P-wave complexity in normal subjects and computer models.

BACKGROUND: P waves reported in electrocardiology literature uniformly appear smooth. Computer simulation and signal analysis studies have shown much more complex shapes. OBJECTIVE: We systematically investigated P-wave complexity in normal volunteers using high-fidelity electrocardiographic techniques without filtering. METHODS: We recorded 5-min multichannel ECGs in 16 healthy volunteers. Noise and interference were reduced by averaging over 300 beats per recording. In addition, normal P waves were simulated with a realistic model of the human atria. RESULTS: Measured P waves had an average of 4.1 peaks (range 1-10) that were reproducible between recordings. Simulated P waves demonstrated similar complexity, which was related to structural discontinuities in the computer model of the atria. CONCLUSION: The true shape of the P wave is very irregular and is best seen in ECGs averaged over many beats.

Reduced acute myocardial ischemia-reperfusion injury in IL-6-deficient mice employing a closed-chest model.

OBJECTIVE AND DESIGN: We examined the role of IL-6 in the temporal development of cardiac ischemia-reperfusion injury employing a closed-chest I/R model. MATERIALS/METHODS: Infarction, local and systemic inflammation, neutrophil infiltration, coagulation and ST elevation/resolution were compared between wild-type (WT) and IL-6-deficient (IL-6(-/-)) mice after 1 h ischemia and 0, ½, 3, and 24 h reperfusion. RESULTS: IL-6 deficiency reduced infarct size at 3 h reperfusion (28.8 ± 4.5 % WT vs 17.6 ± 2.5 % IL-6(-/-)), which reduction persisted and remained similar at 24 h reperfusion (25.1 ± 3.0 % WT vs 14.6 ± 4.4 % IL-6(-/-)). Serum Amyloid A was reduced at 24 h reperfusion only (57.5 ± 4.9 WT vs 24.8 ± 5.6 ug/ml IL-6(-/-) mice). Cardiac cytokines (IL-6, IL-1ß and TNFα) peaked at 3 h reperfusion, but IL-1ß and TNFα levels were unaffected by IL-6 deficiency. Significant neutrophil influx was only detected at 24 h reperfusion and was similar for WT and IL-6(-/-). Tissue factor peaked at 24 h reperfusion, whereas fibrin/fibrinogen peaked at 3 h reperfusion and was completely resolved at 24 h reperfusion; both coagulation factors were unaltered by IL-6 deficiency. Prolonged ST elevation was observed during ischemia that completely resolved for both genotypes at early reperfusion. CONCLUSIONS: The data suggest that, in the absence of major surgical intervention, IL-6 contributes to the development of infarct size in the early phase of reperfusion; this contribution did not depend on neutrophil influx, IL-1ß and TNFα, tissue factor and fibrin.

Correlation of atrial fibrillation cycle length and fractionation is associated with atrial fibrillation free survival.

AIMS: Fractionation of electrograms in atrial fibrillation (AF) is associated with structural and electrical remodeling. We hypothesized that fractionation can also be associated with the AF cycle length (AFCL). This study was aimed at calculating the mean AFCL to fractionation correlation coefficient (mAFCC) and assessing its association with AF free survival after pulmonary vein isolation (PVI). METHODS: In twenty-eight patients, 15-second electrograms during AF were recorded with a twenty-polar catheter at the left and right atrial appendages. The AFCL was determined manually and the number of activations per second was automatically calculated into a fractionation score. The correlation between AFCL and fractionation was assessed with the mAFCC. RESULTS: Mean age was 53 ± 8 years and 86% had paroxysmal AF. 64% of patients were AF free after a median follow-up of 5.5 years. Baseline characteristics, mean AFCL and fractionation score were not associated with AF free survival after PVI. The mAFCC assessed at the left atrial appendage predicted long-term AF free survival (area under the curve: 0.871. P=0.002), but the mAFCC recorded at the right atrial appendage did not (0.690, P=0.131). CONCLUSION: The mean AFCL mAFCC recorded at the left atrial appendage was a significant predictor of long-term AF free survival. Although not a significant predictor of AF free survival, there was a significant association between mAFCC recorded at the right atrial appendage and AF free survival.

Disparate response of high-frequency ganglionic plexus stimulation on sinus node function and atrial propagation in patients with atrial fibrillation.

BACKGROUND: In patients with atrial fibrillation (AF), the autonomic nervous system is supposed to play an role in triggering AF; however, little is known of the effect on atrial conduction characteristics. OBJECTIVE: The purpose of this study was to study the effect of ganglionic plexus (GP) stimulation during sinus rhythm on atrial and pulmonary vein conduction in patients during thoracoscopic surgery for AF METHODS: In 25 patients, the anterior right ganglionic plexus (ARGP) was stimulated (16 Hz, at 1, 2, and 5 mA). Epicardial electrograms were recorded using a 48-electrode map from the right pulmonary vein (RPV) or right atrial (RA). Intra-atrial activation time (IAT), local activation time (LAT), and inhomogeneity of conduction (IIC) were determined. ECG parameters (P-P, P-R interval) were measured. RESULTS: P-P interval was 956 ± 157 ms (range 768-1368 ms), and P-R interval was 203 ± 37 ms (range 136-280 ms). After ARGP stimulation, a short-lasting increase of P-P interval was observed, more prominent at higher output (1 mA = 82 ms, 2 mA = 180 ms, 5 mA = 268 ms, all P <.01 vs baseline). P-R interval remained unchanged. IAT was 34.4 ms (range 5.6-50.3 ms) at the RA and 105.8 ms (range 79.7-163.3 ms) at the RPV. After 1-mA stimulation IAT increased, in patients taking beta-blockers (P = .001), or it decreased, and this change persisted after subsequent stimulation at higher current (1 mA, P = .001; 2 mA, P = .401; 5 mA, P = .593). Similar changes were observed for LAT and IIC. CONCLUSION: ARGP stimulation results in a short-lasting, output-dependent decrease in sinus node frequency due to a parasympathetic response. Stimulation of the ARGP induced a prolonged increase or decrease in conduction characteristics in patients with AF, consistent with a persistent differential parasympathetic and/or sympathetic response.

How to measure propagation velocity in cardiac tissue: a simulation study.

To estimate conduction velocities from activation times in myocardial tissue, the "average vector" method computes all the local activation directions and velocities from local activation times and estimates the fastest and slowest propagation speed from these local values. The "single vector" method uses areas of apparent uniform elliptical spread of activation and chooses a single vector for the estimated longitudinal velocity and one for the transversal. A simulation study was performed to estimate the influence of grid size, anisotropy, and vector angle bin size. The results indicate that the "average vector" method can best be used if the grid- or bin-size is large, although systematic errors occur. The "single vector" method performs better, but requires human intervention for the definition of fiber direction. The average vector method can be automated.

Electrophysiologic remodeling of the left ventricle in pressure overload-induced right ventricular failure.

OBJECTIVES: The purpose of this study was to analyze the electrophysiologic remodeling of the atrophic left ventricle (LV) in right ventricular (RV) failure (RVF) after RV pressure overload. BACKGROUND: The LV in pressure-induced RVF develops dysfunction, reduction in mass, and altered gene expression, due to atrophic remodeling. LV atrophy is associated with electrophysiologic remodeling. METHODS: We conducted epicardial mapping in Langendorff-perfused hearts, patch-clamp studies, gene expression studies, and protein level studies of the LV in rats with pressure-induced RVF (monocrotaline [MCT] injection, n = 25; controls with saline injection, n = 18). We also performed epicardial mapping of the LV in patients with RVF after chronic thromboembolic pulmonary hypertension (CTEPH) (RVF, n = 10; no RVF, n = 16). RESULTS: The LV of rats with MCT-induced RVF exhibited electrophysiologic remodeling: longer action potentials (APs) at 90% repolarization and effective refractory periods (ERPs) (60 ± 1 ms vs. 44 ± 1 ms; p < 0.001), and slower longitudinal conduction velocity (62 ± 2 cm/s vs. 70 ± 1 cm/s; p = 0.003). AP/ERP prolongation agreed with reduced Kcnip2 expression, which encodes the repolarizing potassium channel subunit KChIP2 (0.07 ± 0.01 vs. 0.11 ± 0.02; p < 0.05). Conduction slowing was not explained by impaired impulse formation, as AP maximum upstroke velocity, whole-cell sodium current magnitude/properties, and mRNA levels of Scn5a were unaltered. Instead, impulse transmission in RVF was hampered by reduction in cell length (111.6 ± 0.7 µm vs. 122.0 ± 0.4 µm; p = 0.02) and width (21.9 ± 0.2 µm vs. 25.3 ± 0.3 µm; p = 0.002), and impaired cell-to-cell impulse transmission (24% reduction in Connexin-43 levels). The LV of patients with CTEPH with RVF also exhibited ERP prolongation (306 ± 8 ms vs. 268 ± 5 ms; p = 0.001) and conduction slowing (53 ± 3 cm/s vs. 64 ± 3 cm/s; p = 0.005). CONCLUSIONS: Pressure-induced RVF is associated with electrophysiologic remodeling of the atrophic LV.

Complex fractionated electrograms in the right atrial free wall and the superior/posterior wall of the left atrium are affected by activity of the autonomic nervous system.

BACKGROUND: Complex fractionated atrial electrograms (CFAEs) are supposed to be related to structural and electrical remodeling. Animal studies suggest a role of the autonomic nervous system (ANS). However, this has never been studied in humans. OBJECTIVE: The goal of this study was to investigate the influence of ANS on CFAEs in patients with idiopathic atrial fibrillation (AF). METHODS: Thirty-six patients (28 men, 55 ± 9 years) were included before undergoing catheter ablation. In the 24 hours preceding the procedure, 20 patients were in AF (group 1) and 16 were in sinus rhythm (SR, group 2). With 2 decapolar catheters, 1 in the right atrium (RA) and 1 in the left atrium (LA), 20 unipolar electrograms were simultaneously recorded during a 100-second AF-period (in group 2 after induction of AF). After atropine and metoprolol administration, a second 100-second AF-period was recorded 30 minutes later. Five patients of group 2 served as controls and did not receive atropine and metoprolol prior to the second recording. CFAEs were assessed and the prevalence of CFAEs was expressed as percentage of the recording time. RESULTS: The prevalence of CFAEs was greater in group 1 than in group 2 in both RA and LA (P = 0.026, P < 0.001, respectively). Atropine and metoprolol significantly reduced CFAEs in group 1 (P < 0.001) and prevented the time-dependent increase of CFAEs in group 2. CONCLUSION: The prevalence of CFAEs is greater in long-lasting AF episodes. Atropine and metoprolol administration reduces CFAEs in both atria. Thus, CFAEs are at least partly influenced by the ANS.

Epicardial confirmation of conduction block during thoracoscopic surgery for atrial fibrillation--a hybrid surgical-electrophysiological approach.

BACKGROUND: Totally thoracoscopic epicardial pulmonary vein ablation is an emerging treatment of atrial fibrillation (AF). A hybrid surgical-electrophysiological procedure with periprocedural confirmation of conduction block might reduce recurrences of AF or atrial tachycardia and improve surgical success. METHODS AND RESULTS: We report our joint surgical-electrophysiological approach for confirmation of conduction block across pulmonary vein ablation lines and those compartmentalizing the left atrium during totally thoracoscopic surgery. A diagnostic electrophysiology (EP) catheter positioned under the left atrium is used as reference and a custom-made multi-electrode for recording. Determination of conduction block across the pulmonary vein (PV) ablation lines requires measurement of activation time differences of milliseconds. Second, a stable reference electrogram to which to relate local activation time is required. Third, the recording electrode terminals and the inter-electrode distance should be small to prevent recording of far field activity and to allow recording of very small electrograms. We confirm entry and exit block and determine conduction block across linear ablation lines with differential pacing. CONCLUSION: A joint surgical-electrophysiological protocol for confirmation of conduction block across PV isolation lines and left atrial ablation lines is feasible and might prevent recurrences and further improve the success of minimally invasive surgery for AF.

Thoracoscopic video-assisted pulmonary vein antrum isolation, ganglionated plexus ablation, and periprocedural confirmation of ablation lesions: first results of a hybrid surgical-electrophysiological approach for atrial fibrillation.

BACKGROUND: Thoracoscopic pulmonary vein isolation (PVI) and ganglionated plexus ablation is a novel approach in the treatment of atrial fibrillation (AF). We hypothesize that meticulous electrophysiological confirmation of PVI results in fewer recurrences of AF during follow-up. METHODS AND RESULTS: Surgery was performed through 3 ports bilaterally. Ganglionated plexi were localized and subsequently ablated. PVI was performed and entry and exit block was confirmed. Additional left atrial ablation lines were created and conduction block verified in patients with nonparoxysmal AF. The left atrial appendage was removed. Freedom of AF was assessed by ECGs and Holter monitoring every 3 months or during symptoms of arrhythmia. Antiarrhythmic drugs were discontinued after 3 months and oral anticoagulants were discontinued according to the guidelines. Thirty-one patients were treated (16 paroxysmal AF, 13 persistent AF, 2 long-standing persistent AF). Thirteen patients with nonparoxysmal received additional left atrial ablation lines. After 1 year, 19 of 22 patients (86%) had no recurrences of AF, atrial flutter, or atrial tachycardia and were not using antiarrhythmic drugs (11/12 paroxysmal, 7/9 persistent, and 1/1 long-standing persistent). Three patients had a sternotomy because of uncontrolled bleeding during thoracoscopic surgery. Four adverse events were 1 hemothorax, 1 pneumothorax, and 2 pneumonia. No thromboembolic complications or mortality occurred. CONCLUSIONS: Thoracoscopic surgery with PVI and ganglionated plexus ablation for AF is a safe and successful procedure with a single procedure success rate of 86% at 1 year. Electrophysiological guided thorough PVI and additional left atrial ablation line creation presumably contributes in achieving a high success rate in the surgical treatment of AF.

Mapping and surgical ablation of focal epicardial left ventricular tachycardia.

We describe a technical challenge in a 17-year-old patient with incessant epicardial focal ventricular arrhythmia and diminished LV function. Failure of ablation at the earliest activated endocardial site during ectopy suggested an epicardial origin, which was supported by specific electrocardiographic criteria. Epicardial ablation was not possible due to the localization of the origin of the ventricular tachycardia adjacent to the phrenic nerve. Minimal invasive surgical multielectrode high-density epicardial mapping was performed to localize the arrhythmia focus. Epicardial surgical RF ablation resulted in the termination of ventricular ectopy. After 2 years, the patient is still free from arrhythmias.

Heterogeneous Connexin43 distribution in heart failure is associated with dispersed conduction and enhanced susceptibility to ventricular arrhythmias.

AIMS: Sudden arrhythmogenic cardiac death is a major cause of mortality in patients with congestive heart failure (CHF). To investigate determinants of the increased arrhythmogenic susceptibility, we studied cardiac remodelling and arrhythmogenicity in CHF patients and in a mouse model of chronic pressure overload. METHODS AND RESULTS: Clinical and (immuno)histological data of myocardial biopsies from CHF patients with (VT+) and without (VT-) documented ventricular arrhythmia were compared with controls. In CHF patients, ejection fraction was decreased and QRS duration was increased. Cell size and interstitial fibrosis were increased, but Connexin43 (Cx43) levels, the most abundant gap junction in ventricular myocardium, were unchanged. No differences were found between VT+ and VT- patients, except for the distribution pattern of Cx43, which was significantly more heterogeneous in VT+. Mice were subjected to transverse aortic constriction (TAC) or sham operated. At 16 weeks, cardiac function was determined by echocardiography and epicardial ventricular activation mapping was performed. Transverse aortic constriction mice had decreased fractional shortening and prolonged QRS duration. Right ventricular conduction velocity was reduced, and polymorphic VTs were induced in 44% TAC and 0% sham mice. Interstitial fibrosis was increased and Cx43 quantity was unchanged in TAC mice with and without arrhythmias. Similar to CHF patients, heterogeneous Cx43 distribution was significantly associated with arrhythmias in TAC mice and with spatial heterogeneity of impulse conduction. CONCLUSION: Heterogeneous Cx43 expression during CHF is associated with dispersed impulse conduction and may underlie enhanced susceptibility to ventricular tachyarrhythmias.

Local depolarization abnormalities are the dominant pathophysiologic mechanism for type 1 electrocardiogram in brugada syndrome a study of electrocardiograms, vectorcardiograms, and body surface potential maps during ajmaline provocation.

OBJECTIVES: We sought to obtain new insights into the pathophysiologic basis of Brugada syndrome (BrS) by studying changes in various electrocardiographic depolarization and/or repolarization variables that occurred with the development of the signature type 1 BrS electrocardiogram (ECG) during ajmaline provocation testing. BACKGROUND: BrS is associated with sudden cardiac death. Its pathophysiologic basis, although unresolved, is believed to reside in abnormal cardiac depolarization or abnormal repolarization. METHODS: Ajmaline provocation was performed in 269 patients suspected of having BrS with simultaneous recording of ECGs, vectorcardiograms, and 62-lead body surface potential maps. RESULTS: A type 1 ECG was elicited in 91 patients (BrS patients), 162 patients had a negative test result (controls), and 16 patients had an abnormal test result. Depolarization abnormalities were more prominent in BrS patients and were mapped to the right ventricle (RV) by longer right precordial filtered QRS complex durations (142 +/- 23 ms vs. 125 +/- 14 ms, p < 0.01) and right terminal conduction delay (60 +/- 11 ms vs. 53 +/- 9 ms, p < 0.01). Repolarization abnormalities remained concordant with depolarization abnormalities as indicated by steady low nondipolar content (12 +/- 8% vs. 8 +/- 4%, p = NS), lower spatial QRS-T integrals (33 +/- 12 mV.ms vs. 40 +/- 16 mV.ms, p < 0.05), similar spatial QRS-T angles (92 +/- 39 degrees vs. 87 +/- 31 degrees , p = NS), similar T(peak)-T(end) interval (143 +/- 36 ms vs. 138 +/- 25 ms, p = NS), and similar T(peak)-T(end) dispersion (47 +/- 37 ms vs. 45 +/- 27 ms, p = NS). CONCLUSIONS: The type 1 BrS ECG is characterized predominantly by localized depolarization abnormalities, notably (terminal) conduction delay in the RV, as assessed with complementary noninvasive electrocardiographic techniques. We could not define a separate role for repolarization abnormalities but suggest that the typical signs of repolarization derangements seen on the ECG are secondary to these depolarization abnormalities.

Left atrial pressure reduction for mitral stenosis reverses left atrial direction-dependent conduction abnormalities.

AIMS: Left atrial (LA) stretch-associated electrophysiological changes in patients with mitral stenosis (MS) predispose to atrial fibrillation. We hypothesized that the normalization of the pressure gradient by percutaneous transvenous mitral balloon valvotomy (PTMV) affects LA but not right atrial (RA) conduction, depending on the site of stimulation. Because direction-dependent (asymmetric) changes of conduction may contribute to arrhythmogenesis, we assessed conduction symmetry in MS patients and tested whether it is restored by PTMV. METHODS AND RESULTS: In nine patients with MS, atrial effective refractory period and local activation times (ATs) were determined during stimulation before and after PTMV, with up to four decapolar catheters (LA and RA). Eight patients with ventricular pre-excitation served as controls. ATs at basic cycle length were similar before and after PTMV. With stimulation from either atrium, they were about 45 ms in the ipsilateral atrium and about 115 ms in the contralateral atrium. With premature stimulation, ATs increased dramatically. The shortest ATs were found in the RA with RA stimulation (78 +/- 9 and 80 +/- 6 ns, before and after PTMV). PTMV caused a shortening in LA-ATs (following LA stimulation) from 118 +/- 14 to 82 +/- 5 ms (before and after; P < 0.05). Asymmetry in conduction properties was therefore normalized by PTMV. PTMV led to a decrease in RA-ATs (following LA stimulation) from 196 +/- 11 to 174 +/- 13 ms (P < 0.02). In addition, following RA stimulation, the dispersion in ATs in the LA decreased significantly by PTMV (from 66 +/- 10 to 34 +/- 7 ms; P < 0.02). CONCLUSION: MS is associated with LA conduction delay, increased LA dispersion of conduction, and conduction asymmetry. These changes are immediately reversible by PTMV.

Mechanism of right precordial ST-segment elevation in structural heart disease: excitation failure by current-to-load mismatch.

BACKGROUND: The Brugada sign has been associated with mutations in SCN5A and with right ventricular structural abnormalities. Their role in the Brugada sign and the associated ventricular arrhythmias is unknown. OBJECTIVE: The purpose of this study was to delineate the role of structural abnormalities and sodium channel dysfunction in the Brugada sign. METHODS: Activation and repolarization characteristics of the explanted heart of a patient with a loss-of-function mutation in SCN5A (G752R) and dilated cardiomyopathy were determined after induction of right-sided ST-segment elevation by ajmaline. In addition, right ventricular structural discontinuities and sodium channel dysfunction were simulated in a computer model encompassing the heart and thorax. RESULTS: In the explanted heart, disappearance of local activation in unipolar electrograms at the basal right ventricular epicardium was followed by monophasic ST-segment elevation. The local origin of this phenomenon was confirmed by coaxial electrograms. Neither early repolarization nor late activation correlated with ST-segment elevation. At sites of local ST-segment elevation, the subepicardium was interspersed with adipose tissue and contained more fibrous tissue than either the left ventricle or control hearts. In computer simulations entailing right ventricular structural discontinuities, reduction of sodium channel conductance or size of the gaps between introduced barriers resulted in subepicardial excitation failure or delayed activation by current-to-load mismatch and in the Brugada sign on the ECG. CONCLUSION: Right ventricular excitation failure and activation delay by current-to-load mismatch in the subepicardium can cause the Brugada sign. Therefore, current-to-load mismatch may underlie the ventricular arrhythmias in patients with the Brugada sign.

Dominant frequency of atrial fibrillation correlates poorly with atrial fibrillation cycle length.

BACKGROUND: Localized sites of high frequency during atrial fibrillation (AF) are used as target sites to eliminate AF. Spectral analysis is used experimentally to determine these sites. The purpose of this study was to compare dominant frequencies (DF) with AF cycle length (AFCL) of unipolar and bipolar recordings. METHODS AND RESULTS: Left and right atrial endocardial electrograms were recorded during AF in 40 patients with lone AF, using two 20-polar catheters. Mean age was 53+/-9.9 years. Unipolar and bipolar electrograms were recorded simultaneously during 16 seconds at 2 right and 4 left atrial sites. AFCLs and DFs were determined. QRS subtraction was performed in unipolar signals. DFs were compared with mean, median, and mode of AFCLs; 4800 unipolar and 2400 bipolar electrograms were analyzed. Intraclass correlation was poor for all spectral analysis protocols. Best correlation was accomplished with DFs from unipolar electrograms compared with median AFCL (intraclass correlation coefficient, 0.67). A gradient in median AFCL of >25% was detected in 16 of 40 patients. In 13 of 16 patients (81%) with a frequency gradient of >25%, the site with highest frequency was located in the left atrium (posterior left atrium in 8 patients). The site with shortest median AFCL and highest DF corresponded in 25% if unipolar and in 31% if bipolar electrograms were analyzed. CONCLUSIONS: DFs from unipolar and bipolar electrograms recorded during AF correlated poorly with mean, median, and mode AFCL. If a frequency gradient >25% existed, the site with highest DF corresponded to the site of shortest median AFCL in only 25% of patients. Because spectral analysis is being used to identify ablation sites, these data may have important clinical implications.

Right-to-left ventricular diastolic delay in chronic thromboembolic pulmonary hypertension is associated with activation delay and action potential prolongation in right ventricle.

BACKGROUND: Delayed left ventricle (LV)-to-right ventricle (RV) peak shortening results in cardiac output reduction in patients with chronic thromboembolic hypertension (CTEPH) and other types of pulmonary arterial hypertension. Why the synchrony between LV and RV is lost is unknown. We hypothesized that RV electrophysiological remodeling, notably, conduction slowing and action potential prolongation, contribute to this loss in synchrony. METHODS AND RESULTS: We conducted epicardial mapping during pulmonary endarterectomy in 26 patients with CTEPH and compared these findings with clinical, hemodynamic, and echocardiographic variables. We consecutively placed a multielectrode grid on the epicardium of the RV free wall and LV lateral wall. These regions corresponded to RV and LV areas where echocardiographic Doppler sample volumes were placed to measure RV-to-LV diastolic interventricular delay. RV and LV epicardial action potential duration was assessed by measuring activation-recovery interval. Onset of diastolic relaxation of RV free wall with respect to LV lateral wall (diastolic interventricular delay) was delayed by 38+/-31 ms in patients with CTEPH versus -12+/-13 ms in control subjects (P<0.001), because, in patients with CTEPH, RV completed electric activation later than LV (65+/-20 versus 44+/-7 ms, P<0.001) and epicardial action potential duration, as assessed by activation-recovery interval measurement, was longer in RV free wall than in LV lateral wall (253+/-29 versus 240+/-22 ms, P<0.001). CONCLUSIONS: Additive effects of electrophysiological changes in RV, notably, conduction slowing and action potential prolongation, assessed by epicardial activation-recovery interval, contribute to diastolic interventricular delay in patients with CTEPH.

Non-invasive imaging of cardiac activation and recovery.

The sequences of activation and recovery of the heart have physiological and clinical relevance. We report on progress made over the last years in the method that images these timings based on an equivalent double layer on the myocardial surface serving as the equivalent source of cardiac activity, with local transmembrane potentials (TMP) acting as their strength. The TMP wave forms were described analytically by timing parameters, found by minimizing the difference between observed body surface potentials and those based on the source description. The parameter estimation procedure involved is non-linear, and consequently requires the specification of initial estimates of its solution. Those of the timing of depolarization were based on the fastest route algorithm, taking into account properties of anisotropic propagation inside the myocardium. Those of recovery were based on electrotonic effects. Body surface potentials and individual geometry were recorded on: a healthy subject, a WPW patient and a Brugada patient during an Ajmaline provocation test. In all three cases, the inversely estimated timing agreed entirely with available physiological knowledge. The improvements to the inverse procedure made are attributed to our use of initial estimates based on the general electrophysiology of propagation. The quality of the results and the required computation time permit the application of this inverse procedure in a clinical setting.

Engineering physiologically controlled pacemaker cells with lentiviral HCN4 gene transfer.

BACKGROUND: Research on biological pacemakers for the heart has so far mainly focused on short-term gene and cell therapies. To develop a clinically relevant biological pacemaker, long-term function and incorporation of autonomic modulation are crucial. Lentiviral vectors can mediate long-term gene expression, while isoform 4 of the Hyperpolarization-activated Cyclic Nucleotide-gated channel (encoded by HCN4) contributes to pacemaker function and responds maximally to cAMP, the second messenger in autonomic modulation. MATERIAL AND METHODS: Action potential (AP) properties and pacemaker current (I(f)) were studied in single neonatal rat ventricular myocytes that overexpressed HCN4 after lentiviral gene transduction. Autonomic responsiveness and cycle length stability were studied using extracellular electrograms of confluent cultured monolayers. RESULTS: Perforated patch-clamp experiments demonstrated that HCN4-transduced single cardiac myocytes exhibited a 10-fold higher I(f) than non-transduced single myocytes, along with slow diastolic depolarization, comparable to pacemaker cells of the sinoatrial node, the dominant native pacemaker. HCN4-transduced monolayers exhibited a 47% increase in beating rate, compared to controls. Upon addition of DBcAMP, HCN4-transduced monolayers had beating rates which were 54% faster than baseline and significantly more regular than controls. CONCLUSIONS: Lentiviral vectors efficiently transduce cardiac myocytes and mediate functional gene expression. Because HCN4-transduced myocytes demonstrate an increase in spontaneous beating rate and responsiveness to autonomic modulation, this approach may be useful to create a biological pacemaker.

Slow and discontinuous conduction conspire in Brugada syndrome: a right ventricular mapping and stimulation study.

BACKGROUND: Brugada syndrome (BrS) is associated with lethal arrhythmias, which are linked to specific ST-segment changes (type-1 BrS-ECG) and the right ventricle (RV). The pathophysiological basis of the arrhythmias and type-1 BrS-ECG is unresolved. We studied the electrophysiological characteristics of the RV endocardium in BrS. METHODS AND RESULTS: RV endocardial electroanatomical mapping and stimulation studies were performed in controls (n=12) and BrS patients with a type-1 (BrS-1, n=10) or type-2 BrS-ECG (BrS-2, n=12) during the studies. BrS-1 patients had prominent impairment of RV endocardial impulse propagation when compared with controls, as represented by: (1) prolonged activation-duration during sinus rhythm (86+/-4 versus 65+/-3 ms), (2) increased electrogram fractionation (1.36+/-0.04 versus 1.15+/-0.01 deflections per electrogram), (3) longer electrogram duration (83+/-3 versus 63+/-2 ms), (4) activation delays on premature stimulation (longitudinal: 160+/-26 versus 86+/-9 ms; transversal: 112+/-5 versus 58+/-6 ms), and (5) abnormal transversal conduction velocity restitution (42+/-8 versus 18+/-2 ms increase in delay at shortest coupling intervals). Wider and more fractionated electrograms were also found in BrS-2 patients. Repolarization was not different between groups. CONCLUSIONS: BrS-1 and BrS-2 patients are characterized by wide and fractionated electrograms at the RV endocardium. BrS-1 patients display additional conduction slowing during sinus rhythm and premature stimulation along with abnormal transversal conduction velocity restitution. These patients may thus exhibit a substrate for slow and discontinuous conduction caused by abnormal active membrane processes and electric coupling. Our findings support the emerging notion that BrS is not solely attributable to abnormal electrophysiological properties but requires the conspiring effects of conduction slowing and tissue discontinuities.

Monophasic action potentials and activation recovery intervals as measures of ventricular action potential duration: experimental evidence to resolve some controversies.

BACKGROUND: Activation recovery intervals (ARIs) and monophasic action potential (MAP) duration are used as measures of action potential duration in beating hearts. However, controversies exist concerning the correct way to record MAPs or calculate ARIs. We have addressed these issues experimentally. OBJECTIVES: To experimentally address the controversies concerning the correct way to record MAPs or calculate ARIs. METHODS: Left ventricular local electrograms were recorded in isolated pig hearts with an exploring electrode grid, with a KCl reference electrode on the left ventricular myocardium, the aortic root, or the left atrium. Local activation was determined from calculated Laplacian electrograms. RESULTS: With the KCl electrode on the aortic root, local electrograms represented local activation. However, with the KCl electrode on the myocardium remote from the exploring electrode, a combined electrogram emerged consisting of local activation recorded from the grid and remote activation recorded from the reference electrode. The remote, inverted monophasic component did not show propagation and did not correlate with the Laplacian complex. When the KCl electrode was placed on the atrium during AV block, remote atrial monophasic components were completely dissociated from local, ventricular deflections. At left ventricular sites with a positive T wave, the Laplacian signal showed that the end of the T wave was caused by remote repolarization. During cooling-induced regional action potential prolongation, the T wave became negative, whereby the positive flank of the T wave remained correlated with repolarization (recorded with a MAP at the same site). CONCLUSIONS: MAPs are recorded from the depolarizing electrode. In both negative and positive T waves, the moment of maximum dV/dt corresponds to local repolarization.