Effects of 5-Week Oral Acetazolamide on Incremental Cycling Exercise in Pulmonary Arterial and Chronic Thromboembolic Pulmonary Hypertension: A Randomized Placebo-Controlled, Double-Blinded, Crossover Trial.

INTRODUCTION: Acetazolamide (AZA) improves nocturnal and daytime blood oxygenation in patients with pulmonary vascular disease (PVD), defined as pulmonary arterial and distal chronic thromboembolic pulmonary hypertension (CTEPH), and may improve exercise performance. METHODS: We investigated the effect of 5 weeks of AZA (250 mg bid) versus placebo on maximal load during incremental cycling ramp exercise in patients with PVD studied in a randomized controlled, double-blind, crossover design, separated by > 2 weeks of washout. RESULTS: Twenty-five patients (12 pulmonary arterial hypertension, 13 CTEPH, 40% women, age 62 ± 15 years) completed the trial according to the protocol. Maximum load was similar after 5 weeks of AZA versus placebo (113 ± 9 vs. 117 ± 9 watts [W]), mean difference -4 W (95% CI: -9 to 1, p = 0.138). With AZA, maximum (max)-exercise partial pressure of O2 (PaO2) was significantly higher by 1.1 kPa (95% CI: 0.5-1.8, p = 0.003), while arterial pH and partial pressure of CO2 were significantly lower. Gas exchange threshold was reached at a higher load with AZA (108 ± 8 W vs. 97 ± 8 W) and was therefore delayed by 11 W (95% CI: 3-19, p = 0.013), while the ventilatory equivalent for O2 and CO2 were significantly higher at both the max-exercise and gas exchange threshold with AZA versus placebo. CONCLUSION: AZA for 5 weeks did not significantly change maximum exercise capacity in patients with PVD despite a significant increase in PaO2. The beneficial effects of increased blood oxygenation may have been diminished by increased ventilation due to AZA-induced metabolic acidosis and increased dyspnea.

[Vaskuläre Dyspnoe: Pulmonale Hypertonie]. / Vaskuläre Dyspnoe: Pulmonale Hypertonie.

INTRODUCTION: Pulmonary hypertension (PH) is defined by a mean pulmonary artery pressure > 20 mmHg [1] [2]. Echocardiography is used to screen for pulmonary hypertension, but right heart catheterization is required to confirm the diagnosis. Right heart catheterization is used to measure hemodynamic parameters such as pulmonary arterial pressures and pulmonary artery wedge pressure (PAWP), which normally corresponds to the left ventricular end-diastolic pressure. In addition, cardiac output (CO) is measured using the direct Fick method or thermodilution. The pulmonary vascular resistance (PVR) can be derived from these values. Precapillary PH is defined by PAWP ≤15 mmHg and PVR >2 WU (wood units), postcapillary PH is defined by increased PAWP > 15 mmHg with PVR 2 WU due to passive backflow [3]. However, there are also combined pre- and post-capillary PH with a PAWP > 15 mmHg and elevated PVR > 2 WU. Supportive therapies for all forms of PH include diuretics, supplemental oxygen in case of hypoxemia, gentle exercise under specialized supervision, and anticoagulants for some forms. Specific drug or interventional therapies are available only for pulmonary vascular disease subgroups pulmonary arterial hypertension (group 1) and chronic thromboembolic PH (CTEPH, group 4), while for PH due to heart and lung diseases (groups 2 and 3) as well as mixed forms the therapy of the underlying disease is of major importance. Drug therapy for pulmonary vascular diseases includes endothelin receptor antagonists, phosphodiesterase-5 inhibitors and prostanoids. CTEPH requires clarification regarding surgical pulmonary endarterectomy or interventional balloon angioplasty [4]. Since the diagnosis and therapy of PH is very complex, it must be carried out in an experienced center.

Effects of Acute Hypoxia on Heart Rate Variability in Patients with Pulmonary Vascular Disease.

Pulmonary vascular diseases (PVDs), defined as arterial or chronic thromboembolic pulmonary hypertension, are associated with autonomic cardiovascular dysregulation. Resting heart rate variability (HRV) is commonly used to assess autonomic function. Hypoxia is associated with sympathetic overactivation and patients with PVD might be particularly vulnerable to hypoxia-induced autonomic dysregulation. In a randomised crossover trial, 17 stable patients with PVD (resting PaO2 ≥ 7.3 kPa) were exposed to ambient air (FiO2 = 21%) and normobaric hypoxia (FiO2 = 15%) in random order. Indices of resting HRV were derived from two nonoverlapping 5-10-min three-lead electrocardiography segments. We found a significant increase in all time- and frequency-domain HRV measures in response to normobaric hypoxia. There was a significant increase in root mean squared sum difference of RR intervals (RMSSD; 33.49 (27.14) vs. 20.76 (25.19) ms; p < 0.01) and RR50 count divided by the total number of all RR intervals (pRR50; 2.75 (7.81) vs. 2.24 (3.39) ms; p = 0.03) values in normobaric hypoxia compared to ambient air. Both high-frequency (HF; 431.40 (661.56) vs. 183.70 (251.25) ms2; p < 0.01) and low-frequency (LF; 558.60 (746.10) vs. 203.90 (425.63) ms2; p = 0.02) values were significantly higher in normobaric hypoxia compared to normoxia. These results suggest a parasympathetic dominance during acute exposure to normobaric hypoxia in PVD.

Cardiorespiratory Adaptation to Short-Term Exposure to Altitude vs. Normobaric Hypoxia in Patients with Pulmonary Hypertension.

Prediction of adverse health effects at altitude or during air travel is relevant, particularly in pre-existing cardiopulmonary disease such as pulmonary arterial or chronic thromboembolic pulmonary hypertension (PAH/CTEPH, PH). A total of 21 stable PH-patients (64 ± 15 y, 10 female, 12/9 PAH/CTEPH) were examined by pulse oximetry, arterial blood gas analysis and echocardiography during exposure to normobaric hypoxia (NH) (FiO2 15% ≈ 2500 m simulated altitude, data partly published) at low altitude and, on a separate day, at hypobaric hypoxia (HH, 2500 m) within 20−30 min after arrival. We compared changes in blood oxygenation and estimated pulmonary artery pressure in lowlanders with PH during high altitude simulation testing (HAST, NH) with changes in response to HH. During NH, 4/21 desaturated to SpO2 < 85% corresponding to a positive HAST according to BTS-recommendations and 12 qualified for oxygen at altitude according to low SpO2 < 92% at baseline. At HH, 3/21 received oxygen due to safety criteria (SpO2 < 80% for >30 min), of which two were HAST-negative. During HH vs. NH, patients had a (mean ± SE) significantly lower PaCO2 4.4 ± 0.1 vs. 4.9 ± 0.1 kPa, mean difference (95% CI) −0.5 kPa (−0.7 to −0.3), PaO2 6.7 ± 0.2 vs. 8.1 ± 0.2 kPa, −1.3 kPa (−1.9 to −0.8) and higher tricuspid regurgitation pressure gradient 55 ± 4 vs. 45 ± 4 mmHg, 10 mmHg (3 to 17), all p < 0.05. No serious adverse events occurred. In patients with PH, short-term exposure to altitude of 2500 m induced more pronounced hypoxemia, hypocapnia and pulmonary hemodynamic changes compared to NH during HAST despite similar exposure times and PiO2. Therefore, the use of HAST to predict physiological changes at altitude remains questionable. (ClinicalTrials.gov: NCT03592927 and NCT03637153).

Disease characteristics and clinical outcome over two decades from the Swiss pulmonary hypertension registry.

Pulmonary hypertension (PH), especially pulmonary arterial and chronic thromboembolic pulmonary hypertension (PAH/CTEPH), are rare and progressive conditions. Despite recent advances in treatment and prognosis, PH is still associated with impaired quality of life and survival. Long-term PH-registry data provide information on the changing PH-epidemiology and may help to direct resources to patient's needs. This retrospective analysis of the Swiss Pulmonary Hypertension Registry includes patients newly diagnosed with PH (mainly PAH/CTEPH) registered from January 2001 to June 2019 at 13 Swiss hospitals. Patient characteristics (age, body mass index, gender, diagnosis), hemodynamics at baseline, treatment, days of follow-up, and events (death, transplantation, pulmonary endarterectomy, or loss to follow-up) at last visit were analyzed. Patients were stratified into four time periods according to their date of diagnosis. Survival was analyzed overall and separately for PAH/CTEPH and time periods. 1427 PH patients were included (thereof 560 PAH, 383 CTEPH). Over the years, age at baseline (mean ± SD) significantly increased from 59 ± 14 years in 2001-2005 to 66 ± 14 years in 2016-2019 (p < 0.001) while the gender distribution tended toward equality. Mean pulmonary artery pressure and pulmonary vascular resistance significantly decreased over time (from 46 ± 15 to 41 ± 11 mmHg, respectively, 9 ± 5 to 7 ± 4 WU, p < 0.001). Three-year survival substantially increased over consecutive periods from 69% to 91% (for PAH 63%-95%, for CTEPH 86%-93%) and was poorer in PAH than CTEPH independently of time period (p < 0.001). Most patients were treated with mono- or combination therapy and an increasing number of CTEPH underwent pulmonary endarterectomy (40% 2016-2019 vs. 15% 2001-2005). This long-term PH registry reveals that over two decades of observation, newly diagnosed patients are older, less predominantly female, have less impaired hemodynamics and a better survival.

The Impact of Breathing Hypoxic Gas and Oxygen on Pulmonary Hemodynamics in Patients With Pulmonary Hypertension.

BACKGROUND: Pure oxygen breathing (hyperoxia) may improve hemodynamics in patients with pulmonary hypertension (PH) and allows to calculate right-to-left shunt fraction (Qs/Qt), whereas breathing normobaric hypoxia may accelerate hypoxic pulmonary vasoconstriction (HPV). This study investigates how hyperoxia and hypoxia affect mean pulmonary artery pressure (mPAP) and pulmonary vascular resistance (PVR) in patients with PH and whether Qs/Qt influences the changes of mPAP and PVR. STUDY DESIGN AND METHODS: Adults with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) underwent repetitive hemodynamic and blood gas measurements during right heart catheterization (RHC) under normoxia [fractions of inspiratory oxygen (FiO2) 0.21], hypoxia (FiO2 0.15), and hyperoxia (FiO2 1.0) for at least 10 min. RESULTS: We included 149 patients (79/70 PAH/CTEPH, 59% women, mean ± SD 60 ± 17 years). Multivariable regressions (mean change, CI) showed that hypoxia did not affect mPAP and cardiac index, but increased PVR [0.4 (0.1-0.7) WU, p = 0.021] due to decreased pulmonary artery wedge pressure [-0.54 (-0.92 to -0.162), p = 0.005]. Hyperoxia significantly decreased mPAP [-4.4 (-5.5 to -3.3) mmHg, p < 0.001] and PVR [-0.4 (-0.7 to -0.1) WU, p = 0.006] compared with normoxia. The Qs/Qt (14 ± 6%) was >10 in 75% of subjects but changes of mPAP and PVR under hyperoxia and hypoxia were independent of Qs/Qt. CONCLUSION: Acute exposure to hypoxia did not relevantly alter pulmonary hemodynamics indicating a blunted HPV-response in PH. In contrast, hyperoxia remarkably reduced mPAP and PVR, indicating a preserved vasodilator response to oxygen and possibly supporting the oxygen therapy in patients with PH. A high proportion of patients with PH showed increased Qs/Qt, which, however, was not associated with changes in pulmonary hemodynamics in response to changes in FiO2.

Influence of Upright Versus Supine Position on Resting and Exercise Hemodynamics in Patients Assessed for Pulmonary Hypertension.

Background The aim of the present work was to study the influence of body position on resting and exercise pulmonary hemodynamics in patients assessed for pulmonary hypertension (PH). Methods and Results Data from 483 patients with suspected PH undergoing right heart catheterization for clinical indications (62% women, age 61±15 years, 246 precapillary PH, 48 postcapillary PH, 106 exercise PH, 83 no PH) were analyzed; 213 patients (main cohort, years 2016-2018) were examined at rest in upright (45°) and supine position, such as under upright exercise. Upright exercise hemodynamics were compared with 270 patients (historical cohort) undergoing supine exercise with the same protocol. Upright versus supine resting data revealed a lower mean pulmonary artery pressure 31±14 versus 32±13 mm Hg, pulmonary artery wedge pressure 11±4 versus 12±5 mm Hg, and cardiac index 2.9±0.7 versus 3.1±0.8 L/min per m2, and higher pulmonary vascular resistance 4.1±3.1 versus 3.9±2.8 Wood P<0.001. Exercise data upright versus supine revealed higher work rates (53±26 versus 33±22 watt), and adjusting for differences in work rate and baseline values, higher end-exercise mean pulmonary artery pressure (52±19 versus 45±16 mm Hg, P=0.001), similar pulmonary artery wedge pressure and cardiac index, higher pulmonary vascular resistance (5.4±3.7 versus 4.5±3.4 Wood units, P=0.002), and higher mean pulmonary artery pressure/cardiac output (7.9±4.7 versus 7.1±4.1 Wood units, P=0.001). Conclusions Body position significantly affects resting and exercise pulmonary hemodynamics with a higher pulmonary vascular resistance of about 10% in upright versus supine position at rest and end-exercise, and should be considered and reported when assessing PH.

Effect of oxygen therapy on exercise performance in patients with cyanotic congenital heart disease: Randomized-controlled trial.

BACKGROUND: Patients with unrepaired cyanotic congenital heart disease (CHD) suffer from aggravated hypoxemia during exercise. We tested the hypothesis that supplemental oxygen improves exercise performance in these patients. METHODS: In this randomized, sham-controlled, single-blind, cross-over trial cyanotic CHD-patients underwent four cycle exercise tests to exhaustion, while breathing either oxygen-enriched (FiO2 0.50, oxygen) or ambient air (FiO2 0.21, air) using incremental (IET) or constant work-rate (CWRET) exercise test protocols (75% of maximal work rate achieved under FiO2 0.21). Pulmonary gas-exchange, electrocardiogram, arterial blood gases, oxygen saturation (SpO2), cerebral and quadriceps muscle tissue oxygenation (CTO and QMTO) by near-infrared spectroscopy were measured. RESULTS: We included seven patients with cyanotic CHD (4 Eisenmenger syndrome, 3 unrepaired cyanotic defects, 4 women) median (quartiles) age 36 (32;50) years, BMI 23 (20;26) kg/m2 and SpO2 at rest 87 (83;89) %. When comparing supplemental oxygen with air during exercise, maximal work-rate in IET increased from 76 (58;114) Watts to 83 (67;136) Watts, median difference 9 (0;22) W (p = 0.046) and CWRET-time increased from 412 s (325;490) to 468 s (415;553), median increase 56 (39;126) s (p = 0.018). In both IET and CWRET SpO2 was significantly higher and ventilatory equivalent for carbon dioxide significantly lower at end-exercise with oxygen compared to air, whereas CTO and QMTO did not significantly differ. CONCLUSIONS: Patients with cyanotic CHD significantly improved their exercise performance, in terms of maximal work-rate and endurance time along with an improved arterial oxygenation and ventilatory efficiency with supplemental oxygen compared to air.

Comparison of Repetitive Cardiac Output Measurements at Rest and End-Exercise by Direct Fick Using Pulse Oximetry vs. Blood Gases in Patients With Pulmonary Hypertension.

Background: Exact and simultaneous measurements of mean pulmonary artery pressure (mPAP) and cardiac output (CO) are crucial to calculate pulmonary vascular resistance (PVR), which is essential to define pulmonary hypertension (PH). Simultaneous measurements of mPAP and CO are not feasible using the direct Fick (DF) method, due to the necessity to sample blood from the catheter-tip. We evaluated a modified DF method, which allows simultaneous measurement of mPAP and CO without needing repetitive blood samples. Methods: Twenty-four patients with pulmonary arterial or chronic thromboembolic PH had repetitive measurements of CO at rest and end-exercise during three phases of a crossover trial. CO was assessed by the original DF method using oxygen uptake, measured by a metabolic unit, and arterial and mixed venous oxygen saturations from co-oximetry of respective blood gases served as reference. These CO measurements were then compared with a modified DF method using pulse oximetry at the catheter- and fingertip. Results: The bias among CO measurements by the two DF methods at rest was -0.26 L/min with limits of agreement of ±1.66 L/min. The percentage error was 28.6%. At the end-exercise, the bias between methods was 0.29 L/min with limits of agreement of ±1.54 L/min and percentage error of 16.1%. Conclusion: Direct Fick using a catheter- and fingertip pulse oximetry (DFp) is a practicable and reliable method for assessing CO in patients with PH. This method has the advantage of allowing simultaneous measurement of PAP and CO, and frequent repetitive measurements are needed during exercise. Clinical Trial Registration: https://clinicaltrials.gov/ct2/show/NCT02755259, identifier: NCT02755259.

Effect of a day-trip to altitude (2500†m) on exercise performance in pulmonary hypertension: randomised crossover trial.

QUESTION ADDRESSED BY THE STUDY: To investigate exercise performance and hypoxia-related health effects in patients with pulmonary hypertension (PH) during a high-altitude sojourn. PATIENTS AND METHODS: In a randomised crossover trial in stable (same therapy for >4 weeks) patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH) with resting arterial oxygen tension (P aO2 ) ≥7.3 kPa, we compared symptom-limited constant work-rate exercise test (CWRET) cycling time during a day-trip to 2500 m versus 470 m. Further outcomes were symptoms, oxygenation and echocardiography. For safety, patients with sustained hypoxaemia at altitude (peripheral oxygen saturation <80% for >30 min or <75% for >15 min) received oxygen therapy. RESULTS: 28 PAH/CTEPH patients (n=15/n=13); 13 females; mean±sd age 63±15 years were included. After >3 h at 2500 m versus 470 m, CWRET-time was reduced to 17±11 versus 24±9 min (mean difference -6, 95% CI -10 to -3), corresponding to -27.6% (-41.1 to -14.1; p<0.001), but similar Borg dyspnoea scale. At altitude, P aO2 was significantly lower (7.3±0.8 versus 10.4±1.5 kPa; mean difference -3.2 kPa, 95% CI -3.6 to -2.8 kPa), whereas heart rate and tricuspid regurgitation pressure gradient (TRPG) were higher (86±18 versus 71±16 beats·min-1, mean difference 15 beats·min-1, 95% CI 7 to 23 beats·min-1) and 56±25 versus 40±15 mmHg (mean difference 17 mmHg, 95% CI 9 to 24 mmHg), respectively, and remained so until end-exercise (all p<0.001). The TRPG/cardiac output slope during exercise was similar at both altitudes. Overall, three (11%) out of 28 patients received oxygen at 2500 m due to hypoxaemia. CONCLUSION: This randomised crossover study showed that the majority of PH patients tolerate a day-trip to 2500 m well. At high versus low altitude, the mean exercise time was reduced, albeit with a high interindividual variability, and pulmonary artery pressure at rest and during exercise increased, but pressure-flow slope and dyspnoea were unchanged.

Effect of Breathing Oxygen-Enriched Air on Exercise Performance in Patients With Pulmonary Hypertension Due to Heart Failure With Preserved Ejection Fraction: A Randomized, Placebo-Controlled, Crossover Trial.

Objective: To evaluate the effects of breathing oxygen-enriched air (oxygen) on exercise performance in patients with pulmonary hypertension due to heart failure with preserved ejection fraction (PH-HFpEF). Methods: Ten patients with PH-HFpEF (five women, age 60 ± 9 y, mPAP 37 ± 14 mmHg, PAWP 18 ± 2 mmHg, PVR 3 ± 3 WU, resting SpO2 98 ± 2%) performed two-cycle incremental exercise tests (IET) and two constant-work-rate exercise test (CWRET) at 75% maximal work-rate (W max), each with ambient air (FiO2 0.21) and oxygen (FiO2 0.5) in a randomized, single-blinded, cross-over design. The main outcomes were the change in W max (IET) and cycling time (CWRET) with oxygen vs. air. Blood gases at rest and end-exercise, dyspnea by Borg CR10 score at end-exercise; continuous SpO2, minute ventilation (V'E), carbon dioxide output (V'CO2), and cerebral and quadricep muscle tissue oxygenation (CTO and QMTO) were measured. Results: With oxygen vs. air, W max (IET) increased from 94 ± 36 to 99 ± 36 W, mean difference (95% CI) 5.4 (0.9-9.8) W, p = 0.025, and cycling time (CWRET) from 532 ± 203 to 680 ± 76 s, +148 (31.8-264) s, p = 0.018. At end-exercise with oxygen, Borg dyspnea score and V'E/V'CO2 were lower, whereas PaO2 and end-tidal PaCO2 were higher. Other parameters were unchanged. Conclusion: Patients with PH-HFpEF not revealing resting hypoxemia significantly improved their exercise performance while breathing oxygen-enriched air along with less subjective dyspnea sensation, a better blood oxygenation, and an enhanced ventilatory efficiency. Future studies should investigate whether prolonged training with supplemental oxygen would increase the training effect and, potentially, daily activity for PH-HFpEF patients. Clinical Trial Registration: [clinicaltrials.gov], identifier [NCT04157660].

Acute Hemodynamic Effect of Acetazolamide in Patients With Pulmonary Hypertension Whilst Breathing Normoxic and Hypoxic Gas: A Randomized Cross-Over Trial.

Aims: To test the acute hemodynamic effect of acetazolamide in patients with pulmonary hypertension (PH) under ambient air and hypoxia. Methods: Patients with pulmonary arterial or chronic thromboembolic PH (PAH/CTEPH) undergoing right heart catheterization were included in this randomized, placebo-controlled, double-blinded, crossover trial. The main outcome, pulmonary vascular resistance (PVR), further hemodynamics, blood- and cerebral oxygenation were measured 1 h after intravenous administration of 500 mg acetazolamide or placebo-saline on ambient air (normoxia) and at the end of breathing hypoxic gas (FIO2 0.15, hypoxia) for 15 min. Results: 24 PH-patients, 71% men, mean ± SD age 59 ± 14 years, BMI 28 ± 5 kg/m2, PVR 4.7 ± 2.1 WU participated. Mean PVR after acetazolamide vs. placebo was 5.5 ± 3.0 vs. 5.3 ± 3.0 WU; mean difference (95% CI) 0.2 (-0.2-0.6, p = 0.341). Heart rate was higher after acetazolamide (79 ± 12 vs. 77 ± 11 bpm, p = 0.026), pH was lower (7.40 ± 0.02 vs. 7.42 ± 0.03, p = 0.002) but PaCO2 and PaO2 remained unchanged while cerebral tissue oxygenation increased (71 ± 6 vs. 69 ± 6%, p = 0.017). In acute hypoxia, acetazolamide decreased PVR by 0.4 WU (0.0-0.9, p = 0.046) while PaO2 and PaCO2 were not changed. No adverse effects occurred. Conclusions: In patients with PAH/CTEPH, i.v. acetazolamide did not change pulmonary hemodynamics compared to placebo after 1 hour in normoxia but it reduced PVR after subsequent acute exposure to hypoxia. Our findings in normoxia do not suggest a direct acute pulmonary vasodilator effect of acetazolamide. The reduction of PVR during hypoxia requires further corroboration. Whether acetazolamide improves PH when given over a prolonged period by stimulating ventilation, increasing oxygenation, and/or altering vascular inflammation and remodeling remains to be investigated.

Favorable Pregnancy Outcomes in Women With Well-Controlled Pulmonary Arterial Hypertension.

Introduction: Since pregnancy in women with pulmonary arterial hypertension (PAH) is associated with a high risk of morbidity and mortality, it is recommended that pregnancy should be avoided in PAH. However, some women with mild PAH may consider this recommendation as unsuitable. Unfortunately knowledge on pregnancy outcomes and best management of PAH during pregnancy is limited. Methods: Data from all women with PAH who were followed during pregnancy by a multidisciplinary team at a tertiary referral center for PAH and who delivered between 2004 and 2020 were retrospectively analyzed in a case series. PAH risk factor profiles including WHO functional class (WHO-FC), NT-pro-BNP, echocardiographic pulmonary arterial pressure (PAP) and right heart function were analyzed prior to, during and following pregnancy. Results: In seven pregnancies of five women with PAH (median age 29 (27; 31) years), there were no abortions or terminations. Five pregnancies were planned (all in WHO-FC I-II), two incidental (WHO-FC II, III). During pregnancy none of the women had complications or clinical worsening of PAH. After a median pregnancy duration of 37 1/7 weeks all gave birth to healthy babies by cesarean section in spinal anesthesia. During pregnancy, PAP tended to increase, whilst the course of WHO-FC and NT-pro-BNP were variable and no trend could be detected. Conclusion: Women with PAH with a low risk profile closely followed by a multidisciplinary team had a favorable course during and after pregnancy, resulting in successful deliveries of healthy newborns.

Effect of Normobaric Hypoxia on Exercise Performance in Pulmonary Hypertension: Randomized Trial.

BACKGROUND: Many patients with pulmonary arterial or chronic thromboembolic pulmonary hypertension (PH) wish to travel to altitude or by airplane, but their risk of hypoxia-related adverse health effects is insufficiently explored. RESEARCH QUESTION: How does hypoxia, compared with normoxia, affect constant work-rate exercise test (CWRET) time in patients with PH, and which physiologic mechanisms are involved? STUDY DESIGN AND METHODS: Stable patients with PH with resting Pao2 ≥ 7.3 kPa underwent symptom-limited cycling CWRET (60% of maximal workload) while breathing normobaric hypoxic air (hypoxia; Fio2, 15%) and ambient air (normoxia; Fio2, 21%) in a randomized cross-over design. Borg dyspnea score, arterial blood gases, tricuspid regurgitation pressure gradient, and mean pulmonary artery pressure/cardiac output ratio (mean PAP/CO) by echocardiography were assessed before and during end-CWRET. RESULTS: Twenty-eight patients (13 women) were included: median (quartiles) age, 66 (54; 74) years; mean pulmonary artery pressure, 41 (29; 49) mm Hg; and pulmonary vascular resistance, 5.4 (4; 8) Wood units. Under normoxia and hypoxia, CWRET times were 16.9 (8.0; 30.0) and 6.7 (5.5; 27.3) min, respectively, with a median difference (95% CI) of -0.7 (-3.1 to 0.0) min corresponding to -7 (-32 to 0.0)% (P = .006). At end-exercise in normoxia and hypoxia, respectively, median values and differences in corresponding variables were as follows: Pao2: 8.0 vs 6.4, -1.7 (-2.7 to -1.1) kPa; arterial oxygen content: 19.2 vs 17.2, -1.7 (-3 to -0.1) mL/dL; Paco2: 4.7 vs 4.3, -0.3 (-0.5 to -0.1) kPa; lactate: 3.7 vs 3.7, 0.9 (0.1 to 1.6) mM (P < .05 all differences). Values for Borg scale score: 7 vs 6, 0.5 (0 to 1); tricuspid pressure gradient: 89 vs 77, -3 (-9 to 16) mm Hg; and mean PAP/CO: 4.5 vs 3.3, 0.3 (-0.8 to 1.4) Wood units remained unchanged. In multivariable regression, baseline pulmonary vascular resistance was the sole predictor of hypoxia-induced change in CWRET time. INTERPRETATION: In patients with PH, short-time exposure to hypoxia was well tolerated but reduced CWRET time compared with normoxia in association with hypoxemia, lactacidemia, and hypocapnia. Because pulmonary hemodynamics and dyspnea at end-exercise remained unaltered, the hypoxia-induced exercise limitation may be due to a reduced oxygen delivery causing peripheral tissue hypoxia, augmented lactic acid loading and hyperventilation. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT03592927; URL: www.clinicaltrials.gov.

Right Atrial Pressure During Exercise Predicts Survival in Patients With Pulmonary Hypertension.

Background We investigated changes in right atrial pressure (RAP) during exercise and their prognostic significance in patients assessed for pulmonary hypertension (PH). Methods and Results Consecutive right heart catheterization data, including RAP recorded during supine, stepwise cycle exercise in 270 patients evaluated for PH, were analyzed retrospectively and compared among groups of patients with PH (mean pulmonary artery pressure [mPAP] ≥25 mm Hg), exercise-induced PH (exPH; resting mPAP <25 mm Hg, exercise mPAP >30 mm Hg, and mPAP/cardiac output >3 Wood Units (WU)), and without PH (noPH). We investigated RAP changes during exercise and survival over a median (quartiles) observation period of 3.7 (2.8-5.6) years. In 152 patients with PH, 58 with exPH, and 60 with noPH, median (quartiles) resting RAP was 8 (6-11), 6 (4-8), and 6 (4-8) mm Hg (P<0.005 for noPH and exPH versus PH). Corresponding peak changes (95% CI) in RAP during exercise were 5 (4-6), 3 (2-4), and -1 (-2 to 0) mm Hg (noPH versus PH P<0.001, noPH versus exPH P=0.027). RAP increase during exercise correlated with mPAP/cardiac output increase (r=0.528, P<0.001). The risk of death or lung transplantation was higher in patients with exercise-induced RAP increase (hazard ratio, 4.24; 95% CI, 1.69-10.64; P=0.002) compared with patients with unaltered or decreasing RAP during exercise. Conclusions In patients evaluated for PH, RAP during exercise should not be assumed as constant. RAP increase during exercise, as observed in exPH and PH, reflects hemodynamic impairment and poor prognosis. Therefore, our data suggest that changes in RAP during exercise right heart catheterization are clinically important indexes of the cardiovascular function.

Haemodynamic phenotypes and survival in patients with systemic sclerosis: the impact of the new definition of pulmonary arterial hypertension.

BACKGROUND: In this study, we investigated the impact of the new haemodynamic definition of pulmonary arterial hypertension (PAH) as proposed by the 6th PH World Symposium on phenotypes and survival in patients with systemic sclerosis (SSc). METHODS: In SSc patients who were prospectively and consecutively screened for PAH including right heart catheterisation in Heidelberg or Zurich, haemodynamic and clinical variables have been reassessed according to the new PAH definition. Patients have been followed for 3.7±3.7 (median 3.4) years; Kaplan-Meier survival analysis was performed. Patients with significant lung or left heart disease were excluded from comparative analyses. RESULTS: The final dataset included 284 SSc patients, 146 patients (49.2%) had mean pulmonary arterial pressure (mPAP) ≤20 mm Hg, 19.3% had mPAP 21-24 mm Hg and 29.4% had mPAP ≥25 mm Hg. In the group of mildly elevated mPAP, only four patients (1.4% of the whole SSc cohort) had pulmonary vascular resistance (PVR) values ≥3 Wood Units (WU) and could be reclassified as manifest SSc-APAH. Twenty-eight (9.8%) patients with mPAP of 21-24 mm Hg and PVR ≥2 WU already presented with early pulmonary vascular disease with decreased 6 min walking distance (6MWD) (p<0.001), TAPSE (p=0.004) and pulmonary arterial compliance (p<0.001). A PVR ≥2 WU was associated with reduced long-term survival (p=0.002). PVR and 6MWD were independent prognostic predictors in multivariate analysis. CONCLUSION: The data of this study show that a PVR threshold ≥3 WU is too high to enable an early diagnosis of PAH. A PVR threshold ≥2 WU was already associated with pulmonary vascular disease, significantly reduced survival and would be more appropriate in SSc patients with mild PAH.

Physical activity in incident patients with pulmonary arterial and chronic thromboembolic hypertension.

INTRODUCTION: The cardinal symptom of pulmonary hypertension (PH) is dyspnea on exertion, leading to decreased activity in daily living. The aim of this study was to analyze daily physical activity in incident patients with arterial or chronic thromboembolic PH (PAH/CTEPH) and to investigate its correlation with pulmonary hemodynamics, symptoms, exercise capacity, and other outcomes. METHODS: Incident patients with PAH/CTEPH had a 1-week activity assessment by the arm-worn accelerometer SenseWear within - 3 months/+ 2 weeks of the diagnostic right heart catheterization (RHC) and baseline assessments including 6-minute walking distance (6MWD). Activity was correlated to RHC data at rest and exercise and to other outcomes. RESULTS: Thirty-nine PH-patients (24 PAH, 15 CTEPH, 23 females, 65(54;73) years, mean pulmonary artery pressure (mPAP) 38(30;46) mmHg, cardiac output (CO) 5.2(4.6;6.3) l/min, 6MWD 458(300;593) m) were included. 64% had a sedentary lifestyle ( < 5000 steps/day), 26% were moderately active (5000-9999 steps/day), and 10% were active. In a multivariate stepwise regression analysis including age, gender, 6MWD and hemodynamics at rest and during exercise (heart rate, mPAP, stroke volume), the 6MWD was the only independent predictor of steps/day (B = 16.8 (95% CI 11.6-22.0), p < 0.001). CONCLUSION: Daily physical activity as steps/day assessed in incident patients with PAH/CTEPH did not well correlate with invasive hemodynamics at rest or during exercise, but very well with the 6MWD. Whether daily activity assessments provide additional information to simple walk distance on risk factor profiles during follow-up in patients with PAH/CTEPH remains to be clarified.

Real-Life Experience with Selexipag as an Add-On Therapy to Oral Combination Therapy in Patients with Pulmonary Arterial or Distal Chronic Thromboembolic Pulmonary Hypertension: A Retrospective Analysis.

BACKGROUND: Patients with pulmonary arterial hypertension (PAH) and distal chronic thromboembolic pulmonary hypertension (CTEPH) who still reveal risk factors of worse prognosis on double combination therapy may benefit from add-on therapy with the novel oral selective prostacyclin receptor agonist selexipag. METHODS: We reviewed all patients with PAH/distal CTEPH in the Zurich cohort who received selexipag as add-on to oral combination therapy and retrieved New York Heart Association (NYHA) functional class, 6-min walk distance (6MWD), NT-pro-BNP, quality of life questionnaires (CAMPHOR and EuroQoL), tricuspid pressure gradient (TPG) by echocardiography and cardiopulmonary exercise test parameters (power output and oxygen uptake). RESULTS: Twenty-three patients with PAH/CTEPH (20/3), 14 females, median (quartiles) age 56 (46; 66) years received an oral triple therapy containing selexipag at a median dose of 2000 (1600; 3100) mcg during 221 (113; 359) days. The following parameters were stabilized from baseline to last FU: 6MWD (440 (420; 490) to 464 (420; 526) m), NYHA class (three to two), NT-pro-BNP (326 (167; 1725) to 568 (135; 1856)  ng/l), TPG, power output, and oxygen uptake. Quality of life reflected by the CAMPHOR and EuroQoL improved. CONCLUSIONS: Early initiation of triple oral combination therapy including selexipag in PAH/CTEPH with intermediate risk factor profile may help to stabilize functional class, exercise performance, and pulmonary hemodynamics in a real-life setting and potentially improves quality of life. Whether these beneficial effects can be truly attributed to the addition of selexipag should be addressed in future randomized controlled trials.