Inhaled Iloprost and Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction
Inhaled Iloprost and Exercise Hemodynamics and Ventricular Performance in Heart Failure With Preserved Ejection Fraction
BACKGROUND There is no effective medical treatment for heart failure with preserved ejection
 fraction (HFpEF). Increases in pulmonary capillary wedge pressure (PCWP) develop in patients
 with HFpEF. Prostacyclin analogo can possible reduced PA pressure along with PWCP pressure,
 as with exercise.

 OBJECTIVES This study try to determine whether inhlalation of iloprost improves exercise
 hemodynamics and cardiac reserve in HFpEF.

 METHODS In a double-blind, randomized, placebo-controlled, parallel-group trial, subjects
 with HFpEF underwent invasive cardiac catheterization with simultaneous expired gas analysis
 at rest and during exercise, before and 15 min after treatment with either inhaled iloprost
 or matching placebo.
Study participants and study design The ILO-HOPE trial is a prospective, randomized,
 double-blind, single center trial conducted at the National Taiwan University Hospital
 (NTUH). This study was performed in accordance with the Declaration of Helsinki and was
 approved by the institutional review board of the National Taiwan University Hospital, and
 all subjects provided their written informed consent prior to participation in the study.
 Patients referred to National Taiwan University Hospital cardiac catheterization laboratory
 for invasive hemodyanamic exercise stress testing were enrolled. HFpEF was defined according
 to 2016 European society of cardiology heart failure guidelines and our previous studies. In
 brief, HFpEF was determined by (1) presence of typical HF symptoms and signs (2) LV ejection
 fraction ≥ 50 (3) elevated levels of NT-proBNP (at least >125 pg/ml) (4) echocardiographic
 structural (a left atrial volume index > 34 mL/m2 or a left ventricular mass index ≥115 g/m2
 for males and ≥95 g/m2 for females) or functional alterations (E/e'≥13 and a mean e' septal
 and lateral wall < 9 cm/s). The exclusion criteria were chronic renal failure (creatinine >
 250 μmol/L), significant hepatic disease, secondary hypertension, pericardial disease,
 valvular heart disease (echocardiographic evidence of at least mild stenosis or at least
 moderate regurgitation), cancer, cor pulmonale, congenital heart disease, left-to-right
 shunt, myocardial infarction within 60 days, high-output heart failure, long-term treatment
 with phosphodiesterase 5 inhibitors, and chronic atrial fibrillation. The patients will be
 asked to hold nitrate for 3 days before the test if they receive any oral nitrate.

 Trial protocol Investigators will perform cardiac catheterization with simultaneous expired
 gas analysis at rest and during supine exercise at a 20-W workload for 6 min, as previously
 described. Hemodynamic values will be recorded for the ﬁrst exercise phase (before any drug
 administration) and after return to steady state baseline hemodynamic values, and the second
 exercise phase (after drug administration). Subjects will be randomized 1:1 to inhalation of
 placebo (normal saline solution) or iloprost (50 mg/kg/min) (Bayer Pharmaceuticals,
 Scottsdale, Ari-zona) for 5 min. The iloprost/placebo inhalation will be identical in
 appearance and prepared by the research pharmacy, ensuring double-blinding of inhalation
 content. After finishing inhalation process for 10 min, hemodynamic measurements will be
 repeated at rest, followed by repeat supine exercise at a 20-W workload for 6 min, identical
 to the study's ﬁrst phase. Arterial and venous blood samples and hemodynamic and expired gas
 data will be acquired during each stage of the protocol. Right heart catheterization will be
 performed through a 7-F sheath via the internal jugular vein. Transducers were zeroed at
 mid-axilla. Right atrial pressure (RAP), pulmonary artery (PA) pressure, and PCWP will be
 measured at end-expiration using swan-Ganz catheter 2-F, high-ﬁdelity micromanometer-tipped
 cathe-ters (Millar Instruments, Houston, Texas) advanced through the lumen of a 7-F,
 ﬂuid-ﬁlled catheter (Arrow, Teleﬂex, Morrisville, North Carolina)(). Mean RAP and PCWP will
 be taken at mid A wave. Arterial blood pressure (BP) will be measured continuously through a
 5-F radial arterial cannula. Oxygen consumption (VO2) will be measured from expired gas
 analysis (MedGraphics, St. Paul, Minnesota) taken as the average from the 60 s preceding
 arterial and mixed venous blood sampling. Ventilatory efﬁciency will be assessed by the
 increase in minute ventilation relative to carbon dioxide production (VE/VCO2). CO and stroke
 volume (SV) will be determined by the direct Fick method and heart rate as previous
 described. Investigators also will calculate pulmonary vascular resistance, PA compliance
 (SV/PA pulse pressure), and systemic vascular resistance (SVR) using standard formulas. LV
 systolic performance will be assessed by LV stroke work using standard formula as well.

 Assessments of outcomes The primary endpoint of the trial is the PCWP during exercise.
 Secondary endpoints are changes of other hemodynamic data including alterations in resting
 PCWP, rest and exercise changes in RAP, PA pressure, PVR, PA compliance, systemic BP, heart
 rate, SV, stroke work.

 Statistical analysis Statistical analyses will be done on an intention to treat basis.
 Results are reported as mean ± SD, median (interquartile range) or n (%).Within-group
 differences are assessed by the paired Student t test. Between-group differences in rest or
 exercise hemodynamic responses were compared by an unpaired Student t test., Wilcoxon rank
 sum test, or Fisher exact test. Linear regression will be performed to compare hemodynamic
 responses to exercise before and after study drug inhalation, with variables log-transformed
 as necessary for analysis. All tests were 2-sided, with p < 0.05 considered signiﬁcant. We
 used G-power (version 3.1.9.2, Heinrich-Heine-Universität Düsseldorf, Germany;
 http://www.gpower.hhu.de/) to calculate the sample size. A sample size of 34 total patients
 would be needed to provide 80% power (assuming a SD of 2.76 mmHg) to detect a 2 mmHg
 difference in the primary efficacy parameter, change in exercising PCWP, with a 5% type I
 error rate for a 2-sided test.
Inclusion Criteria:

 1. presence of typical HF symptoms and signs

 2. LV ejection fraction ≥ 50

 3. elevated levels of NT-proBNP (at least >125 pg/ml)

 4. echocardiographic structural (a left atrial volume index > 34 mL/m2 or a left
 ventricular mass index ≥115 g/m2 for males and ≥95 g/m2 for females) or functional
 alterations (E/e'≥13 and a mean e' septal and lateral wall < 9 cm/s).

 Exclusion Criteria:

 1. chronic renal failure (creatinine > 250 μmol/L)

 2. significant hepatic disease, significant coronary artery disease (CAD) (coronary
 artery stenosis >70% without intervention or positive stress test),

 3. secondary hypertension,

 4. pericardial disease

 5. significant valvular heart disease (>mild stenosis, >moderate regurgitation),

 6. active cancer,

 7. cor pulmonale

 8. congenital heart disease

 9. high-output heart failure

 10. subjects receiving long-term treatment with phosphodiesterase 5 in-hibitors

 11. chronic atrial fibrillation.