Publications by authors named "Marc A Vos"

179 Publications

Severe Bradycardia Increases the Incidence and Severity of Torsade de Pointes Arrhythmias by Augmenting Preexistent Spatial Dispersion of Repolarization in the CAVB Dog Model.

Front Physiol 2021 26;12:642083. Epub 2021 Apr 26.

Department of Medical Physiology, Universitair Medisch Centrum Utrecht, Utrecht, Netherlands.

Introduction: Torsade de pointes arrhythmias (TdP) in the chronic atrioventricular block (CAVB) dog model result from proarrhythmic factors, which trigger TdP and/or reinforce the arrhythmic substrate. This study investigated electrophysiological and arrhythmogenic consequences of severe bradycardia for TdP.

Methods: Dofetilide (25 μg/kg per 5 min) was administered to eight anesthetized, idioventricular rhythm (IVR) remodeled CAVB dogs in two serial experiments: once under 60 beats per minute (bpm), right ventricular apex paced (RVA60) conditions, once under more bradycardic IVR conditions. Recordings included surface electrocardiogram and short-term variability (STV) of repolarization from endocardial unipolar electrograms. TdP inducibility (three or more episodes within 10 min after start of dofetilide) and arrhythmic activity scores (AS) were established. Mapping experiments in 10 additional dogs determined the effect of lowering rate on STV and spatial dispersion of repolarization (SDR) in baseline.

Results: IVR-tested animals had longer baseline RR-interval (1,403 ± 271 ms) and repolarization intervals than RVA60 animals. Dofetilide increased STV similarly under both rhythm strategies. Nevertheless, TdP inducibility and AS were higher under IVR conditions (6/8 and 37 ± 27 vs. 1/8 and 8 ± 12 in RVA60, respectively, both 0.05). Mapping: Pacing from high (128 ± 10 bpm) to middle (88 ± 10 bpm) to experimental rate (61 ± 3 bpm) increased all electrophysiological parameters, including interventricular dispersion, due to steeper left ventricular restitution curves, and intraventricular SDR: maximal cubic dispersion from 60 ± 14 (high) to 69 ± 17 (middle) to 84 ± 22 ms ( < 0.05 vs. high and middle rate).

Conclusion: In CAVB dogs, severe bradycardia increases the probability and severity of arrhythmic events by heterogeneously causing electrophysiological instability, which is mainly reflected in an increased spatial, and to a lesser extent temporal, dispersion of repolarization.
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http://dx.doi.org/10.3389/fphys.2021.642083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8110054PMC
April 2021

The canine chronic atrioventricular block model in cardiovascular preclinical drug research.

Br J Pharmacol 2021 Mar 8. Epub 2021 Mar 8.

Department of Medical Physiology, University Medical Center Utrecht, Utrecht, The Netherlands.

Ventricular cardiac arrhythmia is a life threating condition arising from abnormal functioning of many factors in concert. Animal models mirroring human electrophysiology are essential to predict and understand the rare pro- and anti-arrhythmic effects of drugs. This is very well accomplished by the canine chronic atrioventricular block (CAVB) model. Here we summarize canine models for cardiovascular research, and describe the development of the CAVB model from its beginning. Understanding of the structural, contractile and electrical remodelling processes following atrioventricular (AV) block provides insight in the many factors contributing to drug-induced arrhythmia. We also review all safety pharmacology studies, efficacy and mechanistic studies on anti-arrhythmic drugs in CAVB dogs. Finally, we compare pros and cons with other in vivo preclinical animal models. In view of the tremendous amount of data obtained over the last 100 years from the CAVB dog model, it can be considered as man's best friend in preclinical drug research.
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http://dx.doi.org/10.1111/bph.15436DOI Listing
March 2021

Segment length in cine (SLICE) strain analysis: a practical approach to estimate potential benefit from cardiac resynchronization therapy.

J Cardiovasc Magn Reson 2021 01 11;23(1). Epub 2021 Jan 11.

Department of Cardiology, Amsterdam Cardiovascular Sciences (ACS), Amsterdam University Medical Centers (AUMC), Location VU University Medical Center, De Boelelaan 1118, 1081 HV, Amsterdam, The Netherlands.

Background: Segment length in cine (SLICE) strain analysis on standard cardiovascular magnetic resonance (CMR) cine images was recently validated against gold standard myocardial tagging. The present study aims to explore predictive value of SLICE for cardiac resynchronization therapy (CRT) response.

Methods And Results: Fifty-seven patients with heart failure and left bundle branch block (LBBB) were prospectively enrolled in this multi-center study and underwent CMR examination before CRT implantation. Circumferential strains of the septal and lateral wall were measured by SLICE on short-axis cine images. In addition, timing and strain pattern parameters were assessed. After twelve months, CRT response was quantified by the echocardiographic change in left ventricular (LV) end-systolic volume (LVESV). In contrast to timing parameters, strain pattern parameters being systolic rebound stretch of the septum (SRS), systolic stretch index (SSI), and internal stretch factor (ISF) all correlated significantly with LVESV change (R - 0.56; R - 0.53; and R - 0.58, respectively). Of all strain parameters, end-systolic septal strain (ESS) showed strongest correlation with LVESV change (R - 0.63). Multivariable analysis showed ESS to be independently related to LVESV change together with age and QRS.

Conclusion: The practicable SLICE strain technique may help the clinician to estimate potential benefit from CRT by analyzing standard CMR cine images without the need for commercial software. Of all strain parameters, end-systolic septal strain (ESS) demonstrates the strongest correlation with reverse remodeling after CRT. This parameter may be of special interest in patients with non-strict LBBB morphology for whom CRT benefit is doubted.
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http://dx.doi.org/10.1186/s12968-020-00701-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7798189PMC
January 2021

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.

J Am Heart Assoc 2020 12 20;9(23):e018133. Epub 2020 Nov 20.

Department of Medical Physiology University Medical Center Utrecht Utrecht The Netherlands.

Background Short-term variability of the QT interval (STV) has been proposed as a novel electrophysiological marker for the prediction of imminent ventricular arrhythmias in animal models. Our aim is to study whether STV 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). STV was determined from 31 beats with fiducial segment averaging and calculated as [Formula: see text], where represents the QT interval. STV was determined before the ventricular arrhythmia or 8:00 am in the control group and between 1:30 and 4:30 am as baseline. STV at baseline was 0.84±0.47 ms and increased to 1.18±0.74 ms (<0.05) before the ventricular arrhythmia, whereas the STV 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). STV increased before nonsustained ventricular arrhythmia, nonsustained ventricular tachycardia, and sustained ventricular tachycardia from 0.80±0.43 ms to 1.18±0.78 ms (<0.05), from 0.90±0.49 ms to 1.14±0.70 ms (<0.05), and from 1.05±0.22 ms to 2.33±1.25 ms (<0.05). This rise in STV was significantly higher in sustained ventricular tachycardia compared with nonsustained ventricular arrhythmia (+1.28±1.05 ms versus +0.24±0.57 ms [<0.05]) and compared with nonsustained ventricular arrhythmia (+0.34±0.87 ms [<0.05]). Conclusions STV increases before imminent ventricular arrhythmias in patients, and the extent of the increase is associated with the severity of the ventricular arrhythmia.
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http://dx.doi.org/10.1161/JAHA.120.018133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7763775PMC
December 2020

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

Front Physiol 2020 21;11:1005. Epub 2020 Aug 21.

Department of Medical Physiology, University Medical Center Utrecht, Utrecht, Netherlands.

: 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 STV measurement by the device. : To evaluate a newly developed automatic measurement of STV for prediction of dofetilide-induced torsade de pointes (TdP) arrhythmias in the CAVB-dog. : Two retrospective analyses were done on data from recently performed dog experiments. (1) In seven anesthetized CAVB-dogs, the new automatic STV method was compared with the gold standard STV 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 STV methods, i.e., slope method and fiducial segment averaging (FSA) method, in 11 inducible (≥3 TdP arrhythmias) and 10 non-inducible CAVB-dogs. : (1) The automatic measurement of STV had good correlation with STV ( = 0.89; < 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) STV 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, STV measured with the automatic method had a sensitivity of 0.91 and specificity of 0.90 in differentiating inducible from non-inducible subjects. : We developed a fully-automatic method for measurement of STV 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.
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http://dx.doi.org/10.3389/fphys.2020.01005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7472439PMC
August 2020

High-rate pacing guided by short-term variability of repolarization prevents imminent ventricular arrhythmias automatically by an implantable cardioverter-defibrillator in the chronic atrioventricular block dog model.

Heart Rhythm 2020 12 22;17(12):2078-2085. Epub 2020 Jul 22.

Department of Medical Physiology, Division Heart and Lungs, University Medical Center Utrecht, Utrecht, The Netherlands. Electronic address:

Background: The anesthetized, complete chronic atrioventricular block (CAVB) dog model allows reproducible inducibility of torsades de pointes (TdP) arrhythmias due to ventricular remodeling and after a challenge with an I blocker. High-rate pacing (HRP) prevents ventricular arrhythmias but has long-term detrimental effects on cardiac function when applied continuously. Temporal dispersion of repolarization, quantified as short-term variability (STV), increases before ventricular arrhythmias and has been proposed as a marker to guide HRP.

Objective: The purpose of this proof-of-principle study was to show that automatically determined STV can guide HRP to prevent imminent ventricular arrhythmias.

Methods: Eight CAVB dogs were implanted with an implantable cardioverter-defibrillator (ICD) with software to automatically determine STV (STV) in real time. During HRP, STV was measured offline from right ventricular (RV) electrograms (EGMs) and left ventricular (LV) monophasic action potential durations (MAPDs) (STV). The CAVB dogs were challenged twice with dofetilide (0.025 mg/kg intravenously over 5 minutes or until the first TdP). In experiment 1, the individual STV threshold before the first arrhythmic event was determined and programmed into the ICD. In experiment 2, HRP with 100 bpm was initiated automatically once the STV threshold was reached.

Results: In experiment 1, 8 of 8 dogs had repetitive TdP, and STV increased from 0.96 ± 0.42 ms to 2.10 ± 1.26 ms (P <.05). In experiment 2, all dogs reached the STV threshold. HRP decreased STV from 2.02 ± 1.12 ms to 0.78 ± 0.28 ms, which was accompanied by prevention of TdP in 7 of 8 dogs.

Conclusion: STV can guide HRP automatically by an ICD to prevent ventricular arrhythmias.
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http://dx.doi.org/10.1016/j.hrthm.2020.07.023DOI Listing
December 2020

The value of septal rebound stretch analysis for the prediction of volumetric response to cardiac resynchronization therapy.

Eur Heart J Cardiovasc Imaging 2021 Jan;22(1):37-45

Department of Cardiology, University Medical Center Utrecht, Heidelberglaan 100, 3584 CX Utrecht, the Netherlands.

Aims: Patient selection for cardiac resynchronization therapy (CRT) may be enhanced by evaluation of systolic myocardial stretching. We evaluate whether systolic septal rebound stretch (SRSsept) derived from speckle tracking echocardiography is a predictor of reverse remodelling after CRT and whether it holds additive predictive value over the simpler visual dyssynchrony assessment by apical rocking (ApRock).

Methods And Results: The association between SRSsept and change in left ventricular end-systolic volume (ΔLVESV) at 6 months of follow-up was assessed in 200 patients. Subsequently, the additive predictive value of SRSsept over the assessment of ApRock was evaluated in patients with and without left bundle branch block (LBBB) according to strict criteria. SRSsept was independently associated with ΔLVESV (β 0.221, P = 0.002) after correction for sex, age, ischaemic cardiomyopathy, QRS morphology and duration, and ApRock. A high SRSsept (≥optimal cut-off value 2.4) also coincided with more volumetric responders (ΔLVESV ≥ -15%) than low SRSsept in the entire cohort (70.0% and 56.4%), in patients with strict LBBB (83.3% vs. 56.7%, P = 0.024), and non-LBBB (70.7% vs. 46.3%, P = 0.004). Moreover, in non-LBBB patients, SRSsept held additional predictive information over the assessment of ApRock alone since patients that showed ApRock and high SRSsept were more often volumetric responder than those with ApRock but low SRSsept (82.8% vs. 47.4%, P = 0.001).

Conclusion: SRSsept is strongly associated with CRT-induced reduction in left ventricular end-systolic volume and holds additive prognostic information over QRS morphology and ApRock. Our data suggest that CRT patient selection may be improved by assessment of SRSsept, especially in the important subgroup without strict LBBB.

Clinical Trial Registration: The MARC study was registered at clinicaltrials.gov: NCT01519908.
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http://dx.doi.org/10.1093/ehjci/jeaa190DOI Listing
January 2021

A combined CaMKII inhibition and mineralocorticoid receptor antagonism via eplerenone inhibits functional deterioration in chronic pressure overloaded mice.

J Cell Mol Med 2020 08 23;24(15):8417-8429. Epub 2020 Jun 23.

Division of Heart & Lungs, Department of Medical Physiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

In the diseased and remodelled heart, increased activity and expression of Ca calmodulin-dependent protein kinase II (CaMKII), an excess of fibrosis, and a decreased electrical coupling and cellular excitability leads to disturbed calcium homeostasis and tissue integrity. This subsequently leads to increased arrhythmia vulnerability and contractile dysfunction. Here, we investigated the combination of CaMKII inhibition (using genetically modified mice expressing the autocamtide-3-related-peptide (AC3I)) together with eplerenone treatment (AC3I-Epler) to prevent electrophysiological remodelling, fibrosis and subsequent functional deterioration in a mouse model of chronic pressure overload. We compared AC3I-Epler mice with mice only subjected to mineralocorticoid receptor (MR) antagonism (WT-Epler) and mice with only CaMKII inhibition (AC3I-No). Our data show that a combined CaMKII inhibition together with MR antagonism mitigates contractile deterioration as was manifested by a preservation of ejection fraction, fractional shortening, global longitudinal strain, peak strain and contractile synchronicity. Furthermore, patchy fibrosis formation was reduced, potentially via inhibition of pro-fibrotic TGF-β/SMAD3 signalling, which related to a better global contractile performance and a slightly depressed incidence of arrhythmias. Furthermore, the level of patchy fibrosis appeared significantly correlated to eplerenone dose. The addition of eplerenone to CaMKII inhibition potentiates the effects of CaMKII inhibition on pro-fibrotic pathways. As a result of the applied strategy, limiting patchy fibrosis adheres to a higher synchronicity of contraction and an overall better contractile performance which fits with a tempered arrhythmogenesis.
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http://dx.doi.org/10.1111/jcmm.15355DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7412412PMC
August 2020

Automated electrocardiographic quantification of myocardial scar in patients undergoing primary prevention implantable cardioverter-defibrillator implantation: Association with mortality and subsequent appropriate and inappropriate therapies.

Heart Rhythm 2020 10 17;17(10):1664-1671. Epub 2020 May 17.

Department of Cardiology, University Hospital Basel, Basel, Switzerland.

Background: Myocardial scarring from infarction or nonischemic fibrosis forms an arrhythmogenic substrate. The Selvester QRS score has been developed to estimate myocardial scar from the 12-lead electrocardiogram.

Objective: We aimed to assess the value of an automated version of the Selvester QRS score for the prediction of implantable cardioverter-defibrillator (ICD) therapy and death in patients undergoing primary prevention ICD implantation.

Methods: Unselected patients undergoing primary prevention ICD implantation were included in this retrospective, observational, multicenter study. The QRS score was calculated automatically from a digital standard preimplantation 12-lead electrocardiogram and was correlated to the occurrence of death and appropriate and inappropriate shocks during follow-up. Analyses were performed in groups defined by QRS duration < 130 ms vs ≥ 130 ms.

Results: Overall, 1047 patients (872 [83%] men; median age 64 years IQR [55-71]) with ischemic (648, 62%) or nonischemic (399, 38%) cardiomyopathy were included. The median QRS duration was 123 ms (interquartile range [IQR] 111-157 ms), and the median QRS score was 5 (IQR 2-8). The QRS duration was <130 ms in 59% and ≥130 ms in 41%. During a median follow-up of 45 months (IQR 24-72 months), a QRS score of ≥5 was independently associated with a significantly higher risk of mortality (hazard ratio [HR] 1.67; 95% confidence interval [CI] 1.05-2.66; P = .031) and appropriate (HR 1.83; 95% CI 1.07-3.14; P = .028) and inappropriate (HR 2.32; 95% CI 1.04-5.17; P = .039) shocks in patients with QRS duration ≥ 130 ms. No association of the QRS score and outcome was observed in patients with QRS duration < 130 ms (P > .05).

Conclusion: The automatically calculated Selvester QRS score, an indicator of myocardial scar burden, predicts mortality and appropriate and inappropriate shocks in patients undergoing primary prevention ICD implantation with a prolonged QRS duration.
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http://dx.doi.org/10.1016/j.hrthm.2020.05.016DOI Listing
October 2020

Electrocardiogram as a predictor of survival without appropriate shocks in primary prophylactic ICD patients: A retrospective multi-center study.

Int J Cardiol 2020 06 10;309:78-83. Epub 2020 Mar 10.

Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland. Electronic address:

Background: Abnormal 12-lead electrocardiogram (ECG) can predict cardiovascular events, including sudden cardiac death. We tested the hypothesis that ECG provides useful information on guiding implantable cardioverter defibrillator (ICD) therapy into individuals with impaired left ventricular ejection fraction (LVEF).

Methods: Retrospective data of primary prevention ICD implantations from 14 European centers were gathered. The registry included 5111 subjects of whom 1687 patients had an interpretable pre-implantation ECG available (80.0% male, 63.3 ± 11.4 years). Primary outcome was survival without appropriate ICD shocks or heart transplantation. A low-risk ECG was defined as a combination of ECG variables that were associated with the primary outcome.

Results: A total of 1224 (72.6%) patients survived the follow-up (2.9 ± 1.7 years) without an ICD shock, 224 (13.3%) received an appropriate shock and 260 (15.4%) died. Low-risk ECG defined as QRS duration <120 ms, QTc interval <450 ms for men and <470 ms for women, and sinus rhythm, were met by 515 patients (30.5%). Multivariable Cox regression showed that the hazard (HR) for death, heart transplantation or appropriate shock were reduced by 42.5% in the low-risk group (HR 0.575; 95% CI 0.45-0.74; p < 0.001), compared to the high-risk group. The HR for the first appropriate shock was 42.1% lower (HR 0.58; 95% CI 0.41-0.82; p = 0.002) and the HR for death was 48.0% lower (HR 0.52; 95% CI 0.386-0.72; p < 0.001) in the low-risk group.

Conclusion: Sinus rhythm, QRS <120 ms and normal QTc in standard 12-lead ECG provides information about survival without appropriate ICD shocks and might improve patient selection for primary prevention ICD therapy.
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http://dx.doi.org/10.1016/j.ijcard.2020.03.024DOI Listing
June 2020

Association between heart failure aetiology and magnitude of echocardiographic remodelling and outcome of cardiac resynchronization therapy.

ESC Heart Fail 2020 04 28;7(2):645-653. Epub 2020 Jan 28.

Department of Cardiology, University of Groningen, University Medical Centre Groningen, PO Box 30.001, Groningen, 9700, RB, The Netherlands.

Aims: Echocardiographic response after cardiac resynchronization therapy (CRT) is often lesser in ischaemic cardiomyopathy (ICM) than non-ischaemic dilated cardiomyopathy (NIDCM) patients. We assessed the association of heart failure aetiology on the amount of reverse remodelling and outcome of CRT.

Methods And Results: Nine hundred twenty-eight CRT patients were retrospectively included. Reverse remodelling and endpoint occurrence (all-cause mortality, heart transplantation, or left ventricular assist device implantation) was assessed. Two response definitions [≥15% reduction left ventricular end systolic volume (LVESV) and ≥5% improvement left ventricular ejection fraction] and the most accurate cut-off for the amount of reverse remodelling that predicted endpoint freedom were assessed. Mean follow-up was 3.8 ± 2.4 years. ICM was present in 47%. ICM patients who were older (69 ± 7 vs. 63 ± 11), more often men (83% vs. 58%), exhibited less LVESV reduction (13 ± 31% vs. 23 ± 32%) and less left ventricular ejection fraction improvement (5 ± 11% vs. 10 ± 12%) than NIDCM patients (all P < 0.001). Nevertheless, every 1% LVESV reduction was associated with a relative reduction in endpoint occurrence: NIDCM 1.3%, ICM 0.9%, and absolute risk reduction was similar (0.4%). The most accurate cut-off of LVESV reduction that predicted endpoint freedom was 17.1% in NIDCM and 13.2% in ICM.

Conclusions: ICM patients achieve less reverse remodelling than NIDCM, but the prognostic gain in terms of survival time is the same for every single percentage of reverse remodelling that does occur. The assessment and expected magnitude of reverse remodelling should take this effect of heart failure aetiology into account.
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http://dx.doi.org/10.1002/ehf2.12624DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7160473PMC
April 2020

Point of View: Electrophysiological Endpoints Differ When Comparing the Mode of Action of Highly Successful Anti-arrhythmic Drugs in the CAVB Dog Model With TdP.

J Cardiovasc Pharmacol 2019 12;74(6):499-507

Department of Medical Physiology, Faculty of Medicine, UMC Utrecht, Utrecht, The Netherlands.

In the anaesthetized, chronic atrioventricular block (CAVB) dog, ventricular ectopic beats and Torsade de pointes arrhythmias (TdP) are believed to ensue from an abrupt prolongation of ventricular repolarization and increased temporal dispersion of repolarization, quantified as short-term variability (STV). These TdP stop spontaneously or, when supported by substantial spatial dispersion of repolarization (SDR), degenerate into ventricular fibrillation. However, most studies involving ventricular arrhythmias do not quantify SDR by means of an electrophysiological parameter. Therefore, we reviewed the effects of 4 highly effective anti-arrhythmic drugs (flunarizine, verapamil, SEA-0400, and GS-458967) on the repolarization duration and associated STV. All drugs were tested as anti-arrhythmic strategies against TdP in CAVB dogs, their high anti-arrhythmic efficacy was defined as suppressing drug-induced TdP in 100% of the experiments. This comparison demonstrates that even though the anti-arrhythmic outcome was similar for all drugs, distinct responses of repolarization duration and associated STV were observed. Moreover, the aforementioned and commonly adopted electrophysiological parameters were not always sufficient in predicting TdP susceptibility, and additional quantification of the SDR proved to be of added value in these studies. The variability in electrophysiological responses to the different anti-arrhythmic drugs and their inconsistent adequacy in reflecting TdP susceptibility, can be explained by distinct modes of interference with TdP development. As such, this overview establishes the separate involvement of temporal and spatial dispersion in ventricular arrhythmogenesis in the CAVB dog model and proposes SDR as an additional parameter to be included in future fundamental and/or pharmaceutical studies regarding TdP arrhythmogenesis.
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http://dx.doi.org/10.1097/FJC.0000000000000748DOI Listing
December 2019

Appropriate Shocks and Mortality in Patients With Versus Without Diabetes With Prophylactic Implantable Cardioverter Defibrillators.

Diabetes Care 2020 01 23;43(1):196-200. Epub 2019 Oct 23.

Research Unit of Internal Medicine, Medical Research Center Oulu, Oulu University Hospital and University of Oulu, Oulu, Finland.

Objective: Diabetes increases the risk of all-cause mortality and sudden cardiac death (SCD). The exact mechanisms leading to sudden death in diabetes are not well known. We compared the incidence of appropriate shocks and mortality in patients with versus without diabetes with a prophylactic implantable cardioverter defibrillator (ICD) included in the retrospective EU-CERT-ICD registry.

Research Design And Methods And Results: A total of 3,535 patients from 12 European EU-CERT-ICD centers with a mean age of 63.7 ± 11.2 years (82% males) at the time of ICD implantation were included in the analysis. A total of 995 patients (28%) had a history of diabetes. All patients had an ICD implanted for primary SCD prevention. End points were appropriate shock and all-cause mortality. Mean follow-up time was 3.2 ± 2.3 years. Diabetes was associated with a lower risk of appropriate shocks (adjusted hazard ratio [HR] 0.77 [95% CI 0.62-0.96], = 0.02). However, patients with diabetes had significantly higher mortality (adjusted HR 1.30 [95% CI 1.11-1.53], = 0.001).

Conclusions: All-cause mortality is higher in patients with diabetes than in patients without diabetes with primary prophylactic ICDs. Subsequently, patients with diabetes have a lower incidence of appropriate ICD shocks, indicating that the excess mortality might not be caused primarily by ventricular tachyarrhythmias. These findings suggest a limitation of the potential of prophylactic ICD therapy to improve survival in patients with diabetes with impaired left ventricular function.
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http://dx.doi.org/10.2337/dc19-1014DOI Listing
January 2020

Required G to Suppress Automaticity of iPSC-CMs Depends Strongly on I Model Structure.

Biophys J 2019 12 13;117(12):2303-2315. Epub 2019 Sep 13.

University Medical Center Utrecht, Utrecht, the Netherlands. Electronic address:

Human-induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) are a virtually endless source of human cardiomyocytes that may become a great tool for safety pharmacology; however, their electrical phenotype is immature: they show spontaneous action potentials (APs) and an unstable and depolarized resting membrane potential (RMP) because of lack of I. Such immaturity hampers their application in assessing drug safety. The electronic overexpression of I (e.g., through the dynamic clamp (DC) technique) is an option to overcome this deficit. In this computational study, we aim to estimate how much I is needed to bring hiPSC-CMs to a stable and hyperpolarized RMP and which mathematical description of I is most suitable for DC experiments. We compared five mature I formulations (Bett, Dhamoon, Ishihara, O'Hara-Rudy, and ten Tusscher) with the native one (Paci), evaluating the main properties (outward peak, degree of rectification), and we quantified their effects on AP features (RMP, V˙, APD, APD (AP duration at 50 and 90% of repolarization), and APD/APD) after including them in the hiPSC-CM mathematical model by Paci. Then, we automatically identified the critical conductance for I ( G), the minimally required amount of I suppressing spontaneous activity. Preconditioning the cell model with depolarizing/hyperpolarizing prepulses allowed us to highlight time dependency of the I formulations. Simulations showed that inclusion of mature I formulations resulted in hyperpolarized RMP and higher V˙, and observed G and the effect on AP duration strongly depended on I formulation. Finally, the Ishihara I led to shorter (-16.3%) and prolonged (+6.5%) APD in response to hyperpolarizing and depolarizing prepulses, respectively, whereas other models showed negligible effects. Fine-tuning of G is an important step in DC experiments. Our computational work proposes a procedure to automatically identify how much I current is required to inject to stop the spontaneous activity and suggests the use of the Ishihara I model to perform DC experiments in hiPSC-CMs.
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http://dx.doi.org/10.1016/j.bpj.2019.08.040DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6990378PMC
December 2019

The Increment of Short-term Variability of Repolarisation Determines the Severity of the Imminent Arrhythmic Outcome.

Arrhythm Electrophysiol Rev 2019 Jul;8(3):166-172

Department of Medical Physiology, University Medical Center Utrecht Utrecht, the Netherlands.

Ventricular remodelling can make the heart more susceptible to ventricular arrhythmias like torsades de pointes. Understanding the underlying mechanisms of initiation of ventricular arrhythmias and the determining factors for its severity has the potential to uncover new interventions. Beat-to-beat variation of repolarisation, quantified as short-term variability of repolarisation (STV), has been identified as an important factor contributing to arrhythmogenesis. This article provides an overview of experimental data about STV in relation to the initiation of torsades de pointes in a canine model of complete chronic atrioventricular block susceptible to torsades de pointes arrhythmias. Furthermore, it explores STV in relation to the severity of the arrhythmic outcome.
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http://dx.doi.org/10.15420/aer.2019.16.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6766692PMC
July 2019

Present criteria for prophylactic ICD implantation: Insights from the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in EUrope) project.

J Electrocardiol 2019 Nov - Dec;57S:S34-S39. Epub 2019 Sep 4.

Dept. of Cardiology, KBC Sestre Milosrdnice, Zagreb, Croatia.

Background: The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. It is urgently needed to better identify patients who benefit from prophylactic ICD therapy. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) completed in 2019 will assess this issue.

Summary: The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicenter observational cohort study done in 44 centers across 15 European countries. A total of 2327 patients with heart failure due to ischemic heart disease or dilated cardiomyopathy indicated for primary prophylactic ICD implantation were recruited between 2014 and 2018 (>1500 patients at first ICD implantation, >750 patients non-randomized non-ICD control group). The primary endpoint was all-cause mortality, and first appropriate shock was co-primary endpoint. At baseline, all patients underwent 12‑lead ECG and Holter-ECG analysis using multiple advanced methods for risk stratification as well as documentation of clinical characteristics and laboratory values. The EU-CERT-ICD data will provide much needed information on the survival benefit of preventive ICD therapy and expand on previous prospective risk stratification studies which showed very good applicability of clinical parameters and advanced risk stratifiers in order to define patient subgroups with above or below average ICD benefit.

Conclusion: The EU-CERT-ICD study will provide new and current data about effectiveness of primary prophylactic ICD implantation. The study also aims for improved risk stratification and patient selection using clinical risk markers in general, and advanced ECG risk markers in particular.
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http://dx.doi.org/10.1016/j.jelectrocard.2019.09.001DOI Listing
May 2021

Pro-Arrhythmic Ventricular Remodeling Is Associated With Increased Respiratory and Low-Frequency Oscillations of Monophasic Action Potential Duration in the Chronic Atrioventricular Block Dog Model.

Front Physiol 2019 23;10:1095. Epub 2019 Aug 23.

Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.

In addition to beat-to-beat fluctuations, action potential duration (APD) oscillates at (1) a respiratory frequency and (2) a low frequency (LF) (<0.1 Hz), probably caused by bursts of sympathetic nervous system discharge. This study investigates whether ventricular remodeling in the chronic AV block (CAVB) dog alters these oscillations of APD and whether this has consequences for arrhythmogenesis. We performed a retrospective analysis of 39 dog experiments in sinus rhythm (SR), acute AV block (AAVB), and after 2 weeks of chronic AV block. Spectral analysis of left ventricular monophasic action potential duration (LV MAPD) was done to quantify respiratory frequency (RF) power and LF power. Dofetilide (0.025 mg/kg in 5 min) was infused to test for inducibility of Torsade de Pointes (TdP) arrhythmias. RF power was significantly increased at CAVB compared to AAVB and SR (log[RF] of -1.13 ± 1.62 at CAVB vs. log[RF] of -2.82 ± 1.24 and -3.29 ± 1.29 at SR and AAVB, respectively, < 0.001). LF power was already significantly increased at AAVB and increased even further at CAVB (-3.91 ± 0.70 at SR vs. -2.52 ± 0.85 at AAVB and -1.14 ± 1.62 at CAVB, < 0.001). In addition, LF power was significantly larger in inducible CAVB dogs (log[LF] -0.6 ± 1.54 in inducible dogs vs. -2.56 ± 0.43 in non-inducible dogs, < 0.001). In conclusion, ventricular remodeling in the CAVB dog results in augmentation of respiratory and low-frequency (LF) oscillations of LV MAPD. Furthermore, TdP-inducible CAVB dogs show increased LF power.
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http://dx.doi.org/10.3389/fphys.2019.01095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6716537PMC
August 2019

Plakophilin-2 Haploinsufficiency Causes Calcium Handling Deficits and Modulates the Cardiac Response Towards Stress.

Int J Mol Sci 2019 Aug 21;20(17). Epub 2019 Aug 21.

Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, Utrecht 3584CM, The Netherlands.

Human variants in plakophilin-2 (PKP2) associate with most cases of familial arrhythmogenic cardiomyopathy (ACM). Recent studies show that PKP2 not only maintains intercellular coupling, but also regulates transcription of genes involved in Ca cycling and cardiac rhythm. ACM penetrance is low and it remains uncertain, which genetic and environmental modifiers are crucial for developing the cardiomyopathy. In this study, heterozygous PKP2 knock-out mice (PKP2-Hz) were used to investigate the influence of exercise, pressure overload, and inflammation on a PKP2-related disease progression. In PKP2-Hz mice, protein levels of Ca-handling proteins were reduced compared to wildtype (WT). PKP2-Hz hearts exposed to voluntary exercise training showed right ventricular lateral connexin43 expression, right ventricular conduction slowing, and a higher susceptibility towards arrhythmias. Pressure overload increased levels of fibrosis in PKP2-Hz hearts, without affecting the susceptibility towards arrhythmias. Experimental autoimmune myocarditis caused more severe subepicardial fibrosis, cell death, and inflammatory infiltrates in PKP2-Hz hearts than in WT. To conclude, PKP2 haploinsufficiency in the murine heart modulates the cardiac response to environmental modifiers via different mechanisms. Exercise upon PKP2 deficiency induces a pro-arrhythmic cardiac remodeling, likely based on impaired Ca cycling and electrical conduction, versus structural remodeling. Pathophysiological stimuli mainly exaggerate the fibrotic and inflammatory response.
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http://dx.doi.org/10.3390/ijms20174076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6747156PMC
August 2019

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

Br J Pharmacol 2019 10 30;176(19):3871-3885. Epub 2019 Aug 30.

Department of Medical Physiology, University Medical Centre Utrecht, Utrecht, The Netherlands.

Background And Purpose: K 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 K 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 I and canine I 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 I by inhibiting inactivation. In vitro, LUF7244 (10 μM) had no effects on I , I , I , and I , doubled I , shortened human and canine action potential duration by approximately 50%, and inhibited dofetilide-induced early afterdepolarizations. LUF7244 (2.5 mg·kg ·15 min ) 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 K 11.1 channels might neutralize adverse cardiac effects of existing drugs and newly developed compounds that display QTc lengthening.
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http://dx.doi.org/10.1111/bph.14798DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6780032PMC
October 2019

Sex hormones and jumping heart beats.

J Cardiovasc Electrophysiol 2019 06 21;30(6):950-951. Epub 2019 Apr 21.

Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, The Netherlands.

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http://dx.doi.org/10.1111/jce.13939DOI Listing
June 2019

The influence of hERG1a and hERG1b isoforms on drug safety screening in iPSC-CMs.

Prog Biophys Mol Biol 2019 12 27;149:86-98. Epub 2019 Feb 27.

Department of Medical Physiology, Division Heart & Lungs, University Medical Center Utrecht, the Netherlands. Electronic address:

The human Ether-à-go-go Related Gene (hERG) encodes the pore forming subunit of the channel that conducts the rapid delayed rectifier potassium current I. I drives repolarization in the heart and when I is dysfunctional, cardiac repolarization delays, the QT interval on the electrocardiogram (ECG) prolongs and the risk of developing lethal arrhythmias such as Torsade de Pointes (TdP) increases. TdP risk is incorporated in drug safety screening for cardiotoxicity where hERG is the main target since the I channels appear highly sensitive to blockage. hERG block is also included as an important read-out in the Comprehensive in Vitro Proarrhythmia Assay (CiPA) initiative which aims to combine in vitro and in silico experiments on induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) to screen for cardiotoxicity. However, the hERG channel has some unique features to consider for drug safety screening, which we will discuss in this study. The hERG channel consists of different isoforms, hERG1a and hERG1b, which individually influence the kinetics of the channel and the drug response in the human heart and in iPSC-CMs. hERG1b is often underappreciated in iPSC-CM studies, drug screening assays and in silico models, and the fact that its contribution might substantially differ between iPSC-CM and healthy but also diseased human heart, adds to this problem. In this study we show that the activation kinetics in iPSC-CMs resemble hERG1b kinetics using Cs as a charge carrier. Not including hERG1b in drug safety testing might underestimate the actual role of hERG1b in repolarization and drug response, and might lead to inappropriate conclusions. We stress to focus more on including hERG1b in drug safety testing concerning I.
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http://dx.doi.org/10.1016/j.pbiomolbio.2019.02.003DOI Listing
December 2019

Sex-specific influence on cardiac structural remodeling and therapy in cardiovascular disease.

Biol Sex Differ 2019 02 4;10(1). Epub 2019 Feb 4.

Department of Medical Physiology, Division of Heart and Lungs, University Medical Center, Utrecht, Utrecht University, Yalelaan 50, 3584CM, Utrecht, The Netherlands.

Background: Cardiovascular diseases (CVDs) culminating into heart failure (HF) are major causes of death in men and women. Prevalence and manifestation, however, differ between sexes, since men mainly present with coronary artery disease (CAD) and myocardial infarction (MI), and post-menopausal women predominantly present with hypertension. These discrepancies are probably influenced by underlying genetic and molecular differences in structural remodeling pathways involved in hypertrophy, inflammation, fibrosis, and apoptosis. In general, men mainly develop eccentric forms, while women develop concentric forms of hypertrophy. Besides that, women show less inflammation, fibrosis, and apoptosis upon HF. This seems to emerge, at least partially, from the fact that the underlying pathways might be modulated by estrogen, which changes after menopause due to declining of the estrogen levels.

Conclusion: In this review, sex-dependent alterations in adverse cardiac remodeling are discussed for various CVDs. Moreover, potential therapeutic options, like estrogen treatment, are reviewed.
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http://dx.doi.org/10.1186/s13293-019-0223-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6360698PMC
February 2019

QRS Area Is a Strong Determinant of Outcome in Cardiac Resynchronization Therapy.

Circ Arrhythm Electrophysiol 2018 12;11(12):e006497

Department of Cardiology, Maastricht University Medical Centre, The Netherlands (A.M.W.v.S., H.J.G.M.C., K.V.).

Background: The combination of left bundle branch block (LBBB) morphology and QRS duration is currently used to select patients for cardiac resynchronization therapy (CRT). These parameters, however, have limitations. This study evaluates the value of QRS area compared with that of QRS duration and morphology in the association with clinical and echocardiographic outcomes in a large cohort of CRT patients.

Methods: A retrospective multicentre study was conducted in 1492 CRT patients. LBBB morphology, QRS duration, and QRS area in the baseline 12-lead ECG were evaluated for their association with the occurrence of the combined primary end point of all-cause mortality, cardiac transplantation, and left ventricular assist device implantation. Secondary end points were heart failure hospitalization within the first year after implantation and echocardiographic reduction in left ventricular end-systolic volume.

Results: During a mean follow-up period of 3.4 years, 32% of patients reached the primary end point. The association of QRS area with all outcomes was stronger than that of LBBB morphology and QRS duration separately and at least as strong as their combination. QRS area identified patients who did not experience the primary end point better than QRS morphology and QRS duration (area under the curve, 0.61 versus 0.55 and 0.51, respectively; P<0.001). Furthermore, QRS area identifies patients with echocardiographic remodeling in response to CRT better than QRS morphology and duration (area under the curve, 0.69 versus 0.58 and 0.58, respectively; P<0.001). QRS area was the only independent electrocardiographic determinant associated with the primary end point; hazard ratio, 0.50 (0.35-0.71). Furthermore, QRS area showed significant association with outcomes in both patients with and without LBBB and QRS ≥150 ms.

Conclusions: QRS area has a strong association to clinical and echocardiographic response to CRT, at least as strong as current patient selection parameters. QRS area may be particularly useful to predict CRT response in patients without a wide LBBB.
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http://dx.doi.org/10.1161/CIRCEP.118.006497DOI Listing
December 2018

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

Data Brief 2018 Dec 9;21:2110-2116. Epub 2018 Nov 9.

University Medical Center Göttingen, Dept. of Cardiology and Pneumology, Göttingen, Germany.

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].
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http://dx.doi.org/10.1016/j.dib.2018.11.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6262164PMC
December 2018

Flotillins in the intercalated disc are potential modulators of cardiac excitability.

J Mol Cell Cardiol 2019 01 17;126:86-95. Epub 2018 Nov 17.

Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Utrecht, the Netherlands.

Background: The intercalated disc (ID) is important for cardiac remodeling and has become a subject of intensive research efforts. However, as yet the composition of the ID has still not been conclusively resolved and the role of many proteins identified in the ID, like Flotillin-2, is often unknown. The Flotillin proteins are known to be involved in the stabilization of cadherins and desmosomes in the epidermis and upon cancer development. However, their role in the heart has so far not been investigated. Therefore, in this study, we aimed at identifying the role of Flotillin-1 and Flotillin-2 in the cardiac ID.

Methods: Location of Flotillins in human and murine cardiac tissue was evaluated by fluorescent immunolabeling and co-immunoprecipitation. In addition, the effect of Flotillin knockout (KO) on proteins of the ID and in electrical excitation and conduction was investigated in cardiac samples of wildtype (WT), Flotillin-1 KO, Flotilin-2 KO and Flotilin-1/2 double KO mice. Consequences of Flotillin knockdown (KD) on cardiac function were studied (patch clamp and Multi Electrode Array (MEA)) in neonatal rat cardiomyocytes (NRCMs) transfected with siRNAs against Flotillin-1 and/or Flotillin-2.

Results: First, we confirmed presence in the ID and mutual binding of Flotillin-1 and Flotillin-2 in murine and human cardiac tissue. Flotillin KO mice did not show cardiac fibrosis, nor hypertrophy or changes in expression of the desmosomal ID proteins. However, protein expression of the cardiac sodium channel Na1.5 was significantly decreased in Flotillin-1 and Flotillin-1/2 KO mice compared to WT mice. In addition, sodium current density showed a significant decrease upon Flotillin-1/2 KD in NRCMs as compared to scrambled siRNA-transfected NRCMs. MEA recordings of Flotillin-2 KD NRCM cultures showed a significantly decreased spike amplitude and a tendency of a reduced spike slope when compared to control and scrambled siRNA-transfected cultures.

Conclusions: In this study, we demonstrate the presence of Flotillin-1, in addition to Flotillin-2 in the cardiac ID. Our findings indicate a modulatory role of Flotillins on Na1.5 expression at the ID, with potential consequences for cardiac excitation.
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http://dx.doi.org/10.1016/j.yjmcc.2018.11.007DOI Listing
January 2019

Rationale and design of the EU-CERT-ICD prospective study: comparative effectiveness of prophylactic ICD implantation.

ESC Heart Fail 2019 02 9;6(1):182-193. Epub 2018 Oct 9.

Department of Cardiology, Magdalena Klinika, Krapinske Toplice, Croatia.

Aims: The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) aims to assess its current clinical value.

Methods And Results: The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicentre observational cohort study performed in 44 centres across 15 European Union countries. We will recruit 2250 patients with ischaemic or dilated cardiomyopathy and a guideline indication for primary prophylactic ICD implantation. This sample will include 1500 patients at their first ICD implantation and 750 patients who did not receive a primary prevention ICD despite having an indication for it (non-randomized control group). The primary endpoint is all-cause mortality; the co-primary endpoint in ICD patients is time to first appropriate shock. Secondary endpoints include sudden cardiac death, first inappropriate shock, any ICD shock, arrhythmogenic syncope, revision procedures, quality of life, and cost-effectiveness. At baseline (and prior to ICD implantation if applicable), all patients undergo 12-lead electrocardiogram (ECG) and Holter ECG analysis using multiple advanced methods for risk stratification as well as detailed documentation of clinical characteristics and laboratory values. Genetic biobanking is also organized. As of August 2018, baseline data of 2265 patients are complete. All subjects will be followed for up to 4.5 years.

Conclusions: The EU-CERT-ICD study will provide a necessary update about clinical effectiveness of primary prophylactic ICD implantation. This study also aims for improved risk stratification and patient selection using clinical and ECG risk markers.
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http://dx.doi.org/10.1002/ehf2.12367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6351896PMC
February 2019

Optogenetic sensors in the zebrafish heart: a novel in vivo electrophysiological tool to study cardiac arrhythmogenesis.

Theranostics 2018 9;8(17):4750-4764. Epub 2018 Sep 9.

Department of Medical Physiology, Division of Heart & Lungs, University Medical Center Utrecht, Yalelaan 50, 3584 CM, Utrecht, The Netherlands.

Cardiac arrhythmias are among the most challenging human disorders to diagnose and treat due to their complex underlying pathophysiology. Suitable experimental animal models are needed to study the mechanisms causative for cardiac arrhythmogenesis. To enable analysis of cardiac cellular electrophysiology with a high spatial and temporal resolution, we generated and carefully validated two zebrafish models, one expressing an optogenetic voltage indicator (chimeric VSFP-butterfly CY) and the other a genetically encoded calcium indicator (GCaMP6f) in the heart. High-speed epifluorescence microscopy was used to image chimeric VSFP-butterfly CY and GCaMP6f in the embryonic zebrafish heart, providing information about the spatiotemporal patterning of electrical activation, action potential configuration and intracellular Ca dynamics. Plotting VSFP or GCaMP6f signals on a line along the myocardial wall over time facilitated the visualization and analysis of electrical impulse propagation throughout the heart. Administration of drugs targeting the sympathetic nervous system or cardiac ion channels was used to validate sensitivity and kinetics of both zebrafish sensor lines. Using the same microscope setup, we imaged transparent juvenile fish expressing GCaMP6f, demonstrating the feasibility of imaging cardiac optogenetic sensors at later stages of development. Isoproterenol slightly increased heart rate, diastolic Ca levels and Ca transient amplitudes, whereas propranolol caused a profound decrease in heart rate and Ca transient parameters in VSFP-Butterfly and GCaMP6f embryonic fish. Ik blocker E-4031 decreased heart rate and increased action potential duration in VSFP-Butterfly fish. I blocker nifedipine caused total blockade of Ca transients in GCaMP6f fish and a reduced heart rate, altered ventricular action potential duration and disrupted atrial-ventricular electrical conduction in VSFP-Butterfly fish. Imaging of juvenile animals demonstrated the possibility of employing an older zebrafish model for cardiac electrophysiology studies. We observed differences in atrial and ventricular Ca recovery dynamics between 3 dpf and 14 dpf fish, but not in Ca upstroke dynamics. By introducing the optogenetic sensors chimeric VSFP-butterfly CY and GCaMP6f into the zebrafish we successfully generated an cellular electrophysiological readout tool for the zebrafish heart. Complementary use of both sensor lines demonstrated the ability to study heart rate, cardiac action potential configuration, spatiotemporal patterning of electrical activation and intracellular Ca homeostasis in embryonic zebrafish. In addition, we demonstrated the first successful use of an optogenetic sensor to study cardiac function in older zebrafish. These models present a promising new research tool to study the underlying mechanisms of cardiac arrhythmogenesis.
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http://dx.doi.org/10.7150/thno.26108DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6160779PMC
September 2019

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.

Front Physiol 2018 8;9:1086. Epub 2018 Aug 8.

Department of Medical Physiology, Division of Heart and Lungs, University Medical Center Utrecht, Utrecht, Netherlands.

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 markers of contractile remodeling and TdP inducibility. In 18 anesthetized dogs, the maximal first derivative of left ventricular pressure (LV dP/dt) 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. After infusion of dofetilide, 1/18 dogs and 12/18 were susceptible to TdP-arrhythmias at AAVB and CAVB2, respectively ( = 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, < 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, < 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 ( = 0.73, = 0.002), the slope of the FFR ( = -0.58, = 0.01) and the TC of MR ( = 0.66, = 0.003). Thus, more severe arrhythmias were seen in dogs with the most pronounced contractile remodeling. 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 Ca handling and Ca-overload, which predispose the heart to delayed- and early afterdepolarizations that could trigger TdP-arrhythmias.
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http://dx.doi.org/10.3389/fphys.2018.01086DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6092493PMC
August 2018

Strain imaging to predict response to cardiac resynchronization therapy: a systematic comparison of strain parameters using multiple imaging techniques.

ESC Heart Fail 2018 12 26;5(6):1130-1140. Epub 2018 Jul 26.

Department of Cardiology, and Amsterdam Cardiovascular Sciences (ACS), VU University Medical Center, Amsterdam, The Netherlands.

Aims: Various strain parameters and multiple imaging techniques are presently available including cardiovascular magnetic resonance (CMR) tagging (CMR-TAG), CMR feature tracking (CMR-FT), and speckle tracking echocardiography (STE). This study aims to compare predictive performance of different strain parameters and evaluate results per imaging technique to predict cardiac resynchronization therapy (CRT) response.

Methods And Results: Twenty-seven patients were prospectively enrolled and underwent CMR and echocardiographic examination before CRT implantation. Strain analysis was performed in circumferential (CMR-TAG, CMR-FT, and STE-circ) and longitudinal (STE-long) orientations. Regional strain values, parameters of dyssynchrony, and discoordination were calculated. After 12 months, CRT response was measured by the echocardiographic change in left ventricular (LV) end-systolic volume (LVESV). Twenty-six patients completed follow-up; mean LVESV change was -29 ± 27% with 17 (65%) patients showing ≥15% LVESV reduction. Measures of dyssynchrony (SD-TTP ) and discoordination (ISF ) were strongly related to CRT response when using CMR-TAG (R 0.61 and R 0.57, respectively), but showed poor correlations for CMR-FT and STE (all R  ≤ 0.32). In contrast, the end-systolic septal strain (ESS ) parameter showed a consistent high correlation with LVESV change for all techniques (CMR-TAG R 0.60; CMR-FT R 0.50; STE-circ R 0.43; and STE-long R 0.43). After adjustment for QRS duration and QRS morphology, ESS remained an independent predictor of response per technique.

Conclusions: End-systolic septal strain was the only parameter with a consistent good relation to reverse remodelling after CRT, irrespective of assessment technique. In clinical practice, this measure can be obtained by any available strain imaging technique and provides predictive value on top of current guideline criteria.
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http://dx.doi.org/10.1002/ehf2.12335DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6300826PMC
December 2018