Marcus Vinicius Simões

Pathogenesis of Chronic Chagas Heart Disease

Background— Chagas disease remains a significant public health issue and a major cause of morbidity and mortality in Latin America. Despite nearly 1 century of research, the pathogenesis of chronic Chagas cardiomyopathy is incompletely understood, the most intriguing challenge of which is the complex host-parasite interaction. Methods and Results— A systematic review of the literature found in MEDLINE, EMBASE, BIREME, LILACS, and SCIELO was performed to search for relevant references on pathogenesis and pathophysiology of Chagas disease. Evidence from studies in animal models and in anima nobile points to 4 main pathogenetic mechanisms to explain the development of chronic Chagas heart disease: autonomic nervous system derangements, microvascular disturbances, parasite-dependent myocardial aggression, and immune-mediated myocardial injury. Despite its prominent peculiarities, the role of autonomic derangements and microcirculatory disturbances is probably ancillary among causes of chronic myocardial damage. The pathogenesis of chronic Chagas heart disease is dependent on a low-grade but incessant systemic infection with documented immune-adverse reaction. Parasite persistence and immunological mechanisms are inextricably related in the myocardial aggression in the chronic phase of Chagas heart disease. Conclusions— Most clinical studies have been performed in very small number of patients. Future research should explore the clinical potential implications and therapeutic opportunities of these 2 fundamental underlying pathogenetic mechanisms.

Noninvasive Imaging of Transgene Expression by Use of Positron Emission Tomography in a Pig Model of Myocardial Gene Transfer

Background—Radionuclide imaging of reporter gene expression may be useful for noninvasive monitoring of clinical cardiac gene therapy. Experience until now, however, has been limited to small animals. Methods and Results—To evaluate feasibility in a clinically applicable setting, pigs were studied by conventional positron emission tomography (PET) 2 days after regional intramyocardial injection of control adenovirus or adenovirus carrying herpesviral thymidine kinase reporter gene (HSV1-tk). Myocardial blood flow was quantified by use of [13N]ammonia. Subsequently, kinetics of the reporter substrate [124I]-2′-fluoro-2′-deoxy-5-iodo-1-&bgr;-d-arabino-furanosyluracil (FIAU) were assessed over a period of 2 hours. Areas infected with adenovirus expressing HSV1-tk showed significantly elevated FIAU retention during the first 30 minutes after injection. At later times, washout was observed, and retention was not different from that in areas infected with control virus or remote myocardium. Early in vivo FIAU uptake correlated with ex vivo images, autoradiography, and immunohistochemistry for reporter gene product after euthanasia. After intramyocardial injection of both adenoviruses, myocardial blood flow was mildly elevated compared with that in remote areas, consistent with histological signs of regional inflammation. Conclusions—In vivo quantification of regional myocardial transgene expression is feasible with clinical PET methodology, the radioiodinated reporter probe FIAU, and the HSV1-tk reporter gene. Radioactivity efflux after specific initial uptake was not observed previously in tumor studies, suggesting that tissue-specific differences in nucleoside metabolism influence reporter probe kinetics. By coregistering reporter gene expression with additional biological parameters such as myocardial blood flow, PET allows for noninvasive characterization of the success of cardiac gene transfer along with its functional correlates.

Sustained Ventricular Tachycardia Is Associated with Regional Myocardial Sympathetic Denervation Assessed with 123I-Metaiodobenzylguanidine in Chronic Chagas Cardiomyopathy

Cardiac sympathetic denervation and ventricular arrhythmia are frequently observed in chronic Chagas cardiomyopathy (CCC). This study quantitatively evaluated the association between cardiac sympathetic denervation and sustained ventricular tachycardia (SVT) in patients with CCC. Methods: We prospectively investigated patients with CCC and left ventricular ejection fraction (LVEF) greater than 35% with SVT (SVT group: n = 15; mean age ± SD, 61 ± 8 y; LVEF, 51% ± 8%) and patients without SVT (non-SVT group: n = 11; mean age ± SD, 55 ± 10 y; LVEF, 57% ± 10%). Patients underwent myocardial scintigraphy with 123I-metaiodobenzylguanidine (123I-MIBG) for the evaluation of sympathetic innervation and resting perfusion with 99mTc-methoxyisobutylisonitrile (99mTc-MIBI) for the evaluation of myocardial viability. A visual semiquantitative score was attributed for regional uptake of each radiotracer using a 17-segment left ventricular segmentation model (0, normal; 4, absence of uptake). A mismatch defect was defined as occurring in segments with a 99mTc-MIBI uptake score of 0 or 1 and a 123I-MIBG score of 2 or more. Results: Compared with the non-SVT group, the SVT group had a similar 99mTc-MIBI summed score (6.9 ± 7.5 vs. 4.4 ± 5.2, respectively, P = 0.69) but a higher 123I-MIBG summed score (10.9 ± 7.8 vs. 22.4 ± 9.5, respectively, P = 0.007) and a higher number of mismatch defects per patient (2.0 ± 2.2 vs. 7.1 ± 2.0, respectively, P < 0.0001). The presence of more than 3 mismatch defects was strongly associated with the presence of SVT (93% sensitivity, 82% specificity; P = 0.0002). Conclusion: In CCC, the amount of sympathetically denervated viable myocardium is associated with the occurrence of SVT. Myocardial sympathetic denervation may participate in triggering malignant ventricular arrhythmia in CCC patients with relatively well-preserved ventricular function.

Nuclear Cardiology Core Laboratory: State of the Art

Considering the low mortality rate related to cardiovascular diseases achieved by the currently available therapeutic options, proving the superiority of a new drug/intervention over standard treatment using mortality as the end point requires the inclusion of several thousands of patients in a prospective randomized clinical trial. The high costs involved in such trials represent a severe limitation for the development of new therapeutic strategies. At the same time, however, there is increasing acceptance that cardiac functional parameters, changes in which are directly related to the beneficial effect of an intervention, can be used as surrogate end points in small-sample size pilot-phase studies. This study design has been shown to be advantageous not only regarding cost-saving aspects but also for providing objective evaluation of the beneficial effect of a new treatment. In addition, the design helps in establishing the number of patients to be included in the definitive trial as well as determining the best dosage to be used. This review describes the available information supporting the use of nuclear cardiology imaging to reliably assess multiple cardiac function parameters constituting adequate surrogate end points for the assessment of therapeutic effects in several cardiovascular diseases. In addition, the technical aspects, feasibility and clear advantages of the use of nuclear cardiology core laboratories for centralized imaging processing/analysis in the context of multicenter clinical trials are also presented.

Tônus e diâmetro arterial coronário não se correlacionam com o grau de denervação autonômica em pacientes com cardiopatia chagásica crônica

BACKGROUND: Chronic Chagas Cardiomyopathy (CCC) induces early severe cardiac dysautonomia, potentially causing derangements in the regulation of coronary vasomotion and leading to myocardial ischemia and fibrosis. We assessed the correlation between dysautonomia severity and coronary artery diameter and tonus. METHODS: Eighteen patients with CCC (55±9 yrs, 8 males) and 23 normal volunteers (37±11 yrs, 16 males) were investigated. Both groups underwent evaluation of baroreflex sensitivity (BRS) by means of invasive arterial pressure (AP) monitoring and transient increases of AP induced by intravenous phenilephrinefrin injections (50-150µg). Patients with CCC had cardiac catheterization and coronary angiography at baseline and 5 min. after administration of 5mg of isosorbidedinitrate (ISDN). Quantitative coronary analysis was performed off-line for both conditions (baseline and post-ISDN). Baseline coronary artery tonus was calculated by the percent diameter increase after ISDN. LVEF was calculated by Dodge biplane method from contrast ventriculography and 2D-echocardiogram was used for the measurement of LV diastolic diameter and mass. RESULTS: CCC patients showed severe reduction of the BRS (4.1 ± 1.7 ms/mmHg) as compared to controls (15.0 ± 1.5 ms/mmHg), p < 0.001. Mean coronary artery diameter was 2.2 ± 0.3 mm, and was significantly correlated with parameters of LV remodeling: LEFF (p = 0.017, R = 0.554), LVDD (p = 0.0036, R = 0.648) and LV mass (p = 0.022, R = 0.534). No significant correlation occurred between coronary diameter and the BRS (p = 0.457, R = 0.187). Baseline coronary tonus was 13 ± 17%, without correlation with any variables, including coronary diameter (p = 0.386, R = 0.218) and BRS (p = 0.822, R = 0.057). CONCLUSIONS: Cardiac parasympathetic impairment does not seem to determine coronary artery diameter and tonus in patients with CCC.