A multicenter prospective randomized controlled trial of cardiac resynchronization therapy guided by invasive dP/dt.

BACKGROUND: No periprocedural metric has demonstrated improved cardiac resynchronization therapy (CRT) outcomes in a multicenter setting. OBJECTIVE: We sought to determine if left ventricular (LV) lead placement targeted to the coronary sinus (CS) branch generating the best acute hemodynamic response (AHR) results in improved outcomes at 6 months. METHODS: In this multicenter randomized controlled trial, patients were randomized to guided CRT or conventional CRT. Patients in the guided arm had LV dP/dtmax measured during biventricular (BIV) pacing. Target CS branches were identified and the final LV lead position was the branch with the best AHR and acceptable threshold values. The primary endpoint was the proportion of patients with a reduction in LV end-systolic volume (LVESV) of ≥15% at 6 months. RESULTS: A total of 281 patients were recruited across 12 centers. Mean age was 70.8 ± 10.9 years and 54% had ischemic etiology. Seventy-three percent of patients in the guided arm demonstrated a reduction in LVESV of ≥15% at 6 months vs 60% in the conventional arm (P = .02). Patients with AHR ≥ 10% were more likely to demonstrate a reduction of ESV ≥ 15% (84% of patients with an AHR ≥10% vs 28% with an AHR <10%; P < 0.001). Procedure duration and fluoroscopy times were longer in the pressure wire-guided arm (104 ± 39 minutes vs 142 ± 39 minutes; P < .001 and 20 ±16 minutes vs 28 ± 15 minutes; P = .002). CONCLUSIONS: AHR determined by invasively measuring LV dP/dtmax during BIV pacing predicts reverse remodeling 6 months after CRT. Patients in whom LV dP/dtmax was used to guide LV lead placement demonstrated better rates of reverse remodeling.

Improved identifiability of myocardial material parameters by an energy-based cost function.

Myocardial stiffness is a valuable clinical biomarker for the monitoring and stratification of heart failure (HF). Cardiac finite element models provide a biomechanical framework for the assessment of stiffness through the determination of the myocardial constitutive model parameters. The reported parameter intercorrelations in popular constitutive relations, however, obstruct the unique estimation of material parameters and limit the reliable translation of this stiffness metric to clinical practice. Focusing on the role of the cost function (CF) in parameter identifiability, we investigate the performance of a set of geometric indices (based on displacements, strains, cavity volume, wall thickness and apicobasal dimension of the ventricle) and a novel CF derived from energy conservation. Our results, with a commonly used transversely isotropic material model (proposed by Guccione et al.), demonstrate that a single geometry-based CF is unable to uniquely constrain the parameter space. The energy-based CF, conversely, isolates one of the parameters and in conjunction with one of the geometric metrics provides a unique estimation of the parameter set. This gives rise to a new methodology for estimating myocardial material parameters based on the combination of deformation and energetics analysis. The accuracy of the pipeline is demonstrated in silico, and its robustness in vivo, in a total of 8 clinical data sets (7 HF and one control). The mean identified parameters of the Guccione material law were [Formula: see text] and [Formula: see text] ([Formula: see text], [Formula: see text], [Formula: see text]) for the HF cases and [Formula: see text] and [Formula: see text] ([Formula: see text], [Formula: see text], [Formula: see text]) for the healthy case.

Coupling of ventricular action potential duration and local strain patterns during reverse remodeling in responders and nonresponders to cardiac resynchronization therapy.

BACKGROUND: The high risk of ventricular arrhythmias in patients with heart failure remains despite the benefit of cardiac resynchronization therapy (CRT). An electromechanical interaction between regional myocardial strain patterns and the electrophysiological substrate is thought to be important. OBJECTIVE: We investigated the in vivo relation between left ventricular activation recovery interval (ARI), as a surrogate measure of action potential duration (APD), and local myocardial strain patterns in responders and nonresponders to CRT. METHODS: ARIs were recorded from the left ventricular epicardium in 20 patients with CRT 6 weeks and 6 months post implantation. Two-dimensional speckle tracking echocardiography was performed at the same time to assess myocardial strains. Patients with ≥15% reduction in end-systolic volume at 6 months were classified as responders. RESULTS: ARI decreased in responders (263 ± 46 ms vs 246 ± 47 ms, P < .01) and increased in nonresponders (235 ± 23 ms vs 261 ± 20 ms; P < .01). Time-to-peak radial, circumferential, and longitudinal strains increased in responders (41 ± 27, 35 ± 25, 56 ± 37 ms; P < .01) and decreased in nonresponders (-58 ± 26, -47 ± 26, -64 ± 27 ms; P < .01). There was a nonlinear correlation between changes in time-to-peak strain and ARIs (Spearman correlation coefficient r ≥ 0.70; P < .01). Baseline QRS duration >145 ms and QRS duration shortening with biventricular pacing were associated with ARI shortening following CRT. CONCLUSION: Changes in ventricular wall mechanics predict local APD lengthening or shortening during CRT. Nonresponders have a worsening of myocardial strain and local APD. Baseline QRS duration >145 ms and QRS duration shortening with biventricular pacing identified patients who exhibited improvement in APD.

In Heart Failure Patients with Left Bundle Branch Block Single Lead MultiSpot Left Ventricular Pacing Does Not Improve Acute Hemodynamic Response To Conventional Biventricular Pacing. A Multicenter Prospective, Interventional, Non-Randomized Study.

INTRODUCTION: Recent efforts to increase CRT response by multiSPOT pacing (MSP) from multiple bipols on the same left ventricular lead are still inconclusive. AIM: The Left Ventricular (LV) MultiSPOTpacing for CRT (iSPOT) study compared the acute hemodynamic response of MSP pacing by using 3 electrodes on a quadripolar lead compared with conventional biventricular pacing (BiV). METHODS: Patients with left bundle branch block (LBBB) underwent an acute hemodynamic study to determine the %change in LV+dP/dtmax from baseline atrial pacing compared to the following configurations: BiV pacing with the LV lead in a one of lateral veins, while pacing from the distal, mid, or proximal electrode and all 3 electrodes together (i.e. MSP). All measurements were repeated 4 times at 5 different atrioventricular delays. We also measured QRS-width and individual Q-LV durations. RESULTS: Protocol was completed in 24 patients, all with LBBB (QRS width 171±20 ms) and 58% ischemic aetiology. The percentage change in LV+dP/dtmax for MSP pacing was 31.0±3.3% (Mean±SE), which was not significantly superior to any BiV pacing configuration: 28.9±3.2% (LV-distal), 28.3±2.7% (LV-mid), and 29.5±3.0% (LV-prox), respectively. Correlation between LV+dP/dtmax and either QRS-width or Q-LV ratio was poor. CONCLUSIONS: In patients with LBBB MultiSPOT LV pacing demonstrated comparable improvement in contractility to best conventional BiV pacing. Optimization of atrioventricular delay is important for the best performance for both BiV and MultiSPOT pacing configurations. TRIAL REGISTRATION: ClinicalTrials.gov NTC01883141.

Focal But Not Diffuse Myocardial Fibrosis Burden Quantification Using Cardiac Magnetic Resonance Imaging Predicts Left Ventricular Reverse Modeling Following Cardiac Resynchronization Therapy.

INTRODUCTION: Many heart failure patients with dyssynchrony do not reverse remodel (RR) in response to cardiac resynchronization therapy (CRT). The presence of focal and diffuse interstitial myocardial fibrosis may explain this high nonresponse rate. T1 mapping is a new cardiac magnetic resonance imaging (CMR) technique that overcomes the limitations of conventional contrast CMR and provides reliable quantitative assessment of diffuse myocardial fibrosis. The study tested the hypothesis that focal and diffuse fibrosis quantification would correlate with a lack of left ventricular (LV) RR to CRT. METHODS AND RESULTS: In a prospective study of 48 consecutive patients (27 ischemic cardiomyopathy, 21 dilated cardiomyopathy) LV scar burdens were quantified (scar core and gray zone using late gadolinium enhancement LGE CMR; interstitial fibrosis using T1 mapping) before CRT implant. LV RR was defined by a ≥ 15% reduction in LV end-systolic volume 6 months postimplant. Twenty-seven (56%) patients were responders with RR. Association between scar quantification and LV RR was assessed using the Poisson regression model. Univariate analysis showed that QRS duration/morphology, scar core, and gray zone volumes expressed as % of LV mass and extracellular volume index (ECV) (a measure of interstitial fibrosis from T1 mapping) to be significant predictors of LV RR. Multivariable-adjusted analyses demonstrated scar core quantification (≥ 13.7% LV mass) to be the only independent predictor of LV RR (prevalence ratio 0.40, P = 0.038). CONCLUSIONS: Focal scar burden detected by LGE CMR is associated with a poor response to CRT. Diffuse interstitial fibrosis assessment by T1 mapping, however, is not independently predictive of CRT response.

Mechanistic insights into the benefits of multisite pacing in cardiac resynchronization therapy: The importance of electrical substrate and rate of left ventricular activation.

BACKGROUND: Multisite pacing (MSP) of the left ventricle is proposed as an alternative to conventional single-site LV pacing in cardiac resynchronization therapy (CRT). Reports on the benefits of MSP have been conflicting. A paradigm whereby not all patients derive benefit from MSP is emerging. OBJECTIVE: We sought to compare the hemodynamic and electrical effects of MSP with the aim of identifying a subgroup of patients more likely to derive benefit from MSP. METHODS: Sixteen patients with implanted CRT systems incorporating a quadripolar LV pacing lead were studied. Invasive hemodynamic and electroanatomic assessment was performed during the following rhythms: baseline (non-CRT); biventricular (BIV) pacing delivered via the implanted CRT system (BIV(implanted)); BIV pacing delivered via an alternative temporary LV lead (BIV(alternative)); dual-vein MSP delivered via 2 LV leads; MultiPoint Pacing delivered via 2 vectors of the quadripolar LV lead. RESULTS: Seven patients had an acute hemodynamic response (AHR) of <10% over baseline rhythm with BIV(implanted) and were deemed nonresponders. AHR in responders vs nonresponders was 21.4% ± 10.4% vs 2.0% ± 5.2% (P < .001). In responders, neither form of MSP provided incremental hemodynamic benefit over BIV(implanted). Dual-vein MSP (8.8% ± 5.7%; P = .036 vs BIV(implanted)) and MultiPoint Pacing (10.0% ± 12.2%; P = .064 vs BIV(implanted)) both improved AHR in nonresponders. Seven of 9 responders to BIV(implanted) had LV endocardial activation characterized by a functional line of block during intrinsic rhythm that was abolished with BIV pacing. All these patients met strict criteria for left bundle branch block (LBBB). No nonresponders exhibited this line of block or met strict criteria for LBBB. CONCLUSION: Patients not meeting strict criteria for LBBB appear most likely to derive benefit from MSP.

A randomized prospective mechanistic cardiac magnetic resonance study correlating catheter stability, late gadolinium enhancement and 3 year clinical outcomes in robotically assisted vs. standard catheter ablation.

AIMS: To prospectively compare cardiac magnetic resonance late gadolinium enhancement (LGE) findings created by standard vs. robotically assisted catheter ablation lesions and correlate these with clinical outcomes. METHODS AND RESULTS: Forty paroxysmal atrial fibrillation patients (mean age 54 ± 13.8 years) undergoing first left atrial ablation were randomized to either robotic-assisted navigation (Hansen Sensei(®) X) or standard navigation. Pre-procedural, acute (24 h post-procedure) and late (beyond 3 months) scans were performed with LGE and T2W imaging sequences and percentage circumferential enhancement around the pulmonary vein (PV) antra were quantified. Baseline pre-procedural enhancements were similar in both groups. On acute imaging, mean % encirclements by LGE and T2W signal were 72% and 80% in the robotic group vs. 60% (P = 0.002) and 76%(P = 0.45) for standard ablation. On late imaging, the T2W signal resolved to baseline in both groups. Late gadolinium enhancement remained the predominant signal with 56% encirclement in the robotic group vs. 45% in the standard group (P = 0.04). At 6 months follow-up, arrhythmia-free patients had an almost similar mean LGE encirclement (robotic 64%, standard 60%, P = 0.45) but in recurrences, LGE was higher in the robotic group (43% vs. 30%, P = 0.001). At mean 3 years follow-up, 1.3 procedures were performed in the robotic group compared with 1.9 (P < 0.001) in the standard to achieve a success rate of 80% vs. 75%. CONCLUSION: Robotically assisted ablation results in greater LGE around the PV antrum. Effective lesions created through improved catheter stability and contact force during initial treatment may have a role in reducing subsequent re-do procedures.

Velocity-based cardiac contractility personalization from images using derivative-free optimization.

Model personalization is a key aspect for biophysical models to impact clinical practice, and cardiac contractility personalization from medical images is a major step in this direction. Existing gradient-based optimization approaches show promising results of identifying the maximum contractility from images, but the contraction and relaxation rates are not accounted for. A main reason is the limited choices of objective functions when their gradients are required. For complicated cardiac models, analytical evaluations of gradients are very difficult if not impossible, and finite difference approximations are computationally expensive and may introduce numerical difficulties. By removing such limitations with derivative-free optimization, we found that a velocity-based objective function can properly identify regional maximum contraction stresses, contraction rates, and relaxation rates simultaneously with intact model complexity. Experiments on synthetic data show that the parameters are better identified using the velocity-based objective function than its position-based counterpart, and the proposed framework is insensitive to initial parameters with the adopted derivative-free optimization algorithm. Experiments on clinical data show that the framework can provide personalized contractility parameters which are consistent with the underlying physiologies of the patients and healthy volunteers.

Repeat left atrial catheter ablation: cardiac magnetic resonance prediction of endocardial voltage and gaps in ablation lesion sets.

BACKGROUND: Studies have reported an inverse relationship between late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) signal intensity and left atrial (LA) endocardial voltage after LA ablation. However, there is controversy regarding the reproducibility of atrial LGE CMR and its ability to identify gaps in ablation lesions. Using systematic and objective techniques, this study examines the correlation between atrial CMR and endocardial voltage. METHODS AND RESULTS: Twenty patients who had previous ablation for atrial fibrillation and represented with paroxysmal atrial fibrillation or atrial tachycardia underwent preablation LGE CMR. During the ablation procedure, high-density point-by-point Carto voltage maps were acquired. Three-dimensional CMR reconstructions were registered with the Carto anatomies to allow comparison of voltage and LGE signal intensity. Signal intensities around the left and right pulmonary vein antra and along the LA roof and mitral lines on the CMR-segmented LA shells were extracted to examine differences between electrically isolated and reconnected lesions. There were a total of 6767 data points across the 20 patients. Only 119 (1.8%) of the points were ≤ 0.05 mV. There was only a weak inverse correlation between either unipolar (r = -0.18) or bipolar (r = -0.17) voltage and LGE CMR signal intensities with low voltage occurring across a large range of signal intensities. Signal intensities were not statistically different for electrically isolated and reconnected lesions. CONCLUSIONS: This study demonstrates that there is only a weak point-by-point relationship between LGE CMR and endocardial voltage in patients undergoing repeat LA ablation. Using an objective method of assessing gaps in ablation lesions, LGE CMR is unable to reliably predict sites of electrical conduction.

The Effect of Contact Force in Atrial Radiofrequency Ablation: Electroanatomical, Cardiovascular Magnetic Resonance, and Histological Assessment in a Chronic Porcine Model.

OBJECTIVES: This study sought to determine the effect of contact force (CF) on atrial lesion size, quality, and transmurality by using a chronic porcine model of radiofrequency ablation. BACKGROUND: CF is a major determinant of ventricular lesion formation, but uncertainty exists regarding the most appropriate CF parameters to safely achieve permanent, transmural lesions in the atria. METHODS: Intercaval linear ablation (30 W, 42°C, 17 ml/min irrigation) was performed in 8 Göttingen minipigs by using a force-sensing catheter with CF >20 g (high force) or <10 g (low force) at alternate ends of the line, separated by an intentional gap. Voltage mapping and cardiovascular magnetic resonance (CMR) imaging were performed pre-ablation, immediately after ablation, and at 2 months' post-procedure. Lesions were sectioned orthogonal to the axis of ablation to assess transmurality. RESULTS: Mean CF was 22.6 ± 11.4 g and 7.8 ± 4.0 g in the high and low CF regions. Acute tissue edema was greater with high CF, both caudally (7.0 mm vs. 4.6 mm; p = 0.016) and cranially (6.9 mm vs. 4.6 mm; p = 0.038). There was no difference in chronic lesion size (voltage mapping) or volume (late gadolinium enhancement CMR) between high and low CF regions. There was no difference in scar density (assessed by low-voltage criteria and late gadolinium enhancement signal intensity) or histological transmurality between high and low CF regions. CONCLUSIONS: Although high CF (>20 g) resulted in more acute tissue edema than low CF (<10 g), chronically there was no difference in lesion size, quality, or transmurality. Appropriate CF targets for atrial ablation may be lower than previously thought.

Myocardial tissue characterization by cardiac magnetic resonance imaging using T1 mapping predicts ventricular arrhythmia in ischemic and non-ischemic cardiomyopathy patients with implantable cardioverter-defibrillators.

BACKGROUND: Diffuse myocardial fibrosis may provide a substrate for the initiation and maintenance of ventricular arrhythmia. T1 mapping overcomes the limitations of the conventional delayed contrast-enhanced cardiac magnetic resonance (CE-CMR) imaging technique by allowing quantification of diffuse fibrosis. OBJECTIVE: The purpose of this study was to assess whether myocardial tissue characterization using T1 mapping would predict ventricular arrhythmia in ischemic and non-ischemic cardiomyopathies. METHODS: This was a prospective longitudinal study of consecutive patients receiving implantable cardioverter-defibrillators in a tertiary cardiac center. Participants underwent CMR myocardial tissue characterization using T1 mapping and conventional CE-CMR scar assessment before device implantation. The primary end point was an appropriate implantable cardioverter-defibrillator therapy or documented sustained ventricular arrhythmia. RESULTS: One hundred thirty patients (71 ischemic and 59 non-ischemic) were included with a mean follow-up period of 430 ± 185 days (median 425 days; interquartile range 293 days). At follow-up, 23 patients (18%) experienced the primary end point. In multivariable-adjusted analyses, the following factors showed a significant association with the primary end point: secondary prevention (hazard ratio [HR] 1.70; 95% confidence interval [95% CI] 1.01-1.91), noncontrast T1(_native) for every 10-ms increment in value (HR 1.10; CI 1.04-1.16; 90-ms difference between the end point-positive and end point-negative groups), and Grayzone(_2sd-3sd) for every 1% left ventricular increment in value (HR 1.36; CI 1.15-1.61; 4% difference between the end point-positive and end point-negative groups). Other CE-CMR indices including Scar(_2sd), Scar(_FWHM), and Grayzone(_2sd-FWHM) were also significantly, even though less strongly, associated with the primary end point as compared with Grayzone(_2sd-3sd). CONCLUSION: Quantitative myocardial tissue assessment using T1 mapping is an independent predictor of ventricular arrhythmia in both ischemic and non-ischemic cardiomyopathies.

A statistical method for retrospective cardiac and respiratory motion gating of interventional cardiac x-ray images.

PURPOSE: Image-guided cardiac interventions involve the use of fluoroscopic images to guide the insertion and movement of interventional devices. Cardiorespiratory gating can be useful for 3D reconstruction from multiple x-ray views and for reducing misalignments between 3D anatomical models overlaid onto fluoroscopy. METHODS: The authors propose a novel and potentially clinically useful retrospective cardiorespiratory gating technique. The principal component analysis (PCA) statistical method is used in combination with other image processing operations to make our proposed masked-PCA technique suitable for cardiorespiratory gating. Unlike many previously proposed techniques, our technique is robust to varying image-content, thus it does not require specific catheters or any other optically opaque structures to be visible. Therefore, it works without any knowledge of catheter geometry. The authors demonstrate the application of our technique for the purposes of retrospective cardiorespiratory gating of normal and very low dose x-ray fluoroscopy images. RESULTS: For normal dose x-ray images, the algorithm was validated using 28 clinical electrophysiology x-ray fluoroscopy sequences (2168 frames), from patients who underwent radiofrequency ablation (RFA) procedures for the treatment of atrial fibrillation and cardiac resynchronization therapy procedures for heart failure. The authors established end-systole, end-expiration, and end-inspiration success rates of 97.0%, 97.9%, and 97.0%, respectively. For very low dose applications, the technique was tested on ten x-ray sequences from the RFA procedures with added noise at signal to noise ratio (SNR) values of √50, √10, √8, √6, √5, √2 and √1 to simulate the image quality of increasingly lower dose x-ray images. Even at the low SNR value of √2, representing a dose reduction of more than 25 times, gating success rates of 89.1%, 88.8%, and 86.8% were established. CONCLUSIONS: The proposed technique can therefore extract useful information from interventional x-ray images while minimizing exposure to ionizing radiation.

Combined identification of septal flash and absence of myocardial scar by cardiac magnetic resonance imaging improves prediction of response to cardiac resynchronization therapy.

BACKGROUND AND AIMS OF STUDY: Septal flash (SF) describes early inward motion of the ventricular septum in patients with left bundle branch block (LBBB), and correction corresponds to increased response to cardiac resynchronization therapy (CRT). SF has traditionally been assessed by echocardiography. We sought to determine if cardiac magnetic resonance (CMR) imaging could identify SF and if the additional assessment of scar would improve the ability of CMR to predict CRT response. METHODS: Fifty-two patients with LBBB and heart failure underwent prospective CMR scanning prior to CRT implantation. The presence of SF was assessed visually and by using endocardial contour-tracking software. Presence and extent of myocardial scar was assessed by delayed enhancement imaging during CMR. The association between SF, scar and reverse remodelling (RR) at 6 months was explored. RESULTS: RR rate to CRT at 6 months was 52%. CMR-derived SF was identified in 24 (46%) patients. RR was seen in more patients with SF than those without (88% vs 21%; P < 0.001). The absence of scar combined with the presence of SF had 96% specificity for predicting RR. In a multivariate regression model, the presence of SF was the only independent predictor of RR. CONCLUSION: SF can be assessed by CMR and predicts increased response to CRT. The additional value of CMR is the assessment of scar. The presence of SF with no scar is a highly specific predictor of CRT response.

Delayed trans-septal activation results in comparable hemodynamic effect of left ventricular and biventricular endocardial pacing: insights from electroanatomical mapping.

BACKGROUND: We sought to compare left ventricular (LVepi) and biventricular epicardial pacing (BIVepi) with LV (LVendo) and BIV endocardial pacing (BIVendo) in patients with chronic heart failure with an emphasis on the underlying electrophysiological mechanisms and hemodynamic effects. METHODS AND RESULTS: Ten patients with chronically implanted cardiac resynchronization devices underwent temporary LVendo and BIVendo pacing with an LV endocardial roving catheter. A pressure wire and noncontact mapping array were placed to the LV cavity to measure LVdP/dtmax and perform electroanatomical mapping. At the optimal endocardial position, the acute hemodynamic response (AHR) was superior to epicardial stimulation, the AHR to BIVendo pacing and LVendo pacing being comparable (21±15% versus 22±17%; P=NS). During intrinsic conduction, QRS duration was 185±30 ms, endocardial LV total activation time 92±27 ms, and trans-septal activation time 60±21 ms. With LVendo pacing, QRS duration (187±29 ms; P=NS) and endocardial LV total activation time (91±23 ms; P=NS) were comparable with intrinsic conduction. There was no significant difference in endocardial LV total activation time between LVendo and BIVendo pacing (91±23 versus 85±15 ms; P=NS). Assessment of isochronal maps identified slow trans-septal conduction with both LVendo and BIVendo pacing resulting in activation of almost the entire LV endocardium prior to septal breakout, thereby limiting any possible fusion with either pacing mode. CONCLUSIONS: The equivalent AHR to LVendo and BIVendo pacing may be explained by prolonged trans-septal conduction limiting fusion of electrical wavefronts. The optimal AHR was associated with predominantly LV pre-excitation and depolarization. Our results suggest that LV pacing alone may offer a viable endocardial stimulation strategy to achieve cardiac resynchronization.