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- Molecular changes in cardiac tissue as a new marker to predict cardiac dysfunction induced by radiotherapyPublication . Ribeiro, Sónia; Simões, Ana Rita; Rocha, Filipe; Vala, Inês Sofia; Pinto, Ana Teresa; Ministro, Augusto; Poli, Maria Esmeralda; Diegues, Isabel Maria; Pina, Maria Filomena; Benadjaoud, Mohamed Amine; Flamant, Stephane; Tamarat, Radia; Osório, Hugo; Pais, Diogo; Casal, Diogo; Pinto, Fausto J.; Matthiesen, Rune; Fiuza, Manuela; Santos, Susana Constantino RosaThe contribution of radiotherapy, per se, to late cardiotoxicity remains controversial. To clarify its impact on the development of early cardiac dysfunction, we developed an experimental model in which the hearts of rats were exposed, in a fractionated plan, to clinically relevant doses of ionizing radiation for oncological patients that undergo thoracic radiotherapy. Rat hearts were exposed to daily doses of 0.04, 0.3, and 1.2 Gy for 23 days, achieving cumulative doses of 0.92, 6.9, and 27.6 Gy, respectively. We demonstrate that myocardial deformation, assessed by global longitudinal strain, was impaired (a relative percentage reduction of >15% from baseline) in a dose-dependent manner at 18 months. Moreover, by scanning electron microscopy, the microvascular density in the cardiac apex was significantly decreased exclusively at 27.6 Gy dosage. Before GLS impairment detection, several tools (qRT-PCR, mass spectrometry, and western blot) were used to assess molecular changes in the cardiac tissue. The number/expression of several genes, proteins, and KEGG pathways, related to inflammation, fibrosis, and cardiac muscle contraction, were differently expressed in the cardiac tissue according to the cumulative dose. Subclinical cardiac dysfunction occurs in a dose-dependent manner as detected by molecular changes in cardiac tissue, a predictor of the severity of global longitudinal strain impairment. Moreover, there was no dose threshold below which no myocardial deformation impairment was detected. Our findings i) contribute to developing new markers and exploring non-invasive magnetic resonance imaging to assess cardiac tissue changes as an early predictor of cardiac dysfunction; ii) should raise red flags, since there is no dose threshold below which no myocardial deformation impairment was detected and should be considered in radiation-based imaging and -guided therapeutic cardiac procedures; and iii) highlights the need for personalized clinical approaches.
- Low-dose ionizing radiation modulates the expression of proangiogenic genes in critical limb ischemia patients : preliminary resultsPublication . Ministro, Augusto; Pereira, Rita; Pinto, Vanda; Santos, Susana Constantino Rosa; Pedro, LuisObjective: Low-dose ionizing radiation (LDIR), namely, 0.3 Gy, delivered during 4 consecutive days, has been reported to stimulate angiogenesis and arteriogenesis in a preclinical model of hindlimb ischemia. Here we performed a single-center, investigator-blinded, randomized, shamcontrolled clinical trial to evaluate the effects of LDIR exposure in the expression of proangiogenic genes in endothelial cells isolated from muscles of patients with critical limb ischemia.
- Echocardiographic assessment of cardiac anatomy and function in adult ratsPublication . Ribeiro, Sónia; Pereira, Ana Rita S.; Pinto, Ana Teresa; Rocha, Filipe; Ministro, Augusto; Fiuza, Manuela; Pinto, Fausto J.; Santos, Susana Constantino RosaThe use of experimental animal models has become crucial in cardiovascular science. Most studies using rodent models are focused on two-dimensional imaging to study the cardiac anatomy of the left ventricle and M-mode echo to assess its dimensions. However, this could limit a comprehensive study. Herein, we describe a protocol that allows an assessment of the heart chamber size, left ventricular function (systolic and diastolic) and valvular function. A conventional medical ultrasound machine was used in this protocol and different echo views were obtained through left parasternal, apical and suprasternal windows. In the left parasternal window, the long and short axis were acquired to analyze left chamber dimensions, right ventricle and pulmonary artery dimensions, and mitral, pulmonary and aortic valve function. The apical window allows the measurement of heart chamber dimensions and evaluation of systolic and diastolic parameters. It also allows Doppler assessment with detection and quantification of heart valve disturbances (regurgitation or stenosis). Different segments and walls of the left ventricle are visualized throughout all views. Finally, the ascending aorta, aortic arch, and descending aorta can be imaged through the suprasternal window. A combination of ultrasound imaging, Doppler flow and tissue Doppler assessment have been obtained to study cardiac morphology and function. This represents an important contribution to improve the assessment of cardiac function in adult rats with impact for research using these animal models.
- Early impairment of paracrine and phenotypic features in resident cardiac mesenchymal stromal cells after thoracic radiotherapyPublication . Picchio, Vittorio; Gaetani, Roberto; Pagano, Francesca; Derevyanchuk, Yuriy; Pagliarosi, Olivia; Floris, Erica; Cozzolino, Claudia; Bernava, Giacomo; Bordin, Antonella; Rocha, Filipe; Pereira, Ana; Ministro, Augusto; Pinto, Ana; De Falco, Elena; Serino, Gianpaolo; Massai, Diana; Tamarat, Radia; Pesce, Maurizio; Santos, Susana Constantino Rosa; Messina, Elisa; Chimenti, IsottaRadiotherapy-induced cardiac toxicity and consequent diseases still represent potential severe late complications for many cancer survivors who undergo therapeutic thoracic irradiation. We aimed to assess the phenotypic and paracrine features of resident cardiac mesenchymal stromal cells (CMSCs) at early follow-up after the end of thoracic irradiation of the heart as an early sign and/or mechanism of cardiac toxicity anticipating late organ dysfunction. Resident CMSCs were isolated from a rat model of fractionated thoracic irradiation with accurate and clinically relevant heart dosimetry that developed delayed dose-dependent cardiac dysfunction after 1 year. Cells were isolated 6 and 12 weeks after the end of radiotherapy and fully characterized at the transcriptional, paracrine, and functional levels. CMSCs displayed several altered features in a dose- and time-dependent trend, with the most impaired characteristics observed in those exposed in situ to the highest radiation dose with time. In particular, altered features included impaired cell migration and 3D growth and a and significant association of transcriptomic data with GO terms related to altered cytokine and growth factor signaling. Indeed, the altered paracrine profile of CMSCs derived from the group at the highest dose at the 12-week follow-up gave significantly reduced angiogenic support to endothelial cells and polarized macrophages toward a pro-inflammatory profile. Data collected in a clinically relevant rat model of heart irradiation simulating thoracic radiotherapy suggest that early paracrine and transcriptional alterations of the cardiac stroma may represent a dose- and time-dependent biological substrate for the delayed cardiac dysfunction phenotype observed in vivo.