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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.
- Hybrid surgery in lower limb revascularization : a real-world experience from a single centerPublication . Soares, Tony; Manuel, Viviana; Amorim, Pedro; Martins, Carlos; Melo, Ryan; Ministro, Augusto; Sobrinho, Gonçalo; Silvestre, Luís; Fernandes E Fernandes, Ruy; Pedro, Luís MBackground Through the association of endovascular and open procedures, hybrid surgery for lower limb revascularization allows the treatment of multilevel occlusive disease with a lower risk when compared to extensive open interventions. The aim of this study is to evaluate the immediate and midterm clinical outcomes of hybrid techniques for lower limb revascularization in a cohort of patients with multilevel arterial disease. Methods Data from elective procedures between 2012 and 2017 were retrospectively collected regarding hybrid lower limb revascularization procedures. The outcomes of the study were categorical clinical improvement, patency rates, major amputation rates, and mortality. Results A total of 81 patients, 89 limbs, with a median age of 69 years (interquartile range [IQR] 61–73) were submitted to hybrid lower limb revascularization, with a median follow-up of 10.7 months (IQR 2.5–25.1). Treatment indications were chronic limb-threatening ischemia in 80.9% of the cases (rest pain in 18.0% and tissue loss in 62.9%). One-year primary, primary-assisted, and secondary patency rates were 78.28% (95% confidence interval [CI] 65.20–86.92), 85.12% (95% CI 72.96–92.09), and 90.19% (95% CI 79.13–95.54), respectively. Overall categorical clinical improvement was observed in 56.2%. Major amputation and mortality rates were 14.6% and 16.0%, respectively. Multilevel Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC) C or D and stage IV Leriche-Fontaine classification were strongly associated with decreased categorical clinical improvement (adjusted odds ratio [aOR] 0.08, P < 0.0001 and aOR 0.25, P = 0.013, respectively). Multilevel TASC C or D was also related to higher amputation rates, contrary to clinical presentation (adjusted hazard ratio [aHR] 11.37, P = 0.002 and aHR 4.70, P = 0.091, respectively). Primary-assisted and secondary patency rates were associated with higher categorical clinical improvement (aOR 4.30, P = 0.036 and aOR 7.36, P = 0.021, respectively) and decreased major amputation rates (aHR 0.11, P = 0.003 and aHR 0.09, P = 0.001, respectively) but were not related to multilevel TASC and Leriche-Fontaine classifications. Conclusions The present study reports a real-world experience with a large proportion of patients with chronic limb-threatening ischemia. Hybrid interventions for lower limb revascularization revealed to be a potential approach for patients with complex arterial disease that would beneficiate from less invasive procedures.
- 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.
- A catastrophic seronegative anti-phospholipid syndrome: case and literature reviewPublication . Pinto, Vanda; Ministro, Augusto; Carreira, Nuno; Cardoso, Ana; Gonçalves, Catarina Sousa; Henriques, Mickael; Rato, João; Silva, Emanuel; Pedro, Luís MBackground: Antiphospholipid Syndrome (APS) is a multisystemic autoimmune disease characterized by arterial and venous thrombosis and / or obstetric morbidity in the presence of at least one circulating anti-phospholipid antibody. The spectrum of vascular events varies from deep venous thrombosis to catastrophic APS, a rare form characterized by acute multiorgan thrombosis and high mortality. Case report: We present the case of a 32-week pregnant woman arriving in the hospital emergency room with bilateral acute lower limb ischemia. In the obstetric evaluation, fetal death was declared. Computerized Tomography angiography showed pulmonary embolism of both pulmonary arteries, areas of splenic and right renal infarction and multiple arterial and venous thrombosis. The patient underwent urgent caesarean section and axillary-bifemoral bypass. No events registered. In the postoperative period, in an intensive care unit, treatment with rituximab and plasmapheresis were added to anticoagulant therapy. The laboratorial investigation was negative for thrombophilia and autoimmune diseases. Conclusion: Catastrophic APS develops quickly, with multiorgan involvement and high mortality rate. The presented case poses a multidisciplinary challenge, with the surgical approach of extra-anatomical revascularization being less invasive and guaranteeing immediate perfusion of the lower limbs. Although the serological tests were negative for anti-phospholipid antibodies, this case hardly fits into another diagnosis. Therefore, it was treated as a catastrophic APS, having shown a favorable evolution.
- Clinical aspects and present challenges of the seat belt aortaPublication . Melo, Ryan; Amorim, Pedro; Soares, Tony; Fernandes E Fernandes, Ruy; Ministro, Augusto; Garrido, Pedro; Fernandes e Fernandes, José; Pedro, Luís MObjective: Seat belt aorta is rare and difficult to manage. The lack of data and follow-up increases the complexity of treating such patients. We aimed to create a decision algorithm by reviewing our current experience and analyzing the presentation and management of our patients. Methods: We performed a descriptive case series based on retrospective analysis of all consecutive patients admitted with the diagnosis of seat belt aorta from 2008 to 2018. Seat belt aorta was defined as any blunt abdominal aortic lesion resulting from a seat belt compression mechanism after a car accident. Results: Nine consecutive patients were admitted with the diagnosis of seat belt aorta, all of whom developed lesions in the infrarenal aorta. Eight patients were assessed in the acute phase and one patient presented with late-onset symptoms. Associated injuries were present in all acute patients, and seat belt sign and small bowel injury were present in 88%. One patient presented with a small intimal tear and was treated conservatively. All other patients diagnosed with large intimal flaps (seven patients) and pseudoaneurysm (one patient) underwent open repair in five cases and endovascular repair in three cases. In-hospital mortality for the acute cases was 38%, with no mortality seen during follow-up. Two patients submitted to endovascular repair required reinterventions. Conclusions: Seat belt aorta is a deadly condition, frequently associated with blunt thoracoabdominal trauma with concomitant injuries; the presence of a seat belt sign or lower limb ischemia must lead to a high diagnostic suspicion. Management must take into account the other concomitant injuries. Follow-up is crucial as most patients are young; they may develop complications and subsequently require further intervention.
- 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.
- Clinical outcomes of aortic arch hybrid repair in a real-world single-center experiencePublication . Soares, Tony; Melo, Ryan; Amorim, Pedro; Ministro, Augusto; Sobrinho, Gonçalo; Silvestre, Luís; Fernandes E Fernandes, Ruy; Martins, Carlos; Fernandes e Fernandes, José; Pedro, Luís MObjective: Aortic arch aneurysmal disease remains a therapeutic challenge. For patients unsuitable for standard open surgery, hybrid repair with debranching of the supra-aortic arteries followed by thoracic endovascular grafting has been shown to be an effective solution. The aim of this study was to report the clinical outcomes of a single-institution experience using hybrid aortic arch repair. Methods: The cases of all consecutive patients submitted to hybrid aortic arch repair between January 2010 and June 2018 were prospectively collected and retrospectively analyzed. The outcomes of the study were 30-day mortality, perioperative complications, 2-year survival, endoleak, and reintervention rates. Results: A total of 35 patients with a median age of 71 years (interquartile range, 62-77 years) were submitted to hybrid aortic arch repair, with a median follow-up of 26.9 months (interquartile range, 2.4-63.6 months). Ten procedures (28.6%) were performed urgently for contained rupture. The most common etiology was degenerative (n ¼ 14 [40.0%]). The proximal landing zones according to the Ishimaru classification were zone 2 in 20 patients (57.1%), zone 1 in 12 patients (34.3%), and zone 0 in 3 patients (8.6%). Early endoleaks were observed in six patients (17.1%), equally distributed between type I and type II. Late endoleaks were identified in 4 of 24 patients (16.7%; type I, n ¼ 2 [8.3%]; type II, n ¼ 1 [4.2%]; and type III, n ¼ 1 [4.2%]). Thirty-day mortality rate was 14.3% (n ¼ 5) with an early death rate of 8.7% (2/23) in elective cases and 30.0% (3/10) in urgent cases (odds ratio [OR], 4.93; confidence interval [CI], 0.68-35.67; P ¼ .128). Except in one patient, 30-day mortality was associated with landing zone 0 or zone 1 (26.7% vs 5.0%; OR, 6.91; CI, 0.68-69.86; P ¼ .141). Three patients (8.6%) suffered a postoperative stroke, and no episodes of spinal cord ischemia were observed. Two-year survival rate was 67.8% (CI, 49.4%- 80.8%). Survival rates were significantly lower with increasing age (hazard ratio [HR], 1.10; CI, 1.03-1.18; P ¼ .004), urgent procedure (HR, 4.80; CI, 1.56-14.80; P ¼ .003), zone 0 or zone 1 (HR, 6.34; CI, 1.73-23.18; P ¼ .001), presence of arrhythmia (HR, 3.76; CI, 1.22-11.62; P ¼ .013), and cerebrovascular disease (HR, 4.12; CI, 1.38-12.35; P ¼ .006). A multivariate analysis identified age (HR, 1.11; P ¼ .047) and zone 0 or zone 1 (HR, 4.93; P ¼ .033) as the only predictors for overall mortality. Conclusions: Hybrid aortic arch repair seems to be an alternative for higher risk patients not suitable for open repair, but selection of patients is crucial and may benefit from further refinement. In this study, worse outcomes were seen in older patients and those who required more proximal landing zones.
- The evolution of management of type B aortic dissection in a series of 100 consecutive cases in a tertiary centerPublication . Lopes, Alice; Pedro, Luís M; Melo, Ryan; Moutinho, Mariana; Sobrinho, Gonçalo; Amorim, Pedro; Silvestre, Luís; Fernandes E Fernandes, Ruy; Ministro, Augusto; Martins, Carlos; Almeida, Ana G.; Nobre, Angelo; Pinto, Fausto J.; Fernandes E Fernandes, JoseIntroduction and objectives: Management of aortic dissection is rapidly evolving. The present study aims to assess paradigm shifts in type B aortic dissection (TBAD) treatment modalities and their outcomes according to clinical presentation and type of treatment. We also aim to assess the impact of endovascular technology in TBAD management in order to define organizational strategies to provide an integrated cardiovascular approach. Methods: We performed a retrospective review with descriptive analysis of the last 100 consecutive patients with TBAD admitted to the Vascular Surgery Department of Centro Hospitalar Universitário Lisboa Norte over a 16-year period. Results were stratified according to treatment modality and stage of the disease. The study was further divided into two time periods, 2003-2010 and 2011-2019, respectively before and after the introduction of a dedicated endovascular program for aortic dissections. Results: A total of 100 patients (83% male; mean age 60 years) were included, of whom 59 were admitted in the acute stage (50.8% with complicated dissections). The other 41 patients were admitted for chronic dissections, most of them for surgical treatment of aneurysmal degeneration. Temporal analysis demonstrated an increase in the number of patients operated for aortic dissection, mainly due to an increase in chronic patients (33.3% in 2003-2010 vs. 64.4% in 2011-2019) and a clear shift toward endovascular treatment from 2015 onward. Overall in-hospital mortality was 14% and was significantly higher in the chronic phase (acute 5.1% vs. chronic 26.8%; OR 5.30, 95% CI 1.71-16.39; p=0.003) and in patients with aneurysmal degeneration, regardless of the temporal phase. Only one death was recorded in the endovascular group. Conclusion: Management of TABD carried an overall mortality of 14% during a 16-year period, but the appropriate use of endovascular technology has substantially reduced in-hospital mortality.
- A novel approach for therapeutic angiogenesis : low doses of ionizing radiationPublication . Ministro, Augusto; Constantino, Susana; Gama, A. Dinis da, 1942-Peripheral arterial disease (PAD) is a vascular occlusive disease accompanied by an insufficient angiogenic response, resulting in hypoperfusi on of the affected extremities. When arterial lesions impair blood flow to such an extent that the nutritive requirements of the tissues cannot be met, limb pain is chronically present at rest, frequently with trophic and necrotic skin lesions. This condition corresponds to the most advanced clinical stage of PAD, known as critical limb ischemia (CLI). Although just a minority of PAD patients progress to CLI, as PAD is highly prevalent among diabetics, smokers and people over 70 years, this condition remains very common, with 500 to 1000 new cases per million inhabitants every year, in the developed countries. The goals of CLI treatment are ischemic pain relief, ulcer healing, improvement of muscle function and quality of life, limb loss prevention, and overall survival increase. The most important aspect of CLI is the poor prognosis, no matter what treatment is employed. Any kind of surgical/endovascular revascularization, the therapy of choice in CLI patients, should be done whenever technically possible. Attempts to manipulate and normalize the microcirculatory flow pharmacologically may enhance the results of revascularization or be one option in patients in whom revascularization is impossible or has failed. In patients with CLI not eligible for arterial revascularization, the “non-option” patients, most pharmacological agents have reduced or no real effect. Amputation is often recommended, even if it is associated to morbidity and mortality. The need for alternative treatment in CLI patients is therefore compelling, and therapeutic angiogenesis is an undoubtedly promising tool to treat these patients. There are three major processes that contribute to neovascularization and are essential for the establishment of functional collateral networks, namely angiogenesis, arteriogenesis and vasculogenesis. While angiogenesis describes the process of growth of new blood vessels from pre-existing ones, arteriogenesis is characterized by the enlargement of arteriolar anastomoses to collateral vessels through growth and proliferation and vasculogenesis is de novo formation of blood vessels. These vessels can grow considerably, enough even to take over the role of a large artery when occluded. Several strategies have been pursued to stimulate therapeutic angiogenesis, ranging from recombinant protein and gene transfer therapies to the use of progenitor cell therapies. During this research, in collaboration with the biotechnology company ECBio (Amadora, Portugal), cell based therapeutic angiogenesis was addressed, as we evaluated the possibility of UCX®, a specific population of human umbilical cord derived-mesenchymal stromal cells (UC-MSCs), to induce therapeutic angiogenesis. Using a C57BL/6 mouse model of hindlimb ischemia (HLI), we demonstrated that UCX® delivered via intramuscular injection enhance blood perfusion (evaluated by laser Doppler imaging) by stimulating angiogenesis (capillary density determined by CD31 immunohistochemistry) and arteriogenesis (collateral vessel density determined by diaphonization) in ischemic muscles. This is achieved through a new mechanism in which durable and simultaneous up-regulation of several proangiogenic genes in endothelial cells (ECs) are induced by UCX®. Cryopreservation and subsequent thawing, both in vitro and in vivo, did not impair phenotype, immunomodulatory and angiogenic potencials of this specific UC-MSCs population. These data demonstrate that UCX® improve the angiogenic potency of ECs in the murine ischemic limb, suggesting the potential of UCX® as a new therapeutic tool for CLI. This study also suggests that potency impairment related to cryopreservation in a given tissue source can be avoided by the production process. The results have positive implications for the development of an advanced therapy medicinal product. However, the use of UCX® in patients with CLI is conditioned by the lack of studies to ensure its safety and the absence of significant adverse effects. The scope of our work, in the search for a new therapeutic approach that could overcome the current lack of available medical treatments for a large number of CLI patients, led us to consider therapeutic angiogenesis beyond its cellular component, in a unique perspective based on the use of low-dose ionizing radiation (LDIR). Our previous research has demonstrated that LDIR (<0.8 Gy) induces a proangiogenic phenotype in ECs in vitro, modulating endothelial dysfunction, promoting survival, migration and preventing ECs apoptosis. Likewise, LDIR promotes neovascularization in vivo by inducing angiogenic sprouting in the transgenic fluorescent zebrafish Tg (fli1:EGFP) embryos and by increasing vessel density in adult fli1:EGFP zebrafish after caudal fin regeneration. Therefore, according to our previous results, LDIR induces angiogenesis in vitro and in vivo; however, there is no evidence so far, that it enhances neovascularization in vascular occlusive disease, our overall objective. After surgical induction of unilateral HLI, both hindlimbs of female C57BL/6 mice were sham-irradiated or irradiated with four daily fractions of 0.3 Gy, in consecutive days and limb perfusion, capillary density and collateral vessel formation were measured. We found that LDIR (4 x 0.3 Gy) improves limb perfusion by enhancing arteriogenesis through EPCs recruitment to sites of collateral vessel development, an effect dependent on exposure of the ischemic niche to LDIR, but not on the local recruitment of myeloid cells. Likewise, LDIR also favours angiogenesis through simultaneous activation of a repertoire of pro-angiogenic factors in mature ECs in a mechanism dependent of VEGFR signaling, with no short-term side effects and no effects on resting vasculature, opening a possibility to new therapeutic strategies in lower limb vascular insufficiency. The vasculature in an irradiated non-ischemic bed was not affected and after 52-wk of LDIR exposure no differences in the incidence of morbidity and mortality were noticed. Moreover, it was found that a dose of 0.3 Gy administered during 4 consecutive days does not induce toxicity in C57BL/mice and this dose fraction was identified as the lowest dose that is still able to induce therapeutic angiogenesis. The outcome of these in vivo experiments performed in a mice model suggests that LDIR may have a potential clinical use in the treatment of lower limb vascular insufficiency, emerging as a novel approach in the treatment of CLI patients. Accordingly, we designed an already approved and ongoing clinical trial – Low-dose ionizing radiation modulates the expression of pro-angiogenic genes in Critical Limb Ischemia Patients – and report our preliminary results. To date, 16 “non-option” CLI patients were enrolled in the study, but only 12 patients, corresponding to 13 limbs, were considered for analysis. As the expected amputation number (12 major limb amputations) for analysis of the primary endpoint was not reached, the trial is still ongoing. Concerning the primary endpoint, preliminary results suggest that LDIR induces a pro-angiogenic effect through the modulation of several pro-angiogenic factors in ECs collected from “non-option” CLI gastrocnemius muscles. The primary endpoint is corroborated by the finding that LDIR is associated with an increase in capillary density and a significant increase (P = 0.03) in vessel density (VD), 30 days post-intervention. It is also interesting to report that in the non-amputated patients, 6 months after irradiation, only the one muscle exposed to LDIR showed a persistent and continuous increase of VD. Regarding the surrogate clinical endpoints of ischemia and as expected, no significant differences were found between LDIR limbs and controls. LDIR has a biological rationale widely investigated and discussed in the work developed by our research group. Therefore, based on these preliminary results and considering that up to 40% of CLI patients are not candidates to revascularization, LDIR may be considered as a novel approach for the management of these patients.