Synchronization of repolarization after cardiac resynchronization therapy: A combined clinical and modeling study.

INTRODUCTION: The changes in ventricular repolarization after cardiac resynchronization therapy (CRT) are poorly understood. This knowledge gap is addressed using a multimodality approach including electrocardiographic and echocardiographic measurements in patients and using patient-specific computational modeling. METHODS: In 33 patients electrocardiographic and echocardiographic measurements were performed before and at various intervals after CRT, both during CRT-ON and temporary CRT-OFF. T-wave area was calculated from vectorcardiograms, and reconstructed from the 12-lead electrocardiography (ECG). Computer simulations were performed using a patient-specific eikonal model of cardiac activation with spatially varying action potential duration (APD) and repolarization rate, fit to a patient's ECG. RESULTS: During CRT-ON T-wave area diminished within a day and remained stable thereafter, whereas QT-interval did not change significantly. During CRT-OFF T-wave area doubled within 5 days of CRT, while QT-interval and peak-to-end T-wave interval hardly changed. Left ventricular (LV) ejection fraction only increased significantly increased after 1 month of CRT. Computer simulations indicated that the increase in T-wave area during CRT-OFF can be explained by changes in APD following chronic CRT that are opposite to the change in CRT-induced activation time. These APD changes were associated with a reduction in LV dispersion in repolarization during chronic CRT. CONCLUSION: T-wave area during CRT-OFF is a sensitive marker for adaptations in ventricular repolarization during chronic CRT that may include a reduction in LV dispersion of repolarization.

T-wave area as biomarker of clinical response to cardiac resynchronization therapy.

AIMS: There is increasing evidence that left bundle branch block (LBBB) morphology on the electrocardiogram is a positive predictor for response to cardiac resynchronization therapy (CRT). We previously demonstrated that the vectorcardiography (VCG)-derived T-wave area predicts echocardiographic CRT response in LBBB patients. In the present study, we investigate whether the T-wave area also predicts long-term clinical outcome to CRT. METHODS AND RESULTS: This is a retrospective study consisting of 335 CRT recipients. Primary endpoint were the composite of heart failure (HF) hospitalization, heart transplantation, left ventricular assist device implantation or death during a 3-year follow-up period. HF hospitalization and death alone were secondary endpoints. The patient subgroup with a large T-wave area and LBBB 36% reached the primary endpoint, which was considerably less (P < 0.01) than for patients with LBBB and a small T-wave area or non-LBBB patients with a small or large T-wave area (48, 57, and 51%, respectively). Similar differences were observed for the secondary endpoints, HF hospitalization (31 vs. 51, 51, and 38%, respectively, P < 0.01) and death (19 vs. 42, 34, and 42%, respectively, P < 0.01). In multivariate analysis, a large T-wave area and LBBB were the only independent predictors of the combined endpoint besides high creatinine levels and use of diuretics. CONCLUSION: T-wave area may be useful as an additional biomarker to stratify CRT candidates and improve selection of those most likely to benefit from CRT. A large T-wave area may derive its predictive value from reflecting good intrinsic myocardial properties and a substrate for CRT.

T-wave area predicts response to cardiac resynchronization therapy in patients with left bundle branch block.

INTRODUCTION: Chronic heart failure patients with a left ventricular (LV) conduction delay, mostly due to left bundle branch block (LBBB), generally derive benefit from cardiac resynchronization therapy (CRT). However, 30-50% of patients do not show a clear response to CRT. We investigated whether T-wave analysis of the ECG can improve patient selection. METHODS AND RESULTS: The study population comprised 244 CRT recipients with baseline 12-lead electrocardiogram recordings. Echocardiographic response after 6-month CRT was defined as a ≥5% increase in LV ejection fraction (LVEF). Vectorcardiograms (VCGs) were constructed from the measured 12-lead ECGs using an adapted Kors algorithm on digitized ECGs. Logistic regression models indicated repolarization variables as good predictors of CRT response. The VCG-derived T-wave area predicted CRT response (odds ratio [OR] per 10 µVs increase 1.172 [P < 0.001]) even better than QRS-wave area (OR = 1.116 [P = 0.001]). T-wave area had especially predictive value in the LBBB patient group (OR = 2.77 in LBBB vs. 1.09 in non-LBBB). This predictive value persisted after adjustment of multiple covariates, such as gender, ischemia, age, hypertension, coronary artery bypass graft, and the usage of diuretics and ß-blockers. In LBBB patients, the increase in LVEF was 6.1 ± 9.7% and 11.3 ± 9.1% in patients with T-wave area below and above the median value, respectively (P < 0.01). CONCLUSION: In patients with LBBB morphology of the QRS complex, a larger baseline T-wave area is an important independent predictor of LVEF increase following CRT.

Vectorcardiographic QRS area as a novel predictor of response to cardiac resynchronization therapy.

BACKGROUND: QRS duration and left bundle branch block (LBBB) morphology are used to select patients for cardiac resynchronization therapy (CRT). We investigated whether the area of the QRS complex (QRSAREA) on the 3-dimensional vectorcardiogram (VCG) can improve patient selection. METHODS: VCG (Frank orthogonal lead system) was recorded prior to CRT device implantation in 81 consecutive patients. VCG parameters, including QRSAREA, were assessed, and compared to QRS duration and morphology. Three LBBB definitions were used, differing in requirement of mid-QRS notching. Responders to CRT (CRT-R) were defined as patients with ≥15% reduction in left ventricular end systolic volume after 6months of CRT. RESULTS: Fifty-seven patients (70%) were CRT-R. QRSAREA was larger in CRT-R than in CRT non-responders (140±42 vs 100±40 µVs, p<0.001) and predicted CRT response better than QRS duration (AUC 0.78 vs 0.62, p=0.030). With a 98µVs cutoff value, QRSAREA identified CRT-R with an odds ratio (OR) of 10.2 and a 95% confidence interval (CI) of 3.4 to 31.1. This OR was higher than that for QRS duration >156ms (OR=2.5; 95% CI 0.9 to 6.6), conventional LBBB classification (OR=5.5; 95% CI 0.9 to 32.4) or LBBB classification according to American guidelines (OR=4.5; 95% CI 1.6 to 12.6) or Strauss (OR=10.0; 95% CI 3.2 to 31.1). CONCLUSION: QRSAREA is an objective electrophysiological predictor of CRT response that performs at least as good as the most refined definition of LBBB. CONDENSED ABSTRACT: In 81 candidates for cardiac resynchronization therapy (CRT) we measured the area of the QRS complex (QRSAREA) using 3-dimensional vectorcardiography. QRSAREA was larger in echocardiographic responders than in non-responders and predicted CRT response better than QRS duration and than simple LBBB criteria. QRSAREA is a promising electrophysiological predictor of CRT response.

The synthesized vectorcardiogram resembles the measured vectorcardiogram in patients with dyssynchronous heart failure.

BACKGROUND: The use of vectorcardiography (VCG) has regained interest, however, original Frank-VCG equipment is rare. This study compares the measured VCGs with those synthesized from the 12-lead electrocardiogram (ECG) in patients with heart failure and conduction abnormalities, who are candidate for cardiac resynchronization therapy (CRT). METHODS: In 92 CRT candidates, Frank-VCG and 12-lead ECG were recorded before CRT implantation. The ECG was converted to a VCG using the Kors method (Kors-VCG) and the two methods were compared using correlation and Bland-Altman analyses. RESULTS: Variables calculated from the Frank- and Kors-VCG showed correlation coefficients between 0.77 and 0.90. There was a significant but small underestimation by the Kors-VCG method, relative bias ranging from -1.9% ± 4.6% (QRS-T angle) to -9.4% ± 20.8% (T area). CONCLUSION: The present study shows that it is justified to use Kors-VCG calculations for VCG analysis, which enables retrospective VCG analysis of previously recorded ECGs in studies related to CRT.

Comparison of septal strain patterns in dyssynchronous heart failure between speckle tracking echocardiography vendor systems.

AIM: To analyze inter-vendor differences of speckle tracking echocardiography (STE) in imaging cardiac deformation in patients with dyssynchronous heart failure. METHODS AND RESULTS: Eleven patients (all with LBBB, median age 60.7 years, 9 males) with implanted cardiac resynchronization therapy devices were prospectively included. Ultrasound systems of two vendors (i.e. General Electric and Philips) were used to record images in the apical four chamber view. Regional longitudinal strain patterns were analyzed with vendor specific software in the basal, mid and apical septal segments. Systolic strain (SS), time to peak strain (TTP) and septal rebound stretch (SRS) were determined during four pacing settings, resulting in 44 unique strain patterns per segment (total 132 patterns). Cross correlation was used to analyze the comparability of the shape of 132 normalized strain patterns. Correlation of strain patterns of the two systems was high (R(2) median: 0.68, interquartile range: 0.53-0.82). Accordingly, strain patterns of intrinsic rhythm were recognized equally using both systems, when divided into three types. GE based SS (18.9 ± 4.7%) was significantly higher than SS determined by the Philips system (13.4 ± 4.3%). TTP was slightly but non-significantly lower in GE (384 ± 77 ms) compared to Philips (404 ± 83 ms) derived strain signals. Correlation of SRS between the systems was poor, due to minor differences in the strain signal and timing of aortic valve closure. CONCLUSIONS: The two systems provide similar shape of strain patterns. However, important differences are found in the amplitude, timing of systole and SRS. Until STE is standardized, clinical decision making should be restricted to pattern analysis.

The value of the 12-lead ECG for evaluation and optimization of cardiac resynchronization therapy in daily clinical practice.

Based on existing literature and some new data we propose a simple three-step strategy using the standard 12-lead ECG for patient selection and optimal delivery of cardiac resynchronization therapy (CRT). (1) Complete LBBB with regard to the indication for CRT can probably best be identified by a QRS duration of ≥ 130 ms for women and ≥ 120 ms for men with the presence of mid-QRS notch-/slurring in ≥ 2 contiguous leads of V1, V2, V5, V6, I and aVL. (2) Left ventricular (LV) free wall pacing should result in a positive QRS complex in lead V1, with estimation of the exact LV lead position in the circumferential and apico-basal direction using lead aVF and the precordial leads, respectively. Wide and fractionated LV-paced QRS complexes may indicate pacing in scar tissue. (3) Atrioventricular and interventricular stimulation intervals may be optimized by adjusting them until precordial leads show fusion patterns between left and right ventricular activation wavefronts in the QRS complex.

Repolarization changes in patients with heart failure receiving cardiac resynchronization therapy-signs of cardiac memory.

BACKGROUND AND PURPOSE: Cardiac memory is known as T-wave inversions and other repolarization changes after a period of altered ventricular activation, previously mainly studied in structurally normal hearts. We investigated repolarization changes in failing hearts undergoing cardiac resynchronization therapy (CRT). METHODS: Electrocardiogram and vectorcardiogram were recorded before and 1 day and 2 weeks after initiation of CRT in 23 patients with heart failure and left bundle-branch block. RESULTS: After 1 day of CRT, the T vector during intrinsic conduction (left bundle-branch block) had rotated toward the direction of the paced QRS vector; T-vector size had increased with further increase after 2 weeks (T-vector amplitude, 889 ± 277 vs 651 ± 225 µV; T area, 169 ± 70 vs 102 ± 39 µVs; P < .01) accompanied by prolonged repolarization (T peak-to-end, 174 ± 34 vs 127 ± 16; QT interval corrected for heart rate, 541 ± 59 vs 493 ± 33 milliseconds; P < .01). CONCLUSIONS: Repolarization changes are present in patients with heart failure, although less pronounced compared with after right ventricular pacing in structurally normal hearts.

Vectorcardiography for optimization of stimulation intervals in cardiac resynchronization therapy.

Current optimization of atrioventricular (AV) and interventricular (VV) intervals in cardiac resynchronization therapy (CRT) is time consuming and subject to noise. We aimed to prove the principle that the best hemodynamic effect of CRT is achieved by cancelation of opposing electrical forces, detectable from the QRS morphology in the 3D vectorcardiogram (VCG). Different degrees of left (LV) and right ventricular (RV) pre-excitation were induced, using variation in AV intervals during LV pacing in 20 patients with left bundle branch block (LBBB) and variation in VV intervals during biventricular pacing in 18 patients with complete AV block or atrial fibrillation. The smallest QRS vector area identified stimulation intervals with minimal systolic stretch (median difference [IQR] 20 ms [-20, 20 ms] and maximal hemodynamic response (10 ms [-20, 40 ms]). Reliability of VCG measurements was superior to hemodynamic measurements. This study proves the principle that VCG analysis may allow easy and reliable optimization of stimulation intervals in CRT patients.

Strategies to improve cardiac resynchronization therapy.

Cardiac resynchronization therapy (CRT) emerged 2 decades ago as a useful form of device therapy for heart failure associated with abnormal ventricular conduction, indicated by a wide QRS complex. In this Review, we present insights into how to achieve the greatest benefits with this pacemaker therapy. Outcomes from CRT can be improved by appropriate patient selection, careful positioning of right and left ventricular pacing electrodes, and optimal timing of electrode stimulation. Left bundle branch block (LBBB), which can be detected on an electrocardiogram, is the predominant substrate for CRT, and patients with this conduction abnormality yield the most benefit. However, other features, such as QRS morphology, mechanical dyssynchrony, myocardial scarring, and the aetiology of heart failure, might also determine the benefit of CRT. No single left ventricular pacing site suits all patients, but a late-activated site, during either the intrinsic LBBB rhythm or right ventricular pacing, should be selected. Positioning the lead inside a scarred region substantially impairs outcomes. Optimization of stimulation intervals improves cardiac pump function in the short term, but CRT procedures must become easier and more reliable, perhaps with the use of electrocardiographic measures, to improve long-term outcomes.

Transseptal conduction as an important determinant for cardiac resynchronization therapy, as revealed by extensive electrical mapping in the dyssynchronous canine heart.

BACKGROUND: Simple conceptual ideas about cardiac resynchronization therapy assume that biventricular (BiV) pacing results in collision of right and left ventricular (LV) pacing-derived wavefronts. However, this concept is contradicted by the minor reduction in QRS duration usually observed. We investigated the electric mechanisms of cardiac resynchronization therapy by performing detailed electric mapping during extensive pacing protocols in dyssynchronous canine hearts. METHODS AND RESULTS: Studies were performed in anesthetized dogs with acute left bundle-branch block (LBBB, n=10) and chronic LBBB with tachypacing-induced heart failure (LBBB+HF, n=6). Activation times (AT) were measured using LV endocardial contact and noncontact mapping and epicardial contact mapping. BiV pacing reduced QRS duration by 21±10% in LBBB but only by 5±12% in LBBB+HF hearts. Transseptal impulse conduction was significantly slower in LBBB+HF than in LBBB hearts (67±9 versus 44±16 ms, respectively), and in both groups significantly slower than transmural LV conduction (≈30 ms). In both groups QRS duration and vector and the epicardial AT vector amplitude and angle were significantly different between LV and BiV pacing, whereas the endocardial AT vector was similar. During variation of atrioventricular delay while LV pacing, and ventriculo-ventricular delay while BiV pacing, the optimal hemodynamic effect was achieved when epicardial AT and QRS vectors were minimal and endocardial AT vector indicated LV preexcitation. CONCLUSIONS: Due to slow transseptal conduction, the LV electric activation sequence is similar in LV and BiV pacing, especially in failing hearts. Optimal hemodynamic cardiac resynchronization therapy response coincides with minimal epicardial asynchrony and QRS vector and LV preexcitation.

Endocardial left ventricular pacing improves cardiac resynchronization therapy in chronic asynchronous infarction and heart failure models.

BACKGROUND: Studies in canine hearts with acute left bundle branch block (LBBB) showed that endocardial left ventricular (LV) pacing improves the efficacy of cardiac resynchronization therapy (CRT) compared with conventional epicardial LV pacing. The present study explores the efficacy of endocardial CRT in more compromised hearts and the mechanisms of such beneficial effects. METHODS AND RESULTS: Measurements were performed in 22 dogs, 9 with acute LBBB, 7 with chronic LBBB combined with infarction (embolization; LBBB plus myocardial infarction, and concentric remodeling), and 6 with chronic LBBB and heart failure (rapid pacing, LBBB+HF, and eccentric remodeling). A head-to-head comparison was performed of the effects of endocardial and epicardial LV pacing at 8 sites. LV activation times were measured using ≈100 endocardial and epicardial electrodes and noncontact mapping. Pump function was assessed from right ventricular and LV pressures. Endocardial CRT resulted in better electric resynchronization than epicardial CRT in all models, although the benefit was larger in concentrically remodeled LBBB plus myocardial infarction than in eccentrically remodeled LBBB+HF hearts (19% versus 10%). In LBBB and LBBB+HF animals, endocardial conduction was ≈50% faster than epicardial conduction; in all models, transmural impulse conduction was ≈25% faster when pacing from the endocardium than from the epicardium. Hemodynamic effects were congruent with electric effects. CONCLUSIONS: Endocardial CRT improves electric synchrony of activation and LV pump function compared with conventional epicardial CRT in compromised canine LBBB hearts. This benefit can be explained by a shorter path length along the endocardium and by faster circumferential and transmural impulse conduction during endocardial LV pacing.

Vectorcardiography as a tool for easy optimization of cardiac resynchronization therapy in canine left bundle branch block hearts.

BACKGROUND: In cardiac resynchronization therapy (CRT), optimization of left ventricular (LV) stimulation timing is often time consuming. We hypothesized that the QRS vector in the vectorcardiogram (VCG) reflects electric interventricular dyssynchrony, and that the QRS vector amplitude (VAQRS), halfway between that during left bundle branch block (LBBB) and LV pacing, reflects optimal resynchronization, and can be used for easy optimization of CRT. METHODS AND RESULTS: In 24 canine hearts with LBBB (12 acute, 6 with heart failure, and 6 with myocardial infarction), the LV was paced over a wide range of atrioventricular (AV) delays. Surface ECGs were recorded from the limb leads, and VAQRS was calculated in the frontal plane. Mechanical interventricular dyssynchrony (MIVD) was determined as the time delay between upslopes of LV and right ventricular pressure curves, and systolic function was assessed as LV dP/dtmax. VAQRS and MIVD were highly correlated (r=0.94). The VAQRS halfway between that during LV pacing with short AV delay and intrinsic LBBB activation accurately predicted the optimal AV delay for LV pacing (1 ms; 95% CI, -5 to 8 ms). Increase in LV dP/dtmax at the VCG predicted AV delay was only slightly lower than the highest observed LV dP/dtmax (-2.7%; 95% CI, -3.6 to -1.8%). Inability to reach the halfway value of VAQRS during simultaneous biventricular pacing (53% of cases) was associated with suboptimal hemodynamic response, which could be corrected by sequential pacing. CONCLUSIONS: The VAQRS reflects electric interventricular dyssynchrony and accurately predicts optimal timing of LV stimulation in canine LBBB hearts. Therefore, VCG may be useful as a reliable and easy tool for individual optimization of CRT.

Myocardial infarction does not preclude electrical and hemodynamic benefits of cardiac resynchronization therapy in dyssynchronous canine hearts.

BACKGROUND: Several studies suggest that patients with ischemic cardiomyopathy benefit less from cardiac resynchronization therapy. In a novel animal model of dyssynchronous ischemic cardiomyopathy, we investigated the extent to which the presence of infarction influences the short-term efficacy of cardiac resynchronization therapy. METHODS AND RESULTS: Experiments were performed in canine hearts with left bundle branch block (LBBB, n=19) and chronic myocardial infarction, created by embolization of the left anterior descending or left circumflex arteries followed by LBBB (LBBB+left anterior descending infarction [LADi; n=11] and LBBB+left circumflex infarction [LCXi; n=7], respectively). Pacing leads were positioned in the right atrium and right ventricle and at 8 sites on the left ventricular (LV) free wall. LV pump function was measured using the conductance catheter technique, and synchrony of electrical activation was measured using epicardial mapping and ECG. Average and maximal improvement in electric resynchronization and LV pump function by right ventricular+LV pacing was similar in the 3 groups; however, the site of optimal electrical and mechanical benefit was LV apical in LBBB hearts, LV midlateral in LBBB+LCXi hearts and LV basal-lateral in LBBB+LADi hearts. The best site of pacing was not the site of latest electrical activation but that providing the largest shortening of the QRS complex. During single-site LV pacing the range of atrioventricular delays yielding > or =70% of maximal hemodynamic effect was approximately 50% smaller in infarcted than noninfarcted LBBB hearts (P<0.05). CONCLUSIONS: Cardiac resynchronization therapy can improve resynchronization and LV pump function to a similar degree in infarcted and noninfarcted hearts. Optimal lead positioning and timing of LV stimulation, however, require more attention in the infarcted hearts.