The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement may manifest in different ways, but the syndromes resulting from impairment of the myocardium and pericardium are the most frequent. The myocardium may be invaded by parasites that trigger local inflammatory response with subsequent myocarditis or cardiomyopathy, as occurs in Chagas disease, African trypanosomiasis, toxoplasmosis, trichinellosis and infection with free-living amoebae. In amoebiasis and echinococcosis, the pericardium is the structure most frequently involved with consequent pericardial effusion, acute pericarditis, cardiac tamponade or constrictive pericarditis. Chronic hypereosinophilia due to helminth infections, especially filarial infections, has been associated with the development of tropical endomyocardial fibrosis, a severe form of restrictive cardiomyopathy. Schistosomiasis-associated lung vasculature involvement may cause pulmonary hypertension (PH) and cor pulmonale. Tropical pulmonary eosinophilia, which is characterised by progressive interstitial fibrosis and restrictive lung disease, may lead to PH and its consequences may occur in the course of filarial infections. Intracardiac rupture of an Echinococcus cyst can cause membrane or secondary cysts embolisation to the lungs or organs supplied by the systemic circulation. Although unusual causes of cardiac disease outside the endemic areas, heart involvement by parasites should be considered in the differential diagnosis especially of myocardial and/or pericardial diseases of unknown aetiology in both immunocompetent and immunocompromised individuals. In this review, we updated and summarised the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.
- Secondary pulmonary hypertension
- Chagas disease
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Parasitic infections due to protozoa and helminths account for a great burden of morbidity and mortality in extensive areas of the world, especially in developing countries. Some of these infections may affect structures of the heart, such as the myocardium and pericardium, and also the pulmonary vasculature producing a wide variety of cardiac manifestations, which present clinically as myocarditis, cardiomyopathy, pericarditis, pericardial effusion, pulmonary hypertension (PH)1–3 or space-occupying lesions.3
Although previously observed only in endemic areas, parasite infections, currently, may be diagnosed anywhere around the world due to growing migration, worldwide travel, as well as the immunosuppressive effects of increasing numbers of HIV infection and organ transplant.1 2 4 Thus, clinicians from anywhere must be aware of the potential cardiac manifestations of the parasitic diseases in both immunocompetent and immunocompromised subjects. The clinical diagnosis of protozoal and helminth infections occurring outside endemic areas is especially dependent on considering this possibility in the differential diagnosis. Thus, the aim of this review is to update and summarise the current knowledge on the major heart diseases caused by protozoan and metazoan parasites, which either involve the heart directly or otherwise influence the heart adversely.
The protozoans known to involve the heart are a diverse group. Table 1 summarises the clinical manifestations due to the major protozoal infections that cause human disease and their adverse effects on the heart. The most important protozoosis involving the heart are discussed in the following topics with emphasis on the most prevalent.
Chagas disease (American trypanosomiasis)
Chagas disease, caused by the protozoan Trypanosoma cruzi, remains one of the most prevalent parasitic diseases in Latin American, and has become a health problem in non-endemic countries as a result of widespread migration.5 This disease is transmitted to humans by infected triatomine bugs, or occasionally, by blood transfusion, organ transplantation, congenital transmission or oral ingestion of contaminated materials. In the last decades, large-scale vector control programs and screening of blood donors have substantially decreased the burden of Chagas disease in Latin America. Thus, the estimated global prevalence of T. cruzi infection declined from 18 million in 1991 to 5.7 million in 2010.6
The initial phase of infection with T. cruzi lasts 4–8 weeks, and the chronic phase persists for the host's lifespan.7 Although the acute phase is usually asymptomatic and resolves spontaneously, it may present as a non-specific febrile illness; and, in less than 1% of the infections, this phase may be life-threatening due to the development of meningoencephalitis or myocarditis.8 During this early phase, the parasite disseminates and can be observed by direct blood examination.
The chronic phase generally starts with a long period of clinical latency called indeterminate form, which lasts decades or throughout life.7 The indeterminate form is characterised by presence of antibodies against T. cruzi in serum, a normal 12-lead ECG and normal radiological examination of the chest, oesophagus and colon.9 About 20%–40% of the patients will subsequently progress to clinically manifest disease related to the involvement especially of the heart, oesophagus, colon and nervous system, characterising specific clinical forms. Reactivation of Chagas disease may also occur in chronically infected patients who become immucompromised.
Chagas cardiomyopathy is the most serious form of the disease. Clinical manifestations depend on myocardial dysfunction, damage to the conduction system, thromboembolic events and arrhythmias.10 Indeed, Chagas heart disease is considered an arrhythmogenic cardiomyopathy, characterised by atrial and ventricular arrhythmias as well as a wide variety of abnormalities of the conduction system. The most common ECG abnormalities are right bundle branch block with or without left anterior and/or atrioventricular blocks, and frequent premature ventricular contractions.9 11 The presence of fibrosis that typically involves the posterior and apical regions of the left ventricle distinguishes Chagas disease from other cardiomyopathies. Moreover, clinical progression and survival were significantly worse in patients with Chagas cardiomyopathy than in those with non-inflammatory forms of dilated cardiomyopathy.12
The pathogenesis of Chagas cardiomyopathy is complex and incompletely understood. Parasite persistence and immune-mediated myocardial injury are the main mechanisms related to myocardial aggression in the chronic phase of Chagas heart disease.13 In addition, autonomic nervous system derangements and microvascular disturbances may contribute to the pathogenesis of cardiac disease.
Segmental left ventricular wall motion abnormalities, most commonly in the apical and inferolateral walls, represent an interesting aspect of Chagas disease. Apical aneurysm is a typical lesion and one of the distinguishing hallmarks of Chagas disease (figure 1), and is often associated with mural thrombi and embolic events14 (figure 2). Although MRI is the best method to demonstrate this aneurysm, echocardiography is the most used technique because of its widespread availability and low cost. Myocardial perfusion disturbances, sympathetic myocardial dennervation and myocardial fibrosis have been detected by nuclear imaging methods and cardiac MRI.15 16
The diagnosis of chronic Chagas disease is based on serological assays as the very low levels or even absence of parasitaemia hinder direct parasites detection.17 Several techniques with different sensitivities are employed for antibody detection.18 Traditionally, Chagas disease has been screened by two different parallel assays.
Therapeutic management of Chagas disease involves parasite-specific therapy and treatment of heart failure, arrhythmias and thromboembolic events.19 Antiparasitic therapy (nifurtimox or benznidazole) is indicated for patients with acute infection, children, congenital infection and reactivation due to immunosuppression. Although it has been suggested that antitrypanosomal treatment can slow the progression of cardiac disease, a recent randomised control trial demonstrated no benefit of treatment on outcome.20 21 The therapeutic management of heart failure due to Chagas disease follows the standard recommendations.19 Implantable cardioverter defibrillators should be considered to prevent sudden cardiac death in high-risk patients. Heart transplantation is the treatment of choice for patients with refractory end-stage heart failure.
Chagas disease is a risk factor for death. The most important predictors of death are the New York Heart Association functional class, left ventricular systolic dysfunction and non-sustained ventricular tachycardia, which reflect severity of the myocardial damage.22
The agents of African trypanosomiasis (sleeping sickness) are protozoans belonging to the genus Trypanosoma. They are transmitted by the bite of various species of tsetse flies, which are found only in Africa. There are two forms of the disease: the West and East African trypanosomiasis that are caused by T. brucei gambiense and T. b. rhodesiense, respectively.3 23 This condition is an important public health problem in endemic areas of sub-Saharan Africa.3
The disease is classified into stages I (haemolymphatic) and II (meningoencephalitic). Stage-I disease is a systemic febrile illness that develops as the parasites disseminate through the bloodstream and lymphatics and stage II is characterised by the development of neurological manifestations. In T. b. rhodesiense infection, the disease follow a more acute course without a clear distinction between the stages.24
Cardiac involvement is more frequent during the haemolymphatic stage. Myocarditis and occasionally pancarditis leading to arrhythmias and heart failure have been reported.2 23 25 The conduction system may also be affected as well as the autonomic innervation of the heart.26 Abnormal ECG is common and the most frequent abnormalities include low voltage, PR segment depression, non-specific ST-T wave changes and prolonged QT interval.2 25 Histopathological examination demonstrates chronic pancarditis26 and as the infection progresses, myocytolysis and fibrosis may develop.4 Heart failure has also been occasionally reported in association with late T. b. rhodesiense infection.
The diagnosis of African trypanosomiasis requires demonstration of the parasite in inoculation chancre fluid, lymph node aspirates, blood or cerebrospinal fluid.2 23 24 Untreated disease is almost invariably fatal.2 Therefore, specific therapy is recommended for all patients. Suramin, pentamidine, organic arsenicals and eflornithine are the most commonly used drugs to treat the infection. The choice of the agent depends especially on the presence of CNS involvement and drug side effects.24 Aetiological treatment may induce ECG alterations, which have been assigned to inflammation of the myocardium as a consequence of the host immune response to the parasite.2
Leishmaniasis refers to a heterogeneous group of clinical syndromes caused by a protozoan of the genus Leishmania. Most transmission occurs by phlebotomine sand fly bite. It is a neglected disease found in more than 90 countries in the tropics, subtropics and southern Europe.27
Cardiac involvement assigned to leishmania infection is limited to rare case reports of myocarditis and/or pericarditis.28 29 However, the disease treatment has cardiac complications. The main therapeutic options are pentavalent antimonials (SbV) and amphotericin B (deoxycholate or liposomal).
The cardiotoxicity of SbV is represented especially by dose-dependent ECG changes. According to a systematic review concerning the adverse effects of cutaneous leishmaniasis treatment,30 cardiac abnormalities were recorded in 17.8% of the patients treated with meglumine antimoniate (glucantime) and in 9.5% of those that received sodium stibogluconate (pentostam). The most frequent ECG changes include T-wave inversion and prolonged QT interval. Arrhythmias such as premature atrial and ventricular contraction, and torsades de pointes occur especially with doses higher than 20 mg of SbV/kg/day. These abnormalities reverse after stopping the drug. Sudden death has also been reported in association with the use of SbV, particularly with high daily dose (30–60 mg of SbV/kg).
Amphotericin B has numerous adverse effects, and hypokalaemia and kidney dysfunction are the most important. ECG changes due to hypokalaemia are common, but genuine cardiotoxicity is a rare adverse event. Nevertheless, reversible dilated cardiomyopathy has been reported especially in patients with a predisposing factor for heart failure.31
The helminths that infest or infect humans include the platyhelminths (flatworms), which encompass the trematodes (schistosomes and other flukes) and the cestodes (tapeworms), and the nematodes (intestinal and tissue roundworms). Some helminth worms, their larval forms or their eggs may involve the heart directly or indirectly causing different syndromes that are summarised below and/or in table 2.
Schistosomiasis is a tropical helminth infection caused by digenetic trematode of the genus Schistosoma. Of an estimated 207 million persons infected with schistosomes in more than 70 countries, about 120 million have symptoms and 20 million have severe disease. Five major Schistosoma species infect humans, but S. mansoni, S. haematobium and S. japonicum are the most important. Although socioeconomic development and control programs have nearly eliminated schistosomiasis or reduced its morbidity in some countries, progress has been slow in extensive areas, especially in sub-Saharan Africa. The disease has also been spread into regions that were not previously endemic due to the development of water resource projects and migrations. Furthermore, the growth of tourism has resulted in increasing number of infections in travellers.32
These blood-dwelling worms use man and other mammals as definitive hosts, and aquatic and amphibian snails as intermediate hosts. Transmission of the infection requires direct contact with snail-infested water. After penetrating the skin of the definitive host, the worms migrate in the blood and reach the liver, where they mature, mate and migrate to the mesenteric veins (S. mansoni and S. japonicum) or to the vesical plexus (S. haematobium) where the eggs are laid. Eggs not excreted in faeces or urine remain trapped in the intestinal or bladder wall or are carried by the bloodstream to the liver and other sites. After egg deposition into the tissues, the embryos mature and secrete antigens that elicit a cell-mediated periovular granulomatous reaction. Most of schistosome pathology results from the eggs surrounded by granulomas.33
Schistosome infections are classified into acute and chronic phases and different clinical forms.34 The acute phase is usually unapparent in people who live in endemic areas. However, systemic symptoms are common in non-immune people. The chronic phase is usually asymptomatic, but clinical manifestations may occur. In sustained heavy infection with the species whose habitat is the mesenteric veins, the patients may develop the hepatosplenic form that results from periportal collagen deposition leading to fibrosis, progressive block of the portal blood flow and portal hypertension. Likewise, in schistosomiasis haematobia, the patients may develop obstructive uropathy. Fibrosis, and ultimately calcification of the bladder wall, causes reflux and obstruction of urine flow and its consequences. In hepatosplenic shcistosomiasis, the eggs may bypass the liver through portosystemic collateral vessels and may be deposited into the lungs. In schistosomiasis haematobia, the eggs may escape the vesical plexus reaching the lungs directly. Pulmonary arterial hypertension (PAH) may develop in these situations.
Schistosomiasis-associated PAH is one of the most common causes of PAH worldwide. Some of its pathological findings are similar to those observed in other forms of PAH such as idiopathic PAH35–37 ; thus, it is categorised as group-1 disease according to the WHO classification of PH.38 Schistosomiasis causes PAH in about 6.1% of the patients chronically infected in approximately 15.1% of those with the hepatosplenic form and is considered cause of 30.8% of all cases of PH.39 PAH due to schistosomiasis is particularly associated with the hepatosplenic form of S. mansoni infection.40
Although the pathogenesis of schistosomiasis-associated PAH is largely unknown, mechanical obstruction of lung vasculature by the eggs and pulmonary vascular inflammation and remodelling have been suggested as the major potential pathogenic mechanisms for this condition (figure 3). Available evidence suggests that after reaching the lung by the portosystemic shunts, the antigenic eggs elicit a predominantly T helper type-2 cells immune response resulting in periovular granuloma formation. Interleukin (IL)−4 and IL-13 along with other immune mediators lead to the release of transforming growth factor-β, which, in turn, cause pulmonary vascular inflammation and remodelling with the development of angiomatoid and plexiform lesions.35 41
In addition, some authors suggest that patients with hepatosplenic schistosomiais may develop portopulmonary hypertension. This condition is a serious complication of cirrhosis and other chronic liver diseases that course with portal hypertension. Its pathogenesis is unknown. Genetic predisposition, pulmonary thromboembolism from the portal venous system and effects of circulating mediators that escape hepatic metabolism and reach the lungs through portosystemic collaterals causing sequentially pulmonary vasoconstriction increased pulmonary vascular resistance, and vascular remodelling have been proposed as possible causes of portopulmonary hypertension.42
Although patients with schistosomiasis-associated PAH may be asymptomatic, most of them develop right heart failure.40 Clinical presentation of the patients with schistosomiasis-associated PAH is similar to that of patients with PAH due to other aetiologies. Chest radiography suggests an insidious process with remarkable dilatation of the pulmonary arteries (figure 4). Transthoracic echocardiography is a useful screening tool and provides significant information on the severity of the disease and right ventricular function (figure 5). However, the prevalence of PH estimated by echocardiography is much higher than the actual pulmonary artery pressure measured by invasive haemodynamic procedure.35
The diagnosis of schistosomiasis is usually established by the demonstration of schistosome eggs in stool, urine or rectal snips. Several techniques are available to search for antibodies against schistosome antigens in serum, but they are of limited diagnostic value in endemic areas, as the detected antibodies may cross-react with antigens of other helminth and none of the tests can distinguish between past and current infections. Serology is a more specific diagnostic tool in travellers. Ultrasonography is a major method for the diagnosis of hepatosplenic schistosomiasis and advanced urinary tract pathology. Standardised protocols are available.43
All patients with evidence of infection should be treated regardless of symptoms. Praziquantel is the treatment of choice for all schistosome species. Treatment of schistosomiasis-associated PAH is still a matter of study. Although scarce, reported data suggest that patients with schistosomiasis-associated PAH do not generally have substantial improvement after treatment with the antihelminth agent, especially those with advanced disease.35 40 Case reports and small case series have demonstrated success in treating schistosomiasis-associated PAH with PAH-specific medications such as phosphodiesterase-5 inhibitors and endothelin receptor antagonist.44
Tropical endomyocardial fibrosis
Endomyocardial fibrosis (EMF) is characterised by the deposition of fibrous tissue on endocardial surfaces, leading to restrictive physiology.45 46 EMF affects mainly the poorest populations and is believed to be the most common type of restrictive cardiomyopathy worldwide. First reported in Uganda, it has been found in tropical regions of Africa, Asia and South America.47 A community-based study in a rural area of Mozambique using echocardiography reported a prevalence of 20%.
The cause and pathogenesis of the disease are poorly understood.46 48 Diet, poverty, parasitic disease, genetic predisposition and ethnicity have been implicated in its pathogenesis.46 49 Pathological similarities with the Loffler syndrome and the high prevalence of parasites in areas where EMF is more observed led to consider chronic hypereosinophilia and infections as potential primary triggers. Although no consistent unifying infectious cause has been established, filariae is the nematode most frequently found to induce chronic eosinophilia, and therefore, EMF.2–4 23 A combination of dietary, environmental and infectious factors in a susceptible individual may cause the inflammatory process leading to endomyocardial damage and scar formation.46
EMF usually have an initial active febrile stage associated with pancarditis and hypereosinophilia.50 The recurrence of active episodes may facilitate the evolution to the chronic phase, characterised by ventricular thrombosis usually affecting the apices and the subvalvar apparatus. This causes obliteration of the ventricular cavity, interfere with valve mechanism and subsequently evolves to thrombus organisation and typical endocardial fibrosis.48 In the chronic phase, biventricular involvement is the most common presentation, followed by isolated right-sided heart disease and, rarely, isolated left-sided disease.46
The clinical picture of EMF depends on the activity of the disease, the chamber affected and the severity of the lesions. Usually, by the time of clinical presentation, most patients have advanced disease with heart failure. In most cases, right ventricular restriction predominates. Typically, ascites is disproportional to peripheral oedema (figure 6A).46 48 It has been proposed that EMF may be a systemic syndrome with peritoneal inflammation that leads to abundant ascites with lymphocytic exudates and peritoneal fibrosis, but without pedal oedema.46
Echocardiography is the standard method for defining EMF diagnosis and prognosis. A set of echocardiographic criteria was proposed for early diagnosis, especially to detect morphological features that occur before chamber dilatation or valve distortion.51 Echocardiographic features used for diagnosing EMF are restrictive filling with apical fibrosis that commonly involves the mitral and tricuspid subvalvular apparatus, reduction of the ventricles accompanied by atrial enlargement and valve dysfunction. In advanced right-sided EMF, the cardiac apex becomes severely retracted, and the trabecular chamber is almost virtually obliterated with dilatation of the right ventricular outflow tract, parietal thrombosis and dilatation of the right atrium (figure 6B). Obliterative fibrosis results in tricuspid valve adherence to the endocardium with severe tricuspid regurgitation, dilatation of the inferior vena cava and pericardial effusion. In left EMF, the most important features are endocardial hyperdensity in the apex associated with small left ventricle, and dilatation and hypercontractility of the basal portion.52 The left atrium is markedly dilated, the mitral inflow pattern is restrictive and PH is common.
The prognosis of EMF is poor with a high prevalence of sudden death from fatal arrhythmias or thromboembolism. Medical management consists of symptomatic treatment of heart failure, arrhythmias and anticoagulation. Paracentesis offers only short-term relief, because ascites often reaccumulates rapidly. Open heart surgery with endocardial resection combined with valve repair or replacement improves symptoms and survival compared with medical treatment.53 54 However, surgery is technically challenging and not available in most endemic areas. In addition, as the disease is usually detected in late stages, surgery cannot be performed without a very high risk of death and complications.
The heart may be affected directly or indirectly by a variety of protozoa and helminths. This involvement can manifest in different ways, although the syndromes resulting from the involvement of the myocardium and pericardium are the most frequent. Nowadays, as a consequence of the increase in both travelling and number of immunocompromised patients, the parasitic infections can be found anywhere in the world. The key to diagnosing heart involvement by a parasite is the knowledge of the epidemiological risk factors and most common forms of clinical presentation. Thus, physicians anywhere should be aware of these data to consider the possibility of a parasitic infection in the differential diagnosis. Management often requires expertise with the use of both diagnostic tests and specific drugs to treat the infection.
Additional material is published online only. To view please visit the journal online (http:// dx. doi. org/ 10.1136/heartjnl-2016-309870)
Competing interests None declared.
Provenance and peer review Commissioned; externally peer reviewed.