 |
|
The Risk of the Development of Aortic Stenosis in Patients With "Benign" Aortic Valve Thickening
John E. Cosmi, MD;
Smadar Kort, MD;
Paul A. Tunick, MD;
Barry P. Rosenzweig, MD;
Robin S. Freedberg, MD;
Edward S. Katz, MD;
Robert M. Applebaum, MD;
Itzhak Kronzon, MD
Arch Intern Med. 2002;162:2345-2347.
ABSTRACT
| |
Background Aortic valve thickening (AVT) without aortic stenosis (AS) is common and was often considered benign. However, it has recently been found to be associated with increased morbidity and mortality. It is unknown whether patients with AVT are at risk for the development of AS.
Methods Our echocardiography database from 1987 to 1993 was searched for cases of AVT with at least 1 year of echocardiographic follow-up. The risk of the development of AS was compared in patients with and without AVT.
Results There were 2131 patients with AVT and at least 1 year of echocardiographic follow-up. Aortic stenosis developed in 338 patients (15.9%) (mild, 10.5%; moderate, 2.9%; and severe, 2.5%). Multivariate analysis, including age, left ventricular hypertrophy, and mitral annular calcification, revealed that only mitral annular calcification was independently and significantly associated with progression to AS.
Conclusions Aortic valve thickening without stenosis is common, and it may progress to significant AS. It is possible that this development of AS may be responsible for some of the increased morbidity and mortality in patients with AVT.
INTRODUCTION
AORTIC VALVE thickening (AVT) without aortic stenosis (AS) is a common echocardiographic finding. Its prevalence is 26% in adults older than 65 years1 and up to 40% in those older than 75 years.2 In an echocardiographic study of nonagenarians, only 10% had a normal aortic valve.3 The fact that the majority of elderly people do not have AVT implies that risk factors other than age play a role in its pathogenesis.
Although AVT is often considered benign, it is known that patients with AVT have risk factors for the development of cardiac disease.4 Moreover, an association between AVT and an increased risk of cardiovascular morbidity and mortality has been demonstrated.5 However, to our knowledge, there has been no systematic evaluation of the risk of AS developing in patients with AVT to date. The present study was undertaken to investigate the possible progression of AVT to AS in a large cohort of patients.
METHODS
We searched our echocardiography database from 1987 to 1993 for patients with AVT and at least 1 year of echocardiographic follow-up. They had been referred for a variety of clinical indications. Aortic valve thickening was defined as focal or diffuse leaflet thickening or calcification, normal valve excursion, and peak Doppler flow velocity of less than 2 m/s. Follow-up echocardiograms were evaluated for the development of AS. Mild AS was defined as a peak gradient between 16 and 36 mm Hg or a mean gradient of less than 25 mm Hg. Moderate AS was defined as a peak gradient between 36 and 63 mm Hg or a mean gradient between 25 and 44 mm Hg. Severe AS was defined as a peak gradient of 64 mm Hg or more or a mean gradient of 45 mm Hg or more. For the purposes of this study, left ventricular function was not taken into account. Persons who developed significant (moderate or severe) AS (patients) were matched for time of follow-up to those with AVT who did not develop any AS (controls). We excluded those who had moderate or severe aortic regurgitation.
The patients were compared with the controls with respect to predictors associated with the progression of established AS, ie, age, sex, and the echocardiographic variables of mitral annular calcification (MAC), left ventricular hypertrophy (LVH) (wall thickness  12 mm), left ventricular function (decreased ejection fraction [<50%]), and mitral regurgitation. Also, 100 subjects with normal aortic valves (no AVT) were matched for age and time of echocardiography follow-up to those with AVT, and evaluated for the development of AS.
Continuous variables were analyzed using a t test. Discontinuous variables were analyzed using  2 analysis. Any variables with a P value of .10 or less on univariate analysis were entered into a model for multivariate analysis (stepwise logistic regression) (SPSS Software, Version 10; SPSS Inc, Chicago, Ill). A P value of .05 or less was considered statistically significant.
RESULTS
Over the 6-year period from 1987 to 1993, we found 2131 patients with AVT and at least 1 year of echocardiographic follow-up. These patients made up the study group. Aortic stenosis of any degree developed in 338 patients (15.9%) with AVT. This was a significantly higher incidence of AS than we found in the subjects with normal valves (without AVT), among whom just 1 patient (1%; P <.001) developed only mild AS (Figure 1). These 2 groups were matched for age (69.3 years vs 69.7 years) and time of follow-up (7.3 years vs 7.4 years).
|
|
|
|
Figure 1. The development of aortic stenosis. AVT indicates aortic valve thickening.
|
|
|
Mild AS developed in 223 patients (10.5%) with AVT; moderate AS developed in 61 patients (2.9%); and severe AS developed in 54 patients (2.5%). The mean ± SD time to follow-up of the 115 patients with AVT who developed moderate or severe AS was 7.4 ± 2.4 years, and this follow-up time was matched to that of the patients with AVT who did not develop any AS (7.4 ± 2.3 years, P = .84). The 2 groups were compared and the findings are presented in Table 1. The years at which moderate and severe AS developed are shown in Figure 2 and Figure 3. The largest number of patients who developed moderate AS were observed to do so at 6 years; severe AS was observed most often with 2 more years of follow-up (ie, at 8 years).
|
|
|
|
Comparison Between Patients With AVT Who Progressed to Significant AS and Controls With AVT Who Did Not*
|
|
|
|
|
|
|
Figure 2. The number of years from aortic valve thickening to moderate aortic stenosis.
|
|
|
|
|
|
|
Figure 3. The number of years from aortic valve thickening to severe aortic stenosis.
|
|
|
There was no significant difference in sex between the 115 patients and the 115 controls: 66 (57%) male vs 70 (61%) male (P = .60). There was a trend toward older age in the patients compared with the controls (70.8 ± 7.8 [mean ± SD] years vs 68.6 ± 10.9 years), but it was not statistically significant (P = .08). Mitral annular calcification was found in significantly more patients (those with AVT who developed AS) than controls (AVT with no development of AS): 42 (36.5%) vs 22 (19.1%) (P = .003). Left ventricular hypertrophy was also found in significantly more patients than controls: 40 (34.8%) vs 24 (20.9%) (P = .02). Moderate or severe mitral regurgitation was found in 16 patients (13.9%) and 18 controls (15.6%) (P = .71). Decreased left ventricular function was found in 10 patients (8.7%) and 8 controls (6.9%) (P = .62).
Multivariate analysis using a model that included age, MAC, and LVH revealed that only MAC (P = .02) was significantly and independently associated with a progression from AVT to significant AS when age and LVH were controlled for. Age (P = .44) and LVH (P = 0.10) were not independently associated with progression of AVT to AS.
COMMENT
Although usually thought of as a common, benign valvular condition, AVT has been shown by 3 independent investigations to be associated with increased morbidity and mortality.5-7 In a study by Otto et al,5 there was a 50% increase in the risk of cardiovascular mortality and myocardial infarction in patients with AVT.
Exactly how AVT influences cardiovascular morbidity and mortality has not been determined. Aortic valve thickening has been associated with risk factors for cardiovascular disease, such as increasing age, male sex, smoking, hypertension, hypercholesterolemia, diabetes mellitus, increased levels of lipoprotein(a), and reduced levels of high-density lipoprotein.1, 8-9 These associations may partially explain the increased risk for cardiovascular disease in patients with AVT.
We have found that AS may develop in a significant number of patients with AVT. Although we did not have natural history data available, it is possible that the development of AS may also be an important element in the increased cardiovascular morbidity and mortality. Aortic stenosis and AVT appear to represent different stages in a continuum of aortic valve disease.
Predictors of the progression of established AS have been identified: age, coronary artery disease, left ventricular dysfunction, left ventricular wall thickness, valvular calcification, mitral regurgitation, and worsening symptoms.10-11 However, the factors that may predict the progression of AVT to AS are unknown. We analyzed some of the factors that are known to predict the progression of established AS to determine whether they may also serve to predict the progression of AVT to AS. On univariate analysis, the development of AS from AVT was associated with LVH and MAC, and there was a trend for an association with age. A similar association was not demonstrated for left ventricular dysfunction or mitral regurgitation. However, our multivariate analysis model revealed only MAC, not age or LVH, as independently predictive of progression to AS.
The process of aortic valve calcification has similarities to that of atherosclerosis.12 Therefore, calcification of the aortic valve and coronary arteries as well as of the mitral annulus may represent a unified process of inflammation and/or degeneration,13 and the association of the progression of AVT to AS with MAC may be a manifestation of this process. Although further investigation is needed to firmly link the pathogenesis of these entities, the presence of a common pathway of tissue injury leading to sclerosis and calcification would imply that calcific aortic valve disease is an active process that might be modified by treating associated risk factors.12
The major limitation of this study was its retrospective nature. Because all of our patients were referred to the echocardiography laboratory for various indications, this is a source of bias. Furthermore, we were limited to the examination of available follow-up echocardiograms, and therefore could not identify the exact time at which AS developed. There is also selection bias in the referral of patients for echocardiographic follow-up, and patients who developed AS may have been more likely to have been referred for echocardiographic follow-up. However, the large size of the population studied would tend to offset some of these limitations.
Gradient, rather than valve area, was used to grade the severity of AS. Therefore, some patients may have developed more or less severe AS than the degree reported. However, the low prevalence of left ventricular dysfunction and the large number of patients both offset this limitation.
We do not have other clinical information about these patients, such as their history of risk factors for, or clinical manifestations of, atherosclerosis. We also do not have information about subsequent morbidity and mortality, which have been previously evaluated by others.
CONCLUSIONS
Aortic valve thickening is a common echocardiographic finding, and it may progress to hemodynamically significant AS. The presence of MAC may serve to predict which patients with AVT are at risk of developing AS. A prospective study of the progression of AVT to AS would be important.
It remains to be seen whether or not the development of AS is responsible for part of the increase in complications seen in patients with AVT. Further investigation may focus on the duration of time between the appearance of AVT and the development of AS. Finally, the possible impact of risk factor modification (to reduce the risk of AS) on the large numbers of patients with AVT is a question for future study.
AUTHOR INFORMATION
Accepted for publication April 3, 2002.
Corresponding author and reprints: Paul A. Tunick, MD, 560 First Ave, New York, NY 10016 (e-mail: Paul.Tunick{at}med.nyu.edu).
From the Noninvasive Cardiology Laboratory, Department of Medicine, New York University School of Medicine, New York, NY.
REFERENCES
| |
1. Stewart BF, Siscovick D, Lind B, et al. Clinical factors associated with calcific aortic valve disease. J Am Coll Cardiol. 1997;29:630-634.
ABSTRACT
2. Lindroos M, Kupari M, Heikkila J, Tilvis R. Prevalence of aortic valve abnormalities in the elderly: an echocardiographic study of a random population sample. J Am Coll Cardiol. 1993;21:1220-1225.
ABSTRACT
3. Tunick PA, Freedberg RS, Kronzon I. Cardiac findings in the very elderly: analysis of echocardiography in fifty-eight nonagenarians. Gerontology. 1990;36:206-211.
ISI
| PUBMED
4. Aronow WS, Schwartz KS, Koenigsberg M. Correlation of serum lipids, calcium, and phosphorus, diabetes mellitus and history of systemic hypertension with presence or absence of calcified or thickened aortic cusps or root in elderly patients. Am J Cardiol. 1987;59:998-999.
FULL TEXT
|
ISI
| PUBMED
5. Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med. 1999;341:142-147.
FREE FULL TEXT
6. Aronow WS, Ahn C, Shirani J, Kronzon I. Comparison of frequency of new coronary events in older subjects with and without valvular aortic sclerosis. Am J Cardiol. 1999;83:599-600, A8.
FULL TEXT
|
ISI
| PUBMED
7. Teerlink JR, Newman TB, Schiller NB, Foster E. Aortic sclerosis, as well as aortic stenosis, is a significant predictor of mortality [abstract]. Circulation. 1997;96(suppl I):I-82.
8. Gotoh T, Kuroda T, Yamasawa M, et al. Correlation between lipoprotein(a) and aortic valve sclerosis assessed by echocardiography (the JMS Cardiac Echo and Cohort Study). Am J Cardiol. 1995;76:928-932.
FULL TEXT
|
ISI
| PUBMED
9. 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.
FREE FULL TEXT
10. Faggiano P, Aurigemma GP, Rusconi C, Gaasch WH. Progression of valvular aortic stenosis in adults: literature review and clinical implications. Am Heart J. 1996;132:408-417.
FULL TEXT
|
ISI
| PUBMED
11. Wagner S, Selzer A. Patterns of progression of aortic stenosis: a longitudinal hemodynamic study. Circulation. 1982;65:709-712.
FREE FULL TEXT
12. Otto CM, Kuusisto J, Reichenbach DD, Gown AM, O'Brien KD. Characterization of the early lesion of "degenerative" valvular aortic stenosis: histological and immunohistochemical studies. Circulation. 1994;90:844-853.
FREE FULL TEXT
13. Roberts WC. The senile cardiac calcification syndrome. Am J Cardiol. 1986;58:572-574.
FULL TEXT
|
ISI
| PUBMED
THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES
|
An elderly man who suddenly lost consciousness
Ramaraj
BMJ 2009;338:a3009-a3009.
FULL TEXT
Aortic stenosis
Chambers
Eur J Echocardiogr 2009;10:i11-i19.
ABSTRACT
| FULL TEXT
Management of Asymptomatic Severe Aortic Stenosis
Dal-Bianco et al.
J Am Coll Cardiol 2008;52:1279-1292.
ABSTRACT
| FULL TEXT
2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease): Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons
2006 WRITING COMMITTEE MEMBERS et al.
Circulation 2008;118:e523-e661.
FULL TEXT
Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis
Rossebo et al.
NEJM 2008;359:1343-1356.
ABSTRACT
| FULL TEXT
2008 Focused Update Incorporated Into the ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Endorsed by the Society of Cardiovascular Anesthesiologists, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons
Bonow et al.
J Am Coll Cardiol 2008;52:e1-e142.
FULL TEXT
Hot topics in aortic stenosis: Proceedings of a satellite symposium organized by the Scientific Committee of the Simvastatin and Ezetimibe in Aortic Stenosis (SEAS) Study in conjunction with the European Association of Echocardiography of the European Society of Cardiology, which was held during the meeting of the European Association of Echocardiography, EUROECHO, Lisbon, 6 December 2007
Gohlke-Barwolf and Zamorano
Eur Heart J Suppl 2008;10:E2-E3.
FULL TEXT
Natural History of Asymptomatic Patients With Normally Functioning or Minimally Dysfunctional Bicuspid Aortic Valve in the Community
Michelena et al.
Circulation 2008;117:2776-2784.
ABSTRACT
| FULL TEXT
Degenerative aortic stenosis
Ramaraj and Sorrell
BMJ 2008;336:550-555.
FULL TEXT
Clinical Factors, But Not C-Reactive Protein, Predict Progression of Calcific Aortic-Valve Disease: The Cardiovascular Health Study
Novaro et al.
J Am Coll Cardiol 2007;50:1992-1998.
ABSTRACT
| FULL TEXT
Glycosaminoglycan synthesis and structure as targets for the prevention of calcific aortic valve disease
Grande-Allen et al.
Cardiovasc Res 2007;76:19-28.
ABSTRACT
| FULL TEXT
Aortic Valve Calcification: Determinants and Progression in the Population
Messika-Zeitoun et al.
Arterioscler. Thromb. Vasc. Bio. 2007;27:642-648.
ABSTRACT
| FULL TEXT
Correlation of High Sensitivity C-Reactive Protein and Calcific Aortic Valve Disease
Jeevanantham et al.
Mayo Clin. Proc. 2007;82:171-174.
ABSTRACT
| FULL TEXT
Multimodality Molecular Imaging Identifies Proteolytic and Osteogenic Activities in Early Aortic Valve Disease
Aikawa et al.
Circulation 2007;115:377-386.
ABSTRACT
| FULL TEXT
Indications for Aortic Valve Replacement in Aortic Stenosis
Stout and Otto
J Intensive Care Med 2007;22:14-25.
ABSTRACT
ACC/AHA 2006 Guidelines for the Management of Patients With Valvular Heart Disease: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons
Bonow et al.
J Am Coll Cardiol 2006;48:e1-e148.
FULL TEXT
ACC/AHA 2006 Practice Guidelines for the Management of Patients With Valvular Heart Disease: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Revise the 1998 Guidelines for the Management of Patients With Valvular Heart Disease) Developed in Collaboration With the Society of Cardiovascular Anesthesiologists Endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons
Bonow et al.
J Am Coll Cardiol 2006;48:598-675.
FULL TEXT
Pathogenesis of Calcific Aortic Valve Disease: A Disease Process Comes of Age (and a Good Deal More)
O'Brien
Arterioscler. Thromb. Vasc. Bio. 2006;26:1721-1728.
ABSTRACT
| FULL TEXT
Features of the Metabolic Syndrome and Diabetes Mellitus as Predictors of Aortic Valve Calcification in the Multi-Ethnic Study of Atherosclerosis
Katz et al.
Circulation 2006;113:2113-2119.
ABSTRACT
| FULL TEXT
Aortic sclerosis: not an innocent murmur but a marker of increased cardiovascular risk
Nightingale and Horowitz
Heart 2005;91:1389-1393.
ABSTRACT
| FULL TEXT
Spectrum of Calcific Aortic Valve Disease: Pathogenesis, Disease Progression, and Treatment Strategies
Freeman and Otto
Circulation 2005;111:3316-3326.
FULL TEXT
Aortic stenosis
Chambers
BMJ 2005;330:801-802.
FULL TEXT
Systolic murmur in an asymptomatic 70 year old man
Heart 2005;91:125-125.
FULL TEXT
Aortic stenosis: even mild disease is significant
Otto
Eur Heart J 2004;25:185-187.
FULL TEXT
Why is aortic sclerosis associated with adverse clinical outcomes?
Otto
J Am Coll Cardiol 2004;43:176-178.
FULL TEXT
Is aortic stenosis a preventable disease?
Chan
J Am Coll Cardiol 2003;42:593-599.
ABSTRACT
| FULL TEXT
|
