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Pulmonary artery hypertension in adult patients with symptomatic valvular aortic stenosis
Pulmonary Artery Hypertension in Adult Patients With Symptomatic Valvular Aortic Stenosis Pompilio Faggiano, MD, Francesco Antonini-Canterin, MD, Flavio Ribichini, Antonio D’Aloia, MD, Valeria Ferrero, MD, Eugenio Cervesato, PhD, Daniela Pavan, MD, Claudio Burelli, MD, and Gianluigi Nicolosi, MD
MD,
Pulmonary hypertension (PH) has been reported in patients with valvular aortic stenosis (AS) and has been found to be associated with a more severe clinical picture and a poor prognosis after aortic valve replacement. The aim of this study was to assess the prevalence of PH in adult patients with symptomatic AS undergoing cardiac catheterization, and to evaluate the relation between pulmonary artery (PA) systolic pressure and hemodynamic and clinical variables to further clarify the pathogenetic mechanisms. We assessed right-sided heart hemodynamics during cardiac catheterization in 388 patients with symptomatic isolated or predominant AS. PA systolic pressure between 31 and 50 mm Hg was used to define mild to moderate PH, whereas PA systolic pressure >50 mm Hg was used to define severe PH. PA systolic pressure showed no significant difference according to age and sex, although it was significantly higher in patients in New York Heart Association functional classes III and IV and in patients with coexistent systemic hypertension than in the others. PH was absent
in 136 patients (35%, group 1), mild to moderate in 196 patients (50%, group 2), and severe in 58 patients (15%, group 3). Only the prevalence of overt heart failure was significantly higher in group 3 patients. AS severity was similar among the 3 groups, and PA systolic pressure showed no relation to aortic valve area in the entire population. Also, a poor correlation was found between PA pressure and left ventricular (LV) ejection fraction (r ⴝ ⴚ0.28), with several patients having moderate or severe PH despite a preserved LV systolic function. PA systolic pressure significantly correlated with LV enddiastolic pressure (r ⴝ 0.50) and with PA wedge pressure (r ⴝ 0.84). Furthermore, transpulmonary pressure gradient, an index of resistance across the pulmonary vascular bed (obtained as the difference between PA mean and PA wedge pressure), was significantly higher in patients with PH, especially in those with a marked increase in PA systolic pressure, suggesting a reactive component of PH. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:204 –208)
ulmonary hypertension (PH) is present in a variable percentage (29% to 56%) of adult patients P with valvular aortic stenosis (AS), depending on the
AS, and (2) to identify clinical and hemodynamic variables eventually related to PH in these subjects to further clarify its pathogenetic mechanisms.
cutoff level of pulmonary artery (PA) pressure used to define PH and on the different selection criteria of populations evaluated in previous studies.1–3 The major limitation of these studies is represented by the relatively small size of the sample population examined, usually ⬍100 patients. Assessment of PH seems to have a clinical relevance, because an elevated PA pressure preoperatively has been found to be significantly related to relatively poor survival after valve replacement.4 However, other studies do not confirm these results.1,2 Furthermore, understanding the mechanisms responsible for PH in patients with symptomatic AS may have a physiopathologic and therapeutic relevance. Thus, in this study we attempted (1) to determine the prevalence of PH in a large group of adult patients with symptomatic isolated or prevalent From the Divisione di Cardiologia, Ospedale S. Orsola-Fatebenefratelli, Brescia; Divisione di Cardiologia, Ospedale S. Maria degli Angeli, Pordenone; Divisione di Cardiologia, Ospedale di Cuneo; and Divisione di Cardiologia, Spedali Civili, Italy. Manuscript received May 3, 1999; revised manuscript received August 18, 1999, and accepted August 20, 1999. Address for reprints: Pompilio Faggiano, MD, Via S. Antonio 6, 25133 Brescia, Italy. E-mail: [email protected].
204
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 15, 2000
METHODS
Study group: The study population consisted of 388 consecutive patients who underwent right- and leftsided cardiac catheterization for symptomatic valvular AS. Because other valvular heart diseases and pulmonary diseases are known to possibly induce PH, patients with mitral valve disease and/or more than mild aortic regurgitation (ⱖ2 on a 0 to 4 scale on the aortic angiogram) and those with a history of chronic obstructive lung disease or pulmonary embolism were excluded. Hemodynamics: Right- and left-sided cardiac catheterization was performed in all patients using standard techniques.5 Triple-lumen Swan-Ganz catheters were used to measure right atrial, PA, and PA wedge pressure. Cardiac output was measured by the Fick or thermodilution methods simultaneously with transvalvular pressure gradient recordings by pullback of a fluid-filled single catheter. Aortic valve area was calculated by the Gorlin equation,6 and aortic valvular resistance, a functional index of stenosis severity,7 was calculated according to the formula of Kegel et al.8 Qualitative grading of mitral and aortic regurgita0002-9149/00/$–see front matter PII S0002-9149(99)00643-8
TABLE I Demographic, Clinical, and Hemodynamic Characteristics of Patients With Valvular Aortic Stenosis (n ⫽ 388) Age (yrs) Men Cardiac rhythm Sinus Atrial fibrillation Other Clinical presentation* Angina pectoris Syncope Heart failure (mild to severe) New York Heart Association functional class III and IV Aortic valve area (cm2) Cardiac index (L/min/m2) Pulmonary artery systolic pressure (mm Hg) Pulmonary artery wedge pressure (mm Hg) Left ventricular end-diastolic pressure (mm Hg) Left ventricular ejection fraction (%) Left ventricular ejection fraction ⬍50% Coronary artery stenosis ⱖ50%
TABLE II Distribution of Clinical Features in Three Groups of Patients Divided According to the Value of Pulmonary Artery Systolic Pressure
67 ⫾ 8 240 (62%) 350 (90%) 36 (9.3%) 2 (0.5%) 148 41 216 108
(38%) (10.5%) (56%) (28%)
0.65 2.9 38 16 24 59 89 114
⫾ 0.22 ⫾ 0.63 ⫾ 15 ⫾8 ⫾ 11 ⫾ 16 (25%) (29%)
*Some patients had ⬎1 symptom.
tion was performed on left ventricular (LV) and aortic angiograms. LV ejection fraction was calculated by the area-length method for a single-plane right anterior oblique projection9; this parameter was available for 353 of the 388 patients. Dropouts were mainly due to premature beats or technical reasons. Selective coronary arteriography was performed in all patients; coronary artery disease was considered present when a ⱖ50% stenosis of at least 1 coronary artery was found. Patients were divided into 3 groups according to the level of PA pressure measured during cardiac catheterization: group 1, normal PA (PA systolic pressure ⱕ30 mm Hg); group 2, mild to moderate PH (PA systolic pressure 31 to 50 mm Hg); and group 3, severe PH (PA systolic pressure ⬎50 mm Hg). Furthermore, the transpulmonary pressure gradient, an index of vascular resistance across the pulmonary vascular bed,10,11 was calculated as the difference between PA mean pressure and PA wedge pressure (data available in 382 patients); a value of transpulmonary pressure gradient ⬎10 mm Hg is usually considered to indicate reactive PH.10 Statistical analysis: Data are expressed as mean value ⫾ SD.The chi-square test was used to compare subgroups with discrete variables. Differences among groups were calculated using analysis of variance. A p value of ⬍0.05 was considered statistically significant. Correlation between variables was examined by simple regression analysis.
RESULTS Demographic, clinical, and hemodynamic characteristics of all patients with AS are presented in Table I. All patients were symptomatic, with mild to severe heart failure being the most common clinical presentation and indication for hemodynamic evaluation. PA systolic pressure showed no differences according to
Group 1 2 (n ⫽ 136) (n ⫽ 194)
3 (n ⫽ 58)
PA systolic pressure (mm Hg) ⱕ30 31–50 ⬎50 Heart failure* 65 (48%) 106 (55%) 45 (78%)* Syncope 18 (13%) 20 (10%) 2 (3%) Angina pectoris 55 (40%) 75 (39%) 15 (26%) Coronary artery stenosis 39 (29%) 63 (32%) 12 (21%) (⬎50% in at least 1 artery) *p ⬍0.05.
sex (36 ⫾ 14 mm Hg in women vs 40 ⫾ 14 mm Hg in men), age (39 ⫾ 16 mm Hg in 160 patients aged ⱖ70 years compared with 37 ⫾ 14 mm Hg in 228 patients aged ⬍70 years), or presence of coronary artery disease (35 ⫾ 16 mm Hg in 114 patients with stenosis of at least 1 coronary artery compared with 38 ⫾ 15 mm Hg in 274 patients without significant coronary artery stenosis). However, PA systolic pressure was significantly higher in 108 patients in New York Association functional classes III and/or IV than in 280 patients in functional classes I and/or II (46 ⫾ 19 vs 35 ⫾ 12 mm Hg, p ⬍0.001). PA systolic pressure was also significantly higher in 82 patients with systemic hypertension (aortic systolic pressure ⱖ160 mm Hg at cardiac catheterization) than in 306 patients without systolic hypertension (43 ⫾ 15 vs 36 ⫾ 14 mm Hg, p ⬍0.001). According to the adopted definition of PH, 136 patients (35%) had normal PA pressure (group 1, mean value 25.5 ⫾ 3.5 mm Hg), 194 patients (50%) had mild to moderate PH (group 2, mean value 37.9 ⫾ 5.4 mm Hg), and 58 patients (15%) had severe PH (group 3, mean value 66.7 ⫾ 13 mm Hg). Congestive heart failure was found most often in group 3 patients than in the other groups, whereas prevalence of angina and syncope was similar among the 3 groups in addition to the prevalence of significant coronary artery stenosis (Table II). The hemodynamic profile of the 3 groups is presented in Table III. There was no difference in the severity of valvular stenosis among the 3 groups. The mean value for LV ejection fraction was significantly lower in group 3 patients. However, only 27 of 51 patients (53%) in group 3, in whom this parameter was measured, had an ejection fraction below the normal limit (50%), indicating that LV systolic function was normal in roughly one half of patients with severe PH. A reduced ejection fraction was observed in 17% (19 of 112) of group 1 patients, and in 23% (43 of 190) of group 2 patients. PA wedge pressure was progressively and significantly higher in group 2 and 3 patients, paralleling the behavior of PA systolic pressure. Also, the transpulmonary pressure gradient was increasingly higher in groups 1 to 3; in particular, its mean value in group 3 patients was ⬎10 mm Hg, suggesting of a reactive component of PH
VALVULAR HEART DISEASE/PULMONARY HYPERTENSION IN AORTIC STENOSIS
205
TABLE III Hemodynamic Profile of the Three Groups Divided According to the Value of Pulmonary Artery Systolic Pressure Group
PA systolic pressure (mm Hg) Aortic valve area (cm2) Peak pressure gradient (mm Hg) Aortic valve resistance (dyne 䡠 s 䡠 cm⫺5) LV ejection fraction (%)* Cardiac index (L/min/m2)* Pulmonary artery wedge pressure (mm Hg)* Transpulmonary pressure gradient (mm Hg)*
1 (n ⫽ 136)
2 (n ⫽ 194)
3 (n ⫽ 58)
ⱕ30
30–50
⬎50
0.68 ⫾ 0.21 0.64 ⫾ 0.22 0.61 ⫾ 0.25 71 ⫾ 29
77 ⫾ 30
76 ⫾ 34
465 ⫾ 227
493 ⫾ 237
542 ⫾ 282
62 ⫾ 14
61 ⫾ 14
49 ⫾ 16
2.87 ⫾ 0.55 2.98 ⫾ 0.62 2.59 ⫾ 0.65 9.2 ⫾ 3.0
16 ⫾ 5.5
29 ⫾ 7.1
6.5 ⫾ 2.1
8.8 ⫾ 3.4
15 ⫾ 6.6
*p ⫽ 0.001.
that was not evident in the other 2 groups. Furthermore, 44 of 56 patients (78.6%) in group 3 had a transpulmonary pressure gradient ⬎10 mm Hg, versus only 6 of 134 patients (4.5%) in group 1 and 49 of 192 (25.5%) in group 2 (p ⬍0.001). Because reactive PH is reported to develop from a long-standing increase in left atrial pressure, we also analyzed, according to the approach proposed by Dalen et al,10 the relation between transpulmonary pressure gradient and PA wedge pressure (Figure 1). Most group 3 patients (41 of 56, 73.2%) had both an increase in transpulmonary pressure gradient (⬎10 mm Hg) and a relevant increase in PA wedge pressure (⬎20 mm Hg) compared with only 5 patients (2.6%) in group 2 and no patient in group 1. In contrast, 128 of 134 group 1 patients (95.5%) had both a transpulmonary pressure gradient ⱕ10 mm Hg and a PA wedge pressure ⱕ20 mm Hg compared with 109 of 191 group 2 patients (56.8%) and no patient in group 3. A transpulmonary pressure gradient ⱕ10 mm Hg associated with a PA wedge pressure ⬎20 mm Hg was observed in no patient in group 1, 34 patients (17.7%) in group 2, and 12 patients (21.4%) in group 3, whereas a transpulmonary pressure gradient ⬎10 mm Hg associated with a PA wedge pressure ⱕ20 mm Hg was observed in 6 group 1 patients (4.5%), 44 group 2 patients (22.9%), and 3 group 3 (5.4%) patients. The different distribution of hemodynamic profiles among the 3 groups was statistically significant (p ⬍0.001). Finally, we found a poor correlation between PA systolic pressure and aortic valve area (r ⫽ ⫺0.15, p ⫽NS) and LV ejection fraction (r ⫽ ⫺0.28, p ⬍0.001). In contrast, PA systolic pressure showed a linear relation of moderate degree with LV end-diastolic pressure (r ⫽ 0.50, p 206 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 1. Transpulmonary pressure gradient plotted against pulmonary artery wedge pressure in symptomatic patients with AS without PH (group 1, top), in those with mild to moderate PH (PA systolic pressure between 31 and 50 mm Hg, group 2, middle), and in those with severe PH (PA systolic pressure >50 mm Hg, group 3, bottom). See text for details.
⬍0.001), and of a high degree with PA wedge pressure (r ⫽ 0.84, p ⬍0.001). Such correlations are presented in Figure 2.
DISCUSSION The results of our study, obtained in a large group of consecutive patients with symptomatic valvular AS, confirm those obtained previously in smaller populations,1–3,12–15 with a high prevalence of PH (65%). Furthermore, a relevant group of patients (58 of 388, 15%) had a marked increase in PA systolic pressure (⬎50 mm Hg). Of interest, our data indicate that the presence and degree of PH in these patients was unrelated to the severity of valve stenosis. Furthermore, although LV ejection fraction was significantly lower in patients with severe PH, we found a poor correlation between PA pressure and ejection fraction. JANUARY 15, 2000
FIGURE 2. Relation between pulmonary artery systolic pressure (sPAP) and different hemodynamic variables in symptomatic patients with valvular aortic stenosis. See text for details. AVA ⴝ aortic valve area; LVEDP ⴝ left ventricular end-diastolic pressure.
In fact, normal LV systolic function was found in a large percentage of patients (77% in group 2 and 47% in group 3 patients). Johnson et al1 reported a normal ejection fraction in less than half of their patients with severe PH and Aragam et al2 found similar results in 64% of their patients with mild to severe PH.2 According to these results, a reduction of LV systolic function does not appear to play a major role in the pathogenesis of PH in these patients. In contrast, we found significantly higher LV end-diastolic and PA wedge pressures in patients with than without PH; both pressures also showed a correlation of moderate to high degree with PA systolic pressure (Figure 2). An increase in LV filling pressure mainly reflects the abnormalities of LV diastolic properties, frequently observed as a consequence of chronic pressure overload-induced hypertrophy, especially when systolic function is preserved. Also, the coexistence of AS and systemic hypertension, through a double afterload on the left ventricle,16 may probably induce a further increase in LV wall thickness and diastolic dysfunction, and hence in left atrial and PA pressure. This may explain, at least in part, the significantly higher PA pressure we observed in our patients with than without systemic hypertension recorded during routine cardiac catheterization. Although data on LV mass and hemodynamic indexes of diastolic function were not included in this study, we believe that the presence of a high filling pressure, despite that LV systolic function was often in the normal range, supports the hypothesis that diastolic dysfunction may be a major determinant of PH in patients with symptomatic AS. Another point of interest is the finding of a high
transpulmonary pressure gradient (⬎10 mm Hg) in several patients with PH. This parameter has been proposed to differentiate passive from reactive PH (the latter characterized by functional and structural changes in pulmonary arterioles) both in patients with valvular heart disease10 and in those with congestive heart failure evaluated for heart transplantation.17 We found a high transpulmonary pressure gradient in most patients (78%) with severe PH, and in 25% of those with mild to moderate PH, whereas it was in the normal range in ⬎95% of patients without PH. The frequent association between a high transpulmonary pressure gradient and a marked increase in PA wedge pressure (41 of 44 group 3 patients with transpulmonary pressure gradient ⬎10 mm Hg also had a PA wedge pressure ⬎20 mm Hg) suggests that reactive PH is the consequence of long-standing elevation of left atrial pressure. A high transpulmonary pressure gradient associated with a PA wedge pressure ⱕ20 mm Hg, as observed in one fourth of patients with mild to moderate PH, still suggests a reactive component of PH due to a persistent but only moderate increase in left atrial pressure (⬎12 but ⱕ20 mm Hg). However, the simultaneous presence of other mechanisms accounting for the elevated gradient cannot be completely excluded. In fact, coexistent chronic lung disease, not evident on clinical evaluation (overt disease was an exclusion criterion in this study), could be responsible for an increase in PA pressure but a normal left atrial pressure. Another potential mechanism is the presence of mitral regurgitation (even in the absence of intrinsic mitral valve disease). Silver et al3 showed that some patients with AS and even trivial
VALVULAR HEART DISEASE/PULMONARY HYPERTENSION IN AORTIC STENOSIS
207
mitral regurgitation had a high transpulmonary pressure gradient, despite a concomitantly low PA wedge pressure. Clinical implications: The assessment of PA pressure in patients with AS may have clinical relevance. First, in symptomatic patients with severe PH, a high incidence of severe heart failure progressing to cardiogenic shock, and of sudden death, even soon after cardiac catheterization and/or while awaiting cardiac surgery has been reported.12,13 Furthermore, Copeland et al4 found that patients with PH had a higher mortality after aortic valve replacement than those without PH. However, other investigators1,2 did not find any relation between the level of PA pressure and postoperative survival (early and late). Thus, the prognostic significance of PH and the effects of valve replacement in these subjects require further studies. Second, differentiation between the potential pathogenetic mechanism (in particular systolic vs diastolic dysfunction), and the different forms of PH (passive vs reactive) may contribute to the decision-making process in the individual patient. For example, this could suggest earlier intervention in asymptomatic or minimally symptomatic patients with significant AS and moderate to severe PH before irreversible changes in pulmonary circulation can occur. Furthermore, concomitant systemic hypertension should be treated to reduce the double afterload on the left ventricle and its deleterious consequences. Third, a reduction in PA pressure and normalization of pulmonary vascular resistance usually occurred early after valve replacement.14,15,18 Roithinger et al,19 by assessing the severity of PH before and shortly after aortic valve replacement, reported that patients receiving larger valve prostheses (ⱖ25 mm diameter) had a greater reduction in PA pressure than others. A smaller valve prosthesis represents an independent risk factor for unsatisfactory long-term outcome in surgically treated patients with AS.20 Accordingly, it may be hypothesized that the hemodynamic profile of small prostheses not only reduce the exercise capacity of patients,21,22 but may also influence the outcome through partial or absent reversibility of PH. Further studies on larger populations are necessary to confirm these results to justify the use of larger prosthetic valves, at least in AS patients with concomitant PH.
208 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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1. Johnson LW, Hapanowicz MB, Buonanno C, Bowser MA, Marvasti MA, Parker FB. Pulmonary hypertension in isolated aortic stenosis. Hemodynamic correlations and follow-up. J Thorac Cardiovasc Surg 1988;95:603– 607. 2. Aragam JR, Folland ED, Lapsley D, Sharma S, Khuri SK, Sharma GVRK. Cause and impact of pulmonary hypertension in isolated aortic stenosis on operative mortality for aortic valve replacement in men. Am J Cardiol 1992;69: 1365–1367. 3. Silver K, Aurigemma G, Krendel S, Barry N, Ockene I, Alpert J. Pulmonary artery hypertension in severe aortic stenosis: incidence and mechanism. Am Heart J 1993;125:146 –150. 4. Copeland JG, Griepp RB, Stinson EB, Shumway NE. Long-term follow-up after isolated aortic valve replacement. J Thorac and Cardiovasc Surg 1977;74: 875– 885. 5. Baim DS, Grossman W. Percutaneous approach, including transseptal catheterization and apical left ventricular puncture. In: Grossman W, Baim DS, Eds. Cardiac catheterization, angiography and intervention. Philadelphia: Lea & Febiger, 1991:62– 81. 6. Gorlin R, Gorlin SG. Hemodynamic formula for calculation of the stenotic mitral valve, other cardiac valves and central circulatory shunts. Am Heart J 1951;41:1–29. 7. Ford LE, Feldman T, Chiu YC, Carroll JD. Hemodynamic resistance as a measure of functional impairment in aortic valvular stenosis. Circ Res 1990;66: 1–7. 8. Kegel JG, Shalet BD, Corin WJ, Iskandrian AS. Simplified method for calculating aortic valve resistance: correlation with valve area and standard formula. Cathet Cardiovasc Diagn 1993;30:15–21. 9. Gault JH. Angiographic estimation of left ventricular volume. Cathet Cardiovasc Diagn 1975;1:7–16. 10. Dalen JE, Dexter L, Ockene IS, Carlson J. Precapillary pulmonary hypertension: its relationship to pulmonary venous hypertension. Trans Am Clin Climatol Assoc 1974;86:207–218. 11. Costard-Jackle A, Fowler MB. Influence of preoperative pulmonary artery pressure on mortality after heart transplantation: testing of potential reversibility of pulmonary hypertension with nitroprusside is useful in defining a high risk group. J Am Coll Cardiol 1992;19:48 –54. 12. McHenry MM, Rice J, Matlof HJ, Flamm MD. Pulmonary hypertension and sudden death in aortic stenosis. Br Heart J 1979;41:463– 467. 13. Gould L, Venkataraman K, Goswami M, DeMartino A, Gomprecht RF. Right-sided heart failure in aortic stenosis. Am J Cardiol 1973;31:381–383. 14. Riegel N, Ambrose JA, Mindich BP, Fuster V. Isolated aortic stenosis with severe pulmonary hypertension. Cathet Cardiovasc Diagn 1985;11:181–185. 15. Snopek G, Pogorzelska H, Zielinski T, Rajecka A, Korewicki J, Biederman A, Kotlinski Z. Valve replacement for aortic stenosis with severe congestive heart failure and pulmonary hypertension. J Heart Valve Dis 1996;5:268 –272. 16. Carroll JD, Hellman K, Feldman T. Systolic hypertension complicating aortic stenosis: the double-loaded ventricle (abstr). Circulation 1993;88(suppl I): I-102 17. Murali S, Kormo R, Uretsky B, Schechter D, Reddy S, Denys BG, Armitage JM, Hardesty RL, Griffith BP. Preoperative pulmonary hemodynamics and early mortality after orthotopic cardiac transplantation: the Pittsburgh experience. Am Heart J 1993;126:896 –904. 18. Tracy GP, Proctor MS, Hizny CS. Reversibility of pulmonary artery hypertension in aortic stenosis after aortic valve replacement. Ann Thorac Surg 1990; 50:89 –93. 19. Roithinger FX, Krennmair G, Deutsch M, Pachinger O. The influence of aortic valve prosthesis diameter on the reversibility of pulmonary hypertension in isolated aortic stenosis. J Heart Valve Dis 1994;3:185–189. 20. Lund O. Preoperative risk evaluation and stratification of long-term survival after valve repalcement for aortic stenosis. Circulation 1990;82:124 –139. 21. Tatineni S, Barner HB, Pearson AC, Halbe D, Woodruff R, Labovitz AJ. Rest and exercise evaluation of the St. Jude Medical and Medtronic-Hall prostheses. Influence of primary lesion, valvular type, valvular size and left ventricular function. Circulation 1989;80(suppl I):I-16 –I-23. 22. Teoh KH, Fulop JC, Weisel RD, Ivanov J, Tong CP, Slattery SA, Rakowski H. Aortic valve replacement with a small prosthesis. Circulation1987;76(suppl III):III-123–III-131.
JANUARY 15, 2000
MD,
Pulmonary hypertension (PH) has been reported in patients with valvular aortic stenosis (AS) and has been found to be associated with a more severe clinical picture and a poor prognosis after aortic valve replacement. The aim of this study was to assess the prevalence of PH in adult patients with symptomatic AS undergoing cardiac catheterization, and to evaluate the relation between pulmonary artery (PA) systolic pressure and hemodynamic and clinical variables to further clarify the pathogenetic mechanisms. We assessed right-sided heart hemodynamics during cardiac catheterization in 388 patients with symptomatic isolated or predominant AS. PA systolic pressure between 31 and 50 mm Hg was used to define mild to moderate PH, whereas PA systolic pressure >50 mm Hg was used to define severe PH. PA systolic pressure showed no significant difference according to age and sex, although it was significantly higher in patients in New York Heart Association functional classes III and IV and in patients with coexistent systemic hypertension than in the others. PH was absent
in 136 patients (35%, group 1), mild to moderate in 196 patients (50%, group 2), and severe in 58 patients (15%, group 3). Only the prevalence of overt heart failure was significantly higher in group 3 patients. AS severity was similar among the 3 groups, and PA systolic pressure showed no relation to aortic valve area in the entire population. Also, a poor correlation was found between PA pressure and left ventricular (LV) ejection fraction (r ⴝ ⴚ0.28), with several patients having moderate or severe PH despite a preserved LV systolic function. PA systolic pressure significantly correlated with LV enddiastolic pressure (r ⴝ 0.50) and with PA wedge pressure (r ⴝ 0.84). Furthermore, transpulmonary pressure gradient, an index of resistance across the pulmonary vascular bed (obtained as the difference between PA mean and PA wedge pressure), was significantly higher in patients with PH, especially in those with a marked increase in PA systolic pressure, suggesting a reactive component of PH. 䊚2000 by Excerpta Medica, Inc. (Am J Cardiol 2000;85:204 –208)
ulmonary hypertension (PH) is present in a variable percentage (29% to 56%) of adult patients P with valvular aortic stenosis (AS), depending on the
AS, and (2) to identify clinical and hemodynamic variables eventually related to PH in these subjects to further clarify its pathogenetic mechanisms.
cutoff level of pulmonary artery (PA) pressure used to define PH and on the different selection criteria of populations evaluated in previous studies.1–3 The major limitation of these studies is represented by the relatively small size of the sample population examined, usually ⬍100 patients. Assessment of PH seems to have a clinical relevance, because an elevated PA pressure preoperatively has been found to be significantly related to relatively poor survival after valve replacement.4 However, other studies do not confirm these results.1,2 Furthermore, understanding the mechanisms responsible for PH in patients with symptomatic AS may have a physiopathologic and therapeutic relevance. Thus, in this study we attempted (1) to determine the prevalence of PH in a large group of adult patients with symptomatic isolated or prevalent From the Divisione di Cardiologia, Ospedale S. Orsola-Fatebenefratelli, Brescia; Divisione di Cardiologia, Ospedale S. Maria degli Angeli, Pordenone; Divisione di Cardiologia, Ospedale di Cuneo; and Divisione di Cardiologia, Spedali Civili, Italy. Manuscript received May 3, 1999; revised manuscript received August 18, 1999, and accepted August 20, 1999. Address for reprints: Pompilio Faggiano, MD, Via S. Antonio 6, 25133 Brescia, Italy. E-mail: [email protected].
204
©2000 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 85 January 15, 2000
METHODS
Study group: The study population consisted of 388 consecutive patients who underwent right- and leftsided cardiac catheterization for symptomatic valvular AS. Because other valvular heart diseases and pulmonary diseases are known to possibly induce PH, patients with mitral valve disease and/or more than mild aortic regurgitation (ⱖ2 on a 0 to 4 scale on the aortic angiogram) and those with a history of chronic obstructive lung disease or pulmonary embolism were excluded. Hemodynamics: Right- and left-sided cardiac catheterization was performed in all patients using standard techniques.5 Triple-lumen Swan-Ganz catheters were used to measure right atrial, PA, and PA wedge pressure. Cardiac output was measured by the Fick or thermodilution methods simultaneously with transvalvular pressure gradient recordings by pullback of a fluid-filled single catheter. Aortic valve area was calculated by the Gorlin equation,6 and aortic valvular resistance, a functional index of stenosis severity,7 was calculated according to the formula of Kegel et al.8 Qualitative grading of mitral and aortic regurgita0002-9149/00/$–see front matter PII S0002-9149(99)00643-8
TABLE I Demographic, Clinical, and Hemodynamic Characteristics of Patients With Valvular Aortic Stenosis (n ⫽ 388) Age (yrs) Men Cardiac rhythm Sinus Atrial fibrillation Other Clinical presentation* Angina pectoris Syncope Heart failure (mild to severe) New York Heart Association functional class III and IV Aortic valve area (cm2) Cardiac index (L/min/m2) Pulmonary artery systolic pressure (mm Hg) Pulmonary artery wedge pressure (mm Hg) Left ventricular end-diastolic pressure (mm Hg) Left ventricular ejection fraction (%) Left ventricular ejection fraction ⬍50% Coronary artery stenosis ⱖ50%
TABLE II Distribution of Clinical Features in Three Groups of Patients Divided According to the Value of Pulmonary Artery Systolic Pressure
67 ⫾ 8 240 (62%) 350 (90%) 36 (9.3%) 2 (0.5%) 148 41 216 108
(38%) (10.5%) (56%) (28%)
0.65 2.9 38 16 24 59 89 114
⫾ 0.22 ⫾ 0.63 ⫾ 15 ⫾8 ⫾ 11 ⫾ 16 (25%) (29%)
*Some patients had ⬎1 symptom.
tion was performed on left ventricular (LV) and aortic angiograms. LV ejection fraction was calculated by the area-length method for a single-plane right anterior oblique projection9; this parameter was available for 353 of the 388 patients. Dropouts were mainly due to premature beats or technical reasons. Selective coronary arteriography was performed in all patients; coronary artery disease was considered present when a ⱖ50% stenosis of at least 1 coronary artery was found. Patients were divided into 3 groups according to the level of PA pressure measured during cardiac catheterization: group 1, normal PA (PA systolic pressure ⱕ30 mm Hg); group 2, mild to moderate PH (PA systolic pressure 31 to 50 mm Hg); and group 3, severe PH (PA systolic pressure ⬎50 mm Hg). Furthermore, the transpulmonary pressure gradient, an index of vascular resistance across the pulmonary vascular bed,10,11 was calculated as the difference between PA mean pressure and PA wedge pressure (data available in 382 patients); a value of transpulmonary pressure gradient ⬎10 mm Hg is usually considered to indicate reactive PH.10 Statistical analysis: Data are expressed as mean value ⫾ SD.The chi-square test was used to compare subgroups with discrete variables. Differences among groups were calculated using analysis of variance. A p value of ⬍0.05 was considered statistically significant. Correlation between variables was examined by simple regression analysis.
RESULTS Demographic, clinical, and hemodynamic characteristics of all patients with AS are presented in Table I. All patients were symptomatic, with mild to severe heart failure being the most common clinical presentation and indication for hemodynamic evaluation. PA systolic pressure showed no differences according to
Group 1 2 (n ⫽ 136) (n ⫽ 194)
3 (n ⫽ 58)
PA systolic pressure (mm Hg) ⱕ30 31–50 ⬎50 Heart failure* 65 (48%) 106 (55%) 45 (78%)* Syncope 18 (13%) 20 (10%) 2 (3%) Angina pectoris 55 (40%) 75 (39%) 15 (26%) Coronary artery stenosis 39 (29%) 63 (32%) 12 (21%) (⬎50% in at least 1 artery) *p ⬍0.05.
sex (36 ⫾ 14 mm Hg in women vs 40 ⫾ 14 mm Hg in men), age (39 ⫾ 16 mm Hg in 160 patients aged ⱖ70 years compared with 37 ⫾ 14 mm Hg in 228 patients aged ⬍70 years), or presence of coronary artery disease (35 ⫾ 16 mm Hg in 114 patients with stenosis of at least 1 coronary artery compared with 38 ⫾ 15 mm Hg in 274 patients without significant coronary artery stenosis). However, PA systolic pressure was significantly higher in 108 patients in New York Association functional classes III and/or IV than in 280 patients in functional classes I and/or II (46 ⫾ 19 vs 35 ⫾ 12 mm Hg, p ⬍0.001). PA systolic pressure was also significantly higher in 82 patients with systemic hypertension (aortic systolic pressure ⱖ160 mm Hg at cardiac catheterization) than in 306 patients without systolic hypertension (43 ⫾ 15 vs 36 ⫾ 14 mm Hg, p ⬍0.001). According to the adopted definition of PH, 136 patients (35%) had normal PA pressure (group 1, mean value 25.5 ⫾ 3.5 mm Hg), 194 patients (50%) had mild to moderate PH (group 2, mean value 37.9 ⫾ 5.4 mm Hg), and 58 patients (15%) had severe PH (group 3, mean value 66.7 ⫾ 13 mm Hg). Congestive heart failure was found most often in group 3 patients than in the other groups, whereas prevalence of angina and syncope was similar among the 3 groups in addition to the prevalence of significant coronary artery stenosis (Table II). The hemodynamic profile of the 3 groups is presented in Table III. There was no difference in the severity of valvular stenosis among the 3 groups. The mean value for LV ejection fraction was significantly lower in group 3 patients. However, only 27 of 51 patients (53%) in group 3, in whom this parameter was measured, had an ejection fraction below the normal limit (50%), indicating that LV systolic function was normal in roughly one half of patients with severe PH. A reduced ejection fraction was observed in 17% (19 of 112) of group 1 patients, and in 23% (43 of 190) of group 2 patients. PA wedge pressure was progressively and significantly higher in group 2 and 3 patients, paralleling the behavior of PA systolic pressure. Also, the transpulmonary pressure gradient was increasingly higher in groups 1 to 3; in particular, its mean value in group 3 patients was ⬎10 mm Hg, suggesting of a reactive component of PH
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TABLE III Hemodynamic Profile of the Three Groups Divided According to the Value of Pulmonary Artery Systolic Pressure Group
PA systolic pressure (mm Hg) Aortic valve area (cm2) Peak pressure gradient (mm Hg) Aortic valve resistance (dyne 䡠 s 䡠 cm⫺5) LV ejection fraction (%)* Cardiac index (L/min/m2)* Pulmonary artery wedge pressure (mm Hg)* Transpulmonary pressure gradient (mm Hg)*
1 (n ⫽ 136)
2 (n ⫽ 194)
3 (n ⫽ 58)
ⱕ30
30–50
⬎50
0.68 ⫾ 0.21 0.64 ⫾ 0.22 0.61 ⫾ 0.25 71 ⫾ 29
77 ⫾ 30
76 ⫾ 34
465 ⫾ 227
493 ⫾ 237
542 ⫾ 282
62 ⫾ 14
61 ⫾ 14
49 ⫾ 16
2.87 ⫾ 0.55 2.98 ⫾ 0.62 2.59 ⫾ 0.65 9.2 ⫾ 3.0
16 ⫾ 5.5
29 ⫾ 7.1
6.5 ⫾ 2.1
8.8 ⫾ 3.4
15 ⫾ 6.6
*p ⫽ 0.001.
that was not evident in the other 2 groups. Furthermore, 44 of 56 patients (78.6%) in group 3 had a transpulmonary pressure gradient ⬎10 mm Hg, versus only 6 of 134 patients (4.5%) in group 1 and 49 of 192 (25.5%) in group 2 (p ⬍0.001). Because reactive PH is reported to develop from a long-standing increase in left atrial pressure, we also analyzed, according to the approach proposed by Dalen et al,10 the relation between transpulmonary pressure gradient and PA wedge pressure (Figure 1). Most group 3 patients (41 of 56, 73.2%) had both an increase in transpulmonary pressure gradient (⬎10 mm Hg) and a relevant increase in PA wedge pressure (⬎20 mm Hg) compared with only 5 patients (2.6%) in group 2 and no patient in group 1. In contrast, 128 of 134 group 1 patients (95.5%) had both a transpulmonary pressure gradient ⱕ10 mm Hg and a PA wedge pressure ⱕ20 mm Hg compared with 109 of 191 group 2 patients (56.8%) and no patient in group 3. A transpulmonary pressure gradient ⱕ10 mm Hg associated with a PA wedge pressure ⬎20 mm Hg was observed in no patient in group 1, 34 patients (17.7%) in group 2, and 12 patients (21.4%) in group 3, whereas a transpulmonary pressure gradient ⬎10 mm Hg associated with a PA wedge pressure ⱕ20 mm Hg was observed in 6 group 1 patients (4.5%), 44 group 2 patients (22.9%), and 3 group 3 (5.4%) patients. The different distribution of hemodynamic profiles among the 3 groups was statistically significant (p ⬍0.001). Finally, we found a poor correlation between PA systolic pressure and aortic valve area (r ⫽ ⫺0.15, p ⫽NS) and LV ejection fraction (r ⫽ ⫺0.28, p ⬍0.001). In contrast, PA systolic pressure showed a linear relation of moderate degree with LV end-diastolic pressure (r ⫽ 0.50, p 206 THE AMERICAN JOURNAL OF CARDIOLOGY姞
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FIGURE 1. Transpulmonary pressure gradient plotted against pulmonary artery wedge pressure in symptomatic patients with AS without PH (group 1, top), in those with mild to moderate PH (PA systolic pressure between 31 and 50 mm Hg, group 2, middle), and in those with severe PH (PA systolic pressure >50 mm Hg, group 3, bottom). See text for details.
⬍0.001), and of a high degree with PA wedge pressure (r ⫽ 0.84, p ⬍0.001). Such correlations are presented in Figure 2.
DISCUSSION The results of our study, obtained in a large group of consecutive patients with symptomatic valvular AS, confirm those obtained previously in smaller populations,1–3,12–15 with a high prevalence of PH (65%). Furthermore, a relevant group of patients (58 of 388, 15%) had a marked increase in PA systolic pressure (⬎50 mm Hg). Of interest, our data indicate that the presence and degree of PH in these patients was unrelated to the severity of valve stenosis. Furthermore, although LV ejection fraction was significantly lower in patients with severe PH, we found a poor correlation between PA pressure and ejection fraction. JANUARY 15, 2000
FIGURE 2. Relation between pulmonary artery systolic pressure (sPAP) and different hemodynamic variables in symptomatic patients with valvular aortic stenosis. See text for details. AVA ⴝ aortic valve area; LVEDP ⴝ left ventricular end-diastolic pressure.
In fact, normal LV systolic function was found in a large percentage of patients (77% in group 2 and 47% in group 3 patients). Johnson et al1 reported a normal ejection fraction in less than half of their patients with severe PH and Aragam et al2 found similar results in 64% of their patients with mild to severe PH.2 According to these results, a reduction of LV systolic function does not appear to play a major role in the pathogenesis of PH in these patients. In contrast, we found significantly higher LV end-diastolic and PA wedge pressures in patients with than without PH; both pressures also showed a correlation of moderate to high degree with PA systolic pressure (Figure 2). An increase in LV filling pressure mainly reflects the abnormalities of LV diastolic properties, frequently observed as a consequence of chronic pressure overload-induced hypertrophy, especially when systolic function is preserved. Also, the coexistence of AS and systemic hypertension, through a double afterload on the left ventricle,16 may probably induce a further increase in LV wall thickness and diastolic dysfunction, and hence in left atrial and PA pressure. This may explain, at least in part, the significantly higher PA pressure we observed in our patients with than without systemic hypertension recorded during routine cardiac catheterization. Although data on LV mass and hemodynamic indexes of diastolic function were not included in this study, we believe that the presence of a high filling pressure, despite that LV systolic function was often in the normal range, supports the hypothesis that diastolic dysfunction may be a major determinant of PH in patients with symptomatic AS. Another point of interest is the finding of a high
transpulmonary pressure gradient (⬎10 mm Hg) in several patients with PH. This parameter has been proposed to differentiate passive from reactive PH (the latter characterized by functional and structural changes in pulmonary arterioles) both in patients with valvular heart disease10 and in those with congestive heart failure evaluated for heart transplantation.17 We found a high transpulmonary pressure gradient in most patients (78%) with severe PH, and in 25% of those with mild to moderate PH, whereas it was in the normal range in ⬎95% of patients without PH. The frequent association between a high transpulmonary pressure gradient and a marked increase in PA wedge pressure (41 of 44 group 3 patients with transpulmonary pressure gradient ⬎10 mm Hg also had a PA wedge pressure ⬎20 mm Hg) suggests that reactive PH is the consequence of long-standing elevation of left atrial pressure. A high transpulmonary pressure gradient associated with a PA wedge pressure ⱕ20 mm Hg, as observed in one fourth of patients with mild to moderate PH, still suggests a reactive component of PH due to a persistent but only moderate increase in left atrial pressure (⬎12 but ⱕ20 mm Hg). However, the simultaneous presence of other mechanisms accounting for the elevated gradient cannot be completely excluded. In fact, coexistent chronic lung disease, not evident on clinical evaluation (overt disease was an exclusion criterion in this study), could be responsible for an increase in PA pressure but a normal left atrial pressure. Another potential mechanism is the presence of mitral regurgitation (even in the absence of intrinsic mitral valve disease). Silver et al3 showed that some patients with AS and even trivial
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mitral regurgitation had a high transpulmonary pressure gradient, despite a concomitantly low PA wedge pressure. Clinical implications: The assessment of PA pressure in patients with AS may have clinical relevance. First, in symptomatic patients with severe PH, a high incidence of severe heart failure progressing to cardiogenic shock, and of sudden death, even soon after cardiac catheterization and/or while awaiting cardiac surgery has been reported.12,13 Furthermore, Copeland et al4 found that patients with PH had a higher mortality after aortic valve replacement than those without PH. However, other investigators1,2 did not find any relation between the level of PA pressure and postoperative survival (early and late). Thus, the prognostic significance of PH and the effects of valve replacement in these subjects require further studies. Second, differentiation between the potential pathogenetic mechanism (in particular systolic vs diastolic dysfunction), and the different forms of PH (passive vs reactive) may contribute to the decision-making process in the individual patient. For example, this could suggest earlier intervention in asymptomatic or minimally symptomatic patients with significant AS and moderate to severe PH before irreversible changes in pulmonary circulation can occur. Furthermore, concomitant systemic hypertension should be treated to reduce the double afterload on the left ventricle and its deleterious consequences. Third, a reduction in PA pressure and normalization of pulmonary vascular resistance usually occurred early after valve replacement.14,15,18 Roithinger et al,19 by assessing the severity of PH before and shortly after aortic valve replacement, reported that patients receiving larger valve prostheses (ⱖ25 mm diameter) had a greater reduction in PA pressure than others. A smaller valve prosthesis represents an independent risk factor for unsatisfactory long-term outcome in surgically treated patients with AS.20 Accordingly, it may be hypothesized that the hemodynamic profile of small prostheses not only reduce the exercise capacity of patients,21,22 but may also influence the outcome through partial or absent reversibility of PH. Further studies on larger populations are necessary to confirm these results to justify the use of larger prosthetic valves, at least in AS patients with concomitant PH.
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