Letter | Published:

Electromechanical vortex filaments during cardiac fibrillation

Nature volume 555, pages 667672 (29 March 2018) | Download Citation

Abstract

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 systems1,2,3,4. In the heart, filament-like phase singularities5,6 that are associated with three-dimensional scroll waves7 are considered to be the organizing centres of life-threatening cardiac arrhythmias7,8,9,10,11,12,13. The mechanisms that underlie the onset, maintenance and control14,15,16 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.

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Acknowledgements

We thank U. Parlitz and N. Otani for discussions, M. Kunze, D. Hornung and U. Schminke for technical assistance, L. Bess for linguistic advice and FujiFilm VisualSonics Inc. and Siemens HealthCare for their technical support. This work was supported by the German Ministry for Education and Research through FKZ 031A147 (S.L.); by the German Center for Cardiovascular Research (S.L. and G.H.); by the German Research Foundation through SFB 1002 Modulatory Units in Heart Failure (S.L., J.C. and G.H.) and SFB 937 Collective Behavior of Soft and Biological Matter (S.L. and J.C.); by the National Science Foundation (NSF) grants 1341190 and 1413037 (F.H.F.); by the American Heart Association (AHA) grant 15POST25700285 (I.U.); by the Human Frontiers Science Program through fellowship LT000840/2014-C (P.B.) and by the Max Planck Society.

Author information

Affiliations

  1. Max Planck Institute for Dynamics and Self-Organization, Göttingen, Germany

    • J. Christoph
    • , C. Richter
    • , J. Schröder-Schetelig
    • , S. Stein
    •  & S. Luther
  2. German Center for Cardiovascular Research (DZHK), Partner Site Göttingen, Göttingen, Germany

    • J. Christoph
    • , M. Chebbok
    • , C. Richter
    • , J. Schröder-Schetelig
    • , G. Hasenfuß
    •  & S. Luther
  3. Institute for Nonlinear Dynamics, University of Göttingen, Göttingen, Germany

    • J. Christoph
    • , J. Schröder-Schetelig
    • , S. Stein
    •  & S. Luther
  4. Department for Cardiology and Pneumology, University Medical Center Göttingen, Göttingen, Germany

    • M. Chebbok
    • , C. Richter
    •  & G. Hasenfuß
  5. BioCircuits Institute, University of California San Diego, La Jolla, California, USA

    • P. Bittihn
  6. School of Physics, Georgia Institute of Technology, Atlanta, Georgia, USA

    • I. Uzelac
    •  & F. H. Fenton
  7. University of Prince Edward Island, Charlottetown, Prince Edward Island, Canada

    • R. F. Gilmour Jr.
  8. Institute of Pharmacology, University Medical Center Göttingen, Göttingen, Germany

    • S. Luther
  9. Department of Bioengineering, Northeastern University, Boston, Massachusetts, USA

    • S. Luther
  10. Department of Physics, Northeastern University, Boston, Massachusetts, USA

    • S. Luther

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Contributions

J.C. and S.L. designed research and wrote the paper with F.H.F., G.H., P.B. and R.F.G.; J.C., S.L. and J.S.-S. designed the experiments; I.U. and F.H.F. contributed to the experimental setup; J.C. performed the experiments and analysed the data; M.C., J.S.-S., C.R., I.U. and F.H.F. contributed to the experiments; J.C., P.B. and S.S. provided the numerical simulations. All authors read and approved the manuscript.

Competing interests

J.C. and S.L. are registered as inventors of patent application PCT/EP2015/077001.

Corresponding authors

Correspondence to J. Christoph or S. Luther.

Reviewer Information thanks A. Holden, J. Jalife, E. Konofagou and the other anonymous reviewer(s) for their contribution to the peer review of this work.

Publisher's note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Extended data

Supplementary information

PDF files

  1. 1.

    Life Sciences Reporting Summary

  2. 2.

    Supplementary Information

    This file contains Supplementary Methods, a Supplementary Discussion, Supplementary Table 1 and Supplementary References.

Videos

  1. 1.

    Vortex filament measured during ventricular tachycardia inside ventricular wall of isolated pig heart imaged at high temporal resolution with panoramic fluorescence imaging (500fps) and 4D ultrasound (Siemens Acuson sc2000, 134vps, 6cm lat. depth, 52×90° opening angle).

    The filament was obtained from measurement of mechanical tissue deformation (strain-rate) caused by an action potential scroll wave rotating within the heart wall (c.f. Fig. 1). The u-shaped filament touches the epicardial surface in the same region (near to the left anterior descending coronary artery), where two cores of a figure-of-eight or double action potential spiral wave are located (Extended Data Fig. 1a-b).

  2. 2.

    Filament breakthrough and pairwise phase singularity creation on epicardial surface of left ventricular wall during ventricular fibrillation in isolated pig heart imaged using 4D ultrasound (Siemens Acuson sc2000, 104vps, 6cm lat. depth, 56×90° opening angle).

    The creation of a pair of two counter-rotating phase singularities is observed on the surface filming taction potential waves on the epicardium (500fps). Prior to the creation of the phase singularity pair, a u-shaped mechanical filament loop emerges from the depths of the ventricular wall and breaks up into two filaments as it touches the epicardial surface. The phase singularity pair is created at the same time (Extended Data Fig. 1c).

  3. 3.

    Computer simulation of scroll wave activity in bulk-shaped tissue volume.

    The electrical action potential scroll wave (green) and corresponding phase rotating around the electrical vortex filament (green line). Rotating elastomechanical rate of deformation pattern (red: contracting, blue: dilating) and corresponding phase. An electromechanical filament of a coupled electromechanical scroll wave consists of a co-localized pair of electrical (green) and mechanical (red) filaments. Fibre orientation is organized in sheets co-planar to the large surfaces of the bulk. The main fibre orientation (uniform linearly transverse in each sheet) rotates throughout the bulk.

  4. 4.

    Motion tracking and motion stabilization of fluorescence imaging recordings showing the contracting, fibrillating left ventricular surface of a rabbit heart (c.f. Fig 3c).

    The left image shows the raw unregistered video data including motion artifacts. The right video image shows the tracked and stabilized video data with a significant reduction of motion artifacts. Black dots indicate the tracking following the moving tissue. The action potential wave is retrieved by normalizing the amplitude of the signal in the time-series in each pixel in the co-moving frame. Video showing turbulent electrical action potential wave activity (voltage-sensitive dye di-4-ANEPPS) during ventricular fibrillation.

  5. 5.

    Motion tracking and motion stabilization of fluorescence imaging recordings showing the contracting, fibrillating left ventricular surface of a rabbit heart (c.f. Fig 3c).

    The left image shows the raw unregistered video data including motion artifacts. The right video image shows the tracked and stabilized video data with significant reduction of motion artifacts. Black dots indicate the tracking following the moving tissue. The action potential wave is retrieved by normalizing the time-series in each pixel in the co-moving frame. Video showing action potential rotor (voltagesensitive dye di-4-ANEPPS) during ventricular fibrillation.

  6. 6.

    Rotating electrical and mechanical patterns during ventricular fibrillation on the surface of contracting rabbit heart (c.f. Fig 3c, Extended Data Fig. 4a-b).

    Action potential spiral wave (left image, green, voltage-sensitive-dye di-4-ANEPPS) produces phase singularity (green circle) in corresponding phase maps indicating rotational core region of electrical activity. Corresponding deformation of the ventricular wall (right image, red-blue) exhibits rotational elasto-mechanical pattern (strain-rate, red: contracting, blue: dilating rates of deformation), which also produces a phase singularity (red circle) in a similar location.

  7. 7.

    Rotating electrical and mechanical patterns during ventricular fibrillation on the surface of contracting rabbit heart.

    Turbulent electrical excitation waves with multiple vortices (left, green) produces a similar elasto-mechanical deformation pattern (right, red-blue), where one main counter-clock-wise rotating vortex causes also a counter-clock-wise rotating deformation pattern in the same region. Both patterns exhibit electrical (green circles) and mechanical phase singularities (red circles) which appear in similar locations throughout the sequence.

  8. 8.

    Simultaneous tri-modal measurement of voltage, calcium and strain-rate rotors on the left ventricular surface of a rabbit heart during ventricular fibrillation (c.f. Fig. 3e,f).

    Action potential (green) and calcium (orange) vortex waves and elastic deformations (red-blue) and respective phase maps were measured on the contracting epicardium using multi-modal, multi-parametric (tri-modal) fluorescence imaging (voltage-sensitive dye di-4-ANBDQPQ, calcium-sensitive dye Rhod-2AM). Co-localizing vortex core regions displayed by phase singularities (PS, voltage: green circles, calcium: orange circles, strain-rate: red circles).

  9. 9.

    Simultaneous measurement of electrical and mechanical activity on the surface and inside the contracting left ventricular wall of a rabbit heart during ventricular fibrillation (see also Extended Data Fig. 9 a-c).

    Action potential vortex waves and elastic deformations were measured on the epicardium using fluorescence imaging (voltage-sensitive, di-4-ANEPPS). Simultaneously, elastic deformations were measured in a co-planar cross-section beneath the filmed surface using 2D ultrasound (279 fps). Similarly rotating rate of deformation patterns (strain-rate, red: contracting, blue: dilating) could be observed on the surface and at midwall. Both mechanical patterns exhibit the same rotational sense and a core region displayed by a phase singularity (red circles). The mechanical patterns are accompanied by electrical action potential vortex wave patterns similarly rotating and exhibiting phase singularities across the heart surface.

  10. 10.

    Arrhythmic pig heart exhibiting wave-like deformations and spiral wave-like rotating deformation and contraction patterns on the ventricular muscle surface in situ.

    Two rotational centres are located on the left ventricle (bottom left) and right ventricle (top right), respectively.

  11. 11.

    Electromechanical vortex filament imaged inside contracting and deforming left ventricular wall using 4D ultrasound (91vps, 7cm lateral field of view, 70° × 90° degrees opening angle of pyramid-shaped field of view).

    Simultaneously, a counter-clockwise rotating spiral action potential wave was imaged on the ventricular surface using fluorescence imaging (voltage-sensitive, 500fps). Both the action potential spiral wave and the underlying 3D strain-rate pattern exhibit counter- clockwise rotations. The filament touches the epicardial surface close to the spiral wave core. The heart is the same heart as shown in Supplementary Videos 13 and 14.

  12. 12.

    Electromechanical dissociation during very rapid ventricular fibrillation (rapid VF > 20 Hz) in pig heart (c.f. Extended Data Fig.7).

    Left: normal VF, heart contracts (dominat frequency electrical waves: 10 Hz). Right: very rapid VF, heart does not exhibit contractile activity even though the heart is electrically active and fibrillates (dominant frequency approximately twice as large: 20 Hz). At the end of the video (t = 26 s), both windows show the heart after the application of Cromakalim and during rapid pacing and induction of VF. The cardiac muscle at first contracts and deforms, but almost immediately stops to contract and exhibits only residual swinging motion, which vanishes after a few seconds.

  13. 13.

    Isolated pig heart imaged with 3D ultrasound.

    asystolic non-moving heart (62vps, 12cm lateral field of view, 70° × 90°, recording consists of 45 volume frames, which were repeated 8 times in the video). Right: fibrillating contracting heart (91vps, 7cm lateral field of view, 70° × 90°, >900 volume frames). The influence of the perfusion pump onto the movements of the heart is minimal as the non-contracting, quiet (asystolic) heart does not exhibit any visible and measurable movements in the ultrasound movie. In comparison, the motion of the fibrillating contracting heart is substantially larger and immediately apparent (quantitative motion analysis in Extended Data Fig. 9 d). The asystolic heart did not beat and remained in the same location as shown in the video for several minutes. If the fibrillating heart was imaged at slower volume rates (i.e. 62vps) the visual perception of motion would be even stronger and computed displacement vectors even be larger. The smaller field of view corresponds to about the lower 2/3 part of the heart shown in the right. Both recordings (left, right) were made with the same heart and the spatial resolution is the same. The heart is the same heart as shown in Supplementary Videos 11 and 14.

  14. 14.

    Isolated pig heart imaged with 3D ultrasound (51vps, 12cm lateral field of view, 90° × 90° degrees opening angle of pyramid-shaped field of view).

    The heart beats periodically due to the application of electrical pacing stimuli (stimulation site indicated by red dot). After the application of a pacing stimulus, the ventricular wall starts to contract at the stimulation site. The corresponding strain-rate pattern that is obtained after motion tracking reveals a focal, concentric spatio-temporal pattern with contracting rates of strain emanating away from the stimulation site. The heart is the same heart as shown in Supplementary Videos 11 and 13.

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https://doi.org/10.1038/nature26001

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