Suppression of canonical Wnt/beta-catenin signaling by nuclear plakoglobin recapitulates phenotype of arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is a genetic disease caused by mutations in desmosomal proteins. The phenotypic hallmark of ARVC is fibroadipocytic replacement of cardiac myocytes, which is a unique phenotype with a yet-to-be-defined molecular mechanism. We established atrial myocyte cell lines expressing siRNA against desmoplakin (DP), responsible for human ARVC. We show suppression of DP expression leads to nuclear localization of the desmosomal protein plakoglobin and a 2-fold reduction in canonical Wnt/beta-catenin signaling through Tcf/Lef1 transcription factors. The ensuing phenotype is increased expression of adipogenic and fibrogenic genes and accumulation of fat droplets. We further show that cardiac-restricted deletion of Dsp, encoding DP, impairs cardiac morphogenesis and leads to high embryonic lethality in the homozygous state. Heterozygous DP-deficient mice exhibited excess adipocytes and fibrosis in the myocardium, increased myocyte apoptosis, cardiac dysfunction, and ventricular arrhythmias, thus recapitulating the phenotype of human ARVC. We believe our results provide for a novel molecular mechanism for the pathogenesis of ARVC and establish cardiac-restricted DP-deficient mice as a model for human ARVC. These findings could provide for the opportunity to identify new diagnostic markers and therapeutic targets in patients with ARVC.

Preserved left ventricular twist and circumferential deformation, but depressed longitudinal and radial deformation in patients with diastolic heart failure.

AIMS: To examine myocardial deformation and rotation in patients with heart failure, and elucidate the underlying mechanisms that account for normal ejection fraction (EF) in patients with diastolic heart failure (DHF). METHODS AND RESULTS: Fifty consecutive patients presenting with congestive heart failure (age: 58 +/- 16 years) underwent simultaneous right heart catheterization and transthoracic echocardiography. Left ventricular (LV) volumes, mass, EF, meridional, and circumferential wall stress were measured in addition to haemodynamic measurements. 2-D speckle tracking was applied to measure longitudinal, radial, and circumferential strain and twist. Twist was reduced only in patients with systolic heart failure (SHF: 5 +/- 2 degrees, DHF: 13 +/- 6 degrees, control: 14 +/- 5 degrees, P < 0.001). Circumferential strain was not different between DHF (-15 +/- 5%) and control groups (-20 +/- 3%, P > 0.05), though it was significantly lower in patients with SHF (-7 +/- 3%, P < 0.05). Importantly, longitudinal (DHF:-12%, SHF: -4%, control: -19%, P < 0.001) and radial (DHF: 28 +/- 9%, SHF: 14 +/- 8%, control: 47 +/- 7%, P < 0.001) strains were significantly lower in both heart failure groups than in controls, and were depressed to a larger extent in SHF patients than in those with DHF (both P < 0.05). CONCLUSION: LV longitudinal and radial strains are reduced, but circumferential deformation and twist are normal in DHF patients. On the other hand, in patients with SHF, longitudinal, radial, and circumferential deformation, and twist are all reduced. Multivariable regression analysis suggests that preserved LV twist and circumferential strain may contribute to normal EF in patients with DHF.

Global diastolic strain rate for the assessment of left ventricular relaxation and filling pressures.

BACKGROUND: Diastolic strain rate (SR) measurements that comprise all left ventricular (LV) segments are advantageous over myocardial velocity for assessment of diastolic function. Mitral early diastolic velocity (E)/SR ratio during the isovolumetric relaxation (IVR) period can be used to estimate LV filling pressures. METHODS AND RESULTS: Simultaneous echocardiographic imaging and LV pressure measurements (7F catheters) were performed in 7 adult dogs. Loading conditions were altered by saline infusion and caval occlusion, and lusitropic state was changed by dobutamine and esmolol infusion. A curve depicting global SR was derived from each of the 3 apical views, and SR was measured during IVR (SR(IVR)) and early LV filling (SR(E)). SR(IVR) had a strong correlation with time constant of LV pressure decay during the IVR period (tau) (r=-0.83, P<0.001), whereas SR(E) was significantly related to LV end-diastolic pressure (r=0.52, P=0.005) in the experimental stages where tau was <40 ms. In 50 patients with simultaneous right heart catheterization and echocardiographic imaging, mitral E/SR(IVR) ratio had the best correlation with mean wedge pressure (r=0.79, P<0.001), as well as in 24 prospective patients (r=0.84, P=0.001). E/SR(IVR) was most useful in patients with ratio of E to mitral annulus early diastolic velocity (E/Ea ratio) 8 to 15 and was more accurate than E/Ea in patients with normal ejection fraction and regional dysfunction (both P<0.01). CONCLUSIONS: Global SR(IVR) by 2-dimensional speckle tracking is strongly dependent on LV relaxation. E/SR(IVR) can predict LV filling pressures with reasonable accuracy, particularly in patients with normal ejection fraction and in those with regional dysfunction.

Left ventricular untwisting rate by speckle tracking echocardiography.

BACKGROUND: Recent studies validated the measurement of left ventricular (LV) untwisting rate (UR) by speckle tracking echocardiography. A few reports suggest that it may provide additional noninvasive insight into LV diastolic function. METHODS AND RESULTS: Simultaneous echocardiographic imaging and LV pressure measurements (7F Millar catheters) were performed in 8 adult dogs. Loading conditions were altered by caval occlusion, whereas lusitropic state was changed by dobutamine and esmolol infusion. Inferior vena cava occlusion at all experimental stages (baseline, dobutamine, esmolol) led to a significant decrease (P < or = 0.01) in LV end-systolic volume (ESV) and a significant increase in UR (P = 0.03). The best relation was observed between LV UR and ESV (r = -0.8, P < 0.001). The clinical study was conducted in 67 patients (age 57+/-17 years, 19 women) undergoing simultaneous right heart catheterization and echocardiographic imaging, with 20 healthy subjects as a control group. There were 34 patients with ejection fraction (EF) <50% (25+/-9%), and 33 patients with normal EF and diastolic dysfunction (64+/-7%). Patients with LV systolic dysfunction had a significantly lower UR (-55 omicron/s) in comparison with the control group (-89 omicron/s) and patients with normal EF (-104 omicron/s, P < 0.05), and the determinants of LV UR were twist, ESV, and tau (r2 = 0.83, P < 0.001). In patients with diastolic dysfunction and normal EF, twist and ESV were the independent predictors (r2 = 0.71, P < 0.001). CONCLUSIONS: LV UR is reduced in patients with depressed EF, but not in those with diastolic dysfunction and normal EF, and is primarily determined by twist and ESV.

Transgenic mouse model of ventricular preexcitation and atrioventricular reentrant tachycardia induced by an AMP-activated protein kinase loss-of-function mutation responsible for Wolff-Parkinson-White syndrome.

BACKGROUND: We identified a gene (PRKAG2) that encodes the gamma-2 regulatory subunit of AMP-activated protein kinase (AMPK) with a mutation (Arg302Gln) responsible for familial Wolff-Parkinson-White (WPW) syndrome. The human phenotype consists of ventricular preexcitation, conduction abnormalities, and cardiac hypertrophy. METHODS AND RESULTS: To elucidate the molecular basis for the phenotype, transgenic mice were generated by cardiac-restricted expression of the wild-type (TG(WT)) and mutant(TG(R302Q)) PRKAG2 gene with the cardiac-specific promoter alpha-myosin heavy chain. ECG recordings and intracardiac electrophysiology studies demonstrated the TG(R302Q) mice to have ventricular preexcitation (PR interval 10+/-2 versus 33+/-5 ms in TG(WT), P<0.05) and a prolonged QRS (20+/-5 versus 10+/-1 ms in TG(WT), P<0.05). A distinct AV accessory pathway was confirmed by electrical and pharmacological stimulation and substantiated by induction of orthodromic AV reentrant tachycardia. Enzymatic activity of AMPK in the mutant heart was significantly reduced (0.009+/-0.003 versus 0.025+/-0.001 nmol x min(-1) x g(-1) in nontransgenic mice), presumably owing to the mutation disrupting the AMP binding site. Excessive cardiac glycogen was observed. Hypertrophy was confirmed by increases in heart weight (296 versus 140 mg in TG(WT)) and ventricular wall thickness. CONCLUSIONS: We have developed a genetic animal model of WPW that expresses a mutation responsible for a familial form of WPW syndrome with a phenotype identical to that of the human, including induction of supraventricular arrhythmia. The defect is due to loss of function of AMPK. Elucidation of the molecular basis should provide insight into development of the cardiac conduction system and accessory pathways.

Assessment of left ventricular diastolic function by early diastolic mitral annulus peak acceleration rate: experimental studies and clinical application.

We sought to examine the hemodynamic determinants and clinical application of the peak acceleration rate of early (Ea) diastolic velocity of the mitral annulus by tissue Doppler. Simultaneous left atrial and left ventricular (LV) catheterization and Doppler echocardiography were performed in 10 dogs. Preload was altered using volume infusion and caval occlusion, whereas myocardial lusitropic state was altered with dobutamine and esmolol. The clinical application was examined in 190 consecutive patients (55 control, 41 impaired relaxation, 46 pseudonormal, and 48 restrictive LV filling). In addition, in 60 consecutive patients, we examined the relation between it and mean wedge pressure with simultaneous Doppler echocardiography and right heart catheterization. In canine studies, a significant positive relation was present between peak acceleration rate of Ea and transmitral pressure gradient only in the stages with normal or enhanced LV relaxation, but with no relation in the stages where the time constant of LV relaxation (tau) was > or =50 ms. Its hemodynamic determinants were tau, LV minimal pressure, and transmitral pressure gradient. In clinical studies, peak acceleration rate of Ea was significantly lower in patients with impaired LV relaxation irrespective of filling pressures (P < 0.001) and with similar accuracy to peak Ea velocity (area under the curve for septal and lateral peak acceleration rates: both 0.78) in identifying these patients. No significant relation was observed between peak acceleration rate and mean wedge pressure. Peak acceleration rate of Ea appears to be a useful index of LV relaxation but not of filling pressures and can be applied to identify patients with impaired LV relaxation irrespective of their filling pressures.

Time interval between onset of mitral inflow and onset of early diastolic velocity by tissue Doppler: a novel index of left ventricular relaxation: experimental studies and clinical application.

OBJECTIVES: The goal of this study was to examine the diagnostic utility of the time to onset of early (Ea) diastolic velocity of the mitral annulus by tissue Doppler (TD) in comparison with the time to onset of mitral inflow (T(Ea-E)) for the assessment of left ventricular (LV) relaxation. BACKGROUND: Tissue Doppler imaging of the mitral annulus provides useful information about myocardial function. So far, studies have focused on the measurement of peak Ea, but have not evaluated the diagnostic utility of the time to onset of Ea. METHODS: Simultaneous left heart catheterization and Doppler echocardiography (DE) were performed in 10 dogs. Left atrial pressures and LV volumes and pressures were measured before and after constriction of the circumflex (cx) coronary artery. The delay in Ea was next examined in 60 consecutive patients, undergoing simultaneous right heart catheterization and DE. Furthermore, (T(Ea-E)) was used to predict filling pressures in a prospective group of 33 patients. RESULTS: In canine studies, significant prolongation in the time interval (T(Ea-E)) was noted after cx constriction, which had a significant relation with tau (tau) (r = 0.93, p < 0.01). In human studies, Ea was significantly delayed in patients with impaired relaxation and pseudonormal LV filling in comparison with age-matched controls. In the prospective group, pulmonary capillary wedge pressure (PCWP) derived as: PCWP(Doppler) = LV(end-systolic pressure) x e(-IVRT/(T(Ea-E))), where IVRT is isovolumetric relaxation time; PCWP(Doppler) related well to PCWP(catheter) (r = 0.84, p < 0.001). CONCLUSIONS: T(Ea-E) is a useful novel index of LV relaxation. It can be used to identify patients with diastolic dysfunction and predict PCWP.

Disruption of Rho signaling results in progressive atrioventricular conduction defects while ventricular function remains preserved.

Recent studies suggest that RhoA and Rac1 mediate hypertrophic signals in cardiac myocyte hypertrophy. However, effects on cardiac function caused by inhibition of their activity in the heart have yet to be evaluated. Cardiac-specific inhibition of Rho family protein activities was achieved by expressing Rho GDIalpha, an endogenous specific GDP dissociation inhibitor for Rho family proteins, using the alpha-myosin heavy-chain promoter. Increased expression of Rho GDIalpha led to atrial arrhythmias and mild ventricular hypertrophy in adult mice (4-7 months). However, left ventricular systolic and diastolic function was largely preserved before and after the development of cardiac hypertrophy, indicating that Rho GTPases are not required to maintain ventricular contractile function under basal physiological condition. Electrocardiography and intracardiac electrophysiological studies revealed first-degree atrioventricular (AV) block in the transgenic heart at 1 week of age, which further progressed into second-degree AV block at 4 weeks of age before the development of cardiac hypertrophy. Expression of connexin 40 dramatically decreased from 1 week to 4 weeks of age in the transgenic heart, which may contribute in part to the conduction defects in the transgenic mice. This study provides novel evidence for an important role of Rho GTPases in regulating AV conduction.

Dynamic three-dimensional visualization of the left ventricle by intracardiac echocardiography.

Cardiac function and hemodynamics are routinely evaluated during catheterization in patients with heart disease. Although intracardiac echocardiography (ICE) has been employed in guiding electrophysiology procedures, it has not been effectively used in assessing hemodynamics. We tested the utility of ICE in measuring left ventricular (LV) volume throughout the cardiac cycle. In four normal dogs (weight = 26 to 37 kg), a 10-F sheath was inserted through the femoral artery and placed inside the LV along its major axis. An ICE catheter (9 F, 9 MHz) was then inserted through the sheath into the LV. The ICE catheter was pulled back inside the sheath in 1-mm intervals starting from the apex, and 2-D tomographic images were continuously acquired while gating to respiration. Subsequently, the ICE catheter was replaced by a conductance catheter to measure single-beat volume signals. Stroke volume was determined by thermodilution for validation. All measurements were made in each dog while pacing the atrium at two different cycle lengths (range = 300 to 500 ms). The endocardial boundary was digitized from the ICE images throughout the cardiac cycle and LV volume was computed by integrating multiple segments along the major axis (range = 55 to 70 mm). We found that ICE accurately reconstructed LV 3-D anatomy. Stroke volume by ICE was in excellent agreement with thermodilution (error = 3.8 +/- 3.0%, r = 0.99, n = 8) and was highly reproducible. Morphology of LV volume signals correlated well with corresponding instantaneous volume signals derived by conductance (r = 0.93, n = 8). In conclusion, ICE accurately reconstructs LV anatomy and volume throughout the cardiac cycle in the normal heart. This approach could facilitate interventional diagnostic and therapeutic procedures.

Solving the inverse problem of electrocardiography using a Duncan and Horn formulation of the Kalman filter.

Numeric regularization methods most often used to solve the ill-posed inverse problem of electrocardiography are spatial and ignore the temporal nature of the problem. In this paper, a Kalman filter reformulation incorporated temporal information to regularize the inverse problem, and was applied to reconstruct left ventricular endocardial electrograms based on cavitary electrograms measured by a noncontact, multielectrode probe. These results were validated against in situ electrograms measured with an integrated, multielectrode basket-catheter. A three-dimensional, probe-endocardium model was determined from multiplane fluoroscopic images. The boundary element method was applied to solve the boundary value problem and determine a linear relationship between endocardial and probe potentials. The Duncan and Horn formulation of the Kalman filter was employed and was compared to the commonly used zero- and first-order Tikhonov spatial regularization as well as the Twomey temporal regularization method. Endocardial electrograms were reconstructed during both sinus and paced rhythms. The Paige and Saunders solution of the Duncan and Horn formulation reconstructed endocardial electrograms at an amplitude relative error of 13% (potential amplitude) which was superior to solutions obtained with zero-order Tikhonov (relative error, 31%), first-order Tikhonov (relative error, 19%), and Twomey regularization (relative error, 44%). Likewise, activation time error in the inverse solution using the Duncan and Horn formulation (2.9 ms) was smaller than that of zero-order Tikhonov (4.8 ms), first-order Tikhonov (5.4 ms), and Twomey regularization (5.8 ms). Therefore, temporal regularization based on the Duncan and Horn formulation of the Kalman filter improves the solution of the inverse problem of electrocardiography.

Determinants of cardiac electrophysiological properties in mice.

INTRODUCTION: The transgenic mouse is a popular model for human inherited cardiac disease. Electrophysiology (EP) studies have recently been performed in transgenic mice to characterize the electrical phenotype of the heart. However, little is known regarding the impact of experimental conditions or model selection on the outcome of EP studies in mice. METHODS AND RESULTS: We investigated the effects of experimental conditions on mouse cardiac EP by (1) comparing the findings of transesophageal pacing with those of invasive intracardiac pacing, (2) elucidating the effects of commonly used anesthetic agents, and (3) determining the impact of changes in body temperature. We also investigated the effects of model selection by (1) studying the dependence on mouse strain, and (2) exploring the effects of age. We found that EP parameters derived by both transesophageal and intracardiac pacing/recordings methods were similar. On the other hand, the anesthetic mixture of ketamine, xylazine, and acepromazine had profound effects on cardiac EP compared to sodium pentobarbital or isoflurane. Meanwhile, compared to normal body temperature (97-99 F), low body temperature (92-94 F) prolonged most cardiac EP parameters, while high body temperature (102-104 F) had little effect. Heart rate was a sensitive indicator of changes in body temperature. Significant differences were observed in specialized conduction system properties among the mouse strains studied (FVB, C57, and DBA). Furthermore, atrial electrical remodeling was evidently associated with age, while ventricular electrical properties were virtually unaltered. In comparison with corresponding invasive EP parameters, we found that the QT interval was not a reliable EP index in the mouse. CONCLUSIONS: Cardiac EP variability may result from differences in experimental techniques including anesthesia and body temperature and from differences in mouse selection including strain and age. The influence of these factors should be considered when characterizing the electrical phenotype of transgenic mice in cardiovascular research.

Speckle tracking in intracardiac echocardiography for the assessment of myocardial deformation.

Intracardiac echocardiography (ICE) has proven to be useful for online anatomical imaging during catheterization. Our objective was to develop a speckle tracking method for myocardial motion estimation from ICE image sequences in order to provide a mean for regional functional imaging. Our approach was to solve two problems in motion estimation from 2-D ICE image sequences: nonrigid myocardial deformation and speckle decorrelation. To achieve robust noise resistance, we employed maximum likelihood estimation while fully exploiting ultrasound speckle statistics, and treated the maximization of motion probability as the minimization of an energy function. Nonrigid myocardial deformation was estimated by optimizing this energy function within a framework of parametric elastic registration. Evaluation of the method was carried out using a computer model that synthesized echocardiographic image sequences, and subsequently an animal model that provided continuous ICE images as well as reference measurements using sonomicrometry crystals. In conclusion, accurate estimation of regional myocardial deformation from ICE by novel speckle tracking is feasible. This approach may have important clinical implications for multimodal imaging during catheterization.

Left ventricular twist mechanics in a canine model of reversible congestive heart failure: a pilot study.

BACKGROUND: Left ventricular (LV) twist dynamics play an important role in LV systolic and diastolic function. The aim of this preliminary study was to investigate LV twist dynamics in a canine model of reversible congestive heart failure (CHF). METHODS: Pacing systems were implanted in adult dogs, and continuous chronic right ventricular pacing (230-250 beats/min) was applied until CHF induction. Pacing was then stopped to allow the heart to recover. Echocardiography and LV catheterization were performed at baseline, during CHF while pacing was temporarily switched off, and during recovery. LV twist was computed as the difference between apical and basal rotation measured using 2-dimensional speckle tracking. Torsion was further calculated as LV twist divided by the LV long axis. The untwisting rate was computed as the peak diastolic time derivative of twist. RESULTS: In 6 dogs that completed the study, we found that CHF developed after 2 to 4 weeks of pacing, with LV end-diastolic volume, end-systolic volume, end-diastolic pressure, and the time constant of relaxation during isovolumic relaxation period (tau) all increasing significantly compared with baseline and recovering to normal levels 2 to 4 weeks after pacing was stopped. LV twist, torsion, and untwisting rate decreased significantly with CHF compared with baseline and improved during recovery from CHF. CONCLUSION: LV twist dynamics reflect pacing-induced CHF and its reversal as assessed by echocardiographic speckle tracking.

Assessment of left ventricular relaxation by untwisting rate based on different algorithms.

BACKGROUND: This study was performed in both animals and human subjects to test whether different approaches to calculate untwisting rate may lead to different results in the assessment of left ventricular (LV) relaxation. METHODS: In animal experiments, congestive heart failure was successfully induced in 8 adult dogs. Transthoracic echocardiography was performed with simultaneous LV pressure recording at baseline and the stage of heart failure. In the clinical study, 72 patients undergoing right-sided heart catheterization were studied by transthoracic echocardiography. LV twist was calculated as the difference between apical and basal rotations measured using two-dimensional speckle tracking. Untwisting rate was calculated using 3 different algorithms as the peak negative time derivative of twist (UR(max)) during early diastole, the slope of the linear regression of untwisting over time (UR(slope)), or the average untwisting over the isovolumic relaxation period (UR(mean)). RESULTS: UR(max) significantly correlated with tau and -dP/dt in dogs (r=-0.81 and 0.77, respectively, both P < .001) and was reduced at the stage of heart failure (P < .01). In 55 patients (76%) with adequate image quality, only UR(max) among untwisting rates calculated by 3 different algorithms was significantly related to tau (r=-0.51, P < .001). UR(max) was significantly lower in patients with tau>/=48 ms than in patients with tau<48 ms (P=.004), most of whom had a depressed LV ejection fraction. CONCLUSION: UR(max) best reflects LV relaxation in comparison with the 2 other algorithms.

Ethanol infusion in the vein of Marshall: Adjunctive effects during ablation of atrial fibrillation.

BACKGROUND: The vein of Marshall (VOM) is a left atrial (LA) vein that contains autonomic innervation and triggers of AF. Its location coincides with areas usually ablated during pulmonary vein (PV) antral isolation (PVAI). OBJECTIVE: This study sought to delineate the safety and ablative effects of ethanol infusion in the VOM during catheter ablation of atrial fibrillation (AF). METHODS: Patients undergoing PVAI (n = 14) gave consent for adjunctive VOM ethanol infusion. In 10 of 14 patients, the VOM was cannulated with an angioplasty wire and balloon. Echocardiographic contrast was injected in the VOM under echocardiographic monitoring. Two infusions of 100% ethanol (1 ml each) were delivered via the angioplasty balloon in the VOM. LA bipolar voltage maps were created before and after ethanol infusion. Radiofrequency ablation times required to isolate each PV and other procedural data were compared with those of 10 age-, sex-, AF type- and LA size-matched control subjects undergoing conventional PVAI. RESULTS: The VOM communicated with underlying myocardium, as shown by echocardiographic contrast passage into the LA. There were no acute complications related to VOM ethanol infusion, which led to the creation of a low-voltage area in the LA measuring 10.6 +/- 7.6 cm(2) and isolation of the left inferior PV in 4 of 10 patients. Radiofrequency ablation time required to achieve isolation of the left inferior PV was reduced (2.2 +/- 4 min vs. 11.4 +/- 10.3 min in control subjects, P <.05). CONCLUSION: VOM ethanol infusion is safe in humans, decreases radiofrequency ablation time in the left inferior PV, and may have a role as an adjunct to PVAI.

Retrograde ethanol infusion in the vein of Marshall: regional left atrial ablation, vagal denervation and feasibility in humans.

BACKGROUND: The vein of Marshall (VOM) is an attractive target during ablation of atrial fibrillation due to its autonomic innervation, its location anterior to the left pulmonary veins and drainage in the coronary sinus. METHODS AND RESULTS: We studied 17 dogs. A coronary sinus venogram showed a VOM in 13, which was successfully cannulated with an angioplasty wire and balloon. In 5 dogs, electroanatomical maps of the left atrium were performed at baseline and after ethanol infusion in the VOM, which demonstrated a new crescent-shaped scar, extending from the annular left atrium towards the posterior wall and left pulmonary veins. In 4 other dogs, effective refractory periods (ERP) were measured at 3 sites in the left atrium, before and after high-frequency bilateral vagal stimulation. The ERP decreased from 113.6+/-35.0 ms to 82.2+/-25.4 ms (p<0.05) after vagal stimulation. After VOM ethanol infusion, vagally-mediated ERP decrease was eliminated (from 108.6+/-24.1 ms to 96.4 +/-16.9ms, p=NS). The abolition of vagal effects was limited to sites near the VOM (ERP: 104+/-14 ms, vs 98.6+/-12.2 ms post vagal stimulation, p=ns), as opposed to sites remote to VOM (ERP: 107.2+/-14.9 ms, vs 78.6+/-14.7ms post vagal stimulation, p<0.05). To test feasibility in humans, 5 patients undergoing pulmonary vein antral isolation had successful VOM cannulation and ethanol infusion: left atrial voltage maps demonstrated new scar involving the infero-posterior left atrial wall extending towards the left pulmonary veins. CONCLUSIONS: Ethanol infusion in then VOM achieves significant left atrial tissue ablation, abolishes local vagal responses and is feasible in humans.

Ambulatory monitoring of congestive heart failure by multiple bioelectric impedance vectors.

OBJECTIVES: This study was designed to investigate the properties of multiple bioelectric impedance signals recorded during congestive heart failure (CHF) by utilizing various electrode configurations of an implanted cardiac resynchronization therapy system. BACKGROUND: The monitoring of CHF has relied mainly on right-side heart sensors. METHODS: Fifteen normal dogs underwent implantation of cardiac resynchronization therapy systems using standard leads. An additional left atrial (LA) pressure lead sensor was implanted in 5 dogs. Continuous rapid right ventricular (RV) pacing was applied over several weeks. Left ventricular (LV) catheterization and echocardiography were performed biweekly. Six steady-state impedance signals, utilizing intrathoracic and intracardiac vectors, were measured through ring (r), coil (c), and device Can electrodes. RESULTS: Congestive heart failure developed in all animals after 2 to 4 weeks of pacing. Impedance diminished gradually during CHF induction, but at varying rates for different vectors. Impedance during CHF decreased significantly in all measured vectors: LV(r)-Can, -17%; LV(r)-RV(r), -15%; LV(r)-RA(r), -11%; RV(r)-Can, -12%; RV(c)-Can, -7%; and RA(r)-Can, -5%. The LV(r)-Can vector reflected both the fastest and largest change in impedance in comparison with vectors employing only right-side heart electrodes, and was highly reflective of changes in LV end-diastolic volume and LA pressure. CONCLUSIONS: Impedance, acquired by different lead electrodes, has variable responses to CHF. Impedance vectors employing an LV lead are highly responsive to physiologic changes during CHF. Measuring multiple impedance signals could be useful for optimizing ambulatory monitoring in heart failure patients.

Model study of imaging myocardial infarction by intracardiac electrical impedance tomography.

Electrical impedance tomography (EIT) detects tissue composition inside a medium by determining its resistive properties, and uses various electrode configurations to pass a small electric current and measure corresponding potential. We investigated the feasibility of reconstructing scarred tissue inside the heart wall by employing EIT on the basis of a catheter carrying a plurality of electrodes and placed inside the blood-filled heart cavity. We built a computer model of the biological medium, and reconstructed the resistivity distribution using the finite element method and Tikhonov regularization. The results established the successful implementation of the numeric methods and the possibility of localizing and quantifying scarred myocardium. Novel application of EIT from inside the heart cavity could be useful during catheterization and may complement other diagnostic modalities. Further research is necessary to assess the impact of several factors on the accuracy of the reconstruction and include number of electrodes, catheter location, and scar size.

A novel feature-tracking echocardiographic method for the quantitation of regional myocardial function: validation in an animal model of ischemia-reperfusion.

OBJECTIVES: The aim of this study was to validate a novel, angle-independent, feature-tracking method for the echocardiographic quantitation of regional function. BACKGROUND: A new echocardiographic method, Velocity Vector Imaging (VVI) (syngo Velocity Vector Imaging technology, Siemens Medical Solutions, Ultrasound Division, Mountain View, California), has been introduced, based on feature tracking-incorporating speckle and endocardial border tracking, that allows the quantitation of endocardial strain, strain rate (SR), and velocity. METHODS: Seven dogs were studied during baseline, and various interventions causing alterations in regional function: dobutamine, 5-min coronary occlusion with reperfusion up to 1 h, followed by dobutamine and esmolol infusions. Echocardiographic images were acquired from short- and long-axis views of the left ventricle. Segment-length sonomicrometry crystals were used as the reference method. RESULTS: Changes in systolic strain in ischemic segments were tracked well with VVI during the different states of regional function. There was a good correlation between circumferential and longitudinal systolic strain by VVI and sonomicrometry (r = 0.88 and r = 0.83, respectively, p < 0.001). Strain measurements in the nonischemic basal segments also demonstrated a significant correlation between the 2 methods (r = 0.65, p < 0.001). Similarly, a significant relation was observed for circumferential and longitudinal SR between the 2 methods (r = 0.94, p < 0.001 and r = 0.90, p < 0.001, respectively). The endocardial velocity relation to changes in strain by sonomicrometry was weaker owing to significant cardiac translation. CONCLUSIONS: Velocity Vector Imaging, a new feature-tracking method, can accurately assess regional myocardial function at the endocardial level and is a promising clinical tool for the simultaneous quantification of regional and global myocardial function.

Integrated multimodal-catheter imaging unveils principal relationships among ventricular electrical activity, anatomy, and function.

Multiple imaging modalities are employed independent of one another while managing complex cardiac arrhythmias. To combine electrical, anatomical, and functional imaging in a single catheter system, we developed a balloon catheter that carried 64 electrodes on its surface and an intracardiac echocardiography (ICE) catheter through a central lumen. The catheter system was inserted, and the balloon was inflated inside the left ventricle (LV) of eight dogs with 6-wk-old infarction, created by occlusion in the left anterior descending coronary artery. Anatomy was constructed by ICE imaging (9 MHz) through the balloon. Single-beat noncontact mapping (NCM) was performed via the multielectrode array to reconstruct unipolar endocardial electrograms during sinus rhythm. Standard contact mapping (CM) of the endocardium was also carried out for reference. Myocardial infarction in anterior LV extending from the middle to apical regions was localized both by ICE and NCM and validated by CM and pathology. The overall difference in the activation times between NCM and CM was 3 +/- 1 ms. Unipolar voltage in infarcted middle anterior LV was smaller than the voltage in normal middle inferior LV both by NCM (11 +/- 4 vs. 16 +/- 3 mV; P = 0.002) and CM (11 +/- 3 vs. 20 +/- 4 mV; P < 0.001). Unipolar voltage was also inversely related to infarct transmurality, both by NCM (r = -0.87; P = 0.005) and CM (r = -0.94; P < 0.001). The infarct area by ICE (7.7 +/- 2.9 cm(2)) was in agreement with CM (bipolar voltage, <1 mV; and area, 7.6 +/- 3.3 cm(2); r = 0.80; P = 0.016). Meanwhile, the voltage threshold that depicted the infarct area by NCM was directly related to the smallest unipolar voltage reconstructed within the infarct (r = 0.96; P < 0.001). In conclusion, combining NCM and ICE imaging in a single catheter system is feasible. The preclinical development of such an integrated system and its evaluation in experimental myocardial infarction demonstrate capabilities for single-beat mapping at multiple sites as well as the online assessment of anatomy and myocardial function.