Gabriel Laurent

Multifocal ectopic Purkinje-related premature contractions: a new SCN5A-related cardiac channelopathy.

OBJECTIVES The aim of this study was to describe a new familial cardiac phenotype and to elucidate the electrophysiological mechanism responsible for the disease. BACKGROUND Mutations in several genes encoding ion channels, especially SCN5A, have emerged as the basis for a variety of inherited cardiac arrhythmias. METHODS Three unrelated families comprising 21 individuals affected by multifocal ectopic Purkinje-related premature contractions (MEPPC) characterized by narrow junctional and rare sinus beats competing with numerous premature ventricular contractions with right and/or left bundle branch block patterns were identified. RESULTS Dilated cardiomyopathy was identified in 6 patients, atrial arrhythmias were detected in 9 patients, and sudden death was reported in 5 individuals. Invasive electrophysiological studies demonstrated that premature ventricular complexes originated from the Purkinje tissue. Hydroquinidine treatment dramatically decreased the number of premature ventricular complexes. It normalized the contractile function in 2 patients. All the affected subjects carried the c.665G>A transition in the SCN5A gene. Patch-clamp studies of resulting p.Arg222Gln (R222Q) Nav1.5 revealed a net gain of function of the sodium channel, leading, in silico, to incomplete repolarization in Purkinje cells responsible for premature ventricular action potentials. In vitro and in silico studies recapitulated the normalization of the ventricular action potentials in the presence of quinidine. CONCLUSIONS A new SCN5A-related cardiac syndrome, MEPPC, was identified. The SCN5A mutation leads to a gain of function of the sodium channel responsible for hyperexcitability of the fascicular-Purkinje system. The MEPPC syndrome is responsive to hydroquinidine.

n-3 Polyunsaturated fatty acids alter expression of fibrotic and hypertrophic genes in a dog model of atrial cardiomyopathy.

BACKGROUND We previously showed that omega-3 polyunsaturated fatty acids (PUFAs) reduce vulnerability to atrial fibrillation (AF). The mechanisms underlying this effect are unknown. OBJECTIVE The purpose of this study was to use a genome-wide approach to identify gene expression profiles involved in a new model of AF vulnerability and to determine whether they were altered by PUFA therapy. METHODS Thirty-six dogs were randomized evenly into three groups. Two groups were paced using simultaneous atrioventricular pacing (SAVP) at 220 bpm for 14 days to induce atrial enlargement, fibrosis, and susceptibility to AF. One group was supplemented with oral PUFAs (850 mg/day) for 21 days, commencing 7 days before the start of pacing (SAVP-PUFAs). The second group received no PUFAs (SAVP-No PUFAs). The remaining dogs were unpaced, unsupplemented controls (CTRL). Atrial tissue was sampled at the end of the protocol. Gene expression was analyzed in four dogs randomly selected from each group (n = 12) via microarray. Results were confirmed with quantitative real-time polymerase chain reaction (RT-PCR) and histology on all 36 dogs. RESULTS Microarray or quantitative RT-PCR results showed that SAVP-No PUFAs dogs had significantly increased mRNA levels of protein kinase B (Akt), epidermal growth factor (EGF), JAM3, myosin heavy chain alpha (MHCalpha), and CD99 and significantly decreased levels of Smad6 compared with CTRL dogs. Quantitative RT-PCR showed that PUFA supplementation was associated with significant down-regulation of Akt, EGF, JAM3, MHCalpha, and CD99 levels compared with SAVP-No PUFAs dogs. CONCLUSION The effect of PUFAs on these fibrosis, hypertrophy, and inflammation related genes suggests that, in this model, PUFA-mediated prevention of AF may be due to attenuation of adverse remodeling at the genetic level in response to mechanical stress.

Atrial dyssynchrony syndrome: an overlooked phenomenon and a potential cause of ‘diastolic’ heart failure

The purpose of the present study was too explore the role of interatrial dyssynchrony in heart failure with preserved ejection fraction (HFPEF).

Effects of Chronic Gap Junction Conduction-Enhancing Antiarrhythmic Peptide GAP-134 Administration on Experimental Atrial Fibrillation in Dogs

Background—Abnormal intercellular communication caused by connexin dysfunction may contribute to atrial fibrillation (AF). The present study assessed the effect of the gap junction conduction–enhancing antiarrhythmic peptide GAP-134 on AF inducibility and maintenance in a dog model of atrial cardiomyopathy. Methods and Results—Twenty-four dogs subject to simultaneous atrioventricular pacing (220 bpm for 14 days) were randomly assigned to placebo treatment (PACED-CTRL; 12 dogs) or oral GAP-134 (2.9 mg/kg BID; PACED-GAP-134; 12 dogs) starting on day 0. UNPACED-CTRL (4 dogs) and UNPACED-GAP-134 (4 dogs) served as additional control groups. Change in left atrial (LA) systolic area from baseline to 14 days was calculated using transoesophageal echocardiography. At 14 days, animals underwent an open-chest electrophysiological study. PACED-CTRL dogs (versus UNPACED-CTRL) had a shorter estimated LA wavelength (8.0±1.4 versus 24.4±2.5 cm, P<0.05) and a greater AF vulnerability (mean AF duration, 1588±329 versus 25±34 seconds, P<0.05). Oral GAP-134 had no effect on AF vulnerability in UNPACED dogs. Compared with PACED-CTRL dogs, PACED-GAP-134 dogs had a longer estimated LA wavelength (10.2±2.8 versus 8.0±1.4 cm, respectively, P<0.05). Oral GAP-134 did not significantly reduce AF inducibility or maintenance in the entire group of 24 PACED dogs; in a subgroup of dogs (n=11) with less than 100% increase in LA systolic area, oral GAP-134 reduced AF induction from 100% to 40% and mean AF duration from 1737±120 to 615±280 seconds (P<0.05). Conclusions—Oral GAP-134 reduces pacing-induced decrease in LA wavelength and appears to attenuate AF vulnerability in dogs with less atrial mechanical remodeling. Gap junction modulation may affect AF in some circumstances.

Matrix Metalloproteinase Inhibition Attenuates Atrial Remodeling and Vulnerability to Atrial Fibrillation in a Canine Model of Heart Failure

BACKGROUND Atrial structural remodeling occurs in evolving heart failure (HF) and is an important substrate for the development of atrial fibrillation (AF). The matrix metalloproteinases (MMPs) play a role in extracellular remodeling, and recent studies have demonstrated increased atrial MMP activity in HF. Whether increased MMP activity directly contributes to atrial remodeling and AF in the setting of HF remains unclear. The current study examined the effects of MMP inhibition on atrial structural remodeling and AF vulnerability during HF progression. METHODS AND RESULTS Three groups of dogs (n = 5 each)--control normal dogs (controls) and 10 dogs subjected to simultaneous atrioventricular pacing (SAVP) for 2 weeks to induce HF and randomly assigned to treatment with placebo (SAVP-placebo) or a MMP inhibitor PGE-7113313, a MMP-1-sparing MMP inhibitor, 6 mg/kg orally twice daily (SAVP-MMPi)--were studied. SAVP-MMPi dogs had less AF inducibility (percent of burst attempts leading to AF episodes: 1.7 +/- 2.9 seconds vs. 23+/-19 seconds, mean +/- SD, P < .05) and maintenance (AF duration: 253 [105 to 326] vs. 1932 [1296 to 2724] seconds, median [25th-75th quartile], P < .05) than SAVP-placebo dogs. The SAVP-MMPi dogs had significantly smaller increases in atrial myocyte cross sectional area, collagen area fraction, and MMP-9 activity relative to controls than SAVP-placebo. There were, however, no significant differences in the changes in chamber dimension and function in the left atrium. CONCLUSIONS This unique finding of an attenuation of the vulnerability to AF in conjunction with reduced myocyte hypertrophy and fibrosis after MMP inhibition suggests that heightened MMP activity in the atria contributes to atrial structural remodeling and AF promotion during evolving HF.

Permanent left atrial pacing therapy may improve symptoms in heart failure patients with preserved ejection fraction and atrial dyssynchrony: a pilot study prior to a national clinical research programme.

Our group has recently shown that in some patients, heart failure with preserved ejection fraction (HFPEF) may be explained by ‘atrial dyssynchrony syndrome’ (ADS) due to interatrial conduction delay (IACD), a short left atrioventricular interval (LAVI), and increased left atrial (LA) stiffness. Our primary objective was to evaluate LA pacing therapy as a new treatment to restore left ventricular active filling in patients with no other known causes for HF than ADS.

Simultaneous Right Atrioventricular Pacing: A Novel Model to Study Atrial Remodeling and Fibrillation in the Setting of Heart Failure

BACKGROUND Atrial fibrillation (AF) is a common arrhythmia which contributes to morbidity and mortality in patients with heart failure (HF). Atrial remodeling is a key substrate for the development of AF in HF. However, experimental models that study AF in the setting of HF have important limitations. We evaluated a new dog model of atrial remodeling and AF. METHODS AND RESULTS Twenty-two mongrel dogs were randomized into 2 groups: 14 dogs with simultaneous atrioventricular pacing (SAVP) for 2 weeks (220 beats/min, no AV delay) and 8 control dogs with no pacing. SAVP for 2 weeks induced marked changes in atrial mechanical function and conduction. Left atrial area fractional shortening decreased 61 +/- 17%, whereas left ventricular area fractional shortening decreased by 38 +/- 18% from baseline (both P < .05). Conduction slowed and conduction heterogeneity increased. AF was induced in 83% of SAVP dogs, lasting a median of 1600 seconds, versus no dogs with induced AF in the controls. SAVP significantly increased nonfibrillar collagen in the mid-myocardium of both atrial appendages and matrix metalloproteinase-9 activity. CONCLUSIONS SAVP in dogs induces structural and electrical remodelling that form the substrate for reproducibly inducible AF. This novel model may be useful for studies of the pathophysiology and treatment of AF in heart failure.

Clinical impact of the implantable loop recorder in patients with isolated syncope, bundle branch block and negative workup: A randomized multicentre prospective study

BACKGROUND Few studies have compared conventional testing with prolonged monitoring using an implantable loop recorder (ILR) following the first syncope episode in patients with bundle branch block (BBB) and negative workup. OBJECTIVES To compare two syncope evaluation strategies-primary use of an ILR (Group 1) versus conventional testing (Group 2)-and to estimate the prevalence of significant arrhythmias in the ILR patient subset. METHODS From January 2005 to December 2010, 78 patients admitted after one syncope episode were randomized to ILR (n=41) or conventional follow-up (n=37). Mean follow-up was 27 ± 12 months. RESULTS Mean age was 76 ± 8 years and 30 patients were women (38.5%); 18 presented cardiomyopathy (23%) and 12 had a history of atrial fibrillation (15.4%). Mean left ventricular ejection fraction was 56.5 ± 11% and mean His-to-ventricle interval was 55 ± 6ms based on negative electrophysiological study (EPS). Electrocardiogram abnormalities involved: 34 left bundle branch blocks (BBBs); 11 right BBBs; and 33 bifascicular blocks. Overall, 21 patients (27%) developed significant arrhythmic events: ventricular tachycardia (n=1; 1.3%); sudden death (n=2; 2.6%); third-degree atrioventricular (AV) block (n=14; 18%); sick sinus syndrome (n=4; 5.1%). In 19 (24.4%) patients, relevant arrhythmias were detected, with a significant difference between the ILR group (n=15/41; 36.6%) and the conventional follow-up group (n=4/37; 10.8%) (P=0.02). Eighteen patients were implanted with pacemakers; one received an implantable defibrillator. No predictors of AV block were identified in the ILR group. CONCLUSIONS In this randomized prospective study, the ILR strategy proved largely superior to conventional follow-up in detecting recurrent events, with a potential impact on therapeutic management. This observation highlights the usefulness of early monitoring in patients with BBB and negative EPS even after the first syncope episode but an empiric pacemaker strategy remains to be validated in this selected population.

Docosahexaenoic Acid, But Not Eicosapentaenoic Acid, Supplementation Reduces Vulnerability to Atrial Fibrillation

Background—The potential health benefits of &ohgr;-3 polyunsaturated fatty acids (PUFAs) usually are studied using a combination of docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA). This combination reduces vulnerability to experimentally induced atrial fibrillation (AF). It is unknown whether EPA and DHA have differential effects when taken alone. Using a model of pacing-induced atrial hemodynamic overload, we investigated the individual effects of EPA and DHA on vulnerability to AF and atrial remodeling. Methods and Results—Thirty-four dogs were randomized into 3 groups, all of which underwent simultaneous atrial and ventricular pacing at 220 beats per minute for 14 days. One group received purified DHA (≈1 g/d) orally for 21 days beginning 7 days before pacing began. Similarly, 1 group received ≈1 g/d purified EPA. In a third (control) group (No-PUFAs), 8 dogs received ≈1 g/d olive oil, and 12 were unsupplemented. Electrophysiological and echocardiographic measurements were taken at baseline and 21 days. Atrial tissue samples were collected at 21 days for histological and molecular analyses. Persistent AF inducibility was significantly reduced by DHA compared with No-PUFAs median [25–75 percentiles], 0% [0%–3%] for DHA versus 3.1% [2.2%–11%] for No-PUFAs; P=0.007) but not by EPA (3.4% [1.9%–8.9%]). DHA also reduced atrial fibrosis compared with No-PUFAs (11±6% versus 20±4%, respectively; P<0.05), whereas EPA did not (15±5%; P>0.05). Conclusions—DHA is more effective than EPA in attenuating AF vulnerability and atrial remodeling in structural remodeling–induced AF.

Experimental studies of atrial fibrillation: a comparison of two pacing models

Rapid ventricular pacing (RVP) is a well-established animal model of atrial fibrillation (AF). However, this model is limited by a high mortality rate and severe heart failure. The purpose of our study was to assess a new canine model of inducible AF. We performed acute, short-term, simultaneous atrioventricular pacing (SAVP) and RVP (in random order) in 14 dogs for 30 s. SAVP produced more echocardiographic pulmonary venous flow reversal, a greater increase in mean pulmonary capillary wedge pressure, and a significantly greater decrease in left atrial emptying function (-84.4 +/- 38.6% vs. -23.7 +/- 27.1%, P < 0.05) than RVP. Thirty dogs were randomized to three, longer-term, study groups: eight dogs in the control group (no pacing), eight dogs in the RVP group (2 wk at 240 beats/min followed by 3 wk at 220 beats/min), and fourteen dogs in the SAVP group (2 wk at 220 beats/min). SAVP induced less left ventricular dysfunction but more left atrial dysfunction than RVP. SAVP dogs had similar atrial effective refractory periods as RVP dogs but more heterogeneity in conduction and more AF inducibility (83% vs. 40%, P < 0.05) and maintenance (median 1,660 vs. 710 s, P < 0.05) than RVP dogs. SAVP induced more collagen turnover and was associated with a significantly greater increase in type III collagen in the atria compared with RVP dogs (6.9 +/- 1.5 vs. 4.8 +/- 1.6, respectively, P < 0.05 vs. 1.1 +/- 0.7 in unpaced control dogs). In conclusion, the SAVP model induced profound mechanical and substrate atrial remodeling and reproducible sustained AF. This new model is clinically relevant and may be useful for testing AF interventions.