Randomized controlled trial of mechanical thrombectomy vs catheter-directed thrombolysis for acute hemodynamically stable pulmonary embolism: Rationale and design of the PEERLESS study.

BACKGROUND: The identification of hemodynamically stable pulmonary embolism (PE) patients who may benefit from advanced treatment beyond anticoagulation is unclear. However, when intervention is deemed necessary by the PE patient's care team, data to select the most advantageous interventional treatment option are lacking. Limiting factors include major bleeding risks with systemic and locally delivered thrombolytics and the overall lack of randomized controlled trial (RCT) data for interventional treatment strategies. Considering the expansion of the pulmonary embolism response team (PERT) model, corresponding rise in interventional treatment, and number of thrombolytic and nonthrombolytic catheter-directed devices coming to market, robust evidence is needed to identify the safest and most effective interventional option for patients. METHODS: The PEERLESS study (ClinicalTrials.gov identifier: NCT05111613) is a currently enrolling multinational RCT comparing large-bore mechanical thrombectomy (MT) with the FlowTriever System (Inari Medical, Irvine, CA) vs catheter-directed thrombolysis (CDT). A total of 550 hemodynamically stable PE patients with right ventricular (RV) dysfunction and additional clinical risk factors will undergo 1:1 randomization. Up to 150 additional patients with absolute thrombolytic contraindications may be enrolled into a nonrandomized MT cohort for separate analysis. The primary end point will be assessed at hospital discharge or 7 days post procedure, whichever is sooner, and is a composite of the following clinical outcomes constructed as a hierarchal win ratio: (1) all-cause mortality, (2) intracranial hemorrhage, (3) major bleeding, (4) clinical deterioration and/or escalation to bailout, and (5) intensive care unit admission and length of stay. The first 4 components of the win ratio will be adjudicated by a Clinical Events Committee, and all components will be assessed individually as secondary end points. Other key secondary end points include all-cause mortality and readmission within 30 days of procedure and device- and drug-related serious adverse events through the 30-day visit. IMPLICATIONS: PEERLESS is the first RCT to compare 2 different interventional treatment strategies for hemodynamically stable PE and results will inform strategy selection after the physician or PERT determines advanced therapy is warranted.

Mapping-guided characterization of mechanical and electrical activation patterns in patients with normal systolic function using a sensor-based tracking technology.

AIMS: In times of evolving cardiac resynchronization therapy, intra-procedural characterization of left ventricular (LV) mechanical activation patterns is desired but technically challenging with currently available technologies. In patients with normal systolic function, we evaluated the feasibility of characterizing LV wall motion using a novel sensor-based, real-time tracking technology. METHODS AND RESULTS: Ten patients underwent simultaneous motion and electrical mapping of the LV endocardium during sinus rhythm using electroanatomical mapping and navigational systems (EnSite™ NavX™ and MediGuide™, SJM). Epicardial motion data were also collected simultaneously at corresponding locations from accessible coronary sinus branches. Displacements at each mapping point and times of electrical and mechanical activation were combined over each of the six standard LV wall segments. Mechanical activation timing was compared with that from electrical activation and preoperative 2D speckle tracking echocardiography (echo). MediGuide-based displacement data were further analysed to estimate LV chamber volumes that were compared with echo and magnetic resonance imaging (MRI). The lateral and septal walls exhibited the largest (12.5 [11.6-15.0] mm) and smallest (10.2 [9.0-11.3] mm) displacement, respectively. Radial displacement was significantly larger endocardially than epicardially (endo: 6.7 [5.0-9.1] mm; epi: 3.8 [2.4-5.6] mm), while longitudinal displacement was significantly larger epicardially (endo: 8.0 [5.0-10.6] mm; epi: 10.3 [7.4-13.8] mm). Most often, the anteroseptal/anterior and lateral walls showed the earliest and latest mechanical activations, respectively. 9/10 patients had concordant or adjacent wall segments of latest mechanical and electrical activation, and 6/10 patients had concordant or adjacent wall segments of latest mechanical activation as measured by MediGuide and echo. MediGuide's LV chamber volumes were significantly correlated with MRI (R2= 0.73, P < 0.01) and echo (R2= 0.75, P < 0.001). CONCLUSION: The feasibility of mapping-guided intra-procedural characterization of LV wall motion was established. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov; Unique identifier: CT01629160.

Three-Dimensional Cardiac Mapping Characterizes Ventricular Contractile Patterns during Cardiac Resynchronization Therapy Implant: A Feasibility Study.

BACKGROUND: Electroanatomic mapping systems track the position of electrodes in the heart. We assessed the feasibility of characterizing left ventricular (LV) performance during cardiac resynchronization therapy (CRT) implant utilizing an electroanatomic mapping system to track the motion of CRT lead electrodes, thus deriving ventricular contractility surrogates. METHODS: During CRT implant, atrial, right ventricular (RV), and LV leads were connected to the EnSite NavX™ mapping system (St. Jude Medical Inc., St. Paul, MN, USA). The relative displacement of electrodes was averaged over 10 cardiac cycles during RV, LV, and biventricular (BiV) pacing in DOO mode. Three contractility surrogates indicative of ventricular performance were extracted from the RV-LV distance waveform: systolic slope (SS), time to peak systolic contraction (TPSC), and fractional shortening (FS). RESULTS: In the 20 patients included, there were detectable differences in each of the three contractility surrogates responding to the different pacing configurations. Median SS varied 42%, median TPSC varied 35%, and median FS varied 19% across RV, LV, and BiV pacing interventions. The RV-LV distance waveform showed subtle sensitivity to varying pacing timing cycles when measured in a subset of patients. For all pacing configurations, RV-LV distance waveforms were stable during 2-minute recordings. CONCLUSIONS: Tracking the motion of CRT pacing electrodes with a mapping system to derive contractility surrogates during implant is feasible.

A comparison of left ventricular endocardial, multisite, and multipolar epicardial cardiac resynchronization: an acute haemodynamic and electroanatomical study.

AIMS: Alternative forms of cardiac resynchronization therapy (CRT), including biventricular endocardial (BV-Endo) and multisite epicardial pacing (MSP), have been developed to improve response. It is unclear which form of stimulation is optimal. We aimed to compare the acute haemodynamic response (AHR) and electrophysiological effects of BV-Endo with MSP via two separate coronary sinus (CS) leads or a single-quadripolar CS lead. METHODS AND RESULTS: Fifteen patients with a previously implanted CRT system received a second temporary CS lead and left ventricular (LV) endocardial catheter. A pressure wire and non-contact mapping array were placed into the LV cavity to measure LVdP/dtmax and perform electroanatomical mapping. Conventional CRT, BV-Endo, and MSP were then performed (MSP-1 via two epicardial leads and MSP-2 via a single-quadripolar lead). The best overall AHR was found using BV-Endo pacing with a 19.6 ± 13.6% increase in AHR at the optimal endocardial site over baseline (P < 0.001). There was an increase in LVdP/dtmax with MSP-1 and MSP-2 compared with conventional CRT, but this was not statistically significant. Biventricular endocardial pacing from the optimal site was significantly superior to conventional CRT (P = 0.039). The AHR achieved when BV-Endo pacing was highly site specific. Within individuals, the best pacing modality varied and was affected by the underlying substrate. Left ventricular activation times did not predict the optimal haemodynamic configuration. CONCLUSION: Biventricular endocardial pacing and not MSP was superior to conventional CRT, but was highly site specific. Within individuals, however, different methods of stimulation are optimal and may need to be tailored to the underlying substrate.

Simultaneous electrical and mechanical mapping using 3D cardiac mapping system: novel approach for optimal cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) restores synchrony in heart failure patients. However, a significant proportion of patients implanted with CRT devices do not realize any benefit from CRT. Placing a left ventricular (LV) lead at the sites of electrical or mechanical delay has been advocated to maximize response to CRT, but there is currently no technique described to measure mechanical delay in real-time. We describe a novel technique that can be used intraoperatively to assess mechanical and electrical activation of the coronary sinus for guidance of LV pacing site optimization during CRT implantation.

Attenuation of left ventricular adverse remodeling with epicardial patching after myocardial infarction.

BACKGROUND: Previous studies suggested that epicardial patch applied to the infarcted site after acute myocardial infarction (MI) can alleviate left ventricular (LV) remodeling and improve cardiac performance; however, the effects of regional epicardial patch on chronic phase of LV remodeling remain unclear. METHODS AND RESULTS: We studied 20 pigs with MI induced by distal embolization and impaired LV ejection fraction (LVEF < 45%) as detected by gadolinium-enhanced cardiac magnetic resonance imaging (MRI). Eight weeks post-MI, all animal underwent open chest procedure for sham surgery (control, n = 12) or patch implantation over the infarcted lateral LV wall (patch group, n = 12). In the patch group, +dP/dt increased and LV end-diastolic pressure decreased at 20 weeks compared with immediately post-MI and at 8 weeks (P < .05), but not in the control group (P > .05). As determined by cardiac MRI, LV end-diastolic and end-systolic volumes increased at 20 weeks compared with 8 weeks in both groups (P < .05). However, the increase in LV end-diastolic volume (+14.1 +/- 1.8% vs. +6.6 +/- 2.1%, P = .015) and LV end-systolic volume (+12.1 +/- 2.4% vs. -4.7 +/- 3.7%, P = .0015) were significantly greater in the control group compared with the patch group. Furthermore, the percentage increase in LVEF (+17.3 +/- 4.9% vs. +4.1 +/- 3.9%, P = .048) from 8 to 20 weeks was significantly greater in the patch group compared with the control group. Histological examination showed that LV wall thickness at the infarct region and adjacent peri-infarct regions were significantly greater in the patch group compared with the control group (P < .05). CONCLUSION: Regional application of a simple, passive synthetic epicardial patch increased LV wall thickness at the infarct region, attenuated LV dilation, and improved LVEF and +dP/dt in a large animal model of MI.

Modeling dermatome selectivity of single-and multiple-current source spinal cord stimulation systems.

A recently published computational modeling study of spinal cord stimulation (SCS) predicted that a multiple current source (MCS) system could generate a greater number of central points of stimulation in the dorsal column (DC) than a single current source (1 CS) system. However, the clinical relevance of this finding has not been established. The objective of this work was to compare the dermatomal zone selectivity of MCS and 1 CS systems. A finite element method (FEM) model was built with a representation of the spinal cord anatomy and a 2 × 8 paddle electrode array. Using a contact configuration with two aligned tripoles, the FEM model was used to solve for DC field potentials across incremental changes in current between the two cathodes, modeling the MCS and 1 CS systems. The activation regions within the DC were determined by coupling the FEM output to a biophysical nerve fiber model, and coverage was mapped to dermatomal zones. Results showed marginal differences in activated dermatomal zones between 1 CS and MCS systems. This indicates that a MCS system may not provide incremental therapeutic benefit as suggested in prior analysis.

Computational modeling analysis of a spinal cord stimulation paddle lead reveals broad, gapless dermatomal coverage.

Spinal cord stimulation (SCS) is an effective therapy for treating chronic pain. The St. Jude Medical PENTA(TM) paddle lead features a 4 × 5 contact array for achieving broad, selective coverage of dorsal column (DC) fibers. The objective of this work was to evaluate DC activation regions that correspond to dermatomal coverage with use of the PENTA lead in conjunction with a lateral sweep programming algorithm. We used a two-stage computational model, including a finite element method model of field potentials in the spinal cord during stimulation, coupled to a biophysical cable model of mammalian, myelinated nerve fibers to determine fiber activation within the DC. We found that across contact configurations used clinically in the sweep algorithm, the activation region shifted smoothly between left and right DC, and could achieve gapless medio-lateral coverage in dermatomal fiber tract zones. Increasing stimulation amplitude between the DC threshold and discomfort threshold led to a greater area of activation and number of dermatomal zones covered on the left and/or right DC, including L1-2 zones corresponding to dermatomes of the lower back. This work demonstrates that the flexibility in contact selection offered by the PENTA lead may enable patient-specific tailoring of SCS.

Spinal cord stimulation is safe and feasible in patients with advanced heart failure: early clinical experience.

AIMS: Pre-clinical work suggests that upper thoracic spinal cord stimulation (SCS) may have therapeutic effects in the treatment of heart failure (HF). We therefore aim to assess the safety and feasibility of SCS in HF patients. METHODS AND RESULTS: A prospective, randomized, double-blind, crossover pilot study was conducted in symptomatic HF patients receiving optimal medical therapy. Patients were implanted with an SCS system and randomized to an SCS-ACTIVE, delivered at 90% paraesthesia threshold, or an SCS-INACTIVE phase for 3 months, followed by a 1-month washout period and crossover to the alternative phase. The safety of SCS therapy was assessed by death and cardiac events. Implantable cardioverter defibrillator (ICD) function in the presence of SCS was tested by defibrillation testing during SCS system implant and review of real-time and stored electrograms during follow-up. The efficacy of SCS therapy was assessed by changes in patient symptoms, LV function, and BNP level. Nine patients were investigated. In all cases, ICD sensing, detection, and therapy delivery were unaffected by SCS. During follow-up, one patient died and one was hospitalized for HF while in the SCS-INACTIVE phase, and two patients had HF hospitalizations during the SCS-ACTIVE phase. Symptoms were improved in the majority of patients with SCS, while markers of cardiac structure and function were, in aggregate, unchanged. CONCLUSION: This study shows that an SCS system can be safely implanted in patients with advanced HF and that the SCS system does not interfere with ICD function.

The freedom to heal: nonrigid immobilization by a halo orthosis.

Halo orthoses present a paradox. On the one hand, the nominally rigid immobilization they provide to the head aims to remove loads on the cervical spine following injury or surgery, and the devices are retightened routinely to maintain this. On the other hand, bone growth and remodeling are well known to require mechanical stressing. How are these competing needs balanced? To understand this trade-off in an effective, commercial halo orthosis, the authors quantified the response of a commercial halo orthosis to physiological loading levels, applied symmetrically about the sagittal plane. They showed for the first time that after a few cycles of loading analogous to a few steps taken by a patient, the support presented by a standard commercial halo orthosis becomes nonlinear. When analyzed through straightforward structural modeling, these data revealed that the nonlinearity permits mild head motion while severely restricting larger motion. These observations are useful because they open the possibility that halo orthosis installation could be optimized to transfer mild spinal loads that support healing while blocking pathological loads.

Intraoperative characterization of interventricular mechanical dyssynchrony using electroanatomic mapping system--a feasibility study.

BACKGROUND: Interventricular mechanical dyssynchrony (VVMD) is a strong predictor of cardiac resynchronization therapy (CRT) response. However, no simple and reliable clinical method of measuring VVMD during CRT implant is currently available. We tested the hypothesis that the EnSite™ NavX™ system (St. Jude Medical, St. Paul, MN, USA) can be used intraoperatively to determine VVMD, thereby facilitating CRT optimization. METHODS: During CRT implant, the leads in the right atrium (RA), right ventricle (RV), and left ventricle (LV) were connected to the EnSite™ NavX™ system to record the real-time 3D motion of the lead electrodes. The distances from RA to RV lead electrodes (RA-RV) and RA to LV lead electrodes (RA-LV) were computed over ten cardiac cycles during each of RV pacing and biventricular (BiV) pacing, respectively. The degree of synchrony was computed from the distance waveforms between RA-RV and RA-LV by a cross-covariance method to characterize VVMD. Septal-to-posterior wall motion delay (SPWMD) from M-mode echocardiography (echo) was measured for reference at each pacing intervention. VVMD was present in all five patients undergoing CRT implant. RESULTS: Four of the five patients demonstrated clear improvement in EnSite™ NavX™-derived VVMD during BiV versus RV pacing, which corresponded to the SPWMD results by echo. CONCLUSIONS: It is feasible to characterize VVMD and resynchronization in CRT patients with the EnSite™ NavX™ system during implant, demonstrating its potential as a tool for intraoperative CRT optimization.

Spinal cord stimulation protects against atrial fibrillation induced by tachypacing.

BACKGROUND: Spinal cord stimulation (SCS) has been shown to modulate atrial electrophysiology and confer protection against ischemia and ventricular arrhythmias in animal models. OBJECTIVE: To determine whether SCS reduces the susceptibility to atrial fibrillation (AF) induced by tachypacing (TP). METHODS: In 21 canines, upper thoracic SCS systems and custom cardiac pacing systems were implanted. Right atrial and left atrial effective refractory periods were measured at baseline and after 15 minutes of SCS. Following recovery in a subset of canines, pacemakers were turned on to induce AF by alternately delivering TP and searching for AF. Canines were randomized to no SCS therapy (CTL) or intermittent SCS therapy on the initiation of TP (EARLY) or after 8 weeks of TP (LATE). AF burden (percent AF relative to total sense time) and AF inducibility (percentage of TP periods resulting in AF) were monitored weekly. After 15 weeks, echocardiography and histology were performed. RESULTS: Effective refractory periods increased by 21 ± 14 ms (P = .001) in the left atrium and 29 ± 12 ms (P = .002) in the right atrium after acute SCS. AF burden was reduced for 11 weeks in EARLY compared with CTL (P <.05) animals. AF inducibility remained lower by week 15 in EARLY compared with CTL animals (32% ± 10% vs 91% ± 6%; P <.05). AF burden and inducibility were not significantly different between LATE and CTL animals. There were no structural differences among any groups. CONCLUSIONS: SCS prolonged atrial effective refractory periods and reduced AF burden and inducibility in a canine AF model induced by TP. These data suggest that SCS may represent a treatment option for AF.