Hasenfuß, G. et al. (2016) A transcatheter intracardiac shunt device for heart failure with preserved ejection fraction (REDUCE LAP-HF): a multicentre, open-label, single-arm, phase 1 trial. Lancet, 387(10025), pp. 1298-1304. There may be differences between this version and the published version. You are advised to consult the publisher’s version if you wish to cite from it.

http://eprints.gla.ac.uk/123112/

Deposited on: 22 August 2016

Enlighten – Research publications by members of the University of Glasgow http://eprints.gla.ac.uk

A Transcatheter Intracardiac Shunt Device for 1

Heart Failure with Preserved Ejection Fraction 2

3 4 5 Gerd Hasenfuβ, MD, Chris Hayward MD, Dan Burkhoff, MD, Frank E. Silvestry, MD, Scott McKenzie, 6

MD, Filip Malek, MD, Jan Van der Heyden, MD, Professor Irene Lang, MD, Professor Mark C Petrie, 7

MD, Professor John GF Cleland, MD, Professor Martin Leon, MD and Professor David M Kaye MD*, 8

on behalf of the REDUCE LAP-HF study investigators. *Corresponding author. 9

10 Affiliations/Title (Full Professors): 11 Professor Gerd Hasenfuβ, MD, Georg-August Universität, Gottingen, Germany; 12 Professor Chris Hayward MD, St Vincent Hospital, Sydney, Australia; 13 Dan Burkhoff, MD, MD, PhD, Columbia University, New York, NY, USA; 14 Frank Silvestry, MD, Hospital of the University of Pennsylvania, Philadelphia PA, USA; 15 Scott McKenzie, MD, The Prince Charles Hospital, Brisbane, Australia 16 Filip Malek, MD, Na Homolce Hospital, Prague, Czech Republic 17 Jan Van der Heyden, MD, St Antonius Ziekenhuis, Nieuwegein, The Netherlands 18 Professor Irene Lang, MD, Allgemeines Krankenhaus Universitätskliniken, Vienna, Austria 19 Mark C Petrie, MD, Golden Jubilee National Hospital, Glasgow, Scotland, Great Britain; 20 Professor John GF Cleland, MD, National Heart & Lung Institute, Royal Brompton and Harefield 21

Hospitals, Imperial College, London, Great Britain; 22 Professor Martin Leon, MD, Columbia University Medical Center, New York, NY, USA; 23 Professor David Kaye, MD, Alfred Hospital and Baker IDI Heart & Diabetes Institute Melbourne. 24 25 26

27

28

Address for Correspondence 29

Professor David M Kaye 30

Dept. of Cardiology 31

Alfred Hospital 32

Commercial Rd 33

Melbourne 3004 34

Victoria 35

Australia 36

Tel + 61 3 9076 3263 37

Email david.kaye@bakeridi.edu.au 38

2

Abstract (250 words) 39 40 41 Background: Heart failure with preserved ejection fraction (HFPEF) is common but no treatment has 42

yet been shown to improve symptoms or prognosis. The pathophysiology of HFPEF is complex but 43

characterized by increased left atrial pressure, especially during exertion, which may be a key 44

therapeutic target. 45

46

Methods: The REDUCE LAP-HF (REDUCe Elevated Left Atrial Pressure in Patients with Heart 47

Failure) study was an open-label single arm study designed to evaluate the performance and safety of 48

a trans-catheter inter-atrial shunt device (IASD, Corvia Medical) in patients with symptoms of HFPEF 49

despite pharmacological therapy, LVEF>40%, and an elevated pulmonary capillary wedge pressure 50

(PCWP) at rest (>15mmHg) or during exercise (>25mmHg). The primary objectives were to assess 51

device safety and performance at six months, together with measures of clinical efficacy, including 52

functional capacity and clinical status. 53

54

Findings: IASD placement was successful in 64 patients (mean age 69±8years; 66% women; median 55

[IQR] NT-proBNP 377 [222-925] pg/ml) and appeared safe and well tolerated. Sustained device 56

patency was confirmed by left-to-right shunting (pulmonary/systemic flow: 1.06±0.32 baseline; 57

1.27±0.20 at 6 months; p=0.0004). Exercise PCWP was lower at 6 months at 20 watts (32±8 vs 29±9; 58

p=0.0124) and peak (34±8 vs32±8; p=0.0255) despite increased exercise duration (7.3±3.1 vs 59

8.2±3.4 minutes, p=0.03). Minnesota quality of life scores (49±20 vs 36±23, p<0.0001) and 6 minute 60

walk distance (313±105 vs 345±106 metres (p=0.0023) had improved by six months. 61

62

Interpretation: Implantation of an interatrial shunt device is feasible, appears safe, reduces left atrial 63

pressure during exercise and may be a novel strategy for the management of HFPEF. The 64

effectiveness of IASD compared to current therapy for patients with HFPEF requires validation in a 65

randomized controlled trial. 66

67

Funding: Corvia Medical Inc. (Formerly DC Devices Inc.) 68

69

70

3

Introduction 71

72

Many patients with symptoms of heart failure do not have evidence of reduced left ventricular systolic 73

function; a syndrome which has been termed heart failure with preserved ejection fraction (HFPEF) 1,2

74

to distinguish it from those with heart failure and a reduced ejection fraction (HFREF). Epidemiological 75

studies suggest that the incidence of HFPEF is rising 3,4

, although it is unclear whether this is primarily 76

due to improved recognition, the presence of an aging population or increases in the prevalence of 77

co-morbid diseases such as hypertension, chronic kidney disease and diabetes; each likely making a 78

contribution. 79

80

Whilst pharmacological treatment has improved symptoms and reduced morbidity and mortality for 81

patients with HFREF, finding an effective treatment for patients with HFPEF has proved elusive 5-10

. 82

The hallmark of HFPEF is effort intolerance which is associated with a profound and rapid increase in 83

left atrial pressure during exercise reflecting impaired left ventricular diastolic reserve11,12

, with 84

consequent pulmonary congestion. This disproportionate rise in left atrial pressure is thought to 85

provoke symptoms and contribute to increased morbidity and mortality in HFPEF 13

. 86

87

In 1916, Lutembacher described the combination of mitral stenosis, which mimics some of the 88

pathophysiology of HFPEF, and an atrial septal defect (ASD). Patients with Lutembacher’s syndrome 89

may have fewer symptoms and better outcomes compared with patients with pure mitral stenosis and 90

closure of their ASD may cause a rise in pulmonary artery pressure and pulmonary oedema in some 91

patients. An iatrogenic left to right atrial shunt is thus a potentially attractive intervention which might 92

have therapeutic value. Haemodynamic modelling based upon clinical measurements suggests that 93

an appropriately-sized iatrogenic ASD could attenuate exercise induced increases in left atrial 94

pressure in patients with HFPEF 14

. We postulated that a novel device-based therapy targeting a 95

common pathophysiologic feature of HFPEF might succeed where pharmacological therapies have 96

failed. The REDUCE LAP-HF study (REDUCe Elevated Left Atrial Pressure in Patients with Heart 97

Failure) was designed to evaluate the device performance and safety of a trans-catheter, transvenous 98

inter-atrial shunt device (IASD, Corvia Medical Inc.) in symptomatic patients with HFPEF. 99

100 101

4

Methods 102 103

Study Design 104

The study was a multi-centre prospective, non-randomized, open label, single-arm study designed to 105

investigate the safety and performance of a trans-catheter interatrial shunt device (IASD system II, 106

Figure 1). The study design has been described in detail elsewhere 15

(clin.trials.gov #: 107

NCT01913613). 108

109

Patient population 110

Patients with known HFPEF were eligible for study inclusion if they had evidence of chronic 111

symptomatic HF (NYHA class II-IV), a left ventricular ejection fraction >40% and an elevated 112

pulmonary capillary wedge pressure (PCWP) at rest (>15mmHg) or during exercise (>25mmHg) 113

measured by right heart catheterization. Patients with significant right ventricular dysfunction including 114

a central venous pressure (CVP) >14 mmHg and tricuspid annular plane systolic excursion (TAPSE) 115

<14 mm were excluded. 116

117

Cardiac catheterization and device implantation 118

All patients underwent right heart catheterization with assessment of cardiac output and central 119

haemodynamics (right atrial pressure, pulmonary artery pressure and PCWP) at rest and during 120

supine bicycle exercise before (during a separate screening evaluation) and 6 months after device 121

implantation. Following baseline haemodynamic measurements, symptom-limited supine bicycle 122

exercise commenced at 20 Watts (W) with 20W increments every 3 minutes until the patient achieved 123

maximum effort. Blood samples were collected from the pulmonary artery and vena cavae at baseline 124

and follow-up study to measure oxygen saturation and to evaluate left to right shunting as reflected by 125

the Qp:Qs ratio. Device insertion was conducted within 45 days of screening. Implantation was 126

performed percutaneously via the femoral vein on a separate occasion16

. Standard trans-septal 127

puncture of the interatrial septum was performed using the operator’s preferred technique including 128

fluoroscopy and transoesophageal or intra-cardiac echocardiography and the device was positioned 129

using an “over the wire technique”. Patients not taking oral anticoagulants were treated with aspirin 130

(75 – 325 mg daily) indefinitely, and clopidogrel (75 mg daily) for 6 months. Patients treated with oral 131

5

anticoagulants continued on oral anticoagulants after the procedure. Endocarditis prophylaxis was 132

advised for a minimum of 6 months post implant. 133

134

Device performance, safety and efficacy end points at follow-up 135

The primary objectives of the study were to assess device performance and safety. The study sample 136

size was calculated as that required to demonstrate a device and procedure safety profile to other 137

comparable procedures15

. The primary device performance end-points were defined as the 138

proportion of patients with successful device implantation, the percentage of patients with a reduction 139

in PCWP at 6 months either at rest or during exercise compared to baseline, and the presence of 140

persistent left to right trans-device blood flow at 6 months. The primary safety end-points were peri-141

procedural and 6 month major adverse cardiac and cerebrovascular events (MACCE) defined as 142

death, stroke, myocardial infarction or a systemic embolic event (excluding pulmonary 143

thromboembolism), or need for cardiac surgical device removal within 6 months. Echocardiograms 144

performed at the implanting site per protocol were analysed at an independent core laboratory. 145

Secondary outcome measures included the incidence of major adverse events, heart failure 146

hospitalization over the entire study together with changes in echocardiographic parameters, 147

functional capacity (6 minute walk), natriuretic peptides and quality of life assessments (Minnesota 148

Living with Heart Failure Questionnaire, MLWHFQ). All patients gave written informed consent and 149

the protocol was approved by each institutional ethics committee, and competent authorities. 150

151

Statistical methods 152

Normally distributed data are presented as mean ± standard deviation and non-parametric data as 153

median and interquartile range. As appropriate a paired t test or Wilcoxon matched pairs sign-rank 154

test were used to compare follow-up to baseline data. The null hypothesis was rejected at p<0.05. 155

156

Role of the funding source 157

The study was funded by Corvia Medical Incorporated. Data collection and analysis was performed by 158

Medpass International Limited, Windsor House, Worcestershire, United Kingdom. Interpretation of the 159

results and preparation of the manuscript was the responsibility of the steering committee and 160

principal investigators. Corvia played no role in the collection, analysis, interpretation of data or the 161

6

decision to submit the manuscript. All study authors reviewed the manuscript and endorsed its 162

submission. 163

164

7

Results 165 166

Study population characteristics 167

Of 102 patients enrolled from 21 centres, 68 met the inclusion and exclusion criteria. The commonest 168

reasons for exclusion were failure to meet the haemodynamic inclusion criteria (PCWP too low in 22, 169

and CVP too high in 3 patients). One patient was excluded for each of the following reasons: LVEF< 170

40%; cardiac index < 2.0 L/min/m2; renal impairment; cerebrovascular disease; tricuspid regurgitation; 171

mitral regurgitation; coronary disease; elevated pulmonary vascular resistance; and pneumonia. Two 172

patients withdrew after qualification. Implantation of the IASD system was abandoned in two patients 173

and was successful in 64. The baseline demographics of those implanted are shown in Table 1. 174

Consistent with the HFPEF phenotype, the PCWP increased during exercise from 18±5 to 35±8 175

mmHg (p<0.0001), the mean pulmonary pressure rose from 25±7 to 44±9 mmHg (p<0.0001) and the 176

mean right atrial pressure increased from 9±4 to 18±5 mmHg (p<0.0001). The cardiac output rose 177

from 5.6±1.7 to 8.4±2.7 L/min (p<0.0001). The mean exercise time during haemodynamic testing was 178

7.3±3.1 minutes at a workload of 43±18 Watts. 179

180

Primary safety end point 181

No patient experienced a peri-procedural or major adverse cardiac or cerebrovascular event 182

(MACCE), including death, stroke, myocardial infarction, pulmonary or systemic embolism or need for 183

cardiac surgical intervention for device related complications, during six months follow-up. One patient 184

declined a final clinical follow-up due to non-cardiovascular illness. 185

186

Primary device performance end points 187

The implant procedure was not completed due to a trans-septal puncture complication without further 188

sequelae in one patient, and perceived unsuitable atrial septal anatomy in another. In three patients 189

the initial device was removed due to unsuitable position (n=2) or a suspected small mobile thrombus 190

in the right atrium (n=1) with a second device deployed in all three without incident. Sixty patients 191

underwent right heart catheterisation for haemodynamic evaluation at 6 months, and exercise 192

haemodynamic responses were evaluated in 59 patients. At follow-up, 42 patients (71%) met the 193

primary device performance definition of a reduction in PCWP either at rest or during exertion as 194

compared to their baseline values (n = 37). Of these patients, 52% (31/60) had a reduction in PCWP 195

8

at rest, 58% 34/59) had a lower PCWP during exertion and 39% (23/59) fulfilled both criteria. All 196

patients with adequate echocardiographic image quality (n=50), had evidence of left to right flow 197

through the device by colour flow Doppler flow at 6 months. Right to left flow by colour flow Doppler 198

was not observed. Haemodynamic and echocardiographic data were evaluated in a blinded manner 199

in core laboratories. 200

201

202

Secondary efficacy and safety end points 203

By six months, median [IQR] NYHA class had improved from 3 [2-3] to 2 [2-3] (p<0.001), MLWHF 204

score from 49±20 to 36±23 (p<0.0001), 6 minute walk distance from 313±105 to 345±106 metres, 205

p=0.0023) and supine exercise duration at the time of right heart catheterisation from 7.3±3.1 to 206

8.2±3.4 minutes (p=0.0275; Figure 2). 207

208

At the 6 month follow up evaluation, there was a modest but significant increase in cardiac output at 209

rest measured by thermodilution, consistent with increased right sided cardiac output due to the inter-210

atrial shunt (Figure 3). Oximetry was used to estimate left ventricular forward cardiac output at rest, 211

which showed no change from baseline to follow-up (4.6±1.2 vs 4.8±1.3 L/min, p=0.43). The 212

augmentation in thermodilution right-sided cardiac output during exercise was similar at baseline (rest 213

vs exercise: 5.5±1.6 vs 8.7±2.6 L/min, p<0.0001) and 6 months (rest vs exercise: 6.7±1.5 vs 10.2±2.7 214

L/min, p<0.0001). Whilst resting PCWP was similar compared to the baseline study (17±5 vs 215

17±7mmHg, p=0.24), exercise PCWP was reduced, both at 20W (32±8 vs 29±9, p=0.0124) and at 216

peak exercise (34±8 vs.32±8, p=0.0255) (Figure 3). At peak exertion, PCWP normalised for workload 217

was lower at follow-up compared to baseline (69±40 vs 84±45 mmHg/Watt/kg, p=0.0001). There was 218

no change in pulmonary vascular resistance (baseline vs. 6 months: 1.3±0.3 vs. 1.1±0.2 Wood units, 219

p=0.36). Right atrial pressure was higher at follow-up than at baseline (9±4 vs. 11±5 mmHg, 220

p=0.0270). At baseline the gradient between PCWP and RA was 8±4 mmHg, which fell to 6±3 mmHg 221

at 6 months post IASD implantation (p<0.0001). Similarly, at peak exercise the gradient between 222

PCWP and RA was 17±8 mmHg and this fell to 12±6 mmHg at 6 months post IASD implantation 223

(p=0.0002).Consistent with the echocardiographic evaluation of device patency, measurement of 224

oxygen saturations during cardiac catheterization confirmed a rise in pulmonary artery oxygen 225

9

saturation from 69±6 to 75±5% (p<0.0001) with a left-to-right shunt (pulmonary/systemic flow at 226

baseline vs. 6 months: 1.06±0.32 6 months vs. 1.27±0.20; p=0.0004). 227

228

Echocardiography demonstrated small changes in chamber volumes at follow-up compared to 229

baseline. The LV diastolic volume index decreased from 68±13 to 62±17 ml/m2 (p=0.004) whilst the 230

right ventricular end diastolic volume index increased from 22±9 to 27±11 ml/m2 (p<0.001). The RA 231

volume index increased from baseline to follow-up: 35±17 vs 40±22 ml/m2 (p=0.014) whilst the LA 232

volume index (34±17 vs 35±22 ml/m2 was unchanged. Tricuspid annular plane systolic excursion 233

(TAPSE) was also unchanged (20±4 vs. 20±4 mm). 234

235

Compared with baseline, there was a small reduction in body weight (90.1±18.3 to 88.4±18.6 kg/m2, 236

p=0.008). Neither NT-proBNP (median, IQR; 377 (222-925) vs. 382 (170-1075) pg/mL) nor eGFR 237

(62±21 vs 61±20 ml/min/m2) changed during the study. In the 6 months prior to trial participation, 20% 238

(13/64) of patients required hospitalization for heart failure compared to 14% (9/63) in the 6 months 239

subsequent to enrolment. The median dose of frusemide at baseline was 35mg/day (IQR 12.5 – 240

92.5). At 6 months the median dose was 35 mg/day (IQR 12.5 – 180), however the difference 241

between groups was significant (by paired sign rank test, p=0.0176). The median difference in 242

frusemide dose between 6 months and baseline was 0mg (IQR: 0 – 15mg/d), and only 7 patients had 243

an increase in their diuretic dose. Because the difference was small, it is unlikely that a change in 244

dose accounted for the observed effects. 245

246

10

Discussion 247

In this open-label study of a novel trans-catheter interatrial shunt device, developed for the 248

management of patients with HFPEF, we observed reductions in left atrial pressure during exercise 249

with improvements in functional capacity and quality of life 6 months after implantation. The procedure 250

was well tolerated, and echocardiographic and oximetric studies demonstrated the presence of 251

continuing device patency and left to right shunting at 6 months. 252

253

HFPEF is characterized by complex cardiovascular pathophysiology. Originally, attention focussed on 254

the role of diastolic dysfunction 11,12

as a cause of a rapid rise in left ventricular diastolic and left atrial 255

pressure during exertion. The underlying myocardial biology of HFPEF is controversial. It has been 256

ascribed to myocardial fibrosis 17

, myocyte hypertrophy and altered post-translation modification of 257

myocardial proteins such as titin 18,19

. Additionally, many other factors contribute to the clinical profile 258

of HFPEF patients, including hypertension 4,6

myocardial and systemic microvascular dysfunction 20,21

259

and left ventricular long-axis systolic dysfunction 22

, as well as extra-cardiac co-morbidities such as 260

renal insufficiency 23

, anaemia, obesity and sleep apnoea 24

. 261

262

To date, pharmacological management of HFPEF has not reduced morbidity and mortality. Even the 263

impact of pharmacological therapy on symptoms or exercise capacity is uncertain. Therapeutic failure 264

may reflect both diagnostic uncertainty and the complexity of the disorder. Identifying a homogenous 265

patient population has also been challenging in HFPEF 25

. In the current study, we used invasive 266

hemodynamic assessment both at rest and during exertion to identify, reliably, patients with objective 267

evidence of impaired diastolic reserve. The use of exercise PCWP as a study end-point has only been 268

reported once previously to assess the effectiveness of an intervention in HFPEF patients 26

, although 269

this is clearly relevant given the dynamic nature of the physiologic abnormality in HFPEF 11,12

. 270

271

The current study was an open-label non-randomised study, thus we are unable to exclude a placebo 272

effect. However, reduction in exercise pulmonary capillary wedge pressure is consistent with atrial 273

decompression and the reduction in left ventricular end diastolic volume consistent with LV 274

decompression. Peak exercise PCWP was reduced following shunt implantation despite an increase 275

in exercise capacity and accordingly, PCWP normalized to workload, a measurement that has 276

11

predicted mortality in patients with HFPEF 13

, was reduced. Left atrial decompression should lead to a 277

reduction in left atrial volumes but this may have been attenuated by the increased venous return to 278

the left atrium due to the shunt flow. Alternatively, the observation period may have been too short or 279

a larger sample size may be required to detect changes, particularly in the setting of chronic atrial 280

remodelling and atrial fibrillation. There were small increases in right atrial pressure and volume and 281

right ventricular volume which may represent the effect of shunting per se or an increase in circulating 282

volume. The latter possibility is unlikely as body weight fell during the study period. There was a 283

modest increase in right sided cardiac output consistent with volume loading, whilst left sided output, 284

as measured from oximetric observations was unchanged. The long-term sequelae of modest 285

increases in right ventricular output are not known and therefore we excluded patients with significant 286

right ventricular dysfunction. 287

288

Current guidelines for the diagnosis of HFPEF include evidence of elevated natriuretic peptides and 289

echocardiographic measures of elevated filling pressures, as reflected by the E/e’ ratio 27

. In this 290

study, device implantation was not accompanied by reduction in either of these non-invasive 291

measurements. This finding may be explained by the fact that these measures were conducted at rest 292

or by the relatively modest overall reduction in filling pressures. 293

294

Taken together the current open-label non-randomized study demonstrates that trans-catheter trans-295

venous placement of an interatrial shunt device is feasible and may be associated with improvements 296

in exercise haemodynamics, functional capacity and quality of life. These findings require validation in 297

a randomized controlled blinded study. 298

299

300

Author Contribution: GH, DB, FES, JGFC, MP, ML and DK contributed to the analysis of data and 301

preparation of the manuscript. CH, SM, JVH, FM , DK and IL contributed to data collection. 302

303

304

305

306

12

307

308

13

REFERENCES 309 310 1. Vasan RS, Larson MG, Benjamin EJ, Evans JC, Reiss CK, Levy D. Congestive heart failure 311 in subjects with normal versus reduced left ventricular ejection fraction: Prevalence and mortality in a 312 population-based cohort. Journal of the American College of Cardiology 1999; 33(7): 1948-55. 313 314 2. Yancy CW, Lopatin M, Stevenson LW, De Marco T, Fonarow GC. Clinical presentation, 315 management, and in-hospital outcomes of patients admitted with acute decompensated heart failure 316 with preserved systolic function: A report from the Acute Decompensated Heart Failure National 317 Registry (ADHERE) database. Journal of the American College of Cardiology 2006; 47(1): 76-84. 318 319 3. Steinberg BA, Zhao X, Heidenreich PA, et al. Trends in patients hospitalized with heart failure 320 and preserved left ventricular ejection fraction: Prevalence, therapies, and outcomes. Circulation 321 2012; 126(1): 65-75. 322 323 4. Owan TE, Hodge DO, Herges RM, Jacobsen SJ, Roger VL, Redfield MM. Trends in 324 prevalence and outcome of heart failure with preserved ejection fraction. New England Journal of 325 Medicine 2006; 355(3): 251-9. 326 327 5. Massie BM, Carson PE, McMurray JJ, et al. Irbesartan in patients with heart failure and 328 preserved ejection fraction. N Engl J Med 2008; 359(23): 2456-67. 329 330 6. Cleland JGF, Tendera M, Adamus J, Freemantle N, Polonski L, Taylor J. The perindopril in 331 elderly people with chronic heart failure (PEP-CHF) study. European Heart Journal 2006; 27(19): 332 2338-45. 333 334 7. Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartan in patients with chronic heart 335 failure and preserved left-ventricular ejection fraction: the CHARM-Preserved Trial. Lancet 2003; 336 362(9386): 777-81. 337 338 8. Pitt B, Pfeffer MA, Assmann SF, et al. Spironolactone for heart failure with preserved ejection 339 fraction. New England Journal of Medicine 2014; 370(15): 1383-92. 340 341 9. Redfield MM, Chen HH, Borlaug BA, et al. Effect of phosphodiesterase-5 inhibition on 342 exercise capacity and clinical status in heart failure with preserved ejection fraction: A randomized 343 clinical trial. JAMA - Journal of the American Medical Association 2013; 309(12): 1268-77. 344 345 10. Redfield MM, Anstrom KJ, Levine JA, et al. Isosorbide Mononitrate in Heart Failure with 346 Preserved Ejection Fraction. N Engl J Med 2015; 373(24): 2314-24. 347 348 11. Maeder MT, Thompson BR, Brunner-La Rocca HP, Kaye DM. Hemodynamic basis of 349 exercise limitation in patients with heart failure and normal ejection fraction. Journal of the American 350 College of Cardiology 2010; 56(11): 855-63. 351 352 12. Borlaug BA, Nishimura RA, Sorajja P, Lam CSP, Redfield MM. Exercise hemodynamics 353 enhance diagnosis of early heart failure with preserved ejection fraction. Circulation: Heart Failure 354 2010; 3(5): 588-95. 355 356 13. Dorfs S, Zeh W, Hochholzer W, et al. Pulmonary capillary wedge pressure during exercise 357 and long-term mortality in patients with suspected heart failure with preserved ejection fraction. Eur 358 Heart J 2014; 35(44): 3103-12. 359 360 14. Kaye D, Shah SJ, Borlaug BA, et al. Effects of an interatrial shunt on rest and exercise 361 hemodynamics: results of a computer simulation in heart failure. J Card Fail 2014; 20(3): 212-21. 362 363 15. Hasenfuss G, Gustafsson F, Kaye D, et al. Rationale and Design of the Reduce Elevated Left 364 Atrial Pressure in Patients With Heart Failure (Reduce LAP-HF) Trial. J Card Fail 2015; 21(7): 594-365 600. 366 367 16. Sondergaard L, Reddy V, Kaye D, et al. Transcatheter treatment of heart failure with 368

14

preserved or mildly reduced ejection fraction using a novel interatrial implant to lower left atrial 369 pressure. Eur J Heart Fail 2014; 16(7): 796-801. 370 371 17. van Heerebeek L, Borbely A, Niessen HW, et al. Myocardial structure and function differ in 372 systolic and diastolic heart failure. Circulation 2006; 113(16): 1966-73. 373 374 18. Hamdani N, Franssen C, Lourenço A, et al. Myocardial titin hypophosphorylation importantly 375 contributes to heart failure with preserved ejection fraction in a rat metabolic risk model. Circulation: 376 Heart Failure 2013; 6(6): 1239-49. 377 378 19. Kruger M, Kotter S, Grutzner A, et al. Protein kinase G modulates human myocardial passive 379 stiffness by phosphorylation of the titin springs. Circ Res 2009; 104(1): 87-94. 380 381 20. Borlaug BA, Melenovsky V, Russell SD, et al. Impaired chronotropic and vasodilator reserves 382 limit exercise capacity in patients with heart failure and a preserved ejection fraction. Circulation 2006; 383 114(20): 2138-47. 384 385 21. Poole DC, Hirai DM, Copp SW, Musch TI. Muscle oxygen transport and utilization in heart 386 failure: Implications for exercise (IN)tolerance. American Journal of Physiology - Heart and Circulatory 387 Physiology 2012; 302(5): H1050-H63. 388 389 22. Tan YT, Wenzelburger F, Lee E, et al. The pathophysiology of heart failure with normal 390 ejection fraction: exercise echocardiography reveals complex abnormalities of both systolic and 391 diastolic ventricular function involving torsion, untwist, and longitudinal motion. J Am Coll Cardiol 392 2009; 54(1): 36-46. 393 394 23. Gori M, Senni M, Gupta DK, et al. Association between renal function and cardiovascular 395 structure and function in heart failure with preserved ejection fraction. Eur Heart J 2014; 35(48):3442-396 51. 397 398 24. Ather S, Chan W, Bozkurt B, et al. Impact of noncardiac comorbidities on morbidity and 399 mortality in a predominantly male population with heart failure and preserved versus reduced ejection 400 fraction. Journal of the American College of Cardiology 2012; 59(11): 998-1005. 401 402 25. Butler J, Fonarow GC, Zile MR, et al. Developing therapies for heart failure with preserved 403 ejection fraction: current state and future directions. JACC Heart Failure 2014; 2(2): 97-112. 404 405 26. Borlaug BA, Koepp KE, Melenovsky V. Sodium nitrite improves exercise hemodynamics and 406 ventricular performance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2015; 407 66(15): 1672-82. 408 409 27. Paulus WJ, Tschope C, Sanderson JE, et al. How to diagnose diastolic heart failure: a 410 consensus statement on the diagnosis of heart failure with normal left ventricular ejection fraction by 411 the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur 412 Heart J 2007; 28(20): 2539-50. 413 414 415

15

FIGURE LEGENDS 416 417 Figure 1. Schematic diagram of interatrial septal device (IASD) allowing communication between left 418

and right atria (left panel) and echocardiographic image demonstrating Doppler colour flow from left to 419

right atrium (right panel). 420

421

Figure 2. Bar graphs showing New York Heart Association Class, Minnesota Living with Heart Failure 422

score, six minute walk test distance and exercise time during right heart catheterisation at baseline 423

and follow-up. 424

425

Figure 3. Bar graphs showing cardiac output and pulmonary capillary wedge pressure (PCWP) at rest 426

and exercise at baseline and follow-up. PCWP normalized to workload is also presented. 427

428

429

430

16

Table 1. Patient characteristics at baseline 431

432

433

434

435

436

437

438

439

440

441

442

443

444

445

446

447

448

449

450

451

452

453

454

455

456

457

458

459

460

461

Data are mean±standard deviation, except *NT-BNP (median, IQR). 462

463

464

465

466

Variable

Age (years) 69±8

Gender (n, M/F) 22/42

NYHA Class (n, II/III/IV) 18/46/0

BMI, kg/m2 33±6

eGFR (ml/min/1.73m2) 62±21

Haemoglobin (g/L) 133±5

Co-Morbidities n(%)

Diabetes 21 (33) Hypertension 52 (81) Atrial fibrillation 23 (36) CAD 23 (36)

Echocardiography

LV end diastolic volume index (ml/m2) 68±13

LVEF (%) 47±7 LV mass index (g/m2) 119±36

LA diastolic volume index (ml/m2) 34±17 RV diastolic volume index (ml/m2) 22±9

RA volume index (ml/m2) 35±17

E/A ratio 1.3±0.8

E/e’ ratio 13.9±5.9

TAPSE (mm) 20±4

NT-Pro BNP (pg/mL)* 377 (222-925)

Resting Haemodynamics

9±4

Mean PA Pressure (mmHg) 25±7

17±5

5.5±1.6

Mean RA Pressure (mmHg) 9±4

Mean PA Pressure (mmHg) 25±7

Mean PCWP (mmHg) 17±5

Cardiac output (L/min) 5.5±1.6

17

Figure 1 467 468

469

Left  atrium

Right  atrium LA

RA

18

Figure 2 470 471

472 473

Baseline Follow-up0

20

40

60

80

No

. o

f p

ati

en

ts

IVIIIIII

NYHA Class

p<0.001

Baseline Follow-up

100

200

300

400

500

metr

es

6 MWT

p=0.003

Baseline Follow-up

20

40

60

80

sco

re

MLWHF

p<0.001

Baseline Follow-up

2468

1012

min

ute

s

Exercise time

p=0.03

19

Figure 3 474 475

476 477

Baseline Follow-up

5

10

15

L/m

inCardiac Output

rest

p<0.001

10

20

30

40

50

mm

Hg

Baseline Follow-up

PCWPrest

Baseline Follow-up

5

10

15

L/m

in

Cardiac Outputpeak exercise

p<0.001

10

20

30

40

50

mm

Hg

Baseline Follow-up

p=0.012

PCWP 20 W exercise

50

100

150

200

mm

Hg

/W/k

g

Baseline Follow-up

p<0.001

Work normalized PCWPpeak exercise

10

20

30

40

50

mm

Hg

Baseline Follow-up

p=0.025

PCWPpeak exercise

20

Author’s Statement: 478 479 All authors have read and approved the submission of the final draft of the manuscript. 480 481 All authors contributed to the acquisition and/or analysis of the study data. 482 483 Members of the study steering committee (GH, MCP, JGFC, ML and DMK) prepared the manuscript. 484 485 486 Financial Declarations: 487 488 No authors had any relevant financial disclosures related to this study, including consulting fees or 489 stock ownership. 490 491 The study was funded by Corvia Medical Inc. 492 493 494 495

21

REDUCE LAP-HF study investigators 496 497 Gerd Hasenfuβ, MD, Chris Hayward MD, Dan Burkhoff, MD, Frank E. Silvestry, MD, David Muller, MD

498

Scott McKenzie, MD, Darren Walters, MD Filip Malek, MD, Petr Neuzil, MD, Jan Van der Heyden, 499 MD, Marco C Post, MD, Antony S Walton, MD, Irene Lang, MD, Rob Doughty, MD, Peter Ruygrok, 500 MD, Jean-Noël Trochu, MD, Patrice Guerin, MD, Finn Gustafsson, MD, Lars Søndergaard, MD, Adam 501 Kolodziej, MD, Ralf Westenfeld, MD, Martin Penicka, MD, Jozef Bartunek, MD Mark Rosenberg, MD, 502 Jörg Hausleiter, MD, Philip Raake, MD, Raffi Bekeredjian, MD, Mark C Petrie, MD, Niki Walker, 503

MBChB, Guillaume Jondeau, MD, Gregory Ducrocq, MD, Martin Bergmann, MD, John GF Cleland, 504

MD, Martin Leon, MD and David M Kaye MD*

505

506

Affiliations: 507

Gerd Hasenfuβ, MD, Georg-August Universität, Gottingen, Germany; Chris Hayward MD, St Vincent 508 Hospital, Sydney, Australia; Dan Burkhoff, MD, MD, PhD, Columbia University, New York, NY, USA; 509 Frank Silvestry, MD, Hospital of the University of Pennsylvania, Philadelphia PA, USA; David Muller, 510 MD

St Vincent Hospital, Sydney, Australia; Scott McKenzie, MD, The Prince Charles Hospital, 511

Brisbane, Australia; Darren Walters, MD, The Prince Charles Hospital, Brisbane, Australia; Filip 512 Malek, MD, Na Homolce Hospital, Prague, Czech Republic; Petr Neuzil, MD, Na Homolce Hospital, 513 Prague, Czech Republic; Jan Van der Heyden, MD, St Antonius Ziekenhuis, Nieuwegein, The 514 Netherlands; Marco Post, MD, St Antonius Ziekenhuis, Nieuwegein, The Netherlands; Antony S 515 Walton, MD, Alfred Hospital, Melbourne, Australia; Irene Lang, MD, Allgemeines Krankenhaus 516 Universitätskliniken, Vienna, Austria; Rob Doughty, MD, University of Auckland, Auckland, New 517 Zealand; Peter Ruygrok, MD, Auckland City Hospital, Auckland, New Zealand; Jean-Noël Trochu, 518 MD, CHU de Nantes, Nantes, France; Patrice Guerin, MD, CHU de Nantes, Nantes, France; Finn 519 Gustafsson, MD, Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; Lars 520 Søndergaard, MD, Department of Cardiology, Rigshospitalet, Copenhagen, Denmark; Adam 521 Kolodziej, MD, Fourth Military Hospital, Wroclaw, Poland; Ralf Westenfeld, MD, Universitätklinikum 522 Dusseldorf, Dusseldorf, Germany; Martin Penicka, MD, Onze Lieve Vrouwen Ziekenhuis, Aalst, Aalst, 523 Belgium; Jozef Bartunek, MD, Onze Lieve Vrouwen Ziekenhuis, Aalst, Aalst, Belgium; Mark 524 Rosenberg, MD, Universtitaätklinikum Schlewig Holstein, Kiel, Germany; Jörg Hausleiter, MD, 525 Klinikum der Universität Munchen, Munich, Germany; Philip Raake, MD, University of Heidelberg, 526 Heidelberg, Germany; Raffi Bekeredjian, MD, University of Heidelberg, Heidelberg, Germany; Mark C 527 Petrie, MD, Golden Jubilee National Hospital, Glasgow, Scotland, Great Britain; Niki Walker, MD, 528 Golden Jubilee National Hospital, Glasgow, Scotland, Great Britain; Guillaume Jondeau, MD, Bichat 529 Hospital, Paris, France; Gregory Ducrocq, MD, Bichat Hospital, Paris, France; Martin Bergmann, 530 Cardiologicum Hamburg, Hamburg, Germany; John GF Cleland, MD, National Heart & Lung Institute, 531 Royal Brompton and Harefield Hospitals, Imperial College, London, Great Britain; Martin Leon, MD, 532 Columbia University Medical Center, New York, NY, USA; David Kaye, MD, Alfred Hospital and Baker 533 IDI Heart & Diabetes Institute Melbourne. 534 535