Left ventricular dyssynchrony predicts response and prognosis after cardiac resynchronization therapy

OBJECTIVES This study was designed to predict the response and prognosis after cardiac resynchronization therapy (CRT) in patients with end-stage heart failure (HF). BACKGROUND Cardiac resynchronization therapy improves HF symptoms, exercise capacity, and left ventricular (LV) function. Because not all patients respond, preimplantation identification of responders is needed. In the present study, response to CRT was predicted by the presence of LV dyssynchrony assessed by tissue Doppler imaging. Moreover, the prognostic value of LV dyssynchrony in patients undergoing CRT was assessed. METHODS Eighty-five patients with end-stage HF, QRS duration >120 ins, and left bundle-branch block were evaluated by tissue Doppler imaging before CRT. At baseline and six months follow-up, New York Heart Association functional class, quality of life and 6-min walking distance, LV volumes, and LV ejection fraction were determined. Events (death, hospitalization for decompensated HF) were obtained during one-year follow-up. RESULTS Responders (74%) and nonresponders (26%) had comparable baseline characteristics, except for a larger dyssynchrony in responders (87 +/- 49 ms vs. 35 +/- 20 ms, p < 0.01). Receiver-operator characteristic curve analysis demonstrated that an optimal cutoff value of 65 ms for LV dyssynchrony yielded a sensitivity and specificity of 80% to predict clinical improvement and of 92% to predict LV reverse remodeling. Patients with dyssynchrony :65 ms had an excellent prognosis (6% event rate) after CRT as compared with a 50% event rate in patients with dyssynchrony <65 ins (p < 0.001). CONCLUSIONS Patients with LV dyssynchrony greater than or equal to65 ms respond to CRT and have an excellent prognosis after CRT. (C) 2004 by the American College of Cardiology Foundation.

Use of intracardiac echocardiography as a guide during interventricular septum puncture in a patient undergoing cardiac resynchronization therapy

SIN FINANCIACIÓN

Development and Validation of Predictive Models of Cardiac Mortality and Transplantation in Resynchronization Therapy

AbstractBackground:30-40% of cardiac resynchronization therapy cases do not achieve favorable outcomes.Objective:This study aimed to develop predictive models for the combined endpoint of cardiac death and transplantation (Tx) at different stages of cardiac resynchronization therapy (CRT).Methods:Prospective observational study of 116 patients aged 64.8 ± 11.1 years, 68.1% of whom had functional class (FC) III and 31.9% had ambulatory class IV. Clinical, electrocardiographic and echocardiographic variables were assessed by using Cox regression and Kaplan-Meier curves.Results:The cardiac mortality/Tx rate was 16.3% during the follow-up period of 34.0 ± 17.9 months. Prior to implantation, right ventricular dysfunction (RVD), ejection fraction < 25% and use of high doses of diuretics (HDD) increased the risk of cardiac death and Tx by 3.9-, 4.8-, and 5.9-fold, respectively. In the first year after CRT, RVD, HDD and hospitalization due to congestive heart failure increased the risk of death at hazard ratios of 3.5, 5.3, and 12.5, respectively. In the second year after CRT, RVD and FC III/IV were significant risk factors of mortality in the multivariate Cox model. The accuracy rates of the models were 84.6% at preimplantation, 93% in the first year after CRT, and 90.5% in the second year after CRT. The models were validated by bootstrapping.Conclusion:We developed predictive models of cardiac death and Tx at different stages of CRT based on the analysis of simple and easily obtainable clinical and echocardiographic variables. The models showed good accuracy and adjustment, were validated internally, and are useful in the selection, monitoring and counseling of patients indicated for CRT.

Improvement in cardiac sympathetic nerve activity in responders to resynchronization therapy

AIMS: To assess changes in cardiac adrenergic activity with cardiac resynchronization therapy (CRT), and to investigate whether these changes are related to improvement in left ventricular ejection fraction (LVEF). METHODS AND RESULTS: Sixteen patients (13 males, age 66 +/- 7 years) were studied at baseline and after > or =6 months of CRT (mean follow-up 9.2 +/- 3.2 months). LVEF was assessed by nuclear angiography. Responders were defined as patients showing > or =5% absolute increase in LVEF + improvement in > or =1 NYHA class + absence of heart failure hospitalization. Cardiac sympathetic nerve activity was studied by (123)I-metaiodobenzyl-guanidine ((123)I-MIBG) scintigraphy. Responders (n = 8) showed lower (123)I-MIBG washout at follow-up when compared with non-responders (P = 0.002), indicating lower cardiac sympathetic nerve activity. The decrease in (123)I-MIBG washout at follow-up when compared with baseline was only seen in the responder group (P = 0.036). There was a moderate correlation between increase in LVEF and decrease in (123)I-MIBG washout (r = 0.52, P = 0.04). CONCLUSION: CRT induces a reduction in cardiac sympathetic nerve activity in responders, that parallels an improvement in LVEF, whereas non-responders do not show any significant changes.

Health related quality of life in patients with refractory chronic heart failure undergoing cardiac resynchronization: type of therapeutic response

The benefits of cardiac resynchronization therapy (CRT) in the health-related quality of life (HRQL) are largely demonstrated in selected patients with severe congestive heart failure (CHF). However, the differences between responders and non-responders, with regard to the effect of CRT in the various dimensions that constitute HRQL are still a matter of discussion. Objective: To evaluate the impact of CRT on the HRQL of patients with CHF refractory to optimal pharmacological therapy, within 6 months after CRT. Methods: 43 patients, submitted to successful implantation of CRT, were evaluated in hospital just before intervention and in the outpatient clinic within 6 months after CRT. HRQL was analyzed based on the Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients were classified as super-responders (ejection fraction of left ventricle - LVEF - ≥45% post-CRT), n=15, responders (sustained improvement in functional class and LVEF increased by 15%), n=19, and non-responders (no clinical or LVEF improvement), n=9. Results: In the group of super-responders, CRT was associated with an improvement in HRQL for the various fields and sums assessed (ρ<0.05); in responders, CRT has been associated with an improvement of HRQL in the various fields and sums, except in the self-efficacy dimension (ρ<0.05); in non-responders, CRT was not associated with improvement of HRQL. Conclusion: In a population with severe CHF undergoing CRT, the patients with clinical and echocardiographic positive response, obtained a favorable impact in all dimensions of HRQL, while the group without response to CRT showed no improvement. These data reinforces the importance of HRQL as a multidimensional tool for assessment of benefits in clinical practice.

Evaluating the quality of life in patients with refractory chronic heart failure undergoing cardiac resynchronization regarding the type of therapeutic response

The benefits of cardiac resynchronization therapy (CRT) in the quality of life have been largely demonstrated in selected patients with severe congestive heart failure (CHF). However, the differences between responders and non-responders, with regard to the effect of CRT in the various dimensions of quality of life is still a matter of discussion. Objective: to evaluate the impact of CRT on the quality of life of patients with CHF refractory to optimal pharmacological therapy, within 6 months after CRT.

National Registry on Cardiac Electrophysiology (2012)

Based on a survey sent to Portuguese centers that perform diagnostic and interventional electrophysiology and/or implantable cardioverter-defibrillator (ICD) implantations, the authors analyze the number and type of procedures performed during 2012 and compare these data with previous years. In 2012, a total of 2561 diagnostic electrophysiologic studies were performed, which were followed by ablation in 2017 cases, representing a steady situation compared with the previous year. There was a 12% increase in the number of ablation procedures for atrial fibrillation, making it for the first time the most frequent indication for ablation, overtaking atrioventricular nodal reentrant tachycardia. The total number of first ICD implantations was 1048 (around 100 per million population), of which 375 were cardiac resynchronization devices (BiV ICDs). This represents a slight decrease (3.3%) in the total number of new implants, with an increase of 10% in the number of BiV ICDs compared to the previous year. However, there was a considerable increase in the number of ICD generator replacements, resulting in an overall increase of 3.5% in implantations performed in 2012. Some comments are made regarding developments in this activity and its current status, and on some factors that may influence the dynamics of this area of interventional cardiology.

Défibrillateur automatique implantable (DAI): principes de base et indications cliniques actuelles [Implantable cardiac defibrillator (ICD): basics and present clinical guidelines].

An implantable cardiac defibrillator (ICD) is a cardiac implantable electronic device that is capable of identifying and treating ventricular arrhythmias. Consideration about the type of ICD to select for a given patient include whether the patient has bradycardia requiring pacing support, has associated atrial tachyarrhythmias, or would benefit from cardiac resynchronization therapy. The ICD functions by continuously monitoring the patient's cardiac rate and delivering therapies (anti-tachycardia pacing, shocks) when the rate exceeds the programmed rate "cutoff". Secondary prevention trials have demonstrated that ICDs reduce the incidence of arrhythmic death and total mortality in patients presenting with a cardiac arrest. ICDs are also indicated for primary prevention of sudden cardiac death in specific high-risk subgroups of patients.

Predictors of mortality from pump failure and sudden cardiac death in patients with systolic heart failure and left ventricular dyssynchrony: results of the CARE-HF trial.

BACKGROUND: Determining a specific death cause may facilitate individualized therapy in patients with heart failure (HF). Cardiac resynchronization therapy (CRT) decreased mortality in the Cardiac Resynchronization in Heart Failure trial by reducing pump failure and sudden cardiac death (SCD). This study analyzes predictors of specific causes of death. METHODS AND RESULTS: Univariate and multivariate analyses used 8 baseline and 3-month post-randomization variables to predict pump failure and SCD (categorized as "definite," "probable," and "possible"). Of 255 deaths, 197 were cardiovascular. There were 71 SCDs with a risk reduction by CRT of 0.47 (95% confidence interval 0.29-0.76; P = .002) with similar reductions in SCD classified as definite, probable, and possible. Univariate SCD predictors were 3-month HF status (mitral regurgitation [MR] severity, plasma brain natriuretic peptide [BNP], end-diastolic volume, and systolic blood pressure), whereas randomization to CRT decreased risk. Multivariate SCD predictors were randomization to CRT 0.56 (0.53-0.96, P = .035) and 3-month MR severity 1.82 (1.77-2.60, P = .0012). Univariate pump failure death predictors related to baseline HF state (quality of life score, interventricular mechanical delay, end-diastolic volume, plasma BNP, MR severity, and systolic pressure), whereas randomization to CRT and nonischemic cardiomyopathy decreased risk; multivariate predictors of pump failure death were baseline plasma BNP and systolic pressure and randomization to CRT. CONCLUSION: CRT decreased SCD in patients with systolic HF and ventricular dyssynchrony. SCD risk was increased with increased severity of MR (including the 3-month value for MR as a time-dependent covariate) and reduced by randomization to CRT. HF death was increased related to the level of systolic blood pressure, log BNP, and randomization to CRT. These results emphasize the importance and interdependence of HF severity to mortality from pump failure and SCD.

Optimization Studies to Improve MSC-based Cardiac Cell Therapy : Cytokine Preconditioning and Nanoparticle Coupling

Contexte: La cardiopathie ischémique (IHD) reste une cause majeure de mortalité en Amérique du Nord. La thérapie cellulaire cardiaque (CCT) a émergé comme une thérapie prometteuse pour aider à guérir certaines malades cardiaques. Parmi les cellulaires avec propriétés pluripotentes, les cellules stromales mésenchymateuses (MSC) sont prometteuses. Cependant, plusieurs questions demeurent non résolues et certaines défis empêchent l'application clinique de la CCT se dans l'IHD, tels que le faible taux de rétention cellulaire in situ, le suivi des cellules in vivo post-implantation et post-acheminements et l`apoptose. Ici, le traitement préliminaire des MSC avec des facteurs de croissance et leur couplage avec des nanoparticules (NP) seront étudiés comme des méthodes pour optimiser MSC. Méthodes: Des MSCs provenant du rat (rMSC) et du cochon (pMSC) ont été isolés à partir de moelle osseuse. Les rMSC ont été préconditionnées avec SDF-1a, TSG-6 et PDGF-BB, et ensuite soumises à une hypoxie, une privation de sérum et a un stress oxydatif. Des études de cicatrisation ont également été effectués avec rMSCs préconditionnées. En parallèle, de nouvelles NP ferromagnétiques liées aux silicones ont été synthétisées. Les NPs ont été couplées aux pMSCs suivant leur fonctionnalisation avec l`anticorps, CD44, un antigène de surface du MSC bien connu. Par la suite, les études de biocompatibilité ont été réalisées sur pMSC-NP et en incluant des tests des processus cellulaires tels que la migration, l'adhésion, la prolifération et les propriétés de la différenciation. Résultats: Parmi toutes les cytokines testées, PDGF-BB a démontré la plus grande capacité à améliorer la survie de MSC dans des conditions d'hypoxie, de privation de sérum et en reponse au stress oxydatif. La conjugaison de NP a atténué la migration et la prolifération des pMSCs, mais n`a pas changé leur capacité de différenciation. Enfin, la complexe du MSC-NP est détectable par IRM. Conclusion: Nos données suggèrent que de nouvelles stratégies, telles que traitement préliminaire de PDGF-BB et le couplage des nanoparticules ferromagnétiques, peuvent être considérés comme des avenues prometteuse pour optimiser les MSCs pour la CCT.

Parameters and algorithms to evaluate cardiac mechanics by conductance catheter

This work is structured as follows: In Section 1 we discuss the clinical problem of heart failure. In particular, we present the phenomenon known as ventricular mechanical dyssynchrony: its impact on cardiac function, the therapy for its treatment and the methods for its quantification. Specifically, we describe the conductance catheter and its use for the measurement of dyssynchrony. At the end of the Section 1, we propose a new set of indexes to quantify the dyssynchrony that are studied and validated thereafter. In Section 2 we describe the studies carried out in this work: we report the experimental protocols, we present and discuss the results obtained. Finally, we report the overall conclusions drawn from this work and we try to envisage future works and possible clinical applications of our results. Ancillary studies that were carried out during this work mainly to investigate several aspects of cardiac resynchronization therapy (CRT) are mentioned in Appendix. -------- Ventricular mechanical dyssynchrony plays a regulating role already in normal physiology but is especially important in pathological conditions, such as hypertrophy, ischemia, infarction, or heart failure (Chapter 1,2.). Several prospective randomized controlled trials supported the clinical efficacy and safety of cardiac resynchronization therapy (CRT) in patients with moderate or severe heart failure and ventricular dyssynchrony. CRT resynchronizes ventricular contraction by simultaneous pacing of both left and right ventricle (biventricular pacing) (Chapter 1.). Currently, the conductance catheter method has been used extensively to assess global systolic and diastolic ventricular function and, more recently, the ability of this instrument to pick-up multiple segmental volume signals has been used to quantify mechanical ventricular dyssynchrony. Specifically, novel indexes based on volume signals acquired with the conductance catheter were introduced to quantify dyssynchrony (Chapter 3,4.). Present work was aimed to describe the characteristics of the conductancevolume signals, to investigate the performance of the indexes of ventricular dyssynchrony described in literature and to introduce and validate improved dyssynchrony indexes. Morevoer, using the conductance catheter method and the new indexes, the clinical problem of the ventricular pacing site optimization was addressed and the measurement protocol to adopt for hemodynamic tests on cardiac pacing was investigated. In accordance to the aims of the work, in addition to the classical time-domain parameters, a new set of indexes has been extracted, based on coherent averaging procedure and on spectral and cross-spectral analysis (Chapter 4.). Our analyses were carried out on patients with indications for electrophysiologic study or device implantation (Chapter 5.). For the first time, besides patients with heart failure, indexes of mechanical dyssynchrony based on conductance catheter were extracted and studied in a population of patients with preserved ventricular function, providing information on the normal range of such a kind of values. By performing a frequency domain analysis and by applying an optimized coherent averaging procedure (Chapter 6.a.), we were able to describe some characteristics of the conductance-volume signals (Chapter 6.b.). We unmasked the presence of considerable beat-to-beat variations in dyssynchrony that seemed more frequent in patients with ventricular dysfunction and to play a role in discriminating patients. These non-recurrent mechanical ventricular non-uniformities are probably the expression of the substantial beat-to-beat hemodynamic variations, often associated with heart failure and due to cardiopulmonary interaction and conduction disturbances. We investigated how the coherent averaging procedure may affect or refine the conductance based indexes; in addition, we proposed and tested a new set of indexes which quantify the non-periodic components of the volume signals. Using the new set of indexes we studied the acute effects of the CRT and the right ventricular pacing, in patients with heart failure and patients with preserved ventricular function. In the overall population we observed a correlation between the hemodynamic changes induced by the pacing and the indexes of dyssynchrony, and this may have practical implications for hemodynamic-guided device implantation. The optimal ventricular pacing site for patients with conventional indications for pacing remains controversial. The majority of them do not meet current clinical indications for CRT pacing. Thus, we carried out an analysis to compare the impact of several ventricular pacing sites on global and regional ventricular function and dyssynchrony (Chapter 6.c.). We observed that right ventricular pacing worsens cardiac function in patients with and without ventricular dysfunction unless the pacing site is optimized. CRT preserves left ventricular function in patients with normal ejection fraction and improves function in patients with poor ejection fraction despite no clinical indication for CRT. Moreover, the analysis of the results obtained using new indexes of regional dyssynchrony, suggests that pacing site may influence overall global ventricular function depending on its relative effects on regional function and synchrony. Another clinical problem that has been investigated in this work is the optimal right ventricular lead location for CRT (Chapter 6.d.). Similarly to the previous analysis, using novel parameters describing local synchrony and efficiency, we tested the hypothesis and we demonstrated that biventricular pacing with alternative right ventricular pacing sites produces acute improvement of ventricular systolic function and improves mechanical synchrony when compared to standard right ventricular pacing. Although no specific right ventricular location was shown to be superior during CRT, the right ventricular pacing site that produced the optimal acute hemodynamic response varied between patients. Acute hemodynamic effects of cardiac pacing are conventionally evaluated after stabilization episodes. The applied duration of stabilization periods in most cardiac pacing studies varied considerably. With an ad hoc protocol (Chapter 6.e.) and indexes of mechanical dyssynchrony derived by conductance catheter we demonstrated that the usage of stabilization periods during evaluation of cardiac pacing may mask early changes in systolic and diastolic intra-ventricular dyssynchrony. In fact, at the onset of ventricular pacing, the main dyssynchrony and ventricular performance changes occur within a 10s time span, initiated by the changes in ventricular mechanical dyssynchrony induced by aberrant conduction and followed by a partial or even complete recovery. It was already demonstrated in normal animals that ventricular mechanical dyssynchrony may act as a physiologic modulator of cardiac performance together with heart rate, contractile state, preload and afterload. The present observation, which shows the compensatory mechanism of mechanical dyssynchrony, suggests that ventricular dyssynchrony may be regarded as an intrinsic cardiac property, with baseline dyssynchrony at increased level in heart failure patients. To make available an independent system for cardiac output estimation, in order to confirm the results obtained with conductance volume method, we developed and validated a novel technique to apply the Modelflow method (a method that derives an aortic flow waveform from arterial pressure by simulation of a non-linear three-element aortic input impedance model, Wesseling et al. 1993) to the left ventricular pressure signal, instead of the arterial pressure used in the classical approach (Chapter 7.). The results confirmed that in patients without valve abnormalities, undergoing conductance catheter evaluations, the continuous monitoring of cardiac output using the intra-ventricular pressure signal is reliable. Thus, cardiac output can be monitored quantitatively and continuously with a simple and low-cost method. During this work, additional studies were carried out to investigate several areas of uncertainty of CRT. The results of these studies are briefly presented in Appendix: the long-term survival in patients treated with CRT in clinical practice, the effects of CRT in patients with mild symptoms of heart failure and in very old patients, the limited thoracotomy as a second choice alternative to transvenous implant for CRT delivery, the evolution and prognostic significance of diastolic filling pattern in CRT, the selection of candidates to CRT with echocardiographic criteria and the prediction of response to the therapy.

Determination of Three-Dimensional Left Ventricle Motion to Analyze Ventricular Dyssyncrony in SPECT Images

A method to compute three-dimension (3D) left ventricle (LV) motion and its color coded visualization scheme for the qualitative analysis in SPECT images is proposed. It is used to investigate some aspects of Cardiac Resynchronization Therapy (CRT). The method was applied to 3D gated-SPECT images sets from normal subjects and patients with severe Idiopathic Heart Failure, before and after CRT. Color coded visualization maps representing the LV regional motion showed significant difference between patients and normal subjects. Moreover, they indicated a difference between the two groups. Numerical results of regional mean values representing the intensity and direction of movement in radial direction are presented. A difference of one order of magnitude in the intensity of the movement on patients in relation to the normal subjects was observed. Quantitative and qualitative parameters gave good indications of potential application of the technique to diagnosis and follow up of patients submitted to CRT.