Rapid quantification of myocardial fibrosis: a new macro-based automated analysis

Background: Fibrosis is associated with various cardiac pathologies and dysfunction. Current quantification methods are time-consuming and laborious. We describe a semi-automated quantification technique for myocardial fibrosis and validated this using traditional methods

Therapeutic efficacy of TBC3711 in monocrotaline-induced pulmonary hypertension

Background: Endothelin-1 signalling plays an important role in pathogenesis of pulmonary hypertension. Although different endothelin-A receptor antagonists are developed, a novel therapeutic option to cure the disease is still needed. This study aims to investigate the therapeutic efficacy of the selective endothelin-A receptor antagonist TBC3711 in monocrotaline-induced pulmonary hypertension in rats. Methods: Monocrotaline-injected male Sprague-Dawley rats were randomized and treated orally from day 21 to 35 either with TBC3711 (Dose: 30 mg/kg body weight/day) or placebo. Echocardiographic measurements of different hemodynamic and right-heart hypertrophy parameters were performed. After day 35, rats were sacrificed for invasive hemodynamic and right-heart hypertrophy measurements. Additionally, histologic assessment of pulmonary vascular and right-heart remodelling was performed. Results: The novel endothelin-A receptor antagonist TBC3711 significantly attenuated monocrotaline-induced pulmonary hypertension, as evident from improved hemodynamics and right-heart hypertrophy in comparison with placebo group. In addition, muscularization and medial wall thickness of distal pulmonary vessels were ameliorated. The histologic evaluation of the right ventricle showed a significant reduction in fibrosis and cardiomyocyte size, suggesting an improvement in right-heart remodelling. Conclusion: The results of this study suggest that the selective endothelin-A receptor antagonist TBC3711 demonstrates therapeutic benefit in rats with established pulmonary hypertension, thus representing a useful therapeutic approach for treatment of pulmonary hypertension

Assessment of inflammation in patients with arrhythmogenic right ventricular cardiomyopathy/dysplasia

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a myocardial disease that predominantly affects the right ventricle (RV). Its hallmark feature is fibro-fatty replacement of RV myocardium. However, patchy inflammatory infiltrates in the RV are also consistently reported using autopsy and myocardial biopsy. Although the role of inflammation in ARVC/D is unresolved, the ability to assess inflammation non-invasively may aid in the diagnostic process. We aimed to establish whether cardiac inflammation can be assessed non-invasively in ARVC/D patients. In eight ARVC/D patients and nine controls (haematology/oncology patients), the level of inflammatory activation was assessed by measuring plasma levels of inflammatory cytokines. Regional myocardial inflammation was assessed with Ga-67 scintigraphy. ARVC/D patients had higher plasma levels than controls of the pro-inflammatory cytokines interleukin (IL)-1 beta (1.22 +/- 0.07 vs 0.08 +/- 0.01 pg/ml, p < 0.0001), IL-6 (3.16 +/- 0.44 vs 0.38 +/- 0.04 pg/ml, p < 0.0001) and tumour necrosis factor (TNF)-alpha (9.16 +/- 0.90 vs 0.40 +/- 0.06 pg/ml, p < 0.0001), while levels of the anti-inflammatory cytokine IL-10 were not significantly different (1.36 +/- 0.15 vs 1.20 +/- 0.30 pg/ml, p = 0.74). Ga-67 uptake in the RV was higher in ARVC/D patients than in controls. In ARVC/D patients, Ga-67 uptake in the RV wall was higher than in the interventricular septum or left ventricular wall. Inflammation in the RV wall of ARVC/D patients can be detected non-invasively with the combined analysis of plasma levels of inflammatory cytokines and cardiac Ga-67 scintigraph

Sequence of echocardiographic changes during development of right ventricular failure in rat

BACKGROUND: The temporal relations between the onset of echocardiographic changes and clinical diagnosis of right ventricular (RV) failure are unresolved. We have characterized such relations in a rat monocrotaline (MCT) model of RV failure. METHODS: Eight-week-old male Wistar rats were injected with MCT (60 mg/kg) or vehicle and underwent serial echocardiography. RV free-wall thickness (RVWT), pulmonary artery acceleration time normalized to cycle length (PAAT/CL), RV end-diastolic diameter (RVEDD), and tricuspid annular plane systolic excursion (TAPSE) were measured. RESULTS: Significant differences in echocardiographic parameters between MCT-treated and control rats were found as early as 14 days before RV failure for RVWT, 10 days for PAAT/CL, and 7 days for RVEDD and TAPSE. The time intervals between the onset of changes in RVWT, PAAT/CL, RVEDD, and TAPSE and diagnosis of RV failure were 11.3 +/- 0.8, 10.9 +/- 0.7, 6.5 +/- 0.5, and 5.4 +/- 0.7 days, respectively. The sequence of echocardiographic changes was consistent in all animals during development of RV failure. CONCLUSIONS: Pulmonary hypertension (assessed by PAAT/CL) and RV free-wall thickening (characterized by RVWT) precede RV dilation and RV systolic dysfunction (measured by RVEDD and TAPSE, respectively). Echocardiographic analysis permits accurate determination of the stage of disease development in MCT-induced RV failur

Early inflammatory response during the development of right ventricular heart failure in a rat model

Inflammatory activation plays an important role in the pathogenesis and progression of left ventricular (LV) heart failure. In right ventricular (RV) heart failure, little is known about the role of inflammatory activation. We aimed to study the role of inflammatory activation in RV heart failure by serial monitoring during disease progression. Right ventricular heart failure was induced in male Wistar rats by intraperitoneal injection of monocrotaline (MCT). Two groups were studied: MCT-treated rats (MCT-rats), and age-matched controls (CON-rats). Serial echocardiography and in vivo 67-Gallium (Ga-67) scintigraphy were performed. Local inflammation in the RV was assessed by (i) ex vivo semi-quantitative Ga-67 autoradiography, (ii) immunohistochemistry of myeloperoxidase (MPO), a marker of neutrophil activity, and (iii) mRNA assays of tumour necrosis factor-alpha (TNF-alpha). In MCT-rats, Ga-67 scintigraphy showed increased myocardial uptake which started during the early stages of RV disease. Ga-67 autoradiography revealed that this increased Ga-67 uptake occurred in the RV and inter-ventricular septum, but not in the LV. The stage-dependent increases of in vivo Ga-67 RV myocardial uptake were paralleled by increases in mRNA gene expression for TNF-alpha in RV, and increased MPO staining in RV. Development and progression of RV heart failure is associated with an early increase in RV inflammation. Ga-67 scintigraphy may be used for the serial assessment of inflammation and monitoring of disease progression in RV heart failur