Background: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm ... more Background: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). We evaluated the impact of sac shrinkage on secondary interventions, on survival and its association with endoleaks, and on compliance with instructions for use (IFU). Methods: This observational retrospective study was conducted on all consecutive patients receiving EVAR for an infrarenal abdominal aortic aneurysm (AAA) using exclusively Endurant II/IIs endograft from 2014 to 2018. Sixty patients were entered in the study. Aneurysm sac shrinkage was defined as decrease ≥5 mm of the maximum aortic diameter. Univariate methods and Kaplan–Meier plots assessed the potential impact of shrinkage. Results: Twenty-six patients (43.3%) experienced shrinkage at one year, and thirty-four (56.7%) had no shrinkage. Shrinkage was not significantly associated with any demographics or morbidity, except hypertension (p = 0.01). No aneurysm characteristics were associated with shrinkage. N...
La contraction des cellules musculaires est due a la propagation d'un stimulus electrique app... more La contraction des cellules musculaires est due a la propagation d'un stimulus electrique appele potentiel d'action (PA). Il est produit par l'ouverture sequentielle de plusieurs canaux ioniques generant des courants a travers les membranes cellulaires. Les canaux sodiques dependant du voltage (Nav) declenchent la premiere phase du PA. Les variants Nav1. 4 et Nav1. 5 sont exprimes respectivement dans le muscle et le coeur. Des mutations de leurs genes (SCN4A et SCN5A) provoquent respectivement des pathologies neuromusculaires et des arythmies cardiaques. Mon travail de these a consiste a etudier les canalopathies. J'ai ainsi examine les consequences de deux mutations sur les proprietes biophysiques des canaux en les exprimant dans des cellules HEK293. La mutation du gene SCN4A engendrait des modifications importantes de la fonction de Nav1. 4 expliquant certains aspects de la myotonie observee chez les patients. Le patient de la deuxieme etude, atteint d'un syndr...
BACKGROUND In the recent years, an increased use of marginal donors and grafts and a growing prev... more BACKGROUND In the recent years, an increased use of marginal donors and grafts and a growing prevalence of peripheral arterial disease in the recipients have been observed. Meanwhile, the open surgical technique for kidney transplantation has not changed. The aim of this study is to analyze all surgical complications occurring in the first year after kidney transplant and to determine potential predictive risk factors. METHOD Data of the 399 patients who underwent kidney transplant in our University Hospital between January 2006 and December 2015 were retrospectively reviewed. The primary endpoint was the overall rate of vascular, parietal and urological complications at 1 year following kidney transplantation. The secondary outcomes were graft and patient' survival rates, and the identification of predictive factors of the surgical complications. RESULTS Twenty-four percent of patients developed 134 complications. Vascular complication represented 39% of all complications and resulted in 9 graft losses. Parietal and urological complications represented 46% and 15% of all complications, respectively, No parietal or urological complications were associated with graft loss. Five patients died during the first year, none of these cases was associated with graft loss. The graft survival rate reached 96% at 1 year, including patients still alive. The occurrence of surgical complication was associated with reduced graft survival at 1 year. Using a multivariate analysis, 4 predictive factors were identified: age, deceased donor, operative time and dyslipidemia. CONCLUSION Surgical complications after kidney transplantation remained frequent and age, deceased kidney donors, and operative time were identified as risk factors. As vascular complications were a major cause of early graft loss, efforts should aim to reduce their occurrence to increase graft survival.
Background: Congenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain-of-... more Background: Congenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain-of-function mutations in SCN5A, the gene encoding the sodium channel Nav1.5. This channel can be regulated via the ubiquitin ligase Nedd4-2 which binds to the PY-motif of Nav1.5.
Aim: We have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY-motif (p.Y1981N) of Nav1.5.
Results: In HEK cell, co-immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4-2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down-regulated upon Nedd4-2 co-expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock-in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT.
Conclusions: These results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes.
Funding from the European Community’s Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.
A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 o... more A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 of the Na(v)1.5 sodium channel and leading to a non-expression of the mutant allele, was prescribed the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Floxyfral), 100 mg per day. His normal baseline ECG changed to a characteristic Brugada-Type-1-ECG pattern. To investigate whether fluvoxamine may reduce the cardiac sodium current, the effect of this drug was studied on the wild-type voltage-gated cardiac sodium channel Na(v)1.5 stably expressed in HEK293 cells. Patch-clamp recording showed a 50% inhibition of the current at a concentration of 57.3 microM. In our patient, no arrhythmia occurred but the proarrhythmic potential of SSRI in patients with SCN5A mutations cannot be excluded. Therefore, we advise 12-lead ECG control after administering SSRI in these patients.
Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is ca... more Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 ...
Background: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm ... more Background: Aneurysm shrinkage has been proposed as a marker of successful endovascular aneurysm repair (EVAR). We evaluated the impact of sac shrinkage on secondary interventions, on survival and its association with endoleaks, and on compliance with instructions for use (IFU). Methods: This observational retrospective study was conducted on all consecutive patients receiving EVAR for an infrarenal abdominal aortic aneurysm (AAA) using exclusively Endurant II/IIs endograft from 2014 to 2018. Sixty patients were entered in the study. Aneurysm sac shrinkage was defined as decrease ≥5 mm of the maximum aortic diameter. Univariate methods and Kaplan–Meier plots assessed the potential impact of shrinkage. Results: Twenty-six patients (43.3%) experienced shrinkage at one year, and thirty-four (56.7%) had no shrinkage. Shrinkage was not significantly associated with any demographics or morbidity, except hypertension (p = 0.01). No aneurysm characteristics were associated with shrinkage. N...
La contraction des cellules musculaires est due a la propagation d'un stimulus electrique app... more La contraction des cellules musculaires est due a la propagation d'un stimulus electrique appele potentiel d'action (PA). Il est produit par l'ouverture sequentielle de plusieurs canaux ioniques generant des courants a travers les membranes cellulaires. Les canaux sodiques dependant du voltage (Nav) declenchent la premiere phase du PA. Les variants Nav1. 4 et Nav1. 5 sont exprimes respectivement dans le muscle et le coeur. Des mutations de leurs genes (SCN4A et SCN5A) provoquent respectivement des pathologies neuromusculaires et des arythmies cardiaques. Mon travail de these a consiste a etudier les canalopathies. J'ai ainsi examine les consequences de deux mutations sur les proprietes biophysiques des canaux en les exprimant dans des cellules HEK293. La mutation du gene SCN4A engendrait des modifications importantes de la fonction de Nav1. 4 expliquant certains aspects de la myotonie observee chez les patients. Le patient de la deuxieme etude, atteint d'un syndr...
BACKGROUND In the recent years, an increased use of marginal donors and grafts and a growing prev... more BACKGROUND In the recent years, an increased use of marginal donors and grafts and a growing prevalence of peripheral arterial disease in the recipients have been observed. Meanwhile, the open surgical technique for kidney transplantation has not changed. The aim of this study is to analyze all surgical complications occurring in the first year after kidney transplant and to determine potential predictive risk factors. METHOD Data of the 399 patients who underwent kidney transplant in our University Hospital between January 2006 and December 2015 were retrospectively reviewed. The primary endpoint was the overall rate of vascular, parietal and urological complications at 1 year following kidney transplantation. The secondary outcomes were graft and patient' survival rates, and the identification of predictive factors of the surgical complications. RESULTS Twenty-four percent of patients developed 134 complications. Vascular complication represented 39% of all complications and resulted in 9 graft losses. Parietal and urological complications represented 46% and 15% of all complications, respectively, No parietal or urological complications were associated with graft loss. Five patients died during the first year, none of these cases was associated with graft loss. The graft survival rate reached 96% at 1 year, including patients still alive. The occurrence of surgical complication was associated with reduced graft survival at 1 year. Using a multivariate analysis, 4 predictive factors were identified: age, deceased donor, operative time and dyslipidemia. CONCLUSION Surgical complications after kidney transplantation remained frequent and age, deceased kidney donors, and operative time were identified as risk factors. As vascular complications were a major cause of early graft loss, efforts should aim to reduce their occurrence to increase graft survival.
Background: Congenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain-of-... more Background: Congenital long QT syndrome type 3 (LQT3) is a cardiac arrhythmias caused by gain-of-function mutations in SCN5A, the gene encoding the sodium channel Nav1.5. This channel can be regulated via the ubiquitin ligase Nedd4-2 which binds to the PY-motif of Nav1.5.
Aim: We have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY-motif (p.Y1981N) of Nav1.5.
Results: In HEK cell, co-immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4-2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down-regulated upon Nedd4-2 co-expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock-in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT.
Conclusions: These results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes.
Funding from the European Community’s Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.
A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 o... more A patient with an SCN5A p.W822X nonsense mutation, localized in the transmembrane region DII-S4 of the Na(v)1.5 sodium channel and leading to a non-expression of the mutant allele, was prescribed the selective serotonin reuptake inhibitor (SSRI) fluvoxamine (Floxyfral), 100 mg per day. His normal baseline ECG changed to a characteristic Brugada-Type-1-ECG pattern. To investigate whether fluvoxamine may reduce the cardiac sodium current, the effect of this drug was studied on the wild-type voltage-gated cardiac sodium channel Na(v)1.5 stably expressed in HEK293 cells. Patch-clamp recording showed a 50% inhibition of the current at a concentration of 57.3 microM. In our patient, no arrhythmia occurred but the proarrhythmic potential of SSRI in patients with SCN5A mutations cannot be excluded. Therefore, we advise 12-lead ECG control after administering SSRI in these patients.
Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is ca... more Brugada syndrome (BrS) is characterized by arrhythmias leading to sudden cardiac death. BrS is caused, in part, by mutations in the SCN5A gene, which encodes the sodium channel alpha-subunit Na(v)1.5. Here, we aimed to characterize the biophysical properties and consequences of a novel BrS SCN5A mutation. SCN5A was screened for mutations in a male patient with type-1 BrS pattern ECG. Wild-type (WT) and mutant Na(v)1.5 channels were expressed in HEK293 cells. Sodium currents (I(Na)) were analysed using the whole-cell patch-clamp technique at 37 degrees C. The electrophysiological effects of the mutation were simulated using the Luo-Rudy model, into which the transient outward current (I(to)) was incorporated. A new mutation (C1850S) was identified in the Na(v)1.5 C-terminal domain. In HEK293 cells, mutant I(Na) density was decreased by 62% at -20 mV. Inactivation of mutant I(Na) was accelerated in a voltage-dependent manner and the steady-state inactivation curve was shifted by 11.6 ...
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Papers by Séverine Petitprez
Aim: We have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY-motif (p.Y1981N) of Nav1.5.
Results: In HEK cell, co-immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4-2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down-regulated upon Nedd4-2 co-expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock-in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT.
Conclusions: These results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes.
Funding from the European Community’s Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.
Aim: We have investigated the mechanisms underlying the phenotype of a LQT3 family harboring a SCN5A mutation located in the PY-motif (p.Y1981N) of Nav1.5.
Results: In HEK cell, co-immunoprecipitation experiments revealed that the interaction of Nav1.5 with Nedd4-2 was abolished by the mutation. While the WT protein was ubiquitylated and the sodium current (INa) down-regulated upon Nedd4-2 co-expression, no such regulation was observed with the mutant channel. In vivo relevance of this mechanism was assessed by generating a knock-in (KI) mouse line bearing the p.Y1981N mutation. Ubiquitylation of the mutant channel expressed in KI hearts mice was reduced, and the total level of Nav1.5 protein was increased compared to WT littermates. INa and action potential duration were increased in KI cardiomyocytes compare to WT.
Conclusions: These results demonstrate a central role for Nav1.5 ubiquitylation in the regulation of sodium channel density in cardiomyocytes.
Funding from the European Community’s Seventh Framework Programme, EUTrigTreat, the Swiss National Science Foundation, and the Swiss Heart Foundation.