PowerPoint Presentation Virtual Electrode Hypothesis of Stimulation of the Heart

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Igor R. Efimov, Ph.D., F.A.H.A., F.H.R.S Cardiac
Bioelectricity and Arrhythmia Center Department
of Biomedical Engineering
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???????????? 1 ??????. P.-S.Chen et al,
Computerized mapping of fibrillation in normal
ventricular myocardium, Chaos, 8 127-136, 1998
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The cost of cardiovascular diseases and stroke in
the United States for 2007 is estimated at
431.8 billion
American Heart Association
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Annual Pacemaker and Implantable
Cardioverter-Defibrillator (ICD) Implants in the
United States
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Maisel et al, Pacemaker and ICD Generator
Malfunctions Analysis of Food and Drug
Administration Annual Reports, JAMA, 2006, 295
1901-6.
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Egyptian papyrus, circa 1550 BC, discovered,
translated and published by Georg Ebers as
Fundamentals of the Medical Mystery,
Understanding the Hearts Movement and Knowledge
of the Heart Itself, 1875.
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Timeline of stimulation history
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1781
silver copper
zinc copper
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?????? ???? (Charles Kite),An Essay on the
Recovery of the Apparently Dead, London, 1788.
Twenty minutes had at least elapsed before he
could apply the shock, which he gave to various
parts of the body without any apparent success
but at length, on transmitting a few shocks
through the thorax, he perceived a small
pulsation soon after the child began to breathe,
though with great difficulty. In about ten
minutes she vomited. A kind of stupor remained
for some days but the child was restored to
perfect health and spirits in about a week.
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M. Hoffa C. Ludwig, Einige neue Versuche ueber
Herzbewegung. Zeitschrift Rationelle Medizin
9107-144, 1850
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???????? 1849
Kymograph
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J.-L. Prevost and F. Battelli, La Mort Par Les
Déscharges Électriques, Journ. de Physiol., 1
1085-1100, 1899
???????? ???????????? 1899
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?????? ??????? ???????????, 1939. ?????? -
?????? ????? - ??????? Prevost.
???? ?. ?????? (1905-1981) ???? ?. ?????
(1878-1968)

• 24 mF ???????????
• 0.28 Hn ????????
• b. 24 mF ???????????

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C.S. Beck, W.H. Pritchard, H.S. Feil, Ventricular
fibrillation of long duration abolished by
electric shock. Jour. Amer. Med. Assoc. 135 985,
1947
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Success
Minutes
Cummins RO. Annals Emerg Med. 1989181269-1275.
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• Mirowski M, Mower MM, Staewen WS, Tabatznik B,
  Mendeloff AL. Standby automatic defibrillator An
  approach to prevention of sudden coronary death.
  Arch Intern Med. 1970 126158-161.
• Schuder JC, Stoeckle H, Golg JH, et al.
  Experimental ventricular defibrillation with an
  automatic and completely implanted system. Trans
  Am soc Artif Organs. 1970 16207-212.
• Mirowski M, Reid PR, Mower MM, Watkins L, Gott
  VL, Schauble JF, Langer A, Heilman MS, Kolenik
  SA, Fischell RE, Weisfeldt ML. Termination of
  malignant ventricular arrhythmias with an
  implanted automatic defibrillator in human
  beings. N Engl J Med. 1980 303322-4.

Michel Mirowski, 1924-1990
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Automatic Implantable Cardioverter Defibrillator
(ICD)
Dr. Becks defibrillator 1947
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Implantable Device Therapy
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Automatic External Defibrillator
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Automatic external defibrillator
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Phase 0 1 2
3 4
Calcium influx into cell triggers
contraction of cardiac fiber
0 mV - - - - - - -
ICa
-90 mV (resting potential)
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Marban. Nature. 2002.
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??????????? ?????? 2003 ???? Roderick MacKinnon
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Priori et al., Circulation, 1999
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Priori et al., Circulation, 1999
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Change of BKCa function In smooth
muscle --Hypertension --Urinary
Incontinence --Erectile Dysfunction In
brain --epilepsy
Jianmin Cui, David Sept, Washington University
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• the cardiomyopathies due to alterations in
  sarcomeric and in cytoskeletal proteins
• the arrhythmogenic diseases that are caused by
  mutations in ion channels and ion
  channel-controlling proteins such as
• the long-QT syndromes (LQTS),
• the Brugada syndromes (BrS),
• catecholaminergic polymorphic ventricular
  tachycardias (CPVT),
• Andersen syndrome.

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• Hypertrophy increased muscle mass accommodate
  increased load clinically documents increase in
  ventricular wall thickness increase in the size
  of myocytes, not the number often associated
  with increases in interstitial fibrosis, which
  increases cardiac stiffness and impairs
  ventricular relaxation.
• Normal heart
• Dilation increase in cardiac chamber volume
  compensatory response to diminished contractile
  function improve pressure-volume relationships
  within the heart so as to augment cardiac output.

Seidman Seidman, 2001
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???????????? ?????? ???????? ???????? QT (Long QT
syndrome)
Keating Sanguinetti, Cell, 2001
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??????????? ?????????? (?????????? ???????????
?????????????? AF)
Chen et al., Science, 2003
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Mutations in KVLQT1 minK IKs LQTS
Keating Sanguinetti, 2001
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Mutations that remodel the human heart
Human mutations in sarcomere protein are
currently the only known genetic causes of
hypertrophic remodeling. Mutations in proteins of
the thin and thick filament of the sarcomere,
cytoskeletal sarcoglycans, intermediate filament
proteins, and nuclear envelope proteins can cause
cardiac dilation. Genetic studies in man and
model organisms indicate calcium dysregulation
occurs in response to gene mutations that trigger
cardiac remodeling. (Fatkin et al., 2000b)
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Familial hypertrophic cardiomyopathy
Priori et al, Circ. 2000
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• Human hypertrophic mutations have been located in
  myosin head domain residues that interface with
  actin or that surround the ATP binding pocket.
• Also in residues that comprise a flexible fulcrum
  in myosin, or that bind myosin light chains.
• Blue residues mutated in hypertrophic
  cardiomyopathy, red residues are mutated in
  dilated cardiomyopathy

Seidman Seidman, 2001
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Jenkins, Rollins, Case Western Reserve
University, 2007
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Vimentin, Connexin 43, a-actinin
Vimentin, Connexin 43, a-actinin
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SVC
CT
IAS
RA
IVC
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Cx43 in Human Right Atrium
Red Cx43 Green a-actinin Blue
Vimentin
40 µm
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????? ??? AF

• Two pathways
• Vagus nerve, M2 receptor, inhibitory G protein
  (Gi), decrease of conduction in the AV node
• Sympathetic nerve, B1 receptor, stimulatory G
  protein (Gs), increase of conduction in the AV
  node
• Infection of porcine AV node with an adenoviral
  vector overexpressing the inhibitory G protein
  (Gai2) suppresses baseline AV conduction and
  slows heart rate during atrial fibrillation

Donahue et al., 2000
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Cardiac tissue engineering
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Medical School, University of Montpellier,
France. Official status given by Cardinal Conrad
in 1220.