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1.
Theranostics ; 13(15): 5435-5451, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37908733

RESUMO

Doxorubicin (Dox) is an effective anticancer molecule, but its clinical efficacy is limited by strong cardiotoxic side effects. Lysosomal dysfunction has recently been proposed as a new mechanism of Dox-induced cardiomyopathy. However, to date, there is a paucity of therapeutic approaches capable of restoring lysosomal acidification and function in the heart. Methods: We designed novel poly(lactic-co-glycolic acid) (PLGA)-grafted silica nanoparticles (NPs) and investigated their therapeutic potential in the primary prevention of Dox cardiotoxicity in cardiomyocytes and mice. Results: We showed that NPs-PLGA internalized rapidly in cardiomyocytes and accumulated inside the lysosomes. Mechanistically, NPs-PLGA restored lysosomal acidification in the presence of doxorubicin or bafilomycin A1, thereby improving lysosomal function and autophagic flux. Importantly, NPs-PLGA mitigated Dox-related mitochondrial dysfunction and oxidative stress, two main mechanisms of cardiotoxicity. In vivo, inhalation of NPs-PLGA led to effective and rapid targeting of the myocardium, which prevented Dox-induced adverse remodeling and cardiac dysfunction in mice. Conclusion: Our findings demonstrate a pivotal role for lysosomal dysfunction in Dox-induced cardiomyopathy and highlight for the first time that pulmonary-driven NPs-PLGA administration is a promising strategy against anthracycline cardiotoxicity.


Assuntos
Cardiomiopatias , Nanopartículas , Camundongos , Animais , Cardiotoxicidade/tratamento farmacológico , Cardiotoxicidade/prevenção & controle , Doxorrubicina/farmacologia , Miócitos Cardíacos/metabolismo , Cardiomiopatias/metabolismo , Estresse Oxidativo , Lisossomos/metabolismo
2.
J Card Surg ; 37(12): 5567-5570, 2022 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-36378932

RESUMO

Management of aortic arch pathologies remains challenging. Open total arch replacements have been associated with significant morbidity and mortality owing to the need for cardiopulmonary bypass and circulatory arrest. On the other hand, aortic arch-branched stent grafts are not widely available. In this context, hybrid techniques combining open arch debranching with endovascular graft placement have been identified as an attractive option in select patients. However, there still is a paucity of literature on their application and outcomes. A case is presented of an elderly frail patient diagnosed with a pseudoaneurysm of the aortic arch and who was successfully treated by an off-pump arch debranching followed by endovascular arch repair. This case highlights (i) the feasibility of hybrid debranching techniques, (ii) their technical challenges, and (iii) the need for long-term follow-up data.


Assuntos
Aneurisma da Aorta Torácica , Implante de Prótese Vascular , Procedimentos Endovasculares , Humanos , Idoso , Aneurisma da Aorta Torácica/cirurgia , Procedimentos Endovasculares/métodos , Aorta Torácica/cirurgia , Prótese Vascular , Implante de Prótese Vascular/métodos , Stents , Resultado do Tratamento
3.
Interact Cardiovasc Thorac Surg ; 34(3): 488-491, 2022 02 21.
Artigo em Inglês | MEDLINE | ID: mdl-34606581

RESUMO

This new and easily reproducible pulmonary valve-sparing technique for the correction of Tetralogy of Fallot is based on a conservative management of the native pulmonary valve to preserve its growth potential. From July 2015 to December 2019, 67 children presenting with a Tetralogy of Fallot were operated consecutively in a single centre using this technique in all cases. A T-shaped infundibulotomy is used to release the anterior pulmonary annulus from any muscular attachment. After myocardial resection and ventricular septal defect closure, an extensive commissurotomy is achieved. Finally, the right ventricular outflow tract remodelling is completed by a shield-shaped bovine patch with an oversized square superior edge, attached directly on the pulmonary valve annulus, with an effect of systolic traction. Sixty patients (89.5%) had a Tetralogy of Fallot repair with preservation of the pulmonary valve. To date, with a median follow-up of 38.2 [14-64] months, no patient has needed a surgical or interventional procedure for pulmonary valve stenosis or regurgitation, with low residual gradients. This procedure could provide a significant increase in native pulmonary valve preservation. Long-term studies are needed to assess pulmonary valve growth and the consequent reduction in surgical or interventional reoperations.


Assuntos
Insuficiência da Valva Pulmonar , Valva Pulmonar , Tetralogia de Fallot , Animais , Bovinos , Criança , Humanos , Lactente , Valva Pulmonar/diagnóstico por imagem , Valva Pulmonar/cirurgia , Insuficiência da Valva Pulmonar/diagnóstico por imagem , Insuficiência da Valva Pulmonar/etiologia , Insuficiência da Valva Pulmonar/cirurgia , Estudos Retrospectivos , Tetralogia de Fallot/diagnóstico por imagem , Tetralogia de Fallot/cirurgia , Resultado do Tratamento
4.
Cell Death Dis ; 12(9): 824, 2021 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-34471096

RESUMO

Cyclic adenosine monophosphate (cAMP) is a master regulator of mitochondrial metabolism but its precise mechanism of action yet remains unclear. Here, we found that a dietary saturated fatty acid (FA), palmitate increased intracellular cAMP synthesis through the palmitoylation of soluble adenylyl cyclase in cardiomyocytes. cAMP further induced exchange protein directly activated by cyclic AMP 1 (Epac1) activation, which was upregulated in the myocardium of obese patients. Epac1 enhanced the activity of a key enzyme regulating mitochondrial FA uptake, carnitine palmitoyltransferase 1. Consistently, pharmacological or genetic Epac1 inhibition prevented lipid overload, increased FA oxidation (FAO), and protected against mitochondrial dysfunction in cardiomyocytes. In addition, analysis of Epac1 phosphoproteome led us to identify two key mitochondrial enzymes of the the ß-oxidation cycle as targets of Epac1, the long-chain FA acyl-CoA dehydrogenase (ACADL) and the 3-ketoacyl-CoA thiolase (3-KAT). Epac1 formed molecular complexes with the Ca2+/calmodulin-dependent protein kinase II (CaMKII), which phosphorylated ACADL and 3-KAT at specific amino acid residues to decrease lipid oxidation. The Epac1-CaMKII axis also interacted with the α subunit of ATP synthase, thereby further impairing mitochondrial energetics. Altogether, these findings indicate that Epac1 disrupts the balance between mitochondrial FA uptake and oxidation leading to lipid accumulation and mitochondrial dysfunction, and ultimately cardiomyocyte death.


Assuntos
AMP Cíclico/metabolismo , Fatores de Troca do Nucleotídeo Guanina/metabolismo , Ácido Palmítico/toxicidade , Adenilil Ciclases/metabolismo , Sequência de Aminoácidos , Animais , Animais Recém-Nascidos , Proteína Quinase Tipo 2 Dependente de Cálcio-Calmodulina/metabolismo , Catecolaminas/metabolismo , Fatores de Troca do Nucleotídeo Guanina/química , Humanos , L-Lactato Desidrogenase/metabolismo , Lipoilação/efeitos dos fármacos , Mitocôndrias/efeitos dos fármacos , Mitocôndrias/metabolismo , Modelos Biológicos , Miócitos Cardíacos/metabolismo , Oxirredução , Fosfoproteínas/metabolismo , Ratos Sprague-Dawley , Transdução de Sinais/efeitos dos fármacos , Solubilidade , Estresse Fisiológico/efeitos dos fármacos
5.
Interact Cardiovasc Thorac Surg ; 27(4): 622-623, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-29617802

RESUMO

We describe the case of a 32-month-old patient from a developing country with tetralogy of Fallot associated with a severe biventricular dysfunction. This association is rare but makes the surgical strategy complex and potentially contraindicated. An acute severe hypoxic episode led us to perform palliative rescue intervention involving the placement of an undersized systemic-to-pulmonary shunt. This surgery was well tolerated and allowed a fast and impressive recovery of the ventricular function, making complete repair possible.


Assuntos
Ventrículos do Coração/diagnóstico por imagem , Tetralogia de Fallot/cirurgia , Disfunção Ventricular Esquerda/etiologia , Disfunção Ventricular Direita/etiologia , Função Ventricular/fisiologia , Procedimentos Cirúrgicos Cardíacos , Pré-Escolar , Ecocardiografia , Ventrículos do Coração/fisiopatologia , Humanos , Masculino , Tetralogia de Fallot/complicações , Tetralogia de Fallot/diagnóstico , Disfunção Ventricular Esquerda/diagnóstico , Disfunção Ventricular Esquerda/cirurgia , Disfunção Ventricular Direita/diagnóstico , Disfunção Ventricular Direita/cirurgia
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