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Prevalence and Prognosis of Aortic Valve Disease in Subjects Older than 85 Years of Age

2013; Elsevier BV; Volume: 112; Issue: 3 Linguagem: Inglês

10.1016/j.amjcard.2013.03.044

1879-1913

David Leibowitz, Jochanan Stessman, Jeremy M. Jacobs, Irit Stessman‐Lande, Dan Gilon,

Cardiac Imaging and Diagnostics

Although degenerative aortic valve disease is common with increasing age, limited data exist regarding prevalence and prognosis of aortic valve disease among the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed at home in 498 randomly selected subjects. Subjects were divided into 3 groups; normal subjects, subjects with valve calcium but without stenosis (AVC), and subjects with aortic stenosis (AS). Survival status at 5-year follow-up was assessed via the centralized population registry. AVC was noted in 55% of the study subjects and AS was seen in 8.2%. There were no significant differences between the 3 groups in any of the clinical parameters examined including risk factors for atherosclerotic heart disease. Of the 498 subjects, 107 (21%) had died at the time of 5-year follow-up. Five-year mortality was similar among the normal (17%) and AVC (20%) subjects but was significantly higher among the subjects with AS (46%; p <0.0001). AS was associated with a nearly fourfold increased likelihood of mortality (hazard ratio 3.7, 95% confidence interval 1.4 to 9.3). In conclusion, among subjects ≥85 years of age, the prevalence of AS is higher than previously reported and not associated with traditional vascular risk factors. AS but not AVC alone was independently predictive of 5-year mortality. Although degenerative aortic valve disease is common with increasing age, limited data exist regarding prevalence and prognosis of aortic valve disease among the oldest old. Subjects were recruited from the Jerusalem Longitudinal Cohort Study. Echocardiography was performed at home in 498 randomly selected subjects. Subjects were divided into 3 groups; normal subjects, subjects with valve calcium but without stenosis (AVC), and subjects with aortic stenosis (AS). Survival status at 5-year follow-up was assessed via the centralized population registry. AVC was noted in 55% of the study subjects and AS was seen in 8.2%. There were no significant differences between the 3 groups in any of the clinical parameters examined including risk factors for atherosclerotic heart disease. Of the 498 subjects, 107 (21%) had died at the time of 5-year follow-up. Five-year mortality was similar among the normal (17%) and AVC (20%) subjects but was significantly higher among the subjects with AS (46%; p 140 mm Hg systolic or 90 mm Hg diastolic on examination. Hyperlipidemia was defined as use of cholesterol-lowering medications. Diagnosis of diabetes mellitus was a composite of hypoglycemic medications, personal history, or a medical record diagnosis. Congestive heart failure was based on hospital discharge diagnosis and according to examining research physician diagnosis at the time of examination at home. Self-rated health was assessed according to the question how do you rate your general health? Responses were good or poor. A cognitive assessment was performed according to a standardized Mini-Mental State Examination with cognitive impairment defined as ≤24 out of 30.13Folstein M.F. Folstein S.E. McHugh P.R. Mini-Mental State: a practical method for grading the cognitive state of patients for the clinician.J Psychiat Res. 1975; 12: 189-198Abstract Full Text PDF PubMed Scopus (70862) Google Scholar Dependence in functional status was defined as requiring the help of another person in ≥1 of the following activities of daily living: eating, dressing, bathing, personal hygiene, toileting, and transfer.14Katz S. Ford A.B. Moscowitz R.W. Jackson B.A. Jaffe M.W. Studies of illness in the aged. The index of ADL: a standardized measure of biological and psychosocial function.J Am Med Assoc. 1963; 185: 914-919Crossref PubMed Scopus (8939) Google Scholar Four hundred ninety-eight subjects had standard 2-dimensional and Doppler echocardiography at their place of residence with a portable echocardiograph (Vivid I, GE Healthcare, Haifa, Israel). All subjects underwent standard 2-dimensional and Doppler echocardiography with measurements according to the recommendations of the European Association of Echocardiography and American Society of Echocardiography.15Lang R.M. Bierig M. Devereaux R.B. Flachskampf F.A. Foster E. Pellikka P.A. Picard M.H. Roman M.J. Seward J. Shanewise J. Solomon S. Spencer K.T. St John Sutton M. Stewart W. Recommendations for chamber quantification.Eur J Echocardiogr. 2006; 7: 79-108Crossref PubMed Scopus (2865) Google Scholar Measurements were performed for 3 consecutive cardiac cycles and averaged. Left ventricular (LV) mass was calculated according to a necropsy validated formula of LV mass (grams) = 0.8 × (1.04 × ((septal thickness + LV internal diameter + posterior wall thickness)3−(LV internal diameter)3)) + 0.6 and indexed to body surface area.16Devereux R.B. Alonso D.R. Lutas E.M. Gottleib G.J. Campo E. Sachs I. Reichek N. Echocardiographic assessment of left ventricular hypertrophy: comparison to necropsy findings.Am J Cardiol. 1986; 57: 450-458Abstract Full Text PDF PubMed Scopus (5532) Google Scholar Left atrial (LA) volumes were calculated at end-systole from the apical 4-chamber view using the area-length method.17Lester S.J. Ryan E.W. Schiller N.B. Foster E. Best method in clinical practice and in research studies to determine left atrial size.Am J Cardiol. 1999; 84: 829-832Abstract Full Text Full Text PDF PubMed Scopus (440) Google Scholar Ejection fraction was calculated by averaging measurements of end-diastolic and end-systolic volumes from the apical 4-chamber view using the area-length method for 3 consecutive beats. In patients with atrial fibrillation (n = 25), measurements were averaged for 5 consecutive beats. Peak systolic mitral annular function (s wave) was measured as an additional index of systolic function. Diastolic parameters were measured from the apical 4-chamber view using pulsed-wave Doppler at the level of the mitral annulus (e and a waves) and tissue Doppler imaging (e′ and a′ waves) of the septal and lateral myocardial walls. The ratio of E/e′ using the average of septal and lateral tissue velocities obtained was calculated as an index of diastolic function.18Boon A. Cheriex E. Lodder J. Kessels F. Cardiac valve calcification: characteristics of patients with calcification of the mitral annulus or aortic valve.Heart. 2007; 78: 473-474Google Scholar Patients with atrial fibrillation were excluded from analyses of a wave velocities. Two-dimensional assessment of the aortic valve was performed in parasternal long- and short-axis views. Patients who underwent aortic valve replacement (n = 5) were excluded from the study. Calcifications were defined as bright echoes >1 mm in size on ≥1 cusps.19Volzke H. Haring R. Lorbeer R. Wallaschofski H. Reffelmann T. Empen K. Rettig R. John U. Felix S.B. Dorr M. Heart valve sclerosis predicts all-cause and cardiovascular mortality.Atherosclerosis. 2010; 209: 606-610Abstract Full Text Full Text PDF PubMed Scopus (80) Google Scholar The maximal velocity across the aortic valve was measured with continuous Doppler from apical views. Aortic stenosis was defined as reduced systolic opening on 2-dimensional imaging with a velocity of at least 2.5 m/s across the valve.3Stewart B.F. Siscovick D. Lind B.K. Gardin J.M. Gottdiener J.S. Smith V.E. Kitzman D.W. Otto C.M. Clinical factors associated with calcific aortic valve disease.J Am Coll Cardiol. 1997; 29: 630-634Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar, 4Lindroos M. Kupari M. Valvanne J. Strandberg T. Heikkila J. Tilvis R. Factors associated with calcific valve degeneration in the elderly.Eur Heart J. 1994; 15: 865-870PubMed Google Scholar, 8Otto C.M. Lind B.K. Kitzman D.W. Gersh B.J. Siscovick D.S. Association of aortic valve sclerosis with cardiovascular mortality and morbidity in the elderly.N Engl J Med. 1999; 341: 142-147Crossref PubMed Scopus (1052) Google Scholar For the purpose of analysis, subjects were divided into 3 groups: normal control subjects, subjects with valve calcification but without stenosis, and subjects with AS. Descriptive statistics were performed and percentages were calculated as appropriate. Because cardiac data was normally distributed, results are described as means and standard deviations. For continuous variables differences between means were calculated using 1-way analysis of variance and multiple comparisons was performed using Tukey's method. p values were performed as appropriate. Categorical variables were examined using chi-square tests. Cumulative survival was assessed by Kaplan-Meier analysis and log-rank test for statistical significance. To detect significant difference in mortality, 144 events were necessary. Adjusted and unadjusted Cox proportional hazard models were performed. Models were adjusted for gender, physical activity, diabetes, ischemic heart disease, congestive heart failure, hypertension, renal disease, LA volume, LV mass, and E:e′; further adjustment was made for AS as a dummy variable where "normal" was the reference group. All p values were 2-tailed, and p <0.05 was considered significant. The data storage and analysis was performed using SAS version 9.1e (SAS Institute, Inc., Cary, North Carolina). Aortic valve calcium was noted in 55% of the study subjects, and aortic stenosis was seen in 8.2%. Clinical characteristics of the subjects are depicted in Table 1. There were no significant differences between the 3 groups in any of the clinical parameters examined including risk factors for atherosclerotic heart disease. Echocardiographic parameters in the 3 groups are shown in Table 2. There were no significant differences between the normal subjects and the subjects with AVC except for a significantly lower tissue Doppler septal e wave in the AVC group. When compared with the normal controls and to subjects with AVC, subjects with AS had significantly higher LA volumes, LV mass, mitral valve e and a waves, deceleration time, and E:e′. Of note, there were no significant differences in ejection fraction among the 3 groups.Table 1Clinical characteristics of the study populationVariableTotal Population (n = 498)Normal (n = 183)AVC (n = 274)AS (n = 41)Total36.8%55%8.2%Men46.8%50.3%44.5%46.3%Low education48.6%47.5%54%51.2%Low SES26.2%22.8%29.4%20%Not married48.2%48.3%48%48.8%Not physically active70.1%70.6%70.1%68.3%Poor self-rated health68.7%68.4%69.6%65%Depression32.7%27.2%35.2%40%Difficulty in ADLs28.9%27%30%29.3%Renal disease10.1%12.1%9.2%7.3%Diabetes mellitus19%20.3%19.6%9.8%Ischemic heart disease36.4%36.8%36.2%36.6%Heart failure11.1%11.5%10.3%14.6%Hypertension71.2%72%72%63.4%Dementia17.6%15.7%18.4%20%Never smoked59.3%57.5%58.5%73.2%No significant differences between groups.ADLs = activities of daily living; SES = socioeconomic status. Open table in a new tab Table 2Echocardiographic parameters in the 3 groupsVariableNormal (n = 183)AVC (n = 274)AS (n = 41)p ValueLA volume index (ml/m2)60.9 ± 2363 ± 21.775.5 ± 26.9∗p <0.05 compared with normal aortic function (column 1).0.002LV end diastolic volume index (ml/m2)66.3 ± 1768.8 ± 1973.3 ± 190.13LV end systolic volume index (ml/m2)30.5 ± 13.531.3 ± 14.732.1 ± 10.80.8LV mass index (g/m2)116.7 ± 35.7123.1 ± 33.1144.6 ± 36∗p <0.05 compared with normal aortic function (column 1).0.0002LV ejection fraction (%)55.1 ± 10.6%55.6 ± 10.1%56.6 ± 7.80.69Tissue Doppler lateral s wave (cm/s)7.6 ± 2.17.9 ± 2.17.7 ± 2.20.64Tissue Doppler septal s wave (cm/s)7 ± 26.6 ± 1.86.5 ± 1.90.13Mitral valve E wave (cm/s)75.3 ± 1975.4 ± 22.985.4 ± 20.4∗p <0.05 compared with normal aortic function (column 1).0.022Mitral valve A wave (cm/s)89.2 ± 22.888.1 ± 23.8103.7 ± 31.1∗p <0.05 compared with normal aortic function (column 1).0.0014E/A ratio0.93 ± 0.51.02 ± 1.31 ± 0.680.68Deceleration time (m/s)193.4 ± 63.5207.7 ± 63.5232.7 ± 77.8∗p <0.05 compared with normal aortic function (column 1).0.0019Tissue Doppler lateral e′ wave (cm/s)7.3 ± 1.97.1 ± 2.26.6 ± 2.030.16Tissue Doppler lateral a wave (cm/s)10.3 ± 3.39.8 ± 3.48.9 ± 3.60.07Tissue Doppler septal e′ wave (cm/s)6.4 ± 25.8 ± 1.9∗p <0.05 compared with normal aortic function (column 1).5.4 ± 1.9∗p <0.05 compared with normal aortic function (column 1).0.004Tissue Doppler septal a wave (cm/s)8.52 ± 2.98.1 ± 2.67.8 ± 2.90.22E/e′11.6 ± 4.212.4 ± 515.1 ± 6.3∗p <0.05 compared with normal aortic function (column 1).0.0004∗ p <0.05 compared with normal aortic function (column 1). Open table in a new tab No significant differences between groups. ADLs = activities of daily living; SES = socioeconomic status. Of the 498 subjects, 107 (21%) had died at the time of 5-year follow-up. Five-year mortality was similar between the normal (17%) and AVC (20%) groups but was significantly higher among the subjects with AS (46%; p 65 years with AVC.8Otto C.M. Lind B.K. Kitzman D.W. Gersh B.J. Siscovick D.S. Association of aortic valve sclerosis with cardiovascular mortality and morbidity in the elderly.N Engl J Med. 1999; 341: 142-147Crossref PubMed Scopus (1052) Google Scholar The reasons for the discrepancy with our study are unclear but may be in part due to ethnic differences or the fact that our study included an older population. It is important to note that in that study, the increase in mortality with AVC was significant only in subjects without coronary heart disease at entry. In addition, risks of mortality were much higher in subjects with AS compared with normals or subjects with AVC, a finding consistent with our results. Iivanainen et al showed that moderate and severe, but not mild, AS was associated with mortality in subjects aged 76 to 85 years in the Helsinki Heart Study, again consistent with our finidngs.9Ivaninen A.M. Lindroos M. Tilvis R. Heikkila J. Kupari M. Natural history of aortic valve stenosis of varying severity in the elderly.Am J Cardiol. 1996; 78: 97-101Abstract Full Text PDF PubMed Scopus (141) Google Scholar AVC was not reported separately in this study, which, unlike ours, was performed in a clinic and not the home setting. Our findings have important clinical implications. They extend the poor prognosis of AS in subjects beyond the age of 85 years. Decisions regarding invasive procedures in this elderly and frequently frail population are particularly difficult, and our timely findings should contribute to the handling of these clinical dilemmas. Given the recent development of percutaneous aortic valve replacement, which may be particularly suitable for the elderly population, aggressive therapy for AS should be considered when clinically relevant.21Leon M.B. Smith C.R. Mack M. Miller C. Moses J.W. Svensson L.G. Tuzcu M. Webb J.G. Fontana G.P. Makkar R.R. Brown D.L. Block P.C. Guyton R.A. Pichard A.D. Bavaria J.E. Herrmann H.C. Douglas P.S. Petersen J.L. Akin J.J. Anderson W.N. Wang D. Pocock S. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery.N Engl J Med. 2010; 363: 1597-1607Crossref PubMed Scopus (5369) Google Scholar Importantly, our findings underscore the relatively benign nature of AVC alone, which appears to have limited prognostic significance in this population and should not lead to clinical intervention. AVC was not associated with vascular risk factors in these very elderly individuals, therefore treatment of vascular risk factors in this population would not be expected to influence progression of aortic valve disease, a finding similar to younger populations.22Cowell S.J. Newby D.E. Prescott R.J. Bloomfield P. Reid J. Northridge D.B. Boon N.A. A randomized trial of intensive lipid lowering therapy in calcific aortic stenosis.N Engl J Med. 2005; 352: 2389-2397Crossref PubMed Scopus (831) Google Scholar Previous findings that many patients with AS do not have evidence of atherosclerotic disease on angiography also supports a distinction between AVD and atherosclerosis.23Rapp A.H. Hillis L.D. Lange R.A. Cigarroa J.E. Prevalence of coronary artery disease in patients with aortic stenosis with and without angina pectoris.Am J Cardiol. 2001; 87: 1216-1217Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar Pathways involving calcium accumulation and ossification may be more relevant in the pathogenesis of AVD particularly in the elderly population.24Mohler E.R. Gannon F. Reynolds C. Zimmerman R. Keane M.G. Kaplan F.S. Bone formation and inflammation in cardiac valves.Circulation. 2001; 103: 1522-1528Crossref PubMed Scopus (835) Google Scholar Consistent with our study, data from the Multi-Ethnic Study of Atherosclerosis (MESA) study indicate that the association between low-density lipoprotein levels and AVC is only significant for subjects under age 65 years.25Owens D.S. Katz R. Johnson E. Shavelle D.M. Probstfield J.L. Takasu J. Crouse J.R. Carr J.J. Kronmal R. Budoff M.J. O'Brien K.D. Interaction of age with lipoproteins as predictors of aortic valve calcification in the Multi-Ethnic Study of Atherosclerosis.Arch Intern Med. 2008; 168: 1200-1207Crossref PubMed Scopus (25) Google Scholar In patients older than 60 years examined with electron-beam computed tomography, progression of established AVC was independent of vascular risk factors, consistent with our results.2Messika-Zeitoun D. Bielak L.F. Peyser P.A. Sheedy P.F. Turner S.T. Nkomo V.T. Breen J.F. Maalouf J. Scott C. Tajik A.J. Enriquez-Sarano M. Aortic valve calcification; determinants and progression in the population.Arterioscler Thromb Vasc Biol. 2007; 27: 642-648Crossref PubMed Scopus (141) Google Scholar On the other hand, a recent study reported that genetic variations in the Lipoprotein(a) subclass locus were associated with AVC, suggesting a role for lipoprotein abnormalities in this disorder at least in younger populations.26CHARGE Extracoronary Calcium Working Group Genetic associations with valvular calcifications and aortic stenosis.N Engl J Med. 2013; 368: 503-512Crossref PubMed Scopus (606) Google Scholar Further study is necessary to clarify mechanisms of AVC in the very elderly. Degenerative aortic valve disease is clearly associated with aging; however, few data are available in subjects aged ≥85 years. Our study had a higher prevalence of AS than that noted in previous studies, a finding probably due to the use of home echocardiography, which presumably allowed for the inclusion of a broader and more representative range of subjects.1Lindroos 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: 1220-1225Abstract Full Text PDF PubMed Scopus (937) Google Scholar, 3Stewart B.F. Siscovick D. Lind B.K. Gardin J.M. Gottdiener J.S. Smith V.E. Kitzman D.W. Otto C.M. Clinical factors associated with calcific aortic valve disease.J Am Coll Cardiol. 1997; 29: 630-634Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar In a home-based study of subjects aged >80, Vaes et al reported severe AS in 5.9%, a figure in line with our findings.27Vaes B. Rezzaug N. Pasquet A. Wallemacq P. Van Pottelbergh G. Mathei C. Vanorverschelde J.-L. Degryse J. The prevalence of cardiac dysfunction and the correlation with poor functioning among the very elderly.Int J Cardiol. 2012; 155: 134-143Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar Data on AVC was not reported in this study. The major strengths of our study are the use of an age-homogenous cohort to minimize variability of the clinical findings and the use of home echocardiography, which ensures a more representative sample of this age group. The major limitation is the use of echocardiography in a subset of the total cohort; however, this was a random subgroup, and the chance of selection bias is minimal. The study sample was relatively small, limiting our ability to detect differences in mortality between the normal and AVC groups. Nonetheless, there is no separation in the Kaplan-Meier analysis after 5 years, making such a difference unlikely. We defined AS by pressure gradient without the use of aortic valve area given limitations of the continuity equation in the elderly population methodology similar to other studies in the field.1Lindroos 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: 1220-1225Abstract Full Text PDF PubMed Scopus (937) Google Scholar, 3Stewart B.F. Siscovick D. Lind B.K. Gardin J.M. Gottdiener J.S. Smith V.E. Kitzman D.W. Otto C.M. Clinical factors associated with calcific aortic valve disease.J Am Coll Cardiol. 1997; 29: 630-634Abstract Full Text Full Text PDF PubMed Scopus (1576) Google Scholar In subjects with low cardiac output, gradients may be low even in the presence of significant AS such that the prevalence of AS may be underestimated. We were only able to examine the relationship of aortic valve disease with an end point of total mortality as cause of death is not available from the centralized database. The authors have no conflicts of interest to disclose.