A G613A missense in the Hutchinson's progeria lamin A/C gene causes a lone, autosomal dominant atrioventricular block.

BACKGROUND: LMNA/C mutations have been linked to the premature aging syndrome Hutchinson's progeria, dilated cardiomyopathy 1A, skeletal myopathies (such as the autosomal dominant variant of Emery-Dreifuss muscular dystrophy and limb-girdle muscular dystrophy), Charcot-Marie-Tooth disorder type 2B1, mandibuloacral dysplasia, autosomal dominant partial lipodystrophy, and axonal neuropathy. Atrioventricular block (AVB) can be associated with several cardiac disorders and it can also be a highly heritable, primitive disease. One of the most common pathologies associated with AVB is dilated cardiomyopathy (DCM), which is characterized by cardiac dilatation and reduced systolic function. In this case, onset has been correlated with several mutations in genes essential for the proper maturation of cardiomyocytes, such as the gene for lamin A/C. However, no clear genotype-phenotype relationship has been reported to date between LMNA/C mutations and cardiomyopathies. RESULTS: DNA and medical histories were collected from (n = 11) members of different generations of one family, the proband of which was implanted with a pacemaker for lone, type II AVB. Exome sequencing analysis was performed on three relatives with AVB, and the mutations therein identified validated in a further three AVB-affected family members. In the initial three AVB family members, we identified 10 shared nonsynonymous single-nucleotide variations with a rare or unreported allele frequency in the 1000 Genomes Project database. Follow-up genetic screening in the additional three affected relatives disclosed a correlation between the lone AVB phenotype and the single-nucleotide polymorphism rs56816490, which generates an E317K change in lamin A/C. Although this mutation has already been described by others in a DCM-affected proband with familiarity for AVB and sudden death, the absence of DCM in our large, AVB-affected family is indicative of genotype-phenotype correlation between rs56816490 and a familial, autosomal dominant form of lone AVB. CONCLUSIONS: Screening for G613A in LMNA/C in patients with lone AVB and their relatives might prevent sudden death in families affected by AVB but without familiarity for DCM. Lone AVB is an age-related disease caused by mutations in LMNA/C gene rather than a complication of DCM.

Cryoballoon ablation for atrial fibrillation guided by real-time three-dimensional transoesophageal echocardiography: a feasibility study.

AIMS: Cryoballoon ablation (CBA; Arctic Front, Medtronic) has proven very effective in achieving pulmonary vein isolation. Real-time three-dimensional transoesophageal echocardiography (RT 3D TEE) is a novel technology, which permits detailed visualization of cardiac structures in a 3D perspective. The aim of the present study was to assess the feasibility, advantages, and safety of RT 3D TEE in guiding CBA in a series of patients affected by paroxysmal atrial fibrillation. METHODS AND RESULTS: Forty-five patients (34 males, mean age: 63 ± 12 years) underwent CBA guided by 3D TEE. A total of 190 veins could be documented by TEE. Real-time three-dimensional transoesophageal echocardiography successfully guided the operator to position the CB in the pulmonary vein (PV) ostium and obtain complete occlusion in all 190 (100%) veins. Transoesophageal echocardiography identified leakages in 25 (13%) veins led to successful elimination of PV-left atrium (LA) backflow by guiding correct balloon repositioning. In four (2%) veins, this imaging tool led to perform successful pull-down manoeuvres. After a mean 2.6 ± 1.4 applications, isolation could be documented in 190 (100%) PVs. Median procedural and fluoroscopy times were 145 and 24 min. During a median follow-up of 278 days, 37 (82%) patients did not experience atrial fibrillation recurrence following a 3-month blanking period. CONCLUSION: Cryoballoon ablation is safe and feasible under RT 3D TEE guidance. This imaging tool permits perfect visualization of all PV ostia and neighbouring LA structures. Most importantly, it proved very efficient in guiding the operator to achieve complete occlusion and successful isolation in all veins.

Heart rate variability monitored by the implanted device predicts response to CRT and long-term clinical outcome in patients with advanced heart failure.

BACKGROUND: Few data exist on the long-term changes and the prognostic value of heart rate variability (HRV) assessed by implanted devices in heart failure (HF) patients treated with resynchronization therapy (CRT). AIMS: To analyze the long-term changes in the standard deviation of 5-minute median atrial-atrial sensed intervals (SDANN), and assess its role in predicting CRT efficacy and major cardiovascular events. METHODS AND RESULTS: We included 509 consecutive patients implanted with CRT devices. At 12-month follow-up, 44 patients had died and 86 patients had at least one HF hospitalisation. A significant increase in SDANN occurred after 4 weeks of CRT (from 69+/-22 ms to 82+/-27 ms, p<0.001). A further increase in SDANN was observed 6 months after implantation. Multivariable analysis identified SDANN as the sole predictor of major cardiovascular events (p=0.03) among several baseline parameters. SDANN< or =65 ms at the first week and SDANN< or =76 ms after 4 weeks of CRT yielded the best prediction of all-cause mortality and urgent heart transplantation on Kaplan-Meier analysis (log-rank test p=0.015 and p=0.011, respectively for week 1 and 4 values). Moreover, relative reduction in LVESV after CRT significantly correlated with SDANN at week 1 (r=-0.596, p=0.012), and week 4 (r=-0.703, p=0.001). CONCLUSIONS: Device-monitored HRV is a useful tool to identify, early after implantation, patients with a low likelihood of long-term benefits from CRT and at high risk for cardiovascular events.

Arrhythmic risk evaluation during exercise at high altitude in healthy subjects: role of microvolt T-wave alternans.

BACKGROUND: Altitude-induced sympathetic hyperactivity can elicit rhythm disturbances in healthy subjects, in particular during exercise. AIM: To asses the real susceptibility of healthy myocardium to malignant ventricular arrhythmias during exercise at high altitude using microvolt T-wave alternans (MTWA). METHODS: We evaluated eight healthy trained participants (one female, 42 +/- 9 years) during a mountain climbing expedition on Gashembrum II (Pakistan, 8,150 m). MTWA and heart rate variability (HRV) were measured in each subject at sea level and at high altitude, both under rest conditions and during exercise. MTWA was determined with the modified moving average method. HRV was expressed as root mean square of successive differences. RESULTS: Rest HRV at high altitude was significantly lower compared to rest HRV at sea level (36 +/- 5 vs 56 +/- 9 ms, P = 0.003). HRV during exercise was significantly lower with respect to rest condition both in normoxia (46 +/- 7 vs 56 +/- 9 ms, P = 0.0001) and hypoxia (27 +/- 4 vs 36 +/- 5 ms, P = 0.005). Moreover, HRV was significantly lower during exercise at high altitude compared to exercise at sea level (27 +/- 4 vs 46 +/- 7 ms, P = 0.0002) and arrhythmias were more frequent during exercise in hypoxia. Nevertheless, MTWA was absent under rest conditions both at sea level and at high altitude and minimally evoked during exercise in both conditions (22 +/- 3 microV and 23 +/- 3 microV, respectively, P = 0.2). CONCLUSIONS: In spite of an enhanced sympathetic activity, MTWA testing during exercise at high altitude was negative in all participants. Healthy trained subjects during exercise under hypoxia seem to be at low risk for dangerous arrhythmias.

Atrial flutter: a focus on treatment options for a common supraventricular tachyarrhythmia.

Atrial flutter (AFl), a re-entrant atrial tachycardia, is a cardiac rhythm disturbance that arises in the upper chambers of the heart. This usually non-life-threatening condition can be treated by a number of medical intervention strategies, which include electrical cardioversion, pharmacological therapy, and catheter ablation. These options have been available in clinical practice for a number of years. However, catheter ablation, in the form of radiofrequency catheter ablation and cryo catheter ablation, is increasingly utilised as a first-line treatment option for AFl in certain patients. The purpose of this review article is two-fold: first, to briefly present an overview of AFl and the more familiar treatment options for this arrhythmia, and second to provide more in-depth coverage of catheter ablation technologies as a treatment option for patients with AFl. As part of the latter objective, recent clinical studies documenting the use of radiofrequency catheter ablation and cryo catheter ablation for AFl are presented and their results briefly discussed.

Low clinical recurrence and procedure benefits following treatment of common atrial flutter by electrogram-guided hot spot focal cryoablation.

BACKGROUND: The study sought to evaluate whether electrogram-aided identification of hot spot targets produces additional clinical and/or procedure benefits when using a non-traditional focal cryo ablation method to treat common atrial flutter. METHODS: A preliminary study identified a specific electrogram criterion (e.g., a stimulus to onset of electrogram time of 74 [+/- 5] ms) that produced successful cryo testing plus subsequent cryoablation with demonstrable bi-directional isthmus block created at intervention site. In the present study, 26 consecutive patients with symptomatic common atrial flutter were ablated with a 9FR 8 mm tip cryo catheter using electrogram-aided identification of hot spot targets with a stimulus to onset of electrogram time of > or =70 ms. Outcomes measured were bi-directional isthmus block at intervention, symptom and conduction recurrence at 3 month follow-up, symptom recurrence at 6 month follow-up, and procedure characteristics. RESULTS: Acute success rate at intervention was 100%. The percentage of patients with symptom recurrence by 3 month follow-up was 4.5% and no additional patients had arrhythmia symptoms documented by 12 month follow-up. Repeat electrophysiological study (EPS) at 3 month follow-up identified 44% of patients with conduction recurrence. The mean +/- SD number of cryo tests and ablations were 11 +/- 9 and 2 +/- 1, respectively. Procedure, fluoroscopy and cryoapplication times were 77 +/- 29 min, 11 +/- 7 min, and 28 +/- 11 min, respectively. CONCLUSIONS: A high acute success rate, plus low long-term clinical recurrence rate and procedure benefits may be achieved with electrogram-aided identification of hot spots for focal cryo ablation treatment of common atrial flutter using a 9FR 8 mm tip cryo catheter. The population of patients who were asymptomatic and had demonstrated conduction recurrence on repeat EPS at 3 month follow-up require close scrutiny over the long-term to ascertain whether they eventually experience arrhythmic symptoms. However, should these patients remain symptom-free over the long-term it would suggest that the entire isthmus may not be needed to support symptomatic common atrial flutter.

Current treatment options for atrial flutter and results with cryocatheter ablation.

Rhythm disturbances arising in the upper chambers of the heart are not uncommon. They are associated with a heavy burden of illness for the affected individual, as well as society in general. Atrial flutter, a re-entrant atrial tachycardia, is one such rhythm disturbance. The objective of this review article is twofold: first, to provide a brief insight into atrial flutter and the typical treatments for this arrhythmia in clinical practice; and second, to give an in-depth account of cryocatheter ablation as a relatively new treatment option for this potentially debilitating condition. The many recent clinical studies documenting the use of cryocatheter ablation for treatment of atrial flutter are presented, and their results briefly discussed. Overall, as cryocatheter ablation embeds itself among the arsenal of treatments for atrial flutter, the promising results from clinical studies appear destined to elevate cryocatheter ablation to a premier position among the treatment options for atrial flutter.

Comparison between a 7 French 6 mm tip cryothermal catheter and a 9 French 8 mm tip cryothermal catheter for cryoablation treatment of common atrial flutter.

BACKGROUND: Larger tipped cryothermal catheters may deliver efficacy and procedure benefits in the treatment of patients with atrial flutter. OBJECTIVE: To compare 7 French 6 mm and 9 French 8 mm tip cryothermal catheters (Freezor, Xtra or Freezor, MAX, CryoCath Technologies Inc., Kirkland, Canada) in terms of acute and chronic efficacy, and procedure characteristics in the treatment of atrial flutter. METHODS: This non-randomized clinical investigation determined bi-directional isthmus block at intervention, procedure characteristics, and symptom and conduction recurrence rates post procedure in consecutive patients with symptomatic atrial flutter ablated either with the 7 French 6 mm tip cryothermal catheter (n = 43) at -75 degrees C for 4 minutes or the 9 French 8 mm tip cryothermal catheter (n = 51) at -75 degrees C for 8 minutes. RESULTS: Clinical data showed a higher acute success rate for the larger tipped catheter (100% vs. 88%). Symptom recurrence rates were 0% for both catheters at 3, 6, and 9 month follow-up. Conduction recurrence rates were similar for both catheters on repeat electrophysiological study at 3 months post procedure (35% vs. 32%). Procedure benefits were fewer cryotests (20 +/- 17 vs. 26 +/- 21) and ablations (4 +/- 4 vs. 12 +/- 18), and shorter procedure (80 +/- 61 min vs. 87 +/- 48 min), fluoroscopy (14 +/- 9 min vs. 24 +/- 10 min), and cryoapplication times (37 +/- 18 min vs. 44 +/- 23 min) with the larger tipped catheter. There were no adverse events reported. CONCLUSIONS: Clinical results showed differences in catheter performance that favoured the larger tipped catheter. However, increased acute success rate did not translate into reduced conduction recurrence rate post ablation, although clinical recurrence was completely absent long-term.

Long-term efficacy of cryo catheter ablation for the treatment of atrial flutter: results from a repeat electrophysiologic study.

OBJECTIVES: We investigated the long-term efficacy of cryo ablation for treatment of atrial flutter. BACKGROUND: To our knowledge, no study has assessed the long-term efficacy of cryo ablation by assessing both symptom and conduction recurrence. METHODS: A total of 45 consecutive patients with symptomatic atrial flutter were ablated with a 7-F, 6-mm-tip, quadripolar cryo catheter (Freezor Xtra, CryoCath Technologies Inc., Kirkland, Canada). Electrophysiologic studies (EPS) were performed with diagnostic catheters. Cryo ablation was at -75 degrees C for 4 min, beginning at the inferior rim of the coronary sinus os and creating a posterior line to the Eustachian ridge. Safety, bi-directional isthmus block at intervention, and recurrence at three, six, and nine months post procedure were assessed. RESULTS: There were no adverse events reported. All patients were free of discomfort on cryo energy delivery. The acute success rate at intervention was 87%. Follow-up data from 39 acutely successful patients showed 27 (69%) without conduction recurrence on repeat EPS at three months, and none (0%) had symptom recurrence documented by Holter monitoring, electrocardiogram, and/or patient diary records at three, six, and nine months follow-up. CONCLUSIONS: Our experience with a new 7-F, 6-mm-tip, quadripolar cryo catheter yielded a fairly high success rate at intervention, an excellent safety profile, and a good chronic success rate in terms of symptom recurrence. However, further monitoring is necessary to determine whether all asymptomatic patients continue to remain free of symptoms, given the small pool of patients demonstrated to have conduction recurrence.

Cryothermal ablation treatment of atrial flutter--experience with a new 9 French 8 mm tip catheter.

BACKGROUND: Cardiac cryoablation has been used to successfully treat a variety of arrhythmias. OBJECTIVE: This study documents our experience with a new 9 French (FR) 8 mm cryocatheter for ablation treatment of symptomatic atrial flutter. METHODS: A total of 77 consecutive patients with symptomatic atrial flutter were treated. Electrophysiological studies (EPS) were performed with diagnostic catheters and ablation was performed with a 9FR, 8 mm tip, quadripolar cryocatheter (Freezor MAX catheter, CryoCath Technologies Inc., Kirkland, Canada). Cryoablation at -75 degrees C for 8 minutes was performed, beginning at the inferior rim of the coronary sinus (CS) os and creating a posterior line to the Eustachian ridge. Safety, bidirectional isthmus block at intervention, and recurrence at 3 months post procedure were assessed. RESULTS: There were no adverse events reported. All patients remained free of discomfort on cryoenergy delivery. The acute success rate at intervention was 96% for all patients and 100% for those with common atrial flutter. Follow-up data from 47 patients showed 33 (70%) patients without conduction recurrence on repeat EPS at 3 months. Although, 1 (2%) patient had both symptom and conduction recurrence. Data available from 53 acutely successful patients at 6 month clinical follow-up showed that 48 (91%) patients were asymptomatic and 5 (9%) patients had recurrence documented by ECG and/or patient diary records. CONCLUSIONS: Our experience with a new 9FR, 8 mm tip, quadripolar cryocatheter yielded a high success rate at intervention and an excellent safety profile. Although repeat EPS at 3 months post ablation identified conduction recurrence in 30% of patients, at 6 month clinical follow-up only 9% of patients had recurrence. Further monitoring is necessary to assess whether the relatively low recurrence rate observed at 6 month clinical follow-up is maintained over the long term.

Implantable loop recorders: a novel method to judge patient perception of atrial fibrillation. Preliminary results from a pilot study.

INTRODUCTION: At the present time, several techniques are used or are under investigation for atrial fibrillation (AF) therapy. Nowadays, no well-defined target for such therapies has been yet completely identified. Furthermore, AF is an arrhythmia with high rates of recurrences, both symptomatic and asymptotic. Thus the measure of therapy success rates not only based on symptom perception remains a goal to be reached. AIMS OF THE STUDY: This study investigates the role of an implantable loop recorder (ILR) as an additional tool to identify initiating and perpetuating mechanisms of AF. The role of right atrial linear ablation (RALA) procedures is also investigated using the monitoring capabilities of the ILR. METHODS AND RESULTS: Nine patients (mean age 63.8 +/- 5.9) with paroxysmal AF were referred to our institution as candidates for AF ablation. All patients (pts) had in their medical history several years of AF episodes. Therefore pts were aware of AF related symptoms. Six of them were implanted with an ILR before ablation and were monitored one month before and six months after the procedure. The ILRs stored 54 patient activated events (PAE) and 124 automatically activated events (AAE). 68% of PAEs and 67% of AAEs were classified as appropriate. Most common reasons for inappropriate detections were premature atrial or ventricular contractions among PAEs and undersensing among AAEs. The arrhythmia onset was properly identified in 4 pts (44%). The average AF recurrence rate was 10.8 +/- 3.5 ep/month before ablation and 5.0 +/- 1.8 ep/month after the procedure ( p = 0.042). CONCLUSION: The ILR may be a helpful tool in monitoring pts undergoing ablation. Dedicated AF detection characteristics could give additional value to the device. RALA appears as a feasible, safe and relatively effective first approach in AF therapy.