- Email: [email protected]
Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis
Accepted Manuscript Title: Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis Author: Siyuan P. Sheng, Lucius A. Howell, Melissa C. Caughey, Michael Yeung, John P. Vavalle PII: DOI: Reference:
S0002-9149(17)31619-3 https://doi.org/doi:10.1016/j.amjcard.2017.10.011 AJC 22952
To appear in:
The American Journal of Cardiology
Received date: Accepted date:
9-7-2017 4-10-2017
Please cite this article as: Siyuan P. Sheng, Lucius A. Howell, Melissa C. Caughey, Michael Yeung, John P. Vavalle, Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis, The American Journal of Cardiology (2017), https://doi.org/doi:10.1016/j.amjcard.2017.10.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis
Siyuan P. Sheng, BSa, Lucius A. Howell, MDb, Melissa C. Caughey, PhDb, Michael Yeung, MDb, John P. Vavalle, MD, MHSb a
University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States
b
Division of Cardiology, Department of Medicine, University of North Carolina School of
Medicine, Chapel Hill, NC, United States
Corresponding Author: John P. Vavalle, MD, MHS University of North Carolina School of Medicine 160 Dental Circle, CB #7075 Chapel Hill, NC 27599-7075 Tel: 984-974-7921 Fax: 984-974-4366 Email: [email protected]
Running Head: Cardiac Calcification in Aortic Stenosis
Page 1 of 19
2 Abstract Patients with calcific aortic stenosis (AS) often have diffuse cardiac calcification involving the mitral valve apparatus and coronary arteries. We examined the association between global cardiac calcification quantified by a previously-validated echocardiographic calcium score (eCS) with the severity of mitral stenosis (MS) and coronary artery disease (CAD) in patients with a clinical diagnosis of severe calcific AS. In this sample of 147 patients (mean age 81±9 years, 50% male), 81 patients (55%) were determined by echocardiography to have some degree of MS. Higher mean eCS was observed in patients with more severe MS (r=0.54, p<0.0001). Higher eCS was also inversely associated with mitral valve area (r=-0.31, p=0.001) and positively associated with mitral valve mean pressure gradient (r=0.46, p<0.0001) and mitral valve peak flow velocity (r=0.55, p<0.0001). The area under the Receiver Operating Characteristic curve for using eCS to predict the presence of MS was 0.76. An eCS ≥8 predicted MS with a sensitivity of 68%, specificity of 76%, positive predictive value of 77%, and negative predictive value of 66%. High eCS, relative to low eCS, was associated with 2.70 times the adjusted odds of CAD (OR=2.70, 95% CI 1.02–7.17). In conclusion, global cardiac calcification is associated with MS and CAD in patients with severe calcific AS, and eCS shows ability to predict the presence of MS. This study suggests that a simple eCS may be used as part of a riskstratification tool in patients with severe calcific aortic valve stenosis.
Keywords: aortic valve stenosis, calcification, coronary artery disease, mitral valve stenosis
Page 2 of 19
3 Introduction Aortic valve calcification occurs progressively with aging and affects 30% of adults over 65 years old.1 The pathological process is believed to involve mechanical damage, lipid accumulation, inflammatory pathways, and genetic predisposition.2,3 Aortic stenosis (AS) is the most common valvular heart disease lesion in developed countries with a prevalence approaching 10% in octogenarians.4,5 In patients with aortic stenosis, concomitant cardiac calcification may also affect the coronary arteries and mitral apparatus, potentially leading to obstructive coronary artery disease (CAD) and mitral stenosis (MS).6,7 Mitral annular calcification in patients with severe AS has important implications for aortic valve replacement. For example, the degree and pattern of calcification, especially along the aortomitral continuity, is associated with new atrial fibrillation and the need for permanent pacemaker after transcatheter aortic valve replacement.8,9 A previously-described and validated echocardiographic calcium score (eCS) has been used to quantify the degree of global cardiac calcification seen on transthoracic echocardiography and has been shown to be associated with mitral valve disease in patients with end-stage renal disease.7,10 In this study, we applied this eCS to patients with severe calcific AS to determine if eCS is associated with, and has the ability to predict, the presence and severity of MS and CAD. Methods This cross-sectional study included 147 patients with a clinical diagnosis of severe calcific AS who had undergone transthoracic echocardiography at the University of North Carolina Hospitals from January 2011 through December 2014. Patients under 65 years old and those with bicuspid or prosthetic valves were excluded from the sample. This study was approved by the institutional review board of the University of North Carolina at Chapel Hill.
Page 3 of 19
4 Demographic data, including age, sex, and race, and medical history at the time of echocardiography were collected from the hospital electronic health records system. Patients were noted as having hypertension, hyperlipidemia, diabetes, or CAD based on diagnoses in medical records. Chronic kidney disease stage was determined from glomerular filtration rate. New York Heart Association class was assessed based on symptoms detailed in clinical notes. Echocardiographic measurements were made according to guidelines set by the American Society of Echocardiography, using Philips iE33 ultrasound machines. Aortic and mitral valve areas were derived using the continuity equation. The peak flow velocities were measured using continuous-wave Doppler echocardiography, and mean pressure gradients were calculated using the modified Bernoulli equation. MS severity was assessed based on the mean pressure gradient to be absent (<3 mm Hg), mild (3–4 mm Hg), moderate (5–10 mm Hg), or severe (>10 mm Hg). Global cardiac calcification was assessed using a semiquantitative algorithm developed by Pressman et al that produces a score ranging from 0 to 13.10 (Figure 1) The assessments were made by 2 independent reviewers who were blinded to patient characteristics. If the 2 scores differed by ≥2, a third independent reviewer assessed the echocardiograms. All reviewers’ scores were averaged to determine a final eCS for each patient, which was then stratified into low (eCS 0 – 6.99), medium (eCS 7 – 8.99), and high (eCS 9 – 13) calcium groups. In our patient population with severe calcific AS, we examined the following: (1) prevalence of MS; (2) association between global cardiac calcification as quantified by eCS with the severity of MS and presence of CAD; (3) ability of using eCS to predict MS and CAD. Demographic, echocardiographic, and clinical data were compared between patients stratified into low, medium, and high eCS groups. Continuous variables were assessed for normality and compared across groups using analysis of variance. Categorical variables were
Page 4 of 19
5 compared across groups using χ2 tests for ordinal data. Linear relationships between eCS and echocardiographic parameters were assessed using visual scatterplots and Pearson correlation. Associations between eCS and the prevalence of CAD were assessed using multivariable logistic regression, which analyzed medium vs. low and high vs. low eCS with adjustments for demographics (age, race, sex) and CAD risk factors (hypertension, hyperlipidemia, diabetes, and smoking history). Receiver Operating Characteristic curves were constructed for using eCS as a continuous variable to predict the presence of MS (mild, moderate, or severe) and CAD. The sensitivities, specificities, positive predictive values, and negative predictive values were also calculated for using eCS ≥8 to predict MS and CAD. Statistical analyses were carried out using SAS 9.4 (SAS Institute; Cary, NC). Results Our study sample included 147 patients with a mean age of 81 ± 9 years, 50% being male, and 84% being white. (Table 1) Calcium scoring by 2 independent readers differed by ≥2 for 33 echocardiograms (22%), which were then assessed by a third independent reader. Final eCS ranged from 3.5 to 12.5 with mean 8.0 ± 2.0. Representative echocardiographic still images for patients with high, medium, and low eCS have been provided. (Figure 2 A-C) Some degree of MS was present in 81 patients (55%), and there was a statistically significant association between MS severity and eCS. (Table 2, Figure 3) Medium and high eCS groups had higher percentages of patients with more severe MS. (Figure 4) Higher eCS was associated with decreased mitral valve area, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity. (Table 3, Figure 5 A-C) A multivariable analysis showed a statistically significant association between eCS and a clinical diagnosis of CAD while controlling for demographics (age, race, sex) and CAD risk
Page 5 of 19
6 factors (hypertension, hyperlipidemia, diabetes, smoking history). Compared to low eCS, high eCS was associated with almost 3 times the adjusted odds of CAD (OR = 2.70, CI 1.02 – 7.17). (Table 4, Figure 6) The area under the Receiver Operating Characteristic curve for using eCS to predict presence of MS of any degree was 0.76 and CAD was 0.57. (Figure 7) An eCS ≥8 predicted MS with a sensitivity of 68%, specificity of 76%, positive predictive value of 77%, and negative predictive value of 66%. (Table 5) Discussion This study is the first to use eCS to quantify global cardiac calcification in patients with severe calcific AS. Over half of these patients had some degree of MS with a statistically significant association between eCS and MS severity. Higher eCS was associated with decreased mitral valve area, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity. Compared to low eCS, high eCS was also associated with increased adjusted odds of CAD. In addition, eCS showed good ability to predict MS but less ability to predict CAD. Mitral annular calcification has previously been shown to be a predictor of the presence and severity of CAD.11 In addition, global cardiac calcification quantified by eCS predicted cardiac events in patients with CAD.12 Longitudinal epidemiological studies have shown that aortic valve calcification and mitral annular calcification share many of the same risk factors relating to atherosclerosis including age, body mass index, hypertension, hypercholesterolemia, smoking history, and diabetes mellitus.13,14 Similarly in our study, we observed a high prevalence of hypertension, hyperlipidemia, heart failure, and chronic kidney disease in patient with severe calcific AS and a statistically significant association between eCS and the presence of CAD.
Page 6 of 19
7 These results fit the paradigm of shared risk factors between cardiac calcification and atherosclerosis. Patients with AS have previously been found to have decreased mitral valve area, decreased mitral leaflet opening angles, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity.15 In another study, 53% of patients who had aortic valve replacement were observed to also have mitral annular calcification.16 These findings are consistent with our results showing the prevalence of MS in patients with severe calcific AS to be around half, and higher degrees of calcification being associated with negative changes in mitral valve hemodynamics. The motion of diastolic relaxation is important for mitral valve function, so mitral annular calcification can result in dysfunction.17 Our results support this idea by showing that anatomic changes related to calcification are associated with physiologic changes in valve function. There are several limitations to this study. The patient population is from a single institution and predominately white. Calcification was measured using a semiquantitative scoring algorithm, which may have added some subjectivity to the results. This is the first report of an eCS demonstrating that increased global cardiac calcification is associated with worsening degrees of MS and increased rates of CAD in patients with severe calcific AS. Furthermore, we were able to demonstrate that eCS can predict the presence of MS. This simple score from routine echocardiography takes less than 5 minutes to apply and can be used to help risk-stratify patients being evaluated for treatment of valvular heart disease based on the degree of cardiac calcification observed. Whether eCS can be used to predict clinical outcomes requires further study.
Page 7 of 19
8 References 1. 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. 2. Otto CM. Calcific aortic stenosis – time to look more closely at the valve. N Engl J Med 2008;359:1395-1398. 3. Arsenault BJ, Boekholdt SM, Dubé MP, Rhéaume É, Wareham NJ, Khaw KT, Sandhu MS, Tardif JC. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014;7:304-310. 4. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on valvular heart disease. Eur Heart J 2003;24:1231-1243. 5. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromso study. Heart 2013;99:396-400. 6. Allison MA, Cheung P, Criqui MH, Langer RD, Wright CM. Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis. Circulation 2006;113:861-866. 7. Movva R, Murthy K, Romero-Corral A, Seetha Rammohan HR, Fumo P, Pressman GS. Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function. J Am Soc Echocardiogr 2013;26:1135-1142.
Page 8 of 19
9 8. Baan J, Yong ZY, Koch KT, Henriques JP, Bouma BJ, Vis MM, Cocchieri R, Piek JJ, de Mol BAJM. Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis. Am Heart J 2010;159:497-503. 9. Spaziano M, Sawaya F, Roy A, Neylon A, Piazza N, Hovasse T, Benamer H, Unterseeh T, Garot P, Lefevre T, Chevalier B. Aortomitral continuity calcification predicts new pacemaker insertion and new atrial fibrillation in patients undergoing TAVI. Poster session presented at EuroPCR 2016; 2016 May 17-20; Paris, France. 10. Pressman GS, Crudu V, Parameswaran-Chandrika A, Romero-Corral A, Purushottam B, Figueredo VM. Can total cardiac calcium predict the coronary calcium score? Int J Cardiol 2011;146:202-206. 11. Adler Y, Herz I, Vaturi M, Fusman R, Shohat-Zabarski R, Fink N, Porter A, Shapira Y, Assali A, Sagie A. Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 1998;82:1183-1186. 12. Gaibazzi N, Porter TR, Agricola E, Cioffi G, Mazzone C, Lorenzoni V, Albertini L, Faden G, Pasha MC, Biabhav B, Regazzoli D, Di Lenarda A, Faggiano P. Prognostic value of echocardiographic calcium score in patients with a clinical indication for stress echocardiography. JACC Cardiovasc Imaging 2015;8:389-396. 13. Elmariah S, Budoff MJ, Delaney JAC, Hamirani Y, Eng J, Fuster V, Kronmal RA, Halperin JL, O’Brien KD. Risk factors associated with the incidence and progression of mitral annulus calcification: the multi-ethnic study of atherosclerosis. Am Heart J 2013;166:904-912.
Page 9 of 19
10 14. Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O'Brien KD. Incidence and progression of aortic valve calcium in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Cardiol 2010;105:701-708. 15. Iwataki M, Takeuchi M, Otani K, Kuwaki H, Yoshitani H, Abe H, Lang RM, Levine RA, Otsuji Y. Calcific extension towards the mitral valve causes non-rheumatic mitral stenosis in degenerative aortic stenosis: real-time 3D transoesophageal echocardiography study. Open Heart 2014;1:e000136. 16. Takami Y, Tajima K. Mitral annular calcification in patients undergoing aortic valve replacement for aortic valve stenosis. Heart Vessels 2016;31:183-188. 17. Osterberger LE, Goldstein S, Khaja F, Lakier JB. Functional mitral stenosis in patients with massive mitral annular calcification. Circulation 1981;64:472-476.
Page 10 of 19
11 FIGURES Figure 1. Echocardiographic calcium scoring algorithm.10 Criteria Posterior mitral annulus calcification Posterior mitral leaflet restriction Anterior mitral annular calcification Anterior mitral leaflet restriction Mitral valve calcification Subvalvular mitral apparatus calcification Aortic valve calcification Aortic root calcification Total
Value None = 0; 1/3 calcified = 1; 2/3 calcified = 2; 3/3 calcified = 3 No = 0; Yes = 1 No = 0; Yes = 1 No = 0; Yes = 1 No = 0; Mild = 1; More than mild = 2 No = 0; Yes = 1 None = 0; Nodules in <3 leaflets = 1; Nodules in 3 leaflets = 2; Leaflet restriction = 3 No = 0; Yes = 1 13
Page 11 of 19
12 Figure 2. Sample still images of echocardiograms demonstrating (A) high echocardiographic calcium score, (B) medium echocardiographic calcium score, and (C) low echocardiographic calcium score.
Page 12 of 19
13
Echocardiographic Calcium Score
Figure 3. Mean echocardiographic calcium scores of patients with severe aortic stenosis, stratified by severity of concomitant mitral stenosis. (p <0.0001 by analysis of variance) 14.0
10.8 (95% CI 8.3-13.2)
p <0.0001
12.0 10.0 8.0
7.0 (95% CI 6.6-7.4)
8.0 (95% CI 7.5-8.6)
9.6 (95% CI 9.0-10.2)
6.0 4.0 2.0 0.0 Absent (n=66)
Mild (n=48)
Moderate (n=29)
Severe (n=4)
Mitral Stenosis Severity
Figure 4. Distributions of mitral stenosis severity in patients with severe aortic stenosis, stratified by echocardiographic calcium score. (P <0.0001 by χ2 test for ordinal data)
Prevalence of Mitral Stenosis Severity
100%
80%
60% Severe Moderate 40%
Mild Absent
20% p<0.0001 0% Low
Medium Echocardiographic Calcium Score
High
Page 13 of 19
14
Figure 5. Linear relationships between echocardiographic calcium score and (A) mitral valve area, (B) mitral valve mean pressure gradient, and (C) mitral valve peak flow velocity in patients with severe aortic stenosis. 6
A
r = -0.31, p = 0.001
Mitral Valve Area (cm2)
5 4 3 2 1 0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score Mitral Valve Mean Pressure Gradient (mmHg)
18
B
r = 0.46, p <0.0001
16 14 12 10 8 6 4 2 0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score
Page 14 of 19
15
Mtiral Valve Peak Flow Velocity (m/s)
3.0
C
r = 0.55, p <0.0001
2.5 2.0 1.5 1.0 0.5 0.0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score
Figure 6. Prevalence of coronary artery disease among patients with severe aortic stenosis, stratified by echocardiographic calcium score. (p = 0.07 by χ2 test for ordinal data)
Prevalence of Coronary Artery Disease
60% p=0.07 50%
48%
49%
Medium Echocardiographic Calcium Score
High
40% 30% 30% 20% 10% 0%
Low
Page 15 of 19
16
Figure 7. Receiver Operating Characteristic curve for using echocardiographic calcium score as a continuous variable to predict presence of mitral stenosis of any severity. (Area under curve = 0.76)
Page 16 of 19
17
TABLES
Table 1. Demographics and characteristics of severe aortic stenosis patients, stratified by echocardiographic calcium score Variable
Echocardiographic Calcium Score Low Medium High (n = 44) (n = 58) (n = 45)
Age (years)
Total
P-Value*
(n = 147)
79 ± 9
82 ± 9
81 ± 9
81 ± 9
0.3
Body Mass Index (kg/m )
26.3 ± 5.7
26.3 ± 5.5
27.0 ± 6.3
26.5 ± 5.8
0.7
Male
27 (61%)
33 (57%)
14 (31%)
74 (50%)
0.004
2
Race
0.03
White
40 (91%)
52 (90%)
31 (69%)
123 (84%)
Black
2 (5%)
3 (5%)
9 (20%)
14 (10%)
Other
2 (5%)
3 (5%)
5 (11%)
10 (7%)
Hypertension
30 (68%)
47 (81%)
37 (82%)
114 (78%)
0.1
Hyperlipidemia
19 (43%)
33 (57%)
24 (53%)
76 (52%)
0.3
Diabetes Mellitus
9 (20%)
19 (33%)
14 (31%)
42 (29%)
0.3
Dialysis
3 (7%)
0 (0%)
3 (7%)
6 (4%)
1.0
13 (30%)
28 (48%)
22 (49%)
63 (43%)
0.07
Coronary Artery Disease Smoking History**
0.9
Current
3 (7%)
2 (4%)
3 (7%)
8 (6%)
Former
15 (35%)
22 (39%)
15 (33%)
52 (36%)
25 (58%)
33 (58%)
27 (60%)
85 (59%)
Never Chronic Kidney Disease Stage**
0.4
1 or 2
19 (50%)
17 (32%)
21 (49%)
57 (43%)
3
15 (39%)
29 (55%)
14 (33%)
58 (43%)
4
3 (8%)
6 (11%)
4 (9%)
13 (10%)
1 (3%)
1 (2%)
4 (9%)
6 (4%)
5 New York Heart Association Class**
0.07
1
23 (53%)
24 (44%)
9 (23%)
56 (41%)
2
7 (16%)
13 (24%)
15 (38%)
35 (26%)
3
9 (21%)
10 (19%)
12 (30%)
31 (23%)
4 4 (9%) 7 (13%) 4 (10%) 15 (11%) *P-values are based on comparisons across low, medium, and high echocardiographic calcium scores, using analysis of variance (ANOVA) or χ2 test for ordinal data **Two patients had unknown smoking history, 13 patients had unknown chronic kidney disease stage, and 10 patients had unknown New York Heart Association class. These patients were excluded from calculations of percentages
Page 17 of 19
18 Table 2. Mitral stenosis severity of patients with severe aortic stenosis, stratified by echocardiographic calcium score Mitral Stenosis
Echocardiographic Calcium Score Low Medium High (n = 44) (n = 58) (n = 45)
(n = 147)
Absent
31 (70%)
26 (45%)
9 (20%)
66 (45%)
Mild
12 (27%)
22 (38%)
14 (31%)
48 (33%)
1 (2%)
9 (16%)
19 (42%)
29 (20%)
Moderate
Total
Severe 0 (0%) 1 (2%) 3 (7%) 4 (3%) P-value <0.001 based on comparisons of counts across low, medium, and high echocardiographic calcium scores using Cochran-Mantel-Haenszel chi square test for ordinal data
Table 3. Aortic and mitral valve characteristics of severe aortic stenosis patients, stratified by echocardiographic calcium score Variable
Echocardiographic Calcium Score Low Medium High 0.7 ± 0.2 0.7 ± 0.2 0.6 ± 0.2
P-value*
Aortic Valve Area (cm2) 0.04 Aortic Valve Mean Pressure Gradient (mmHg) 43 ± 18 41 ± 17 43 ± 16 0.8 Aortic Valve Peak Velocity (m/s) 4.2 ± 0.8 4.2 ± 0.8 4.2 ± 0.7 0.8 2 Mitral Valve Area (cm ) 2.1 ± 0.6 1.9 ± 0.8 1.6 ± 0.7 0.003 Mitral Valve Mean Pressure Gradient (mmHg) 2.3 ± 1.2 3.4 ± 2.5 5.0 ± 3.3 <.0001 Mitral Valve Peak Velocity (m/s) 1.2 ± 0.3 1.4 ± 0.3 1.7 ± 0.5 <.0001 *P-values are based on comparisons across low, medium, and high echocardiographic calcium scores, using analysis of variance (ANOVA)
Table 4. Multivariable logistic regression models analyzing prevalence of coronary artery disease in severe aortic stenosis patients with medium vs. low and high vs. low echocardiographic calcium scores Unadjusted Effect
Odds Ratio
High Score vs. Low Score Med Score vs. Low Score
2.28 2.23
95% CI 0.95 0.97
5.46 5.09
Adjusted for demographics and coronary artery disease risk factors* Effect
Odds Ratio
High Score vs. Low Score
2.70
95% CI 1.02
7.17
Med Score vs. Low Score 2.18 0.91 5.24 *Demographic variables that were adjusted included age, sex, race; coronary artery disease risk factors that were adjusted included hypertension, hyperlipidemia, smoking history, and diabetes mellitus
Page 18 of 19
19 Table 5. Sensitivity, specificity, positive predictive value, and negative predictive value of using echocardiographic calcium score ≥8 to predict the presence of coronary artery disease and mitral stenosis of any severity in severe aortic stenosis patients Coronary Artery Disease
Mitral Stenosis
Sensitivity
52%
68%
Specificity
55%
76%
Positive Predictive Value
46%
77%
Negative Predictive Value
61%
66%
Page 19 of 19
S0002-9149(17)31619-3 https://doi.org/doi:10.1016/j.amjcard.2017.10.011 AJC 22952
To appear in:
The American Journal of Cardiology
Received date: Accepted date:
9-7-2017 4-10-2017
Please cite this article as: Siyuan P. Sheng, Lucius A. Howell, Melissa C. Caughey, Michael Yeung, John P. Vavalle, Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis, The American Journal of Cardiology (2017), https://doi.org/doi:10.1016/j.amjcard.2017.10.011. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
1
Relation of an Echocardiographic-Based Cardiac Calcium Score to Mitral Stenosis Severity and Coronary Artery Disease in Patients with Severe Aortic Stenosis
Siyuan P. Sheng, BSa, Lucius A. Howell, MDb, Melissa C. Caughey, PhDb, Michael Yeung, MDb, John P. Vavalle, MD, MHSb a
University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States
b
Division of Cardiology, Department of Medicine, University of North Carolina School of
Medicine, Chapel Hill, NC, United States
Corresponding Author: John P. Vavalle, MD, MHS University of North Carolina School of Medicine 160 Dental Circle, CB #7075 Chapel Hill, NC 27599-7075 Tel: 984-974-7921 Fax: 984-974-4366 Email: [email protected]
Running Head: Cardiac Calcification in Aortic Stenosis
Page 1 of 19
2 Abstract Patients with calcific aortic stenosis (AS) often have diffuse cardiac calcification involving the mitral valve apparatus and coronary arteries. We examined the association between global cardiac calcification quantified by a previously-validated echocardiographic calcium score (eCS) with the severity of mitral stenosis (MS) and coronary artery disease (CAD) in patients with a clinical diagnosis of severe calcific AS. In this sample of 147 patients (mean age 81±9 years, 50% male), 81 patients (55%) were determined by echocardiography to have some degree of MS. Higher mean eCS was observed in patients with more severe MS (r=0.54, p<0.0001). Higher eCS was also inversely associated with mitral valve area (r=-0.31, p=0.001) and positively associated with mitral valve mean pressure gradient (r=0.46, p<0.0001) and mitral valve peak flow velocity (r=0.55, p<0.0001). The area under the Receiver Operating Characteristic curve for using eCS to predict the presence of MS was 0.76. An eCS ≥8 predicted MS with a sensitivity of 68%, specificity of 76%, positive predictive value of 77%, and negative predictive value of 66%. High eCS, relative to low eCS, was associated with 2.70 times the adjusted odds of CAD (OR=2.70, 95% CI 1.02–7.17). In conclusion, global cardiac calcification is associated with MS and CAD in patients with severe calcific AS, and eCS shows ability to predict the presence of MS. This study suggests that a simple eCS may be used as part of a riskstratification tool in patients with severe calcific aortic valve stenosis.
Keywords: aortic valve stenosis, calcification, coronary artery disease, mitral valve stenosis
Page 2 of 19
3 Introduction Aortic valve calcification occurs progressively with aging and affects 30% of adults over 65 years old.1 The pathological process is believed to involve mechanical damage, lipid accumulation, inflammatory pathways, and genetic predisposition.2,3 Aortic stenosis (AS) is the most common valvular heart disease lesion in developed countries with a prevalence approaching 10% in octogenarians.4,5 In patients with aortic stenosis, concomitant cardiac calcification may also affect the coronary arteries and mitral apparatus, potentially leading to obstructive coronary artery disease (CAD) and mitral stenosis (MS).6,7 Mitral annular calcification in patients with severe AS has important implications for aortic valve replacement. For example, the degree and pattern of calcification, especially along the aortomitral continuity, is associated with new atrial fibrillation and the need for permanent pacemaker after transcatheter aortic valve replacement.8,9 A previously-described and validated echocardiographic calcium score (eCS) has been used to quantify the degree of global cardiac calcification seen on transthoracic echocardiography and has been shown to be associated with mitral valve disease in patients with end-stage renal disease.7,10 In this study, we applied this eCS to patients with severe calcific AS to determine if eCS is associated with, and has the ability to predict, the presence and severity of MS and CAD. Methods This cross-sectional study included 147 patients with a clinical diagnosis of severe calcific AS who had undergone transthoracic echocardiography at the University of North Carolina Hospitals from January 2011 through December 2014. Patients under 65 years old and those with bicuspid or prosthetic valves were excluded from the sample. This study was approved by the institutional review board of the University of North Carolina at Chapel Hill.
Page 3 of 19
4 Demographic data, including age, sex, and race, and medical history at the time of echocardiography were collected from the hospital electronic health records system. Patients were noted as having hypertension, hyperlipidemia, diabetes, or CAD based on diagnoses in medical records. Chronic kidney disease stage was determined from glomerular filtration rate. New York Heart Association class was assessed based on symptoms detailed in clinical notes. Echocardiographic measurements were made according to guidelines set by the American Society of Echocardiography, using Philips iE33 ultrasound machines. Aortic and mitral valve areas were derived using the continuity equation. The peak flow velocities were measured using continuous-wave Doppler echocardiography, and mean pressure gradients were calculated using the modified Bernoulli equation. MS severity was assessed based on the mean pressure gradient to be absent (<3 mm Hg), mild (3–4 mm Hg), moderate (5–10 mm Hg), or severe (>10 mm Hg). Global cardiac calcification was assessed using a semiquantitative algorithm developed by Pressman et al that produces a score ranging from 0 to 13.10 (Figure 1) The assessments were made by 2 independent reviewers who were blinded to patient characteristics. If the 2 scores differed by ≥2, a third independent reviewer assessed the echocardiograms. All reviewers’ scores were averaged to determine a final eCS for each patient, which was then stratified into low (eCS 0 – 6.99), medium (eCS 7 – 8.99), and high (eCS 9 – 13) calcium groups. In our patient population with severe calcific AS, we examined the following: (1) prevalence of MS; (2) association between global cardiac calcification as quantified by eCS with the severity of MS and presence of CAD; (3) ability of using eCS to predict MS and CAD. Demographic, echocardiographic, and clinical data were compared between patients stratified into low, medium, and high eCS groups. Continuous variables were assessed for normality and compared across groups using analysis of variance. Categorical variables were
Page 4 of 19
5 compared across groups using χ2 tests for ordinal data. Linear relationships between eCS and echocardiographic parameters were assessed using visual scatterplots and Pearson correlation. Associations between eCS and the prevalence of CAD were assessed using multivariable logistic regression, which analyzed medium vs. low and high vs. low eCS with adjustments for demographics (age, race, sex) and CAD risk factors (hypertension, hyperlipidemia, diabetes, and smoking history). Receiver Operating Characteristic curves were constructed for using eCS as a continuous variable to predict the presence of MS (mild, moderate, or severe) and CAD. The sensitivities, specificities, positive predictive values, and negative predictive values were also calculated for using eCS ≥8 to predict MS and CAD. Statistical analyses were carried out using SAS 9.4 (SAS Institute; Cary, NC). Results Our study sample included 147 patients with a mean age of 81 ± 9 years, 50% being male, and 84% being white. (Table 1) Calcium scoring by 2 independent readers differed by ≥2 for 33 echocardiograms (22%), which were then assessed by a third independent reader. Final eCS ranged from 3.5 to 12.5 with mean 8.0 ± 2.0. Representative echocardiographic still images for patients with high, medium, and low eCS have been provided. (Figure 2 A-C) Some degree of MS was present in 81 patients (55%), and there was a statistically significant association between MS severity and eCS. (Table 2, Figure 3) Medium and high eCS groups had higher percentages of patients with more severe MS. (Figure 4) Higher eCS was associated with decreased mitral valve area, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity. (Table 3, Figure 5 A-C) A multivariable analysis showed a statistically significant association between eCS and a clinical diagnosis of CAD while controlling for demographics (age, race, sex) and CAD risk
Page 5 of 19
6 factors (hypertension, hyperlipidemia, diabetes, smoking history). Compared to low eCS, high eCS was associated with almost 3 times the adjusted odds of CAD (OR = 2.70, CI 1.02 – 7.17). (Table 4, Figure 6) The area under the Receiver Operating Characteristic curve for using eCS to predict presence of MS of any degree was 0.76 and CAD was 0.57. (Figure 7) An eCS ≥8 predicted MS with a sensitivity of 68%, specificity of 76%, positive predictive value of 77%, and negative predictive value of 66%. (Table 5) Discussion This study is the first to use eCS to quantify global cardiac calcification in patients with severe calcific AS. Over half of these patients had some degree of MS with a statistically significant association between eCS and MS severity. Higher eCS was associated with decreased mitral valve area, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity. Compared to low eCS, high eCS was also associated with increased adjusted odds of CAD. In addition, eCS showed good ability to predict MS but less ability to predict CAD. Mitral annular calcification has previously been shown to be a predictor of the presence and severity of CAD.11 In addition, global cardiac calcification quantified by eCS predicted cardiac events in patients with CAD.12 Longitudinal epidemiological studies have shown that aortic valve calcification and mitral annular calcification share many of the same risk factors relating to atherosclerosis including age, body mass index, hypertension, hypercholesterolemia, smoking history, and diabetes mellitus.13,14 Similarly in our study, we observed a high prevalence of hypertension, hyperlipidemia, heart failure, and chronic kidney disease in patient with severe calcific AS and a statistically significant association between eCS and the presence of CAD.
Page 6 of 19
7 These results fit the paradigm of shared risk factors between cardiac calcification and atherosclerosis. Patients with AS have previously been found to have decreased mitral valve area, decreased mitral leaflet opening angles, increased mitral valve mean pressure gradient, and increased mitral valve peak flow velocity.15 In another study, 53% of patients who had aortic valve replacement were observed to also have mitral annular calcification.16 These findings are consistent with our results showing the prevalence of MS in patients with severe calcific AS to be around half, and higher degrees of calcification being associated with negative changes in mitral valve hemodynamics. The motion of diastolic relaxation is important for mitral valve function, so mitral annular calcification can result in dysfunction.17 Our results support this idea by showing that anatomic changes related to calcification are associated with physiologic changes in valve function. There are several limitations to this study. The patient population is from a single institution and predominately white. Calcification was measured using a semiquantitative scoring algorithm, which may have added some subjectivity to the results. This is the first report of an eCS demonstrating that increased global cardiac calcification is associated with worsening degrees of MS and increased rates of CAD in patients with severe calcific AS. Furthermore, we were able to demonstrate that eCS can predict the presence of MS. This simple score from routine echocardiography takes less than 5 minutes to apply and can be used to help risk-stratify patients being evaluated for treatment of valvular heart disease based on the degree of cardiac calcification observed. Whether eCS can be used to predict clinical outcomes requires further study.
Page 7 of 19
8 References 1. 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. 2. Otto CM. Calcific aortic stenosis – time to look more closely at the valve. N Engl J Med 2008;359:1395-1398. 3. Arsenault BJ, Boekholdt SM, Dubé MP, Rhéaume É, Wareham NJ, Khaw KT, Sandhu MS, Tardif JC. Lipoprotein(a) levels, genotype, and incident aortic valve stenosis: a prospective Mendelian randomization study and replication in a case-control cohort. Circ Cardiovasc Genet 2014;7:304-310. 4. Iung B, Baron G, Butchart EG, Delahaye F, Gohlke-Bärwolf C, Levang OW, Tornos P, Vanoverschelde JL, Vermeer F, Boersma E, Ravaud P, Vahanian A. A prospective survey of patients with valvular heart disease in Europe: the Euro Heart Survey on valvular heart disease. Eur Heart J 2003;24:1231-1243. 5. Eveborn GW, Schirmer H, Heggelund G, Lunde P, Rasmussen K. The evolving epidemiology of valvular aortic stenosis. The Tromso study. Heart 2013;99:396-400. 6. Allison MA, Cheung P, Criqui MH, Langer RD, Wright CM. Mitral and aortic annular calcification are highly associated with systemic calcified atherosclerosis. Circulation 2006;113:861-866. 7. Movva R, Murthy K, Romero-Corral A, Seetha Rammohan HR, Fumo P, Pressman GS. Calcification of the mitral valve and annulus: systematic evaluation of effects on valve anatomy and function. J Am Soc Echocardiogr 2013;26:1135-1142.
Page 8 of 19
9 8. Baan J, Yong ZY, Koch KT, Henriques JP, Bouma BJ, Vis MM, Cocchieri R, Piek JJ, de Mol BAJM. Factors associated with cardiac conduction disorders and permanent pacemaker implantation after percutaneous aortic valve implantation with the CoreValve prosthesis. Am Heart J 2010;159:497-503. 9. Spaziano M, Sawaya F, Roy A, Neylon A, Piazza N, Hovasse T, Benamer H, Unterseeh T, Garot P, Lefevre T, Chevalier B. Aortomitral continuity calcification predicts new pacemaker insertion and new atrial fibrillation in patients undergoing TAVI. Poster session presented at EuroPCR 2016; 2016 May 17-20; Paris, France. 10. Pressman GS, Crudu V, Parameswaran-Chandrika A, Romero-Corral A, Purushottam B, Figueredo VM. Can total cardiac calcium predict the coronary calcium score? Int J Cardiol 2011;146:202-206. 11. Adler Y, Herz I, Vaturi M, Fusman R, Shohat-Zabarski R, Fink N, Porter A, Shapira Y, Assali A, Sagie A. Mitral annular calcium detected by transthoracic echocardiography is a marker for high prevalence and severity of coronary artery disease in patients undergoing coronary angiography. Am J Cardiol 1998;82:1183-1186. 12. Gaibazzi N, Porter TR, Agricola E, Cioffi G, Mazzone C, Lorenzoni V, Albertini L, Faden G, Pasha MC, Biabhav B, Regazzoli D, Di Lenarda A, Faggiano P. Prognostic value of echocardiographic calcium score in patients with a clinical indication for stress echocardiography. JACC Cardiovasc Imaging 2015;8:389-396. 13. Elmariah S, Budoff MJ, Delaney JAC, Hamirani Y, Eng J, Fuster V, Kronmal RA, Halperin JL, O’Brien KD. Risk factors associated with the incidence and progression of mitral annulus calcification: the multi-ethnic study of atherosclerosis. Am Heart J 2013;166:904-912.
Page 9 of 19
10 14. Owens DS, Katz R, Takasu J, Kronmal R, Budoff MJ, O'Brien KD. Incidence and progression of aortic valve calcium in the Multi-Ethnic Study of Atherosclerosis (MESA). Am J Cardiol 2010;105:701-708. 15. Iwataki M, Takeuchi M, Otani K, Kuwaki H, Yoshitani H, Abe H, Lang RM, Levine RA, Otsuji Y. Calcific extension towards the mitral valve causes non-rheumatic mitral stenosis in degenerative aortic stenosis: real-time 3D transoesophageal echocardiography study. Open Heart 2014;1:e000136. 16. Takami Y, Tajima K. Mitral annular calcification in patients undergoing aortic valve replacement for aortic valve stenosis. Heart Vessels 2016;31:183-188. 17. Osterberger LE, Goldstein S, Khaja F, Lakier JB. Functional mitral stenosis in patients with massive mitral annular calcification. Circulation 1981;64:472-476.
Page 10 of 19
11 FIGURES Figure 1. Echocardiographic calcium scoring algorithm.10 Criteria Posterior mitral annulus calcification Posterior mitral leaflet restriction Anterior mitral annular calcification Anterior mitral leaflet restriction Mitral valve calcification Subvalvular mitral apparatus calcification Aortic valve calcification Aortic root calcification Total
Value None = 0; 1/3 calcified = 1; 2/3 calcified = 2; 3/3 calcified = 3 No = 0; Yes = 1 No = 0; Yes = 1 No = 0; Yes = 1 No = 0; Mild = 1; More than mild = 2 No = 0; Yes = 1 None = 0; Nodules in <3 leaflets = 1; Nodules in 3 leaflets = 2; Leaflet restriction = 3 No = 0; Yes = 1 13
Page 11 of 19
12 Figure 2. Sample still images of echocardiograms demonstrating (A) high echocardiographic calcium score, (B) medium echocardiographic calcium score, and (C) low echocardiographic calcium score.
Page 12 of 19
13
Echocardiographic Calcium Score
Figure 3. Mean echocardiographic calcium scores of patients with severe aortic stenosis, stratified by severity of concomitant mitral stenosis. (p <0.0001 by analysis of variance) 14.0
10.8 (95% CI 8.3-13.2)
p <0.0001
12.0 10.0 8.0
7.0 (95% CI 6.6-7.4)
8.0 (95% CI 7.5-8.6)
9.6 (95% CI 9.0-10.2)
6.0 4.0 2.0 0.0 Absent (n=66)
Mild (n=48)
Moderate (n=29)
Severe (n=4)
Mitral Stenosis Severity
Figure 4. Distributions of mitral stenosis severity in patients with severe aortic stenosis, stratified by echocardiographic calcium score. (P <0.0001 by χ2 test for ordinal data)
Prevalence of Mitral Stenosis Severity
100%
80%
60% Severe Moderate 40%
Mild Absent
20% p<0.0001 0% Low
Medium Echocardiographic Calcium Score
High
Page 13 of 19
14
Figure 5. Linear relationships between echocardiographic calcium score and (A) mitral valve area, (B) mitral valve mean pressure gradient, and (C) mitral valve peak flow velocity in patients with severe aortic stenosis. 6
A
r = -0.31, p = 0.001
Mitral Valve Area (cm2)
5 4 3 2 1 0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score Mitral Valve Mean Pressure Gradient (mmHg)
18
B
r = 0.46, p <0.0001
16 14 12 10 8 6 4 2 0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score
Page 14 of 19
15
Mtiral Valve Peak Flow Velocity (m/s)
3.0
C
r = 0.55, p <0.0001
2.5 2.0 1.5 1.0 0.5 0.0 3
4
5
6
7
8
9
10
11
12
13
Echocardiographic Calcium Score
Figure 6. Prevalence of coronary artery disease among patients with severe aortic stenosis, stratified by echocardiographic calcium score. (p = 0.07 by χ2 test for ordinal data)
Prevalence of Coronary Artery Disease
60% p=0.07 50%
48%
49%
Medium Echocardiographic Calcium Score
High
40% 30% 30% 20% 10% 0%
Low
Page 15 of 19
16
Figure 7. Receiver Operating Characteristic curve for using echocardiographic calcium score as a continuous variable to predict presence of mitral stenosis of any severity. (Area under curve = 0.76)
Page 16 of 19
17
TABLES
Table 1. Demographics and characteristics of severe aortic stenosis patients, stratified by echocardiographic calcium score Variable
Echocardiographic Calcium Score Low Medium High (n = 44) (n = 58) (n = 45)
Age (years)
Total
P-Value*
(n = 147)
79 ± 9
82 ± 9
81 ± 9
81 ± 9
0.3
Body Mass Index (kg/m )
26.3 ± 5.7
26.3 ± 5.5
27.0 ± 6.3
26.5 ± 5.8
0.7
Male
27 (61%)
33 (57%)
14 (31%)
74 (50%)
0.004
2
Race
0.03
White
40 (91%)
52 (90%)
31 (69%)
123 (84%)
Black
2 (5%)
3 (5%)
9 (20%)
14 (10%)
Other
2 (5%)
3 (5%)
5 (11%)
10 (7%)
Hypertension
30 (68%)
47 (81%)
37 (82%)
114 (78%)
0.1
Hyperlipidemia
19 (43%)
33 (57%)
24 (53%)
76 (52%)
0.3
Diabetes Mellitus
9 (20%)
19 (33%)
14 (31%)
42 (29%)
0.3
Dialysis
3 (7%)
0 (0%)
3 (7%)
6 (4%)
1.0
13 (30%)
28 (48%)
22 (49%)
63 (43%)
0.07
Coronary Artery Disease Smoking History**
0.9
Current
3 (7%)
2 (4%)
3 (7%)
8 (6%)
Former
15 (35%)
22 (39%)
15 (33%)
52 (36%)
25 (58%)
33 (58%)
27 (60%)
85 (59%)
Never Chronic Kidney Disease Stage**
0.4
1 or 2
19 (50%)
17 (32%)
21 (49%)
57 (43%)
3
15 (39%)
29 (55%)
14 (33%)
58 (43%)
4
3 (8%)
6 (11%)
4 (9%)
13 (10%)
1 (3%)
1 (2%)
4 (9%)
6 (4%)
5 New York Heart Association Class**
0.07
1
23 (53%)
24 (44%)
9 (23%)
56 (41%)
2
7 (16%)
13 (24%)
15 (38%)
35 (26%)
3
9 (21%)
10 (19%)
12 (30%)
31 (23%)
4 4 (9%) 7 (13%) 4 (10%) 15 (11%) *P-values are based on comparisons across low, medium, and high echocardiographic calcium scores, using analysis of variance (ANOVA) or χ2 test for ordinal data **Two patients had unknown smoking history, 13 patients had unknown chronic kidney disease stage, and 10 patients had unknown New York Heart Association class. These patients were excluded from calculations of percentages
Page 17 of 19
18 Table 2. Mitral stenosis severity of patients with severe aortic stenosis, stratified by echocardiographic calcium score Mitral Stenosis
Echocardiographic Calcium Score Low Medium High (n = 44) (n = 58) (n = 45)
(n = 147)
Absent
31 (70%)
26 (45%)
9 (20%)
66 (45%)
Mild
12 (27%)
22 (38%)
14 (31%)
48 (33%)
1 (2%)
9 (16%)
19 (42%)
29 (20%)
Moderate
Total
Severe 0 (0%) 1 (2%) 3 (7%) 4 (3%) P-value <0.001 based on comparisons of counts across low, medium, and high echocardiographic calcium scores using Cochran-Mantel-Haenszel chi square test for ordinal data
Table 3. Aortic and mitral valve characteristics of severe aortic stenosis patients, stratified by echocardiographic calcium score Variable
Echocardiographic Calcium Score Low Medium High 0.7 ± 0.2 0.7 ± 0.2 0.6 ± 0.2
P-value*
Aortic Valve Area (cm2) 0.04 Aortic Valve Mean Pressure Gradient (mmHg) 43 ± 18 41 ± 17 43 ± 16 0.8 Aortic Valve Peak Velocity (m/s) 4.2 ± 0.8 4.2 ± 0.8 4.2 ± 0.7 0.8 2 Mitral Valve Area (cm ) 2.1 ± 0.6 1.9 ± 0.8 1.6 ± 0.7 0.003 Mitral Valve Mean Pressure Gradient (mmHg) 2.3 ± 1.2 3.4 ± 2.5 5.0 ± 3.3 <.0001 Mitral Valve Peak Velocity (m/s) 1.2 ± 0.3 1.4 ± 0.3 1.7 ± 0.5 <.0001 *P-values are based on comparisons across low, medium, and high echocardiographic calcium scores, using analysis of variance (ANOVA)
Table 4. Multivariable logistic regression models analyzing prevalence of coronary artery disease in severe aortic stenosis patients with medium vs. low and high vs. low echocardiographic calcium scores Unadjusted Effect
Odds Ratio
High Score vs. Low Score Med Score vs. Low Score
2.28 2.23
95% CI 0.95 0.97
5.46 5.09
Adjusted for demographics and coronary artery disease risk factors* Effect
Odds Ratio
High Score vs. Low Score
2.70
95% CI 1.02
7.17
Med Score vs. Low Score 2.18 0.91 5.24 *Demographic variables that were adjusted included age, sex, race; coronary artery disease risk factors that were adjusted included hypertension, hyperlipidemia, smoking history, and diabetes mellitus
Page 18 of 19
19 Table 5. Sensitivity, specificity, positive predictive value, and negative predictive value of using echocardiographic calcium score ≥8 to predict the presence of coronary artery disease and mitral stenosis of any severity in severe aortic stenosis patients Coronary Artery Disease
Mitral Stenosis
Sensitivity
52%
68%
Specificity
55%
76%
Positive Predictive Value
46%
77%
Negative Predictive Value
61%
66%
Page 19 of 19