An association between volumes of the cardiac chambers and troponin levels in individuals submitted to cardiac coronary computed tomography

Abstract

Background

Previous echocardiographic studies have revealed an association between enlarged cardiac chamber volumes and elevated troponin concentrations. An automatic 4‐chamber volumetric analysis tool was adopted to investigate this association in patients who underwent cardiac‐gated computed tomography angiography (CCTA).

Hypothesis

We hypothesized that troponin concentration within the normal range correlates with cardiac chambers' volumes.

Methods

Serum troponin was obtained from 157 ambulatory patients before undergoing CCTA for nonacute coronary artery evaluation. Volumes of the cardiac chambers and the left ventricular mass were automatically analyzed and indexed to body surface area. Patients with a troponin concentrations within the upper quartile (>0.007 ng/mL, n = 39) were compared to patients with a troponin concentrations within the 3 lower quartiles of troponin concentrations (≤0.007 ng/mL, n = 118).

Results

None of the patients had a troponin concentration >0.05 ng/mL (the 99th percentile of the general population). There were no significant differences in baseline characteristics between the groups. There were significant correlations between troponin and ventricular volumes after adjustments for age and gender. In an analysis that included 107 patients without any known heart diseases, including those pathological findings in the current CCTA, there were significant correlations between troponin and the left and right ventricular volumes after adjustments for age, gender, and baseline characteristics (odds ratio [OR]: 1.08, 95% confidence interval [CI]: 1.03‐1.14, P = 0.002 and OR: 1.11, 95% CI: 1.04‐1.19, P = 0.002; respectively).

Conclusions

Using the technology of automatic volumetric analysis in individuals undergoing CCTA, an association between larger right and left cardiac chambers and higher levels of troponin concentration was shown.

1. INTRODUCTION

Cardiac troponin concentration in the serum is a widely used assay, and the preferred marker of myocardial necrosis.1 Not uncommonly, elevated troponin concentrations are documented in patients without coronary artery disease.2, 3 There is a graded correlation between troponin levels in the normal range and cardiovascular outcomes.4, 5, 6

An association between troponin concentration and left cardiac chamber enlargement, as assessed by various imaging methods, was previously reported.7, 8, 9 During the last few years, a computed tomography (CT)‐based 4‐chamber volumetric analysis software (4CVA) was applied to automatically assess the cardiac chambers’ volumes in patients who underwent a nongated CT pulmonary angiography10, 11 as well as cardiac‐gated coronary computed tomography angiography (CCTA).12 Part of the advantage of the 4CVA technology is its capability to provide the volumes of both the right and left atria and ventricles automatically and simultaneously. The application of 4CVA on patients who underwent gated CCTA to reveal the relation of cardiac chambers' volumes and troponin concentration has never been studied. Thus, the present study was performed to assess the relations between the volumes of the 4 cardiac chambers based on analysis of CCTA data, and cardiac stress, as marked by troponin concentration. Moreover, such an association may reveal additional information regarding the pathophysiology of troponin release with regard to both right and left compartments’ volumes.

2. METHODS

2.1. Study design and patient selection

The data in this study were collected from the Tel Aviv Prospective Angiographic Survey (TAPAS) database. The TAPAS is a prospective, single‐center registry that enrolls all patients undergoing any cardiac test (angiogram, echo, CCTA) at the Tel Aviv Medical Center.13, 14 All the enrollees signed a written informed consent for participation in the study, which was approved by the institutional ethics committee. The study cohort consisted of 166 consecutive patients referred for elective ambulatory CCTA in our institution to rule out coronary artery disease, who had available blood sampling for troponin concentration at the time of the CCTA. The medical history of each patient was documented via individual questionnaires.

2.2. CCTA acquisition

CCTA was performed with a 128 × 0.625 mm or 64 × 0.625 mm detector rows scanner (iCT 256 or Brilliance 64; Philips HealthCare, Cleveland, OH) using our routine coronary arteries assessment protocol. Briefly, an average of 70 to 90 mL of iodinated contrast material at a concentration of 400‐mg iodine per mL (Iomeron; Bracco, Milano, Italy) and at rates of 5 to 6 mL/s were injected and timed using an automated bolus‐tracking technique placed at the descending aorta. To permit visualization of the right heart, we use 3 injection phases: first is the phase of contrast only (55–70 mL), second is the phase of mixed 50% contrast and 50% saline (total of 30–40 mL), and a third phase of 40 mL of saline flush. We used prospective (step and shoot) mode scan for every patient with a heart rate under 70 bpm or retrospective gating with dose modulation in patients with higher heart rates. Data were reconstructed at slice thickness of 0.8 mm with an increment of 0.4 mm. For the analysis of the coronary arteries, the phase that had less motion artifacts was selected, whereas all volumetric analysis were done on a mid‐diastolic phase scan (78% or 75% of the R to R interval). Oral β‐blockers (metoprolol 50 mg) were given to patients who were not pretreated with β‐blockers (n = 63) in case of a heart rate above 60 bpm.

2.3. Coronary artery and volumetric analysis of the cardiac chambers

Automated volumetric measurements of the right ventricle (RV), right atrium (RA), left ventricle (LV), the left atrium (LA), and the LV mass were obtained using fully automatic software (Comprehensive Cardiac Analysis, Extended Brilliance Workspace, Version 4.5 or IntelliSpace, Portal Version 6; Philips Healthcare, Cleveland, OH). The software adapts an anatomical model of the heart chambers to the CT image volume.15, 16, 17 The output consists of a 3‐dimensional graphic display of the heart segmented into its main structures. We analyzed the volumes of the RV, RA, LV, and LA. The volume of each cardiac chamber was automatically calculated as the product of a single voxel volume and the sum of all voxels included in it. The software allows the relevant segmentation structure to be color‐coded and viewed simultaneously in both 3 dimensions and 2 dimensions, and superimposed on the reference image in the axial, coronal, sagittal, or cardiac views (short axis, vertical long axis, horizontal long axis). Each structure was inspected visually on the reference images for conformity to the imaged cardiac anatomy to validate the correctness of the segmentation. In the event that the automatic segmentation was visually assessed as incorrect, the patient's data were excluded from the study (n = 9). In addition, using dedicated coronary analysis software of the same workspace unit, the coronary arteries were evaluated for the presence of coronary artery disease. Obstructive coronary artery disease was defined as evidence of ≥50% reduction of the diameter in 1 or more of the coronary arteries on CCTA. All volumetric measurements were divided by the body surface area (BSA) and reported as milliliter/square meter. Figure 1 demonstrates the output of the 4CVA software.

Figure 1.

Demonstration of the fully automated 4‐chamber volumetric analysis output. (Upper right) Volumetric model of the 4 cardiac chambers. (Upper left) Horizontal long axis. (Lower right) Short axis oblique reformation. (Lower left) Vertical long axis reformation (4‐chamber view). Color code: left atrium = purple, left ventricle = pink (blue on the volumetric model), right atrium = yellow, and right ventricle = orange. Abbreviations: LA, left atrium; LV, left ventricle; RA, right atrium; RV, right ventricle.

2.4. Troponin testing

Venous blood samples were obtained from all participants via their venous access puncture site before undergoing CCTA and following 6 hours of fasting. Serum troponin I (TnI) concentrations were measured by ADVIA Centaur (Siemens Healthcare GmbH, Erlangen Germany) with a chemiluminescent reaction. The above‐mentioned test meets the guidelines criterion for ≤10% coefficient of variation at the 99th percentile18, 19, 20 and is considered a sensitive assay for TnI measurement.

2.5. Statistical analysis

Categorical variables were expressed as number and percentages. Distribution of continuous variables was assessed using a histogram and Q‐Q plot. Normally distributed continuous variables were described using mean and standard deviation, and non‐normally distributed continuous variables were expressed using median and interquartile range (IQR). Categorical variables were compared using χ² test or Fisher exact test, and continuous variables were compared using independent samples t test or Mann–Whitney test, as appropriate. Multivariate logistic regressions were used to evaluate the association between each chamber's volume and TnI category. Adjusted odds ratio (OR) with 95% confidence interval (CI) were reported. The covariates included in the multivariate regression were age, gender, and variables when P < 0.2 in the univariate analysis. All logistic regressions were evaluated for goodness of fit using the Hosmer‐Lemeshow test. A 2‐tailed P ≤ 0.05 was considered statistically significant. Analyses were performed with SPSS version 22.0. (IBM Corp., Armonk, NY).

3. RESULTS

3.1. Patient characteristics

Out of 166 patients who met the inclusion criteria, 9 patients (5%) were excluded due to failure of accurate automatic volumetric assessment of their CCTA, leaving a final cohort of 157 patients. The median age was 57 years (IQR, 48.5–62.5 years), and 73.9% of the cohort population were males. Patients included in the study were divided according to TnI concentration, equal or below 0.007 ng/mL (the lower quartiles; Q1–Q3, n = 118) and greater than 0.007 ng/mL (the upper quartile; Q4, n = 39). None of the patients had a TnI concentration above 0.05 ng/mL (the 99th percentile of the general population). Baseline characteristics are reported in Table 1. There were no significant differences between the groups (TnI ≤0.007 ng/mL versus TnI >0.007 ng/mL) including age, gender, cardiovascular risk factors, and a history of ischemic heart disease.

Table 1.

Baseline characteristics according to troponin concentration

	Troponin ≤0.007, ng/mL, n = 118	Troponin >0.007, ng/mL, n = 39	P Value
Troponin	0.002(0–0.004)	0.015(0.009–0.021)
Age, y	57.0 (50.0–64.0)	57.0 (48.0–62.0)	0.626
Male gender	85 (72%)	31 (79.5%)	0.358
Hypertension	40 (37.4%)	17 (47.2%)	0.297
Diabetes mellitus	19 (17.4%)	5 (14.3%)	0.664
Hyperlipidemia	36 (45.6%)	12 (48%)	0.832
Overweight	34 (39.1%)	17 (53.1%)	0.170
Current smoker	22 (19.6%)	7 (18.4%)	0.734
Past smoker	36 (32.1%)	10 (26.3%)
Nonsmoker	54 (48.2%)	21 (55.3%)
Prior CABG	1 (1.0%)	0 (0.0%)	>0.999
Prior PCI	5 (5.0%)	5 (15.2%)	0.119
Prior MI	5 (4.6%)	3 (8.1%)	0.418
Chronic heart failure	1 (1.0%)	0 (0.0%)	>0.999
Valvulopathy	3 (3.1%)	0 (0.0%)	>0.999
Prior CVA/TIA	2 (1.9%)	1 (2.8%)	>0.999
COPD/asthma	4 (3.8%)	4 (11.8%)	0.980
Chronic kidney disease	1 (0.9%)	0 (0.0%)	>0.999
eGFR (mL/min/1.73 m2)	86.8 (71.3–101.9)	90.5 (73.7–111.2)	0.164
Hyperthyrodism	0 (0.0%)	1 (3.8%)	0.236
Hypothyrodism	4 (4.8%)	1 (3.7%)	>0.999
Anemia	10 (8.5%)	5 (12.8%)	0.529
Any cardiac diseasea	33 (28%)	17 (43.6%)	0.069
CAD according to CCTA	29 (24.6%)	12 (30.8%)	0.445
No. of stenotic vessels	0.42(0–0.25)	0.49(0–1)	0.496

Abbreviations: CABG, coronary artery bypass graft; CAD, coronary artery disease; CCTA, cardiac computed tomography angiography; COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; MI, myocardial infarction; PCI, percutaneous coronary intervention; TIA, transient ischemic attack.

Values are presented as number of patients, median (interquartile range), or percentages.

^aAny cardiac disease includes prior CABG, prior PCI, prior MI, chronic heart failure, valvulopathy, and CAD according to CCTA.

A subgroup analysis of patients without any known cardiac disease (nor coronary artery disease per the current CCTA), was investigated separately. A total of 107 patients were included in this analysis (Table 2), and divided into the same TnI categories (≤0.007 ng/mL, n = 85; and >0.007 ng/mLl, n = 22). Similarly, there were no significant differences in baseline characteristics between the groups, including age, gender, and comorbidities.

Table 2.

Baseline characteristics according to troponin concentration of patients without cardiac diseases

	Troponin ≤0.007, ng/mL, n = 85	Troponin >0.007, ng/mL, n = 22	P Value
Troponin	0.002(0–0.004)	0.015(0.008–0.019)
Age, y	56 (47.5‐62)	55.5 (43.7–60.2)	0.454
Male gender	59 (69.4%)	17 (77.3%)	0.469
Hypertension	29 (37.2%)	9 (45.0%)	0.522
Diabetes mellitus	13 (16.7%)	3 (15.8%)	>0.999
Hyperlipidemia	28 (50.0%)	6 (40.0%)	0.491
Overweight	25 (37.3%)	7 (41.2%)	0.770
Current smoker	19 (23.5%)	4 (18.2%)	0.660
Past smoker	23 (28.4%)	5 (22.7%)
Nonsmoker	39 (48.1%)	13 (59.1%)
Prior CVA/TIA	1 (1.3%)	1 (4.8%)	0.384
COPD/asthma	4 (3.8%)	3 (15.8%)	0.133
Chronic kidney disease	1 (1.3%)	0 (0.0%)	>0.999
eGFR (mL/min/1.73 m2)	87.6 (71.2–102.5)	94.8 (77.9–117.8)	0.125
Hyperthyroidism	0 (0.0%)	1 (7.1%)	0.192
Hypothyroidism	4 (6.8%)	1 (6.7%)	>0.999
Anemia	7 (8.2%)	3 (13.6%)	0.426

Abbreviations: COPD, chronic obstructive pulmonary disease; CVA, cerebrovascular accident; eGFR, estimated glomerular filtration rate; TIA, transient ischemic attack.

Values are presented as number of patients, median (interquartile range), or percentages.

3.2. Volumetric analysis

Table 3 shows the results of the volumetric analysis. A univariate as well as an analysis adjusting for gender and age demonstrated a significant correlation to TnI concentrations in the upper quartile (>0.007 ng/mL). A multivariate analysis adjusted for age and gender demonstrated that larger LV and RV volumes (indexed to BSA) among all of the cohort population, were significantly associated with TnI concentrations in the upper quartile (>0.007 ng/mL) (OR: 1.04, 95% CI: 1.01‐1.07, P = 0.01 and OR: 1.04, 95% CI: 1.01‐1.08, P = 0.01, respectively). That is to say, for every 1 mL/m² increase in the volume of the LV/BSA, the probability for a TnI value to be in the upper quartile rises 1.04‐fold, and by 1.04 with for every 1 mL/m² increase in the RV volume. The atrial volumes did not show such an association. The above‐mentioned associations were not statistically significant after adjustments for all baseline characteristics (Table 3 and Figure 2A).

Table 3.

Chamber volumes according to troponin concentration

Chamber	Troponin ≤0.007, ng/mL, N = 118	Troponin >0.007, ng/mL, N = 39	P Value for Univariate Analysis	OR Adjusted for Age and Gender	P Value Adjusted for Age and Gender	ORa	P Value for Multivariate Analysis
LV/BSA	57.7 (50.8–65.6)	62.6 (56.2–73.5)	0.011	1.04 (1.01–1.07)	0.01	1.03 (0.99–1.07	0.078
LA/BSA	35.9 (30.1–43.6)	41.4 (33.9–45.3)	0.262	1.02 (0.99–1.06)	0.246	1.00 (0.96–1.05)	0.866
RV/BSA	70.5 (61.4–82.8)	76.4 (68.3–88.4)	0.022	1.04 (1.01–1.08)	0.01	1.03 (0.99–1.07)	0.088
RA/BSA	40.9 (34.7–48.7)	41.2 (36.8–48.0)	0.718	0.87 (1.01–0.96)	0.873	0.99 (0.94–1.04)	0.635
Chamber, Excluding Cardiac Diseases	Troponin ≤0.007, ng/mL, N = 85	Troponin >0.007, ng/mL, N = 22	P Value for Univariate Analysis	OR Adjusted for Age and Gender	P Value Adjusted for Age and Gender	ORb	P Value for Multivariate Analysis
LV/BSA	58 (51–66)	66.1 (56.1–82.9)	0.018	1.04 (1.01–1.08)	0.019	1.08 (1.03–1.14)	0.002
LA/BSA	34.7 (29.9–42.7)	41.4 (35–45.7)	0.162	1.03 (0.99–1.08)	0.141	1.03 (0.97–1.09)	0.307
RV/BSA	70.7 (61.7–82.5)	86.2 (68.6–94.4)	0.006	1.04 (1.01–1.08)	0.01	1.11 (1.04–1.19)	0.002
RA/BSA	41.1 (34.3–48)	43.5 (39.4–49.3)	0.235	1.01 (0.96–1.05)	0.873	1.05 (0.98–1.12)	0.173

Abbreviations: BSA, body surface area; OR, odds ratio; RA, right atrium; RV, right ventricle; LA, left atrium; LV, left ventricle.

Values are presented as median in milliliters (interquartile range).

^aAdjusted for age, gender, and baseline variables with P < 0.15 in univariate analysis: chronic obstructive pulmonary disease/asthma, any heart diseases, and LV mass/BSA.

^bAdjusted for age, gender, and baseline variables with P < 0.15 in univariate analysis: chronic obstructive pulmonary disease/asthma, estimated glomerular filtration rate, and LV mass/BSA.

Figure 2.

(A) Results of 4‐chamber volumetric analysis of all patients according to troponin I concentration. (B) Results of 4‐chamber volumetric analysis of patients without cardiac diseases according to troponin I concentration. Troponin I is expressed in ng/mL. Abbreviations: BSA, body surface area.

In the subgroup analysis (n = 107) of patients without known cardiac diseases, including those pathological findings in the current CCTA, the RV and LV were larger in patients within the upper quartile TnI concentrations after adjustments for age, gender, and baseline characteristics (OR: 1.08, 95% CI: 1.03‐1.14, P = 0.002 and OR: 1.11, 95% CI: 1.04‐1.19, P = 0.002, respectively). Namely, for every 1 mL/m² increase in the volume, the probability for a TnI value to be in the upper quartile rises 1.08, and 1.11‐fold, respectively. The differences in atrial volumes did not reach a statistical significance between the groups (Table 3).

A detailed comparison stratified according to gender of the analysis, which included all patients, and the subgroup analysis of patients without known cardiac diseases may be viewed in Supporting Table 1 and Supporting Table 2, respectively, in the online version of this article.

4. DISCUSSION

This is the first study to report an association between cardiac chambers' volumes and higher TnI concentrations by using the technology of 4CVA in patients who underwent CCTA.

CCTA is nowadays widely used for the diagnosis and assessment of coronary artery disease.21 The same imaging study may provide viable information on the volumes of the heart chambers, in addition to the assessment of coronary artery disease.22 It is well known that higher volumes of the cardiac chambers are interdependent, and perhaps interchangeable, with prolonged exposure to higher pressures.23 In circumstances where chamber pressures rise, cardiac troponin may be released, as increased wall strain may lead to subendocardial ischemia and injury.24 Patients with larger chambers, and therefore presumably higher pressures, had higher TnI concentrations in our cohort. This association was first reported using echocardiography imaging for evaluation of the chambers’ dimensions.7, 8, 9, 25, 26 It has been previously shown that even asymptomatic patients have a higher chance for heart failure when they have detectable troponin.27 In the PARAMOUNT (Prospective comparison of angiotensin receptor neprilysin inhibitor with angiotensin receptor blocker on Management Of heart failUre with preserved ejectioN fraction) trial, a population of heart failure patients with preserved ejection fraction was studied. Patients with high‐sensitivity troponin T (TnT) above 0.014 µg/L were shown to have higher LA and LV volumes compared to patients with lower TnT levels.8 A detailed simultaneous assessment of all 4 cardiac chambers’ volumes with correlation to troponin concentrations, however, has not been described to date. Furthermore, the above trials included patients with known cardiac structural or ischemic diseases. In the present cohort, all cardiac chambers of the patients with and without cardiac diseases were simultaneously analyzed and correlated to the TnI concentration. Because the volumes and pressures of the chambers are interdependent and comprise 1 hemodynamic system, the evaluation of both heart sides is of important value. Moreover, the lack of such a thorough analysis in previous trials, and the frequent difficulties visualizing right cardiac chambers by echocardiography, emphasizes the pathophysiological value of the present data. Using magnetic resonance imaging, 1 study assessed the LV volumes among individuals in the general population.7 They reported increased LV end‐diastolic volumes and LV hypertrophy in subjects with higher TnT concentrations. There were no assessments of atrial volumes or of RV volumes. A different cohort9 assessed only the volumes of the left cardiac chambers using CT data in patients who underwent CCTA due to acute chest pain. The study showed a correlation between the LA volumes, LV volumes and mass, and TnT concentrations in all patients (including those with acute coronary syndrome). Although the correlation was only 0.13 to 0.3 (Spearman correlation), statistical significance was demonstrated. In a subanalysis that excluded patients with acute coronary syndrome, the association remained.

The current literature has very limited information regarding the association between troponin concentrations and cardiac chambers’ volumes, particularly the right‐sided chambers, based on CT data. It is essential to emphasize the importance of assessing the right cardiac chambers, for the right ventricle may be subjected to high pressures resulting from numerous pathologies that present as pulmonary hypertension,28 thus creating wall tension stress and release of troponin. These changes may have no apparent effect on the left cardiac chambers’ volumes, at least initially.29, 30 In our cohort, all 4 cardiac chambers' volumes were analyzed. Even after exclusion of patients with a history of cardiac diseases or coronary artery disease, the differences between the groups (high vs low TnI concentrations) were demonstrated (Figure 2B). The ventricles account for most of the myocardial mass; therefore, it is reasonable to assume that a chronic ischemic assault will cause more release of troponin from ventricular myocytes compared with atrial myocytes. Our study showed a better correlation between TnI concentration and higher ventricular volumes in a multivariate analysis. Nevertheless, the LA is more compliant than the LV,31 and therefore may endure ongoing stress. Accordingly, a significant correlation between TnI concentration and higher LA volume was found after an adjustment for age and gender. The RA, however, which is subjected to relatively lower pressures than the LA,32 was not shown to be significantly enlarged in patients with higher TnI concentrations.

5. CONCLUSION

Using the 4CVA technology, our data demonstrate an association between larger left and right cardiac chambers and higher levels of TnI concentrations. These findings shed more light on the potential pathophysiological relevance of heart chamber enlargement as detected by the 4CVA technology.

Conflicts of interest

The authors declare no potential conflicts of interest.

Supporting information

Supporting Table 1: Chamber volumes according to troponin concentration stratified to gender

Supporting Table 2: Chamber volumes according to troponin concentration stratified to gender in patients without cardiac diseases

Rozenbaum Z, Arbe Y, Granot Y, et al. An association between volumes of the cardiac chambers and troponin levels in individuals submitted to cardiac coronary computed tomography. Clin Cardiol. 2017;40:879–885. 10.1002/clc.22739