QRS micro-fragmentation as a mortality predictor.

AIMS: Fragmented QRS complex with visible notching on standard 12-lead electrocardiogram (ECG) is understood to represent depolarization abnormalities and to signify risk of cardiac events. Depolarization abnormalities with similar prognostic implications likely exist beyond visual recognition but no technology is presently suitable for quantification of such invisible ECG abnormalities. We present such a technology. METHODS AND RESULTS: A signal processing method projects all ECG leads of the QRS complex into optimized three perpendicular dimensions, reconstructs the ECG back from this three-dimensional projection, and quantifies the difference (QRS 'micro'-fragmentation, QRS-µf) between the original and reconstructed signals. QRS 'micro'-fragmentation was assessed in three different populations: cardiac patients with automatic implantable cardioverter-defibrillators, cardiac patients with severe abnormalities, and general public. The predictive value of QRS-µf for mortality was investigated both univariably and in multivariable comparisons with other risk factors including visible QRS 'macro'-fragmentation, QRS-Mf. The analysis was made in a total of 7779 subjects of whom 504 have not survived the first 5 years of follow-up. In all three populations, QRS-µf was strongly predictive of survival (P < 0.001 univariably, and P < 0.001 to P = 0.024 in multivariable regression analyses). A similar strong association with outcome was found when dichotomizing QRS-µf prospectively at 3.5%. When QRS-µf was used in multivariable analyses, QRS-Mf and QRS duration lost their predictive value. CONCLUSION: In three populations with different clinical characteristics, QRS-µf was a powerful mortality risk factor independent of several previously established risk indices. Electrophysiologic abnormalities that contribute to increased QRS-µf values are likely responsible for the predictive power of visible QRS-Mf.

Short-Term Variability of the QT Interval Can be Used for the Prediction of Imminent Ventricular Arrhythmias in Patients With Primary Prophylactic Implantable Cardioverter Defibrillators.

Background Short-term variability of the QT interval (STVQT) has been proposed as a novel electrophysiological marker for the prediction of imminent ventricular arrhythmias in animal models. Our aim is to study whether STVQT can predict imminent ventricular arrhythmias in patients. Methods and Results In 2331 patients with primary prophylactic implantable cardioverter defibrillators, 24-hour ECG Holter recordings were obtained as part of the EU-CERT-ICD (European Comparative Effectiveness Research to Assess the Use of Primary Prophylactic Implantable Cardioverter Defibrillators) study. ECG Holter recordings showing ventricular arrhythmias of >4 consecutive complexes were selected for the arrhythmic groups (n=170), whereas a control group was randomly selected from the remaining Holter recordings (n=37). STVQT was determined from 31 beats with fiducial segment averaging and calculated as [Formula: see text], where Dn represents the QT interval. STVQT was determined before the ventricular arrhythmia or 8:00 am in the control group and between 1:30 and 4:30 am as baseline. STVQT at baseline was 0.84±0.47 ms and increased to 1.18±0.74 ms (P<0.05) before the ventricular arrhythmia, whereas the STVQT in the control group remained unchanged. The arrhythmic patients were divided into three groups based on the severity of the arrhythmia: (1) nonsustained ventricular arrhythmia (n=32), (2) nonsustained ventricular tachycardia (n=134), (3) sustained ventricular tachycardia (n=4). STVQT increased before nonsustained ventricular arrhythmia, nonsustained ventricular tachycardia, and sustained ventricular tachycardia from 0.80±0.43 ms to 1.18±0.78 ms (P<0.05), from 0.90±0.49 ms to 1.14±0.70 ms (P<0.05), and from 1.05±0.22 ms to 2.33±1.25 ms (P<0.05). This rise in STVQT was significantly higher in sustained ventricular tachycardia compared with nonsustained ventricular arrhythmia (+1.28±1.05 ms versus +0.24±0.57 ms [P<0.05]) and compared with nonsustained ventricular arrhythmia (+0.34±0.87 ms [P<0.05]). Conclusions STVQT increases before imminent ventricular arrhythmias in patients, and the extent of the increase is associated with the severity of the ventricular arrhythmia.

Evaluation of a Fully Automatic Measurement of Short-Term Variability of Repolarization on Intracardiac Electrograms in the Chronic Atrioventricular Block Dog.

Background: Short-term variability (STV) of repolarization of the monophasic action potential duration (MAPD) or activation recovery interval (ARI) on the intracardiac electrogram (EGM) increases abruptly prior to the occurrence of ventricular arrhythmias in the chronic AV-block (CAVB) dog model. Therefore, this parameter might be suitable for continuous monitoring of imminent arrhythmias using the EGM stored on an implanted device. However, 24/7 monitoring would require automatic STVARI measurement by the device. Objective: To evaluate a newly developed automatic measurement of STVARI for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog. Methods: Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STVARI method was compared with the gold standard STVMAPD at baseline and after dofetilide administration (0.025 mg/kg in 5 min). (2) The predictive value of the automatic method was compared to currently used STVARI methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs. Results: (1) The automatic measurement of STVARI had good correlation with STVMAPD (r 2 = 0.89; p < 0.001). Bland-Altman analysis showed a small bias of 0.06 ms with limits of agreement between -0.63 and 0.76 ms. (2) STVARI of all three methods was significantly different between inducible and non-inducible dogs after dofetilide. The automatic method showed the highest predictive performance with an area under the ROC-curve of 0.93, compared to 0.85 and 0.87 of the slope and FSA methods, respectively. With a threshold of STV set at 1.69 ms, STVARI measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects. Conclusion: We developed a fully-automatic method for measurement of STVARI on the intracardiac EGM that can accurately predict the occurrence of ventricular arrhythmias in the CAVB-dog. Future integration of this method into implantable devices could provide the opportunity for 24/7 monitoring of arrhythmic risk.

Lazarus in asystole: a case report of autoresuscitation after prolonged cardiac arrest.

BACKGROUND: Third-degree atrioventricular (AV) block can result in sudden cardiac death if no reliable escape rhythm is present. Here, we report a case of an 86-year-old female patient who developed a third-degree AV block leading to cardiac arrest. Surprisingly, sinus rhythm returned after 4 min of asystole, and she showed complete neurological recovery. CASE SUMMARY: Emergency services were contacted by the husband of an 86-year-old woman after she was found unconscious. Ambulance personnel diagnosed a third-degree AV block without an escape rhythm and transcutaneous pacing was started. At arrival on the emergency ward, pacing was inadequate, resulting in absence of circulation for ∼10 min. After consultation with the family, the patient turned out to have signed a 'do not resuscitate' order. Given the impression that the considerable delay deemed favourable neurological recovery unlikely, it was decided together with the family to stop the resuscitation. Subsequently, she had an intermittent junctional escape rhythm but eventually developed a documented asystole of more than 4 min. Against all expectations, she regained sinus rhythm and fully recovered. Eventually, a pacemaker was implanted and she was discharged home without neurological sequalae of the cardiac arrest. DISCUSSION: Autoresuscitation, also known as the Lazarus syndrome, is the spontaneous return of circulation after cardiac arrest and is incidentally seen after failed cardiopulmonary resuscitation (CPR). Autoresuscitation in the absence of CPR is highly unusual, but could, in this case, be due to the total AV block as the cause of the cardiac arrest.

LUF7244, an allosteric modulator/activator of Kv 11.1 channels, counteracts dofetilide-induced torsades de pointes arrhythmia in the chronic atrioventricular block dog model.

BACKGROUND AND PURPOSE: Kv 11.1 (hERG) channel blockade is an adverse effect of many drugs and lead compounds, associated with lethal cardiac arrhythmias. LUF7244 is a negative allosteric modulator/activator of Kv 11.1 channels that inhibits early afterdepolarizations in vitro. We tested LUF7244 for antiarrhythmic efficacy and potential proarrhythmia in a dog model. EXPERIMENTAL APPROACH: LUF7244 was tested in vitro for (a) increasing human IKv11.1 and canine IKr and (b) decreasing dofetilide-induced action potential lengthening and early afterdepolarizations in cardiomyocytes derived from human induced pluripotent stem cells and canine isolated ventricular cardiomyocytes. In vivo, LUF7244 was given intravenously to anaesthetized dogs in sinus rhythm or with chronic atrioventricular block. KEY RESULTS: LUF7244 (0.5-10 µM) concentration dependently increased IKv11.1 by inhibiting inactivation. In vitro, LUF7244 (10 µM) had no effects on IKIR2.1 , INav1.5 , ICa-L , and IKs , doubled IKr , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg-1 ·15 min-1 ) in dogs with sinus rhythm was not proarrhythmic and shortened, non-significantly, repolarization parameters (QTc: -6.8%). In dogs with chronic atrioventricular block, LUF7244 prevented dofetilide-induced torsades de pointes arrhythmias in 5/7 animals without normalization of the QTc. Peak LUF7244 plasma levels were 1.75 ± 0.80 during sinus rhythm and 2.34 ± 1.57 µM after chronic atrioventricular block. CONCLUSIONS AND IMPLICATIONS: LUF7244 counteracted dofetilide-induced early afterdepolarizations in vitro and torsades de pointes in vivo. Allosteric modulators/activators of Kv 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.

Data on differential multivariable risk prediction of appropriate shock vs. competing mortality.

This data article features supplementary figures and tables related to the article "Differential Multivariable risk prediction of appropriate shock vs. competing mortality - a prospective cohort study to estimate benefits from implantable cardioverter defibrillator therapy" (Bergau et al., 2018) [1]. The figures show the clinical study CONSORT graph (data that show the number of patients not-analyzable as well as a distribution of patients by outcomes) and the correlation scatter plot for risk scores of appropriate shock vs. mortality (data that show the calculated score values of the two scores plotted against each other). The tables show the results for the univariate Cox regressions for prediction of mortality and appropriate shock. For further information, please see Bergau et al. (2018) [1].

An Augmented Negative Force-Frequency Relationship and Slowed Mechanical Restitution Are Associated With Increased Susceptibility to Drug-Induced Torsade de Pointes Arrhythmias in the Chronic Atrioventricular Block Dog.

Introduction: In the chronic AV-block (CAVB) dog model, structural, contractile, and electrical remodeling occur, which predispose the heart to dofetilide-induced Torsade de Pointes (TdP) arrhythmias. Previous studies found a relation between electrical remodeling and inducibility of TdP, while structural remodeling is not a prerequisite for arrhythmogenesis. In this study, we prospectively assessed the relation between in vivo markers of contractile remodeling and TdP inducibility. Methods: In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dtmax) was assessed at acute AV-block (AAVB) and after 2 weeks of chronic AV-block (CAVB2). Using pacing protocols, three markers of contractile remodeling, i.e., force-frequency relationship (FFR), mechanical restitution (MR), and post-extrasystolic potentiation (PESP) were determined. Infusion of dofetilide (0.025 mg/kg in 5 min) was used to test for TdP inducibility. Results: After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively (p = 0.001). The inducible dogs at CAVB2 showed augmented contractility at a CL of 1200 ms (2354 ± 168 mmHg/s in inducible dogs versus 1091 ± 59 mmHg/s in non-inducible dogs, p < 0.001) with a negative FFR, while the non-inducible dogs retained their positive FFR. The time constant (TC) of the MR curve was significantly higher in the inducible dogs (158 ± 7 ms versus 97 ± 8 ms, p < 0.0001). Furthermore, a linear correlation was found between a weighted score of the number and severity of arrhythmias and contractile parameters, i.e., contractility at CL of 1200 ms (r = 0.73, p = 0.002), the slope of the FFR (r = -0.58, p = 0.01) and the TC of MR (r = 0.66, p = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling. Conclusion: Contractile remodeling is concomitantly observed with susceptibility to dofetilide-induced TdP-arrhythmias. The inducible dogs show augmented contractile remodeling compared to non-inducible dogs, as seen by a negative FFR, higher maximal response of MR and PESP and slowed MR kinetics. These altered contractility parameters could reflect disrupted Ca2+ handling and Ca2+-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.

Differential multivariable risk prediction of appropriate shock versus competing mortality - A prospective cohort study to estimate benefits from ICD therapy.

BACKGROUND AND OBJECTIVE: We prospectively investigated combinations of risk stratifiers including multiple EP diagnostics in a cohort study of ICD patients. METHODS: For 672 enrolled patients, we collected history, LVEF, EP study and T-wave alternans testing, 24-h Holter, NT-proBNP, and the eGFR. All-cause mortality and first appropriate ICD shock were predefined endpoints. RESULTS: The 635 patients included in the final analyses were 63 ±â€¯13 years old, 81% were male, LVEF averaged 40 ±â€¯14%, 20% were inducible at EP study, 63% had a primary prophylactic ICD. During follow-up over 4.3 ±â€¯1.5 years, 108 patients died (4.0% per year), and appropriate shock therapy occurred in n = 96 (3.9% per year). In multivariate regression, age (p < 0.001), LVEF (p < 0.001), NYHA functional class (p = 0.007), eGFR (p = 0.024), a history of atrial fibrillation (p = 0.011), and NT-pro-BNP (p = 0.002) were predictors of mortality. LVEF (p = 0.002), inducibility at EP study (p = 0.007), and secondary prophylaxis (p = 0.002) were identified as independent predictors of appropriate shocks. A high annualized risk of shocks of about 10% per year was prevalent in the upper quintile of the shock score. In contrast, a low annual risk of shocks (1.8% per year) was found in the lower two quintiles of the shock score. The lower two quintiles of the mortality score featured an annual mortality <0.6%. CONCLUSIONS: In a prospective ICD patient cohort, a very good approximation of mortality versus arrhythmic risk was possible using a multivariable diagnostic strategy. EP stimulation is the best test to assess risk of arrhythmias resulting in ICD shocks.

Beat-to-beat variations in activation-recovery interval derived from the right ventricular electrogram can monitor arrhythmic risk under anesthetic and awake conditions in the canine chronic atrioventricular block model.

BACKGROUND: In the chronic atrioventricular block (CAVB) dog model, beat-to-beat variation of repolarization in the left ventricle (LV) quantified as short-term variability of the left monophasic action potential duration (STVLVMAPD) increases abruptly upon challenge with a proarrhythmic drug. This increase occurs before the first ectopic beat (EB), specifically in subjects who demonstrate subsequent repetitive torsades de pointes arrhythmias (TdP). OBJECTIVE: The purpose of this study was to demonstrate that STV is feasible to monitor arrhythmic risk through use of the intracardiac electrogram (EGM) derived from the right ventricular (RV) lead from pacemakers or implantable cardioverter-defibrillators. METHODS: In 30 anaesthetized, inducible (≥3 TdP) CAVB dogs, STV between LV and RV monophasic action potential duration (STVLVMAPD and STVRVMAPD) was compared. In prospectively enrolled CAVB dogs, STV of the activation-recovery interval (ARI) derived from the RV EGM (STVRVARI) was measured before and after a challenge with dofetilide under anesthesia (2a; n = 10) and cisapride under awake conditions (2b; n = 8). RESULTS: Both STVLVMAPD and STVRVMAPD increased before the first EB (1.29 ± 0.58 ms to 3.05 ± 1.70 ms and 1.11 ± 0.53 ms to 2.18 ± 1.43 ms, respectively; P = 0.001). STVRVARI increased from 2.82 ± 0.33 ms to 3.77 ± 0.69 ms (P = .001). Inducible subjects (4/8) showed an increase in STVRVARI from 2.65 ± 0.55 ms to 3.45 ± 0.33 ms (in the first hour; P = .02) and 4.20 ± 1.33 ms (before the first EB; P = .04). CONCLUSION: Behavior of STV from the RV and LV is comparable. STVRVARI increases significantly before the occurrence of an arrhythmia in awake and anaesthetized conditions. This finding can be integrated into devices to monitor arrhythmic risk.

Circadian pattern of short-term variability of the QT-interval in primary prevention ICD patients - EU-CERT-ICD methodological pilot study.

OBJECTIVE: Short-term variability of the QT-interval (STV-QT) was shown to be associated with an increased risk of ventricular arrhythmias. We aimed at investigating (a) whether STV-QT exhibits circadian pattern, and (b) whether such pattern differs between patients with high and low arrhythmia risk. METHODS: As part of the ongoing EU-CERT-ICD study, 24h high resolution digital ambulatory 12-lead Holter recordings are collected prior to ICD implantation for primary prophylactic indication. Presently available patients were categorized based on their arrhythmia score (AS), a custom-made weighted score of the number of arrhythmic events on the recording. STV-QT was calculated every hour in 30 patients of which 15 and 15 patients had a high and a low AS, respectively. RESULTS: The overall dynamicity of STV-QT showed high intra- and inter-individual variability with different circadian patterns associated with low and high AS. High AS patients showed a prominent peak both at 08:00 and 18:00. At these times, STV-QT was significantly higher in the high AS patients compared to the low AS patients (1.22ms±0.55ms vs 0.60ms±0.24ms at 08:00 and 1.12ms±0.39ms vs 0.64ms±0.29ms at 18:00, both p < 0.01). CONCLUSION: In patients with high AS, STV-QT peaks in the early morning and late afternoon. This potentially reflects increased arrhythmia risk at these times. Prospective STV-QT determination at these times might thus be more sensitive to identify patients at high risk of ventricular arrhythmias.

Post-extrasystolic Potentiation: Link between Ca(2+) Homeostasis and Heart Failure?

Post-extrasystolic potentiation (PESP) describes the phenomenon of increased contractility of the beat following an extrasystole and has been attributed to changes in Ca(2+) homeostasis. While this effect has long been regarded to be a normal physiological phenomenon, a number of reports describe an enhanced potentiation of the post-extrasystolic beat in heart failure patients. The exact mechanism of this increased PESP is unknown, but disruption of normal Ca(2+) handling in heart failure may be the underlying cause. The use of PESP as a prognostic marker or therapeutic intervention have recently regained new attention, however, the value of the application of PESP in the clinic is still under debate. In this review, the mechanism of PESP with regard to Ca(2+) in the normal and failing heart will be discussed and the possible diagnostic and therapeutic role of this phenomenon will be explored.