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Registries of patients with pulmonary arterial hypertension (PAH) have been instrumental in characterizing the presentation and natural history of the disease and provide a basis for prognostication. Since the initial accumulation of data conducted in the 1980s, subsequent registry databases have yielded information about the demographic factors, treatment, and survival of patients and have permitted comparisons between populations in different eras and environments. Inclusion of patients with all subtypes of PAH has also allowed comparisons of these subpopulations. We describe herein the basic methodology by which PAH registries have been conducted, review key insights provided by registries, summarize issues related to interpretation and comparison of the results, and discuss the utility of data to predict survival outcomes. Potential sources of bias, particularly related to the inclusion of incident and/or prevalent patients and missing data, are addressed. A fundamental observation of current registries is that survival in the modern treatment era has improved compared with that observed previously and that outcomes among PAH subpopulations vary substantially. Continuing systematic clinical surveillance of PAH will be important as treatment evolves and as understanding of mechanisms advance. Considerations for future directions of registry studies include enrollment of a broader population of patients with pulmonary hypertension of all clinical types and severity and continued globalization and collaboration of registry databases. (J Am Coil Cardiol 2013;62:D51-9) ©2013 by the American College of Cardiology Foundation.

In the past decade, three classes of medications have been approved for the treatment of pulmonary arterial hypertension. A review of the clinical trial data for the prostanoids, endothelin antagonists, and phosphodiesterase-5 inhibitors has shown that all agents have similar efficacy on the 6-min walk distance over 12 to 16 weeks, which was the primary end point in the randomized clinical trials. However, little is known about their long-term efficacy or about how these drugs affect the underlying disease, if at all. Successful therapy is currently defined as an improvement in exercise tolerance over a 4-month period. Future trials need to better characterize how therapies affect the pulmonary vasculature pathologically, biologically, and hemodynamically, and whether survival is actually improved.

Background— Vasoreactivity tests are fundamental in evaluating pulmonary arterial hypertension (PAH). Mutations of the transforming growth factor-β type II receptor gene, BMPR2 , predispose to the development of pulmonary hypertension and may alter the response to vasodilators. Previous investigations have not examined the relationship of BMPR2 mutations to vasoreactivity. Methods and Results— We identified 133 consecutive unrelated patients with either idiopathic or familial PAH. Sixty-six patients were excluded because we lacked either DNA samples (n=18) or complete data from a vasoreactivity test (n=48). The remaining 67 patients were screened for BMPR2 DNA sequence variations, and specific variations were confirmed by gene sequencing. The vasoreactivity of patients with nonsynonymous BMPR2 variations was compared with that of patients without nonsynonymous BMPR2 variations. We found nonsynonymous BMPR2 variations in 27 of 67 patients with idiopathic (n=16 of 52) or familial (n=11 of 15) PAH. Vasoreactivity was identified in 3.7% of 27 patients with nonsynonymous BMPR2 variations and in 35% of 40 patients without nonsynonymous BMPR2 variations ( P =0.003). Five of the 27 nonsynonymous variations occur commonly in healthy individuals. None of the remaining 22 patients with BMPR2 variations demonstrated vasoreactivity, and the analysis remained unchanged when we assumed that nonsynonymous BMPR2 variations were present in all 15 patients with familial PAH. Conclusions— Patients with familial or idiopathic PAH and nonsynonymous BMPR2 variations are unlikely to demonstrate vasoreactivity. Further trials are required to determine whether long-term therapy can be directed by tests for BMPR2 variations.

Study objectives: Cellular growth in the vascular wall, including endothelial and smooth-muscle cell proliferation, is recognized as a component of the obstructive vasculopathy observed in the small vessels of the lungs in pulmonary arterial hypertension (PAH). We hypothesized that angiogenic growth factors may have a role in the molecular mechanisms underlying this cellular proliferation. Design: Case-control study. Setting: Multicenter, tertiary care hospitals. Participants: We studied 117 patients with PAH and 60 control subjects. Measurements: We measured levels of basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF) in the blood and urine of these subjects using an enzyme-linked immunoassay. Results: Median levels of urinary and plasma bFGF were significantly higher in patients with PAH compared to normal control subjects. There was a difference in levels of urine and plasma bFGF according to etiology of pulmonary hypertension, with the highest levels seen in patients with primary pulmonary hypertension. Levels of urine or plasma VEGF were not significantly different between patients and control subjects. Conclusion: Patients with PAH have substantial alterations in urine and plasma levels of bFGF. This molecule may have a role as a mitogenic factor in the endothelial and smooth-muscle cell proliferation seen in PAH.

In 1998, during the Second World Symposium on Pulmonary Hypertension (PH) held in Evian, France, a clinical classification of PH was proposed. The aim of the Evian classification was to individualize different categories sharing similarities in pathophysiological mechanisms, clinical presentation, and therapeutic options. The Evian classification is now well accepted and widely used in clinical practice, especially in specialized centers. In addition, this classification has been used by the U.S. Food and Drug Administration and the European Agency for Drug Evaluation for the labeling of newly approved medications in PH. In 2003, during the Third World Symposium on Pulmonary Arterial Hypertension held in Venice, Italy, it was decided to maintain the general architecture and philosophy of the Evian classification. However, some modifications have been proposed, mainly to abandon the term "primary pulmonary hypertension" and to replace it with "idiopathic pulmonary hypertension"; to reclassify pulmonary veno-occlusive disease and pulmonary capillary hemangiomatosis; to update risk factors and associated conditions for pulmonary arterial hypertension and to propose guidelines in order to improve the classification of congenital systemic-to-pulmonary shunts.

The endothelin (ET) system is comprised of 4 active ETs, with ET-1 being the predominant isoform in the cardiovascular system. Because of the potent vasoconstricting and mitogenic effects of ET-1 and its involvement in various cardiovascular diseases, blockade of the ET receptor has received considerable attention. ET receptor antagonism has been demonstrated to be beneficial in patients with pulmonary hypertension. The nonselective ET receptor antagonist bosentan improves exercise capacity and increases time to clinical worsening in patients with pulmonary arterial hypertension. The selective ET A receptor antagonist sitaxsentan also improves hemodynamics and exercise capacity in patients with pulmonary arterial hypertension. Results with ET receptor antagonists in congestive heart failure have been disappointing. Although some studies have suggested benefit, larger studies have been neutral. The use of ET receptor antagonists for other conditions has not been fully explored. Future studies with the use of ET receptor antagonists as part of a multidrug regimen are also needed.

This discussion was moderated by Sean Gaine, MD, Director, Pulmonary Hypertension Unit, Mater Misericordiae Hospital, University College, Dublin, Ireland. The physicians participating included Stuart Rich, MD, Professor of Medicine, and Director, Rush Heart Institute Center for Pulmonary Heart Disease, Rush Presbyterian-St. Luke's Medical Center, Chicago, Illinois, Norbert Voelkel, MD, The Hart Family Professor of Emphysema Research, University of Colorado Health Sciences Center, Denver, Colorado, and Nicholas W. Morrell, MD, Director, Pulmonary Vascular Diseases Unit, Papworth and Addenbrooke's Hospitals, University of Cambridge School of Clinical Medicine, Cambridge, UK.

Background— Primary pulmonary hypertension (PPH) is a severe and progressive disease. Without treatment, the median survival is 2.8 years, with survival rates of 68%, 48%, and 34% at 1, 3, and 5 years, respectively. Intravenous epoprostenol was the first Food and Drug Administration–approved therapy for PPH. The long-term impact that epoprostenol has made on PPH remains to be defined. Methods and Results— One hundred sixty-two consecutive patients diagnosed with PPH and treated with epoprostenol were followed for a mean of 36.3 months (median, 31 months). Data including functional class, exercise tolerance, and hemodynamics were recorded in a customized database. Vital status was verified in each patient. Observed survival with epoprostenol therapy at 1, 2, and 3 years was 87.8%, 76.3%, and 62.8% and was significantly greater than the expected survival of 58.9%, 46.3%, and 35.4% based on historical data. Baseline predictors of survival included exercise tolerance, functional class, right atrial pressure, and vasodilator response to adenosine. Predictors of survival after the first year of therapy included functional class and improvement in exercise tolerance, cardiac index, and mean pulmonary artery pressure. Conclusions— Intravenous epoprostenol improves long-term survival in PPH.

Hyperlipidemia has been seen in patients receiving protease inhibitor-based antiretroviral therapy, prompting concern that such patients are at risk for accelerated coronary artery disease (CAD). To assess the risk of CAD in antiretroviral-treated HIV-infected men, we quantified coronary artery calcium (CAC), a sensitive and established marker of subclinical CAD, using electron beam computed tomography (EBCT) of coronary vessels. Sixty HIV-infected men who met the following criteria (cases) were enrolled in the study: age of 40 years or older; naive to antiretroviral therapy or use of a stable antiretroviral regimen for >or=6 months (mean duration, 25.9 months; 41 patients were receiving protease inhibitor therapy); and no known CAD or no use of lipid-lowering agents. EBCT-derived CAC scores, serum lipid levels, history of antiretroviral therapy, and risk factors for CAD were obtained. Each case was compared with three age-, sex-, and race-matched HIV-negative controls randomly selected from a database including >9000 patients who had undergone EBCT. We determined differences in the proportion of cases and controls with CAC scores of >0 (detectable calcium) and clinically significant CAC for age range. There were no statistically significant differences between the number of cases and controls with detectable CAC (33% and 39%, respectively) and clinically significant CAC (18% and 17%, respectively). This study suggests that the rate of coronary atherosclerosis among HIV-infected patients who receive short-term antiretroviral therapy with or without protease inhibitors is not higher than that among age-, sex-, and race-matched HIV-negative controls. These results need to be confirmed in larger long-term studies, with controls well matched for coronary risk factors.

Study objectives To evaluate the safety and efficacy of sitaxsentan, an endothelin-A receptor antagonist, in a 12-week, open-label trial of patients with pulmonary arterial hypertension (PAH). Patients Six children and 14 adults with New York Heart Association (NYHA) functional class II, III, or IV primary pulmonary hypertension or PAH associated with either congenital systemic-to-pulmonary shunts or collagen vascular disease were enrolled. Measurements Sitaxsentan was administered orally at 100 to 500 mg bid for 12 weeks. Cardiopulmonary hemodynamics via cardiac catheterization were obtained at baseline and week 12. Six-minute walk test distance was measured at baseline, week 6, and week 12. Results Sitaxsentan treatment resulted in significant improvement in exercise capacity as assessed by the 6-min walk distance (baseline [mean ± SD], 466 ± 132 m; week 12, 515 ± 141 m, n = 20, p = 0.006). Mean pulmonary artery pressure and pulmonary vascular resistance index also improved (63 ± 20 to 52 ± 22 mm Hg, n = 17, p = 0.0002; and 20 ± 11 to 14 ± 13 U × m 2 , n = 17, p = 0.008, respectively). Serious adverse events included two cases of acute hepatitis (fatal in one patient). Conclusions Patients with NYHA functional class II, III, or IV PAH showed a significant improvement in exercise capacity and cardiopulmonary hemodynamics over a 12-week period of treatment with sitaxsentan, an endothelin-A receptor antagonist. Further investigation is warranted to evaluate the safety and efficacy of sitaxsentan in patients with PAH.

> “It is better to lose the battle and win the war.” > > —Sun Tzu (circa 6th century BCE Chinese General and military strategist) In 1995, the first successful randomized controlled trial (RCT) for pulmonary arterial hypertension (PAH) led to the approval of the pulmonary vasodilator epoprostenol.1 Under the assumption that PAH was a disease of inappropriate pulmonary vasoconstriction, testing a drug that had vasodilator properties seemed reasonable. The 6-minute walk test was the primary end point in the trial because it was in keeping with the Food and Drug Administration precedent that an outcome assessment in a patient with cardiopulmonary disease needs to reflect how the patient feels, functions, or survives. Article see p 2985 There are now 7 vasodilator therapies for PAH, all approved because they improved exercise capacity for 3 to 4 months.2 Whether they affect long-term survival remains a valid question.3 Recently, a sobering report from a highly respected referral center in France noted that the current 3-year survival for patients with pulmonary hypertension managed with state-of-the-art multiple drug therapy was only 58%, marginally better than in 1980s when there were no treatments at all.4 In addition, it appears that these drugs do not protect patients from developing severe pulmonary vascular disease.5,6 Our knowledge of the pathobiology of PAH today is quite different from what it was 20 years ago. Scientific studies have demonstrated that cellular proliferation, inflammation, and thrombosis are the dominant underlying pathobiological processes and that chronic pulmonary vasoconstriction appears to play a relatively minor role.7 It is therefore understandable why the RCT by Kawut et al8 in this issue of Circulation chose to study the safety and efficacy of simvastatin and/or aspirin, therapies directed at normalizing endothelial cell function and platelet activation, as a treatment for …

Background— Heterogeneity in response to treatment of pulmonary arterial hypertension (PAH) is a major challenge to improving outcome in this disease. Although vasodilator-responsive PAH (VR-PAH) accounts for a minority of cases, VR-PAH has a pronounced response to calcium channel blockers and better survival than vasodilator-nonresponsive PAH (VN-PAH). We hypothesized that VR-PAH has a different molecular cause from VN-PAH that can be detected in the peripheral blood. Methods and Results— Microarrays of cultured lymphocytes from VR-PAH and VN-PAH patients followed at Vanderbilt University were performed with quantitative polymerase chain reaction performed on peripheral blood for the 25 most different genes. We developed a decision tree to identify VR-PAH patients on the basis of the results with validation in a second VR-PAH cohort from the University of Chicago. We found broad differences in gene expression patterns on microarray analysis including cell-cell adhesion factors and cytoskeletal and rho-GTPase genes. Thirteen of 25 genes tested in whole blood were significantly different: EPDR1 , DSG2 , SCD5 , P2RY5 , MGAT5 , RHOQ , UCHL1 , ZNF652 , RALGPS2 , TPD52 , MKNL1 , RAPGEF2 , and PIAS1. Seven decision trees were built with the use of expression levels of 2 genes as the primary genes: DSG2 , a desmosomal cadherin involved in Wnt/β-catenin signaling, and RHOQ , which encodes a cytoskeletal protein involved in insulin-mediated signaling. These trees correctly identified 5 of 5 VR-PAH patients in the validation cohort. Conclusions— VR-PAH and VN-PAH can be differentiated with the use of RNA expression patterns in peripheral blood. These differences may reflect different molecular causes of the 2 PAH phenotypes. This biomarker methodology may identify PAH patients who have a favorable treatment response.

Choices of pharmacologic therapies for pulmonary arterial hypertension (PAH) are ideally guided by high-level evidence. The objective of this guideline is to provide clinicians advice regarding pharmacologic therapy for adult patients with PAH as informed by available evidence.This guideline was based on systematic reviews of English language evidence published between 1990 and November 2013, identified using the MEDLINE and Cochrane Library databases. The strength of available evidence was graded using the Grades of Recommendations, Assessment, Development, and Evaluation methodology. Guideline recommendations, or consensus statements when available evidence was insufficient to support recommendations, were developed using a modified Delphi technique to achieve consensus.Available evidence is limited in its ability to support high-level recommendations. Therefore, we drafted consensus statements to address many clinical questions regarding pharmacotherapy for patients with PAH. A total of 79 recommendations or consensus statements were adopted and graded.Clinical decisions regarding pharmacotherapy for PAH should be guided by high-level recommendations when sufficient evidence is available. Absent higher level evidence, consensus statements based upon available information must be used. Further studies are needed to address the gaps in available knowledge regarding optimal pharmacotherapy for PAH.

Electron beam tomography (EBT) is a noninvasive method used to detect coronary artery calcium (CAC). Due to the age-associated increase in incidence and magnitude of CAC, interpretation of results can be difficult. The purpose of this study was to develop a set of age- and gender-stratified CAC distributions to serve as standards for the clinical interpretation of EBT scans. Between 1993 and 1999, 35,246 asymptomatic subjects, 30 to 90 years of age, were self-referred for CAC screening using an Imatron EBT scanner. CAC score was calculated based on the number, areas, and peak computed tomographic density for each detected calcific lesion. CAC score in each coronary artery was equal to the sum of all lesions for that artery and the total CAC score was equal to the sum of the score of each artery. Total CAC scores were assigned to a percentile according to age and gender. CAC scores were reported at the 10th, 25th, 50th, 75th, and 90th percentiles for 16 age and/or gender groups. The prevalence of CAC increased with age for men and women. The extent of CAC differed significantly between men and women in the same age group. In summary, this study reports the distribution of CAC score by age and gender. Knowledge of the distribution of CAC, the effect of age on the total CAC score as well as the differences in total CAC scores that exist between men and women of similar age will assist the clinician in interpreting EBT CAC results.

Pulmonary hypertension has many causes and therapies. A meticulous evaluation is critical. Substantial advances in medical therapy have occurred over the past decade, and the future treatment of this syndrome is promising, with many new medications on the horizon.

OBJECTIVE— Coronary artery disease is the major cause of morbidity and mortality in patients with diabetes. Detection of coronary artery disease before the first myocardial infarction and before anginal symptoms will allow for strategies designed to reduce the cardiovascular event rate in this group of patients. Electron beam—computed tomography (EBCT)is a noninvasive technology for evaluating the extent of coronary artery atherosclerosis that relies on the detection of coronary artery calcium (CAC). We used EBCT to detect significant coronary artery atherosclerosis in diabetic patients without symptoms of heart disease. RESEARCH DESIGN AND METHODS— We used EBCT to evaluate calcium in the coronary arteries of 139 consecutive diabetic patients scanned over a 20-month period. The CAC scores in this group were compared with a randomly selected nondiabetic control group and a control group that was selected to match a number of established cardiovascular risk factors. RESULTS— Patients with diabetes had a significant increase in the prevalence of CAC scores ≥400 (25.9%) compared with the randomly selected (7.2%) and matched (14.4%) nondiabetic control groups. Scores in this range have been reported to be highly predictive for abnormal stress myocardial perfusion tomography and subsequent coronary events. CONCLUSIONS— Our results, therefore, indicate a substantial prevalence of significant coronary artery disease in an asymptomatic diabetic patient population compared with non-diabetic control subjects. They also suggest that EBCT may be a useful approach for selecting a group of diabetic subjects who would benefit most from additional evaluation for subclinical coronary artery disease.

Abstract —Primary pulmonary hypertension (PPH) is a syndrome of dyspnea, chest pain, and syncope defined by increased pulmonary vascular resistance and the absence of a known cause. It also occurs in a familial form, which is linked to unidentified genes on chromosome 2. This syndrome is characterized by abnormalities of pulmonary vascular biology in each compartment of the blood vessel. The lumen has a prothrombotic diathesis, the endothelium displays an excessive production of vasoconstrictors relative to vasodilators, and the smooth muscle cells are depolarized and calcium-overloaded, which is due in part to reduced expression of voltage-gated potassium channels (Kv). This causes vasoconstriction and may promote cell proliferation. The adventitia displays excessive remodeling, which is associated with exaggerated metalloproteinase and elastase activity. Conceptually, PPH seems to require a permissive genotype, a susceptible phenotype (eg, endothelial dysfunction) and, in many cases, an exogenous trigger (eg, an anorexigen). Although there is not a generally accepted, unifying hypothesis regarding its cause, impaired function and the expression of vascular and platelet Kv channels suggest PPH may be a disease of the ion channels. Abnormal matrix metalloproteinase and elastase activity could also explain the abnormal vascular tone, platelet activation, and remodeling in PPH. Although calcium-channel blockers and prostacyclin, particularly when coadministered with warfarin, improve survival, PPH has a 5-year mortality rate of ≈50%. Pharmacological and gene therapies aimed at enhancing the activity of prostacyclin, nitric oxide synthases, and Kv channels or at inhibiting endothelin and matrix metalloproteinases are promising areas for future development.

Primary pulmonary hypertension has become a very treatable disease given the recent advances in medical therapy. Any patient with unexplained right ventricular enlargement or pulmonary hypertension needs a thorough workup to determine the cause. Patients with primary pulmonary hypertension should be referred to a specialized "Center of Excellence" to evaluate potential therapies on a case-by-case basis. Warfarin anticoagulation is generally recommended in all patients. Some patients (approximately 20%) will have a dramatic response to high doses of calcium channel blockers; the remainder are generally helped by the use of continuous intravenous prostacyclin therapy. Lung transplantation remains the final treatment option for patients in whom medical therapy fails.

A young woman with primary pulmonary hypertension presented with interstitial lung disease approximately 5 years after successful treatment with IV prostacyclin. The pathology was consistent with nonspecific interstitial pneumonitis and was unresponsive to steroids and immunosuppressive medications. We speculate that further cases of this syndrome may be reported as more patients are living beyond 5 years with prostacyclin.

Objective: Studies on the effects of digoxin in patients with right ventricular failure and normal left ventricular function have not been performed. We evaluated the short-term effects of digoxin administration in patients with primary pulmonary hypertension on hemodynamics, neurohormones, and baroreceptor responsiveness. Design: This was a prospective study with patients serving as their own controls. Setting: University Hospital Intensive Care Unit with central monitoring. Patients: Seventeen patients with primary pulmonary hypertension and symptomatic heart failure were enrolled. Interventions: Following baseline hemodynamics, neurohormonal samples were drawn and the heart rate response to change in blood pressure following a challenge of phenylephrine and nitroprusside were recorded. One mg of intravenous digoxin was given and the measurements repeated after 2 hours. Results: Following digoxin there was a significant increase in cardiac output (3.49±1.2 to 3.81±1.2 L/min., p=0.028), a significant fall in norepinephrine (680±89 to 580±85 pg/ml, p=.013), and a significant increase in atrial natriuretic peptide (311±44 to 421±9 pg/ml, p=0.01). All of the patients had changes in heart rate and blood pressure following phenylephrine and nitroprusside challenge, but there was no significant difference in the change in heart rate response to change in blood pressure when rechallenged after digoxin treatment. Conclusion: Digoxin produces a modest increase in cardiac output in patients with pulmonary hypertension and right ventricular failure, as well as a significant reduction in circulating norepinephrine. No detectable effects of digoxin on baroreceptor responsiveness were apparent. The use of digoxin in pulmonary hypertension is warranted. (CHEST 1998; 114:787–792) Abbreviations: ANP=atrial natriuretic peptide; EDTA=edetic acid; PPH=primary pulmonary hypertension

Many studies have suggested that hormone replacement therapy reduces the risk of coronary heart disease. Electron beam tomography is a highly sensitive noninvasive method by which to detect coronary artery disease. Our objective was to investigate whether hormone replacement therapy had an effect on coronary artery disease as determined by electron beam tomography in postmenopausal women. Nine hundred fourteen self-referred postmenopausal women older than 50 years underwent electron beam tomography. Each woman completed a questionnaire regarding age, risk factors, menopausal status, and hormone replacement therapy. Women taking hormone replacement therapy were slightly younger (57.8 years) than those not (60.7 years). A significantly higher incidence of a family history of myocardial infarction and smoking history was found in the group taking hormone replacement therapy, whereas more diabetics were in the group not taking hormone replacement therapy. The mean total coronary artery scores for women receiving hormone replacement therapy and not receiving hormone replacement therapy were 54.2 and 86.2, respectively (p = 0.02). Independent predictive variables of a positive coronary artery calcium score with multiple logistic regression analysis were age, hypercholesterolemia, diabetes, and estrogen use. These results suggest that hormone replacement therapy is associated with less coronary artery disease in postmenopausal women as determined by electron beam tomography.

Pulmonary arterial hypertension (PAH) is characterized by abnormalities in endothelial and smooth muscle cell function. Prostacyclin released by endothelial cells is a potent vasodilator by increasing cyclic adenosine monophosphate. Sildenafil, an inhibitor of phosphodiesterase-5, increases cyclic guanosine monophosphate in the lungs, producing vasodilation. To test for a therapeutic benefit of the combination of a prostacyclin analogue, subcutaneous treprostinil, and sildenafil, a proof-of-concept, open-label investigational trial was initiated. Subjects with PAH in World Health Organization (WHO) functional classes II to IV receiving subcutaneous treprostinil foror =6 months were evaluated with an exercise treadmill test using the Naughton-Balke protocol at baseline and after 12 weeks. Sildenafil 50 mg 3 times daily was added to the treprostinil. Mean treadmill times in seconds were compared before and after 12 weeks of therapy. Nine subjects enrolled in the trial; 7 were women (mean age 35 years). At baseline, 3 subjects were in WHO functional class II and 6 subjects were in WHO functional class III. The mean treadmill time at baseline was 465 +/- 167 seconds and at 12 weeks was 656 +/- 205 seconds (42% improvement, p = 0.049). All patients had symptomatic improvement. In conclusion, this pilot study of subcutaneous treprostinil with sildenafil for PAH suggests additive beneficial effects.

Background. The operative mortality associated with surgical thromboendarterectomy of the pulmonary arteries has decreased at the University of California in San Diego with the application of new techniques. For universal performance of the procedure, however, those factors that contribute to the high operative mortality must be identified. We analyzed our results in 34 consecutive patients undergoing pulmonary thromboendarterectomy to determine those preoperative factors that contribute to operative mortality. Methods. Since 1983, 34 patients with severe, surgically correctable chronic thromboembolic pulmonary hypertension who were judged to be operable by pulmonary arteriography underwent pulmonary thromboendarterectomy. No patient was excluded because of right ventricular failure or hemodynamic severity of disease; the mean pulmonary artery pressure (PAP) was 54 mm Hg, the mean pulmonary vascular resistance (PVR) was 1,094 dynes · s · cm −5 , and all patients were in New York Heart Association functional class III or IV. Results. Postoperative course was characterized either by swift recovery (mean length of stay, 13 days) or by rapid demise resulting from pulmonary or right ventricular failure, or both (overall operative mortality, 23%). In survivors, the mean PAP, PVR, cardiac output, and New York Heart Association functional class were significantly improved ( p p −5 ; p −5 and a mean PAP of more than 50 mm Hg could accurately predict operative mortality: operative mortality was six times greater in patients with a preoperative PVR of greater than 1,100 dynes · s · cm −5 (41% versus 5.85%) and almost five times greater in those with a mean PAP of greater than 50 mm Hg (37% versus 8%). No intraoperative factors, including the use or duration of circulatory arrest, affected outcome. Conclusions. Patients with severe hemodynamic disease (PVR >1,100 dynes · s · cm −5 and PAP >50 mm Hg) have a high likelihood of operative mortality and perhaps should not undergo pulmonary thromboendarterectomy, except at institutions where the operation is performed frequently.

Background Recently in France, primary pulmonary hypertension developed in a cluster of patients exposed to derivatives of fenfluramine in appetite suppressants (anorexic agents), which are used for weight control. We investigated the potential role of anorexic agents and other suspected risk factors for primary pulmonary hypertension. Methods In a case–control study, we assessed 95 patients with primary pulmonary hypertension from 35 centers in France, Belgium, the United Kingdom, and the Netherlands and 355 controls recruited from general practices and matched to the patients' sex and age. Results The use of anorexic drugs (mainly derivatives of fenfluramine) was associated with an increased risk of primary pulmonary hypertension (odds ratio with any anorexic-drug use, 6.3; 95 percent confidence interval, 3.0 to 13.2). For the use of anorexic agents in the preceding year, the odds ratio was 10.1 (95 percent confidence interval, 3.4 to 29.9). When anorexic drugs were used for a total of more than three m...

In patients with primary pulmonary hypertension who respond to nifedipine during acute drug testing, there is a significant linear correlation of serum nifedipine concentration with pulmonary artery pressure and resistance. Although most demonstrate an initial response at readily attainable nifedipine concentrations with conventional dosages, a subset of patients seem to display delayed or incomplete oral absorption; these results may facilitate the clinical use of nifedipine in patients with primary pulmonary hypertension.

Background Ultrafast computed tomography (CT), by acquiring images of the proximal coronary arteries, detects coronary calcifications and has been demonstrated to be highly sensitive for the detection of coronary artery disease in many small studies. The aim of this study was to determine the relationship between ultrafast CT scanning and coronary angiography in a large number of symptomatic patients. Methods and Results The study population consisted of 710 patients from six participating centers. A multivariate logistic regression model was used to evaluate the individual contributions of age, number of calcified vessels, and the calcium score for the probability of angiographically significant disease. Of the 710 patients enrolled, 427 patients had significant angiographic disease, and coronary calcification was detected in 404, yielding a sensitivity of 95%. Of the 23 patients without calcifications, 19 (83%) had single-vessel disease at angiography. Of the 283 patients without angiographically significant disease, 124 had negative ultrafast CT coronary studies, for a specificity of 44%. An increasing number of vessels with calcification present on ultrafast CT was found to increase specificity for the presence of obstructive coronary artery disease in at least one vessel ( P P Conclusions Ultrafast CT scanning is a noninvasive, non–exercise-dependent test with an excellent sensitivity for the detection of coronary artery disease. The presence of calcifications in multiple vessels and in younger populations correlates with higher specificities for obstructive disease, making ultrafast CT coronary scanning a very useful diagnostic test.

Objectives.This study sought to determine whether neurohormonal activation occurs in isolated right heart failure.Background.Neurohormonal activation appears to parallel the severity of left heart failure, but little is known about its role in right heart failure.Methods.We evaluated neurohormonal activation and endothelin levels in 21 patients with primary pulmonary hypertension at the time of right heart catheterization.Results.Plasma norepinephrine levels correlated significantly with pulmonary artery pressure (r = 0.66, p < 0.01), cardiac index (r = −0.56, p < 0.01) and pulmonary vascular resistance (r = 0.69, p < 0.001). Atrial natriuretic peptide levels were higher in the pulmonary artery than the right atrium and femoral artery and correlated closely with pulmonary artery oxygen saturation (r = −0. 73, p < 0.0001). Plasma renin levels were not elevated. Endothelin levels were increased and correlated with right atrial pressure (r = 0.74, p < 0.0001) and pulmonary artery oxygen saturation (r = −0.070, p < 0.0004).Conclusions.Neurohormonal activation occurs in patients with isolated right ventricular failure and inherently normal left ventricles and appears to be related to the overall severity of cardiopulmonary derangements. The elevation in endothelin levels is consistent with its release in response to pulmonary hypertension.

The effort limitation in primary pulmonary hypertension (PPH) is thought to result from an inability to increase cardiac output with exercise. The precise mechanism, however, is unknown. We studied right ventricular (RV) and left ventricular (LV) function and interactions in 16 patients with PPH with electron beam computed tomography (EBCT) at rest and during supine bicycle exercise. RV and LV volumes and masses were measured at systole and diastole, and ejection fraction and cardiac index computed. Resting RV end-diastolic volume (215 +/- 72 ml) and mass (110 +/- 45 g) were increased, whereas stroke volume (65 +/- 26 ml) and ejection fraction (31 +/- 8%) were decreased. LV end-diastolic volume (80 +/- 31 ml) was decreased, whereas ejection fraction remained normal (66 +/- 9%). Cardiac index was at the lower limit of normal (2.26 +/- 0.72 L/min/m2). During exercise, RV end-diastolic volume was unchanged (196 +/- 63 ml, p = NS) but stroke volume (52 +/- 29 ml, p < 0.05) and ejection fraction (26 +/- 10%, p = 0.08) decreased. LV end-diastolic (52 +/- 22 ml, p < 0.001), end-systolic (17 +/- 8 ml, p < 0.001), and stroke volumes (35 +/- 20 ml, p < 0.001) decreased, whereas ejection fraction (65 +/- 15%, p = NS) and cardiac index remained unchanged (2.17 +/- 0.93 L/min/m2, p = NS). the ratio of RV/LV stroke volume at rest (1.21 +/- 1.06) increased with exercise (1.74 +/- 1.13, p = 0.09).(ABSTRACT TRUNCATED AT 250 WORDS)

To test whether the clinical presentation and prognosis of fenfluramine-induced pulmonary hypertension (PH) differs from primary PH (PPH), we compared the clinical profile and outcome of 10 patients with fenfluramine-induced PH with that of 70 patients with PPH referred to our center over the same time frame and treated identically. Patients with diet pill PH were similar to those with PPH with respect to hemodynamics. However, patients with fenfluramine-induced PH had poorer survival: 1-year survival 50% versus 88%, and 3-year survival 17% versus 60%.

Background The high mortality rate of pulmonary arterial hypertension (PAH) mainly relates to progressive right ventricular (RV) failure. With limited efficacy of medical therapies, mechanical circulatory support for the RV has been considered. However, there is lack of understanding of the hemodynamic effects of mechanical support in this setting. Methods We modeled the cardiovascular system, simulated cases of PAH and RV dysfunction and assessed the theoretical effects of a continuous flow micro-pump as an RV assist device (RVAD). RVAD inflow was sourced either from the RV or RA and outflow was to the pulmonary artery. RVAD support was set at various flow rates and additional simulations were carried out in the presence of atrial septostomy (ASD) and tricuspid regurgitation (TR). Results RVAD support increased LV filling, thus improving cardiac output and arterial pressure, unloading the RA and RV, while raising pulmonary arterial and capillary pressures in an RVAD flow-dependent manner. These effects diminished with increasing disease severity. The presence of TR did not significantly impact the hemodynamic effects of RVAD support. ASD reduced the efficacy of RVAD support, since right-to-left shunting decreased and ultimately reversed with increasing RVAD support due to the progressive drop in RA pressure. Conclusions The results of this theoretical analysis suggest that RVAD support can effectively increase cardiac output and decreases RA pressure with the consequence of increasing pulmonary artery and capillary pressures. Especially in advanced PAH, low RVAD flow rates may mitigate these potentially detrimental effects while effectively increasing systemic hemodynamics.

Continuous infusion of prostacyclin analogues improves survival in advanced pulmonary arterial hypertension. In addition to its vasodilatory effects, prostacyclin has the potential to decrease inflammation, thrombosis, and smooth muscle proliferation. The aim of this retrospective study was to determine whether pathological data support the ability of prostanoids to prevent progression of vascular disease.Twenty-two autopsied patients with World Health Organization category 1 pulmonary arterial hypertension (primarily idiopathic and connective tissue disease-associated) were divided into those who received long-term prostacyclin (n = 12, PG-long, mean treatment 3.9 years) and those who received 0-1 month of prostacyclin (n = 10, PG-short). Surprisingly, PG-long patients had larger plexiform lesions (P 0.05), with no decrease in medial and intimal thicknesses as compared with PG-short patients. Plexiform lesion size and density increased with increasing treatment time. Also, PG-long patients had fewer platelet thrombi and more frequent acute diffuse alveolar haemorrhage. Quantification of macrophages and T cells revealed no differences in inflammatory infiltrates.Although long-term prostacyclin therapy may have an antithrombotic effect in addition to its vasodilatory actions, it was not associated with the prevention of advanced vascular lesions. The mechanism by which prostacyclin analogues improve survival in pulmonary arterial hypertension remains uncertain.

The status of the right ventricle (RV) largely determines the functional state and prognosis of patients with many forms of pulmonary hypertension (PH). Some PH patients are adaptive remodelers and develop concentric RV hypertrophy (RVH) that is associated with retained RV function; others are maladaptive remodelers and rapidly develop right ventricular failure (RVF). RVF is the leading cause of death in patients with pulmonary arterial hypertension (PAH). Although inotropic support may be of transient benefit in the intensive care unit, the subsequent prognosis of such patients is poor. Here we review the embryology of the RV, with an emphasis on its early divergence from the left ventricle. Emerging concepts that suggest future therapies for RVF are considered, including excessive autonomic activation, chamber-specific dysregulation of key enzymes (e.g. phosphodiesterase 5 and pyruvate dehydrogenase), and an ischemia-induced metabolic shift to glycolysis. The hypertrophied RV has features of hibernating myocardium and these can be noninvasively measured using fluorodeoxyglucose positron emission tomography and cardiac magnetic resonance imaging. Several diseases affecting the RV are reviewed, including congenital heart diseases, arrhythmogenic RV cardiomyopathy, RV infarction, and transthyretin-related amyloidosis. Effective therapies for RV failure are needed.

Primary pulmonary hypertension (PPH) had been considered a uniformly fatal disease. In the past several years, there have been several published reports on new therapies for the treatment of PPH that appear to improve quality of life and survival. Data on four such treatments regarding their efficacy and recommendations for their use will be reviewed

We treated a patient with Huntington's disease and exhibitionism using leuprolide acetate (Lupron Depot, TAP Pharmaceuticals), a gonadotropin-releasing hormone agonist. The result was elimination of his deviant sexual behavior with few side effects. This regimen may be a safe and effective pharmacological treatment of the paraphilias. The occurrence of paraphilias in basal ganglia disorders is reviewed.

The Human Pulmonary Circulation: Historical Introduction.- Microcirculation of the Lung: Functional and Anatomic Aspects.- Pulmonary Vascular Development.- Pulmonary Vascular Function.- Pulmonary Vascular Mechanics.- Modeling of the Pulmonary Vasculature.- Metabolic and Clearance Function at the Pulmonary Microvascular Endothelial Surface in Pulmonary Hypertension.- The Pharmacology of the Major Vasoactive Mediators Relevant to the Pathogenesis of Pulmonary Hypertension.- The Normal Fetal and Neonatal Pulmonary Circulation.- Excitation-contraction Coupling and Regulation of Pulmonary Vascular Contractility.- Endothelial Regulation of Pulmonary Vascular Tone.- Acute Lung Injury: The Injured Lung Endothelium, Therapeutic Strategies for Barrier Protection and Vascular Biomarkers.- Ion Channels and Transporters in the Pulmonary Vasculature: A Focus on Smooth Muscle.- Receptor-mediated Signal Transduction and Cell Signaling.- Role of Calcium as a Second Messenger in Signaling: A Focus on Endothelium.- Caveolae and Signaling in Pulmonary Vascular Endothelial and Smooth Muscle Cells.- The Chemistry of Biological Gases.- Role of Oxygen-derived Species in the Regulation of Pulmonary Vascular Tone.- Mitochondrial ROS and Redox State in Pulmonary Vascular O2 Sensing.- Cellular and Molecular Mechanisms of Pulmonary Vascular Smooth Muscle Cell Proliferation.- Role of Ca2+ in Vascular Smooth Muscle Gene Expression and Proliferation.- Biochemistry and Cellular Mechanisms of Apoptosis in Vascular Smooth Muscle and Endothelial Cells.- The Coagulation Cascade and its Regulation.- Platelets in Pulmonary Vascular Physiology and Pathology.- Lysis and Organization of Pulmonary Thromboemboli.- Interactions of Leukocytes and Coagulation Factors with the Vessel Wall.- Interaction of the Plasminogen System with the Vessel Wall.- Endothelial Apoptosis and Repair in Pulmonary Arterial Hypertension.- Bronchial Arterial Circulation in the Human.- Animal Models of Pulmonary Hypertension.- Transgenic and Gene Targeted Mouse Models for Pulmonary Hypertension.- Animal Models of Increased Lung Vascular Permeability.- Isolation and Culture of Pulmonary Vascular Smooth Muscle and Endothelial Cells.- Conventional Patch Clamp Techniques and High-throughput Patch Clamp Recordings on a Chip for Measuring Ion Channel Activity.- Measurement of Pulmonary Vascular Structure and Pulmonary Blood Distribution by MDCT and MR Imaging Techniques.- Quantification of DNA, RNA and Protein Expression.- Gene Cloning, Transfection and Mutagenesis.- Approaches for Manipulation of Gene Expression.- Bioinformatics, Genomics, and Functional Genomics: Overview.- Genomic Application to Study Pulmonary Hypertension.- Proteomics and Functional Proteomics.- Maintenance, Propagation and Differentiation of Human Embryonic Stem Cells and Induced Pluripotent Stem Cells.- Identification of Adult Stem and Progenitor Cells in the Pulmonary Vasculature.- Differentiation of Embryonic Stem Cells to Vascular Cell Lineages.- Statistics and Clinical Data Analysis: A Reference Guide.- Hypoxic Pulmonary Vasoconstriction.- Pathogenic Roles of Ca2+ and Ion Channels in Hypoxia-mediated Pulmonary Hypertension.- Roles of Endothelium-derived Vasoactive and Mitogenic Factors in the Development of Chronic Hypoxia-mediated Pulmonary Hypertension.- Oxygen-sensitive Transcription Factors and Hypoxia-mediated Pulmonary Hypertension.- Developmental Regulation of Pulmonary Vascular Oxygen Sensing.- Pulmonary Vascular Remodeling by High Oxygen.- Pulmonary Vascular Remodeling: Cellular and Molecular Mechanisms.- Carbon Monoxide and Heme Oxygenase in the Regulation of Pulmonary Vascular Function and Structure.- Shear Stress, Cell Signaling and Pulmonary Vascular Remodeling.- Pulmonary Hypertension and the Extracellular Matrix.- Role of Progenitor Cells in Pulmonary Vascular Remodeling.- Receptor Signaling in Pulmonary Arterial Hypertension.- Role of Endothelium in the Development of Pulmonary Hypertension.- Coagulation and the Vessel Wall in Pulmonary Embolism.- Alveolar Epithelial Fluid Transport in Lung Injury.- High Altitude Pulmonary Edema .- Statins and Acute Lung Injury.- Genomics of Acute Lung Injury and Vascular Barrier Dysfunction.- Ventilator-induced Mechanical Stress and Lung Vascular Dysfunction.- Classification of Pulmonary Hypertension: History and Perspectives.- Epidemiology of Pulmonary Arterial Hypertension.- Air Pollution and the Pulmonary Vasculature.- Idiopathic Pulmonary Arterial Hypertension.- Genetics of Familial and Idiopathic Pulmonary Arterial Hypertension.- Pulmonary Arterial Hypertension Related to Scleroderma and Collagen Vascular Diseases.- Pathology and Management of Portopulmonary Hypertension.- Pathobiology and Treatment of Pulmonary Hypertension in HIV Disease.- Pulmonary Arterial Hypertension Secondary to Anorexigens and Other Drugs and Toxins.- Pulmonary Arterial Hypertension Related to Gauchers, Sarcoidosis and Other Disorders.- Pediatric Pulmonary Hypertension: An Integrated View from Pediatric Subspecialists.- Persistent Pulmonary Hypertension of the Newborn: Mechanisms and Treatment.- The Pulmonary Circulation in Congenital Heart Disease.- Pulmonary Hypertension Secondary to Congenital Systemic to Pulmonary (Left-to-Right) Shunts.- Surgical Evaluation of Congenital Heart Disease-associated Pulmonary Hypertension.- Pulmonary Veno-occlusive Disease.- Left Ventricular Diastolic Heart Function and Pulmonary Hypertension.- Pulmonary Hypertension Associated with Chronic Obstructive Pulmonary Diseases.- Pulmonary Hypertension Associated with Interstitial Lung Disease.- High Altitude Pulmonary Hypertension.- Pulmonary Hypertension and Congenital Heart Defects at High Altitude.- Pulmonary Embolism and Deep Vein Thrombosis.- Pulmonary Hypertension Due to Pulmonary Embolism and Thromboembolic Obstruction of Proximal and Distal Pulmonary Arteries.- Risk Factors for Chronic Thromboembolic Pulmonary Hypertension.- Evaluation of Small Vessel Arteriopathy in Chronic Thromboembolic Pulmonary Hypertension.- Hemolytic Anemia Associated Pulmonary Hypertension: Sickle Cell Disease and Thalassemia-associated Pulmonary Hypertension.- Pulmonary Hypertension due to Schistosomiasis.- Pulmonary Hypertension due to Capillary Hemangiomatosis.- Molecular Basis of Right Ventricular Hypertrophy and Failure in Pulmonary Vascular Disease.- Right Ventricular Dysfunction in Pulmonary Hypertension.- Large Vessel Pulmonary Arteritis.- Tumors of the Pulmonary Vascular Bed.- Cor Pulmonale.- Pregnancy and Contraception in Patients with Pulmonary Arterial Hypertension.- Cardiac Catheterization in the Patient with Pulmonary Hypertension.- Imaging of Pulmonary Vascular Diseases.- Histological and Pathological Diagnosis of Pulmonary Hypertension: Pathological Classification of Pulmonary Vascular Lesions.- Echocardiography in Pulmonary Vascular Disease.- Calcium Channel Blockers in the Treatment of Pulmonary Arterial Hypertension.- Prostacyclin and Prostaglandins.- Endothelin Receptor Antagonists for the Treatment of Pulmonary Arterial Hypertension.- Phosphodiesterase Inhibitors in the Treatment of Pulmonary Hypertension.- Nitric Oxide for Children.- The Serotonin System as a Therapeutic Target in Pulmonary Hypertension.- Combination Therapy for Pulmonary Arterial Hypertension.- Thrombolytic and Anti-coagulant Therapy for Pulmonary Embolism and Chronic Thromboembolic Pulmonary Hypertension.- Nursing Care of Patients with Pulmonary Arterial Hypertension.- Atrial Septostomy.- Evaluation of Patients with Chronic Pulmonary Thromboembolic Pulmonary Hypertension for Pulmonary Endarterectomy.- Pulmonary Endarterectomy.- Evaluation of Patients with Pulmonary Hypertension for Lung Transplantation.- Lung Transplantation for Pulmonary Hypertension.- Living-donor Lower Lobar Lung Transplantation for Pulmonary Arterial Hypertension.- Results of Lung Transplantation.- Index.

Objectives . The purpose of this study was to evaluate the effects of vasodilator combination therapy in patients with primary pulmonary hypertension. Background . Calcium channel blockers and adenosine have each been shown to be effective in reducing pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension. However, the effects of combining these vasodilators have not been studied. Methods . To test the combination, 12 patients were placed on oral nifedipine and 3 on diltiazem therapy, using a dose titrated to maximal effect (mean nifedipine dose 103 ± 24 mg, mean diltiazem dose 300 ± 49 mg). Patients were then given maintenance doses of the calcium channel blocker at half the cumulative loading dose at 6-h intervals. One hour after the maintenance dose of calcium blocker, all patients received an infusion of adenosine, starting with 50 μg/kg per min and increasing by 50 μg/kg per min at 2-min intervals to a miximally tolerated dose (180 ± 63 μg/kg per min). Results . Ten patients responded to calcium channel blockers (defined as a ≥20% decrease in pulmonary vascular resistance), with a 16% decrease in mean pulmonary artery pressure (p = 0.057), a 39% decrease in pulmonary vascular resistance (p = 0.002) and a 24% increase in stroke volume (p = 0.007). Five patients were nonresponders, with no significant changes in pulmonary artery pressure, pulmonary vascular resistance, cardiac index or stroke volume. In the calcium channel blocker responders, the combination of adenosine and calcium blocker reduced pulmonary vascular resistance by 49%, increased stroke volume by 33% and decreased mean pulmonary artery pressure by 14% compared with drug-free baseline values. In nonresponders, combination therapy resulted in nonsignificant changes in pulmonary artery pressure and pulmonary vascular resistance. Conclusions . Adenosine has the ability to further decrease pulmonary artery pressure and pulmonary vascular resistance in patients with primary pulmonary hypertension who respond to calcium channel blockers. Those who fail to respond to these agents have little added effect from adenosine.

Calcium channel blockers (CCBs) are considered a standard treatment of pulmonary arterial hypertension (PAH) in a specifically defined subset of patients, and the only treatment that has resulted in a chronic reduction in pulmonary artery pressure (PAP) associated with dramatically improved survival.

Pulmonary venous hypertension is now one of the most common causes of pulmonary hypertension (PH) diagnosed by both pulmonologists and cardiologists. Patients with pulmonary venous hypertension will typically have elevated pulmonary venous pressure (as reflected in the pulmonary capillary wedge pressure), most frequently as a reflection of increased left ventricular end-diastolic pressure. Although mitral stenosis was the most common cause of this entity decades ago, left ventricular diastolic dysfunction is the most common cause of pulmonary venous hypertension seen in the Western world today. The mechanisms for the hypertension in mitral stenosis and in left ventricular diastolic abnormalities are thought to be similar. A chronic elevation in the diastolic filling pressure of the left side of the heart causes a backward transmission of the pressure to the pulmonary venous system which appears to trigger vasoconstriction in the pulmonary arterial bed. The current accepted designation is PH secondary to heart failure with a preserved ejection fraction.

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.

Recent studies suggest that Doppler echocardiography (DE)-based estimates of pulmonary artery systolic pressure (PASP) may not be as accurate as previously believed. We sought to determine the accuracy of PASP measurements using DE compared with right-sided heart catheterization (RHC) in patients with pulmonary hypertension (PH).We compared DE estimates of PASP to invasively measure PASP during RHC in 160 consecutive patients with PH (part one). To account for possible changes in hemodynamics between DE and RHC, we then prospectively determined PASP in an additional 23 consecutive patients undergoing simultaneous RHC and DE (part two). Bland-Altman analyses were performed to evaluate the agreement between RHC and DE measurements of PASP. Accuracy was predefined as 95% limits of agreement within ± 10 mm Hg for PASP estimates.In part one, there was moderate correlation between DE and RHC measurements of PASP (r = 0.68, P.001). However, using Bland-Altman analysis, the bias for DE estimates of PASP was 2.2 mm Hg with 95% limits of agreement ranging from -34.2 to 38.6 mm Hg. DE estimates of PASP were determined to be inaccurate in 50.6% of patients. In part two, there was moderate correlation between DE and RHC measurements of PASP (r = 0.71, P.01). However, despite simultaneous DE and RHC measurements, the bias for DE estimates of PASP was 8.0 mm Hg with 95% limits of agreement ranging from -28.4 to 44.4 mm Hg.DE estimates of PASP are inaccurate in patients with PH and should not be relied on to make the diagnosis of PH or to follow the efficacy of therapy.