RESUMO
BACKGROUND: Myocardial perfusion defect (MPD) is common in chronic Chagas cardiomyopathy (CCC) and is associated with inflammation and development of left ventricular systolic dysfunction. We tested the hypothesis that pentoxifylline (PTX) could reduce inflammation and prevent the development of MPD in a model of CCC in hamsters. METHODS AND RESULTS: We investigated with echocardiogram and rest myocardial perfusion scintigraphy at baseline (6-months after T. cruzi infection/saline) and post-treatment (after additional 2-months of PTX/saline administration), female Syrian hamsters assigned to 3 groups: T. cruzi-infected animals treated with PTX (CH + PTX) or saline (CH + SLN); and uninfected control animals (CO). At the baseline, all groups showed similar left ventricular ejection fraction (LVEF) and MPD areas. At post-treatment evaluation, there was a significant increase of MPD in CH + SLN group (0.8 ± 1.6 to 9.4 ± 9.7%), but not in CH + PTX (1.9 ± 3.0% to 2.7 ± 2.7%) that exhibited MPD area similar to CO (0.0 ± 0.0% to 0.0 ± 0.0%). The LVEF decreased in both infected groups. Histological analysis showed a reduced inflammatory infiltrate in CH + PTX group (395.7 ± 88.3 cell/mm2), as compared to CH + SLN (515.1 ± 133.0 cell/mm2), but larger than CO (193.0 ± 25.7 cell/mm2). The fibrosis and TNF-α expression was higher in both infected groups. CONCLUSIONS: The prolonged use of PTX is associated with positive effects, including prevention of MPD development and reduction of inflammation in the chronic hamster model of CCC.
Assuntos
Cardiomiopatia Chagásica , Doença de Chagas , Pentoxifilina , Cricetinae , Animais , Feminino , Cardiomiopatia Chagásica/diagnóstico por imagem , Pentoxifilina/farmacologia , Pentoxifilina/uso terapêutico , Volume Sistólico , Função Ventricular Esquerda , Tomografia Computadorizada por Raios X , Inflamação , PerfusãoRESUMO
INTRODUCTION: Myocardial ischemia is common in patients with chronic Chagas cardiomyopathy (CCC), but only recently clinical and experimental studies highlighted the involvement of this abnormality as contributing to the progression of myocardial damage. AREAS COVERED: Despite the absence of obstructive epicardial coronary artery disease at angiography, and limited evidence of abnormal flow regulation at the macrovascular level, remarkable functional and structural microvascular abnormalities are consistently reported by independent investigations of CCC. These derangements occur early and contribute to myocardial dysfunction. Recent research focused on reversing microvascular dysfunction as a target to positively impact the course of CCC. We conducted an extensive review of the scientific literature, aiming to summarize the role of coronary dysfunction causing myocardial ischemia in CCC, with a focus on implications for clinical management of individuals affected by this disease. EXPERT OPINION: Preclinical studies showed a clear correlation between perfusion defects and inflammation in viable but impaired dysfunctional myocardium. These findings provided further insight into the CCC complex pathophysiology and support the role of very few recent therapeutic interventions aiming to relieve myocardial ischemia. Further research is warranted to assess the efficacy of new interventions addressing reversal of microvascular ischemia and inflammation modulation and halting ventricular dysfunction progression in CCC.
Assuntos
Cardiomiopatias , Cardiomiopatia Chagásica , Doença de Chagas , Doença da Artéria Coronariana , Isquemia Miocárdica , Humanos , Isquemia Miocárdica/etiologia , Doença de Chagas/complicações , Inflamação , Vasos CoronáriosRESUMO
Chagas disease (CD) has been changing from an endemic Latino-American disease to a condition found outside endemic regions, due to migratory movements. Although often subclinical, its acute phase can be lethal. This study aimed to assess survival during the acute phase of CD and its relationship with ventricular function in an experimental model. To this end, 30 Syrian hamsters were inoculated with Trypanosoma cruzi (IG) and other 15 animals received saline solution (CG). Groups were monitored daily and submitted to echocardiography in two moments: before the challenge and 15 days post-infection. Left ventricular ejection fraction (LVEF) and global longitudinal myocardial strain (GLS) of the LV were measured. The IG was divided into groups of animals with and without clinical signs of disease. ANOVA for mixed models was used to compare ventricular function parameters. Survival analysis was studied using Kaplan-Meier curves and the log-rank test. The follow-up lasted 60 days. LVEF in IG was reduced through time (53.80 to 43.55%) compared to CG (57.86 to 59.73%) (p=0.002). There was also a reduction of GLS (-18.97% to -12.44%) in the IG compared to CG (p=0.012). Twelve animals from IG died compared to one animal from CG. Eleven out of the 12 animals from the IG group died before presenting with clinical signs of infection. Survival was reduced in the IG compared to CG over time (p=0.02). The reduced survival during the acute phase of this experimental model of Chagas disease was related to the significant reduction of LV function. The mortality rate in the IG was higher in the group presenting with clinical signs of infection.
Assuntos
Doença de Chagas , Disfunção Ventricular Esquerda , Animais , Cricetinae , Modelos Animais , Estudos Prospectivos , Volume Sistólico , Função Ventricular EsquerdaRESUMO
Abstract Several different imaging methods can be used to evaluate patients with Chagas heart disease (CHD) for diagnostic and prognostic purposes, including plain chest radiography; echocardiography; myocardial perfusion scintigraphy, for detection of ischemia and fibrosis; radionuclide gated-angiography, for evaluation of biventricular function; 123I-MIBG labeling of sympathetic myocardial innervation; MRI, for detection and quantitation of myocardial fibrosis; and coronary angiography. This study aims to review the contributions of these nuclear medicine methods to understanding of the pathophysiology of chronic Chagas cardiomyopathy (CCC). Careful analysis and integration of findings provided by these imaging methods in patients with CCC at different stages has contributed significantly to improving understanding of several peculiarities of the disease. Clinical and experimental studies in animal models show that perfusion abnormalities detected in association with dysfunctional but viable myocardium are a common finding in CCC patients and correspond to areas of cardiac sympathetic denervation, as assessed by 123I-MIBG imaging. Furthermore, recent reports have demonstrated a close relationship between coronary microvascular disturbances and myocardial inflammation. Thus, ongoing research, mainly focused on refinements of 18F-FDF -PET techniques and further exploration of nuclear methods, such as SPECT, have the potential to contribute to detection and monitoring of early subclinical myocardial damage thereby enabling evaluation of therapeutic strategies targeting inflammation and microvascular ischemia that could result in better prognostic stratification of patients with CHD.
Assuntos
Ventriculografia com Radionuclídeos , Tomografia Computadorizada de Emissão de Fóton Único , Cardiomiopatia Chagásica/diagnóstico por imagem , Imagem de Perfusão do Miocárdio , Prognóstico , Ecocardiografia , Espectroscopia de Ressonância Magnética , Radiografia , Cardiomiopatia Chagásica/fisiopatologia , Angiografia Coronária , Microvasos/patologiaRESUMO
BACKGROUND AND AIMS: Iron deficiency (ID) is a common comorbidity in patients with chronic heart failure (HF) and is associated with worse prognosis. We aimed at comparing the currently European Society of Cardiology (ESC) criterion for diagnosis of ID (ferritin < 100 µg/L or ferritin 100-299 µg/L with transferrin saturation [TSAT] < 20%) with either isolated low TSAT or isolated low ferritin on survival, in a cohort of HF patients. METHODS: This was an observational prospective study, investigating ambulatory patients with HF and reduced ejection fraction (n = 108). All patients were assessed for clinical aspects and iron indexes. The primary endpoint was all-cause death. RESULTS: Abnormal iron status was observed in 50 (46%) of patients. During the median follow-up time of 857.5 [647-899] days, 31 patients died (29%). In univariate analyses ESC-criterion (p = 0.022) and isolated TSAT <20% (p = 0.002), but not isolated ferritin <100 µg/L (p = 0.439), were significantly related to an increased risk of all-cause death. However, in multivariate analyses only TSAT <20% (HR = 2.3; [95% CI: 1.11-4.85]; p = 0.026) was independently related to all-cause mortality. CONCLUSIONS: Our results indicated that diagnosis of ID based on isolated TSAT <20% identifies HF patients with worse prognosis, while ferritin was not associated with mortality risk, suggesting that ferritin should not be taken into account for evaluation of clinical impact of ID in HF patients.
Assuntos
Anemia Ferropriva , Insuficiência Cardíaca , Anemia Ferropriva/diagnóstico , Ferritinas , Insuficiência Cardíaca/complicações , Insuficiência Cardíaca/diagnóstico , Humanos , Ferro , Estudos ProspectivosRESUMO
BACKGROUND: We tested the hypothesis that a normal sodium diet could be associated with preservation of serum sodium during treatment of acute decompensated heart failure (ADHF). METHODS AND RESULTS: Forty-four patients hospitalized for ADHF were blindly randomized by using block method to a low sodium diet (LS: 3 g/day of dietary sodium chloride; n = 22, 59.5 ± 11.9 y.o., 50% males. LVEF = 30.0 ± 13.6%); and a normal sodium diet (NS: 7 g/day; n = 22, 56.4 ± 10.3 y.o., 68% males; LVEF = 27.8 ± 11.7%), and both groups were submitted to fluid restriction of 1.000 mL/day. At the 7th day of intervention 16 patients of LS group and 15 patients of NS group were assessed for difference in serum sodium. Both groups had equivalent decongestion, reflected by similar percent reduction of body weight (LS: -5.0 ± 4.7% vs NS: -4.5 ± 5.2%. p = 0.41). Reduction of the N terminal fragment of type B natriuretic peptide (NT-proBNP) was significant only in the NS (-1497.0 [-18843.0 - 1191.0]. p = 0.04). The LS group showed lower levels of serum sodium (135.4 ± 3.5 mmol/L) compared to the NS group (137.5 ± 1.9 mmol/L; p = 0.04). Four cases of hyponatremia were observed only in the LS group (22%). The NS group exhibited higher mean blood pressure values (79.4 ± 2.4 mmHg vs 75.5 ± 3.0 mmHg. p = 0.03), and lower heart rate (73.2 ± 1.6 bpm vs 75.5 ± 2.1 bpm. p = 0.02). CONCLUSIONS: These results suggest that a normal sodium diet, when compared to a low sodium diet, is associated with similar degrees of decongestion, but with higher levels of natremia, blood pressure and lower neurohormonal activation during ADHF treatment. TRIAL REGISTRATION: clinicaltrials.gov Identifier no. NCT03722069.
Assuntos
Dieta Hipossódica , Insuficiência Cardíaca/terapia , Sódio/sangue , Método Duplo-Cego , Feminino , Insuficiência Cardíaca/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Resultado do TratamentoRESUMO
BACKGROUND: Myocardial perfusion defects (MPD) due to coronary microvascular dysfunction is frequent in chronic Chagas cardiomyopathy (CCC) and may be involved with development of myocardial damage. We investigated whether MPD precedes left ventricular systolic dysfunction and tested the hypothesis that prolonged use of dipyridamole (DIPY) could reduce MPD in an experimental model of CCC in hamsters. METHODS AND RESULTS: We investigated female hamsters 6-months after T. cruzi infection (baseline condition) and control animals, divided into T. cruzi-infected animals treated with DIPY (CH + DIPY) or placebo (CH + PLB); and uninfected animals treated with DIPY (CO + DIPY) or placebo (CO + PLB). The animals were submitted to echocardiogram and rest SPECT-Sestamibi-Tc99m myocardial perfusion scintigraphy. Next, the animals were treated with DIPY (4 mg/kg bid, intraperitoneal) or saline for 30 days, and reevaluated with the same imaging methods. At baseline, the CH + PLB and CH + DIPY groups showed larger areas of perfusion defect (13.2 ± 13.2% and 17.3 ± 13.2%, respectively) compared with CO + PLB and CO + DIPY (3.8 ± 2.2% e 3.5 ± 2.7%, respectively), P < .05. After treatment, we observed: reduction of perfusion defects only in the CH + DIPY group (17.3 ± 13.2% to 6.8 ± 7.6%, P = .001) and reduction of LVEF in CH + DIPY and CH + PLB groups (from 65.3 ± 9.0% to 53.6 ± 6.9% and from 69.3 ± 5.0% to 54.4 ± 8.6%, respectively, P < .001). Quantitative histology revealed greater extents of inflammation and interstitial fibrosis in both Chagas groups, compared with control group (P < .001), but no difference between Chagas groups (P > .05). CONCLUSIONS: The prolonged use of DIPY in this experimental model of CCC has reduced the rest myocardial perfusion defects, supporting the notion that those areas correspond to viable hypoperfused myocardium.
Assuntos
Cardiomiopatia Chagásica/diagnóstico por imagem , Cardiomiopatia Chagásica/tratamento farmacológico , Dipiridamol/administração & dosagem , Coração/diagnóstico por imagem , Animais , Cricetinae , Modelos Animais de Doenças , Ecocardiografia , Feminino , Ventrículos do Coração/diagnóstico por imagem , Imagem de Perfusão do Miocárdio , Perfusão , Tecnécio Tc 99m Sestamibi , Tomografia Computadorizada de Emissão de Fóton Único , Tomografia Computadorizada por Raios X , Trypanosoma cruzi , Vasodilatadores/administração & dosagemRESUMO
Altered myocardial perfusion is a common finding in chronic Chagas cardiomyopathy (CCC), but its underlying histologic changes have not been elucidated. We investigated the occurrence of myocardial perfusion defects (MPDs) and the correlated regional changes to histology in an experimental model of CCC in hamsters. Methods: Female Syrian hamsters (n = 34) were infected with 3.5 × 104 to 105 trypomastigote forms of Trypanosoma cruzi, Y strain, and 6-10 mo afterward underwent in vivo imaging including resting 99mTc-sestamibi SPECT, segmental and global left ventricular function assessment using 2-dimensional echocardiography, and 18F-FDG PET for evaluation of myocardial viability. Histologic analysis included quantification of fibrosis, inflammatory infiltration, and the diameter and density of myocardial microcirculation. Results: MPDs were present in 17 (50%) of the infected animals. Histologic analysis revealed no transmural scar in segments with an MPD, and normal or mildly reduced 18F-FDG uptake, indicating viable myocardium. Infected animals with an MPD, in comparison to infected animals without an MPD and control animals, showed a lower left ventricular ejection fraction (P = 0.012), a higher wall motion score index (P = 0.004), and a higher extent of inflammatory infiltration (P = 0.018) but a similar extent of fibrosis (P = 0.15) and similar microvascular diameter and density (P > 0.05). Segments with an MPD (n = 65), as compared with normally perfused regions in the same animal (n = 156), showed a higher wall motion score index (P = 0.005) but a similar extent of inflammatory infiltration, a similar extent of fibrosis, and a similar microvascular diameter and density. Conclusion: Resting MPDs are frequent in experimental CCC and are associated with myocardial inflammation but do not designate scar tissue, corresponding to regions with metabolically viable myocardium.
Assuntos
Cardiomiopatia Chagásica/fisiopatologia , Circulação Coronária , Animais , Cardiomiopatia Chagásica/diagnóstico por imagem , Cardiomiopatia Chagásica/patologia , Doença Crônica , Cricetinae , Modelos Animais de Doenças , Feminino , Fluordesoxiglucose F18 , Microvasos/diagnóstico por imagem , Microvasos/fisiopatologia , Imagem de Perfusão do Miocárdio , Miocárdio/patologia , Tomografia por Emissão de Pósitrons , Sístole/fisiologia , Sobrevivência de Tecidos , Disfunção Ventricular Esquerda/fisiopatologiaRESUMO
Apesar de a doença de Chagas ter sido intensamente estudada ao longo de mais de um século desde sua descoberta, existem lacunas de conhecimento com relação aos mecanismos fisiopatogênicos que levam ao desenvolvimento tardio da cardiomiopatia chagásica crônica. Um aspecto intrigante da doença é a complexa interação entre o hospedeiro e o parasita e suas repercussões. A ocorrência de documentada inflamação tecidual, presente mais intensamente na fase aguda, mas persistente em baixa intensidade também na fase crônica, pode ser consequência do tropismo cardíaco do parasita ou de alterações autoimunes. Nesta revisão, nós abordaremos as evidências do papel patológico da persistência do parasita e da autoimunidade na patogênese da doença de Chagas
Although Chagas disease has been studied intensely for more than a century since it was first discovered, there are gaps in the knowledge of the physiopathogenic mechanism that lead to the late development of chronic chagasic cardiomyopathy. An intriguing aspect of the disease is the complex interaction between the host and the parasite and its repercussions. The occurrence of documented tissue inflammation, which is more intensely present in the acute phase but also persists with lower intensity in the chronic phase, may be a consequence of cardiac tropism of the parasite or of autoimmune changes. In this review, we address the evidence of the pathological role of persistence of the parasite and autoimmunity in the pathogenesis of Chagas disease