Dissertations / Theses on the topic 'Cardiac Resynchronization Therapy Devices'

The general purpose of this thesis was to investigate new cardiac resynchronization therapy (CRT) optimization techniques and to assess their reliability when compared to invasive measurements of left ventricular contractility (LV dP/dtmax).We first assessed whether cardiac output (CO) measured by trans-thoracic impedance cardiography could correctly identify the optimal interventricular (VV) pacing interval while using invasive measurements of LV dP/dtmax as reference. We did not find any significant statistical correlation between the two optimizing methods when their corresponding optimal VV intervals were compared. We also tested the hypothesis that measurements of right ventricular contractility (RV dP/dtmax) could be used to guide VV delay optimization in CRT. The comparison of optimal VV intervals obtained from the left and right ventricular dP/dtmax did not show a statistically significant correlation; however, a positive correlation was found when broader VV intervals were evaluated and we concluded that this finding deserves further investigation. An interesting alternative for CRT optimization is the use of device integrated algorithms or sensors capable to adapt the CRT settings to the current needs of the individual patient. In this respect we investigated the use of cardiogenic impedance (CI) measurements obtained through the CRT-D device as a method for CRT optimization with invasive measurements of LV dP/dtmax as a reference. Our results showed that CI could be measured through the device after implantation and that a patient-specific impedance-based prediction model was capable to accurately predict the optimal AV and VV delays. To follow up on these positive results we re-evaluated the patient-specific impedance-based prediction models 24 hours post implantation and investigated the possibility of calibrating them using parameters derived from non-invasive measurements of arterial pressure obtained by finger pelthysmography at implantation.The results showed that the patient-specific impedance-based prediction models did not perform as well on the follow-up data as they did on the data from implantation day and that they correlated poorly with plethysmographic parameters. Our studies suggest that novel methods for CRT optimization should be thoroughly evaluated and compared to established measures of left ventricular function prior to introduction into clinical practice.

Heart failure carries a very poor prognosis, unless treated with the appropriate pharmacological agents which, have been evaluated in large randomized clinical trials and have demonstrated improvements in morbidity and mortality of this cohort of patients. A significant proportion of these patients develop conduction abnormalities involving both the atrioventricular node and also the specialised conduction tissue (bundle of His and Purkinje fibers) of the ventricular myocardium which is most commonly evidenced by the presence of a wide QRS, typically left bundle branch block. The net effect of these conduction abnormalities is inefficient filling and contraction of the left ventricle. The presence of these conduction abnormalities is an additional strong marker of poor prognosis. Over the last 15 years pacing treatments have been developed aimed at mitigating the conduction disease. Large scale randomized multicentre trials have repeatedly demonstrated the effectiveness of cardiac pacing, officially recognized as cardiac resynchronization therapy (CRT). This mode of pacing therapy has undoubtedly had a positive impact on both the morbidity and mortality of these patients. Despite the large advancement in the management of heart failure patients by pacing therapies, a significant proportion of patients (30%) being offered CRT are classed as non-responders. Many explanations have been put forward for the lack of response. The presence of scar at the pacing site with failure to capture or delayed capture of myocardium, too much left ventricular scar therefore minimal contractile response, incorrect pacing site due to often limited anatomical options of lead placement and insufficient programming i.e optimization, of pacemaker settings such as the AV and VV delay are just some of the suggested areas perceived to be responsible for the lack of patients' response to cardiac resynchronization therapy. The effect of optimization of pacemaker settings is a field that has been investigated extensively in the last decade. Disappointingly, current methods of assessing the effect of optimization of pacemaker settings on several haemodynamic parameters, such as cardiac output and blood pressure, are marred with very poor reproducibility, so measurement of any effect of optimization is close to being meaningless. Moreover, detailed understanding of the effects of CRT on coronary physiology and cardiac mechanoenergetics is equally, disappointingly, lacking. In this thesis, I investigated the acute effects of cardiac resynchronization therapy and AV optimization on coronary physiology and cardiac mechanoenergetics. This was accomplished using very detailed and demanding series of invasive catheterization studies. I used novel analytical mathematical techniques, such as wave intensity analysis, which have been developed locally and this provided a unique insight of the important physiological entities defining coronary physiology and cardiac mechanics. I explored in detail the application and reliability of photoplethysmography as a tool for non-invasive optimization of the AV delay. Photoplethysmography has the potential of miniaturization and therefore implantation alongside pacemaker devices. I compared current optimization techniques (Echocardiography and ECG) of VV delay against beat-to-beat blood pressure using the Finometer device and defined the criteria that a technique requires if such a technique can be used meaningfully for the optimization of pacemaker settings both in clinical practice and in clinical trials. Finally, I investigated the impact of atrial pacing and heart rate on the optimal AV delay and attempted to characterize the mechanisms underlying any changes of the optimal AV delay under these varying patient and pacing states. In this thesis I found that optimization of AV delay of cardiac resynchronization therapy not only improved cardiac contraction and external cardiac work, but also cardiac relaxation and coronary blood flow, when compared against LBBB. I found that most of the increase in coronary blood flow occurred during diastole and that the predominant drive for this was ventricular microcirculatory suction as evidenced by the increased intracoronary diastolic backward-travelling decompression wave. I showed that non-invasive haemodynamic optimization using the plethysmograph signal of an inexpensive pulse oximeter is as reliable as using the Finometer. Appropriate processing of the oximetric signal improved the reproducibility of the optimal AV delay. The advantage of this technology is that it might be miniaturized and implanted to provide automated optimization. In this thesis I found that other commonly used modalities of VV optimization such as echocardiography and ECG lack internal validity as opposed to non-invasive haemodynamic optimization using blood pressure. This finding will encourage avoidance of internally invalid modalities, which may cause more harm than good. In this thesis I found that the sensed and paced optimal AV delays have, on average, a bigger difference than the one assumed by the device manufacturers and clinicians. As a significant proportion of patients will be atrially paced, especially during exercise, optimization during this mode of pacing is equally crucial as it is during atrial sensing. Finally, I found that the optimal AV delay decreases with increasing heart rate, and the slope of this is within the range of existing pacemaker algorithms used for rate adaptation of AV delay, strengthening the argument for the rate adaptation to be programmed on.

Cardiac dyssynchrony (CD) causes some heart muscle regions to contract at different times, and current treatments do not help 30 ? 50% of patients. In this thesis, multi-site pacing control schemes are created to quantitatively and automatically reduce the CD of ventricular wall accelerations by adjusting pacing times. Two and four left ventricular region models are investigated containing model variables that represent numerous muscle parameters. Optimization is performed using exhaustive search and genetic algorithm techniques, with particular attention paid to the latter with regard to development, parameter selection, and limitations. Relative to treatments firing all regions simultaneously, timing adjustment improves acceleration CD by up to 56%. Furthermore, simulations also demonstrate improvements to dyssynchronous region power generation and workload by up to 50% and up to 15% decrease in healthy region workload. Thus, the current model indicates it may be possible to improve acceleration CD by adjustments to regional firing times.

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.

Aims: Non-responder rates for CRT vary from 11 to 46 %. Retrospective data imply a better outcome with stimulation of the latest contracting LV region. Our study analyzed feasibility, safety and clinical outcome of prospectively planned LV lead placement at the site of latest mechanical activation. Methods: Thirty-eight heart failure patients with CRT indication were assessed by 3D TEE and rotation angiography of the coronary sinus. Both images were merged into a single 3D-model to identify CS target veins close to the site of latest mechanical activation. Subsequently LV lead deployment was attempted at the desired target position. Patients were clinically and echocardiographically evaluated at baseline, after 3 and 6 months. Results: The area of latest mechanical activation covered 6 ± 2 segments (38 ± 13 % of LV surface) and was found lateral in 24/37 (65 %), anterior in 11/37 (30 %), inferior in 2/37 (5 %) and septal in 1/37 (3 %) patients. In 36/37 (97 %) patients an appropriate target vein was identified and successful implantation could be performed in 34/37 (92%) patients. Among those patients clinical and echocardiographic response was observed in 91 % and 81 %, respectively. Conclusions: Individualized lead placement at the latest contracting LV site can be performed safely and successfully in the majority of patients. Initial clinical outcome data are encouraging. Identification of target sites requires multimodality integration between LV wall motion data and CS anatomy. Future developments need to improve those technologies and require randomized data on clinical outcome parameters.

Includes bibliographical references (leaves 52-56).
The expanding application of cardiac resynchronization (CRT) and implantable cardioverter-defibrillator therapy (lCD) to include patients with congenital heart disease requires careful evaluation of selection criteria and unconventional adaptive strategies to ensure clinical efficacy. A single centre prospective analysis of adults post atrial redirection surgery (Mustard operation) for dextro-transposition of the great arteries (d-TGA) presenting with systemic right ventricular (sRV) dysfunction and at risk of sudden cardiac death (SCD). All patients ( mean age 25 years, range 18-35) with varying functional disability{New York Heart Association (NYHA) II-III} receiving ICDs ± concomitant CRT were evaluated. Total follow-up period was 24 months. A patient individualized approach was used for device implantation. Endocardial, epicardial and transthoracic defibrillation strategies were examined in 5 consecutive cases. A hybridized form of CRT was employed in two patients. Only one patient demonstrated response to therapy while the other deteriorated during biventricular pacing (BVP). This prompted a novel approach to CRT using noncontact mapping (NCM) and acute intra-arterial blood pressure response to guide endocardialsRV lead placement in a single patient. The ejection fraction increased from 23 -33% within 1week post procedure and clinical improvement was sustained after 6-months follow-up. Application of CRT II CD therapy to patients with sRV dysfunction requires individualized and adaptive strategies to overcome anatomical constraints. This study represents a chronological and evolutionary account of these measures.

La terapia di resincronizzazione cardiaca (CRT) è un trattamento per pazienti affetti da scompenso cardiaco cronico, che consiste nell’impianto di un dispositivo che stimola il ventricolo sinistro. Circa il 30% dei pazienti non mostrano miglioramenti significativi a seguito della terapia. Un fattore determinante per la risposta è la posizione dell’elettrodo in seno coronarico (CS). Un metodo per la ricostruzione della traiettoria 3D del catodo in seno coronarico a partire da acquisizioni fluoroscopiche è stato sviluppato in un primo studio condotto in un singolo centro e su un piccolo gruppo di pazienti. I risultato dello studio hanno permesso di individuare un indice predittivo della riposta: la variazione indotta in acuto dal pacing biventricolare (BiV) sul rapporto tra i due principali valori singolari della traiettoria. Il metodo necessita di essere testato in una popolazione maggiore e multicentrica. L’obiettivo del presente lavoro di tesi è stato di valutare se le variazioni nella traiettoria del catodo in CS, indotte dal pacing BiV, siano predittive della risposta clinica a 6 mesi. La risposta clinica è definita da una riduzione del ESV ≥ del 15% al follow-up. Trentasei pazienti arruolati in 3 diversi centri sono stati analizzati; per 14 soggetti è disponibile la valutazione al f.u. In 11 casi la riposta è stata predetta correttamente, registrando quindi una concordanza del 79%. Questi primi risultati sembrano essere promettenti. Per ulteriori conferme bisogna attendere i f.u. degli altri 22 pazienti analizzati.

Randomized trials and cohort studies have shown sex differences in the implantation and response to Cardiac Resynchronization Therapy (CRT). Furthermore, gender roles are associated with precipitants of congestive heart failure. Cohort studies are well-suited to assessing implantation rates, long-term outcomes, and the role of sex and gender. Therefore, we systematically identified cohort studies that reported outcomes of CRT and evaluated the following: 1) prevalence and temporal changes in sex and gender reporting and analysis; and 2) sex differences in the implantation and response to CRT. Sex was increasingly considered but remained inadequately reported and analyzed. Gender was not considered in the studies. In clinical practice, fewer women received devices, despite benefiting from CRT more than men. Of note, the difference in response may be confounded by differences in the clinical profiles of men and women. There is a need for better integration of sex and gender in studies to understand better the reasons leading to the observed differences.

The definition of optimal selection criteria for maximizing the response rate to Cardiac Resynchronization Therapy (CRT) is still an issue under active debate. Recent clinical approaches propose a classification of patients into classes of mechanisms that could lead to heart failure and study their response to the therapy. In this line of research, the computation of a metric between the motion and deformation patterns of a given subject and well identified classes of CRT responders is considered in this thesis, as the basis of a new strategy to compute patient selection indexes. The thesis proposes first an improved design for the construction of statistical atlases of myocardial motion and deformation, and applies it to the characterization of populations of patients involved in CRT. The added-value of our approach is highlighted in a clinical study, applying the methodology to a large population of patients with a given pattern of dyssynchrony (septal flash) and understanding the link between its correction and CRT response. Finally, we propose a method to extend the analysis to the comparison of individuals to reference populations, either healthy or pathological, using manifold learning techniques to model a disease as progressive deviations from normality along a manifold structure, and demonstrate the potential of our method for inter-subject comparison in CRT patients.
La definición de un criterio óptimo para mejorar la respuesta a la Terapia de Resincronización Cardíaca (TRC) sigue siendo un debate abierto. Estudio clínicos recientemente publicados proponen clasificar pacientes según diversos mecanismos patofisiológicos que pueden inducir insuficiencia cardíaca y estudian su respuesta a la terapia. Siguiendo esta línea de investigación, esta tesis considera el cálculo de una distancia entre los patrones de movimiento y deformación de un individuo y las clases de respondedores a la TRC, siendo la base de una nueva estrategia para calcular índices para seleccionar pacientes. Esta tesis presenta primero un método para construir un atlas estadístico de movimiento y deformación miocárdica, y su aplicación posterior a la caracterización de poblaciones de potenciales candidatos a la TRC. El valor añadido de nuestro método se enfatiza en un estudio clínico, en el cual se aplica la metodología a una gran población de pacientes con un patrón específico de disincronía cardíaca (llamado septal flash), y se relaciona su corrección y la respuesta a la TRC. Finalmente, se extiende el método para comparar individuos a una población de referencia, sana o patológica, usando técnicas de manifold learning para representar una patología como una desviación progresiva de la normalidad, con una estructura no lineal específica, y se demuestra el potencial de nuestro método para comparar entre sí candidatos a la TRC.

L'objectif de ce travail était de mieux appréhender les mécanismes impliqués dans la réponse à la resynchronisation biventriculaire (BIV) en insistant sur la caractérisation du substrat électrique éligible à la thérapie et l'intérêt de la resynchronisation électrique. Nous avons démontré qu'il existe une relation forte entre l'asynchronisme électrique de base défini tant par l'ECG de surface que par cartographie détaillée de l'activation ventriculaire (ECM) et la réponse hémodynamique à la stimulation BIV. Par rapport à l'ECG de surface, l'ECM permet une caractérisation plus fine de l'asynchronisme électrique ventriculaire avec une meilleure prédiction de la réponse clinique à la stimulation BIV. La présence d'un asynchronisme de base minimum, en particulier d'un retard d'activation ventriculaire gauche (VG) par rapport au ventricule droit (typiquement >SOms), est un prérequis à l'efficacité de la thérapie. Les patients avec bloc de branche gauche présentent un haut degré d'asynchronisme et la stimulation BIV agit sur ce substrat par resynchronisation de l'activation électrique. A contrario, la stimulation BIV dégrade la séquence d'activation ainsi que l'hémodynamique des patients à QRS fins (dyssynchronie iatrogène). Les patients présentant un trouble de conduction aspécifique présentent des degrés variables d'asynchronie électrique et en conséquence des réponses contrastées à la stimulation BIV. De même, l'analyse ECM de l'asynchronisme des patients chroniquement stimulés sur le ventricule droit a permis de mettre en évidence des degrés variables de retard d'activation du VG. Si la resynchronisation électrique est garante d'une amélioration de la fonction cardiaque, d'autres mécanismes sont impliqués telle la redistribution du travail segmentaire au sein du myocarde ventriculaire. L'efficacité de la stimulation mono-VG implique une participation accrue du ventricule droit au travail global (interaction ventriculaire)
We aimed to characterize the electrical substrate amenable to biventricular pacing (BVP) and to assess the actual value of electrical resynchronization. We showed, both with respect to surface ECG and detailed ventricular electrocardiographic mapping (ECM), a strong relationship between the baseline electrical dyssnchrony and the hemodynamic response to BIV pacing. Compared with standard ECG, ECM allows a more detailed analysis of the ventricular dyssynchrony and better predicts clinical outcomes after BVP. A minimal amount of electrical dyssynchrony, in particular a sufficient LV activation delay relative to right ventricular activation, is a prerequisite to the hemodynamic response to BVP. Due to their advanced electrical dyssynchrony, patients with left bundle branch block present potential for BVP positive response which acts by electrical resynchronization. Conversely, BVP worsens the electrical activation (iatrogenic dyssynchrony) and hemodynamics in patients with narrow QRS suffering from insufficient electrical dyssynchrony at baseline. Patients with unspecified conduction disorders show variable levels of electrical dyssynchrony and as a consequence mixed results to BVP. Similarly, ECM reveals a variable degree of left ventricular activation delay in patients chronically paced in the right ventricle. Beside the electrical resynchronization, other mechanisms are involved in the cardiac pump function improvement such as the redistribution of the mechanical work over the right and left ventricles. Through ventricular interaction, the RV myocardium importantly contributes to the improvement in LV pump function induced by single site LV pacing

La resynchronisation biventriculaire est un traitement recommandé chez les patients avec dysfonction ventriculaire gauche (VG) sévère et QRS large. Si les résultats en termes de bénéfice clinique sont globalement positifs, toutes les études retrouvent un pourcentage non négligeable de patients non répondeurs à la thérapeutique. Dans ce travail, en couplant données expérimentales animales et études cliniques, nous avons 1) investigué l’impact de la resynchronisation biventriculaire chez des patients avec Tétralogie de Fallot opérée 2) évalué l’impact hémodynamique associé avec une stimulation VG multipoints et avec une stimulation VG endocardique 3) analysé l’intérêt de l’optimisation des paramètres de stimulation à l’effort. Nous avons mis en évidence que 1) la resynchronisation permet un bénéfice hémodynamique significatif sur un modèle animal de dysfonction ventriculaire droite et chez des patients avec Tétralogie de Fallot opérée 2) la stimulation multipoints et la stimulation endocardique VG permettent un bénéfice hémodynamique significatif sur des modèles animaux d’insuffisance cardiaque et chez des patients avec insuffisance cardiaque sévère 3) l’optimisation à l’effort des paramètres de programmation permet un bénéfice hémodynamique. Un capteur intégré dans la prothèse de stimulation pourrait permettre une optimisation automatique.L’ensemble de ces données permet d’espérer une optimisation de la réponse clinique et d’envisager de nouveaux champs d’application pour cette thérapeutique
Cardiac resynchronization therapy is recommanded in patients with severe left ventricular (LV) dysfunction and wide QRS. Despite positive clinical results, a significant proportion of implanted patients do not demonstrate positive response to the therapy. Coupling experimental data and clinical studies, we have 1) investigated the impact of cardiac resynchronization in patients with repaired Tetralogy of Fallot 2) assessed the hemodynamic impact associated with multisite LV pacing and endocardial LV pacing 3) analyzed the impact of an exercise-optimization of the programmed parameters.We have demonstrated that 1) biventricular pacing is associated with a significant hemodynamic improvement in an animal model of right ventricular dysfunction and in patients with repaired Tetralogy of Fallot 2) multisite LV pacing and endocadial LV pacing are associated with significant hemodynamic improvement in animal models and in humans with severe heart failure 3) optimization during exercise of AV and VV delays induce acute hemodynamic improvement and could be automatically performed by an integrated hemodynimc sensor. Our data suggest a posible improvement in clinical response after cardiac resynchronization and a posible extension of the indications

The objective of this thesis is to evaluate the use of Doppler echocardiography markers ofglobal dyssynchrony [total isovolumic time (t-IVT)] in the following 6 studies: 1) Its prognostic role in predicting cardiac events in patients undergoing CABG surgery,compared with conventional global systolic and diastolic measurements. 2) Its additional value in predicting six minute walk test (6-MWT) in patients with leftventricular (LV) ejection fraction (EF) <45%. 3) Its prognostic value in comparison with other clinical, biochemical and echocardiographicvariables in patients with chronic systolic heart failure (HF). 4) The relationship between 6-MWT and cardiac function measurements in a consecutivegroup of patients, irrespective of EF and to identify predictors of exercise capacity. 5) To investigate the effect of age on LV t-IVT and Tei index compared with conventionalsystolic and diastolic parameters. 6) To assess potential additional value of markers of global LV dyssynchrony in predictingcardiac resynchronization therapy (CRT) response in HF patients. Study I Methods: This study included 74 patients before routine CABG who were followed up for18±12 months. Results: At follow-up, 29 patients were hospitalized for a cardiac event or died. LV-ESD wasgreater (P=0.003), fractional shortening (FS) lower (p<0.001), E:A ratio and Tei index higher(all P<0.001), and t-IVT longer (P<0.001) in patients with events. Low FS [0.66 (0.50–0.87),P<0.001], high E:A ratio [l4.13 (1.17–14.60), P=0.028], large LV-ESD [0.19 (0.05–0.84),P=0.029], and long t-IVT [1.37 (1.02–1.84), P=0.035] predicted events and deaths. Conclusion: Despite satisfactory surgical revascularization, long t-IVT and systolicdysfunction suggest persistent ventricular dyssynchrony that contributes to post-CABGcardiac events. Study II Methods: We studied 77 patients (60±12 year, and 33.3% females) with stable HF using 6-MWT.iii Results: E’ wave (r=0.61, p<0.001), E/e’ ratio (r=-0.49, p<0.001), t-IVT (r=-0.44, p<0.001),Tei index (r=-0.43, p<0.001) and NYHA class (r=-0.53, p<0.001) had the highest correlationwith the 6-MWT distance. In multivariate analysis, only E/e’ ratio [0.800 (0.665-0.961),p=0.017], and t-IVT [0.769 (0.619-0.955), p=0.018] independently predicted poor 6-MWTperformance (<300m). Conclusions: In HF, the higher the filling pressures and the more dyssynchronous the LV, thepoorer is the patient’s exercise capacity. Study III Methods: We studied 107 systolic HF patients; age 68±12 year, 25% females and measuredplasma NT-pro-BNP. Results: Over a follow-up period of 3718 months, t-IVT ≥12.3 sec/min, mean E/Em ratio≥10, log NT-pro-BNP levels ≥2.47 pg/ml and LV EF ≤32.5% predicted clinical events. Theaddition of t-IVT and NT-pro-BNP to conventional clinical and echocardiographic variablessignificantly improved the χ2 for the prediction of outcome from 33.1 to 38.0, (p<0.001). Conclusions: Prolonged t-IVT adds to the prognostic stratification of patients with systolicHF. Study IV Methods: We studied 147 HF patients (61±11 year, 50.3% male) with 6-MWT.Results: The 6-MWT correlated with t-IVT (r=-0.49, p<0.001) and Tei index (r=-0.43,p<0.001) but not with any of the other clinical or echocardiographic parameters. Group Ipatients (<300m) had lower Hb (p=0.02), lower EF (p=0.003), larger left atrium (p=0.02),thicker septum (p=0.02), lower A wave (p=0.01) and lateral wall a’ (p=0.047), longerisovolumic relaxation time (r=0.003) and longer t-IVT (p= 0.03), compared with Group II(>300m). Only t-IVT ratio [1.257 (1.071-1.476), p=0.005], LV EF [0.947 (0.903-0.993),p=0.02], and E/A ratio [0.553 (0.315-0.972), p=0.04] independently predicted poor 6-MWTperformance. Conclusion: In HF, the limited 6-MWT is related mostly to severity of global LVdyssynchrony, more than EF or raised filling pressures. Study V Methods: We studied 47 healthy individuals (age 62±12 year, 24 female), arbitrarilyclassified into: M (middle age), S (seniors), and E (elderly). Results: Age strongly correlated with t-IVT (r=0.8, p<0.001) and with Tei index (r=0.7,p<0.001), E/A ratio (r=-0.6, p<0.001), but not with global or segmental systolic function measurements or QRS duration. The normal upper limit of the t-IVT (95% CI) for the three groups was 8.3 s/min, 10.5 s/min and 14.5 s/min, respectively, being shorter in the S compared with the E group (p=0.001). T-IVT correlated with A wave (r=0.66, p<0.001), E/Aratio (r=-0.56, p<0.001), septal e’ (r=-0.49, p=0.001) and septal a’ (r=0.4, p=0.006), but notwith QRS. Conclusions: In normals, age is associated with exaggerated LV global dyssynchrony anddiastolic function disturbances, but systolic function remains unaffected. Study VI Methods: We studied 103 HF patients (67±12 year, 82.5% male) recruited for CRTtreatment. Results: Prolonged t-IVT [0.878 (0.802-0.962), p=0.005], long QRS duration [0.978 (0.960-0.996), p=0.02] and high tricuspid regurgitation pressure drop (TRPD) [1.047 (1.001-1.096),p=0.046] independently predicted response to CRT. A t-IVT ≥11.6 s/min was 67% sensitiveand 62% specific (AUC 0.69, p=0.001) in predicting CRT response. Respective values for aQRS ≥ 151ms were 66% and 62% (AUC 0.65, p=0.01). Combining the two variables had asensitivity of 67% but higher specificity of 88% in predicting CRT response. In atrialfibrillation (AF) patients, only prolonged t-IVT ≥11 s/min [0.690 (0.509-0.937), p=0.03]independently predicted CRT response with a sensitivity of 69% and specificity of 79% (AUC0.78, p=0.015). Conclusion: Combining prolonged t-IVT and broad QRS had higher specificity in predictingresponse to CRT, with the former the sole predictor of response in AF patients.

INTRODUÇÃO: Os benefícios na morbi-mortalidade obtidos pela terapia de ressincronização cardíaca (TRC) em pacientes com insuficiência cardíaca estão bem estabelecidos. Métodos invasivos e não invasivos têm sido utilizados para identificar aqueles que realmente se beneficiarão da TRC, mas 30% destes pacientes não apresentam melhora clínica/funcional. Poucos estudos avaliaram o comportamento elétrico dos pacientes submetidos à TRC. OBJETIVO: Utilizamos um método não invasivo, o mapeamento eletrocardiográfico de superfície (MES) para caracterizar o padrão da ativação elétrica ventricular em pacientes após a TRC. MÉTODOS: Estudamos 91 pacientes submetidos à TRC, com insuficiência cardíaca e bloqueio de ramo esquerdo (BRE), sendo 36 excluídos devido a FA (20), BRD (3), cardiopatias hipertrófica (3) e congênita (1) ou dependentes de marcapasso antes da TRC (9). Idade média:61±10 anos, FEVE:0,28±0,9, QRS:182±24ms, classe funcional NYHA: III(78%) e IV(22%). Com o ressincronizador ligado e desligado, todos realizaram o MES, o qual fornece 87 derivações simultâneas (58 anteriores e 29 posteriores). Os mapas isócronos obtidos pelo MES forneceram os tempos de ativação ventricular (TAV) global máximo e médio nas 87 derivações. Os TAVs obtidos foram regionalizados, sendo calculados os valores médios nas áreas do VD, do septo e do VE. Analisamos a diferença do TAV entre o VD e o VE, entre o septo e o VD e entre o septo e o VE, definidos como TAV Inter-Regional. Utilizados os testes de Mann-Whitney, Kruskall-Wallis, Fisher. Nível de significância: P0.05. RESULTADOS: O MES durante ritmo sinusal e BRE mostrou que os pacientes apresentavam prolongado TAV Global máximo e médio (138ms e 64,8ms, respectivamente) com significativa diferença Regional (54,5 x 56,4 x 95,9ms; p<0,0001; VD, septo e VE, respectivamente). A TRC reduziu o TAV Global máximo (138ms x 131ms; p=0,007) e o TAV Regional do VE (95,9 x 77,3ms; p=0,001). Houve aumento do TAV Regional do VD (54,5 x 78,9ms; p=0,001), sem alteração do TAV Regional do septo (56,4 x 59,6ms; p=ns). O comportamento do TAV Inter-Regional foi: Redução do TAV VE-VD (43,8 x 17,0ms; p=0,001) e do TAV septo-VE (42,6 x 16,3ms; p=0,001) e aumento do TAV septo-VD (6,9 x 16,0ms; p=0,002). CONCLUSÃO: O Mapeamento Eletrocardiográfico de Superfície possibilitou a caracterização detalhada da ativação elétrica ventricular de pacientes portadores de ressincronizador cardíaco através do comportamento elétrico global, regional e Inter-Regional durante ritmo sinusal com bloqueio de ramo esquerdo e estimulação biventricular
INTRODUCTION: The benefits of lower morbidity and mortality obtained with cardiac resynchronization therapy (CRT) in patients with heart failure are already well established. Invasive and noninvasive methods have been used to identify those who will really benefit from CRT, however 30% of these patients do not improve clinically/functionally. Few studies evaluated the cardiac electrical development of patients undergoing CRT. OBJECTIVE: To obtain through the body surface potential mapping (BSPM), a noninvasive approach, characterization of the ventricular electrical activation development in patients after CRT. METHODS: We studied 91 patients with heart failure and left bundle-branch block (LBBB) who underwent CRT, 36 of whom were excluded for AF (20), RBBB (3), hypertrophic (3) or congenital (1) cardiomyopathy, or depended upon a pacemaker before CRT (9). Mean age was 61±10 years, LVEF 0.28±0.9, QRSd 182±24ms, NYHA functional class III(78%) and IV(22%). All underwent BSPM examination of 87 simultaneous leads (58 on the anterior chest, 29 on the back) with the resynchronization device on, then in intrinsic rhythm and LBBB (device off). The BSPM isochronal maps provided maximal and mean global ventricular activation times (VAT) for all the 87 leads. From VATs thus obtained, separate mean values for the RV, septum and LV areas were then calculated. VAT differences between RV-LV, septum-RV and septum-LV, were analyzed and denominated inter-regional VATs. Mann-Whitney, Kruskall-Wallis and Fisher statistics were used, with P.05 established as the significance level. RESULTS: During sinus rhythm/LBBB the BSPM showed patients evidencing prolonged maximal and mean global VATs (138ms and 64.8ms, respectively), with significant regional differences (54.5 vs 56.4 vs 95.9ms; RV, septum and LV, respectively; p<0.0001). CRT reduced the maximal global VAT (138ms vs 131ms; p=0.007) and the LV regional VAT (95.9 vs 77.3ms; p=0.001). The RV regional VAT increased (54.5 vs 78.9ms; p=0.001), with no alteration of the septum regional VAT (56.4 vs 59.6ms; p=ns). The inter-regional VAT developed as follows: decrease in VATLV-RV (43.8 vs 17.0ms; p=0.001) and VATseptum-LV (42.6 vs 16.3ms; p=0.001), and increase in VATseptum-RV (6.9 vs 16.0ms; p=0.002). CONCLUSION: The body surface potential mapping permitted a detailed characterization of the ventricular electrical activation of patients carrying a cardiac resynchronization device, by mapping the global, regional and inter-regional electrical activation development during sinus rhythm with left bundle-branch block, and in biventricular pacing

INTRODUÇÃO: A estimulação cardíaca artificial convencional em ponta do ventrículo direito é o tratamento de eleição para os quadros de bradicardia severa, contudo, apesar de excelente para corrigir a frequência cardíaca, favorece o surgimento de dissincronia ventricular mecânica, podendo agravar ou originar insuficiência cardíaca. Neste contexto, desde a década de 90 são utilizadas no Instituto Dante Pazzanese as estimulações septal (ou para-Hissiana) e bifocal de ventrículo direito (septal e apical). Postula-se que a estimulação em posição septal teria melhores resultados tanto em termos clínicos quanto às medidas elétricas e ecocardiográficas de função sistólica quando comparada à posição apical. Esta nova estimulação ainda não foi amplamente testada frente à estimulação convencional com as novas tecnologias de avaliação da sincronia cardíaca. MÉTODOS: Pacientes portadores de fibrilação atrial permanente, sem possibilidade de estimulação atrial, com disfunção sistólica leve ou moderada e bradicardia com indicação de marca-passo definitivo foram submetidos à implante de marca-passo bifocal de ventrículo direito com eletrodos em posição septal e apical em todos os casos. Os pacientes foram randomizados para estimulação unifocal por dois meses e a seguir submetidos à crossover no ponto de estimulação cardíaca. Após cada período de estimulação eram realizados eletrocardiograma e ecocardiograma transtorácico bidimensional com avaliação de parâmetros de sincronia do miocárdio ventricular. RESULTADOS: Foram incluídos 25 pacientes em cada grupo de estimulação na análise final do estudo. A estimulação em posição septal demonstrou uma menor duração do QRS estimulado (153 ± 12 ms vs. 174 ± 16 ms, p < 0,001) e melhor fração de ejeção do ventrículo esquerdo (44 ± 9% vs. 40 ± 8%, p < 0,001) quando comparada com a posição apical. A classe funcional (NYHA) também foi menor com a estimulação septal (1,8 ± 0,6 vs. 2,2 ± 0,7, p < 0,001). A avaliação da sincronia cardíaca evidenciou menos dissincronia interventricular (p < 0,001) e intraventricular com a estimulação septal (Septal to posterior delay: 33,1 ± 28,7 vs. 80,7 ± 46,2 ms, p < 0,001; Índice de Yu: 33,4 ± 8,6 ms vs. 50,2 ± 14,0 ms, p < 0,001; Strain radial: 78,8 ± 57,1 ms vs. 137,2 ± 50,2 ms, p < 0,001). CONCLUSÃO: A avaliação intrapaciente mostrou que, em comparação com a estimulação apical convencional, a estimulação em posição septal esteve associada à menor dissincronia cardíaca medida pela ecocardiografia, o que pode estar relacionado à melhor função sistólica do ventrículo esquerdo e consequentemente melhores resultados clínicos observados.
INTRODUCTION: Conventional artificial cardiac pacing in the right ventricle apex is the treatment of choice for severe bradycardia. Although it is excellent for correcting heart rate, it favors the onset of electromechanical ventricular dyssynchrony, which may aggravate or even lead to heart failure. In this context, the Septal (or para-Hissian) and bifocal (septal and apical) stimulation were used since the 90\'s in the Dante Pazzanese Institute. It was observed that the septal stimulation could have better results both in clinical terms and in the electrical and echocardiographic measurements of systolic function when compared to the apical stimulation. This new stimulation has not been yet extensively tested against conventional one with the new technologies of cardiac synchrony evaluation. METHODS: Patients with permanent atrial fibrillation, without possibility of atrial stimulation, with mild or moderate systolic dysfunction and bradycardia with indication of pacemaker were submitted to implantation of bifocal pacemaker in the right ventricle with electrodes in a septal and apical position in all cases. The patients were randomized to unifocal stimulation for two months and then underwent crossover, changing the point of cardiac stimulation. After each stimulation period, electrocardiogram and two-dimensional transthoracic echocardiography were performed with evaluation of ventricular myocardial synchrony parameters. RESULTS: Twenty-five patients were included in each stimulation group in the final analysis of the study. Septal pacing demonstrated a shorter duration of the QRS (153 ± 12 ms vs. 174 ± 16 ms, p < 0.001) and a better left ventricular ejection fraction (44 ± 9% vs. 40 ± 8%, p < 0.001) when compared to the apical position. NYHA functional class was also lower with septal pacing (1.8 ± 0.6 vs. 2.2 ± 0.7, p < 0.001). The cardiac synchrony evaluation showed less interventricular (p < 0.001) and intraventricular dyssynchrony with septal pacing (Septal to posterior delay: 33.1 ± 28.7 vs. 80.7 ± 46.2 ms, p < 0.001; Yu index: 33.4 ± 8.6 ms vs. 50.2 ± 14.0 ms, p < 0.001; Radial strain: 78.8 ± 57.1 ms vs. 137.2 ± 50.2 ms, p < 0.001). CONCLUSION: The intrapatient comparision showed that, compared to the apical conventional stimulation, the septal pacing was associated with lower cardiac dyssynchrony measured by echocardiography, which may be related to the better left ventricular systolic function and consequently better clinical results observed.

Os efeitos da utilização da terapia de ressincronização cardíaca (TRC) em pacientes com cardiopatia chagásica (CCC) são pouco conhecidos. O objetivo desse trabalho foi comparar o efeito dessa terapia em pacientes com CCC e não-chagásica. Foram estudados, retrospectivamente, todos os pacientes submetidos à ressincronização cardíaca, associados ou não ao cardioversor-desfibrilador implantável (CDI) no Hospital das Clínicas da Faculdade de Medicina de Ribeirão Preto da Universidade de São Paulo no período de julho de 2007 a dezembro de 2017. Para comparar a mesma variável em dois momentos diferentes foi utilizado Teste de Wilcoxon. Para a comparação de proporções foi utilizado o teste exato de Fisher. A análise de sobrevida foi feita utilizando-se o método de Kaplan-Meier com o \"Long rank test\" para comparar a sobrevida entre os grupos. Para a análise das variáveis associadas à mortalidade pós-implante utilizou-se a análise de regressão de Cox. Noventa e oito pacientes foram incluídos e divididos em três grupos de cardiopatia: chagásica (CCC) com 42 pacientes (42,9%); isquêmicos (ISQ) com 13 (13,3%) e nãoisquêmico não-chagásico (NINC) com 43 (43,9%). Os pacientes que receberam implante de TRC foram 71,4% e TRC associado ao CDI foram 28,5%. Não havia diferença estatisticamente significativa entre os grupos na avaliação das características clínicas, exceto pela predominância de pacientes do gênero masculino no grupo ISQ. Em relação aos bloqueios de condução intraventriculares, havia menor quantidade de bloqueio de ramo esquerdo (BRE) espontâneo e maior quantidade de BRE induzido no grupo CCC. As demais características eletrocardiográficas e ecocardiográficas eram semelhantes entre os grupos. A sobrevida de pacientes que recebem a TRC foi baixa após 48 meses de implante, independentemente do tipo de miocardiopatia e a despeito da melhora significativa da classe funcional e estreitamento do QRS dos pacientes. Todavia, a sobrevida em pacientes chagásicos foi significativamente menor quando comparada as demais miocardiopatias. Ademais, a melhora da fração de ejeção do ventrículo esquerdo (FEVE) e a redução do diâmetro diastólico final do ventrículo esquerdo (DDFVE) ocorreram significativamente apenas no grupo NINC. O aumento da idade, FEVEreduzida, presença de atraso da condução intraventricular não especificada (ACINE) e de bloqueio de ramo direito (BRD) e baixa classe funcional estão associadas a maior risco de morte após implante. As taxas de complicações cirúrgicas foram baixas em todos os grupos. A taxa de óbito cirúrgico é compatível com a gravidade desses pacientes. Conclui-se que a CCC apresenta resposta clínica à TRC, mas a mortalidade após 48 meses é maior que em outras cardiopatias.
The effects of using cardiac resynchronization therapy (CRT) in patients with Chagas\' heart disease (CCC) are poorly understood. The objective of this study was to compare the effect of this therapy in patients with CCC and non-Chagas\' disease. We retrospectively studied all patients submitted to cardiac resynchronization associated or not with the implantable cardioverter defibrillator (ICD) at the Clinical Hospital of Ribeirão Preto Medical School at the São Paulo University from July 2007 to December 2017. We use Wilcoxon\'s test to compare the same variable in two different times. Fisher\'s exact test was used to compare proportions. Survival analysis was done using the Kaplan-Meier method with the Long rank test to compare survival between groups. Cox regression analysis was used to analyze the variables associated with post-implantation mortality. Ninety-eight patients were included and divided into three groups: cardiopathy: chagasic (CCC) with 42 patients (42.9%); ischemic (ISQ) with 13 patients (13.3%) and non-ischemic non-chagasic (NINC) with 43 (43.9%). The patients who received CRT implantation were 71.4% and CRI associated CRT were 28.5%. There was no statistically significant difference between the groups in the assessment of clinical characteristics, except for the predominance of male patients in the ISQ group. In relation to intraventricular conduction blockades, there was a lower amount of spontaneous left bundle branch block (LBBB) and greater amount of LBBB induced in the CCC group. The other electrocardiographic and echocardiographic characteristics were similar between groups. The survival of patients receiving CRT was low after 48 months of implantation, regardless of the type of cardiomyopathy and despite significant improvement in functional class and QRS narrowing of patients. However, survival in chagasic patients was significantly lower when compared to other cardiomyopathies. In addition, the improvement of left ventricular ejection fraction (LVEF) and the reduction of the left ventricular end-diastolic dimension (LVEDF) occurred significantly only in the NINC group. Increased age, reduced LVEF, presence of unspecified intraventricular conduction delay and left bundle branch block, and low functional class are associated with a higher risk of death after implantation. Therates of surgical complications were low in all groups. The surgical death rate is compatible with the severity of these patients. It is concluded that CCC presents a clinical response to CRT, but mortality after 48 months is higher than in the other cardiopathies.

Introdução. Sabe-se que a terapia de ressincronização cardíaca (TRC) aumenta a capacidade ao esforço e reduz a ativação simpática em pacientes com insuficiência cardíaca (IC). Por outro lado, existem evidências de que o treinamento físico (TF) melhora o controle neurovascular, tolerância ao exercício e qualidade de vida dos pacientes com IC. Neste estudo, nós testamos a hipótese de que o TF associado à TRC diminuiria a atividade nervosa simpática muscular (ANSM) e a vasoconstrição periférica. Adicionalmente, esta associação de TRC e TF melhoraria a função cardíaca, consumo de oxigênio pico e qualidade de vida nesses pacientes. Métodos. Vinte e oito pacientes com IC submetidos há um mês de TRC e fração de ejeção < 35% foram consecutivamente e aleatoriamente divididos em dois grupos: treinados (TRCt, n=14, 54 ± 4 anos) e não-treinados (TRCs, n=14, 57 ± 1 anos). Um grupo de indivíduos controles saudáveis também foi incluído no estudo (n=11, 43 ± 4 anos). A ANSM foi avaliada diretamente pela técnica de microneurografia. O fluxo sanguíneo muscular foi avaliado pela técnica de pletismografia de oclusão venosa. A capacidade física foi avaliada pelo teste cardiopulmonar, a função cardíaca pelo ecocardiograma e a qualidade de vida pelo questionário Minnesota Living with Heart Failure. O TF foi realizado em esteira ergométrica por 40 minutos, 3 vezes por semana, durante 4 meses. Resultados. No período pré-intervenção, a ANSM foi significativamente maior (p=0,01) nos pacientes com IC quando comparados com os indivíduos saudáveis. O fluxo sanguíneo muscular não foi diferente entre os grupos estudados (p=0,24). Após quatro meses de treinamento físico, a ANSM foi reduzida (65 ± 7 vs 43 ± 8 disparos/100batimentos, p < 0,001), atingindo níveis semelhantes àqueles observados nos indivíduos saudáveis (43 ± 8 vs 31 ± 3 disparos/100batimentos, p=0,44). Além disso, o TF associado a TRC aumentou o FSM (1,63 ± 0,14 vs 1,85 ± 0,12 ml/min/100ml, p=0,02), a fração de ejeção (28 ± 3 vs 33 ± 4%, p=0,04) e a capacidade funcional (18,5 ± 1,1 vs 21,5 ± 1,7 ml/kg/min, p=0,04), o que não foi observado no grupo TRCs. Não houve alteração significativa na qualidade de vida dos pacientes (26 ± 4 vs 20 ± 4, p=0,11). Conclusão. O treinamento físico associado à TRC melhora expressivamente o controle neurovascular, a função cardíaca e a capacidade física em pacientes com IC. Estes achados destacam a importância da inclusão do treinamento físico no tratamento de pacientes com IC submetidos à TRC
Background. Cardiac Resynchronization Therapy (CRT) is known to increase exercise capacity and decrease sympathetic activation in HF. On the other hand, there is evidence that exercise training improves neurovascular control, physical capacity and quality of life in HF patients. We tested the hypothesis that exercise training (ET) associated with CRT would reduce muscle sympathetic nerve activity (MSNA) and peripheral vasoconstriction in chronic heart failure patients. In addition, the association of CRT and ET would improve cardiac function, peak oxygen consumption and quality of life in these patients. Methods. Twenty-eight HF patients submitted a month of CRT, EF < 35%, with CRT for 1 month were consecutively and randomly divided into two groups: Exercise-trained (CRTt, n=14, 54 ± 4 years old) and untrained (CRTs, n=14, 57 ± 1 years old). A control group was also involved in the study (n=11, 43 ± 4 years). MSNA was directly evaluated by microneurography technique and forearm blood flow by venous occlusion plethysmography. Peak VO2 was determined by cardiopulmonary exercise test, cardiac function by echocardiography and quality of life by Minnesota Living with Heart Failure questionnaire. ET consisted of three 40-minute exercise sessions per week on a treadmill for four months. Results. Baseline MSNA was significantly higher (p=0.01) in heart failure patients when compared with healthy controls. The forearm blood flow was not different between groups (p=0.24). After four months of ET, MSNA was significantly reduced (65±7 vs 43±8 bursts/100 heart beats, p < 0.001) reaching levels similar to those observed in healthy subjects (43±8 vs. 31±3 bursts/100 heart beats, p=0.44). Furthermore, ET associated with CRT increased forearm blood flow (1.63±0.14 vs. 1.85±0.12 ml/min/100ml, p=0.02), EF (28±3 vs. 33±4%, p=0.04) and peak VO2 (18.5±1.1 vs 21.5 ± 1.7 ml/kg/min, p=0.04), which was not observed in the CRTs. There was not significant changes in the quality of life of patients (26 ± 4 vs. 20 ± 4, p=0.11). Conclusions. ET associated with CRT improves neurovascular control, cardiac function and functional capacity in heart failure patients. These findings highlight the importance of including ET in the treatment of heart failure patients submitted to CRT

This thesis focuses on the development of machine learning tools to better characterize the cardiac anatomy and function in the context of heart failure, and in particular their extension to consider multiple parameters that help identifying the pathophysiological aspects underlying disease. This advanced and personalized characterization may eventually allow assigning patients to clinically-meaningful phenogroups with a uniform treatment response and/or disease prognosis. Specifically, the thesis copes with the technical difficulties that multivariate analyses imply, paying special attention to properly combine different descriptors that might be of different nature (e.g., patterns, continuous, or categorical variables) and to reduce the complexity of large amounts of data up to a meaningful representation. To this end, we implemented an unsupervised dimensionality reduction technique (Multiple Kernel Learning), which highlights the main characteristics of complex, high-dimensional data into fewer dimensions. For our computational analysis to be useful for the clinical community, it should remain fully interpretable. We made special emphasis in allowing the user to be aware of how the input to the learning process models the obtained output, through the use of multi-scale kernel regression techniques among others.
Esta tesis se centra en el desarrollo de herramientas de aprendizaje automático para mejorar la caracterización de la anatomía y la función cardíaca en el contexto de insuficiencia cardíaca, y, en particular, su extensión para considerar múltiples parámetros que ayuden a identificar los aspectos pato-fisiológicos subyacentes a la enfermedad. Esta caracterización avanzada y personalizada podría en última instancia permitir asignar pacientes a fenogrupos clínicamente relevantes, que demuestren una respuesta uniforme a un determinado tratamiento, o un mismo pronóstico. Específicamente, esta tesis lidia con las dificultades técnicas que implican los análisis multi-variable, prestando especial atención a combinar de forma apropiada diferentes descriptores que pueden ser de diferente naturaleza (por ejemplo, patrones, o variables continuas o categóricas), y reducir la complejidad de grandes cantidades de datos mediante una representación significativa. Con este fin, implementamos una técnica no supervisada de reducción de dimensionalidad (Multiple Kernel Learning), que destaca las principales características de datos complejos y de alta dimensión utilizando un número reducido de dimensiones. Para que nuestro análisis computacional sea útil para la comunidad clínica debería ser enteramente interpretable. Por eso, hemos hecho especial hincapié en permitir que el usuario sea consciente de cómo los datos entrantes al algoritmo de aprendizaje modelan el resultado obtenido mediante el uso de técnicas de regresión kernel multi-escala, entre otras.

L’insuffisance cardiaque est un problème de santé publique dans les pays développés, touchant 1 à 2% de la population générale, mais dont la prévalence atteint 10% après 70 ans. Les progrès thérapeutiques ont permis d’améliorer le pronostic des patients, notamment ceux ayant une altération de la fonction systolique ventriculaire gauche. Les troubles du rythme sont fréquents et nécessitent une pris en charge particulière au cours des situations d’insuffisance cardiaque. Cependant, il reste des questions non résolues : comment améliorer l’efficacité du traitement de l’insuffisance cardiaque à fonction systolique préservée, comment mieux sélectionner les patients pouvant bénéficier de la prévention primaire de la mort subite par un défibrillateur implantable, les patients âgés peuvent-ils bénéficier de la même prise en charge que les patients plus jeunes, et pour finir comment améliorer les résultats de l’ablation de fibrillation auriculaire dans les situations d’insuffisance cardiaque. Nous avons mis en place une étude prospective chez des patients présentant une dysfonction diastolique pour évaluer l’intérêt de l’algorithme de surveillance de l’apnée du sommeil disponible dans des stimulateurs cardiaques. En parallèle, nous avons analysé l’impact de l’évaluation par résonance magnétique des patients candidats à un défibrillateur sur la prédiction des évènements rythmiques, mais aussi le devenir des patients de plus de 75 ans appareillés avec un système de resynchronisation cardiaque. Enfin, nous nous sommes intéressés aux résultats d’un nouveau système de cartographie électroanatomique ultra-haute densité pour guider les procédures d’ablation de troubles du rythme supraventriculaires complexes chez des patients insuffisants cardiaques comparés à des patients contrôles
Heart failure is a major public health issue in developed countries, with a prevalence of 1-2% of global population, rising to 10% after 70 years of age. Therapeutic progresses have succeeded in improving patients’ prognosis, particularly in case of reduced left ventricular ejection fraction. Rhythm abnormalities are frequent, and need special consideration in case of heart failure. Meanwhile, there are still some gaps in the evidence: heart failure with preserved systolic function is complex and difficult to treat, primary prevention of sudden cardiac death is effective but there is a need to better select candidates, whether elderly patients should be treated as younger individuals, and finally how to improve outcomes of atrial fibrillation catheter ablation. Firstly, we have conducted a prospective study to evaluate the Sleep Apnea Monitoring algorithm provided in a novel pacemaker in patients with diastolic dysfunction. Besides, we analyzed whether magnetic resonance imaging could predict cardiac outcomes in patients with an implantable cardioverter defibrillator better than echocardiography. We also reported the outcomes of the cardiac resynchronization therapy in patients ≥75 years old compared to younger patients. Finally, we studied the results of a novel ultra-high density mapping system to guide ablation procedures of complex atrial arrhythmias in heart failure patients compared to controls

INTRODUÇÃO: A terapia de ressincronização cardíaca(TRC) tem se mostrado alternativa eficiente para pacientes com Insuficiência Cardíaca (IC) em uso terapia medicamentosa otimizada, com fração de ejeção reduzida e QRS largo. Apesar dos resultados positivos em pacientes de diversas etiologias, dados a despeito do efeito dessa terapia na cardiopatia chagásica são extremamente raros na literatura. OBJETIVOS: Avaliar a evolução clínica e funcional de pacientes chagásicos submetidos à terapia de ressincronização cardíaca, por meio de estudo clínico randomizado. CASUÍSTICA E MÉTODOS: Foram incluídos pacientes com cardiopatia chagásica, em Classe funcional II, III ou IV da NYHA, em uso de terapia medicamentosa otimizada, fração de ejeção <= 35% e duração do QRS largo. O presente estudo clínico é prospectivo, de intervenção, randomizado, cego, com crossover e comparou as respostas clínicas e funcionais após duas fases: período de 2 meses com a TRC ligada e período de 2 meses com a TRC desligada. As variáveis analisadas foram distância percorrida no teste de caminhada de 6 minutos, classe funcional (NYHA), pontuação no teste de qualidade de vida do questionário de Minnesota, pontuação no teste de capacidade funcional no questionário SF 36, pico de extração de oxigênio no teste cardiopulmonar e fração de ejeção do ventrículo esquerdo. RESULTADOS: Foram randomizados 34 pacientes sendo que seis não conseguiram completar as duas fases do estudo. A média da distância percorrida no Teste de Caminhada de 6 minutos foi 60 metros maior no grupo TRC ligada (500,3 versus 439,8 metros; p<0,01), o teste de Qualidade de Vida (Questionário de Minnesota) apresentou escores estatisticamente melhores nos pacientes com TRC ligada (diferença entre os dois grupos de 12,2 pontos, p<0,05). A Capacidade Funcional avaliada pelo questionário SF 36 apresentou resultado a favor da TRC ligada (p<0,01). De modo semelhante, a Classe Funcional (NYHA) média foi significativamente inferior neste grupo (p<0,05). As variáveis estudadas no Teste Cardiopulmonar e os parâmetros Ecocardiográficos não atingiram diferenças com significância estatística entre os dois grupos. CONCLUSÃO: Os resultados encontrados neste estudo suportam o valor terapêutico da TRC em indivíduos com insuficiência cardíaca de etiologia chagásica com QRS largo. A estimulação biventricular promoveu melhora significativa dos sintomas, qualidade de vida, capacidade funcional e da distância percorrida no teste de caminhada. Estudos subsequentes são necessários para avaliação dos efeitos clínicos a longo prazo e o impacto em mortalidade desta modalidade terapêutica nos pacientes com cardiopatia chagásica.
BACKGROUND: Cardiac Resynchronization Therapy (CRT) has been shown one effective alternative for patients under optimal medical therapy, reduced ejection fraction (EF) and wide QRS. Despite the positive results in patients of several etiologies, data from this therapy in Chagas heart disease are extremely rare in the literature. OBJECTIVES: To evaluate the clinical and functional results of Chagas patients undergoing CRT through a randomized clinical trial. METHODS: There were included patients with Chagas cardiomyopathy, functional class II, III or IV of NYHA, under optimal drug therapy, EF <= 35% and wide QRS. This prospective, randomized, blinded, crossover study compared the clinical and functional responses after two phases: a two-month period of CRT-on and a two-month period of CRT-off. The outcomes analyzed were: walked distance in 6 minutes, functional class (NYHA), quality of life by the Minnesota Living with Heart Failure Questionnaire score, functional capacity by the questionnaire SF 36 score, Oxygen Extraction Peak in Cardiopulmonary Test and EF of the Left Ventricle. RESULTS: Thirty four patients were randomized but six patients failed to complete both study periods. The average distance walked in 6 minutes was 60 meters higher in CRT-on group (500.3 vs. 439.8 meters, p <0.01), the Quality of Life (Minnesota Questionnaire) showed scores significantly better in patients with CRT- on (difference of scores between the two groups: 12.2, p <0.05). The functional capacity assessed by the SF-36 questionnaire showed better results in favor of CRT-on group (p <0.01). Similarly, the functional class (NYHA) was significantly lower in this group (p <0.05). The variables studied in Cardiopulmonary Testing and Echocardiographic parameters did not reach statistical significance between the two groups. CONCLUSION: The results of this study support the therapeutic value of CRT in patients with heart failure due to Chagas disease with wide QRS. The biventricular pacing significantly improved symptoms, quality of life, functional capacity and the distance walked in 6 minutes. Further studies are needed to evaluate the clinical long-term effects and the impact on mortality of this therapeutic modality in patients with Chagas heart disease.

Les procédures d’électrophysiologie cardiaque ont démontré leur efficacité pour la suppression de symptômes d’arythmie et d’insuffisance cardiaque. Leur taux de succès dépend de la bonne connaissance de l’état du cœur du patient, en termes de conductivité électrique, de qualité tissulaire, et de propriétés mécaniques. Cette intégration d’informations est un enjeu clinique majeur pour ces thérapies. Cette thèse porte sur le développement et l’exploitation de modèles multimodaux spécifiques au patient, pour la planification et l’assistance de l’ablation par radiofréquences (ARF) et de la thérapie de resynchronisation cardiaque (CRT). Des méthodes de segmentation, de recalage et de fusion d’informations multimodales ont dans un premier temps été établies pour la création de ces modèles, permettant de planifier ces procédures. Puis, des approches spécifiques à chacune ont été mises en œuvre pour intégrer ces modèles dans le bloc opératoire, pour assister le geste clinique. Enfin, une analyse postopératoire a permis la synthèse d’un nouveau descripteur multimodal, visant à prédire la réponse de la CRT suivant le site choisi de stimulation du ventricule gauche. Ces études ont été appliquées et validées pour des patients candidats à la CRT et à l’ARF. Elles ont montré la faisabilité et l’intérêt d’intégrer ces modèles multimodaux dans le workflow clinique pour l’assistance à ces gestes interventionnels
Cardiac electrophysiology procedures have been proved to be efficient to suppress arrythmia and heart failure symptoms. Their success rate depends on patient’s heart condition’s knowledge, including electrical and mechanical functions and tissular quality. It is a major clinical concern for these therapies. This work focuses on the development of specific patient multimodal model to plan and assist radio-frequency ablation (RFA) and cardiac resynchronization therapy (CRT). First, segmentation, registration and fusion methods have been developped to create these models, allowing to plan these interventional procedures. For each therapy, specific means of integration within surgical room have been established, for assistance purposes. Finally, a new multimodal descriptor has been synthesized during a post-procedure analysis, aiming to predict the CRT’s response depending on the left ventricular stimulation site. These studies have been applied and validated on patients candidate to CRT and ARF. They showed the feasibility and interest of integrating such multimodal models in the clinical workflow to assist these procedures

Introdução: A terapia de ressincronização cardíaca (TRC) é um tratamento recomendado pelas principais diretrizes mundiais para pacientes com insuficiência cardíaca congestiva (ICC), disfunção ventricular esquerda (FE <= 35%), com tratamento otimizado e distúrbio da condução intraventricular, principalmente pelo ramo esquerdo. Entretanto, 30%-40% dos pacientes selecionados não respondem ao tratamento. As razões desse insucesso não são completamente conhecidas. Existe, portanto, necessidade de desenvolvimento de índices multifatoriais para melhor selecionar e acompanhar a evolução e o prognóstico destes pacientes. Objetivo: Elaborar modelos preditores de risco de óbito cardíaco ou transplante (Tx), em diferentes fases da TRC. Métodos e Casuística: Estudo observacional, prospectivo e analítico, com inclusão de 116 pacientes, entre 01/2008 a 03/2013, sendo 69,8% do sexo masculino, com CF III (68,1%) e IV ambulatorial (31,9%), com BRE em 71,55% e com idade de 64,89 ± 11,18 anos e fração de ejeção (FE) de 29%. Avaliações foram feitas no período pré-implante (tempo 1), 6-12 meses (tempo 2) e 18-24 meses (tempo 3) e correlacionadas com a mortalidade cardíaca/Tx no final do seguimento. Foram estudadas variáveis clínicas, eletrocardiográficas e ecocardiográficas e realizadas análises de regressão de Cox e regressão logística, com a construção da curva ROC. As curvas de sobrevidas foram realizadas pelo método de Kaplan-Meier e comparadas pelo log-rank. Modelos e escores foram elaborados pelas pontuações do \"hazard ratio\", utilizado como variável independente no modelo de regressão logística. Resultados: Ocorreram 29 (25%) óbitos/Tx durante o seguimento de 34,09 ± 17,9 meses. A mortalidade cardíaca/Tx foi de 16,3 % (19 pacientes). Seis pacientes foram transplantados durante o tempo do estudo. No período préimplante (tempo 1), a presença de disfunção de ventrículo direito (VD), FE < 25% e o uso de altas doses de diuréticos (dois ou mais comprimidos de furosemida) mostraram-se com valor independente, com aumento de risco de óbito cardíaco/Tx de 3,9; 4,8 e 5,9 vezes, respectivamente. No tempo 2 (1° ano), as variáveis disfunção de VD, altas doses de diuréticos e internações por ICC foram as variáveis significativas, com aumento de risco 3,5; 5,3 e 12,5 respectivamente. No tempo 3 (2° ano), as variáveis disfunção de VD e classe funcional III/IV foram significativas no modelo multivariado de Cox, com aumento de risco de 12,1 e 7,7. As acurácias dos modelos foram 84,6%; 93% e 90,5%, respectivamente. Conclusão: Os modelos preditores de óbito cardíaco desenvolvidos a partir de variáveis clínicas e ecocardiográficas, obtidas em diferentes fases da TRC, mostraram boa acurácia e podem ajudar na seleção, seguimento, definição de resposta e aconselhamento destes pacientes
Introduction: Cardiac resynchronization therapy (CRT) is indicated for patients with congestive heart failure (CHF), ejection fraction (EF) <= 35%, and bundle branch block. However, 30%-40% do not respond to CRT. Therefore, there is a need to develop multifactorial indexes to better select and follow these patients. Objective: This work aims to develop predictive models for the risk of cardiac death or transplantation (Tx) at different stages of CRT. Methods: We performed a prospective observational study of 116 patients, 69.8% males, functional class (FC) III (68.1%) and IV (31.9%), LBBB in 71.55%, age 64.89 ± 11.18 years. We studied clinical, electrocardiographic, and echocardiographic variables and performed Cox and logistic regression with ROC and Kaplan- Meier curves. Results: The cardiac mortality was 16.3% (19 patients) in the 34.09 ± 17.9 follow-up months. Pre-implantation, the right ventricular dysfunction (RVD), EF <25%, and the use of high doses of diuretics (HDD) increased risk of cardiac death or Tx of 3.9, 4.8, and 5.9 fold, respectively, and in the first year, the variables RVD, HDD, and hospitalizations for CHF increased risk of death of 3.5, 5.3, and 12.5, respectively. In the 2nd year, the variables RVD and FC III / IV (NYHA) were significant in the multivariate Cox model. The accuracies of the models were 84.6%, 93%, and 90.5%, respectively. Conclusions: Cardiac death predictive models were developed in different stages of CRT, and were based on the analysis of simple clinical and echocardiographic variables. The models showed good accuracy and can help in the selection and follow-up of these patients

This thesis deals with the analysis of high-frequency ECG, namely by parameters for the determination of cardiac asynchrony from the amplitude envelopes ultra-high-frequency ECG. In the theoretical part is described the conventional and high-frequency ECG, procedure of their scanning and parameters of the acquired record. Also is described the electrical conduction system of the heart and its blockade. This issue is followed by chapters about cardiac asynchrony and its treatments by biventricular pacemaker – resynchronization therapy. The chapter about resynchronization includes a description of the methods used for the indication for therapy based on conventional and high-frequency ECG. In the practical part are proposed new parameters for determining heart asynchrony from high-frequency ECG, programmed their detection in environment MATLAB and described realization of detection and obtained results. In the last part of thesis is described statistical evaluation of data and is decided about suitability of use the proposed parameters.

Cette thèse porte sur la caractérisation cardiaque, qui représente un enjeu méthodologique et clinique important, à la fois pour améliorer le diagnostic des pathologies et optimiser les moyens de traitement. Des méthodes de recalage et de fusion de données sont proposées pour amener dans un même référentiel des images IRM, scanner, échographiques et électro-anatomiques et ainsi décrire le cœur suivant des caractéristiques anatomiques, électriques, mécaniques et tissulaires. Les méthodes proposées pour recaler des données multimodales reposent sur deux processus principaux : l'alignement temporel et le recalage spatial. Les dimensions temporelles des images considérées sont mises en synchronisées par une méthode de déformation temporelle dynamique adaptative. Celle-ci permet de compenser les modifications temporelles non-linéaires entre les différentes acquisitions. Pour le recalage spatial, des méthodes iconiques ont été développées pour corriger les artefacts de mouvements dans les séquences ciné-IRM, pour recaler les séquences ciné-IRM avec les séquences d'IRM de rehaussement tardif et pour recaler les ciné-IRM avec les images scanner. D'autre part, une méthode basée contours, développée dans un précédent travail, a été améliorée pour prendre en compte des acquisitions échographiques multi-vues. Ces méthodes ont été évaluées sur données réelles pour sélectionner les métriques les plus adaptées et pour quantifier les performances des approches iconiques et pour estimer la précision du recalage entre échographies et ciné-IRM. Ces méthodes sont appliquées à la caractérisation de cardiomyopathies hypertrophiques (CMH) et d'asynchronismes cardiaques. Pour la CMH, l'objectif était de mieux interpréter les données échographiques par la fusion de l'information de fibrose issue de l'IRM de rehaussement tardif avec l'information mécanique issue de l'échographie de speckle tracking. Cette analyse a permis d'évaluer le strain régional en tant qu'indicateur de la présence locale de fibrose. Concernant l'asynchronisme cardiaque, nous avons établi une description du couplage électromécanique local du ventricule gauche par la fusion de données échographiques, électro-anatomiques, scanner et, dans les cas appropriés, d'IRM de rehaussement tardif. Cette étude de faisabilité ouvre des perspectives pour l'utilisation de nouveaux descripteurs pour la sélection des sites de stimulation optimaux pour la thérapie de resynchronisation cardiaque
This work concerns cardiac characterization, a major methodological and clinical issue, both to improve disease diagnostic and to optimize its treatment. Multisensor registration and fusion methods are proposed to bring into a common referential data from cardiac magnetic resonance (CMRI), dynamic cardiac X-ray computed tomography (CT), speckle tracking echocardiography (STE) and electro-anatomical mappings of the inner left ventricular chamber (EAM). These data is used to describe the heart by its anatomy, electrical and mechanical function, and the state of the myocardial tissue. The methods proposed to register the multimodal datasets rely on two main processes: temporal registration and spatial registration. The temporal dimensions of input data (images) are warped with an adaptive dynamic time warping (ADTW) method. This method allowed to handle the nonlinear temporal relationship between the different acquisitions. Concerning the spatial registration, iconic methods were developed, on the one hand, to correct for motion artifacts in cine acquisition, to register cine-CMRI and late gadolinium CMRI (LGE-CMRI), and to register cine-CMRI with dynamic CT. On the other hand, a contour-based method developed in a previous work was enhanced to account for multiview STE acquisitions. These methods were evaluated on real data in terms of the best metrics to use and of the accuracy of the iconic methods, and to assess the STE to cine-CMRI registration. The fusion of these multisensor data enabled to get insights about the diseased heart in the context of hypertrophic cardiomyopathy (HCM) and cardiac asynchronism. For HCM, we aimed to improve the understanding of STE by fusing fibrosis from LGE-CMRI with strain from multiview 2D STE. This analysis allowed to assess the significance of regional STE strain as a surrogate of the presence of regional myocardial fibrosis. Concerning cardiac asynchronism, we aimed to describe the intra-segment electro-mechanical coupling of the left ventricle using fused data from STE, EAM, CT and, if relevant, from LGE-CMRI. This feasibility study provided new elements to select the optimal sites for LV stimulation

The development of novel technologies is allowing a complete description of the heart structure and function, including geometrical, myocardial tissue viability and electrical activation information. The joint analysis of this information helps to improve clinical interventions such as radio-frequency ablation of cardiac arrhythmias. However, the acquired data and related indices need to be integrated onto a common reference space for its analysis. This integration is not straightforward due to the different characteristics of acquisition systems. The aim of this thesis was to develop and evaluate different mapping strategies for the integration and joint analysis of multi-modal data of the heart. A new integration methodology was developed and compared with state-of-the-art techniques in several applications with synthetic and clinical data, within the framework of three different clinical scenarios: a) integration of electrical with tissue viability; b) analysis of electrical activation data; and c) validation of myocardial tissue characterization with histological data.
El desarrollo de nuevas tecnologías permite una completa descripción de la estructura y funcionalidad cardíaca incluyendo la geometría la viabilidad del tejido y la información de activación eléctrica. Un análisis conjunto de esta información permite mejorar intervenciones clínicas como la ablación por radio frecuencia en arritmias. Sin embargo, los datos adquiridos deben ser integrados en un mismo sistema de referencia para su análisis. Esta integración no es trivial debido a las diferentes características de adquisición de datos. El objetivo de esta tesis es desarrollar y evaluar diferentes estrategias para la integración y el análisis de datos multimodales del corazón. La nueva metodología de integración ha sido comparada y evaluada con otras técnicas en datos sintéticos y clínicos. Se han evaluado en tres escenarios clínicos distintos: a) integración de datos eléctricos con viabilidad de tejido; b) análisis de activación eléctrica; y c) validación de la caracterización del tejido con datos histológicos.

[ES] Una mejor comprensión de los mecanismos subyacentes a las arritmias ventriculares, así como una mejora de las terapias eléctricas y farmacológicas asociadas, son un factor clave para prevenir la muerte súbita cardíaca en pacientes con cardiopatías estructurales y eléctricas. Una miocardiopatía importante que puede provocar arritmias ventriculares potencialmente mortales es la insuficiencia cardíaca (HF). Los pacientes con HF a menudo sufren también de bloqueo de rama izquierda (LBBB) que deteriora su condición. Actualmente, el tratamiento más eficaz para estos pacientes es la terapia de resincronización cardíaca (CRT). Sin embargo, no se alcanza una respuesta positiva en todos los casos, por lo que es necesario un mayor estudio para mejorar este tratamiento. Una segunda patología cardíaca que también produce arritmias letales es la isquemia miocárdica. Evidencia experimental ha demostrado que las alteraciones electrofisiológicas en el miocardio ventricular constituyen un sustrato para la generación de arritmias durante la fase aguda de isquemia. Estas alteraciones son inducidas por los tres componentes isquémicos principales: hipercalemia, hipoxia y acidosis. Sin embargo, la influencia de cada componente en los mecanismos de inicio y mantenimiento de las arritmias no se comprende aún con claridad. Una primera parte de esta tesis doctoral, se centra en la optimización de la CRT durante su aplicación en un corazón que padece HF y LBBB. Para esto, se modificó el modelo de potencial de acción (AP) de O'Hara para simular una velocidad de conducción realista tanto en condiciones sanas como patológicas. Además, se estimó e incorporó un sistema de His-Purkinje (HPS) dentro de un modelo biventricular/torso humano 3D para simular un LBBB realista. A continuación, se desarrolló un conjunto de simulaciones computacionales para diferentes configuraciones de la CRT a fin de determinar la posición y el instante de estimulación óptimo que conducen a la duración más corta del QRS. Posteriormente, los resultados se compararon con otros criterios de optimización. Los principales hallazgos de este estudio mostraron la necesidad de definir criterios de optimización mejores o complementarios, como un índice basado en el tiempo hasta alcanzar el 90% del área del QRS sugerido en este trabajo, para alcanzar la mejor sincronía eléctrica ventricular durante la aplicación de la CRT. Además, nuestros resultados también muestran que el septo superior cercano al tracto de salida es un sitio alternativo para la estimulación del ventrículo derecho, lo cual evita los problemas de perforación de la pared apical durante el procedimiento típico de la CRT. Por último, para obtener mejores resultados de la CRT se deben considerar protocolos de estimulación endocárdica en el ventrículo izquierdo. En la segunda parte de esta tesis se investigó los efectos de los tres componentes principales de la isquemia sobre la vulnerabilidad a una reentrada, así como el papel del HPS y sus mecanismos de acción en la generación y mantenimiento de arritmias ventriculares. Para lograr este objetivo, en primer lugar, se modificó el modelo AP ventricular para simular de forma realista las principales alteraciones provocadas por la isquemia miocárdica aguda. Las simulaciones se realizaron en un modelo biventricular humano 3D, acoplado en un torso virtual, que incluye una geometría realista de las zonas isquémicas central y de borde, así como un HPS detallado. Se simularon cuatro escenarios de severidad isquémica correspondientes a diferentes minutos de oclusión de la arteria coronaria para evaluar los efectos de la evolución de la isquemia en el tiempo. Luego, se evaluó la influencia individual de la hipercalemia, hipoxia y acidosis en el ancho de la ventana vulnerable (VW) a reentradas durante siete escenarios de isquemia aguda. Finalmente, se repitió este último conjunto de simulaciones isquémicas utilizando el modelo anatómico sin el HPS para evaluar el efecto de este último en la VW. Los resultados muestran que una condición isquémica moderada es el peor escenario para la generación de una reentrada. La hipoxia es el componente isquémico con el efecto más significativo en el ancho de la VW. Además, el flujo de corriente retrógrado desde el miocardio hacia el HPS en la región isquémica, los bloqueos de conducción en secciones discretas del HPS y el grado de hiperkalemia que afecta a las células de Purkinje, son sugeridos como mecanismos que podrían favorecer la aparición de arritmias ventriculares.
[EN] A better understanding of the mechanisms underlying ventricular arrhythmias, as well as an improvement of the associated electrical and pharmacological therapies, are a key factor to prevent sudden cardiac death in patients with structural and electrical heart diseases. An important cardiomyopathy that can lead to life-threatening ventricular arrhythmias is heart failure (HF). Patients with HF also often suffer from left bundle branch block (LBBB), which worsens their condition. Currently, the most effective treatment to these patients is cardiac resynchronization therapy (CRT). However, many patients are non-responders, so further studies are needed to improve this treatment. A second cardiac pathology that also produces lethal arrhythmias is myocardial ischemia. Substantial experimental evidence has shown that electrophysiological alterations in the ventricular myocardium constitute a substrate for the generation of arrhythmias during the acute phase of ischemia. These alterations are induced by the three main ischemic components: hyperkalemia, hypoxia and acidosis. However, the influence of each component in the mechanisms of arrhythmia initiation and maintenance is still not completely understood. In the first section of this doctoral thesis, we focus on the optimization of CRT during its application in a heart suffering from HF and LBBB. For this purpose, we modified the O'Hara action potential (AP) model to simulate a realistic conduction velocity both in healthy and pathological conditions. In addition, a His-Purkinje system (HPS) was generated and incorporated into a 3D human biventricular/torso model to simulate realistic LBBB. A set of computational simulations were performed for different CRT configurations to determine the optimal pacing leads location and delay values leading to the shortest QRS duration. Subsequently, results were compared with other optimization criteria. The main findings of this study showed the need of better or complementary optimization criteria, such as an index based on the time to reach the 90% of the QRS area suggested in this work, to reach the best ventricular electrical synchrony during the CRT application. In addition, our results also show that the upper septum close to the outflow tract is an alternative site for the right ventricle (RV) stimulation, which avoids the perforation problems of the RV apical wall during the typical CRT procedure. Finally, protocols of left ventricle endocardial pacing should be considered to obtain better CRT results. In the second section of this thesis, we investigated the effects of the three main components of ischemia on the vulnerability to reentry, as well as the role of the HPS and its mechanisms of action in the generation and maintenance of ventricular arrhythmias. In order to achieve our goal, we first modified the ventricular AP model to realistically simulate the major alterations caused by acute myocardial ischemia. Simulations were performed in a 3D human biventricular model, embedded in a virtual torso, which includes a realistic geometry of the central and border ischemic zones, as well as a detailed HPS. Four scenarios of ischemic severity corresponding to different minutes after coronary artery occlusion were simulated to evaluate the effects of the evolution of ischemia over time. Then, the individual influence of hyperkalemia, hypoxia and acidosis in the width of the vulnerable window (VW) for reentry was assessed during seven scenarios of acute ischemia. Finally, this last set of ischemic simulations was repeated using the anatomical model without the HPS to evaluate the effect of the latter in the VW. Results show that a moderate ischemic condition is the worst scenario for reentry generation. Hypoxia is the ischemic component with the most significant effect on the width of the VW. Furthermore, the retrograde current flow from the myocardium to the HPS in the ischemic region, conduction blocks in discrete sections of the HPS, and the degree of hyperkalemia affecting the Purkinje cells, are suggested as HPS mechanisms that could favor the triggering of ventricular arrhythmias.
[CA] Una millor comprensió dels mecanismes subjacents a les arrítmies ventriculars, així com una millora de les teràpies elèctriques i farmacològiques associades, són un factor clau per a previndre la mort sobtada cardíaca en pacients amb cardiopaties estructurals i elèctriques. Una miocardiopatia important que pot provocar arrítmies ventriculars potencialment mortals és la insuficiència cardíaca (HF). Els pacients amb HF sovint pateixen també de bloqueig de branca esquerra (LBBB) que deteriora la seua condició. Actualment, el tractament més eficaç per a aquests pacients és la teràpia de resincronització cardíaca (CRT). No obstant això, no s'aconsegueix una resposta positiva en tots els casos, per la qual cosa és necessari un major estudi per a millorar aquest tractament. Una segona patologia cardíaca que també produeix arrítmies letals és la isquèmia miocàrdica. Evidència experimental ha demostrat que les alteracions electrofisiològiques en el miocardi ventricular constitueixen un substrat per a la generació d'arrítmies durant la fase aguda d'isquèmia. Aquestes alteracions són induïdes pels tres components isquèmics principals: hipercalèmia, hipòxia i acidosi. No obstant això, la influència de cada component en els mecanismes d'inici i manteniment de les arrítmies no es comprén encara amb claredat. Una primera part d'aquesta tesi doctoral, se centra en l'optimització de la CRT durant la seua aplicació en un cor que pateix HF i LBBB. Per a això, es va modificar el model de potencial d'acció (AP) de O'Hara per a simular una velocitat de conducció realista tant en condicions sanes com patològiques. A més, es va estimar i es va incorporar un sistema de His-Purkinje (HPS) dins d'un model biventricular/tors humà 3D per a simular un LBBB realista. A continuació, es va desenvolupar un conjunt de simulacions computacionals per a diferents configuracions de la CRT a fi de determinar la posició i l'instant d'estimulació òptim que condueixen a la duració més curta del QRS. Posteriorment, els resultats es van comparar amb altres criteris d'optimització. Les principals troballes d'aquest estudi van mostrar la necessitat de definir millors o complementaris criteris d'optimització, com un índex basat en el temps fins a aconseguir el 90% de l'àrea del QRS suggerida en aquest treball, per a aconseguir la millor sincronia elèctrica ventricular durant l'aplicació de la CRT. A més, els nostres resultats també mostren que el septe superior pròxim al tracte d'eixida és un lloc alternatiu per a l'estimulació del ventricle dret, la cual cosa evita els problemes de perforació de la paret apical durant el procediment típic de la CRT. Finalment, per a obtindre millors resultats de la CRT s'han de considerar protocols d'estimulació endocárdica en el ventricle esquerre. En la segona part d'aquesta tesi es va investigar els efectes dels tres components principals de la isquèmia sobre la vulnerabilitat a una reentrada, així com el paper del HPS i els seus mecanismes d'acció en la generació i manteniment d'arrítmies ventriculars. Per a aconseguir aquest objectiu, en primer lloc es va modificar el model AP ventricular per a simular de manera realista les principals alteracions provocades per la isquèmia miocàrdica aguda. Les simulacions es van realitzar en un model biventricular humà 3D, acoblat en un tors virtual, que inclou una geometria realista de les zones isquèmiques central i de vora, així com un HPS detallat. Es van simular quatre escenaris de severitat isquèmica corresponents a diferents minuts d'oclusió de l'artèria coronària per a avaluar els efectes de l'evolució de la isquèmia en el temps. Després, es va avaluar la influència individual de la hipercalèmia, hipòxia i acidosi en l'ample de la finestra vulnerable (VW) a reentradas durant set escenaris d'isquèmia aguda. Finalment, es va repetir aquest últim conjunt de simulacions isquèmiques utilitzant el model anatòmic sense el HPS per a avaluar l'efecte d'aquest últim en la VW. Els resultats mostren que una condició isquèmica moderada és el pitjor escenari per a la generació d'una reentrada. La hipòxia és el component isquèmic amb l'efecte més significatiu en l'ample de la VW. A més, el flux de corrent retrògrad des del miocardi cap al HPS a la regió isquèmica, els bloquejos de conducció en seccions discretes del HPS i el grau d'hiperkalèmia que afecta les cèl·lules de Purkinje, són suggerits com a mecanismes que podrien afavorir l'aparició d'arrítmies ventriculars.
Carpio Garay, EF. (2021). Contribution to the improvement of electrical therapies and to the comprehension of electrophysiological mechanisms in heart failure and acute ischemia using computational simulation [Tesis doctoral]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/163041
TESIS

Le nombre d'adultes porteurs de cardiopathies congénitales, de plus en plus sévères est constante progression. A moyen voire long terme certain d’entre eux posent des problèmes d’insuffisance cardiaque et de troubles du rythme parfois létaux. La physiologie de ces complications est multi factorielle et s’écarte souvent des schémas habituels. L’asynchronisme ventriculaire présentent chez un nombre important d’entre eux est connu pour favoriser un remodelage ventriculaire conduisant à l’insuffisance cardiaque sur cœur sain.Dans ce travail en couplant données expérimentales animales et études cliniques, nous avons étudié : 1) l’impact aigu puis chronique de la resynchronisation biventriculaire sur un modèle animal d’insuffisance cardiaque droite mimant la tétralogie de Fallot et sur une population de patients ; 2) le rôle et la conséquence d’une stimulation conventionnelle sur une physiologie de ventricule droit systémique ; 3) l’effet délétère de la stimulation VD prolongée sur un modèle de cœur animal en cours de développement.Nous avons appris que 1) la resynchronisation biventriculaire permet un bénéfice hémodynamique significatif chez l’animal mais aussi sur une population de Fallot implantées ; 2) que l’asynchronisme généré par la stimulation conventionnelle est délétère pour la fonction du ventricule systémique mais aussi pour le cœur de l’enfant en cours développement. La resynchronisation est un traitement prometteur pour traiter l’insuffisance cardiaque mais pourrait aussi l’être pour en prévenir sa survenue. De nouvelles techniques d’implantation nous permettent aujourd’hui d’implanter des patients qui présentent beaucoup d’obstacles anatomiques et d’éviter nombre de complications grave de la stimulation
The number of adults with severe congenital heart disease is constantly growing. At medium to long-term follow up, these patients may present with heart failure or conduction disorders, which may lead to death. The pathophysiology and clinical course of these complications is multi-factorial and may be different from that in patients without congenital heart disease. In normal hearts, electromechanical dyssynchrony is known to induce ventricular remodeling and heart failure. Ventricular asynchrony is also present in a substantial number of adults with congenital heart disease. In this study, we combined animal experiments and clinical studies to investigate: 1) the acute and chronic effect of biventricular resynchronization therapy on cardiac function in an animal model mimicking right ventricular heart failure in Tetralogy of Fallot, as well as in patients with Tetralogy of Fallot; 2) the consequences of conventional ventricular pacing in patients with ‘systemic right ventricle physiology’; 3) the effects of chronic right ventricular pacing in an animal model of the developing heart.We found that: 1) biventricular resynchronization induces significant hemodynamic benefit in the animal model of Tetralogy of Fallot as well as in Fallot patients; 2) ventricular asynchrony induced by conventional ventricular pacing is deleterious to the function of the systemic right ventricle; 3) chronic right ventricular pacing is harmful to the developing (pediatric) heart with normal biventricular anatomy. Cardiac resynchronization therapy is promising as a treatment for heart failure, but may also prevent heart failure. Nowadays, new implantation techniques allow us to implant pacing devices in patients with limited anatomical access due to prior surgery and help to avoid numerous severe complications of conventional pacing therapy

The effect of CRT on incidence of AF development in patients with severe HF was explored by comparing 36 patients with conventional indication for the CRT to 36 HF patients without CRT, matched for age, sex and LV systolic function (Publication 5). After a follow up of 3 years, the annual incidence of AF in the CRT group was 2.8%, which was significantly lower than the control group (10.2%). Moreover, the echocardiographic benefit by CRT was compared between these 36 patients with SR and 15 patients with persistent AF. The results showed that the echocardiographic response was similar between the two groups. These findings suggested that CRT may have the potential to reduce AF burden in patients with severe HF and that patients with persistent AF may also benefit from CRT.
The objective of the study (Publication 1) was to assess the feasibility of using non-contact LV mapping to delineate the LV endocardial activation pattern in 7 HF patients in NYHA class III, with low LVEF and wide QRS complex (>120ms). Non-contact mapping was safely performed and there were two endocardial conduction patterns identified, namely homogenous (Type I) and conduction block (Type II). The second part of the study (Publication 2) was to determine the implication of these two distinct activation patterns to echocardiographic and clinical response to CRT. 23 patients in NYHA class III, with LVEF <35% and QRS duration >120ms were recruited in this study. 15 patients had Type II pattern and 8 Type I. The QRS duration between the two types of conduction patterns were comparable. Patients with Type II pattern had a more favourable echocardiographic and clinical response to CRT than those with Type I. It was concluded that, despite the similar QRS duration between the two types of LV endocardial activation patterns, patients with Type II pattern had a more favourable response to CRT.
The significance of baseline renal function in CRT was assessed in 85 consecutive patients with conventional indication for the CRT (Publication 7). There was no significant relationship between baseline renal function and significant LV reverse remodeling after CRT, suggesting baseline renal insufficiency probably would not affect the response to CRT. (Abstract shortened by UMI.)
This study (Publication 3) was to determine the effect of CRT in patients with narrow QRS complex and evidence of mechanical dyssynchrony as determined by TDI. 51 patients in NYHA class III or IV, with LV ejection fraction <35%, and QRS duration <120ms were recruited for the CRT. The effect of the device therapy on LV systolic function in this cohort was compared to 51 patients who fulfilled the current criteria with wide QRS complex. CRT significantly improved the LV systolic function, NYHA class and exercise capacity in those with narrow complex to a similar extent in those with wide complex. With co-existing mechanical dyssynchrony determined by TDI, patients in both narrow and wide QRS complex groups showed more favourable response to CRT than those without significant mechanical dyssynchrony. This confirmed that QRS was a poor marker of mechanical dyssynchrony and the current selection criteria are probably not adequate to include more potential responders to the therapy.
This study (Publication 4) was to determine the role of optimal medical therapy in CRT recipients before implantation. The echocardiographic and clinical effect of CRT in 30 patients without the optimal combination of ACEi or ARB and beta-blockers was compared to 30 patients matched for age, sex, NYHA class and HF etiology. Patients with optimal medical therapy had significantly better echocardiographic and clinical response to CRT. The results confirmed that optimal medical therapy is necessary to achieve maximal response by CRT.
This study (Publication 6) was to determine if patients with moderate LV systolic function and wide QRS complex would benefit from the CRT. Significant improvement in LV systolic function was observed in 15 patients with LVEF between 35 and 45%, NYHA class III and QRS duration >120ms after CRT, suggesting that presence of LV systolic dysfunction and cardiac dyssynchrony may be the major determining factors for favourable CRT response. Therefore, patients with less advanced HF may also benefit from the CRT.
"May 2007."
Adviser: Yu Cheuk Man.
Source: Dissertation Abstracts International, Volume: 69-08, Section: B, page: 4657.
Thesis (M.D.)--Chinese University of Hong Kong, 2007.
Includes bibliographical references (p. 133-151).
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
School code: 1307.

Echocardiography has an prominent role in the era of CRT by virtue of its non-invasive nature with high feasibility and reproducibility. The clinical applications include not only quantification of the change in systolic function, hemodynamics, LV volume, or mitral regurgitation, but also assessment of systolic dyssynchrony. A number of new echocardiographic techniques were employed in this study, such as tissue Doppler imaging (TDI) and its post-processing modalities including strain, strain rate and displacement mappings, tissue synchronization imaging (TSI), as well as three-dimentional (3D) echocardiography.
For heart failure patients with wide QRS complexes who received CRT, LV volumes, cardiac function and synchronicity were shown to change acutely between CRT-on and CRT-off modes by both 2D and 3D echocardiography methods. Furthermore, the usefulness of 3D echocardiography and its accuracy in assessing volumetric changes
Systolic dyssynchrony, which illustrates discoordinated contraction of the heart, is relatively common in heart failure patients, in particular those with prolonged QRS complexes. It is caused by electromechanical delay in some regions of the failing heart and will result in further reduction of cardiac function. Cardiac resynchronization therapy (CRT) is a rapidly evolving pacing modality for advanced heart failure, characterized by implantation of the left ventricular (LV) lead through coronary sinus to the free wall region. It is recommended to patients who have refractory heart failure despite optimal medical treatment, LV dilatation with ejection fraction lower than 35%, and prolonged QRS duration on surface ECG.
The main findings were as followed: The Ts-SD was 17.0+/-7.8ms in normal control, 33.8+/-16.9ms in narrow QRS group and 42.0+/-16.5ms in wide QRS group, respectively. The prevalence of systolic dyssynchrony in heart failure population was 43% in the narrow QRS group, and 64% in the wide QRS group, when a Ts-SD of > 32.6 ms (+2 SD of normal controls) was used to define significant dyssynchrony. QRS duration does not have a linear relationship with systolic dyssynchrony.
TSI was useful to predict a reverse remodeling and gain in ejection fraction after CRT. Qualitative identification of the latest peak systolic contraction at the lateral wall was a quick and specific guide to predict a favorable reverse remodeling response while quantitative computation of "Asynchrony Index" from 12 LV segments in ejection phase was beneficial in the absence of lateral wall delay. In conclusion, the improvement of cardiac function and LV reverse remodeling after CRT is more obvious in heart failure patients with wide QRS complex and echocardiographic evidence of significant systolic dyssynchrony. Reverse remodeling is not only an objective measure of favorable responses, but also a prognosticator of disease outcomes. "Asynchrony Index" is a strong predictor of LV reverse remodeling response after CRT. Assessment of systolic dyssynchrony by various echocardiographic tools is promising, however, further studies are needed to compare the predictive values of different parameters objectively and prospectively.
We performed echocardiography with TDI in 200 subjects, including 67 patients with heart failure and narrow QRS complexes (≤ 120ms), 45 patients with heart failure and wide QRS complexes (>120ms), and 88 normal controls, which served as a polit study. Severity and prevalence of systolic dyssynchrony were assessed by the maximal difference in time to peak myocardial systolic velocity (Ts-dif-12) and the standard deviation (Ts-SD) of the 12 LV segments.
We recruited a group of seventy patients with chronic heart failure who fulfilled the established criteria and received CRT. Serial echocardiographic assessment with clinical evaluation was performed at baseline, predischarge, 1-month, 3-month, 6-month and long-term follow up. The objective was to demonstrate the improvement of cardiac function and dyssynchrony after CRT by echocardiographic parameters, in particular the reduction of LV end-systolic volume (LVESV) which is also known as reverse remodeling, and its relationship with the improvement in clinical status and prognosis. We also attempted to identify dyssynchrony parameters which are useful in predicting LV reverse remodeling after CRT.
Zhang Qing.
"October 2006."
Adviser: Yu Cheuk-Man.
Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5852.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2006.
Includes bibliographical references.
Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web.
Abstract in English and Chinese.
School code: 1307.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Introdução: A terapêutica de ressincronização cardíaca (TRC) é uma opção comprovada para pacientes com insuficiência cardíaca (IC) selecionados adequadamente. Contudo, pelo menos 30% dos pacientes não apresentam os resultados esperados. Vários estudos já abordaram este problema, tentando identificar preditores de resposta à TRC, mas, à luz do conhecimento dos autores, ainda não existe uma revisão sistemática com meta-análise, usando dados do mundo real, a abordar este tema.Objetivos: Identificar potenciais preditores de resposta à TRC, usando dados do mundo real.Métodos: Uma pesquisa sistemática foi realizada, recorrendo às bases de dados PubMed, Embase e Cochrane Central Register of Controlled Trials (CENTRAL), com um limite temporal relativo às publicações entre 31 de outubro de 2010 e 31 de outubro de 2020, pesquisando-se estudos observacionais prospetivos com um desenho de estudo que, de alguma forma, envolvesse a avaliação de resposta à TRC, definida como uma diminuição do volume telessistólico do ventrículo esquerdo ≥ 15%, aos 6 meses de follow-up, através de ecografia bidimensional. A avaliação da elegibilidade dos artigos, primeiro através dos títulos e resumos, depois através do texto completo, foi realizada, de forma independente, pelos autores, de acordo com os critérios de inclusão. Após colheita e processamento dos dados relevantes, foram aplicadas meta-análise e análise de curvas ROC (Receiver Operating Characteristic), seguidas da identificação do ponto de corte ótimo pelo índice de Youden, com análise de concordância (Kappa de Cohen) aplicada à tabela de classificação, ponderadas de acordo com a precisão dos estudos. É apresentada a probabilidade de resposta à terapêutica dada a presença ou ausência de cada uma das características identificadas.Resultados: 2462 citações foram encontradas e um total de 24 estudos foram incluídos nas análises qualitativa e quantitativa. A meta-análise mostrou que o género feminino (p = 0.018; adj p = 0.077), a cardiomiopatia de etiologia não-isquémica (CMNI) (p < 0.001; adj p = 0.023), o bloqueio de ramo esquerdo (BRE) (p = 0.001; adj p = 0.046), o QRS longo (p < 0.001; adj p = 0.023) e a classe New York Heart Association (NYHA) II (p = 0.014; adj p = 0.062) parecem favorecer a resposta à TRC. Após análise ROC e regressão logística, o género feminino (kappa = 0.450; p < 0.001), a CMNI (kappa = 0.636; p < 0.001), o BRE (kappa = 0.935; p < 0.001), e a classe NYHA II (kappa = 0.647; p < 0.001) foram identificados como preditores independentes de resposta à TRC, sendo o BRE o mais fiável (sensibilidade = 97.24%; especificidade = 98.86%).Conclusões: Género feminino, CMNI, BRE e classe NYHA II são as variáveis basais com uma aparente capacidade de predizer, de forma independente e com elevada acuidade, a resposta à TRC – populações com proporções maiores de pacientes com estas características têm maior probabilidade de apresentar benefício com esta terapêutica. De acordo com os dados, o BRE é o preditor mais fiável de resposta à TRC.
Introduction: Cardiac resynchronization therapy (CRT) is an established device therapy for appropriately selected patients with heart failure (HF). However, at least 30% of the patients do not achieve the expected outcomes. Many studies have addressed this problem by trying to identify predictors of response to CRT, but, to the authors’ knowledge, it still does not exist a systematic review with meta-analysis of real-world data assessing this topic.Objectives: To identify potential predictors of response to CRT, using real-world evidence.Methods: A systematic search was conducted in PubMed, Embase and Cochrane Central Register of Controlled Trials (CENTRAL), from October 31st of 2010 to October 31st of 2020, for observational prospective studies, referring, somehow, a study design that involved the evaluation of response to CRT, defined as a decrease in left ventricle end-systolic volume (LVESV) ≥ 15% at 6-month follow-up, via two-dimensional echocardiography. Screening, first of titles and abstracts, then from full text, was performed independently by the authors, according to the inclusion criteria. After collection and processing of the relevant data, meta-analysis techniques were applied and also Receiver Operating Characteristic (ROC) curve analysis, followed by optimal threshold identification by Youden Index, with concordance analysis (Cohen’s kappa) applied to the classification table, were conducted, weighted by studies precision. Probability of response is given according to the presence or absence of each one of the identified characteristics.Results: 2462 citations were retrieved, being a total of 24 studies included in qualitative and quantitative synthesis. The meta-analysis showed that female gender (p = 0.018; adj p = 0.077), non-ischemic cardiomyopathy (NICM) (p < 0.001; adj p = 0.023), left bundle branch morphology (LBBB) (p = 0.001; adj p = 0.046), longer QRS (p < 0.001; adj p = 0.023) and New York Heart Association (NYHA) class II (p = 0.014; adj p = 0.062) appear to favor response to CRT. After ROC analysis and logistic regression procedures, female gender (kappa = 0.450; p < 0.001), NICM (kappa = 0.636; p < 0.001), LBBB (kappa = 0.935; p < 0.001), and NYHA class II (kappa = 0.647; p < 0.001) were identified as independent predictors of response to CRT, being LBBB the most reliable one (sensitivity = 97.24%; specificity = 98.86%).Conclusions: Female gender, NICM, LBBB and NYHA class II are baseline variables with an apparent capability to independently predict response to CRT – populations with higher proportion of patients with these characteristics are more likely to benefit from this therapy. According to these data, LBBB is the most reliable predictor of CRT response.

Mestrado em Exercício e Saúde
Background: Cardiac resynchronization therapy (CRT) is an established treatment modality for moderate to severe heart failure (HF) but 30–40% of patients treated with CRT do not experience clinical improvement. Purpose: the aim of this study was to identify predictors of response to CRT, in two different definitions of responders, by using the cardiopulmonary exercise testing (CPET) before CRT implantation. In definition A, responders were defined as ≥15% improvement in left ventricular ejection fraction (LVEF); in definition B combined parameters were defined as ≥5% improvement in LVEF and ≤1 level NYHA classification. Methods: this is a prospective observational study of 15 HF patients undergoing CRT. Clinical CPET and echocardiography assessment using standard methods were performed at baseline and 5 months. Results: the number of patients classified as responders in definition A was 9 (60%) and 6 (40%) as non-responders; the number of responders in definition B was 11 (73.3%) and 4 (26.7%) as non-responders at 5 months after CRT. The responders according to definition A did not present any statistically significant difference. According to definition B, the heart rate (HR) response during CPET was higher in non-responders: HR peak (157±13bpm vs. 118±18bpm, p<0.05) and HR recovery at minute 3 (54±13bpm vs. 31 ± 14bpm, p<0.05). Overall, the responders were older (68±9years vs. 55±9years, p<0.05). Conclusions: baseline measurements of CPET may be utilized to identify patients that benefit from CRT. The use of combined criteria is a better predictor than LVEF alone.

RESUMO: Introdução A insuficiência cardíaca crónica é conhecida como síndrome complexa, associada a elevada mortalidade e incapacidade, envolvendo múltiplos mecanismos fisiopatológicos, neuro-hormonais, endoteliais e inflamatórios. Além da terapêutica médica optimizada, a terapêutica não farmacológica, como a ressincronização cardíaca e o treino de exercício, assume um papel fundamental. Na insuficiência cardíaca avançada, doentes com critérios para terapêutica de ressincronização cardíaca (CRT) têm sido exaustivamente estudados, apesar da maioria dos estudos não se ter dedicado à diversidade de efeitos e mecanismos fisiopatológicos envolvidos, nos doentes mais gravemente sintomáticos. Nesta população com insuficiência cardíaca avançada tratada com CRT, estudos relativos aos efeitos e mecanismos do treino de exercício, especificamente exercício intervalado de alta intensidade, são ainda poucos e de pequena dimensão. Hipótese Hpótese principal formulada: Existe benefício em associar um programa de treino de exercício de alta intensidade, de longa duração, após ressincronização cardíaca em doentes com insuficiência cardíaca avançada. Hipótese secundária: 2 Estão envolvidos vários mecanismos fisiopatológicos, contribuindo diferentemente para o benefício do treino de exercício após CRT e para o benefício de CRT sem programa de exercício subsequente, em doentes com insuficiência cardíaca avançada. Objectivos O objectivo primário desta tese foi determinar os efeitos do programa de exercício intervalado de alta intensidade (HIIT), de longa duração, sobre a classe funcional clínica, qualidade de vida, capacidade funcional de exercício, função cardíaca e remodelagem ventricular, em doentes com insuficiência cardíaca avançada após implante do ressincronizador. O objectivo secundário pretendeu avaliar o papel potencial de diferentes mecanismos fisiopatológicos nos benefícios do treino de exercício após CRT, HIIT, e após CRT sem exercício subsequente: função endotelial, função do sistema nervoso autónomo, processo inflamatório e apoptose. Metodologia Efectuámos um ensaio controlado aleatorizado para determinar os efeitos da intervenção de exercício, HIIT, em doentes com insuficiência cardíaca avançada após CRT. Os critérios de inclusão foram, doentes com insuficiência cardíaca estável, em classe III-IV (NYHA), sob terapêutica farmacológica optimizada, referenciados para CRT pelas recomendações actuais presentes, etiologia isquémica e não isquémica, com idade superior a 18 anos. Os critérios de exclusão incluiram insuficiência cardíaca instável, doença ortopédica ou muscular incapacitante para exercício e residência geograficamente distante do hospital. Os doentes que preencheram os critérios de inclusão foram aleatorizados para treino de exercício intervalado de alta intensidade ou para grupo controlo (EXTG e CG, respectivamente). 3 A aleatorização, realizada por um investigador independente, foi estratificada, baseada na idade (<65 ou >65 anos), sexo, etiologia (isquémica e não isquémica) e gravidade de disfunção ventricular esquerda (fracção de ejecção ventricular esquerda <20 ou >20%). Os doentes com os mesmos critérios de inclusão, que não aceitaram a intervenção exercício ou que viviam longe, sem os restantes critérios de exclusão, foram adicionalmente estudados como cohort prospectivo para avaliação dos efeitos e mecanismos da intervenção CRT. Durante o periodo de Janeiro 2012 a Março 2015, todos os doentes com insuficiência cardíaca e critérios para ressincronização cardíaca elegíveis foram estudados. O programa de treino de exercício foi iniciado 1 mês após implante de cardioressincronizador e durou 6 meses com frequência bissemanal, consistindo em sessões de 60 minutos, realizadas no hospital, monitorizadas e supervisionadas. Incluiu treino aeróbio intervalado de alta intensidade (HIIT), adaptado a partir do protocolo de Wisloff, e exercícios de resistência, flexibilidade e coordenação. Os momentos do estudo usados para avaliação das variáveis independentes foram: momento basal, pré implante do ressincronizador (M1), aos 3 meses após exercício, correspondendo a 4 meses após implante (M2) e aos 6 meses após exercício, correspondendo a 7 meses após implante (M3). As variáveis dependentes estudadas foram: classe functional clínica (NYHA), scores de qualidade de vida (questionário HeartQol), parâmetros de função cardíaca e remodelagem reversa (determinadas por ecocardiografia e doseamento plasmático de péptido natriurético, BNP), de capacidade funcional de exercício (determinadas por prova de esforço cardio-respiratória, CPT), de função do sistema nervoso autonómico, SNA (por cintigrafia cardíaca com 123I-MIBG, prova de esforço cardio-respiratória e análise da variabilidade da frequência cardíaca no Holter-24 horas), de função endotelial e rigidez arterial (determinada por doseamento de NO, óxido nítrico, e por PAT, tonometria arterial periférica), marcadores de inflamação e apoptose (medição de proteína C reactiva de alta sensibilidade, hs-CPR, factor de necrose tumoral alfa, TNF-α, interleucina-6, IL-6, fracção solúvel do cluster de diferenciação 40, sCD40, fracção solúvel do ligando Fas, sFasL) e frequência de eventos major cardiovasculares aos 6 meses de exercício. 4 As excepções aos 3 momentos de avaliação foram: 123I-MIBG cintigrafia cardíaca, realizada antes do CRT (M1) e aos 6 meses de exercício (M3), análise de variabilidade da frequência cardíaca por estudo Holter-24horas, realizado apenas basal, pre-CRT (M1) e frequência de eventos, avaliada em M3. A segurança do treino de exercício HIIT foi avaliada. A resposta ecocardiográfica foi definida pelo aumento de pelo menos 5% da fracção de ejecção ventricular esquerda (LVEF), em valor absoluto e a resposta clínica como melhoria de pelo menos 1 classe funcional clínica (NYHA). A resposta funcional foi definida como o aumento de pelo menos 1 ml/kg/min de VO2p. Resultados A partir de um cohort inicial de 121 doentes com insuficiência cardíaca selecionados para CRT, foram aleatorizados 62 doentes. Realizaram programa de treino de exercício HIIT, 22 doentes (EXTG), idade média 67,5±9,8%, 22,7% do sexo feminino, 40% isquémicos, LVEF basal 26,68±6,21%, enquanto 28 doentes foram incluídos no grupo controlo (CG). As características demográficas e clínicas basais foram idênticas estatisticamente. No grupo aleatorizado (n=50), todos os doentes tiveram benefício significativo, aos 6 meses após início do exercício, relativamente a: diminuição da classe clínica de NYHA (p <0,001), melhoria do score de qualidade de vida HeartQol (p <0,001), aumento da LVEF, fracção de ejecção ventricular esquerda (p <0,005), diminuição dos volumes ventriculares esquerdos, LVED, tele-diastólico (p < 0,05) e LVES, tele-sistólico (p <0,02). Verificou-se uma diferença significativa da classe funcional clínica (NYHA), nos dois grupos aleatorizados, com maior diminuição no EXTG (p=0,034). Apenas no EXTG, se encontrou um aumento significativo da duração da prova de esforço cardio-respiratória, aos 3 meses (p=0,017) e aos 6 meses (p=0,008). O tempo para o limiar anaeróbio, VAT, aumentou significativamente no EXTG aos 3 meses (p= 0,006) e aos 6 meses (p=0,004), sendo significativamente diferente do CG aos 3 meses (p=0,006) e apresentando uma tendência para significado estatístico aos 6 meses (p=0,064), momento em que a variação foi também significativa no CG. O TNF-α diminuiu significativamente apenas no EXTG, aos 6 meses (p=0,016), com uma diferença estatística significativa em relação ao 5 CG (p=0,008). Não se verificaram diferenças significativas nas variações dos parâmetros ecocardiográficos entre os dois grupos aleatorizados. Relativamente ao número de respondedores, no grupo de treino de exercício foram identificados mais respondedores clínicos (95%) e ecocardiográficos (81,8%) que no grupo controlo (78,5% e 72,7%, respectivamente), após 6 meses de exercício. A diferença no número de respondedores entre os 2 grupos aleatorizados, não atingiu contudo significado estatístico (provavelmente pela dimensão da amostra), mas com uma tendência para mais respondedores clínicos no grupo de exercício. A diferença no numero de respondedores funcionais, apesar de em numero tendencialmente superior no grupo de exercício (77,2%) não foi significativa. O programa HIIT mostrou ser seguro, sem eventos major ou minor durante o exercício. Aos 6 meses de exercício (7 meses após implantação do ressincronizador), registaram-se 9% de eventos no grupo exercício e 10,7% no grupo controlo. Verificou-se ocorrência de morte ou internamento hospitalar em 1/22 doentes (4,5%) do grupo de exercício e em 3/28 doentes (10,7%) do grupo controlo. A única morte nos doentes aleatorizados ocorreu no grupo controlo, 1/28 doentes (3,5%). No total do cohort de doentes com CRT verificou-se um benefício significativo após 7 meses de implantação: redução da classe funcional NYHA (p <0,001), aumento do score HeartQol (p <0,001), aumento da LVEF (p < 0,001), diminuição do volume tele-sistólico ventricular esquerdo (p=0,001), aumento do valor absoluto de GLS, strain global longitudinal, (p=0,003), relação E/e’, rácio entre onda E do fluxo de câmara de entrada do ventrículo esquerdo e e’ médio de doppler tecidular do anel mitral, (p=0,009), redução da massa ventricular esquerda (p=0,026), redução do VE/VCO2 slope, declive da razão entre ventilação minuto e produção de CO2, (p=0,003), aumento da duração do teste cardiopulmonar (p=0,002), aumento do tempo para VAT, limiar anaeróbio (p=0,001), redução do HRR1 (frequência cardíaca de recuperação ao primeiro minuto), (p=0,015), redução do HRR6 (frequência cardíaca de recuperação ao 6º minuto), (p=0,033) e aumento do VO2p, consumo de oxigénio pico, (p=0,04). Na amostra total dos doentes insuficientes cardíacos com CRT (incluindo 18% dos doentes submetidos a exercício) 75,6% foram respondedores clínicos, 63,9% respondedores ecocardiográficos e 62,8% respondedores funcionais. Os respondedores ecocardiográficos ao CRT tinham diferenças significativas nos parâmetros de base e na variação de alguns parâmetros: M1, menores volumes ventriculares esquerdos, maior TAPSE, maior SDNN (standard 6 deviation NN interval), maior heart-mediastinum ratio precoce (HMRe) e tardio (HMRl); M3-M1, maior aumento de LVEF, maior redução de volume LVES, maior aumento do valor absoluto de GLS e tendência para maior aumento de VO2p. Os respondedores tiveram menor número de eventos major registados em M3. Analizando todos os doentes com CRT, valores de 123MIBG HMRl>1,5 identificaram mais respondedores ecocardiográficos (probabilidade 2 vezes superior), apenas em não isquemicos. Os eventos aos 7 meses após CRT, M3, morte ou admissão hospitalar ou arritmia ocorreram em 14,8% da população total e em 16,1% dos doentes não submetidos a exercício.A morte ocorreu em 4,9% no grupo total e em 6% do grupo não submetido a exercício. Conclusão No presente ensaio aleatorizado e controlado, realizado numa amostra de doentes com insuficiência cardíaca avançada, referenciada para CRT, o exercício HIIT após implante do ressincronizador provou ser benéfico e seguro, associado a um maior número de respondedores ecocardiográficos e clínicos, acompanhado de uma melhoria clínica mais significativa, evidenciando o benefício adicional ao CRT. A melhoria do componente periférico da insuficiência cardíaca condicionada pelo exercício foi demonstrada pelo aumento significativo da capacidade funcional ao esforço e do tempo para VAT, acompanhada de maior número de respondedores funcionais, tendo-se verificado um efeito modulatório sobre a inflamação que poderá ter contribuído para este efeito. Não foram demonstrados benefícios do exercício na função endotelial, no sistema nervoso autonómico e na apoptose. Ocorreram menos eventos major aos 6 meses em doentes submetidos a HIIT. A avaliação adicional dos doentes com CRT no estudo observacional demonstrou melhoria clínica, de qualidade de vida e de função ventricular sistólica e diastólica significativa, mesmo excluindo aqueles que fizeram treino de exercício. O efeito central do CRT na remodelagem cardíaca demonstrou ser crucial, com melhoria das diversas variáveis ecocardiográficas. Contrariamente, não se demonstraram efeitos periféricos benéficos do CRT, VO2p, duração CPT ou tempo VAT, aos 7 meses, uma vez excluídos os 7 doentes que fizeram programa de exercício. O sistema nervoso autónomo demonstrou ser um mecanismo relevante na resposta ao CRT, mas apenas em insuficientes cardíacos não isquémicos. Não foram demonstrados efeitos benéficos do CRT na função endotelial, inflamação ou apoptose. Registaram-se mais eventos em doentes sem terapêutica de exercício. Dos resultados desta tese, que verificam as hipóteses colocadas, podemos salientar que em doentes com insuficiência cardíaca avançada a intervenção de treino de exercício intervalado de alta intensidade, supervisionado, , após implantação de ressincronizador cardíaco é uma terapêutica não farmacológica segura e tem benefício adicional demonstrado relativo à CRT, resultando em menor número de doentes não respondedores. Esta intervenção não teve efeito deletério sobre a remodelagem reversa e alguns resultados apontam para potencial benefício. Os mecanismos envolvidos estão ligados particularmente ao componente periférico da insuficiência cardíaca, resultando em diminuição da gravidade dos sintomas clínicos, melhoria da capacidade funcional e modulação positiva da resposta fisiopatológica inflamatória.
ABSTRACT: Introduction Chronic heart failure is known to be a complex syndrome, associated to high mortality and disability, involving multiple pathophysiologic mechanisms, neuro-hormonal, endothelial and inflammatory. Besides optimized medication, the nonpharmacologic therapy, like cardiac resynchronization and exercise training, plays a fundamental role. In advanced heart failure, patients with criteria for cardiac resynchronization therapy (CRT) have been studied extensively, though most of the studies were not dedicated to the diversity of effects and involved pathophysiologic mechanisms, in most severely symptomatic patients. In this advanced heart failure population treated with CRT, studies regarding exercise training effects and mechanisms, specifically high intensity interval exercise, are still few and small-sized. 8 Hypothesis Main hypothesis formulated: It is beneficial to associate a high intensity interval training exercise program, long duration, after cardiac resynchronization in advanced Heart Failure Patients. Secondary hypothesis: Several pathophysiologic mechanisms are involved, contributing differently to the exercise training benefit after CRT and to the benefit of CRT without subsequent exercise program in advanced HF patients. Aims The primary aim of this thesis was to determine the effects of a long-term High Intensity Interval Exercise Training (HIIT) program on clinical functional class, quality of life, exercise functional capacity, cardiac function and remodeling, in advanced heart failure patients after cardiac resynchronizer implant. Secondary aim intends to evaluate the potential role of different pathophysiologic mechanisms in the benefits of exercise training after CRT, HIIT, and of CRT without subsequent exercise: endothelial function, autonomic nervous system function, inflammatory process and apoptosis. Methodology A randomized controlled trial was performed to determine the effects of exercise intervention, HIIT, in advanced heart failure patients after CRT. The inclusion criteria considered patients with stable heart failure, class III-IV (NYHA), receiving optimal pharmacologic therapy, assigned to CRT by present guidelines, ischemic and non ischemic etiology, older than 18 years. Exclusion criteria included unstable HF patients, exercise incapacitating orthopedic or muscular disease and geographically long distance living. 9 Patients who fulfilled the inclusion criteria were randomized for long duration high intensity interval exercise training or for control group (EXTG and CG, respectively). Randomization, performed by an independent investigator, was stratified, based on age (1.5 identified more CRT echocardiographic responders (2-fold probability), only in nonischemic. Events at 7 months after CRT, M3, cardiac death or hospital admission or arrhythmia occurred in 14.8% of total population and in 16.2% of nonrandomized patients. Death occurred in 4.9% in total group and in 6% in nonrandomized group. Conclusion In this controlled randomized trial, performed in a sample of advanced HF patients referred to CRT, HIIT exercise after cardiac resynchronizer implant proved to be beneficial and safe, associated to an increased number of clinical and echocardiographic responders and with more significant clinical improvement, suggesting an additional benefit to CRT. The improvement of the peripheral component of heart failure caused by exercise was demonstrated by CPT duration and time to VAT significant increase, associated with more functional responders, along with positive modulation of inflammation, which might have contributed to this effect. No significant effects were demonstrated in endothelial or autonomic nervous system function. Less major events occurred in the HIIT group after the 6 months of training. The additional evaluation of CRT patients in the observational study of the total HF sample, showed a beneficial effect on symptoms severity, quality of life and systolic and diastolic LV function, even excluding those who performed exercise. Central effect of CRT on cardiac remodeling demonstrated to be crucial, with echocardiographic improvement of several variables. Once EXTG patients were excluded, the restant CRT patients did not show significant improvement at 7 months of VO2p, CPT duration or time to VAT, meaning CRT had no effect on HF peripheral component. Autonomic nervous system demonstrated to be a relevant mechanism for CRT response, but only in nonischemic HF. No beneficial effects of CRT were noticed in endothelial function, inflammation or apoptosis. More events were registered in patients who did not exercise. From these thesis results, we may accept, in advanced heart failure patients, exercise (HIIT) as safe and beneficial nonpharmacologic therapy with demonstrated additional benefit, regarding CRT, resulting in fewer patients with CRT nonresponse. This 13 intervention had no deleterious effect on reverse remodeling and some results point out to a potential benefit. The involved mechanism especially regards the peripheral component of HF, manifested by the decrease in clinical symptoms severity, improvement in functional capacity and positive modulation of pathophysiologic inflammatory response.
FCT PTDC/DES/120249/2010

Background: Heart failure is characterized by an autonomic nervous system dysfunction which leads to sympathetic overactivation and parasympathetic imbalance, culminating in central and peripheral dysfunction. In advanced HF, cardiac resynchronization therapy (CRT) and exercise training seem toimprove these conditions and result in improved functional and clinical parameters. A growing body of evidence supports the benefits of aerobic interval training (AIT) in other several HF populations, but less is known about its influence on autonomic function. Here we assessed the effects of AIT on the heart rate recovery (HRR), an indicator of parasympathetic activity. All participants had HF with a reduced ejection fraction, and six days before the intervention, underwent cardiac surgery. Our objective was to compare if the additive effect of AIT to CRT could indeed result in improved vagal reactivation, measured by the difference between the peak heart rate and the HRR at one minute (HRR1diff). Methods: Twenty-nine stable patients (aged 68.96 ± 9.92; VEF< 27 ; and a V O2Peak= 15 mL.kg-1.min-1) who were receiving optimal medical treatment, were randomized either to the control group, or the AIT group. The AIT group exercised twice a week, and began each session with a 10 minute warm-up (50-60% of the peak heart rate), followed by four intervals of 2-minutes (90-95% of the peak heart rate) and a 2-minute recovery (60-70% of the peak heart rate). After the first month, the 2-minute intervals were changed to 4-minute intervals and 3-minutes recovery. After cardiopulmonary exercise testing (CPET) to maximal volitional exertion, using the modified Bruce protocol, patients were seated and the HRR was immediately assessed. Results: After the six months of intervention our main effects were significant for V O2Peak (p= .010) and CPET duration (p= .025). Thus, after testing for simple main effects, only the AIT group depicted significant changes in the post-intervention for: V O2Peak (p= .013), CPET duration (p= .020), heart rate reserve (p= .035), peak pulse pressure (p= .036), and the HRR1diff (p= .025). Conclusions: After six months of intervention, the simple main effects suggest that AIT could improve vagal reactivation, assessed through HRR1diff, in patients that underwent CRT and were engaged in optimal medical treatment. Our findings also suggest that differences between groups in exercise capacity could be due to peripheral factors.
Contexto: A insuficiência cardíaca (IC) é caraterizada por uma disfunção do sistema nervoso autónomo (SNA) que conduz a uma hiperativação simpática e desiquilíbrio parassimpático, culminando em disfunções centrais e periféricas. Nos casos mais avançados de IC, a terapêutica de ressincronização cardíaca (TRC) e o exercício parecem melhorar estas condições e, outros parâmetros clínicos e funcionais. O emergir de evidência robusta valoriza o treino intervalado aeróbio (TIA) em várias populações com IC, sabendo-se pouco acerca da sua influência sobre o SNA. Nesta análise, avaliámos os efeitos do TIA sobre a frequência cardíaca de recuperação (FCR), um indicador de ativação parasimpática. Todos os participantes possuíam uma fração de ejeção diminuída para ventrículo esquerdo, e colocaram o implante cardíaco seis dias antes do início da intervenção. O nosso objetivo foi o de avaliar se o TIA adicionado à TRC poderia melhorar a reativação vagal, medida pela diferença entre a frequência cardíaca pico e a FCR no primeiro minuto (FCR1dif). Métodos: Vinte e nove participantes idade 68 96 9 92; FEVE< 27 ; e o V O2Pico= 15 mL.kg-1.min-1) que estavam a receber tratamento médico otimizado (TMO), foram randomizados diferencialmente para os grupos de TIA e de controlo. O grupo de TIA realizou duas sessões de treino semanais, iniciando as mesmas com 10 minutos de aquecimento (50 a 60% da FC pico), seguido de quatro intervalos de 2 minutos (90 a 95% da FC pico) e 2 minutos de recuperação ativa (60 a 70% da FC pico). Depois de concluído o segundo mês, os intervalos de 2 minutos foram substituídos por intervalos de 4 minutos, enquanto os intervalos de recuperação por outros de 3 minutos. Recorrendo à prova de stress cardiopulmonar (PSCP), a qual foi efetuada até a capacidade volitiva máxima usando o protocolo de Bruce modificado, a FCR foi avaliada imediatamente a seguir ao mesmo. Resultados: A seguir aos seis meses de interven o, os efeitos principais foram significativos para V O2Pico (p= .010) e a duração da PSCP (p= .025). Contudo, depois de se testarem os simple main effects, apenas o grupo de TIA apresentou altera es significativas no per odo pós-interven o para: V O2Pico (p= .013), duração da PSCP (p= .020), frequência cardíaca de reserva (p= .035), pressão de pulso pico (p= .036), e FCR1dif (p= .025). Conclusões: Depois de seis meses de intervenção, os simple main effects sugerem-nos que o TIA pode melhorar a reativação vagal, medida pela FCR1dif a seguir ao exercício em pacientes que se encontram em TRC e TMO. Os resultados sugerem-nos ainda que as diferenças encontradas na capacidade funcional devem-se a fatores periféricos.

Trabalho Final do Mestrado Integrado em Medicina apresentado à Faculdade de Medicina
Introdução: Estudos recentes sugerem que as células progenitoras endoteliais (EPCs) circulantes podem participar na resposta à terapêutica de ressincronização cardíaca (TRC). O objetivo deste estudo foi avaliar o efeito da TRC nos níveis de EPCs circulantes e avaliar o impacto das EPCs no prognóstico a longo prazo. População e métodos: Estudo prospetivo de 50 doentes submetidos a TRC. Antes da implantação, foram quantificadas 2 populações de EPCs circulantes por citometria de fluxo: células CD34+KDR+ e CD133+KDR+. Os níveis destas EPCs foram reavaliados 6 meses após TRC. Os endpoints durante o seguimento a longo prazo foram mortalidade por todas as causas, transplantação cardíaca e hospitalização por insuficiência cardíaca (IC). Resultados: A proporção de não respondedores à TRC foi de 42%, tendendo a ser maior nos doentes com etiologia isquémica versus não isquémica (64% vs 35%, p = 0.098). Os doentes com miocardiopatia isquémica (MCI) apresentavam níveis significativamente mais baixos de EPCs CD34+KDR+ quando comparados aos doentes com miocardiopatia dilatada não isquémica (MCD) (0.0010 ± 0.0007 vs 0.0030 ± 0.0024 células/100 leucócitos, p = 0.032). Não se verificaram diferenças significativas nos níveis basais de EPCs entre sobreviventes e não sobreviventes, nem entre doentes com ou sem necessidade de internamento para tratamento da IC durante o seguimento. Aos 6 meses de seguimento, os níveis de EPCs circulantes eram significativamente maiores do que os níveis basais (0.0024 ± 0.0023 vs 0.0047 ± 0.0041 CD34+KDR+/100 leucócitos, p = 0.010 e 0.0007 ± 0,0004 vs 0.0016 ± 0.0013 CD133+KDR+/100 leucócitos, p = 0.007). Conclusões: Os doentes com MCI apresentam níveis basais de EPCs circulantes significativamente mais baixos que os seus homólogos. A TRC parece melhorar o pool endógeno de EPCs circulantes e níveis basais reduzidos de EPCs não parecem influenciar os outcomes a longo prazo após a TRC.
Aims: Recent studies suggest that circulating endothelial progenitor cells (EPCs) may influence the response to cardiac resynchronization therapy (CRT). The aim of this study was to evaluate the effect of CRT on EPCs levels and to assess the impact of EPCs on long-term clinical outcomes. Population and methods: Prospective study of 50 patients submitted to CRT. Two populations of circulating EPCs were quantified previously to CRT implantation: CD34+KDR+ and CD133+KDR+ cells. EPCs levels were reassessed 6 months after CRT. Endpoints during the long-term follow-up were all-cause mortality, heart transplantation and hospitalization for heart failure (HF) management. Results: The proportion of non-responders to CRT was 42% and tended to be higher in patients with an ischemic vs non-ischemic etiology (64% vs 35%, p = 0.098). Patients with ischemic cardiomyopathy (ICM) showed significantly lower CD34+KDR+ EPCs levels when compared to non-ischemic dilated cardiomyopathy patients (DCM) (0.0010 ± 0.0007 vs 0.0030 ± 0.0024 cells/100 leukocytes, p = 0.032). There were no significant differences in baseline EPCs levels between survivors and non-survivors nor between patients who were rehospitalized for HF management during follow-up or not. At 6-month follow-up, circulating EPCs levels were significantly higher than baseline levels (0.0024 ± 0.0023 vs 0.0047 ± 0.0041 CD34+KDR+ cells/100 leukocytes, p = 0.010 and 0.0007 ± 0.0004 vs 0.0016 ± 0.0013 CD133+KDR+ cells/100 leukocytes, p = 0.007). Conclusions: Patients with ICM showed significantly lower levels of circulating EPCs when compared to their counterparts. CRT seems to improve the pool of endogenously circulating EPCs and reduced baseline EPCs levels seem not influence long-term outcomes after CRT.

博士
國立陽明大學
公共衛生研究所
105
Background: The development of both electrical reverse remodeling and mechanical reverse remodeling (ERR+MRR) after cardiac resynchronization therapy (CRT) implantation could reduce the incidence of lethal arrhythmia, hence the prediction of ERR+MRR is clinically important. Methods and Results: Eighty-three patients (54 male; 67±12 years old) with CRT >6 months were enrolled. ERR was defined as baseline intrinsic QRS duration (iQRSd) shortening ≥10 ms in lead II on ECG after CRT, and MRR as improvement in LVEF ≥25% on echocardiography after CRT. Acute ECG changes were measured by comparing the pre-implant and immediate post-implant ECG. Ventricular arrhythmia episodes, including ventricular tachycardia and ventricular fibrillation, detected by the implanted device were recorded. Patients were classified as ERR only (n=12), MRR only (n=23), ERR+MRR (n=26), or non-responder (ERR− & MRR−, n=22). On multivariate regression analysis, difference between baseline intrinsic QRS and paced QRS duration (∆QRSd) >35 ms was a significant predictor of ERR+MRR (sensitivity, 68%; specificity, 64%; AUC, 0.7; P=0.003), and paced QTc >443 ms was a negative predictor of ERR+MRR (sensitivity, 78%; specificity, 60%; AUC, 0.7; P=0.002). On Cox proportional hazard modeling, ERR+MRR may reduce the risk of ventricular arrhythmia around 70% compared with non-responder (HR, 0.29; 95% CI: 0.13–0.65). Conclusions: Acute ECG changes after CRT were useful predictors of ERR+MRR. ERR+MRR was also a protective factor for ventricular arrhythmia.

博士
長庚大學
電機工程學系
98
Assessing myocardial coordination is critical for predicting response to cardiac resynchronization therapy (CRT) for patients with heart failure. Principal strain vectors and phase space reconstruction are purposed to quantify myocardial coordination based on radial strain by speckle-tracking echocardiography. Principal strain vectors were conducted by unifying regional peak-strain timing and strain fractions separately into vectors for detecting spatial disequilibrium. Different myocardial discoordination related to different types of bundle branch blocks is revealed by the length and angle of principal strain vectors. Phase space reconstruction was performed by converting strain data from different regions to phase space trajectories for describing nonlinear behavior of myocardial coordination. Classifying maps were newly developed by this study for acquiring parameters from phase space trajectories. By the parameters, significantly differences in myocardial coordination are shown related to not only reduction in systolic function, but also prognosis to CRT. The parameters were also applied and tested with indexes acquired by conventional dyssynchrony measurement and principal strain vectors to establish an intelligent classifier for assisting in predicting response after CRT. The best classification performance achieved is correct rate = 88.6 +/- 11.1 %, sensitivity = 88.8 +/- 16.7 % and specificity = 88.3 +/- 17.6 % based on cross-validation.

Cardiac conduction abnormalities can often lead to heart failure, stroke and sudden cardiac death. Heart disease stands as the leading cause of mortality and morbidity in the United States, accounting for 30% of all deaths. Early detection of malfunctions such as arrhythmias and systolic heart failure, the two heart conditions studied in this dissertation, would definitely help reduce the burden cardiovascular diseases have on public health and overcome the current clinical challenges. The imaging techniques currently available to doctors for cardiac activation sequence mapping are invasive, ionizing, time-consuming and costly. Thus, there is an undeniable urgent need for a non-invasive and reliable imaging tool, which could play a crucial role in the early diagnosis of conduction diseases and allow physicians to choose the best course of action. The 12-lead electrocardiogram (ECG) is the current non-invasive clinical tool routinely used to diagnose and localize cardiac arrhythmias prior to intracardiac catheter ablation. However, it has limited accuracy and can be subject to operator bias. Besides, QRS complex narrowing on the clinical ECG after pacing device implantation is also used for response assessment in patients undergoing Cardiac Resynchronization Therapy (CRT). The latter is an established treatment for systolic heart failure patients who have Left Bundle Branch Block as well as a reduced ejection fraction and prolonged QRS duration. Yet, it is still not well understood why 30 to 40 % of CRT recipients do not respond. Echocardiography, due to its portability and ease-of-use, is the most frequently used imaging modality in clinical cardiology. In this dissertation, we assess the clinical performance of Electromechanical Wave Imaging (EWI) as a high frame rate ultrasound-based functional modality that can non-invasively map the electromechanical activation of the heart, i.e., the transient deformations immediately following the electrical activation. The objective of this dissertation is to demonstrate the potential clinical value of EWI for both arrhythmia detection and CRT characterization applications. The first step in translating EWI to the clinic was ensuring that the technique could reli- ably and reproducibly measure the electromechanical activation sequence independently of the probe angle and imaging view in healthy human volunteers (n=7). This dissertation then demonstrated the accuracy of EWI for localizing a variety of ventricular and atrial arrhythmias (accessory pathways in Wolff-Parkinson-White (WPW) syndrome, premature ventricular contractions, focal atrial tachycardia and macro-reentrant atrial flutter) in pediatric (n=14) and adult (n=55) patients prior to catheter ablation more accurately than 12-lead ECG predictions, as validated against electroanatomical mapping. Additionally, 3D-rendered EWI isochrones were illustrated to be capable of significantly distinguishing different biventricular pacing conditions (p≤0.05) with the RWAT and LWAT metrics, assessing the ventricular dyssynchrony change in heart failure patients (n=16) undergoing CRT, and visualizing it in 3D. EWI also provided quantification of %𝘙𝘔𝘓𝘝 in CRT patients (n=38): the amount of left-ventricular resynchronized myocardium, which was found to be a reliable response predictor at 3-, 6-, or 9-month clinical follow-up through its post-CRT values by significantly identifying super-responders from non-responders within 24 hours of implantation (p≤0.05). Furthermore, 3D-rendered isochrones successfully characterized the ventricular activation resulting from His Bundle pacing for the first time (n=4), which was undistinguishable from true physiological activation in sinus rhythm healthy volunteers with the EWI-based activation time distribution dispersion metric. The dispersion was, however, reported to significantly discriminate novel His pacing from other more conventional biventricular pacing schemes (p≤0.01). Finally, we developed and optimized a fully automated zero-crossing algorithm towards a faster, more robust and less observer dependent EWI isochrone generation process. The support vector machine (SVM) and Random Forest machine learning models were both shown capable of successfully identifying the accessory pathway in WPW patients and the pacing electrode location in paced canines. Nevertheless, the best performing algorithm was hereby proven to be the Random Forest classifier with n=200 trees with a precision rising to 97%, and a predictivity that was not impacted by the type of testing dataset it was applied to (human or canine). Overall, in this dissertation, we established the clinical potential of EWI as a viable assisting visual feedback tool, that could not only be used for diagnosis and treatment planning prior to surgical procedures, but also for monitoring during, and assessing long-term resolution of arrhythmia after catheter ablation or heart failure after a CRT implant.

博士
中國醫藥大學
臨床醫學研究所博士班
100
Objects: The purpose of this study was to evaluate atrial and ventricular function and synchrony in patients undergoing cardiac resynchronization therapy. Background: Right atrial pacing in cardiac resynchronization therapy induces dyssynchrony in electrical and mechanical activation of the left atrium. The impact of atrial sensing versus atrial pacing on left ventricular performance in cardiac resynchronization therapy and the underlying mechanisms leading to differences between these two pacing modes in cardiac resynchronization therapy have not been fully elucidated. Methods: Fifty-five patients with heart failure undergoing cardiac resynchronization therapy for 9± 12.5 months and 22 control subjects with dual pacemaker for conduction disorders were enrolled. Conventional and tissue Doppler echocardiography was performed to examine atrial and ventricular mechanics and hemodynamic status. Results: Left ventricular (LV) outflow tract time-velocity integral (22± 7 cm vs. 20± 7 cm, p= 0.001), diastolic filling period (468± 124 ms vs. 380± 93 ms, p= 0.001), and global strain (-32± 24% vs. -27± 22%, p= 0.001) were greater in atrial sensing compared with atrial pacing mode. Atrial strain was higher in atrial sensing compared with atrial pacing mode in the right atrium (-28.2± 8.6% vs. -22.6± 7.6%, p= 0.0007), interatrial septum (-17.1± 6.5% vs. -13.2± 5.4%, p= 0.002), and left atrium (-16.4± 11.0% vs. -13.6± 8.5%, p= 0.02). There was no difference in intra-ventricular dyssynchrony but significantly lower atrial dyssynchrony in atrial sensing compared with atrial pacing mode (31± 19 ms vs. 42 ± 24 ms, p= 0.0002). Conclusion: Atrial sensing is associated with preserved atrial contractility and synchrony, with the results of optimal LV diastolic filling, stroke volume, and LV systolic mechanics consequently. This pacing mode maximizes LV performance and the hemodynamic benefit of cardiac resynchronization therapy in patients with heart failure.

Aims: Non-responder rates for CRT vary from 11 to 46 %. Retrospective data imply a better outcome with stimulation of the latest contracting LV region. Our study analyzed feasibility, safety and clinical outcome of prospectively planned LV lead placement at the site of latest mechanical activation. Methods: Thirty-eight heart failure patients with CRT indication were assessed by 3D TEE and rotation angiography of the coronary sinus. Both images were merged into a single 3D-model to identify CS target veins close to the site of latest mechanical activation. Subsequently LV lead deployment was attempted at the desired target position. Patients were clinically and echocardiographically evaluated at baseline, after 3 and 6 months. Results: The area of latest mechanical activation covered 6 ± 2 segments (38 ± 13 % of LV surface) and was found lateral in 24/37 (65 %), anterior in 11/37 (30 %), inferior in 2/37 (5 %) and septal in 1/37 (3 %) patients. In 36/37 (97 %) patients an appropriate target vein was identified and successful implantation could be performed in 34/37 (92%) patients. Among those patients clinical and echocardiographic response was observed in 91 % and 81 %, respectively. Conclusions: Individualized lead placement at the latest contracting LV site can be performed safely and successfully in the majority of patients. Initial clinical outcome data are encouraging. Identification of target sites requires multimodality integration between LV wall motion data and CS anatomy. Future developments need to improve those technologies and require randomized data on clinical outcome parameters.

This doctoral thesis describes a clinical, prospective, single-center pilot study, investigating the feasibility and the outcome of a novel optimization concept for heart failure patients who are not responding to a device-based therapy, so called Cardiac Resynchronization Therapy (CRT).

Ένας μεγάλος αριθμός μελετών παρατήρησης καθώς και τυχαιοποιημένων ελεγχομένων κλινικών δοκιμών έχει πλέον τεκμηριώσει την ασφάλεια, την αποτελεσματικότητα, καθώς και τις μακροπρόθεσμες επιδράσεις της θεραπείας καρδιακού επανασυγχρονισμού (ΘΚΕ) σε ασθενείς με προχωρημένη καρδιακή ανεπάρκεια, επηρεασμένη συσταλτικότητα της αριστεράς κοιλίας (ΑΚ) και ευρύ σύμπλεγμα QRS. Οι περισσότερες τυχαιοποιημένες κλινικές μελέτες με ΘΚΕ αναφέρουν την αποτελεσματικότητα της θεραπείας αυτής σε περίοδο 3 έως 12 μηνών. Αντίθετα, τα δεδομένα σχετικά με την μακροπρόθεσμη έκβαση, ειδικά των ασθενών με προχωρημένη καρδιακή ανεπάρκεια (λειτουργική κλάση III και IV), είναι περιορισμένα και όχι εντελώς σαφή. Σε αντίθεση με τον πλούτο των δεδομένων που αφορούν την αποτελεσματικότητα της ΘΚΕ όμως, και τα οποία έχουν προέλθει από πολλαπλές κλινικές δοκιμές, οι αναφορές σχετικά με την απόδοση της ΘΚΕ στην κλινική πράξη (εκτός δηλαδή ερευνητικών πρωτοκόλλων) είναι σχετικά περιορισμένες και οι μελέτες μακροχρόνιας παρακολούθησης είναι ακόμα λιγότερες. Οι μελέτες που έχουν ασχοληθεί ειδικά με την ηχοκαρδιογραφική ανταπόκριση μετά από ΘΚΕ είναι ως επί το πλείστον μέρος μιας μεγαλύτερης κλινικής δοκιμής. Τόσο σε μελέτες στα πλαίσια κλινικών δοκιμών όσο και σε μελέτες παρατήρησης όμως, οι έρευνες έχουν επικεντρώσει κυρίως σε περιόδους παρακολούθησης 3 έως 6 μηνών, ενώ λίγα μόνο δεδομένα υπάρχουν πέραν των 12 μηνών. Η αντίστροφη αναδιαμόρφωση της ΑΚ, κυρίως κατά την άμεση περίοδο μετά την εμφύτευση, φαίνεται να είναι και ο ισχυρότερος προγνωστικός δείκτης επιβίωσης των ασθενών με καρδιακή ανεπάρκεια που λαμβάνουν ΘΚΕ. Ωστόσο, καθώς η ΑΚ συνεχίζει να αναδιαμορφώνεται και μετά την εμφύτευση, είναι ασαφές κατά πόσον η βραχυπρόθεσμη ευνοϊκή ανταπόκριση που παρατηρείται στο 60% -70% των ασθενών διατηρείται μακροπρόθεσμα. Η ηχοκαρδιογραφία παραμόρφωσης έχει χρησιμοποιηθεί για την εξαγωγή δεικτών καρδιακού δυσυγχρονισμού και την εκτίμηση της λειτουργίας της ΑΚ πριν την εμφύτευση συσκευής ΘΚΕ (αμφικοιλιακού βηματοδότη με ή χωρίς δυνατότητα απινιδωτή). Η ανταπό-κριση των δεικτών παραμόρφωσης της ΑΚ μπορεί να έχει σημαντικές προγνωστικές επιπτώσεις για τους ασθενείς που υποβάλλονται σε ΘΚΕ, λαμβάνοντας υπ’ όψιν ότι οι δείκτες παραμόρφωσης πρόσφατα εδείχθησαν να έχουν ισχυρότερη συσχέτιση με την πρόγνωση των ασθενών με καρδιακή ανεπάρκεια σε σχέση με το κλάσμα εξώθησης ή άλλους κλασσικούς δείκτες της λειτουργικής κατάστασης της ΑΚ. Παρ’ όλα αυτά, ελάχιστα ηχοκαρδιογραφικά δεδομένα υπάρχουν σχετικά με την ανταπόκριση των δεικτών παραμόρφωσης μετά από θεραπεία επανασυγχρονισμού, ενώ δεν υπάρχουν καθόλου στοιχεία πέραν των 6 μηνών. Σε αυτή τη μελέτη, εκτιμήσαμε τη μακροπρόθεσμη ανταπόκριση της λειτουργίας της ΑΚ, όπως αυτή καταγράφεται ηχο¬καρδιο¬γραφικά μετά από τουλάχιστον 12 μήνες παρακολούθησης, μετά από εμφύτευση συσκευής καρδιακού επανασυγχρονισμού με δυνατότητες απινιδωτή (CRT-D). Ο πρωτογενής μας στόχος ήταν να καταγράψουμε συστηματικά, χρησιμοποιώντας συμβατικούς αλλά και νεώτερους ηχοκαρδιογραφικούς δείκτες (απεικόνιση παρα-μόρφωσης), τη μακροπρόθεσμη ανταπόκριση της λειτουργίας της ΑΚ μετά από εμφύτευση συσκευής ΘΚΕ με δυνατότητες απινιδωτή (CRT device with defibrillator capacity, CRT-D) σε ασθενείς με προχωρημένη καρδιακή ανεπάρκεια οι οποίοι λαμβάνουν βέλτιστη φαρμακευτική αγωγή. Οι δευτερογενείς μας στόχοι ήταν (α) να καταγράψουμε τη μακροπρόθεσμη (>12 μήνες) ανταπόκριση του δυσσυγχρονισμού της ΑΚ, όπως αυτή καταγράφεται με ηχοκαρδιογραφική απεικόνιση παραμόρφωσης (β) να συσχετίσουμε τους δείκτες δυσσυγχρονισμού της ΑΚ πριν από την εμφύτευση με τη μακροπρόθεσμη ανταπόκριση της λειτουργίας της ΑΚ, και (γ) να συσχετίσουμε τους συμβατικούς και νεώτερους ηχοκαρδιογραφικούς δείκτες λειτουργίας της αριστεράς κοιλίας πριν από την εμφύτευση με τη μακροπρόθεσμη ανταπόκριση της λειτουργίας της ΑΚ.
Several observational studies and randomized controlled trials (RCTs) have demonstrated the safety, efficacy, and long-term effects of cardiac resynchronization therapy (CRT) in patients with advanced heart failure, reduced left ventricular systolic function, and wide QRS complex. Most clinical trials with CRT report efficacy within a 3-to-12 month time frame. However, data on long-term effects, especially for advanced heart failure patients with NYHA class III-IV, are limited and unclear. In contrast to the wealth of data on efficacy of CRT, reports on effectiveness of CRT in clinical practice (i.e. outside the context of RCTs) are limited and data on long-term effectiveness are scarce. Studies dealing with echocardio-graphic responses come largely from sub-studies of larger RCTs. However, both these sub-studies as well as observational studies have focused on short-term echocardiographic responses, whereas very limited data exist beyond 12 months. Reverse remodeling of the left ventricle in response to CRT in the immediate post-implant period is the strongest predictor of long-term prognosis in these patients. However, as the left ventricle continues to remodel long after CRT device implantation, it is unclear whether the initial favorable response observed in 60% to 70% of CRT recipients is maintained long term. Deformation echocardiography has been used to derive ventricular dyssynchrony indices and assess left ventricular function prior to CRT device implantation (biventricular pacemaker with or without defibrillator capacity). The response of myocardial deformation indices of the left ventricle may have important prognostic implications for CRT recipients, considering that deformation parameters have been shown to have a stronger association with prognosis compared with ejection fraction or other conventional indices of left ventricular function. Nevertheless, limited echocardiographic data exist on the response of myocardial deformation indices to CRT, whereas no data exist beyond 6 months post CRT. In this study, we have evaluated the long-term echocardiographic response of left ventricle to CRT after a minimum of 12 months of follow up after implantation of a CRT device with defibrillator capacity (CRT-D). Our primary aim was to systematically record, using both conventional and novel echocardiographic indices (myocardial deformation), the long-term (12 months or longer) response of the left ventricle after CRT-D device implantation in patients with advanced heart failure receiving optimal medical therapy. Our secondary aims were to (a) record the long-term response of left ventricular dyssynchrony assessed with myocardial deformation indices in these patients; (b) correlate left ventricular dyssynchrony indices before CRT-D device implantation with long-term response of the left ventricle, and (c) correlate both conventional and novel left ventricular function indices before implantation with long-term response of the left ventricle after CRT-D device implantation.