Lamin A/C cardiomyopathy: young onset, high penetrance, and frequent need for heart transplantation.

Aims: Lamin A/C (LMNA) mutations cause familial dilated cardiomyopathy (DCM) with frequent conduction blocks and arrhythmias. We explored the prevalence, cardiac penetrance, and expressivity of LMNA mutations among familial DCM in Norway. Furthermore, we explored the risk factors and the outcomes in LMNA patients. Methods and results: During 2003-15, genetic testing was performed in patients referred for familial DCM. LMNA genotype-positive subjects were examined by electrocardiography, Holter monitoring, cardiac magnetic resonance imaging, and echocardiography. A positive cardiac phenotype was defined as the presence of atrioventricular (AV) block, atrial fibrillation/flutter (AF), ventricular tachycardia (VT), and/or echocardiographic DCM. Heart transplantation was recorded and compared with non-ischaemic DCM of other origin. Of 561 unrelated familial DCM probands, 35 (6.2%) had an LMNA mutation. Family screening diagnosed an additional 93 LMNA genotype-positive family members. We clinically followed up 79 LMNA genotype-positive [age 42 ± 16 years, ejection fraction (EF) 45 ± 13%], including 44 (56%) with VT. Asymptomatic LMNA genotype-positive family members (age 31 ± 15 years) had a 9% annual incidence of a newly documented cardiac phenotype and 61% (19/31) of cardiac penetrance during 4.4 ± 2.9 years of follow-up. Ten (32%) had AV block, 7 (23%) AF, and 12 (39%) non-sustained VT. Heart transplantation was performed in 15 of 79 (19%) LMNA patients during 7.8 ± 6.3 years of follow-up. Conclusion: LMNA mutation prevalence was 6.2% of familial DCM in Norway. Cardiac penetrance was high in young asymptomatic LMNA genotype-positive family members with frequent AV block and VT, highlighting the importance of early family screening and cardiological follow-up. Nearly 20% of the LMNA patients required heart transplantation.

Cardiac resynchronization therapy when no lateral pacing option exists: vectorcardiographic guided non-lateral left ventricular lead placement predicts acute hemodynamic response.

Aims: A difficult cardiac resynchronization therapy (CRT) implantation scenario emerges when no lateral pacing option exists. The aim of this study was to explore the effect of biventricular pacing (BIVP) on vectorcardiographic parameters in patients with a non-lateral left ventricular (LV) lead position. We hypothesized that perimeter and area reduction for both the QRS complex and T-wave would predict acute CRT response. Methods and results: Twenty-six patients (14 ischaemic) with a mean age of 63 ± 10 years and standard CRT indication underwent device implantation with continuous LV pressure registration. The LV lead was placed in either an anterior or apical position. Biventricular pacing was performed at a rate 10% above intrinsic rhythm with acute CRT response defined as LV ΔdP/dtmax >10%. Using this criterion 12 patients were identified as acute CRT responders (responders: 16.7 ± 4.8% vs. non-responders: 1.9 ± 5.3%, P < 0.001). Vectorcardiographic assessment of the QRS complex and T-wave were performed at baseline and under BIVP. Based on the observed changes in three-dimensional area and perimeter, ΔQRS-area (responders: -46.7 ± 39.6% vs. non-responders: 1.1 ± 50.9%, P = 0.006) was considered as the preferred parameter. Receiver operating characteristic curve analysis identified -40% as the optimal cut-off value (sensitivity 67% and specificity 93%) for prediction of acute CRT response (AUC = 0.81, P < 0.01). A significant correlation was observed between LV ΔdP/dtmax and ΔQRS-area (R2 = 0.37, P = 0.001). Conclusion: ΔQRS-area is correlated to LV ΔdP/dtmax and predicts acute CRT response in patients with a non-lateral LV lead position. Assessment of ΔQRS-area might be a useful tool for patient specific LV lead placement when no lateral pacing option exists.

Contractility surrogates derived from three-dimensional lead motion analysis and prediction of acute haemodynamic response to CRT.

Background: Patient-specific left ventricular (LV) lead optimisation strategies with immediate feedback on cardiac resynchronisation therapy (CRT) effectiveness are needed. The purpose of this study was to compare contractility surrogates derived from biventricular lead motion analysis to the peak positive time derivative of LV pressure (dP/dtmax) in patients undergoing CRT implantation. Methods: Twenty-seven patients underwent CRT implantation with continuous haemodynamic monitoring. The right ventricular (RV) lead was placed in apex and a quadripolar LV lead was placed laterally. Biplane fluoroscopy cine films facilitated construction of three-dimensional RV-LV interlead distance waveforms at baseline and under biventricular pacing (BIVP) from which the following contractility surrogates were derived; fractional shortening (FS), time to peak systolic contraction and peak shortening of the interlead distance (negative slope). Acute haemodynamic CRT response was defined as LV ∆dP/dtmax ≥ 10 %. Results: We observed a mean increase in dP/dtmax under BIVP (899±205 mm Hg/s vs 777±180 mm Hg/s, p<0.001). Based on ΔdP/dtmax, 18 patients were classified as acute CRT responders and nine as non-responders (23.3%±10.6% vs 1.9±5.3%, p<0.001). The baseline RV-LV interlead distance was associated with echocardiographic LV dimensions (end diastole: R=0.61, p=0.001 and end systole: R=0.54, p=0.004). However, none of the contractility surrogates could discriminate between the acute CRT responders and non-responders (ΔFS: -2.5±2.6% vs - 2.0±3.1%, p=0.50; Δtime to peak systolic contraction: -9.7±18.1% vs -10.8±15.1%, p=0.43 and Δpeak negative slope: -8.7±45.9% vs 12.5±54.8 %, p=0.09). Conclusion: The baseline RV-LV interlead distance was associated with echocardiographic LV dimensions. In CRT recipients, contractility surrogates derived from the RV-LV interlead distance waveform could not discriminate between acute haemodynamic responders and non-responders.

Focal impulse and rotor modulation as a stand-alone procedure for the treatment of paroxysmal atrial fibrillation: A within-patient controlled study with implanted cardiac monitoring.

BACKGROUND: Focal impulse and rotor modulation (FIRM) has been proposed as a novel approach for the treatment of atrial fibrillation (AF). OBJECTIVE: This study aimed to investigate the efficacy of FIRM as a stand-alone procedure for the treatment of paroxysmal AF. METHODS: A total of 27 patients with paroxysmal AF underwent sequential biatrial computational mapping. Sites with repetitive centrifugal or spiral reentry-like activity were considered to be AF-sustaining sources and targeted by irrigated radiofrequency (RF) ablation. All patients were seen in the outpatient clinic after 1, 3, and 6 months and thereafter every 6 months. Cardiac monitors were implanted 3 months before ablation in 17 patients (63%). RESULTS: Repetitive activity interpreted as sustained AF sources was found in all patients, with an average of 3.0 ± 1.1 sources located in the left atrium and 0.6 ± 0.6 sources in the right atrium. The majority of sources were rotors (95%). The total source-ablation radiofrequency time was 20.0 ± 9.0 minutes. At 15.2 ± 3.9 months of follow-up, the prespecified end point of <1% AF burden (outside a 3-month blanking period) was achieved in 2 of the 17 continuously monitored patients (12%). Of all the 27 patients who underwent FIRM, AF episodes of ≥30 minutes were recorded in 23 (85%), while AF episodes ≥60 minutes were recorded in 21 patients (78%). CONCLUSION: This study suggest that biatrial ablation of localized patient-specific sources alone, as detected by this method, is not sufficient to reduce paroxysmal AF burden in the majority of patients.