- Email: [email protected]
Factors leading to progression of valvular aortic stenosis
Factors Leading to Progression of Valvular Aortic Stenosis Robert C. Bahler, MD, Dana R. Desser, BS, Robert S. Finkelhor, Sorin J. Brener, MD, and Mojtaba Youssefi, MD
MD,
The rate of progression of aortic stenosis (AS) in adults is variable. To determine whether clinical or echocardiographic variables are associated with more rapid hemodynamic progression, we identified 91 AS patients (initial valve area <2.0 cm2) with 2 technically adequate studies separated by >6 months. From the first study, left ventricular dimensions and AS severity were measured by standard Doppler-echocardiographic methods. Each aortic valve was graded for severity of calcification and degree of restricted leaflet motion; the sum of these grades provided a severity index reflecting leaflet pathology. Clinical and electrocardiographic variables were abstracted from medical records. Mean age was 68 years (range 29 to 89) and 61 were women. Initial AS severity ranged from an aortic valve area of 0.6 to 2.0 cm2 (median 1.3 cm2). During a mean follow-up of
1.8 years the aortic valve area decreased 0.04 cm2/ year. The patient group with more rapid progression (decrease in aortic valve area >0.1 cm2/year) had a larger proportion of men (p <0.01) and patients with an elevated serum creatinine (p ⴝ 0.04), a higher left ventricular mass index (p ⴝ 0.01), and a higher severity index (p <0.001). Multivariable regression analysis identified the severity index (direct relation) and the initial aortic valve area (inverse relation) as the only independent variables associated with more rapid progression. In conclusion, the rate of AS progression, although highly variable, is more rapid when leaflet calcification is more marked. 䊚1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;84:1044 –1048)
oppler echocardiography has provided a valuable method for the noninvasive assessment of aortic D stenosis (AS). Recent studies have used serial Doppler
M-mode dimensions in accord with the American Society of Echocardiography standards.6 Left ventricular mass index was calculated using the M-mode derived formula of Woythaler et al.7 Standard images of the left ventricle were reviewed to identify wall motion abnormalities. Left ventricular ejection fraction was estimated visually from the apical 4- and 2-chamber views. Doppler echocardiographic evaluation of AS followed standard methods.8 Peak velocity beneath the aortic valve (V1) was assessed by pulsed Doppler from the apical 5-chamber view with the sample volume beneath the aortic annulus just proximal to the region of flow acceleration. The peak velocity across the valve (V2) was recorded from multiple windows using continuous-wave Doppler. Peak velocities were recorded as the average of 3 to 5 measurements. Pressure gradients were calculated using the modified Bernoulli equation: gradient (mm Hg) ⫽ 4 (V22 ⫺ V12). Left ventricular outflow tract (D1) was measured in midsystole 4 to 5 mm below the aortic annulus as seen from the parasternal long-axis view. Aortic valve area was calculated by the continuity equation. Because measurement of the outflow tract diameter (D1) is the least reproducible variable in this equation, the value from the first study was used to calculate the aortic valve area for the second study. Mitral regurgitation was described by a semiquantitive approach using the ratio of the mitral jet area to left atrial area,9 and aortic regurgitation was graded by the jet area just beneath the valve10; severity was expressed with a 1 to 4 scale. Aortic valve leaflet morphology at the first echocardiographic study was assessed qualitatively by 1
echocardiographic data to advance our knowledge as to the rate of progression of AS in selected populations.1–5 Not surprisingly, these investigations have reported that patients with more severe stenosis are more likely to have clinical progression and/or require surgical intervention, yet identification of clinical or echocardiographic variables associated with the varying rates of hemodynamic progression of AS has been elusive. This study assesses whether any clinical or echocardiographic variables are associated with more rapid hemodynamic progression of AS.
METHODS
Patient selection: The adult echocardiographic laboratory database at MetroHealth Medical Center was queried from 1992 through June 1997 (n ⫽ 13,952) to identify all patients with an echocardiographic diagnosis of AS (n ⫽ 852). All patients with ⱖ2 studies separated by a minimum of 6 months were included, if the initial valve area was ⱕ2.0 cm2. The initial and most recent studies were selected for analysis. Echocardiographic data: The initial echocardiograms were reviewed for the off-line determination of From the Department of Medicine, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio. This study was supported in part by the Northeast Ohio Affiliate of the American Heart Association, Summer Student Research Program, Cleveland, Ohio. Manuscript received December 16, 1998; revised manuscript received June 14, 1999, and accepted June 16. Address for reprints: Robert C. Bahler, MD, Division of Cardiology, Metrohealth Medical Center, MetroHealth Drive. Cleveland, Ohio 44109-1998.
1044
©1999 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 84 November 1, 1999
0002-9149/99/$–see front matter PII S0002-9149(99)00496-8
only if they were obtained within 3 months of the initial echocardiographic examination. Coronary artery disease was considered present if the patient had had a myocardial infarction, typical angina pectoris, a positive cardiac stress test, or coronary angiographic confirmation. Hypertension was considered present if a patient was receiving antihypertensive therapy or had ⱖ2 blood pressure recordings of ⱖ150/95 mm Hg. Rheumatic heart disease was the presumed etiology of AS if there was concomitant mitral leaflet disease. Arterial blood pressure is routinely recorded at completion of each echocardiogram in our laboratory; this value was used to evaluate whether the level of blood pressure was associated with AS progression. Electrocardiograms were reviewed for evidence of (1) left ventricular hyFIGURE 1. The severity of aortic valve calcification was graded from parasternal pertrophy by either the Romhilt-Estes short-axis views. criteria11 or the Cornell criteria,12 (2) prior myocardial infarction, (3) left atrial enlargement, (4) intraventricular observer (RB) blinded to both the initial severity and conduction abnormality (left or right bundle branch the rate of progression of AS. Aortic valve leaflets block or nonspecific intraventricular conduction delay were evaluated from the parasternal long- and short- with a QRS duration ⱖ120 ms), and (5) presence of axis views. A bicuspid valve was said to be present atrial fibrillation. when only 2 leaflets were present and the commisStatistics: Between-group comparisons were persures were in locations distinct from those of a normal formed using 1-way analysis of variance for continutricuspid valve. Calcification of the aortic leaflets was ous variables and Pearson’s chi-square statistic for described as follows: 1 ⫽ none, 2 ⫽ ⱖ1 localized area categorical variables. The cutpoint for groups (a deof increased reflectivity but no areas of dense “calci- crease in aortic valve area ⱖ0.1 cm2/year) was sefication,” 3 ⫽ markedly increased reflectivity (calci- lected from the non-Gaussian distribution of aortic fication) in 1 leaflet but equal to or less than grade 2 valve area/year. Changes is valve area ⬍0.1 cm2 are changes in other leaflets, 4 ⫽ markedly increased within the measurement error and changes ⱖ0.1 cm2/ reflectivity in 2 leaflets but equal to or less than grade year have clinical importance.13 Multivariable step2 changes in the third leaflet, 5 ⫽ moderately in- wise linear regression analysis was used to identify creased reflectivity in all leaflets, and 6 ⫽ severely independent variables associated with progression of increased reflectivity in all leaflets (Figure 1). Leaflet stenosis. Logistic regression analysis was used to mobility was graded as follows: 1 ⫽ normal leaflet identify independent variables associated with more mobility, 2 ⫽ restriction of only 1 leaflet with normal rapid progression. All data were expressed as mean ⫾ mobility of the other leaflets or mild restriction of all SD. Calculations were performed using BMDP statisleaflets, 3 ⫽ marked restriction of 2 leaflets or mod- tical software (University of California Press, Berkeerate restriction of all leaflets, and 4 ⫽ almost no ley, California). mobility of any leaflet. Intra- (RB) and interobserver (RB, RF) variability Calcification and mobility scores were summed to for the indexes of calcification and mobility were form the severity index, a score reflecting the extent of determined by the reassessment of 20 randomly seleaflet pathology. These classification schemes were lected studies. The statistic was used to define the arbitrary but based on extensive experience in the degree of agreement between repeated assessments.14 echocardiographic assessment of aortic leaflet pathol- With agreement defined as either an equal score or a ogy. score within 1 grade, for calcification was 0.88 for Mitral annular calcification was determined from the intraobserver variability and 0.82 for interobserver parasternal short axis and graded by the degree to which variability; for assessing leaflet mobility, was 1.0 the increased echo density extended throughout the cir- and 0.67, respectively. cumference of the annulus: 1 ⫽ small, localized area, 2 ⫽ involvement of less than one fourth, 3 ⫽ between one fourth to one half, and 4 ⫽ more than one half. RESULTS Patient characteristics: The severity of AS for the Clinical data: Medical records were reviewed for clinical variables. Laboratory values were included entire group of 91 patients, as expressed by the aortic VALVULAR HEART DISEASE/PROGRESSION OF AORTIC STENOSIS
1045
TABLE I Patient Characteristics Severity of Aortic Stenosis 2
Aortic valve area (cm ) Maximum aortic jet velocity (m/s) Mean aortic gradient (mm Hg) Peak aortic gradient (mm Hg) Etiology of aortic stenosis Bicuspid valve Rheumatic Idiopathic calcification Aortic regurgitation Mild Moderate to moderately severe Mitral regurgitation Mild Moderate to moderately severe Age (yrs) Follow-up interval (mo)
TABLE III Initial Echocardiographic Data Baseline
Final Study*
Decrease in Aortic Valve Area
1.24 ⫾ 0.34 2.64 ⫾ 0.62
1.16 ⫾ 0.32 2.99 ⫾ 0.73
⬍0.1 cm2/yr Group 1
15.8 ⫾ 9.27
20.92 ⫾ 11.71
27.6 ⫾ 14.8
35.6 ⫾ 19.2
4 15 72 48 35 13
(4%) (16%) (79%) (53%) (38%) (14%)
38 (42%) 25 (27%) 13 (14%) 68 ⫾ 13.2 21.9 ⫾ 11.4
*p ⬍0.001 for all variables.
TABLE II Clinical Characteristics of Each Group Decrease in Aortic Valve Area ⬍0.1 cm2/yr Group 1 (n ⫽ 65) Continuous variables Age (yrs) Body surface area (m2) Blood urea nitrogen (mg/dl) Creatinine (mg/dl) Cholesterol (mg/dl) Hematocrit (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Follow-up interval (mo) Categorical variables Men:women Smoker Diabetes mellitus Systemic hypertension Coronary artery disease Atrial fibrillation Hypothyroidism
67.1 1.84 22.8 1.4 200 37.9 145
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13.3 0.26 16.5 1.2 54 5.0 27
ⱖ0.1 cm2/yr Group 2 (n ⫽ 26) 69.7 1.82 29.7 1.9 198 35.3 142
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13.0 0.22 22.7* 1.9 69 5.9 24
79 ⫾ 14
76 ⫾ 16
22.0 ⫾ 11.6
21.5 ⫾ 11.3
16:49 21 (32%) 24 (37%) 40 (62%) 30 (46%) 10 (15%) 3 (5%)
14:12† 8 (31%) 14 (54%) 22 (85%) 14 (54%) 2 (8%) 7 (27%)
*p ⫽ 0.05; †p ⬍0.01.
valve area, ranged from 0.6 to 2.0 cm2 and the follow-up interval was 6 to 51 months (Table I). Clinical variables and rate of progression: Clinical and echocardiographic variables were compared between a patient group with little or no progression of AS, defined as a decrease in aortic valve area ⬍0.1 cm2/year (group 1, n ⫽ 65), versus those having more rapid progression with a decrease in aortic valve area ⱖ0.1 cm2/ year (group 2). The only clinical variables associated with more rapid progression were male gender and renal failure (Table II). Serum creatinine and blood urea nitrogen data were available in 73 patients; 5 of the 8 with an abnormal elevation in serum creatinine (ⱖ2.2 for men and ⱖ1.8 for women) 1046 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 84
ⱖ0.1 cm2/yr Group 2
Two-dimensional variables Left ventricular internal diameter 4.5 ⫾ 0.7 4.9 ⫾ 0.8 in diastole (cm) Left ventricular internal diameter 3.2 ⫾ 0.8 3.9 ⫾ 1.1* in systole (cm) Interventricular septal thickness (cm) 1.2 ⫾ 0.3 1.3 ⫾ 0.3 Posterior wall thickness (cm) 1.3 ⫾ 0.3 1.3 ⫾ 0.3 Left ventricular mass index (g/m2) 127.4 ⫾ 46.0 162.4 ⫾ 69.2* Left ventricular ejection fraction (%) 54.8 ⫾ 11.8 49.4 ⫾ 17.4 Doppler and Doppler-derived variables Aortic valve area (cm2) 1.19 ⫾ 0.34 1.34 ⫾ 0.32 Aortic valve area (cm2) 0.01 ⫾ 0.17 0.30 ⫾ 0.18 Peak gradient (mm Hg) 27.7 ⫾ 13.7 27.6 ⫾ 17.4 Peak velocity beneath the aortic 1.05 ⫾ 0.24 1.08 ⫾ 0.20 valve (m/s) Peak velocity through the aortic 2.66 ⫾ 0.60 2.60 ⫾ 0.68 valve (m/s) Assessment of valve pathology Bicuspid valve (no.) 6 2 Rheumatic disease (no.) 9 6 Aortic valve calcium (grade) 3.4 ⫾ 1.3 4.5 ⫾ 1.1† Aortic valve mobility (grade) 2.8 ⫾ 0.7 3.0 ⫾ 0.5‡ Severity index (score) 6.1 ⫾ 1.8 7.4 ⫾ 1.4† Mitral annular calcium (grade) 1.7 ⫾ 1.2 1.9 ⫾ 1.4 *p ⫽ 0.01; †p ⬍0.001; ‡p ⬍0.05.
belonged to group 2 (p ⫽ 0.04). There were no between-group differences for any electrocardiographic variables except for QRS duration, which was greater in group 2 (109 ⫾ 24 vs 99 ⫾ 17, p ⫽ 0.05).
Echocardiographic variables and rate of progression: There were no between-group differences for
cardiac dimensions, Doppler echocardiographic variables, degree of mitral or aortic regurgitation, prevalence of left ventricular wall motion abnormalities, or initial severity of AS. Patients with more rapid progression had a greater left ventricular mass index and increased end-systolic dimension (Table III). The severity of aortic leaflet calcification and the degree of leaflet restriction were greater in patients with more rapid progression (Table III). Patients with a severity index ⱖ8 (n ⫽ 9) tended to be older (p ⫽ 0.05) and more often men (p ⫽ 0.01); they had a higher initial peak gradient (p ⫽ 0.05), a greater rate of progression (p ⫽ 0.005), and a trend toward greater left ventricular mass index (p ⫽ 0.07). Neither the presence nor degree of mitral annular calcification differed between groups. Multivariable analysis: Stepwise linear regression identified the severity index (direct relation) and the initial aortic valve area (inverse relation) as the only significant independent variables (multiple R ⫽ 0.42) predicting the change in aortic valve area/year. Logistic regression analysis with the outcome variable being a decrease in aortic valve area of ⱖ0.1 cm2/year identified the severity index as the only independent variable associated with more rapid regression (p ⫽ 0.03). NOVEMBER 1, 1999
DISCUSSION Echocardiographic evidence of more extensive fibrocalcific changes within the aortic leaflets identified a subgroup of patients with a greater likelihood of progression of AS. Clinical variables associated with a more rapid progression were male gender and laboratory signs of renal failure. Other variables such as age, hypercalcemia, hypertension, and coronary risk factors considered to be associated with the development of calcific AS did not appear to be related to the rate of progression of stenosis. Both the genesis of the initial aortic leaflet calcification and the pathophysiology of increased calcification with progressive AS remain uncertain. Recent studies have identified an active inflammatory process in many human specimens of stenotic aortic valves,15,16 and this inflammatory process is associated with an increased prevalence of Chlamydia pneumonia in the valve tissue.17,18 Whether this association is casual remains unclear, particularly since Chlamydia pneumonia has also been identified in nonstenotic valves.17 Alterations in calcium homeostasis are likely to play an important role in the progression of AS as suggested by the greater prevalence of AS in patients with renal failure19 and our data indicating that renal dysfunction is more frequent in patients with more rapid progression. Paget’s disease,20 hypercalcemia,21,22 and hyperparathyroidism are additional examples of altered calcium metabolism when the prevalence of AS is increased. Some of the pathologic features of AS resemble atherosclerosis with calcification.15, 23 Arterial calcification and osteoporosis are known to be associated and a recent study showed that serum levels of vitamin D are inversely correlated with the extent of coronary artery calcification, again implicating altered calcium metabolism in the pathogenesis of arterial calcification in these patients.24 Thus, echocardiographic visualization of significant aortic leaflet calcification may identify subjects with subtle alterations in calcium homeostasis that contribute to further leaflet calcification and progression of the hemodynamic severity of AS. More marked valve calcification also identified a group with more rapid hemodynamic progression of AS in a cohort of 65 patients studied with serial cardiac catheterization.25 Both the presence and the severity of calcification, as assessed by angiography, were associated with greater increases in peak-to-peak gradients over an average 7-year follow-up. Another longitudinal study using cardiac catheterization found that patients with more rapid progression were more likely to have degenerative calcific AS, whereas those with little progression more often had a congenital or rheumatic etiology.26 Marked variability in the rate of hemodynamic progression of AS that we observed was also evident in prior studies.1–5 Although these studies showed a gradual worsening for the entire cohort over follow-up intervals of 18 to 37 months, some patients had an actual decrease in severity of AS, whereas others had significant progression of AS. Only the study of Peter et al5 identified any clinical variables related to more
rapid progression: they reported that increasing age and coronary artery disease were associated with more rapid progression in their relatively younger group (mean age 58 years) of 49 patients. The rate of progression of AS in our community hospital population was substantially less than reported in all prior echocardiographic series that came predominately from tertiary centers.1–5 One possible explanation for these rather marked differences in rate of progression is that the initial severity of AS in our patients was less than in previous reports. However, Brener et al1 reported that their patients with less severe disease at initial evaluation had greater rates of progression. Alternatively, the reported rates of progression may be influenced by unknown selection factors either in the clinical decision for repeat echocardiography or in the decision to include a patient in a follow-up study. The slower overall rate of progression we observed could be closer to the true rate because it seems improbable that our patients were uniquely devoid of the pathophysiologic factors leading to worsening AS. Patients with an increased rate of progression had an increased left ventricular mass index and a greater QRS duration at initial examination even though their Doppler echocardiographic parameters of AS severity and their resting arterial blood pressures were similar to those with little or no progression. Because their valve leaflets were more calcified and leaflet motion more restricted, one could hypothesize that these patients would have no or little increase in the actual valve area during periods of increased flow and therefore greater transvalvular pressure gradients with increased flow resulting in a greater stimulus to left ventricular hypertrophy. Thus, the pressure gradient and aortic valve area at rest may not correctly reflect left ventricular pressure overload occurring during daily activities. The in vitro study of stenotic valves by Montarello et al27 supports this concept; more heavily calcified valves showed little or no increase in the planimetered orifice area as flow increased, whereas the valve area of normal valves was flow dependent.27 That leaflet pathology affects the degree to which valve area varies during differing flow rates is also supported by a recent transesophageal echocardiographic study demonstrating that the slope of the line relating aortic valve area to aortic valve flow was predicted by the patient’s aortic valve morphology.28 Our study is limited by the relatively brief follow-up interval because it is uncertain whether decreases in valve area for a specific patient are linear over time, or valve area is stable for long intervals followed by nonlinear decreases in area.29 Our study, like most previous studies of AS progression, is limited by a modest sample size. A quite large cohort followed at prespecified intervals over a long period of time may be required to identify the most important variables associated with more rapid progression. Importantly, our study focused only on hemodynamic progression, which is not synonymous with clinical progression. Multiple factors apart from valve area contribute to clinical progression.1,2,13 Finally, a more
VALVULAR HEART DISEASE/PROGRESSION OF AORTIC STENOSIS
1047
sophisticated measure of valve calcification than can be derived from either transthoracic echocardiography or fluoroscopy would be needed for this parameter of leaflet pathology to have clinical use in predicting AS progression. In summary, more severe leaflet calcification and restricted leaflet motion are associated with more rapid hemodynamic progression of AS. 1. Brener SJ, Duffy CI, Thomas JD, Stewart WJ. Progression of aortic stenosis in
394 patients: relation to changes in myocardial and mitral valve dysfunction. J Am Coll Cardiol 1995;25:305–310. 2. Otto CM, Burwash IG, Legget ME, Munt BI, Fuijoka M, Healy NL, Kraft CD, Miyake-Hall CY, Schwaegler RG. Prospective study of asymptomatic valvular stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262–2270. 3. Roger VL, Tajik AJ, Bailey KR, Oh JK, Taylor CL, Seward JB. Progression of aortic stenosis in adults: new appraisal using Doppler echocardiography. Am Heart J 1990;199:331–338. 4. Faggione P, Ghizzoni G, Sorgato A, Sabatini T, Simoncelli U, Gardini A, Rusconi C. Rate of progression of valvular aortic stenosis in adults. Am J Cardiol 1992;70:229 –233. 5. Peter M, Hoffman A, Parker C, Luscher T, Burckhardt D. Progression of aortic stenosis: role of age and concomitant coronary artery disease. Chest 1993;103: 1715–1719. 6. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 7. Woythaler JN, Singer SL, Kwan OL. Accuracy of echocardiography versus electrocardiography in detecting left ventricular hypertrophy: comparison with postmortem mass measurements. J Am Coll Cardiol 1983;2:305–311. 8. Otto CM, Pearlman AS. Valvular stenosis: diagnosis, quantitation, and clinical approach. In: Otto CM, Pearlman AS, eds. Textbook of Clinical Echocardiography. Philadelphia: WB Saunders, 1995:209 –242. 9. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, Gatewood RP. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation 1987;75:175–183. 10. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol 1987;9:952– 959. 11. Romhilt DW, Estes EH. A point score system for electrocardiographic diagnosis of left ventricular hypertrophy. Am Heart J 1968;75:752–758. 12. Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Miller DH, Chaudhary BS, Phillips MC. Electrocardiographic detection of left ventricular hypertrophy:
1048 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 84
development and prospective validation of improved criteria. J Am Coll Cardiol 1985;6:572–580. 13. Rahimtoola SH. “Prophylactic” valve replacement for mild aortic valve disease at time of surgery for other cardiovascular disease?...No. J Am Coll Cardiol 1999;33:2009 –2015. 14. Woolson RF. Statistical Methods for the Analysis of Biomedical Data. New York: John Wiley, 1987:149 –156. 15. Otto CM, Kuusisto J, Reichenbach DD, Gown Am, O’Brien KD. Characterization of the early lesion of “degenerative” valvular aortic stenosis: histologic and immunohistochemical studies. Circulation 1994;90:844 – 853. 16. Olsson M, Dalsgaard C, Haegarstrand A, Rosequist M, Ryden L, Nilsson J. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol 1994;23:1162–1170. 17. Juvonen J, Juvonen T, Laurila A, Kuusisto J, Alarakkola E, Sa¨rkioja T, Bodian CA, Kairaluoma MI, Saikku P. Can degenerative aortic valve stenosis be related to persistent Chlamydia pneumoniae infection? Ann Intern Med 1998; 128:74 –744. 18. Nystro¨m-Rosander C, Thelin S, Hjelm E, Lindquist O, Pahlson C, Friman G. High incidence of Chlamydia pneumoniae in sclerotic heart valves of patients undergoing aortic valve replacement. Scand J Infect Dis 1997;29:361–365. 19. Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uremia. Nephron 1987;47:119 –122. 20. Strickberger SA, Schulman SP, Hutchins GM. Association of Paget’s disease of bone and calcific aortic valve disease. Am J Med 1987;82:953–956. 21. Lindroos M, Kupari M, Valvanne J, Strandberg T, Heikkila¨ J, Tilvis R. Factors associated with calcific aortic valve degeneration in the elderly. Eur Heart J 1994;15:865– 870. 22. Roberts WC, Walker BF. Effects of chronic hypercalcemia on the heart: an analysis of 18 necropsy patients. Am J Med 1981;71:371–384. 23. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apoliproteins B, (a) and E accumulate in the morphologically early lesion of degenerative valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16: 523–532. 24. Watson KE, Abrolar ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 1997;96:1755–1760. 25. Davies SW, Gershlick AH, Balcon R. Progression of valvular aortic stenosis. A long term retrospective study. Eur Heart J 1991;12:10 –14. 26. Wagner S, Selzer A. Patterns of progression of aortic stenosis: a longitudinal hemodynamic study. Circulation 1982;65:709 –712. 27. Montarello JK, Perakis AC, Rosenthal E, Boyd ECGA, Yates AK, Deverall PB, Sowton E, Curry PVL. Normal and stenotic human valve opening: in vitro assessment of orifice area changes with flow. Eur Heart J 1990;11:484 – 491. 28. Shively BK, Charlton GA, Crawford MH, Chaney RK. Flow dependence of valve area in aortic stenosis: relation to valve morphology. J Am Coll Cardiol 1998;31:654 – 660. 29. Thoreau WA, Siu SC, Thoreau DH, Vandervoort PM, Thomas JD, Weyman AE. The rate and pattern of change of valve area in aortic stenosis: long term Doppler follow-up (abstr). J Am Coll Cardiol 1992;19:331A.
NOVEMBER 1, 1999
MD,
The rate of progression of aortic stenosis (AS) in adults is variable. To determine whether clinical or echocardiographic variables are associated with more rapid hemodynamic progression, we identified 91 AS patients (initial valve area <2.0 cm2) with 2 technically adequate studies separated by >6 months. From the first study, left ventricular dimensions and AS severity were measured by standard Doppler-echocardiographic methods. Each aortic valve was graded for severity of calcification and degree of restricted leaflet motion; the sum of these grades provided a severity index reflecting leaflet pathology. Clinical and electrocardiographic variables were abstracted from medical records. Mean age was 68 years (range 29 to 89) and 61 were women. Initial AS severity ranged from an aortic valve area of 0.6 to 2.0 cm2 (median 1.3 cm2). During a mean follow-up of
1.8 years the aortic valve area decreased 0.04 cm2/ year. The patient group with more rapid progression (decrease in aortic valve area >0.1 cm2/year) had a larger proportion of men (p <0.01) and patients with an elevated serum creatinine (p ⴝ 0.04), a higher left ventricular mass index (p ⴝ 0.01), and a higher severity index (p <0.001). Multivariable regression analysis identified the severity index (direct relation) and the initial aortic valve area (inverse relation) as the only independent variables associated with more rapid progression. In conclusion, the rate of AS progression, although highly variable, is more rapid when leaflet calcification is more marked. 䊚1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;84:1044 –1048)
oppler echocardiography has provided a valuable method for the noninvasive assessment of aortic D stenosis (AS). Recent studies have used serial Doppler
M-mode dimensions in accord with the American Society of Echocardiography standards.6 Left ventricular mass index was calculated using the M-mode derived formula of Woythaler et al.7 Standard images of the left ventricle were reviewed to identify wall motion abnormalities. Left ventricular ejection fraction was estimated visually from the apical 4- and 2-chamber views. Doppler echocardiographic evaluation of AS followed standard methods.8 Peak velocity beneath the aortic valve (V1) was assessed by pulsed Doppler from the apical 5-chamber view with the sample volume beneath the aortic annulus just proximal to the region of flow acceleration. The peak velocity across the valve (V2) was recorded from multiple windows using continuous-wave Doppler. Peak velocities were recorded as the average of 3 to 5 measurements. Pressure gradients were calculated using the modified Bernoulli equation: gradient (mm Hg) ⫽ 4 (V22 ⫺ V12). Left ventricular outflow tract (D1) was measured in midsystole 4 to 5 mm below the aortic annulus as seen from the parasternal long-axis view. Aortic valve area was calculated by the continuity equation. Because measurement of the outflow tract diameter (D1) is the least reproducible variable in this equation, the value from the first study was used to calculate the aortic valve area for the second study. Mitral regurgitation was described by a semiquantitive approach using the ratio of the mitral jet area to left atrial area,9 and aortic regurgitation was graded by the jet area just beneath the valve10; severity was expressed with a 1 to 4 scale. Aortic valve leaflet morphology at the first echocardiographic study was assessed qualitatively by 1
echocardiographic data to advance our knowledge as to the rate of progression of AS in selected populations.1–5 Not surprisingly, these investigations have reported that patients with more severe stenosis are more likely to have clinical progression and/or require surgical intervention, yet identification of clinical or echocardiographic variables associated with the varying rates of hemodynamic progression of AS has been elusive. This study assesses whether any clinical or echocardiographic variables are associated with more rapid hemodynamic progression of AS.
METHODS
Patient selection: The adult echocardiographic laboratory database at MetroHealth Medical Center was queried from 1992 through June 1997 (n ⫽ 13,952) to identify all patients with an echocardiographic diagnosis of AS (n ⫽ 852). All patients with ⱖ2 studies separated by a minimum of 6 months were included, if the initial valve area was ⱕ2.0 cm2. The initial and most recent studies were selected for analysis. Echocardiographic data: The initial echocardiograms were reviewed for the off-line determination of From the Department of Medicine, Case Western Reserve University at MetroHealth Medical Center, Cleveland, Ohio. This study was supported in part by the Northeast Ohio Affiliate of the American Heart Association, Summer Student Research Program, Cleveland, Ohio. Manuscript received December 16, 1998; revised manuscript received June 14, 1999, and accepted June 16. Address for reprints: Robert C. Bahler, MD, Division of Cardiology, Metrohealth Medical Center, MetroHealth Drive. Cleveland, Ohio 44109-1998.
1044
©1999 by Excerpta Medica, Inc. All rights reserved. The American Journal of Cardiology Vol. 84 November 1, 1999
0002-9149/99/$–see front matter PII S0002-9149(99)00496-8
only if they were obtained within 3 months of the initial echocardiographic examination. Coronary artery disease was considered present if the patient had had a myocardial infarction, typical angina pectoris, a positive cardiac stress test, or coronary angiographic confirmation. Hypertension was considered present if a patient was receiving antihypertensive therapy or had ⱖ2 blood pressure recordings of ⱖ150/95 mm Hg. Rheumatic heart disease was the presumed etiology of AS if there was concomitant mitral leaflet disease. Arterial blood pressure is routinely recorded at completion of each echocardiogram in our laboratory; this value was used to evaluate whether the level of blood pressure was associated with AS progression. Electrocardiograms were reviewed for evidence of (1) left ventricular hyFIGURE 1. The severity of aortic valve calcification was graded from parasternal pertrophy by either the Romhilt-Estes short-axis views. criteria11 or the Cornell criteria,12 (2) prior myocardial infarction, (3) left atrial enlargement, (4) intraventricular observer (RB) blinded to both the initial severity and conduction abnormality (left or right bundle branch the rate of progression of AS. Aortic valve leaflets block or nonspecific intraventricular conduction delay were evaluated from the parasternal long- and short- with a QRS duration ⱖ120 ms), and (5) presence of axis views. A bicuspid valve was said to be present atrial fibrillation. when only 2 leaflets were present and the commisStatistics: Between-group comparisons were persures were in locations distinct from those of a normal formed using 1-way analysis of variance for continutricuspid valve. Calcification of the aortic leaflets was ous variables and Pearson’s chi-square statistic for described as follows: 1 ⫽ none, 2 ⫽ ⱖ1 localized area categorical variables. The cutpoint for groups (a deof increased reflectivity but no areas of dense “calci- crease in aortic valve area ⱖ0.1 cm2/year) was sefication,” 3 ⫽ markedly increased reflectivity (calci- lected from the non-Gaussian distribution of aortic fication) in 1 leaflet but equal to or less than grade 2 valve area/year. Changes is valve area ⬍0.1 cm2 are changes in other leaflets, 4 ⫽ markedly increased within the measurement error and changes ⱖ0.1 cm2/ reflectivity in 2 leaflets but equal to or less than grade year have clinical importance.13 Multivariable step2 changes in the third leaflet, 5 ⫽ moderately in- wise linear regression analysis was used to identify creased reflectivity in all leaflets, and 6 ⫽ severely independent variables associated with progression of increased reflectivity in all leaflets (Figure 1). Leaflet stenosis. Logistic regression analysis was used to mobility was graded as follows: 1 ⫽ normal leaflet identify independent variables associated with more mobility, 2 ⫽ restriction of only 1 leaflet with normal rapid progression. All data were expressed as mean ⫾ mobility of the other leaflets or mild restriction of all SD. Calculations were performed using BMDP statisleaflets, 3 ⫽ marked restriction of 2 leaflets or mod- tical software (University of California Press, Berkeerate restriction of all leaflets, and 4 ⫽ almost no ley, California). mobility of any leaflet. Intra- (RB) and interobserver (RB, RF) variability Calcification and mobility scores were summed to for the indexes of calcification and mobility were form the severity index, a score reflecting the extent of determined by the reassessment of 20 randomly seleaflet pathology. These classification schemes were lected studies. The statistic was used to define the arbitrary but based on extensive experience in the degree of agreement between repeated assessments.14 echocardiographic assessment of aortic leaflet pathol- With agreement defined as either an equal score or a ogy. score within 1 grade, for calcification was 0.88 for Mitral annular calcification was determined from the intraobserver variability and 0.82 for interobserver parasternal short axis and graded by the degree to which variability; for assessing leaflet mobility, was 1.0 the increased echo density extended throughout the cir- and 0.67, respectively. cumference of the annulus: 1 ⫽ small, localized area, 2 ⫽ involvement of less than one fourth, 3 ⫽ between one fourth to one half, and 4 ⫽ more than one half. RESULTS Patient characteristics: The severity of AS for the Clinical data: Medical records were reviewed for clinical variables. Laboratory values were included entire group of 91 patients, as expressed by the aortic VALVULAR HEART DISEASE/PROGRESSION OF AORTIC STENOSIS
1045
TABLE I Patient Characteristics Severity of Aortic Stenosis 2
Aortic valve area (cm ) Maximum aortic jet velocity (m/s) Mean aortic gradient (mm Hg) Peak aortic gradient (mm Hg) Etiology of aortic stenosis Bicuspid valve Rheumatic Idiopathic calcification Aortic regurgitation Mild Moderate to moderately severe Mitral regurgitation Mild Moderate to moderately severe Age (yrs) Follow-up interval (mo)
TABLE III Initial Echocardiographic Data Baseline
Final Study*
Decrease in Aortic Valve Area
1.24 ⫾ 0.34 2.64 ⫾ 0.62
1.16 ⫾ 0.32 2.99 ⫾ 0.73
⬍0.1 cm2/yr Group 1
15.8 ⫾ 9.27
20.92 ⫾ 11.71
27.6 ⫾ 14.8
35.6 ⫾ 19.2
4 15 72 48 35 13
(4%) (16%) (79%) (53%) (38%) (14%)
38 (42%) 25 (27%) 13 (14%) 68 ⫾ 13.2 21.9 ⫾ 11.4
*p ⬍0.001 for all variables.
TABLE II Clinical Characteristics of Each Group Decrease in Aortic Valve Area ⬍0.1 cm2/yr Group 1 (n ⫽ 65) Continuous variables Age (yrs) Body surface area (m2) Blood urea nitrogen (mg/dl) Creatinine (mg/dl) Cholesterol (mg/dl) Hematocrit (%) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Follow-up interval (mo) Categorical variables Men:women Smoker Diabetes mellitus Systemic hypertension Coronary artery disease Atrial fibrillation Hypothyroidism
67.1 1.84 22.8 1.4 200 37.9 145
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13.3 0.26 16.5 1.2 54 5.0 27
ⱖ0.1 cm2/yr Group 2 (n ⫽ 26) 69.7 1.82 29.7 1.9 198 35.3 142
⫾ ⫾ ⫾ ⫾ ⫾ ⫾ ⫾
13.0 0.22 22.7* 1.9 69 5.9 24
79 ⫾ 14
76 ⫾ 16
22.0 ⫾ 11.6
21.5 ⫾ 11.3
16:49 21 (32%) 24 (37%) 40 (62%) 30 (46%) 10 (15%) 3 (5%)
14:12† 8 (31%) 14 (54%) 22 (85%) 14 (54%) 2 (8%) 7 (27%)
*p ⫽ 0.05; †p ⬍0.01.
valve area, ranged from 0.6 to 2.0 cm2 and the follow-up interval was 6 to 51 months (Table I). Clinical variables and rate of progression: Clinical and echocardiographic variables were compared between a patient group with little or no progression of AS, defined as a decrease in aortic valve area ⬍0.1 cm2/year (group 1, n ⫽ 65), versus those having more rapid progression with a decrease in aortic valve area ⱖ0.1 cm2/ year (group 2). The only clinical variables associated with more rapid progression were male gender and renal failure (Table II). Serum creatinine and blood urea nitrogen data were available in 73 patients; 5 of the 8 with an abnormal elevation in serum creatinine (ⱖ2.2 for men and ⱖ1.8 for women) 1046 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 84
ⱖ0.1 cm2/yr Group 2
Two-dimensional variables Left ventricular internal diameter 4.5 ⫾ 0.7 4.9 ⫾ 0.8 in diastole (cm) Left ventricular internal diameter 3.2 ⫾ 0.8 3.9 ⫾ 1.1* in systole (cm) Interventricular septal thickness (cm) 1.2 ⫾ 0.3 1.3 ⫾ 0.3 Posterior wall thickness (cm) 1.3 ⫾ 0.3 1.3 ⫾ 0.3 Left ventricular mass index (g/m2) 127.4 ⫾ 46.0 162.4 ⫾ 69.2* Left ventricular ejection fraction (%) 54.8 ⫾ 11.8 49.4 ⫾ 17.4 Doppler and Doppler-derived variables Aortic valve area (cm2) 1.19 ⫾ 0.34 1.34 ⫾ 0.32 Aortic valve area (cm2) 0.01 ⫾ 0.17 0.30 ⫾ 0.18 Peak gradient (mm Hg) 27.7 ⫾ 13.7 27.6 ⫾ 17.4 Peak velocity beneath the aortic 1.05 ⫾ 0.24 1.08 ⫾ 0.20 valve (m/s) Peak velocity through the aortic 2.66 ⫾ 0.60 2.60 ⫾ 0.68 valve (m/s) Assessment of valve pathology Bicuspid valve (no.) 6 2 Rheumatic disease (no.) 9 6 Aortic valve calcium (grade) 3.4 ⫾ 1.3 4.5 ⫾ 1.1† Aortic valve mobility (grade) 2.8 ⫾ 0.7 3.0 ⫾ 0.5‡ Severity index (score) 6.1 ⫾ 1.8 7.4 ⫾ 1.4† Mitral annular calcium (grade) 1.7 ⫾ 1.2 1.9 ⫾ 1.4 *p ⫽ 0.01; †p ⬍0.001; ‡p ⬍0.05.
belonged to group 2 (p ⫽ 0.04). There were no between-group differences for any electrocardiographic variables except for QRS duration, which was greater in group 2 (109 ⫾ 24 vs 99 ⫾ 17, p ⫽ 0.05).
Echocardiographic variables and rate of progression: There were no between-group differences for
cardiac dimensions, Doppler echocardiographic variables, degree of mitral or aortic regurgitation, prevalence of left ventricular wall motion abnormalities, or initial severity of AS. Patients with more rapid progression had a greater left ventricular mass index and increased end-systolic dimension (Table III). The severity of aortic leaflet calcification and the degree of leaflet restriction were greater in patients with more rapid progression (Table III). Patients with a severity index ⱖ8 (n ⫽ 9) tended to be older (p ⫽ 0.05) and more often men (p ⫽ 0.01); they had a higher initial peak gradient (p ⫽ 0.05), a greater rate of progression (p ⫽ 0.005), and a trend toward greater left ventricular mass index (p ⫽ 0.07). Neither the presence nor degree of mitral annular calcification differed between groups. Multivariable analysis: Stepwise linear regression identified the severity index (direct relation) and the initial aortic valve area (inverse relation) as the only significant independent variables (multiple R ⫽ 0.42) predicting the change in aortic valve area/year. Logistic regression analysis with the outcome variable being a decrease in aortic valve area of ⱖ0.1 cm2/year identified the severity index as the only independent variable associated with more rapid regression (p ⫽ 0.03). NOVEMBER 1, 1999
DISCUSSION Echocardiographic evidence of more extensive fibrocalcific changes within the aortic leaflets identified a subgroup of patients with a greater likelihood of progression of AS. Clinical variables associated with a more rapid progression were male gender and laboratory signs of renal failure. Other variables such as age, hypercalcemia, hypertension, and coronary risk factors considered to be associated with the development of calcific AS did not appear to be related to the rate of progression of stenosis. Both the genesis of the initial aortic leaflet calcification and the pathophysiology of increased calcification with progressive AS remain uncertain. Recent studies have identified an active inflammatory process in many human specimens of stenotic aortic valves,15,16 and this inflammatory process is associated with an increased prevalence of Chlamydia pneumonia in the valve tissue.17,18 Whether this association is casual remains unclear, particularly since Chlamydia pneumonia has also been identified in nonstenotic valves.17 Alterations in calcium homeostasis are likely to play an important role in the progression of AS as suggested by the greater prevalence of AS in patients with renal failure19 and our data indicating that renal dysfunction is more frequent in patients with more rapid progression. Paget’s disease,20 hypercalcemia,21,22 and hyperparathyroidism are additional examples of altered calcium metabolism when the prevalence of AS is increased. Some of the pathologic features of AS resemble atherosclerosis with calcification.15, 23 Arterial calcification and osteoporosis are known to be associated and a recent study showed that serum levels of vitamin D are inversely correlated with the extent of coronary artery calcification, again implicating altered calcium metabolism in the pathogenesis of arterial calcification in these patients.24 Thus, echocardiographic visualization of significant aortic leaflet calcification may identify subjects with subtle alterations in calcium homeostasis that contribute to further leaflet calcification and progression of the hemodynamic severity of AS. More marked valve calcification also identified a group with more rapid hemodynamic progression of AS in a cohort of 65 patients studied with serial cardiac catheterization.25 Both the presence and the severity of calcification, as assessed by angiography, were associated with greater increases in peak-to-peak gradients over an average 7-year follow-up. Another longitudinal study using cardiac catheterization found that patients with more rapid progression were more likely to have degenerative calcific AS, whereas those with little progression more often had a congenital or rheumatic etiology.26 Marked variability in the rate of hemodynamic progression of AS that we observed was also evident in prior studies.1–5 Although these studies showed a gradual worsening for the entire cohort over follow-up intervals of 18 to 37 months, some patients had an actual decrease in severity of AS, whereas others had significant progression of AS. Only the study of Peter et al5 identified any clinical variables related to more
rapid progression: they reported that increasing age and coronary artery disease were associated with more rapid progression in their relatively younger group (mean age 58 years) of 49 patients. The rate of progression of AS in our community hospital population was substantially less than reported in all prior echocardiographic series that came predominately from tertiary centers.1–5 One possible explanation for these rather marked differences in rate of progression is that the initial severity of AS in our patients was less than in previous reports. However, Brener et al1 reported that their patients with less severe disease at initial evaluation had greater rates of progression. Alternatively, the reported rates of progression may be influenced by unknown selection factors either in the clinical decision for repeat echocardiography or in the decision to include a patient in a follow-up study. The slower overall rate of progression we observed could be closer to the true rate because it seems improbable that our patients were uniquely devoid of the pathophysiologic factors leading to worsening AS. Patients with an increased rate of progression had an increased left ventricular mass index and a greater QRS duration at initial examination even though their Doppler echocardiographic parameters of AS severity and their resting arterial blood pressures were similar to those with little or no progression. Because their valve leaflets were more calcified and leaflet motion more restricted, one could hypothesize that these patients would have no or little increase in the actual valve area during periods of increased flow and therefore greater transvalvular pressure gradients with increased flow resulting in a greater stimulus to left ventricular hypertrophy. Thus, the pressure gradient and aortic valve area at rest may not correctly reflect left ventricular pressure overload occurring during daily activities. The in vitro study of stenotic valves by Montarello et al27 supports this concept; more heavily calcified valves showed little or no increase in the planimetered orifice area as flow increased, whereas the valve area of normal valves was flow dependent.27 That leaflet pathology affects the degree to which valve area varies during differing flow rates is also supported by a recent transesophageal echocardiographic study demonstrating that the slope of the line relating aortic valve area to aortic valve flow was predicted by the patient’s aortic valve morphology.28 Our study is limited by the relatively brief follow-up interval because it is uncertain whether decreases in valve area for a specific patient are linear over time, or valve area is stable for long intervals followed by nonlinear decreases in area.29 Our study, like most previous studies of AS progression, is limited by a modest sample size. A quite large cohort followed at prespecified intervals over a long period of time may be required to identify the most important variables associated with more rapid progression. Importantly, our study focused only on hemodynamic progression, which is not synonymous with clinical progression. Multiple factors apart from valve area contribute to clinical progression.1,2,13 Finally, a more
VALVULAR HEART DISEASE/PROGRESSION OF AORTIC STENOSIS
1047
sophisticated measure of valve calcification than can be derived from either transthoracic echocardiography or fluoroscopy would be needed for this parameter of leaflet pathology to have clinical use in predicting AS progression. In summary, more severe leaflet calcification and restricted leaflet motion are associated with more rapid hemodynamic progression of AS. 1. Brener SJ, Duffy CI, Thomas JD, Stewart WJ. Progression of aortic stenosis in
394 patients: relation to changes in myocardial and mitral valve dysfunction. J Am Coll Cardiol 1995;25:305–310. 2. Otto CM, Burwash IG, Legget ME, Munt BI, Fuijoka M, Healy NL, Kraft CD, Miyake-Hall CY, Schwaegler RG. Prospective study of asymptomatic valvular stenosis. Clinical, echocardiographic, and exercise predictors of outcome. Circulation 1997;95:2262–2270. 3. Roger VL, Tajik AJ, Bailey KR, Oh JK, Taylor CL, Seward JB. Progression of aortic stenosis in adults: new appraisal using Doppler echocardiography. Am Heart J 1990;199:331–338. 4. Faggione P, Ghizzoni G, Sorgato A, Sabatini T, Simoncelli U, Gardini A, Rusconi C. Rate of progression of valvular aortic stenosis in adults. Am J Cardiol 1992;70:229 –233. 5. Peter M, Hoffman A, Parker C, Luscher T, Burckhardt D. Progression of aortic stenosis: role of age and concomitant coronary artery disease. Chest 1993;103: 1715–1719. 6. Sahn DJ, DeMaria A, Kisslo J, Weyman A. Recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation 1978;58:1072–1083. 7. Woythaler JN, Singer SL, Kwan OL. Accuracy of echocardiography versus electrocardiography in detecting left ventricular hypertrophy: comparison with postmortem mass measurements. J Am Coll Cardiol 1983;2:305–311. 8. Otto CM, Pearlman AS. Valvular stenosis: diagnosis, quantitation, and clinical approach. In: Otto CM, Pearlman AS, eds. Textbook of Clinical Echocardiography. Philadelphia: WB Saunders, 1995:209 –242. 9. Helmcke F, Nanda NC, Hsiung MC, Soto B, Adey CK, Goyal RG, Gatewood RP. Color Doppler assessment of mitral regurgitation with orthogonal planes. Circulation 1987;75:175–183. 10. Perry GJ, Helmcke F, Nanda NC, Byard C, Soto B. Evaluation of aortic insufficiency by Doppler color flow mapping. J Am Coll Cardiol 1987;9:952– 959. 11. Romhilt DW, Estes EH. A point score system for electrocardiographic diagnosis of left ventricular hypertrophy. Am Heart J 1968;75:752–758. 12. Casale PN, Devereux RB, Kligfield P, Eisenberg RR, Miller DH, Chaudhary BS, Phillips MC. Electrocardiographic detection of left ventricular hypertrophy:
1048 THE AMERICAN JOURNAL OF CARDIOLOGY姞
VOL. 84
development and prospective validation of improved criteria. J Am Coll Cardiol 1985;6:572–580. 13. Rahimtoola SH. “Prophylactic” valve replacement for mild aortic valve disease at time of surgery for other cardiovascular disease?...No. J Am Coll Cardiol 1999;33:2009 –2015. 14. Woolson RF. Statistical Methods for the Analysis of Biomedical Data. New York: John Wiley, 1987:149 –156. 15. Otto CM, Kuusisto J, Reichenbach DD, Gown Am, O’Brien KD. Characterization of the early lesion of “degenerative” valvular aortic stenosis: histologic and immunohistochemical studies. Circulation 1994;90:844 – 853. 16. Olsson M, Dalsgaard C, Haegarstrand A, Rosequist M, Ryden L, Nilsson J. Accumulation of T lymphocytes and expression of interleukin-2 receptors in nonrheumatic stenotic aortic valves. J Am Coll Cardiol 1994;23:1162–1170. 17. Juvonen J, Juvonen T, Laurila A, Kuusisto J, Alarakkola E, Sa¨rkioja T, Bodian CA, Kairaluoma MI, Saikku P. Can degenerative aortic valve stenosis be related to persistent Chlamydia pneumoniae infection? Ann Intern Med 1998; 128:74 –744. 18. Nystro¨m-Rosander C, Thelin S, Hjelm E, Lindquist O, Pahlson C, Friman G. High incidence of Chlamydia pneumoniae in sclerotic heart valves of patients undergoing aortic valve replacement. Scand J Infect Dis 1997;29:361–365. 19. Maher ER, Pazianas M, Curtis JR. Calcific aortic stenosis: a complication of chronic uremia. Nephron 1987;47:119 –122. 20. Strickberger SA, Schulman SP, Hutchins GM. Association of Paget’s disease of bone and calcific aortic valve disease. Am J Med 1987;82:953–956. 21. Lindroos M, Kupari M, Valvanne J, Strandberg T, Heikkila¨ J, Tilvis R. Factors associated with calcific aortic valve degeneration in the elderly. Eur Heart J 1994;15:865– 870. 22. Roberts WC, Walker BF. Effects of chronic hypercalcemia on the heart: an analysis of 18 necropsy patients. Am J Med 1981;71:371–384. 23. O’Brien KD, Reichenbach DD, Marcovina SM, Kuusisto J, Alpers CE, Otto CM. Apoliproteins B, (a) and E accumulate in the morphologically early lesion of degenerative valvular aortic stenosis. Arterioscler Thromb Vasc Biol 1996;16: 523–532. 24. Watson KE, Abrolar ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL. Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 1997;96:1755–1760. 25. Davies SW, Gershlick AH, Balcon R. Progression of valvular aortic stenosis. A long term retrospective study. Eur Heart J 1991;12:10 –14. 26. Wagner S, Selzer A. Patterns of progression of aortic stenosis: a longitudinal hemodynamic study. Circulation 1982;65:709 –712. 27. Montarello JK, Perakis AC, Rosenthal E, Boyd ECGA, Yates AK, Deverall PB, Sowton E, Curry PVL. Normal and stenotic human valve opening: in vitro assessment of orifice area changes with flow. Eur Heart J 1990;11:484 – 491. 28. Shively BK, Charlton GA, Crawford MH, Chaney RK. Flow dependence of valve area in aortic stenosis: relation to valve morphology. J Am Coll Cardiol 1998;31:654 – 660. 29. Thoreau WA, Siu SC, Thoreau DH, Vandervoort PM, Thomas JD, Weyman AE. The rate and pattern of change of valve area in aortic stenosis: long term Doppler follow-up (abstr). J Am Coll Cardiol 1992;19:331A.
NOVEMBER 1, 1999