Impairment of sinus node autonomic control and myocardial perfusion disturbances have been described in patients with chronic Chagas' cardiomyopathy. However, it is not clear how these conditions contribute to myocardial damage. In this investigation, iodine-123 (I-123) meta-iodobenzylguanidine (MIBG) and thallium-201 myocardium segmental uptake were studied in correlation with the severity of left ventricular (LV) dysfunction detected in various phases of Chagas' heart disease. Group I consisted of 12 subjects (43 +/- 4 years, 7 men) with no symptoms and no cardiac involvement on electrocardiogram (ECG) or echocardiography; group II consisted of 13 patients (48 +/- 3 years, 9 men) with abnormal resting ECG and/or echocardiographic segmental abnormalities, and LV ejection fraction of > or = 0.5; group III was comprised of 12 patients (59 +/- 3 years, 10 men) with more severe heart disease, LV dilation, and LV ejection fraction of < 0.5. Eighteen control volunteers (38 +/- 3 years, 9 men) were also included in the study. I-123 MIBG single-photon emission computed tomographic (SPECT) segmental uptake defects were observed in group I (33%), group II (77%), and group III (92%). Quantitative analysis showed mean areas of reduced LV I-123-MIBG uptake: group I was 3.7 +/- 2.1%; group II was 8.3 +/- 2.3%; and group III was 19.0 +/- 3.3%. The differences between group I and both groups II and III were statistically significant (p < 0.001, analysis of variance test). Myocardial perfusion defects (reversible, fixed, and paradox) were observed in group I (83%), group II (69%), and group III (83%). A marked topographic association between perfusion, innervation, and wall motion abnormalities (assessed by gated-SPECT perfusion studies) was observed in all the groups. Defects predominated in the inferior, posterior lateral, and apical LV regions. Thus, extensive impairment of cardiac sympathetic function at the ventricular level occured early in the course of Chagas' cardiomyopathy and was related to regional myocardial perfusion disturbances, before wall motion abnormalities. Both conditions are associated with progression of ventricular dysfunction.