(12) United States Patent
`Deno et al.
`
`USOO6738667B2
`(10) Patent No.:
`US 6,738,667 B2
`(45) Date of Patent:
`May 18, 2004
`
`(54) IMPLANTABLE MEDICAL DEVICE FOR
`TREATING CARDIAC MECHANICAL
`DYSFUNCTION BY ELECTRICAL
`STIMULATION
`
`(75) Inventors: D. Curtis Deno, Andover, MN (US);
`Lawrence J. Mulligan, Andover, MN
`(US); Tom D. Bennett, Shoreview, MN
`(US); David A. Igel, Lino Lakes, MN
`(US); Michael R. S. Hill, Minneapolis,
`MN (US); Richard J. Shaw, St.
`Francis, MN (US)
`(73) Assignee: Medtronic, Inc., Minneapolis, MN
`(US)
`Subject to any disclaimer, the term of this
`patent is extended or adjusted under 35
`U.S.C. 154(b) by 568 days.
`
`(*) Notice:
`
`(21) Appl. No.: 09/750,631
`(22) Filed:
`Dec. 28, 2000
`O
`O
`(65)
`Prior Publication Data
`US 2003/0074029 A1 Apr. 17, 2003
`(51) Int. Cl. .................................................. A61N 1/18
`(52) U.S. Cl. ......................................................... 607/23
`(58) Field of Search .............................. 607/23, 18, 17,
`607/9
`
`(56)
`
`FR
`WO
`
`References Cited
`U.S. PATENT DOCUMENTS
`3,857,399 A 12/1974 Zacouto
`3,939,844 A 2/1976 Pequignot
`4,541,417 A 9/1985 Krikorian .................. 12871 D
`4,554,922 A 11/1985 Prystowsky et al. ... 128/419 PG
`4,674,518 A 6/1987 Salo ........................... 128/695
`(List continued on next page.)
`FOREIGN PATENT DOCUMENTS
`2790967
`10/2000 .......... A61N/1/368
`WO 97/25098
`7/1997 ............ A61N/1/OO
`
`WO
`WO
`
`WO 98/O2209
`WO OO/04947
`
`1/1998 .......... A61N/1/375
`3/2000
`
`OTHER PUBLICATIONS
`Cooper, M., “Postextrasystolic Potentiation: Do We Really
`Know What It Means and How to Use It?,’ Circulation, vol.
`88, No. 6, p. 2962–2971 (Dec. 1993).
`(List continued on next page.)
`Primary Examiner Mark Bockelman
`(74) Attorney, Agent, or Firm-Girma Wolde-Michael;
`Michael C. Soldner; Paul H. McDowall
`(57)
`ABSTRACT
`An implantable Stimulator and monitor measures a group of
`heart failure parameters indicative of the state of heart
`failure employing EGM Signals, measures of blood preSSure
`including absolute pressure P, developed pressure (DP=
`systolic P-diastolic P), and/or dP/dt, and measures of heart
`chamber Volume (V) over one or more cardiac cycles. These
`parameters ES relaxation or contraction time con
`Stant tau (t); (2) mechanical restitution (MR), i.e., the
`mechanical response of a heart chamber to premature Stimuli
`applied to the heart chamber; (3) recirculation fraction (RF),
`i.e., the rate of decay of PESP effects over a series of heart
`cycles; and (4) end Systolic elastance (Es), i.e., the ratios of
`end systolic blood pressure P to volume V. These heart
`failure parameters are determined periodically regardless of
`patient posture and activity level. The physician can deter
`mine whether a particular therapy is appropriate, prescribe
`the therapy for a period of time while again accumulating the
`Stored patient data for a later review and assessment to
`determine whether the applied therapy is beneficial or not,
`thereby enabling periodic changes in therapy, if appropriate.
`Drug therapies and electrical Stimulation therapies, includ
`ing PESP Stimulation, and pacing therapies including Single
`chamber, dual chamber and multi-chamber (bi-atrial and/or
`bi-ventricular) pacing can be delivered. In patient's prone to
`malignant tachyarrhythmias, the assessment of heart failure
`State can be taken into account in Setting parameters of
`detection or classification of tachyarrhythmias and the thera
`pies that are delivered.
`
`8 Claims, 21 Drawing Sheets
`
`
`
`S414 - ELASTANCEPARAMETER
`
`LUMENIS EX1040
`Page 1
`
`

`

`US 6,738,667 B2
`Page 2
`
`U.S. PATENT DOCUMENTS
`
`5,024.222 A 6/1991 Thacker ................ 128/419 PG
`5,213,098 A 5/1993 Bennett et al. ....... 128/419 PG
`5,328,442 A 7/1994 Levine ........................ 600/17
`5,331966 A 7/1994 Bennett et al.
`... 128/696
`5,417,717 A
`5/1995 Salo et al. .................... 607/18
`5,564,434 A 10/1996 Halperin et al. ............ 128/748
`5,626,623 A 5/1997 Kieval et al. ................. 607/23
`5,800.464 A 9/1998 Kieval ........................... 607/9
`6,021,345 A 2/2000 Karagueuzian et al. ..... 600/518
`6,090,047 A 7/2000 Kass et al. .................. 600/485
`6,104,949 A 8/2000 Pitts Crick et al. ......... 600/547
`6,141,586 A 10/2000 Mower .......................... 607/9
`
`
`
`OTHER PUBLICATIONS
`
`Dell'Italia, Louis, “Mechanism of Postextrasystolic Poten
`tiation in the Right Ventricle,” Amer: Jour. Of Cardiol., vol.
`65, p. 736–741 (Mar. 15, 1990).
`Franz et al., “Electrical and Mechanical Restitution of the
`Human Heart at Different Rates of Stimulation.” Circulation
`Research, vol. 53, No. 6, p. 815–822 (Dec. 1983).
`Freeman et al., “Evaluation of Left Ventricular Mechanical
`Restitution in Closed-chest Dogs Based on Single-Beat
`Elastance,” Circulation Research, vol. 67, No. 6, p.
`1437–1445 (Dec. 1990).
`Geschwind et al., “Sympathetic Nervous System Activation
`in Postextrasystolic Potentiation: Role of Catecholamine
`Release in Enhancement of Ventricular Function, JACC,
`vol. 4, No. 2, p. 215-225 (Aug. 1984).
`
`Juggi et al., “Intracellular Kinetics of the Activator Calcium
`of Rat Heart after Ischemic Arrest and Cardioplegia: Quan
`titative Comparison of Right and Left Ventricles,” Can. J.
`Cardiol., vol. 8, No. 4, p. 387–395 (May 1992).
`Kuijer et al., “Post-Extrasystolic Potentiation Without a
`Compensatory Pause in Normal and Diseased Hearts.”
`Abstract (accepted for publication Dec. 20, 1989).
`Mesaeli et al., “Mechanical Restitution and Post Extrasys
`tolic Potentiation of Perfused Rat Heart: Quantitative Com
`parison of Normal Right and Left Ventricular Responses,”
`Can. J. Cardiol., vol. 8, No. 2, p. 164–172 (Mar. 1992).
`Pidgeon, et al., “The Relationship Between the Strength of
`the Human Heart Beat and the Interval Between Beats,”
`Circulation, vol. 65, No. 7, p. 1404–1410 (Jun. 1982).
`Prabhu et al., “Effect of Tachycardia Heart Failure on the
`Restitution of Left Ventricular Function in Closed-Chest
`Dogs.” Circulation, vol. 91, No. 1, p. 177-185 (Jan. 1,
`1995).
`Prabhu et al., “Kinetics of Restitution of Left Ventricular
`Relaxation.” Circulation Research, vol. 70, No. 1, p. 29-38
`(Jan. 1992).
`ter Keurs et al., “Characterization of Decay of Frequency
`Induced Potentiation and Post-Extrasystolic Potentiation,”
`Cardiovascular Research, vol. 24, p. 903-910 (1990).
`van der Werf et al., “Postextrasystolic Potentiation in Man,”
`European Journal of Cardiology, Vol. 4/Supplement, p.
`131-141 (1976).
`Wisenbaugh et al., “Mechanics of Postextrasystolic Poten
`tiation in Normal Subjects and Patients With Valvular Heart
`Disease.” Circulation, vol. 74, No. 1, p. 10–20 (Jul 1986).
`
`LUMENIS EX1040
`Page 2
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 1 of 21
`
`US 6,738,667 B2
`
`
`
`LUMENIS EX1040
`Page 3
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 2 of 21
`
`US 6,738,667 B2
`
`t??v?s
`
`| |
`
`|-
`
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`
`
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`
`
`
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`
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`
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`
`
`
`
`
`
`Z "SOI
`
`LUMENIS EX1040
`Page 4
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 3 of 21
`
`US 6,738,667 B2
`
`
`
`ET£VNE BY AT SWEW BONVOJEdW|
`
`
`
`100 BONVOIEc|W|
`
`
`
`LNHAE EISNES
`
`
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`ETHVNE BSNES
`
`
`
`
`
`
`
`
`
`
`
`LUMENIS EX1040
`Page 5
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 4 of 21
`
`US 6,738,667 B2
`
`S4OO
`
`MDIMPANTED
`
`FIG. 4A
`
`S402
`
`PROGRAMEACH PARAMETER
`ON/OFF, PROGRAMEACH
`PARAMEEREVENT TRIGGER
`AND MEASUREMENT CRITERA,
`AND PROGRAM THERAPY
`PARAMETERS
`
`PRForMPARAMEter
`MEASUREMENTS FOREACH
`S404 PROGRAMMEd PARAMETER
`ANDUPLINK TELEMETER
`DATA TO PROVIDE BASELNE
`PARAMETER DATASET
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`TRGGER CRERAME
`7
`
`S408
`
`HALT THERAPY DEVERY
`
`DETERMINE HEART RATE
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`PERFORM PARAMETER
`MEASUREMENT FOREVENT
`TRIGGERED PARAMTER
`
`S416
`
`S418
`PARAMETER
`MEASUREMENT
`COMPLETED
`
`YES
`
`STORE PARAMER
`MEASUREMENT OATA With DATE
`AND MESTAMP NMD MMORY
`
`DEERMINE STATE OF HEART
`FAILURE FROMMEASURED
`PARAMETERS
`
`S422
`
`HEAR FAILURE
`SATE CHANGEO
`
`NO
`
`AdjuSHRAPY
`PARAMERS
`
`RATE/RHYTHM CRTERAMET
`
`S428
`
`
`
`
`
`
`
`DELIVER THERAPY
`
`LUMENIS EX1040
`Page 6
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 5 of 21
`
`US 6,738,667 B2
`
`S430
`
`DETERMNE BURS PACNG
`PULSE PARAMETERS
`FROM CHANGEN
`HEAR FAURE STATE
`
`FIG. 4B
`
`S426 - S428
`
`S444
`
`YES
`
`S446
`
`DELIVER PESP PULSE 1
`
`S434 DETERMINE INTRINSIC El
`
`S448
`
`TIME OUT BP
`
`
`
`S436
`
`DEERMNE PACNG
`E AND ES FOR FIRST
`BURS PACE PULSE
`FROM INTRINSICE
`
`
`
`BP TIMED OU
`
`
`
`S438
`
`TEME OUT E AND ESI
`FROM SENSE EVENT
`
`S452
`
`OELVER NEXT
`BURST PACE PULSE
`
`- S440
`
`YES
`
`S442
`
`DELIVER PACE PULSEAT
`DETERMINED PACNG El
`
`S454
`
`INCREMENT BP COUNT
`
`
`
`S456
`
`BP COUNT MET
`
`YES
`
`LUMENIS EX1040
`Page 7
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 6 of 21
`
`US 6,738,667 B2
`
`
`
`
`
`
`
`
`
`S504
`
`c YES
`
`S506
`
`DETERMINENTRNSCE
`
`
`
`S508
`
`OETERMNE PACNGE
`ANONTIAL ES FROMNTRINSIC El
`
`
`
`DETERMINE RVDP (SS),
`sso dPlat MAX (SS) AND dPlat MIN (SS)
`FIGSB
`
`
`
`DETERMNERVOP (ES),
`ss34 dPlat MAX (ES) AND dPlat MIN (ES)
`F.G. 5C
`
`F.G. 5A
`
`S414 - MR PARAMETER
`
`S554
`
`NCREMENTES BY2OMS
`
`NCREMENTED
`ES > 0.9. PACNGE
`
`S558
`
`STAR 15 second TIMEr
`
`SECONDS TIMED OUT
`
`NO
`
`
`
`DETERMINE tomre FROM
`RVDP (ES) AND RVDP (SS) oR
`dPict MAX (ES), dipidt MIN (ES),
`dPfat MAX (SS), and
`dPldt MIN (SS) AND
`STORE IN MEMORY
`
`S562
`
`O to
`
`Dss
`
`LUMENIS EX1040
`Page 8
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 7 of 21
`
`US 6,738,667 B2
`
`FROM
`S508
`
`FIG. 5B
`S414 - MR PARAMETER
`
`
`
`
`
`
`
`S512
`
`S514
`
`
`
`ME OUT PACNGE
`FROM SENSE EVENT OR
`PACE PULSE
`
`
`
`PACINGE
`TIMED OUT
`2
`
`S516
`
`DEVER PACE PUSE
`
`
`
`
`
`S518
`
`NCREMENT PACE
`PULSE COUNT
`
`
`
`
`
`PACE PULSE
`COUNT = 8
`
`
`
`
`
`
`
`
`
`
`
`PACE PULSE
`COUN = 7
`
`S528
`
`
`
`SOP SAMPLNG BLOOD
`PRESSURE PAND di?dt
`
`DETERMINE
`dPfat MAX (SS),
`dPldt MIN (SS)
`AND RVDP (SS)
`
`TEMPORARLY STORE
`dPict MAX (SS),
`dPfdt MiN (SS),
`AND RVDP (SS)
`
`PACE PULSE
`COUNT = 6
`2
`
`
`
`
`
`START SAMPLING BLOOD
`PRESSURE P AND dipfdt
`
`LUMENIS EX1040
`Page 9
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 8 of 21
`
`US 6,738,667 B2
`
`()
`
`S536
`
`TIME OUTES FROM
`EIGHTH PACE PULSE
`
`NO
`
`S538
`
`FIG. 5C
`S414 - MR PARAMETER
`
`S534
`
`YES
`
`STOP SAMPLNG BLOOD
`S548 PRESSURE P AND di?cit
`
`S540 IDELIVERESI PACE PULSE
`
`START SAMPLING BLOOD
`S542 PRESSURE PAND dipfot
`
`
`
`S550
`
`DETERMINE
`dP?dt MAX (ES),
`dPfeit MIN (ES),
`AND RVDP (ES)
`
`S544
`
`STAR PACNG E TIME
`OUT
`
`S552
`
`TEMPORARLY STORE
`dPldt MAX (ES),
`dPfdt MIN (ES),
`AND RVDP (ES)
`
`S546
`
`
`
`
`
`PACING SE
`MED OUT
`2
`
`YES
`
`LUMENIS EX1040
`Page 10
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 9 of 21
`
`US 6,738,667 B2
`
`FIG 6
`
`S414 - RF PARAMETER
`
`--> YES
`
`S622
`
`OEVER PACNGPULSE AND
`SAR PACNGEME-OUT
`
`MEASURE Pt
`
`
`
`
`
`
`
`NCREMENE COUNT
`
`
`
`DETERMINE INTRINSIC E
`
`
`
`S608
`
`DETERMINE PACNGE
`AND ES FROMNTRINSICE
`
`OEVER"M" PACE PULSESA
`DEERMNEO PACNGEO
`SABILIZE HEART RAE
`
`S61O
`
`S612
`
`MEASURE Pict. AND
`ETERMINE REFERENCE
`dPidt MAX (SS) DURING
`A LEAST ONE PACNGE
`
`S614 TIME OUT ES AND E FROM
`OEVERED PACNG PULSE
`
`YES
`
`S618
`
`DEVERES PULSE
`
`LUMENIS EX1040
`Page 11
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 10 of 21
`
`US 6,738,667 B2
`
`S7OO
`
`START
`
`FIG. 7
`S414 - ELASTANCE PARAMETER
`
`S7O2
`
`YES
`
`S704
`
`DETERMNE PACNGE
`
`S718
`
`DETERMINE END SYSOLCPON
`PsAND Vs SIGNALS
`
`S7O6
`
`S720
`
`TEMPORARLY STORE END
`SYSTOLIC PAND Ves SIGNAS
`
`TME OUT PACNGE
`
`S708
`
`PACNGE
`TIMED out
`
`YES
`
`OLVER PACE PULSE
`
`S712
`
`SAMPLE HEART CHAMBER BLOOD
`PRESSURE To devel OPN
`PRESSURE SGNALS
`OVER HEAR CYCLE
`
`MEASURE HEART CHAMBER
`WOUMEATEACHSAMPLED
`S714 BLOOD PRESSURE TO DEVELOP
`NVOLUMESGNALS
`OVER HEART CYCLE
`
`DIGITIZEN PRESSURE SIGNALS
`AND NWOLUMESGNAS
`
`S722 INCREMENTE DATASET COUNT
`
`
`
`NO
`
`
`
`EEs
`DATA Set COUNT
`= PROGRAMMED COUNT
`
`S724
`
`DETERMINE THE SLOPE AND R2 OF
`S726 THEPLOT OF n END SYSTOLIC
`PsAND VEssIGNALS
`
`NO
`
`SAMPLE r >
`THRESHold R'
`7
`
`
`
`S728
`
`STORE THE DETERMINED SOPE
`OF THEn END SYSTOLIC Ps
`AND vs SIGNALS
`
`
`
`
`
`
`
`
`
`
`
`S732
`
`ENO
`
`
`
`
`
`
`
`LUMENIS EX1040
`Page 12
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 11 of 21
`
`US 6,738,667 B2
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`REPEA SEPS S4C3, S42
`K-1 MESOTERMINE
`RR INSTEP S410
`
`S8O2
`
`
`
`S804
`
`NTRINSICPACED
`MODE
`
`NTRINSIC
`
`SAMPLE BLOOD PRESSUREN
`HEAR CHAMBERO DEVELOP
`NPSIGNALS ANN did
`SiGNALS over RR HEART CYCLE
`
`RRWITHIN RR
`ATESTABILITYBolinD
`
`S816 determine time of dpa Min
`WITHINRR
`
`S818
`
`
`
`
`
`S414 - TAU PARAMETER
`
`DETERMINE PACING El FROMRR
`To PROVIDE PACEDRR
`
`S824
`
`YES
`
`TIME OUPACNGE
`
`S828
`
`PACNGE
`TMED OU
`
`YES
`
`DEVER PACE PUSE
`
`SAMPLE BLOOD PRESSUREN
`HEART CHAMBERTC DEVELOP
`NPSIGNALS AND N PRT
`SIGNALS OVER RR HEART CYCLE
`
`S834
`
`YES
`
`NO
`
`PACNGE
`TIMED OUT
`
`YES
`
`LUMENIS EX1040
`Page 13
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 12 of 21
`
`US 6,738,667 B2
`
`FG. 9
`
`0.
`
`0, 6
`
`0.2
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`G
`
`c
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`i
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`A
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`f
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`A
`
`&
`
`A
`
`A
`f
`
`Control
`
`CCCM
`
`FIG. 14.
`
`
`
`400
`
`RV dr/dt MTN (Es)
`
`RV diastolic parameter (SS)
`
`RV systolic parameter (ES)
`RV systolic parameter (SS)
`
`100
`
`Extra Systolic interval
`
`LUMENIS EX1040
`Page 14
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 13 of 21
`
`US 6,738,667 B2
`
`Au
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`utu?
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`LUMENIS EX1040
`Page 15
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 14 of 21
`
`US 6,738,667 B2
`
`s/6Huu
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`LUMENIS EX1040
`Page 16
`
`

`

`U.S. Patent
`
`May 18, 2004
`
`Sheet 15 Of 21
`
`US 6,738,667 B2
`
`RV dest Following PESP
`
`--RV6Podtmax
`
`exponential decay fi
`ponential decay it
`
`F.G. 12
`
`5
`
`ce
`
`36.500
`
`38. SOO
`Time (s)
`
`4.O.5OO
`
`Recirculation Fraction
`RV dPldt
`
`550
`
`o
`G
`
`y = 0.7252x + 79.184
`
`450 -
`
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`
`RF = 0.725
`
`1.
`
`/
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`
`n 350 -
`O
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`4.
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`
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`
`550
`
`FIG. 13
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`U.S. Patent
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`May 18, 2004
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`Sheet 16 of 21
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`US 6,738,667 B2
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`F.G. 15
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`Determination of RV Relaxation Time Constant, Tau
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`U.S. Patent
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`May 18, 2004
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`Sheet 17 of 21
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`US 6,738,667 B2
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`U.S. Patent
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`May 18, 2004
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`Sheet 18 of 21
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`US 6,738,667 B2
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`
`
`LV PV Loops
`
`FIG. 18
`
`G
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`LV Ees Determination
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`FIG. 19
`
`125
`
`120
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`
`110
`
`105
`
`y = 9.6942x - 133.48
`R = 0.998
`
`100 -----
`24
`25
`26
`27
`28
`LV Volume ES (ml)
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`Page 20
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`U.S. Patent
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`May 18, 2004
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`Sheet 19 of 21
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`US 6,738,667 B2
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`LV PV Loops
`
`
`
`FIG. 20
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`FIG. 21
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`R = 0.3218
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`58
`LV Volume ES (ml)
`- - -
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`Sheet 20 of 21
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`May 18, 2004
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`US 6,738,667 B2
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`1
`IMPLANTABLE MEDICAL DEVICE FOR
`TREATING CARDIAC MECHANICAL
`DYSFUNCTION BY ELECTRICAL
`STIMULATION
`
`CROSS-REFERENCE TO RELATED
`APPLICATION
`Reference is hereby made to commonly assigned,
`co-pending U.S. patent application Ser. No. (P-9633.00)
`filed on even date here with entitled IMPLANTABLE
`MEDICAL DEVICE FORMONITORING CONGESTIVE
`HEART FAILURE by Lawence J. Mulligan et al.
`
`FIELD OF THE INVENTION
`The present invention relates generally to implantable
`medical devices and more specifically to monitoring Signs of
`acute or chronic cardiac mechanical dysfunction Such as
`congestive heart failure (CHF) or cardiogenic shock and
`providing appropriate therapies.
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`15
`
`BACKGROUND OF THE INVENTION
`Patients suffering from chronic CHF manifest an eleva
`tion of left ventricular end-diastolic pressure, according to
`the well-known heterometric autoregulation principles
`espoused by Frank and Starling. This may occur while left
`Ventricular end-diastolic Volume remains normal due to a
`decrease in left ventricular compliance concomitant with
`increased ventricular wall stiffness. CHF due to chronic
`hypertension, ischemia, infarct or idiopathic cardiomyopa
`thy is associated with compromised Systolic and diastolic
`function involving decreased atrial and Ventricular muscle
`compliance. These may be conditions associated with
`chronic disease processes or complications from cardiac
`Surgery with or without Specific disease processes. Most
`heart failure patients do not normally Suffer from a defect in
`the conduction System leading to Ventricular bradycardia,
`but rather suffer from symptoms which may include a
`general weakening of the contractile function of the cardiac
`muscle, attendant enlargement thereof, impaired myocardial
`relaxation and depressed Ventricular filling characteristics in
`the diastolic phase following contraction. Pulmonary edema,
`ShortneSS of breath, and disruption in Systemic blood pres
`Sure are associated with acute exacerbations of heart failure.
`All these disease processes lead to insufficient cardiac output
`to Sustain mild or moderate levels of exercise and proper
`function of other body organs, and progressive worsening
`eventually results in cardiogenic shock, arrhythmias, elec
`tromechanical dissociation, and death.
`Such patients are normally treated with drug therapies,
`including digitalis, which may lead to toxicity and loss of
`effectiveness. Many inotropic drugs have recently become
`available, targeted at various receptors in the myocyte and
`designed for the purpose of directly Stimulating cardiac
`tissue in order to increase contractility. However, there exist
`many possible undesirable Side effects, in addition to the fact
`that these drugs do not always work for their intended
`purpose. This is especially characteristic of the patient
`Suffering from end-stage heart failure.
`In the early days of implantable cardiac pacing, it was
`observed that paired pacing (two or more closely spaced
`pacing pulses delivered at the time-out of an escape interval)
`and triggered or coupled pacing (one or more pacing pulses
`delivered following the detection of a P-wave or R-wave
`terminating an escape interval) with relatively short inter
`pulse intervals (150 to 250 milliseconds in dogs and about
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`300 milliseconds in human subjects) beneficially slowed
`heart rate and increased cardiac output. The result of the
`Second pulse, applied within the relative refractory period of
`the first paced or spontaneous depolarization, is to prolong
`the refractory period and effect a Slowing of the heart rate
`from its Spontaneous rhythm without an attendant mechani
`cal myocardial contraction. This slowing effect has been
`employed Since that time in many applications, including the
`treatment of atrial and Ventricular tachycardias, where a
`Single pulse or a burst of pulses are coupled to a spontaneous
`tachycardia event with a coupling interval that is shorter
`than and can be set as a fraction of the tachycardia interval
`as taught, for example, in U.S. Pat. Nos. 3,857,399 and
`3,939,844. The slowing of the heart rate by coupled pacing
`is accompanied by the ability to increase or decrease the rate
`with Subsequent coupled pacing within wide limits.
`Paired and coupled Stimulation of a heart chamber also
`cause a potentiation of contractile force effect through a
`phenomenon known as post-extrasystolic potentiation
`(PESP) described in detail in commonly assigned U.S. Pat.
`No. 5,213,098. The force of contraction of the heart is
`increased during the heart cycle that the paired or coupled
`Stimulation is applied, and the increase persists but gradually
`diminishes over a number of Succeeding heart cycles. Other
`measurable PESP effects that also persist but gradually
`decline Over a number of heart cycles include changes in the
`peak Systolic blood preSSure, the rate of contraction of the
`Ventricular muscle with a resulting increase of the rate of rise
`of intraventricular pressure (dP/dt), an increase in coronary
`blood flow, and an increase in the oxygen uptake of the heart
`per beat. Investigators observed that PESP was accompanied
`by an increase in the myocardial oxygen consumption of
`35% to 70% as compared with single pulse stimulation at the
`Same rate and was associated with a significant improvement
`in ejection fraction. The addition of a third stimulus
`increased the myocardial oxygen uptake even further with
`out any attendant observed increase in cardiac contractile
`force. The alterations in coronary flow roughly parallel the
`oxygen consumption of the heart as observed in Such
`Studies.
`The marked potentiation effect produced by paired Stimu
`lation led certain investigators to speculate that PESP stimu
`lation would be beneficial in treating heart failure in humans
`and conducted Studies using the technique in the treatment
`of acute heart failure induced in dogs. Improvements in left
`Ventricular performance and cardiac output produced by
`Such paired pacing in these dogs was observed by Several
`investigators. In other Studies conducted on relatively nor
`mal dogs hearts, it was confirmed that paired pacing offered
`no increase in cardiac output, most likely due to refleX
`compensation. Early investigators conducted a large number
`of animal and human Studies employing paired and coupled
`Stimulation of the atrial and Ventricular chambers, and
`medical devices were made available by Medtronic, Inc. and
`other companies in an effort to employ the PESP effect.
`However, it was realized that the application of closely
`timed paired and coupled pacing pulses, particularly the
`high energy pacing pulses that were employed at that time
`in implantable pacemakers, could trigger a tachyarrhythmia
`in patient's hearts that were susceptible. The efforts to
`capitalize on the PESP effects were largely abandoned. A
`history of the investigations and Studies conducted is Set
`forth in the above-referenced '098 patent.
`Since dual chamber pacing was developed, conventional,
`atrioventricular (AV) Synchronous pacing Systems, includ
`ing DDD and DDDR pacing systems, marketed by
`Medtronic, Inc. and other companies, have also been pre
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`scribed for treatment of CHF as well as a variety of
`bradycardia conditions. Certain patient groups Suffering
`heart failure symptoms with or without bradycardia tend to
`do much better hemodynamically with AV synchronous
`pacing due to the added contribution of atrial contraction to
`Ventricular filling and Subsequent contraction. However,
`fixed or physiologic Sensor driven rate responsive pacing in
`Such patients does not always lead to improvement in
`cardiac output and alleviation of the Symptoms attendant to
`Such disease processes because it is difficult to assess the
`degree of compromise of cardiac output caused by CHF and
`to determine the pacing parameters that are optimal for
`maximizing cardiac output. The magnitude of the AV delay
`is one factor that requires obtaining pressure data involving
`an extensive patient work-up as Set forth in commonly
`assigned U.S. Pat. No. 5,626,623.
`The above-referenced 098 patent discloses PESP cardiac
`pacing energy Stimulator for applying paired and/or trig
`gered pacing Stimulation pulses to the right atrium and/or
`Ventricle incorporating one or more Sensors and Signal
`processing circuitry for controlling the frequency of or
`number of heart cycles between periodic delivery of trig
`gered or paired pacing to induce and optimize the PESP
`effect for the treatment of CHF or other cardiac dysfunc
`tions. A first Sensor, e.g., a Ventricular or arterial blood
`preSSure or flow Sensor, is employed to monitor the perfor
`mance of the heart and to develop a cardiac performance
`index (CPI). A second sensor, e.g., an oxygen Saturation
`Sensor positioned in the coronary Sinus, is employed to
`monitor cardiac muscle StreSS and develop a cardiac StreSS
`index (CSI) to balance performance and stress. The dis
`closed PESP stimulator may be incorporated into a dual
`chamber (DDD) pacing System with or without physiologic
`rate control and with or without backup cardioversion/
`defibrillation therapy capabilities or in a separate, Single
`purpose device. The PESP stimulator has particular appli
`cation in atrial Stimulation for augmenting filling of the
`Ventricles.
`A series of PCT publications including, for example, PCT
`WO 97/25098 describe the application of one or more
`40
`“non-excitatory' anodal or cathodal Stimulation pulses to the
`heart and maintain that improvements in LV performance
`may be realized without capturing the heart. In a further
`commonly assigned U.S. Pat. No. 5,800,464, Sub-threshold
`anodal Stimulation is provided to the heart to condition the
`heart to mechanically respond more vigorously to the con
`ventional cathodal Supra-threshold pacing pulses.
`Thus, various Stimulation regimens have been proposed
`for the treatment of heart failure including CHF which
`involve application of Supra-threshold and/or Sub-threshold
`Stimulation paired or coupled pacing pulses or pulse trains.
`Moreover, various electrodes have been proposed for Single
`Site and multi-site delivery of the Stimulation pulses to one
`or more heart chamber in the above-referenced patents and
`publications. However, it remains difficult to economically
`determine appropriate candidates that would benefit from
`Such Stimulation and to measure the efficacy of a given
`Stimulation regimen and/or electrode array. Extensive cath
`eterization procedures must be conducted of a heart failure
`patient to determine if he or she is a candidate for implan
`tation of Such a System. Then, the efficacy of any given
`treatment must be assessed at implantation and in periodic
`post-implant follow-up clinical tests. The patient work-up
`and follow-up testing must take into account or Simulate
`known patient activities, patient posture, and whether the
`patient is awake or asleep in order to be representative of the
`heart failure condition over a daily time span.
`
`4
`Physiologic and device operating data gathering capabili
`ties have been included in modern implantable cardiac
`pacemakers and implantable cardioverter/defibrillators
`(ICDs) in order to provide a record of bradycardia or
`tachyarrhythmia episodes and the response to Same provided
`by the pacemaker or ICD. The stored physiologic device
`operations and patient data as well as real-time EGM data
`can be uplink telemetered to an external programmer for
`display and analysis by medical heath care providers, as is
`well known in the art.
`In addition, implantable cardiac monitors have been clini
`cally used or proposed for use for monitoring hemodynamic
`and electrical signals of a patient's heart that do not pres
`ently include any Stimulation capabilities, e.g., cardiac pac
`ing or cardioversion/defibrillation. Such implantable moni
`tors are implanted in patients to develop data over a longer
`time period than in the clinical Setting that can be retrieved
`in the same manner and used to diagnose a cardiac
`dysfunction, including CHF, that manifests itself sporadi
`cally or under certain loads and stresses of daily living.
`One such implantable EGM monitor for recording the
`cardiac electrogram from electrodes remote from the heart
`as disclosed in commonly assigned U.S. Pat. No. 5,331,966
`and PCT publication WO 98/02209 is embodied in the
`Medtronic(R) REVEAL(R) Insertable Loop Recorder having
`spaced housing EGM electrodes. More elaborate implant
`able hemodynamic monitors (IHMs) for recording the EGM
`from electrodes placed in or about the heart and other
`physiologic Sensor derived signals, e.g., one or more of
`blood pressure, blood gases, temperature, electrical imped
`ance of the heart and/or chest, and patient activity have also
`been proposed. The Medtronic(R) CHRONICLE(E) IHM is an
`example of Such a monitor that is coupled through a lead of
`the type described in commonly assigned U.S. Pat. No.
`5,564,434 having capacitive blood pressure and temperature
`sensors as well as EGM sense electrodes. Such implantable
`monitors when implanted in patients Suffering from cardiac
`arrhythmias or heart failure accumulate date and time
`Stamped data that can be of use in determining the condition
`of the heart over an extended period of time and while the
`patient is engaged in daily activities.
`A CHF monitor/stimulator is disclosed in commonly
`assigned U.S. Pat. No. 6,104,949 that senses the trans
`thoracic impedance as well as patient posture and provides
`a record of Same to diagnose and assess the degree and
`progression of CHF. The Sensed trans-thoracic impedance is
`dependent on the blood or fluid content of the lungs and
`assists in the detection and quantification of pulmonary
`edema Symptomatic of CHF. Trans-thoracic impedance is
`affected by posture, i.e. whether the Subject is lying down or
`Standing up, and the Sensed trans-thoracic impedance is
`correlated to the output of the patient posture detector to
`make a determination of presence of and the degree of
`pulmonary edema for therapy delivery and/or physiologic
`data Storage decisions.
`A monitor/stimulator is disclosed in U.S. Pat. No. 5,417,
`717, that monitors and assesses level of cardiac function
`then permits a physician to arbitrate the therapy mode, if
`therapy is indicated. The monitor Stimulator assesses
`impedance, EGM, and/or preSSure measurements, and then
`calculates various cardiac parameters. The results of these
`calculations determine the mode of therapy to be chosen.
`Therapy may be administered by the device itself or a
`control Signal may be telemetered to various peripheral
`devices aimed at enhancing the hearts function.
`Alternatively, the device may be programmed to monitor
`and either Store or telemeter information without delivering
`therapy.
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`Particularly, the implantable monitor/stimulator monitors
`conventional parameters of cardiac function and contractile
`State, including all phases of the cardiac cycle. Thus, assess
`ments of contractile State measured include indices of both
`cardiac relaxation and contraction. Utilizing the dual Source
`Ventricular impedance plethysmography technique
`described in U.S. Pat. No. 4,674,518, the monitor/stimulator
`monitors cardiac function by assessing hemodynamic
`changes in Ventricular filling and ejection or by calculating
`isoVolumic phase indices by known algorithms. The primary
`calculations involve: (1) the time rate of change in pressure
`or volume, dP/dt or dV/dt, as isovolumic indicators of
`contractility; (2) ejection fraction as an ejection phase index
`of cardiac function according to the known quotient of
`stroke volume divided by end diastolic volume; (3) Maximal
`elastance, E, (4) regression slope through maximal
`preSSure-volume points as a further ejection phase index of
`contractility using the method of Sagawa; (5) Stroke work
`according to the known pressure-volume integration; (6) the
`time course of minimum (end) diastolic pressure-volume
`measurements according to the method of Glantz as a
`measure of diastolic function; and (7) cardiac output calcu
`lation according to the known product of heart rate and
`Stroke Volume as an index of level of global function.
`While measurement and Storage of this group of param
`eters of cardiac function and contractile State can provide
`valuable information about the state of heart failure, there
`are other parameters that of even greater value. Momentary
`changes to a patient's autonomic State can change blood
`pressure (P), heart rate, and pressure rate of change (dP/dt)
`contractility measures and not be reflective of a “true”
`functional State change of the heart.