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Failure of SA and AV nodes are Indications for Implantable Pacemakers!

Annual US diagnosed

Atrioventricular block

50,000

Sinus bradicardia

200,000

AV node ablation

20,000

Ventricular Arrhythmias: !Major Cause of Death!

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Winston Churchill’s “Iron Curtain” speech, Fulton, Missouri, March 5, 1946!

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“I have a strong admiration and regard for the valiant Russian people and for my wartime comrade, Marshal Stalin. There is deep sympathy and goodwill in Britain -- and I doubt not here also -- toward the peoples of all the Russias and a resolve to persevere through many differences and rebuffs in establishing lasting friendships.

It is my duty, however, to place before you certain facts about the present position in Europe.

From Stettin in the Baltic to Trieste in the Adriatic an iron curtain has descended across the Continent. Behind that line lie all the capitals of the ancient states of Central and Eastern Europe.

Warsaw, Berlin, Prague, Vienna, Budapest, Belgrade, Bucharest and Sofia; all these famous cities and the populations around them lie in what I must call the Soviet sphere, and all are subject, in one form or another, not only to Soviet influence but to a very high and in some cases increasing measure of control from Moscow”.

Sir Winston Churchill, March 5, 1946 Westminster College, Fulton, Missouri

Krasnoyarsk-26: A Cold War High-Tech Center in Siberia!

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Krasnoyarsk-26:!

Still not on the map !

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From Plutonium and Spy Satellites to the Gore-Chernomyrdin Commission!

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Alma Mater: Moscow Institute of Physics and Technology!

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  1934. Peter Kapitsa (British citizen, FRC, Director of the Mond Laboratory and Professor, Cambridge University, UK) was forcefully detained by Stalin during his vacation in Russia. On requests of the British Government, Stalin replied: “Send me Rutherford and then we will send Kapitsa back to England”

  1938. Lev Landau was arrested. Released after Peter Kapitsa sends a letter to Stalin, requesting Landau’s liberation.

  October 23, 1945. Dr. Peter Kapitsa sends a proposal to Premier-Minister Georgy Malenkov to establish an Institute of Physics and Technology that would employ innovative methods for selection and training the future elite physicists and engineers

  March 10, 1946 (5 days after the “Iron Curtain” speech) Stalin’s government approves establishment of the Higher School of Physics and Technology

My “exciting” undergraduate and graduate school years (1980-1992)!

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Leonid Brezhnev Yuri Andropov Konstantin Chernenko Mikhail Gorbachev Boris Yeltsin (1964-1982) (1982-1984) (1984-1985) (1985-1991) (1991-…)

I moved to the United States in 1992

Journey to Heart Physiology!  1963, Born in Krasnoyarsk-26, a.k.a. “Iron City” – a high-tech “closed”

city in Siberia   1978-1980, Krasnoyarsk Summer School for Natural Sciences   1980-1986, Moscow Institute of Physics and Technology, M.Sc. in

Nuclear Physics   1986-1992, Institute of Biophysics, Russian Academy of Sciences,

Ph.D. in Biophysics. Laboratory of Professor Valentin Krinsky   1992-1994, Postdoctoral training in University of Pittsburgh. Laboratory

of Professor Guy Salama   1994-2000, Department of Cardiology, Cleveland Clinic Foundation   2000-2004, Department of Biomedical Engineering, Case Western

Reserve University   2004, Washington University in Saint Louis

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Cardiovascular Research Pendulum: !From Reductionism to Integration!

integration

reduction

Projects!

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  Cardiac protection in hibernating species   Mechanisms of physiological cardiac pacing by the Sino-

Atrial and Atrio-Ventricular nodes   Tissue-engineered cardiac pacemaking structures   Mechanisms of conduction and arrhythmia in the settings

of infarction   Mechanisms of electric pacing and defibrillation   Mechanisms of electroporation and associated cardiac

dysfunction   Low-voltage implantable device therapy for atrial and

ventricular arrhythmias

Projects!

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  Cardiac protection in hibernating species   Mechanisms of physiological cardiac pacing by the Sino-

Atrial and Atrio-Ventricular nodes   Tissue-engineered cardiac pacemaking structures   Mechanisms of conduction and arrhythmia in the settings

of infarction   Mechanisms of electric pacing and defibrillation   Mechanisms of electroporation and associated cardiac

dysfunction   Low-voltage implantable device therapy for atrial and

ventricular arrhythmias

Projects!

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  Cardiac protection in hibernating species   Mechanisms of physiological cardiac pacing by the Sino-

Atrial and Atrio-Ventricular nodes   Tissue-engineered cardiac pacemaking structures   Mechanisms of conduction and arrhythmia in the settings

of infarction   Mechanisms of electric pacing and defibrillation   Mechanisms of electroporation and associated cardiac

dysfunction   Low-voltage implantable device therapy for atrial and

ventricular arrhythmias

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Cardiac Protection during Hibernation!

11/25/08

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Connexin 43 forms cell-cell communication channels!

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Human failing heart

Connexin 43 α-actinin

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5 0 m

µ

1 0 m

µ

0

1 SA WA WH

0 2 4 6 8

10 12 14 16 18 20

Summer Active

Winter Hibernating

Winter Active

Projects!

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  Cardiac protection in hibernating species   Mechanisms of physiological cardiac pacing by the Sino-

Atrial and Atrio-Ventricular nodes   Tissue-engineering cardiac pacemaking structures   Mechanisms of conduction and arrhythmia in the settings

of infarction   Mechanisms of electric pacing and defibrillation   Mechanisms of electroporation and associated cardiac

dysfunction   Low-voltage implantable device therapy for atrial and

ventricular arrhythmias

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We Use Transgenic Mouse Approach to Study Ionic Mechanisms of SA Node !

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Functional and Molecular Anatomy !of the Canine SAN!

Molecular Definition of the Human Atrio-Ventricular Node!

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Engineering Cardiac Pacemaking Structures of the SA and AV Nodes!

The Lucy & Stanley Lopata Distinguished Professorship in Biomedical Engineering

Projects!

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  Cardiac protection in hibernating species   Mechanisms of physiological cardiac pacing by the Sino-

Atrial and Atrio-Ventricular nodes   Tissue-engineering cardiac pacemaking structures   Mechanisms of conduction and arrhythmia in the settings

of infarction   Mechanisms of electric pacing and defibrillation   Mechanisms of electroporation and associated cardiac

dysfunction   Low-voltage implantable device therapy for atrial and

ventricular arrhythmias

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Optical Mapping of Ventricular Tachycardia in Infarcted Hearts!

Virtual Electrode Polarization!

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Virtual Electrode Induced Phase Singularity: Cause of Arrhythmia!

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Defibrillation with a Biphasic Shock!

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Cardialen Low-energy pain-free defibrillation

Low-energy Painless !Atrial Defibrillation!

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•  New approach to defibrillation:  Most arrhythmias maintained by reentrant activation  Reentry stabilizes at “anchor points”, e.g. scar tissue, etc  Low-energy shock attracted to same “anchor points”  Allows unpinning of reentrant circuit with low-energy

monophasic shock using proprietary multiple-pulse protocol

D. Graeme Thomas, President and CEO

Ongoing Grant projects!

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  NIH R01 HL085369, “Structure/function of the pacemaking and conduction system of the heart”

  NIH R01 HL67322 "Virtual electrode hypothesis of defibrillation”

  NIH R01 HL074283, “The role of electroporation in defibrillation”

  AHA “Structure of the human AV junction”

  NIH, R01 HL082729, Collaboration with Natalia Trayanova, Johns Hopkins University

  NIH R01 HL083393 and GM075200, Collaboration with Larry Taber

  NIH R01 EB008999, Collaboration with Cheri Deng, University of Michigan, Ann Arbor, MI

  NIH R01 HL095010, Collaboration with Colin Nichols, Washington University in Saint Louis, MO

Acknowledgements:

Vadim Fedorov Christina Ambrosi Qing Lou Alexey Glukhov Wenwen Li Ai-Li Cai Li Li Fujian Qu Kelley Foyil Bill Hucker Crystal Ripplinger Vladimir Nikolski

Current Collaborators: • Richard Schuessler, Nader Moazami, Richard Gross, Colin Nichols, Larry Taber, Eliot Elson, Shelly Sakiyama-Elbert, Don Elbert, Yoram Rudy, Washington University in St. Louis • Andrew Rollins, Cheri Deng, Case Western Reserve University, Cleveland, OH • Halina Dobrzynski, Mark Boyett, University of Manchester, Manchester, UK • Natalia Trayanova, Johns Hopkins University, Baltimore MD • Patrick Tchou, David Van Wagoner, Yuanna Cheng, Cleveland Clinic Foundaiton, OH • Leo Rosenschtraukh, Yuri Egorov, Irina Shishkina, Tatiana Mikheeva, Cardiology Research Center, Moscow, Russia • Brian Barnes, Vadim Fedorov, University of Alaska, Fairbanks • Paul Iazzio, Matthew Andrews, University of Minnesota

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Thank you!!

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