Synchronization of repolarization after cardiac resynchronization therapy: A combined clinical and modeling study.

INTRODUCTION: The changes in ventricular repolarization after cardiac resynchronization therapy (CRT) are poorly understood. This knowledge gap is addressed using a multimodality approach including electrocardiographic and echocardiographic measurements in patients and using patient-specific computational modeling. METHODS: In 33 patients electrocardiographic and echocardiographic measurements were performed before and at various intervals after CRT, both during CRT-ON and temporary CRT-OFF. T-wave area was calculated from vectorcardiograms, and reconstructed from the 12-lead electrocardiography (ECG). Computer simulations were performed using a patient-specific eikonal model of cardiac activation with spatially varying action potential duration (APD) and repolarization rate, fit to a patient's ECG. RESULTS: During CRT-ON T-wave area diminished within a day and remained stable thereafter, whereas QT-interval did not change significantly. During CRT-OFF T-wave area doubled within 5 days of CRT, while QT-interval and peak-to-end T-wave interval hardly changed. Left ventricular (LV) ejection fraction only increased significantly increased after 1 month of CRT. Computer simulations indicated that the increase in T-wave area during CRT-OFF can be explained by changes in APD following chronic CRT that are opposite to the change in CRT-induced activation time. These APD changes were associated with a reduction in LV dispersion in repolarization during chronic CRT. CONCLUSION: T-wave area during CRT-OFF is a sensitive marker for adaptations in ventricular repolarization during chronic CRT that may include a reduction in LV dispersion of repolarization.

Exploring the cause of conduction delays in patients with repaired Tetralogy of Fallot.

AIMS: Cardiac dyssynchrony in patients with repaired Tetralogy of Fallot (rToF) has been attributed to right bundle branch block (RBBB), fibrosis and/or the patches that are inserted during repair surgery. We aimed to investigate the basis of abnormal activation in rToF patients by mapping the electrical activation sequence during sinus rhythm (SR) and right ventricular (RV) pacing. METHODS AND RESULTS: A total of 17 patients were studied [13 with rToF, 2 with left bundle branch block (LBBB), and 2 without RBBB or LBBB (non-BBB)] during medically indicated cardiac surgery. During SR and RV pacing, measurements were performed using 112-electrode RV endocardial balloons (rToF only) and biventricular epicardial sock arrays (four of the rToF and all non-rToF patients). During SR, functional lines of block occurred in five rToF patients, while RV pacing caused functional blocks in four rToF patients. The line of block persisted during both SR and RV pacing in only 2 out of 13 rToF patients. Compared to SR, RV pacing increased dispersion of septal activation, but not dispersion of endocardial and epicardial activation of the RV free wall. During pacing, RV and left ventricular activation dispersion in rToF patients were comparable to that of the non-rToF patients. CONCLUSION: The results of the present study indicate that the delayed activation in the right ventricle of rToF patients is predominantly due to block(s) in the Purkinje system and that conduction in RV tissue is fairly normal.

Germinal Center-Derived Antibodies Promote Atherosclerosis Plaque Size and Stability.

BACKGROUND: Atherosclerosis progression is modulated by interactions with the adaptive immune system. Humoral immunity can help protect against atherosclerosis formation; however, the existence, origin, and function of putative atherogenic antibodies are controversial. How such atherosclerosis-promoting antibodies could affect the specific composition and stability of plaques, as well as the vasculature generally, remains unknown. METHODS: We addressed the overall contribution of antibodies to atherosclerosis plaque formation, composition, and stability in vivo (1) with mice that displayed a general loss of antibodies, (2) with mice that had selectively ablated germinal center-derived IgG production, or (3) through interruption of T-B-cell interactions and further studied the effects of antibody deficiency on the aorta by transcriptomics. RESULTS: Here, we demonstrate that atherosclerosis-prone mice with attenuated plasma cell function manifest reduced plaque burden, indicating that antibodies promote atherosclerotic lesion size. However, the composition of the plaque was altered in antibody-deficient mice, with an increase in lipid content and decreases in smooth muscle cells and macrophages, resulting in an experimentally validated vulnerable plaque phenotype. Furthermore, IgG antibodies enhanced smooth muscle cell proliferation in vitro in an Fc receptor-dependent manner, and antibody-deficient mice had decreased neointimal hyperplasia formation in vivo. These IgG antibodies were shown to be derived from germinal centers, and mice genetically deficient for germinal center formation had strongly reduced atherosclerosis plaque formation. mRNA sequencing of aortas revealed that antibodies are required for the sufficient expression of multiple signal-induced and growth-promoting transcription factors and that aortas undergo large-scale metabolic reprograming in their absence. Using an elastase model, we demonstrated that absence of IgG results in an increased severity of aneurysm formation. CONCLUSIONS: We propose that germinal center-derived IgG antibodies promote the size and stability of atherosclerosis plaques, through promoting arterial smooth muscle cell proliferation and maintaining the molecular identity of the aorta. These results could have implications for therapies that target B cells or B-T-cell interactions because the loss of humoral immunity leads to a smaller but less stable plaque phenotype.

Pathobiology of cardiac dyssynchrony and resynchronization therapy.

Synchronous ventricular electrical activation is a prerequisite for adequate left ventricular (LV) systolic function. Conduction abnormalities such as left bundle branch block, and ventricular pacing lead to a dyssynchronous electrical activation sequence, which may have deleterious consequences. The present review attempts to connect the various processes involved in the development of 'dyssynchronopathy', and its correction by cardiac resynchronization therapy (CRT). Abnormal electrical impulse conduction leads to abnormal contraction, characterized by regional differences in timing as well as shortening patterns and amount of external work performed. Early activated regions may show 'wasted work', which leads to inefficient action of the entire left ventricle. Moreover, both the development of heart failure (HF) in general and the regional differences in mechanical load lead to structural, electrical, and contractile remodelling processes. These have been demonstrated at the level of the myocardium (asymmetric hypertrophy, fibrosis, prolongation of activation and reduction in repolarization forces, decrease in LV ejection fraction), cell (gap junctional remodelling, derangement of the T-tubular structure), and molecule (under or overexpression of ion channels and contractile proteins subtypes and abnormal calcium handling). The myocardial adaptations to dyssynchrony are 'maladaptive'. This also explains why CRT, unlike most pharmacological treatments, continues to increase its therapeutic effect over time. Finally, better understanding of all processes involved in dyssynchrony and CRT may also lead to new pharmacological agents for treating HF and to novel pacing strategies.

Left atrial remodeling in mitral regurgitation: A combined experimental-computational study.

AIMS: Progressive changes to left atrial (LA) structure and function following mitral regurgitation (MR) remain incompletely understood. This study aimed to demonstrate potential underlying mechanisms using experimental canine models and computer simulations. METHODS: A canine model of MR was created by cauterization of mitral chordae followed by radiofrequency ablation-induced left bundle-branch block (LBBB) after 4 weeks (MR-LBBB group). Animals with LBBB alone served as control. Echocardiography was performed at baseline, acutely after MR induction, and at 4 and 20 weeks, and correlated with histology and computer simulations. RESULTS: Acute MR augmented LA reservoir and contractile strain (40±4 to 53±6% and -11±5 to -22±9% respectively, p<0.05). LA fractional area change increased significantly (47±4 to 56±4%, p<0.05) while LA end-systolic area remained unchanged (7.2±1.1 versus 7.9±1.1 cm2 respectively, p = 0.08). LA strain 'pseudonormalized' after 4 weeks and decompensated at 20 weeks with both strains decreasing to 25±6% and -3±2% respectively (p<0.05) together with a progressive increase in LA end-systolic area (7.2±1.1 to 14.0±6.3 cm2, p<0.05). In the LBBB-group, LA remodeling was less pronounced. Histology showed a trend towards increased interstitial fibrosis in the LA of the MR-LBBB group. Computer simulations indicated that the progressive changes in LA structure and function are a combination of progressive eccentric remodeling and fibrosis. CONCLUSION: MR augmented LA strain acutely to supranormal values without significant LA dilation. However, over time, LA strain gradually decreases (pseudornormal and decompensated) with LA dilation. Histology and computer simulations indicated a correlation to a varying degree of LA eccentric remodeling and fibrosis.