Primary (idiopathic) pulmonary hypertension

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1 Echocardiographic Features of Primary Pulmonary Hypertension Eduardo Bossone, MD, PhD, Thanh H. Duong-Wagner, MD, Giuseppe Paciocco, MD, Hakan Oral, MD, Mark Ricciardi, MD, David S. Bach, MD, Melvyn Rubenfire, MD, and William F. Armstrong, MD, Ann Arbor, Michigan Primary pulmonary hypertension (PPH) is essentially a diagnosis of exclusion and usually is made late because of the nonspecific nature of the early signs and symptoms. Echocardiography is a key screening test in the diagnostic algorithm of patients with suspected PPH. The purpose of this study was to define the echocardiographic Doppler features in patients with PPH at the time of diagnosis. From 1992 to 1997, 51 patients were diagnosed with PPH at our institution. All underwent a standardized transthoracic echocardiographic examination, including a contrast study and transthoracic echocardiographic examination if indicated. Pulmonary artery systolic pressure was calculated from the tricuspid regurgitation jet. The majority of patients had pulmonary artery systolic pressure greater than 60 mm Hg (96%) associated with systolic flattening of the interventricular septum (90%), enlarged right atrium (92%) and ventricle (98%), and reduced right ventricular systolic function (76%). There was an increase in the interventricular septal thickness (>1.2 cm) in 21 (43%) of 49 patients, accompanied by a septal/ posterior wall ratio greater than 1.3 in 11 (22%) of 49. Although a reduction in both left ventricular systolic and diastolic volumes was noted, global left ventricular systolic function was preserved in all patients. Mitral E/A ratio was less than 0.7 in 7 (22%) patients studied. Color Doppler revealed moderate to severe tricuspid regurgitation and pulmonic insufficiency in 41 (80%) of 51 and 16 (31%) of 51 of cases, respectively. Pericardial effusion (7 small and 1 moderate) and patent foramen ovale (n = 12) were also frequently detected. At the time of initial diagnosis, PPH is associated with secondary cardiac abnormalities in the majority of patients. (J Am Soc Echocardiogr 1999;12: ) Primary (idiopathic) pulmonary hypertension (PPH) is a condition characterized by sustained elevation of pulmonary artery pressure (mean pulmonary artery systolic pressure [PASP] >25 mm Hg at rest or >30 mm Hg with exercise) without a demonstrable cause. 1 It affects both sexes equally in childhood; however, there is a 5:1 female-to-male ratio after puberty. 1,2 It is an uncommon disease with an estimated incidence of approximately 2 cases per million population. 3 The diagnosis is essentially one of exclusion and often is made in its advanced stages because of the nonspecific nature of the early symptoms and signs of this condition. 1,4-7 Although clinical assessment is essential in the initial From the Division of Cardiology, Department of Internal Medicine, University of Michigan, Ann Arbor, Mich. Reprint requests: William F. Armstrong, MD, University of Michigan Hospital, Division of Cardiology, Women s L3119, 1500 E Medical Center Dr, Ann Arbor, MI WFA@UMICH.EDU. Copyright 1999 by the American Society of Echocardiography /99 $ /1/99069 evaluation of patients with suspected PPH, echocardiography is a key screening tool in the diagnostic algorithm. 1,3,4 Echocardiography not only can provide an estimate of PASP but also excludes other causes of pulmonary hypertension such as primary myocardial, valvular, or hemodynamically significant congenital heart disease. 1,3,4 The purpose of this study was to define the echocardiographic features present at the time of PPH diagnosis. METHODS Study Population We analyzed 51 consecutive patients referred to the University of Michigan for evaluation of known or suspected pulmonary hypertension or who were initially diagnosed to have PPH at the University of Michigan after referral for another presumed diagnosis (Table 1). All patients underwent a detailed history, physical examination, electrocardiography, chest radiography, and comprehensive transthoracic echocardiography (TTE), including Doppler studies.the diagnosis of PPH was established by 655

2 656 Bossone et al August 1999 Table 1 Demographic data Women Men Total No. (%) 45 (88) 6 (12) 51 Age (y) Mean ± SD 41.7 ± ± ± 12.2 Range New York Heart Association classification (No., %) Class II 10 (22) 1 (17) 11 (21) Class III 30 (67) 5 (83) 35 (69) Class IV 5 (11) - 5 (10) Initial symptoms * (No., %) Dyspnea on exertion 42 (95) 5 (83) 47 (94) Syncope 6 (14) 4 (67) 10 (20) Leg edema 6 (14) 3 (50) 9 (18) Lightheadedness 7 (16) 2 (33) 9 (18) Fatigue 7 (16) 1 (17) 8 (16) Chest pain 6 (14) 2 (33) 8 (16) Palpitation 3 (7) 3 (6) * Data available in 50 of 51 patients (44 women, 6 men). use of the criteria from the National Institutes of Health Patient Registry for the characterization of Primary Pulmonary Hypertension. 4 Imaging Protocol Standardized TTE and Doppler examinations were performed with commercially available equipment in all patients. Specific views included the parasternal long- and short-axis views (at the mitral valve and papillary muscle level), apical 4-, 2-, and 3-chamber views, and subcostal views. Pulsed and continuous wave Doppler interrogation was performed on all 4 cardiac valves. Contrast echocardiography (n = 24) and transesophageal echocardiography (TEE) (n = 5) studies 8,9 were also performed if indicated. Measurement of the inferior vena cava was not a routine part of the imaging protocol at the time of this study. All echocardiograms were interpreted at the time of the referral by an experienced faculty echocardiographer and subsequently reviewed by an independent observer for specific off-line calculations and data tabulation. Two-Dimensional Echocardiographic Doppler Measurements Standard 2-dimensional echocardiographic measurements were obtained from the parasternal long-axis view.a qualitative assessment of right atrial and ventricular sizes, right ventricular hypertrophy, and global systolic function was routinely performed on-line with each echocardiogram. 10 Valvular regurgitation was quantified from color Doppler imaging and categorized as absent, minimal (within normal limits), mild, moderate, or severe. 11 Table 2 Qualitative data Variable n % RA dilation 47/ RV dilation 50/ RV hypertrophy 24/ RV abnormal systolic function 39/ Dilated pulmonary artery 13/ RVPO pattern of IVS 46/ IAS bows R L 12/ R L shunt on contrast 14/ RA, Right atrium; RV, right ventricle; RVPO, right ventricular pressure overload; IVS, interventricular septum; IAS, interatrial septum. Pulmonary Artery Systolic Pressure Maximal tricuspid regurgitation peak velocity was measured from the spectral profile of the tricuspid regurgitation jet in the right ventricular inflow projection of the parasternal long-axis view, the parasternal short-axis view, or the apical 4-chamber view. The highest transvalvular velocity was used for calculation of right ventricular systolic pressure. PASP was then calculated by adding a fixed value of 14 mm Hg (assumed right atrial pressure) to the systolic transtricuspid gradient (PASP = 4V , where V = maximal velocity of tricuspid regurgitation jet) Right Ventricular Velocity Curve Indexes The right ventricular outflow tract velocity curve (RVOT vc ) was recorded from the parasternal short-axis view at the aortic valve level with the pulsed wave Doppler sample volume positioned in the center of the right ventricular outflow tract just proximal to the pulmonary valve. The area under the velocity curve was traced off-line. Derived flow parameters from the RVOT vc were calculated as a mean of at least 2 consecutive beats. Left Ventricular Systolic Function Global left ventricular systolic function was subjectively assessed as normal versus abnormal (mild, moderate, or severe impairment) from the real-time 2-dimensional echocardiogram. Additionally, fractional shortening (%) and ejection fraction (%) were computed off-line. Simpson s rule was used for calculation of left ventricular ejection fraction. 15 Left Ventricular Diastolic Function Mitral inflow velocities were measured by pulsed wave Doppler, with the sample volume placed between the leaflet tips. The following diastolic filling indexes were obtained: peak flow velocity of early diastolic filling (peak E), peak flow velocity of late atrial filling (peak A), and the ratio between early and late flow velocity peaks (E/A ratio). Additionally, the fraction of filling during atrial systole, defined as the integrated velocity during late filling

3 Volume 12 Number 8 Bossone et al 657 Table 3 Two-dimensional echocardiographic measurements Measurable Mean ± SD Range LV diameter-diastole (cm) 45/51 (88%) 3.8 ± LV diameter-systole (cm) 38/51 (75%) 2.6 ± Fractional shortening (%) 38/51 (75%) 34.7 ± LV end-diastolic volume (ml) 31/51 (61%) 33.3 ± LV end-systolic volume (ml) 31/51 (61%) 11.3 ± LV ejection fraction (%) 31/51 (61%) 68.8 ± PW (cm) 49/51 (96%) 1 ± IVS (cm) 49/51 (96%) 1.2 ± IVS/PW ratio 49/51 (96%) 1.2 ± Left atrium (cm) 48/51 (94%) 3.4 ± Aortic root (cm) 46/51 (90%) 2.9 ± Heart rate (beats/min) 51/51 (100%) 82 ± LV, Left ventricular; PW, posterior wall; IVS, interventricular septum. divided by the total diastolic integrated velocity (VTI A/Total), and the deceleration time were calculated. Diastolic time-velocity integrals were derived by digitizing the areas under the diastolic velocity envelope. Diastolic parameters were measured for at least 2 consecutive beats and means subsequently calculated Pericardial Effusion Pericardial effusion was graded as absent, minimal (within normal limits), small (an echo-free space only seen posteriorly), moderate (a circumferential echo-free space 1 cm in width at its widest point), and large (a circumferential echo-free space >1 cm in width at any point). 22 Right Heart Catheterization Right heart catheterization with pressure measurement and thermodilution cardiac output was performed within 30 days of echocardiography (mean 5.4 days; 60% within 24 hours) in 25 (49%) of 57 patients from either the internal jugular or femoral vein approach. Hemodynamic measurements included right atrial, right ventricular, pulmonary arterial, and pulmonary capillary wedge pressure. Statistical Analysis Pearson s correlation coefficients were used to describe the association between Doppler and invasive PASP. A paired t test was used to compare the average values of these measurements; the average absolute difference was also examined. Mean, standard deviation, and range are provided for all continuous variables. RESULTS Patient Demographics Demographic data are presented in Table 1. The female-to-male ratio was 7.5:1. Of the total patients, Table 4 Right ventricular outflow tract and tricuspid valve Doppler parameter Variable Mean ± SD Range TRv (m/s) 4.4 ± PASP (mm Hg) 94 ± PV (m/s) 0.84 ± VTI (m) 0.15 ± VTImax (m) 0.04 ± AT (s) 0.07 ± ET (s) 0.3 ± AT/ET 0.27 ± PV, Peak velocity; AT, acceleration time; VTI, velocity time integral; VTImax, velocity-time integral of the RVOT vc at peak velocity; ET, ejection time. TRv, tricuspid regurgitation peak velocity; PASP, pulmonary artery systolic pressure. 78% were in New York Heart Association functional class III or IV.The mean time from the onset of the initial symptoms to diagnosis was 20.6 ± 20.2 months (median 12), with a range from 1 to 84 months, confirming that the diagnosis of PPH is usually made late in the course of disease. TTE was available in all 51 subjects. Additionally, contrast TTE was available in 24 and TEE in 5. TEE confirmed the diagnosis already established on TTE and in no case added new diagnostic information. Chamber Sizes and Function Table 2 outlines qualitative results of TTE in the study population; quantitative data are presented in Table 3.The majority of patients had enlarged rightsided chambers with reduced global right ventricular systolic function.this was accompanied by systolic flattening of the interventricular septum (IVS) (Figures 1 and 2).The IVS thickness was increased in 21 (43%) of 49 patients, and 11 (22%) of 49 patients had IVS/posterior wall thickness ratio of

4 658 Bossone et al August 1999 A B Figure 1 Parasternal long-axis view of a patient with primary pulmonary hypertension. In diastole (A) the right ventricle is dilated and ventricular septum appears hypertrophied compared with posterior wall. Note small left internal dimension of the left ventricle. Normal contractility (systole) (B) of the left ventricle is noted and small pericardial effusion is appreciated. A B Figure 2 Parasternal short-axis view of the patient presented in Figure 1. In diastole (A) note flattening of the ventricular septum and marked right ventricular dilation. In systole (B) there is reversed septal curvature consistent with severe pulmonary hypertension. Infundibular hypertrophy of the right ventricular outflow tract is also noted. Table 5 Left ventricular diastolic filling parameters Mean ± SD Range Peak E (cm/s) 0.55 ± Peak A (cm/s) 0.63 ± E/A 0.93 ± Velocity time integral 53 ± A/Total (%) Deceleration time (s) ± Peak E, Peak flow velocity of early diastolic filling; peak A, peak flow velocity of late atrial filling; E/A, ratio between early and late flow velocity peaks. 1.3 or greater (1.7 ± 0.4, range 1.4 to 2.67).The left atrium was enlarged ( 4 cm) in 10 (19.6%) patients. Persistent bowing of the interatrial septum into the left atrium was noted in 12 (23%) patients. Although both left ventricular systolic and diastolic volumes were diminished compared with normal, global left ventricular systolic function was pre- served in all patients. Because of the distortion of septal geometry and paradoxical septal motion, fractional shortening was abnormal in some patients, whereas overall left ventricular systolic function as assessed with 2-dimensional echocardiography was normal. Doppler Tricuspid valve and pulmonary outflow tract Doppler parameters are outlined in Table 4.PASP greater than 60 mm Hg was found in 49 (96%) patients. Two patients had milder elevations in PASP (41 and 50 mm Hg). In a subgroup of 17 patients (2 men and 15 women; mean age 47 ± 12 years, range 28 to 62), analysis of right ventricular outflow tract indexes was feasible. An acceleration time less than 0.1 second was noted in 16 (94%) patients. In 32 patients, transmitral Doppler could be analyzed (age 42.2 ± 13,range 17 to 68 years).reversal of the E/A ratio was seen in 22 (69%) patients (age 40.6 ±

5 Volume 12 Number 8 Bossone et al 659 A B Figure 3 A, Apical 4-chamber view of the right ventricle and right atrium showing tricuspid regurgitation. B, Spectral profile of tricuspid regurgitation can be seen from which a right ventricle to right atrial gradient of 87.8 mm Hg can be defined. Table 6 Hemodynamic results Mean ± SD Range Normal range Elevated n = (%) RA (mm Hg) 12.8 ± RV-Systolic (mm Hg) 96.4 ± RV-Diastolic (mm Hg) 15.4 ± PA Systolic (mm Hg) 97.5 ± PA Diastolic (mm Hg) 44.6 ± PA Mean (mm Hg) 62.2 ± PCWP (mm Hg) 12 ± CO (L/min) 3.7 ± CI (L/min/m 2 ) 1.9 ± PVR (Wood Units) 15.5 ± RA, Right atrium; RV, right ventricular; PA, pulmonary arterial; PCWP, pulmonary arterial wedge pressure; CO, cardiac output; CI, cardiac index; PVR, pulmonary vascular resistance. 11, range 23 to 62 years); an E/A ratio less than 0.7 was seen in 7 (22%) of 32 patients (mean age 47 ± 12 years, range 28 to 62) (Table 5). Color Doppler flow images (Figure 3) revealed moderate to severe tricuspid regurgitation in 41 (80.4%) patients and moderate to severe pulmonic insufficiency in 16 (31.4%) but mild to moderate mitral insufficiency in only 1 (1.9%) patient. Pericardial Effusion and Other Associated Findings Pericardial effusion (7 small and 1 moderate) was noted in 8 (15.7%) patients. Right-to-left interatrial shunts (12 patent foramen ovale and 1 small atrial septal defect) were documented by contrast TTE in 13 patients (11 women and 2 men, mean age 37 ± 9.2, range 23 to 50). In 1 patient (a 28-year-old woman), a perimembranous interventricular septal defect (0.1 cm) with right-to-left shunting was detected by contrast TTE.The ventricular septal defect was small and was not believed to be a cause of pulmonary hypertension. Hemodynamic Data Right heart catheterization data were available in 25 patients. Hemodynamic variables are summarized in Table 6. The correlation between PASP by Doppler and by catheterization was low (r = 0.31, P =.13) and when restricted to patients undergoing both tests within 1 day increased slightly (r = 0.41, P =.14).The average PASP measured by Doppler was 99.7 ± 26 mm Hg (range 65 to 166); this was similar to the average reading by catheterization: 97.5 ± 13 mm Hg (range 75 to 126). Larger discrepancies were confined to patients with invasive PASP values of 100 or greater, in which the measurements differed by an average of 26.0 mm Hg.Among patients with PASP less than 100, the mean discrepancy was only 11.7 mm Hg. DISCUSSION PPH is a rare disease of the pulmonary vasculature that primarily affects otherwise healthy young adults. It usually follows a rapidly fatal course and has

6 660 Bossone et al August 1999 a median survival of only 2.8 years after diagnosis. Five-year survival rate is 34%. 23 Because of the nonspecific symptoms and the subtlety of the signs of less advanced disease, the mean length of time from the onset of symptoms to definitive diagnosis averages 2 years. 1 A high level of clinical suspicion is important for prompt diagnosis of these patients before reaching advanced stages of their disease. 24 For the specific diagnosis of PPH to be made, secondary causes of pulmonary hypertension must be excluded. Echocardiography is useful in the identification and assessment of this patient population because it helps to (1) exclude valvular, primary myocardial, and congenital causes for elevated rightsided pressure; (2) qualitatively and quantitatively estimate the hemodynamic abnormalities associated with PPH 25 ;and (3) monitor the effects of therapy. 26,27 Recognizing the characteristic baseline echocardiographic and Doppler features of PPH is of paramount importance both in the initial and serial evaluation of these patients. Although prior investigators have described several echocardiographic features in PPH, the current study comprises the largest series that includes consecutive patients with PPH evaluated at one institution. In our study we have focused on the description of the full spectrum of TTE/Doppler abnormalities in PPH. Virtually all patients had elevated PASP associated with significant right-sided chamber dilation and reduced right ventricular systolic function. An increased septal/posterior wall ratio was also noted; there was no evidence of dynamic left ventricular outflow obstruction at rest in any patient. 3,28 Because the ventricular septum is a shared wall between the right ventricle and left ventricle, it may hypertrophy in response to a pressure overload of either chamber. Because of hypertrophied trabeculations on the right ventricular side of the septum, it may be difficult to obtain a precise measurement of the true septal thickness. Pulsed Doppler of the mitral inflow suggested relative underfilling of the left ventricle in early diastole and redistribution of left ventricular filling into late diastole. 29,30 Potential causes for this include actual impairment of left ventricular filling caused by altered septal relaxation, low left-sided pressures, and tachycardia. This alteration in transmitral flow has 2 possible clinical implications: first, atrial fibrillation may not be well tolerated in patients with PPH because of marked dependence on atrial contraction for ventricular filling 4 ; second, there may be a potential for detrimental effects of vasodilator therapy on diastolic loading of the left ventricle in this clinical setting unless accompanied by an increase in rightsided output. 29 It was possible to investigate the right ventricular ejection flow dynamics in only 33% of the patients. Several recent studies have suggested that RVOT vc indexes may have a value in the early detection of PPH and in distinguishing primary from thromboembolic pulmonary hypertension Because the patients described in this study had PPH of unknown cause, we were unable to confirm these findings. We have also confirmed the presence of pericardial effusion and intracardiac shunts. Although the mechanism of pericardial effusion remains unclear, previous observers have suggested that it may result from impaired drainage of the myocardium caused by high venous and lymphatic pressures. 26,27,37 Finally, we recommend that cardiovascular shunts be carefully sought in these patients in light of the potential for life-threatening cerebrovascular complications 38 and associated prognostic implications. 3,39 Most of the shunts noted in this patient population were due to patent foramen ovale.two patients had anatomic congenital lesions (1 small atrial septal defect and 1 small ventricular septal defect). Because of the small size of the defects, neither was believed to be a causative factor in the development of PPH, although spontaneous closure or reduction in size over time of a larger and presumably causative defect in childhood cannot be excluded. Limitations There are several limitations of this study that deserve comment. The study population represents a homogenous group of patients, all of whom were seen at a tertiary care referral center with either known or suspected pulmonary hypertension or illnesses sufficient to warrant referral for other, initially misdiagnosed conditions. As such, they represent a population in large part comprised of individuals with fully developed signs and symptoms of pulmonary hypertension. In view of this, our results cannot be extrapolated to individuals with preclinical pulmonary hypertension. This study also represents a description of the resting echocardiographic and hemodynamic findings in patients with pulmonary hypertension.the degree to which right and left ventricular function and PASP would vary with exercise and affect functional status is not addressed in this study. Finally, although 25 (49%) patients underwent right heart catheterization, the studies were not performed simultaneously. Because of the relatively nar-

7 Volume 12 Number 8 Bossone et al 661 row range of PASP in this patient population, we are unable to address issues regarding correlation of Doppler and hemodynamic data at more physiologic ranges. Conclusions At the time of initial diagnosis, PPH is associated with secondary cardiac abnormalities in the majority of patients. TTE is an essential component of the diagnostic algorithm for suspected PPH.Once PPH is suspected on clinical grounds,tte allows (1) confirmation of the diagnosis; (2) evaluation of the extent of secondary effects on cardiac structures; (3) quantification of right and left ventricular function; (4) detection of coincident pathology; and (5) estimation of the efficacy of specific therapeutic interventions designed to reduce pulmonary artery pressure. REFERENCES 1. Rubin LJ. Primary pulmonary hypertension. N Engl J Med 1997;336: Morales D, Loscalzo J. Pulmonary hypertension: newer concepts in diagnosis and management. Clin Cardiol 1997;20: Rich S, Braunwald E, Grossman W. Pulmonary hypertension. In: Braunwald E, editor. Heart disease: a textbook of cardiovascular medicine. 5th edition. Philadelphia, Pa: WB Saunders Co; p Rubin LJ. ACCP consensus statement: primary pulmonary hypertension. Chest 993;104: Abenhaim L, Moride Y, Rich S, et al. The international primary pulmonary hypertension study. Chest 1994;105:92: 37S-41S. 6. Hatano S, Strasser T, eds. Primary pulmonary hypertension: report on a WHO meeting. Geneva: World Health Organization; p Rich S, Dantzker DR, Ayres SM, et al. Primary pulmonary hypertension: a national prospective study. Ann Intern Med 1987;107: Blanchard DG, Dittrich HG. Pericardial adaptation in severe chronic pulmonary hypertension: an intraoperative transesophageal echocardiographic study. Circulation 1992;85: Chen WJ, Kuan P, Lien W, et al. Detection of patient with foramen ovale by contrast transesophageal echocardiography. Chest 1992;101: Feigenbaum H. Echocardiography. 5th edition. Philadelphia: Lea & Febiger; p Oh JK, Seward JB, Tajik AJ. The echo manual. 1st edition. Boston: Little Brown & Co; p Yock PG, Popp RL. Noninvasive estimation of right ventricular systolic pressure by Doppler ultrasound in patients with tricuspid regurgitation. Circulation 1984;70: Hatle L, Angelsen BAJ, Tromsodal A. Non-invasive estimation of pulmonary artery systolic pressure. Br Heart J 1981;45: Chan KL, Currie PJ, Seward JB, et al. Comparison of 3 Doppler ultrasound methods in the prediction of pulmonary artery pressure. J Am Coll Cardiol 1987;9: Schiller NB, Shah PM, Crawford M, et al. Recommendations for quantitation of the left ventricle by 2-dimensional echocardiography. J Am Soc Echocardiogr 1989;2: Zoghbi WA, Habib GB, Quinones MA. Doppler assessment of right ventricular filling in a normal population: comparison with left ventricular filling dynamics. Circulation 1990;82: Watschinger B, Brunner C, Wagner A, et al. Left ventricular diastolic impairment in type I diabetic patients with microalbuminuria. Nephron 1993;63(2): Feigenbaum H. Echocardiography. 5th edition. Philadelphia: Lea & Febiger; p Oh JK, Seward JB, Tajik AJ. The echo manual. 1st edition. Boston: Little Brown & Co; p Cohen GI, Pietrolungo JF, Thomas JD, et al. A practical guide to assessment of ventricular diastolic function using Doppler echocardiography. J Am Coll Cardiol 1996;27: Nishimura RA, Tajik J. Evaluation of diastolic filling of left ventricle in health and disease: Doppler echocardiography is the clinician s Rosetta stone. J Am Coll Cardiol 1997;30: Eisenberg MJ, Oken K, Guerrero S, et al. Prognostic value of echocardiography in hospitalized patients with pericardial effusion. Am J Cardiol 1992;70: Barst RJ. Treatment of primary pulmonary hypertension with continuous intravenous prostacyclin. Heart 1997;77(4): D Alonzo GE, Dantzker DR. Diagnosing primary pulmonary hypertension. In: Rubin LJ, Rich S, editors. Primary pulmonary hypertension. New York: Marcel Dekker; p Georgiou D, Cao T, Shapiro SM, et al. Hemodynamic evaluation in primary pulmonary hypertension. In: Rubin LJ, Rich S, editors. Primary pulmonary hypertension. New York: Marcel Dekker; p Eysmann SB, Palevsky HI, Reicheck N, et al. Two-dimensional and Doppler echocardiographic and cardiac catheterization correlates of survival in primary pulmonary hypertension. Circulation 1989;80: Hinderliter AL, Willis PW, Barst RJ, et al. Effects of longterm infusion of prostacyclin (epoprostenol) on echocardiographic measures of right ventricular structure and function in primary pulmonary hypertension. Circulation 1997;95: Goodman DJ, Harrison DC, Popp RL. Echocardiographic features of primary pulmonary hypertension. Am J Cardiol 1974;33: Louie EK, Rich S, Brundage BH. Doppler echocardiographic assessment of impaired left ventricular filling in patients with right ventricular pressure overload due to primary pulmonary hypertension. J Am Coll Cardiol 1986;8: Stojnic BB, Brecker SJD, Xiao HB, et al. Left ventricular filling characteristic in pulmonary hypertension: a new mode of ventricular interaction. Br Heart J 1992;68(1): Migueres M, Escamilla R, Coca F, et al. Pulsed Doppler echocardiography in the diagnosis of pulmonary hypertension in COPD. Chest 1990;98: Dabestani A, Mahan G, Gardin JM, et al. Evaluation of pulmonary artery pressure and resistance by pulsed Doppler echocardiography. Am J Cardiol 1987;59:662-8.

8 662 Bossone et al August Ebeid MR, Ferrer PL, Robinson B, et al. Doppler echocardiographic evaluation of pulmonary vascular resistance in children with congenital heart disease. J Am Soc Echocardiogr 1996;9: Nakayama Y, Nakanishi N, Sugimachi M, et al. Characteristics of pulmonary artery pressure waveform for differential diagnosis of chronic pulmonary thromboembolism and primary pulmonary hypertension. J Am Coll Cardiol 1997;29: Bossone E, Bach DS, Ricciardi M, et al. Diagnostic value of right ventricular flow dynamics in exercise-induced pulmonary hypertension [abstract]. Circulation 1997;96(suppl I):I Nakayama Y, Sugimachi M, Nakanishi N, et al. Noninvasive differential diagnosis between chronic pulmonary thromboembolism and primary pulmonary hypertension by means of Doppler ultrasound measurement. J Am Coll Cardiol 1998;31(6): Park B, Dittrich HC, Policar R, et al. Echocardiographic evidence of pericardial effusion in severe chronic pulmonary hypertension. Am J Cardiol 1989;63: Raffy O, Sleiman C, Mal H, et al. Paradoxical acute brain thromboembolism during prostacyclin (PGI2) acute challenge for primary pulmonary hypertension. Eur Heart J 1996;17(1): Young D, Mark H. Fate of the patient with Eisenmenger s syndrome. Am J Cardiol 1971;28(6):