’ Ratio in Subjects with Normal Left Ventricular Ejection Fraction Associations among Coronary Artery Calcium Score, Left Ventricular Mass Index and Septal E/E

Received May 26, 2020; revised September 20, 2020; accepted October 14, 2020.

Corresponding author: Sang-Ho Park, Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, 31 Suncheonhyang 6-gil, Dongnam-gu, Cheonan 31151, Korea. E-mail: matsalong@schmc.ac.kr

Copyright Ⓒ 2020 The Korean Academy of Clinical Geriatrics

This is an open access article distributed under the term s of the Creative Com m ons Attribution Non-Com m ercial License (http://creativecom m ons.org/licenses/by-nc/4.0) which perm its unrestricted non-com m ercial use, distribution, and reproduction in any m edium , provided the original work is properly cited.

Associations among Coronary Artery Calcium Score, Left Ventricular Mass Index and Septal E/E’ Ratio in Subjects with Normal Left Ventricular Ejection Fraction

Ung Jeon , Sang-Ho Park

Division of Cardiology, Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea

Background: The objective of this study is to determine if associations among the coronary artery calcium (CAC) score (CACS), left ventricular mass index (LVMI), and septal E/E’ ratio.

Methods: We investigated 1230 consecutive subjects with a normal left ventricular ejection fraction who underwent multidetector computed tomography and echocardiography. The CACS was measured using the Agatstone method. Participants were classified as follows, in a two-fold manner: first, negative CAC (CACS=0) group and positive CAC (CACS ＞0) group; second, no (CACS=0), mild (1-100), moderate (101-400), and severe CAC deposits ( ＞400).

Results: In multivariate binary logistic regression adjusted for covariates, the LVMI and septal E/E’ ratio were independent pre- dictors of positive CAC deposits (CACS ＞0) and severe CACS (CACS ＞400). Regarding the “composite score” based on a septal E/E’ ratio ≥15 and LVMI ≥90 g/m

, a higher score was associated with a greater CACS. Per the severity criteria of the CACS, severe CAC deposits were significantly associated with “composite score 2” group and the odds ratios in each group were 1.790, 2.126, and 5.705, respectively.

Conclusion: In our study, the LVMI and septal E/E’ ratio were associated with the CACS, independent of classic risk factors in patients with chest pain or without symptoms with a normal left ventricular ejection fraction.

Key Words: Calcium, Coronary, Echocardiography, Multidetector computed tomography

INTRODUCTION

Coronary artery calcium score (CACS) is a good marker of atherosclerosis which represents the degree of atheromatous plaque burden [1,2]. Coronary artery calcification (CAC) can be quantified by multidetected row computed tomography (MDCT), and the CACS is proportionally related to the se- verity of atherosclerotic disease [3].

Population-based studies indicate that at least one third of

all patients with symptomatic heart failure have normal LV ejection fractions [4] and a part of these patients have coro- nary artery disease (CAD) [5]. Left ventricular diastolic dys- function is a common condition associated with increased risk for heart failure and mortality [6]. Left ventricular (LV) dia- stolic dysfunction is commonly seen in patients with LV hy- pertrophy [7].

Tissue doppler imaging (TDI) is a rapid, inexpensive and

non-invasive method for the assessment of both systolic and

diastolic cardiac function. Also, it has been proven to be a useful prognostic tool in the general population [8,9].

However, although there have been several studies for the relathionship of CACS with left ventricular mass index (LVMI) [10-13] and with tissue Doppler imaging (E/E’) [14,15] reflecting LV diastolic function, it has not been es- tablished whether there is an independent association between CACS and LVMI and septal E/E’ ratio in patient presented with chest pain with normal LV systolic function or asympto- matic subjects with high coronary risk factors.

The purpose of this study is to determine if a meaningful relation between CACS and LVMI and tissue Doppler imag- ing (E/E’) reflecting diastolic function exists in patient pre- sented by chest pain or asymptomatic subjects with normal LV ejection fraction. Additionally, the relationship between the CAC and traditional or possible biomarkers [lipid profile, high sensitivity C-reactant protein (hs-CRP), uric acid, mean platelet volume (MPV), calcium, phosphate] that play a role in coronary artery calcification was assessed.

MATERIALS AND METHODS

1. Study population

We retrospectively enrolled 1230 consecutive subjects (mean age±standard deviation, 67.64±12.85) who were clin- ically indicated to undergo MDCT angiography for coronary artery evaluation from September 2007 to August 2011 at Soonchunhyang University Cheonan Hospital. Clinical in- dication for MDCT coronary scanning were as follows: pa- tients with typical or atypical chest pain, asymptomatic pa- tients who were required to take a preoperative coronary ar- tery evaluation due to coronary risk factors (age ＞70, dia- betes, hypertension), other cardiovascular disease such as valv- ular heat disease, congenital heart disease. Exclusion criteria were as follows; acute coronary syndrome, left ventricular ejection fraction ＜50%, baseline creatinine ≥2.0 mg/dL, at- rial fibrillation, frequent extrasystoles, previous percutaneous coronary intervention or bypass surgery. The study protocol was approved by the ethics committee, and was conducted ac- cording to the principles of the Declaration of Helsinki. All patients enrolled in this study provided written informed consent.

2. Cardiovascular risk factors

Basic demographic data including age, gender, hypertension, diabetes mellitus, and smoking history were acquired from electronic medical record. Hypertension was defined as systolic pressure ≥140 mmHg, diastolic pressure ≥90 mmHg, or cur- rent use of antihypertensive medication. Diabetes was defined as fasting glucose ＞125 mg/dL (if untreated) or previous physician diagnosis and treatment with diet, oral hypo- glycemic drugs, or insulin. Current or past history of smok- ing was relevant if the subject had smoked ＞10 cigarettes/day for at least 1 year.

3. Biochemical determinations

Blood samples were drawn by venipuncture after a fasting period of 12 hours. Total cholesterol, triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), creatinine, uric acid, total calcium, and phosphate concentrations were determined by Hitachi 7600 automated clinical chemistry analyzer (Hitachi, Tokyo, Japan). The hs-CRP and glycated hemoglobin (HbA1c) were determined by Cobas Integra 800 (Roche Diagnostics, Mannheim, Germany) using reagent for immunoassay. For whole blood cell counts, tubes containing K3-ethylenediaminetertraacetic acid (EDTA) were used. Hemoglobin, platelet, and MPV were measured using Sysmex XE-2100 (Sysmex, Kobe, Japan) hematology analyzer within an hour of blood sampling, in or- der to prevent EDTA-induced platelet swelling. The intra-assay coefficient of variation was ＜5% for all tests.

The level of kidney function was ascertained by estimated glomerular filtration rate (eGFR) calculated using the formula developed and validated in the MDRD study [16] as follows:

eGFR=(mL/min/1.73 m

)=186.3×(serum creatinine [mg/dL]−

1.154)×(age [years]−0.203)×(0.742, if female).

4. Echocardiographic measurements

Two-dimensional echocardiography was performed using a

Vivid T-dimension (GE, VingMed, Horten, Norway) with a

3.5 MHz probe in subjects lying in the left decubitus posi-

tion by experienced (10 year) echocardiographers blinded to

all clinical details about the patients. All findings were con-

firmed by the cardiologist blinded to all of the patients’ clin-

ical details. Left ventricle (LV) mass was normalized for body surface area and expressed as the LV mass index (LVMI, g/m

). The LV mass was obtained by the LV short-axis dimension and a simple geometric cube formula.

According to Devereux et al. [17], the following equation provides a reasonable determination of LV mass in grams:

1.04×{(LVID+PWT+IVST)

−LVID

}×0.8+0.6, where left ventricular internal diameter at end-diastole (LVID) repre- sents the internal dimension at diastole, posterior wall thick- ness (PWT) represents the PWT, interventricular septal thickness (IVST) represents the interventricular septal thick- ness, 1.04 is the specific gravity of the myocardium, and 0.8 is the correction factor. The definition of LVH was LVMI

≥89 g/m

in female, LVMI ≥103 g/m

in male [18]. Pulse wave Doppler and tissue Doppler image echocardiography was used to assess LV diastolic function. The peaks velocity of the early diastolic filling wave (E wave) were recorded. The ven- tricular filling pressure was estimated by combining the mitral inflow early diastolic velocity (E) and the septal annulus ve- locity (E’). The E/E’ ratio at rest in the all patients was recorded. Increased LV filling pressure was defined as septal E/E’ ratio ≥15 [19].

5. Coronary calcium imaging and quantification MDCT examinations were performed using a 64-slice MDCT scanner (GE Lightspeed VCT, GE Healthcare, Milwaukee, WI, USA). Subjects with a heart rate ＞70 beats/min were given beta-blocking agents before MDCT imaging. Intravenous contrast material was not required to determine CACS. A stand- ard scanning protocol was utilized, with 64×0.625 mm slice collimation, 350 ms rotation time, 120 kV tube voltage, and 300-600 mA tube current, according to subject body habitus.

Electrocardiographic triggering was used. Trigger delay was 70%. Images were reconstructed by 2.5 mm thickness, 2.5 mm interval and 25 cm DFOV. CACSs were measured on a remote workstation (Advantage Workstation; General Electric, Milwaukee, WI) using the Agaston method [20]. A sum to- tal across all four arteries (left main, left anterior descending, left circumflex, and right coronary arteries) was defined CACS. Participants, on the basis of the CACS, were catego- rized in the two following manner that have been known as

predictors for coronary events or acute myocardial infarction in previous studies [21,22]: first, negative CAC (CACS=0) group and positive CAC (CACS ＞0); second, no (CACS =0), mild (0.1 to 100), moderate (100.1 to 400), and severe calci- fication ( ＞400).

6. Statistical analysis

The association between coronary artery calcification and variables (demographic, biochemical, echocardiographic varia- bles) was assessed. Continuous variables were expressed as mean±standard deviation (SD) and analyzed using Student’s t-test. Categorical variables were expressed as percentages and compared using chi-square test.

The Pearson correlation was used to identify the correla- tion between CACS and biochemical and echocaridographic variables. CACS was not normal distribution. So, CACS was analyzed to be transformed into log CACS when Pearson correlation was used.

Variables that showed significant relationships in previous studies and those with a P ＜0.3 on univariate logistic regression analysis were regarded as confounding variables related to the dependent and independent variables. These included age, gender, diabetes, hypertension, smoking, and MDRD eGFR.

To assess the association with dependent variables (including positive CAC and severe CACS) and independent variables (including hemoglobin, MPV glucose, HbA1c, uric acid, cal- cium, phosphate, hs-CRP ＞2.0, triglyceride, total cholesterol, LDL-cholesterol, HDL-cholesterol, LVMI, LVH, septal E/E’

ratio, and septal E/E’ ratio ≥15), multivariate logistic re- gression analysis was used. The covariate-adjusted odds ratios (OR) and their 95% confidence intervals (CI) for each depend- ent variable (positive CAC and severe CACS) were calculated.

We used “the composite score” composed of E/E’ and LVMI, more accurately to predict the severity of coronary ar- tery calcification. The “composite score” were classified into three groups (score 0, 1, 2) according to the presence of E/E’

≥15 and positive LVH (LVMI ≥90 g/m

), that each one point was scored; 1. score 0 (E/E’ ＜15 and LVMI ＜90 g/m

), 2.

score 1 (E/E’ ＜15 and LVMI ≥90 g/m

or E/E’ ≥15 and LVMI ＜90 g/m

), 3. score 2 (E/E’ ≥15 and LVMI ≥90 g/m

).

ANOVA with Bonferroni test for post hoc analysis and co-

Table 1. Comparison between negative and positive coronary artery calcium (CAC) Total

(n=1230)

Negative CAC (n=428)

Positive CAC

(n=802) P value

CACS 243.74±572.66 0 373.14±674.36 ＜0.001

Dermographic variables

Age, years 67.66±12.84 60.95±13.87 71.24±10.66 ＜0.001

Gender, female, n (%) 678 (55.1) 248 (57.9) 430 (53.6) 0.146

Diabetes, n (%) 425 (34.6) 117 (27.3) 308 (38.4) ＜0.001

Hypertension, n (%) 762 (62.0) 223 (54.6) 529 (66.0%) ＜0.001

Smoking, n (%) 174 (14.1) 76 (17.7) 171 (21.3) 0.206

Laboratory variables

eGFR, mL/min/kg 103.83±41.08 113.69±44.16 98.57±38.33 ＜0.001

Hemoglobin, g/dL 12.44±1.98 12.90±1.99 12.20±1.93 ＜0.001

MPV (fL) 10.10±0.94 10.08±0.87 10.11±0.97 0.606

Glucose, mg/dL 127.02±48.03 122.92±39.03 129.21±52.10 0.017

HbA1c, % 6.92±1.52 6.80±1.51 6.97±3.04 0.140

Uric acid, mg/dL 4.83±1.75 4.68±1.67 4.90±1.79 0.033

Calcium, mg/dL 8.77±0.69 8.86±0.72 8.72±0.66 0.001

Phosphate, mg/dL 3.52±0,84 3.60±0.87 3.48±0.82 0.021

hs-CRP ＞2.0 mg/dL, n (%) 524 (42.6) 110 (25.7) 298 (37.2) ＜0.001

Triglyceride, mg/dL 149.56±105.06 150.91±98.13 148.84±108.63 0.743

Total cholesterol, mg/dL 176.01±45.33 177.66±41.62 175.13±47.19 0.334

LDL-cholesterol, mg/dL 93.40±26.77 94.77±30.38 93.13±27.94 0.569

HDL-cholesterol, mg/dL 42.30±13.38 44.54±13.00 41.10±13.44 0.001

Echocardiographic variables

LVMI, g/m

93.90±29.58 88.16±23.77 96.85±31.77 ＜0.001

LVH, n (%) 446 (36.3) 128 (29.9) 318 (39.7) 0.001

Septal E/E’ ratio 12.84±4.32 11.63±3.61 13.47±4.52 ＜0.001

Septal E/E’ ≥15 257 (20.9) 51 (11.9) 206 (25.7) ＜0.001

Data are expressed as mean±SD or n (%).

CACS, coronary artery calcium score; eGFR, estimated glomerular filtration rate; MPV, mean platelet volume; hs-CRP, high sensitivity C-reactant protein; LDL, low density lipoprotein; HDL, high density lipoprotein; LVMI, left ventricular.

variate-adjusted linear regresssion analysis were performed to identify the association of the severity of CACS and

“composite score”. Also, to assess the association with the composite score 2 group according to the CACS severity, multivariate logistic regression analysis adjusted by co-varia- teds was used.

A probability value of a P ＜0.05 was considered statisti- cally significant. All statistical analyses were performed using Statistical Package for Social Science (SPSS) for windows (version 18.0; SPSS, Inc., Chicago, IL, USA).

RESULTS

The clinical characteristics of study subjects according to positive and negative CAC are shown in Table 1. The mean

age was 67.66±12.84 years, and 678 (55.1%) of subjects were female. In addition, 425 (34.6%) of subjects had dia- betes, 762 (62.0%) hypertension, and 174 (14.1%) smoking.

The average of CACS was 243.74±572.66 and the median was 23.50. The number of negative CAC (CACS=0) group was 428 of 1230 and positive CAC (CACS ＞0), 802 of 1230. Age was older in positive CAC group (P ＜0.001).

Diabetes (P ＜0.001), hypertension (P＜0.001), and hs-CRP

＞2.0 mg/dL (P＜0.001) were more frequent in the positive

CAC group, compared to the negative CAC group. Fasting

glucose (P=0.017), uric acid (P=0.033), LVMI (P ＜0.001),

septal E/E’ ratio (P ＜0.001) were higher in the positive CAC

group, compared to the negative CAC group. Conversely,

eGFR (P=0.001), hemoglobin (P ＜0.001), calcium (P=0.001),

phosphate (P=0.021), and HDL-C (P=0.001) were lower in

Table 3. Multivariate binary logistic regression analysis of factors associated with severe CACS (CACS ＞400)

P value* OR 95% CI

for OR*

Hemoglobin 0.957 1.003 0.907-1.109

MPV 0.448 0.929 0.768-1.124

Glucose 0.266 1.002 0.999-1.005

HbA1c 0.867 1.015 0.855-1.205

Uric acid 0.558 0.969 0.871-1.708

Calcium 0.712 0.952 0.735-1.234

Phosphate 0.946 0.993 0.799-1.234

hs-CRP ＞2.0 0.622 1.130 0.695-1.837

Triglyceride 0.788 1.000 0.998-1.002

Total cholesterol 0.296 0.998 0.994-1.002 LDL-cholesterol 0.393 0.998 0.992-1.003 HDL-cholesterol 0.884 0.999 0.984-1.014

LVMI 0.017 1.008 1.001-1.015

LVH 0.001 1.921 1.311-2.815

E/E’ 0.017 1.049 1.009-1.091

E/E’ ≥15 0.020 1.648 1.081-2.512

CACS, coronary artery calcium score; OR, odds ratio; CI, con- fidence interval; MPV, mean platelet volume; hs-CRP, high sensi- tivity C-reactant protein; LDL, low density lipoprotein; HDL, high density lipoprotein; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy.

*Adjusted by gender, age, diabetes, hypertension, smoking, and es- timated glomerular filter rate.

Table 2. Multivariate binary logistic regression analysis of factors associated with positive CAC (CACS ＞0)

P value* OR 95% CI

for OR*

Hemoglobin 0.136 0.936 0.857-1.021

MPV 0.105 1.148 0.971-1.356

Glucose 1.001 0.653 0.997-1.004

HbA1c 0.261 1.090 0.938-1.267

Uric acid 0.233 1.064 1.961-1.178

Calcium 0.210 0.869 0.698-1.082

Phosphate 0.635 1.043 0.877-1.247

hs-CRP ＞2.0 0.088 1.352 0.956-1.910

Triglyceride 0.077 1.001 1.000-1.003

Total cholesterol 0.231 1.002 0.999-1.006 LDL-cholesterol 0.523 0.997 0.989-1.006 HDL-cholesterol 0.018 0.984 0.970-0.997

LVMI ＜0.001 1.018 1.010-1.026

LVH 0.004 1.693 1.186-2.418

Septal E/E’ ratio 0.002 1.075 1.026-1.126 Septal E/E’ ratio ≥15 0.009 1.808 1.160-2.817 CACS, coronary artery calcium score; OR, odds ratio; CI, con- fidence interval; MPV, mean platelet volume; hs-CRP, high sensi- tivity C-reactant protein; LDL, low density lipoprotein; HDL, high density lipoprotein; LVMI, left ventricular mass index; LVH, left ventricular hypertrophy.

*Adjusted by gender, age, diabetes, hypertension, smoking, and es- timated glomerular filter rate.

the positive CAC group. Two groups did not differ with re- gard to gender, smoking, MPV, HbA1c, TG, total cholester- ol, and LDL-C levels.

In multivarate logistric regression analysis adjusted by gen- der, age, diabetes, hypertension, smoking, eGFR for the asso- ciation between classic risk factors and positive CAC, male (P value=0.015; OR, 1.546, 95% CI, 1.086-2.200), age (P value

＜0.001; OR, 1.072, 95% CI, 1.057-1.087), diabetes (P value

＜0.001; OR, 2.368, 95% CI, 1.666-3.367), eGFR (P value=

0.002; OR, 0.994, 95% CI, 0.990-0.998) were associated with the positive CAC.

As seen in Table 2, HDL-cholesterol (OR: 0.984, 95%

CI: 0.970-0.997, P=0.018), LVMI (OR: 1.018, 95% CI:

1.010-1.026, P ＜0.001), LVH (OR: 1.693, 95% CI:

1.186-2.418, P=0.004), septal E/E’ (OR: 1.075, 95% CI:

1.026-1.126, P=0.002), and septal E/E’ ≥15 (OR: 1.808, 95% CI: 1.160-2.817, P=0.009) were independent risk fac- tors of positive CAC, when adjusting for co-variates includ- ing age, gender, diabetes, hypertension, smoking, and eGFR,

but the others not.

Also, in the multivariate logistic regression analysis to as- sess the association with severe CACS (CACS ＞400) and in- dependent variables (including hemoglobin, MPV glucose, HbA1c, uric acid, calcium, phosphate, hs-CRP ＞2.0, trigly- ceride, total cholesterol, LDL-cholesterol, HDL-cholesterol, LVMI, LVH, septal E/E’ ratio, and septal E/E’ ratio ≥15), LVMI (OR: 1.008, 95% CI: 1.001-1.015, P=0.017), LVH (OR: 1.693, 95% CI: 1.186-2.418, P=0.004), septal E/E’

(OR: 1.049, 95% CI: 1.009-1.091, P=0.017), and septal E/E’ ≥15 (OR: 1.648, 95% CI: 1.081-2.512, P=0.020) were independent risk factors of severe CACS (Table 3). We additionally evaluated the relationship between log CACS and LVMI, E/E’, and HDL-C. The significant relationship was observed as follows; LVMI (r=0.161, P ＜0.001), septal E/E’

ratio (r=0.215, P ＜0.001), and HDL-cholesterol (r=−0.126, P=0.001). After adjusted by age and sex, there still continued the statistic significance; LVMI (r=0.185, P ＜0.001), E/E’

(r=0.139, P=0.001), and HDL-C (r=−0.108, P=0.008).

Table 4. Linear regression analysis showing the scoring composed of septal E/E’ ratio ≥15 and LVH is a significant independent predictor of coronary artery calcium score

B coefficient (SE) P value*

Composite score 0, 1, 2

158.244 (27.611) ＜0.001

*Adjusted by age, sex, diabetes, hypertension, smoking history, es- timated glomerular filter rate. LVH, left ventricular hypertrophy.

†

If septal E/E’ ratio ≥15 and the presence of LVH, one point was scored respectively. Therefore, the score composed of E/E’

≥15 and LVH is the one of 0, 1 or 2 points.

Table 5. Association with the composite score 2 group (LVH and septal E/E’ ratio ≥15) according to the CACS severity

P value* OR* 95% CI*

CACS=0 reference reference reference

CACS 1-100 0.045 1.790 1.014-3.161

CACS 101-400 0.015 2.126 1.158-3.903

CACS ＞400 ＜0.001 5.705 3.213-10.130

*Multivariate binary logistic regression adjusted by age, sex, dia- betes, hypertension, smoking history, estimated glomerular filter rate.

LVH, left ventricular hypertrophy; CACS, coronary artery calcium score; OR, odd ratio; CI, confidence interval.

Figure 1. The association of coronary artery calcium score and the composite of LVMI and septal E/E’ ratio. In the presenting data, left ventricular hypertrophy was defined as the LVMI ≥89 g/m

in female and the LVMI ≥103 g/m

in male. In the criteria of septal E/E’ ratio ≥15 and the presense or absence of LVH, the mean CACS of three group (composite score 0, 1, 2) was 149.30±395.29, 271.49±626.16, and 537.59±836.53, respectively (P＜0.001). The post hoc analysis by Bonferroni showed the statistical signficance among three groups.

As suggested in the Table 4, in the multivariate linear re- gression analysis adjusted by age, sex, diabetes, hypertension, smoking, and eGFR, the “composite score” is a significant in- dependent predictor of CACS (B coefficient=158.244, P ＜0.001).

The mean CACS of three group (composite score 0, 1, 2) was 149.30±395.29, 271.49±626.16, and 537.59±836.53, re- spectively (ANOVA, P ＜0.001). The post hoc analysis by Bonferroni showed the statistical signficance among three groups (Figure 1). Also, in the criteria of severity of CACS, the “composite score 2” group was significantly associated with mild, moderate, and severe CACS group except negative CAC and the Odd Ratio of each group was 1.790, 2.126, 5.705, respectively (Table 5). In the “composite score” based

on septal E/E’ ratio ≥15 and the presense or absence of LVH, the higher the score, the greater the CACS.

DISCUSSION

In the present study, LVMI and septal E/E’ ratio that is one of tissue Doppler image were associated with presence and severity of CACS in stable angina pectoris or asympto- matic subjects with normal LV ejection fraction, independent of age, sex, diabetes, hypertension, smoking, and renal func- tion known as classic risk factors of CAC. Simutaneously,

“echo scoring system” composed of LVMI and E/E’ ratio more increased the prediction of presence and severity of CACS, compared to separate LVMI or E/E’ ratio in Table 5 and Figure 1. Also, male gender, age, diabetes, eGFR, and HDL cholesterol were found to be associated with the pres- ence of CAC in adjusted analysis.

1. The association between CACS and LVMI and septal E/E’ ratio

The increased LV mass is associated with significantly in-

creased cardiovascular mortality and morbity [23,24]. Coronary

artery calcium score is a highly sensitive marker for detecting

coronary artery atherosclerosis and coronary artery disease

(CAD) [25,26]. Coronary artery calcium score can be quan-

tified by multidetected row computed tomography (MDCT),

and the score is proportionally related to the severity of athe-

rosclerotic disease [3]. Also, Several studies have shown that

the risk of cardiac events and all causes of mortality increases

proportionally to CACS after adjustment for conventional risk

factors [1].

Untill now, it is a little controversial whether LVMI was associated with CACS; the previous several studies reported that CAC was associated with LVMI or LV hypertrophy [10-13]. Conversely, Eleid et al. [14] reported that LV hy- pertrophy and diastolic dysfunction did not have independent relations with CACS.

In this study, the enrolled subjects were adults with nor- mal LV ejection fraction without regional wall motion abnor- mality of LV. The subjects of our study had higher average (243.74±572.66) and median CACS (23.50) and were older (mean±SD, 67.66±12.84 years), compared with those study.

Also, the symptomatic patients presented with chest pain was included in addition to asymptomatic patients and classic risk factors such as diabetes and hypertension were higher. This findings of our study means that LVMI and septal E/E’ ra- tio can be useful predictors for presence and severity of CACS, especially in patients with high risk factor than low risk factor.

On the other hand, it has been demonstrated that septal E/E’ ratio reflects global diastolic function and is associated to LV preload [19,27]. Although Hoffmann et al. [15] re- ported that E/E’ measured by colour TDI was positively cor- related to the number of vessels with significant stenosis, upto date, there has been no study for association with CACS and E/E’ ratio, except only one recently published study.

However, the result of this study was opposite to our result;

which reported that coronary artery plaque burden as assessed by CACS does not affect left ventricular diastolic function in asymptomatic adults with normal ejection fraction. Our study showed septal E/E’ ratio that tissue Doppler image evaluated by septal E/E’ ratio was associated with presence and severity of CACS. This result may be similar in that Hoffmann et al.

[15] reported that E/E’ measured by colour TDI was pos- itively correlated to the number of vessels with significant stenoses, because CACS was correlated with the number of vessels with signifcant stenoses.

Although positive CAC (CACS ＞0) in Table 2 and se- vere CACS (CACS ＞400) in Table 3 was associated with LVMI, LVH, septal E/E’ ratio, and septal E/E’ ratio ≥15, CACS was only weakly correlated with LVMI (r=0.161, P

＜0.001) and septal E/E’ (r=0.215, P＜0.001). So, we design

“composite score” system,more accurately to be evaluated due to the weak correlation; As shown in Figure 1 and Table 4, in three groups or score composed of LVH and septal E/E’

ratio ≥15, there were significant differences in CACS among each group and the higher “composite score” had the higher CACS. Also, as shown in Table 5, the “compostie score 2”

was independent predictors of CACS severity. Therefore, the combination with LVH and septal E/E’ ratio can be more useful predictors of CASC than separate LVH or septal E/E’

ratio. To our knowledge, the present study is the first study investigating both septal E/E’ ratio and LVMI in relation to different degrees of CACS.

2. The association between CACS and laboratory markers

In addition, we found a significant association between CACS and HDL-C but not the other markers (uric acid, MPV, calcium, phosphate). LDL-cholesterol is traditionally atherogenic laboratory marker. In the presenting study, the average LDL-C level was 93.40±26.77 mg/dL and similar in both negative CAC and positive CAC groups (mean±SD, 94.77±30.38 and 93.13±27.94, respectively; P=0.569). This finding may suggests that it is a quite possibly that our study subjects might take a statin, although we could not inves- tigate drug history including statin. Also, usually, statin can slightly increase HDL-cholesterol or has less of an effect on that. In the presenting study, HDL-cholesterol was associated with CAC, independent of age, gender, diabetes, hyper- tension, smoking, eGFR.

Uric acid has been known as inflammatory marker and cardiovascular risk factor [28]. However, it is controversial that uric acid independently affect the prevalence of coronary artery disease and coronary atherosclerosis [29]. In the pre- senting study, uric acid was associated with presence of CAC, but not independently of conventional risk factors. MPV is one of the platelet function indices that represent platelet stimulation and production rate [30]. MPV is easily meas- urable marker and checking it is cheap. It has been reported that a larger MPV is an indicator of increased platelet activation.

The previous several studies have suggested that MPV was

elevated in vascular diseases such as cerebral and myocardial infarction [30]. However, there are little studies for the di- rect relationship between CAC and MPV. In the presenting study, there was no significant association between CAC and MPV, although Jung et al. reported that MPV was related to CAC in general population. Major consequences of ele- vated serum calcium and phosphate in patients with chronic kidney disease are vascular calcification and increased risk of cardiovascular morbidity and mortality. As aforementioned, CAC is associated with cardiovascular morbidity and mortality.

Although several previous studies have shown that serum cal- cium and phosphate are associated with high rates of cardi- vascular disease even with normal or near-normal kidney function, there is still controversial and little data for associa- tion between CAC and serum calcium and phosphate in sub- jects with normal or near-normal kidney function. In the pre- senting study, calcium and phosphate were higher in CAC positive group, compare with negative. However, when adjusted by age, the calcium and phosphate level were not associated with CAC (respectively, OR, 0.145; 95% CI, 0.709-1.031, P=0.101 and OR, 1.033; 95% CI, 0.833-1.123; P=0.664).

It suggest that serum calcium and phosphate level seems to be unrelated with CAC in subjects with normal or near-nor- mal renal function.

3. Limitations

Severeal limitation to the study should be acknowledged.

First, this is a retrospective, cross-sectional study performed at a single center. Second, the enrolled patients had hetero- genous indications for MDCT. Those were composed of asymptomatic subjects and patients with chest pain except acute coronary syndrome. That makes it uncertain whether the results will be equally applicable to the general clinical practice. Third, the criteria of LVH might be different ac- cording to the ethnicity. Fourth, we could not exclude the possibility that our laboratory findings were influenced by medications that might confound the association between CAC measured by MDCT and serum biomarker and lipid profiles.

Although there were several limitations, it was inferred that our study model and result might be relevant and significant

because our results were consistent with previous outcomes documenting that old age, male gender, diabetes, and eGFR were associated with posivite CAC. Also, this study enrolled a large number of 1230 subjects. Above all, our study, for the first time, suggested that the combination with LVMI and septal E/E’ ratio can be more powerful predictor of CACS in addition to separate LVMI and septal E/E’ ratio.

In our study, LVMI and septal E/E’ ratio were associated with positive CAC and CACS severity, independent of classic risk factors such as age, gender, diabetes, hypertension, smoking, eGFR in the patient with chest pain or without symptom with normal left ventricular ejection fraction except acute coronary syndrome. “Composite score” might be useful in prediction for the severity of CASC. HDL cholesterol is to be associated with the presence of CAC.

CONFLICTS OF INTEREST

No potential conflict of interest relevant to this article was reported.

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