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Author's personal copy Letters to the Editor
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Cardiac calcification at transthoracic echocardiography predicts stress echo results: A multicentre study☆ Nicola Gaibazzi a,⁎, Rosa Sicari b, Eustachio Agricola c, Giovanni Cioffi d, Carmine Mazzone e, Lisa Albertini a, Giacomo Faden f, Sabrina Molinaro b, Damiano Regazzoli c, Andrea Di Lenarda e, Pompilio Faggiano f a
Cardiology Department, Parma University Hospital, Parma, Italy CNR Institute of Clinical Physiology, Pisa, Italy c Division of noninvasive Cardiology, IRCCS Ospedale San Raffaele, Milano d Echocardiography Laboratory, Villa Bianca Hospital, Trento, Italy e Cardiovascular Centre, ASS 1, Trieste, Italy f Cardiology, University of Brescia, Brescia, Italy b
a r t i c l e
i n f o
Article history: Received 9 March 2014 Accepted 1 April 2014 Available online 12 April 2014 Keywords: Echocardiography Cardiac calcium score Stress-echocardiography Coronary artery disease
Several studies established that either aortic valve sclerosis/ calcification (AVC) or mitral annular calcification (MAC), as detected by echocardiography, independently predicts cardiovascular morbidity and mortality [1–4] and is additionally associated with reversible perfusion defects [5–8]. Echocardiographic total heart calcification score index (CSI) has been correlated to CCS, Framingham risk score, Duke score, and coronary artery disease (CAD) extent [9–11], but its relationship with stress-echocardiography (SE) results has never been established. The aim of the present retrospective analysis was to evaluate the value of a simple semiquantitative CSI to predict SE results, in a large, multicentre cohort of subjects with suspected CAD, who underwent SE for clinical purposes. 1117 patients were evaluated at six Italian Cardiology Institutions during 2012 for enrollment in a study assessing the value of CSI and its relation to SE in the setting of suspected CAD. Patients were prospectively enrolled in the databank but retrospectively analyzed and underwent SE with wall motion analysis and CSI assessment at transthoracic rest echo. Patients fulfilled the following inclusion criteria: 1) chest pain or anginal equivalent symptoms; 2) no history of CAD; 3) no significant valvular disease; and 4) adequate acoustic window. Informed consent to research participation and collection of follow-up data was obtained at the time of SE. Patient's age, gender, and CAD risk factors were recorded at the time of SE. Exercise SE was conducted using a semi-supine bicycle ergometer with 25 W incremental loading, dipyridamole (0.84 mg over 10 min plus atropine or 0.84 mg over 6 min) and dobutamine (up to 40 mg/kg/min plus atropine) SE was performed and interpreted according to the established protocols. Beta-blockers, calcium-antagonists and nitrates were withheld at least 24 h before the test [12]. Ischemia (abnormal test) was defined as stress-induced new and/or worsening of preexisting wall motion abnormality. Patients underwent standard rest transthoracic echocardiography as part of their examination before SE. Both the images ☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Parma University Hospital, 43123 Parma, Italy. Tel.: +39 3281056134; fax: + 39 0521 702189. E-mail address:
[email protected] (N. Gaibazzi).
acquired before starting SE and the rest clips of the SE protocol (parasternal long-axis and short-axis, apical 4 chamber and 2chamber) were selected for the assessment of semiquantitative CSI. Criteria for judging AVC, MAC, ascending aorta and papillary muscle calcium were similar to grading systems used in the previous studies [9–11] and are detailed in Table 1. A final score was derived by consensus of 2 readers in each study site, as the sum of all cardiac calcific deposits and was in the range of 0 (no calcium visible) to 8 (extensive cardiac and ascending aorta calcific deposits). The null hypothesis was that no association exists between CSI and myocardial ischemia determined by wall motion abnormalities at peak stress. We initially tested χ2 analysis of the association between age and gender stratified by CSI and SE results. Multivariable logistic regression analysis was applied to evaluate the association between abnormal SE results after adjusting for age, sex
Table 1 Grading system of cardiac and ascending aortic calcium. Grade
Papillary muscle calcium
Mitral annular calcium
Aortic valve sclerosis
Ascending aorta calcium
0 1 2 3
Absent Present
Absent Mild b 5 mm Moderate 5–10 mm Severe N 10 mm
Absent Mild Moderate Severe
Absent Present
Aortic valve sclerosis graded as follows: Absent = Normal cusp thickness (b2 mm), and normal reflectivity; Mild = Cusp thickness N 2 mm and/or increased reflectivity; Moderate = Thickness N 4 mm and/or diffuse or focal cusp hyperreflectivity; Severe = Thickness N 6 mm and/or marked echoreflectivity. Final score was graded from 0 to 8.
Table 2 Baseline characteristics of the study population (n = 1117) and echocardiography results. Mean age ± SD
64 ± 11
Age ≥ 70 y/o, n (%) Male gender, n (%) Family history of CAD, n (%) Current cigarette smoke, n (%) Hypercholesterolemia, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Obesity, n (%)
385 (34) 667 (60) 268 (24) 220 (20) 570 (51) 241 (22) 715 (64) 145 (13)
Rest-echocardiography Reduced rest LVEF (b 50%), n (%) Cardiac Ca score index (CSI), mean ± SD Cardiac Ca score index (CSI) N 0 Ca score—MVC only N 0 Ca score—AVC only N 0
118 (10) 0.87 ± 1.24 487 (43) 254 (23) 311 (28)
Stress-echocardiography result Inducible WM abnormalities, n (%)
158 (14)
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Table 3 Baseline characteristics of the study population divided according to the presence of reversible wall motion abnormalities at stress-echocardiography (myocardial ischemia).
Mean age ± SD Male gender, n (%) Family history of CAD, n (%) Current cigarette smoke, n (%) Hypercholesterolemia, n (%) Diabetes mellitus, n (%) Hypertension, n (%) Obesity, n (%) Rest-echocardiography Reduced rest LVEF (b 50%), n (%) Cardiac Ca score index (CSI) mean ± SD Cardiac Ca score index (CSI) N 0 Ca score—MVC only N 0 Ca score—AVC only N 0
Normal SE (n = 959)
Ischemia at SE (n = 158)
p value
63.6 ± 11.3 560 (58) 224 (23) 185 (19) 484 (50) 200 (21) 611 (64) 127 (13)
67.6 ± 8.6 107 (67) 44 (28) 35 (22) 86 (54) 41 (26) 104 (66) 18 (11)
b 0.0001 0.03 ns ns ns ns ns ns
87 (9) 0.77 ± 1.16
31 (20) 1.44 ± 1.54
b 0.0001 b 0.0001
384 (40) 201 (21) 235 (25)
103 (65) 53 (34) 76 (48)
b 0.0001 b 0.001 b 0.0001
and reduced left ventricle ejection fraction (LVEF). For the purpose of univariable and multivariable analyses, CSI was tested as a dichotomous variable, to provide easier clinical application, using the complete absence (CSI = 0) or presence (CSI N 0) of calcium in at least one site. Variables entered were age, gender, diabetes mellitus, hypertension, hypercholesterolemia, family history, smoking, mitral annular calcium and CSI. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. A p value b 0.05 was considered statistically significant. 30 patients were analyzed again 1 month later in the coordinating center, by consensus of the same 2 readers, to assess CSI intracenter agreement, according to weighted Cohen's κ test and intraclass correlation coefficient; those 30
exams were also shared with the remaining 6 participating centers for intercenter agreement, according to intraclass correlation coefficient. Statistical analyses were performed using standard software (STATA release 10 and R 2.11, College Station, TX and Statsdirect ltd, Cheshire, UK). Baseline characteristics of the study group (n = 1117) are shown in Table 2; Table 3 shows the baseline characteristics in the 2 subgroups based on SE result. Bivariate evaluation of individual risk factors showed that patients with ischemia were more likely to be older (p b 0.001), and male (p b 0.05), while other known risk factors for CAD had only a non-significant trend towards higher prevalence in patients with ischemic SE. Rest echocardiographic variables such as reduced LVEF, CSI (absolute value or dichotomized as CSI N 0), MVC N 0 or AVC N 0, were significantly higher or more prevalent in patients showing ischemia at SE. The frequency of abnormal SE among patients with CSI N 0 was significantly higher than in patients with a CSI = 0 (103/487, 21.1% versus 55/630, 8.7%, p b 0.0001) and the frequency of an ischemic SE result increased with increasing CSI (Fig. 1); for example, the odds of an individual with a CSI of N4 having ischemia at SE was 47.3%. Table 4 shows that the presence of age, male gender, LVEF b50% and either the full CSI N 0 or the AVC N 0 or the MVC N 0 were all significantly associated with the presence of ischemic response at SE at univariate analysis, and the same variables (AVC and MVC were not further tested in multivariable analysis because highly correlated to CSI) maintained their value at multivariable logistic regression analysis. CSI N 0 was the strongest independent predictor of ischemia at SE, conferring more than twice (OR 2.15, 95%CI 1.48–3.13) the probability of an ischemic result after correcting for age, gender and LVEF, compared with patients with no calcium on left heart structures.
Fig. 1. Calcium score distribution (%) based on the occurrence of reversible ischemia or not at following stress-echocardiography. CSI = calcium score index.
Table 4 Univariate and multivariate logistic regression analyses for the endpoint of ischemic response at stress-echo. Univariate
Age Gender (male) Family history of CAD Current cigarette smoke Hypercholesterolemia Diabetes mellitus Hypertension Obesity LVEF reduction (b 50%) Cardiac Ca score index (CSI) N 0 Ca score—MVC only N 0 Ca score—AVC only N 0
Multivariate
OR (95%CI)
p value
OR (95%CI)
p value
1.04 (1.02–1.06) 1.49 (1.04–2.14) 1.27 (0.87–1.85) 1.17 (.78–1.78) 1.13 (0.81–1.59) 1.32 (0.89–1.95) 1.16 (0.81–1.66) 0.84 (0.50–1.42) 2.12 (1.33–3.40) 2.81 (1.98–3.99) 1.90 (1.32–2.74) 2.66 (1.89–3.77)
p b 0.0001 p = 0.027 p = 0.23 p = 0.44 p = 0.48 p = 0.17 p = 0.41 p = 0.51 p b 0.001 p b 0.0001 p b 0.001 p b 0.0001
1.03 (1.01–1.05) 1.79 (1.23–2.62) – – – – – – 1.80 (1.10–2.95) 2.15 (1.48–3.13) – –
p = 0.001 p b 0.01 – – – – – – p b 0.05 p b 0.0001 – –
Ca score—MVC only and Ca score—AVC only were not tested in multivariate analysis because highly correlated with total cardiac Ca score (CSI) but relatively less predictive at univariate analysis. AVC = aortic valve calcification; MVC = mitral valve calcification; OR = odds ratio, CI = confidence interval.
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Fig. 2. Bar graph depicts the incremental predictive value of variables to predict reversible wall motion abnormalities (ischemic response) at SE. Model χ2 values are presented for a series of logistic regression models. The only significantly predictive clinical risk factors were age and gender; the addition of CSI on top of clinical variables and reduced global LV function (LVEF b 50%) resulted in significantly higher global chi square of the model. * indicates p b 0.01 compared with the previous modeling step. LVEF = left ventricular ejection fraction.
Fig. 2 shows the significant incremental predictive value of the logistic model by adding the variable CSI N 0 (step 3, global χ2 =53.25, p b 0.001) on top of clinical variables (step 1, global χ2 =27.97) and reduced global LV function-LVEF b 50% (step 2, global χ2 = 36.63, p b 0.01 compared to step 1) to predict reversible wall motion abnormalities (ischemic response) at SE. Reassessment of CSI on 30 random exams resulted in a weighted Cohen's κ = 0.765 and intra-class correlation coefficient = 0.91 for intracenter variability, and an intra-class correlation coefficient = 0.80 for intercenter variability. Echographic calcium score efficiently risk-stratified patients who were clinically considered candidates for SE, and repeatability of this score among the involved centers was good (intraclass correlation coefficient = 0.8) and sufficiently robust to be applied in clinical practice. References [1] Otto CM, Lind BK, Kitzman DW, Gersh BJ, Siscovick DS. Association of aorticvalve sclerosis with cardiovascular mortality and morbidity in the elderly. N Engl J Med 1999;341:142–7. [2] Fox CS, Vasan RS, Parise H, et al. Framingham Heart Study. Mitral annular calcification predicts cardiovascular morbidity and mortality: the Framingham Heart Study. Circulation 2003;107:1492–6. [3] Kohsaka S, Jin Z, Rundek T, et al. Impact of mitral annular calcification on cardiovascular events in a multiethnic community: the Northern Manhattan Study. JACC Cardiovasc Imaging 2008;1:617–23.
http://dx.doi.org/10.1016/j.ijcard.2014.04.007 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
[4] Barash E, Gottdiener JS, Marino Larsen EK, Chaves PH, Newman AB. Cardiovascular morbidity and mortality in community-dwelling elderly individuals with calcification of the fibrous skeleton of the base of the heart and aortosclerosis (The Cardiovascular Health Study). Am J Cardiol 2006;97:1281–6. [5] Pradelli D, Faden G, Mureddu G, et al. Impact of aortic or mitral valve sclerosis and calcification on cardiovascular events and mortality: a meta-analysis. Int J Cardiol 2013 Dec 10;170(2):e51–5. [6] Holtz JE, Upadhyaya DS, Cohen BE, Na B, Schiller NB, Whooley MA. Mitral annular calcium, inducible myocardial ischemia, and cardiovascular events in outpatients with coronary heart disease (from the Heart and Soul Study). Am J Cardiol 2012;109:1092–6. [7] Choi MJ, Kim JK, Kim SG, et al. Association between cardiac valvular calcification and myocardial ischemia in asymptomatic high-risk patients with end-stage renal disease. Atherosclerosis 2013;229:369–73. [8] Yamazato R, Yamamoto H, Tadehara F, et al. Association between aortic valve calcification and myocardial ischemia, especially in asymptomatic patients. J Nucl Med 2012;53:1216–21. [9] 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;146:202–6. [10] Corciu AI, Siciliano V, Poggianti E, Petersen C, Venneri L, Picano E. Cardiac calcification by transthoracic echocardiography in patients with known or suspected coronary artery disease. Int J Cardiol 2010;142:288–95. [11] Nucifora G, Schuijf JD, van Werkhoven JM, et al. Usefulness of echocardiographic assessment of cardiac and ascending aorta calcific deposits to predict coronary artery calcium and presence and severity of obstructive coronary artery disease. Am J Cardiol 2009;103:1045–50. [12] Sicari R, Nihoyannopoulos P, Evangelista A, et al. Stress echocardiography expert consensus statement from the European Association of Echocardiography. Eur J Echocardiogr 2008;9:415–37.
