Impact of low-level cardiomyocyte injury on prognosis in patients with non-obstructive coronary artery disease: a retrospective cohort study

doi:10.21203/rs.3.rs-1539823/v1

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Impact of low-level cardiomyocyte injury on prognosis in patients with non-obstructive coronary artery disease: a retrospective cohort study

https://doi.org/10.21203/rs.3.rs-1539823/v1

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Background: Mild elevation of serum cardiac troponin (Tn) reflects myocardial injury and is associated with cardiovascular events, even without overt cardiovascular disease. The purpose of this study was to investigate the possible mechanism of mild elevation of high-sensitivity cardiac troponin I (hs-cTnI) and its impact on prognosis in patients with non-obstructive coronary artery disease (CAD).

Methods: 474 consecutive patients with suspected CAD and without significant coronary artery stenosis (<50%) who underwent adenosine triphosphate disodium (ATP) stress MCE were followed up (median, 41months) for endpoint events. Hs-cTnI was tested before MCE. Replenishment velocity (β), relative myocardial blood flow (rBV) and myocardial blood flow reserve (MBFR) were measured by stress MCE.

Results: A total of 214 (45.1%) patients had hs-cTnI concentrations exceeding the limitation of detection (LOD) (0.001 ng/ml). Compared to patients with hs-cTnI below LOD, patients with higher hs-cTnI were older (p<0.05), had higher prevalence of atrial fibrillation (p<0.001) and lower MBFR (p<0.001). After adjustment, the association was still significant between detectable hs-cTnI and MBFR (odds ratio = 0.200; 95% CI: 0.043,0.923, P = .039). Detectable hs-cTnI was associated with endpoint events independent of MBFR (adjusted hazard ratio 8.927,95%CI 1.341-149.48, P=0.028). Hs-cTnI higher than LOD had greater cumulative event rate (log-rank P=0.004). The risk of incident endpoint events was greater for higher hs-cTnI (≥0.001 versus <LOD; adjusted hazard ratio, 13.398; 95% CI, 1.243, 144.371) (P<0.001).

Conclusions: In patients with non-obstructive CAD, mild myocardial injury was associated with impaired myocardial perfusion as measured by quantitative MCE; both of them independently affect prognosis; low-level hs-cTnI elevation predicts adverse events independent of myocardial ischemia due to microvascular dilation dysfunction.

Non-obstructive CAD

troponin

myocardial contrast echocardiography

Even in adults without obvious cardiovascular disease, a small amount of cardiomyocyte damage can be detected by high-sensitivity cardiac troponin (hs-cTn). A slight increase in hs-cTn may exhibit the biochemical characteristics of early subclinical heart disease and is associated with surrogate fibrosis and progressive changes in left ventricular structure, and is therefore strongly associated with an increased risk of heart failure (HF), coronary artery disease (CAD), and cardiovascular death. [1] In studies of communities at risk for atherosclerosis, the predictive effects of hS-CTN and N-terminal pro-B type diuretic peptide on HF or major cardiovascular adverse events appear to be complementary, reflecting different mechanisms of HF. [2]

In non-acute coronary syndrome, mechanisms for elevated TnI may include increased burden of coronary atherosclerosis and microembolization following chronic clinically asymptomatic rupture of mixed plaques, involving tumor necrosis factor -α and nitric oxide mechanisms that trigger myocardial apoptosis pathways [3]. It may also be related to coronary microvascular dysfunction (CMVD), with coronary microvascular spasm triggering transient ischemia and repeated ischemia-reperfusion leading to myocardial cell injury [4], or impaired coronary flow reserve (CFR) and mismatching of microcirculation supply and demand, exacerbating endothelial dysfunction and subendocardial ischemia leading to low-level myocardial cell injury [5].

Therefore, we hypothesized that in patients with non-obstructive CAD, low-level elevated hs-cTnI may be associated with decreased perfusion at the microcirculatory level, and that induced ischemic cardiomyocyte injury may be a major contributor to poor prognosis.

Ultrasound contrast agents are tracers of microvascular flow, so quantitative MCE has the potential to provide more accurate estimates of myocardial flow and seems to better reflect microcirculation physiopathology [6, 7] It has been used to assess hemodynamics and predict cardiogenic death and heart transplantation in patients with non-ischemic dilated cardiomyopathy [8].

To test our hypothesis, vasodilator stress MCE was used to measure coronary microcirculation perfusion in subjects with computed tomography angiography (CTA) or coronary angiography without significant obstructive CAD.

2.1 Study population

Enrolled study participants were patients who underwent stress MCE for suspected CAD in cardiology department of the First Affiliated Hospital of Harbin Medical University, from 2011 to 2017. Exclusion criteria were known CAD (including prior revascularization and/or myocardial infarction), cardiomyopathy, flow-restricted CAD (epicardial coronary artery stenosis > 50% demonstrated by coronary angiography or CTA, left ventricular ejection fraction (LVEF) < 50%. In the end, a total of 489 patients enrolled in the study.

Detailed clinical data were acquired for all patients, including relevant medical history (atrial fibrillation (AF)) and conventional cardiovascular risk factors (age, gender, hypertension, diabetes, dyslipidemia, smoking). AF, including paroxysmal and persistent AF, is identified by medical records or changes in electrocardiogram. Patients with blood pressure ≥ 140/90 mmHg or taking antihypertensive drugs were considered hypertensive. Diabetes was defined as a history of diabetes treated with hypoglycemic medication or insulin. Smoking history (former or current smoking). Blood samples were analyzed for cholesterol levels (total cholesterol, low-density lipoprotein [LDL] cholesterol) and creatinine levels.

The Ethics Committee of the First Affiliated Hospital of Harbin Medical University approved this study, and informed consents were signed by all participants. This study was conducted according to relevant guidelines and regulations.

2.2 hs-cTnI measurement

Hs-cTnI of peripheral venous blood samples was analyzed prior to MCE. Serum hs-cTnI levels was tested using the hs-TnI assay (chemi luminescence) by VITROS 3600 automatic immunoassay analyzer (Ortho-Clinical Diagnostics, Inc.). This assay has a limit of detection (LOD) of 0.001ng / ml. ^[9] Hs-cTnI ≥ 0.001ng/ml was defined as elevated.

2.3 Stress myocardial contrast echocardiography examination

Continuous dynamic images were acquired in apical 2, 3 and 4 views using a Philips IE33 echocardiography system (Philips Ultrasound, Bothell, WA). The ultrasound contrast agent SonoVue was administered as a slow bolus (Bracco Research SA, Geneva, Switzerland) (1.0-1.5 ml/min) followed by a slow flush of 5 ml of saline for 20 seconds. Using a disruptive refill technique, myocardial perfusion was measured by collecting more than 15 cardiac cycles with a low MI (MI = 0.1) after a high mechanical index (MI > 0.9) "flash" pulse. Contrast echocardiography was performed before ATP infusion and 3 min after ATP infusion. ATP was administered by a syringe infusion pump, the dosage form of ATP was 20mg/2ml, the infusion rate was 140ug/kg/min, and the total infusion time was 6 minutes. The images were independently assessed by two expert readers (N.Y. and H.L.).

2.4. Quantitative analysis of MCE

Myocardial perfusion was quantified using QLAB version 7.1 (Phillips Medical Systems, Best, Netherlands) on apical 2, 3 and 4 views, for a total of 17 segments. [10] Manually track the area of interest in the myocardial segment and the adjacent left ventricular cavity at end-systole.

According to the exponential curve fitting formula: y = A×(1–e^−ßt), the software automatically calculates the signal intensity of the myocardial platform (A_M) and the adjacent left ventricular platform (A_LV) in each region of interest, as well as the signal intensity exchange rate (β). Dividing A_M by A_LV expresses relative myocardial blood volume (rBV), while ß reflects myocardial blood flow velocity. rBV×ß stands for MBF. [11] Stress MBF divided by resting MBF represents MBFR.

2.5 Composite endpoints and follow-up

All eligible patients were followed up by telephone or by checking hospital records. The composite end point event consisted of cardiovascular death and nonfatal myocardial infarction. Follow-up time was defined as the date of the last telephone follow-up or hospitalization record. Time to first event was analyzed.

2.6 Statistical analysis

Patients were classified according to quartiles of hs-cTnI distribution. Baseline data are shown as median (25th and 75th percentile) and interquartile range, or numbers and percentages (%), where appropriate. Chi-square test or Kruskal-Wallis H test was used to detect differences between hS-TNI quartiles. We used MBFR, β reserve and rBV as continuous variables for analysis.

Perform univariate and multivariate logistic regression analysis to determine factors associated with outcomes. Multivariate analysis was performed by including variables with P values < .05 in the univariate model to avoid overfitting. Linear regression were performed to detect significant interactions between MBFR and low levels of hs-cTnI.

Kaplan- Meier survival function curves of endpoint events were calculated based on hs-TnI quartiles. Cox proportional risk models were used to estimate the hazard ratio (HR) and 95% CIs for associations between hs-TnI and incident endpoint events. Model was adjusted for age, sex, LVEF, AF and MBFR.

50 segments were randomly selected to test the intra-observer and inter-observer variability of rBV reserve, β reserve, and MBFR, expressed as intra-group correlation coefficients (ICC). Inter-observer and intra-observer variability were assessed using 2-way, random, single-measure ICC and 1-way, random, 2-measure ICC, respectively. P values < .05 was considered statistically significan, and tests were 2-sided. SPSS 24.0 statistical software and GraphPad Prism 8.0 software were used for data analyses.

The median age was 57 years (49, 62 years). Women accounted for 61%. The prevalence of hypertension, dyslipidemia and diabetes was 55.7%, 38.6% and 26.2%, respectively.

3.1 Haemodynamic characteristics

Heart rate increased significantly during ATP stress compared to baseline (90 (83–97) vs. 70 (65–79) beats/min, P < .001), systolic blood pressure remained unchanged (106 (95–121) vs. 113 (101–124) mmHg; P = .212), while diastolic blood pressure decreased significantly (53 (46–59) vs. 60 (52–69) mmHg; P =. 015)

3.2 Feasibility of MCE measurements

MBFR, β reserve and rBV measurements were available in 474 (97%) patients (Fig. 1). For measurements of rBV, ß, and rBV×ß, ICC values for interobserver consistency were rBV 0.744 (95% consistency limit: 0.566–0.812, P < .001), ß 0.656 (95% consistency limit: 0.392–0.778, P < .001), and rBV×ß 0.755 (95% consistency limit: 0.605–0.853, P < .001), respectively. The ICCs of intraobserver consistency were rBV 0.792 (95% consistency limit: 0.689–0.867, P < .001), ß 0.722 (95% consistency limit: 0.525–0.846, P < .001), and rBV×ß 0.787 (95% consistency limit: 0.634–0.883, P < .001), respectively.

3.3 Evaluation of factors associated with hs-cTnI release

The hs-cTnI concentration exceeded LOD (0.001 ng/ mL) in 214 patients (45.1%). Compared with patients with hs-cTnI below the LOD, patients with higher hs-cTnI levels had older age (p < 0.05), higher incidence of atrial fibrillation (p < 0.001) and lower MBFR (p < 0.001). (Table 1)

Table 1

Baseline Characteristics, by concentration of hs-cTNI
Characteristic	Hs-cTnI concentration			χ²/H	P
Characteristic	Quartile 1 (n = 217) (0.000-0.001ng/ml)	Quartile 2 (n = 136) (≥ 0.001-0.007ng/ml)	Quartile 3 (n = 121) (≥ 0.007 ng/ml)	χ²/H	P
Age	55(48,60)	56(50,63)	58(50,64.5)	6.831	0.033
Gender				2.160	0.340
Male	79(36.4)	60(44.1)	46(38.0)
Female	138(63.6)	76(55.9)	75(62.0)
Clinical history
Atrial fibrillation	2(0.9)	13(9.6)	3(2.5)	17.845	༜0.001
Hypertension	115(53.0)	81(30.7)	68(56.2)	1.476	0.478
Diabetes	65(30.0)	32(23.5)	27(22.3)	3.031	0.220
Dyslipidemia	87(40.1)	47(34.6)	49(40.5)	1.324	0.516
Smoking	54(24.9)	43(31.6)	35(28.9)	1.980	0.372
LVEF(%)	67(62,70)	66(60,70)	66(60,70)	3.282	0.194
Quantitative MCE
MBFR	2.56(2.22,2.78)	2.36(1.91,2.60)	2.20(1.82,2.50)	47.511	༜0.001
βreverse	2.11(1.88,2.26)	1.95(1.65,2.14)	1.78(1.55,2.09)	46.640	༜0.001
rBV reserve	1.2(1.17,1.25)	1.20(1.17,1.23)	1.20(1.16,1.24)	4.337	0.114
Bio-humoral variables
hs-cTnI, ng/mL	0.00(0.00,0.00)	0.00(0.00,0.00)	0.01(0.01,0.02)	435.078	༜0.001
Creatinine, umol/l	62.3(53.4,70.4)	62.9(55.2,73.9)	62.3(53.5,72.9)	2.242	0.326
Medications
Aspirin	168(77.4)	105(77.2)	82(67.8)	4.390	0.111
Lipid lowering drug	185(85.3)	115(84.6)	100(82.6)	0.406	0.816
Beta blocker	119(54.8)	56(41.2)	57(47.1)	6.464	0.039

After adjustment, the association was still significant between detectable hs-cTnI and lower MBFR (OR = 0.200; 95% CI: 0.043,0.923, P = .039) (Table 2)

Table 2

Predictive Indicators of hs-cTnI
Variable	Univariate analysis		Multivariate analysis
Variable	OR (95% CI)	P	OR (95% CI)	P
Age	1.027(1.009–1.045)	0.004	0.998(0.976–1.020)	0.839
Male	1.298(0.896–1.880)	0.168
Atrial fibrillation	2.449(0.903–6.638)	0.078
Hypertension	1.194(0.829–1.719)	0.340
Diabetes	0.810(0.535–1.225)	0.318
Dyslipidemia	0.938(0.647–1.360)	0.736
Smoking	1.376(0.920–2.059)	0.120
LVEF	0.958(0.931–0.985)	0.003	0.969(0.940-1.000)	0.047
MBFR	0.291(0.188–0.450)	༜0.001	0.200(0.043–0.923)	0.039
β reserve	0.189(0.105–0.341)	༜0.001	0.608(0.112–3.315)	0.566
rBV reserve	0.014(0.001–0.339)	0.008	92.009(0.686-12341.876)	0.07
β- blocker	0.637(0.442–0.916)	0.015	0.690(0.468–1.015)	0.06
Aspirin	0.745(0.492–1.130)	0.166
Lipid lowering drug	0.818(0.498–1.344)	0.428

3.4 Association of hs-cTnI level with endpoint events

The mean follow-up interval was 41 months (29,56 months), 420 patients completed the follow-up, and 54 (11.4%) were lost (40 patients changed the contact information, and 14 patients did not coordinate). A total of 12 (2.9%) patients met 12 endpoint events (cardiovascular death: n = 10; non-fatal myocardial infarction: n = 2).

In unadjusted analysis, the incidence of endpoint events was significantly associated with male (hazard ratio, 3.552; 95%CI, 1.040-12.128; P = .043), MBFR (hazard ratio, 0.001; 95%CI, 0.000-0.024; P༜.001), β reserve (hazard ratio, 0.001; 95%CI, 0.000-0.020; P༜.001), LVEF (hazard ratio, 0.911; 95%CI, 0.855–0.971; P = .004) and detectable hs-cTnI (hazard ratio, 17.501; 95%CI, 2.254-135.908; P = .006).

On multivariate analysis, impaired MBFR (adjusted hazard ratio, 0.001; 95%CI, 0.000-0.406; P = .030) and detectable hs-cTnI (adjusted hazard ratio, 8,927; 95%CI, 1.341–149.48; P = .028) were independently associated with endpoint events. (Table 3) In adjusted analysis, there was not significant interaction between hs-cTnI status and MBFR as a continuous variable, P_interaction=.709.

Table 3

Predictors of events by univariate and multivariate analysis
	Univariate analysis(P༜0.05)			Multivariate analysis(P༜0.05)
Variable	HR	95%CI	P	HR	95%CI	P
Age	1.021	0.966–1.079	0.459
Male	3.552	1.040-12.128	0.043	6.28	1.416–27.855	0.016
Atrial fibrillation	3.339	0.426–26.153	0.251
Hypertension	1.157	0.371–3.609	0.802
Diabetes	1.078	0.235–4.944	0.923
Hyperlipidemia	0.590	0.152–2.293	0.446
Smoking	2.785	0.898–8.642	0.076
MBFR	0.001	0.000-0.024	༜0.001	0.001	0.000-0.406	0.030
βreverse	0.001	0.000-0.020	༜0.001	0.159	0.001–36.346	0.507
LVEF(%)	0.911	0.855–0.971	0.004	0.966	0.918–1.044	0.514
Hs-cTnI ≥ LOD	17.501	2.254-135.908	0.006	8.927	1.341–149.48	0.028
Lipoprotein a	1.000	0.994–1.006	0.948

Figure 2 showed the event-free survival curve. Compared to patients with hs-cTnI below LOD, patients with higher levels of hs-cTnI had significantly greater cumulative incidence of endpoint event. (log-rank P = .004)

COX regression analysis showed that the unadjusted hazard ratio for those in higher levels of hs-cTnI versus those < LOD were 15.372 ( 95%CI 1.880-125.665) (P = .003). The addition of age, gender, AF, LVEF and MBFR into multivariate analysis, higher levels of hs-cTnI(adjusted hazard ratio 13.398, 95%CI 1.243, 144.371)(P < .001) remained statistically significant associated with incident events. (Table 4)

Table 4

**Association of incident events with hs-cTNI by quartile**
Endpoint event	hs-cTnI, (ng/ml)			P Trend
Endpoint event	Quartile 1 (0.000-0.001)	Quartile 2 (≥ 0.001–0.007)	Quartile 3 (≥ 0.007)	P Trend
n/N	1/217	7/136	4/121
Unadjusted Hazard Ratios	Reference	15.372 (1.880,125.665)	10.427 (1.155,94.104)	0.003
Adjusted Hazard Ratios	Reference	13.398 (1.243, 144.371 )	4.680 (0.458, 47.799)	༜0.001
Data are presented as hazard ratio (95% CI).
Adjusted for age ,sex, LVEF, AF and MBFR

In patients with non-obstructive CAD, minor elevation of hs-cTnI was associated with impaired myocardial perfusion as measured by quantitative MCE; both of them independently affect prognosis; low-level hs-cTnI elevation predicts adverse events independent of myocardial ischemia due to microvascular dilation dysfunction.

4.1 Mechanisms affecting hs-cTnI levels

Studies have shown that in an animal experiment in which diabetes, hyperlipidemia and chronic kidney disease were combined with a swine model to simulate ischemia and non-obstructive CAD, even if there was no obvious structural change and overt atherosclerosis, increased coronary blood flow at baseline rather than changes in maximum blood flow after hyperemia resulted in decreased adenosine recruited myocardial perfusion, and in this setting, CMVD is severe enough to produce perturbations in myocardial oxygen balance, resulting in a mismatch between supply and demand. [12]

Clinical studies [13] and animal experiments [14] have shown that the pro-inflammatory environment created by comorbidities such as hypertension, diabetes and dyslipidemia may contribute to CMVD by promoting microvascular inflammation and rarefaction, and ultimately lead to adverse left ventricular remodeling, cardiometabolic dysfunction, and extracellular fibrosis.

All of these may increase coronary microvascular resistance and cardiomyocyte burden, [15] further aggravate endothelial dysfunction and subendocardial ischemia [16], leading to mild cardiomyocyte injury.

Our previous studies have shown that comorbidities such as hypertension, diabetes and dyslipidemia are prone to CMVD. [17] In this study, non-obstructive CAD patients had a relatively high incidence of comorbidities, which may lead to CMVD and reduced myocardial perfusion. The impaired myocardial perfusion further leads to a low level of hs-cTnI elevation.

4.2 Hs-cTnI and cardiovascular events

In the present study, minor myocardial injury in patients with non-obstructive CAD was associated with events independent of impaired myocardial perfusion as measured by quantitative MCE. There was no significant interaction between impaired myocardial perfusion and detectable hs-cTnI on cardiovascular events. These results may suggested that the effect of minor elevated hs-cTnI on cardiovascular events in patients with non-obstructive CAD may have a mechanism other than ischemia.

A slight increase in hs-cTn may exhibit the biochemical characteristics of early subclinical heart disease and is associated with surrogate fibrosis and progressive changes in left ventricular structure, and is therefore strongly associated with an increased risk of heart failure (HF),

Recent studies have shown that in adults without overt cardiovascular disease, a small increase in hs-cTnT at baseline is related to replacement fibrosis and changes in left ventricular structure, and ultimately contributes to HF, a process independent of ischemia-induced subendocardial fibrosis.[1] Hs-cTnI has a worse prognosis in heart failure patients with preserved ejection fraction than in patients with reduced ejection fraction. These findings suggest that increased TnI may reflect cardiomyocyte loss secondary to chronic inflammation or other unknown, ischemia-unrelated pathologies in patients with preserved ejection fraction.[18]

As shown in this study, in patients with non-obstructive CAD, even though hs-cTnI changes are within the normal measurement range, there is a high-risk population for progression to non-fatal myocardial infarction and cardiovascular death. Therefore, we believe that hS-CTNI levels can be used for preventive intervention in high-risk populations. For example, therapeutic trials based on Tn levels, remodeling and fibrosis could be considered as early interventions to prevent symptomatic HF progression.[1]

4.3 Study limitations

This study has a number of limitations. First, this is a single-center retrospective study. Larger multicenter prospective studies are needed to further elucidate the mechanism and prognostic significance of minor elevated hs-cTnI in patients with non-obstructive CAD. Second, the quantitative MCE has not been validated against the gold standard for CMVD in patients. However, many studies have applied quantitative MCE to estimate myocardial blood flow [6,7] and compared it with CFR measured by transthoracic doppler ultrasound, showing that quantitative MCE parameters have good predictive value. [8] Third, lost to follow-up percentage is slightly higher (11.2%), which may have a certain impact on the follow-up results.

In patients with non-obstructive CAD, minor myocardial injury was associated with impaired myocardial perfusion as measured by quantitative MCE; both of them independently affect prognosis; low-level hs-cTnI elevation predicts adverse events independent of myocardial ischemia due to microvascular dilation dysfunction.

Acknowledgement

Not applicable.

Authors’contributions

All authors mentioned contributed to the study. All authors read and approved the final manuscript. Bochen Sun, Yujia Sun, HuanHuan An, Xingyue Zhang, Fei Xiang gathered the data. Biyu Wang, Yuwei Song, Shuhan Qi, Jianan Liu analysed the data.

Ning Yang, Chaoqun Zhao and Rongzhen Zhang reviewed the literature, analysed and interpreted the data, and drafted the manuscript. Ning Yang and Hui Liu reviewed the literature and revised the manuscript for important intellectual content. Wei Han and Ning Yang reviewed the literature and revised the manuscript for important intellectual content. Wei Han designed the study, and revised the manuscript for important intellectual content. All authors read and approved the final manuscript.

Funding

None.

Availability of data and materials

Data from the full survey is available upon request.

Ethics approval and consent to participate

The Ethics Committee of the First Affiliated Hospital of Harbin Medical University approved this study, and informed consents were signed by all participants.

The First Affiliated Hospital of Harbin Medical University Ethics Committee nr. IRB-AF/SC-08/05.0, received on February 01, 2018.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing

Author details

1.Department of Cardiology, The First Affiliated Hospital of Harbin Medical University, Harbin, 150001, Heilongjiang, P. R. China

2.Department of Cardiology, Heart Center，Qingdao Fuwai Cardiovascular Hospital, Qingdao 266034, Shandong, P.R.China

3.Department of Cardiology, Qingdao Third People’s Hospital, Qingdao 266041, Shandong, P.R.China

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No competing interests reported.

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Impact of low-level cardiomyocyte injury on prognosis in patients with non-obstructive coronary artery disease: a retrospective cohort study

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Abstract

Figures

1 Introduction

2 Methods

2.1 Study population

2.2 hs-cTnI measurement

2.3 Stress myocardial contrast echocardiography examination

2.4. Quantitative analysis of MCE

2.5 Composite endpoints and follow-up

2.6 Statistical analysis

3 Results

3.1 Haemodynamic characteristics

3.2 Feasibility of MCE measurements

3.3 Evaluation of factors associated with hs-cTnI release

3.4 Association of hs-cTnI level with endpoint events

4 Discussion

Conclusions

Declarations

References

Additional Declarations

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