a b s t r a c t

Introduction: right ventricular dysfunction has proved to be an important predictor of morbidity and mor- tality in patients with pulmonary embolism (PE). tricuspid annular plane systolic excursion is one of the parameters that have been validated as predictor of outcomes. The aim of our study was to evaluate the perfor- mance (sensitivity and specificity) of high-sensitivity cardiac troponin T (hs-cTnT) to predict RV dysfunction de- fined as TAPSE b 16 mm.

Methods: We conducted a single-center retrospective analysis of 40 patients prospectively included. Median age was 66 years (59-76) and PESI score was 81 (67-100).

Results: right ventricular dysfunction was present in 30% of the patients and was associated with higher median troponin values (33.5 ng/L vs 16 ng/L; P= .03). A logarithmic relation was observed between hs-cTnT and lower TAPSE values (r²= 0.36; Pb .0001). The area under the ROC curve of hs-cTnT to predict RV dysfunction was 0.77 (0.63-0.92).

Conclusion: hs-cTnT is a biomarker with good performance to identify RV dysfunction in PE.

(C) 2016

Introduction and objective

Pulmonary embolism (PE) is a common condition with a hospital mortality rate ranging from 3% to 25%. Hemodynamic decompensation and refractory hypotension are the best predictors of adverse outcome [1,2]. However, most of the patients with PE are normotensive, and, in them, Right ventricular dysfunction has demonstrated to be an im- portant predictor of morbidity and mortality [3,4].

Tricuspid annular plane systolic excursion (TAPSE) is considered a good echocardiographic parameter to evaluate RV dysfunction [5,6], and recent studies have reported that it is a very useful echocardio- graphic marker to predict mortality at 30 days in PE [7,8].

The recommendations of the current guidelines for risk stratification of patients with PE include imaging evaluation of RV function and mea- surement of biomarkers as high-sensitivity cardiac troponin T (hs-cTnT) and B-type Natriuretic Peptide [1,9]. Yet, there is insufficient evi- dence about the correlation between RV function and hs-cTnT values [10,11].

The aim of our study was to evaluate the performance (sensitivity and specificity) of hs-cTnT to predict RV dysfunction defined as TAPSE b 16 mm in patients with acute PE.

* Corresponding author. Tel.: +54 11 4787 7500×3240.

E-mail address: [email protected] (G. Daquarti).

Methods

We conducted a single-center retrospective analysis using the elec- tronic database and the clinical records of all the patients consecutively discharged from the Instituto Cardiovascular de Buenos Aires (ICBA) with a diagnosis of acute PE between June 2012 and May 2015. Patients were excluded if hs-cTnT or TAPSE were not measured during hospital- ization. We did not exclude patients with other Potential causes of tro- ponin elevation or modifiers of troponin levels in order to show the real population that suffers PE.

The diagnosis of PE was confirmed by contrast-enhanced multi-slice computed tomography and defined as a filling defect or amputation of a pulmonary arterial branch in patients witha Wells score >=4 [12]. Patients with contraindications to receive Contrast agents underwent ventilation- perfusion scintigraphy, and the diagnosis of PE was made by the presence of ventilation/perfusion mismatch. Patients were treated with low molec- ular weight heparin unless contraindicated. Thrombolytic therapy was only reserved for patients with hemodynamic decompensation.

Right ventricular dysfunction was defined as TAPSE b 16 mm. According to guidelines and several publications, TAPSE is the echocar- diographic parameter that provides the best correlation with RV ejec- tion fraction evaluated by magnetic resonance imaging, and identifies the risk of clinical events in PE [7,8]. Echocardiography assessment and measurements were performed within the first 48 hours after ad- mission by cardiologists with advanced training in echocardiography endorsed by the Argentine Society of Cardiology.

http://dx.doi.org/10.1016/j.ajem.2016.05.071

0735-6757/(C) 2016

1580 G. Daquarti et al. / American Journal of Emergency Medicine 34 (2016) 1579-1582

Table 1

Characteristics of patients with and without RV dysfunction

Variables	TAPSE b 16	TAPSE >= 16	P
Women (%)	7 (58%)	13 (46%)	0.49
Age, (years)	64 (56-73)	67.5 (56-76)	0.70
DVT, n (%)	5 (42%)	13 (46%)	0.87
Cancer, n (%)	2 (17%)	5 (18%)	0.93
COPD, n (%)	1 (8%)	3 (10%)	0.82
Coronary artery disease, n (%)	3 (25%)	4 (15%)	0.44
creatinine clearance, (ml/min)	74 (53-98)	71 (57-80)	0.47
HR at admission, (bpm)	100 (83-120)	75 (70-90)	0.01
AF, n (%)	1 (8%)	1 (4%)	0.42
Beta blockers, n (%)	4 (33%)	5 (18%)	0.28
PESI	115 (70-152)	74 (64-98)	0.04
PASP, (mm Hg)	49.5 (39-54)	40 (28-52)	0.19
RV dilation, n (%)	10 (80%)	6 (22%)	b0.0001
Lobar involvement, n (%)	8 (80%)	24 (89%)	0.48

High-sensitivity cardiac troponin T was measured when the patient was admitted to the Emergency Department using Roche Diagnostics Elecsys 2010 Immunoassay System, following the international stan- dards. The cutoff value based on the normal distribution curve that in- cludes the 99th percentile of the healthy population is 14 ng/L, and the analytical range is 3-10,000 ng/L [13].

Creatinine clearance was estimated using the CKD-EPI equation [14], and the PESI score [15] was used to determine the risk of mortality.

The study was conducted following the recommendations of the Declaration of Helsinki and was approved by the institutional Teaching and Research Committee and by an independent Committee on Ethics. All the patients signed an informed consent form.

Statistical analysis

Categorical variables were expressed as percentages and continuous variables as means and standard deviation or medians and interquartile ranges, and were compared using the chi square test or the Mann- Whitney test, respectively. The correlation between TAPSE and hs- cTnT was analyzed using the curve estimation procedure and the linear association was evaluated with the Spearman’s correlation coefficient. The analysis of the receiver-operating characteristic (ROC) curve was used to calculate the sensitivity and the specificity of the different values of hs-cTnT to predict RV dysfunction. A multivariate analysis was per- formed. A two-tailed P value b.05 was considered statistically significant.

Statistical analysis was performed using SPSS 20.0 statistical package for Windows (SPSS Inc., Chicago, Ill).

Results

Between June 2012 and May 2015, 69 patients were discharged with a diagnosis of PE; 40 of them fulfilled the inclusion criteria. Mean age was 65 years and 45% were men, 7% had chronic obstructive pulmonary disease (COPD) and 16% had a history of cancer. Median PESI score was

81. At admission, systolic blood pressure was 126 mm Hg (IQR 25-75, 112-140) and 97% of the patients were hemodynamically stable. In 30% of the patients TAPSE was b 16 mm and 38% presented RV dilation. Mean pulmonary artery pressure was 40 mm Hg (IQR 25-75, 30-50).

Patients with TAPSE b 16 mm had higher prevalence of RV dilation (83% vs 22%; Pb .0001), higher PESI score (115 vs 74; P= .04) and higher median hs-cTnT (33.5 ng/L vs 16 ng/L; P= .03) compared with those with TAPSE >= 16 mm (Table 1) (Fig. 1). The correlation analysis showed that higher levels of hs-cTnT were associated with lower TAPSE values in a logarithmic fashion (r²= 0.36; Pb .0001) (Fig. 2). In multivariable linear regression adjusting for age, PESI, chronic obstructive pulmonary disease, and creatinine clearance, natural log (ln) of hs-cTnT was inde- pendently associated with TAPSE (? = -25,775, [-35,654-13,99] Pb

.001). Hs-cTnT level was weakly correlated to age (Spearman’s ? = 0.29, P= .022).

When we analyzed patients according to the need of fibrinolysis, 5 of 40 patients included evolved with shock requiring thrombolytic admin- istration. Initial TAPSE value was below 16 in all patients that received thrombolytic while the value was low in only 7 of the 35 patients who did not receive (P= .001). Median hs-cTnT in patients who received thrombolytic was 49 (29,5-90) versus 20 (8-36) in patients who did not. (P= 0,021).

The area under the ROC curve of hs-cTnT to predict RV dysfunction was 0.77 (95% CI, 0.63-0.92). Table 2 details the different values of sen- sitivity and specificity of the different cutoff points of hs-cTnT.

Discussion

Our study evaluates the sensitivity and specificity of hs-cTnT as a marker of RV dysfunction in patients with PE.

Patients with PE constitute a heterogeneous population in terms of outcome; thus, it is fundamental to define the Short-term risk for treat- ment decisions [16]. There is sufficient evidence about the poor out- come of patients presenting hypotension with or without shock. However, most patients are normotensive and 70% are considered at in- termediate risk, according to the scores recommended by the guidelines [17-21]. TAPSE has been validated as a prognostic parameter in PE, is easy to measure and has very low Interobserver variability [8,22]; yet, it requires a bedside ultrasound, which is not available in many emer- gency departments. Troponin has emerged as an indirect marker of RV dysfunction [23,24]. The rationale for its use is based on the leading role of ischemia in the genesis of RV dysfunction produced by impaired coronary artery perfusion due to the sudden increase in RV pressure. Troponin is a biomarker or myocardial injury that can be early detected in blood samples and remains detectable for 3 days after an acute PE [25].

In 2012, Hong Sang Choi et al published the association between di- verse biomarkers and their usefulness to predict RV dysfunction [26], and reported an area under the ROC curve of 0.77 for troponin that is similar the our finding. However, it should be noted that the definition of RV dysfunction was subjective and they did not use hs-cTnT.

It has been demonstrated that hs-cTnT offers superior efficacy than Conventional troponin To predict mortality in patients with PE [27]. The cutoff value of 14 ng/L, corresponding to the 99th percentile of the healthy population, has an excellent negative predictive value; how- ever, as the specificity to predict events and RV dysfunction is low (48% in our study) new cutoff values should be explored. Recently, Kaeberich et al have suggested a cutoff value of 45 ng/L, instead of 14 ng/L, to pre- dict the risk of RV dysfunction in patients N 75 years with acute PE [28].

1000

High-sensitivity Toponin T (ng/L)

100

10

1

0

Without RV dysfunction With RV dysfunction

Fig. 1. Boxplot. hs-cTnT values according to RV dsyfunction defined as TAPSE b16 mm.

G. Daquarti et al. / American Journal of Emergency Medicine 34 (2016) 1579-1582

A B

1581

300 300

250 250

TAPSE (mm)

TAPSE (mm)

200 200

150 150

100 100

0 50 100 150 200 1,00 2,00 3,00 4,00 5,00 6,00

hs-cTnT (ng/L) ln hs-cTnT (ng/L)

Fig. 2. Logarithmic relation between hs-cTnT and TAPSE (A) and its correspondent linear transformation using the natural logarithm of hs-cTnT (ln hs-cTnT) (B). R² 0.36; Pb 0.0001.

Finally, a recent study has reported the performance of hs-cTnT for identifying RV dysfunction confirmed by TAPSE in patients with amy- loidosis [29]. Our study is one of the first to describe the association be- tween TAPSE and hs-cTnT in PE.

We believe that knowing the performance of hs-cTnT to predict RV dysfunction will be particularly useful when echocardiography cannot be performed due to lack of equipment or human resources or to a sub- optimal ultrasonic window. The emergency departments would be par- ticularly benefited from this method.

Study limitations

The retrospective nature of the study and the low number of patients are the main limitations.

The hypothesis proposed in our study should undergo external val- idation and should be reproduced prospectively with a larger cohort of patients to produce an impact in daily practice.

Conclusion

High-sensitivity cTnT is a biomarker associated with RV dysfunction in PE and its performance (sensitivity and specificity) varies with the cutoff point selected.

Table 2

Sensitivity and specificity for each value of hs-cTnT

hs-cTnT value (ng/L) Sensitivity Specificity

12 100% 45%

14	92%	48%	Ann Emerg Med 2004;44(5):503-10.
18	83%	48%	[13] Giannitsis E, Kurz K, Hallermayer K, Jarausch J, Jaffe AS, Katus HA. Analytical valida-
22	83%	71%	tion of a high-sensitivity cardiac troponin T assay. Clin Chem 2010;56(2):254-61.
25	75%	71%	[14] Levey AS, Stevens LA, Schmid CH, Zhang YL, Castro III AF, Feldman HI, et al. A new equa-
30	58%	75%	tion to estimate glomerular filtration rate. Ann Intern Med 2009;150(9):604-12.
37	42%	78%	[15] Aujesky D, Obrosky DS, Stone RA, Auble TE, Perrier A, Cornuz J, et al. Derivation and
42	42%	85%	validation of a prognostic model for pulmonary embolism. Am J Respir Crit Care Med
46	42%	88%	2005;172(8):1041-6.
50	33%	89%	[16] Hakemi EU, Alyousef T, Dang G, Hakmei J, Doukky R. The prognostic value of unde-

Conflicts of interest

None declared.

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