_17_KP_7_8_2021__Chabior
  • „ ORIGINAL ARTICLE

Expression of versican mRNA transcript to predict cardiac remodeling after myocardial infarction

Aleksandra Chabior1*, Aleksandra Gąsecka1*, Michał Marchel1, Roksana Gozdowska1, Agnieszka Makowska1, Karolina Maciak2, Monika Góra2, Krzysztof J Filipiak1, Beata Burzyńska2, Grzegorz Opolski1

11st Chair and Department of Cardiology, Medical University of Warsaw, Warszawa, Poland

2Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warszawa, Poland

*Both authors equally contributed to the study and share the first authorship..

Correspondence to:

Michał Marchel, MD, PhD,

1st Chair and Department of Cardiology, Medical University of Warsaw,

Banacha 1, 02–097 Warszawa, Poland,

phone: +48 22 599 19 58,

e-mail: michal.marchel@wum.edu.pl

Copyright by the Author(s), 2021

Kardiol Pol. 2021; 79 (7–8): 833–840; DOI: 10.33963/KP.a2021.0042

Received: March 11, 2021

Revision accepted: June 16, 2021

Published online: June 17, 2021

 

ABSTRACT

Background: Adverse left-ventricular remodeling (LVR) is defined as a 20% increase in end-diastolic left-ventricular volume 6 months after acute myocardial infarction (AMI). LVR is associated with cardiac dysfunction, therefore deteriorating the prognosis.

Aims: We aimed at comparing the concentrations of messenger RNA transcripts in the peripheral blood of patients with and without LVR at 6 months.

Methods: The study included 75 patients with first ST-elevation myocardial infarction (STEMI) treated with percutaneous coronary intervention. Whole blood concentrations of 6 transcripts were determined 24 hours after AMI using droplet digital polymerase chain reaction. The correlations between mRNA transcript expression and left ventricular ejection fraction (LVEF) and N-terminal-pro B type natriuretic peptide (NT-proBNP) concentration were evaluated.

Results: Among 75 patients, 4 were lost to follow-up, and 71 were included in the analysis. Seventeen (24%) patients developed LVR at 6 months. Versican (VCAN) mRNA expression was lower in patients who developed LVR, compared to those who did not (P = 0.02), and discriminated between these patients (area under the ROC curve 67%; P = 0.04). Expression of VCAN transcript <75.3 normalized units predicted LVR with 71% sensitivity and 67% specificity. In a multivariable regression analysis, VCAN expression remained the only independent predictor of LVR (OR 3.475; 95% CI, 1.00012.075; P = 0.04).

Conclusions: Dysregulation of VCAN expression in the acute phase of AMI may contribute to LVR at 6 months. Whether decreased expression of VCAN might be a useful tool to predict LVR in clinical practice remains to be established.

Key words: cardiac remodeling, mRNA transcripts, myocardial infarction, versican

Kardiol Pol 2021; 79, 78: –840

WHAT’S NEW?

Cardiac remodeling after acute myocardial infarction is associated with ventricular dysfunction and deteriorates the prognosis. Remodeling involves genetic and molecular changes in response to cardiac injury. The present study tested the concentrations of mRNA transcripts in the peripheral blood of patients after myocardial infarction with and without cardiac remodeling. Our results revealed that versican (VCAN) expression was lower in patients who developed left ventricular remodeling (LVR), compared to those who did not. Further studies are needed to assess whether VCAN might be a useful tool to predict cardiac remodeling in clinical practice.

INTRODUCTION

Heart failure (HF) is an important public health challenge, that occurrs in 1%–2% of the adult population, and this prevalence increases to 10% among people over 70 years of age [1]. Acute myocardial infarction (AMI) is responsible for over 50% of cases of HF [2]. In patients with AMI, the loss of contractile tissue and left ventricular remodeling (LVR) anticipated by the structural and functional alterations to the left ventricle, including fibrosis and inflammation [3]. The most common definition of LVR, applied also in the present study, is a 20% increase in left ventricular end-diastolic volume (LVEDV) at 6 months after AMI [4]. LVR affects 25% of patients after AMI and deteriorates the prognosis [5]. Clinical, biochemical, and imaging parameters increasing the risk of LVR after AMI include the extension and anterior location of AMI, late or unsuccessful revascularization [6], high concentrations of natriuretic peptides and cardiac troponins [7], and enlarged left ventricle (LV) on echocardiography [8]. However, at present, there are no reliable biomarkers to predict cardiac remodeling. Due to their role in the development of adverse cardiac remodeling after AMI, novel markers including microRNA and messenger RNA (mRNA) transcripts might be superior to the currently available biomarkers of HF and cardiac remodeling, such as N-terminal pro-B-type natriuretic peptide (NT-proBNP). Hence, identification of the crucial genes involved in the process of remodeling and associated mRNA transcripts might help to individualize the treatment strategy and improve cardiovascular risk stratification and prediction of outcomes [9].

Messenger RNA is a single-stranded molecule of ribonucleic acid that corresponds to the sequence of a gene and is read in the process of translation (synthesizing a protein) [10]. Previously, we showed that the expression of mRNA transcripts is altered in the peripheral blood of patients after AMI, compared to controls [11]. Using genome-wide gene expression profiling, we selected several transcripts involved in the development of HF after AMI. Here, we hypothesized that the post-AMI expression of mRNA differs in patients with and without LVR. We compared the level of selected mRNA transcripts in patients after AMI with and without LVR and evaluated their predictive value for LVR.

METHODS

Study design

We designed an investigator-initiated, prospective study, conducted at the 1st Chair and Department of Cardiology, Medical University of Warsaw, Poland, in collaboration with the Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland. The study protocol, designed in compliance with the Declaration of Helsinki, was approved by the Ethics Committee of the Medical University of Warsaw (KB/176/2015). All participants provided written informed consent. The study design is showed in Figure 1A.

6050.png

Figure 1. Study design and flow chart

Abbreviations: AMI, acute myocardial infarction; eGFR, estimated glomerular filtration rate; mRNA, messenger RNA; NSTEMI, non-ST-elevation myocardial infarction; PCI, percutaneous coronary intervention

Study participants

Participant inclusion and exclusion criteria are listed in Table 1.

Table 1. Eligibility criteria for the study

Inclusion criteria

Exclusion criteria

Age ≥18 years

Informed consent to participate in the study

ST-elevation myocardial infarction

PCI with stent implantation

Non-ST-elevation acute coronary syndrome

Cardiogenic shock

Severe chronic renal failure

(eGFR <30 ml/min/1.73 m2)

Severe liver insufficiency

(Child-Pugh class C)

Known pregnancy or breast-feeding

Abbreviations: eGFR, estimated glomerular filtration rate; PCI, percutaneous coronary intervention

Patients were eligible for enrolment if they (a) were admitted to the hospital due to ST-segment elevation of acute myocardial infarction (STEMI), and (b) underwent percutaneous coronary intervention (PCI) with stent implantation. STEMI was diagnosed based on persistent ST-segment elevation of at least 0.1 mV in at least two contiguous electrocardiography leads or a new left bundle-branch block [12].

Clinical data collection

At baseline, data regarding demographics (age, gender), body mass index, cardiovascular risk factors, routine laboratory parameters. All patients received standard treatment after STEMI according to the guidelines, including dual antiplatelet therapy, β-blocker, angiotensin-converting enzyme inhibitor or angiotensin receptor blocker, aldosterone receptor antagonist, and protein pump inhibitor [12].

The concentration of NT-proBNP was measured within 24 hours after AMI and at 6-month follow-up in whole blood sample. Transthoracic echocardiography was conducted within 24 hours after AMI and repeated at the follow-up visit. LVR was defined as a 20% increase in LVEDV at6 months after AMI, compared to baseline echocardiography.

Messenger RNA transcripts analysis

Whole blood concentrations of 6 transcripts (ribonuclease 1 [RNASE1], Jun dimerization protein 2 [JDP2], cluster of differentiation 163 [CD163], cytochrome P450 family 27 subfamily A member 1 [CYP27A], versican [VCAN], interleukin type 1, receptor 2 [IL1R2]) were determined within 24 hours after AMI using droplet digital polymerase chain reaction (ddPCR). The selection of specific transcripts was based on the results of our earlier study, which showed that the genes responsible for the expression of these transcripts differ between patients with AMI and healthy controls, and between patients who developed post-infarct HF at 6 months vs those who did not [11]. In the past study, the expression of genes encoding the selected transcripts differed two-fold to three-fold between the groups (post-infarct HF vs no HF: RNASE1 2.044-fold change; P = 0.002; JDP2 1.825-fold change; P = 0.001; CD163: 1.768-fold change, P = 0.003; IL1R2: 3.167-fold change; P = 0.008; AMI vs controls: CYP27A 1.712-fold change; P = 0.005; VCAN 1.16-fold change; P = 0.001). In the past study, we used both peripheral blood mononuclear cells and whole blood as the RNA source. The obtained results showed that the choice of material (whole blood vs peripheral blood mononuclear cells) and analytical method (microarrays vs RT-qPCR) does not affect the obtained results, indicating the robustness of the proposed approach. In the current research, using a different cohort of patients and different methodology (ddPCR), we focused on the evaluation of previously selected mRNA transcripts in patients with and without LVR. Briefly, whole blood was collected into PAXgene Blood RNA tubes and total RNA was isolated using the PAXgene Blood RNA kit (Qiagen, Hilden, Germany). Reverse transcription was performed using 400 ng of total RNA and the QuantiTect Reverse Transcription kit (Qiagen). Primer sets were designed using Clone Manager Professional Suite software, version 6.00 (Sci Ed Software, NC, USA). Droplet digital PCR was carried out using QX200™ Droplet Digital™ PCR System (Bio-Rad, CA, USA). The cDNA templates were diluted to a concentration of 4 ng/μl (total RNA equivalent) with nuclease-free water and 2 µl was assayed in a 22 µl reaction volume using EvaGreen (Bio-Rad) and thermal cycling conditions recommended for EvaGreen assays. After amplification, the plates were loaded into the QX200 Droplet Reader and the ddPCR results were analyzed with QuantaSoft software v.1.7.4.0917 and QuantaSoft Analysis Pro software v.1.0.596 (Bio-Rad). The absolute number of target molecules in the ddPCR reaction was determined using Poisson statistical analysis and background-corrected based on the no-template control. Data were expressed as normalized units, according to mRNA level of the reference gene HPRT1. In our study, we applied the droplet digital PCR approach to determine the mRNA expression level of studied genes. Droplet digital PCR fractionates templates into individual reaction systems, then transitional PCRs are run in individual wells and DNA content can be quantitated by direct counting PCR positive percentage among all reactions. The use of absence and presence of signals to indicate target DNA makes a ‘digital’ direct measurement of samples. The digital PCR concept has many potential advantages over classical real-time PCR, including the capability to obtain absolute quantification without external references and robustness to variations.

Endpoints

The primary endpoint was the difference between the expression of mRNA transcripts after AMI in patients with and without LVR at 6 months. The secondary endpoint was the predictive value of mRNA transcripts for LVR at 6 months.

Statistical analysis

About 25% of patients after AMI develop LVR [5]. Since there are currently no data in the literature regarding the differences in mRNA transcript expression of the investigated genes in patients with and without LVR, our sample size calculation was based on the previous study, where we investigated gene expression in patients who did and did not develop post-infarct HR 6 months after STEMI [11]. In this study, the expression of most genes differed two-fold to three-fold between the groups, resulting in the nominal difference of at least 1. Hence, the sample size was calculated based on the following assumptions: (I) significance level for two-sided testing 0.05; (II) test power 0.8; (III) standard deviation ± 1; (IV) estimated difference in mean transcript expression between the group with and without LVR 1. Based on these assumptions, the study should include at least 17 patients who will develop LVR (25% of the group). Assuming 10% of patients lost to follow-up, the required sample size was 75 patients.

Statistical analysis was conducted using IBM SPSS Statistics, version 27.0 (IBM). Categorical variables were presented as number and percent and compared using Fischer’s exact test. A ShapiroWilk test was used to assess normal distribution of continuous variables. Continuous variables were presented as mean (SD) or median with interquartile range. Correlations were analyzed using a Spearman correlation coefficient test. Transcript expressions were compared between the groups using an unpaired t-test or Mann-Whitney U test. The diagnostic ability of mRNA transcripts to discriminate between patients with and without LVR and the cut-offs were calculated using a receiver operating characteristic (ROC) curve. For analysis of LVR predictors, univariable logistic regression analysis was used. Next, multivariable analysis was performed, where LVR was used as a dependent variable and predictors which were significant in univariable analysis were used as independent variables. Results were expressed as odds ratio (OR) and 95% confidence interval (CI). Mortality and other adverse events were reported descriptively. A P value below 0.05 was considered significant.

RESULTS

The inclusion and exclusion charts are shown in Figure 1B. Between March 2015 and April 2019, 74 patients with first STEMI treated with PCI provided informed written consent and were included in the study.

Clinical data

Among 75 patients, 4 were lost to follow-up and 71 were included in the analysis. Patient characteristics are shown in Table 2.

Table 2. Main characteristics of patients with and without left ventricular remodeling at 6 months after ST-elevation myocardial infarction

Characteristic

LVR (n = 17)

No LVR (n = 54)

P-value

Age, years, mean (SD)

56.0 (6.8)

57.9 (11.4)

0.039

Male gender, n (%)

10 (59)

40 (74)

0.229

BMI, kg/m2, mean (SD)

28.9 (4.3)

27.3 (4.3)

0.293

Anterior AMI, n (%)

6 (35)

15 (36)

0.135

Cardiovascular risk factors, n (%)

Arterial hypertension

8 (47)

29 (69)

0.413

Diabetes mellitus

3 (18)

15 (36)

0.845

Dyslipidemia

10 (59)

30 (71)

0.075

Smoking

6 (35)

26 (62)

0.908

Previous AMI

1 (6)

2 (5)

0.486

Laboratory parameters at baseline

NT-proBNP, pg/ml, median (IQR)

1055 (473–2076)

607 (269–1872)

0.154

Creatinine, mg/dl, mean (SD)

0.9 (0.2)

0.8 (0.2)

0.578

Hemoglobin, g/dl, mean (SD)

14.2 (0.8)

14.3 (2.1)

0.847

Troponin I, ng/ml, median (IQR)

25.8 (6.2–41.9)

14.6 (3.6–54.2)

0.630

Laboratory parameters at 6 months

NT-proBNP, pg/ml, median (IQR)

96 (82–356)

228 (113–347)

0.207

Echocardiography at baseline, mean (SD)

LVEDV, ml

102.8 (27.5)

118.6 (45.6)

0.343

LVESV, ml

53.5 (18.7)

64.7 (29.7)

0.312

LVEF, %

48.9 (7.8)

46.2 (8.9)

0.823

Echocardiography at 6 months, mean (SD)

LVEDV, ml

152.7 (46.9)

115.5 (31.7)

0.043

LVESV, ml

65.3 (28.1)

56.3 (25.3)

0.350

LVEF, %

57.8 (8.5)

52.5 (8.8)

0.393

Pharmacotherapy at discharge, n (%)

Aspirin

17 (100)

54 (100)

1.00

P2Y12 inhibitor

17 (100)

54 (100)

1.00

Statin

17 (100)

53 (98)

0.57

β-blocker

15 (88)

52 (96)

0.21

ACE-inhibitor or ARB

16 (94)

53 (98)

0.38

Aldosterone receptor antagonist

2 (1)

5 (10)

0.76

Abbreviations: ACE, angiotensin-converting enzyme; ARB, angiotensin-receptor blockers; BMI, body mass index — weight in kilograms divided by square of the height in meters; IQR, interquartile range; LVEDV, left ventriclar end-diastolic volume; LVEF, left ventriclar ejection fraction; LVESV, left ventriclar end-systolic volume; LVR, left ventricular remodeling; NT-proBNP, N-terminal pro-B-type natriuretic peptide; SD, standard deviation

Seventeen (24%) patients did and 54 patients (76%) did not develop LVR at 6 months. Patients with LVR were younger than patients without LVR (mean age, 56.0 [SD, 6.8] years vs 57.9 [SD, 11.4] years, respectively; P = 0.039). There were no other clinical differences between patients with and without LVR. Baseline echocardiography parameters and pharmacotherapy were comparable between the groups. All patients received dual antiplatelet therapy, all patients except for one received statin, and more than 88% of patients received a β-blocker and an angiotensin-converting enzyme inhibitor.

At 6 months follow-up LVEDV was larger with patients with LVR, compared to those without LVR (P = 0.04). The LVEF was comparable in both groups. There were no deaths and only one recurrent hospitalization due to HF during the study in a patient from the LVR group.

VCAN expression is an independent predictor of LVR

Figure 2 shows the mRNA transcripts expression after AMI in patients with and without LVR at 6 months. VCAN expression was lower in patients who developed LVR, compared to those who did not (P = 0.02; Figure 2A), and discriminated between these patients (area under the ROC curve, 67%; P = 0.04; Figure 2B).

6061.png

T

Figure 2. A. Messenger RNA transcript expression levels measured at baseline after AMI in patients with or without LVR at 6 months follow-up. Data are expressed as median and interquartile range and compared using Mann-Whitney U-test. B. Receiver operating characteristic curve showing VCAN expression after AMI to predict LVR. C. Correlation between VCAN expression measured at baseline and NTproBNP concentration measured at baseline and 6 months after AMI, analyzed using Spearman correlation coefficient test. D. Correlation between VCAN expression measured at baseline and LVEF at baseline and 6 months after AMI, analyzed using Spearman correlation coefficient test

Abbreviations: LVEF, left ventricular ejection fraction; LVR, left ventricle remodeling; VCAN, versican; other see Figure 1

he expression of other mRNA transcripts did not differ between the groups. Expression of VCAN transcript <75.3 normalized units predicted LVR with 71% sensitivity and 67% specificity. Statistical estimates for the prediction of LVR by VCAN expression, including the cut-off values determined based on the ROC curve, are shown in Table 3.

Table 3. Statistical estimates for prediction of LVR by VCAN transcript expression

 

AUC (95% CI)

P-value

Cut-off

Sensitivity

Specificity

VCAN

0.67(0.53–0.81)

0.04

<75.3 NU

71%

67%

Abbreviations: AUC, area under the curve; CI, confidence interval; NU, normalized units; VCAN, versican

To determine the clinical predictors of LVR, we performed an univariable logistic regression analysis (Table 4).

Table 4. Results of univariable logistic regression analysis for prediction of LVR including pre-operative VCAN expression transcript above the cut-off value and clinical risk factors

Variable

OR

95% CI

P-value

 

 

Lower

Upper

 

VCAN <75.3 NU AUC

4.050

1.204

13.619

0.024

Age

0.944

0.892

0.999

0.047

Gender (female)

3.250

0.648

16.301

0.152

BMI

1.082

0.935

1.252

0.292

Anterior AMI

2.417

0.648

9.015

0.189

Arterial hypertension

1.417

0.367

5.473

0.613

Diabetes mellitus

1.033

0.233

4.578

0.966

Dyslipidemia

2.885

0.556

14.957

0.207

Smoking

0.952

0.263

3.448

0.941

Previous AMI

1.773

0.147

21.423

0.652

NT-proBNP

1.000

0.999

1.000

0.316

Creatinine

1.000

0.999

1.001

0.763

Hemoglobin

1.048

0.657

1.672

0.843

Troponin I

0.996

0.982

1.010

0.571

LVEDV

0.992

0.972

1.012

0.421

LVESV

0.988

0.958

1.018

0.437

LVEF

0.997

0.936

1.063

0.935

Aspirin

1.000

0.999

1.000

0.678

P2Y12 inhibitor

3.621

0.726

18.066

0.117

Statin

1.000

0.999

1.000

0.520

β-blocker

722.712

0.001

2347.72

0.999

ACE-inhibitor or ARB

686.576

0.001

6852.21

0.999

Aldosterone receptor antagonist

0.182

0.022

1.533

0.117

Abbreviations: OR, odds ratio; other see Table 2 and 3

We found that VCAN expression level below the determined cut-off and age were the only predictors of LVR (OR, 4.050; 95% CI, 1.20413.619; P = 0.024 for VCAN; OR, 0.944; 95% CI, 0.8920.999; P = 0.047 for age). Next, we incorporated VCAN expression and age in the multivariable regression model. VCAN was the only independent predictor of LVR (OR, 3.475; 95% CI, 1.00012.075; P = 0.047; Table 5).

Table 5. Multivariable logistic regression model for prediction of LVR including significant predictors of LVR in univariable analysis (pre-operative VCAN expression transcript above the cut-off value and age)

Variable

OR

95% CI

P-value

 

 

Lower

Upper

 

VCAN <75.3 NU AUC

3.475

1.000

12.075

0.047

Age

0.951

0.897

1.009

0.099

Abbreviations: see Table 2–4

VCAN expression correlates with NT-proBNP concentration

Figures 2C and 2D show the correlations between VCAN expression at 24 hours and NT-proBNP and LVEF at 24 hours and 6 months after AMI. There was a trend towards a positive correlation between VCAN expression and NT-proBNP concentration at 24 hours (R = 0.23; P = 0.07) and an intermediate, positive correlation at 6 months (R = 0.33; P = 0.01). There were no correlations between VCAN expression and LVEF.

DISCUSSION

The main finding of our study is that decreased VCAN expression is an independent predictor of LVR after AMI, increasing the odds of LVR 3.5-fold. The second important finding is the positive correlation between VCAN expression and NT-proBNP concentrations in patients after AMI.

VCAN is a protective proteoglycan regulating cell survival and extracellular matrix assembly [11]. Many studies demonstrated the role of VCAN in cardiac remodeling. For example, VCAN was showed to induce myofibroblast differentiation during lung remodeling [14]. In addition, human cardiomyocyte differentiation is accompanied by changes in the expression and accumulation of VCAN [15]. VCAN favors transforming growth factor β-mediated signaling in cardiomyocytes, thereby accelerating healing of the infarcted myocardium [16]. Upregulation of VCAN in the infarcted myocardium mediates chemotaxis and cytokine release in an animal model. The transient expression of VCAN by infiltrating monocytes in the infarcted area of the heart suggests the role of VCAN in the inflammatory response [17]. Furthermore, a post-mortem analysis of 20 infarcted cardiac muscles demonstrated the similar localization of the fragmented VCAN and ADAM metallopeptidase with thrombospondin type 1 motif 1 (ADAMTS1) in the necrotic areas. ADAMTS1 is produced by infiltrating macrophages, suggesting that inflammatory processes after AMI lead to VCAN fragmentation [18]. Altogether, down-regulation of VCAN transcript expression in whole blood samples may be a sign of dysfunctional repair mechanisms after AMI, increasing the risk of LVR.

NT-proBNP is an established biomarker of HF and the fragment of the brain natriuretic hormone (BNP) propeptide, which is released in response to the increased atrial and ventricular wall stretch [19]. BNP secretion counteracts the increased cardiac overload, resulting in vasodilation, diuresis, natriuresis, and inhibition of cardiac remodeling [20]. The positive correlation between VCAN expression and NT-proBNP observed in our cohort indicated that similarly to BNP increased VCAN transcript level might be a protective mechanism in patients after AMI. Concurrently, dysregulated VCAN expression might be a sign of the compensatory mechanisms’ failure. However, since we only observed a correlation between both markers, without any causal relationship, we may only speculate about its pathophysiological relevance.

Limitations

The main limitation of our study is the single-center design and a relatively small sample size included in the analysis. Moreover, since our study was not powered for hard clinical end-points including hospitalizations or death due to HF, our results remain hypothesis-generating and required confirmation in future trials. Finally, the wide confidence interval of VCAN expression in the multivariable logistic regression model requires caution when interpreting the results. Altogether, our results should be confirmed in a larger, preferably multi-center study before implementation in clinical practice.

CONCLUSIONS

In our cohort of patients after STEMI, low VCAN expression was an independent predictor of LVR at 6 months. Whether decreased expression of VCAN might be a useful tool to predict LVR in clinical practice remains to be established.

Article information

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