Controlling the complex spatio-temporal dynamics underlying life-threatening cardiac arrhythmias such as fibrillation is extremely difficult due to the nonlinear interaction of excitation waves within a heterogeneous anatomical substrate1–4. Lacking a better strategy, strong, globally resetting electrical shocks remain the only reliable treatment for cardiac fibrillation5–7. Here, we establish the relation between the response of the tissue to an electric field and the spatial distribution of heterogeneities of the scale-free coronary vascular structure. We show that in response to a pulsed electric field E, these heterogeneities serve as nucleation sites for the generation of intramural electrical waves with a source density ρ(E), and a characteristic time τ for tissue depolarization that obeys a power law τ∝Eα. These intramural wave sources permit targeting of electrical turbulence near the cores of the vortices of electrical activity that drive complex fibrillatory dynamics. We show in vitro that simultaneous and direct access to multiple vortex cores results in rapid synchronization of cardiac tissue and therefore efficient termination of fibrillation. Using this novel control strategy, we demonstrate, for the first time, low-energy termination of fibrillation in vivo. Our results give new insights into the mechanisms and dynamics underlying the control of spatio-temporal chaos in heterogeneous excitable media and at the same time provide new research perspectives towards alternative, life-saving low-energy defibrillation techniques.

The increasing number of patients with end stage chronic kidney disease not only calls for novel therapeutics but also for pioneering research using convincing preclinical disease models and innovative analytical techniques. The aim of this study was to introduce a virtual histology approach using micro computed tomography (µCT) for the entire murine kidney in order to close the gap between single slice planar histology and a 3D high resolution dataset. An ex vivo staining protocol based on phosphotungstic acid diffusion was adapted to enhance renal soft tissue x-ray attenuation. Subsequent CT scans allowed (i) the detection of the renal cortex, medulla and pelvis in greater detail, (ii) the analysis of morphological alterations, (iii) the quantification of the volume as well as the radio-opacity of these portions and (iv) the quantification of renal fibrotic remodeling based on altered radio-opacity using the unilateral ureteral obstruction model. Thus, virtual histology based on PTA contrast enhanced CT will in future help to refine the outcome of preclinical research on kidney associated murine disease models.

Rationale: Discordant alternans, a phenomenon in which the action potential duration (APDs) and/or intracellular calcium transient durations (CaDs) in different spatial regions of cardiac tissue are out of phase, present a dynamical instability for complex spatial dispersion that can be associated with long-QT syndrome (LQTS) and the initiation of reentrant arrhythmias. Because the use of numerical simulations to investigate arrhythmic effects, such as acquired LQTS by drugs is beginning to be studied by the FDA, it is crucial to validate mathematical models that may be used during this process.Objective: In this study, we characterized with high spatio-temporal resolution the development of discordant alternans patterns in transmembrane voltage (V m ) and intracellular calcium concentration ([Ca i ] +2 ) as a function of pacing period in rabbit hearts. Then we compared the dynamics to that of the latest state-of-the-art model for ventricular action potentials and calcium transients to better understand the underlying mechanisms of discordant alternans and compared the experimental data to the mathematical models representing V m and [Ca i ] +2 dynamics. Methods and Results:We performed simultaneous dual optical mapping imaging of V m and [Ca i ] +2 in Langendorff-perfused rabbit hearts with higher spatial resolutions compared with previous studies. The rabbit hearts developed discordant alternans through decreased pacing period protocols and we quantified the presence of multiple nodal points along the direction of wave propagation, both in APD and CaD, and compared these findings with results from theoretical models. In experiments, the nodal lines of CaD alternans have a steeper slope than those of APD alternans, but not as steep as predicted by numerical simulations in rabbit models. We further quantified several additional discrepancies between models and experiments.Uzelac et al. Simultaneous Quantification of Voltage and Intracellular CalciumConclusions: Alternans in CaD have nodal lines that are about an order of magnitude steeper compared to those of APD alternans. Current action potential models lack the necessary coupling between voltage and calcium compared to experiments and fail to reproduce some key dynamics such as, voltage amplitude alternans, smooth development of calcium alternans in time, conduction velocity and the steepness of the nodal lines of APD and CaD.

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.