Table 1.

Currently published clinical trials of regulation of NO-cGMP-PKG axis in HFpEF.

study name	year	intervention	setting	study size	identifier ID	primary outcome	ref.
Inorganic nitrates/nitrites
NEAT-HFpEF	2015	isosorbide mononitrate	EF≥50%	110	NCT02053493	no change in QOL or 6-MWD	83
Acute Effects of Inorganic Nitrite on Cardiovascular Hemodynamics in HFpEF	2015	inorganic nitrite infusion	EF≥50%	28	NCT01932606	reduce PCWP during exercise	86
Effect of Inorganic Nitrates on Arterial Hemodynamics and Exercise Capacity	2015	dietary inorganic nitrate	EF≥50%	17	NCT01919177	improve submaximal aerobic endurance	88, 89
Pharmacokinetics, Pharmacodynamics, and Impact of Inorganic Nitrate on Exercise in HFpEF	2017	oral inorganic nitrate	EF>50%	12	NCT02256345	improve exercise duration and QOL	90
INDIE-HFpEF	2018	inhaled inorganic nitrite	EF≥50%	105	NCT02742129	no effect in peak VO2, and the NYHA classification, NT-proBNP, E/E' and QOL	92
Inhaled Sodium Nitrite on HFpEF Fraction	2016	inhaled inorganic nitrite	EF≥50%	26	NCT02262078	reduce ventricular filling pressure and PAP	94
Soluble guanylyl cyclase stimulators and activators
DILATE-1	2014	riociguat	EF>50%	39	NCT01172756	improvement of diastolic function	95
SOCRATES-PRESERVED	2017	vericiguat	EF≥45%	477	NCT01951638	improve QOL	96, 97
VITALITY-HFpEF	2020	vericiguat	EF≥45%	789	NCT03547583	No change in QOL	98
CAPACITY-HFpEF	2020	praliciguat	EF≥40%	196	NCT03254485	No change in peak VO2	99
Phosphodiesterase-5 inhibitors
PDE5i and PH in Diastolic Heart Failure	2011	sildenafil	EF>50%	44	NCT01156636	improved pulmonary hemodynamics	102
Sildenafil in HFpEF and PH	2015	sildenafil	EF≥45%	52	NCT01726049	no change in QOL	104, 105
RELAX	2013	sildenafil	EF≥50%	216	NCT00763867	no change in QOL or 6-MWD	106
Angiotensin receptor neprilysin inhibiton
PARAMOUNT	2012	sacubitril- valsartan	EF≥45%	307	NCT00887588	reduced NT-proBNP level and improved NYHA classification	109
PARAGON-HF	2019	sacubitril- valsartan	EF≥45%	4822	NCT01920711	no change in HF hospitalizations and cardiovascular death	110
Sodium-dependent glucose transporters 2 inhibitor
SOLOIST-WHF	2021	sotagliflozin	--	1222	NCT03521934	reduce cardiovascular death and hospitalization for HF	120
EMPEROR-Preserved	2021	empagliflozin	EF>40 %	5988	NCT03057951	reduce cardiovascular death and hospitalization for HF, improve QOL	11, 121
CHIEF-HF trial	2022	canagliflozin	--	476	NCT04252287	improve QOL	122
PRESERVED-HF	2021	dapagliflozin	EF≥ 45%	324	NCT03030235	improve QOL or 6-MWD	12

QOL: quality of life, 6-MWD: 6-min walking distance, PCWP: pulmonary capillary wedge pressure, VO₂: oxygen consumption, NYHA classification: New York Heart Association classification, PAP: pulmonary artery pressure, NT-proBNP: N-terminal pro B-type natriuretic peptide, PH: pulmonary hypertension, HF: heart failure