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Hypertrophic cardiomyopathy (HCM) is a frequent genetic cardiac disease and the most common cause of sudden cardiac death in young individuals. Most of the currently known HCM disease genes encode sarcomeric proteins. Previous studies have shown an association between CSRP3 missense mutations and either dilated cardiomyopathy (DCM) or HCM, but all these studies were unable to provide comprehensive genetic evidence for a causative role of CSRP3 mutations. We used linkage analysis and identified a CSRP3 missense mutation in a large German family affected by HCM. We confirmed CSRP3 as an HCM disease gene. Furthermore, CSRP3 missense mutations segregating with HCM were identified in four other families. We used a newly designed monoclonal antibody to show that muscle LIM protein (MLP), the protein encoded by CSRP3, is mainly a cytosolic component of cardiomyocytes and not tightly anchored to sarcomeric structures. Our functional data from both in vitro and in vivo analyses suggest that at least one of MLP's mutated forms seems to be destabilized in the heart of HCM patients harbouring a CSRP3 missense mutation. We also present evidence for mild skeletal muscle disease in affected persons. Our results support the view that HCM is not exclusively a sarcomeric disease and also suggest that impaired mechano-sensory stress signalling might be involved in the pathogenesis of HCM.

Stored electrograms or marker channels are available in most of modern cardiac pacemaker models. We sought to analyse these information to uncover terminal events of pacemaker patients dying suddenly. Method and results We made post-mortem pacemaker (PM) interrogations in 19 patients dying suddenly out of hospital between the years 1997 and 2005 (mean age 59 +/- 13 years, 90% males). The systems had activated arrhythmia monitoring algorithms. Indications of pacing were sick sinus syndrome in seven, AV-block in five, and heart failure due to asynchrony in seven cases. The interrogated pacemakers were CHORUS 7034 (n = 12), CONTAK TR (n = 2), and INSYNC III (n = 5). For interpretation stored marker channels and electrograms were analysed. The mean observation time after PM implantation prior death was 2.11 +/- 1.44 years, the mean left ventricular ejection fraction from the last available echo examination in the year prior death was 27.5 +/- 8%, mean age was 63 +/- 12 years. In 17/19 cases (89%), a tachycardia (most likely ventricular tachycardia) was found correlating to the time of death. The mean cycle length of the terminal arrhythmia was 307 +/- 144 (250-344) ms, corresponding to a heart rate of 195 +/- 95 (174-240) bpm. We found no evidence of specific pacemaker-related problems such as electronic failure, battery depletion, or undersensing.Post-mortem analysis of arrhythmia monitoring of pacemaker patients revealed tachycardias (most likely ventricular tachycardia) to be related to sudden death. These findings give some insight in mechanisms of terminal events in this group.

Aims Coronary sinus (CS) lead implantation is a technically challenging procedure owing to variable vein anatomies and a high dislocation rate. Therefore, CS lead technology has undergone evolutionary changes during the last 10 years. The mode of fixation has been a passive one up to now. We want to describe our first clinical experience with the newly available active fixation lead 4195 in terms of dislocation rate and stability of thresholds compared with conventional models. Methods and results From 1999 to February 2007, we implanted 403 CS leads in 368 patients. Leads were categorized into three different groups on the basis of their fixation mechanism: straight (Easytrak I and Situs OTW; n ¼ 54), curved (Attain 4193 and 4194, Corox, Aescula, Situs ULD; n ¼ 308), and active (Attain 4195; n ¼ 41). Operative and follow-up data were prospectively noted and checked for significance between groups during the first 3 months after implantation. Kaplan–Meier analysis of long-term lead function was also performed. Straight and curved CS leads suffered from significantly more dislocations compared with active fixation (P , 0.001). The active fixation lead (4195) has a stable threshold over time compared with a significant rise after 24 h and thereafter in straight (62%) and curved leads (20%). However, retraction of an active fixation CS lead may be a difficult issue as outlined in two cases requiring pullback of a 4195 lead owing to phrenic nerve stimulation (one unsuccessful despite vigorous traction). Conclusion The active fixation lead 4195 using retention lobes yielded stable thresholds over time and seems to be superior to conventional leads in terms of dislocation. However, extraction may be a difficult or even impossible task.

Aims To evaluate the utility of intrathoracic impedance monitoring for detecting heart failure (HF) deterioration in patients with an implanted cardiac resynchronization/defibrillation device. Methods and results Patients enrolled in the European InSync Sentry Observational Study were audibly alerted by a device algorithm if a decrease in intrathoracic impedance suggested fluid accumulation. Clinical HF status and device data were assessed at enrolment, during regular follow-up, and if patients presented with an alert or HF deterioration. Data from 373 subjects were analysed. Fifty-three alert events and a total of 53 clinical events (HF deterioration defined by worsening of HF signs and symptoms) were reported during a median of 4.2 months. Adjusted for multiple events per patient, the alert detected clinical HF deterioration with 60% sensitivity (95% CI 46–73) and with a positive predictive value of 60% (95% CI 46–73). Higher NYHA class at baseline was predictive for adequate alert events during follow-up (P , 0.05). In 11 of 20 HF deteriorations without preceding alert, an upstroke of the fluid index occurred without reaching the programmed alert threshold. Conclusion A device-based algorithm that alerts patients in case of decreasing intrathoracic impedance facilitates the detection of HF deterioration. Future randomized, controlled trials are needed to test whether the tailored use of intrathoracic impedance monitoring can improve the ambulatory management of patients with chronic HF and an implanted device.

This report describes the reversal of a cardiac resynchronization therapy non-responder status in a patient with a surgically placed left ventricular lead by the use of a newly available active fixation coronary sinus lead.

This editorial refers to ‘Midterm experience with implantable cardioverter-defibrillators in children and young adults’ by A. Celiker et al ., on page 1732 The article by Celiker et al .1 adds a further experience to a very challenging clinical problem: the primary and secondary prevention of sudden cardiac death in children and adolescents with implantable cardioverter defibrillators (ICDs). As no randomized ICD trials in this population are available, treatment protocols have to be extrapolated from the results of ICD studies in adults. However, children differ from adults in many ways and make this therapy … *Corresponding author. Tel: +49 407 280 5158, Email: herbert_naegele{at}yahoo.de