Visual dysfunction in dementia with Lewy bodies.

PURPOSE OF REVIEW: To review the literature on visual dysfunction in dementia with Lewy bodies (DLB), including its mechanisms and clinical implications. RECENT FINDINGS: Recent studies have explored novel aspects of visual dysfunction in DLB, including visual texture agnosia, mental rotation of 3-dimensional drawn objects, and reading fragmented letters. Recent studies have shown parietal and occipital hypoperfusion correlating with impaired visuoconstruction performance. While visual dysfunction in clinically manifest DLB is well recognized, recent work has focused on prodromal or mild cognitive impairment (MCI) due to Lewy body pathology with mixed results. Advances in retinal imaging have recently led to the identification of abnormalities such as parafoveal thinning in DLB. Patients with DLB experience impairment in color perception, form and object identification, space and motion perception, visuoconstruction tasks, and illusions in association with visual cortex and network dysfunction. These symptoms are associated with visual hallucinations, driving impairment, falls, and other negative outcomes.

Differential roles of two delayed rectifier potassium currents in regulation of ventricular action potential duration and arrhythmia susceptibility.

KEY POINTS: Arrhythmias result from disruptions to cardiac electrical activity, although the factors that control cellular action potentials are incompletely understood. We combined mathematical modelling with experiments in heart cells from guinea pigs to determine how cellular electrical activity is regulated. A mismatch between modelling predictions and the experimental results allowed us to construct an improved, more predictive mathematical model. The balance between two particular potassium currents dictates how heart cells respond to perturbations and their susceptibility to arrhythmias. ABSTRACT: Imbalances of ionic currents can destabilize the cardiac action potential and potentially trigger lethal cardiac arrhythmias. In the present study, we combined mathematical modelling with information-rich dynamic clamp experiments to determine the regulation of action potential morphology in guinea pig ventricular myocytes. Parameter sensitivity analysis was used to predict how changes in ionic currents alter action potential duration, and these were tested experimentally using dynamic clamp, a technique that allows for multiple perturbations to be tested in each cell. Surprisingly, we found that a leading mathematical model, developed with traditional approaches, systematically underestimated experimental responses to dynamic clamp perturbations. We then re-parameterized the model using a genetic algorithm, which allowed us to estimate ionic current levels in each of the cells studied. This unbiased model adjustment consistently predicted an increase in the rapid delayed rectifier K+ current and a drastic decrease in the slow delayed rectifier K+ current, and this prediction was validated experimentally. Subsequent simulations with the adjusted model generated the clinically relevant prediction that the slow delayed rectifier is better able to stabilize the action potential and suppress pro-arrhythmic events than the rapid delayed rectifier. In summary, iterative coupling of simulations and experiments enabled novel insight into how the balance between cardiac K+ currents influences ventricular arrhythmia susceptibility.

There and back again: Iterating between population-based modeling and experiments reveals surprising regulation of calcium transients in rat cardiac myocytes.

While many ion channels and transporters involved in cardiac cellular physiology have been identified and described, the relative importance of each in determining emergent cellular behaviors remains unclear. Here we address this issue with a novel approach that combines population-based mathematical modeling with experimental tests to systematically quantify the relative contributions of different ion channels and transporters to the amplitude of the cellular Ca(2+) transient. Sensitivity analysis of a mathematical model of the rat ventricular cardiomyocyte quantified the response of cell behaviors to changes in the level of each ion channel and transporter, and experimental tests of these predictions were performed to validate or invalidate the predictions. The model analysis found that partial inhibition of the transient outward current in rat ventricular epicardial myocytes was predicted to have a greater impact on Ca(2+) transient amplitude than either: (1) inhibition of the same current in endocardial myocytes, or (2) comparable inhibition of the sarco/endoplasmic reticulum Ca(2+) ATPase (SERCA). Experimental tests confirmed the model predictions qualitatively but showed some quantitative disagreement. This guided us to recalibrate the model by adjusting the relative importance of several Ca(2+) fluxes, thereby improving the consistency with experimental data and producing a more predictive model. Analysis of human cardiomyocyte models suggests that the relative importance of outward currents to Ca(2+) transporters is generalizable to human atrial cardiomyocytes, but not ventricular cardiomyocytes. Overall, our novel approach of combining population-based mathematical modeling with experimental tests has yielded new insight into the relative importance of different determinants of cell behavior.

Slow Delayed Rectifier Current Protects Ventricular Myocytes From Arrhythmic Dynamics Across Multiple Species: A Computational Study.

BACKGROUND: The slow and rapid delayed rectifier K+ currents (IKs and IKr, respectively) are responsible for repolarizing the ventricular action potential (AP) and preventing abnormally long APs that may lead to arrhythmias. Although differences in biophysical properties of the 2 currents have been carefully documented, the respective physiological roles of IKr and IKs are less established. In this study, we sought to understand the individual roles of these currents and quantify how effectively each stabilizes the AP and protects cells against arrhythmias across multiple species. METHODS: We compared 10 mathematical models describing ventricular myocytes from human, rabbit, dog, and guinea pig. We examined variability within heterogeneous cell populations, tested the susceptibility of cells to proarrhythmic behavior, and studied how IKs and IKr responded to changes in the AP. RESULTS: We found that (1) models with higher baseline IKs exhibited less cell-to-cell variability in AP duration; (2) models with higher baseline IKs were less susceptible to early afterdepolarizations induced by depolarizing perturbations; (3) as AP duration is lengthened, IKs increases more profoundly than IKr, thereby providing negative feedback that resists excessive AP prolongation; and (4) the increase in IKs that occurs during ß-adrenergic stimulation is critical for protecting cardiac myocytes from early afterdepolarizations under these conditions. CONCLUSIONS: Slow delayed rectifier current is uniformly protective across a variety of cell types. These results suggest that IKs enhancement could potentially be an effective antiarrhythmic strategy.