[SAMHD1 acts at stalled replication forks to prevent interferon induction]. / SAMHD1 agit sur les fourches de réplication bloquées pour empêcher l'induction d'interféron.

DNA replication is an extremely complex process, involving thousands of replication forks progressing along chromosomes. These forks are frequently slowed down or stopped by various obstacles, such as secondary DNA structures, chromatin-acting proteins or a lack of nucleotides. This slowing down, known as replicative stress, plays a central role in tumour development. Complex processes, which are not yet fully understood, are set up to respond to this stress. Certain nucleases, such as MRE11 and DNA2, degrade the neo-replicated DNA at the level of blocked forks, allowing the replication to restart. The interferon pathway is a defense mechanism against pathogens that detects the presence of foreign nucleic acids in the cytoplasm and activates the innate immune response. DNA fragments resulting from genomic DNA metabolism (repair, retrotransposition) can diffuse into the cytoplasm and activate this pathway. A pathological manifestation of this process is the Aicardi-Goutières syndrome, a rare disease characterized by chronic inflammation leading to neurodegenerative and developmental problems. In this encephalopathy, it has been suggested that DNA replication may generate cytosolic DNA fragments, but the mechanisms involved have not been characterized. SAMHD1 is frequently mutated in the Aicardi-Goutières syndrome as well as in some cancers, but its role in the etiology of these diseases was largely unknown. We show that cytosolic DNA accumulates in SAMHD1-deficient cells, particularly in the presence of replicative stress, activating the interferon response. SAMHD1 is important for DNA replication under normal conditions and for the processing of stopped forks, independent of its dNTPase activity. In addition, SAMHD1 stimulates the exonuclease activity of MRE11 in vitro. When SAMHD1 is absent, degradation of neosynthesized DNA is inhibited, which prevents activation of the replication checkpoint and leads to failure to restart the replication forks. Resection of the replication forks is performed by an alternative mechanism which releases DNA fragments into the cytosol, activating the interferon response. The results obtained show, for the first time, a direct link between the response to replication stress and the production of interferons. These results have important implications for our understanding of the Aicardi-Goutières syndrome and cancers related to SAMHD1. For example, we have shown that MRE11 and RECQ1 are responsible for the production of DNA fragments that trigger the inflammatory response in cells deficient for SAMHD1. We can therefore imagine that blocking the activity of these enzymes could decrease the production of DNA fragments and, ultimately, the activation of innate immunity in these cells. In addition, the interferon pathway plays an essential role in the therapeutic efficacy of irradiation and certain chemotherapeutic agents such as oxaliplatin. Modulating this response could therefore be of much wider interest in anti-tumour therapy.

La réplication de l'ADN est un processus extrêmement complexe, impliquant des milliers de fourches de réplication progressant le long des chromosomes. Ces fourches sont fréquemment ralenties ou arrêtées par différents obstacles, tels que des structures secondaires de l'ADN, des protéines agissant sur la chromatine ou encore un manque de nucléotides. Ce ralentissement, qualifié de stress réplicatif, joue un rôle central dans le développement tumoral. Des processus complexes, qui ne sont pas encore totalement connus, sont mis en place pour répondre à ce stress. Certaines nucléases, comme MRE11 et DNA2, dégradent l'ADN néorépliqué au niveau des fourches bloquées, ce qui permet le redémarrage des réplisomes. La voie interféron est un mécanisme de défense contre les agents pathogènes qui détecte la présence d'acides nucléiques étrangers dans le cytoplasme et active la réponse immunitaire innée. Des fragments d'ADN issus du métabolisme de l'ADN génomique (réparation, rétrotransposition) peuvent diffuser dans le cytoplasme et activer cette voie. Une manifestation pathologique de ce processus est le syndrome d'Aicardi-Goutières, une maladie rare caractérisée par une inflammation chronique générant des problèmes neurodégénératifs et développementaux. Dans le cadre de cette encéphalopathie, il a été suggéré que la réplication de l'ADN pouvait générer des fragments d'ADN cytosoliques, mais les mécanismes impliqués n'avaient pas été caractérisés. SAMHD1 est fréquemment muté dans le syndrome d'Aicardi-Goutières ainsi que dans certains cancers, mais son rôle dans l'étiologie de ces maladies était jusqu'à présent largement inconnu. Nous montrons que de l'ADN cytosolique s'accumule dans les cellules déficientes pour SAMHD1, particulièrement en présence de stress réplicatif, activant la réponse interféron. Par ailleurs, SAMHD1 est important pour la réplication de l'ADN en conditions normales et pour le processing des fourches arrêtées, indépendamment de son activité dNTPase. De plus, SAMHD1 stimule l'activité exonucléase de MRE11 in vitro. Lorsque SAMHD1 est absent, la dégradation de l'ADN néosynthétisé est inhibée, ce qui empêche l'activation du checkpoint de réplication et entraine un défaut de redémarrage des fourches de réplication. De plus, la résection des fourches de réplication est réalisée par un mécanisme alternatif qui libère des fragments d'ADN dans le cytosol, activant la réponse interféron. Les résultats obtenus montrent, pour la première fois, un lien direct entre la réponse au stress réplicatif et la production d'interférons. Ces résultats ont des conséquences importantes dans notre compréhension du syndrome d'Aicardi Goutières et des cancers liés à SAMHD1. Par exemple, nous avons démontré que MRE11 et RECQ1 sont responsables de la production des fragments d'ADN qui déclenchent la réponse inflammatoire dans les cellules déficientes pour SAMHD1. Nous pouvons donc imaginer que bloquer l'activité de ces enzymes pourrait diminuer la production des fragments d'ADN et, in fine, l'activation de l'immunité innée dans ces cellules. Par ailleurs, la voie interférons joue un rôle essentiel dans l'efficacité thérapeutique de l'irradiation et de certains agents chimiothérapiques comme l'oxaliplatine. Moduler cette réponse pourrait donc avoir un intérêt beaucoup plus large en thérapie anti-tumorale.

XPC is an RNA polymerase II cofactor recruiting ATAC to promoters by interacting with E2F1.

The DNA damage sensor XPC is involved in nucleotide excision repair. Here we show that in the absence of damage, XPC co-localizes with RNA polymerase II (Pol II) and active post-translational histone modifications marks on a subset of class II promoters in human fibroblasts. XPC depletion triggers specific gene down-expression due to a drop in the deposition of histone H3K9 acetylation mark and pre-initiation complex formation. XPC interacts with the histone acetyltransferase KAT2A and specifically triggers the recruitment of the KAT2A-containing ATAC complex to the promoters of down-expressed genes. We show that a strong E2F1 signature characterizes the XPC/KAT2A-bound promoters and that XPC interacts with E2F1 and promotes its binding to its DNA element. Our data reveal that the DNA repair factor XPC is also an RNA polymerase II cofactor recruiting the ATAC coactivator complex to promoters by interacting with the DNA binding transcription factor E2F1.

Increased prevalence of psoriasis in patients with coronary artery disease: results from a case-control study.

BACKGROUND: The incidence of myocardial events has been reported to be increased in patients with psoriasis. OBJECTIVES: To investigate whether psoriasis is an independent risk factor for coronary artery disease (CAD). METHODS: We compared the prevalence of psoriasis between case patients with a diagnosis of CAD based on coronary angiography findings and control patients with no CAD referred to the emergency surgery department for an acute noncardiovascular condition. Case and control patients were examined for the presence of psoriasis by two dermatologists. The prevalence of psoriasis was compared among patients with CAD according to CAD severity. Five-hundred cases and 500 age- and sex-matched controls were included. RESULTS: Using matched univariate analysis, the prevalence of psoriasis was about twofold higher in CAD case patients than in control patients [8·0% vs. 3·4%, odds ratio (OR) 2·64; 95% confidence interval (CI) 1·42-4·88]. Using unconditional multivariate analysis, the association of psoriasis with CAD appeared to be borderline significant (OR 1·84; 95% CI 0·99-3·40). Psoriasis in patients with CAD was significantly associated with three-vessel involvement relative to one-or two-vessel involvement (13·1% vs. 6·1%; OR 3·07; 95% CI 1·50-6·25). CONCLUSIONS: The prevalence of psoriasis is twofold higher in patients with CAD than in control patients without CAD. It is associated with a more severe coronary artery involvement.

Multimodal imaging in the diagnosis of isolated left ventricular noncompaction.

Left ventricular noncompaction (LNVC), first described in 1984, is a rare congenital cardiomyopathy that is thought to be caused by arrest of normal embryogenesis of the endocardium and the myocardium, and characterized by multiple prominent trabeculations with deep intertrabecular recesses. LVNC can be associated with other congenital cardiac abnormalities such as atrial septal defect and ventricular septal defect, but it can occur in isolation. The clinical manifestations of the disease are variable, ranging from no symptoms to signs of heart failure, systemic emboli, and ventricular arrhythmias. The diagnosis is established by two dimensional echocardiography or magnetic resonance imaging. We report the case of a 44-year-old man with LVNC and discuss the role of multimodal imaging in the diagnosis and assessment of the disease.

MR delayed enhancement imaging findings in suspected acute myocarditis.

The purpose of the study was to prospectively assess the clinical impact of routinely performed delayed enhancement imaging in suspected acute myocarditis. A two-centre prospective study was performed in patients with suspected acute myocarditis. The protocol included horizontal long axis, vertical long axis and short axis ciné MR and delayed enhancement imaging after Gd-DTPA infusion (0.2 mmol/kg). Sixty consecutive patients were enrolled (aged 49.4 +/- 17.8 years). MRI demonstrated delayed enhancement sparing the subendocardicardial layer in 51.6% of patients, concordant with the diagnosis of acute myocarditis; 16.7% of patients exhibited delayed enhancement involving the subendocardial layer with irregular margins, concordant with the diagnosis of acute myocardial infarction; 31.7% of patients had delayed enhancement imaging that was considered normal. Routine imaging to identify delayed enhancement provided crucial information in suspected acute myocarditis by reinforcing the diagnosis in 51.6% of patients and correcting a misdiagnosed acute myocardial infarction in 16.7% of patients.

[Percutaneous treatment of aortic stenosis]. / Traitement percutané du rétrécissement aortique.

Degenerative aortic stenosis is the most frequent valvular disease in developed countries. The reference treatment is surgical valve replacement but one third of the patients are not eligible for surgery. Alternative options have been recently proposed using transcatheter valve implantation (transfemoral or trans-apical approaches) in this subset of patients. Two models of valve (balloon expandable or self-expandable) have demonstrated their efficacy and have been implanted to date in over 4000 patients worldwide. These techniques are promising but several issues remain such as the selection of patients, and the safety and durability of the devices currently used.

Mechanical circulatory assistance in myocardial infarction with refractory cardiogenic shock: clinical experience in 10 patients at a teaching hospital in Rouen.

BACKGROUND: In patients with acute myocardial infarction (MI), cardiogenic shock (CS) remains associated with a high mortality (close to 50%) despite optimal therapeutic strategy. For those patients who are unlikely to survive, mechanical circulatory support (MCS) might be an additional life saving strategy. OBJECTIVE: To evaluate the efficacy of circulatory assistance in myocardial infarction complicated by cardiogenic shock. METHODS: We retrospectively studied the characteristics and clinical outcome of 10 patients hospitalized with acute MI and CS who required MCS. Mean age was 52+/-8 years; location of MI was anterior in 80% of cases. Immediate coronary angiography was performed in all cases 5.8+/-7.0 hours from the onset of symptoms. Intra-aortic balloon pumping was used in 70% of patients and 30% received thrombolysis. Angioplasty with stent implantation was performed in 8 patients. RESULTS: In all patients MCS was placed within a mean of 57+/-92 hours after admission for hemodynamic instability (systolic aortic pressure: 85+/-13 mmHg; mean: 64+/-10 mmHg). Extracorporeal membrane oxygenation (ECMO) was implanted in 8 patients followed by Thoratec in one. The other 2 patients received a Thoratec and a Heartmate II system respectively. Survival rate was 40% (4 patients): 3 patients underwent heart transplantation at a mean of 93+/-97 days and one patient is alive with definitive implantable Heartmate. The other six patients died in hospital. CONCLUSION: Mechanical circulatory support appeared life saving in 4 out of 10 patients with acute MI and cardiogenic shock refractory to optimal treatment. In this situation, circulatory assistance deserves discussion and the choice of optimal device should be further evaluated.

Transcatheter aortic valve implantation: technical aspects, results and indications.

The development of the percutaneous heart valve (PHV) may become a primary therapeutic modality for the high risk and inoperable patients with critical symptomatic aortic stenosis. The first human percutaneous aortic valve implant was performed by our group in April 2002. To date, more than 500 Cribier-Edwards-PHV have been implanted worldwide using arterial trans-femoral or trans-apical approach. Data on the retrograde transfemoral approach is growing with more than 270 patients implanted as of October 2007. Procedural success rate is high (86%) and the 30-day mortality is 12%. Today, 2 patients are alive at a follow-up of more than 4 years. The same Cribier-Edwards-PHV can be implanted using trans-apical approach. In this procedure, PHV is introduced under direct vision into the left ventricle via a mini-thoracotomy. This obviates the concerns regarding vascular access in the presence of small caliber vessels and/or vascular occlusive disease. More than 200 patients have been treated with this approach. In the European experience 30-day mortality is 14%. There is intense interest in PHV technology, and there are multiple devices at various stages of development in animals and humans. The most developed is the CoreValve Revalving Technology. More than 350 patients have been treated with this technique. The immediate and mid-term results with this device are promising with a procedural success of 92% and a 30-day mortality of 15%. The future of this technology and its application is dependent on the continued collaboration between general internists, cardiologists, surgeons, engineers, and industry.

Preoperative tissue Doppler imaging differentiates beneficial from detrimental left ventricular hypertrophy in patients with surgical aortic stenosis. A postoperative morbidity study.

BACKGROUND: In a pressure overloaded left ventricle, regional systolic function has often deteriorated despite normal ejection fraction. OBJECTIVE: To correlate regional systolic function obtained by tissue Doppler imaging (TDI) with improvement in functional status after aortic valve replacement in patients with aortic stenosis (AS). METHODS AND RESULTS: 24 hours before aortic valve replacement, 32 patients with severe AS underwent conventional and TDI echocardiography for systolic peak velocity, peak strain and peak strain rate measurement in the short-axis posterior wall. At follow-up, a composite end point of cardiovascular death, worsening of heart failure and limited exercise capacity was recorded. Before surgery, mean (SD) aortic valve area and pressure gradient were 0.69 (0.22) cm(2) and 50 (14) mm Hg, respectively. Ejection fraction was 61 (10)% and septal thickness was 15 (3) mm. Fourteen events were recorded but no cardiac death. By using the multivariate regression analysis, systolic peak strain rate (p = 0.003) was the strongest predictor of limited recovery after aortic valve replacement. The peak strain rate cut-off point was 2/s by receiver operating characteristic analysis. CONCLUSION: Irrespective of ejection fraction and thickness, strain rate is a determinant which predicts recovery after aortic valve replacement in patients with severe AS.

[Revascularisation of unprotected left main coronary artery disease: an update]. / Revascularisation du tronc commun coronaire gauche non protégé.

Coronary bypass grafting is the reference treatment of unprotected left main coronary disease. Nevertheless, the experience of invasive cardiologists and the introduction of active stents make angioplasty possible in selected cases. Only the results of controlled clinical trials (SYNTAX trial currently under way) will enable physicians to choose the most appropriate method of revascularisation for their patients.

[Aortic bioprosthesis implanted percutaneously: three year follow up]. / Bioprothèse aortique implantée par voie percutanée: suivi à trois ans.

Percutaneous implantation of a bioprosthesis for the treatment of degenerative aortic stenosis ushered in a new era for interventional cardiology, and now represents the best therapeutic option for a growing number of patients for whom surgical aortic replacement would be too risky. This is the case in about a third of symptomatic patients affected. Between 2003 and 2005, we performed initial feasibility studies (I-REVIVE and RECAST) in Rouen, on non-operable patients in a critical state, included for purely compassionate reasons. The valve used was a pericardial bioprosthesis mounted in an expandable balloon stent. The mean age of the patients was 80 years, all had multiple co-morbidity and had been turned down by the cardiac surgeons. In 33 of the 36 included patients, the technique was attempted by the anterograde trans-septal approach (n=27, success rate 80%) or by the retrograde arterial route (n=7, success rate 57%). Echocardiography following implantation revealed a final aortic surface area of 1.70 cm2 and a transvalvular gradient of 9 mmHg. A significant paravalvular aortic leak was noted in 5 cases. There were 6 deaths by 1 month, related to the procedure, and 10 deaths by 6 months, from non-cardiac causes and not related to the procedure. There was no occurrence of coronary occlusion, secondary displacement or dysfunction of the prosthesis. In December 2006, 8 patients reached 2 years of follow up, and two others reached 3 years, symptom free and still with an unchanged valvular function. Significant technological improvements have made the technique simpler, quicker and safer, with very much improved short and long term results. The new trans-apical approach is under evaluation with some promising initial results. More than 280 patients have been implanted to date. Other implantable prostheses are under evaluation. This therapeutic modality looks likely to develop rapidly, and in the near future it should offer a new and optimal solution for all high surgical risk or non-operable patients.

[Immediate results and clinical follow-up of patients treated with drug eluting stents implantation in routine clinical practice]. / Résultats immédiats et suivi clinique des patients traités par implantation de stents actifs en pratique courante.

Multiple recent randomized studies have demonstrated the superiority of drug eluting stents (DES) compared to bare stents for reduction of restenosis rates after angioplasty. We sought to study if the results obtained in these studies with highly selected patients could be translated to patients treated in routine clinical practice. To this end, we retrospectively reviewed hospital charts of 134 consecutive patients treated in our center with 202 DES implantation between November 2002 and January 2004. Thirty nine % of patients had diabetes and 59% had multivessel disease. Coronary lesions were often complex (type B2: 24%, type C: 35%). Mean percent diameter stenosis was 68 +/- 13% with a reference artery diameter of 2.62 +/- 0.5 mm. One patient (0.75%) died in-hospital from cardiogenic shock. At a mean follow-up of 12 +/- 2.6 months, 7 patients (5.3%) died, including 2 extracardiac deaths. Recurrent chest pain occurred in 16 patients (12%), with only 3 (2.3%) in-stent restenosis. Major adverse cardiac event rate was 8.2%. This study confirms that in a non-selected population, the rate of subsequent revascularization after DES implantation is very low. It can be hoped that the indications of implantations will progressively spread with a lowered cost of these DES.

[Balloon aortic valvuloplasty in the adult. Immediate results and in-hospital complications in the latest series of 141 consecutive patients at the University Hospital of Rouen (2002-2005)]. / Valvuloplastie aortique par ballonnet chez l'adulte. Résultats immédiats et complications intrahospitalières dans la dernière série de 141 patients consécutifs au CHU de Rouen (2002-2005).

UNLABELLED: With the aging population, elderly patients with degenerative, severely calcified, and symptomatic aortic stenosis are becoming a frequent problem in medical decision making, particularly because many are declined for surgical valve replacement. For these patients, balloon aortic dilatation could be a palliative treatment. PATIENTS AND METHODS: we analyzed retrospectively our techniques and complications during hospitalization for percutaneous aortic balloon dilatation in 141 consecutive patients (45% women, mean age 83 +/- 10 y) from January 2002 to April 2005. The Parsonnet's score was 41 +/- 8 and the Euroscore was 10 +/- 2. We excluded the patients enrolled for percutaneous aortic valve implantation. This technique was performed under local anesthesia, from retrograde or antegrade approach. Rapid pacing stimulation (220/bpm) with a pacing-lead placed in the right ventricle was performed during balloon inflation. RESULTS: the aortic valve area was increased from 0.59 +/- 0.19 to 1.02 +/- 0.34 cm2 (p < 0.001) and the transvalvular mean gradient decreased from 49.3 +/- 21.2 to 22.2 +/- 11.8 mmHg (p < 0.001). Six patients (4%) died (3 during aortic valve dilatation) and 9 patients (6%) had non fatal complications: 2 transitory strokes, 8 non surgical vascular complications and 5 episodes of atrio-ventricular complete block (these complication were non exclusive). The patients were discharged at 5, 6 +/- 3 days. CONCLUSION: In the hands of skilled operators, aortic percutaneous balloon dilatation has become a simple technique, associated with a low risk of complications despite a very ill patient population. This technique remains a good option for a number of patients before the onset of percutaneous aortic valve implantation.

[Intra-stent restenosis following implantation of a bare endoprosthesis]. / Resténose intra-stent après implantalion d'une endoprothèse nue.

The aim of this retrospective study was to evaluate the immediate and long-term results of various treatments for patients with a primary lesion of intra-stent restenosis (ISR). The study included 214 patients (233 endoprostheses, site of a primary ISR), with an average age of 61+/-11 years. These patients had received one of the following treatments: balloon angioplasty alone (101 patients), implantation of a second endoprosthesis (32 patients), medical treatment (65 patients), or revascularisation surgery with aorto-coronary bypass (16 patients). After retrospective analysis of the initial data, clinical follow-up was studied for all patients, and severe cardiac events were recorded. The immediate treatment of the ISR with angioplasty or bypass had an initial success rate of 100%. At the end of follow up (26+/-1.8 months) for the series as a whole, 9 patients (4.1%) had died, 7 (3.2%) had suffered a myocardial infarction, and 22 (10.3%) had had to undergo a secondary revascularisation procedure. 111 (52%) patients had angiographic follow up. A second ISR was noted in 43 cases (39%). The type of treatment provided was not a predictive factor for the occurrence of a severe cardiac event. In conclusion, whatever treatment of ISR is used, the immediate result is satisfactory. The rate of severe cardiac events is acceptable and in 10.3% of cases necessitates a secondary revascularisation procedure within 2 years. The very promising recent development of new active endoprostheses could alter the management of coronary patients in the years to come.

[Treatment of acute myocardial infarction due to embolism by a thromboaspiration catheter]. / Traitement d'un infarctus du myocarde aigu d'origine embolique par catheter de thrombo-aspiration.

Although rare, coronary embolism poses a therapeutic problem. Thromboaspiration is an elegant alternative to implantation of a stent. The place of stenting in acute myocardial infarction depends on the results of randomised trials. The authors report the case of a 69 year old woman who presented with an apico-lateral infarction probably due to a coronary embolism after postoperative thrombosis of a mechanical mitral valve prosthesis. The authors performed a percutaneous revascularisation by thromboaspiration with a good result.

[Percutaneous correction of acquired aortic stenosis and mitral insufficiency in adults]. / Traitement percutané du rétrécissement aortique et de l'insuffisance mitrale de l'adulte.

Aortic stenosis and mitral regurgitation are the most common valvular diseases in western countries. Surgical treatment, aortic valve replacement or mitral valve repair, is the treatment of choice. Innovative technologies could offer an alternative therapeutic option to the patients with increased operative risk. This article will report the early experience with these promising techniques as presented at the High-Tech 2004 meeting.

[Non-invasive coronary angiography by multidetector spiral computed tomography and magnetic resonance imaging]. / Imagerie coronaire non invasive par scanner spirale multi détecteurs et imagerie par resonance magnétique.

Coronary angiography is the reference standard to confirm the presence and severity of coronary stenoses. Given the invasiveness of this procedure, a noninvasive mean allowing to visualize coronary anatomy would be of obvious clinical interest. Multidetector spiral computed tomography and magnetic resonance imaging are new and promising techniques for noninvasive detection of significant coronary stenoses. The purpose of this article is to review the present knowledge on these noninvasive techniques.

[Treatment of intrastent restenosis]. / Traitement de la resténose intra-stent.

In-stent restenosis (ISR) remains an important limitation after stent implantation occurring in 20-30% of patients. Different techniques and treatments have been evaluated in this setting. Repeat balloon angioplasty alone has been rapidly followed by ablative techniques such as laser, rotational atherectomy or implantation of a second stent within the stent. Cutting balloon represents another alternative technique. None of these techniques has proven its superiority over plain balloon angioplasty alone. Brachytherapy is the only effective treatment for ISR by significantly decreasing recurrent restenosis rate at follow-up. However, its use is limited by cost and infrastructure associated with the risk of late thrombosis requiring prolonged antiplatelet therapy. Surgical treatment can be proposed in recurrent ISR as well as medical therapy alone in pauci-symptomatic patients. New drug-eluting stents are under evaluation in this indication.