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A right heart catheterization with measurements of pulmonary artery wedge pressure (PAWP) may be necessary for the diagnosis of left heart failure as a cause of pulmonary hypertension or unexplained dyspnea. Diagnostic cutoff values are a PAWP of ≥ 15 mm Hg at rest or a PAWP of ≥ 25 mm Hg during exercise. However, accurate measurement of PAWP can be challenging and heart failure may be occult. Left heart catheterization, with measurement of left ventricular end-diastolic pressure, may also be indecisive. Measurements are then best repeated in stress conditions. Exercise is an option, but the equipment is not universally available, and interpretation can be difficult in patients with wide respiratory pressure swings. An alternative is offered by a fluid challenge. Studies have gathered data supporting infusion of 500 mL or 7 mL/kg saline and a PAWP of 18 mm Hg as a diagnostic cutoff. The procedure is simple and does not take much catheterization laboratory time. Combining echocardiography with invasive measurements may increase the diagnostic accuracy of diastolic dysfunction. Cardiac output after a fluid challenge may be of prognostic relevance., (Copyright © 2020. Published by Elsevier Inc.)

Background: Combinations of therapies are currently recommended for patients with severe pulmonary arterial hypertension (PAH), and excellent results have been reported with triple upfront combination of these drugs. We evaluated the effects of this approach on right ventricular (RV) function and outcome in patients with severe PAH., Methods: Twenty-one patients (age, 44 ± 15 years) with newly diagnosed high-risk idiopathic PAH that was nonreversible by the inhalation of nitric oxide were treated upfront with a combination of ambrisentan, tadalafil, and subcutaneous treprostinil between 2014 and 2018. Clinical evaluation, World Health Organization functional class, 6-min walk distance, biomarkers, echocardiography, and right-sided heart catheterization data were recorded at baseline and during follow-up., Results: At a median follow-up of 2 years, all patients were still alive. The Registry to Evaluate Early and Long-term Pulmonary Arterial Hypertension Disease Management score decreased from 10 ± 1 to 5 ± 1, right-sided atrial pressure decreased from 13 ± 3 to 5 ± 2 mm Hg, mean pulmonary artery pressure decreased from 60 ± 9 to 42 ± 5 mm Hg, pulmonary vascular resistance (PVR) decreased from 16.4 ± 4.4 to 5.5 ± 1.3 Wood units, N-terminal pro-brain natriuretic peptide decreased from 3,379 ± 1,921 to 498 ± 223 pg/mL, and World Health Organization functional class decreased from 3.4 ± 0.5 to 2.0 ± 0.4 (all P < .001). Cardiac index increased from 1.8 ± 0.3 to 3.5 ± 0.8 L/min/m 2 and 6-min walk distance increased from 158 ± 130 to 431 ± 66 m (both P < .001). Echocardiography showed decreased right-sided atrial and RV areas, improved left ventricular eccentricity index, and increased fractional area change (all P < .001) in proportion to treatment-induced decrease in PVR., Conclusions: Triple upfront combination therapy with ambrisentan, tadalafil, and subcutaneous treprostinil in severe nonreversible PAH is associated with considerable clinical and hemodynamic improvement and right-sided heart reverse remodeling., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) dysfunction is associated with shortened life expectancy in heart failure with preserved ejection fraction (HFpEF). The contribution of pulmonary vascular dysfunction to RV dysfunction in HFpEF is not well understood., Methods: We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in 67 patients with HFpEF (of whom 28 had an abnormal pulmonary vascular response during exercise referred to as HFpEF+PVR group and 39 had a normal pulmonary vascular response during exercise referred to as HFpEF group) and in 21 matched control subjects., Results: Both groups of patients with HFpEF had a markedly decreased peak oxygen consumption (Vo 2 ), decreased oxygen delivery, and impaired chronotropic response. Single beat analysis of RV pressure waveforms was used to compute the end-systolic elastance (Ees) and pulmonary arterial elastance (Ea). Right ventricular-pulmonary artery (RV-PA) coupling was measured as the ratio of Ees/Ea. Exercise was associated with a preserved Ees response but a decreased Ees/Ea in patients with HFpEF with a normal PVR response, indicating partially preserved RV contractile reserve. In HFpEF+PVR, exercise-induced increase in Ees was markedly reduced, resulting in decreased Ees/Ea and RV-PA uncoupling. Patients with HFpEF+PVR with an exercise-induced decrease in Ees/Ea had lower pulmonary artery compliance, lower peak Vo 2 , and lower stroke volume than patients with HFpEF., Conclusions: We conclude that RV-PA uncoupling is common in HFpEF and is caused by both intrinsic RV contractile impairment and afterload mismatch. Resting and dynamic RV-PA uncoupling in HFpEF is driven by an increase in RV pulsatile rather than resistive afterload. However, with the additive effects of increased RV resistive afterload, RV-PA uncoupling worsens dynamically during exercise., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Exercise stress testing of the pulmonary circulation may uncover decreased pulmonary vascular (PV) distensibility as a cause of impaired aerobic exercise capacity and right ventricular (RV)-pulmonary arterial (PA) uncoupling. As such, it may help in the differential diagnosis of unexplained dyspnea, including pulmonary hypertension (PH) and/or heart failure with preserved ejection fraction (HFpEF). We investigated rest and exercise invasive pulmonary hemodynamics, ventilation, and gas exchange in patients with unexplained dyspnea, including 44 patients with HFpEF (of whom 20 had a normal pulmonary vascular resistance [PVR] during exercise [ie, passive HFpEF] and 24 had a higher than normal exercise PVR), 22 patients with exercise PH, 19 patients with pulmonary arterial hypertension (PAH), and 24 age- and sex-matched normal control subjects., Methods: A PV distensibility coefficient α (%/mm Hg) was determined from multipoint PV pressure-flow plots. RV-PA coupling was quantified from the analysis of RV pressure curves to determine ratios of end-systolic to arterial elastances (Ees/Ea). Aerobic exercise capacity was estimated by peak oxygen consumption., Results: The α coefficient decreased from 1.35 ± 0.58%/mm Hg in control subjects and 1.1 ± 0.48%/mm Hg in patients with passive HFpEF to 0.62 ± 0.32%/mm Hg in exercise PH, 0.54 ± 0.27%/mm Hg in HFpEF with high exercise PVR, and 0.18 ± 0.16%/mm Hg in PAH. On multivariate analysis, PV distensibility was associated with decreased Ees/Ea and maximal volume of oxygen consumed., Conclusions: PV distensibility is an early and sensitive hemodynamic marker of PV disease that is associated with RV-PA uncoupling and decreased aerobic exercise capacity., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Exercise stress testing of the pulmonary circulation for the diagnosis of latent or early-stage pulmonary hypertension (PH) is gaining acceptance. There is emerging consensus to define exercise-induced PH by a mean pulmonary artery pressure > 30 mm Hg at a cardiac output < 10 L/min and a total pulmonary vascular resistance> 3 Wood units at maximum exercise, in the absence of PH at rest. Exercise-induced PH has been reported in association with a bone morphogenetic receptor-2 gene mutation, in systemic sclerosis, in left heart conditions, in chronic lung diseases, and in chronic pulmonary thromboembolism. Exercise-induced PH is a cause of decreased exercise capacity, may precede the development of manifest PH in a proportion of patients, and is associated with a decreased life expectancy. Exercise stress testing of the pulmonary circulation has to be dynamic and rely on measurements of the components of the pulmonary vascular equation during, not after exercise. Noninvasive imaging measurements may be sufficiently accurate in experienced hands, but suffer from lack of precision, so that invasive measurements are required for individual decision-making. Exercise-induced PH is caused either by pulmonary vasoconstriction, pulmonary vascular remodeling, or by increased upstream transmission of pulmonary venous pressure. This differential diagnosis is clinical. Left heart disease as a cause of exercise-induced PH can be further ascertained by a pulmonary artery wedge pressure above or below 20 mm Hg at a cardiac output < 10 L/min or a pulmonary artery wedge pressure-flow relationship above or below 2 mm Hg/L/min during exercise., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Fluid challenge may help in the differential diagnosis between pre- and postcapillary pulmonary hypertension (PH). However, the test is still in need of standardization and better defined clinical relevance., Methods: Two hundred twelve patients referred for PH underwent a right-sided heart catheterization with measurements before and after rapid infusion of 7 mL/kg of saline. PH was defined as mean pulmonary artery pressure ≥ 25 mm Hg, and postcapillary PH was defined as pulmonary artery wedge pressure (PAWP) > 15 mm Hg. An increase in PAWP ≥ 18 mm Hg was considered diagnostic for postcapillary PH. At baseline, 66 patients received a diagnosis of no PH; 22, of postcapillary PH; and 124, of precapillary PH (mostly pulmonary arterial hypertension)., Results: After fluid challenge, five of 66 patients with no PH (8%) and eight of 124 with precapillary PH (6%) had the diagnosis reclassified as postcapillary PH. Fluid challenge was associated with an increase in PAWP by 7 ± 2 mm Hg in postcapillary PH and 3 ± 1 mm Hg in both precapillary PH and no-PH groups. Between-group differences were significant, but there was overlap. There were no adverse events related to fluid challenge. Prediction bands calculated from quadratic fits of the PAWP responses in pooled control subjects with no PH and patients with precapillary PH helped confirm 18 mm Hg as the cutoff for diagnosing postcapillary PH., Conclusions: Fluid challenge with 7 mL/kg saline increases PAWP, more in postcapillary than in precapillary PH or in control subjects with no PH. A cutoff value of 18 mm Hg allows reclassification of 6% to 8% of patients with precapillary PH or normal hemodynamic characteristics at baseline., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) function is a major determinant of exercise intolerance and outcome in idiopathic pulmonary arterial hypertension. The aim of the study was to evaluate the incremental prognostic value of echocardiography of the right ventricle and cardiopulmonary exercise testing (CPET) on long-term prognosis in these patients., Methods: One hundred and thirty treatment-naïve patients with idiopathic pulmonary arterial hypertension were enrolled and prospectively followed. Clinical worsening (CW) was defined by a reduction in 6-min walk distance plus an increase in functional class, or nonelective hospitalization for PAH, or death. Baseline evaluation included clinical, hemodynamic, echocardiographic, and CPET variables. Cox regression modeling with c-statistic and bootstrapping validation methods were done., Results: During a mean period of 528 ± 304 days, 54 patients experienced CW (53%). Among demographic, clinical, and hemodynamic variables at catheterization, functional class and cardiac index were independent predictors of CW (model 1). With addition of echocardiographic and CPET variables (model 2), peak O 2 pulse (peak V˙o 2 /heart rate) and RV fractional area change (RVFAC) independently improved the power of the prognostic model (area under the curve, 0.81 vs 0.66, respectively; P = .005). Patients with low RVFAC and low O 2 pulse (low RVFAC + low O 2 pulse) and high RVFAC + low O 2 pulse showed a 99.8 and 29.4 increase in the hazard ratio, respectively (relative risk, 41.1 and 25.3, respectively), compared with high RVFAC + high O 2 pulse (P = .0001)., Conclusions: Echocardiography combined with CPET provides relevant clinical and prognostic information. A combination of low RVFAC and low O 2 pulse identifies patients at a particularly high risk of clinical deterioration., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Pulmonary hypertension, which is related to right ventricular (RV) failure, indicates a poor prognosis in heart failure (HF). Increased ventilatory response and exercise oscillatory ventilation (EOV) also have a negative impact. We hypothesized that the severity classification of HF and risk prediction could be improved by combining functional capacity with cardiopulmonary exercise testing (CPET) and RV-pulmonary circulation coupling, as evaluated by the tricuspid annular plane systolic excursion (TAPSE)-pulmonary artery systolic pressure (PASP) relationship., Methods: Four hundred fifty-nine patients with HF were assessed with Doppler echocardiography and CPET and were tracked for outcome. The subjects were followed for major cardiac events (cardiac mortality, left ventricular assist device implant, or heart transplant). Cox regression and Kaplan-Meier analyses were performed with TAPSE and PASP as individual measures that were then combined into a ratio form., Results: The TAPSE/PASP ratio (TAPSE/PASP) was the strongest predictor, whereas the New York Heart Association classification and EOV added predictive value. A four-quadrant group prediction risk was created based on TAPSE (< 16 mm or ≥ 16 mm) vs PASP (< 40 mm Hg or ≥ 40 mm Hg) thresholds and the CPET variables distribution as follows: group A (TAPSE > 16 mm and PASP < 40 mm Hg) presented the lowest risk (hazard ratio, 0.17) and best ventilation; group B exhibited a low risk (hazard ratio, 0.88) with depressed TAPSE (< 16 mm) and normal PASP, a preserved peak oxygen consumption (V.o2), but high ventilation. Group C had an increased risk (hazard ratio, 1.3; TAPSE ≥ 16 mm, PASP ≥ 40 mm Hg), a reduced peak V.o2, and a high EOV prevalence. Group D had the highest risk (hazard ratio, 5.6), the worse RV-pulmonary pressure coupling (TAPSE < 16 and PASP ≥ 40 mm Hg), the lowest peak V.o2, and the highest EOV rate., Conclusions: TAPSE/PASP, combined with exercise ventilation, provides relevant clinical and prognostic insights into HF. A low TAPSE/PASP with EOV identifies patients at a particularly high risk of cardiac events.

Background: Stress testing of the pulmonary circulation (via increasing pulmonary blood flow) can reveal abnormal mean pulmonary artery pressure-cardiac output (mPpa-Q) responses, which may facilitate early diagnosis of pulmonary vascular disease. We investigated the application of dobutamine stress echocardiography (DSE) for the noninvasive assessment of mPpa-Q relationships., Methods: DSE using an incremental dose protocol (≤ 20 μg/kg/min) was performed in 38 subjects (16 patients with pulmonary arterial hypertension [PAH] and 22 healthy control subjects). An additional 22 healthy control subjects underwent exercise stress echocardiography as a comparator group. Multipoint mPpa-Q plots were analyzed, and the pulmonary vascular distensibility coefficient α was calculated., Results: DSE was feasible and informative in 93% of subjects. The average dobutamine-induced mPpa-Q slope was 1.1 ± 0.7 mm Hg/L/min in healthy control subjects and 5.1 ± 2.5 mm Hg/L/min in patients with PAH (P < .001). The dobutamine-induced α was markedly reduced in patients with PAH (0.003 ± 0.001 mm Hg vs 0.02 ± 0.01 mm Hg in control subjects, P < .001). When exercise and dobutamine stress were compared in healthy control subjects, the exercise-induced mPpa-Q slope was modestly higher (1.6 ± 0.7 mm Hg/L/min, P = .03 vs dobutamine). In patients with PAH, lower functional class status was associated with lower dobutamine-induced mPpa-Q slopes (P = .014), but not with resting total pulmonary vascular resistance., Conclusions: Noninvasive assessment of mPpa-Q relationships is feasible with dobutamine stress. DSE may potentially be a useful noninvasive technique for stress testing of the pulmonary vasculature.

Background: Although transthoracic echocardiography (TTE) is an excellent noninvasive screening test for pulmonary hypertension, the physiologic range of Doppler echocardiography-derived pulmonary pressures remains not completely investigated. The aim of the present study was, therefore, to explore the full spectrum of pulmonary pressures and right ventricular (RV) functional indexes by TTE in healthy subjects and to investigate clinical and echocardiographic correlates., Methods: A random sample of 1,480 healthy individuals (mean age, 36.1 ± 15.5 years; range, 20-80 years; 905 men) underwent a comprehensive TTE. Pulmonary artery systolic pressure (PASP), mean pressure, and pulmonary vascular resistance were estimated by standard Doppler echocardiography formulas. In addition, RV diastolic (Doppler transtricuspid inflow measurements) and systolic indexes (RV fractional area change, RV tissue Doppler peak systolic velocity, tricuspid annular plane systolic excursion) were calculated., Results: PASP and mean pulmonary artery pressure values were significantly higher in subjects aged &gt; 50 years and in those with a BMI &gt; 30 kg/m2. In particular, a PASP &gt; 40 mm Hg was found in 118 subjects (8%) of those aged &gt; 50 years and in 103 (7%) of those with a BMI &gt; 30 kg/m2. No differences by age were registered in RV systolic indexes and in pulmonary vascular resistances. On multivariate analysis, in the overall study population, age, BMI, mitral E/e' ratio, and left ventricular stroke volume were the only independent predictors of PASP., Conclusions: This study delineates an estimate of pulmonary hemodynamics in a wide age range cohort of healthy subjects. Pulmonary pressures increased with age and BMI, as expected.

Background: Reduced pulmonary arterial compliance (Ca) is a marker of poor prognosis in idiopathic pulmonary arterial hypertension. We tested the hypothesis that pulmonary arterial Ca could be a predictor of outcome in patients with chronic heart failure (CHF)., Methods: We enrolled 306 patients with CHF due to systolic left ventricular dysfunction (sLVD) who underwent a clinically driven right-sided heart catheterization. Pulmonary arterial Ca was measured by the ratio between stroke volume and pulse pressure (SV/PP). The primary end point was cardiovascular death; secondary end point was the composite of cardiovascular death, urgent heart transplantation, and appropriately detected and treated episode of ventricular fibrillation., Results: An inverse relationship was observed between SV/PP and pulmonary vascular resistance, the mean resistance-compliance product (RC-time) being 0.30 ± 0.2 s. In patients with pulmonary capillary wedge pressure (PCWP) &lt; 15 mm Hg, the mean RC-time was 0.34 ± 0.14 s, and in patients with PCWP ≥ 15 mm Hg it was 0.28 ± 0.22 s. Eighty-seven patients died in a follow-up period of 50 ± 32 months. At receiver operating characteristic curve analysis, the optimal prognostic cutoff point of SV/PP was 2.15 mL/mm Hg. An elevated (&gt; 2.15) SV/PP was more strongly associated with survival than any other hemodynamic variable; it was associated with poor prognosis both in patients with high (P = .003) and in patients with normal pulmonary vascular resistance (P = .005)., Conclusions: Pulmonary arterial Ca is a strong prognostic indicator in patients with CHF with sLVD. Most importantly, its prognostic role is retained in patients with normal pulmonary vascular resistance.

Background: Exercise stress echocardiography has not been recommended in the diagnostic workup of pulmonary hypertension because of insufficient certainty about feasibility and limits of normal., Methods: Doppler echocardiography pulmonary hemodynamic measurements were performed at a progressively increased workload in 56 healthy male and 57 healthy female volunteers aged 19 to 63 years. Mean pulmonary artery pressure (mPAP) was estimated from the maximal tricuspid regurgitation jet velocity. Cardiac index was calculated from the left ventricular outflow velocity-time integral. Pulmonary vascular distensibility a index, the percentage change of vessel diameter permm Hg of mPAP, was calculated from multipoint mPAP-cardiac output (CO) plots., Results: Peak exercise at 175 ±50 W was associated with an mPAP of 33±7 mm Hg and a CO of 18 ±5 L/min. The slope of mPAP-CO relationships was 1.5 ± 0.5 mm Hg/L/min, and the distensibility coefficient ( α ) was 1.3%± 1.0%/mm Hg. Maximal workload and cardiac index were higher in men than in women ( P , .05), but mPAP-cardiac index relationships were not different. However,women had a higher a (1.6%± 1.3%/mm Hg vs 1.1%± 0.6%/mm Hg, P < .05). The average mPAP-cardiac index slope was higher and a lower in subjects ≥50 years old. Upper limits of normal of mPAP at exercise were 34 mm Hg at a CO , 10 L/min, 45 mm Hg at a CO <20 L/min, and 52 mm Hg at a CO<30 L/min. These values are in keeping with previously reported invasive measurements., Conclusions: Exercise stress echocardiography of the pulmonary circulation is feasible and allows for fl ow-corrected definition of upper limits of normal. Women have a more distensible pulmonary circulation.

Background: Chronic mountain sickness (CMS) is characterized by a combination of excessive erythrocytosis,severe hypoxemia, and pulmonary hypertension, all of which affect exercise capacity., Methods: Thirteen patients with CMS and 15 healthy highlander and 15 newcomer lowlander control subjects were investigated at an altitude of 4,350 m (Cerro de Pasco, Peru). All of them underwent measurements of diffusing capacity of lung for nitric oxide and carbon monoxide at rest, echocardiography for estimation of mean pulmonary arterial pressure and cardiac output at rest and at exercise, and an incremental cycle ergometer cardiopulmonary exercise test., Results: The patients with CMS, the healthy highlanders, and the newcomer lowlanders reached a similar maximal oxygen uptake at 32 1, 32 2, and 33 2 mL/min/kg, respectively, mean SE( P 5 .8), with ventilatory equivalents for C O 2 vs end-tidal P CO 2 , measured at the anaerobic threshold,of 0.9 0.1, 1.2 0.1, and 1.4 0.1 mm Hg, respectively ( P , .001); arterial oxygen content of 26 1, 21 2, and 16 1 mL/dL, respectively ( P , .001); diffusing capacity for carbon monoxide corrected for alveolar volume of 155% 4%, 150% 5%, and 120% 3% predicted, respectively( P , .001), with diffusing capacity for nitric oxide and carbon monoxide ratios of 4.7 0.1 at sea level decreased to 3.6 0.1, 3.7 0.1, and 3.9 0.1, respectively ( P , .05) and a maximal exercise mean pulmonary arterial pressure at 56 4, 42 3, and 31 2 mm Hg, respectively ( P , .001)., Conclusions: The aerobic exercise capacity of patients with CMS is preserved in spite of severe pulmonary hypertension and relative hypoventilation, probably by a combination of increased oxygen carrying capacity of the blood and lung diffusion, the latter being predominantly due to an increased capillary blood volume.

Background: Although the physiologic range of pulmonary artery systolic pressure (PASP) has been reported, data on how it is manifested in athletes are limited. The aim of the present study was to explore the full spectrum of PASP and the long-term training impact in a large population of highly trained athletes., Methods: Six hundred fifteen consecutive athletes (370 endurance-trained athletes [ATEs] vs 245 strength-trained athletes [ATSs]; 28.4 ± 10.1 years old) and 230 healthy control subjects (27.5 ± 11.3 years old) underwent transthoracic echocardiography. PASP was estimated by measuring maximal tricuspid regurgitant jet velocity (TRV) with the modified Bernoulli equation. The ratio of TRV to right ventricular outflow tract time-velocity integral (TRV/RVOTTVI) was obtained as a correlate of pulmonary vascular resistance (PVR)., Results: Left ventricular (LV) mass index and ejection fraction did not differ significantly between the two groups of athletes. Conversely, ATSs showed an increased sum of wall thickness and relative wall thickness, whereas LV end-diastolic diameter, LV stroke volume, peak TRV, and PASP were significantly higher in ATEs. The ratio between transmitral E wave and tissue Doppler e' wave was not different among the three groups. The ratio TRV/RVOTTVI was ≤ 0.2 (ie, normal PVR) in all subjects. A TRV value > 2.5 m/s was observed in 76 athletes (12.3%). By multivariable analysis, age (P < .01), type and duration of training (P < .01), and LV stroke volume (P < .001) were the only independent predictors of PASP in athletes., Conclusions: This study delineates the full range of resting TRV and derived PASP in highly trained athletes. The upper physiologic limit of PASP in endurance athletes may reach 40 mm Hg, in line with the greater increase in stroke volume. This should be considered a "physiologic phenomenon" when evaluating athletes for sports eligibility.

Background: Pulmonary endarterectomy (PEA) provides a potential cure for patients with chronic thromboembolic pulmonary hypertension (CTEPH). However, successfully operated patients can continue to suffer from a limitation of exercise capacity, despite normalization of pulmonary vascular resistance (PVR). The purpose of the present study was to explore the cardiopulmonary exercise test (CPET) profile and the pulmonary hemodynamic response to exercise in these patients., Methods: Thirteen successfully operated patients with CTEPH and persistent dyspnea and control subjects underwent a CPET and a right-sided heart catheterization at rest and during exercise., Results: The CPET profile of the patients was characterized by mild hyperventilation and decreased peak oxygen uptake (VO2). While there were no differences in resting hemodynamics between patients and control subjects, PVR was higher in the patients after 10 min of exercise (111 ± 46 dynes/s/cm(5) vs 71 ± 42 dynes/s/cm(5), P = .04), and pulmonary arterial compliance (Ca) was lower (5.5 ± 2.3 mL/mm Hg vs 8.1 ± 3.5 mL/mm Hg, P = .048). Ca under exercise correlated with peak VO2 in the patients (R(2) = 0.825, P = .022)., Conclusions: After successful PEA, patients with persistent exertional dyspnea display an abnormal pulmonary hemodynamic response to exercise, characterized by increased PVR and decreased Ca. Decreased Ca under exercise is a strong predictor of limited exercise capacity in these patients.

Background: Altitude exposure is associated with mild pulmonary hypertension and decreased exercise capacity. We tested the hypothesis that pulmonary vascular resistance (PVR) contributes to decreased exercise capacity in hypoxic healthy subjects., Methods: An incremental cycle ergometer cardiopulmonary exercise test and echocardiographic estimation of pulmonary artery pressure (Ppa) and cardiac output to calculate total PVR were performed in 11 healthy volunteers in normoxia and after 1 h of hypoxic breathing (12% O(2)). The measurements were performed in a random order at 1-week intervals after the receiving either a placebo or bosentan, following a double-blind randomized crossover design. Bosentan was administered twice a day for 3 days, 62.5 mg on the first day and 125 mg on the next 2 days., Results: Hypoxic breathing decreased the mean (+/- SE) pulse oximetric saturation (Spo(2)) from 99 +/- 1% to 3 +/- 1% and increased the mean PVR from 5.6 +/- 0.3 to 7.2 +/- 0.5 mm Hg/L/min/m(2), together with a decrease in mean maximum O(2) uptake (Vo(2)max) from 47 +/- 2 to 35 +/- 2 mL/kg/min. Bosentan had no effect on normoxic measurements and did not affect hypoxic Spo(2), but decreased PVR to 5.6 +/- 0.3 mm Hg/L/min/m(2) (p < 0.01) and increased Vo(2)max to 39 +/- 2 mL/kg/min (p < 0.01) in hypoxia. Bosentan therapy, on average, restored 30% of the hypoxia-induced decrease in Vo(2)max. Bosentan-induced changes in Ppa and Vo(2)max were correlated (p = 0.01)., Conclusions: We conclude that hypoxic pulmonary hypertension partially limits exercise capacity in healthy subjects, and that bosentan therapy can prevent it.

Background: Despite advances in the management of pulmonary arterial hypertension (PAH), the mortality rate remains excessive. Long-term efficacy evaluations are needed to guide therapeutic management. The purpose of this study is to present 1-year observational data with two endothelin antagonists, sitaxsentan and bosentan, in a prospective, open-label study., Methods: The present study was a prospective, international, multicenter, randomized, open-label extension of the Sitaxsentan To Relieve Impaired Exercise-2 trial. All-cause mortality, time to discontinuation (all causes) from monotherapy, time to discontinuation due to adverse events, time to elevations in and time to discontinuation due to elevated hepatic transaminases, and time to first clinical worsening event were evaluated. Patients initially receiving sitaxsentan at 50 mg were excluded from the main analysis. The distributions of time-to-event variables are estimated using Kaplan-Meier methods, and treatment effects are evaluated using the Cox proportional hazards model., Results: Patients treated with sitaxsentan at 100 mg had 96% overall survival and a 34% risk for a clinical worsening event by 1 year. In addition, there was a 6% risk of elevated aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) levels > 3 x upper limit of normal range (ULN) at 1 year and a 15% risk of discontinuation due to adverse events. Patients treated with bosentan had 88% overall survival and a 40% risk of a clinical worsening event by 1 year. In addition, there was a 14% risk for elevated AST and/or ALT levels > 3 x ULN at 1 year and a 30% risk of discontinuation due to adverse events., Conclusions: At 1 year, sitaxsentan therapy appears safe and efficacious for patients with PAH; reductions in mortality and the risk for clinical worsening events provide support for durability of efficacy.

Background: We have reported previously that the sympathetic nervous system is activated in patients with pulmonary arterial hypertension (PAH), and that this is only partly explained by a decrease in arterial oxygenation. Possible causes for increased muscle sympathetic nerve activity (MSNA) in patients with PAH include right atrial distension and decreased cardiac output. Both may be improved by atrial septostomy, but this intervention also further decreases arterial oxygenation. In the present study, we wanted to investigate the effect of atrial septostomy on MSNA in patients with PAH., Methods: We recorded BP, heart rate (HR), arterial O2 saturation (SaO2), and MSNA before and after atrial septostomy in PAH patients (mean [+/- SE] age, 48 +/- 5 years) and in closely matched control subjects. Measurements were also performed after septostomy, while SaO2 was brought to the preprocedure level by supplemental O2 therapy., Results: Compared to the control subjects (n = 10), the PAH patients (n = 11) had a lower mean BP (75 +/- 2 vs 96 +/- 3 mm Hg, respectively; p < 0.001), lower mean SaO2 (92 +/- 1% vs 97 +/- 0%, respectively; p < 0.001), increased mean HR (84 +/- 4 vs 68 +/- 3 beats/min; p < 0.01), and markedly increased mean MSNA (76 +/- 5 vs 29 +/- 2 bursts per minute; p < 0.001). Atrial septostomy decreased mean SaO2 (to 85 +/- 2%; p < 0.001) and mean MSNA (to 69 +/- 4 bursts per minute; p < 0.01), but did not affect HR or BP. Therapy with supplemental O2 did not affect MSNA, BP, or HR. The decrease in MSNA was correlated to the decrease in right atrial pressure (r = 0.62; p < 0.05)., Conclusions: Atrial septostomy in PAH patients decreases sympathetic hyperactivity despite an associated decrease in arterial oxygenation, and this appears to be related to decreased right atrial distension.

Background: The peripheral chemoreceptors are the dominant reflex mechanism responsible for the rise in ventilation and muscle sympathetic nerve activity (MSNA) in response to hypoxia. Animal studies have suggested that endothelin (ET) plays an important role in chemosensitivity. Moreover, several human clinical conditions in which circulating ET levels are increased are accompanied by enhanced chemoreflex sensitivity. Whether ET plays a role in normal human chemosensitivity is unknown., Methods: We determined whether bosentan, a nonspecific ET receptor antagonist, would decrease chemoreflex sensitivity in 14 healthy subjects. We assessed the effects of bosentan on the response to isocapnic hypoxia, using a randomized, crossover, double-blinded study design., Results: Bosentan increased mean (+/- SEM) plasma ET levels from 1.97 +/- 0.28 to 2.53 +/- 0.23 pg/mL (p = 0.01). Hypoxia increased mean minute ventilation from 6.7 +/- 0.3 to 8+/0.4 L/min (p < 0.01), mean MSNA from 100 to 111 +/- 5% (p < 0.01), mean heart rate from 67 +/- 3 to 86 +/- 3 beats/min (p < 0.01), and mean systolic BP from 116 +/- 3 to 122 +/- 3 mm Hg (p < 0.01). However, none of these responses differed between therapy with bosentan and therapy with placebo (p = 0.26). Bosentan did not affect the mean MSNA responses to the apneas, during normoxia (change from baseline: placebo, 259 +/- 58%; bosentan, 201 +/- 28%; p = 0.17) or during hypoxia (change from baseline: placebo, 469 +/- 139%; bosentan, 329 +/- 46%; p = 0.24). The durations of the voluntary end-expiratory apneas in normoxia and hypoxia, and the subsequent reductions in oxygen saturation, were also similar with therapy using bosentan and placebo (p = 0.42)., Conclusion: In healthy men, ET does not play an important role in peripheral chemoreceptor activation by acute hypoxia.

Study Objectives: The aim of this long-term multicenter analysis was to investigate whether subcutaneously infused treprostinil could provide sustained improvements of exercise capacity and survival benefits in patients with pulmonary arterial hypertension (PAH) and inoperable chronic thromboembolic pulmonary hypertension (CTEPH). Subcutaneous administration of the prostacyclin analog treprostinil is an effective treatment for PAH that, unlike epoprostenol, does not require the insertion of a permanent central venous catheter., Design: Multicenter retrospective study., Setting: Three European university hospitals., Methods: Ninety-nine patients with PAH and 23 patients with CTEPH in New York Heart Association (NYHA) classes II-IV were followed up for a mean of 26.2 +/- 17.2 months (+/- SE) [range, 3 to 57 months]. Long-term efficacy was assessed by 6-min walking distance (SMWD), Borg dyspnea score, and NYHA class. Clinical events were monitored to assess survival and event-free survival., Results: At 3 years, significant improvements from baseline were observed in mean SMWD (305 +/- 11 to 445 +/- 12 m, p = 0.0001), Borg dyspnea score (5.7 +/- 0.2 to 4.5 +/- 1, p = 0.0006), and NYHA class (3.20 +/- 0.04 to 2.1 +/- 0.1, p = 0.0001). These changes were observed under a mean dose of subcutaneously infused treprostinil at 40 +/- 2.6 ng/kg/min (range, 16 to 84 ng/kg/min). Subcutaneously infused treprostinil was well tolerated, and local pain at the subcutaneous site accounted for treatment interruption in only 5% of the cases. Survival was 88.6% and 70.6% at 1 year and 3 years, respectively. At the same time points, the event-free survival rates, defined as survival without hospitalization for clinical worsening, transition to IV epoprostenol, and need for combination therapy or atrial septostomy, were 83.2% and 69%, respectively., Conclusions: Long-term subcutaneous therapy with treprostinil appears to continuously improve exercise tolerance and symptoms in patients with PAH and inoperable CTEPH. Moreover, treatment may provide a significant survival benefit.

Objectives: Right ventricular (RV) afterload is best described by a pulmonary arterial impedance (PVZ) spectrum, which integrates pulmonary vascular resistance (PVR), elastance, and wave reflection. We evaluated the feasibility of PVZ determinations in patients with pulmonary arterial hypertension (PAH) during routine right heart catheterization and Doppler echocardiography., Design: Prospective study., Setting: Academic hospital., Patients: Twenty-two patients with PAH., Interventions: Right heart catheterization with a fluid-filled Swan-Ganz catheter, Doppler echocardiography, and administration of inhaled nitric oxide (NO) [10 to 20 ppm; 17 patients], maximum tolerated dose of IV epoprostenol (average, 8.5 ng/kg/min; 5 patients), and IV dobutamine (8 micro g/kg/min; 8 patients)., Measurements and Results: PVZ was calculated from the spectral analysis of synchronized pulmonary artery pressure (Ppa) and flow waves. The mean (+/- SE) Ppa was 63 +/- 3 mm Hg, and the mean PVR was 16 +/- 2 Wood units. The PVZ spectrum was markedly shifted to higher than normal pressures and frequencies, with a mean 0-Hz impedance (Z(0)) of 1,506 +/- 138 dyne. s. cm(-5), and a mean characteristic impedance (Zc) of 124 +/- 11 dyne. s. cm(-5), which are in keeping with data from previous studies. Inhaled NO levels decreased Ppa, PVR, Z(0), and Zc without a change in cardiac output. Epoprostenol administration did not affect Ppa, increased cardiac output, and decreased Z(0) and Zc. Dobutamine administration increased cardiac output and Ppa, and decreased PVR and Z(0), without changing Zc., Conclusions: The determination of PVZ to quantify RV afterload is feasible during routine right heart catheterization and Doppler echocardiography. The measurement is sensitive to pharmacologic interventions.

Objective: Continuous i.v. epoprostenol (prostacyclin) therapy improves survival and quality of life in patients with pulmonary arterial hypertension (PAH). i.v. epoprostenol therapy may be limited by serious complications related to the need for an implanted central venous catheter, and its chemical instability and short half-life. Treprostinil is a longer-acting prostacyclin analog, chemically stable, and suitable for continuous subcutaneous administration. We report successful transitioning to subcutaneous treprostinil of patients who presented with life-threatening complications of i.v. epoprostenol delivery., Design: Open, uncontrolled study., Setting: ICUs and departments of cardiology at academic hospitals., Patients: Eight patients with PAH treated with continuous i.v. epoprostenol., Intervention: Transition to subcutaneous treprostinil following an empiric protocol., Results: Transition to treprostinil was achieved successfully in 21 to 96 h, with no major adverse side effects, and no change in the improved clinical status achieved with i.v. epoprostenol. Doses of epoprostenol before transition ranged from 3.5 to 75 ng/kg/min (mean, 27 ng/kg/min). Doses of treprostinil at completion of the transition ranged from 3 to 65 ng/kg/min (mean, 22 ng/kg/min). Four to 11 months later, the patients remained clinically improved. In spite of mild-to-moderate infusion site pain, all patients reported an improved sense of comfort and well-being., Conclusion: Patients with PAH can be safely transitioned from treatment with i.v. epoprostenol to subcutaneous treprostinil.

A 43-year-old woman had two episodes of lung edema at moderate altitudes. She had taken slimming pills containing fenfluramine hydrochloride and diethylpropion hydrochloride. At sea level, catheterization of the right side of the heart showed a mean pulmonary artery pressure of 16 mm Hg, which increased to 34 mm Hg with mild exercise in a supine position. An extensive workup failed to identify a cardiac or a pulmonary cause of pulmonary hypertension. This patient experienced mild primary pulmonary hypertension related to the intake of anorexigens, which was revealed by high-altitude pulmonary edema.

Impairment of hypoxic pulmonary vasoconstriction (HPV) is frequently cited as an explanation for the hypoxemia of liver cirrhosis. We investigated the pulmonary and systemic hemodynamic responses to acute inspiratory hypoxia, 12.5 percent oxygen in nitrogen during 10 minutes, in 24 patients with mildly to moderately decompensated liver cirrhosis and arterial hypoxemia. A mean increase of 50 percent in pulmonary vascular resistance (PVR) was observed, which is comparable to reported responses of normal subjects to a similar degree of hypoxia. Seven of the 24 patients showed an increase in PVR of less than 20 percent. Compared with the other patients, no difference could be found between both groups in baseline blood gas and hemodynamic determinations, physical examination, liver function tests, and laboratory tests that may be disturbed by circulating endotoxin. Five of the 24 patients had a hyperkinetic circulatory state, but only one of them failed to increase PVR in response to hypoxia. Considering the whole group of 24 patients, there was no correlation between PaO2, PVR, and PVR response to hypoxia. Impairment of HPV is probably not the right explanation for most cirrhotic patients with arterial hypoxemia.

Arterial blood gas levels, lung volumes, and diffusing properties for carbon monoxide were measured in 22 patients with uncomplicated acute pancreatitis who had no clinical or radiographic evidence of pulmonary involvement. Mild arterial hypoxemia (less than 75 mm Hg) was present in four patients. The mean values of inspiratory lung volumes were clearly reduced, and the diffusing properties were sharply altered; the mean value for the diffusing capacity of carbon monoxide per unit of lung volume (Krogh's constant [KCO]) was 78 percent of predicted. Four patients with a low KCO in the first four days after an acute episode had normal values when reevaluated one week later. These findings suggest the occurrence, even in mild acute pancreatitis, of transient pulmonary injury mainly localized at the level of the capillaries, leading to decreased gas transfer.

The effects of nifedipine on hemodynamics and pulmonary gas exchange were investigated in two patients with primary pulmonary hypertension. After 20 mg of the drug taken sublingually, pulmonary and systemic vascular resistances decreased, cardiac output increased, and blood oxygenation was improved. As assessed by the multiple inert gas elimination technique, nifedipine induced a deterioration in ventilation/perfusion (VA/Q) relationships consisting in an increased perfusion of units with low VA/Q. In spite of this negative effect on gas exchange, arterial PO2 increased as a consequence of increased mixed venous PO2 in relation to an augmented cardiac output, and in one patient there was a decrease in the secondary atrial shunt. Both patients were clinically improved by the nifedipine as a long-term treatment.

A reduction of arterial PO2 is generally observed when vasodilators are given to patients with cardiac or pulmonary disease. This has been attributed to a release of preexisting hypoxic pulmonary vasoconstriction (HPV). We investigated the effects of hemodynamics and blood gases of IV nitroglycerin, IV nitroprusside and sublingual nifedipine, at dosages currently used in clinical practice, in 23 healthy volunteers at normoxic conditions (fraction of inspired O2, FIO2 0.21) and at acute inspiratory hypoxia (FIO2 0.125 during 10 min). Breathing FIO2 0.125 elicited pulmonary vasoconstriction in all the subjects. At FIO2 0.21, nitroglycerin reduced preload, nifedipine reduced afterload, nitroprusside had balanced effects, but none of the drugs induced pulmonary vasodilation and only nitroglycerin deteriorated arterial oxygenation. At FIO2 0.125, nitroglycerin did not at all affect the pulmonary pressor response, while both nitroprusside and nifedipine decreased it. An inhibition of HPV was obtained with certainty in only one subject who received nitroprusside. In all the subjects in whom HPV was partially inhibited by vasodilator administration, the alveolar-arterial PO2 gradients remained significantly lowered, suggesting that the pulmonary vascular tone adaptation to alveolar hypoxia still was effective in improving ventilation/perfusion relationships. The role of impaired HPV in the reduction of arterial PO2 in patients under vasodilator therapy may have to be reevaluated.

Hemodynamics, blood gas values, and lung mechanics were investigated in 19 patients with decompensated COPD before and 30 and 60 minutes after a slow (15 minute) intravenous administration of 3 mg/kg enoximone (MDL 17,043). In the first 11 patients who were spontaneously breathing, enoximone significantly decreased pulmonary arterial wedge pressure, right atrial pressure, mean systemic arterial pressure, and mean pulmonary arterial pressure. Cardiac output remained unchanged, while heart rate increased slightly. Lung resistance decreased and dynamic lung compliance increased. Blood gas values remained unchanged. Similar effects were observed in the next eight patients who were artificially ventilated, except for an increase in cardiac output. These results show that enoximone has bronchodilating and pulmonary vasodilating properties.

Almitrine, a peripheral chemoreceptor stimulating drug, was given 100 mg orally to six patients with advanced chronic obstructive pulmonary disease (COPD), and its effects on hemodynamics, blood gases, lung mechanics, and the distribution of ventilation/perfusion ratios (VA/Q), determined by the inert gas elimination technique, were investigated. Arterial Po2 increased from 52 +/- 4 to 59 +/- 3 mm Hg, mean +/- SEM, p less than 0.01, arterial Pco2 decreased from 46 +/- 3 to 43 +/- 3 mm Hg, p less than 0.05, and venous admixture from 30 +/- 6 to 19 +/- 3 percent, p less than 0.02. No change occurred in ventilation, variables of lung mechanics, systemic and pulmonary hemodynamics, except an increase in pulmonary vascular resistance (from 364 +/- 103 to 438 +/- 99 dyne.s.cm-5, p less than 0.05). A reduction in VA/Q inequality could be demonstrated with a redistribution of blood flow into the lungs by a diversion of 15 percent of total blood flow from units with low VA/Q (between 0.08 and 0.4) to units with normal VA/Q (between 0.5 and 1.8). These changes might be explained by an enhancement of hypoxic pulmonary vasoconstriction. Pharmacologic peripheral chemoreceptor stimulation, at an infra-ventilatory analeptic dosage, might be of therapeutic interest to patients with respiratory insufficiency due to VA/Q inequality.