Performance Evaluation of QT-RR Adaptation Time Lag Estimation in Exercise Stress Testing.

BACKGROUND: Slower adaptation of the QT interval to sudden changes in heart rate has been identified as a risk marker of ventricular arrhythmia. The gradual changes observed in exercise stress testing facilitates the estimation of the QT-RR adaptation time lag. METHODS: The time lag estimation is based on the delay between the observed QT intervals and the QT intervals derived from the observed RR intervals using a memoryless transformation. Assuming that the two types of QT interval are corrupted with either Gaussian or Laplacian noise, the respective maximum likelihood time lag estimators are derived. Estimation performance is evaluated using an ECG simulator which models change in RR and QT intervals with a known time lag, muscle noise level, respiratory rate, and more. The accuracy of T-wave end delineation and the influence of the learning window positioning for model parameter estimation are also investigated. RESULTS: Using simulated datasets, the results show that the proposed approach to estimation can be applied to any changes in heart rate trend as long as the frequency content of the trend is below a certain frequency. Moreover, using a proper position of the learning window for exercise so that data compensation reduces the effect of nonstationarity, a lower mean estimation error results for a wide range of time lags. Using a clinical dataset, the Laplacian-based estimator shows a better discrimination between patients grouped according to the risk of suffering from coronary artery disease. CONCLUSIONS: Using simulated ECGs, the performance evaluation of the proposed method shows that the estimated time lag agrees well with the true time lag.

Analysis of age-related changes in the left ventricular myocardium with multiphoton microscopy.

Aging induces cardiac remodeling, resulting in an increase in the risk of suffering heart diseases, including heart failure. Collagen deposition increases with age and, together with sarcomeric changes in cardiomyocytes, may lead to ventricular stiffness. Multiphoton (MP) microscopy is a useful technique to visualize and detect variations in cardiac structures in a label free fashion. Here, we propose a method based on MP imaging (both two-photon excitation fluorescence (TPEF) and second harmonic generation (SHG) modalities) to explore and objectively quantify age-related structural differences in various components of cardiac tissues. Results in transmural porcine left ventricle (LV) sections reveal significant differences when comparing samples from young and old animals. Collagen and myosin SHG signals in old specimens are respectively 3.8x and >6-fold larger than in young ones. Differences in TPEF signals from cardiomyocyte were ∼3x. Moreover, the increased amount of collagen in old specimens results in a more organized pattern when compared to young LV tissues. Since changes in collagen and myosin are associated with cardiac dysfunction, the technique used herein might be a useful tool to accurately predict and measure changes associated with age-related myocardium fibrosis, tissue remodeling and sarcomeric alterations, with potential implications in preventing heart disease.

Experimentally-guided in silico design of engineered heart tissues to improve cardiac electrical function after myocardial infarction.

Engineered heart tissues (EHTs) built from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) showed promising results for cardiac function restoration following myocardial infarction. Nevertheless, human iPSC-CMs have longer action potential and lower cell-to-cell coupling than adult-like CMs. These immature electrophysiological properties favor arrhythmias due to the generation of electrophysiological gradients when hiPSC-CMs are injected in the cardiac tissue. Culturing hiPSC-CMs on three-dimensional (3D) scaffolds can promote their maturation and influence their alignment. However, it is still uncertain how on-scaffold culturing influences the overall electrophysiology of the in vitro and implanted EHTs, as it requires expensive and time consuming experimentation. Here, we computationally investigated the impact of the scaffold design on the EHT electrical depolarization and repolarization before and after engraftment on infarcted tissue. We first acquired and processed electrical recordings from in vitro EHTs, which we used to calibrate the modeling and simulation of in silico EHTs to replicate experimental outcomes. Next, we built in silico EHT models for a range of scaffold pore sizes, shapes (square, rectangular, auxetic, hexagonal) and thicknesses. In this setup, we found that scaffolds made of small (0.2 mm2), elongated (30° half-angle) hexagons led to faster EHT activation and better mimicked the cardiac anisotropy. The scaffold thickness had a marginal role on the not engrafted EHT electrophysiology. Moreover, EHT engraftment on infarcted tissue showed that the EHT conductivity should be at least 5% of that in healthy tissue for bidirectional EHT-myocardium electrical propagation. For conductivities above such threshold, the scaffold made of small elongated hexagons led to the lowest activation time (AT) in the coupled EHT-myocardium. If the EHT conductivity was further increased and the hiPSC-CMs were uniformly oriented parallel to the epicardial cells, the total AT and the repolarization time gradient decreased substantially, thus minimizing the likelihood for arrhythmias after EHT transplantation.

The frequency of atrial fibrillatory waves is modulated by the spatiotemporal pattern of acetylcholine release: a 3D computational study.

In atrial fibrillation (AF), the ECG P-wave, which represents atrial depolarization, is replaced with chaotic and irregular fibrillation waves (f waves). The f-wave frequency, F f, shows significant variations over time. Cardiorespiratory interactions regulated by the autonomic nervous system have been suggested to play a role in such variations. We conducted a simulation study to test whether the spatiotemporal release pattern of the parasympathetic neurotransmitter acetylcholine (ACh) modulates the frequency of atrial reentrant circuits. Understanding parasympathetic involvement in AF may guide more effective treatment approaches and could help to design autonomic markers alternative to heart rate variability (HRV), which is not available in AF patients. 2D tissue and 3D whole-atria models of human atrial electrophysiology in persistent AF were built. Different ACh release percentages (8% and 30%) and spatial ACh release patterns, including spatially random release and release from ganglionated plexi (GPs) and associated nerves, were considered. The temporal pattern of ACh release, ACh(t), was simulated following a sinusoidal waveform of frequency 0.125 Hz to represent the respiratory frequency. Different mean concentrations (ACh¯) and peak-to-peak ranges of ACh (ΔACh) were tested. We found that temporal variations in F f, F f(t), followed the simulated temporal ACh(t) pattern in all cases. The temporal mean of F f(t), F¯f, depended on the fibrillatory pattern (number and location of rotors), the percentage of ACh release nodes and ACh¯. The magnitude of F f(t) modulation, ΔF f, depended on the percentage of ACh release nodes and ΔACh. The spatial pattern of ACh release did not have an impact on F¯f and only a mild impact on ΔF f. The f-wave frequency, being indicative of vagal activity, has the potential to drive autonomic-based therapeutic actions and could replace HRV markers not quantifiable from AF patients.

Prevention of Sudden Death in Sports: A Global and Multidisciplinary Observatory for Scientific Research and Knowledge Transfer (PREMUBID).

Background: The health benefits of sports and exercise training are well known. However, an acute bout of exercise transiently increases the risk of sudden cardiac death (SCD). To minimize the cardiovascular risks of exercise, more insight into the prevention and causes of SCD is needed. Methods: The observatory for the prevention of sudden death in sports, PREMUBID, was created with the aim of fostering research to assess the benefits and risks of exercise at different volumes and intensities and to get insight into the underlying mechanisms of potentially cardiac (mal) adaptations. Results: The observatory gathers researchers from a wide range of disciplines working at institutions in Europe and North America. The guiding principles of PREMUBID are to broaden the understanding of SCD in sports, strengthening collaborative research across the globe, and to develop, implement and evaluate robust pre-participation screening and emergency care strategies to further reduce the number of fatal cardiac events in sport events. During the inaugural meeting of the observatory, members and affiliated researchers discussed possibilities to initiate collaborative research projects and to exchange staff and students to share information and practices to prevent SCD. The final goal is to translate the obtained knowledge to understandable messages for the general population and healthcare workers to ensure that the population at large benefits from it. Conclusions: The PREMUBID consortium aims to produce novel knowledge and insights in SCD prevention, in order to maximize the health benefits associated with acute and long-term exercise training.