Figures
- FIGURE 1
Haemodynamic assessment of pulmonary hypertension (PH) due to heart failure with preserved ejection fraction (HFpEF). RV: right ventricular; RHC: right heart catheterisation; LHD: left heart disease; PAWP: pulmonary arterial wedge pressure; LVEDP: left ventricular end-diastolic pressure; CTEPH: chronic thromboembolic PH. a) Pre-test probability of PH-LHD is based on the features presented in table 1. RHC is recommended in intermediate probability when risk factors of pulmonary arterial hypertension/CTEPH are present and/or if there is evidence of right ventricle abnormality. If the probability is high, patients should be managed according to recommendations for LHD. b) For the assessment of PH, RHC should be performed at expert centres. In patients with intermediate/high probability (table 1) and PAWP between 13 and 15 mmHg, PH-HFpEF is not excluded; provocative testing (tables 2 and 3) should be considered. #: for patients with systemic sclerosis, risk factors for CTEPH and/or unexplained dyspnea; ¶: after [2]; +: if PAWP >15 mmHg, LVEDP validation should be considered.
Tables
- TABLE 1
Pre-test probability of left heart disease (LHD) phenotype
Feature High probability Intermediate probability Low probability Age >70 years 60–70 years <60 years Obesity, systemic hypertension, dyslipidaemia, glucose intolerance/diabetes >2 factors 1–2 factors None Previous cardiac intervention# Yes No No Atrial fibrillation Current Paroxysmal No Structural LHD Present No No ECG LBBB or LVH Mild LVH Normal or signs of RV strain Echocardiography LA dilation; grade >2 mitral flow No LA dilation; grade <2 mitral flow No LA dilation; E/e′ <13 CPET Mildly elevated V′E/V′CO2 slope; EOV Elevated V′E/V′CO2 slope or EOV High V′E/V′CO2 slope; no EOV Cardiac MRI LA strain or LA/RA >1 No left heart abnormalities LBBB: left bundle branch block; LVH: left ventricular hypertrophy; RV: right ventricular; LA: left atrial; E/e′: early mitral inflow velocity/mitral annular early diastolic velocity ratio; CPET: cardiopulmonary exercise testing; V′E: minute ventilation; V′CO2: carbon dioxide production; EOV: exercise oscillatory ventilation; MRI: magnetic resonance imaging; RA: right atrial. #: coronary artery and/or valvular surgical and/or non-surgical procedures, including percutaneous interventions.
- TABLE 2
Pulmonary arterial wedge pressure (PAWP) response to exercise in normal and heart failure with preserved ejection fraction (HFpEF), and response to fluid loading in normal, HFpEF and pulmonary hypertension (PH)
First author [ref.] Subjects n Age (sex) Protocol Average PAWP: rest to peak mmHg Comment Exercise Wright [62] 28 healthy 55 years (12 female) Semi-upright 11±3–22±5 early to 17±6 late Time-variant changes, early increase and late decrease Wolsk [63] 62 healthy 20–80 years (50% female) Supine 8–10 rest; 16 leg raising; 19 at 25% peak V′O2; 23 at 75% peak V′O2 35% elderly had PAWP >25 mmHg Andersen [52] 26 (14 HFpEF, 12 controls) 70 years HFpEF (57% female); 63 years controls (58% female) Supine exercise versus fluid loading Control: 7±3–13±5; HFpEF: 14±3–32±6 Similar increase in healthy subjects; 2-fold increase in all filling pressures during exercise versus fluid loading in HFpEF Fluid loading Fujimoto [53] 60 healthy; 11 HFpEF Young: <50 years; older: ≥50 years 100–200 mL·min−1 Young: 10±2–16±2; older: 9±2–17±2; HFpEF: 14±4–20±4 Normals reach PAWP 18–19 mmHg Andersen [52] 26 (14 HFpEF, 12 controls) 70 years HFpEF (57% female); 63 years controls (58% female) 10 mL·kg−1·min−1 saline (150 mL·min−1) Control: 7±3–13±5; HFpEF: 14±3–21±4 Similar increase of PAWP in healthy subjects Fox [55] 107 SSc with PH suspicion 59 years PAH (94% female); 66 years OPVH (64% female) 500 mL saline (5–10 min) PAH: 8±3–12±2 (LVEPD 9–12); OPVH: 12±3–17±5 (LVEDP 15–21) Retrospective analysis; OPVH defined by increase in PAWP >15 mmHg Robbins [57] 207 PAH 51 years PAH (82% female); 57 years OPVH (74% female) 500 mL saline (5–10 min) PAH: 9±3–11±4; OPVH: 12±2–19±3 Retrospective analysis; 30% had increase in PAWP >15 mmHg, predominantly female, mostly in normal range D’Alto [65] 212 PH evaluation 58 years pre-capillary (68% female); 65 years post-capillary 7 mL·kg−1 rapid infusion PAH: 9±2–12±2; HPH: 11±2–22±3 Overlap between groups; cut-off for PAWP abnormal response at 18 mmHg V′O2: oxygen uptake; SSc: systemic sclerosis; PAH: pulmonary arterial hypertension; LVEDP: left ventricular end-diastolic pressure; OPVH: occult pulmonary venous hypertension (defined as PAWP >15 mmHg after fluid loading); HPH: hidden pulmonary hypertension due to left heart disease.
- TABLE 3
Limitations and advantages of exercise testing and fluid loading in the assessment of pulmonary hypertension
Exercise testing Fluid loading Clinical relevance for symptom assessment + + + + Clinical relevance for differential diagnosis + + + + Main advantages Respects the pathophysiology; comprehensive test, allowing for additional insights in pulmonary vascular disease (dynamic pulmonary vascular resistance); complementary with cardiopulmonary exercise testing Easy to perform, no specific setting; minimal risk of misinterpretation of pressures reading; better established cut-off defining abnormal increase in pulmonary arterial wedge pressure Main limitations Requires a specific complex setting; expertise in conducting the test; pressure reading during exercise; range of normal response uncertain Unknown response in disease state; age dependency of response Standardised protocol +/− + + - TABLE 4
Recently completed randomised controlled trials targeting the phosphodiesterase type 5 inhibitor/nitric oxide and endothelin pathways in pulmonary hypertension due to left heart disease
First author or study [ref.] Study drug Dose Subjects n Duration Population Primary outcome Result Guazzi [74] Sildenafil 50 mg 3 times a day 44 12 months HFpEF PVR, RV performance, CPET Improvement LEPHT [75] Riociguat 0.5, 1 or 2 mg 3 times a day 201 16 weeks HFrEF mPAP versus placebo No change Hoendermis [73] Sildenafil 60 mg 3 times a day 52 12 weeks HFpEF mPAP versus placebo No change SIOVAC [77] Sildenafil 40 mg 3 times a day 231 24 weeks VHD Composite clinical score# Worsening in active group MELODY-1 [76] Macitentan 10 mg once daily 48 12 weeks HF (EF >30%); 75% HFpEF Safety and tolerability +10% fluid retention in active group HF: heart failure; pEF: preserved ejection fraction; PVR: pulmonary vascular resistance; RV: right ventricular; CPET: cardiopulmonary exercise testing; rEF: reduced ejection fraction; mPAP: mean pulmonary arterial pressure; VHD: valvular hear disease. #: combination of death, hospitalisation for HF, change in New York Heart Association Functional Class and patient global self-assessment.
- TABLE 5
Planned and ongoing trials in pulmonary hypertension (PH) due to left heart disease
Study# Study drug Dose Subjects n Duration Population Primary outcome SERENADE (NCT03153111) Macitentan 10 mg once daily 300 52 weeks LVEF ≥40% and ESC-defined HFpEF; HF hospitalisation within 12 months and/or PAWP or LVEDP >15 mmHg within 6 months; elevated NT-proBNP; PVD or RVD % change from baseline in NT-proBNP at week 24 SOPRANO (NCT02554903) Macitentan 10 mg once daily 78 12 weeks LVAD within 45 days; PH by RHC with PAWP ≤18 mmHg and PVR >3 WU PVR ratio of week 12 to baseline DYNAMIC (NCT02744339) Oral riociguat 1.5 mg 3 times a day 114 26 weeks HFpEF; mPAP >25 mmHg and PAWP >15 mmHg Change in CO Oral treprostinil (NCT03037580) Oral treprostinil 310 24 weeks LVEF ≥50%; RHC within 90 days of randomisation; 6MWD >200 m Change in 6MWD from baseline to week 24 PASSION (not registered) Oral tadalafil 40 mg once daily 320 NA HFpEF; PH with PAWP >15 mmHg and mPAP >25 mmHg and PVR >3 WU Time to first event defined as HF-associated hospitalisation (independently adjudicated) or death from any cause #: ClinicalTrials.gov identifier numbers are provided where possible. LVEF: left ventricular ejection fraction; ESC: European Society of Cardiology; HF: heart failure; pEF: preserved ejection fraction; PAWP: pulmonary arterial wedge pressure; LVEDP: left ventricular end-diastolic pressure; NT-proBNP: N-terminal pro-brain natriuretic peptide; PVD: pulmonary vascular disease; RVD: right ventricular dysfunction; LVAD: left ventricular assist device; RHC: right heart catheterisation; PVR: pulmonary vascular resistance; mPAP: mean pulmonary arterial pressure; CO: cardiac output; 6MWD: 6-min walk distance; NA: not available.
