = 1.62; 95% CIs = 1.14 - 2.30) [36]. Given the high incidence of lethal arrhythmias, managing arrhythmias in patients with Chagas cardiomyopathy is currently a major challenge and requires the consideration of more effective and innovative therapies and the exploration of the causes of arrhythmias induced during parasitic infections [37].

Notably, drugs used to treat parasitic diseases can also cause alterations in cardiac electrophysiology, such as pentavalent antimony and amphotericin B, which have significant cardiotoxicity. The cardiotoxicity of pentavalent antimony is particularly manifested by dose-dependent ECG changes, while its most common ECG changes include T-wave inversion and QT interval prolongation; other arrhythmias, such as premature atrial and ventricular beats and tip-twisting ventricular tachycardia, also occur with heavy dosing, and these abnormal ECG manifestations are reversed upon discontinuation of the drug [38]. And amphotericin B also often causes electrocardiographic changes by causing hypokalemia. The antimalarial drug quinine also causes prolongation of the QT interval [39], but this needs to be considered as a short-term change in rhythm after malaria subsides.

In studies of malaria, smaller baseline indices of left ventricular diastolic internal diameter and left ventricular systolic internal diameter were found to have a poor prognosis [40]. In addition, chronic infection with parasites often leads to cardiomyopathy. Patients with advanced Chagas cardiomyopathy often exhibit systolic and diastolic dysfunction, among which a significant reduction in left ventricular systolic function is strongly associated with lethality [26]. African trypanosomiasis also causes dilated cardiomyopathy-like manifestations in the heart. A study in Cameroon showed that antibodies to African trypanosomes were observed in 27% of patients with dilated cardiomyopathy [41]. Tropical endocardial myocardial fibrosis is now the most common cause of restrictive cardiomyopathy, often caused by filariasis, which is similar to eosinophilic myocarditis caused by parasites [42]. Extensive endocardial fibrosis typical of one or both ventricles is characteristic of the disease and is an important cause of heart failure and fatal arrhythmias in this disease [42].

In summary, parasitic cardiac complications can lead to decreased cardiac function and poor prognosis in patients, and these severe effects are not uncommon.

Parasites can directly invade and multiply in the myocardium, which in turn causes myocardial damage, necrosis, and apoptosis. T cruzi can invade numerous intracardiac cells including cardiomyocytes, endothelial cells, neuronal cells, fibroblasts, and other cells, and multiply within the cells to form cysts [28]. In a review of deaths from malaria with cardiovascular complications, histopathological studies in all cases found evidence of plasmodium parasitized red blood cells in the myocardium [32]. In a study of biomarkers of myocardial injury in the serum of 20 hypertensive patients, 20 patients with Chagas disease combined with hypertension, 20 patients with Chagas disease, and 20 normative volunteers, serum from patients with Chagas cardiomyopathy, with or without hypertension, showed more significant elevations of high-sensitive cardiac troponin T (high-sensitive cardiac troponin T (hs-cTnT) and B-type natriuretic peptide (BNP) (hs-cTnT (p < 0.001) and BNP (p = 0.001)) [43].

The main effects of parasites on the respiratory system include pneumonia or pulmonary embolism caused by parasites and parasite products. Hypoxia and carbon dioxide retention mediated by these respiratory pathologies can lead to increased pressure in the pulmonary circulation and subsequently to pulmonary arterial hypertension (PAH). Schistosomiasis is one of the most common causes of PAH, leading to chronic pulmonary heart disease. Potential mechanisms of this PAH include systemic and localized pulmonary inflammation, involvement of other organs, especially portal hypertension associated with the liver and spleen, and direct pre-capillary occlusion caused by embolism of parasitic eggs [6]. In PAH, which is caused by worm eggs, the helper T cell-mediated type 2 cellular immune response, interleukin (IL)-4 and IL-13 with other immune mediators induce the release of transforming growth factor-β as a vital mechanism of pulmonary vascular remodeling [42]. And vasoconstrictors can escape hepatic metabolism and eventually cause ventilation/perfusion imbalance [44].

Through the above mechanisms, hypoxemia may have developed before schistosomiasis caused PAH. It can cause an imbalance in the oxidative and antioxidant systems of cardiomyocytes, causing the accumulation of reactive oxygen species (ROS), which can damage the phospholipid layer of the cell membrane or affect the intracellular calcium ion (Ca²⁺) transport leading to pathophysiological changes of Ca²⁺ overload in cardiomyocytes [45]; in addition, elevated ROS can activate a variety of inflammatory factors, causing myocardial inflammation and fibrosis [46].

Parasites secreted procoagulant substances are an important cause of thromboembolic events in patients. Cardiac remodeling and arrhythmia in severe Chagas cardiomyopathy often lead to hemodynamic changes, presenting as intracardiac aneurysms and mural thrombus [26] [37]. Not only can parasitic cysts in the pericardium or inside the heart cause infarction or infarct-like symptoms, but sepsis due to infection is often associated with microthrombosis and is closely related to complement activation and inflammatory factors after infection. And parasitic infection is a common cause of endocardial elastosis associated with intractable endocardial thrombosis [47]. Embolism can also occur in the brain, as in the case of small and medium-sized intracranial arteries obstructed by the cysts of the tapeworm, resulting in focal neurological symptoms such as hearing loss, extraocular muscle paralysis, and facial nerve palsy [48].

Parasitic infections cause immunosuppression and chronic autoimmune reactions. Autoimmune-induced inflammation may be a significant cause of cardiac involvement due to parasites. The possible mechanisms causing autoimmunity include polyclonal activation, molecular self-mimicry of parasite antigens, or hidden epitopes shared by host and parasite.

Inflammation plays a crucial role in parasite-mediated cardiovascular injury and thus cardiovascular disease. Parasitic infection causes severe inflammation at the heart site by activating the innate immune response, inducing systemic inflammatory response syndrome (SIRS) and cytokine storm [49] [50]. On the one hand, acute myocarditis is the most common cause of death in the acute phase of parasitic infections such as T cruzi [30]. On the other hand, necrotic cardiomyocytes due to inflammation can further drive inflammatory factors into the heart, causing the heart to respond to injury and mediating myocardial remodeling, and disturbances in the function of the myocardium to inhibit inflammation are an essential cause of poor myocardial remodeling [51]. In addition, autonomic dysfunction will also lead to a greater susceptibility to adverse cardiac events due to inflammatory responses and oxidative stress, and elevated levels of catecholamines in patients with parasitemia, the latter of which can mediate myocardial toxicity [52] [53].

Parasites can mediate intestinal microecology and nutrient absorption disturbances through damage to the digestive tract, thereby exacerbating cardiovascular damage. Digestive symptoms such as diarrhea, nausea, and vomiting are common clinical manifestations of parasitic infections. First, the systemic or intestinal inflammation caused by the parasite can alter the microbial spectrum of the intestine [54]. Second, the physiological function of the myocardium is highly susceptible to metabolic disorders such as disordered water and electrolytes. Third, the intestinal barrier weakened by parasitic infection makes it highly likely that metabolites of harmful intestinal bacteria such as lipopolysaccharides will enter the circulation and increase the burden on the heart. In addition, the adverse effects of parasites on intestinal absorption mean that enhancing patient absorption of some of the nutrients previously studied for cardiovascular benefit may be worth considering [55].