Edward J. Ciaccio

High-Density Substrate Mapping in Brugada Syndrome. Combined Role of Conduction and Repolarization Heterogeneities in Arrhythmogenesis

Background— Two principal mechanisms are thought to be responsible for Brugada syndrome (BS): (1) right ventricular (RV) conduction delay and (2) RV subepicardial action potential shortening. This in vivo high-density mapping study evaluated the conduction and repolarization properties of the RV in BS subjects. Methods and Results— A noncontact mapping array was positioned in the RV of 18 BS patients and 20 controls. Using a standard S1-S2 protocol, restitution curves of local activation time and activation recovery interval were constructed to determine local maximal restitution slopes. Significant regional conduction delays in the anterolateral free wall of the RV outflow tract of BS patients were identified. The mean increase in delay was 3-fold greater in this region than in control (P=0<0.001). Local activation gradient was also maximally reduced in this area: 0.33±0.1 (mean±SD) mm/ms in BS patients versus 0.51±0.15 mm/ms in controls (P<0.0005). The uniformity of wavefront propagation as measured by the square of the correlation coefficient, r2, was greater in BS patients versus controls (0.94±0.04 versus 0.89±0.09 [mean±SD]; P<0.05). The odds ratio of BS hearts having any RV segment with maximal restitution slope >1 was 3.86 versus controls. Five episodes of provoked ventricular tachycardia arose from wave breaks originating from RV outflow tract slow-conduction zones in 5 BS patients. Conclusions— Marked regional endocardial conduction delay and heterogeneities in repolarization exist in BS. Wave break in areas of maximal conduction delay appears to be critical in the initiation and maintenance of ventricular tachycardia. These data indicate that further studies of mapping BS to identify slow-conduction zones should be considered to determine their role in spontaneous ventricular arrhythmias.

Electrophysiological abnormalities precede overt structural changes in arrhythmogenic right ventricular cardiomyopathy due to mutations in desmoplakin-A combined murine and human study

Aims Anecdotal observations suggest that sub-clinical electrophysiological manifestations of arrhythmogenic right ventricular cardiomyopathy (ARVC) develop before detectable structural changes ensue on cardiac imaging. To test this hypothesis, we investigated a murine model with conditional cardiac genetic deletion of one desmoplakin allele (DSP ±) and compared the findings to patients with non-diagnostic features of ARVC who carried mutations in desmoplakin. Methods and results Murine: the DSP (±) mice underwent electrophysiological, echocardiographic, and immunohistochemical studies. They had normal echocardiograms but delayed conduction and inducible ventricular tachycardia associated with mislocalization and reduced intercalated disc expression of Cx43. Sodium current density and myocardial histology were normal at 2 months of age. Human: ten patients with heterozygous mutations in DSP without overt structural heart disease (DSP+) and 12 controls with supraventricular tachycardia were studied by high-density electrophysiological mapping of the right ventricle. Using a standard S1–S2 protocol, restitution curves of local conduction and repolarization parameters were constructed. Significantly greater mean increases in delay were identified particularly in the outflow tract vs. controls (P< 0.01) coupled with more uniform wavefront progression. The odds of a segment with a maximal activation–repolarization interval restitution slope >1 was 99% higher (95% CI: 13%; 351%, P= 0.017) in DSP+ vs. controls. Immunostaining revealed Cx43 mislocalization and variable Na channel distribution. Conclusion Desmoplakin disease causes connexin mislocalization in the mouse and man preceding any overt histological abnormalities resulting in significant alterations in conduction–repolarization kinetics prior to morphological changes detectable on conventional cardiac imaging. Haploinsufficiency of desmoplakin is sufficient to cause significant Cx43 mislocalization. Changes in sodium current density and histological abnormalities may contribute to a worsening phenotype or disease but are not necessary to generate an arrhythmogenic substrate. This has important implications for the earlier diagnosis of ARVC and risk stratification.

Living with coeliac disease: survey results from the USA

BACKGROUND The only treatment for coeliac disease is lifelong adherence to a rigorous gluten-free diet. The present study aimed to evaluate the influence of coeliac disease on the social aspects of daily life of individuals in the U.S.A. METHODS The present study used a self-administered survey including the standard Quality of Life questionnaire (12-item short-form) with validated disease-specific questions. sas statistical software 2010 (SAS Institute, Cary, NC, U.S.A.) was used to calculate the mean (SD). RESULTS Individuals with coeliac disease overall had a low positive health perception. Validated diet and disease-specific questions revealed a significant negative impact on quality of life in social settings. Specifically, the areas of travel, dining out and family life are most affected. The negative impact of diet significantly decreased over time, although it did not resolve for the domains of dining out of the home and travel. Those diagnosed in childhood and maintained on the diet had less of an impact on the quality of life as an adult. CONCLUSIONS Individuals with coeliac disease in the U.S.A. have a diminished quality of life, especially in the social aspects of life.

Serum cytokine elevations in celiac disease: Association with disease presentation

Celiac disease (CD) is an autoimmune disorder that is triggered by an immune response to gluten in genetically predisposed individuals. Although considered a primary gastrointestinal disease, CD is now known to have widespread systemic manifestations. We attempted to define the nature and role of systemic cytokine levels in the pathophysiology of CD. Multiplex cytokine assays were performed on four different groups of adult patients; patients with active CD (ACD), patients on a gluten-free diet (GFD) with positive TTG IgA antibodies, patients on a GFD with negative antibodies, and those with refractory CD (RCD). The results were compared with values in healthy adult controls. Patients with active CD and those on GFD with positive antibodies had significantly higher levels of proinflammatory cytokines, such as interferon-gamma, interleukin (IL)-1beta, tumor necrosis factor-alpha, IL-6 and IL-8, and also T(h)-2 cytokines such as IL-4 and IL-10, compared with normal controls and patients on GFD without antibodies. Interestingly patients on GFD for less than 1 year had significantly higher levels of both proinflammatory cytokines and T(h)2 cytokines compared with the patients on GFD for more than 1 year. In addition, a statistically significant correlation between levels of TTG IgA titers and serum levels of T(h)-2 cytokines IL-4 (p < 0.001), IL-10 (p < 0.001) and inflammatory cytokines such as IL-1alpha (p < 0.001), IL-1beta (p < 0.005), and IL-8 (p < 0.05) was observed.

Distinguishing patients with celiac disease by quantitative analysis of videocapsule endoscopy images

BACKGROUND Although videocapsule endoscopy images are helpful in the evaluation of celiac disease, their interpretation is subjective. Quantitative disease markers could assist in determining the extent of villous atrophy and response to treatment. METHOD Capsule endoscopy images were acquired from celiac patients with small bowel pathology (N=11) and from control patients (N=10). Image resolution was 576x576 pixels in dimension, 256 grayscale levels, and had a 2 s(-1) frame rate. Pixel brightness and image texture were measured over 10x10 pixel subimages and then averaged for 56x56 subimages per frame. Measurements were obtained at five locations from proximal to distal small intestine in each patient. At each location, measurements were calculated using 200 consecutive image frames (100s). Mean frame-to-frame pixel brightness, image texture, and periodicity in brightness, an estimate of wall motion or intestinal motility, were computed and used for classification with a nonlinear discriminant function. RESULTS From pooled data, celiac images had greater texture than did images from control patients (p<0.001) and exhibited more frame-to-frame brightness variation as well (p=0.032). The dominant period of brightness was longer in celiacs (p=0.001), possibly indicating decreased motility. Using the markers for three-dimensional nonlinear classification of celiacs versus controls, sensitivity was 92.7% and specificity was 93.5%. The relationship between dominant period and small intestinal transit time was approximately linear for both celiacs and controls (r(2)=0.42 and r(2)=0.55, respectively). CONCLUSIONS Videocapsule images can be quantified to detect villous atrophy throughout the small intestine, and to distinguish individuals with celiac disease from individuals lacking mucosal atrophy.

Comparison of commercially available serologic kits for the detection of celiac disease.

Background The sensitivity and specificity of current antihuman tissue transglutaminase (tTG) IgA assays used to detect celiac disease reportedly approach 100%. In addition, the sensitivity of new generation deamidated gliadin peptide (α-DGP) antibody assays has also been reported to be similar to the tTG IgA assays. In routine clinical practice, however, the sensitivities and specificities of these tests for diagnosing celiac disease seem to be lower. Aim We analyzed sensitivities and specificities of 4 IgA tTG and 3 deamidated gliadin peptide (α-DGP) kits. Methods The performance of 4 tTG IgA assays, A: Inova (Hu red blood cell), B: Binding site (rHu Ag), C: Eurospital (rHu Ag), D: Immco (rHu Ag) and 3 Inova α-DGP assays, E: α-DGP-IgA, F: α-DGP-IgG, and G: α-DGP-IgA+G was evaluated using sera from different subsets of celiac disease patients and controls; group 1: active celiac disease n=28, group 2: gluten-free diet n=54, group 3: healthy controls n=40, group 4: disease controls n=57(Crohns disease n=17, chronic hepatitis n=40). Results Using the manufacturers cut-off values, the sensitivities and specificities of different kits ranged from 71.4% to 96.4% and 87.5% to 100%, respectively. When group 1 was compared with disease controls, sensitivities remained the same but specificities decreased. Receiver operating characteristic plot derived cut-off values modified decision thresholds in all assays except kit (G). Kappa analysis demonstrated variable degrees of agreement. All assays demonstrated higher sensitivities for patients with higher grades of villous atrophy. Conclusions Overall sensitivity was at or below 90%, which is lower than that reported in the literature. Performance of the recombinant and red blood cell antigen-based tTG assays was similar, whereas the α-DGP assays demonstrated lower values. Receiver operating characteristic plot derived cut-off values altered test results. Many factors affect the results of these tests and clinicians should be aware of their limitations.

Mechanisms Causing Sustained Ventricular Tachycardia With Multiple QRS Morphologies Results of Mapping Studies in the Infarcted Canine Heart

BACKGROUND Sustained reentrant ventricular tachycardias (VTs) with different QRS morphologies have been observed to occur spontaneously and during programmed stimulation in human hearts. We determined mechanisms that can cause tachycardias with multiple morphologies in a canine model of myocardial infarction by mapping reentrant circuits. METHODS AND RESULTS Reentrant VT with multiple QRS morphologies was induced in 11 canine hearts with 4-day-old infarcts. Comparison of activation maps of the reentrant circuits in the epicardial border zone associated with each morphology indicated two basic mechanisms. Less frequently, VTs of different morphologies in the same heart were caused by reentrant circuits in different regions of the infarct. Most commonly, the reentrant circuits associated with different morphologies were in the same region. Three different factors caused different exit routes from circuits in the same region, leading to the multiple morphologies. (1) The reentrant wave front for each morphology rotated around the same line of block but in different directions. (2) Reentrant circuits associated with each morphology were similar, but there were small changes in the extent of the central line of block. (3) Reentrant circuits with completely different sizes and shapes caused different morphologies. CONCLUSIONS In this canine model, tachycardias with multiple morphologies most commonly arise from reentrant circuits in the same region of the infarct, suggesting that most often only one area has electrophysiological properties necessary to sustain reentry.

New methods for estimating local electrical activation rate during atrial fibrillation

BACKGROUND Dominant frequency (DF) analysis is sometimes limited in its characterization of atrial fibrillation (AF), thus better methodology is needed. OBJECTIVE To develop methods for analyzing the AF signal without transformation to frequency space, and to compare the methods to DF analysis using both real and simulated data. METHOD Electrograms were obtained in 11 patients with paroxysmal or persistent AF. Atrial rate (AR) was estimated retrospectively from 8.4-s intervals acquired at 8 sites, using DF and 2 new methods: (1) Signals were converted into merged deflections (time complexes [TC]). Mean peak-to-peak cycle length was used to estimate AR. (2) The ensemble average (EA) was calculated with window size (w) ranging from 50 to 500 ms (frequency f = 2 to 20 Hz). The dominant peak in the root-mean-square power spectrum of EA versus w was used to estimate AR. Methods were compared using patient data, and in simulations using a Hanning pulse (2-mV peak, 50-ms duration, 120-ms period) with additive random noise, amplitude changes, and phase shift. Data from 10 atrial flutter patients were used to validate rate estimation under static conditions. RESULTS From pooled AF data (N = 88 sites), mean atrial rate was 5.71 Hz (EA), 5.96 Hz (TC), and 5.72 Hz (DF). The mean absolute rate difference was 0.65 Hz (EA-TC), 0.58 Hz (EA-DF), and 0.50 Hz (TC-DF). In simulations, DF, TC, and EA, respectively, correctly predicted rate with additive random noise up to 0.13 mV, 1.4 mV, and 15.2 mV, random phase shift up to 46.3 ms, 28.8 ms, and 51.3 ms, and random amplitude variation ranging from 0 to 4 mV, 1.3 to 2.7 mV, and 0 to 4 mV. All methods accurately estimated rate during atrial flutter. CONCLUSIONS Accurate rate estimation depends on signal periodicity and is influenced by random noise. The EA provides an accurate rate estimate of the periodic component of AF even at high noise levels.

Localization of the Slow Conduction Zone During Reentrant Ventricular Tachycardia

BACKGROUND Reentrant ventricular tachycardia is sometimes difficult to treat effectively because localizing the slow conduction zone (SCZ) for catheter ablation may be problematic. It was hypothesized that a linear relationship exists between activating wave-front acceleration and deceleration in the SCZ and, respectively, contractions and expansions of the far-field extracellular signal, which could be used for SCZ localization. METHODS AND RESULTS To test the hypothesis, a model was developed to approximate SCZ location on the basis of the time interval between activation at the recording site and shifts in electrogram far-field deflections. Electrograms were recorded during reentry from 196 to 312 epicardial sites (canine model, 8 episodes). Activation maps of reentry were constructed to determine wave-front velocity, and piecewise linear adaptive template matching (PLATM) measured time shifts in far-field electrogram deflections. Linear trends of cycle length change often occurred during tachycardia (mean trend, +15 ms/96.8 cardiac cycles; r(2)=0.92). Alteration in the time interval for activation through the SCZ approximated the change in tachycardia cycle length (mean correspondence, 75.7%). The beginning and end times of far-field extracellular waveform time shifts measured by PLATM predicted the time from recording site activation to activation at the SCZ proximal and distal edges, respectively (mean absolute error with respect to activation mapping, 20.3 ms). CONCLUSIONS During reentry, PLATM estimates the time interval from activation at any recording site near the circuit to SCZ activation. PLATM time intervals are convertible to arc lengths along the circuit for potentially more rapid and accurate update of a hand-held probe toward the SCZ for catheter ablation.

Differences in Repeating Patterns of Complex Fractionated Left Atrial Electrograms in Longstanding Persistent Atrial Fibrillation as Compared With Paroxysmal Atrial Fibrillation

Background— Complex fractionated atrial electrograms (CFAE) are morphologically more uniform in persistent longstanding as compared with paroxysmal atrial fibrillation (AF). It was hypothesized that this may result from a greater degree of repetitiveness in CFAE patterns at disparate left atrial (LA) sites in longstanding AF. Methods and Results— CFAEs were obtained from recording sites outside the 4 pulmonary vein (PV) ostia and at a posterior and an anterior LA site during paroxysmal and longstanding persistent AF (10 patients each, 120 sequences total). To quantify repetitiveness in CFAE, the dominant frequency was measured from ensemble spectra using 8.4-second sequences, and repetitiveness was calculated by 2 novel techniques: linear prediction and Fourier reconstruction methods. Lower prediction and reconstruction errors were considered indicative of increasing repetitiveness and decreasing randomness. In patients with paroxysmal AF, CFAE pattern repetitiveness was significantly lower (randomness higher) at antral sites outside PV ostia as compared with LA free wall sites (P<0.001). In longstanding AF, repetitiveness increased outside the PV ostia, especially outside the left superior PV ostium, and diminished at the LA free wall sites. The result was that in persistent AF, there were no significant site-specific differences in CFAE repetitiveness at the selected LA locations used in this study. Average dominant frequency magnitude was 5.32±0.29 Hz in paroxysmal AF and higher in longstanding AF, at 6.27±0.13 Hz (P<0.001), with the frequency of local activation approaching a common upper bound for all sites. Conclusions— In paroxysmal AF, CFAE repetitiveness is low and randomness high outside the PVs, particularly the left superior PV. As evolution to persistent longstanding AF occurs, CFAE repetitiveness becomes more uniformly distributed at disparate sites, possibly signifying an increasing number of drivers from remote PVs.