The effects of right ventricular apical pacing with transvenous pacemaker and implantable cardioverter defibrillator on mitral and tricuspid regurgitation.

BACKGROUND: The incidence of new or worsening tricuspid regurgitation (TR) or mitral regurgitation (MR) after permanent pacemaker (PPM) or implantable cardioverter defibrillator (ICD) lead placement has not been well investigated. We studied the effect of transvenous leads implantation and right ventricular (RV) pacing on tricuspid and mitral valve regurgitations. METHODS: We reviewed the charts of all patients undergoing PPM or ICD lead placement in our electrophysiology laboratory from December 2001 to December 2006. RESULTS: A total of 206 patients (120 with PPM and 86 with ICD) had baseline echocardiography within 6months before, and a follow up study at least 6months after lead insertion. The mean age was 74±14years; 56% were men. The follow-up period was 29±19months. TR worsened by at least one grade after lead insertion in 44.7% patients (P<0.001). Pre- and post-implant changes in TR severity did not differ with respect to lead type (ICD vs. PPM) or degree of RV pacing dependence. As for MR; patients with high frequency of RV pacing (>40%) had a higher incidence of worsening MR when compared to those with low frequency of RV pacing (44% vs. 19%; P<0.001). CONCLUSION: PPM or ICD lead implantation worsens TR; that effect is probably induced by mechanical interferences with the TV closure and was consistent regardless the lead type or degree of RV Pacing. MR was noted to increase in patients with high frequency of RV pacing frequency; this is probably caused by the mechanical dyssynchrony induced by RV pacing.

The Effects of Right Ventricular Apical Pacing Frequency on Left Ventricle Function and Pulmonary Artery Pressure.

OBJECTIVE: We studied the effect of the frequency of right ventricular (HV) pacing on left ventricle (LV) function pulmonary hypertension. BACKGROUND: The incidence of new or worsening pulmonary hypertension after permanent pacemaker (PPM) or implantable cardioverter defibrillator (lCD) lead placement has not been well investigated. METHODS: We reviewed the charts of all patients undergoing PPM or ICD lead placement in our electrophysiology laboratory from December 2007 to December 2012. RESULTS: Two hundred and six patients (120 with PPM and 86 with ICD) had baseline echocardiography within six months before, and a follow up study at least six months after lead insertion. The mean age was 74 ± 14 years; 56 percent were men. The follow-up period was 29 ± 19 months. RV pacing was associated with a worsening of left ventricular ejection fraction (LVEF) in patients with high frequency of RV (55 ± 16 vs. 44 ± 18; P = 0.001), but not with those with low frequency pacing (55 ± 16 vs. 54 ± 17; P = 0.87). Similarly, RV pacing was associated with a worsening in both right ventricular systolic pressure (RVSP) (42 ± 14 vs. 48 ± 15; P = 0.01) and Pulmonary Artery Systolic Pressure (PASP) (50 ± 17 vs. 56 ± 18; P = 0.005) in patients with high frequency RV, but not in those with low frequency RV pacing [RVSP (43 ± 12 vs. 46 ± 13; P = 0.06) and PASP (51 ± 15 vs. 54 ± 16; P = 0.11)]. ONCLUSION: PPM or IICD lead implantation worsens LV function and pulmonary hypertension in patients with high frequency of RV pacing frequency. This is probably caused by the mechanical dyssynchrony induced by RV pacing.

Real time three-dimensional echocardiography in assessment of left ventricular dyssynchrony and cardiac resynchronization therapy.

Left ventricular (LV) mechanical dyssynchrony is an important prognostic marker for higher morbidity and mortality in patients with symptomatic heart failure. However, the response rate to resynchronization varies among patients meeting current guidelines for Cardiac resynchronization therapy (CRT). Two-dimensional echocardiography and Doppler-based techniques have shown variable results in the assessment of LV dyssynchrony. There is an obvious need for a noninvasive tool that can reliably measure LV dyssynchrony. Accurate prediction of response to CRT will improve patient selection for such therapy. Real time three-dimensional echocardiography (RT3DE) is a novel noninvasive imaging modality that has been recently used in quantitative evaluation of global and regional LV function. A number of published studies have described the use of RT3DE in the measurement of LV dyssynchrony in patients with normal or reduced LV function. The systolic dyssynchrony index derived from RT3DE has been used to quantify LV dysynchrony and to evaluate and predict the response to CRT. This review will discuss the recently published data regarding the role of RT3DE in CRT.

Variability in postpacing intervals predicts global ventricular activation pattern during tachycardia.

INTRODUCTION: Assessment of ventricular activation pattern is critical to the successful ablation of ventricular tachycardia (VT). We have previously shown that the global atrial activation pattern during tachycardia can be rapidly and accurately assessed by calculating the postpacing interval variability (PPIV); PPIV was minimal in circuitous tachycardias and highly variable in centrifugal tachycardias. In the present study, we use the PPIV to determine the ventricular global activation pattern during VT. METHODS: Patients with mappable VT were included. We defined global ventricular activation as either centrifugal (arising from a focus with radial expansion) or circuitous (gross macro-reentrant circuit), based on the findings of electroanatomic mapping. PPIV was calculated as the difference in postpacing interval with right ventricular apical overdrive pacing during tachycardia at cycle lengths (CL) 10 ms and 30-ms shorter than tachycardia, regardless of the origin of the tachycardia. We studied 20 patients with 23 VTs (11 centrifugal, mean CL 390 +/- 36.1 ms; 12 circuitous, mean CL 418 +/- 75.7 ms). RESULTS: The mean PPIV was 45 +/- 16 ms for patients with centrifugal VT and 6.7 +/- 4.1 ms for patients with circuitous VT. Rank sum analysis of PPIV showed a significant difference between the two groups (P < 0.05). CONCLUSIONS: Our data suggest that the global ventricular activation pattern during VT can be rapidly and accurately defined by assessing the PPIV. This technique allows for a rapid confirmation of the tachycardia activation and significantly facilitates mapping and ablation.

A nonsense SCN5A mutation associated with Brugada-type electrocardiogram and intraventricular conduction defects.

Mutations of SCN5A, gene-encoding alpha-subunit of cardiac sodium channel, can cause mixed phenotypes of Brugada syndrome (BrS) and cardiac conduction diseases (CCD). We have identified a nucleotide change of SCN5A (4178T > G), which results in a nonsense mutation, L1393X, in a 36-year-old Caucasian man who presented with intraventricular conduction delays and BrS-type electrocardiogram change. To study biophysical characteristics of L1393X-SCN5A, electrophysiological and immuno-staining studies were performed using mammalian expression systems. While WT-SCN5A showed significant currents (93.3 +/- 10.6 pA/pF; 1 microg plasmid), L1393X (5 microg) did not generate any significant currents in NIH-3T3 cells. The cells cotransfected with WT (0.5 microg) and L1393X (0.5 microg) showed approximately 50% current amplitudes compared to the WT (1 microg). Voltage dependency of a steady-state activation and inactivation was not affected by the cotransfection of L1393X. Immuno-histochemical stainings demonstrated that L1393X proteins were expressed in the plasma membranes. Our study demonstrated that L1393X-SCN5A does not form functional channel proteins, which might account for the patient's mixed phenotypes of BrS and CCD.

Variability in post-pacing intervals predicts global atrial activation pattern during tachycardia.

INTRODUCTION: Knowledge of the global atrial activation pattern is critical to ablation of an atrial arrhythmia. We hypothesized that the variability in post-pacing intervals (PPIs) with pacing at different cycle lengths (CLs) from the same pacing site, regardless of distance to the circuit, can be used to identify atrial activation patterns during tachycardia. METHODS AND RESULTS: Consecutive patients referred for ablation of organized atrial arrhythmias were included (n = 28, 31 total tachycardias). The variability in PPIs (PPIV) was calculated by comparing the difference in PPIs after overdrive pacing with 5-second trains 10, 20, and 30 ms shorter than the tachycardia cycle length (TCL). The global activation pattern was defined as circuitous (macroreentrant atrial circuit) or centrifugal (focal origin with centrifugal radiation) by electroanatomic mapping. Except for one case, all pacing was performed from the proximal coronary sinus bipole. Circuitous tachycardias (n = 17, all macro-reentrant) exhibited minimal variability with pacing at 10 ms and 30 ms shorter than TCL (6.0 +/- 2.5 ms), whereas centrifugal tachycardias (n = 14, 8 microreentrant) displayed a high degree of variability (56.5 +/- 20.6 ms). Rank sum analysis of PPIV suggests that the two groups are indeed distinct (P < 0.001). Using PPIV cutoffs of or=30 ms, circuitous and centrifugal activation patterns could be distinguished with a high degree of sensitivity (94% circuitous, 92.8% centrifugal) and 100% specificity. CONCLUSIONS: Our data support the use of PPIV to rapidly and accurately predict the global activation pattern during atrial arrhythmia.

A common SCN5A variant alters the responsiveness of human sodium channels to class I antiarrhythmic agents.

BACKGROUND: The potential pathophysiological role of common SCN5A polymorphisms in cardiac arrhythmias has been increasingly recognized. However, little is known about the impact of those polymorphisms on the pharmocological response of hNav1.5 to various antiarrhythmic agents. METHODS AND RESULTS: The known SCN5A polymorphism, S524Y, was studied in comparison with the wild type (WT) in [corrected] the SCN5A-Q1077del variant. The ion channel gating kinetics and pharmacology were evaluated using whole-cell patch-clamp methods in HEK-293 cells. Consistent with a previous report, the basal ion channel gating kinetics of S524Y were indistinguishable from the WT. Quinidine (20 microM) caused similar extent of tonic block reduction of sodium currents at -120 mV in WT and S524Y. Surprisingly, quinidine (20 microM) exerted a more use-dependent block by a 10 Hz pulse train in S524Y than in WT at 22 degrees C (Ki: WT, 51.3 microM; S524Y, 20.3 microM). S524Y significantly delayed recovery from the use-dependent block, compared with the WT (tau= 88.6 +/- 7.9 s vs 41.9 +/- 6.6 s, P < 0.005). Under more physiological conditions using a 2 Hz pulse train at 37 degrees C, S524Y similarly enhanced the use-dependent block by quinidine. In addition, S524Y enhanced the use-dependent block by flecainide (12.5 microM), but not by mexiletine (100 microM). CONCLUSION: A common SCN5A polymorphism, S524Y, can enhance a use-dependent block by class Ia and Ic antiarrhythmic agents. Our findings may have clinical implications in pharmacological management of cardiac arrhythmias since this common SCN5A polymorphism might be a contributing factor to the variable antiarrhythmic response.

Outcomes of pre-emptive and rescue use of percutaneous left ventricular assist device in patients with structural heart disease undergoing catheter ablation of ventricular tachycardia.

PURPOSE: Patient selection and timing of percutaneous left ventricular assist device (pLVAD) insertion for maximal benefit during ventricular tachycardia (VT) ablation is not well defined. We aimed to assess the outcomes of pre-emptive and rescue use of pLVAD during VT ablation in patients with ischemic and non-ischemic cardiomyopathy. METHODS: Between January 2009 and October 2011, 93 patients underwent VT ablation. Three groups were compared: (1) Rescue group (n = 12)-patients who required emergent pLVAD insertion due to hemodynamic collapse during VT ablation, (2) Pre-emptive group (n = 24)-patients who had pre-ablation pLVAD insertion, and (3) Non-pLVAD group (n = 57)-patients who did not undergo pLVAD insertion. Procedural outcomes including 30-day mortality were compared. RESULTS: Thirty-day mortality was higher in the Rescue group compared to the Pre-emptive group (58 vs. 4 %, p = 0.003) and non-pLVAD (58 vs. 3 %, p = 0.001) group. There was no significant difference in 30-day mortality or long-term freedom of VT between the pre-emptive and non-pLVAD groups. CONCLUSIONS: Despite rescue pLVAD insertion, hemodynamic collapse during VT ablation is associated with a persistently high 30-day mortality. Further studies are warranted to predict hemodynamic collapse and to refine the role of pLVAD in this setting.

Incidence, Risk Factors, Prognosis, and Electrophysiological Mechanisms of Atrial Arrhythmias after Lung Transplantation.

OBJECTIVE: To investigate incidence and timing, risk factors, prognostic significance, and electrophysiological mechanisms of atrial arrhythmia (AA) after lung transplantation. BACKGROUND: Although new-onset AA is common after thoracic surgery and is associated with poorer outcomes, prognostic and mechanistic data is sparse in lung transplant populations. METHOD: A total of 293 consecutive isolated lung transplant recipients without known AA were retrospectively reviewed. Mean follow-up was 28±17 months. Electrophysiology studies (EPS) were performed in 25 patients with AA. RESULTS: The highest incidence of new-onset AA after lung transplantation occurred within 30 days postoperative AA, (25 % of all patients). In multivariable analysis, postoperative AA was associated with double lung transplantation (OR 2.79; p=0.005) and lower mean pulmonary artery pressure (OR 0.95; p=0.027). Patients with postoperative AA had longer hospital stays (21 days vs 12 days; p<0.001). Postoperative AA was independently associated with late AA (HR 13.52; p<0.001) but not mortality (HR 1.55; p=0.14). In EPS, there were 14 patients with atrial flutter alone and 11 with atrial flutter and fibrillation. Of all EPS patients, 20 (80%) had multiple AA mechanisms, including peritricuspid flutter (48%), perimitral flutter (36%), right atrial incisional reentry (24%), focal tachycardia from recipient pulmonary vein (PV) antrum (32 %), focal PV fibrillation (24%), and left atrial roof flutter (20%). Left atrial mechanisms were present in 80% (20/25) of EPS patients and originated from the anastomotic PV antrum. CONCLUSIONS: Postoperative AA was independently associated with longer length of stay and late AA but not mortality. Pleomorphic PV antral arrhythmogenesis from native PV antrum is the main cause of AA after lung transplantation.

Safety and effectiveness of compassionate use of LARIAT® device for epicardial ligation of anatomically complex left atrial appendages.

BACKGROUND: Percutaneous left atrial appendage (LAA) ligation using an epicardial suture system (LARIAT®, SentreHEART, Palo Alto, CA) has been used in patients with nonvalvular atrial fibrillation (AF) and contraindication to oral anticoagulation. However, complex LAA anatomy may preclude its use. We report the safety and effectiveness of compassionate use of first-generation LARIAT® device for epicardial ligation of large, complex left atrial appendages. METHODS: Between January 2010 and March 2013, 93 patients with AF, high CHADS2 score, and contraindication(s) for oral anticoagulation therapy were evaluated for LAA ligation. Complex anatomy detected by 3D cardiac computed tomography CT angiography led to preclusion of 25 patients (27%). Of these, nine patients who opted for epicardial LAA ligation on compassionate grounds were studied. RESULTS: Mean age was 68.1 ± 8.2 years, four females, all with large LAA width (>40 mm, 45-58 mm) and additional anatomic complexities such as bilobed (two), long C-shaped-like (two), goose neck-like (one), multilobed cauliflower-like (two), cactus-like (one), and chicken wing-like (one) LAA. LAA ligation with LARIAT® was successfully performed with surgical standby in all patients. Seven patients (78%) were safely treated percutaneously and only two patients required minimally invasive thoracotomy (one due to inability to release the epicardial snare from long C-shaped LAA and other due to preexisting adhesions precluding pericardial entry). There were no major complications. Repeat trans-esophageal echocardiography at 3 months showed no remnant flow and none had stroke off Coumadin at 19.3 ± 8.2 months of follow-up. CONCLUSIONS: Despite a high preclusion rate, percutaneous LAA ligation may be safely and effectively performed on compassionate grounds using the first-generation LARIAT® device with surgical standby in patients with large and complex LAA.

The use of echocardiography in Wolff-Parkinson-White syndrome.

Endocardial mapping and radiofrequency catheter ablation are well established modalities for the diagnosis and treatment of patients with Wolff-Parkinson-White (WPW) syndrome associated with tachyarrhythmias. However, the electrophysiologic techniques are invasive, require radiation exposure, and lack spatial resolution of cardiac structures. A variety of echocardiographic techniques have been investigated as a non-invasive alternative for accessory pathway localization. Conventional M-mode echocardiography can detect the fine premature wall motion abnormalities associated with WPW syndrome. However, it is unable to identify the exact site of accessory pathway with sufficient accuracy. 2D, 2D-guided M-mode, and 2D phase analysis techniques are limited by image quality and endocardial border definition. Various modalities of tissue Doppler echocardiography significantly increase the accuracy of left-sided accessory pathway localization to 80-90% even in patients with poor acoustic window. However, right-sided pathways remain a diagnostic challenge. Strain echocardiography by speckle tracking has recently been evaluated and appears promising. Different cardiac abnormalities have been detected by echocardiography in WPW patients. Patients with WPW syndrome and tachyarrhythmias have impaired systolic and diastolic function which improves after radiofrequency ablation. Echocardiography is useful in identifying patient with accessory pathway-associated left ventricular dyssynchrony and dysfunction who may benefit from ablation therapy. Transesophageal and intracardiac echocardiography have been used to guide ablation procedure. Ablation-related complications detected by routine echocardiography are infrequent, rarely clinically relevant, and of limited value.

Heterogeneity of left ventricular signal characteristics in response to acute vagal stimulation during ventricular fibrillation in dogs.

Studies have shown that long-term vagal stimulation is protective against ventricular fibrillation; however, the effects of acute vagal stimulation during ventricular fibrillation in the normal heart have not been investigated. We examined the effects of acute vagal stimulation on ventricular fibrillation in a canine model. In 4 dogs, we induced 30-second periods of ventricular fibrillation by means of intraventricular pacing. During 2 of the 4 periods of fibrillation that we analyzed, vagal stimulation was delivered through electrodes in the caudal ends of the vagus nerves. Noncontact unipolar electrograms were recorded from 3 ventricular regions: the basal septum, apical septum, and lateral free wall. We then computed the most frequent cycle length, mean organization index, and mean electrogram amplitude for each region. During fibrillation, vagal stimulation shortened the most frequent cycle lengths in the basal septum (P=0.02) and apical septum (P=0.0001), but not in the lateral wall (P=0.46). In addition, vagal stimulation significantly reduced the mean organization indices in the apical septum (P <0.001) and lateral wall (P <0.001), but not in the basal septum (P=0.19). Furthermore, vagal stimulation raised the mean electrogram amplitude in the basal septum (P <0.01) but lowered it substantially in the apical septum (P=0.00005) and lateral wall (P=0.00003). We conclude that vagal stimulation acutely affects the characteristics of ventricular fibrillation in canine myocardium in a spatially heterogeneous manner. This nonuniformity of response may have implications with regard to manipulating the autonomic system as a means of modifying the substrate for ventricular dysrhythmias.

A novel SCN5A mutation V1340I in Brugada syndrome augmenting arrhythmias during febrile illness.

BACKGROUND: Mutations in the SCN5A gene, which encodes the cardiac sodium channel, have been implicated in the pathogenesis of Brugada syndrome (BrS). Febrile illnesses have been recognized to unmask and/or trigger the BrS phenotype. However, the pathophysiological mechanism has not been fully elucidated. OBJECTIVE: A novel SCN5A missense mutation, V1340I, was identified in a patient with BrS suffering from frequent episodes of polymorphic ventricular tachycardia (VT) and syncope associated with fever. The biophysical modifications of hNa(v)1.5 by V1340I were studied. METHODS: The effects of the V1340I mutation were studied in the 2 splice variants, SCN5A and SCN5A-Q1077del (delQ), using patch-clamp techniques at various temperatures between 22 degrees C and 40 degrees C. RESULTS: At 22 degrees C, V1340I-SCN5A generated markedly diminished sodium currents compared to the wild-type (WT) SCN5A. On the contrary, V1340I-delQ generated almost identical current density compared to the WT-delQ. However, V1340I-delQ significantly attenuated the peak current density compared to the WT-delQ at 32 degrees C, 37 degrees C and 40 degrees C. The voltage dependency of steady-state activation was leftward shifted both in WT-delQ and V1340I-delQ at 40 degrees C. In addition, the V1340I-delQ accelerated the recovery time course from fast inactivation compared to the WT-delQ at 40 degrees C. Immunohistochemical staining showed that both V1340I-SCN5A and V1340I-dQ were expressed in the plasma membrane. CONCLUSION: Our study supports the concept that febrile illness predisposes individuals who carry a loss of function SCN5A mutation, such as V1340I, to fever-induced ventricular arrhythmias in BrS by significantly reducing the sodium currents in the hyperthermic state.