- Email: [email protected]
An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease
G Model
JJCC-1119; No. of Pages 7 Journal of Cardiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease Satoru Sakuragi (MD, PhD, FJCC)a,*, Keishi Ichikawa (MD)a, Keiji Yamada (MD)a, Masafumi Tanimoto (MD)a, Takashi Miki (MD)a, Hiroaki Otsuka (MD)a, Kazuhiko Yamamoto (MD)a, Kenji Kawamoto (MD)a, Yusuke Katayama (MD, PhD)a, Machiko Tanakaya (MD, PhD)a, Hiroshi Ito (MD, PhD, FJCC)b a b
Department of Cardiovascular Medicine, Iwakuni Clinical Center, Iwakuni, Japan Department of Cardiovascular Medicine, Okayama University Graduate School of Medical and Dentistry, Okayama, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 April 2015 Received in revised form 21 June 2015 Accepted 26 June 2015 Available online xxx
Background: The presence of coronary artery calcification (CAC) and its severity predict future cardiovascular events and is used for risk stratification. However, the association of CAC with heart failure (HF) in patients without a history of coronary artery disease (CAD) remains unclear. This study aimed to determine the correlations of CAC with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and HF events in patients without a history of CAD or HF. Methods: From June 2010 to June 2013, a total of 487 patients without a history of CAD and HF were enrolled. All of the patients underwent plane multi-detector computed tomography. They were divided into four categories according to CAC scores: 10, 11–100, 101–400, and 401. Results: The proportion of patients with high NT-proBNP levels increased with CAC categories (p < 0.0001). The CAC score was associated with NT-proBNP levels 400 pg/ml, with an odds ratio of 2.901 (95% confidence interval: 1.368–6.151, p = 0.0055) for CAC scores 401 compared with CAC scores of 0–10 after adjustment for confounding factors. During the follow-up period of 497 315 days, nine patients were admitted for HF. Kaplan–Meier analysis showed that patients with CAC scores 401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0–10, 11–100, 101–400, and 401, respectively (p < 0.0001). Increasing CAC scores were associated with an increase in incidence of admission for HF, with a hazard ratio of 10.371 for CAC scores 401 (95% CI: 1.062–101.309, p = 0.0443) compared with CAC scores of 0–10 after adjustment for risk factors. Conclusion: Severe CAC is an independent determinant of high NT-proBNP levels and a predictor of admission for HF in a population without a history of CAD or HF. ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Coronary artery calcification N-terminal pro-B-type natriuretic peptide Heart failure
Introduction Heart failure (HF) is associated with reduced life expectancy and ever increasing costs. Therefore, HF is one of the most important health concerns in the industrialized world [1]. Although the survival rate of patients with HF has improved over the past few decades, its prevalence and incidence have been steadily
* Corresponding author at: Department of Cardiovascular Medicine, Iwakuni Clinical Center, 1-1-1 Atago-machi, Iwakuni 740-8510, Japan. Tel.: +81 827 34 1000; fax: +81 87 35 5600. E-mail address: [email protected] (S. Sakuragi).
increasing. Early prediction of patients at high risk for HF is important for preventing the progression of HF. Traditional risk assessment for coronary artery disease (CAD) using coronary risk factors has been refined with the selective use of coronary artery calcium (CAC). This is possible because CAC is pathognomonic of atherosclerosis [2], and a histological study showed its close correlation with the atherosclerotic plaque burden [3,4]. The severity of CAC can be easily quantified by electron beam computed tomography (CT) or multi-detector CT (MDCT). CAC is currently a useful marker of subclinical CAD and an independent predictor of cardiovascular events [5]. CAD is a risk factor for HF, but information on the association of CAC scores with HF is still lacking. In a population-based study, Kalsch et al. demonstrated
http://dx.doi.org/10.1016/j.jjcc.2015.06.014 0914-5087/ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 2
S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
that CAC was higher in patients with HF than in those without HF [6]. Leening et al. showed that the extent of CAC has a clear association with the risk for development of HF in elderly patients [7]. B-type natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP), both of which are increased in relation to cardiac stretch, are associated with the severity and prognosis of left ventricular (LV) dysfunction and HF [8]. NT-proBNP has been shown to independently predict all-cause mortality and cardiovascular events. NT-proBNP has emerged as a useful biomarker for guiding diagnosis, prognosis, and management in patients with cardiovascular disease and HF [9]. Recently, the Japanese Heart Failure Society statement indicated that close examinations by specialized physicians are needed in patients with NT-proBNP levels 400 pg/ ml (Japanese Heart Failure Society statement 2013) [10]. In this study, we investigated the correlation of CAC with NT-proBNP levels in patients without a history of CAD or HF. Additionally, we followed HF events after measurement of CAC to establish the effect of CAC on the development of HF events. Methods Selection of patients From June 2010 to June 2013, a total of 692 patients who visited our hospital and were suspected of having CAD were examined. Among them, we excluded 103 patients who were <40 years old and those with congestive heart failure, acute coronary syndrome, a history of HF, or a history of CAD defined as prior myocardial infarction (MI) or coronary intervention (percutaneous coronary intervention and coronary artery bypass grafting). The other 589 patients underwent MDCT just for measurement of CAC. Of these, 254 patients with positive exercise test results, or symptoms that were likely to be related to myocardial ischemia, or CAC scores 401 were recommended for further examinations, including stress single-photon emission computed tomography (SPECT) or an invasive coronary angiogram, because of suspected CAD. Ten patients who rejected further examinations were excluded. A total of 244 patients underwent stress SPECT or coronary angiogram, and 80 patients with findings of myocardial ischemia in stress SPECT or who had significant coronary artery stenosis in a coronary angiogram were excluded from this study. Another 164 patients who had no significant coronary artery stenosis in a coronary angiogram (n = 98), or had no findings of myocardial ischemia in stress SPECT (n = 66) were enrolled in the analysis. Patients with an estimated glomerular filtration rate (eGFR) of <15 ml/min/ 1.73 m2, severe valvular heart disease, an advanced stage of malignancy, or dysthyroidism (n = 12) were also excluded. Finally, a total of 487 patients were included in the analysis.
in 3.0-mm slices throughout coronary artery regions using a prospectively electrocardiogram-triggered scan acquisition at 75% of the RR intervals. CAC scores were calculated using an automated computer system (Ziostation System 1000, Ziosoft, Tokyo, Japan) by the Agatston method [11]. Analysis of echocardiographic data Standard imaging was performed in the left lateral decubitus position using a commercially available system. Left atrial diameter, end-diastolic interventricular septal and posterior wall thicknesses, and end-diastolic and end-systolic LV internal dimensions were determined according to the recommendations of the American Society of Echocardiography [12]. LV mass was calculated from LV linear dimensions and was expressed as a ratio to body surface area (LVMI). LV hypertrophy was defined by LVMI thresholds of 115 g/m2 for men and 95 g/m2 for women [12]. LV end-diastolic and end-systolic volumes were measured from an apical four-chamber view and were indexed to body surface area. The LV ejection fraction (LVEF) was calculated according to the modified Simpson’s rule. Mitral inflow was assessed by pulsedwave Doppler echocardiography from the apical four-chamber view. On the basis of the mitral inflow profile, E- and A-wave velocities, deceleration time of the E-wave, and the E/A ratio were determined. Tissue Doppler imaging of the mitral annulus was performed from the apical four-chamber view. A sample volume was placed sequentially at the septal mitral annulus, and early diastolic velocity (e0 ) was measured. The ratio of mitral velocity to early diastolic velocity of the medial mitral annulus (E/e0 ), which is a marker of LV diastolic filling pressure, was calculated. Measurement of brachial-ankle pulse wave velocity Brachial-ankle pulse wave velocity (baPWV) was measured using an automatic waveform analyzer (BP-203RPEII; Omron Colin, Tokyo, Japan) just before an echocardiogram. Subjects were examined in the supine position after 5 min of bed rest. Follow-up study The incidence of HF events, defined as admission due to HF, was followed after measurement of CAC scores. HF was defined by modified Framingham criteria as follows: satisfaction of two major criteria (paroxysmal nocturnal dyspnea, orthopnea, rales, jugular venous distension, third heart sound, and radiological signs of pulmonary congestion and/or cardiomegaly) or of one major criterion together with two minor criteria (effort dyspnea, peripheral edema, hepatomegaly, and pleural effusion). Diagnosis of HF was made by a cardiologist or an internist.
Study protocol
Statistical analysis
All of the patients underwent blood sampling, including measurement of NT-proBNP levels, measurement of CAC scores, and an echocardiographic examination. NT-proBNP levels were measured using the commercially available Elecsys proBNP sandwich immunoassay using an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). The study protocol was approved by the appropriate institutional review board of the hospital and all of the participants provided written informed consent.
Patients were divided into four categories based on CAC scores: 10, 11–100, 101–400, and 401 [5]. Comparison of continuous variables among groups was performed by one-way analysis of variance or the Kruskal–Wallis test, as appropriate. Categorical data were compared by chi-square analysis. Patients were also classified into four groups according to NT-proBNP levels as described in the Japanese Heart Failure Society statement 2013: <125 pg/ml, 125 and <400 pg/ml, 400 and <900 pg/ml, and 900 pg/ml [10]. Univariate and multivariate logistic regression analyses were performed to determine which of the following factors were associated with NT-proBNP levels 400 pg/ml: age, sex, and the prevalence of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease (CKD), which was defined as an eGFR <60 ml/min/1.73 m2, LV systolic dysfunction, which
Measurement of the CAC score CAC in epicardial coronary arteries was assessed. CT scanning of the coronary artery was performed using a 64-slice multidetector system (Aquilion 64, Toshiba, Tokyo, Japan). Images were acquired
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
was defined as LVEF <50%, LV hypertrophy, LV diastolic dysfunction, which was defined as e0 < 8 cm/s or E/e0 > 15, and body mass index >25 kg/m2 [13]. Cumulative survival estimates were calculated by the Kaplan–Meier method and were compared between CAC categories by the log-rank test. We used a Cox proportional hazards model to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of HF hospitalization for different CAC categories with adjustment for covariates (age, sex, and prevalence of hypertension, diabetes mellitus, dyslipidemia, and CKD). All statistical analyses were performed using the SPSS statistical software package (Version 21, IBM Corp., Armonk, NY, USA). For all tests, a p-value <0.05 was considered significant. Results Study population Characteristics of the study population were stratified for CAC score categories (Table 1). Higher CAC scores were associated with more advanced age and a higher prevalence of hypertension and diabetes mellitus. Higher CAC scores were also associated with a more reduced eGFR, higher systolic blood pressure, and higher baPWV. Cardiac parameters are shown in Table 2. There was a graded increase in NT-proBNP levels with CAC category (Table 2). LVMI was increased with CAC category. LVEF was comparable between CAC categories. In tissue Doppler imaging, e0 velocity decreased and the E/e0 ratio increased with CAC category (Table 2). Relationship between CAC and NT-proBNP levels The distribution of NT-proBNP class according to CAC categories is shown in Fig. 1. The proportion of patients with high NT-proBNP levels gradually increased with increasing CAC score. The CAC score was associated with high NT-proBNP levels 400 pg/ml, with an odds ratio of 2.747 (95% CI: 1.289–5.855, p = 0.0089) for CAC
3
scores 401 compared with CAC scores of 0–10 after adjustment for confounding factors (Table 3). Clinical outcomes During a mean follow-up period of 497 315 days (range, 30– 1057 days), nine patients were admitted for HF, although there were no coronary events, including MI, and no requirement for coronary artery revascularization, such as percutaneous coronary intervention and coronary artery bypass grafting, during the follow-up period. Clinical characteristics at baseline of these nine patients are shown in Table 4. Many patients had hypertension and CKD. NT-proBNP was higher than 400 pg/ml in all patients. Two patients had a LVEF <50%. One patient died after admission for HF. All of the patients who were admitted for HF underwent coronary angiography after admission, and there was no CAD in any of these patients. Kaplan–Meier analysis showed that patients with CAC scores 401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0–10, 11–100, 101–400, and 401, respectively (p < 0.0001) (Fig. 2). Increasing CAC scores were associated with an increase in incidence of admission for HF, with an HR of 10.371 for CAC scores 401 (95% CI: 1.062–101.309, p = 0.0443) compared with CAC scores of 0–10 after adjustment for risk factors (Table 5). Discussion This study showed several new findings regarding the relationships between CAC and increasing NT-proBNP levels, as well as with development of HF in patients without a history of CAD or HF. First, an increase in CAC was associated with a decrease in e0 velocity and increase in the E/e0 ratio, which suggested LV diastolic dysfunction. Second, CAC was an independent determinant of high NT-proBNP levels. Third, patients with a high CAC score were more likely to have HF events than those with a low CAC score. These
Table 1 Patients characteristics stratified by CAC category. CAC category
All
n CAC score Age, years Male gender (%) Hypertension (%) Diabetes (%) Dyslipidemia (%) CKD (%) Body mass index (kg/m2) Beta blocker (%) Ca channel blocker (%) ACEI or ARB (%) Statin (%) Creatinine (mg/dl) eGFR (ml/min/1.73 m2) Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Blood sugar (mg/dl) HbA1c (%) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (mmHg) baPWV (cm/s)
487 9 (127) 69 11 240 (49) 340 (70) 79 (16) 145 (30) 137 (28) 24 4 57 (12) 175 (36) 155 (32) 106 (22) 0.80 0.24 69 19 196 34 137 82 61 18 117 31 115 34 5.9 0.9 140 20 80 12 70 13 1825 454
p-value
0–10
11–100
101–400
401
249 0 (0, 0) 64 11 102 (41) 151 (60) 27 (11) 61 (24) 38 (15) 24 4 22 (9) 71 (29) 51 (20) 46 (19) 0.74 0.20 73 19 202 34 135 78 63 17 122 32 113 32 5.8 0.9 137 21 80 13 70 13 1672 411
97 52 (31, 77) 72 9 53 (55) 70 (72) 17 (18) 33 (34) 39 (40) 24 3 15 (15) 39 (40) 34 (35) 23 (24) 0.84 0.23 64 17 190 37 150 86 58 18 114 32 114 30 5.9 0.8 141 18 80 12 69 14 1908 361
82 171 (128, 253) 73 9 51 (62) 67 (82) 21 (26) 30 (37) 35 (43) 24 4 14 (17) 34 (41) 38 (46) 18 (22) 0.88 0.34 64 19 190 30 140 89 58 18 114 28 124 46 6.1 1.0 140 19 79 11 70 13 1971 450
59 799 (581, 1311) 74 8 34 (58) 52 (88) 14 (24) 21 (36) 25 (42) 23 4 6 (10) 31 (53) 32 (54) 19 (32) 0.85 0.21 63 15 191 33 120 77 67 19 108 28 116 31 6.0 0.8 149 21 82 12 69 12 2138 509
<0.0001 <0.0001 0.0017 <0.0001 0.0043 0.0743 <0.0001 0.9557 0.1254 0.0019 <0.0001 0.1392 <0.0001 <0.0001 0.0037 0.1695 0.0017 0.0073 0.096 0.1715 0.0017 0.6505 0.8671 <0.0001
All data are presented as mean standard deviation (SD) or median with inter-quartile range (IQR) or as number (percentage) for dichotomous variables. CAC, coronary artery calcification; CKD, chronic kidney disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Hb, hemoglobin; BP, blood pressure; baPWV, brachial-ankle pulse wave velocity.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
4 Table 2 Cardiac parameters stratified by CAC category.
CAC category
All
NT-proBNP (pg/ml) LAD (mm) LVEDVI (ml/m2) LVESVI (ml/m2) LVEF (%) LVEF < 50% LVMI (g/m2) LVH (%) E/A ratio DcT (ms) e0 (cm/s) E/e0
90 (33, 213) 37 7 59 17 20 10 67 10 23 (5) 108 33 233 (48) 0.86 0.34 217 59 7.3 2.6 9.9 3.6
p-value
0–10
11–100
101–400
401
61 (21, 138) 35 6 58 14 19 8 67 9 6 (3) 102 30 105 (42) 0.93 0.37 213 57 7.8 2.8 9.0 2.7
102 (49, 233) 37 7 60 18 19 13 67 12 7 (7) 110 36 50 (52) 0.76 0.22 227 56 6.8 2.0 10.0 3.3
135 (40, 483) 38 7 61 21 21 11 66 10 6 (8) 116 36 43 (52) 0.80 0.31 225 65 6.7 2.0 10.7 3.9
149 (75, 429) 39 8 63 20 20 12 68 12 4 (7) 119 35 35 (59) 0.82 0.31 213 57 6.9 2.7 12.1 5.1
<0.0001 0.0097 0.1276 0.6346 0.7478 0.1112 0.0003 0.0739 <0.0001 0.1577 0.0003 <0.0001
CAC, coronary artery calcification; NT-proBNP, N-terminal pro-B-type natriuretic peptide; LAD, left atrial dimension; LVEDVI, Left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy; DcT, the deceleration time of E-wave; e0 , early diastolic velocity of the medial mitral annulus.
findings suggest that quantification of CAC with MDCT has the potential for identifying not only patients with CAD, but also individuals at high risk for HF. There are several possible explanations for the relationships of CAC with NT-proBNP levels and development of HF. First, common risk factors, including hypertension and kidney disease, are involved in high CAC and an increase in NT-proBNP levels [14]. Hypertension is one of the strongest predictors of CAC, as well as HF. Kalsch et al. showed that subjects with chronic HF had either an elevated CAC burden or hypertension [6]. They also found that subjects with chronic HF had more evidence of electrocardiogram-based LV hypertrophy, ischemia, or MI, and also had reduced exercise capacity [6]. Most of the risk factors for CAC and LV diastolic dysfunction are common, including advanced age, hypertension, obesity, diabetes [15], and renal insufficiency [16]. These risk factors may have been related to the association of a higher CAC score with increased NT-proBNP levels and development of HF in our population.
Second, CAC measurements provide an estimation of coronary atherosclerotic plaque burden [3] and appear to be complementary to myocardial perfusion, which provides information on inducible ischemia. Using cardiac magnetic resonance imaging, Colletti et al. found a correlation between CAC and abnormality of regional wall motion [17]. Half of their patients with abnormality of wall motion had clinical or electrocardiographic evidence of CAD, indicating that patients with advanced CAC may have subtle structural dysfunction caused by limited coronary flow. However, Chang et al. demonstrated that severe CAC identified a subgroup of subjects at high longterm risk for cardiac events, even in the absence of abnormal stress SPECT results [5]. This finding suggests that factors other than myocardial ischemia may be involved in higher mortality in patients with high CAC. In our study, we enrolled patients without a history of CAD or clinical evidence of CAD. None of the patients had ischemic or HF events that occurred with preceding coronary events during the follow-up period. This finding indicates that coronary calcification may affect cardiac performance, especially LV diastolic function.
Fig. 1. Distribution of quartiles of NT-proBNP according to CAC categories. NT-proBNP, N-terminal pro-B-type natriuretic peptide; CAC, coronary artery calcification.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
5
Table 3 Odds ratios for N-terminal pro-B-type natriuretic peptide 400 pg/ml. Multivariate
Univariate Odds ratio Age Male gender Hypertension Diabetes mellitus Dyslipidemia CKD BMI > 25 kg/m2 LVEF < 50% LVH e0 < 8 cm/s E/e0 > 15 CAC score CAC score 0–10 CAC score 11–100 CAC score 101–400 CAC score 401
95% CI
p
Odds ratio
1.087 1.467 2.559 1.817 0.835 5.217 0.535 3.087 1.32 0.878 1.144
1.056–1.119 0.892–2.410 1.335–4.905 1.002–3.297 0.480–1.452 3.111–8.749 0.297–0.964 1.259–7.570 0.801–2.174 0.521–1.480 1.486–6.632
<0.001 0.1308 0.0047 0.0494 0.5227 <0.0001 0.0372 0.0138 0.2753 0.6255 0.0027
Reference 2.9 5.078 5.986
1.413–5.950 2.380–10.819 3.030–11.826
0.0037 <0.0001 <0.0001
95% CI
p
1.054
1.019–1.089
0.0019
1.795 1.735
0.864–3.728 0.879–3.425
0.1166 0.1125
2.973 0.546 2.388
1.662–5.319 0.282–1.057 0.844–6.758
0.0002 0.0725 0.1009
1.583
0.656–3.820
0.3065
Reference 1.348 1.847 2.747
0.610–2.982 0.775–4.405 1.289–5.855
0.4605 0.1663 0.0089
CKD, chronic kidney disease; BMI, body mass index; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; e0 , early diastolic velocity of the medial mitral annulus; E/e0 , the ratio of mitral velocity to early diastolic velocity of the medial mitral annulus; CAC, coronary artery calcification.
Third, an increase in CAC was associated with arterial stiffness assessed by baPWV, as previously reported [18]. Arterial stiffness is a determinant of LV diastolic function [19,20]. An increase in arterial stiffness reduces the Windkessel function of arterial trees and augments the pressure wave reflection, which augments late systolic pressure to increase LV afterload [21]. Another potential mechanism linking CAC to HF is impaired coronary endothelial function associated with coronary calcification [22]. Impairment of coronary endothelial function is involved in LV diastolic dysfunction, which may link CAC to the incidence of HF [23]. A recent study reported that coronary flow reserve, which is a marker of coronary endothelial function, and was more helpful in predicting the prognosis of cardiac events in asymptomatic patients than CAC scores [24]. Coronary artery endothelial function may reflect an earlier stage of atherosclerosis of the coronary artery than coronary artery calcification. Therefore, coronary flow reserve is a more sensitive marker for cardiac events than CAC scores. Unfortunately, information on coronary flow reserve was not available in our study. Therefore, we could not compare the effect of the CAC score and coronary flow reserve on the incidence of HF. During the follow-up period in our study, nine patients developed HF, but there were no CAD events. However, 141 patients had CAC scores >101, which indicate a high risk for CAD events [25]. There are several reasons that could explain
the low incidence of CAD events in our study. Evaluation for myocardial ischemia was carefully performed if patients had CAC scores 401. Additionally, these patients were recommended to take medication to prevent CAD events, but this depended on the physician’s decision. A relatively lower prevalence of risk factors, such as obesity, dyslipidemia, and diabetes mellitus, and the shortness of the follow-up period are other possible reasons for the limited number of CAD events in this study. Based on our results, HF should be considered as an additional outcome measure in possible future cardiac risk assessment programs using CAC screening. CAC burden is associated with a significant increase in subsequent cardiovascular events, but there are no data on the predictive value of CAC for HF as a possible manifestation of coronary atherosclerosis. We showed that CAC measurements are of added value in predicting subclinical HF, an increase in NT-proBNP levels, and future HF events. Classification of HF has been changed, and this stresses the importance of early recognition of risk factors for HF, including hypertension, diabetes mellitus, obesity, dyslipidemia, and smoking. Guidelines emphasize the need to intervene with proven therapies, even before patients become symptomatic with a more advanced stage of HF [26]. Most importantly, physicians are not doing as much as possible to address and treat standard risk factors. In addition to standard risk factor targets, we can now add another marker of the risk for incident HF-elevated CAC. Our
Table 4 Clinical characteristics of the patients with incidence of admission for heart failure. Age (year)
1 2 3 4 5 6 7 8 9
64 64 64 77 89 78 86 82 85
Sex
M F M F M M M F F
Coronary risk factors
CAC score
Hypertension
Diabetes mellitus
Dyslipidemia
CKD
+ + + + + + +
+ +
+ +
+ + + + + + +
0 52 103 172 545 630 1006 2189 3703
baPWV (cm/s) 1047 2012 1664 3183 3009 1647 2842 2045 2374
NT-proBNP (pg/ml) 995 762 693 531 919 433 595 1230 691
Echocardiography E/e0
e0 (cm/s)
LVEF (%)
12.1 12.8 16.9 14.2 19.8 19.5 10.4 12.6 17.2
5.1 6.6 4.1 5.8 4.7 6.6 6.7 9.1 7.1
58 41 52 87 70 75 76 35 80
M, male; F, female; CKD, chronic kidney disease; CAC, coronary artery calcification; baPWV, brachial-ankle pulse wave velocity; NT-proBNP, N-terminal pro-B-type natriuretic peptide; E/e0 , the ratio of mitral velocity to early diastolic velocity of the medial mitral annulus; e0 , early diastolic velocity of the medial mitral annulus; LVEF, left ventricular ejection fraction.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
6
Fig. 2. Kaplan–Meier curve showing the freedom from admission for heart failure according to CAC categories. CAC, coronary artery calcification.
results indicated that attention should be paid to the occurrence of HF events in patients with high values for CAC. Awareness of high CAC may motivate patients to change their lifestyle to achieve better risk factor control, and intense medical management should be enforced in patients with CAC scores >401 [27]. With regard to the use of CAC for risk stratification for CAD, physicians need to be sure that the incremental risk reclassification is worth the cost and radiation exposure [27]. Study limitations Our study has some limitations that need to be addressed. First, in this study, not all patients underwent a coronary angiogram or stress SPECT. Whether patients with CAC had obstructive atherosclerotic lesions is unknown. Severe CAC is associated with a high prevalence of coronary stenosis or occlusion, which causes reduced myocardial perfusion, resulting in myocardial dysfunction. However, in our study, we enrolled patients without a history of CAD or clinical evidence of CAD, and there were no ischemic events during the follow-up period. Therefore, we believe that the effect of myocardial ischemia should have been small. Second, this was a single-center study. A multicenter registry should be performed to prove the relationship between the CAC score and
admission for HF. Third, because of the limited number of HF cases, we could not assess differences in prognosis of CAC in subgroups, such as women and patients with diabetes mellitus or hypertension. Conclusion Severe CAC as determined by MDCT is an independent determinant of NT-proBNP levels, as well as a predictor of HF in a population without a history of CAD or HF. The prognostic significance of these data should be confirmed in larger studies with a longer follow-up period. Funding This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors declare that there is no conflict of interest. Acknowledgments
Table 5 Hazard ratios for heart failure admission by CAC category. CAC score
N
Heart failure admission
HR (95% CI)
p-value
0–10 11–100 101–400 401
249 97 82 59
1 1 2 5
1 (reference) 1.427 (0.084, 24.223) 3.643 (0.305, 43.558) 10.371 (1.062, 101.309)
0.8056 0.3071 0.0443
Adjusted for age, gender, hypertension, diabetes mellitus, dyslipidemia and chronic kidney disease. CAC, coronary artery calcification; HR, hazard ratio; CI, confidence interval.
We thank the staff of the Iwakuni Clinical Center, Ikuko Nakamura, Nao Yonemoto, Yui Marumo, and Tomoko Miyake for their help in data analysis. We also thank our patients for their willing cooperation. References [1] Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, Redfield MM. Congestive heart failure in the community: trends in incidence and survival in a 10-year period. Arch Intern Med 1999;159:29–34. [2] George A, Movahed A. Coronary artery calcium scores: current thinking and clinical applications. Open Cardiovasc Med J 2008;2:87–92.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx [3] Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995;92:2157–62. [4] Papakonstantinou NA, Baikoussis NG, Apostolakis E. Coronary endarterectomy: new flavors from old recipes. J Cardiol 2014;63:397–401. [5] Chang SM, Nabi F, Xu J, Peterson LE, Achari A, Pratt CM, Mahmarian JJ. The coronary artery calcium score and stress myocardial perfusion imaging provide independent and complementary prediction of cardiac risk. J Am Coll Cardiol 2009;54:1872–82. [6] Kalsch H, Lehmann N, Mohlenkamp S, Neumann T, Slomiany U, Schmermund A, Stang A, Moebus S, Bauer M, Mann K, Jockel KH, Erbel R. Association of coronary artery calcium and congestive heart failure in the general population: results of the Heinz Nixdorf Recall study. Clin Res Cardiol 2014;99:175–82. [7] Leening MJ, Elias-Smale SE, Kavousi M, Felix JF, Deckers JW, Vliegenthart R, Oudkerk M, Hofman A, Steyerberg EW, Stricker BH, Witteman JC. Coronary calcification and the risk of heart failure in the elderly: the Rotterdam Study. JACC Cardiovasc Imaging 2012;5:874–80. [8] Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392–7. [9] Linssen GC, Bakker SJ, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, van Veldhuisen DJ, Gans RO, de Zeeuw D. N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. Eur Heart J 2010;31:120–7. [10] Japanese Heart Failure Society statement; 2013 [http://www.asas.or.jp/jhfs/ topics/bnp201300403.html]. [11] Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32. [12] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [13] McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69. [14] Turner ST, Bielak LF, Narayana AK, Sheedy 2nd PF, Schwartz GL, Peyser PA. Ambulatory blood pressure and coronary artery calcification in middle-aged and younger adults. Am J Hypertens 2002;15:518–24.
7
[15] Oei HH, Vliegenthart R, Hofman A, Oudkerk M, Witteman JC. Risk factors for coronary calcification in older subjects. The Rotterdam Coronary Calcification Study. Eur Heart J 2004;25:48–55. [16] Joosen IA, Schiphof F, Versteylen MO, Laufer EM, Winkens MH, Nelemans PJ, Kooman JP, Hofstra L, Wildberger JE, Leiner T. Relation between mild to moderate chronic kidney disease and coronary artery disease determined with coronary CT angiography. PLoS ONE 2012;7:e47267. [17] Colletti PM, Dustin LD, Wong ND, Shriki JE, Kawakubo M, Azen SP, Detrano RC. Does coronary calcium score predict future cardiac function? Association of subclinical atherosclerosis with left ventricular systolic and diastolic dysfunction at MR imaging in an elderly cohort. Radiology 2010;257:64–70. [18] Park JB, Park HE, Choi SY, Kim MK, Oh BH. Relation between cardio-ankle vascular index and coronary artery calcification or stenosis in asymptomatic subjects. J Atheroscler Thromb 2013;20:557–67. [19] Yambe M, Tomiyama H, Hirayama Y, Gulniza Z, Takata Y, Koji Y, Motobe K, Yamashina A. Arterial stiffening as a possible risk factor for both atherosclerosis and diastolic heart failure. Hypertens Res 2004;27:625–31. [20] Seker T, Gur M, Kuloglu O, Kalkan GY, Sahin DY, Turkoglu C, Elbasan Z, Baykan AO, Gozubuyuk G, Cayli M. Serum 25-hydroxyvitamin D is associated with both arterial and ventricular stiffness in healthy subjects. J Cardiol 2013;62:361–5. [21] Eren M, Gorgulu S, Uslu N, Celik S, Dagdeviren B, Tezel T. Relation between aortic stiffness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37–43. [22] Wang L, Jerosch-Herold M, Jacobs Jr DR, Shahar E, Detrano R, Folsom AR. Coronary artery calcification and myocardial perfusion in asymptomatic adults: the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2006;48:1018–26. [23] Galderisi M, de Simone G, D’Errico A, Sidiropulos M, Viceconti R, Chinali M, Mondillo S, de Divitiis O. Independent association of coronary flow reserve with left ventricular relaxation and filling pressure in arterial hypertension. Am J Hypertens 2008;21:1040–6. [24] Naya M, Murthy VL, Foster CR, Gaber M, Klein J, Hainer J, Dorbala S, Blankstein R, Di Carli MF. Prognostic interplay of coronary artery calcification and underlying vascular dysfunction in patients with suspected coronary artery disease. J Am Coll Cardiol 2013;61:2098–106. [25] Tota-Maharaj R, Blaha MJ, Blankstein R, Silverman MG, Eng J, Shaw LJ, Blumenthal RS, Budoff MJ, Nasir K. Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort. Mayo Clin Proc 2014;89:1350–9. [26] Kuznetsova T, Herbots L, Lopez B, Jin Y, Richart T, Thijs L, Gonzalez A, Herregods MC, Fagard RH, Diez J, Staessen JA. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2009;2:105–12. [27] Rozanski A, Gransar H, Shaw LJ, Kim J, Miranda-Peats L, Wong ND, Rana JS, Orakzai R, Hayes SW, Friedman JD, Thomson LE, Polk D, Min J, Budoff MJ, Berman DS. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011;57:1622–32.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
JJCC-1119; No. of Pages 7 Journal of Cardiology xxx (2015) xxx–xxx
Contents lists available at ScienceDirect
Journal of Cardiology journal homepage: www.elsevier.com/locate/jjcc
Original article
An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease Satoru Sakuragi (MD, PhD, FJCC)a,*, Keishi Ichikawa (MD)a, Keiji Yamada (MD)a, Masafumi Tanimoto (MD)a, Takashi Miki (MD)a, Hiroaki Otsuka (MD)a, Kazuhiko Yamamoto (MD)a, Kenji Kawamoto (MD)a, Yusuke Katayama (MD, PhD)a, Machiko Tanakaya (MD, PhD)a, Hiroshi Ito (MD, PhD, FJCC)b a b
Department of Cardiovascular Medicine, Iwakuni Clinical Center, Iwakuni, Japan Department of Cardiovascular Medicine, Okayama University Graduate School of Medical and Dentistry, Okayama, Japan
A R T I C L E I N F O
A B S T R A C T
Article history: Received 2 April 2015 Received in revised form 21 June 2015 Accepted 26 June 2015 Available online xxx
Background: The presence of coronary artery calcification (CAC) and its severity predict future cardiovascular events and is used for risk stratification. However, the association of CAC with heart failure (HF) in patients without a history of coronary artery disease (CAD) remains unclear. This study aimed to determine the correlations of CAC with N-terminal pro-B-type natriuretic peptide (NT-proBNP) and HF events in patients without a history of CAD or HF. Methods: From June 2010 to June 2013, a total of 487 patients without a history of CAD and HF were enrolled. All of the patients underwent plane multi-detector computed tomography. They were divided into four categories according to CAC scores: 10, 11–100, 101–400, and 401. Results: The proportion of patients with high NT-proBNP levels increased with CAC categories (p < 0.0001). The CAC score was associated with NT-proBNP levels 400 pg/ml, with an odds ratio of 2.901 (95% confidence interval: 1.368–6.151, p = 0.0055) for CAC scores 401 compared with CAC scores of 0–10 after adjustment for confounding factors. During the follow-up period of 497 315 days, nine patients were admitted for HF. Kaplan–Meier analysis showed that patients with CAC scores 401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0–10, 11–100, 101–400, and 401, respectively (p < 0.0001). Increasing CAC scores were associated with an increase in incidence of admission for HF, with a hazard ratio of 10.371 for CAC scores 401 (95% CI: 1.062–101.309, p = 0.0443) compared with CAC scores of 0–10 after adjustment for risk factors. Conclusion: Severe CAC is an independent determinant of high NT-proBNP levels and a predictor of admission for HF in a population without a history of CAD or HF. ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Keywords: Coronary artery calcification N-terminal pro-B-type natriuretic peptide Heart failure
Introduction Heart failure (HF) is associated with reduced life expectancy and ever increasing costs. Therefore, HF is one of the most important health concerns in the industrialized world [1]. Although the survival rate of patients with HF has improved over the past few decades, its prevalence and incidence have been steadily
* Corresponding author at: Department of Cardiovascular Medicine, Iwakuni Clinical Center, 1-1-1 Atago-machi, Iwakuni 740-8510, Japan. Tel.: +81 827 34 1000; fax: +81 87 35 5600. E-mail address: [email protected] (S. Sakuragi).
increasing. Early prediction of patients at high risk for HF is important for preventing the progression of HF. Traditional risk assessment for coronary artery disease (CAD) using coronary risk factors has been refined with the selective use of coronary artery calcium (CAC). This is possible because CAC is pathognomonic of atherosclerosis [2], and a histological study showed its close correlation with the atherosclerotic plaque burden [3,4]. The severity of CAC can be easily quantified by electron beam computed tomography (CT) or multi-detector CT (MDCT). CAC is currently a useful marker of subclinical CAD and an independent predictor of cardiovascular events [5]. CAD is a risk factor for HF, but information on the association of CAC scores with HF is still lacking. In a population-based study, Kalsch et al. demonstrated
http://dx.doi.org/10.1016/j.jjcc.2015.06.014 0914-5087/ß 2015 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 2
S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
that CAC was higher in patients with HF than in those without HF [6]. Leening et al. showed that the extent of CAC has a clear association with the risk for development of HF in elderly patients [7]. B-type natriuretic peptide (BNP) and N-terminal proBNP (NTproBNP), both of which are increased in relation to cardiac stretch, are associated with the severity and prognosis of left ventricular (LV) dysfunction and HF [8]. NT-proBNP has been shown to independently predict all-cause mortality and cardiovascular events. NT-proBNP has emerged as a useful biomarker for guiding diagnosis, prognosis, and management in patients with cardiovascular disease and HF [9]. Recently, the Japanese Heart Failure Society statement indicated that close examinations by specialized physicians are needed in patients with NT-proBNP levels 400 pg/ ml (Japanese Heart Failure Society statement 2013) [10]. In this study, we investigated the correlation of CAC with NT-proBNP levels in patients without a history of CAD or HF. Additionally, we followed HF events after measurement of CAC to establish the effect of CAC on the development of HF events. Methods Selection of patients From June 2010 to June 2013, a total of 692 patients who visited our hospital and were suspected of having CAD were examined. Among them, we excluded 103 patients who were <40 years old and those with congestive heart failure, acute coronary syndrome, a history of HF, or a history of CAD defined as prior myocardial infarction (MI) or coronary intervention (percutaneous coronary intervention and coronary artery bypass grafting). The other 589 patients underwent MDCT just for measurement of CAC. Of these, 254 patients with positive exercise test results, or symptoms that were likely to be related to myocardial ischemia, or CAC scores 401 were recommended for further examinations, including stress single-photon emission computed tomography (SPECT) or an invasive coronary angiogram, because of suspected CAD. Ten patients who rejected further examinations were excluded. A total of 244 patients underwent stress SPECT or coronary angiogram, and 80 patients with findings of myocardial ischemia in stress SPECT or who had significant coronary artery stenosis in a coronary angiogram were excluded from this study. Another 164 patients who had no significant coronary artery stenosis in a coronary angiogram (n = 98), or had no findings of myocardial ischemia in stress SPECT (n = 66) were enrolled in the analysis. Patients with an estimated glomerular filtration rate (eGFR) of <15 ml/min/ 1.73 m2, severe valvular heart disease, an advanced stage of malignancy, or dysthyroidism (n = 12) were also excluded. Finally, a total of 487 patients were included in the analysis.
in 3.0-mm slices throughout coronary artery regions using a prospectively electrocardiogram-triggered scan acquisition at 75% of the RR intervals. CAC scores were calculated using an automated computer system (Ziostation System 1000, Ziosoft, Tokyo, Japan) by the Agatston method [11]. Analysis of echocardiographic data Standard imaging was performed in the left lateral decubitus position using a commercially available system. Left atrial diameter, end-diastolic interventricular septal and posterior wall thicknesses, and end-diastolic and end-systolic LV internal dimensions were determined according to the recommendations of the American Society of Echocardiography [12]. LV mass was calculated from LV linear dimensions and was expressed as a ratio to body surface area (LVMI). LV hypertrophy was defined by LVMI thresholds of 115 g/m2 for men and 95 g/m2 for women [12]. LV end-diastolic and end-systolic volumes were measured from an apical four-chamber view and were indexed to body surface area. The LV ejection fraction (LVEF) was calculated according to the modified Simpson’s rule. Mitral inflow was assessed by pulsedwave Doppler echocardiography from the apical four-chamber view. On the basis of the mitral inflow profile, E- and A-wave velocities, deceleration time of the E-wave, and the E/A ratio were determined. Tissue Doppler imaging of the mitral annulus was performed from the apical four-chamber view. A sample volume was placed sequentially at the septal mitral annulus, and early diastolic velocity (e0 ) was measured. The ratio of mitral velocity to early diastolic velocity of the medial mitral annulus (E/e0 ), which is a marker of LV diastolic filling pressure, was calculated. Measurement of brachial-ankle pulse wave velocity Brachial-ankle pulse wave velocity (baPWV) was measured using an automatic waveform analyzer (BP-203RPEII; Omron Colin, Tokyo, Japan) just before an echocardiogram. Subjects were examined in the supine position after 5 min of bed rest. Follow-up study The incidence of HF events, defined as admission due to HF, was followed after measurement of CAC scores. HF was defined by modified Framingham criteria as follows: satisfaction of two major criteria (paroxysmal nocturnal dyspnea, orthopnea, rales, jugular venous distension, third heart sound, and radiological signs of pulmonary congestion and/or cardiomegaly) or of one major criterion together with two minor criteria (effort dyspnea, peripheral edema, hepatomegaly, and pleural effusion). Diagnosis of HF was made by a cardiologist or an internist.
Study protocol
Statistical analysis
All of the patients underwent blood sampling, including measurement of NT-proBNP levels, measurement of CAC scores, and an echocardiographic examination. NT-proBNP levels were measured using the commercially available Elecsys proBNP sandwich immunoassay using an Elecsys 2010 (Roche Diagnostics, Mannheim, Germany). The study protocol was approved by the appropriate institutional review board of the hospital and all of the participants provided written informed consent.
Patients were divided into four categories based on CAC scores: 10, 11–100, 101–400, and 401 [5]. Comparison of continuous variables among groups was performed by one-way analysis of variance or the Kruskal–Wallis test, as appropriate. Categorical data were compared by chi-square analysis. Patients were also classified into four groups according to NT-proBNP levels as described in the Japanese Heart Failure Society statement 2013: <125 pg/ml, 125 and <400 pg/ml, 400 and <900 pg/ml, and 900 pg/ml [10]. Univariate and multivariate logistic regression analyses were performed to determine which of the following factors were associated with NT-proBNP levels 400 pg/ml: age, sex, and the prevalence of hypertension, diabetes mellitus, dyslipidemia, chronic kidney disease (CKD), which was defined as an eGFR <60 ml/min/1.73 m2, LV systolic dysfunction, which
Measurement of the CAC score CAC in epicardial coronary arteries was assessed. CT scanning of the coronary artery was performed using a 64-slice multidetector system (Aquilion 64, Toshiba, Tokyo, Japan). Images were acquired
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
was defined as LVEF <50%, LV hypertrophy, LV diastolic dysfunction, which was defined as e0 < 8 cm/s or E/e0 > 15, and body mass index >25 kg/m2 [13]. Cumulative survival estimates were calculated by the Kaplan–Meier method and were compared between CAC categories by the log-rank test. We used a Cox proportional hazards model to calculate hazard ratios (HRs) with 95% confidence intervals (CIs) for the risk of HF hospitalization for different CAC categories with adjustment for covariates (age, sex, and prevalence of hypertension, diabetes mellitus, dyslipidemia, and CKD). All statistical analyses were performed using the SPSS statistical software package (Version 21, IBM Corp., Armonk, NY, USA). For all tests, a p-value <0.05 was considered significant. Results Study population Characteristics of the study population were stratified for CAC score categories (Table 1). Higher CAC scores were associated with more advanced age and a higher prevalence of hypertension and diabetes mellitus. Higher CAC scores were also associated with a more reduced eGFR, higher systolic blood pressure, and higher baPWV. Cardiac parameters are shown in Table 2. There was a graded increase in NT-proBNP levels with CAC category (Table 2). LVMI was increased with CAC category. LVEF was comparable between CAC categories. In tissue Doppler imaging, e0 velocity decreased and the E/e0 ratio increased with CAC category (Table 2). Relationship between CAC and NT-proBNP levels The distribution of NT-proBNP class according to CAC categories is shown in Fig. 1. The proportion of patients with high NT-proBNP levels gradually increased with increasing CAC score. The CAC score was associated with high NT-proBNP levels 400 pg/ml, with an odds ratio of 2.747 (95% CI: 1.289–5.855, p = 0.0089) for CAC
3
scores 401 compared with CAC scores of 0–10 after adjustment for confounding factors (Table 3). Clinical outcomes During a mean follow-up period of 497 315 days (range, 30– 1057 days), nine patients were admitted for HF, although there were no coronary events, including MI, and no requirement for coronary artery revascularization, such as percutaneous coronary intervention and coronary artery bypass grafting, during the follow-up period. Clinical characteristics at baseline of these nine patients are shown in Table 4. Many patients had hypertension and CKD. NT-proBNP was higher than 400 pg/ml in all patients. Two patients had a LVEF <50%. One patient died after admission for HF. All of the patients who were admitted for HF underwent coronary angiography after admission, and there was no CAD in any of these patients. Kaplan–Meier analysis showed that patients with CAC scores 401 had a lower rate of freedom from admission for HF with cumulative incidences of 0.4%, 1%, 2%, and 8% for CAC scores of 0–10, 11–100, 101–400, and 401, respectively (p < 0.0001) (Fig. 2). Increasing CAC scores were associated with an increase in incidence of admission for HF, with an HR of 10.371 for CAC scores 401 (95% CI: 1.062–101.309, p = 0.0443) compared with CAC scores of 0–10 after adjustment for risk factors (Table 5). Discussion This study showed several new findings regarding the relationships between CAC and increasing NT-proBNP levels, as well as with development of HF in patients without a history of CAD or HF. First, an increase in CAC was associated with a decrease in e0 velocity and increase in the E/e0 ratio, which suggested LV diastolic dysfunction. Second, CAC was an independent determinant of high NT-proBNP levels. Third, patients with a high CAC score were more likely to have HF events than those with a low CAC score. These
Table 1 Patients characteristics stratified by CAC category. CAC category
All
n CAC score Age, years Male gender (%) Hypertension (%) Diabetes (%) Dyslipidemia (%) CKD (%) Body mass index (kg/m2) Beta blocker (%) Ca channel blocker (%) ACEI or ARB (%) Statin (%) Creatinine (mg/dl) eGFR (ml/min/1.73 m2) Total cholesterol (mg/dl) Triglyceride (mg/dl) HDL-cholesterol (mg/dl) LDL-cholesterol (mg/dl) Blood sugar (mg/dl) HbA1c (%) Systolic BP (mmHg) Diastolic BP (mmHg) Heart rate (mmHg) baPWV (cm/s)
487 9 (127) 69 11 240 (49) 340 (70) 79 (16) 145 (30) 137 (28) 24 4 57 (12) 175 (36) 155 (32) 106 (22) 0.80 0.24 69 19 196 34 137 82 61 18 117 31 115 34 5.9 0.9 140 20 80 12 70 13 1825 454
p-value
0–10
11–100
101–400
401
249 0 (0, 0) 64 11 102 (41) 151 (60) 27 (11) 61 (24) 38 (15) 24 4 22 (9) 71 (29) 51 (20) 46 (19) 0.74 0.20 73 19 202 34 135 78 63 17 122 32 113 32 5.8 0.9 137 21 80 13 70 13 1672 411
97 52 (31, 77) 72 9 53 (55) 70 (72) 17 (18) 33 (34) 39 (40) 24 3 15 (15) 39 (40) 34 (35) 23 (24) 0.84 0.23 64 17 190 37 150 86 58 18 114 32 114 30 5.9 0.8 141 18 80 12 69 14 1908 361
82 171 (128, 253) 73 9 51 (62) 67 (82) 21 (26) 30 (37) 35 (43) 24 4 14 (17) 34 (41) 38 (46) 18 (22) 0.88 0.34 64 19 190 30 140 89 58 18 114 28 124 46 6.1 1.0 140 19 79 11 70 13 1971 450
59 799 (581, 1311) 74 8 34 (58) 52 (88) 14 (24) 21 (36) 25 (42) 23 4 6 (10) 31 (53) 32 (54) 19 (32) 0.85 0.21 63 15 191 33 120 77 67 19 108 28 116 31 6.0 0.8 149 21 82 12 69 12 2138 509
<0.0001 <0.0001 0.0017 <0.0001 0.0043 0.0743 <0.0001 0.9557 0.1254 0.0019 <0.0001 0.1392 <0.0001 <0.0001 0.0037 0.1695 0.0017 0.0073 0.096 0.1715 0.0017 0.6505 0.8671 <0.0001
All data are presented as mean standard deviation (SD) or median with inter-quartile range (IQR) or as number (percentage) for dichotomous variables. CAC, coronary artery calcification; CKD, chronic kidney disease; ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Hb, hemoglobin; BP, blood pressure; baPWV, brachial-ankle pulse wave velocity.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
4 Table 2 Cardiac parameters stratified by CAC category.
CAC category
All
NT-proBNP (pg/ml) LAD (mm) LVEDVI (ml/m2) LVESVI (ml/m2) LVEF (%) LVEF < 50% LVMI (g/m2) LVH (%) E/A ratio DcT (ms) e0 (cm/s) E/e0
90 (33, 213) 37 7 59 17 20 10 67 10 23 (5) 108 33 233 (48) 0.86 0.34 217 59 7.3 2.6 9.9 3.6
p-value
0–10
11–100
101–400
401
61 (21, 138) 35 6 58 14 19 8 67 9 6 (3) 102 30 105 (42) 0.93 0.37 213 57 7.8 2.8 9.0 2.7
102 (49, 233) 37 7 60 18 19 13 67 12 7 (7) 110 36 50 (52) 0.76 0.22 227 56 6.8 2.0 10.0 3.3
135 (40, 483) 38 7 61 21 21 11 66 10 6 (8) 116 36 43 (52) 0.80 0.31 225 65 6.7 2.0 10.7 3.9
149 (75, 429) 39 8 63 20 20 12 68 12 4 (7) 119 35 35 (59) 0.82 0.31 213 57 6.9 2.7 12.1 5.1
<0.0001 0.0097 0.1276 0.6346 0.7478 0.1112 0.0003 0.0739 <0.0001 0.1577 0.0003 <0.0001
CAC, coronary artery calcification; NT-proBNP, N-terminal pro-B-type natriuretic peptide; LAD, left atrial dimension; LVEDVI, Left ventricular end-diastolic volume index; LVESVI, left ventricular end-systolic volume index; LVEF, left ventricular ejection fraction; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy; DcT, the deceleration time of E-wave; e0 , early diastolic velocity of the medial mitral annulus.
findings suggest that quantification of CAC with MDCT has the potential for identifying not only patients with CAD, but also individuals at high risk for HF. There are several possible explanations for the relationships of CAC with NT-proBNP levels and development of HF. First, common risk factors, including hypertension and kidney disease, are involved in high CAC and an increase in NT-proBNP levels [14]. Hypertension is one of the strongest predictors of CAC, as well as HF. Kalsch et al. showed that subjects with chronic HF had either an elevated CAC burden or hypertension [6]. They also found that subjects with chronic HF had more evidence of electrocardiogram-based LV hypertrophy, ischemia, or MI, and also had reduced exercise capacity [6]. Most of the risk factors for CAC and LV diastolic dysfunction are common, including advanced age, hypertension, obesity, diabetes [15], and renal insufficiency [16]. These risk factors may have been related to the association of a higher CAC score with increased NT-proBNP levels and development of HF in our population.
Second, CAC measurements provide an estimation of coronary atherosclerotic plaque burden [3] and appear to be complementary to myocardial perfusion, which provides information on inducible ischemia. Using cardiac magnetic resonance imaging, Colletti et al. found a correlation between CAC and abnormality of regional wall motion [17]. Half of their patients with abnormality of wall motion had clinical or electrocardiographic evidence of CAD, indicating that patients with advanced CAC may have subtle structural dysfunction caused by limited coronary flow. However, Chang et al. demonstrated that severe CAC identified a subgroup of subjects at high longterm risk for cardiac events, even in the absence of abnormal stress SPECT results [5]. This finding suggests that factors other than myocardial ischemia may be involved in higher mortality in patients with high CAC. In our study, we enrolled patients without a history of CAD or clinical evidence of CAD. None of the patients had ischemic or HF events that occurred with preceding coronary events during the follow-up period. This finding indicates that coronary calcification may affect cardiac performance, especially LV diastolic function.
Fig. 1. Distribution of quartiles of NT-proBNP according to CAC categories. NT-proBNP, N-terminal pro-B-type natriuretic peptide; CAC, coronary artery calcification.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
5
Table 3 Odds ratios for N-terminal pro-B-type natriuretic peptide 400 pg/ml. Multivariate
Univariate Odds ratio Age Male gender Hypertension Diabetes mellitus Dyslipidemia CKD BMI > 25 kg/m2 LVEF < 50% LVH e0 < 8 cm/s E/e0 > 15 CAC score CAC score 0–10 CAC score 11–100 CAC score 101–400 CAC score 401
95% CI
p
Odds ratio
1.087 1.467 2.559 1.817 0.835 5.217 0.535 3.087 1.32 0.878 1.144
1.056–1.119 0.892–2.410 1.335–4.905 1.002–3.297 0.480–1.452 3.111–8.749 0.297–0.964 1.259–7.570 0.801–2.174 0.521–1.480 1.486–6.632
<0.001 0.1308 0.0047 0.0494 0.5227 <0.0001 0.0372 0.0138 0.2753 0.6255 0.0027
Reference 2.9 5.078 5.986
1.413–5.950 2.380–10.819 3.030–11.826
0.0037 <0.0001 <0.0001
95% CI
p
1.054
1.019–1.089
0.0019
1.795 1.735
0.864–3.728 0.879–3.425
0.1166 0.1125
2.973 0.546 2.388
1.662–5.319 0.282–1.057 0.844–6.758
0.0002 0.0725 0.1009
1.583
0.656–3.820
0.3065
Reference 1.348 1.847 2.747
0.610–2.982 0.775–4.405 1.289–5.855
0.4605 0.1663 0.0089
CKD, chronic kidney disease; BMI, body mass index; LVEF, left ventricular ejection fraction; LVH, left ventricular hypertrophy; e0 , early diastolic velocity of the medial mitral annulus; E/e0 , the ratio of mitral velocity to early diastolic velocity of the medial mitral annulus; CAC, coronary artery calcification.
Third, an increase in CAC was associated with arterial stiffness assessed by baPWV, as previously reported [18]. Arterial stiffness is a determinant of LV diastolic function [19,20]. An increase in arterial stiffness reduces the Windkessel function of arterial trees and augments the pressure wave reflection, which augments late systolic pressure to increase LV afterload [21]. Another potential mechanism linking CAC to HF is impaired coronary endothelial function associated with coronary calcification [22]. Impairment of coronary endothelial function is involved in LV diastolic dysfunction, which may link CAC to the incidence of HF [23]. A recent study reported that coronary flow reserve, which is a marker of coronary endothelial function, and was more helpful in predicting the prognosis of cardiac events in asymptomatic patients than CAC scores [24]. Coronary artery endothelial function may reflect an earlier stage of atherosclerosis of the coronary artery than coronary artery calcification. Therefore, coronary flow reserve is a more sensitive marker for cardiac events than CAC scores. Unfortunately, information on coronary flow reserve was not available in our study. Therefore, we could not compare the effect of the CAC score and coronary flow reserve on the incidence of HF. During the follow-up period in our study, nine patients developed HF, but there were no CAD events. However, 141 patients had CAC scores >101, which indicate a high risk for CAD events [25]. There are several reasons that could explain
the low incidence of CAD events in our study. Evaluation for myocardial ischemia was carefully performed if patients had CAC scores 401. Additionally, these patients were recommended to take medication to prevent CAD events, but this depended on the physician’s decision. A relatively lower prevalence of risk factors, such as obesity, dyslipidemia, and diabetes mellitus, and the shortness of the follow-up period are other possible reasons for the limited number of CAD events in this study. Based on our results, HF should be considered as an additional outcome measure in possible future cardiac risk assessment programs using CAC screening. CAC burden is associated with a significant increase in subsequent cardiovascular events, but there are no data on the predictive value of CAC for HF as a possible manifestation of coronary atherosclerosis. We showed that CAC measurements are of added value in predicting subclinical HF, an increase in NT-proBNP levels, and future HF events. Classification of HF has been changed, and this stresses the importance of early recognition of risk factors for HF, including hypertension, diabetes mellitus, obesity, dyslipidemia, and smoking. Guidelines emphasize the need to intervene with proven therapies, even before patients become symptomatic with a more advanced stage of HF [26]. Most importantly, physicians are not doing as much as possible to address and treat standard risk factors. In addition to standard risk factor targets, we can now add another marker of the risk for incident HF-elevated CAC. Our
Table 4 Clinical characteristics of the patients with incidence of admission for heart failure. Age (year)
1 2 3 4 5 6 7 8 9
64 64 64 77 89 78 86 82 85
Sex
M F M F M M M F F
Coronary risk factors
CAC score
Hypertension
Diabetes mellitus
Dyslipidemia
CKD
+ + + + + + +
+ +
+ +
+ + + + + + +
0 52 103 172 545 630 1006 2189 3703
baPWV (cm/s) 1047 2012 1664 3183 3009 1647 2842 2045 2374
NT-proBNP (pg/ml) 995 762 693 531 919 433 595 1230 691
Echocardiography E/e0
e0 (cm/s)
LVEF (%)
12.1 12.8 16.9 14.2 19.8 19.5 10.4 12.6 17.2
5.1 6.6 4.1 5.8 4.7 6.6 6.7 9.1 7.1
58 41 52 87 70 75 76 35 80
M, male; F, female; CKD, chronic kidney disease; CAC, coronary artery calcification; baPWV, brachial-ankle pulse wave velocity; NT-proBNP, N-terminal pro-B-type natriuretic peptide; E/e0 , the ratio of mitral velocity to early diastolic velocity of the medial mitral annulus; e0 , early diastolic velocity of the medial mitral annulus; LVEF, left ventricular ejection fraction.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx
6
Fig. 2. Kaplan–Meier curve showing the freedom from admission for heart failure according to CAC categories. CAC, coronary artery calcification.
results indicated that attention should be paid to the occurrence of HF events in patients with high values for CAC. Awareness of high CAC may motivate patients to change their lifestyle to achieve better risk factor control, and intense medical management should be enforced in patients with CAC scores >401 [27]. With regard to the use of CAC for risk stratification for CAD, physicians need to be sure that the incremental risk reclassification is worth the cost and radiation exposure [27]. Study limitations Our study has some limitations that need to be addressed. First, in this study, not all patients underwent a coronary angiogram or stress SPECT. Whether patients with CAC had obstructive atherosclerotic lesions is unknown. Severe CAC is associated with a high prevalence of coronary stenosis or occlusion, which causes reduced myocardial perfusion, resulting in myocardial dysfunction. However, in our study, we enrolled patients without a history of CAD or clinical evidence of CAD, and there were no ischemic events during the follow-up period. Therefore, we believe that the effect of myocardial ischemia should have been small. Second, this was a single-center study. A multicenter registry should be performed to prove the relationship between the CAC score and
admission for HF. Third, because of the limited number of HF cases, we could not assess differences in prognosis of CAC in subgroups, such as women and patients with diabetes mellitus or hypertension. Conclusion Severe CAC as determined by MDCT is an independent determinant of NT-proBNP levels, as well as a predictor of HF in a population without a history of CAD or HF. The prognostic significance of these data should be confirmed in larger studies with a longer follow-up period. Funding This research received no grants from any funding agency in the public, commercial, or not-for-profit sectors. Conflicts of interest The authors declare that there is no conflict of interest. Acknowledgments
Table 5 Hazard ratios for heart failure admission by CAC category. CAC score
N
Heart failure admission
HR (95% CI)
p-value
0–10 11–100 101–400 401
249 97 82 59
1 1 2 5
1 (reference) 1.427 (0.084, 24.223) 3.643 (0.305, 43.558) 10.371 (1.062, 101.309)
0.8056 0.3071 0.0443
Adjusted for age, gender, hypertension, diabetes mellitus, dyslipidemia and chronic kidney disease. CAC, coronary artery calcification; HR, hazard ratio; CI, confidence interval.
We thank the staff of the Iwakuni Clinical Center, Ikuko Nakamura, Nao Yonemoto, Yui Marumo, and Tomoko Miyake for their help in data analysis. We also thank our patients for their willing cooperation. References [1] Senni M, Tribouilloy CM, Rodeheffer RJ, Jacobsen SJ, Evans JM, Bailey KR, Redfield MM. Congestive heart failure in the community: trends in incidence and survival in a 10-year period. Arch Intern Med 1999;159:29–34. [2] George A, Movahed A. Coronary artery calcium scores: current thinking and clinical applications. Open Cardiovasc Med J 2008;2:87–92.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014
G Model
JJCC-1119; No. of Pages 7 S. Sakuragi et al. / Journal of Cardiology xxx (2015) xxx–xxx [3] Rumberger JA, Simons DB, Fitzpatrick LA, Sheedy PF, Schwartz RS. Coronary artery calcium area by electron-beam computed tomography and coronary atherosclerotic plaque area. A histopathologic correlative study. Circulation 1995;92:2157–62. [4] Papakonstantinou NA, Baikoussis NG, Apostolakis E. Coronary endarterectomy: new flavors from old recipes. J Cardiol 2014;63:397–401. [5] Chang SM, Nabi F, Xu J, Peterson LE, Achari A, Pratt CM, Mahmarian JJ. The coronary artery calcium score and stress myocardial perfusion imaging provide independent and complementary prediction of cardiac risk. J Am Coll Cardiol 2009;54:1872–82. [6] Kalsch H, Lehmann N, Mohlenkamp S, Neumann T, Slomiany U, Schmermund A, Stang A, Moebus S, Bauer M, Mann K, Jockel KH, Erbel R. Association of coronary artery calcium and congestive heart failure in the general population: results of the Heinz Nixdorf Recall study. Clin Res Cardiol 2014;99:175–82. [7] Leening MJ, Elias-Smale SE, Kavousi M, Felix JF, Deckers JW, Vliegenthart R, Oudkerk M, Hofman A, Steyerberg EW, Stricker BH, Witteman JC. Coronary calcification and the risk of heart failure in the elderly: the Rotterdam Study. JACC Cardiovasc Imaging 2012;5:874–80. [8] Berger R, Huelsman M, Strecker K, Bojic A, Moser P, Stanek B, Pacher R. B-type natriuretic peptide predicts sudden death in patients with chronic heart failure. Circulation 2002;105:2392–7. [9] Linssen GC, Bakker SJ, Voors AA, Gansevoort RT, Hillege HL, de Jong PE, van Veldhuisen DJ, Gans RO, de Zeeuw D. N-terminal pro-B-type natriuretic peptide is an independent predictor of cardiovascular morbidity and mortality in the general population. Eur Heart J 2010;31:120–7. [10] Japanese Heart Failure Society statement; 2013 [http://www.asas.or.jp/jhfs/ topics/bnp201300403.html]. [11] Agatston AS, Janowitz WR, Hildner FJ, Zusmer NR, Viamonte Jr M, Detrano R. Quantification of coronary artery calcium using ultrafast computed tomography. J Am Coll Cardiol 1990;15:827–32. [12] Lang RM, Bierig M, Devereux RB, Flachskampf FA, Foster E, Pellikka PA, Picard MH, Roman MJ, Seward J, Shanewise JS, Solomon SD, Spencer KT, Sutton MS, Stewart WJ. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440–63. [13] McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, Falk V, Filippatos G, Fonseca C, Gomez-Sanchez MA, Jaarsma T, Kober L, Lip GY, Maggioni AP, Parkhomenko A, et al. ESC guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology. Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2012;14:803–69. [14] Turner ST, Bielak LF, Narayana AK, Sheedy 2nd PF, Schwartz GL, Peyser PA. Ambulatory blood pressure and coronary artery calcification in middle-aged and younger adults. Am J Hypertens 2002;15:518–24.
7
[15] Oei HH, Vliegenthart R, Hofman A, Oudkerk M, Witteman JC. Risk factors for coronary calcification in older subjects. The Rotterdam Coronary Calcification Study. Eur Heart J 2004;25:48–55. [16] Joosen IA, Schiphof F, Versteylen MO, Laufer EM, Winkens MH, Nelemans PJ, Kooman JP, Hofstra L, Wildberger JE, Leiner T. Relation between mild to moderate chronic kidney disease and coronary artery disease determined with coronary CT angiography. PLoS ONE 2012;7:e47267. [17] Colletti PM, Dustin LD, Wong ND, Shriki JE, Kawakubo M, Azen SP, Detrano RC. Does coronary calcium score predict future cardiac function? Association of subclinical atherosclerosis with left ventricular systolic and diastolic dysfunction at MR imaging in an elderly cohort. Radiology 2010;257:64–70. [18] Park JB, Park HE, Choi SY, Kim MK, Oh BH. Relation between cardio-ankle vascular index and coronary artery calcification or stenosis in asymptomatic subjects. J Atheroscler Thromb 2013;20:557–67. [19] Yambe M, Tomiyama H, Hirayama Y, Gulniza Z, Takata Y, Koji Y, Motobe K, Yamashina A. Arterial stiffening as a possible risk factor for both atherosclerosis and diastolic heart failure. Hypertens Res 2004;27:625–31. [20] Seker T, Gur M, Kuloglu O, Kalkan GY, Sahin DY, Turkoglu C, Elbasan Z, Baykan AO, Gozubuyuk G, Cayli M. Serum 25-hydroxyvitamin D is associated with both arterial and ventricular stiffness in healthy subjects. J Cardiol 2013;62:361–5. [21] Eren M, Gorgulu S, Uslu N, Celik S, Dagdeviren B, Tezel T. Relation between aortic stiffness and left ventricular diastolic function in patients with hypertension, diabetes, or both. Heart 2004;90:37–43. [22] Wang L, Jerosch-Herold M, Jacobs Jr DR, Shahar E, Detrano R, Folsom AR. Coronary artery calcification and myocardial perfusion in asymptomatic adults: the MESA (Multi-Ethnic Study of Atherosclerosis). J Am Coll Cardiol 2006;48:1018–26. [23] Galderisi M, de Simone G, D’Errico A, Sidiropulos M, Viceconti R, Chinali M, Mondillo S, de Divitiis O. Independent association of coronary flow reserve with left ventricular relaxation and filling pressure in arterial hypertension. Am J Hypertens 2008;21:1040–6. [24] Naya M, Murthy VL, Foster CR, Gaber M, Klein J, Hainer J, Dorbala S, Blankstein R, Di Carli MF. Prognostic interplay of coronary artery calcification and underlying vascular dysfunction in patients with suspected coronary artery disease. J Am Coll Cardiol 2013;61:2098–106. [25] Tota-Maharaj R, Blaha MJ, Blankstein R, Silverman MG, Eng J, Shaw LJ, Blumenthal RS, Budoff MJ, Nasir K. Association of coronary artery calcium and coronary heart disease events in young and elderly participants in the multi-ethnic study of atherosclerosis: a secondary analysis of a prospective, population-based cohort. Mayo Clin Proc 2014;89:1350–9. [26] Kuznetsova T, Herbots L, Lopez B, Jin Y, Richart T, Thijs L, Gonzalez A, Herregods MC, Fagard RH, Diez J, Staessen JA. Prevalence of left ventricular diastolic dysfunction in a general population. Circ Heart Fail 2009;2:105–12. [27] Rozanski A, Gransar H, Shaw LJ, Kim J, Miranda-Peats L, Wong ND, Rana JS, Orakzai R, Hayes SW, Friedman JD, Thomson LE, Polk D, Min J, Budoff MJ, Berman DS. Impact of coronary artery calcium scanning on coronary risk factors and downstream testing the EISNER (Early Identification of Subclinical Atherosclerosis by Noninvasive Imaging Research) prospective randomized trial. J Am Coll Cardiol 2011;57:1622–32.
Please cite this article in press as: Sakuragi S, et al. An increase in the coronary calcification score is associated with an increased risk of heart failure in patients without a history of coronary artery disease. J Cardiol (2015), http://dx.doi.org/10.1016/j.jjcc.2015.06.014