Planar radionuclide ventriculography was one of the first nuclear imaging techniques employed to explore right and left ventricular function and to assess wall-motion abnormalities in patients with CCC.¹⁴ That study¹⁴ reported that radionuclide ventriculography provided reliable information on global LV function and regional wall motion abnormalities, with good correlation between radiologic contrast ventriculography performed during cardiac catheterization and radionuclide ventriculography results.

A prominent feature in patients with Chagas disease is right ventricular dysfunction that may occur in the absence of any detectable LV disorder.¹⁵ These findings were described by Marin Neto et al^15,16 and confirmed previous studies employing planar rest gated equilibrium radionuclide angiography with ^99mTechnetium.^15,16 Both studies showed that reduced right ventricular ejection fraction can be the only functional cardiac disorder detectable in some chronic Chagas patients with the indeterminate or the digestive forms, without any other clinical signs of heart disease.

Application of gated SPECT technique enables tomographic acquisition of blood pool imaging and more detailed assessment of LV dysfunction. Previous studies have used this approach to achieve a more accurate correlation between SPECT myocardial perfusion changes and regional wall motion abnormalities in cohorts of CCC patients with varying myocardial disease severity, demonstrating a close topographic relationship between regional wall motion impairment and reversible or fixed myocardial perfusion defects. ¹⁷

More recently, radionuclide ventriculography image acquisition with the SPECT technique, which produces tomographic images of the ventricular cavity, co-registered with myocardial perfusion gated-SPECT imaging of the ventricular walls, were used to provide complementary information allowing characterization of left ventricle apical aneurysm,¹⁷ the most notable segmental disorder in chronic Chagas’ heart disease. That study described severe perfusion defects in the aneurysmal apical region, although relatively smaller when compared to the aneurysm size, identified by radionuclide ventriculography. Notably, the myocardial segments surrounding the aneurysm have preserved segmental wall motion, resulting in an aneurysm with a narrow neck, and the dyskinetic ventricular cavity has a “glove finger” appearance (figure 1). This aspect clearly diverges from what is classically found in apical aneurysms secondary to ischemic heart disease, in which the LV wall segments of the aneurysmal formation show typically dyskinetic movement. It is important to note that early detection of the aneurysm using several diagnostic nuclear imaging methods is clinically relevant because the apical region is somewhat more difficult to assess when standard echocardiographic methods are used. Furthermore, detection enables risk stratification with therapeutic implications, mainly with relation to the risk of thromboembolism and potential indication of anticoagulation therapy.¹⁷

One particular feature of CCC is the clinical and laboratorial presentation masquerading as coronary artery disease.¹⁸ Previous reports called attention to the occurrence of regional LV dyssynergia associated with rest (fixed) myocardial perfusion defects, mainly in the apical and basal portion of the posterior-lateral wall, that could be misinterpreted as regions of scar tissue resulting from previous myocardial infarction and atherosclerotic coronary artery disease.¹⁹ Furthermore, precordial chest pain is a common manifestation and mimics acute or chronic coronary syndromes usually associated with classic coronary artery disease, but with normal epicardial coronary arteries on angiography. ^20,21 In this scenario, several clinical studies using myocardial perfusion scintigraphy reported findings of reversible defects compatible with reversible myocardial ischemia in CCC patients exhibiting normal coronary arteries, indicating the presence of coronary microvascular dysfunction.

There is now sound evidence in the literature suggesting that myocardial perfusion disturbances (MPD) caused by microvascular dysfunction participate in the pathogenesis of the myocardial damage process that ultimately leads to CCC.^6,22 This hypothesis is also supported by pioneering autopsy studies showing a topographic correlation between coronary microvascular obstruction and ischemic myocardial lesions in CCC patients,^23,24 Use of scintigraphy myocardial perfusion imaging makes a substantial contribution towards confirming the participation of microvascular disturbances in the pathogenesis of CCC.

Cardiac autonomic denervation is another remarkable feature of CCC and was first described in human autopsy studies.³² Although this finding is not specific for CCC, the intensity of the cardiac neuronal depopulation surpasses that seen in any other etiology of heart disease.^33,34 Striking depopulation of the parasympathetic neuronal bodies in the atrial tissue and of the sympathetic paravertebral ganglia has been reported by several independent investigators. As a consequence of these anatomical findings, several methods of investigation have been employed in previous studies and showed functional abnormalities of reflex autonomic control of the heart rate.⁶ Myocardial scintigraphy with ¹²³I-MIBG (MIBG) has been used in several stages of CCC to noninvasively assess myocardial sympathetic innervation and provide accurate information about the integrity of sympathetic nerve fibers and the degree of activation of cardiac sympathetic innervation.^19,35

Assessment of cardiac sympathetic innervation in patients with CCC using ¹²³I-MIBG scintigraphy was first described by Simões et al.¹² In that study, a series of 37 patients with several degrees of LV dysfunction underwent planar and SPECT ¹²³I-MIBG imaging and the results were correlated with myocardial perfusion scintigraphy and LV function assessments. It was observed that defects of MIBG uptake were seen in the majority of patients: in 33% of the patients without any other evidence of cardiac disease and 77% of the patients with regional LV wall motion disturbance. Furthermore, patients with more severe LV dysfunction had a higher prevalence of MIBG defects (92%). Notably, there was a topographic correlation between areas of myocardial sympathetic denervation and areas exhibiting fixed and reversible myocardial perfusion scintigraphy defects and abnormal segmental LV wall motion predominantly involving the inferior, posterior-lateral, and apical LV walls. These initial results indicated that sympathetic denervation is an early derangement in the pathophysiology of CCC, before development of regional LV contraction disturbance or global dysfunction (Figure 4).¹⁹ This hypothesis was corroborated by the results of an independent study showing abnormal MIBG uptake in most CCC patients with no other signs of cardiac involvement.³⁶

A more recent study employed image co-registration in 13 patients with CCC to investigate quantitative and topographic correlations between areas of cardiac sympathetic denervation using ¹²³I-MIBG-SPECT, myocardial hypoperfusion using ^99mTc-sestamibi-SPECT, and myocardial scarring using magnetic resonance imaging (MRI).³⁷ The results showed strong topographic agreement between areas of denervation and areas of stress-hypoperfused myocardium, corresponding to 60.8% of the denervated area. MRI showed that only 16.1% of the denervated area corresponded to areas of fibrosis.³⁷

Miranda et al.,³⁵ addressed the correlation between presence and extent of myocardial sympathetic denervation and occurrence of severe ventricular arrhythmia in CCC patients with normal or mildly reduced LVEF.³⁵ In this study, patients with sustained ventricular tachycardia had higher ¹²³I-MIBG summed defect scores than 11 patients without sustained ventricular tachycardia. These findings indicated a relevant role of myocardial sympathetic denervation as a trigger mechanism for malignant ventricular arrhythmia in CCC.³⁵

Another recent study was conducted with the objective of investigating the correlation between the extent of cardiac sympathetic denervation and occurrence of ventricular arrhythmia of varying severity in CCC patients. In that study, 15 CCC patients with sustained ventricular tachycardia had larger areas of viable but denervated myocardium, assessed by the summed difference defect scores between MIBG and ^99mTc-sestamibi SPECT images (20.0 ± 8.0), than 17 CCC patients with a less severe form of ventricular arrhythmia, i.e., non-sustained ventricular tachycardia, (11.0 ± 8.0, p < 0.05), and also had larger areas than CCC patients without any repetitive ventricular arrhythmia, according to Holter monitoring (2.0 ± 5.0, p < 0.0001).³⁸ It is important to emphasize that severe ventricular arrythmia can lead to sudden death in early phases of the disease, even in patients with preserved global left ventricular function,³⁹ and so a risk stratifying tool such as that provided by assessment of cardiac sympathetic denervation could be useful in this clinical scenario.

In summary, the available data reinforces the notion that the extent of myocardial sympathetic denervation is closely correlated with the incidence of malignant ventricular arrhythmia in CCC patients, and MIBG scintigraphy may be a potential tool for stratification of arrhythmic sudden cardiac death risk.

Positron emission tomography (PET) is a useful tool for in vivo investigation of myocardial metabolism.⁴⁰ The metabolic state of the myocardium can be evaluated by regional uptake of ¹⁸F-FDG, which is an analogue of glucose.⁴¹ Thus, regions with preserved uptake of ¹⁸F-FDG correspond to metabolically viable myocardium.

In experimental studies, a variety of strategies can be employed to improve ¹⁸F-FDG accumulation by cardiomyocytes, such as use of different anesthetic agents, such as isoflurane, enhancing detection of myocardial metabolic viability.⁴² In this scenario, Lemos de Oliveira, et al.³⁰ studied a model of chronic Chagas cardiomyopathy in hamsters using in vivo imaging methods including resting ^99mTc-sestamibi and ¹⁸F-FDG PET under isoflurane anesthesia, observing preserved or only mild reduction of ¹⁸F-FDG uptake in regions with severe myocardial prefusion defects at rest, showing the presence of myocardial viability in those regions (Figure 5). Moreover, histopathological analysis of fibrosis reinforced these findings, since no coalescent fibrosis was found.³⁰

To further improve understanding of the relationship between inflammation and progression of CCC in humans, it is essential to employ an imaging method able to detect and quantify myocardial inflammation in vivo. In this scenario, several studies have demonstrated the possibility of imaging myocardial inflammation using ¹⁸F-FDG-PET imaging under special metabolic myocardial conditions to suppress cardiomyocyte FDG uptake. Several strategies to suppress cardiomyocyte uptake of ¹⁸F-FDG in order to achieve a suitable metabolic state have been reported in clinical and experimental scenarios, including fasting protocols, heparin administration and, in small animals, use of anesthetic combinations such as ketamine and xylazine. Under such conditions, cardiac uptake of FDG is dependent on inflammatory cell infiltrate.^42,43

However, clinical use of PET imaging for evaluation of inflammation in CCC patients is still limited to a few case reports. The first report was published by Garg et al.⁴⁴ These authors described a CCC patient with dyspnea, acute chest pain, and troponin elevation, but normal coronary angiography. Echocardiography images showed a decrease in LV ejection fraction (35%) and apical and aneurysmal ballooning of the apex and of the basal inferolateral wall. PET imaging with ammonia (¹³NH₃) revealed MPD at the apex, basal inferior-lateral, and lateral walls. Additionally, PET imaging with ¹⁸F-FDG showed diffuse uptake throughout the myocardium. Notably, the most intense focal uptake was adjacent to the apical and basal inferior/inferolateral aneurysms that had severe ¹³NH₃ defects and prominent myocardial delayed enhancement on MRI.⁴⁴ Another clinical case with very similar characteristics was recently reported by Salimy and colleagues.⁴⁵

Shapiro and colleagues reported on two patients with CCC presenting arrhythmic storm with recurrent ventricular tachycardia (VT) and demonstrated higher uptake of ¹⁸F-FDG in myocardial regions from which the VT originated, suggesting on-going inflammation contributed to triggering VT.⁴⁶ More recently, Moll-Bernardes et al. published a case report of a CCC patient with episodes of sustained ventricular tachycardia and increased uptake of ¹⁸F-FDG on PET/CT adjacent to hypoperfused or fibrotic areas.⁴⁷

These initial observations therefore suggest a relationship between myocardial inflammation detected by in vivo FDG-PET imaging and the genesis of severe ventricular arrhythmias in CCC. This is consistent with the structural and functional changes described in myocardial inflammation due to other conditions, i.e., irreversible cell damage with scar formation generating reentrant arrhythmias and exacerbated automaticity within inflamed areas.⁴⁸

Although further studies with larger patient populations are needed, preliminary results suggest that detection of inflammation in vivo using ¹⁸F-FDG-PET is a promising tool for monitoring disease progression and even for risk stratification of patients with different degrees of CCC. Future research should therefore consider these potential new clinical applications of PET imaging.