Design and rationale of the MODULAR ATP global clinical trial: A novel intercommunicative leadless pacing system and the subcutaneous implantable cardioverter-defibrillator.

Background: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has demonstrated safety and efficacy for the treatment of malignant ventricular arrhythmias. However, a limitation of the S-ICD lies in the inability to either pace-terminate ventricular tachycardia or provide prolonged bradycardia pacing support. Objective: The rationale and design of a prospective, single-arm, multinational trial of an intercommunicative leadless pacing system integrated with the S-ICD will be presented. Methods: A technical description of the modular cardiac rhythm management (mCRM) system (EMPOWER leadless pacemaker and EMBLEM S-ICD) and the implantation procedure is provided. MODULAR ATP (Effectiveness of the EMPOWER™ Modular Pacing System and EMBLEM™ Subcutaneous ICD to Communicate Antitachycardia Pacing) is a multicenter, international trial enrolling up to 300 patients at risk of sudden cardiac death at up to 60 centers trial design. The safety endpoint of freedom from major complications related to the mCRM system or implantation procedure at 6 months and 2 years are significantly higher than 86% and 81%, respectively, and all-cause survival is significantly >85% at 2 years. Results: Efficacy endpoints are that at 6 months mCRM communication success is significantly higher than 88% and the percentage of subjects with low and stable thresholds is significantly higher than 80%. Substudies to evaluate rate-responsive features and performance of the pacing module are also described. Conclusion: The MODULAR ATP global clinical trial will prospectively test the safety and efficacy of the first intercommunicating leadless pacing system with the S-ICD. This trial will allow for robust validation of device-device communication, pacing performance, rate responsiveness, and system safety.

Understanding Outcomes with the EMBLEM S-ICD in Primary Prevention Patients with Low EF Study (UNTOUCHED): Clinical characteristics and perioperative results.

BACKGROUND: The subcutaneous implantable cardioverter-defibrillator (S-ICD) has shown favorable outcomes in large registries with broad inclusion criteria. The cohorts reported had less heart disease and fewer comorbidities than standard ICD populations. OBJECTIVE: The purpose of this study is to characterize acute performance for primary prevention patients with a left ventricular ejection fraction (LVEF) ≤35% (primary prevention ≤35%). METHODS: Primary prevention ≤35% patients with no prior documented sustained ventricular tachycardia (VT), pacing indication, end-stage heart failure, or advanced renal failure were prospectively enrolled. Analyses included descriptive statistics, Kaplan-Meier time to event, and multivariable linear and logistic regression. RESULTS: In 1112 of 1116 patients, an S-ICD was successfully implanted (99.6%). Predictors for longer procedure time included 3-incision technique, higher body mass index (BMI), performing defibrillation testing (DFT), imaging, younger age, black race, and European vs North American centers. Patients undergoing DFT (82%) were successfully converted (99.2%; 93.5% converting at ≤65 J). Higher BMI was predictive of failing DFT at ≤65 J. The rate of 30-day freedom from complications was 95.8%. Most complications involved postoperative healing (45%) or interventions after DFT or impedance check (19%). CONCLUSION: The procedural outcome data of UNTOUCHED reinforce that S-ICD therapy has low perioperative complication rates and high conversion efficacy of induced ventricular fibrillation, even in a higher-risk cohort with low LVEF and more comorbidities than previous S-ICD studies. Higher BMI warrants more careful attention to implant technique.

Development of a biomarker panel to predict cardiac resynchronization therapy response: Results from the SMART-AV trial.

BACKGROUND: Predicting a favorable cardiac resynchronization therapy (CRT) response holds great clinical importance. OBJECTIVE: The purpose of this study was to examine proteins from broad biological pathways and develop a prediction tool for response to CRT. METHODS: Plasma was collected from patients before CRT (SMART-AV [SmartDelay Determined AV Optimization: A Comparison to Other AV Delay Methods Used in Cardiac Resynchronization Therapy] trial). A CRT response was prespecified as a ≥15-mL reduction in left ventricular end-systolic volume at 6 months, which resulted in a binary CRT response (responders 52%, nonresponders 48%; n = 758). RESULTS: Candidate proteins (n = 74) were evaluated from the inflammatory, signaling, and structural domains, which yielded 12 candidate biomarkers, but only a subset of these demonstrated predictive value for CRT response: soluble suppressor of tumorgenicity-2, soluble tumor necrosis factor receptor-II, matrix metalloproteinase-2, and C-reactive protein. These biomarkers were used in a composite categorical scoring algorithm (Biomarker CRT Score), which identified patients with a high/low probability of a response to CRT (P <.001) when adjusted for a number of clinical covariates. For example, a Biomarker CRT Score of 0 yielded 5 times higher odds of a response to CRT compared to a Biomarker CRT Score of 4 (P <.001). The Biomarker CRT Score demonstrated additive predictive value when considered against a composite of clinical variables. CONCLUSION: These unique findings demonstrate that developing a biomarker panel for predicting individual response to CRT is feasible and holds potential for point-of-care testing and integration into evaluation algorithms for patients presenting for CRT.

Temporal associations between thoracic volume overload and malignant ventricular arrhythmias: a study of intrathoracic impedance.

BACKGROUND: Acute exacerbations of heart failure (HF) are believed to trigger malignant ventricular arrhythmias, but the temporal association between fluid accumulation and ventricular arrhythmias has not been evaluated in an objective manner. We hypothesized that increased intrathoracic fluid accumulation in patients with HF, as measured by an index of intrathoracic impedance, is associated with an increased risk of ventricular arrhythmias. METHODS AND RESULTS: We analyzed interrogations in a cohort of 96 patients with left ventricular dysfunction (EF ≤ 35%) with devices that monitor intrathoracic impedance (OptiVol fluid index). Treated episodes of ventricular tachycardia or fibrillation (VT/VF) were adjudicated and stratified according to predetermined fluid index thresholds (OptiVol indices of 15, 30, 45, 60 Ω-days). VT/VF episodes occurred in 16 patients (17%). VT/VF was more common on days when the fluid index was elevated using threshold values of 15, 30, and 45 Ω-days (P = 0.006, 0.04, 0.02, respectively). There were no differences in the percent of time above any threshold between patients with and without VT/VF. CONCLUSIONS: In patients with HF who develop VT/VF, volume overload, as detected by an index incorporating changes in intrathoracic impedance, was temporally associated with malignant ventricular tachyarrhythmias.

ICD implantation and arrhythmia-free survival in patients with depressed LV function following surgery for valvular heart disease.

BACKGROUND: Although prophylactic implantable cardioverter-defibrillator (ICD) implantation is beneficial in patients with severe ischemic cardiomyopathy, it is unclear whether patients with cardiomyopathy due to valvular heart disease have a similar benefit. METHODS: We followed 17 patients (14 men/three women, age 62 +/- 13 years, left ventricular ejection fraction [LVEF] 29 +/- 10%) who had nonischemic valvular cardiomyopathy, underwent valvular heart surgery (aortic valve replacement, mitral valve replacement, and/or mitral valve repair), and subsequently had an electrophysiology study (EPS), for a median of 2.8 years. These patients were compared with 34 patients with prior myocardial infarction and no significant valvular heart disease, who were matched (1:2) for age, gender, LVEF, EPS result, T-wave alternans result, and ICD placement. Occurrence of arrhythmias was ascertained from ICD device clinic follow-up and vital status was determined using the National Death Index. RESULTS: There were no differences between the groups in overall survival (P = 0.24) or arrhythmia-free survival (P = 0.38), and the 2-year arrhythmia-free survival was 82% for the valvular patients versus 73% for the ischemic patients. Among patients with ICDs, there was no difference between the groups in overall survival (P = 0.34), time to first appropriate ICD therapy (P = 0.54), and arrhythmia-free survival (P = 0.51). CONCLUSION: Patients with valvular cardiomyopathy and residual left ventricular dysfunction following valvular surgery who underwent a tailored approach to ICD implantation had similar overall and arrhythmia-free survival as patients with ischemic cardiomyopathy.

Clinical and electrophysiological spectrum of idiopathic ventricular outflow tract arrhythmias.

OBJECTIVES: This study sought to compare and contrast the clinical and electrophysiological characteristics of outflow tract arrhythmias. BACKGROUND: Idiopathic ventricular outflow tract arrhythmias manifest clinically in 3 forms: 1) paroxysmal sustained monomorphic ventricular tachycardia (SMVT), 2) repetitive nonsustained ventricular tachycardia (NSVT), or 3) premature ventricular contractions (PVCs). Although these arrhythmias have a similar site of origin, it is unknown whether they share a common mechanism or similar clinical features. METHODS: A total of 127 patients (63 female [50%], mean age 51 +/- 15 years) were evaluated for outflow tract arrhythmias. RESULTS: A total of 36 (28%) presented with the index clinical arrhythmia of SMVT, 46 (36%) with NSVT, and 45 (35%) with PVCs. The sites of origin of the arrhythmias were similar among the 3 groups, occurring in the right ventricular outflow tract in 82%. Sustained ventricular tachycardia was more likely to be induced during exercise in the SMVT (10 of 15 patients [67%]) than NSVT or PVCs groups (p < 0.01). Sustained outflow tract ventricular tachycardia was induced at electrophysiology study in 78% of SMVT patients, 48% of NSVT patients, and 4% of PVCs patients. Adenosine was similarly effective in all 3 groups (p = NS). CONCLUSIONS: Patients with outflow tract arrhythmias can be differentiated based on the subtype of arrhythmia. However, the observation that approximately 50% of patients with NSVT and approximately 5% of patients with PVCs have inducible sustained ventricular tachycardia that behaves in an identically unique manner to those who present with sustained ventricular tachycardia (e.g., adenosine-sensitive) suggests that rather than representing distinct entities, outflow arrhythmias may be considered a continuum of a single mechanism.

Adenosine-insensitive focal atrial tachycardia: evidence for de novo micro-re-entry in the human atrium.

OBJECTIVES: The purpose of this work was to describe the entity and mechanism of adenosine-insensitive focal atrial tachycardia (AT). BACKGROUND: The majority of regular focal ATs demonstrate properties consistent with triggered activity, including termination by adenosine. Less commonly, AT may be due to enhanced automaticity, which is transiently suppressed by adenosine. Small re-entrant circuits may also give rise to focal AT, but limited data exist regarding this entity as a de novo arrhythmia in the human atrium. METHODS: Eighty cases of focal AT were mapped in the electrophysiology laboratory and challenged with adenosine. Adenosine-sensitive and -insensitive groups were compared with regard to demographics, anatomical distribution, and electrogram characteristics at the tachycardia origin. RESULTS: In response to adenosine, termination occurred in 67 cases (84%), transient suppression in 5 (6%), 6 were insensitive (8%), and 2 exhibited nonspecific responses. Adenosine-insensitive AT arose near the pulmonary vein ostia (4) and from the right atrium (2), whereas adenosine-sensitive AT arose from a wide distribution in both atria. Electrograms at the site of origin for adenosine-insensitive AT were highly fractionated, with longer durations and lower amplitudes compared with AT that terminated or was transiently suppressed. The electrograms at the origin of adenosine-insensitive ATs comprised 22% to 69% of the tachycardia cycle length, compared with 4% to 21% for adenosine-sensitive ATs. In 3 adenosine-insensitive ATs, entrainment was demonstrated with post-pacing intervals equivalent to the tachycardia cycle length. CONCLUSIONS: The characteristics of adenosine-insensitive focal AT differ from adenosine-sensitive AT and are consistent with small re-entrant circuits. These data provide evidence that focal re-entry is a mechanism of AT and has an electropharmacologic profile that differs from AT due to automaticity and triggered activity.

Right and left ventricular outflow tract tachycardias: evidence for a common electrophysiologic mechanism.

INTRODUCTION: "Idiopathic" ventricular arrhythmias most often arise from the right ventricular outflow tract (RVOT), although arrhythmias from the left ventricular outflow tract (LVOT) are also observed. While previous work has elucidated the mechanism and electropharmacologic profile of RVOT arrhythmias, it is unclear whether those from the LVOT share these properties. The purpose of this study was to characterize the electropharmacologic properties of RVOT and LVOT arrhythmias. METHODS AND RESULTS: One hundred twenty-two consecutive patients (61 male; 50.9 +/- 15.2 years) with outflow tract arrhythmias comprise this series, 100 (82%) with an RVOT origin, and 22 (18%) with an LVOT origin. The index arrhythmia was similar: sustained ventricular tachycardia (VT) (RVOT = 28%, LVOT = 36%), nonsustained VT (RVOT = 40%, LVOT = 23%), and premature ventricular complexes (RVOT = 32%, LVOT = 41%) (P = 0.32). Cardiac magnetic resonance imaging and microvolt T-wave alternans results (normal/indeterminate) were also comparable. In addition, 41% with RVOT foci and 50% with LVOT foci were inducible for sustained VT (P = 0.48), and induction of VT was catecholamine dependent in a majority of patients in both groups (66% and 73%; RVOT and LVOT, respectively; P = 1.0). VT was sensitive to adenosine (88% and 78% in the RVOT and LVOT groups, respectively, P = 0.59) as well as blockade of the slow-inward calcium current (RVOT = 70%, LVOT = 80%; P = 1.00) in both groups. CONCLUSIONS: Electrophysiologic and pharmacologic properties, including sensitivity to adenosine, are similar for RVOT and LVOT arrhythmias. Despite disparate sites of origin, these data suggest a common arrhythmogenic mechanism, consistent with cyclic AMP-mediated triggered activity. Based on these similarities, these arrhythmias should be considered as a single entity, and classified together as "outflow tract arrhythmias."

Structural barrier increases QT-peak dispersion in swine left ventricle in vivo.

QT dispersion (QTD) is thought to represent the regional nonuniformity of ventricular repolarization and can serve as a prognostic marker for vulnerability to ventricular arrhythmias and risk for sudden cardiac death (SCD). In this study, we used an in vivo swine model to investigate the change of QT-peak dispersion before and after the introduction of a left-ventricular (LV) free-wall structural barrier (SB). Baseline and post-ablation pacing were delivered to: (i) the epicardial LV base, (ii) the epicardial LV apex, and (iii) the right ventricular (RV) endocardium. Four unipolar electrograms were measured from LV free wall epicardial sites referenced to an intrathorax electrode. An SB (approximately 4 x 1 x 1 cm (length, width, depth)) was created by cryoablation in the middle of the two electrode pairs. QTD was computed as the difference between QT-peak intervals for each beat from two electrodes across the SB region from one another. A significant increase of QTD occurred (p<0.05) after the introduction of the SB in all six animals. These results may reflect the accentuation of anatomical repolarization heterogeneity due to SB disruption of electrotonic coupling. Given the link between dispersion of repolarization and initiation of reentry, these findings are consistent with the increased arrhythmia risk of structural heart disease.

Single-stage adenosine tilt testing in patients with unexplained syncope.

INTRODUCTION: We previously have shown that a 3-minute single-stage adenosine tilt test has a diagnostic yield comparable to a two-stage protocol consisting of a 30-minute drug-free tilt followed by a 15-minute isoproterenol tilt. In this study, we sought to further define the clinical utility of adenosine tilt testing in patients with unexplained syncope by prospectively evaluating test specificity and determining predictors of a positive test response. METHODS AND RESULTS: The specificity of single-stage adenosine tilt testing was determined using 30 control subjects. To determine the diagnostic yield of this protocol, adenosine tilts were performed in 129 patients with unexplained syncope. The adenosine tilt test protocol had high specificity (100%) but a low overall diagnostic yield (18%). However, the yield was affected significantly by age. In patients /=65 years of age (2/41 patients [5%], P < 0.0001). CONCLUSION: These data support single-stage adenosine tilt testing in patients 40 years of age is low, suggesting that the clinical utility of this protocol is limited in these patients.

Significance of adenosine-induced atrioventricular block in patients with unexplained syncope.

OBJECTIVES: The purpose of this study was to test whether a prolonged (>/=6 seconds) period of AV block in response to adenosine triphosphate (ATP) identifies additional patients at risk for bradycardia who may benefit from pacemaker implantation. BACKGROUND: Bradycardia is a common etiology for syncope in patients without underlying structural heart disease. Conventional testing using electrophysiologic and tilt table studies often fail to identify patients prone to episodes of symptomatic bradycardia. METHODS: Adenosine testing was performed in 92 consecutive patients (64 women, age 55 +/- 21 years) with syncope of uncertain origin referred for tilt table testing. The adenosine test measured the maximal R-R interval after bolus administration of intravenous adenosine 150 mug/kg to upright patients. A positive adenosine AV block response was defined as a maximal R-R interval > or =6 seconds. RESULTS: A total of 21 patients (23%) had a positive response. During mean follow-up of 14.3 +/- 5.9 months, 14 patients (16%) had recurrent syncope. Among patients with a positive adenosine response, 3 patients (14%) had recurrent syncope. In comparison, 11 of 69 patients (16%) without adenosine-induced AV block had recurrent syncope (P = 1.00). CONCLUSIONS: Prolonged adenosine-induced AV block in patients with unexplained syncope failed to predict recurrent syncopal episodes. These data do not support therapeutic interventions (e.g., pacemaker implantation) based on a positive adenosine AV block response alone.

Response to adenosine differentiates focal from macroreentrant atrial tachycardia: validation using three-dimensional electroanatomic mapping.

BACKGROUND: We previously proposed that adenosine has mechanism-specific effects on atrial tachycardia (AT), such that adenosine terminates AT attributable to triggered activity, transiently suppresses automatic rhythms, and has no effect on macroreentrant AT. This, however, remains controversial, because other studies have reported that adenosine terminates reentrant AT. To clarify this issue, we used 3D electroanatomic mapping to delineate the tachycardia circuit and thereby determine whether the response to adenosine differentiates focal from macroreentrant AT. METHODS AND RESULTS: We examined the effect of adenosine on 43 ATs in 42 consecutive patients (59+/-15 years of age; 26 female) who received adenosine during tachycardia and whose mechanism of AT was characterized by pharmacological perturbation, entrainment, 3D electroanatomic mapping, and results of radiofrequency ablation. Eight tachycardias were macroreentrant (noncavotricuspid isthmus-dependent), and 35 ATs were focal (either triggered or automatic). Adenosine administered during AT (at doses sufficient to result in AV block) terminated or transiently suppressed focal AT in 33 of 35 cases, whereas 8 of 8 macroreentrant ATs were adenosine insensitive (P<0.001). Twenty-eight of 35 focal ATs were located along the crista terminalis or tricuspid annulus. CONCLUSIONS: The response of AT to adenosine can immediately differentiate atrial tachycardia arising from a focal source from that attributable to macroreentry. This finding can be exploited to facilitate developing a focused, strategic ablative approach at the onset of a procedure.

Lesional tachycardias related to mitral valve surgery.

OBJECTIVES: The purpose of this study was to define the anatomic distribution of electrically abnormal atrial tissue and mechanisms of atrial tachycardia (AT) after mitral valve (MV) surgery. BACKGROUND: Atrial tachycardia is a well-recognized long-term complication of MV surgery. Because atrial incisions from repair of congenital heart defects provide a substrate for re-entrant arrhythmias in the late postoperative setting, we hypothesized that atriotomies or cannulation sites during MV surgery also contributed to postoperative arrhythmias. METHODS: In 10 patients with prior MV surgery, electroanatomic maps were constructed of 11 tachycardias (6 right atrium [RA], 4 left atrium [LA] and 1 biatrial). Activation and voltage maps were used to identify areas of low voltage, double potentials and conduction block. RESULTS: Lesions were present in the lateral wall of the RA (six of seven maps) and in the LA along the septum adjacent to the right pulmonary veins (four of five maps). In 8 of 10 patients, these findings corresponded to atrial incisions or cannulation sites. Arrhythmia mechanisms were identified for 9 of 11 tachycardias. A macro-re-entrant circuit was mapped in six cases, three involving lesions in the lateral wall of the RA and three involving the LA septum and right pulmonary veins. In three of these cases figure-of-eight re-entry was demonstrated, and in the other three a single macro-re-entrant circuit was observed. In three other cases, a focal origin was identified adjacent to abnormal tissue in the RA (two cases) or within a pulmonary vein (one case). CONCLUSIONS: Surgical incisions for MV surgery provide a substrate for atrial arrhythmias. Both macro-re-entrant and focal mechanisms contribute to AT after MV surgery.