Landmark Evolutions in Time and Indication for Cardiac Resynchronization Therapy: Results from a Multicenter Retrospective Registry.

Background: Cardiac resynchronization therapy (CRT) has evolved into an established therapy for patients with chronic heart failure and a wide QRS complex. Data on long-term outcomes over time are scarce and the criteria for implantation remain a subject of investigation. Methods: An international, multicenter, retrospective registry includes 2275 patients who received CRT between 30 November 2000 and 31 December 2019, with a mean follow-up of 3.6 ± 2.7 years. Four time periods were defined, based on landmark trials and guidelines. The combined endpoint was a composite of all-cause mortality, heart transplantation, or left ventricular assist device implantation. Results: The composite endpoint occurred in 656 patients (29.2%). The mean annual implantation rate tripled from 31.5 ± 17.4/year in the first period to 107.4 ± 62.4/year in the last period. In the adjusted Cox regression analysis, the hazard ratio for the composite endpoint was not statistically different between time periods. When compared to sinus rhythm with left bundle branch block (LBBB), a non-LBBB conduction pattern (sinus rhythm: HR 1.51, 95% CI 1.12-2.03; atrial fibrillation: HR 2.08, 95% CI 1.30-3.33) and a QRS duration below 130 ms (HR 1.64, 95% CI 1.29-2.09) were associated with a higher hazard ratio. Conclusions: Despite innovations, an adjusted regression analysis revealed stable overall survival over time, which can at least partially be explained by a shift in patient characteristics.

Long-term outcome after upgrade to cardiac resynchronization therapy: A propensity score-matched analysis.

AIM: Cardiac resynchronization therapy (CRT) is a cornerstone in the management of chronic heart failure in patients with a broad or paced QRS. However, data on long-term outcome after upgrade to CRT are scarce. METHODS AND RESULTS: This international, multicentre retrospective registry included 2275 patients who underwent a de novo or upgrade CRT implantation with a mean follow-up of 3.6 ± 2.7 years. The primary composite endpoint included all-cause mortality, heart transplantation, or ventricular assist device implantation. The secondary endpoint was first heart failure admission. Multivariable Cox regression and propensity score matching (PSM) analyses were performed. Patients who underwent CRT upgrade (n = 605, 26.6%) were less likely female (19.7% vs. 28.8%, p < 0.001), more often had ischeemic cardiomyopathy (49.8% vs. 40.2%, p < 0.001), and had worse renal function (median estimated glomerular filtration rate 50.3 ml/min/1.73 m2 [35.8-69.5] vs. 59.9 ml/min/1.73 m2 [43.0-76.5], p < 0.001). The incidence rate of the composite endpoint was 10.8%/year after CRT upgrade versus 7.1%/year for de novo implantations (p < 0.001). PSM for the primary endpoint resulted in 488 pairs. After propensity score matching, upgrade to CRT was associated with a higher chance to reach the composite endpoint (multivariable hazard ratio [HR] 1.35, 95% confidence interval [CI] 1.08-1.70), for both upgrade from pacemaker (multivariable HR 1.33, 95% CI 1.03-1.70) and implantable cardioverter-defibrillator (ICD) (multivariable HR 1.40, 95% CI 1.01-1.95). PSM for the secondary endpoint resulted in 277 pairs. After PSM, upgrade to CRT was associated with a higher chance for heart failure admission (HR 1.74, 95% CI 1.26-2.41). CONCLUSION: In this retrospective analysis, the outcome of patients who underwent upgrades to CRT differed significantly from patients who underwent de novo CRT implantation, particularly for upgrades from ICD. Importantly, this difference in outcome does not imply a causal relation between therapy and outcome but rather a difference between two different patient populations.

Electric Field-Based Spatial Analysis of Noncontact Unipolar Electrograms to Map Regional Activation-Repolarization Intervals.

BACKGROUND: Spatial heterogeneity in repolarization plays an important role in generating and sustaining cardiac arrhythmias. Reliable determination of repolarization times remains challenging. OBJECTIVES: The goal of this study was to improve processing of densely sampled noncontact unipolar electrograms to yield reliable high-resolution activation and repolarization maps. METHODS: Endocardial noncontact unipolar electrograms were both simulated and recorded in pig left ventricle. Electrical activity on the endocardial surface was processed in terms of a pseudo-electric field. Activation and repolarization times were calculated by using an amplitude-weighted average on QRS and T waves (ie, the E-field method). This was compared vs the conventional Wyatt method on unipolar electrograms. Timing maps were validated against timing on endocardial action potentials in a simulation study. In vivo, activation and repolarization times determined by using this alternative E-field method were validated against simultaneously recorded endocardial monophasic action potentials (MAPs). RESULTS: Simulation showed that the E-field method provides viable measurements of local endocardial action potential activation and repolarization times. In vivo, correlation of E-field activation times with MAP activation times (rE = 0.76; P < 0.001) was similar to those of Wyatt (rWyatt = 0.80, P < 0.001; P[h1:rE > rWyatt] = 0.82); for repolarization times, correlation improved significantly (rE = 0.96, P < 0.001; rWyatt = 0.82, P < 0.001; P[h1:rE > rWyatt] < 0.00001). This resulted in improved correlations of activation-repolarization intervals to endocardial action potential duration on MAP (rE = 0.96, P < 0.001; rWyatt = 0.86, P < 0.001; P[h1:rE > rWyatt] < 0.00001). Spatial beat-to-beat variation of repolarization could only be calculated by using the E-field methodology and correlated well with the MAP beat-to-beat variation of repolarization (rE = 0.76; P = 0.001). CONCLUSIONS: The E-field method substantially enhances information from endocardial noncontact electrogram data, allowing for dense maps of activation and repolarization times and derived parameters.

A unified framework for multi-lead ECG characterization using Laplacian Eigenmaps.

Background.The analysis of multi-lead electrocardiographic (ECG) signals requires integrating the information derived from each lead to reach clinically relevant conclusions. This analysis could benefit from data-driven methods compacting the information in those leads into lower-dimensional representations (i.e. 2 or 3 dimensions instead of 12).Objective.We propose Laplacian Eigenmaps (LE) to create a unified framework where ECGs from different subjects can be compared and their abnormalities are enhanced.Approach.We conceive a normal reference ECG space based on LE, calculated using signals of healthy subjects in sinus rhythm. Signals from new subjects can be mapped onto this reference space creating a loop per heartbeat that captures ECG abnormalities. A set of parameters, based on distance metrics and on the shape of loops, are proposed to quantify the differences between subjects.Main results.This methodology was applied to find structural and arrhythmogenic changes in the ECG. The LE framework consistently captured the characteristics of healthy ECGs, confirming that normal signals behaved similarly in the LE space. Significant differences between normal signals, and those from patients with ischemic heart disease or dilated cardiomyopathy were detected. In contrast, LE biomarkers did not identify differences between patients with cardiomyopathy and a history of ventricular arrhythmia and their matched controls.Significance.This LE unified framework offers a new representation of multi-lead signals, reducing dimensionality while enhancing imperceptible abnormalities and enabling the comparison of signals of different subjects.

Regional beat-to-beat variability of repolarization increases during ischemia and predicts imminent arrhythmias in a pig model of myocardial infarction.

Ventricular arrhythmia (VT/VF) can complicate acute myocardial ischemia (AMI). Regional instability of repolarization during AMI contributes to the substrate for VT/VF. Beat-to-beat variability of repolarization (BVR), a measure of repolarization lability increases during AMI. We hypothesized that its surge precedes VT/VF. We studied the spatial and temporal changes in BVR in relation to VT/VF during AMI. In 24 pigs, BVR was quantified on 12-lead electrocardiogram recorded at a sampling rate of 1 kHz. AMI was induced in 16 pigs by percutaneous coronary artery occlusion (MI), whereas 8 underwent sham operation (sham). Changes in BVR were assessed at 5 min after occlusion, 5 and 1 min pre-VF in animals that developed VF, and matched time points in pigs without VF. Serum troponin and ST deviation were measured. After 1 mo, magnetic resonance imaging and VT induction by programmed electrical stimulation were performed. During AMI, BVR increased significantly in inferior-lateral leads correlating with ST deviation and troponin increase. BVR was maximal 1 min pre-VF (3.78 ± 1.36 vs. 5 min pre-VF, 1.67 ± 1.56, P < 0.0001). After 1 mo, BVR was higher in MI than in sham and correlated with the infarct size (1.43 ± 0.50 vs. 0.57 ± 0.30, P = 0.009). VT was inducible in all MI animals and the ease of induction correlated with BVR. BVR increased during AMI and temporal BVR changes predicted imminent VT/VF, supporting a possible role in monitoring and early warning systems. BVR correlated to arrhythmia vulnerability suggesting utility in risk stratification post-AMI.NEW & NOTEWORTHY The key finding of this study is that BVR increases during AMI and surges before ventricular arrhythmia onset. This suggests that monitoring BVR may be useful for monitoring the risk of VF during and after AMI in the coronary care unit settings. Beyond this, monitoring BVR may have value in cardiac implantable devices or wearables.

Implantable cardiac defibrillators in octogenarians.

OBJECTIVE: Implantable cardiac defibrillators (ICD) implantation in the very elderly remains controversial. We aimed to describe the experience and outcome of patients over 80 years old implanted with an ICD in Belgium. METHODS: Data were extracted from the national QERMID-ICD registry. All implantations performed in octogenarians between February 2010 and March 2019 were analysed. Data on baseline patient characteristics, type of prevention, device configuration and all-cause mortality were available. To determine predictors of mortality, multivariable Cox proportional hazard regression modelling was performed. RESULTS: Nationwide, 704 primo ICD implantations were performed in octogenarians (median age 82, IQR 81-83 years; 83% male and 45% secondary prevention). During a mean follow-up of 3.1 ± 2.3 years, 249 (35%) patients died, of which 76 (11%) within the first year after implantation. In multivariable Cox regression analysis age (HR = 1.15, P = 0.004), oncological history (HR = 2.43, P = 0.027) and secondary prevention (HR = 2.23, P = 0.001) were independently associated with 1-year mortality. A better preserved left ventricular ejection fraction (LVEF) was associated with a better outcome (HR = 0.97, P = 0.002). Regarding overall mortality multivariable analysis withheld age, history of atrial fibrillation, centre volume and oncological history as significant predictors. Higher LVEF was again protective (HR = 0.99, P = 0.008). CONCLUSIONS: Primary ICD implantation in octogenarians is not often performed in Belgium. Among this population, 11% died within the first year after ICD implantation. Advanced age, oncological history, secondary prevention and a lower LVEF were associated with an increased one-year mortality. Age, low LVEF, atrial fibrillation, centre volume and oncological history were indicative of higher overall mortality.

Impact of Loading and Myocardial Mechanical Properties on Natural Shear Waves: Comparison to Pressure-Volume Loops.

BACKGROUND: Shear wave elastography (SWE) has been proposed as a novel noninvasive method for the assessment of myocardial stiffness, a relevant determinant of diastolic function. It is based on tracking the propagation of shear waves, induced, for instance, by mitral valve closure (MVC), in the myocardium. The speed of propagation is directly related to myocardial stiffness, which is defined by the local slope of the nonlinear stress-strain relation. Therefore, the operating myocardial stiffness can be altered by both changes in loading and myocardial mechanical properties. OBJECTIVES: This study sought to evaluate the capability of SWE to quantify myocardial stiffness changes in vivo by varying loading and myocardial tissue properties and to compare SWE against pressure-volume loop analysis, a gold standard reference method. METHODS: In 15 pigs, conventional and high-frame rate echocardiographic data sets were acquired simultaneously with pressure-volume loop data after acutely changing preload and afterload and after inducting an ischemia/reperfusion (I/R) injury. RESULTS: Shear wave speed after MVC significantly increased by augmenting preload and afterload (3.2 ± 0.8 m/s vs 4.6 ± 1.2 m/s and 4.6 ± 1.0 m/s, respectively; P = 0.001). Preload reduction had no significant effect on shear wave speed compared to baseline (P = 0.118). I/R injury resulted in significantly higher shear wave speed after MVC (6.1 ± 1.2 m/s; P < 0.001). Shear wave speed after MVC had a strong correlation with the chamber stiffness constant ß (r = 0.63; P < 0.001) and operating chamber stiffness dP/dV before induction of an I/R injury (r = 0.78; P < 0.001) and after (r = 0.83; P < 0.001). CONCLUSIONS: Shear wave speed after MVC was influenced by both acute changes in loading and myocardial mechanical properties, reflecting changes in operating myocardial stiffness, and was strongly related to chamber stiffness, invasively derived by pressure-volume loop analysis. SWE provides a novel noninvasive method for the assessment of left ventricular myocardial properties.

Inequality between women and men in ICD implantation.

Background: The impact of sex on ICD implantation practice and survival remain a topic of controversy. To assess sex-specific differences in ICD implantation practice we compared clinical characteristics and survival in women and men. Methods: From a nationwide registry, all new ICD implantations performed between 01/02/2010 and 31/01/2019 in Belgian patients were analyzed retrospectively. Baseline characteristics and survival rates were compared between sexes. To identify predictors of mortality, multivariable Cox regression was performed. Results: Only 3096 (20.9%) of 14,787 ICD implantations were performed in women. Within each type of underlying cardiomyopathy, the proportion women were lower than men. The main indication in men was ischemic vs dilated cardiomyopathy in women. Women were overall younger (59.1 ± 15.1 vs 62.6 ± 13.1 years; p < 0.001) and had less comorbidities except for oncological disease. More women functioned in NYHA-class III (33.6% vs 27.9%; p < 0.001) and had a QRS > 150 ms (29.4% vs 24.3%; p < 0.001), consistent with a higher use of CRT-D devices (31.7% vs 25.1%; p < 0.001). Women had more complications, reflected by the need to more re-interventions within 1 year (4.3% vs 2.7%, p < 0.001). After correction for covariates, sex-category was not a significant predictor of mortality (p = 0.055). Conclusion: There is a significant sex-disparity in ICD implantation rates, not fully explained by epidemiological differences in the prevalence of cardiomyopathies, which could imply an undertreatment of women. Women differ from men in baseline characteristics at implantation suggesting a selection bias. Further research is necessary to evaluate if women receive equal sudden cardiac death prevention.

Temporal Changes in Beat-to-Beat Variability of Repolarization Predict Imminent Nonsustained Ventricular Tachycardia in Patients With Ischemic and Nonischemic Dilated Cardiomyopathy.

Background An increase in beat-to-beat variability of repolarization (BVR) predicts arrhythmia onset in experimental models, but its clinical translation is not well established. We investigated the temporal changes in BVR before nonsustained ventricular tachycardia (nsVT) in patients with implantable cardioverter defibrillator (ICD). Methods and Results Patients with nsVT on 24-hour Holter before ICD implantation for ischemic cardiomyopathy (ischemic cardiomyopathy+nsVT, n=43) or dilated cardiomyopathy (dilated cardiomyopathy+nsVT, n=37), matched ICD candidates without nsVT (ischemic cardiomyopathy-nsVT, n=29 and dilated cardiomyopathy-nsVT, n=26), and patients without ICD without structural heart disease (n=50) were studied. Digital Holter recordings from these patients were analyzed using a modified fiducial segment averaging technique to detect the QT interval. The nsVT episodes were semi-automatically identified and QT-BVR was assessed 1-, 5-, and 30-minutes before nsVT, and at rest (at 3:00 am). Resting BVR was higher in ICD patients compared with controls without structural heart disease. In ICD patients with nsVT, BVR increased significantly 1-minute pre-nsVT in ischemic cardiomyopathy (2.21±0.59 ms, versus 5 minutes pre-nsVT: 1.78±0.50 ms, P<0.001) and dilated cardiomyopathy (2.09±0.57 ms, versus 5-minutes pre-nsVT: 1.58±0.51 ms, P<0.001), but not in patients without nsVT. In multivariable Cox regression analysis, pre-nsVT BVR was a significant predictor for appropriate therapy during follow-up. Conclusions Baseline BVR is elevated and temporal changes in BVR predict imminent nsVT events in patients with ICD independent of underlying cause. Real-time BVR monitoring could be used to predict impending ventricular arrhythmia and allow preventive therapy to be incorporated into ICDs.

A machine learning algorithm for electrocardiographic fQRS quantification validated on multi-center data.

Fragmented QRS (fQRS) is an electrocardiographic (ECG) marker of myocardial conduction abnormality, characterized by additional notches in the QRS complex. The presence of fQRS has been associated with an increased risk of all-cause mortality and arrhythmia in patients with cardiovascular disease. However, current binary visual analysis is prone to intra- and inter-observer variability and different definitions are problematic in clinical practice. Therefore, objective quantification of fQRS is needed and could further improve risk stratification of these patients. We present an automated method for fQRS detection and quantification. First, a novel robust QRS complex segmentation strategy is proposed, which combines multi-lead information and excludes abnormal heartbeats automatically. Afterwards extracted features, based on variational mode decomposition (VMD), phase-rectified signal averaging (PRSA) and the number of baseline-crossings of the ECG, were used to train a machine learning classifier (Support Vector Machine) to discriminate fragmented from non-fragmented ECG-traces using multi-center data and combining different fQRS criteria used in clinical settings. The best model was trained on the combination of two independent previously annotated datasets and, compared to these visual fQRS annotations, achieved Kappa scores of 0.68 and 0.44, respectively. We also show that the algorithm might be used in both regular sinus rhythm and irregular beats during atrial fibrillation. These results demonstrate that the proposed approach could be relevant for clinical practice by objectively assessing and quantifying fQRS. The study sets the path for further clinical application of the developed automated fQRS algorithm.

Ventricular Arrhythmias in Ischemic Cardiomyopathy-New Avenues for Mechanism-Guided Treatment.

Ischemic heart disease is the most common cause of lethal ventricular arrhythmias and sudden cardiac death (SCD). In patients who are at high risk after myocardial infarction, implantable cardioverter defibrillators are the most effective treatment to reduce incidence of SCD and ablation therapy can be effective for ventricular arrhythmias with identifiable culprit lesions. Yet, these approaches are not always successful and come with a considerable cost, while pharmacological management is often poor and ineffective, and occasionally proarrhythmic. Advances in mechanistic insights of arrhythmias and technological innovation have led to improved interventional approaches that are being evaluated clinically, yet pharmacological advancement has remained behind. We review the mechanistic basis for current management and provide a perspective for gaining new insights that centre on the complex tissue architecture of the arrhythmogenic infarct and border zone with surviving cardiac myocytes as the source of triggers and central players in re-entry circuits. Identification of the arrhythmia critical sites and characterisation of the molecular signature unique to these sites can open avenues for targeted therapy and reduce off-target effects that have hampered systemic pharmacotherapy. Such advances are in line with precision medicine and a patient-tailored therapy.

Discrete sites of frequent premature ventricular complexes cluster within the infarct border zone and coincide with high frequency of delayed afterdepolarizations under adrenergic stimulation.

BACKGROUND: Sympathetic activation in ischemic heart disease can cause lethal arrhythmias. These often are preceded by premature ventricular complexes (PVCs), which at the cellular level could result from delayed afterdepolarizations. OBJECTIVE: The purpose of this study was to identify and map vulnerable areas for arrhythmia initiation after myocardial infarction (MI) and to explore the link between PVCs and cellular events. METHODS: Anterior-septal wall MI was induced by 120 minutes of coronary occlusion followed by reperfusion (27 MI and 16 sham pigs). After 4 weeks, EnSite™ electroanatomic mapping combined with imaging was performed to precisely locate PVC sites of origin and subsequently record monophasic action potentials. Cardiomyocytes were isolated from different regions to study regional cellular remodeling. Isoproterenol was used as a surrogate for adrenergic stimulation both in vivo and in cardiomyocytes. RESULTS: PVCs originated from the MI border zone (BZ) and occurred at discrete areas with clusters of PVCs within the BZ. At these sites, frequent delayed afterdepolarizations and occasional associated spontaneous action potentials translating to a PVC were present. Cardiomyocytes isolated from the MI BZ exhibited more spontaneous action potentials than cardiomyocytes from remote regions. Sensitivity to adrenergic stimulation was increased in MI, in vivo and in cardiomyocytes. In awake, freely moving MI animals, frequent PVCs, ventricular arrhythmia, and sudden cardiac death occurred spontaneously at moderately elevated heart rates. CONCLUSION: Post-MI, arrhythmias initiate from discrete vulnerable areas within the BZ, where delayed afterdepolarizations, related to increased adrenergic response of BZ cardiomyocytes, can generate PVCs.