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NeuromodulationNeuromodulationNeuromodulation ininin CardiacCardiacCardiac Diseases:Diseases:Diseases: ClinicalClinicalClinical andandand MechanisticMechanisticMechanistic StudiesStudiesStudies VisceralVisceralVisceral Seminar.Seminar.Seminar. SeptemberSeptemberSeptember 14,14,14, 200920092009 MikeMikeMike JLJLJL DeJongsteDeJongsteDeJongste,,, MD,MD,MD, PhD,PhD,PhD, FESCFESCFESC UniversityUniversity MedicalMedical CenterCenter GroningenGroningen DeptDept ofof ,Cardiology, Thoraxcenter.Thoraxcenter. Groningen.Groningen. NetherlandsNetherlands onon behalfbehalf ofof thethe WorkingWorking GroupsGroups NeuroNeuro CardiologyCardiology

WGNCWGNC !! (Insignificant)(Insignificant) disclosuresdisclosures - steering committee new study (Medtronic) - incidental member advisory group (St Jude Medical)

WGNCWGNC ! Evolving indications in cardiac diseases - failure - - acute coronary syndromes

! Mechanisms of Action of SCS in angina

WGNCWGNC EvolvingEvolving indication:indication: HeartHeart FailureFailure

WGNCWGNC ! HautvastT = 9RWM, (following Szabo 3 monthsBM, DeJongste SCS); MJL,C Hooijschuur = 8 (3 months CAM, no LieSCS) KI, Staal MJ, Meyler WJ, Küthe RF, Zijlstra GJ. Influence of stimulation on left ventricular function in patients with refractory angina pectoris. 2nd international Symposium on Heart Failure- mechanisms and management 1993, Geneva, Switzerland

Hautvast R et al. 2nd Int. Symp. Heart Failure, 1993, Geneva, Switzerland WGNCWGNC Kujavic V et al. Eur Heart J 1993;14:1238-44

Pts 15 SCS; 64 (49-71) years with refractory AP

Methods Echo at rest + following adenosine provocation Pts randomized to active SCS or withheld SCS

Results control LVEF 44% ! 37% (p< 0.05) SCS LVEF 48% ! 44% (ns)

WGNCWGNC

TENS (NMES) in Heart Failure or COPD (Sillen MJ et al. Chest, 2009:136:44-61 {review})

Concl. NMES looks promising as a means of rehabilitating patients with CHF and COPD. WGNCWGNC Effect of on echocardiographic indices Lopshire et al Circulation. 2009 Jul 28;120(4):286-94

WGNCWGNC EvolvingEvolving indication:indication: ArrhythmiasArrhythmias

WGNCWGNC DOG X: no SCS DOG X: SCS pre-treatment

occlusion

SCS “on” release occlusion occlusion

5 min. occlusion

WGNCWGNC release occlusion NN == 2020 caninescanines xx 22

2020 SCSSCS ++ 2020 SCSSCS --

VT/VFVT/VF == 22 VT/VFVT/VF == 88

8th INS World Congress, Acapulco, 2007 WGNCWGNC Experimental studies: Neuromodulation & Arrhythmias (Issa ZF et al. Circulation, 2005: 111:3217-20)

WGNCWGNC SCS + 5/22; SCS - 13/22 VT/VF Effect of neuromodulation on ventricular arrhythmias: phase 1 study

Lopshire, JC et al. Circulation,2009;120:286-94

WGNCWGNC Antianginal Effects of Electrical Neuromodulation

WGNCWGNC Indication:Indication: IschemicIschemic HeartHeart DiseasesDiseases

! Stable angina

! Acute coronary syndromes unstable angina myocardial infarction

WGNCWGNC Health related quality of life (6 RCT; n = 129)

SCS Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI 1.3.1 SCS vs Active comparator ESBY 1998 15 27 45 18 40 45 50.9% -0.09 [-0.50, 0.33] SPiRiT 2006 29.8 12.3 31 24.7 14.1 29 49.1% 0.38 [-0.13, 0.89] Subtotal (95% CI) 76 74 100.0% 0.12 [-0.33, 0.58] Heterogeneity: Tau! = 0.05; Chi! = 1.95, df = 1 (P = 0.16); I! = 49% Test for overall effect: Z = 0.52 (P = 0.60)

1.3.2 SCS ON vs SCS OFF DeJongste, 1994 2.1 0.6 8 1.25 0.8 9 25.1% 1.13 [0.08, 2.18] Eddicks 2007 56.3 10 12 45.9 11 12 28.3% 0.96 [0.10, 1.81] Hauvast 1998 6.8 1 13 6.2 1.1 12 29.1% 0.55 [-0.25, 1.36] Lanza 2005 0.75 0.1 10 0.35 0.1 10 17.5% 3.83 [2.24, 5.42] Subtotal (95% CI) 43 43 100.0% 1.44 [0.37, 2.51] Heterogeneity: Tau! = 0.89; Chi! = 13.25, df = 3 (P = 0.004); I! = 77% Test for overall effect: Z = 2.64 (P = 0.008)

-10 -5 0 5 10 Favours Control Favours SCS

Meta analysis (Björreson et al. ,2008;140:501-8; WGNCWGNC Taylor & DeJongste. BMC Cardiovasc Disord,2009;9:13) Exercise capacity (7 RCTs; n = 140)

SCS Control Std. Mean Difference Std. Mean Difference Study or Subgroup Mean SD Total Mean SD Total Weight IV, Random, 95% CI IV, Random, 95% CI 1.1.1 SCS vs Active comparator SPiRiT 2006 7.3 3.5 32 7.3 3.8 33 48.5% 0.00 [-0.49, 0.49] ESBY 1998 92.2 33.7 53 99 28 47 51.5% -0.22 [-0.61, 0.18] Subtotal (95% CI) 85 80 100.0% -0.13 [-0.44, 0.18] Heterogeneity: Tau! = 0.00; Chi! = 0.46, df = 1 (P = 0.50); I! = 0% Test for overall effect: Z = 0.84 (P = 0.40)

1.1.2 SCS ON vs SCS OFF Jessurun 1999 14.6 3.2 12 15.3 3.4 12 21.9% -0.20 [-1.01, 0.60] Hauvast 1998 19 14 13 -0.2 17 12 20.7% 1.20 [0.33, 2.06] Eddicks 2007 394 55 12 337 55 12 20.9% 1.00 [0.14, 1.86] Lanza 2005 22 10 10 12 7.5 10 19.1% 1.08 [0.13, 2.04] DeJongste 1994 827 138 8 694 67 9 17.4% 1.19 [0.13, 2.24] Subtotal (95% CI) 55 55 100.0% 0.82 [0.25, 1.38] Heterogeneity: Tau! = 0.20; Chi! = 7.90, df = 4 (P = 0.10); I! = 49% Test for overall effect: Z = 2.84 (P = 0.005)

-4 -2 0 2 4 Favours control Favours SCS

Meta analysis (Björreson et al. Pain,2008;140:501-8; Taylor & DeJongste. BMC Cardiovasc Disord,2009;9:13) WGNCWGNC (Chronic)(Chronic) IschemiaIschemia ofof MyocyteMyocyte

Release of pain (& inflammatory) mediators (adenosine, bradykinin, lactate, prostaglandins)

High Nociceptor Threshold

SCS Low Threshold Spinal cord

WGNCWGNC Sensitization Antiischemic Effects of Electrical Neuromodulation

WGNCWGNC Börjesson M et al. Pain, 2008, 140: 501-8

Antiischemic effect of neuromodulation is

“associated with a reduction in myocardial oxygen consumption” 1 + “secondary to reduced myocardial ischaemia” 2

1. Br Heart1988;59:56-61. “ST depression " at comparable workload” 2. Br Med J, 1993;307:477-80. “Improved lactate metabolism”

WGNCWGNC AntiischemicAntiischemic EffectsEffects ofof SCSSCS inin StableStable AnginaAngina (Summary)(Summary)(Summary) # exercise capacity (quality of life measurements; exercise stress testing)

" ST-segment depression & " lactate production (exercise stress testing; ambulatory ECG; R.A. pacing)

#coronary flow in non-stenotic coronary artery (coronary blood flow studies)

altering coronary perfusion ! opening collaterals ! redistributes O2 supply ! decreases O2 demand (PET and flow studies)

WGNCWGNC Indication:Indication: IschemicIschemic HeartHeart DiseasesDiseases

! Stable angina

! Acute coronary syndromes myocardial infarction unstable angina

WGNCWGNC AntiischemicAntiischemic EffectsEffects ofof ElectricalElectrical NeuromodulationNeuromodulation inin AcuteAcute CoronaryCoronary SyndromeSyndrome

A Historic Perspective by Braunwald E. Reflections on efforts to reduce ischemic myocardial damage Cardiovasc Res 2002:56:332-8

“...the observation in 1968 that ST-segment # were reduced in a patient with an AMI during carotid sinus nerve stimulation, supported the suggestion that myocardial was not necessarily irreversible.” (idea was based on Z Busse W, Stubinger HG. Z Gesamte Exp Med 1951)

WGNCWGNC Börjesson M et al. TENS in unstable angina pectoris Coron Artery Dis, 1997:8:543-550

! Hypothesis - Tens may have favorable effects on silent ischemia (predictor of outcome)

! Methods - Continuous vector ECG - 30 patients randomized TENS (14) or Control (16)

! Results * TENS well tolerated, not interfered with standard treatment * TENS group - decrease in # silent ischemia periods (p = 0.02) ; - decrease in duration silent ischemia periods (p =0.01); - ns effect on painful periods (small #) - cardiac enzyme (ns), however, 4 AMI in placebo (1†) vs 1 in TENS

WGNCWGNC DeVries J et al. Neuromodulation, 2007;10:345-8 Chronic Unstable Refractory Angina (Braunwald class IIIb)

• 6.6 ± 4.2 year follow-up • TENS remains effective in 78% • 16 out of 27 still alive WGNCWGNC DeVries J et al. J of Electrocardiology, 2007;40:522-6 38 STEMISTEMI pts cross-overcross-over randomized postpost PCIPCI

15 min 15 min Group 1 Active TENS Sham TENS ST _ 0.65 _ 0.55 =15% 0.55 _ 0.50 = 9% (p =0.02) (p =0.01)

15 min 15 min Group 2 Sham TENS Active TENS

ST _ 0.37 _ 0.33 =11% 0.33 _ 0.28 =15% (ns) (p =0.01)

WGNCWGNC Ardell J et al. Pre-emptive, Spinal Cord Stimulation mitigates Myocardial Infarction via Cardiac Adrenergic Neurons. AJP: Heart & Circulation, 2007;292:H311

------Spinal Cord Stimulation------

Reactive Pre-emptive $-Blocker $+% Blocker

IWGN WGNCWGNC In search of

a common final pathway

to explain the mechanisms of action

of electrical neuromodulation in patients

with cardiac diseases WGNCWGNC Nervous & Humoral Loops Somato-sensory cortex (psychosocial)

Thalamus (coordinating integrating)

Autonomic Spinothalamic tract Nervous System Dorsal horn neurons & Dorsal Root ganglion SCSSCS Cardiac sensory fibers (extrinsic cardiac ganglia)

Intrinsic Cardiac Neurons (intrinsic cardiac ganglia) WGNCWGNC International Working Group on Neurocardiology

CANADA SWEDEN J. Andrew Armour, MD, PhD Bengt Linderoth, MD, PhD Cardiovascular Neurosurgeon Physiologist

NETHERLANDS GERMANY Mike J.L. DeJongste, MD, PhD Heinz Theres, MD Cardiologist Cardiologist

UNITED STATES Robert D. Foreman, PhD Neurophysiologist Jeffrey L. Ardell, PhD Pharmacologist Philip B. Adamson, MD IWGNWGNCWGNC IWGN Cardiologist Intrinsic Cardiac Nervous System aggregates of cardiac neurons and neural interconnections that modulate cardiac function

Right Atrial Ganglionated Plexus IWGNWGNCWGNC SuppressionSuppression ofof IntrinsicIntrinsic CardiacCardiac NerveNerve ActivityActivity ((CardiovascCardiovasc ResRes 2000;47:3672000;47:367 && AutonAuton NeurosciNeurosci 20022002 10;95:7110;95:71

CAO SCS 60 A 50 1000 * 600 40 Imp/min * * 0 IMP/ 30 MIN SCS B 20

1000 10 600 Imp/min * * * 0 0 0 2 5 10 15 20 25 30 35 40 45 MINUTES

Conclusion: SCS obtunds ICN activity,

IWGNIWGNWGNCWGNC even during myocardial ischemia electrico-nervousnervous && humoralhumoral remodelingremodeling

suppression of nociceptive " electroanalgesic transmission effect

stabilizing activity of Intrinsic" antiarrhythmic Cardiac Nervous System effect? SCS Improved at T1-T2 (C1-2?, T4?) Cardiac

release of neuropeptides " _1 adrenergic function (e.g. ) pathways

redistribution blood flow " antiischemic / decrease in demand effect

Wu M et al. Autonomic Neurosci: Basic & Clin, 2008;138:9-23 (adapted)(a WGNCWGNC Electrical Neuromodulation for Angina Conclusions after an estimate of 5,000 implants

& E.N. isis effective patient controlled adjunct therapy with pleiotropic effects and mechanisms

& E.N. is safe - reversible therapy with low complication rate (- anginal pain is not concealed during AMI) (- morbidity/ mortality not adversely affected)

& E.N. enhances ischemic tolerance of the heart (mainly?) through modulation of Intrinsic Cardiac Neurons

& Effects on heart failure and arrhythmias is subject for further studies WGNCWGNC WGNCWGNC