Are echo techniques comparable for measurement of left ventricular dysynchrony? Comparison of real time 3D and tissue Doppler echocardiography in patients with ischaemic cardiomyopathy

Tissue Doppler (TD) assessment of dysynchrony (DYS) is established in evaluation for bi-ventricular pacing. Time to regional minimal volume by real-time 3D echo (3D) has been applied to DYS. 3D offers simultaneous assessment of all segments and may limit errors in localization of maximum delay due to off-axis images.We compared TD and 3D for assessment of DYS. 27 patients with ischaemic cardiomyopathy (aged 60±11 years, 85% male) underwent TD with generation of regional velocity curves. The interval between QRS onset and maximal systolic velocity (TTV) was measured in 6 basal and 6 mid-cavity segments. Onthe same day,3Dwas performed and data analysed offline with Q-Lab software (Philips, Andover, MA). Using 12 analogous regional time-volume curves time to minimal volume (T3D)was calculated. The standard deviation (S.D.) between segments in TTV and T3D was calculated as a measure ofDYS. In 7 patients itwas not possible to measureT3D due to poor images. In the remaining 20, LV diastolic volume, systolic volume and EF were 128±35 ml, 68±23 ml and 46±13%, respectively. Mean TTV was less than mean T3D (150±33ms versus 348±54 ms; p < 0.01). The intrapatient range was 20–210ms for TTV and 0–410ms for T3D. Of 9 patients (45%) with significantDYS (S.D. TTV > 32 ms), S.D. T3D was 69±37ms compared to 48±34ms in those without DYS (p = ns). In DYS patients there was concordance of the most delayed segment in 4 (44%) cases.Therefore, different techniques for assessing DYS are not directly comparable. Specific cut-offs for DYS are needed for each technique.

Relative predictive value of intraventricular dysynchrony in determining long-term outcome in patients with known or suspected coronary disease

Improvement of intra-ventricular dysynchrony (IVD) in pts undergoing bi-ventricular pacing is associated with clinical improvementbut little isknownabout the relationship between IVD and prognosis.We sought whether IVD influences long-term outcome in pts with known or suspected coronary disease (CAD). Tissue Doppler imaging was performed in 184 pts (aged 61±10 years, 67% male) prior to dobutamine echo. From velocity curves the interval between QRS onset and max systolic velocity (Ts) was measured in basal septal, lateral, inferior and anterior segments. The maximal difference in Ts between segments (TsMax) was used as a measure of IVD. The standard deviation (TsSD) between all segments and the septal-lateral difference (TsSL) were also calculated. Pts were followed up for a median interval of 5 years and a Cox model used for survival analysis. The medianwall motion index (WMI) was 1.3 (IQR 1.0–1.8) at rest and 1.4 (IQR 1.3–1.9) at stress. The table shows IVD parameters. Forty-one deaths occurred during follow-up. Pts who died during follow-up, compared to survivors, showed greater IVD. WMI at rest (p = 0.03) and peak stress (p = 0.02), TsSD (p = 0.06), TsSL (p = 0.02) and TsMax (p = 0.05) but not QRS width were univariate predictors of mortality. TsSL was the only independent predictor of death (p = 0.01). Therefore, IVD is common in pts with known or suspected CAD. Pts with more IVD have reduced long-term survival, independent of WMI.

A dual role for ErbB2 signaling in cardiac trabeculation.

Cardiac trabeculation is a crucial morphogenetic process by which clusters of ventricular cardiomyocytes extrude and expand into the cardiac jelly to form sheet-like projections. Although it has been suggested that cardiac trabeculae enhance cardiac contractility and intra-ventricular conduction, their exact function in heart development has not been directly addressed. We found that in zebrafish erbb2 mutants, which we show completely lack cardiac trabeculae, cardiac function is significantly compromised, with mutant hearts exhibiting decreased fractional shortening and an immature conduction pattern. To begin to elucidate the cellular mechanisms of ErbB2 function in cardiac trabeculation, we analyzed erbb2 mutant hearts more closely and found that loss of ErbB2 activity resulted in a complete absence of cardiomyocyte proliferation during trabeculation stages. In addition, based on data obtained from proliferation, lineage tracing and transplantation studies, we propose that cardiac trabeculation is initiated by directional cardiomyocyte migration rather than oriented cell division, and that ErbB2 cell-autonomously regulates this process.

Cardiologie nucléaire du 21ième siècle : nouveautés et réalités

Les maladies cardio-vasculaires demeurent une cause majeure de mortalité et morbidité dans les sociétés développées. La recherche de déterminants prédictifs d’évènements vasculaires représente toujours un enjeu d’actualité face aux coûts croissants des dépenses reliées aux soins médicaux et à l’élargissement des populations concernées, notamment face à l’occidentalisation des pays émergeants comme l’Inde, le Brésil et la Chine. La cardiologie nucléaire occupe depuis trente ans, une place essentielle dans l’arsenal des méthodes diagnostiques et pronostiques des cardiopathies. De plus, de nouvelles percées permettront de dépister d’une façon plus précoce et précise, la maladie athérosclérotique cardiaque et périphérique chez les populations atteintes ainsi qu’en prévention primaire. Nous présenterons dans cette thèse, deux approches nouvelles de la cardiologie nucléaire. La dysfonction endothéliale est considérée comme le signal pathologique le plus précoce de l’athérosclérose. Les facteurs de risques cardiovasculaires traditionnels atteignent la fonction endothéliale et peuvent initier le processus d’athérosclérose même en l’absence de lésion endothéliale physique. La quantification de la fonction endothéliale coronarienne comporte donc un intérêt certain comme biomarqueur précoce de la maladie coronarienne. La pléthysmographie isotopique, méthodologie développée lors de ce cycle d’étude, permet de quantifier la fonction endothéliale périphérique, cette dernière étant corrélée à la fonction endothéliale coronarienne. Cette méthodologie est démontrée dans le premier manuscrit (Harel et. al., Physiol Meas., 2007). L’utilisation d’un radiomarquage des érythrocytes permet la mesure du flot artériel au niveau du membre supérieur pendant la réalisation d’une hyperémie réactive locale. Cette nouvelle procédure a été validée en comparaison à la pléthysmographie par jauge de contrainte sur une cohorte de 26 patients. Elle a démontré une excellente reproductibilité (coefficient de corrélation intra-classe = 0.89). De plus, la mesure du flot artérielle pendant la réaction hyperémique corrélait avec les mesure réalisées par la méthode de référence (r=0.87). Le deuxième manuscrit expose les bases de la spectroscopie infrarouge comme méthodologie de mesure du flot artériel et quantification de la réaction hyperémique (Harel et. al., Physiol Meas., 2008). Cette étude utilisa un protocole de triples mesures simultanées à l’aide de la pléthysmographie par jauge de contrainte, radio-isotopique et par spectroscopie infrarouge. La technique par spectroscopie fut démontrée précise et reproductible quant à la mesure des flots artériels au niveau de l’avant-bras. Cette nouvelle procédure a présenté des avantages indéniables quant à la diminution d’artéfact et à sa facilité d’utilisation. Le second volet de ma thèse porte sur l’analyse du synchronisme de contraction cardiaque. En effet, plus de 30% des patients recevant une thérapie de resynchronisation ne démontre pas d’amélioration clinique. De plus, ce taux de non-réponse est encore plus élevé lors de l’utilisation de critères morphologiques de réponse à la resynchronisation (réduction du volume télésystolique). Il existe donc un besoin urgent de développer une méthodologie de mesure fiable et précise de la dynamique cardiaque. Le troisième manuscrit expose les bases d’une nouvelle technique radio-isotopique permettant la quantification de la fraction d’éjection du ventricule gauche (Harel et. al. J Nucl Cardiol., 2007). L’étude portant sur 202 patients a démontré une excellente corrélation (r=0.84) avec la méthode de référence (ventriculographie planaire). La comparaison avec le logiciel QBS (Cedar-Sinai) démontrait un écart type du biais inférieur (7.44% vs 9.36%). De plus, le biais dans la mesure ne démontrait pas de corrélation avec la magnitude du paramètre pour notre méthodologie, contrairement au logiciel alterne. Le quatrième manuscrit portait sur la quantification de l’asynchronisme intra-ventriculaire gauche (Harel et. al. J Nucl Cardiol, 2008). Un nouveau paramètre tridimensionnel (CHI: contraction homogeneity index) (médiane 73.8% ; IQ 58.7% - 84.9%) permis d’intégrer les composantes d’amplitude et du synchronisme de la contraction ventriculaire. La validation de ce paramètre fut effectuée par comparaison avec la déviation standard de l’histogramme de phase (SDΦ) (médiane 28.2º ; IQ 17.5º - 46.8º) obtenu par la ventriculographie planaire lors d’une étude portant sur 235 patients. Ces quatre manuscrits, déjà publiés dans la littérature scientifique spécialisée, résument une fraction des travaux de recherche que nous avons effectués durant les trois dernières années. Ces travaux s’inscrivent dans deux axes majeurs de développement de la cardiologie du 21ième siècle.

Doppler vortography : detection and quantification of the vortices in the left ventricle

Nous proposons une nouvelle méthode pour quantifier la vorticité intracardiaque (vortographie Doppler), basée sur l’imagerie Doppler conventionnelle. Afin de caractériser les vortex, nous utilisons un indice dénommé « Blood Vortex Signature (BVS) » (Signature Tourbillonnaire Sanguine) obtenu par l’application d’un filtre par noyau basé sur la covariance. La validation de l’indice BVS mesuré par vortographie Doppler a été réalisée à partir de champs Doppler issus de simulations et d’expériences in vitro. Des résultats préliminaires obtenus chez des sujets sains et des patients atteints de complications cardiaques sont également présentés dans ce mémoire. Des corrélations significatives ont été observées entre la vorticité estimée par vortographie Doppler et la méthode de référence (in silico: r2 = 0.98, in vitro: r2 = 0.86). Nos résultats suggèrent que la vortographie Doppler est une technique d’échographie cardiaque prometteuse pour quantifier les vortex intracardiaques. Cet outil d’évaluation pourrait être aisément appliqué en routine clinique pour détecter la présence d’une insuffisance ventriculaire et évaluer la fonction diastolique par échocardiographie Doppler.

Myocardial protection by continuous, blood, antegrade-retrograde cardioplegia in rabbits

OBJETIVO: Estudar a eficácia e a segurança da cardioplegia sanguínea, aterógrada-retrógrada contínua, por meio da avaliação da função ventricular. MÉTODOS: Os coelhos foram divididos em quatro grupos: Controle-C(n=10); isquêmico e cardioplegia cristaloide-IC(n=10; isquêmico e cardioplegia sanguínea-IB(n=10; isquêmico sem cardioplegia-INC(n=10. Após o período isquêmico do protocolo a função ventricular foi analisada pela técnica do balão intra-ventricular. RESULTADOS: a pressão desenvolvida intra-ventricular (IVDP) foi: C(92,90± 6,86mmHg); IC(77,78± 6,15mmHg); IB(93,64 ±5,09mmHg); INC(39,46 ±8,91mmHg) p<0,005. a primeira derivada temporal da pressão ventricular na sua deflexão positiva: C(1137,50± 92,23mmHg/sec); IC(1130,62 ±43,78mmHg/sec); IB(1187,58± 88,38mmHg/sec); INC(620,02± 43,80mmHg/se) p<0,005. A primeira derivada da pressão ventricular na sua deflexão negativa: C(770,00± 73,41mmHg/sec); IC(610,03 ±47,43mmg/sec); IB(762,53 ±46,02mmHg/sec); INC(412,35 ±84,36mmHg/sec) p<0,005. A relação do coeficiente angular logarítmico foi: C(0,108± 0,02); IC(0,159± 0,038); IB(0,114 ±0,016); INC(0,175± 0,038) p<0,05. CONCLUSÃO: No modelo experimental estudado o grupo isquêmico protegido pela cardioplegia sanguínea apresentou melhor função ventricular que os grupos protegidos por cardioplegia cristalóide e não protegido.

Avaliação hemodinâmica e morfológica da cetamina S(+) associada à cardioplegia sanguínea em coração isolado de coelho

Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)

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.

Behavioral Implications of Knockout for the Dyslexia-Risk Gene Dcdc2 in Mice

Several genetic linkage and epidemiological studies have provided strong evidence that DCDC2 is a candidate gene for developmental dyslexia, a disorder that impairs a person’s reading ability despite adequate intelligence, education, and socio-economic status. Studies investigating embryonic intra-ventricular RNA interference (RNAi) of Dcdc2, a rat homolog of the DCDC2 gene in humans, indicate disruptions in neuronal migration in the rat cortex during development. Interestingly, these anatomical anomalies are consistent with post mortem histological analysis of human dyslexic patients. Other rodent models of cortical developmental disruption have shown impairment in rapid auditory processing and learning maze tasks in affected subjects. The current study investigates the rapid auditory processing abilities of mice heterozygous for Dcdc2 (one functioning Dcdc2 allele) and mice with a homozygous knockout of Dcdc2 (no functioning Dcdc2 allele). It is important to note that this genetic model for behavioral assessment is still in the pilot stage. However, preliminary results suggest that mice with a genetic mutation of Dcdc2 have impaired rapid auditory processing, as well as non-spatial maze learning and memory ability, as compared to wildtypes. By genetically knocking out Dcdc2 in mice, behavioral features associated with Dcdc2 can be characterized, along with other neurological abnormalities that may arise due to the loss of the functioning gene.

Perinatal complications associated with preterm deliveries at 24 to 33 weeks and 6 days gestation (2011- 2012): A hospital-based retrospective study

Background: Morbidity and mortality of preterm babies are important issues in perinatal medicine. In developed countries, preterm delivery is the cause of about 70% of mortality and 75% of morbidity in the neonatal period, respectively. Objective: The aim of this study was to determine the risk factors for preterm labor and the outcomes, in terms of perinatal mortality and morbidity at the time of discharge home, among preterm infants at less than 34 weeks gestation. Materials and Methods: A retrospective study was conducted and all infants with a gestational age of 24 to 33 weeks and 6 days who were born from November 1st , 2011 to March 31, 2012 were enrolled in this study. Results: From 1185 preterm infants were born during this period, 475 (40.08%) infants with less than 34 weeks gestational age were included in the study. Our study showed the major obstetrical risk factors for preterm labor were as follows: preeclampsia (21%), premature rupture of membranes (20.3%), abruption of placenta (10%), and idiopathic cases (48.7%). The neonatal mortality rate in less than 34 weeks was 9.05%. Significant perinatal morbidity causesd in less than 34 weeks were as follows: sepsis (46.94%), respiratory distress syndrome (41.47%), patent ductus arteriosus (21.47%), retinopathy of prematurity (3.57%), necrotizing entrocolitis (1.68%), intra-ventricular hemorrhage (9%), and broncho-pulmonary dysplasia (0.84%). Conclusion: Preterm birth is associated with adverse perinatal outcome. This situation needs to be improved by directing appropriately increased resources for improving prenatal health services and providing advanced neonatal care.

A controller for a miniature intra-aortic ventricular assist device.

Two control algorithms have been developed for a minimally invasive axial-flow ventricular assist device (VAD) for placement in the descending aorta. The purpose of the device is to offload the left ventricle and to augment lower body perfusion in patients with moderate congestive heart failure. The VAD consists of an intra-aortic impeller with a built-in permanent magnet rotor and an extra-aortic stator. The control algorithms, which use pressure readings upstream and downstream of the VAD to determine the pump status, have been tested in a mock circulatory system under two conditions, namely with or without afterload sensitivity. The results give an insight into controller design for an intra-aortic blood pump working in series with the heart.