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International audience; BACKGROUND:Previous studies suggested that genetic status affects the clinical course of arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) patients. The aim of this study was to compare the outcome of desmoglein-2 (DSG2) mutation carriers to those who carry the plakophilin-2 (PKP2) mutation, the most common ARVC/D-associated gene.METHODS AND RESULTS:Consecutive ARVC/D patients carrying a pathogenic mutation in PKP2 or DSG2 were selected from a national ARVC/D registry. The cumulative freedom from sustained ventricular arrhythmia and cardiac transplantation/death from heart failure (HF) during follow-up was assessed, compared between PKP2 and DSG2, and predictors for ventricular arrhythmia and HF events determined. Overall, 118 patients from 78 families were included: 27 (23%) carried a DSG2 mutation and 91 (77%) a PKP2 mutation. There were no significant differences between DSG2 and PKP2 mutation carriers concerning gender, proband status, age at diagnosis, T-wave inversion, or right ventricular dysfunction at baseline. DSG2 patients displayed more frequent epsilon wave (37% vs. 17%, P = 0.048) and left ventricular dysfunction at diagnosis (54% vs. 10%, P < 0.001). During a median follow-up of 5.6 years (2.5-16), DSG2 and PKP2 mutation carriers displayed a similar risk of sustained ventricular arrhythmia (log-rank P = 0.20), but DSG2 mutation carriers were at higher risk of transplantation/HF-related death (log-rank P < 0.001). The presence of a DSG2 mutation vs. PKP2 mutation was a predictor of transplantation/HF-related death in univariate Cox analysis (P = 0.0005).CONCLUSIONS:In this multicentre cohort, DSG2 mutation carriers were found to be at high risk of end-stage HF compared to PKP2 mutation carriers, supporting careful haemodynamic monitoring of these patients. The benefit of early HF treatment needs to be assessed in DSG2 carriers.

Arrhythmogenic right ventricular cardiomyopathy/dysplasia (ARVC/D) is a genetic disease predominantly caused by desmosomal gene mutations that account for only ~50% of cases. Ryanodine receptor 2 (RYR2) gene mutations usually cause catecholaminergic polymorphic ventricular tachycardia but have been associated with a peculiar phenotype named ARVC2.We aimed to determine the prevalence and phenotype associated with RYR2 mutations in a large ARVC/D population.We analyzed the whole RYR2 coding sequence by Sanger sequencing in 64 ARVC/D probands without desmosomal gene mutations.We have identified 6 rare missense variants: p.P1583S, p.A2213S, p.G2367R, p.Y2932H, p.V3219M, and p.L4670V. It corresponds to a 9% prevalence of rare RYR2 variants in the ARVC/D population (6 of 64 probands), which is significantly higher than the estimated frequency of rare RYR2 variants in controls (Fisher exact test, P = .03). Phenotypes associated with RYR2 variants were similar to desmosome-related ARVC/D, associating typical electrocardiographic abnormalities at rest, frequent monomorphic ventricular tachycardia, right ventricular dilatation, wall motion abnormalities, and fibrofatty replacement when histopathological examination was available.In this first systematic screening of the whole coding region of the RYR2 gene in a large ARVC/D cohort without mutation in desmosomal genes, we show that putative RYR2 mutations are frequent (9% of ARVC/D probands) and are associated with a conventional phenotype of ARVC/D, which is in contrast with previous findings. The results support the role of the RYR2 gene in conventional ARVC/D.

La Presse Medicale - In Press.Proof corrected by the author Available online since samedi 20 decembre 2014

International audience; Amyloidosis is a severe systemic disease. Cardiac involvement may occur in the three main types of amyloidosis (acquired monoclonal light-chain, hereditary transthyretin and senile amyloidosis) and has a major impact on prognosis. Imaging the heart to characterize and detect early cardiac involvement is one of the major aims in the assessment of this disease. Electrocardiography and transthoracic echocardiography are important diagnostic and prognostic tools in patients with cardiac involvement. Cardiac magnetic resonance imaging better characterizes myocardial involvement, functional abnormalities and amyloid deposition due to its high spatial resolution. Nuclear imaging has a role in the diagnosis of transthyretin amyloid cardiomyopathy. Cardiac biomarkers are now used for risk stratification and staging of patients with light-chain systemic amyloidosis. Different types of cardiac complications may occur, including diastolic followed by systolic heart failure, atrial and/or ventricular arrhythmias, conduction disturbances, embolic events and sometimes sudden death. Senile amyloid and hereditary transthyretin amyloid cardiomyopathy have better prognoses than light-chain amyloidosis. Cardiac treatment of heart failure is usually ineffective and is often poorly tolerated because of its hypotensive and bradycardiac effects. The three main types of amyloid disease, despite their similar cardiac appearance, have specific new aetiological treatments that may change the prognosis of this disease. Cardiologists should be aware of this disease to allow early treatment.

Aims Implantable cardioverter defibrillators (ICDs) are efficient in reducing mortality in patients with left ventricular systolic dysfunction. High-rate cut-off programming may be effective in reducing appropriate and inappropriate therapies, but as the long-term consequences on morbidity and mortality remain unclear, it is underutilized. Methods and results We prospectively studied 365 consecutive patients (mean age 60 ± 10 years), with ischaemic (63%) or non-ischaemic cardiomyopathy and left ventricular dysfunction (mean ejection fraction 25 ± 7%), who were implanted with an ICD in primary prevention of sudden cardiac death (41% single chamber, 31% dual chamber, and 28% biventricular). All devices were programmed with a shock-only zone over 220 beats per minute (b.p.m.) and a monitoring zone between 170 and 220 b.p.m. During a median follow-up of 40 months, 41 patients received appropriate shocks (11.2%) and 24 inappropriate shocks (6.6%). Then, 306 patients never experienced any ICD shock (84%). Inappropriate discharges were related to supraventricular tachyarrhythmia in 10 patients, and noise/oversensing in 14 patients. Ventricular tachycardia episodes, sustained or not, were recorded in the monitoring zone in 43 patients (11.8%). Seven of these patients were symptomatic (1.9%), without lethal consequence. Sixty-two patients (17%) died: 35 from end-stage heart failure, 1 from unexplained sudden death, and 26 from a documented non-cardiac cause. Conclusion High-rate cut-off (220 b.p.m.) shock-only ICD programming, in primary prevention patients with reduced left ventricular ejection fraction, appeared to be safe during a long-term follow-up. It also resulted in a very low rate of discharges, which are known to be deleterious in this population.

In atrial fibrillation (AF), the absence of a clear benefit of a rhythm-control strategy over a rate-control strategy seen in recent trials may be due to the fact that many of the usual antiarrhythmic strategy have significant weaknesses. Besides research efforts to improve the efficacy and safety of conventional antiarrhythmic agents, therapies directed 'upstream'of the electrical aspects of AF, towards the underlying anatomical substrate and atrial remodelling, have been proposed as new pharmacological therapeutic approaches. Potential upstream therapies for AF comprise a variety of agents such as angiotensin-converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARB), statins, N-3 polyunsaturated fatty acids and steroids. On the basis of experimental data, clinical studies have provided information on the potential of upstream therapy for the prevention of AF across a broad spectrum of cardiovascular patient groups. In patients with heart failure or hypertension, data are sufficient to support the use of ACEI or ARB as treatment that may decrease the risk of AF beyond their other beneficial effects. Similarly, it is highly possible that the use of statin in patients with a recognized indication may be associated with a benefit against AF. However, in most clinical settings, the evidence appears to be insufficient to drive changes in therapy management per se, and large-scale, randomized controlled trials with adequately defined endpoints are still needed. The results from these trials may help to understand the complex mechanisms that lead to AF, and may clarify the benefit-to-risk ratio of these new therapeutic approaches.

SummaryIn patients with atrial fibrillation (AF) and an intermediate risk of stroke (CHADS2 score =1), available evidence from clinical trials is inconclusive and the present guidelines for the management of AF indicate that the choice between oral anticoagulant and aspirin in these patients is open. Our goal was to evaluate whether, in patients with AF and only one moderate risk factor for thromboembolism, treatment with an oral anticoagulant is appreciably more beneficial than treatment with an antiplatelet agent. Among 6,517 unselected patients with AF, 1,012 of them (15.5%) had a CHADS2 score of 1 and were liable to treatment with an antiplatelet agent or an anticoagulant. An oral anticoagulant was prescribed for 606 patients (59.9%) and an antiplatelet agent or no antithrombotic treatment for 406 (40.1%). During follow-up (median=793 days, interquartile range=1,332 days), 105 deaths (10.4%) and 19 strokes (1.9%) were recorded. The administration of an anticoagulant was associated with a lower rate of events (relative risk=0.42, 95% confidence interval 0.29–0.60, p

Although β2-adrenoceptors represent 15–25% of β-adrenoceptors in the guinea pig heart, their functionality is controversial. We assessed the inotropic effects of β2-adrenoceptor partial agonists in right papillary muscles. Salbutamol induced a small but significant concentration-dependent negative inotropic effect (NIE, −5% at 60 nM) followed by a moderate positive inotropic effect (+36% at 6 μM) due to activation of β1-adrenoceptors. In the presence of 4 μM atenolol, the concentration-dependent NIE (−12% at 6 μM) was biphasic, best described by a double logistic equation with respective EC50 values of 3 and ∼420 nM, and was insensitive to SR59230A. In muscles from pertussis toxin-treated guinea pigs, the salbutamol-induced positive inotropic effect was sensitive to low concentrations of ICI-118551 in an unusual manner. Experiments in reserpinized animals revealed the importance of the phosphorylation-dephosphorylation processes. PKA inhibition reduced and suppressed the effects obtained at low and high concentrations, respectively, indicating that its activation was a prerequisite to the NIE. The effect occurring at nanomolar concentrations depended upon PKA/phosphatidylinositol 3-kinase/cytosolic phospholipase A2 (cPLA2) activations leading to nitric oxide (NO) release via the arachidonic acid/cyclooxygenase pathway. NO release via PKA-dependent phosphorylation of the receptor was responsible for the inotropic effect observed at submicromolar concentrations, which is negatively controlled by cPLA2. The possibility that these effects are due to an equilibrium between different affinity states of the receptor (Gs/Gi coupled and Gi independent with different signaling pathways) that can be displaced by ICI-118551 is discussed. We conclude that β2-adrenoceptors are functional in guinea pig heart and can modulate the inotropic state.

Background and purpose: Atrial fibrillation (AF) is the most common electrical cardiac disorder in clinical practice. The major trigger for AF is focal ectopic activity of unknown origin in sleeves of cardiac muscle that extend into the pulmonary veins. We examined the role of noradrenaline in the genesis of ectopic activity in the pulmonary vein. Experimental approach: Mechanical activity of strips of pulmonary vein isolated from male Wistar rats was recorded via an isometric tension meter. Twitch contractions of cardiac myocytes were evoked by electrical field stimulation in a tissue bath through which flowed Krebs-Heinseleit solution warmed to 36-37°C and gassed with 95% O2 5% CO2. Key results: The superfusion of noradrenaline induced ectopic contractions in 71 of 76 different isolated pulmonary veins. Ectopic contractions in the pulmonary vein were not associated with electrically evoked twitch contractions. The effect of noradrenaline on the pulmonary vein could be replicated by the simultaneous, but not separate, application of the α adrenoceptor agonist phenylephrine and the β adrenoceptor agonist isoprenaline. The use of selective agonists and antagonists for adrenoceptor subtypes showed that ectopic activity in the pulmonary vein arose from the simultaneous stimulation of α1 and β1 adrenoceptors. The application of noradrenaline to isolated strips of left atrium did not induce ectopic contractions (n=10). Conclusions: These findings suggest an origin for ectopic activity in the pulmonary vein that requires activation of both α and β adrenoceptors. They also open new perspectives towards our understanding of the triggering of AF. British Journal of Pharmacology (2007) 150, 899–905. doi:10.1038/sj.bjp.0707177

The aim of this study was to investigate the in vitro vasomotor properties of rat extra-and intralobar pulmonary veins (PVs) related to their localization and to assess the modulatory role of endothelium on these properties. Segments from PVs were mounted in small vessel myograph and stretched at various diameters (D(10), D(20), D(30)) corresponding to intraluminal pressures of 10, 20 or 30 mmHg. At D(10) or D(20), contractile responses to phenylephrine, U46619 and angiotensin II of distal intralobar part of PVs were smaller compared with those of proximal extralobar part, but no longer different when distal part was stretched at D(30). When submitted to an NO donor, sodium nitroprusside, distal part of PV relaxed more strongly when stretched at D(30) compared with D(10). Acetylcholine and bradykinin were devoid of relaxing effect on distal parts stretched at D(10), but in contrast to acetylcholine, bradykinin slightly relaxed preparations stretched at D(30). Isoprenaline strongly relaxed PVs ( approximately 80% of initial precontraction), with the distal part exhibiting a higher sensitivity to the agonist compared with the proximal part. This relaxation was also observed with salbutamol and suppressed with ICI 118551, which is in favour of the involvement of beta(2)-adrenoceptors in this effect. Preincubation of the preparations with N(G)-nitro-l-arginine methyl ester (10(-4) m) and indomethacin (10(-5) m) did not modify the contractile responses to U46619, nor the relaxing response to isoprenaline, which support that endothelium does not appear to play a significant modulatory role in these responses. Histological and electron microscopical examinations of proximal and distal sections of the same vein show that the layers of smooth muscle cells and cardiomyocytes were thicker in the proximal compared with the distal part. This study shows that, because of morphological heterogeneity of the PVs, the site of dissection and the initial condition of tension can play a significant role upon the sensitivity and the magnitude of the responses to both contractile and relaxing agonists.

Atrial fibrillation, the most frequent arrhythmia, has a growing incidence with increasing age and the most important complication of the disease is thromboembolic events that may be prevented by antivitamin K. They are the most efficient therapeutic class for the prevention of these events but they are associated with an increased haemorrhagic risk leading to a reduced prescription in general practice. Optimisation of the management should be based on an individual evaluation of the thromboembolic and haemorrhagic risks, taking into account age, the presence of an associated heart disease, hypertension, diabetes, history of cerebrovascular event, history of previous haemorrhagic event and the ability to achieve a stable target INR. The challenge in ventricular arrhythmias lies in identifying a high risk of sudden death, mainly related to ventricular fibrillation. In patients with structural heart disease, left ventricular dysfunction is the strongest predictor of sudden death. Non invasive markers such as non sustained ventricular tachycardia, late ventricular potentials, decreased heart rate variability and baroreflex sensitivity, and repolarization altemans are further elements to assess risk. However, most of these markers have a poor positive predictive value and a low specificity. In patients with normal hearts, genetic predisposition may in the future identify high risk patients. The electrophysiologic study with programmed ventricular stimulation remains a costly and invasive method and only has a strong positive predictive value in ischemic cardiomyopathy. More precise algorithms for risk stratification are thus needed that may help the strategy of therapy with prophylactic implantable cardioverter defibrillator in the future.

Brugada syndrome is a primary electrical cardiac disease characterized by an ST segment elevation in V1-V2 leads on surface ECG and an increased risk of polymorphic ventricular tachyarrhythmia (ventricular tachycardia and/or ventricular fibrillation). The objective of the treatment is to prevent sudden death and it therefore includes in some cases the implantation of an automatic implantable cardiac defibrillator (AICD). In secondary prevention (i.e. after a first episode of resuscitated ventricular fibrillation), the implantation of AICD is mandatory (indication of class 1 level A). In primary prevention (i.e. in patients without documented ventricular fibrillation), the guidelines are not definitively established. We may consider two different clinical situations. First, the patient complains from syncope and this justifies the implantation of an AICD. Second, the patient is asymptomatic and the physician has to discuss the implantation of an AICD. Two parameters should be analysed: the pattern of ECG and the result of right programmed ventricular stimulation. An evident ST segment elevation (>2 mm) is associated with a high risk of sudden death. Likewise, the inducibility of a ventricular tachycardia or fibrillation is considered at the present time as a factor linked to sudden death and justifies the implantation of an AICD. On the other hand, a normal resting ECG only associated with a provoked ST segment elevation by class I antiarrhythmic drug (flecainide) defines a group of patients with a low risk of sudden death, and these patients do not require the implantation of an AICD.

This article includes an overview of the actual French control and regulation system of the safety alerts involving pacemakers and implantable cardioverter-defibrillator and an evaluation of the general information and trends about the characteristics of the reported incidents obtained in the last years in that field. The national security agencies have the mission to collect the data on safety and efficacy of medical devices but manufacturers, physicians and patients also have a role to play. The technical appreciation of the necessity of a notification is not easy in some cases but the lack of notification of a severe incident may lead to heavy penal consequences. If doubtful cases, one should keep in mind the spirit of these safety systems: a collective insurance against the risks related to the use of medical devices. In the 10 last years, the annual advisory rate was increased. The pacemakers were recalled more frequently than implantable cardioverter-defibrillators in absolute value but less frequently in relative value (advisories per 100 person-years). This increase may be related to the growing number of device implants and expanding indications for device therapy, to the increasing sophistication of the devices and to the modifications in the regulation aspects of these problems with a closer attention of users and physicians to the several types of malfunctions.

Background: The decrease in heart rate variability (HRV) might be related to the hemodynamic status in heart failure. However, HRV in patients with severe isolated right heart failure has not been extensively studied. Aims: This study compared HRV in patients with congestive heart failure (CHF) and in patients with isolated right heart failure. Methods: Time and frequency domain analysis of HRV on 24-h ECG recording was assessed in 15 healthy subjects and in two groups of patients with severe heart failure awaiting heart or heart/lung transplantation. These were 15 patients with CHF due to idiopathic dilated cardiomyopathy (IDC) and 10 patients with isolated right heart failure due to primary pulmonary hypertension (PPH). Results: Measurement of HRV were significantly decreased in both groups of patients compared with the control group. Patients with IDC had higher pulmonary capillary wedge pressure than patients with PPH (P=0.04) but lower pulmonary artery pressure and lower pulmonary vascular resistance (PVR) (P

International audience; Using Fourier phase analysis of equilibrium radionuclide angiography in both ventricles, inter- and intraventricular delays were correlated with QRS morphology and duration in 103 patients with idiopathic dilated cardiomyopathy. We found that left bundle branch block on the left axis may reflect a high intra-left ventricular dyssynchrony. A precise evaluation of the dyssynchrony appears useful because a high proportion of patients with incomplete bundle branch block, left anterior hemiblock, or "normal" QRS exhibit a marked intra-LV dyssynchrony and may respond to cardiac resynchronization therapy.

Strokes have a high prevalence, with a high rate of recurrence, and about 30–40% remain of unknown cause. Some patients might have asymptomatic paroxysmal atrial fibrillation (AF) which remains the main cause of embolic events. A latent atrial arrhythmogenic substrate may induce recurrent arrhythmias, including functional abnormalities such as nonuniform refractoriness and/or anatomic abnormalities such as atrial septum aneurysm (ASA) and patent foramen ovale (PFO). In 175 patients divided into three groups (Group I: 103 patients with unexplained ischemic stroke, Group II: 48 patients with paroxysmal AF and Group III or control group: 24 patients explored for another cause), such an atrial arrhythmogenic substrate was assessed by electrophysiological study. Groups I and II had a similar high rate of inducible atrial arrhythmias compared to control group III where no arrhythmia was induced. An induced atrial arrhythmia was observed in more than 50% of patients of Group I and in more than 70% of patients of Group II without any significant difference according to age. However, in 26 young patients of Group I who had a transesophageal echocardiography, both a high rate (46%) of ASA and/or PFO and a frequent latent atrial vulnerability (LAV) were observed, compared to older patients where an atrial septum abnormality was observed in only 21% of cases. Thus, among patients with stroke of unknown cause, a high percentage of them might have asymptomatic atrial paroxysmal arrhythmia. The predictive value of the electrophysiological study for spontaneous arrhythmias and recurrence of stroke remains to be demonstrated.

Objectives The study evaluated the prognostic value of interventricular and intraventricular dyssynchrony in idiopathic dilated cardiomyopathy (IDC). Background Biventricular pacing is an emerging treatment for patients with dilated cardiomyopathy and ventricular dyssynchrony. The prognostic values of interventricular and intraventricular dyssynchrony have not been previously compared. Methods A total of 103 patients with IDC were studied. Left bundle branch block was present in 25% of patients. Equilibrium radionuclide angiography was performed and Fourier phase analyses were examined in both ventricles. Difference between the mean phase of left ventricle (LV) and right ventricle (RV) assessed interventricular dyssynchrony, and standard deviations (SDs) of the mean phase in each ventricle assessed intraventricular dyssynchrony. Results The QRS duration was related to both interventricular and intraventricular dyssynchrony. A degradation of the hemodynamic status was associated with an increase in intraventricular dyssynchrony but not in interventricular dyssynchrony. With a follow-up of 27 ± 23 months, 18 patients had a major cardiac event (7 cardiac deaths; 11 worsening, leading to heart transplantation). The SDs of the LV and RV mean phase and QRS duration were predictors of cardiac event (all p Conclusions Intraventricular dyssynchrony evaluated with phase analysis of radionuclide angiography is an independent predictor of cardiac event in IDC. The prognosis is related to intraventricular rather than to interventricular dyssynchrony in IDC.

A 65-year-old patient presented with recurrent cardiac decompensation 12 years after aortic prosthesis replacement and expanded polytetrafluoroethylene (ePTFE) membrane pericardial substitution. Diagnosis of pericardial constriction was difficult. Only one cardiac imaging method, radionuclide ventriculography, was helpful. Upon re-operation, an epicardial fibrous strap which restricted right ventricle (RV) diastolic expansion was found between the anterior free wall and diaphragmatic portion of the RV. Clinical status dramatically improved after surgical removal of this bridle, as did ventricular filling curves in radionuclide imaging. This case shows that delayed cardiac constriction is possible after ePTFE pericardial substitution, especially if the membrane is applied to both anterior and diaphragmatic aspects of the heart.

Phase imaging assessed with a 3-dimensional analysis is particularly interesting for its capacity to detect an area with early contraction corresponding to the site of VT with accuracy and to demonstrate 1 or several areas with delayed contraction because of the loss of contractile tissue by fatty or fibrofatty replacement, as has been suggested with magnetic resonance images. We believe that this 3-dimensional Fourier analysis of SPECT ERNA should be widely used in sinus rhythm and when possible, during episodes of VT before treatment by ablation techniques or surgery.

Alteration of Cardiac Action Potential. Introduction: Alteration of cardiac action potential and its adaptation to heart rate could contribute to cardiac dysfunction and arrhythmias during acute cardiac rejection. Methods and Results: Heterotopic heart transplantation was performed in allogeneic and syngeneic rats in which the action potentials of right and left ventricles were measured at 1, 2.5, 3.3, and 5.7 Hz successively using standard microelectrode techniques and compared with nontransplanted hearts. For each frequency, we measured action potential amplitude, action potential duration, transmembrane resting potential, and Vmax. In the right ventricle, at 1 Hz in the presence of rejection (n = 40), a significant increase was observed in action potential duration at 20%, 50%, and 70% repolarization (82.5%, 75.6%, and 70.8%, respectively) and in action potential amplitude (+17.9 mV), and the resting potential was decreased (-5.3 mV). A lack of adaptation of action potential duration to the driving frequency was observed in the rejecting heart group in contrast to controls (n = 20) and nourejecting hearts (n = 13). Similar results were observed in the left ventricle and surprisingly in the native hearts (n = 11) of recipients with allografted rejecting hearts in the abdominal position. Conclusion: Action potential and its adaptation to the driving frequency is considerably altered during acute rejection. A humoral factor could contribute to cardiac dysfunction.

Heart rate variability is a noninvasive indicator of autonomic nervous system activity. The role of the autonomic nervous system in the genesis of atrial or ventricular arrhythmias is now well established. Little is known about the effects of flecainide on heart rate variability in patients with normal heart structure, the main population receiving flecainide. This study was designed to evaluate the effects of flecainide on heart rate variability in patients without coronary artery disease or congestive heart failure. Time and frequency domain analysis of heart rate variability on 24-hour electrocardiogram recording were assessed in 40 patients with normal echocardiography and without evidence of coronary artery disease before and after 2 months of oral treatment with flecainide (321 +/- 57 mg/day) prescribed for Wolff Parkinson White syndrome with circus movement tachycardia. Flecainide significantly decreased all parameters of heart rate variability in the time domain (median delta% -10% to -25%) and in the frequency domain (median delta% -27% to -38%), including the markers of vagal activity. There was no correlation between plasma concentrations of flecainide and reduction in heart rate variability. It was concluded that in subjects without coronary artery disease or congestive heart failure, flecainide decreases all the measurements of heart rate variability and this decrease is not related to plasma concentrations of flecainide.

The increasing number of heart transplant patients requires that physicians be able to recognize the electrocardiographic (ECG) and electrophysiologic properties of cardiac allografts. Cardiac allografts are characterized by modifications of resting ECGs and frequent arrhythmias in the postoperative period, and the loss of autonomic nervous control illustrated by permanent tachycardia and loss of heart rate variability during 24-hour ambulatory ECG recording. Some clinical and experimental observations suggest a mid-term reinnervation of the cardiac allograft, but this requires histologic confirmation. The electrophysiologic characteristics of the denervated myocardium are similar to those of the innervated myocardium at rest. However, supersensitivity to circulating catecholamines has been observed in cardiac allografts as in experimentally denervated hearts, which is responsible for a progressive increase in heart rate during exercise and a slow decrease during recovery. Supersensitivity of the denervated heart to acetylcholine may explain the high prevalence of donor sinus dysfunction due to impairment of its automaticity. More often, the sinus node dysfunction is transient and can be treated with an adenosine antagonist, such as theophylline, before permanent implantation of a pacemaker. In the case of pacemaker implantation, synchronization of the donor atria with the recipient atria is desirable, and an endocardial lead implantation is preferred. Several electrophysiologic changes have been observed during acute cardiac allograft rejection. From experimental studies, the most important of these are the disturbance of conduction in the atria and the atrioventricular node and a decrease in the amplitude of the ventricular potential. Initial studies on isolated myocytes show profound changes in membrane conductance during experimental cardiac rejection. The development of new noninvasive detection methods of cardiac allograft rejection, such as intramyocardial voltage electrogram monitoring and high-resolution ECG, could help early diagnosis.

International audience; AIMS: Five desmosomal genes have been recently implicated in arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVD/C) but the clinical impact of genetics remains poorly understood. We wanted to address the potential impact of genotyping. METHODS AND RESULTS: Direct sequencing of the five genes (JUP, DSP, PKP2, DSG2, and DSC2) was performed in 135 unrelated patients with ARVD/C. We identified 41 different disease-causing mutations, including 28 novel ones, in 62 patients (46%). In addition, a genetic variant of unknown significance was identified in nine additional patients (7%). Distribution of genes was 31% (PKP2), 10% (DSG2), 4.5% (DSP), 1.5% (DSC2), and 0% (JUP). The presence of desmosomal mutations was not associated with familial context but was associated with young age, symptoms, electrical substrate, and extensive structural damage. When compared with other genes, DSG2 mutations were associated with more frequent left ventricular involvement (P = 0.006). Finally, complex genetic status with multiple mutations was identified in 4% of patients and was associated with more frequent sudden death (P = 0.047). CONCLUSION: This study supports the use of genetic testing as a new diagnostic tool in ARVC/D and also suggests a prognostic impact, as the severity of the disease appears different according to the underlying gene or the presence of multiple mutations.

We report the case of an 18-year-old man with Danon disease, a genetic disorder inclunding a severe hypertrophic cardiomyopathy with very broad QRS, who had an implantable cardioverter defibrillator for primary prevention. Nine months after implantation, he received two inappropriate shocks due to R-wave double counting during sinus tachycardia. We discuss how to avoid such inappropriate therapy.

The physiology of cardiac muscle in thoracic veins is of interest as a source of ectopic activity which can lead to paroxystic atrial fibrillation (Haissaguerre et al. 1998 N Engl J Med 339: 659-666 ; Chen et al. 1999 Circulation 100:1879-1886). We have shown that noradrenalin can induce automatic ectopic activity in the pulmonary vein of the rat (Maupoil et al. 2007 Br J Pharmacol 150:899-905). Here we describe the effects of adrenergic agonists upon the resting membrane potential recorded with intracellular microelectrodes from cardiac muscle in the left atrium (LA), pulmonary veins (PV) and superior vena cava (SVC) of the rat. Isolated tissues were continuously perfused with Krebs-Heinseleit solution aerated with 95 % O2, 5 % CO2 and maintained at 36-37 °C. The quiescent resting membrane potentials were: LA −84±1 mV (n=14), SVC −74±1 mV (n=14), PV −69±1 mV (n=17). In each tissue noradrenalin (10-5M) induced a biphasic response with an initial hyperpolarisation (LA −3±1 mV, SVC −9±1 mV, PV −8±1 mV) followed by a depolarisation (LA +1±2 mV, SVC +15±2 mV, PV +34±1 mV). Only in PV did noradrenalin induce automatic electrical activity when the membrane potential reached ∼−50 mV. The α-adrenergic agonist cirazoline (10-6M) induced a monophasic depolarisation of the resting membrane potential in each tissue: to −80±2 mV in LA, to −49±1 mV in SVC and to −34±1 mV in PV. In no case did cirazoline induce automatic electrical activity. The β-adrenergic agonist isoprenaline (10-7M) induced a monophasic hyperpolarisation of the resting membrane potential in each tissue: to −87±1 mV in LA, to −79±2 mV in SVC and to −80±2 mV in PV. Conclusions 1. There are significant differences between the resting membrane potentials of the left atrium and both thoracic veins. 2. The responses of the resting membrane potential to adrenergic stimulation are qualitatively similar but quantitatively different with LA 3. Depolarisation is not sufficient to induce automatic electrical activity.

Objectives We aimed to determine whether mechanical dyssynchrony assessed by Equilibrium RadioNuclide Angiography (ERNA) may predict response to CRT. Methods 70 patients were consecutively enrolled. ERNA, echocardiography and electrocardiogram were performed before biventricular pacemaker implantation. Positive response to CRT was defined as an improvement in NYHA class in patients alive and not readmitted for HF within 6 months. Results Mean age was 65±9 years, 74 % of patients were men, 84 % were in NYHA class III or IV. Main HF aetiologies were ischemic (36 %) or dilated (50 %). ERNA left ventricular ejection fraction was 21±9 %, QRS duration was 161±34 ms. 96 % of patients received an ACE inhibitor or an angiotensin II receptor antagonist, 66 % a beta-blocker and 36 % an aldosterone antagonist. Non-response rate was 31.5 %. Interventricular delay assessed by ERNA was greater in non-responders versus responders in univariate analysis: respectively 92±39 ms and 57±46 ms, p = 0.005. QRS duration, interventricular and intraventricular delay assessed by echocardiography, intraventricular delay assessed by ERNA, were not significantly different between the two groups. In conclusion, by contrast to other methods, interventricular delay assessed by ERNA before implantation may help to identify responders and non-responders to CRT.

Ectopic activity in cardiac muscle within pulmonary veins (PVs) is associated with the onset and the maintenance of atrial fibrillation in humans. The mechanism underlying this ectopic activity is unknown. Here we investigate automatic activity generated by catecholaminergic stimulation in the rat PV. Intracellular microelectrodes were used to record electrical activity in isolated strips of rat PV and left atrium (LA). The resting cardiac muscle membrane potential was lower in PV [−70 ± 1 (SE) mV, n = 8] than in LA (−85 ± 1 mV, n = 8). No spontaneous activity was recorded in PV or LA under basal conditions. Norepinephrine (10−5 M) induced first a hyperpolarization (−8 ± 1 mV in PV, −3 ± 1 mV in LA, n = 8 for both) then a slowly developing depolarization (+21 ± 2 mV after 15 min in PV, +1 ± 2 mV in LA) of the resting membrane potential. Automatic activity occurred only in PV; it was triggered at approximately −50 mV, and it occurred as repetitive bursts of slow action potentials. The diastolic membrane potential increased during a burst and slowly depolarized between bursts. Automatic activity in the PV was blocked by either atenolol or prazosine, and it could be generated with a mixture of cirazoline and isoprenaline. In both tissues, cirazoline (10−6 M) induced a depolarization (+37 ± 2 mV in PV, n = 5; +5 ± 1 mV in LA, n = 5), and isoprenaline (10−7 M) evoked a hyperpolarization (−11 ± 3 mV in PV, n = 7; −3 ± 1 mV in LA, n = 6). The differences in membrane potential and reaction to adrenergic stimulation lead to automatic electrical activity occurring specifically in cardiac muscle in the PV.

In 39 patients with myotonic dystrophy, we found a high percentage of infrahissian cardiac conduction abnormalities (51%) and late potentials (46%), whereas spontaneous and inducible ventricular arrhythmias were rare. These results suggest that the prolongation of QRSD and the duration of the low-amplitude signal on the signal-averaged electrocardiogram were related to delayed activation of the His and Purkinje tissue rather than true late potentials.

In patients with atrial fibrillation (AF) and heart failure (HF), beta blockers and digoxin reduce the ventricular rate, but controversy exists concerning how these drugs affect prognosis in this setting. This study compared the effects of beta blocker and digoxin on mortality in patients with both AF and HF. In a single-center institution, patients with AF and HF seen between January 2000 and January 2004 were identified and followed until September 2007. Of 1,269 consecutive patients with both AF and HF, 260 were treated with a beta blocker alone, 189 with beta blocker plus digoxin, 402 with digoxin alone, and 418 without beta blocker or digoxin (control group). During a follow-up of 881+/-859 days, 247 patients died. Compared with the control group, treatment with beta blocker was associated with a decreased mortality (relative risk=0.58, 95% confidence interval 0.40 to 0.85, p=0.005 for beta blocker alone and 0.59, 95% confidence interval 0.40 to 0.87, p=0.008 for beta blocker plus digoxin). By contrast, treatment with digoxin alone was not associated with a better survival (relative risk=0.97, 95% confidence interval 0.73 to 1.30, p=NS). Results remained significant after adjustment for potential confounders and similar when we considered, separately, HF with permanent or nonpermanent AF, presence or absence of coronary disease, and patients with decreased or preserved systolic function. In conclusion, in unselected patients with AF and HF, treatments with beta blocker alone or with beta blocker plus digoxin are associated with a similar decrease in the risk of death. Digoxin alone is associated with a worse survival chance, similar to that of patients without any rate control treatment.

Objective— In patients with severe aortic stenosis (AS), we examine the association between: (1) the content of oxidized LDL (oxLDL) in the aortic valve and the degree of inflammation and remodeling; (2) The proportion of small dense LDL particles in the plasma and the presence of oxLDL in the valve along with hemodynamic progression of valve stenosis. Methods and Results— We have examined 102 explanted AS valves. Tissue remodeling, inflammation, and accumulation of oxLDL were determined. A complete plasma lipid profile including the measurement of the relative proportion of small low-density lipoprotein (%LDL ) was obtained. Valves with higher oxLDL content had a significantly higher density of inflammatory cells, expression of tumor necrosis factor (TNF)-α, and increased tissue remodeling score. The %LDL was significantly associated with oxLDL score within the aortic valve. In a subset of 59 patients in whom stenosis progression was measured, the %LDL correlated with the annualized peak gradient ( r =0.29; P =0.04). Conclusion— Increased proportion of circulating small dense LDL particles is associated with faster progression rate of stenosis and greater accumulation of oxLDL in the aortic valve. These findings suggest that therapeutic interventions aimed at lowering the production of small dense LDL particles in patients with AS might represent a potentially interesting therapeutic avenue.

Nonreentrant atrioventricular (AV) nodal tachycardia is a rare form of arrhythmia due to simultaneous anterograde conduction in dual AV pathways, one atrial impulse triggering two ventricular complexes. We report the case of a 74-year-old man referred for incessant palpitations resistant to antiarrhythmic medication, and effort dyspnea. A nonreentrant AV nodal tachycardia is diagnosed with electrophysiological study. A dilated cardiomyopathy with left ventricular dysfunction is found with gated blood pool single-photon emission computed tomography. A radiofrequency catheter ablation of the slow pathway is successfully performed. The patient is reassessed 11 months after ablation. He is asymptomatic and left ventricular function has fully recovered.

International audience; The functional effects of the anti-G21V antibody directed against the second extracellular loop of human heart S-HT4 receptors can differ when the receptors are expressed in different cell lines. Here, we extend these studies to show variation in the responses of 5-HT4(g) receptors to the antibody within the same expression system. In a previous report no effect of the anti-G21V antibodies had been shown upon 5-HT4(g) receptors expressed in CHO cells. Here the same antibodies alone or when added before 5-HT had a functional "inverse-agonist like" effect upon 5-HT4(g) receptors expressed in a separate line of CHO cells. Although these CHO cells showed a lower efficacy of cAMP production evoked by 5-HT than the previous report they express a similar hS-HT4(g) receptor density. Inhibition of either phosphodiesterases or Gi proteins had no effect upon the action of the antibody. Conformational states of the 5-HT4 receptor and/or equilibrium between different states of receptors may then determine the functional effect of antibodies against this receptor. (c) 2006 Elsevier Inc. All rights reserved.

Background: In Brugada syndrome (BSY), most of the ventricular arrhythmic events are nocturnal, suggesting an influence of the autonomic nervous system. Methods: In 46 patients (mean age = 41 ± 14 years, 43 men) with electrocardiograms (ECG) consistent with BSY and structurally normal hearts, we measured heart rate variability (HRV) and QT dynamics (QT/RR slopes) on 24-hour ambulatory ECG. Type 1 BSY-ECG was spontaneous in 23 (50%) and induced in 23 patients. Results: History of syncope was present in 23 patients (50%). Programmed ventricular stimulation induced ventricular tachyarrhythmias (VTA) in 13 patients (28%). A single patient developed ventricular tachycardia during a mean follow-up of 34 months. Compared to a control group matched for age and sex, HRV was decreased over 24 hours and during nighttime in patients with BSY (SDNN 122 ± 44 vs 93 ± 36 ms, P = 0.0008 and SDANN 88 ± 39 vs 54 ± 24 ms, P < 0.0001). QTend /RR slopes were decreased over 24 hours in patients with BSY (0.159 ± 0.05 vs 0.127 ± 0.05, P = 0.003) and particularly at night (0.123 ± 0.04 vs 0.089 ± 0.04, P = 0.0001). QTend /RR slopes were significantly decreased during nighttime in patients with spontaneous versus provoked BSY-ECG patterns. By contrast, HRV and QT/RR slopes were similar in symptomatic and asymptomatic patients, whether VTA were induced or not. Conclusions: Patients with a BSY-ECG pattern had lower HRV and QT/RR slopes than control subjects during nighttime. High-risk patients with spontaneous BSY-ECG patterns had the lowest nocturnal QTend/RR slopes. These unique repolarization dynamics might be related to the frequent nocturnal occurrence of VTA in BSY.

International audience; There are still controversies about pertinent criteria for cardiac resynchronization therapy (CRT) and prophylactic indications for biventricular cardioverter-defibrillators, particularly in idiopathic dilated cardiomyopathy (IDC). This study compared several criteria for resynchronization therapy in IDC among those of several completed trials. In 201 patients with IDC, the relative risk for (1) death from heart failure (HF) or heart transplantation and (2) sudden death or sustained ventricular tachyarrhythmia were calculated separately according to the inclusion criteria of the Multisite Stimulation in Cardiomyopathy (MUSTIC), InSync, Multicenter InSync Randomized Clinical Evaluation (MIRACLE), Pacing Therapies for Congestive Heart Failure (PATH-CHF), Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION), and CONTAK studies. The percentage of patients meeting the criteria ranged from 6% for those of MUSTIC to 23% for those of CONTAK. In a follow-up of 51 +/- 42 months, 28 patients died (15 from progressive HF, 13 from sudden death), 20 underwent heart transplantation, and 12 had sustained ventricular tachyarrhythmia. Relative risks of worsening HF ranged from 3.14 (95% confidence interval [CI] 1.41 to 6.99, p = 0.005) for the MIRACLE criteria to 4.63 (95% CI 1.76 to 12.2, p = 0.0019) for the MUSTIC criteria. Only the CONTAK criteria were significantly associated with a risk for major arrhythmic events (2.65, 95% CI 1.19 to 5.95, p = 0.018). Arrhythmic events constituted 16% of all cardiac events for the MUSTIC patients, 11% for InSync patients, 31% for PATH-CHF patients, 36% for MIRACLE patients, 38% for COMPANION patients, and 42% for CONTAK patients. In conclusion, in IDC, the less restrictive criteria for CRT were associated with the greatest risk for arrhythmic events. In contrast, patients with the MUSTIC criteria for CRT mainly had a risk for worsening HF and may not benefit from biventricular cardioverter-defibrillators.

Background: In idiopathic dilated cardiomyopathy (IDC), the predictive value of QT dispersion is still under debate. Aims: This study assessed the role of QT dispersion for the long-term risk of cardiac death and of major arrhythmic events in IDC. Methods and results: In 162 patients with IDC (age 52±12 years), the QT interval on a 12-lead ECG was measured manually. QT dispersion was evaluated with QT range and QT standard deviation, for both QT and QTc (Bazett formula). With a follow-up of 53±41 months, QT dispersion was not a predictor of cardiac death in univariate or in multivariate analysis, and was of similar value for patients with or without bundle branch block. Using multivariate analysis, increased pulmonary capillary wedge pressure (p=0.003), decreased heart rate variability (Standard deviation of all NN intervals, p=0.01) and non-sustained ventricular tachycardia (NSVT) (p=0.03) were predictors of cardiac death. Sudden death and/or major arrhythmic events were independently predicted by NSVT (p=0.005), decreased heart rate variability (p=0.01) and late ventricular potentials on signal averaged ECG (p=0.02). Conclusion: This study confirms the poor prognostic value of QT dispersion in patients with IDC. Other methods to assess repolarization abnormalities need to be evaluated in such patients.

The initial objective of this work was to examine the effects of an antibody (Anti-G21V) directed against the second extracellular loop of human heart 5-HT4 receptors expressed in Chinese hamster ovary (CHO) cells. The antibody anti-G21V had no effect upon either basal cAMP-or 5-HT-evoked increases in cAMP in CHO cells, whereas it had shown an agonist-like effect in COS-7 cells. Analysis of agonist fractions of h5-HT4(e) receptors in CHO and COS-7 cells revealed that equilibrium constant could underlie the different responses of the receptor toward the anti-G21V antibody. Therefore, different expression systems could give rise to functional differences in 5-HT4 receptor behavior.

International audience; There is considerable variability in segmental wall motion abnormalities and in the prognosis of idiopathic dilated cardiomyopathy (IDC). Radionuclide ventriculography with Fourier analysis was performed in 107 patients with angiographically proved IDC. Amplitude analysis located the wall motion abnormalities. Using phase analysis in the left and right ventricles, the interventricular delay between the mean phase of the right and left ventricles was used to assess interventricular dyssynchrony and SDs of the mean phase in each ventricle was used to assess intraventricular dyssynchrony. Hypokinesis was global in 56 patients (52%) and localized in the anteroseptal wall in 34 (32%), the inferior wall in 12 (11%), the anteroseptal and inferior walls in 2 (2%), and the lateral wall in 3 (3%). Patients with localized wall motion abnormalities had larger left ventricular (LV) end-diastolic diameters (70 +/- 9 vs 66 +/- 8 mm, p = 0.009) and lower LV ejection fractions (25 +/- 9% vs 31 +/- 12%, p = 0.005). Intraventricular dyssynchrony was lower in patients with global hypokinesis (SD of LV mean phase 67 +/- 35 vs 48 +/- 22 ms, p = 0.002). With a follow-up of 27 +/- 23 months, increased SD of the LV phase (p = 0.005), decreased right ventricular ejection fraction (p = 0.006), decreased LV ejection fraction (p = 0.04), and localized wall motion abnormality (p = 0.009) were independent predictors of cardiac death or worsening heart failure leading to heart transplantation. Thus, segmental wall motion abnormalities are frequent in IDC and are associated with severe systolic dysfunction and a worse prognosis.

International audience; In human atrial myocytes, serotonin rather than sympathetic, stimulation is more frequently associated with atrial fibrillation. So does the arrhythmogenic effect of serotonin result from the mechanism of action of the receptor or the context of its action upon cardiac myocytes? The capacity of agonists to produce cAMP followed the sequence 5-HT < Iso < Forskolin to increase ICaL with 5-HT = Iso = Forskolin. The simultaneous application of threshold concentrations of 5-HT and Iso maximally increased ICaL. We will show that the effect of 5-HT upon human atrial myocytes is an imbalance between low production of cAMP and maximal activation of ICaL.

International audience; Biventricular pacing is a new form of treatment for patients with dilated cardiomyopathy and ventricular dyssynchrony. Limited information is available regarding the relationship between ventricular dyssynchrony and risk markers of ventricular arrhythmias in idiopathic dilated cardiomyopathy (IDC). In 103 patients with IDC, Fourier phase analysis of both ventricles was performed from equilibrium radionuclide angiography (ERNA). The difference between the mean phase of the LV and RV was a measure of interventricular dyssynchrony, and the standard deviations of the mean phases in each ventricle measured intraventricular dyssynchrony. There were no significant differences in inter- and intraventricular dyssynchrony between patients with versus without histories of sustained VT or VF, nonsustained VT, abnormal signal-averaged ECG, or induced sustained monomorphic VT. Dyssynchrony was not related to decreased heart rate variability (HRV). LV and interventricular dyssynchrony were weakly related to QT duration and QT dispersion. During a follow-up of 27 +/- 23 months, 21 patients had major adverse cardiac events (MACE), including 7 cardiac deaths, 11 progression of heart failure leading to cardiac transplantation, and 3 sustained VT/VF. The only independent predictors of MACE were an increased standard deviation of LV mean phase (P = 0.003), a decreased HRV (standard deviation of normal-to-normal intervals, P = 0.004), and histories of previous VT/VF (P = 0.03) or nonsustained VT (P = 0.04). In conclusion, left intraventricular dyssynchrony evaluated with ERNA was an independent predictor of MACE in IDC and was not related to usual risk markers of ventricular arrhythmias. This may have implications for resynchronization therapy and/or the use of implantable cardioverter defibrillators in IDC.