Vectorcardiographic evaluation of electrical dyssynchrony and its role in predicting response to cardiac resynchronization therapy

[Doctor of Medicine thesis]. Cardiac resynchronization therapy (CRT) has become an important therapeutic strategy for heart failure (HF) patients with impaired left ventricular (LV) systolic function and prolonged QRS duration. The benefit of CRT as an adjunct to pharmacological therapy is now well established, with sustained improvements in quality of life, hospitalization rates and mortality. However, even in carefully selected patients, the response to CRT is often unpredictable with a considerable number of nonresponders (30-50%). Although the reasons for this nonresponse are not entirely clear, studies have suggested that non-optimal left ventricular (LV) lead positioning, lack of electrical dyssynchrony, suboptimal device programming and myocardial scar burden play an important role. More recently, a wealth of evidence has pointed to the limitations of 12-lead electrocardiography, suggesting it may not accurately reflect the presence or complexities of electrical dyssynchrony in the failing heart. As the efficacy of CRT is primarily achieved through LV resynchronization, there has been renewed interest in the development of techniques that enable better characterization of cardiac electric activation patterns and identification of electrical dyssynchrony. This approach would appear logical, given that CRT is primarily an ‘electrical therapy’, designed to treat an underlying electrical conduction abnormality. Vectorcardiography (VCG), which was first described in 1920, offers an alternative interpretation of the 12-lead ECG. Its resurgence in the field of CRT has emerged from the recognition that VCG parameters can provide information on dyssynchrony beyond that currently provided by the 12-lead ECG. Prominent amongst these is vectorcardiographic QRS area (QRSarea), which has been shown to be superior to QRSd and QRS morphology in predicting response to CRT. The work presented herein is structured into two major sections. First, we investigate the role of QRSarea as a novel predictor of response to CRT. Using a combination of different study designs, our results demonstrate that QRSarea is a better predictor of CRT response than QRSd and QRS morphology. We also show that CRT-induced ΔQRSarea can be used to help quantify LV resynchronization and to predict long-term clinical outcomes following CRT. Importantly, we are the first to show that a concomitant reduction in both QRSarea and QRSd is associated with the best clinical outcomes after CRT, indicating that ECG and VCG can be used in conjunction to help improve patient selection for CRT. In the second part of this thesis, we focus on the development and validation of a novel, vector-based 3D electroanatomical modelling system. Using a novel computational method, ECGSync combines the surface ECG-derived vectorcardiogram with cardiac magnetic resonance imaging to estimate, by inverse solution, the 3-dimensional sequence of LV activation. Accordingly, we show that ECGSync can noninvasively map ventricular electrical activity and accurately locate the site of latest electrical activation prior to CRT implantation. Furthermore, we demonstrate that novel ECGSync-derived markers of dyssynchrony can help predict CRT response. Our findings suggest that VCG may have great potential to improve the clinical application of CRT

The Application of Computer Techniques to ECG Interpretation

This book presents some of the latest available information on automated ECG analysis written by many of the leading researchers in the field. It contains a historical introduction, an outline of the latest international standards for signal processing and communications and then an exciting variety of studies on electrophysiological modelling, ECG Imaging, artificial intelligence applied to resting and ambulatory ECGs, body surface mapping, big data in ECG based prediction, enhanced reliability of patient monitoring, and atrial abnormalities on the ECG. It provides an extremely valuable contribution to the field

MRI methods for predicting response to cardiac resynchronization therapy

Cardiac Resynchronization Therapy (CRT) is a treatment option for heart failure patients with ventricular dyssynchrony. CRT corrects for dyssynchrony by electrically stimulating the septal and lateral walls of the left ventricle (LV), forcing synchronous con- traction and improving cardiac output. Current selection criteria for CRT rely upon the QRS duration, measured from a surface electrocardiogram, as a marker of electrical dyssynchrony. Unfortunately, 30-40% of patients undergoing CRT fail to benefit from the treatment. A multitude of studies have shown that presence of mechanical dyssynchrony in the LV is an important factor in determining if a patient will benefit from CRT. Furthermore, recent evidence suggests that patient response can be improved by placing the LV pacing lead in the most dyssynchronous or latest contracting segment. The overall goal of this project was to develop methods that allow for accurate assessment and display of regional mechanical dyssynchrony throughout the LV and at the site of the LV pacing lead. To accomplish this goal, we developed a method for quantifying regional dyssynchrony from standard short-axis cine magnetic resonance (MR) images. To assess the effects of LV lead placement, we developed a registration method that allows us to project the LV lead location from dual-plane fluoroscopy onto MR measurements of cardiac function. By applying these techniques in patients undergoing CRT, we were able to investigate the relationship between regional dyssynchrony, LV pacing lead location, and CRT response.Ph.D

Heart failure syndrome and predicting response to cardiac resynchronisation therapy.

Heart failure results from the heart pumping insufficient quantities of blood to meet the body’s metabolic requirements. This condition affects around 600,000 people in the United Kingdom and carries with it a significant morbidity and mortality. Patients typically complain of reduced exercise capacity and a poor quality of life. Whilst there are various pharmaceutical options available to clinicians, none directly augment cardiac function. Cardiac resynchronisation therapy (CRT) is proven to reverse the progression of left ventricular systolic dysfunction, the most common cause of heart failure. The device resynchronises inefficient cardiac function, reducing symptoms and improving stroke volume and life expectancy. However, only two thirds of patients typically derive benefit from this pacemaker, it being unclear why. Finding a sensitive and specific predictor of response would be invaluable, preventing potential harm to patients, reducing waste and targeting the patient groups who will derive benefit. In this body of work, the heart failure syndrome is delineated; the evidence underpinning CRT discussed and the difficulties in defining response outlined. There are 2 main research themes in this body of work, measuring and predicting response to CRT. In the former, the role of patient specific three-­‐dimensional computational models and biophysical properties are investigated, and, in the latter, the influence of CRT on the heart failure syndrome using biomarkers. It is concluded that CRT response can be predicted using patient specific computational models of the left ventricle, but they are too complex for routine clinical use. Biophysical markers have more merit in the immediate future, being simper and quicker, with measures of endothelial and skeletal muscle function, demonstrating promise in a small cohort of patients. Finally, there exists a significant level of undiagnosed pathology in this patient group, such as hyperuricaemia and hyperparathyroidism, but it remains unclear what impact CRT has on this comorbidity

Arrhythmogenic cardiomyopathy - beyond monogenetic disease

Interpreting genetic variants, describing their associated clinical characteristics, and identifying new genetic loci involved in arrhythmogenic cardiomyopathy (ACM) is the focus of this thesis. By investigating various aspects of these genetic variants, we were able to correctly classify two variants occurring in the lamin A/C (LMNA) and titin (TTN) gene. We demonstrated that the reduced force generation seen in cardiomyocytes with the LMNA variant (LMNA c.992G>A) is due to remodelling within the cardiomyocytes and that patients with this specific variant have a milder phenotype compared to what is known from other pathogenic LMNA variants. By extensive phenotyping of carriers of a truncating TTN variant (TTN c.59926+1G>A) we were the first to show that (paroxysmal) atrial fibrillation is an important clinical feature in carriers of truncated TTN variants, even in the absence of dilated cardiomyopathy, atrial enlargement or generally accepted risk factors for atrial fibrillation. Thanks to extensive international collaboration it was possible to compile one of the largest cohorts of patients carrying truncating variants in desmoplakin (DSP). We showed that the location of such a genetic variant within the gene is associated with disease severity. Moreover, these studies show that enrichment of truncating genetic variants in specific regions of DSP variants in ACM patients, when compared to controls, facilitating interpretation of such variants. The multifactorial nature of ACM was underscored in a systematic analysis of the clinical outcome of patients from ACM cohorts carrying multiple variants in ACM related genes, showing that carrying multiple variants influences disease severity. Finally, by analysing genes encoding the sarcomere, the contractile unit of the heart muscle and the plectin (PLEC) gene for rare variants in ACM patients, we showed that these genes do not have a major role in the development of ACM

Video Kinematic Evaluation: new insights on the cardiac mechanical function

The cardiac mechanical function plays a critical role in governing and regulating its performance under both normal and pathological conditions. The left ventricle has historically received more attention in both congenital and acquired heart diseases and was considered as the mainstay of normal hemodynamics. However, over the past few decades, there has been increasing recognition of the pivotal role of the right ventricle in determining functional performance status and prognosis in multiple conditions. Nonetheless, the ventricles should not be considered separately as they share the septum, are encircled with common myocardial fibers and are surrounded by the pericardium. Thus, changes in the filling of one ventricle may alter the mechanical function of its counterpart. This ventricular interdependence remains even after the removal of the pericardium because of constrictive pericarditis or during open chest surgery. Interestingly, during open chest surgery, only the right ventricle mechanical activity is visually checked by the surgeon and cardiologist due to the absence of an intraoperative imaging technique able to evaluate its complex function. Noteworthy, most of the imaging techniques available to clinicians are established for the assessment of the left ventricle, with the ejection fraction being the most used parameter. However, this value is a measure of global systolic function which comes short in identifying regional myocardial impairment and the mechanical contraction. Therefore, new approaches are needed to deeply investigate the mechanics of both ventricles and correctly assess the cardiac mechanical performance. In this thesis, I studied the mechanical function of the left ventricle through different modalities of cardiac magnetic resonance and employed an innovative imaging technique for the assessment of the right ventricle mechanical function during open chest surgery

Methods for Arrhythmogenic Substrate Identification and Procedural Improvements for Ventricular Arrhythmias.

Ventricular arrhythmias (VA) are a frequent precursor to sudden cardiac death (SCD) in patients with structural heart disease (SHD). Patients with SHD are at risk of recurrent ventricular tachycardia (VT), which generally occurs due to re-entry within and around the presence of an arrhythmogenic scar. Therefore, scarred myocardium forms the necessary substrate for arrhythmogenesis to occur. A scar may occur due to obstructive coronary artery disease, causing ischaemic cardiomyopathy (ICM), or from cardiac injury due to several other causes, including inflammatory, infiltrative, toxin-mediated, or genetic heart disease, termed non-ischaemic cardiomyopathy (NICM). An implantable cardioverting defibrillator (ICD) can abort SCD from recurrent VAs. However, they do not stop VAs from occurring in the first place. Anti-arrhythmic drugs (AADs) may reduce the frequency and burden of VAs but have limited efficacy. Some have a narrow therapeutic window or the potential for multiorgan toxicity and can be poorly tolerated. Catheter ablation (CA) is a class I indication for treating sustained monomorphic VT refractory to AADs. CA reduces VT burden, the number of defibrillator therapies, greater freedom from recurrent ventricular arrhythmia, and improves quality of life. However, recurrences can be experienced in up to 50% of patients with SHD-related VT. Some reasons for the failure of CA include reliable identification of critical components of substrate that can harbour VAs both in sinus rhythm and during ongoing VT using electroanatomic mapping (EAM) and imaging techniques, as well as limitations in assessing intraprocedural endpoints. Further refinement of electroanatomic mapping techniques is required to improve the efficacy of CA. This thesis aims to expand on current techniques for substrate identification and methods to improve the efficacy of VA ablation procedures

Caractéristiques et traitements des cicatrices myocardiques responsables d'arythmie ventriculaire

Radiofrequency (RF) catheter ablation is a recognized treatment for ventricular tachycardia(VT) in patients with structural heart disease. Even if it can be life saving, success rateremains around 53 to 67%.We aimed to better characterized VT substrate in patients with ischemic cardiomyopathy(CMP), non ischemic CMP with subepicardial scar, left ventricular assist device and Brugadasyndrome. We also evaluate the efficacy of new technologies (such as contact force), specificapproaches (epicardial access, intra coronary alcohol ablation), systematic use of cardiacimaging and new end-points for VT ablation.We demonstrated that each substrate had specific electrophysiological properties that helpoptimizing the mapping and the ablation in these patients. We also showed the interest of(1) new technologies to improve RF lesion formation; (2) specific approaches in selectedpatients to eradicate the VT substrate; and (3) cardiac imaging to help identifying thesubstrate and preventing complications. Finally using local abnormal ventricular potentialelimination as an end-point for VT ablation is feasible and associated with lower mortalityduring follow-up when achieved.Knowledge of substrate specificities, use of contact force, cardiac imaging, epicardial accessin selected patients and scar homogenization improve VT ablation efficacy and/or safety.L’ablation par radiofréquence percutanée est un des traitements des tachycardiesventriculaires (TV). Bien que salvateur chez certains patients avec myocardiopathie (MCP),les taux de succès rapportés varient de 53 à 67% dans les centres entrainés.Le but de ce travail est d’essayer de mieux comprendre le substrat des arythmiesventriculaires et d’en améliorer le traitement. Pour cela, nous avons étudié le substrat despatients adressés pour ablation de TV (sur MCP ischémique, sur MCP dilatée à coronairessaines avec cicatrices sous épicardiques, chez les patients avec assistance ventriculairegauche et chez un patient avec syndrome de Brugada). Nous avons également évalué etproposé des outils/attitudes thérapeutiques pour essayer d’améliorer le traitement des TV.Nous avons mis en évidence des particularités électrophysiologiques pour chacun de cessubstrats qui permettent d’optimiser et d’adapter la cartographie et l’ablation chez cespatients. Par ailleurs, nous avons montré l’intérêt : (1) de nouvelles technologies pouraméliorer l’efficacité de l’ablation ; (2) des approches épicardiques ou d’alcoolisation intracoronaire, chez certains patients sélectionnés, qui permettent d’éliminer le substrat et (3)de l’imagerie cardiaque pour mieux identifier le substrat et diminuer les risques perprocédure.La connaissance du substrat spécifique à chaque pathologie, une information sur laforce du contact entre le cathéter et le tissu, l’imagerie cardiaque (scanner et IRM), uneapproche épicardique chez certains patients et l’homogénéisation de la cicatricemyocardique permettent d’être plus efficace lors de l’ablation des TV