This document summarizes Gerd Hasenfuss's presentation on novel strategies to improve diastolic function and reduce elevated left atrial pressure in patients with heart failure with preserved ejection fraction (HFpEF). It discusses an inter-atrial shunt device that creates a small permanent connection between the atria, baroreceptor activation therapy, the Aldo-DHF trial which found spironolactone improved diastolic function in HFpEF, and a study showing exercise training improved exercise capacity and quality of life in HFpEF. The presentation emphasizes that high left atrial pressure is a key factor in morbidity and mortality for HFpEF and these strategies aim to reduce left atrial pressure.

1. Gerd Hasenfuss
Department of Cardiology and Pneumology
Heart Center
University of Göttingen
Germany
Novel Strategies to Improve
Diastolic Function
German Center for CV Research

2. Presenter Disclosure Information
Gerd Hasenfuss
Servier: Honorarium for presentations, Consultant
CVRx: Honorarium for presentations
Impulse Dynamics: Consultant, Honorarium for presentations
Novartis: Consultant
CircuLite: Consultant
AstraZeneca: Honorarium for presentation
Bayer: Honorarium for presentations
DC Devices: Consultant
Orion: Horonarium for presentations

3. Key pathophysiological features
How to diagnose HFpEF
Paulus et al., Eur Heart J 2007
High LAP Surrogates
Relevance of surrogates in 1430 pts. with risk factors for HFpEF

4. Diastolic Dysfunction (High LAP) a
Predictor of Morbidity/Mortality
Wachter & Edelmann, 2013

5. Inter-Atrial Shunt Device - Concept
• Abnormal LV relaxation in
HFpEF results in elevated Left
Atrial Pressure (LAP) and
pulmonary edema
• Transcatheter implant to
create a small* permanent
interatrial shunt
- Shunt allows blood to move from
the higher pressure LA to the
lower pressure more compliant
right side, reducing LAP without
compromising LV cardiac output
* Qp:Qs ratio (Pulmonary to Systemic flow ratio): 1.2-1.3

6. Shunt
EXERCISE
NoShuntWithShunt
REST
LA
RA
Burkhoff, Computer simulation

7. DCD Investigational System
Implant
19mm OD
8mm ASD
1 16F introducer compatible
Catheter1 Handle

8. Implant Delivery System

9. 30 Days after implant
TEE Color Doppler L R Shunt Flow

10. 45 Days after implant
TEE Color Doppler L R Shunt Flow

11. PILOT STUDY
Baseline Demographics (n=11)
Parameter Mean ± SD (Range)
Age (% >75 years) 70 ± 11.9; 45 (55-87)
Female (%) 55
BMI (kg/m2) 33 ± 7.93 (18.7-44.1)
EF (%) 57% ± 9 (40-65)
Advanced HF (%; NYHA III/IV; % on diuretics) 100 (9/2; 82)
Prior HF Hospitalization (%; HFH/Patient Y) 55 (1.36)
MLWHF score (% >45) 53 ± 17.3 (82)
NT-Pro BNP (pmol/L) (n=9) 193 ± 153 (22-461)
Average # of comorbidities 2.6 (0-4)
CAD/Prior CABG/PCI (%) 36
Hypertension (%) 91
Diabetes (%) 45
CVA/TIA (%) 0

12. Mechanistic Impact: PCWP change
Baseline One Month*
10
12
14
16
18
20
22
24
26
m-PCWP
P-value = 0.0014
mmHg
* Performed at 2, 3 months in 2 patients
PILOT STUDY
Resting Pulmonary Capillary Wedge Pressure
• Average decrease 5.4 mm Hg (19.4 14.0)
• Range +1 to -16 mm Hg

13. HF Hospitalizations
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Hospitalizations/Year
Year Prior
Year Post
NYHA III/IV
0
10
20
30
40
50
60
70
80
90
NYHACLASS
Baseline
1 Year
6MWTD (M)
280
290
300
310
320
330
340
350
360
6MinuteWalkDistance
Baseline
1 Year
MLWHF
0
10
20
30
40
50
60
MLWHF
Baseline
1 Year
p =0.030 p = 0.017 p = NS p = 0.057
Survival 11/11 100%
Freedom from HFH 9/11 82%
Improved QOL 8/9 89%
Survival, no HFH & worsening QOL 8/11 73%
PILOT STUDY
Malek et al., Int J Cardiol 2015

14. REDUCE LAP-HF TRIAL
CE-Mark Study
REDUCE LAP-HF TRIAL:
A study to evaluate the DC Devices, Inc. IASD® System II to
REDUCE Elevated Left Atrial Pressure in Patients with Heart Failure
• Symptomatic HF
• Preserved EF (> 40%)
• Elevated PCWP at rest or during exercise
• Monitored by independent DSMB, and CEC
• Independent Core-Laboratories
- Echo
- Hemodynamic
- Sub-studies: Cardiac MRI, CPET
• Three year clinical follow-up

15. Primary Endpoints
Safety
Peri-procedural, and 6 months Major Adverse Cardiac and
Cerebrovascular Events (MACCE) and Systemic Embolic Events (excluding
pulmonary thromboembolism).
The primary safety endpoint is:
• The percent of subjects who experience major adverse cardiac and
cerebrovascular events (MACCE) defined as death, stroke, MI; or who
experience a systemic embolic event (excluding pulmonary
thromboembolism); or who require implant removal cardiac surgery
within 6 months from day of implant.
Device Performance
The primary device performance endpoints are:
• The percent of subjects who have successful device implantation,
defined as deployment at the intended location during the index
procedure
• The percent of subjects with reduction of PCWP, and demonstration
of left to right flow through the device at 6 months

16. Preliminary Baseline Demographics
(n=47)
Parameter Mean ± SD
Age (Y; % >70 years) 70 ± 8.7; 53
Female (%) 68
Peak VO2 (n=19) 13.2 ± 2.6
EF (%) (n=42) 62% ± 7
NYHA II/III (%) 20/80; 82)
Arrhythmia (%); Permanent AF (%) 72; 34
Prior Year HF hospitalization rate 0.42
MLWHF score (% >45) 47 ± 18 (51)
NT-Pro BNP (pmol/L) 87 ± 91
Musculoskeletal/Rheumatological (%) 49
CAD/Prior CABG/PCI (% ) 55
Hypertension (%) 87
Diabetes (%) 32
COPD/Sleep Apnea/Asthma (%) 30

17. Preliminary Serious Adverse Events
≤ 30 D
• 6 Procedural events
- 1 Device related AE
- 4 Vascular access related AE
2 Vascular repairs; 1 Pseudo aneurysm; 1 Hematoma
- 1 Acute urinary retention
• 4 Additional events <30 days
- 1 Pre-syncope (anti-hypertensive medication)
- 1 Worsening asthma
- 1 Acute kidney injury
- 1 Sub-therapeutic INR

18. Preliminary Clinical Results
• At 30 days, IASD placement in the first 34 patients was
associated with significant improvements in quality of life
- MLWHF score decreased
from 46 ± 17, to 35 ± 23; p<0.05)
- Improved NYHA functional class
from 2.7 ± 0.5, to 2.3 ± 0.6; p<0.05)
- Improved 6MWT distance
from 307 ± 105, to 334 ± 131 meters; p<0.05)
• 6 months follow-up for primary endpoint expected to be
complete December 2015

19. V-Wave Ltd., Hod HaSharon, Israel
DC Devices, Tewksbury, Massachusetts
Inter-Atrial Shunt Devices

20. Baroreceptor stimulation Renal denervation
Neuromodulation

21. • Primary endpoint: Change in E/e´
• Number of subjects: n=60
• Follow-up: 1 year
• Estimates: Change in E/e´ = 2.15, SD 2.81
DIASTOLE Trial
Randomized controlled
2x30 pts.

22. LV volume (ml)
60 80 100 120 140 160 180 200 220 240
0
50
100
150
200
baseline
CBA
180 190 200 210 220 230 240
0
5
10
15
20
25
30
19 mmHg
13 mmHg
BAT and Left Ventricular Pressure
Volume Relation
• 78 y/o male with diastolic dysfunction

23. Case report !
Baroreceptor Activation
Baseline
3 months
6 months
47 y patient with severe arterial hypertension
BAT

24. Aldosterone Receptor Blockade
in Diastolic Heart Failure
Frank Edelmann, M.D., Rolf Wachter, M.D., Albrecht Schmidt, M.D., Elisabeth Kraigher-Krainer,M.D., Catharina
Colantonio, M.D., Wolfram Kamke, M.D., André Duvinage, M.D., Raoul Stahrenberg, M.D., Kathleen Dustewitz,
M.D., Markus Löffler, M.D., Hans-Dirk Düngen, M.D., Carsten Tschöpe, M.D., Christoph Herrmann-Lingen, M.D.,
Martin Halle, M.D., Gerd Hasenfuss, M.D., Götz Gelbrich, Ph.D., and Burkert Pieske, M.D.
For the Aldo-DHF Investigators
The Aldo-DHF Trial
Edelmann et al., JAMA 2013
ESC Munich, Aug 26,2012
Clinical Trial Hotline Session I
Aldo-DHF Trial
422 pts. NYHA II, follow up 12 months

25. ChangeinE/e‘
1
0
-1
Baseline 6 months 12 months
p < 0.001 p < 0.001
Placebo
Spironolactone
Time since randomisation
Spironolactone: 12.73.6 to 12.1±3.7
Placebo: 12.84.4 to 13.6±4.3
(P<0.001 for difference between groups)
Primary Endpoint: E/é
• LV Mass
• NT-proBNP
• No increase in peakVO2
• No improvement in
morbidity/mortality
in TOPCAT trial
Edelmann et al., JAMA 2013

26. Primary Endpoint: Change in maximum exercise capacity (peak VO2) at 3 months
compared to baseline
Secondary Endpoints: Quality of life, echo determined diastolic function, submaximal exercise
tolerance, neurohumoral activation; adherence and safety of exercise
training
3 months
n=64
Baseline
Usual care (Controls)
Combined endurance/resistance training
Flow Chart: Baseline characteristics (n=64):
Exercise Training in
Diastolic Heart Failure
Training
(n=44)
Controls
(n=20)
Age (years) 64±8 65, ±6
LVEF (%) 68±7 67±9
NYHA II/III 35/ 9 20/ 1
Grade
diastolic
dysfunction I/
II
33/ 11 13/ 7
RR sys/dia 140/ 82 141/ 82
A prospective, randomised, controlled study to
determine the effects of exercise training
on exercise capacity and quality of life
n.s.
Edelmann et al., J Am Coll Cardiol 2011

27. Echocardiography
• Improvement in peakVO2 and QoL
Edelmann et al., J Am Coll Cardiol 2011

28. Summary
• High LAP: key aspect for M/M in HFpEF
• Novel strategies to improve HFpEF should address reduction
of LAP
- Inter-Atrial Shunt Device
- Baroreceptor activation
- Spironolactone
- Exercise
Thank you!