Upgrade of cardiac resynchronization therapy by utilizing additional His-bundle pacing in a patient with lamin A/C cardiomyopathy: an autopsy case report

We investigated the prevalence of lamin A/C (LMNA) gene defects in familial and sporadic dilated cardiomyopathies (DCM) associated with atrioventricular block (AVB) or increased serum creatine-phosphokinase (sCPK), and the corresponding changes in myocardial and protein expression. It has been reported that familial DCM, associated with conduction disturbances or variable myopathies, is causally linked to LMNA gene defects. The LMNA gene and myocardial ultrastructural and immunochemical changes were analyzed in 73 cases of DCM (49 pure, 15 with AVB [seven familial, eight sporadic], 9 with increased sCPK), four cases of familial AVB and 19 non-DCM heart diseases. The normal controls included eight heart donor biopsies for tissue studies and 107 subjects for LMNA gene studies. Five novel LMNA mutations (K97E, E111X, R190W, E317K, four base pair insertion at 1,713 cDNA) were identified in five cases of familial autosomal dominant DCM with AVB (5/15: 33%). The LMNA expression of the myocyte nuclei was reduced or absent. Western blot protein analyses of three hearts with different mutations showed an additional 30-kDa band, suggesting a degrading effect of mutated on wild-type protein. Focal disruptions, bleb formation and nuclear pore clustering were documented by electron microscopy of the myocyte nuclear membranes. None of these changes and no mutations were found in the nine patients with DCM and increased sCPK or in the disease and normal controls. The LMNA gene mutations account for 33% of the DCMs with AVB, all familial autosomal dominant. Increased sCPK in patients with DCM without AVB is not a useful predictor of LMNA mutation.

Background Cardiac resynchronization therapy (CRT) is an established therapy for patients with cardiomyopathy, left bundle branch block, and heart failure. His bundle pacing (HBP) may also improve clinical outcomes by narrowing QRS duration. The QRS narrowing by HBP may not always be optimal. The aim of the study was to determine if CRT could be optimized by sequential HBP followed by left ventricular (LV) pacing (His-Optimized CRT [HOT-CRT]) to maximize electrical resynchronization. Methods We attempted permanent HBP in 27 patients (left bundle branch block 17, intraventricular conduction defect 5, and right ventricular pacing 5) referred for CRT in addition to LV lead. HBP was followed by LV pacing at a delay equal to His-ventricular interval. QRS duration at baseline, during HBP, biventricular pacing, and HOT-CRT was measured. Echocardiographic parameters and New York Heart Association functional class were assessed at baseline and during follow-up. Results HOT-CRT was successful in 25 of 27 patients (age 72±15 years, men 23, ischemic 21). QRS duration at baseline was 183±27 ms and significantly narrowed to 162±17 ms with biventricular pacing ( P=0.003), to 151±24 ms during HBP ( P<0.0001), and further to 120±16 ms during HOT-CRT ( P<0.0001). During a mean follow-up of 14±10 months, LV ejection fraction improved from 24±7% to 38±10% ( P<0.0001), and New York Heart Association functional class changed from 3.3 to 2.04. Twenty-one of 25 patients (84%) were clinical responders while 23 of 25 (92%) showed echocardiographic response. Conclusions In this feasibility cohort, HOT-CRT resulted in improved electrical resynchronization. HOT-CRT may improve clinical and echocardiographic outcomes in advanced heart failure patients requiring CRT.

Myocardial fibrosis is the excessive deposition of extracellular matrix proteins, including collagens, in the heart. In cardiomyopathies, the formation of interstitial fibrosis and/or replacement fibrosis is almost always part of the pathological cardiac remodeling process. Different forms of cardiomyopathies show particular patterns of myocardial fibrosis that can be considered as distinctive hallmarks. Although formation of fibrosis is initially aimed to be a reparative mechanism, in the long term, on-going and excessive myocardial fibrosis may lead to arrhythmias and stiffening of the heart wall and subsequently to diastolic dysfunction. Ultimately, adverse remodeling with progressive myocardial fibrosis can lead to heart failure. Not surprisingly, the presence of fibrosis in cardiomyopathies, even when subtle, has consistently been associated with complications and adverse outcomes. In the last decade, non-invasive in vivo techniques for visualization of myocardial fibrosis have emerged, and have been increasingly used in research and in the clinic. In this review, we will describe the epidemiology, distribution, and role of myocardial fibrosis in genetic cardiomyopathies, including hypertrophic, dilated, arrhythmogenic, and non-compaction cardiomyopathy, and a few specific forms of genetic cardiomyopathies.