TABLE 3.

Contemporary studies of provocative manoeuvres to improve phenotyping patients with pulmonary hypertension in heart failure with preserved ejection fraction (HFpEF)

First author, year [reference]	Subjects n	Modality of provocation	Response to provocation	Future directions
Vasodilator testing
Schwartzenberg, 2012 [90]	257	i.v. sodium nitroprusside 0.25–0.5 μg·kg−1·min−1 until PAWP <15 mmHg and SBP <90 mmHg or symptoms	HFpEF had a greater reduction in stroke volume with vasodilation when compared to HFrEF	Assess afterload reduction to better delineate severity of fixed pulmonary vascular resistance in HFpEF
Ghio, 2021 [91]	140	i.v. sodium nitroprusside 0.25–0.5 μg·kg−1·min−1 until PAWP <15 mmHg, SBP <90 mmHg or symptoms	DBP of <70 mmHg, PVR >5 WU, and PAC <1.2 mL·mmHg−1 were associated with persistent elevation of PVR despite reduction in PAWP	Identify haemodynamic patterns that indicate clinical benefit or risk of pulmonary vasodilator therapy
Krishtopaytis, 2023 [92]	104	Administered iNO (40 ppm) for 5 min carried by 4 L·min−1 oxygen	mPAP >20 mmHg, PAWP >15 mmHg, and PVR >2 WU: iNO increased PAWP and decreased PVR, neither of which correlated with tolerance of pulmonary vasodilator therapy
Volume loading
Agrawal, 2019 [80]	178	In selected patients with mPAP >25 mmHg and PAWP 15 mmHg Infusion of 500 mL or 10–15 mL·kg−1 of 0.9% sodium chloride over 5 min via central venous access	Early diastolic mitral-inflow velocity was higher and ratio of E velocity to average mitral annular tissue Doppler velocity was higher in patients with occult diastolic dysfunction unmasked by saline challenge or resting diastolic dysfunction	Identify noninvasive measures that correlate with degree of pulmonary vascular disease measured by haemodynamics Clarify “abnormal” response following fluid challenge, and if ULN is age-dependent
Exercise provocation
Gorter, 2018 [93]	161	Supine recumbent bicycle: initial measures when supine, feet on pedals and unloaded then serial measurements with an increase workload by 10–20 W every 3 min until exhaustion	Greater increase in PAWP/CO, reduced PAC, higher PVR with exercise	Define what defines an abnormal RV response to exercise Distinguish exercise haemodynamic parameters that indicate a favourable response to different therapies such as PDEi, SGLT2i, GLP-1
Müller, 2023 [85]	121	Semi-supine exercise on cycle ergometer with stepwise incremental protocol (increase by 10–20 W every 3 min)	PAH and CTEPH patients 50 years had significantly higher PAWP/CO slope than patients <50 years without exceeding PAWP 25 mmHg during exercise	Clarify the population in which iCPET testing is useful clinically Characterise the association between underlying lung disease (or spirometry abnormalities) on pulmonary vascular and RV responses to exercise
Caravita, 2023 [89]	86	Passive leg raise (feet on the pedals) and invasive cycle cardiopulmonary exercise testing	Few HFpEF patients have latent PVD
Comparison of volume, exercise and passive leg raise
Ewert, 2020 [94]	49	Exercise: partially upright cycle ergometer cardiopulmonary exercise testing, unloaded cycling at 45 rpm for 5 min and increase in workload by 25 W every 5 min Volume: after normalisation of haemodynamics and vitals, 500 mL of 0.9% sodium chloride administered by i.v. over 5–10 min	Lack of correlation between volume versus exercise provocation for detection of occult HFpEF	Determine the most reliable protocol
Montané, 2022 [95]	85	Passive leg raise, load-targeted supine bicycle exercise at 60 rpm starting at 20 W and increasing by 20 W every 2 min to a maximum of 60 W or symptoms required termination, and rapid crystalloid fluid infusion by i.v. of 500 mL of 0.9% sodium chloride over 5 min	Moderate correlation between exercise versus volume in RAP, mPAP, PAWP and cardiac index Passive leg raise correlated moderately with volume and exercise

i.v.: intravenous; PAWP: pulmonary artery wedge pressure; SBP: systolic blood pressure; HFrEF: heart failure with reduced ejection fraction; DBP: diastolic blood pressure; PVR: pulmonary vascular resistance; WU: Wood Units; PAC: pulmonary arterial compliance; iNO: inhaled nitric oxide; mPAP: mean pulmonary artery pressure; E: mitral inflow velocity; ULN: upper limit of normal; CO: cardiac output; PVD: pulmonary vascular disease; RV: right ventricular; PDEi: phosphodiesterase inhibitor; SGLT: sodium-glucose transport protein; GLP: glucagon-like peptide; CTEPH: chronic thromboembolic pulmonary hypertension; iCPET: invasive cardiopulmonary exercise testing; rpm: revolutions per minute; RAP: right atrial pressure.