Primary Pulmonary Hypertension Patients Research Articles

Outcomes of heart-lung transplantation in Eisenmenger syndrome compared to primary pulmonary hypertension.

Heart-Lung Transplantation (HLTX) is required both in primary pulmonary hypertension (PPH) and Eisenmenger syndrome (ES) when there is associated end-stage heart disease. Although PPH is associated with an otherwise structurally normal heart, ES is associated with congenital heart defects, which may increase the complexity of the operation. This study analyzes if the diagnosis (PPH vs. ES) is related to short-term outcomes after HLTX. Patients ≥18 years of age with PPH and ES who underwent HLTX were identified in the United Network for Organ Sharing database from 2005 to 2021. Patients were propensity score matched on heart and lung listing status at the time of transplant. Univariable, multivariable, and Kaplan-Meir survival analyses were performed. The unmatched cohort had 128 PPH and 44 ES patients, and the matched cohort had 44 patients in each group. PPH patients had lower waitlist times and PA pressures but higher FEV1, heart, and lung listing status and ECMO bridge. There were no differences in immediate postoperative outcomes such as dialysis, stroke, and airway dehiscence. PPH patients had a higher treatment rejection in the first year. The 30-day, 1-year, and 3-year survival were better in the PPH group. However, a landmark analysis excluding deaths within 30 days eliminated differences in survival between the groups. Post-transplant dialysis and postoperative mechanical ventilation >5 days were risk factors for 1-year mortality in ES. The short-term outcomes of HLTX are inferior in ES compared to PPH and much of the attrition in ES occurs in the immediate postoperative period.

Novel Prognostic Predictor for Primary Pulmonary Hypertension: Focus on Blood Urea Nitrogen.

Background: Primary pulmonary hypertension (PPH) is a life-threatening disease associated with increased mortality. The urea cycle pathway plays a major role in PPH severity and treatment response. Little is known about the association of the blood urea nitrogen (BUN) and PPH prognosis.Methods: Clinical data were extracted from the Medical Information Mart for Intensive Care III (MIMIC-III) database. Adult patients (≥18 years) patients with primary pulmonary hypertension (PPH) in the database were enrolled. Spearman correlation was used to analyze the association of BUN with length of hospital and intensive care unit (ICU) stays. The chi-square test was used to analyze the association of BUN with mortality rate. Survival curves were estimated using the Kaplan-Meier method and compared by the log-rank test. Multivariable logistic regression was used to identify the BUN as an independent prognostic factor of mortality. Receiver operating characteristic (ROC) curves and the area under the curve (AUC) were used to analyze the sensitivity and specificity for mortality.Results: In total, 263 patients who met the selection criteria were enrolled. BUN was significantly positively associated with length of hospital stay and ICU stay (hospital stay: ρ = 0.282, ICU stay: ρ = 0.276; all P < 0.001). Higher hospital, 90-day and 4-year mortality rates were observed in the higher BUN quartile of PPH patients (hospital: P = 0.002; 90-day: P = 0.025; 4-year: P < 0.001). The Kaplan-Meier survival curves showed that patients in higher BUN quartile tended to have lower 4-year survival (Q1:7.65%, Q2: 10.71%; Q3: 14.80%, Q4: 16.84%; P < 0.0001). Logistic regression analyses found a significant association of BUN and mortality (hospital: OR = 1.05, 95% CI = 1.02–1.08, P = 0.001; 90-day: OR = 1.02, 95% CI = 1.00–1.05, P = 0.027; 4-year: OR = 1.05, 95% CI = 1.02–1.08, P = 0.001). Results of ROC and AUC showed that the diagnostic performance of BUN for mortality was moderately good.Conclusion: BUN was positively correlated with the length of hospital stay and ICU stay of PPH patients. Higher BUN was associated with higher hospital, 90-day and 4-year mortality and lower 4-year survival of PPH patients. These findings indicate that BUN can be a novel potential prognostic predictor for PPH.

OPTICAL COHERENCE TOMOGRAPHY ANGIOGRAPHY FINDINGS OF MICROVASCULAR AND NEURAL CHANGES IN PRIMARY PULMONARY HYPERTENSION.

To investigate the microvascular and neural changes in primary pulmonary hypertension (PPH) patients compared with healthy controls. Forty-four eyes of 22 PPH patients were included in this observational clinical cohort study, and 44 eyes of 22 healthy participants were enrolled as controls. Optical coherence tomography angiography images were obtained from each participant using the RTVue XR Avanti device with AngioVue software 2.0. Regarding the total macular-associated vessel density, including that of the superficial and deep retina, the optic disk-associated capillary density, including that of the whole image, capillary density inside the disk, and the peripapillary region, was significantly lower in the PPH group than in the control group. There was a similar trend in the retinal nerve fiber layer thickness and the ganglion cell complex thickness, whereas the focal loss volume and the global loss volume were greater in the PPH group than the control group. Changes in the capillary density and thickness of the retina and the optic nerve head in PPH patients can be detected by optical coherence tomography angiography. Parameters including the macular-associated vessel density, optic disk-associated capillary density, retinal nerve fiber layer, ganglion cell complex, focal loss volume, and global loss volume may provide useful evidence for the early detection of microvascular and neural impairments in patients with PPH.

Retrospective observational analysis of hospital discharge database to characterize primary pulmonary hypertension and its outcomes in Spain from 2004 to 2015.

To examine trends in the incidence, characteristics and outcomes, and to identify factors associated with in-hospital mortality (IHM) of patients hospitalized for primary pulmonary hypertension (PPH) in Spain (2004-2015).We included all patients hospitalized with PPH and included in the Spanish National Hospital Discharge Database.We analyzed 46,883 discharges of patients (7.14% with PPH as their primary diagnosis). Incidence rates decreased from 6.15 cases per 100,000 inhabitants in 2004-06 to 3.40 in 2013-15 (P < .001). Mean age rose from 66.43 ± 21.28 to 69.73 ± 21.12 years (P < .001) and the proportion of females increased over the study period (58.44% vs 60.71%; P < .001). Comorbidity using the Charlson Comorbidity Index (CCI) also increased with 16.07% having CCI ≥3 in 2004-06 vs 21.795 in 2013-15. Median length of hospital stay (LOHS) was 1 day longer in period 2004-06, than in 2013-15 (9 vs 8 days; P < .001). The proportion of patients who were considered a readmission and the mean costs increased from 15.7% and 3712.46&OV0556; in the first period to 17.14% and 4040.28&OV0556; in 2013-15 (P < .001). IHM increased from 8.2% in 2004-06 to 9.93% in 2013-15 (P < .001). The predictors' of IHM among PPH patients included comorbidity and use of mechanical ventilation. Primary diagnosis of PPH did not predict higher IHM (OR 1.07; 95%CI 09-1.26).Our data indicates that the incidence of hospitalizations decreased in Spain between 2004 and 2015. Parallel, LOHS also decreased during this period. By contrast, comorbidity increased over time in PPH patients, as well as readmission rates, costs and IHM.

MYOCARDIAL PERFUSION AND NEUROTROPIC SINGLE-PHOTON EMISSION COMPUTED TOMOGRAPHY FEATURES IN PATIENTS WITH PRIMARY PULMONARY HYPERTENSION

Objective.To compare cardiac123I-MIBG and99m Tc-MIBI single-photon emission computed tomography (SPECT) data in patients with primary pulmonary hypertension (PPH).Material and methods.The study included 22 patients with confirmed diagnosis of PPH, with clinical status assessment, Holter ECG monitoring and rest cardiac ultrasound (US) data. All patients, as well as a group of healthy volunteers (n=20) underwent myocardial perfusion SPECT with99mTc-MIBI at rest and after treadmill exercise test, and myocardial neurotropic SPECT with123I-MIBG, performed in 15 min (early phase) and 4 hours (delayed phase) after MIBG administration. LV perfusion abnormalities were evaluated using standard SSS and SDS parameters, RV was assessed visually, RV/LV and IVS/LW uptake ratios were calculated. Global sympathetic activity (SA) was assessed with delayed heart/mediastinum ratio (H/Md) and MIBG Washout Rate in 4 hours (WR). Regional SA abnormalities were assessed using early Summed MIBG Score (SMSe). MIBG RV/LV and LV IVS/LW uptake ratios were calculated. All parameters were compared with normal database (n=20).Results.The values of a number of myocardial SPECT parameters, both perfusion (SSS, RV/LVMIBI, IVS/LWMIBI) and neurotropic (H/Md, WR, SMSe, IVS/LWMIBG), were significantly worse in PPH patients compared to the control group (all p&lt;0.05). Perfusion SPECT showed no significant (SDS&gt;4) transient LV ischemia in all patients, but in 77% of cases IVS perfusion was stably impaired, causing overall SSS=7 (6–10), presumably due to IVS compression by dilated RV. MIBI RV/LV ratio was 0.61±0.02, indicating that RV was clearly visible, with inhomogeneous MIBI uptake in all cases, but without reliable perfusion defects. Values of H/Mdwere 1.84±0.18, WR: 27±8%, with no reliable correlations with perfusion parameters. Regional SA defects also were located in IVS predominately, causing SMSemean value of 8 (6–10) and IVS/LW of 0.69±0.09, both parameters correlated with SSS (r=0.44, p=0.04 and r=-0.48, p=0.02, respectively). All parameters, except RV/LVMIBG, had reliable correlations with systolic pulmonary artery pressure assessed by cardiac US, especially RV/LVMIBI(r=0.64, p&lt;0.01), WR (r=0.55, p=0.01) and IVS/LWMIBG(r=-0.49, p=0.02).Conclusion.Combination of myocardial neurotropic and perfusion SPECT has a certain diagnostic value in patients with PPH, since MIBG SPECT reflects SA downregulating, and MIBI SPECT reveals specific microcirculatory abnormalities in these patients, both possibly caused by myocardial pressure overload and responsible for angina-like symptoms.

A Comparison of Pattern of Breathing during Incremental Exercise in Patients with Pulmonary Fibrosis and Primary Pulmonary Hypertension

It has previously been proposed that the pattern of breathing during exercise, and particularly maximum tidal volume, can be used to distinguish between interstitial lung disease and pulmonary vascular disease; however this has never been formally investigated. This study looks at the impact of incremental exercise on a bicycle ergometer and the impact that such exercise has on breathing pattern, specifically maximum tidal volume. Method: We retrospectively reviewed the incremental exercise tests of 10 patients with pulmonary fibrosis (PF) and 9 with primary pulmonary hypertension (PPH). Patients were exercised using a bicycle ergometer, seated, and breathing into a mouthpiece. Results: The VE/VCO2 relationship was linear in all patients, but PPH patients had higher VE/VCO2 slopes (0.058±0.03) mean ±SD than PF patients (0.039±0.01, P<0.04). The respiratory rate/VE slopes were also higher in PPH patients (0.48±0.17) than in PF patients (0.30±0.14, P<0.02). There was no correlation between the VTmax/IC at the end of exercise and the IC %predicted in either group. However, VTmax as % of IC at the end of exercise in PPH patients (59.1±7.6) was lower than in PF patients (87.0±14.5%, P<0.001). Conclusion: The pattern of breathing during exercise, specifically maximum tidal volume, is different in patients with primary pulmonary hypertension compared with pulmonary fibrosis patients. These changes in the breathing pattern are unrelated to underlying static and dynamic lung function. Thus, the conclusion is that patients who have lung diseases which restrict their breathing often compensate, likely in an effort to avoid dyspnea, by modifying their natural breathing into a more tightly constrained pattern.

Lung transplantation for pediatric pulmonary hypertension

Lung and heart–lung transplantation are accepted therapies for the treatment of end-stage lung or cardiovascular disease in children for whom there are no medical or surgical treatment options. Worldwide, more than 200 children have undergone this procedure since 1986 and 1987, when respectively, the first pediatric heart–lung transplant and the first pediatric lung transplant procedures were performed. The issues that relate to surgical techniques as well as outcomes are distinctly unique for children compared to adults. End-stage pulmonary vascular disease due to primary pulmonary hypertension (PAH) is one of the primary indications for lung or heart–lung transplantation. Generally, for all pediatric lung transplant recipients, the outcomes are comparable to those of adult recipients, with a median survival of 4.3 years. As well, children experience a marked improvement in quality of life. Even though PAH is one of the leading indicators for lung or heart–lung transplantation in children, the survival outcomes for pediatric PAH lung transplant recipients are difficult to accurately calculate, given the very low total numbers of children who have undergone transplantation. Between January of 2000 and June of 2006, 138 children received lung transplantation worldwide. They account for less than 4% of all lung transplants performed since the inception of the procedure for adults in 1982. Adult PAH patients have decreased survival compared to other indicators. There is a higher mortality rate while on the lung waiting list, an increased 90-day mortality post-operatively, and lower expected survival to 5 years after transplant. The immune suppressants generally utilized consist of a triple drug regimen that includes a calcineurin inhibitor, a lymphocyte anti-proliferative agent, and corticosteroid. Until recently, centers varied widely in the specific protocols for drug doses and for treatment of the various complications that occur post-operatively, such as acute cellular rejection, humoral rejection, post transplant lymphoproliferative disorder (PTLD), and emergence of chronic allograft rejection, aka bronchiolitis obliterans syndrome (BOS). Although survival after pediatric lung and heart–lung transplantation has improved over the last decade, it is still well below that of heart and most other solid organ transplants. BOS is the single most important life-limiting complication of lung and heart–lung transplantation, yet the pathophysiology of BOS appears to be multifactorial and is poorly understood. To date, little advancement has been made in the prevention and treatment for BOS. Ongoing challenges remain to optimize organ allocation as well as treatment regimens. The pediatric lung transplant community is collaborating internationally, and has standardized treatment regimens across centers. In the future, this will permit multi-center studies to compare patient outcome measures head to head and illuminate the pathophysiology of immunological and other mechanisms that lead to graft failure and provide new therapeutic avenues.

Clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for pulmonary arterial hypertension within their licensed indications: a systematic review and economic evaluation

To investigate the clinical and cost-effectiveness of epoprostenol, iloprost, bosentan, sitaxentan and sildenafil for the treatment of adults with pulmonary arterial hypertension (PAH) within their licensed indications. Major electronic databases (including the Cochrane Library, MEDLINE and EMBASE) were searched up to February 2007. Further data were obtained from dossiers submitted to NICE by the manufacturers of the technologies. The systematic clinical and economic reviews were conducted according to accepted procedures. Model-based economic evaluations of the cost-effectiveness of the technologies from the perspective of the UK NHS and personal social services were carried out. In total, 20 randomised controlled trials (RCTs) were included in this assessment, mostly of 12-18 weeks duration and comparing one of the technologies added to supportive treatment with supportive treatment alone. Four published economic evaluations were identified. None produced results generalisable to the NHS. There was no consensus in the industry submissions on the most appropriate model structure for the technology assessment. Improvement in 6-minute walk distance (6MWD) was seen with intravenous epoprostenol in primary pulmonary hypertension (PPH) patients with mixed functional class (FC) (mainly III and IV, licensed indication) compared with supportive care (58 metres; 95% CI 6-110). For bosentan compared with supportive care, the pooled result for improvement in 6MWD for FCIII patients with mixed PAH (licensed indication) was 59 metres (95% CI 20-99). For inhaled iloprost, sitaxentan and sildenafil no stratified data for improvement in 6MWD were available. The odds ratio (OR) for FC deterioration at 12 weeks was 0.40 (95% CI 0.13-1.20) for intravenous epoprostenol compared with supportive care. The corresponding values for inhaled iloprost (FCIII PPH patients; licensed indication), bosentan, sitaxentan (FCIII patients with mixed PAH; licensed indication) and sildenafil (FCIII patients with mixed PAH; licensed indication) were 0.29 (95% CI 0.07-1.18), 0.21 (95% CI 0.03-1.76), 0.18 (95% CI 0.02-1.64) and [Commercial-in-confidence information has been removed] respectively. The incremental cost-effectiveness ratios (ICERs) for the technologies plus supportive care compared with supportive care alone, determined by independent economic evaluation, were 277,000 pounds/quality-adjusted life-year (QALY) for FCIII and 343,000 pounds/QALY for FCIV patients for epoprostenol, 101,000 pounds/QALY for iloprost, 27,000 pounds/QALY for bosentan and 25,000 pounds/QALY for sitaxentan. For the most part sildenafil plus supportive care was more effective and less costly than supportive care alone and therefore dominated supportive care. In the case of epoprostenol the ICERs were sensitive to the price of epoprostenol and for bosentan and sitaxentan the ICERs were sensitive to running the model over a shorter time horizon and with a lower cost of epoprostenol. Two RCTs directly compared the technologies against each other with no significant differences observed between the technologies. Combinations of technologies were investigated in four RCTs, with some showing conflicting results. All five technologies when added to supportive treatment and used at licensed dose(s) were more effective than supportive treatment alone in RCTs that included patients of mixed FC and types of PAH. Current evidence does not allow adequate comparisons between the technologies nor for the use of combinations of the technologies. Independent economic evaluation suggests that bosentan, sitaxentan and sildenafil may be cost-effective by standard thresholds and that iloprost and epoprostenol may not. If confirmed, the use of the most cost-effective treatment would result in a reduction in costs for the NHS. Long-term, double-blind RCTs of sufficient sample size that directly compare bosentan, sitaxentan and sildenafil, and evaluate outcomes including survival, quality of life, maintenance on treatment and impact on the use of resources for NHS and personal social services are needed.

Internal jugular vein valve incompetence in COPD and primary pulmonary hypertension

Under physiologic conditions, intact internal jugular vein valves (IJVVs) efficiently prevent retrograde venous flow during intrathoracic pressure increase. Chronically elevated central venous pressure found in patients with chronic obstructive pulmonary disease (COPD) and primary pulmonary hypertension (PPH) might lead to IJVV incompetence (IJVVI). The aim of this study was to analyze the prevalence of IJVVI in patients with COPD and PPH using duplex sonography (DUS). We included 30 COPD patients, 5 PPH patients, and 100 healthy controls in the study. IJVVI was diagnosed if retrograde jugular blood flow was seen on DUS during a Valsalva maneuver. Retrograde venous flow intensity was evaluated and graded according to extent and duration of reflux. IJVVI was found in 18 (60%) COPD patients and in all 5 (100%) PPH patients, which was significantly different from the controls (27%; p < 0.005). The intensity of venous retrograde flow correlated with the pulmonary artery pressure. Compared with healthy controls, COPDand PPH patients demonstrated a significantlygreater prevalence of IJVVI, which seems to be caused by the elevated central venous pressure. These patients may be at higher risk to develop central nervous system diseases related to cerebral outflow obstruction.

Autoimmune thyroid diseases in patients with primary pulmonary hypertension

Abnormal metabolism due to thyroid disorders could cause the additional significant right ventricular (RV) overload in patients with primary pulmonary hypertension (PPH). The purpose of this study was the prospective determination of autoimmune thyroid status in PPH patients. 45 patients (33 women and 12 men, mean age 38 years+/-13) with moderate and severe PPH (mean pulmonary artery pressure 61 mmHg+/-18 mmHg). PPH was diagnosed when other reason of pulmonary hypertension had been excluded especially thromboembolic, venous and hypoxemic. Titer of antibodies to thyroglobulin and thyroid peroxidase were measured. Thyroid gland dysfunction was determined by biochemical measurements of thyrotropin and free thyroxine; thyroid ultrasonographic examination was also performed. The prevalence of thyroid autoantibodies is estimated at 13% in general population. RESULTS. In 14 patients (31%) increased titer of thyroid antibodies was found in our group. Hyperthyroidism was recognized in 2 patients and in 3 cases we diagnosed hypothyroidism with high antibodies level requiring treatment. Ultrasonographic abnormalities were revealed in 21 patients (nodular changes--11 patients, fibrosis--3 patients, chronic inflammation symptoms--7). Ultrasonographic abnormalities were present in all patients with detectable antithyroid antibodies. We haven't confirmed more frequent prevalence of hormonal disorders in patient treated with prostacyclin's analogues. The prevalence of autoimmune thyroid diseases is about 3 times higher in PPH patients than in general population. The treatment of patients with clinically evident hyper- or hypothyroidism is necessary. The monitoring of clinically silent disorders seems to be recommended especially prior to lung transplantation qualification.

Left Main Stem Bronchus Compression Occurred in Primary Pulmonary Hypertension Patient - A case report -

Eleven year-old boy was scheduled for right encephalo-duro ar terial synangiosis (EDAS). He received left EDAS 4 months ago, and there was no problem during the perioperative period. Mild cardiomegaly was suspected in his preoperative chest PA. After intubaton, we couldn't hear the breathing sound of left chest, and the saturation went down to 95%. There was large opaque hemithorax on emergency chest AP, and on the fiberoptic bronchoscopic examination, left main stem bronchus (LMSB) was observed slit-like appearance. Echocardiography revealed severely dilated right atrium and ventricle. In his chest CT, the LMSB was nearly obliterated. The patient was diagnosed as primary pulmonary hypertension, and received full sedation, controlled ventilation, and NO gas. However, the blood pressure of this patient was not maintained in spite of using high-dose inotropics. He expired two days later and this case warns that suspected mild cardiomegaly might hide more ominous sign of primary

Niveles de péptido natriurético cerebral y su relación con capacidad funcional y hemodinamia pulmonar en pacientes con hipertensión pulmonar primaria: Correlation with functional capacity and hemodynamic parameters

Primary pulmonary hypertension (PPH) is a progressive disease leading to right heart failure and death. Right heart catherization and maximal or submaximal tests are employed to assess the course of the disease. A neurohormonal parameter such as pro-brain natriuretic peptide (BNP) would be helpful in the assessment of these patients. To study the correlation of BNP with functional status and non-invasive hemodynamic determinations in patients with PPH. Twelve patients (mean age: 48 years; 58% female) were evaluated with 6 minutes walk distance test (6-min WT), plasma BNP, systolic pulmonary artery pressure (PAP), pulmonary vascular resistance (PVR) and cardiac output (CO) determined by echocardiogram. Plasma BNP levels were compared with normal subjects. BNP levels were increased in PPH patients (1270+/-547 vs 48+/-8 pg/ml, p-value <0.01). Mean PAPs was 82+/-27 mmHg and the mean distance walked in 6 minutes was 407+/-113 meters. BNP levels were positively correlated with PVR (r=0.58, p-value=0.006) and negatively correlated with 6-min WT (r=-0.83, p-value <0.001). No correlation was found between BNP levels, PAPs and CO. In PPH patients, BNP levels are increased and correlate with functional class and PVR. Follow-up studies are needed to evaluate the role of BNP as a marker of progression and therapeutic response in PPH patients.

Bosentan for treatment of pulmonary arterial hypertension (I)

Evaluation of: McLaughlin VV., Sitbon O., Badesch DB. et al. Survival with first-line bosentan in patients with primary pulmonary hypertension. Eur. Respir. J. 25, 244–249 (2005). Primary pulmonary hypertension is a rare life-threatening form of pulmonary arterial hypertension. Several pharmacologic classes have recently become available for primary pulmonary hypertension treatment – prostacyclin and prostacyclin derivatives, endothelin receptor antagonists and phosphodiesterase inhibitors. Bosentan (Tracleer®) is an oral dual-endothelin receptor antagonist approved in Europe and North America for the treatment of pulmonary arterial hypertension. Several studies focused on the efficacy and safety of bosentan as an add-on or first-line therapy in primary pulmonary hypertension and pulmonary arterial hypertension related with connective tissue diseases. The current study assesses the impact of first-line bosentan therapy on the survival of primary pulmonary hypertension patients, compares it with a predicte...

End-tidal Pco2 Abnormality and Exercise Limitation in Patients With Primary Pulmonary Hypertension

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. 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. 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. 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.

Efficacy of Acute Inhalation of Nitric Oxide in Patients With Primary Pulmonary Hypertension Using Chronic Use of Continuous Epoprostenol Infusion

There have only been a few reports published on combination therapy for patients with primary pulmonary hypertension (PPH). Fifteen patients with PPH (4 men and 11 women, 34.5+/-12.1 years old) had received chronic administration of epoprostenol and the additive effects of inhaled nitric oxide (NO) and the hemodynamic changes were evaluated. In addition, the difference in the effect of acute NO loading before and after the epoprostenol therapy was compared in 6 of these patients. Under chronic use of epoprostenol, mean pulmonary arterial pressure, mean right atrial pressure and pulmonary vascular resistance were decreased with acute inhalation of NO. However, cardiac output, mean aortic pressure and systemic vascular resistance were unchanged. As a result, the pulmonary to systemic vascular resistance ratio was reduced. Moreover, after chronic use of epoprostenol, the change (delta) in cardiac output with NO inhalation was increased and the NO-induced decrease in pulmonary vascular resistance was augmented compared to those before the induction. Nitric oxide inhalation further improved the hemodynamics when combined with chronic use of epoprostenol in PPH patients. These results suggest the possibility that combination therapies can be used in the treatment for PPH patients.

Descriptive patterns of severe chronic pulmonary hypertension by chest radiography

To find chest roentgenographic (CXR) features to help differentiate two representative diseases with severe chronic pulmonary hypertension (PH). Thirty-six consecutive patients with chronic thromboembolic PH (CTEPH), 38 with primary PH (PPH), and 37 with left heart disease and PH. CXRs were reviewed about 6 features (left 2nd arc protrusion, right descending pulmonary artery diameter (rPAD), cardiothoracic ratio (CTR), right 2nd arc width, avascular area and pleural abnormality). Hemodynamic data and the degree of tricuspid regurgitation (TR) on echocardiography were compared with CXR findings. The diagnostic pattern of CTEPH was the presence of one of two findings, an avascular area or marked rPAD (>20mm) together with pleuritic change. The diagnostic pattern of PPH was one of the two features; without pleuritic abnormality, marked left 2nd arc protrusion (>10mm) or moderate left 2nd arc protrusion (5-10mm) with marked rPAD (<20mm). The sensitivity for the diagnosis of CTEPH among the three diseases was 78% and specificity was 92%. The sensitivity for the diagnosis of PPH was 45% and specificity was 88%. CTR and right 2nd arc width were related to the degree of TR in CTEPH and PPH. Characteristic roentgenographic findings can help differentiate two frequent diseases associated with chronic pulmonary hypertension and reflect the severity of disease.

Reverse cardiac remodelling in patients with primary pulmonary hypertension after isolated lung transplantation*1

Pulmonary hypertension eventually leads to severe distortion of the cardiac geometry with consequent impact on cardiac function. The purpose of this study was to prove reverse cardiac remodelling after isolated bilateral lung transplantation (LuTX) in patients with advanced primary pulmonary hypertension (PPH) and severe alterations of cardiac morphology and function. In the period of 2000-2002 17 (10 female, seven male) patients with advanced PPH underwent isolated bilateral LuTX. Median age was 30 years (range 16-53). All patients were in NYHA III or IV, most of them with intractable ascites, established renal impairment, malnutrition and immobility, continuously deteriorating despite various forms of pharmacological treatment including i.v. and inhalative prostacyclin, diuretics, Ca-antagonists, bosentan and catecholamines. Echocardiography and Doppler echocardiography measurements were performed before and 3 months after transplantation. Left and right ventricular diameters and function were assessed and tricuspid valve regurgitation was determined. Mortality after 3 months was 17.5% (cerebral bleeding, multi-organ failure and diffuse myocardial infarction in one patient each). Three months after LuTX the 14 surviving patients were in NYHA I or II. Echocardiography showed normal left ventricular function and markedly improved right ventricular function with normal size of the RV. The leftward shifted flattened interventricular septum had returned in its physiological position and the high-grade tricuspid insufficiency had disappeared in all patients. Advanced alterations of cardiac morphology and function normalize completely and pre-existing tricuspid insufficiency disappears in PPH patients after isolated bilateral LuTX. Quality of life is excellent. Therefore, LuTX is preferred and safe in patients with advanced PPH even with severe cardiac dysfunction.

Characterization of the bone morphogenetic protein (BMP) system in human pulmonary arterial smooth muscle cells isolated from a sporadic case of primary pulmonary hypertension: roles of BMP type IB receptor (activin receptor-like kinase-6) in the mitotic action.

The functional involvement of bone morphogenetic protein (BMP) system in primary pulmonary hypertension (PPH) remains unclear. Here we demonstrate a crucial role of the BMP type IB receptor, activin receptor-like kinase (ALK)-6 for pulmonary arterial smooth muscle cell (pphPASMC) mitosis isolated from a sporadic PPH patient bearing no mutations in BMPR2 gene. A striking increase in the levels of ALK-6 mRNA was revealed in pphPASMC compared with control PASMCs, in which ALK-6 transcripts were hardly detectable. BMP-2 and -7 stimulated the mitosis of pphPASMCs, which was opposite to their suppressive effects on the mitosis of the control PASMCs. BMP-4 and -6 and activin inhibited pphPASMC mitosis, whereas these did not affect control PASMCs. The presence of BMP signaling machinery in pphPASMCs was elucidated based on the analysis on Id-1 transcription and Smad-reporter genes. Overexpression of a dominant-negative ALK-6 construct revealed that ALK-6 plays a key role in the mitosis as well as intracellular BMP signaling of pphPASMCs. Gene silencing of ALK-6 using small interfering RNA also reduced DNA synthesis as well as Id-1 transcription in pphPASMCs regardless of BMP-2 stimulation. Although Id-1 response was not stimulated by BMP-2 in control PASMCs, the gene delivery of wild-type ALK-6 caused significant increase in the Id-1 transcripts in response to BMP-2. Additionally, inhibitors of ERK and p38 MAPK pathways suppressed pphPASMC mitosis induced by BMP-2, implying that the mitotic action is in part MAPK dependent. Thus, the BMP system is strongly involved in pphPASMC mitosis through ALK-6, which possibly leads to activation of Smad and MAPK, resulting in the progression of vascular remodeling of pulmonary arteries in PPH.

Clinical significance of brain natriuretic peptide in primary pulmonary hypertension

ObjectivesThe aim of this study was to investigate the potential role of brain natriuretic peptide (BNP) levels in the assessment of functional status and right heart performance in primary pulmonary hypertension (PPH). BackgroundPrimary pulmonary hypertension is a progressive disease leading to right heart failure and death. Right heart catheterization and maximal or submaximal exercise tests are employed to assess the course of the disease and the effect of therapeutic interventions. Additional noninvasive and reproducible parameters would be helpful to assess the status of patients with PPH. The natriuretic peptide system is up-regulated in PPH patients. Brain natriuretic peptide (BNP) is produced from the cardiac ventricles and elevated in PPH. The aim of our study was to evaluate the clinical significance of BNP in PPH patients. MethodsCorrelation analysis was performed for plasma BNP levels of 28 PPH patients and World Health Organization (WHO) functional class (WHO-class), distance walked in 6 min, peak oxygen uptake (peak Vo2), and oxygen pulse during spiroergometry and various hemodynamic parameters, including pulmonary vascular resistance (PVR), pulmonary artery pressure (PAP), right atrial pressure (RAP), and cardiac index. ResultsThe BNP levels were inversely correlated with the 6-min walk (r = −0.70; p < 0.001) and peak Vo2(r = −0.61; p < 0.01), and positive correlation was observed with WHO-class (r = 0.79; p < 0.001). Moreover, BNP levels were also correlated to PVR (r = 0.61; p < 0.01), PAP (r = 0.48; p < 0.05), and RAP (r = 0.78; p < 0.01), and were inversely related to cardiac index (r = −0.48; p < 0.05). ConclusionsOur data suggest that plasma BNP levels are closely related to the functional impairment of PPH patients and parallel the extent of pulmonary hemodynamic changes and right heart failure. Serial measurements of plasma BNP concentrations may help improve the management of PPH patients.

Transplantation and preoperative treatment with prostacyclin analogs for primary pulmonary hypertension: Benefits and impact on patients survival

Without treatment, survival after primary pulmonary hypertension (PPH) diagnosis is <3 years. We assessed the survival benefits of both transplantation and pretransplant prostanoid therapy in PPH patients.