Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis

INTRODUCTION — Chagas disease (CD) is caused by Trypanosoma cruzi, a protozoan parasite that can cause acute myopericarditis as well as chronic fibrosing myocarditis. CD is the most common cause of nonischemic cardiomyopathy in Latin America [1].

The clinical manifestations, diagnosis, and evaluation of chronic Chagas cardiomyopathy (CCC) will be reviewed here. Other issues related to Chagas heart disease, including monitoring, treatment, and prognosis of CCC, and the diagnosis and management of acute Chagas heart disease, are discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis" and "Chagas heart disease: Acute myocarditis".)

PHASES OF CHAGAS DISEASE — The natural history of CD has an acute phase and a chronic phase (figure 1). The chronic phase includes two forms of disease: an indeterminate (latent, preclinical) form and a determinate (clinical) form, which is subdivided into cardiac, digestive, and cardiodigestive forms. The natural history of CD is described in detail separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

CLINICAL MANIFESTATIONS — Patients with CCC may be asymptomatic or present with symptoms such as dyspnea on exertion, fatigue, palpitations, dizziness, syncope, chest pain (atypical or angina), and edema. Patients with CCC usually present with ventricular arrhythmias, abnormalities of the conduction system, sinus node dysfunction, segmental wall-motion abnormalities, apical aneurysms, mural thrombi with embolic potential, stroke, sudden cardiac death (SCD), and, at a later stage, biventricular HF [2-4].

Cardiac examination typically demonstrates one or more of the following findings (see "Auscultation of cardiac murmurs in adults" and "Auscultation of heart sounds"):

●Murmurs of mitral and/or tricuspid regurgitation

●Wide splitting of the second heart sound due to right bundle branch block

●A prominent diffuse apical thrust

Major clinical syndromes — Clinical manifestations of CCC arise from four major types of disorders: heart failure (HF), cardiac arrhythmias, thromboembolism (systemic and pulmonary), and chest pain syndrome. These disorders frequently occur concurrently.

Heart failure — HF commonly evolves slowly, and isolated left HF may be present in the early stages of cardiac decompensation. With disease progression, biventricular HF may occur. In such patients, the clinical manifestations of right-sided HF (increased jugular venous pressure, peripheral edema, ascites, and hepatomegaly) may predominate.

Both systolic and diastolic dysfunction can occur. Diastolic dysfunction has been observed in the absence of regional or global left ventricular (LV) systolic dysfunction [5,6]. (See "Heart failure: Clinical manifestations and diagnosis in adults" and "Heart failure with preserved ejection fraction: Clinical manifestations and diagnosis".)

Abnormalities in ventricular structure and function are discussed below. (See 'Echocardiography' below and 'CMR' below and 'Radionuclide imaging' below.)

Arrhythmias — Cardiac arrhythmias are common in patients with CCC. Arrhythmias may be asymptomatic or cause palpitations, lightheadedness, dizziness, dyspnea, weakness, syncope, or sudden cardiac arrest.

Virtually all types of atrial and ventricular arrhythmias occur, including sinus node dysfunction, atrial fibrillation, intermittent complete atrioventricular (AV) block, and complex ventricular arrhythmias. Ventricular arrhythmias and AV block or sinus node dysfunction frequently occur concurrently. Electrocardiographic (ECG) findings in patients with CCC are described below. (See 'ECG' below.)

●SCD accounts for approximately 55 to 65 percent of deaths in patients with CCC [4]. SCD is often precipitated by exercise, and can be caused by ventricular tachycardia (VT) or fibrillation, asystole, or complete AV block [7]. Most patients with SCD have severe underlying heart disease, although SCD has been reported in previously asymptomatic patients [8].

In a meta-analysis of 52 longitudinal studies published between 1946 and 2018 of a mixed population of patients with CCC, including 9569 patients and 2250 deaths, the annual all-cause mortality rate was 7.9 percent (95% CI 6.3-10.1) and the annual cardiovascular death rate was 6.3 percent (95% CI 4.9-8.0). The annual mortality rates for HF, sudden death, and stroke were 3.5, 2.6, and 0.4 percent, respectively. This meta-analysis also revealed that the mode of death is associated with the characteristics of the study populations. While the sudden annual death rates were higher than the HF rates in studies that included ambulatory asymptomatic patients, patients without ventricular dysfunction, patients predominantly in New York Heart Association (NYHA) class I or II, and patients with documented ventricular arrhythmias not treated with an implantable cardioverter-defibrillator (ICD), the contrary was observed in cohorts of patients with symptomatic CCC, with LV dysfunction or HF, and with an implanted ICD or cardiac resynchronization therapy [9].

●Complete AV block may cause dizziness, syncope, or SCD.

●Ventricular arrhythmia severity generally correlates with the degree of LV dysfunction, although some patients with VT and complete AV block have preserved global ventricular function, usually with regional wall motion abnormalities [8].

●Autonomic dysfunction in the setting of CD results in marked abnormalities in the heart rate response to stimuli such as the Valsalva maneuver, exercise, and postural changes.

There is evidence suggesting that one mechanism of severe ventricular arrhythmia is related to the regional fibrosis and reentrant circuits. In an electrophysiologic study of 56 patients with CD and VT, patients with spontaneous sustained VT had a higher prevalence of wall motion abnormalities in the inferior and/or posterolateral segments than those with no sustained VT. Scar in those regions was the main source of VT-related reentrant circuits. A reentrant substrate for the development of sustained VT existed in at least 50 percent of patients manifesting only nonsustained VT [10].

Another relevant pathophysiologic mechanism of severe ventricular arrhythmia and sudden death in CCC may be related to the regional myocardial sympathetic denervation found at the ventricular level. Studies involving patients with mild to moderate LV dysfunction showed a correlation between the detection of sustained and nonsustained VT, with larger areas of viable but denervated myocardium identified by using iodine-123 metaiodobenzylguanidine (MIBG-I123) scintigraphy [11,12]. These findings in patients with CD are concordant with findings in patients other forms of heart disease [13,14]. In contrast to those findings, it is now known that in some patients sympathetic denervation may be an effective treatment for VT [15].

Thromboembolism — Thromboembolism is an important cause of stroke and other morbidity in patients with CCC. Many or most strokes in CCC are attributable to emboli from dilated cardiac chambers (particularly LV aneurysm) and/or atrial fibrillation, although atherothrombosis and small vessel disease related strokes also occur [16]. Vascular disease in patients with CD is likely related to traditional atherosclerotic risk factors [17]. Pulmonary emboli arise from venous or right heart thrombi. (See "Stroke: Etiology, classification, and epidemiology", section on 'Thrombosis' and "Overview of secondary prevention of ischemic stroke" and "Epidemiology and pathogenesis of acute pulmonary embolism in adults".)

Limited data are available on overall frequency of clinical thromboembolism, but high rates of intracardiac thrombus and thromboembolic disease have been observed in clinical and autopsy series [18,19]. Small series have reported incidence rates of ischemic stroke in patients with Chagas cardiomyopathy of 0.6 to 2.7 percent per year [20-22]. The increased risk of stroke in patients with CCC was illustrated by a cross-sectional study in which the prevalence of stroke in 329 patients with CCC was 17 percent as compared with 11 percent in 461 patients with non-Chagas cardiomyopathies [23]. Of note, 40 percent of CCC patients with stroke lacked vascular risk factors.

A systematic review and subsequent meta-analysis of eight observational studies comprising 4158 patients examined the association between CD and stroke [24]. CD patients, compared with non-CD patients, presented a higher risk of stroke (odds ratio [OR] 1.70; 95% CI 1.06 to 2.71) for a subanalysis of four studies after exclusion of studies with high potential for bias. In a subanalysis limited to four studies that included only patients with cardiomyopathy, the prevalence of stroke was significantly increased in the CD group (OR 1.74; 95% CI 1.02 to 3.00).

Characteristics of CD patients with stroke were identified in a study of 94 CD patients presenting with acute ischemic stroke who were compared with a control group of 150 stroke patients without CD [25]. Those with CD had significantly higher rates of cardioembolic stroke (56 versus 9 percent), LV dilatation (23 versus 5 percent), mural thrombus (12 versus 2 percent), apical aneurysm (37 versus 1 percent), and atrial fibrillation (14 versus 5 percent). Among patients with CCC, risk factors for cardioembolic stroke include LV systolic dysfunction, apical aneurysm, primary ST-T wave changes, and older age (age >48 years) [21,23]. Use of a risk score to guide therapy is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Thromboembolism treatment'.)

Similar clinical characteristics were observed in an echocardiographic (transthoracic and transesophageal) study of 75 patients CCC in which cardiac sources of embolism were common among patients with no or mild symptoms of HF (baseline NYHA functional class I or II in 88 percent of patients) [18]. Atrial fibrillation was identified in 4 percent, mural LV thrombi in 23 percent, and an apical aneurysm was detected in 47 percent. Apical aneurysm was significantly associated with both mural thrombi and the occurrence of stroke. Four patients had left atrial appendage thrombi and one had thrombus in the right atrial appendage. Fourteen patients had a prior history of embolic stroke. During two-year mean follow-up, there were 13 deaths (seven sudden deaths, five from HF, and one due to stroke) and one non-fatal stroke.

In a review of 1345 autopsies with CCC, thromboemboli and/or intracardiac thrombi were observed in 44 percent of cases, including 36 percent with pulmonary embolism [19]. Thrombi were equally frequent in right and left cardiac chambers. Death was attributable to thromboemboli in 14 percent of patients with thromboembolic disease. Thromboembolic phenomena were more common in the systemic circulation but more deaths were caused by pulmonary embolism.

Chest pain syndrome — Chest pain is a common symptom in patients with CCC with and without HF. It is usually atypical in character but occasionally may mimic angina. Proposed mechanisms for chest pain include myocardial microvascular abnormalities and anomalous regulation of coronary vasomotion [26]. Also, some patients with CCC have concurrent coronary artery disease. (See 'Approach to diagnosis' below and 'Stress testing' below and 'Cardiac catheterization' below and 'Differential diagnosis' below.)

Initial test findings — Findings for preliminary tests frequently performed in patients with cardiovascular symptoms are discussed here. Additional tests used in the diagnosis and evaluation of patients with suspected CCC including echocardiography are discussed below. (See 'Diagnosis' below.)

Chest radiograph — Cardiomegaly is the classic radiographic finding (image 1) of CCC but many patients with CCC have a normal chest radiograph. Pulmonary congestion in many cases is absent or mild. The typical pattern of cardiomegaly with relatively clear lung fields in patients with chronic CD is usually due to right ventricular dysfunction with tricuspid regurgitation [27]. Pericardial effusion (which contributes to the appearance of cardiomegaly) and/or pleural effusion may be present.

ECG — ECG abnormalities are often the first sign of CCC but findings are not specific [28]. The most common ECG abnormalities are intraventricular blocks, particularly right bundle branch block (RBBB) and/or left anterior fascicular block, and diffuse ST-T changes (waveform 1) [29-31]. Other typical findings are ventricular premature beats (VPBs; often polymorphic), runs of VT, abnormal Q waves, various degrees of AV block, abnormal T-wave axis, QT interval prolongation, and variation in the QT interval (QT dispersion). Virtually all types of atrial and ventricular arrhythmias occur. In advanced disease, atrial fibrillation and low QRS voltage may be observed.

A normal ECG does not exclude the presence of CCC. (See 'Arrhythmias' above.)

The role of continuous ambulatory ECG (Holter) monitoring is discussed below. (See 'Ambulatory ECG monitoring' below.)

The potential prognostic significance of ECG findings is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognostic value of ECG'.)

DIAGNOSIS

Approach to diagnosis — The approach to diagnosis of CCC includes identification of patients at risk for chronic CD, serologic testing for chronic CD, and evaluation for symptoms and signs of heart disease.

●Identification of chronic Chagas disease – As discussed separately, chronic CD should be suspected in individuals who have lived in endemic countries of Latin America and offspring of women from endemic countries. While the presence of cardiac (or gastrointestinal) symptoms should prompt evaluation, most infected individuals are asymptomatic. Chronic CD is confirmed by serologic evidence of IgG antibodies to T. cruzi, as discussed separately (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Diagnosis'.)

●Initial cardiac evaluation – Evaluation for heart disease in patients with confirmed chronic CD should include a medical history, physical examination, and resting 12-lead ECG, preferably with a 30-second lead II rhythm strip [32] and chest radiograph [3,30]. Although echocardiography is not a component of the classical evaluation, we also perform echocardiography in these patients. While ECG or chest radiograph abnormalities may suggest cardiac disease, a normal ECG and chest radiograph does not exclude cardiomyopathy. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Diagnosis' and 'Chest radiograph' above and 'ECG' above.)

●When to proceed with further testing

•When to proceed with ambulatory (Holter) monitoring – If a patient with chronic CD has a cardiac symptom or sign, or ECG, chest radiograph, or echocardiographic finding suggestive of Chagas heart disease (see 'Clinical manifestations' above), further cardiac evaluation is warranted, including 24-hour ambulatory (Holter) ECG monitoring. (See 'Ambulatory ECG monitoring' below.)

•When to perform additional cardiac imaging – For patients with chronic CD with nondiagnostic echocardiogram, CMR is suggested to assess ventricular structure and function as well as the presence and degree of myocardial fibrosis. The extent, pattern, and intensity of myocardial fibrosis is a hallmark of the disease. If CMR is not available or contraindicated, radionuclide imaging may be used to assess biventricular size and function and radionuclide myocardial perfusion imaging may also aid in the detection of myocardial fibrosis. (See 'CMR' below and 'Radionuclide imaging' below.)

•When to perform stress testing – Stress testing is indicated in selected patients with chronic CD with symptoms and/or signs that could be caused by either ischemic heart disease or CCC. If stress testing is indeterminate, coronary angiography is helpful in distinguishing epicardial coronary disease from CCC. In CCC patients, epicardial coronary arteries are commonly angiographically normal, and chest pain may be due to microvascular dysfunction [33]. (See 'Differential diagnosis' below and 'Stress testing' below and 'Cardiac catheterization' below.)

●Indeterminate phase – A patient with serologic evidence of chronic CD with no cardiac (or gastrointestinal) symptoms or signs with the above testing has the indeterminate form. The optimal approach to monitoring such patients is uncertain. We suggest serial clinical monitoring as discussed separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Monitoring'.)

●Diagnosis – A diagnosis of CCC or suspected CCC is made based upon identification of one or more abnormalities on ECG, ambulatory ECG (Holter) monitoring, or cardiac imaging. (See 'Diagnosis of CCC' below.)

●Exclusion of other causes – In patients with serologic evidence of chronic CD with evidence of heart disease, other causes of heart disease should be excluded. (See 'Differential diagnosis' below.)

Endomyocardial biopsy is rarely indicated in patients with suspected CCC since the diagnosis is generally established by other testing and biopsy findings in patients with CCC are generally nonspecific. (See 'Endomyocardial biopsy' below.)

Diagnosis of CCC — CCC is diagnosed or suspected in patients with confirmed chronic CD with or without cardiac symptoms (eg, dyspnea, edema, or chest pain) based on the following criteria:

●A clinical diagnosis of CCC is made when one or more of the following key signs of Chagas heart disease is present and other causes of these signs (such as ischemic heart disease) have been excluded (see 'Differential diagnosis' below):

•ECG and/or ambulatory ECG (Holter) abnormalities – Sinus bradycardia with heart rate <40 beats per minute or symptomatic sinus node dysfunction, right bundle branch block (RBBB) with left anterior hemiblock (LAHB), new RBBB, frequent premature VPBs, abnormal Q waves, second-degree AV block or complete heart block, or VT (nonsustained or sustained). (See 'Ambulatory ECG monitoring' below and 'ECG' above.)

•Cardiac imaging (echocardiography and/or CMR) – Left and/or right ventricular regional or global systolic dysfunction, ventricular aneurysm (typically LV apical), or intracavity thrombus (typically apical). (See 'Echocardiography' below and 'CMR' below.)

●CCC is suspected in patients with chronic CD who lack all of the above key findings but have one or more of the following ECG findings: sinus bradycardia with heart rate >40 beats per minute, incomplete RBBB, RBBB (not documented as new) without LAHB, LAHB without RBBB, low limb lead voltage (voltage <0.5 mV in each limb lead), prolonged PR interval (first-degree AV block), or nonspecific ST-T wave changes.

Management of patients diagnosed with CCC or with suspected CCC is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Management'.)

Key diagnostic tests — The key diagnostic tests in patients with chronic CD undergoing evaluation for CCC are echocardiography and ambulatory ECG (Holter) monitoring. These exams are also useful for prognostication. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognosis'.)

Echocardiography — Echocardiography is generally the key test used to identify cardiac structural and functional abnormalities in patients with CD [28]. Echocardiographic abnormalities are observed in symptomatic and asymptomatic patients with chronic CD [34]. LV and RV systolic function ranges from normal to severely impaired.

●In early stages of cardiac involvement, echocardiography may demonstrate one or more areas of dyssynergy with preserved global systolic function. These mild segmental LV wall motion abnormalities may be predictors of subsequent ventricular function deterioration and identify patients at increased risk for adverse clinical outcomes [35,36].

●LV apical aneurysm is common in patients with moderate to severe cardiac impairment (47 to 64 percent) and occurs in up to 9 percent of asymptomatic patients (image 2 and image 3) [34]. Apical aneurysm is a frequent source of systemic emboli leading to stroke and other clinical manifestations (image 4). RV aneurysms are much less frequent, and some patients have apical aneurysms affecting both ventricles. Regional wall motion abnormalities may also occur elsewhere, particularly in the inferolateral wall, which is the most predominant source for macro-reentrant VT.

●More advanced disease is characterized by global ventricular dilatation and diffuse hypokinesis, often associated with mitral and tricuspid regurgitation.

RV systolic function may also be impaired [37], but in most patients these alterations are inadequately assessed or overlooked in echocardiographic assessments.

If echocardiographic images are non-diagnostic, cardiovascular magnetic resonance (or radionuclide imaging) is suggested to assess biventricular size and function and myocardial fibrosis. (See 'CMR' below and 'Radionuclide imaging' below.)

Echocardiographic findings associated with adverse outcomes, such as worse LV systolic function, are discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognostic value of echocardiography'.)

Ambulatory ECG monitoring — Continuous 24-hour ambulatory (Holter) monitoring is also indicated in patients with suspected CCC to evaluate the cause of syncope and other related symptoms, and to assess the mortality risk using the Rassi score. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Rassi score for predicting mortality'.)

Continuous ambulatory ECG (Holter) monitoring may show a wide range of abnormalities, including sinus node dysfunction, various degrees of AV block (including intermittent third degree AV block), atrial fibrillation, and complex ventricular arrhythmias. Frequent findings are premature ventricular depolarizations, runs of nonsustained or sustained VT, atrial fibrillation, and intraventricular conduction disturbances [30].

Tests for selected patients — Selected patients with suspected CCC require additional evaluation with one or more of the following tests as described below: CMR, radionuclide imaging, stress testing, cardiac catheterization, and endomyocardial biopsy [28].

CMR — If echocardiography is suboptimal or nondiagnostic, CMR imaging is recommended for assessment of ventricular size and function, and evaluation of the presence and extent of myocardial fibrosis. Myocardial fibrosis detected by late gadolinium enhancement (image 5) appears to correlate with disease severity. In a series of 51 patients with CD, myocardial fibrosis was evident in 20 percent of patients without clinical cardiac involvement, 85 percent with known cardiac involvement, and 100 percent with VT [38]. The extent of myocardial fibrosis increased across these three groups (percent of LV mass of 0.9, 16, and 25 percent, respectively).

Since CMR is well suited for direct and precise evaluation of dimensions, contractility, and tissue characterization, it may represent the best approach to detect early RV dysfunction, a marker of bad prognosis that has been underused in clinical practice [39]. In fact, investigations using CMR have shown that RV dimensions and function are not readily assessed with routine echocardiography approaches, and usually require specifically focused techniques to be detected in patients with CD [40,41] (See "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Late gadolinium enhancement' and "Clinical utility of cardiovascular magnetic resonance imaging", section on 'Chagas heart disease'.)

The prognostic value of CMR in patients with CCC is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognostic value of cardiovascular magnetic resonance'.)

Radionuclide imaging — Radionuclide imaging is not required in most patients with CCC but is suggested when echocardiography is nondiagnostic and CMR is nondiagnostic or cannot be performed (due to lack of availability or presence of a contraindication to CMR). Radionuclide ventriculography (using planar or tomographic SPECT imaging) enables assessment of LV and RV size and global and regional function. Regional LV wall motion abnormalities and/or global RV dysfunction may be detected in some patients in whom overall LV performance is preserved (image 6) [42]. Rest and stress radionuclide perfusion imaging (using SPECT-MIBI) may also provide an alternative method for identifying the presence and extent of myocardial fibrosis as revealed by the finding of fixed perfusion defects associated with impaired wall motion abnormalities, particularly when not conforming to a typical coronary distribution. (See 'Stress testing' below.)

Stress testing — Stress testing is helpful in selected patients with chronic CD with suspected epicardial coronary artery disease. Chest pain is common with CCC and is usually atypical but occasionally may mimic angina. However, in patients with CCC, ECG changes during exercise are frequently uninterpretable due to baseline ECG abnormalities [43] and abnormal results with stress imaging lack specificity for epicardial coronary disease; thus, coronary angiography is indicated when stress imaging results are inconclusive. (See 'Cardiac catheterization' below.)

Stress imaging with radionuclide perfusion imaging or echocardiography may be helpful in patients with uninterpretable ECG changes, but care is required to distinguish fixed and reversible defects for myocardial infarction and myocardial ischemia. Fixed and reversible perfusion and wall motion abnormalities have been observed in many patients with CCC without epicardial coronary artery disease, as illustrated by the following observations:

●Blunted heart rate responses and abnormal contractile responses were observed in a dobutamine stress echocardiography study of 26 patients with and without underlying segmental wall motion abnormalities, even in those without baseline abnormalities [44]. Ten patients underwent coronary arteriography and results were normal. Some patients had a biphasic response with improvement at low dose and deterioration at peak dose. These findings are similar to those observed in patients with coronary disease, suggesting that ischemia may contribute to the LV dysfunction in Chagas heart disease.

●Reversible, paradoxical, and fixed perfusion defects on radionuclide myocardial perfusion imaging have been observed in patients with CCC with or without atypical angina (image 7) [26]. Perfusion defects are typically located in the posterior-inferior and apical segments, where wall motion abnormalities also predominate and where sympathetic denervation has been identified by iodine-123 metaiodobenzylguanidine (MIBG-I123) uptake [45]. Fixed perfusion defects reflect regional myocardial fibrosis and correspond to regions with impaired wall motion. Reversible perfusion defects occur in the presence of normal epicardial coronary arteries and have been ascribed to coronary microvasculature abnormalities which may be due to underlying inflammatory changes and/or abnormal regulation of coronary vasomotion [46].

The contribution of microvascular dysfunction to myocardial damage in CCC was illustrated by a study of CD patients who underwent serial perfusion scintigraphy over a period of several years [47]. Deterioration of LV function was temporally associated with the extent of microvascular ischemia with evolution to fixed (fibrotic) lesions over time.

The comparative efficacy and relative significance of arrhythmia detected during Holter monitoring versus exercise testing has not been systematically evaluated [48].

Cardiac catheterization — Coronary artery disease may present similarly to CD and is also observed as a comorbid condition in some patients with CCC. Coronary angiography is useful to diagnose coronary artery disease in selected patients with suspected CCC, including those with stress test results consistent with CCC or coronary disease, as well as in patients who have CD and suspected concomitant coronary disease and standard indications for cardiac catheterization. In patients with CCC, the epicardial coronary arteries are most often angiographically normal and chest pain may be due to microvascular dysfunction (image 8) [33]. (See "Non-ST-elevation acute coronary syndromes: Selecting an approach to revascularization" and "Treatment of ischemic cardiomyopathy" and "Chronic coronary syndrome: Overview of care", section on 'Identifying patients for angiography and revascularization'.)

Invasive contrast left ventriculography may reveal characteristic aneurysms, occasionally at multiple sites (posterior-lateral, inferior basal, or apical) (image 9) [8], but it is generally not required since wall motion abnormalities and ventricular aneurysms are generally diagnosed by echocardiography (or CMR or radionuclide ventriculography).

Endomyocardial biopsy — Endomyocardial biopsy (EMB) is not generally required in patients with CCC since the diagnosis is generally established by other testing, and biopsy findings in patients with CCC are generally nonspecific. EMB is rarely performed in uncertain cases to exclude other causes of cardiomyopathy that have diagnostic histologic features. Nonspecific EMB findings in patients with CCC include myocardial cell hypertrophy, degeneration of myocardial fibers, and interstitial edema, fibrosis, and inflammatory infiltrate [49]. Specific findings may include the rare finding of nests of T. cruzi, or even T. cruzi antigens revealed by positive immunohistochemical tests. (See "Endomyocardial biopsy", section on 'Indications'.)

In patients with CCC who undergo heart transplantation, endomyocardial biopsy is performed to monitor for acute cellular rejection (picture 1). Examination of histologic sections for parasite nests and immunohistologic evidence of T. cruzi antigen may help distinguish acute cellular rejection from reactivated Chagas myocarditis [3]. (See "Heart transplantation in adults: Diagnosis of allograft rejection".)

Investigational imaging — A potential role for myocardial SPECT imaging with MIBG-I123 in patients with CCC has been suggested by studies at specialized centers. Using this technique, areas of myocardial sympathetic denervation were demonstrated in most patients with CCC (image 10) [45]. MIBG-I123 defects can be detected even in patients with normal cardiac function and normal ECG, and may precede the development of regional wall motion abnormalities [50]. In some series, the extent of myocardial denervation correlated with the occurrence of VT [11,12]. These findings suggest that derangement of the cardiac autonomic innervation is an early notable feature of CCC that correlates with occurrence of severe ventricular arrhythmia.

DIFFERENTIAL DIAGNOSIS — The differential diagnosis for CCC includes ischemic heart disease as well as hypertrophic cardiomyopathy and other causes of dilated cardiomyopathy. (See "Determining the etiology and severity of heart failure or cardiomyopathy" and "Causes of dilated cardiomyopathy".)

●Ischemic heart disease — As described above, CCC may present similarly to ischemic heart disease. Some patients with CCC have chest pain, which may or may not be typical for angina, and ECG abnormalities may be similar to those of ischemic heart disease. Apical aneurysms similar to those seen in CCC are seen in patients with coronary artery disease with apical infarction. Some (but not all) segmental ventricular abnormalities in CCC are not in typical coronary distributions (eg, posterior and apical thinning). Stress testing may not adequately distinguish CCC from coronary disease since fixed and reversible perfusion and wall motion abnormalities have been observed in many patients with chronic CD without epicardial coronary artery disease. Also, some patients have both CCC and coronary artery disease. Invasive coronary angiography is helpful in establishing the presence and extent of coronary artery disease when the diagnosis following noninvasive testing is uncertain (particularly in patients with multiple risk factors for atherosclerotic disease) or when standard indications for coronary angiography are present. (See 'Cardiac catheterization' above.)

●Hypertrophic cardiomyopathy — The apical aneurysm seen in CCC can generally be distinguished from that seen in some patients with hypertrophic cardiomyopathy by identification of concomitant apical hypertrophy in the latter conditions. (See "Left ventricular aneurysm and pseudoaneurysm following acute myocardial infarction" and "Hypertrophic cardiomyopathy: Morphologic variants and the pathophysiology of left ventricular outflow tract obstruction", section on 'Midcavity obstruction with LV apical aneurysm'.)

●Dilated cardiomyopathy — Advanced CCC with LV cavity dilation and global hypokinesis can be distinguished from other causes of dilated cardiomyopathy by serologic testing and exclusion of other potential concomitant causes (table 1). In rare cases when the cause of cardiomyopathy is uncertain after noninvasive testing, an endomyocardial biopsy may be helpful in identifying an alternative or concomitant cause of cardiomyopathy. (See "Causes of dilated cardiomyopathy" and "Determining the etiology and severity of heart failure or cardiomyopathy" and 'Endomyocardial biopsy' above.)

EVALUATION AFTER DIAGNOSIS — Evaluation after diagnosis of CCC includes clinical assessment of prognosis and evaluation of associated rhythm disturbances, with electrophysiologic testing as indicated.

Assessment of prognosis — Clinical assessment of prognosis based upon clinical features and test results is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis" and "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognosis'.)

Electrophysiologic testing — General indications for electrophysiologic testing apply to patients with CCC. Electrophysiologic testing is generally not required but is warranted in selected patients for assessment of sinus node function and AV conduction when the origin of symptoms remains uncertain after noninvasive evaluation. (See "Invasive diagnostic cardiac electrophysiology studies".)

The potential prognostic value of electrophysiologic testing in patients with CCC is discussed separately. (See "Chronic Chagas cardiomyopathy: Management and prognosis", section on 'Prognostic value of EP testing'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Chagas disease".)

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●Basics topic (see "Patient education: Chagas disease (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Phases of Chagas disease – The natural history of Chagas disease (CD) has an acute phase and a chronic phase (figure 1). The chronic phase includes two forms of disease: an indeterminate (latent, preclinical) form and a determinate (clinical) form, which is subdivided into cardiac, digestive, and cardiodigestive forms. The indeterminate form is composed of patients with evidence of Trypanosoma cruzi infection without specific overt clinical evidence of cardiac or gastrointestinal disease. Approximately one-third to one-half of patients with indeterminate disease eventually develop chronic Chagas cardiomyopathy (CCC). (See 'Phases of Chagas disease' above.)

●Major clinical syndromes – Most patients with CCC come to clinical attention with symptomatic complaints, generally related to one or more of the following four clinical disorders (see 'Major clinical syndromes' above):

•Heart failure – Heart failure (HF) in CCC is usually biventricular. Manifestations of right-sided failure are frequently more pronounced than those of left-sided failure. (See 'Heart failure' above.)

•Arrhythmias – Cardiac arrhythmias in CCC may cause palpitation, lightheadedness, dizziness, or syncope. Dizziness and syncope may occur due to complete heart block or to ventricular tachycardia (VT). Sudden cardiac death (SCD) accounts for approximately 55 to 65 percent of deaths in patients with chronic CD and may occur in previously asymptomatic individuals. (See 'Arrhythmias' above.)

•Thromboembolism – Systemic and pulmonary thromboembolism occur in patients with CCC as a result of intracardiac and venous thrombosis in the setting of left ventricular (LV) systolic dysfunction and dilated cardiac chambers, often with apical aneurysm. (See 'Thromboembolism' above.)

•Chest pain – Chest pain is common and may be atypical or anginal in nature. (See 'Chest pain syndrome' above.)

●Approach to diagnosis – Patients with chronic CD confirmed by serology should undergo a medical history, physical examination, and resting 12-lead ECG, preferably with a 30-second lead II rhythm strip to assess for evidence of cardiac involvement. Although echocardiography is not a component of the classical evaluation, we routinely perform echocardiography. (See "Chagas disease: Chronic Trypanosoma cruzi infection".)

•If any findings from the initial evaluation are suggestive of heart disease, further cardiac evaluation is warranted, including 24-hour ambulatory ECG monitoring. (See 'Diagnosis' above.)

•If echocardiographic images are nondiagnostic, cardiovascular magnetic resonance (CMR) is recommended to assess ventricular structure and the structure and degree of myocardial fibrosis. If CMR is not available or contraindicated, radionuclide imaging may be used to assess biventricular size and function, and radionuclide myocardial perfusion imaging may also aid detection of myocardial fibrosis. (See 'CMR' above and 'Radionuclide imaging' above.)

•Stress testing is indicated in selected patients with chronic CD with symptoms and/or signs that could be caused by either ischemic heart disease or CCC. If stress testing is indeterminate, coronary angiography is helpful in distinguishing epicardial coronary disease from CCC. (See 'Stress testing' above and 'Cardiac catheterization' above.)

●Diagnosis of chronic Chagas cardiomyopathy – A clinical diagnosis of CCC is made in patients with confirmed chronic CD when one or more of the following key signs of Chagas heart disease is present and other causes of these signs (such as ischemic heart disease) have been excluded (see 'Diagnosis of CCC' above):

•ECG and/or ambulatory ECG (Holter) abnormalities – Sinus bradycardia with a heart rate <40 beats per minute or symptomatic sinus node dysfunction, right bundle branch block (RBBB) with left anterior hemiblock (LAHB), new RBBB, frequent premature ventricular premature beats, abnormal Q waves, second-degree atrioventricular (AV) block or complete heart block, or VT (nonsustained or sustained). (See 'Ambulatory ECG monitoring' above and 'ECG' above.)

•Cardiac imaging (echocardiography and/or CMR) – LV and/or right ventricular regional or global systolic dysfunction, ventricular aneurysm (typically LV apical), or intracavity thrombus (typically apical). (See 'Echocardiography' above and 'CMR' above.)

•CCC is suspected in patients with chronic CD who lack all of the above key findings but have one or more of the following less-specific ECG findings: sinus bradycardia with heart rate >40 beats per minute, incomplete RBBB, RBBB (not documented as new) without LAHB, LAHB without RBBB, low limb lead voltage (voltage <0.5 mV in each limb lead), prolonged PR interval (first-degree AV block), or nonspecific ST-T wave changes. (See 'Diagnosis of CCC' above.)

●Differential diagnosis – In patients with clinical findings suggestive of CCC, other causes of heart disease should be excluded, particularly ischemic heart disease and other causes of dilated cardiomyopathy. (See 'Differential diagnosis' above.)