Efficient termination of cardiac arrhythmias using optogenetic resonant feedback pacing.

Malignant cardiac tachyarrhythmias are associated with complex spatiotemporal excitation of the heart. The termination of these life-threatening arrhythmias requires high-energy electrical shocks that have significant side effects, including tissue damage, excruciating pain, and worsening prognosis. This significant medical need has motivated the search for alternative approaches that mitigate the side effects, based on a comprehensive understanding of the nonlinear dynamics of the heart. Cardiac optogenetics enables the manipulation of cellular function using light, enhancing our understanding of nonlinear cardiac function and control. Here, we investigate the efficacy of optically resonant feedback pacing (ORFP) to terminate ventricular tachyarrhythmias using numerical simulations and experiments in transgenic Langendorff-perfused mouse hearts. We show that ORFP outperforms the termination efficacy of the optical single-pulse (OSP) approach. When using ORFP, the total energy required for arrhythmia termination, i.e., the energy summed over all pulses in the sequence, is 1 mJ. With a success rate of 50%, the energy per pulse is 40 times lower than with OSP with a pulse duration of 10 ms. We demonstrate that even at light intensities below the excitation threshold, ORFP enables the termination of arrhythmias by spatiotemporal modulation of excitability inducing spiral wave drift.

Reconstructing in-depth activity for chaotic 3D spatiotemporal excitable media models based on surface data.

Motivated by potential applications in cardiac research, we consider the task of reconstructing the dynamics within a spatiotemporal chaotic 3D excitable medium from partial observations at the surface. Three artificial neural network methods (a spatiotemporal convolutional long-short-term-memory, an autoencoder, and a diffusion model based on the U-Net architecture) are trained to predict the dynamics in deeper layers of a cube from observational data at the surface using data generated by the Barkley model on a 3D domain. The results show that despite the high-dimensional chaotic dynamics of this system, such cross-prediction is possible, but non-trivial and as expected, its quality decreases with increasing prediction depth.

Optogenetic manipulation of cardiac electrical dynamics using sub-threshold illumination: dissecting the role of cardiac alternans in terminating rapid rhythms.

Cardiac action potential (AP) shape and propagation are regulated by several key dynamic factors such as ion channel recovery and intracellular Ca2+ cycling. Experimental methods for manipulating AP electrical dynamics commonly use ion channel inhibitors that lack spatial and temporal specificity. In this work, we propose an approach based on optogenetics to manipulate cardiac electrical activity employing a light-modulated depolarizing current with intensities that are too low to elicit APs (sub-threshold illumination), but are sufficient to fine-tune AP electrical dynamics. We investigated the effects of sub-threshold illumination in isolated cardiomyocytes and whole hearts by using transgenic mice constitutively expressing a light-gated ion channel (channelrhodopsin-2, ChR2). We find that ChR2-mediated depolarizing current prolongs APs and reduces conduction velocity (CV) in a space-selective and reversible manner. Sub-threshold manipulation also affects the dynamics of cardiac electrical activity, increasing the magnitude of cardiac alternans. We used an optical system that uses real-time feedback control to generate re-entrant circuits with user-defined cycle lengths to explore the role of cardiac alternans in spontaneous termination of ventricular tachycardias (VTs). We demonstrate that VT stability significantly decreases during sub-threshold illumination primarily due to an increase in the amplitude of electrical oscillations, which implies that cardiac alternans may be beneficial in the context of self-termination of VT.

Electromechanical vortex filaments during cardiac fibrillation.

The self-organized dynamics of vortex-like rotating waves, which are also known as scroll waves, are the basis of the formation of complex spatiotemporal patterns in many excitable chemical and biological systems. In the heart, filament-like phase singularities that are associated with three-dimensional scroll waves are considered to be the organizing centres of life-threatening cardiac arrhythmias. The mechanisms that underlie the onset, maintenance and control of electromechanical turbulence in the heart are inherently three-dimensional phenomena. However, it has not previously been possible to visualize the three-dimensional spatiotemporal dynamics of scroll waves inside cardiac tissues. Here we show that three-dimensional mechanical scroll waves and filament-like phase singularities can be observed deep inside the contracting heart wall using high-resolution four-dimensional ultrasound-based strain imaging. We found that mechanical phase singularities co-exist with electrical phase singularities during cardiac fibrillation. We investigated the dynamics of electrical and mechanical phase singularities by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart. We show that cardiac fibrillation can be characterized using the three-dimensional spatiotemporal dynamics of mechanical phase singularities, which arise inside the fibrillating contracting ventricular wall. We demonstrate that electrical and mechanical phase singularities show complex interactions and we characterize their dynamics in terms of trajectories, topological charge and lifetime. We anticipate that our findings will provide novel perspectives for non-invasive diagnostic imaging and therapeutic applications.

Electromechanical optical mapping.

Optical mapping is a widely used imaging technique for investigating cardiac electrophysiology in intact, Langendorff-perfused hearts. Mechanical contraction of cardiac tissue, however, may result in severe motion artifacts and significant distortion of the fluorescence signals. Therefore, pharmacological uncoupling is widely used to reduce tissue motion. Recently, various image processing algorithms have been proposed to reduce motion artifacts. We will review these technological developments. Furthermore, we will present a novel approach for the three-dimensional, marker-free reconstruction of contracting Langendorff-perfused intact hearts under physiological conditions. The algorithm allows disentangling the fluorescence signals (e.g. membrane voltage or intracellular calcium) from the mechanical motion (e.g. tissue strain). We will discuss the algorithms reconstruction accuracy, resolution, and robustness using experimental data from Langendorff-perfused rabbit hearts.

Detection and characterization of intermittent complexity variations in cardiac arrhythmia.

OBJECTIVE: A frequent observation during cardiac fibrillation is a fluctuation in complexity where the irregular pattern of the fibrillation is interrupted by more regular phases of varying length. APPROACH: We apply different measures to sliding windows of raw ECG signals for quantifying the temporal complexity. The methods include permutation entropy, power spectral entropy, a measure for the extent of the set of reconstructed states and several wavelet measures. MAIN RESULTS: Using these methods, variations of fibrillation patterns over time are detected and visualized. SIGNIFICANCE: These quantifications can be used to characterize different phases of the ECG during fibrillation and might improve diagnosis and treatment methods for heart diseases.

Modelling far field pacing for terminating spiral waves pinned to ischaemic heterogeneities in cardiac tissue.

In cardiac tissue, electrical spiral waves pinned to a heterogeneity can be unpinned (and eventually terminated) using electric far field pulses and recruiting the heterogeneity as a virtual electrode. While for isotropic media the process of unpinning is much better understood, the case of an anisotropic substrate with different conductivities in different directions still needs intensive investigation. To study the impact of anisotropy on the unpinning process, we present numerical simulations based on the bidomain formulation of the phase I of the Luo and Rudy action potential model modified due to the occurrence of acute myocardial ischaemia. Simulating a rotating spiral wave pinned to an ischaemic heterogeneity, we compare the success of sequences of far field pulses in the isotropic and the anisotropic case for spirals still in transient or in steady rotation states. Our results clearly indicate that the range of pacing parameters resulting in successful termination of pinned spiral waves is larger in anisotropic tissue than in an isotropic medium.This article is part of the themed issue 'Mathematical methods in medicine: neuroscience, cardiology and pathology'.

Mechanisms of vortices termination in the cardiac muscle.

We propose a solution to a long-standing problem: how to terminate multiple vortices in the heart, when the locations of their cores and their critical time windows are unknown. We scan the phases of all pinned vortices in parallel with electric field pulses (E-pulses). We specify a condition on pacing parameters that guarantees termination of one vortex. For more than one vortex with significantly different frequencies, the success of scanning depends on chance, and all vortices are terminated with a success rate of less than one. We found that a similar mechanism terminates also a free (not pinned) vortex. A series of about 500 experiments with termination of ventricular fibrillation by E-pulses in pig isolated hearts is evidence that pinned vortices, hidden from direct observation, are significant in fibrillation. These results form a physical basis needed for the creation of new effective low energy defibrillation methods based on the termination of vortices underlying fibrillation.

Estimability and dependency analysis of model parameters based on delay coordinates.

In data-driven system identification, values of parameters and not observed variables of a given model of a dynamical system are estimated from measured time series. We address the question of estimability and redundancy of parameters and variables, that is, whether unique results can be expected for the estimates or whether, for example, different combinations of parameter values would provide the same measured output. This question is answered by analyzing the null space of the linearized delay coordinates map. Examples with zero-dimensional, one-dimensional, and two-dimensional null spaces are presented employing the Hindmarsh-Rose model, the Colpitts oscillator, and the Rössler system.

Risk assessment of wandering behavior in mild dementia.

OBJECTIVE: This prospective longitudinal study aims to determine the risk factors of wandering-related adverse consequences in community-dwelling persons with mild dementia. These adverse consequences include negative outcomes of wandering (falls, fractures, and injuries) and eloping behavior. METHODS: We recruited 143 dyads of persons with mild dementia and their caregivers from a veteran's hospital and memory clinic in Florida. Wandering-related adverse consequences were measured using the Revised Algase Wandering Scale - Community Version. Variables such as personality (Big Five Inventory), behavioral response to stress, gait, and balance (Tinetti Gait and Balance), wayfinding ability (Wayfinding Effectiveness Scale), and neurocognitive abilities (attention, cognition, memory, language/verbal skills, and executive functioning) were also measured. Bivariate and logistic regression analyses were performed to assess the predictors of these wandering-related adverse consequences. RESULTS: A total of 49% of the study participants had falls, fractures, and injuries due to wandering behavior, and 43.7% demonstrated eloping behaviors. Persistent walking (OR = 2.6) and poor gait (OR = 0.9) were significant predictors of negative outcomes of wandering, while persistent walking (OR = 13.2) and passivity (OR = 2.55) predicted eloping behavior. However, there were no correlations between wandering-related adverse consequences and participants' characteristics (age, gender, race, ethnicity, and education), health status (Charlson comorbidity index), or neurocognitive abilities. CONCLUSION: Our results highlight the importance of identifying at-risk individuals so that effective interventions can be developed to reduce or prevent the adverse consequences of wandering.

Crosstalk of cardiomyocytes and fibroblasts in co-cultures.

Electromechanical function of cardiac muscle depends critically on the crosstalk of myocytes with non-myocytes. Upon cardiac fibrosis, fibroblasts translocate into infarcted necrotic tissue and alter their communication capabilities. In the present in vitro study, we determined a multiple parameter space relevant for fibrotic cardiac tissue development comprising the following essential processes: (i) adhesion to substrates with varying elasticity, (ii) dynamics of contractile function, and (iii) electromechanical connectivity. By combining electric cell-substrate impedance sensing (ECIS) with conventional optical microscopy, we could measure the impact of fibroblast-cardiomyocyte ratio on the aforementioned parameters in a non-invasive fashion. Adhesion to electrodes was quantified via spreading rates derived from impedance changes, period analysis allowed us to measure contraction dynamics and modulations of the barrier resistance served as a measure of connectivity. In summary, we claim that: (i) a preferred window for substrate elasticity around 7 kPa for low fibroblast content exists, which is shifted to stiffer substrates with increasing fibroblast fractions. (ii) Beat frequency decreases nonlinearly with increasing fraction of fibroblasts, while (iii) the intercellular resistance increases with a maximal functional connectivity at 75% fibroblasts. For the first time, cardiac cell-cell junction density-dependent connectivity in co-cultures of cardiomyocytes and fibroblasts was quantified using ECIS.

Changes of sleep-stage transitions due to ageing and sleep disorder.

Transition patterns between different sleep stages are analysed in terms of probability distributions of symbolic sequences for young and old subjects with and without sleep disorder. Changes of these patterns due to ageing are compared with variations of transition probabilities due to sleep disorder.

Phase-specific Raman spectroscopy for fast segmented microfluidic flows.

An intensifier based Raman measuring strategy is introduced which allows for a phase-specific signal detection of one single phase in segmented flows at droplet generation frequencies of potentially up to several kHz.

Expansion of recipient-derived antiviral T cells may influence donor chimerism after allogeneic stem cell transplantation.

Donor chimerism (DC) analysis is an important marker in the hematopoietic stem cell transplant follow-up. Here, we present evidence for a possible relationship of infectious complications and declines in DC. We analyzed the DC in patients experiencing cytomegalovirus (CMV) reactivation. In addition, in some patients chimerism analyses of T-cell subsets were performed. CMV-specific cytotoxic T-lymphocytes (CMV-CTL) were monitored using human leukocyte antigen-restricted multimer staining. Interestingly, CMV reactivation was accompanied by changes in DC in 11 of 67 patients transplanted. For example, DC declined in a cord blood recipient, in both total leukocytes and CD4 and CD8 T-cell subsets upon CMV reactivation. The latter was controlled after only 5 days through expanding CMV-CTL of 96% recipient origin, according to chimerism analysis of CMV-CTL (enriched beyond 50%). In another patient, transplanted after reduced-intensity conditioning from a DQB1 mismatched, CMV seronegative donor, incipient CMV reactivation was completely aborted by CMV-CTL of recipient origin. However, at the same time, mixed chimerism dropped from 51% to 0% donor type, resulting in late graft rejection. Our data indicate that chimerism analyses in subset populations lead to a better understanding of declining total leukocyte chimerism. Furthermore, recipient-derived CMV-CTL may be able to control CMV reactivation after reduced-intensity conditioning. We speculate that autologous CMV-CTL may be instrumental to overcome recurrent CMV reactivations, especially in patients transplanted from CMV-seronegative donors. In addition, the expansion of recipient-derived CMV-CTL may contribute to both, graft failure or to conversion to full DC.

Classifying cardiac biosignals using ordinal pattern statistics and symbolic dynamics.

The performance of (bio-)signal classification strongly depends on the choice of suitable features (also called parameters or biomarkers). In this article we evaluate the discriminative power of ordinal pattern statistics and symbolic dynamics in comparison with established heart rate variability parameters applied to beat-to-beat intervals. As an illustrative example we distinguish patients suffering from congestive heart failure from a (healthy) control group using beat-to-beat time series. We assess the discriminative power of individual features as well as pairs of features. These comparisons show that ordinal patterns sampled with an additional time lag are promising features for efficient classification.

Synchronization based system identification of an extended excitable system.

A basic state and parameter estimation scheme for an extended excitable system is presented, where time series from a spatial grid of sampling points are used to drive and synchronize corresponding model equations. Model parameters are estimated by minimizing the synchronization error. This estimation scheme is demonstrated using data from generic models of excitable media exhibiting spiral wave dynamics and chaotic spiral break-up that are implemented on a graphics processing unit.

Tetramer monitoring to assess risk factors for recurrent cytomegalovirus reactivation and reconstitution of antiviral immunity post allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Reactivation of cytomegalovirus (CMV) is a major cause of morbidity after allogeneic hematopoietic stem cell transplantation (HSCT). In healthy individuals, virus-specific T cells (CMV-CTL) control the reactivation of latent CMV. The monitoring of virus-epitope-binding CD8(+) T cells using major histocompatibility complex-I-peptide complexes (tetramers) has recently been established, allowing assessment of the reconstitution of CMV-CTL post HSCT. PATIENTS AND METHODS: In order to study immune reconstitution and reactivation control through CMV-CTL, we regularly monitored all patients undergoing allogeneic HSCT in our department for 2 years, who matched at least 1 of 6 commercially available tetramers for common human leukocyte antigen (HLA) types. To verify risk factors for CMV reactivations in our cohorts, clinical characteristics of all patients transplanted within the last 10 years were included in statistical analyses determining the relative risk for single and recurrent CMV reactivations. RESULTS: As expected, CMV serostatus, HLA match, and donor source significantly influenced the risk of recurrent CMV reactivation. Applying CMV-CTL tetramer monitoring for 2 years allowed the monitoring of 114 (85%) of 134 patients, by testing a set of tetramers representing 6 epitopes from 3 different CMV proteins. The presence of CMV-CTL before day + 50 and their expansion post reactivation seem to protect against recurrent CMV reactivations. The mean number of CMV-CTL by day +100 was >5-fold higher in the recipient CMV-positive/donor-positive (R +/D +) group (91/µL) compared with the R +/ D- (13/µL) and the R -/D +(2/µL) group. Seventy-nine percent of patients from the R +/D + setting recovered >10 CMV-CTL per µL by day + 100, while almost 50% of the other groups failed to mount a CMV-specific response by that time (R +/D -: 58%; R -/D +: 43%). CONCLUSION: Tetramer monitoring can help to predict (recurrent) CMV reactivation and is a useful approach to monitor individual patients with increased risk for recurrent reactivation post HSCT; thus, it could help to identify patients in need of adoptive transfer of CMV-CTL or to optimize the use of antiviral drugs.

Detection of gunshot residue in blowfly larvae and decomposing porcine tissue using inductively coupled plasma mass spectrometry (ICP-MS).

Blowfly larvae and porcine tissue contaminated with gunshot residue (GSR) were collected during summer and winter months, over a 37-day and a 60-day sampling period, respectively. Wound samples were microwave-digested and analyzed by inductively coupled plasma mass spectrometry (ICP-MS) for the detection of antimony, barium, and lead. During summer, the 37-day sampling period encompassed all stages of decomposition, except skeletonization. The three elements were detected in larvae only on days 3 and 4 after death but were detected at significant levels in tissue samples throughout the entire sampling period. In winter, no significant decomposition was observed throughout the 60-day sampling. Although temperatures were too low for blowfly activity, the three elements were detected in the tissue samples at relatively constant, significant levels. Hence, GSR determination in tissue was more dependent on decomposition stage rather than time since death.

[Mould and dampness in houses: health, environmental and social aspects - results of a study by the Bremen local public health office]. / Feuchteschäden in Wohnräumen: gesundheitliche, umweltbezogene und soziale Aspekte - Kleinräumige Erhebung aus dem Gesundheitsamt Bremen.

Mould and dampness, both long known indoor problems, may cause several health effects. During the last years, this topic has gained increasing importance in the field of environmental hygiene at the Bremen local public health office and has become a major focus of the work. The analysis of the advisory service for private persons has shown: mould and dampness are relevant health and environmental problems in private homes. Data from a questionnaire-based study revealed that mainly people with low social status, especially those with low income, request for information and guidance. This indicates the need for free advice for people with low income.

Prediction of outcome of fetal congenital heart disease using a cardiovascular profile score.

OBJECTIVES: Congestive heart failure in fetuses with congenital heart defects (CHD) is associated with high perinatal mortality. The clinical condition can be characterized by five ultrasound markers that comprise the 10-point cardiovascular profile (CVP) score. Our aim was to assess the value of the CVP score in evaluating the condition and in maintaining surveillance of fetuses with CHD. METHODS: We evaluated retrospectively 131 singleton pregnancies with a diagnosis of fetal CHD, which had been assessed by serial echocardiographic examinations, during which the CVP score was obtained. Fetal and neonatal outcomes, including perinatal mortality and Apgar scores, were assessed. RESULTS: Fetuses with a final CVP score or= 8 (87.5% vs. 15.2% mortality; P < 0.0001, chi square = 24.5). Significance was maintained after controlling for birth weight, lag time between the final examination and delivery and the dichotomized 5-min Apgar score (odds ratio, 22.3; P = 0.024). For low Apgar score and mortality, the CVP score had low sensitivity (0.25 and 0.27, respectively) but high specificity (0.98 and 0.99, respectively). The presence of hydrops and severe cardiomegaly were statistically significantly associated with mortality (P < 0.05). CONCLUSIONS: Fetuses with CHD and a CVP score below 8 are at risk of perinatal death. The CVP score may be used to assess the severity of fetal CHD and to plan perinatal management.