Activation of the peroxisome proliferator-activated receptor α protects against myocardial ischaemic injury and improves endothelial vasodilatation

BACKGROUND: The peroxisome proliferator-activated receptor α (PPARα) plays an important role in the metabolism of lipoproteins and fatty acids, and seems to protect against the development of atherosclerosis. To evaluate the possible protective role of PPARα on cardiovascular function, the effect of the PPARα agonist, fenofibrate was assessed with respect to ischaemia/reperfusion injury and endothelial function in mice. RESULTS: Fenofibrate treatment reduces myocardial infarction size and improves post-ischaemic contractile dysfunction. Hearts from PPARα null mice exhibit increased susceptibility to ischaemic damages and were refractory to protection by fenofibrate treatment suggesting that the beneficial effects of fenofibrate were mediated via PPARα. Furthermore, fenofibrate improves endothelium- and nitric oxide-mediated vasodilatation in aorta and mesenteric vascular bed. A decreased inhibitory effect of reactive oxygen species in the vessel wall accounts for enhanced endothelial vasodilatation. However, the latter cannot be explained by an increase in nitric oxide synthase expression nor by an increase sensitivity of the arteries to nitric oxide. CONCLUSIONS: Altogether the present data suggest that fenofibrate exerts cardioprotective effect against ischaemia and improves nitric oxide-mediated response probably by enhancing antioxidant capacity of the vessel wall. These data underscore new therapeutic perspectives for PPARα agonists in ischaemic myocardial injury and in cardiovascular diseases associated with endothelial dysfunction

196 Non response after cardiac resynchronisation therapy is associated with a more severe cardiomyopathy

BackgroundCardiac resynchronisation therapy (CRT) has been shown to improve clinical status in heart failure patients. Some patients treated by CRT fail to respond to the treatment. Predisposing factors for non-response should be investigated to optimize patient selection.ObjectiveThe purpose of the study was to evaluate before device implantation and 3, 6 and 12 month after, echocardiographic and biological parameters with respect to CRT response.MethodsThirty two patients with heart failure (72% of men; age 66±10 years; 59% non-ischaemic cardiomyopathy; NYHA III–IV; left ventricular ejection fraction (LVEF) 22.7±6.7%; QRS width 146±26ms) were implanted with CRT device and followed during twelve month. Responders (R) were defined as patients with improvement of one or more NYHA functional class, with a significant improvement in quality of life and without episode nor hospitalization for heart failure during follow-up.Results34% of the patients constitute the non-responder group (NR). No difference between R and NR was observed in LVEF, QRS width, NYHA, cardiovascular risk factors nor drug medication. Non-ischaemic dilated cardiomyopathy was significantly more present in R (71% vs 27%; p=0.03). Before CRT, NR had more important left ventricular end-diatolic diameter, left ventricular end-systolic diameter and more elevated left pressions. Atrioventricular dyssynchrony was significantly more observed in R (66% vs 9%; p=0.006) so as intraventricular dyssynchrony (95% vs 27%; p=0.001).BNP is significantly more elevated in NR (602±385 vs 320±361; p=0.03) before CRT.After 3 and 6 month, a significant decrease in left ventricular end-diatolic and end-systolic diameters, LVEF and normalisation of left and right pressions occur in R. Likewise, BNP levels were lower in R.ConclusionsNR patients have before implantation a more severe cardiomyopathy. At follow-up, left ventricular remodelling could only be observed in R patients. These data suggest that cardiac CRT should not be proposed too late so that left ventricular remodelling could be expected

169 Does atrial differences in endothelium damage, leukocyte and platelet activation contribute to chamber specific thrombogenic status in patients with atrial fibrillation?

BackgroundIn atrial fibrillation (AF), the reasons why most of the thrombi form in the left atrium are mainly unknown. In the vasculature, endothelial damage together with platelet activation and inflammation contribute to initiation of blood coagulation and thrombus growth.ObjectiveThe purpose of this study was to investigate whether atrial-specific differences in endothelial damage, leukocyte activation, platelet stimulation occur in patients with AF.MethodsTwenty patients (15 men, 5 women; age 55±8 years, 15 paroxystic AF, 5 persistent AF) with AF undergoing ablation were investigated. Blood samples from the left and right atrium were obtained at the start of the procedure. Procoagulant microparticles (MPs), reliable markers of vascular damage were measured by capture assays. Their procoagulant abilities were quantified by functional prothrombinase assay and their cellular origin were determined (endothelium, platelet, leukocyte). In addition, platelet reactivity was evaluated by whole blood flow cytometry for expression of platelet Pselectin (CD62P), active glycoprotein IIbIIIa receptor (PAC-1). Platelet aggregation was evaluated using Arachidonic acid (AA), ADP, TRAP and collageninduced whole blood aggregometry.ResultsNo atrial-specific differences in the levels of total procoagulant MP, leukocyte-derived-MP and platelet-derived MP could be evidenced. Conversely, endothelial-derived MPs (CD105+) were slightly elevated in the right atrium (RA 0.96±0.53 vs. LA 0.80±0.45nm PhtdSer Eq.; p=0.041). Likewise, collagen-induced platelet aggregation was evidenced in the right atrium (Collagen 1mg/l RA: 48±33% vs LA 37±29%; p 0.035; collagen 2,5mg/l RA: 76±25% vs LA: 60±29%; p=0.001).ConclusionsIn patients with AF, endothelial damage and collageninduced platelet aggregation appear slightly more pronounced in the right atrium. Our data did not substantiate the view that chamber specific enhanced thrombogenic status could be a reliable explanation for the increased propensity for thrombus formation observed in the left atrium in AF patients

Impact of gender on left atrial low-voltage zones in patients with persistent atrial fibrillation: results of a voltage-guided ablation

BackgroundGender-related differences have been reported in atrial fibrotic remodeling and prognosis of atrial fibrillation (AF) patients after ablation. We assessed in persistent AF the regional distribution of left atrial (LA) bipolar voltage and the extent of low-voltage zones (LVZ) according to gender as well as the results of a voltage-guided substrate ablation.MethodsConsecutive patients who underwent a voltage-guided AF ablation were enrolled. LA endocardial voltage maps were obtained using a 3D electro-anatomical mapping system in sinus rhythm. LVZ was defined as <0.5 mV.ResultsA total of 115 patients were enrolled (74 men, 41 women). The LA bipolar voltage amplitude was twice lower in the whole LA (p < 0.01) and in each atrial region in women compared with men, whereas the LA indexed volume was similar. LVZ were found in 56.1% of women and 16.2% of men (p < 0.01). LVZ were also more extensive in women (p = 0.01), especially in the anterior LA. Atrial voltage alteration occurred earlier in women than in men. In a multivariate analysis, the female sex (OR 12.99; 95% CI, 3.23–51.63, p = 0.0001) and LA indexed volume (OR 1.09; 95% CI, 1.04–1.16, p = 0.001) were predictive of LVZ. Atrial arrhythmia-free survival was similar in men and women 36 months after a single ablation procedure.ConclusionThe study reports a strong relationship between the female gender and atrial substrate remodeling. The female gender was significantly associated with higher incidence, earlier occurrence, and greater extent of LVZ compared with men. Despite the female-specific characteristics in atrial remodeling, LVZ-guided ablation may improve the AF ablation outcome in women

0357: Two-dimensional speckle-tracking imaging for the left atrial and ventricular function in patients undergoing atrial fibrillation ablation

IntroductionLeft atrium (LA) structural remodeling associated with atrial fibrillation (AF) contributes to recurrence after AF catheter ablation (CA). Characterizing LA function may be useful to identify patients with higher risk of recurrence and could guide ablation strategy in term of substrate modification. We aimed to identify predictors of recurrence and atrial remodeling by assessing LA and left ventricle (LV) deformation properties using two-dimensional speckle-tracking imaging before and after AF CA.Methods62 patients (age 54±10 years, 90% male) with AF (45 paroxysmal (PAF), 17 persistent (PsAF)) underwent an echocardiography before CA, 3 and 6 months after CA to assess LA strain (S total (S-tot), positive peak (S-pos), negative peak (S-neg)), LA strain rate (SR positive peak (SRs), early (SRe) and late negative peak (SRa)) and LV strain (LV longitudinal and radial S).ResultsPsAF patients baseline had significantly larger LA volumes (41±8 vs 32±10ml/m2), decreased S-tot (10±5 vs 20±6%; p<0.001), SR-LAs (0.6±0.2 vs 1±0.3s−1; p<0.001) and LV strain (−12±3 vs −16±3%; p<0.001) compared to PAF group. After 6 month follow-up, 69% of the patients remained in sinus rhythm. Baseline LA active emptying, reservoir function and LA S-tot (13.2±6.2 vs 20.1±7%, p<0.001), S-neg (−7.2±3.5 vs –10.6±3.3%, p<0.009), SR-s (0.71±0.3 vs 1.01±0.35 s−1, <0.004), SR-a (–0.89±0.56 vs −1.37±0.48 s−1, p<0.01) and LV strain (−13.5±4.8 vs −17.1±3.5%, p<0.003) were significantly decreased in patients with AF recurrence. At multivariate analysis, the unique independent predictor of sinus rhythm maintenance was LA S-tot (HR 0.819 (0.685–0.979), p=0.028). In the overall cohort, LA volumes decreased from baseline to 3 and 6 months but there was no significant change in LA S, LA SR nor LV strain. At multivariate analysis, the unique independent predictor of LA reverse remodeling after CA was the duration of AF history (HR 0.84 (0.73–0.96), p=0.013).ConclusionsAltered global LA and LV strain before CA is associated with AF recurrence. Echocardiographic LA function characterization before ablation procedures may be helpful to guide AF ablation strategy and drug management after CA

A worldwide survey on incidence, management and prognosis of oesophageal fistula formation following atrial fibrillation catheter ablation: The POTTER-AF study.

AIMS Oesophageal fistula represents a rare but dreadful complication of atrial fibrillation catheter ablation. Data on its incidence, management and outcome are sparse. METHODS AND RESULTS This international multicenter registry investigates the characteristics of oesophageal fistulae after treatment of atrial fibrillation by catheter ablation. A total of 553,729 catheter ablation procedures (radiofrequency: 62.9%, cryoballoon: 36.2%, other modalities: 0.9%) were performed at 214 centers in 35 countries. In 78 centers 138 patients (0.025%, radiofrequency: 0.038%, cryoballoon: 0.0015% (p<0.0001)) were diagnosed with an oesophageal fistula. Periprocedural data were available for 118 patients (85.5%). Following catheter ablation, the median time to symptoms and the median time to diagnosis were 18 (7.75, 25; range: 0-60) days and 21 (15, 29.5; range: 2-63) days, respectively. The median time from symptom onset to oesophageal fistula diagnosis was 3 (1, 9; range: 0-42) days. The most common initial symptom was fever (59.3%). The diagnosis was established by chest computed tomography in 80.2% of patients. Oesophageal surgery was performed in 47.4% and direct endoscopic treatment in 19.8%, and conservative treatment in 32.8% of patients. The overall mortality was 65.8%. Mortality following surgical (51.9%) or endoscopic treatment (56.5%) was significantly lower as compared to conservative management (89.5%) (odds ratio 7.463 (2.414, 23.072) p<0.001). CONCLUSIONS Oesophageal fistula after catheter ablation of atrial fibrillation is rare and occurs mostly with the use of radiofrequency energy rather than cryoenergy. Mortality without surgical or endoscopic intervention is exceedingly high

Impact of clinical and genetic findings on the management of young patients with Brugada syndrome.

BACKGROUND: Brugada syndrome (BrS) is an arrhythmogenic disease associated with sudden cardiac death (SCD) that seldom manifests or is recognized in childhood. OBJECTIVES: The objectives of this study were to describe the clinical presentation of pediatric BrS to identify prognostic factors for risk stratification and to propose a data-based approach management. METHODS: We studied 106 patients younger than 19 years at diagnosis of BrS enrolled from 16 European hospitals. RESULTS: At diagnosis, BrS was spontaneous (n = 36, 34%) or drug-induced (n = 70, 66%). The mean age was 11.1 ± 5.7 years, and most patients were asymptomatic (family screening, (n = 67, 63%; incidental, n = 13, 12%), while 15 (14%) experienced syncope, 6(6%) aborted SCD or symptomatic ventricular tachycardia, and 5 (5%) other symptoms. During follow-up (median 54 months), 10 (9%) patients had life-threatening arrhythmias (LTA), including 3 (3%) deaths. Six (6%) experienced syncope and 4 (4%) supraventricular tachycardia. Fever triggered 27% of LTA events. An implantable cardioverter-defibrillator was implanted in 22 (21%), with major adverse events in 41%. Of the 11 (10%) patients treated with hydroquinidine, 8 remained asymptomatic. Genetic testing was performed in 75 (71%) patients, and SCN5A rare variants were identified in 58 (55%); 15 of 32 tested probands (47%) were genotype positive. Nine of 10 patients with LTA underwent genetic testing, and all were genotype positive, whereas the 17 SCN5A-negative patients remained asymptomatic. Spontaneous Brugada type 1 electrocardiographic (ECG) pattern (P = .005) and symptoms at diagnosis (P = .001) were predictors of LTA. Time to the first LTA event was shorter in patients with both symptoms at diagnosis and spontaneous Brugada type 1 ECG pattern (P = .006). CONCLUSION: Spontaneous Brugada type 1 ECG pattern and symptoms at diagnosis are predictors of LTA events in the young affected by BrS. The management of BrS should become age-specific, and prevention of SCD may involve genetic testing and aggressive use of antipyretics and quinidine, with risk-specific consideration for the implantable cardioverter-defibrillator

Genome-wide association analyses identify new Brugada syndrome risk loci and highlight a new mechanism of sodium channel regulation in disease susceptibility.

Brugada syndrome (BrS) is a cardiac arrhythmia disorder associated with sudden death in young adults. With the exception of SCN5A, encoding the cardiac sodium channel Na1.5, susceptibility genes remain largely unknown. Here we performed a genome-wide association meta-analysis comprising 2,820 unrelated cases with BrS and 10,001 controls, and identified 21 association signals at 12 loci (10 new). Single nucleotide polymorphism (SNP)-heritability estimates indicate a strong polygenic influence. Polygenic risk score analyses based on the 21 susceptibility variants demonstrate varying cumulative contribution of common risk alleles among different patient subgroups, as well as genetic associations with cardiac electrical traits and disorders in the general population. The predominance of cardiac transcription factor loci indicates that transcriptional regulation is a key feature of BrS pathogenesis. Furthermore, functional studies conducted on MAPRE2, encoding the microtubule plus-end binding protein EB2, point to microtubule-related trafficking effects on Na1.5 expression as a new underlying molecular mechanism. Taken together, these findings broaden our understanding of the genetic architecture of BrS and provide new insights into its molecular underpinnings

Sénescence, remodelage tissulaire et membranaire, risque thrombotique au cours de la fibrillation auriculaire

Our data evidence that during atrial fibrillation (AF), microparticles (MP) contribute to an enhanced hypercoagulable and pro-inflammatory state. Similar concentrations of MP measured in left and right atria of AF patients highlight the absence of chamber-specific enhanced thrombogenic status. During AF ablation procedures, MP concentrations progress in parallel with cell and platelet activation. We also showed that AF progression is strongly related to human atrial senescence burden pointing toward a possible network that links in human atrium, senescence burden, endothelial dysfunction, thrombogenicity and atrial remodeling. We also developed a model of left atrium endothelial cell replicative senescence providing compelling evidences indicating that atrial endothelial senescence promotes thrombogenicity, inflammation and proteolysis. These data underline the major role of renin-angiotensin system in endothelial atrial cell senescence.Nos travaux montrent qu’au cours de la fibrillation atriale (FA), les microparticules (MP) reflètent et contribuent à un état d’hypercoagulabilité et pro-inflammatoire. Leurs concentrations similaires dans les deux oreillettes de patients en FA témoignent d’une absence de différence de statut pro-thrombotique entre ces deux cavités cardiaques. Au cours des procédures d’ablation de FA, les concentrations de MP évoluent parallèlement à l’augmentation de l’activation cellulaire et plaquettaire. Nous avons également montré dans l'altération tissulaire des oreillettes en FA, l'importance de la sénescence qui évolue avec la progression du trouble du rythme. Nous avons caractérisé un modèle cellulaire de sénescence réplicative de cellules endothéliales auriculaires de porc permettant d'identifier l'apparition d'un phénotype pro-thrombotique, pro-inflammatoire, pro-adhésif et de mieux comprendre la physiologie de la cellule endothéliale atriale sénescente et le rôle majeur du système rénine-angiotensine dans ces mécanismes

Senescence, tissue and membrane remodeling, thrombotic risk in atrial fibrillation

Nos travaux montrent qu’au cours de la fibrillation atriale (FA), les microparticules (MP) reflètent et contribuent à un état d’hypercoagulabilité et pro-inflammatoire. Leurs concentrations similaires dans les deux oreillettes de patients en FA témoignent d’une absence de différence de statut pro-thrombotique entre ces deux cavités cardiaques. Au cours des procédures d’ablation de FA, les concentrations de MP évoluent parallèlement à l’augmentation de l’activation cellulaire et plaquettaire. Nous avons également montré dans l'altération tissulaire des oreillettes en FA, l'importance de la sénescence qui évolue avec la progression du trouble du rythme. Nous avons caractérisé un modèle cellulaire de sénescence réplicative de cellules endothéliales auriculaires de porc permettant d'identifier l'apparition d'un phénotype pro-thrombotique, pro-inflammatoire, pro-adhésif et de mieux comprendre la physiologie de la cellule endothéliale atriale sénescente et le rôle majeur du système rénine-angiotensine dans ces mécanismes.Our data evidence that during atrial fibrillation (AF), microparticles (MP) contribute to an enhanced hypercoagulable and pro-inflammatory state. Similar concentrations of MP measured in left and right atria of AF patients highlight the absence of chamber-specific enhanced thrombogenic status. During AF ablation procedures, MP concentrations progress in parallel with cell and platelet activation. We also showed that AF progression is strongly related to human atrial senescence burden pointing toward a possible network that links in human atrium, senescence burden, endothelial dysfunction, thrombogenicity and atrial remodeling. We also developed a model of left atrium endothelial cell replicative senescence providing compelling evidences indicating that atrial endothelial senescence promotes thrombogenicity, inflammation and proteolysis. These data underline the major role of renin-angiotensin system in endothelial atrial cell senescence