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

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 p < 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 (p < 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

Study protocol: EXERcise and Cognition In Sedentary adults with Early-ONset dementia (EXERCISE-ON)

<p>Abstract</p> <p>Background</p> <p>Although the development of early-onset dementia is a radical and invalidating experience for both patient and family there are hardly any non-pharmacological studies that focus on this group of patients. One type of a non-pharmacological intervention that appears to have a beneficial effect on cognition in older persons without dementia and older persons at risk for dementia is exercise. In view of their younger age early-onset dementia patients may be well able to participate in an exercise program. The main aim of the EXERCISE-ON study is to assess whether exercise slows down the progressive course of the symptoms of dementia.</p> <p>Methods/Design</p> <p>One hundred and fifty patients with early-onset dementia are recruited. After completion of the baseline measurements, participants living within a 50 kilometre radius to one of the rehabilitation centres are randomly assigned to either an <it>aerobic exercise program in a rehabilitation centre</it> or a <it>flexibility and relaxation program in a rehabilitation centre</it>. Both programs are applied three times a week during 3 months. Participants living outside the 50 kilometre radius are included in a feasibility study where participants join in a <it>daily physical activity program set at home making use of pedometers</it>. Measurements take place at baseline (entry of the study), after three months (end of the exercise program) and after six months (follow-up). Primary outcomes are cognitive functioning; psychomotor speed and executive functioning; (instrumental) activities of daily living, and quality of life. Secondary outcomes include physical, neuropsychological, and rest-activity rhythm measures.</p> <p>Discussion</p> <p>The EXERCISE-ON study is the first study to offer exercise programs to patients with early-onset dementia. We expect this study to supply evidence regarding the effects of exercise on the symptoms of early-onset dementia, influencing quality of life.</p> <p>Trial registration</p> <p>The present study is registered within The Netherlands National Trial Register (ref: NTR2124)</p

Stroke genetics informs drug discovery and risk prediction across ancestries

Previous genome-wide association studies (GWASs) of stroke — the second leading cause of death worldwide — were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries

A typology of urban knowledge sharing:From a systematic literature review to an integrated model

This paper provides insight into how the conceptualization of urban knowledge sharing has developed. Based on a structured review and categorization of the literature, we identify three forms of knowledge sharing in and between cities that are distinctly different: knowledge transfer, knowledge exchange, and knowledge co-creation. We find that the three forms have different boosts and barriers, whereby the complexities of knowledge sharing and hence the capacities required of the actors are lowest for knowledge transfer and highest for knowledge co-creation. We would therefore like to qualify the recent emphasis given in literature to co-creation; with its complexities and required capacities, it is not to be considered a panacea for solving all urban problems. We propose a model within which knowledge transfer and exchange are more suitable for less wicked problems and may sometimes fruitfully reduce complexities

Precision medicine in regulatory decision making: Biomarkers used for patient selection in European Public Assessment Reports from 2018 to 2020

Abstract Biomarkers can guide precision medicine in clinical trials and practice. They can increase clinical trials' efficiency through selection of study populations more likely to benefit from treatment, thus increasing statistical power and reducing sample size requirements or study duration. We performed a narrative synthesis to explore biomarker utilization for patient selection to guide precision medicine trials in marketing authorization dossiers of centrally approved medicines in Europe between 2018 and 2020 and analyzed in‐depth those that eventually included biomarkers in the medicines' indications. From 119 eligible products, 26 included a biomarker in the indication, of which most were oncology products (n = 15). Included biomarkers were often known from literature or from previously approved products in the European Union or the United States. Additionally, 52 dossiers mentioned one or more biomarkers for patient selection in their clinical efficacy and safety information. Although these were not always included in the medicines' indication, they were often implicitly embedded in condition definitions adopted from clinical guidelines or practice. In 15 out of the 26 medicines with a biomarker‐guided indication, only biomarker‐positive populations were included in the main clinical studies supporting the marketing authorization. These studies were mostly randomized controlled trials or single‐arm trials; only two products were studied for multiple indications in an innovative basket trial. Definitions of biomarkers could be subject of debate and needed adaptation after post hoc analyses requested by the assessment committee in four cases, stressing the importance of thorough justification of these definitions to include the right population for an optimal benefit–risk balance, enabling precise medicine

Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog

Aims: The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. Methods and results: In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000 – 1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle – LV was similar between inducible and non-inducible dogs at baseline (327 + 30 vs. 345 + 17 ms) and after dofetilide administration (525 + 95 vs. 508 + 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 + 20 vs. 142 + 34 ms) and cubic dispersion (272 + 29 vs. 176 + 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. Conclusion: Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate TdP

Torsade de pointes arrhythmias arise at the site of maximal heterogeneity of repolarization in the chronic complete atrioventricular block dog

The chronic complete atrioventricular block (CAVB) dog is highly sensitive for drug-induced torsade de pointes (TdP) arrhythmias. Focal mechanisms have been suggested as trigger for TdP onset; however, its exact mechanism remains unclear. In this study, detailed mapping of the ventricles was performed to assess intraventricular heterogeneity of repolarization in relation to the initiation of TdP. In 8 CAVB animals, 56 needles, each containing 4 electrodes, were inserted in the ventricles. During right ventricular apex pacing (cycle length: 1000-1500 ms), local unipolar electrograms were recorded before and after administration of dofetilide to determine activation and repolarization times (RTs). Maximal RT differences were calculated in the left ventricle (LV) within adjacent electrodes in different orientations (transmural, vertical, and horizontal) and within a square of four needles (cubic dispersion). Dofetilide induced TdP in five out of eight animals. Right ventricle-LV was similar between inducible and non-inducible dogs at baseline (327 ± 30 vs. 345 ± 17 ms) and after dofetilide administration (525 ± 95 vs. 508 ± 15 ms). All measurements of intraventricular dispersion were not different at baseline, but this changed for horizontal (206 ± 20 vs. 142 ± 34 ms) and cubic dispersion (272 ± 29 vs. 176 ± 48 ms) after dofetilide: significantly higher values in inducible animals. Single ectopic beats and the first TdP beat arose consistently from a subendocardially located electrode terminal with the shortest RT in the region with largest RT differences. Chronic complete atrioventricular block dogs susceptible for TdP demonstrate higher RT differences. Torsade de pointes arises from a region with maximal heterogeneity of repolarization suggesting that a minimal gradient is required in order to initiate Td

Short-lasting episodes of torsade de pointes in the chronic atrioventricular block dog model have a focal mechanism, while longer-lasting episodes are maintained by re-entry

Objectives This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. Background The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the initiation and the perpetuation of TdP. Methods In 5 TdP-sensitive chronic atrioventricular block dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10 s. Software was developed to automatically detect activation times and to create 3-dimensional visualizations of the arrhythmia. For each episode of ectopic activity (ranging from 2 beats to NT episodes), a novel methodology was created to construct directed graphs of the wave propagation and detect re-entry loops by using an iterative depth-first-search algorithm. Results Depending on the TdP definition (number of consecutive ectopic beats), we analyzed 29 to 54 TdP: 29 were longer than 5 beats. In the total group, 9 were NT and 45 were self-terminating. Initiation and termination were always based on focal activity. Re-entry becomes more important in the longer-lasting episodes (>14 beats), whereas in all NT TdP, re-entry was the last active mechanism. During re-entry, excitation fronts were constantly present in the heart, while during focal TdP, there was always a silent interval between 2 consecutive waves (142 ms) during which excitation fronts were absent. Interbeat intervals were significantly smaller for re-entry episodes—220 versus 310 ms in focal. Electrograms recorded in particular areas during NT TdP episodes had significantly smaller amplitude (0.38) than during focal episodes (0.59). Conclusions TdP can be driven by focal activity as well as by re-entry depending on the duration of the episode. NT episodes are always maintained by re-entry, which can be identified in local unipolar electrograms by shorter interbeat intervals and smaller deflection amplitude

Short-Lasting Episodes of Torsade de Pointes in the Chronic Atrioventricular Block Dog Model Have a Focal Mechanism, While Longer-Lasting Episodes Are Maintained by Re-Entry

Objectives This study investigated the arrhythmogenic mechanisms responsible for torsade de pointes (TdP) in the chronic atrioventricular block dog model, known for its high susceptibility for TdP. Background The mechanism of TdP arrhythmias has been under debate for many years. Focal activity as well as re-entry have both been mentioned in the initiation and the perpetuation of TdP. Methods In 5 TdP-sensitive chronic atrioventricular block dogs, 56 needle electrodes were evenly distributed transmurally to record 240 unipolar local electrograms simultaneously. Nonterminating (NT) episodes were defibrillated after 10 s. Software was developed to automatically detect activation times and to create 3-dimensional visualizations of the arrhythmia. For each episode of ectopic activity (ranging from 2 beats to NT episodes), a novel methodology was created to construct directed graphs of the wave propagation and detect re-entry loops by using an iterative depth-first-search algorithm. Results Depending on the TdP definition (number of consecutive ectopic beats), we analyzed 29 to 54 TdP: 29 were longer than 5 beats. In the total group, 9 were NT and 45 were self-terminating. Initiation and termination were always based on focal activity. Re-entry becomes more important in the longer-lasting episodes (>14 beats), whereas in all NT TdP, re-entry was the last active mechanism. During re-entry, excitation fronts were constantly present in the heart, while during focal TdP, there was always a silent interval between 2 consecutive waves (142 ms) during which excitation fronts were absent. Interbeat intervals were significantly smaller for re-entry episodes—220 versus 310 ms in focal. Electrograms recorded in particular areas during NT TdP episodes had significantly smaller amplitude (0.38) than during focal episodes (0.59). Conclusions TdP can be driven by focal activity as well as by re-entry depending on the duration of the episode. NT episodes are always maintained by re-entry, which can be identified in local unipolar electrograms by shorter interbeat intervals and smaller deflection amplitude