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Background: According to the most recent pulmonary hypertension (PH) guidelines, a main pulmonary artery (MPA) diameter > 25 mm on transthoracic echocardiography supports the diagnosis of PH. However, the size of the pulmonary artery (PA) may vary according to body size, age, and cardiac phases., Research Question: (1) What are the reference limits for PA size on transthoracic echocardiography, considering differences in body size, sex, and age? (2) What is the diagnostic value of the PA size for classifying PH? (3) How does the selection of different reference groups (healthy volunteers vs patients referred for right heart catheterization [RHC]) influence the diagnostic OR (DOR)?, Study Design and Methods: The study included a reference cohort of 248 healthy individuals as control patients, 693 patients with PH proven by RHC, and 156 patients without PH proven by RHC. In the PH cohort, 300 had group 1 PH, 207 had group 2 PH, and 186 had group 3 PH. MPA and right PA diameters and areas were measured in the upper sternal short-axis and suprasternal notch views. Reference limits (5th-95th percentile) were based on absolute values and height-indexed measures. Quantile regression analysis was used to derive median and 95th quantile reference equations for the PA measures. DORs and probability diagnostic plots for PH were then determined using healthy control and non-PH cohorts., Results: The 95th percentile for indexed MPA diameter was 15 mm/m in diastole and 19 mm/m in systole in both sexes. Quantile regression analysis revealed a weak age effect (pseudo-R 2 of 0.08-0.10 for MPA diameters). Among measures, the MPA size in diastole had the highest DOR (156.2; 95% CI, 68.3-357.5) for detection of group 1 PH. Similarly, the DORs were also high for groups 2 and 3 PH when compared with the control cohort but significantly lower compared with the non-PH cohort., Interpretation: This study presents novel reference limits for MPA based on height indexing and quantile regression., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: F. H. received funding from Janssen Inc to conduct the research. None declared (S. P. B., B. E. C., E. J. S., M. S., K. C. N., A. J. S., R. T. Z.)., (Published by Elsevier Inc.)

Background: Pulmonary hypertension is a heterogeneous disease, and a significant portion of patients at risk for it have CT imaging available. Advanced automated processing techniques could be leveraged for early detection, screening, and development of quantitative phenotypes. Pruning and vascular tortuosity have been previously described in pulmonary arterial hypertension (PAH), but the extent of these phenomena in arterial vs venous pulmonary vasculature and in exercise pulmonary hypertension (ePH) have not been described., Research Question: What are the arterial and venous manifestations of pruning and vascular tortuosity using CT imaging in PAH, and do they also occur in ePH?, Study Design and Methods: A cohort of patients with PAH and ePH and control subjects with available CT angiograms were retrospectively identified to examine the differential arterial and venous presence of pruning and tortuosity in patients with precapillary pulmonary hypertension not confounded by lung or thromboembolic disease. The pulmonary vasculature was reconstructed, and an artificial intelligence method was used to separate arteries and veins and to compute arterial and venous vascular volumes and tortuosity., Results: A total of 42 patients with PAH, 12 patients with ePH, and 37 control subjects were identified. There was relatively lower (median [interquartile range]) arterial small vessel volume in subjects with PAH (PAH 14.7 [11.7-16.5; P < .0001]) vs control subjects (16.9 [15.6-19.2]) and venous small vessel volume in subjects with PAH and ePH (PAH 8.0 [6.5-9.6; P < .0001]; ePH, 7.8 [7.5-11.4; P = .004]) vs control subjects (11.5 [10.6-12.2]). Higher large arterial volume, however, was only observed in the pulmonary arteries (PAH 17.1 [13.6-23.4; P < .0001] vs control subjects 11.4 [8.1-15.4]). Similarly, tortuosity was higher in the pulmonary arteries in the PAH group (PAH 3.5 [3.3-3.6; P = .0002] vs control 3.2 [3.2-3.3])., Interpretation: Lower small distal pulmonary vascular volume, higher proximal arterial volume, and higher arterial tortuosity were observed in PAH. These can be quantified by using automated techniques from clinically acquired CT scans of patients with ePH and resting PAH., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Right ventricular (RV) dysfunction is associated with poorer outcomes in heart failure with preserved ejection fraction (HFpEF). Although female subjects are more likely to have HFpEF, male subjects have worse prognosis and resting RV function. The contribution of dynamic RV-pulmonary arterial (RV-PA) coupling between sex and its impact on peak exercise capacity (VO 2 ) in HFpEF is not known., Research Question: The goal of this study was to investigate the differential effects of sex on RV-PA coupling during maximum incremental exercise in patients with HFpEF., Study Design and Methods: This study examined rest and exercise invasive pulmonary hemodynamics in 22 male patients with HFpEF and 27 female patients with HFpEF. To further investigate the discrepancy in RV-PA response between sex, 26 age-matched control subjects (11 male subjects and 15 female subjects) were included. Single beat analysis of RV pressure waveforms was used to determine the end-systolic elastance (Ees) and pulmonary arterial elastance. RV-PA coupling was determined as the ratio of end-systolic elastance/PA elastance., Results: Both HFpEF groups experienced decreased peak VO 2 (% predicted). However, male patients with HFpEF experienced a greater decrement in peak VO 2 compared with female patients (58 ± 16% vs 70 ± 15%; P < .05). Male patients with HFpEF had a more pronounced increase in RV afterload, Ea (1.8 ± 0.6 mm Hg/mL/m 2 vs 1.3 ± 0.4 mm Hg/mL/m 2 ; P < .05) and failed to increase RV contractility during exercise, resulting in dynamic RV-PA uncoupling (0.9 ± 0.4 vs 1.2 ± 0.4; P < .05) and subsequent reduced stroke volume index augmentation. In contrast, female patients with HFpEF were able to augment RV contractility in the face of increasing afterload, preserving RV-PA coupling during exercise., Interpretation: Male patients with HFpEF were more compromised regarding dynamic RV-PA uncoupling and reduced peak VO 2 compared with female patients. This finding was driven by both RV contractile impairment and afterload mismatch. In contrast, female patients with HFpEF had preserved RV-PA coupling during exercise and better peak exercise VO 2 compared with male patients with HFpEF., (Copyright © 2020 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.)

Background: The golden ratio (phi, Φ = 1.618) is a proportion that has been found in many phenomena in nature, including the cardiovascular field. We tested the hypothesis that the systolic over mean pulmonary artery pressure ratio (sPAP/mPAP) and the mean over diastolic pressure ratio (mPAP/dPAP) may match Φ in patients with pulmonary arterial hypertension (PAH) and in control patients., Methods: In the first, theoretical part of the study, we discuss why our hypothesis is consistent with three known hemodynamic features of the pulmonary circulation: (1) the 0.61 slope of the mPAP vs sPAP relationship, (2) pulmonary artery pulse pressure and mPAP have an almost 1:1 ratio, and (3) the proportional relationship among sPAP, mPAP, and dPAP. In the second part of the study, fluid-filled pressures were analyzed in 981 incident, untreated PAH and high-fidelity pressures were also analyzed in 44 historical control patients (mPAP range, 9-113 mm Hg)., Results: In PAH (non-normal distribution), median values of sPAP/mPAP and mPAP/dPAP were 1.591 (98%Φ) and 1.559 (96%Φ), respectively. In control patients (normal distribution), mean sPAP/mPAP and mPAP/dPAP were 1.572 (97%Φ) and 1.470 (91%Φ), respectively. In both PAH and control patients, this was consistent with the Φ hypothesis, assuming < 1 mm Hg error in estimation of sPAP, mPAP, and dPAP on average., Conclusions: In PAH and in control patients, the fluctuations in sPAP and dPAP around mPAP exhibited a constant scaling factor matched to Φ. This remarkable property allows linkage of various empirical observations on pulmonary hemodynamics that were hitherto apparently unrelated. These findings warrant further confirmation in other types of pulmonary hypertension and warrant explanation., (Copyright © 2018 American College of Chest Physicians. All rights reserved.)

Background: Pulmonary hypertension (PH) is diagnosed and classified through right-sided heart catheterization, with a number of hemodynamic markers used to help guide treatment decisions. These markers may not reflect the complex remodeling of the right ventricle or the interplay between ventricles and struggle to predict treatment response. This study investigates the use of a novel marker: the ratio of left ventricular end-diastolic pressure to right ventricular end-diastolic pressure (LVEDP/RVEDP) in predicting treatment outcomes in a cohort of patients with PH., Methods: We performed a retrospective analysis of patients with PH at INOVA Fairfax Hospital's advanced lung disease program with simultaneous left-sided and right-sided heart catheterization. The primary end point was the time to clinical improvement, defined by an improvement in distance walked on the 6-min walk test (6MWT) of > 35 m in a year without interceding hospitalization for worsening PH or the need for additional PH therapy., Results: A total of 51 patients were included in the final analysis, 21 of whom (41.2%) had a salutary treatment effect with a mean improvement in the 6MWT of 75 m. Treatment responders were more likely to have a lower LVEDP/RVEDP ratio (1.08 vs 1.62; P = .051). This association persisted in the final multivariate regression model after adjustment for age and sex and controlling for severity of PH (OR, 0.17; 95% CI, 0.03-0.65; P = .024)., Conclusions: The LVEDP/RVEDP ratio is a novel marker for therapeutic response in patients with PH treated with pulmonary vasodilator medications and may offer robust predictive value independent of existing markers of disease severity., (Copyright © 2017 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Cigarette smoking has been associated with diminished vasodilatory function in the airway circulation. It is possible that cigarette smoking similarly affects the pulmonary circulation before resting pulmonary circulatory abnormalities become manifested. The aim of this study was to compare the acute effect of inhaled albuterol on airway and pulmonary hemodynamic function as an index of β 2 -adrenoceptor-mediated vasodilation in smokers and never smokers., Methods: In 30 adults, airway and pulmonary vascular function was assessed before and 15 min after albuterol inhalation (270 μg). From mean systemic arterial pressure, cardiac output, airway blood flow, and mean pulmonary arterial pressure, airway vascular resistance (AVR) and pulmonary vascular resistance (PVR) were derived., Results: Albuterol induced a substantial drop in mean (± SE) PVR (-67.2% ± 5%), with no difference between groups. In contrast, the albuterol-induced decrease in AVR was significantly greater in never smokers than in smokers (-28.6% ± 3% vs -3.1% ± 6%; P < .02)., Conclusions: These results are consistent with a dysfunction in a β 2 -adrenergic signaling pathway mediating vasorelaxation in the airway circulation of current smokers. The vasodilatory deficit in the airway circulation but not in the pulmonary circulation could be related to local differences in the impact of cigarette smoke on the vascular endothelium., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: Exercise can distend the normally compliant, thin-walled pulmonary vessels. Loss of distensibility has been suggested as an early marker of pulmonary vascular remodeling. We hypothesized that in mild pulmonary vascular disease (PVD), a reduction in vascular distensibility during exercise occurs prior to the development of overt resting pulmonary hypertension (PH)., Methods: Distensibility α during exercise (percentage change in vessel diameter per mm Hg increase in transmural pressure) was estimated in 90 subjects using a model of the pulmonary circulation and invasive hemodynamic data. Distensible properties in mild PVD without resting PH (PVD-noPH) (n = 33) were compared with control subjects (n = 26) and PVD with overt resting PH (PVD-PH) (n = 31)., Results: Resting mean pulmonary artery pressure (mPpa) levels were 14 ± 4, 20 ± 3, and 34 ± 10 mm Hg with corresponding exercise mPpa-cardiac output slopes of 1.5 ± 0.6, 3.5 ± 0.9, and 5.7 ± 3.2 mm Hg/L/min for control subjects and the PVD-noPH and PVD-PH groups, respectively. The distensible model produced high accuracy and precision with no mean bias and 95% limits of agreement of -4.5 to 4.5 mm Hg between calculated and measured mPpa. Distensibility α was lowest in the PVD-PH group, intermediate in the PVD-noPH group, and highest in control subjects (0.25 ± 0.14%/mm Hg vs 0.45 ± 0.24%/mm Hg vs 1.40 ± 0.45%/mm Hg, P < .0001). Distensibility α discriminated PVD-noPH from control subjects with a sensitivity of 88% and a specificity of 100%. The discriminatory performance of α was similar for the subgroup of PVD-noPH, with a strictly normal resting mPpa ≤ 20 mm Hg., Conclusions: Loss of pulmonary vascular distensibility during exercise occurs prior to resting PH in PVD. The usefulness of α as a novel vascular index for the early detection of PVD warrants further validation., (Copyright © 2016 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: The hypoxic ventilatory response (HVR) at sea level (SL) is moderately predictive of the change in pulmonary artery systolic pressure (PASP) to acute normobaric hypoxia. However, because of progressive changes in the chemoreflex control of breathing and acid-base balance at high altitude (HA), HVR at SL may not predict PASP at HA. We hypothesized that resting oxygen saturation as measured by pulse oximetry (Spo₂) at HA would correlate better than HVR at SL with PASP at HA., Methods: In 20 participants at SL, we measured normobaric, isocapnic HVR (L/min · -%Spo₂⁻¹) and resting PASP using echocardiography. Both resting Spo₂ and PASP measures were repeated on day 2 (n = 10), days 4 to 8 (n = 12), and 2 to 3 weeks (n = 8) after arrival at 5,050 m. These data were also collected at 5,050 m in life-long HA residents (ie, Sherpa [n = 21])., Results: Compared with SL, Spo₂ decreased from 98.6% to 80.5% (P < .001), whereas PASP increased from 21.7 to 34.0 mm Hg (P < .001) after 2 to 3 weeks at 5,050 m. Isocapnic HVR at SL was not related to Spo₂ or PASP at any time point at 5,050 m (all P > .05). Sherpa had lower PASP (P < .01) than lowlanders on days 4 to 8 despite similar Spo₂. Upon correction for hematocrit, Sherpa PASP was not different from lowlanders at SL but was lower than lowlanders at all HA time points. At 5,050 m, although Spo₂ was not related to PASP in lowlanders at any point (all R² ≤ 0.05, P > .50), there was a weak relationship in the Sherpa (R² = 0.16, P = .07)., Conclusions: We conclude that neither HVR at SL nor resting Spo₂ at HA correlates with elevations in PASP at HA.

Objective: This study aimed to determine whether inhaled prostaglandins are associated with improvement in pulmonary physiology or mortality in patients with ARDS and assess adverse effects., Methods: The following data sources were used: PubMed, EMBASE, CINAHL, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, reference lists, conference proceedings, and ClinicalTrials.gov. Studies selected included randomized controlled trials and nonrandomized studies. For data extraction, two reviewers independently screened titles and abstracts for eligibility. With regard to data synthesis, 25 studies (two RCTs) published over 21 years (1993-2014) were included. The PROSPERO registration number was CRD42014013180., Results: One randomized controlled trial showed no difference in the change in mean Pao2 to Fio2 ratio when comparing inhaled alprostadil to placebo: 141.2 (95% CI, 120.8-161.5) to 161.5 (95% CI, 134.6-188.3) vs 163.4 (95% CI, 140.8-186.0) to 186.8 (95% CI, 162.9-210.7), P = .21. Meta-analysis of the remaining studies demonstrated that inhaled prostaglandins were associated with improvement in Pao2 to Fio2 ratio (16 studies; 39.0% higher; 95% CI, 26.7%-51.3%), and Pao2 (eight studies; 21.4% higher; 95% CI, 12.2%-30.6%), and a decrease in pulmonary artery pressure (-4.8 mm Hg; 95% CI, -6.8 mm Hg to -2.8 mm Hg). Risk of bias and heterogeneity were high. Meta-regression found no association with publication year (P = .862), baseline oxygenation (P = .106), and ARDS etiology (P = .816) with the treatment effect. Hypotension occurred in 17.4% of patients in observational studies., Conclusions: In ARDS, inhaled prostaglandins improve oxygenation and decrease pulmonary artery pressures and may be associated with harm. Data are limited both in terms of methodologic quality and demonstration of clinical benefit. The use of inhaled prostaglandins in ARDS needs further study.

Background: Patients with pulmonary arteriovenous malformations (PAVMs) are unusual because hypoxemia results from right-to-left shunting and not airway or alveolar disease. Their surprisingly well-preserved exercise capacity is not generally appreciated., Methods: To examine why exercise tolerance is preserved, cardiopulmonary exercise tests were performed while breathing room air in 21 patients with radiologically proven PAVMs, including five restudied 3 to 12 months after embolization when their PAVMs had regressed. Where physiologic matching was demonstrable, comparisons were made with 12 healthy control subjects., Results: The majority of patients achieved their predicted work rate despite a resting arterial oxygen saturation (SaO₂) of 80% to 96%. Peak work rate and oxygen consumption (VO₂) were no lower in patients with more hypoxemia. Despite higher SaO₂ following embolization (median, 96% and 90%; P = .009), patients achieved similar work rates and similar peak VO₂. Strikingly, treated patients reset to virtually identical peak oxygen pulses (ie, VO₂ per heart beat) and in many cases to the same point on the peak oxygen pulse/work rate plot. The 21 patients had increased minute ventilation (VE) for given increases in CO₂ production (VE/VCO₂ slope), but perceived dyspnea was no greater than in the 12 control subjects or in the same patients before compared to after embolization comparison. Overall, work rate and peak VO₂ were associated not with oxygenation parameters but with VE/VCO₂ slope, BMI, and anaerobic threshold., Conclusions: Patients with hypoxemia and PAVMs can maintain normal oxygen delivery/VO₂ during peak exercise. Following improvement of SaO₂ by embolization, patients appeared to reset compensatory mechanisms and, as a result, achieved similar peak VO₂ per heart beat and peak work rates.

Background: Right-sided heart catheterization (RHC) and pulmonary digital subtraction angiography (PDSA) are the standard methods used in diagnosing suspected or defi nite chronic thromboembolic pulmonary hypertension (CTEPH). We studied the ability of 320-slice CT imaging to detect simultaneously chronic thromboembolic fi ndings in the pulmonary arteries and pulmonary hemodynamics based on the curvature of the interventricular septum (IVS) in CTEPH ., Methods: Forty-four patients with high clinical suspicion of CTEPH underwent RHC, PDSA, and enhanced double-volume retrospective ECG-gated 320-slice CT scan. We measured the sensitivity and specificity of CT imaging to detect thrombi in the pulmonary arteries compared with PDSA. We also compared IVS bowing (expressed as curvature) measured on the short-axis cine heart image with pulmonary arterial pressure (PAP) obtained by RHC., Results: Compared with PDSA, the sensitivity and specificity of CT imaging to detect chronic thromboembolic findings were 97.0% and 97.1% at the main/lobar level and 85.8% and 94.6% at the segmental level, respectively. The correlation coefficients of IVS curvature with systolic PAP and mean PAP were 2 0.79 ( P , .001) and 2 0.86 ( P , .001), respectively., Conclusions: The use of 320-slice CT imaging allows for less invasive and simultaneous detection of thrombi and evaluation of pulmonary hemodynamics for the diagnostic work-up of CTEPH.

Background: Right ventricular failure does not explain all cases of death in patients with chronic pulmonary hypertension. Searching for alternative explanations, we evaluated the prognostic significance of main pulmonary artery (PA) dilatation in patients with pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH)., Methods: A retrospective outcome analysis was made of 264 patients (aged 46 ± 17 years; women, 69%; PAH, 82%) who underwent both CT scan measurement of the PA and right-sided heart catheterization (mean PA pressure, 57.6 ± 16.5 mm Hg) at initial evaluation., Results: The diameter of the PA ranged from 28 to 120 mm (mean, 39 ± 8.6 mm; median, 38 mm) and was largest in patients with unrepaired congenital defects (42.6 ± 7.6 mm). Pulmonary pulse pressure (P = .04), lower age (P = .03), and duration of symptoms (P &lt; .001) were independently but weakly related to PA diameter. During follow-up (median, 38 months), 99 patients (37%) died. Of these 99 deaths, 73 (74%) were due to heart failure or comorbidities, and 26 (26%) were unexpected deaths (UE-Ds). PA diameter (hazard ratio [HR], 1.06 per 1 mm; 95% CI, 1.03-1.08), heart rate (HR, 1.30 per 10 beats/min; 95% CI, 1.01-1.66), and systolic pulmonary arterial pressure (HR, 1.02 per 1 mm Hg; 95% CI, 1.01-1.04) were the only independent predictors of UE-D and differed from the usual predictors found in the study group for all-cause mortality. PA diameter ≥ 48 mm had 95% specificity and 39% sensitivity and carried 7.5 times higher risk of UE-D (95% CI, 3.4-16.5; P &lt; .0001) during follow-up., Conclusions: PA dilatation emerges as an independent risk factor for death unexplained by right ventricular failure or comorbidities in patients with PAH and CTEPH. The possible mechanisms include, but are not limited to, PA compression of the left main coronary artery, PA rupture, or dissection with cardiac tamponade.

Pulmonary arterial hypertension (PAH) is characterized by pulmonary vascular remodeling of the precapillary pulmonary arteries, with excessive proliferation of vascular cells. Although the exact pathophysiology remains unknown, there is increasing evidence to suggest an important role for inflammation. Firstly, pathologic specimens from patients with PAH reveal an accumulation of perivascular inflammatory cells, including macrophages, dendritic cells, T and B lymphocytes, and mast cells. Secondly, circulating levels of certain cytokines and chemokines are elevated, and these may correlate with a worse clinical outcome. Thirdly, certain inflammatory conditions such as connective tissue diseases are associated with an increased incidence of PAH. Finally, treatment of the underlying inflammatory condition may alleviate the associated PAH. Underlying pathologic mechanisms are likely to be "multihit" and complex. For instance, the inflammatory response may be regulated by bone morphogenetic protein receptor type 2 (BMPR II) status, and, in turn, BMPR II expression can be altered by certain cytokines. Although antiinflammatory therapies have been effective in certain connective-tissue-disease-associated PAH, this approach is untested in idiopathic PAH (iPAH). The potential benefit of antiinflammatory therapies in iPAH is of importance and requires further study.

Background: Despite a major reduction in pulmonary vascular resistance (PVR), patients with chronic thromboembolic pulmonary hypertension (CTEPH) do not always return to functional New York Heart Association (NYHA) class I after pulmonary endarterectomy (PEA). We hypothesized that residual abnormal compliance (Cp) after PEA is associated with incomplete functional recovery despite major improvement in PVR., Methods: The Cp of 34 consecutive patients with CTEPH was assessed before and after PEA. Cp was defined as stroke volume over pulse pressure and was divided into three groups: < 2.0 mL/mm Hg, 2.0 to 3.9 mL/mm Hg, and ≥ 4 mL/mm Hg. To establish predicted Cp after PEA, we collected an age- and gender-matched control group., Results: Before PEA, Cp was < 2.0 mL/mm Hg in 82% (n = 28) of the patients. After PEA, Cp improved to 2.0 to 3.9 mL/mm Hg in 11 patients and to ≥ 4.0 mL/mm Hg in 14 patients. Residual Cp < 2.0 mL/mm Hg was associated with delayed extubation and prolonged hospital stay. At 3 months' follow-up, 13 patients (93%) with postoperative Cp ≥ 4.0 mL/mm Hg returned to NYHA class I, whereas 45% with Cp of 2.0 to 3.9 mL/mm Hg and 25% with Cp < 2.0 mL/mm Hg returned to NYHA class I. In multivariate analysis, postoperative Cp ≥ 4.0 mL/mm Hg was the only predictor of functional recovery to NYHA class I. The group of patients with postoperative Cp ≥ 4.0 mL/mm Hg was also the only group to achieve hemodynamic parameters similar to those of their matched control subjects., Conclusions: Postoperative Cp is an important predictor of recovery after PEA. Residual vascular stiffness after PEA can be associated with persistent functional limitation and lack of complete remodeling of the right ventricle.

Background: Idiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF., Methods: We performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables., Results: The mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship., Conclusions: Higher mPAP in patients with IPF is associated with the development of PGD.

Background: Pulmonary hypertension is defined as resting mean pulmonary artery pressure (MPAP) ≥ 25 mm Hg. MPAP pressure estimation by right-sided heart catheterization (RHC) is considered the gold standard; however, its invasiveness limits repeated and frequent use. The purpose of this study was to compare the accuracy and precision of three echocardiographic methods for estimating MPAP., Methods: We prospectively studied 117 patients with simultaneous RHC and echocardiography. MPAP was calculated by three echocardiographic methods: (1) mean gradient method (adding the right ventricular-right atrial mean systolic gradient to the right atrial pressure), (2) Chemla equation (0.61 × systolic pulmonary artery pressure + 2 mm Hg), and (3) Syyed equation (0.65 × systolic pulmonary artery pressure + 0.55 mm Hg). MPAP calculated by these three methods was compared with that obtained invasively by RHC., Results: The mean ± SD of the differences between invasive MPAP and the three echocardiographic methods were -1.6 ± 7.7 mm Hg for the mean gradient method, -3.7 ± 7.4 mm Hg for the Chemla formula, and -3.2 ± 7.6 mm Hg for the Syyed formula. Median absolute differences were 5.5 mm Hg (mean gradient), 5.7 mm Hg (Chemla; P = .45 vs mean gradient), and 6.0 mm Hg (Syyed; P = .23 vs mean gradient). Accuracy (calculated MPAP within 10 mm Hg of RHC-measured MPAP) was 81% (mean gradient), 77% (Chemla), and 76% (Syyed)., Conclusions: Echocardiographic estimation of MPAP by the mean gradient method had similar accuracy and precision compared with the Chemla and Syyed methods. The acceptable accuracy of these methods suggests that they are equally suitable for clinical use.

Background: Pulmonary artery occlusion pressure (PAOP) is used to differentiate patients with pulmonary hypertension (PH) associated with left-sided heart disease from other etiologies. Technical errors in the measurement of PAOP are common and lead to incorrect classification of the etiology of PH. We investigated the agreement among PAOP measurements obtained from both pulmonary arteries with balloon full (1.5 mL) and half (0.75 mL) inflation in patients undergoing right-sided heart catheterization for suspected PH., Methods: Thirty-seven patients suspected or known to have PH who underwent right-sided heart catheterization were included. Seventy-six percent had PH (mean pulmonary arterial pressure > 25 mm Hg). The validity of the measurements was assessed by using five preestablished criteria based on hemodynamic, fluoroscopic, and gasometric data. For each patient, the measurement that most likely represented the left atrial pressure was labeled "best PAOP.", Results: Seventy percent of all the PAOP measurements met at least four of the five preestablished criteria for validity. In patients with PH (n = 28), the mean ± SE PAOP was 23.1 ± 2 and 19.1 ± 2 mm Hg for balloon full and half inflation, respectively, in the right pulmonary artery and 23.54 ± 2 and 19.07 ± 2 mm Hg for balloon full and half inflation, respectively, in the left pulmonary artery (P = .05). Bland-Altman analysis revealed lower bias and narrower limits of agreement with balloon half inflation. Wedge angiography showed that some balloon inflations failed to occlude upstream flow, whereas others had collateral vessels draining after the occlusion., Conclusions: PAOP can be falsely elevated in patients with PH according to the balloon inflation volume. Balloon half inflation was safe and correlated with higher precision and lower bias in the PAOP measurements.

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.

The current treatment of pulmonary arterial hypertension (PAH) uses vasodilator drugs. Although they improve symptoms associated with PAH, their chronic effects on the pulmonary vasculature and the right ventricle (RV) in humans remain unknown. We report the autopsy findings from a patient with idiopathic PAH treated with epoprostenol successfully for 18 years. The patient died of colon cancer. The pulmonary vasculature surprisingly showed extensive changes of a proliferative vasculopathy. Immunohistochemical studies confirmed ongoing cellular proliferation. Studies of the RV demonstrated concentric hypertrophy with seemingly preserved contractility. The myocardium shifted to glycolytic metabolism. Although the long-term use of epoprostenol contributed to the patient's increased survival, it did not prevent progression of the underlying vascular disease. Remarkably, the RV was able to sustain a normal cardiac output in the face of advanced vascular pathology. The mechanisms by which the RV adapts to chronic PAH need further study.

Background: This study compared the results of exercise Doppler echocardiography (EDE) with right-sided heart catheterization (RHC) and evaluated the combination of EDE and cardiopulmonary exercise testing (CPET) as a screening method for early pulmonary vasculopathy in patients with connective tissue disease., Methods: Patients (N = 52) with connective tissue disease (predominantly systemic sclerosis) and without known pulmonary arterial hypertension underwent both EDE and CPET. If systolic pulmonary arterial pressure (SPAP) was > 40 mm Hg during exercise or peak oxygen uptake (Vo(2)) was < 75% predicted, RHC was suggested., Results: EDE showed an SPAP > 40 mm Hg during exercise in 26/52 patients. Additionally, CPET showed a peak Vo(2) < 75% predicted in 10/26 patients with SPAP 40 mm Hg in 25 patients (n = 1 at rest, n = 24 during exercise). SPAP values assessed by EDE showed no significant difference vs RHC at rest, 25 W, 50 W, and maximal exercise (difference [95% CI]: 0.3 [-2.7; 3.2], -1.3 [-7.1; 4.4], 0.9 [-7.7; 5.9], and -5.6 [-13.5; 2.2] mm Hg). Eight patients with exercise SPAP > 40 mm Hg had an exercise pulmonary arterial wedge pressure > 20 mm Hg, suggesting exercise-induced left ventricular diastolic dysfunction not detectable by EDE., Conclusions: EDE appears to be a reasonable noninvasive method to detect SPAP increase during exercise in connective tissue disease. In combination with CPET, it may be a useful screening tool for early pulmonary vasculopathy, although RHC remains the gold standard for hemodynamic assessment., Trial Registration: clinicaltrials.gov; Identifier: NCT00609349 (Early Recognition of Pulmonary Arterial Hypertension).

Background: No published data have systematically documented pulmonary artery pressure over an intermediate time period after submassive pulmonary embolism (PE). The aim of this work was to document the rate of pulmonary hypertension, as assessed noninvasively by estimated right ventricular systolic pressure (RVSP) of >or= 40 mm Hg 6 months after the diagnosis of submassive PE., Methods: We enrolled 200 normotensive patients with CT angiography-proven PE and a baseline echocardiogram to estimate RVSP. All patients received therapy with unfractionated heparin initially, but 21 patients later received alteplase in response to circulatory shock or respiratory failure. Patients returned at 6 months for repeat RVSP measurement, and assessments of the New York Heart Association (NYHA) score and 6-min walk distance (6MWD)., Results: Six months after receiving a diagnosis, 162 of 180 survivors (90%) returned for follow-up, including 144 patients who had been treated with heparin (heparin-only group) and 18 patients who had been treated with heparin plus alteplase (heparin-plus-alteplase group). Among the heparin-only patients, the RVSP at diagnosis was >or= 40 mm Hg in 50 of 144 patients (35%; 95% CI, 27% to 43%), compared with 10 of 144 patients at follow-up (7%; 95% CI, 3% to 12%). However, the RVSP at follow-up was higher than the baseline RVSP in 39 of 144 patients (27%; 95% CI, 9% to 35%), and 18 of these 39 patients had a NYHA score of >or= 3 or exercise intolerance (6MWD, < 330 m). Among heparin-plus-alteplase patients, the RVSP was >or= 40 mm Hg in 11 of 18 patients at diagnosis (61%; 95% CI, 36% to 83%), compared with 2 of 18 patients at follow-up (11%; 95% CI, 1% to 35%). The RVSP at follow-up was not higher than at the time of diagnosis in any of the heparin-plus-alteplase patients (95% CI, 0% to 18%)., Conclusions: Six months after experiencing submassive PE, a significant proportion of patients had echocardiographic and functional evidence of pulmonary hypertension.

Background: Pulmonary hypertension is a common cause of functional tricuspid regurgitation (TR), but other factors play a role in determining TR severity. The objectives of our study were to determine the distribution of TR severity in relation to pulmonary artery systolic pressure (PASP) and to define the determinants of TR severity., Methods: The echocardiographic reports and selected echocardiographic studies of patients with echocardiographic estimation of PASP were reviewed. Patients with organic tricuspid valve (TV) disease were excluded from the analysis., Results: Among 2,139 patients, the frequency of moderate or severe TR was progressively greater in patients with higher PASP. Nevertheless, TR was only mild in a substantial proportion of patients with high PASP (mild TR in 65.4% of patients with PASP 50-69 mm Hg and in 45.6% of patients with PASP >or= 70 mm Hg). By multivariate analysis, age, female gender, PASP (odds ratio, 2.26 per 10-mm Hg increase; 95% confidence interval, 1.95 to 2.61), pacemaker lead, right atrial (RA) and right ventricular enlargement, left atrial enlargement, and organic mitral valve disease were independently associated with greater degrees of TR. In patients with PASP >or= 70 mm Hg, RA size, tricuspid annular diameter, and TV tethering area were greater in patients with greater degrees of TR., Conclusions: PASP is a strong determinant of TR severity, but many patients with pulmonary hypertension do not exhibit significant TR. In addition to PASP, demographic characteristics, mechanical factors, remodeling of the right heart cavities, and other factors (possibly reflecting the presence of atrial fibrillation or occult organic TV disease) are predictive of TR severity.

Introduction: Pulmonary arterial hypertension (PAH) is the most common cause of scleroderma-related deaths. New medications for PAH patients make it necessary to identify patients with high risk factors for PAH. This study looks at the use of an exercise echocardiogram in identifying patients who may have PAH and may be candidates for early therapeutic intervention., Methods: This study included 54 scleroderma patients with symptoms suggesting they were at risk for pulmonary hypertension, including dyspnea on exertion, diffusing capacity of the lung for carbon monoxide (Dlco)<60% of predicted, FVC<70% of predicted, percentage of predicted FVC/percentage of predicted Dlco (FVC%/Dlco%) ratio>1.6, or resting right ventricular systolic pressure (RVSP)>35 mm Hg. The exercise echocardiogram protocol involved the standard Bruce stress echocardiogram protocol with remeasurement of the RVSP within 1 min of stopping exercise. A positive exercise test result was defined as an increase of at least 20 mm Hg in the RVSP with exercise. Right-heart catheterization with exercise was performed in those with a positive exercise test result., Results: Resting mean RVSP was 34.5 mm Hg, which increased to 51.4 mm Hg with exercise; 44% had at a positive exercise test result, which correlated with a low Dlco, high FVC%/Dlco% ratio (p<0.001), a positive anti-centromere antibody, and RVSP>35 mm Hg (p<0.05). PAH was confirmed by right-heart catheterization in 81% of patients: 19% at rest and 62% of patients with exercise., Conclusions: Exercise-induced pulmonary hypertension is a common finding in patients at high risk for PAH. This may be a sensitive way to identify patients with early PAH. Long-term follow-up and early treatment should be studied in these patients.

Background: Bronchiectasis may have deleterious effects on cardiac function secondary to pulmonary hypertension (PH). This study was designed to assess cardiac function and determine the prevalence of PH in patients with cystic and cylindrical bronchiectasis., Methods: A cross-sectional study of patients with bronchiectasis diagnosed by CT scan was conducted at King Khalid University Hospital, Riyadh, Saudi Arabia between December 2005 and January 2007. Pulmonary function tests were performed, arterial blood gas measurements were made, and cardiac function and systolic pulmonary artery pressure (SPAP) were assessed by echocardiography., Results: Of 94 patients (31% men, n = 29), 62 patients (66%) had cystic bronchiectasis and 32 patients (34%) had cylindrical bronchiectasis. Right ventricular (RV) systolic dysfunction was observed in 12 patients (12.8%), left ventricular (LV) systolic dysfunction was observed in 3 patients (3.3%), and LV diastolic dysfunction was observed in 11 patients (11.7%); all had cystic bronchiectasis. RV dimensions were significantly greater in the cystic bronchiectasis group, and were positively correlated with SPAP (p < 0.0001) and negatively correlated with Pao2 (p < 0.016). Other hemodynamic variables were not different between groups. PH in 31 patients (32.9%) was significantly greater in patients with cystic bronchiectasis compared with cylindrical bronchiectasis (p = 0.04). In cystic bronchiectasis, SPAP was positively correlated with Paco2 (p = 0.001), and inversely correlated with Pao2 (p = 0.03), diffusion capacity of the lung for carbon monoxide percentage (p = 0.02), and FEV1 (p = 0.02)., Conclusions: RV systolic dysfunction and PH were more common than LV systolic dysfunction in bronchiectatic patients. LV diastolic dysfunction was mainly seen in severe PH. We recommend detailed assessment of cardiac function, particularly LV diastolic function, in patients with bronchiectasis.

Aims: Decreased total compliance of the pulmonary vascular bed is associated with increased mortality in patients with pulmonary arterial hypertension (PAH). We investigated whether proximal pulmonary artery stiffness, in terms of area distensibility and noninvasively assessed relative area change (RAC), calculated as relative cross-sectional area change, predicts mortality in patients with PAH., Methods and Results: Eighty-six subjects underwent right-heart catheterization and MRI to assess area distensibility and RAC. Patients were followed up to 48 months. Kaplan-Meier plot and Cox proportional hazards regression analyses assessed the predictive value of area distensibility and RAC. In 70 patients, the diagnosis PAH was confirmed, and 16 subjects served as control subjects. In comparison with control subjects, proximal pulmonary arteries of patients were distended (685 +/- 214 mm2 vs 411 +/- 153 mm2, p < 0.001), less distensible (area distensibility = 0.46 +/- 0.38.10(-2) mm Hg(-1) vs 3.69 +/- 1.96.10(-2) mm Hg(-1), p < 0.0001), and RAC was smaller (20 +/- 10% vs 58 +/- 21%, p < 0.0001) [mean +/- SD]. RAC showed an inverse curvilinear relation with mean pulmonary artery pressure (R2 = 0.47). Eighteen patients (26%) died because of cardiopulmonary causes. Patients with a pulmonary artery RAC 16% (log-rank p < 0.001). RAC predicted mortality better than area distensibility., Conclusion: Noninvasively measured pulmonary artery RAC predicts mortality in patients with PAH.

Pulmonary hypertension can occur from obstruction of the distal pulmonary arteries by thrombus, ova and parasites, and foreign material. We report a 62-year-old patient who had fatal pulmonary hypertension from an 8-cm fragment of a totally implantable venous access device (TIVAD) retained in the pulmonary artery. Despite long-term therapeutic anticoagulation, pulmonary angiography showed chronic occlusion of the posterior branch of the superior right pulmonary artery with paucity of distal vasculature consistent with an old right upper lobe pulmonary embolus. Retrieval of the fragment was attempted via pulmonary artery catheterization techniques but was unsuccessful. In conclusion, progressive pulmonary hypertension may result from retention of a TIVAD fragment in a central pulmonary artery despite therapeutic anticoagulation. Worsening pulmonary hypertension may have been due to partial obstruction of the main pulmonary arteries, resulting in recurrent thromboembolism or in situ thrombosis, and remodeling of small distal pulmonary arteries.

Background: Left ventricular (LV) filling is impaired in patients with severe emphysema manifesting in small end-diastolic dimensions. We hypothesized that the hyperinflated lungs of these patients with high intrinsic positive end-expiratory pressure will decrease intrathoracic blood volume (ITBV) and ventricular preload. We therefore measured ITBV, and LV and right ventricular (RV) dimensions and function using MRI techniques in patients with severe emphysema., Methods: Patients with severe emphysema (n = 13) and matched healthy volunteers (n = 11) were included. The magnetic resonance (MR) examination consisted of three parts: (1) evaluation of RV and LV dimensions and function and interventricular septum curvature using cine MRI; (2) quantification of aortic flow using MR phase velocity mapping; and (3) calculation of the cardiopulmonary peak transit time (PTT) from the pulmonary artery to the ascending aorta using contrast-enhanced, time-resolved, two-dimensional MR angiography., Results: There were no differences between the groups regarding age, height, or weight. In the emphysema patients, ITBV index (- 35%), LV end-diastolic volume index (LVEDVI) [- 21%], RV end-diastolic volume index (- 20%), cardiac index (- 22%), and stroke volume index (SVI) [- 40%] were lower compared to control subjects. LV and RV end-systolic volumes, LV wall mass, septal curvature, and PTT did not differ between the groups. LVEDVI (r = 0.83) as well as SVI (r = 0.82) correlated closely to ITBV index. SVI correlated closely to LVEDVI (r = 0.84)., Conclusions: LV and RV performance is impaired in patients with severe emphysema because of small end-diastolic dimensions. One possible explanation for the decreased biventricular preload in these patients is intrathoracic hypovolemia caused by hyperinflated lungs.

Background: Pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH) are the major classes of pulmonary hypertensive disorders according to the World Health Organization; both lead to right heart failure and death. A better understanding of disease mechanisms has led to the suggestion that the thromboembolic and nonthromboembolic types of pulmonary hypertension may share pathophysiologic features. We therefore compared acute vasoreactivity and proximal pulmonary artery compliance in patients with PAH and CTEPH during the initial diagnostic heart catheterization., Methods: Right heart catheterization using a flow-directed Swan-Ganz catheter was performed in patients with CTEPH (n = 22) and PAH (n = 35). Pulmonary hemodynamics were assessed at baseline, during the inhalation of 40 ppm of nitric oxide, and 30 min after the inhalation of 10 mug of iloprost. To assess the proximal pulmonary artery compliance, the pulse pressure (PP) [systolic-diastolic pressure] and the fractional PP (PPf) [divided by the mean pressure] were calculated., Results: Both vasodilators produced similar hemodynamic improvement, and the difference between CTEPH and PAH was not significant. The baseline PP and PPf did not vary between the two groups., Conclusion: Patients with PAH and CTEPH show similar acute vasoreactivity to inhaled nitric oxide and iloprost, and have similar pulmonary artery compliance. These findings support the presence of some shared pathophysiologic pathways in both disorders and may lead to therapeutic implications in patients with inoperable CTEPH.

Hypoxia-induced pulmonary vasoconstriction (HPV) is an important adaptive process that remains incompletely understood. In preconstricted rat pulmonary arteries (inner diameter, 250 to 400 microm), hypoxia (pO2 approximately 10 mm Hg) induces an initial transient phase and a more slowly developing sustained phase of vasoconstriction. Since the release of calcium ions (Ca2+) from intracellular stores by redox-sensitive intracellular Ca2+ release channels known as ryanodine receptors (RyRs) in pulmonary arterial smooth-muscle cells (PASMCs) may play a role in HPV, and considerable evidence now supports that levels of reactive oxygen species (ROS) are paradoxically increased in PASMC under hypoxia, we investigated whether redox activation of RyRs by ROS may transduce HPV. By reverse transcriptase-polymerase chain reaction, we found that all three RyR isoforms are expressed in rat pulmonary arteries and in PASMCs. The sustained phase, but not the transient phase, of HPV can be prevented by pretreating pulmonary arteries with RyR inhibitors ryanodine (200 micromol/L) or dantrolene (50 micromol/L). The addition of dantrolene, ryanodine or the thiol-reducing agent dithiothreitol (1 mmol/L) during the sustained phase of HPV reversed the hypoxic vasoconstriction. In contrast, the superoxide scavenger nitroblue tetrazolium (500 nmol/L) prevented further hypoxic pulmonary vasoconstriction during the sustained phase of HPV but did not reverse it. Taken together, our data suggest that redox activation of RyRs by ROS has an important role in transducing the sustained contraction of pulmonary arteries under hypoxia.

Chronic hypoxia (CH) is a common cause of pulmonary hypertension (PH). Accumulating evidence suggests that changes in the activity of endothelin (ET)-1 receptors may play an important role in CH-induced PH. After 3 weeks of CH (10% O2) exposure, we found that the isolated intra-pulmonary artery (PA) constrictor response to ET-1 was significantly increased in wild-type (wt) mice. The administration of Cu/Zn superoxide dismutase (SOD) markedly reduced the CH-enhanced maximal PA constrictor response to ET-1, demonstrating the contribution of superoxide to CH-enhanced PA constrictor responses. Using mice that are completely deficient in gp91phox (a subunit protein of the superoxide producing nicotinamide adenine dinucleotide phosphate [NADPH] oxidase), we found that CH-enhanced PA constriction to ET-1 was completely blocked (decreases in mean [+/- SE] maximal isometric tension from 5.43 +/- 0.35 to 3.33 +/- 0.19 mN; n = 7; p < 0.01). Using a lucigenin-enhanced chemiluminescence technique to measure superoxide, we found that the 3 weeks of CH significantly increased superoxide levels in PA isolated from wt mice. The addition of ET-1 further increased superoxide production. To demonstrate that the increased chemiluminescence is due to superoxide generation, we added Cu/Zn SOD, which markedly decreased chemiluminescence, demonstrating the specificity of this assay. When gp91phox knockout mice were exposed to CH, they had significantly reduced levels of superoxide compared to CH-treated wt mice. Our results demonstrate that the CH-enhanced PA constrictor response to ET-1 is mediated by NADPH oxidase (gp91phox)-derived superoxide overproduction that may contribute to the pathogenesis of CH-induced PH.

The hemodynamic effects of ventilation are complex but can be grouped under four clinically relevant concepts. First, spontaneous ventilation is exercise, and critically ill patients may not withstand the increased work of breathing. Initiation of mechanical ventilatory support will improve oxygen delivery to the remainder of the body by decreasing oxygen consumption. To the extent that mixed venous oxygen also increases, Pao(2) will increase without any improvement in gas exchange. Similarly, weaning from mechanical ventilatory support is a cardiovascular stress test. Patients who fail to wean also manifest cardiovascular insufficiency during the failed weaning attempts. Improving cardiovascular reserve or supplementing support with inotropic therapy may allow patients to wean from mechanical ventilation. Second, changes in lung volume alter autonomic tone and pulmonary vascular resistance (PVR), and at high lung volumes compress the heart in the cardiac fossa. Hyperinflation increases PVR and pulmonary artery pressure, impeding right ventricular ejection. Decreases in lung volume induce alveolar collapse and hypoxia, stimulating an increased pulmonary vasomotor tone by the process of hypoxic pulmonary vasoconstriction. Recruitment maneuvers, positive end-expiratory pressure, and continuous positive airway pressure may reverse hypoxic pulmonary vasoconstriction and reduce pulmonary artery pressure. Third, spontaneous inspiration and spontaneous inspiratory efforts decrease intrathoracic pressure (ITP). Since diaphragmatic descent increases intra-abdominal pressure, these combined effects cause right atrial pressure inside the thorax to decrease but venous pressure in the abdomen to increase, markedly increasing the pressure gradient for systemic venous return. Furthermore, the greater the decrease in ITP, the greater the increase in left ventricular (LV) afterload for a constant arterial pressure. Mechanical ventilation, by abolishing the negative swings in ITP, will selectively decrease LV afterload, as long as the increases in lung volume and ITP are small. Finally, positive-pressure ventilation increases ITP. Since diaphragmatic descent increases intra-abdominal pressure, the decrease in the pressure gradient for venous return is less than would otherwise occur if the only change were an increase in right atrial pressure. However, in hypovolemic states, positive-pressure ventilation can induce profound decreases in venous return. Increases in ITP decrease LV afterload and will augment LV ejection. In patients with hypervolemic heart failure, this afterload reducing effect can result in improved LV ejection, increased cardiac output, and reduced myocardial oxygen demand.

Objectives: Primary pulmonary hypertension (PPH) is a pulmonary vasculopathy resulting in exercise intolerance, usually due to dyspnea. We hypothesized that ventilation is increased during exercise in PPH relative to normal because the ventilated lung is underperfused, cardiac output increase is restricted, and arterial hypoxemia may develop. Our aim was to determine the size of the reduction in end-tidal Pco(2) (Petco(2)) as a reflection of the abnormality in ventilatory efficiency and ventilatory drive in PPH patients., Methods: We performed cardiopulmonary exercise testing (CPET) in 52 PPH patients. All had hemodynamic measurements to confirm the diagnosis of PPH. A subgroup of 29 patients who underwent right-heart catheterization within 50 days of CPET were studied to compare their CPET responses to resting hemodynamics. Nine healthy volunteers matched for age and gender served as CPET control subjects., Results: In PPH patients, the percentage of predicted peak oxygen uptake (Vo(2)) correlated significantly with mean pulmonary artery pressure (mPAP) [r = - 0.59, p = 0.0007, n = 29]. Petco(2) values at rest, anaerobic threshold (AT), and peak Vo(2) were proportionately reduced as percentage of predicted peak Vo(2) decreased (r = 0.66 to 0.72, p < 0.0001, n = 52). Petco(2) values at rest, AT, and peak Vo(2) were also reduced as mPAP increased (r = - 0.51 to - 0.53, p < 0.005, n = 29). In contrast to normal subjects in whom Petco(2) increased from rest to AT, Petco(2) decreased in PPH patients, except for two patients with mild PPH in whom there was no change. Also, Petco(2) increased rather than decreased further at the start of recovery, in contrast to normal. Although usually normal at rest, oxyhemoglobin saturation decreased during exercise in most PPH patients., Conclusions: In patients with PPH, Petco(2) at rest and exercise is significantly reduced in proportion to physiologic disease severity. The range of values is unusually low. Furthermore, the directional changes of Petco(2) during exercise and early recovery are in the opposite direction of normal.

Study Objective: In these days, it was reported that bone marrow (BM) cells might take part in the remodeling of some systemic vascular diseases; however, it remains unknown whether the BM cells were involved in the vascular remodeling of pulmonary arteries and the progression of pulmonary hypertension (PH). The purpose of this study was to investigate whether BM-derived cells contribute to pulmonary vascular remodeling in hypoxia-induced PH., Materials and Methods: To investigate the role of BM-derived cells, we transplanted the whole BM of enhanced green fluorescent protein (GFP)-transgenic mice to the lethally irradiated syngeneic mice (n = 30). After 8 weeks, chimera mice were exposed to consistent hypoxia using a hypoxic chamber (10% O(2)) for up to 4 or 8 weeks (10 mice per group). After hemodynamics and the ratio of right ventricular (RV) weight to left ventricle (LV) weight, RV/(LV + septum [S]), were measured, histologic and immunofluorescent staining were performed., Results: BM-transplanted mice showed a high chimerism (mean [+/- SEM], 91 +/- 2.3%). RV systolic pressure and the RV/(LV + S) ratio increased significantly with time in PH mice, indicating RV hypertrophy. Marked vascular remodeling including medial hypertrophy and adventitial proliferation was observed in the pulmonary arteries of PH mice. Strikingly, a number of GFP(+) cells were observed at the pulmonary arterial wall, including the adventitia, in hypoxia-induced PH mice, while very few cells were observed in the control mice. Metaspectrometer measurements using confocal laser scanning microscopy confirmed that this green fluorescence was produced by GFP, suggesting that these GFP(+) cells were mobilized from the BM. Most of them expressed alpha-smooth muscle actin, a smooth muscle cell, or myofibroblast phenotype, and contributed to the pulmonary vascular remodeling. A semiquantitative polymerase chain reaction of the GFP gene revealed that the BM-derived GFP-positive cells in the PH group were observed more than eightfold as often compared with the control mice., Conclusion: The BM-derived cells mobilize to the hypertensive pulmonary arteries and contribute to the pulmonary vascular remodeling in hypoxia-induced PH mice.

Study Objectives: In patients with pulmonary hypertension (PH) secondary to congestive heart failure, inhaled nitric oxide (NO) increases pulmonary vascular smooth-muscle intracellular cyclic guanosine monophosphate (cGMP) concentration, thereby decreasing pulmonary vascular resistance (PVR) and increasing cardiac index (CI). However, these beneficial effects of inhaled NO are limited in magnitude and duration, at least in part due to cGMP hydrolysis by the type 5 isoform of phosphodiesterase (PDE5). The goal of this study was to determine the acute pulmonary and systemic hemodynamic effects of the selective PDE5 inhibitor, sildenafil, administered alone or in combination with inhaled NO in patients with congestive heart failure and PH., Design: Single center, case series, pharmacohemodynamic study., Setting: Cardiac catheterization laboratory of a tertiary care academic teaching hospital., Patients: We studied 11 patients with left ventricular systolic dysfunction due to coronary artery disease or idiopathic dilated cardiomyopathy who had PH., Interventions: We administered oral sildenafil (50 mg), inhaled NO (80 ppm), and the combination of sildenafil and inhaled NO during right-heart and micromanometer left-heart catheterization., Measurements and Results: Sildenafil administered alone decreased mean pulmonary artery pressure by 12 +/- 5%, PVR by 12 +/- 5%, systemic vascular resistance (SVR) by 13 +/- 6%, and pulmonary capillary wedge pressure by 12 +/- 7%, and increased CI by 14 +/- 5% (all p < 0.05) [+/- SEM]. The combination of inhaled NO and sildenafil decreased PVR by 50 +/- 4%, decreased SVR by 24 +/- 3%, and increased CI by 30 +/- 4% (all p < 0.01). These effects were greater than those observed with either agent alone (p < 0.05). In addition, sildenafil prolonged the pulmonary vasodilator effect of inhaled NO. Administration of sildenafil alone or in combination with inhaled NO did not change systemic arterial pressure or indexes of myocardial systolic or diastolic function., Conclusions: PDE5 inhibition with sildenafil improves cardiac output by balanced pulmonary and systemic vasodilation, and augments and prolongs the hemodynamic effects of inhaled NO in patients with chronic congestive heart failure and PH.