From Bench to BedsideFrom Bench to Bedside

Step 1:Step 1: First-time application of DESWT in a rodent model of ischemic HF First-time application of DESWT in a rodent model of ischemic HF (pilot trial); redesign of device(pilot trial); redesign of device

Step 2:Step 2: In-vitro validationIn-vitro validation

Step 3: Step 3: Reproduction of results of pilot trial in a Reproduction of results of pilot trial in a rodent large scale trialrodent large scale trial (320 rodents); human fitting studies(320 rodents); human fitting studies

Step 4: Step 4: Reproduction of the results of the Reproduction of the results of the rodent large scale trialrodent large scale trial in a large in a large animal (pig) model; human fitting studiesanimal (pig) model; human fitting studies

Step 5: Step 5: Phase I clinical trial with external data monitoringPhase I clinical trial with external data monitoring

Pilot TrialsPilot Trials

Trials show promising Trials show promising results, exceeding com-results, exceeding com-parable stem cell trials.parable stem cell trials.

Main problem: size of the Main problem: size of the applicatorapplicator

8 Weeks Later: Cardiac Shock Wave Applicator8 Weeks Later: Cardiac Shock Wave Applicator

CardioGoldCardioGold®® CG050 CG050

CRT CRT –– Cardiac Regeneration Technologies, Woodstock, USA Cardiac Regeneration Technologies, Woodstock, USA (manufactured by MTS-Europe GmbH, Konstanz, Germany)(manufactured by MTS-Europe GmbH, Konstanz, Germany)

Electro-hydraulic, focused, ECG-triggering facilityElectro-hydraulic, focused, ECG-triggering facility

EFD: EFD: 0.38 mJ/mm0.38 mJ/mm22

Frequency: Frequency: 1-5 Hz1-5 Hz

35mm35mm

IIn-vitro Experimentsn-vitro Experiments

heaterheater

adapteradapter temp. sensortemp. sensordistance bardistance bar

appl. fixationappl. fixation

Shock Wave Devices

Water bath – prototypeWater bath – prototype

Degassed water, temperature 37°C Degassed water, temperature 37°C

DermaGoldDermaGold®® CP155 (TRT, USA) CP155 (TRT, USA)

300300 impulses at 0.15 mJ/mm impulses at 0.15 mJ/mm22, 5 Hz, 5 Hz

IIn-vitro Experimentsn-vitro ExperimentsMean cell duplication timeMean cell duplication time Connexine 43 = cell contact, communicationConnexine 43 = cell contact, communication

Cardiomyocytes (= heart muscle cells)Cardiomyocytes (= heart muscle cells)

Endothelial cells (= vessel cells)Endothelial cells (= vessel cells)

Fibroblasts (= cells of connective tissue)Fibroblasts (= cells of connective tissue)

Rodent Large Scale Trial Rodent Large Scale Trial –– Results from 320 rats! Results from 320 rats!

0

10

20

30

40

50

60

70

80

prae MI post MI 6-week FUP 14 week FUP

FS

%

___ SWT___ Controls

* p<.05 to pre MI †p<.05 to post MI ‡ p<.05 SWT Group vs. Controls

**

*

* * *

††‡‡

Next Step: Large Animal Trial

25 Domestic pigs:

Myocardial infarction by LAD ligation

3 Groups: Sham = healthy subjects

SWT = LAD ligation with SWT

Control = LAD ligation without SWT

Timeline:

d0 week 4 week 8

▼_______________ ▼ _______________▼

LAD lig./sham OP SWT/sham OP Termination

LV e

ject

ion

frac

tion

%

* p<.05 vs. pre MI + p<.05 vs. 4 weeks post MI

0

25

50

75

100

d0 week 4 week 8

controlSWTSWT

* *

Ventricular FunctionVentricular FunctionLVEFLVEF

*

+68 ± 0.7%

43 ± 2.5%

62 ± 9.1%

46 ± 5%

First Human Application First Human Application –– Study Design Study DesignTitle: Title: DDESWT - Safety of Myocardial Regeneration by ESWT - Safety of Myocardial Regeneration by DDirect irect EEpicardial picardial SShock hock WWave ave TTherapy in Combination with Coronary herapy in Combination with Coronary Artery Bypass GraftingArtery Bypass Grafting

Design: Design: Prospective, Phase IProspective, Phase I

Enrollment: Enrollment: Commenced September 2008, 10 Patients Commenced September 2008, 10 Patients –– last patient last patient enrolled June 2009enrolled June 2009

Primary Primary Endpoint: Endpoint: SafetySafety

Secondary Endpoint: Secondary Endpoint: EfficacyEfficacy

Study outline:Study outline:

CABG+DESWTCABG+DESWT 8-week FUP 6-month FUP 8-week FUP 6-month FUP ▼_______________▼______________▼ ▼_______________▼______________▼

First Human Application (Sep. 23, 2008) First Human Application (Sep. 23, 2008)

First Human Application (Sep. 23, 2008) First Human Application (Sep. 23, 2008)

First Human Application (Sep. 23, 2008) First Human Application (Sep. 23, 2008)

First Human First Human Application Application

(Sep. 23, 2008) (Sep. 23, 2008)

DeathDeath Myocardial infarctionMyocardial infarction Bleeding, including pericardial tamponadeBleeding, including pericardial tamponade Ventricular arrhythmiasVentricular arrhythmias Bacteriaemia / sepsisBacteriaemia / sepsis Respiratory failureRespiratory failure CPRCPR Lesions related to DESWT (cardiac, intrathoracic)Lesions related to DESWT (cardiac, intrathoracic) Renal failureRenal failure Liver failureLiver failure Low cardiac output syndromeLow cardiac output syndrome CVA (Stroke/Bleeding/TIA)CVA (Stroke/Bleeding/TIA) Re-hospitalizationRe-hospitalization Other non-anticipated events fulfilling the definition for AEs/SAEsOther non-anticipated events fulfilling the definition for AEs/SAEs

Primary Endpoint - SafetyPrimary Endpoint - Safety

Myocardial contractility Myocardial contractility Cardiac MRICardiac MRI Symptoms of heart failureSymptoms of heart failure Minnesota Heart Failure QuestionnaireMinnesota Heart Failure Questionnaire Six-minute walk testSix-minute walk test Serum levels of proBNPSerum levels of proBNP Device failures and malfunctionsDevice failures and malfunctions

Secondary Endpoint - EfficacySecondary Endpoint - Efficacy

Primary Endpoint AE/SAE´sPrimary Endpoint AE/SAE´s

PerioperativePerioperative

1 Pat. 1 Pat. vventricular arrhytmia 1st. entricular arrhytmia 1st. to 3rd p.o. dayto 3rd p.o. day

1 Pat. prolonged ICU stay, mediastinitis1 Pat. prolonged ICU stay, mediastinitis

1 Pat. post-op bleeding (no surgical revision) 1 Pat. post-op bleeding (no surgical revision)

Follow-UpFollow-Up

3 Pat. rehospitalization (embolism, pneumonia, pacemaker implant)3 Pat. rehospitalization (embolism, pneumonia, pacemaker implant)

None of the complications device related!None of the complications device related!

* P < 0.05 to baseline* P < 0.05 to baseline

Left Ventricular Ejection FractionLeft Ventricular Ejection Fraction

**

Gavira JJ JTCVS 2006Gavira JJ JTCVS 2006

**

LV

EF

%L

VE

F %

lless late enhancement in all patientsess late enhancement in all patientsImprovement of wall motion in all patientsImprovement of wall motion in all patients

Left Ventricular Wall MotionLeft Ventricular Wall Motion

GlobalGlobal Treated areas = infarctTreated areas = infarct

* P < 0.05 to baseline* P < 0.05 to baseline

**** ****

Left Ventricular VolumesLeft Ventricular Volumes

* P < 0.05 to baseline* P < 0.05 to baseline

****

End Diastolic VolumeEnd Diastolic Volume End Systolic VolumeEnd Systolic Volume

****

6-Minute Walk Test6-Minute Walk Test

* P < 0.05 to baseline* P < 0.05 to baseline

**

Minnesota Heart Failure QuestionnaireMinnesota Heart Failure Questionnaire

* P < 0.05 to baseline* P < 0.05 to baseline

**

ConclusionConclusion DESWT is SAFEDESWT is SAFE

Neo Neo –– Angiogenesis Angiogenesis VEGF, PIGF, Flt-1VEGF, PIGF, Flt-1 Endogenous angiogenetic pathway activation ?Endogenous angiogenetic pathway activation ? Stem cell homing ?Stem cell homing ?

Improvement of LV functionImprovement of LV function Global and regional LV functionGlobal and regional LV function proBNP surrogate for heart failureproBNP surrogate for heart failure

Improvement of SymptomsImprovement of Symptoms 6-MWT gold standard of symtom assessment in heart failure6-MWT gold standard of symtom assessment in heart failure Patients Patients feel the difference feel the difference –– Minesota Heart Failure Questionnaire Minesota Heart Failure Questionnaire

ConclusionConclusion

Safe and simple method for myocardial regenerationSafe and simple method for myocardial regeneration

Bench to bedside completedBench to bedside completed

Next logical step – prospective randomized trialNext logical step – prospective randomized trial

Continuation of basic research (working mechanism)Continuation of basic research (working mechanism)

Continuation of human trials (histology, stem cells)Continuation of human trials (histology, stem cells)

Continuation of animal trials (dose-reaction, working mechanism)Continuation of animal trials (dose-reaction, working mechanism)

Customized device, disposable therapy headCustomized device, disposable therapy head

Cell cultivation, cell seeding on scaffolds ……… Cell cultivation, cell seeding on scaffolds ………