Cardiology

Soluble low density lipoprotein receptor-related protein-1 levels in the differential diagnosis of myopericarditis versus acute coronary syndrome

a b s t r a c t

Introduction: Differential diagnosis of myopericarditis (MPC) versus acute coronary syndromes can be dif- ficult in the emergency room (ER). Low density lipoprotein receptor-related protein-1 (LRP-1) is a transmem- brane receptor with diverse biological functions. LRP-1 is increased after viral infections as a defense mechanism. sLRP-1 (soluble form) can be measured in the serum. We study the diagnostic sLRP-1 levels in patients with MPC, ACS and healthy controls.

Methods: The study included consecutive patients who were admitted between the dates of 1.1.2018 and 1.1.2019 with the diagnosis of MPC or ACS. All patients reported to the ER with chest pain (CP) and elevated car- diac troponin levels. Control group (n = 61) was selected from healthy subjects. In addition to routine laboratory work up, serum sLRP-1 concentrations were measured on admission.

Results: sLRP-1 levels were significantly higher in MPC, compared to controls (p = 0.005) and ACS (p = 0.001). Median (IQR) sLRP-1 levels in MPC, controls and ACS were 7.39 (22.42), 2.27 (1.74), 2.41 (0.98) ug/ml, respec- tively (p = 0.004). Among the covariates: sLRP-1, age, gender, HDL-C and LDL-C; only sLRP-1 differentiated a diagnosis of MPC versus ACS (OR = 1684, p = 0,046, CI for OR (1008-2812). The area under the curve (AUC) was measured as 0.79 [CI 0.62-0.95] in ROC analysis, p = 0.001; sLRP-1 had 69% sensitivity and 85% specificity for diagnosis of MPC with a cut-off value of 4.3 ug/ml.

Conclusion: sLRP-1 is a potential biomarker in the differential diagnosis of MPC versus ACS in ER. Future studies are needed to evaluate and develop the utility of sLRP-1 as a diagnostic and Prognostic biomarker in MPC.

(C) 2022

  1. Introduction

High-sensitivity cardiac troponin (cTn) assays have revolutionized the Clinical approach to patients with chest pain in the emergency room (ER). Raised cTn in ER is often associated with acute coronary syndromes , while other causes have become common findings in the evaluation of chest pain in the ER [1]. Patients with acute or chronic systemic disorders frequently present with cTn elevations. Sev- eral nonischaemic Cardiac conditions, such as pericarditis, drug toxicity, or heart failure present with elevated cTn levels [1]. Elevated cTn levels

* Corresponding author at: Cardiology, Medeniyet University Hospital Goztepe, 34726 Istanbul, Turkey.

E-mail address: [email protected] (M. Agirbasli).

in the blood are associated with increased rates of cardiac events and mortality, regardless of the Underlying etiology [1,2].

Patients with a clinical presentation of acute pericarditis with elevated cTn levels but without impairment of left ventricular ejection fraction nor left ventricular wall motion abnormalities are being diag- nosed with myopericarditis (MPC) [3]. MPC is a disease of exaggerated inflammation after viral infection. The clinical diagnosis is through the criteria for pericarditis and myocardial involvement, confirmed by elevated cardiac biomarkers such as cardiac troponins [4]. Clinical ob- servation suggests viral infections as the most common etiology for MPC [5]. The diagnosis of MPC is defined as patients presenting with chest pain, ST-segment changes on Electrocardiography sugges- tive of pericarditis, with elevated biomarkers of myocardial damage [6]. History often includes a recent viral infection. Patients usually do not demonstrate focal left ventricular Wall motion abnormality, while

https://doi.org/10.1016/j.ajem.2022.07.038

0735-6757/(C) 2022

selective coronary angiography do not display significant coronary artery disease that can explain the clinical presentation. Novel surrogate biomarkers are needed in the diagnosis of MPC. The differential diagno- sis of MPC versus (vs) Acute Coronary Syndromes can be difficult in the ER setting.

Low density lipoprotein receptor-related protein-1 (LRP-1) is a large multifunctional receptor that plays a role in inflammation [7,8]. LDL receptor family members include LRP-1, LRP5/6, ApoER2, and VLDLR. structure and function of LRP-1 is slowly unfolding [9]. Unlike LDL receptor, the functions of LRP-1 are not limited to lipid metabolism. LRP-1 functions as a signal transducing receptor. Structurally, LRP-1 consists of a large extracellular ligand-binding subunit (? chain) and a short transmembrane subunit (? chain). Soluble LRP-1 (sLRP-1) is de- tected in serum by the presence of the ?-chain and part of the ? chain [10,11]. sLRP-1 is a novel biomarker in myocardial diseases, because LRP-1 has a pivotal role in cardiac inflammation and healing [12]. LRP- 1 increases during acute viral infections. LRP-1 expression is increased after herpesviridae infection as a defense mechanism of the host [13]. On the other hand, LRP-1 in vascular smooth muscle cells and macro- phages shows a potent protective role against atherosclerosis [9]. Low sLRP-1 levels are associated with vascular disease and atherosclerosis [9,14,15]. ACS occur in the setting of advanced atherosclerosis and MPC starts with inflammation after viral infection [1,3,4]. Our hypothesis is that unlike cTn, sLRP-1 levels diverge in MPC and ACS. In this Cross sectional study, we compare sLRP-1 concentrations in patients who apply to the ER with chest pain. The cardiac work up and findings are suggestive of MPC or ACS. We report the sLRP-1 from patients with MPC, ACS versus (vs) healthy controls.

  1. Methods
    1. Study population

We conducted a cross-sectional observational study in a single tertiary care center. We included patients aged between 20 and 80 years, admitted with chest pain, who underwent diagnostic testing, in- cluding coronary angiogram, between the dates of 1.1.2018 and 31.12.2018. We excluded those patients with: chronic renal failure un- dergoing dialysis; a history of active malignant tumor; cirrhosis (Child-Pugh score Class B and C); and pregnant or breastfeeding women. The study was performed prior to the start of coronavirus disease 2019 (COVID-19) pandemic, therefore, none of the patients were evaluated for Sars-Cov2 virus infection. The indications for coro- nary angiograpghy were continuing chest pain and elevated cardiac biomarkers such as elevated cTn. Demographic, clinical, and laboratory parameters were recorded by direct interview and using the institu- tional electronic medical database. The study was conducted according to the 1975 Helsinki and its subsequent revisions. All patients gave their informed consent and the study was approved by the local ethics com- mittee.

    1. Definition of MPC

MPC is characterized by inflammation of the pericardium with con- current involvement of the adjacent myocardial tissue. The diagnosis of MPC was considered in patients who present with: chest pain; ST-segment changes suggestive of pericarditis on ECG; with elevated cardiac troponin (cTn) levels as a biomarker of myocardial damage [3,4]. For study purposes, ACS was defined as: patients presenting with chest pain; ECG and echocardiography findings suggestive of myo- cardial ischemia and/or infarction; elevated cTn levels and coronary angiography demonstrating a tight coronary (> 90%) obstruction of the Culprit coronary artery which could explain the clinical presenta- tion, ECG and echocardiography findings.

Venous blood samples were collected into vacuum tubes containing 3.2% Na-citrate. The serum was obtained by subjecting the blood to centrifugation at 3000 xg for 20 min at Room temperature, 500 uL serum sample was stored at -80 ?C until analysis. Analyses were per- formed in the left over serum samples of the routine tests. Separate Blood draw was not performed for the study purposes. Serum sLRP-1 concentrations were measured using the human-specific sLRP-1 enzyme-linked immunosorbent assay (Human Low Density Lipoprotein Receptor Related Protein 1 ELISA Kit, Cat. No. E2298Hu, Bioassay Tech- nology Laboratory, Shanghai, China), according to the manufacturer’s instructions. Biomarker concentrations cTn and biochemistry panel were routinely determined, using biochemical analysis kits and Roche Cobas 6000 analysis device (Roche Diagnostics, Basel, Switzerland).

    1. Statistical analysis

All analyses were performed using SPSS version 22.0 software. Quantitative data were expressed as the mean +- standard deviation (SD), median (interquartile range (IQR) and number (%) depending on the type and distribution of the data. The sLRP-1 levels displayed nonparametric distribution according to the Kolmogorov-Smirnov test. Nonparametric tests were used to assess the sLRP-1 levels of the groups. The demographic data of the patients with MPC, ACS, and healthy controls were compared using the Pearson chi-squared test or Fisher exact test for categorical variables (e.g., sex), and ANOVA or Kruskall Wallis tests for continuous variables. Categorical variables were expressed as numbers and percentages and compared using the chi-squared test. Spearman rank correlation analysis was used to ana- lyze the relationship between the serum sLRP-1 concentrations and other parameters. Chi-square test was used to assess differences in categorical variables between groups. Student t-test or Mann Whitney U test were used to compare the unpaired samples with normal and skewed distributions, respectively. Multivariate logistic regression anal- ysis were used to identify independent variables of diagnosis of MPC. After performing univariate analysis, variables were selected into the multivariate logistic regression analysis with the stepwise method. The results of univariate and multivariate regression analyses were presented as odds ratio with 95% CI. For the differential diagnosis of MPC vs ACS receiver operating characteristic (ROC) curve was obtained and the optimal values with the greatest total sensitivity and specificity in the prediction of MPC were selected. Significance was assumed at a 2-sided p < 0.05.

  1. Results

The study included 117 patients. According to the study definitions, 102 patients were diagnosed with ACS; 15 patients were diagnosed with MPC and 61 healthy controls were included for comparison. Patient characteristics and demographics were as displayed in Table 1. Median (IQR) sLRP-1 levels in MPC, controls and ACS are displayed in Table 1 and Fig. 1. sLRP levels were similar between ACS and controls (p = 0.573). sLRP-1 levels were significantly higher in MPC, compared to controls (p = 0.005) and ACS (p = 0.001), respectively. The sLRP-1 levels displayed significant differences between 3 groups (p = 0.005) (Table 1 and Fig. 1). Statistical differences were observed between the groups in age and gender (Table 1).

Patients with MPC and ACS presented with chest pain. MPC patients were admitted with pleuro-pericarditis type chest pain with a history viral infection within the 4-6 weeks. ECG showed diffuse concave ST-segment elevation and PR depression. Elevation of cTn and inflam- matory biomarkers were noted. Coronary angiogram did not demon- strate any significant coronary artery disease (> 50%) to explain the symptoms or ECG findings. All patients received non steroidal anti-inflammatory drugs, and colchicine with good Clinical response.

Table 1

Soluble LRP-1 levels, demographic and laboratory characteristics in patients with myopericarditis (MPC), acute coronary syndrome (ACS) and controls. Quantitative data are expressed as the mean +- standard deviation (SD) or median (interquartile range (IQR) for parametric and non-parametric variables, respectively.

Controls

Myopericarditis

ACS

p value

(n = 61)

(n = 15)

(n = 102)

Age (years)

50 +- 15

28 +- 11

59 +- 9

<0.001

Gender (M/F)

(10/51)

(12/3)

(79/23)

<0.001

Soluble LRP ug/mL median (IQR)

Total cholesterol

2.27 (1.74)

272 +- 59

7.39 (22.42)

160 +- 26

2.41 (0.98)

183 +- 50

0.004

<0.001

(mg/dL)

LDL cholesterol

193 +- 64

101 +- 16

115 +- 49

<0.001

(mg/dL)

HDL cholesterol

60 +- 77

35 +- 13

41 +- 14

0.027

(mg/dL)

Triglycerides (mg/dL)

159 +- 62

112 +- 47

157 +- 99

0.234

LVEF (%)

63 +- 2

53 +- 22

48 +- 20

0.314

Urea (mg/dL)

30 +- 11

31 +- 9

36 +- 23

0.121

Creatinine (mg/dL)

0.82 +- 0.21

1.08 +- 0.42

0.94 +- 0.50

0.186

Hs-cTn I (ng/L)

2122 (6074)

1810 (21591)

0.535

mg miligram; ng nanogram; L liter; dL deciliter; SD standard deviation; IQR interquartile range; Hs-cTn I: High sensitive cardiac troponin I.

Upper respiratory tract infection was observed in 4 of the patients; 1 patient used antibiotics due to upper respiratory tract infection. One patient had a history of pericarditis; and 1 patient history of myocardi- tis. Prior emotional and mental stress was observed in 2 patients; gas- trointestinal symptoms and diarrhea in 2 patients. One patient used bisoprolol prior to admission; 1 patient had a history of cannabinoid use. Summary of transthoracic echocardiography findings in the 15 patients with myopericarditis are displayed in Table 2. If present, peri- cardial effusion was trivial (less than minimal <9 mm) in all cases.

Coronary angiographic imaging was performed in 8 patients during the hospitalization. Selective coronary angiography did not display sig- nificant focal coronary artery stenosis (>50%) in patients with MPC. Two-year follow-up was possible in 15 patients. One patient was

Table 2

Summary of transthoracic echocardiography findings and cardiac troponin levels in 15 patients with myopericarditis.

Patient Summary of transthoracic echocardiography findings

  1. normal left ventricular systolic function, trivial pericardial effusion
  2. mild Mitral regurgitation,mild tricuspid regurgitation, normal left ventricular systolic function
  3. normal left ventricular systolic function, mild tricuspid regurgitation, minimal mitral regurgitation, trivial pericardial effusion
  4. normal left ventricular systolic function, trivial pericardial effusion
  5. normal left ventricular systolic function minimal mitral regurgitation minimal tricuspid regurgitation
  6. normal left ventricular systolic function, intraatrial septal aneurysm with no shunt by Color Doppler imaging, mild tricuspid regurgitation, mild mitral regurgitation
  7. normal left ventricular systolic function, trivial pericardial effusion
  8. normal left ventricular systolic function,mild mitral regurgitation,minimal tricuspid regurgitation
  9. normal left ventricular systolic function, left ventricular diastolic dysfunction stage 1, mild mitral regurgitation mild tricuspid regurgitation
  10. normal left ventricular systolic function, trivial pericardial effusion
  11. mildly depressed left ventricular systolic function, ejection fraction is 45%, mild global hypokinesia, mild mitral regurgitation, left ventricular hypertrophy, mild mitral regurgitation
  12. normal left ventricular systolic function, ejection fraction is 55%, mild mitral regurgitation
  13. normal left ventricular systolic function, trivial pericardial effusion
  14. normal left ventricular systolic function, trivial pericardial effusion
  15. normal left ventricular systolic function, trivial pericardial effusion

readmitted to hospital with chest pain, 1 week after the discharge; 1 patient had recurrent chest pain after 1 year following admission.

ACS patients presented with chest pain, which usually began abruptly. They described the chest pain (angina) or discomfort, often as aching, pressure, tightness or burning spreading from the chest to the shoulders, arms, upper abdomen, back, neck or jaw. Associated symptoms included nausea or vomiting, indigestion, dys- pnea, diaphoresis, dizziness, fatigue. All patients with ACS had

Image of Fig. 1

Fig. 1. sLRP-1 levels (ug/ml), demographic and laboratory characteristics in patients with myopericarditis (MPC), acute coronary syndrome (ACS) and controls. sLRP levels were similar between ACS and controls (p = 0.573). sLRP1 levels were significantly higher in MPC (7.39 ug/mL (22.42)), compared to controls (2.27 ug/mL (1.74), p = 0.005) and ACS (2.41 ug/mL (0.98), p = 0.001), respectively (Table 1).

Table 3 The results of logistic regression analysis to predict the diagnosis of myopericarditis (MPC) vs acute coronary syndrome (ACS). The parameters related to the diagnosis of MPC were evaluated in multivariate logistic regression analysis. Patients with ACS and MPC were included in the analysis.

Variables Odds ratio Significance (p) 95% CI for odds ratio

Upper

Lower

sLRP-1 (ug/ml)

1684

0,046

1008

2812

Age (years)

1425

0,118

,914

2220

Gender

,008

0,171

,000

7782

HDL-C (mg/dL)

,926

0,338

,791

1084

LDL-C (mg/dL)

1019

0,207

,989

1050

Constant

,000

0,100

elevated cardiac troponin (cTn) levels and underwent coronary angi- ography. Coronary angiography documented a tight (>90%) lesion explaining the symptoms, physical examination, ECG and echocardi- ography findings. Controls (n = 61) were selected from healthy sub- jects without cardiac history.

    1. Serum sLRP-1 concentrations

Serum sLRP-1 concentrations were measured by ELISA in patients with MPC and ACS. Serum sLRP-1 concentrations could not be obtained in 2 patients with MPC and 11 patients with ACS due to insufficient blood sample. Biochemical and laboratory variables such as total choles- terol and high density lipoprotein cholesterol (HDL-C) were lower, and sLRP-1 levels higher, in patients with MPC compared to ACS or controls (Table 1, Fig. 1). sLRP-1 levels (ug/ml) were significantly higher in MPC

compared to the controls (p = 0.005) and ACS (p = 0.001), but similar between ACS and controls (p = 0.573). Other biochemical and labora- tory variables were similar between all three groups.

Multivariate logistic regression analysis was applied to the parame- ters used in the diagnosis of MPC, in those patients with ACS and MPC. The co-variates were: age, sLRP-1, gender, HDL-C, and low density lipoprotein cholesterol (LDL-C). Only sLRP-1 predicted the diagnosis of MPC (Table 3).

ROC analysis was used to evaluate the specificity and sensitivity of sLRP-1 cut-off values for predicting MPC in patients who present chest pain (Fig. 2). Patients with a diagnosis of ACS or MPC were included. The line represents the sLRP-1 value and the area under the curve (AUC) was measured as 0.79 [CI 0.62-0.95], p = 0.001. sLRP-1 had 69% sensitivity, 85% specificity, with a cut-off value of 4.3 (ug/mL).

  1. Discussion

The differential diagnosis between ACS and MPC can be difficult in ER. cTn elevations are common in diseases that not related to ACS [16]. In this study, cTn levels were similar in patients with MPC or ACS. The 2 conditions present with different mechanisms of myocardial injury. MPC is a primarily pericardial inflammatory syndrome after a viral infection. ACS results usually from atherosclerosis and thrombosis. LRP-1 levels increase in viral infections and decrease in the setting of atherosclerosis. LRP-1 can be used in the differential diagnosis of the 2 conditions.

Here, we compared sLRP-1 levels in patients with MPC, against those with ACS and normal controls: sLRP-1 levels were significantly higher in patients with MPC compared to ACS patients or controls. Our findings

Image of Fig. 2

Fig. 2. The specificity and sensitivity of the cut-off values for sLRP-1 were evaluated by ROC analysis to predict the presence of myopericarditis in patients who present chest pain. Patients with diagnosis of acute coronary syndromes (ACS) or myopericarditis (MPC) were included in the analysis. The line represents the sLRP-1 value and the area under the curve (AUC) was measured as 0.79 [CI 0.62-0.95], p = 0.001. sLRP-1 had 69% sensitivity and 85% specificity with a cut-off value of 4.3 (ug/ml).

support observations from Experimental models, suggesting sLRP-1 can be a biomarker in the pathogenesis of MPC.

MPC is a complication of acute pericarditis, characterized by ex- tension of Pericardial inflammation to the myocardium, which man- ifests as an elevated cTn level. MPC is not an uncommon problem, the likely etiology being viral infection. MPC is regarded as a prominent infectious-inflammatory disease for patients after viral infections.

ACS on the other hand, involves mechanisms through which inflam- mation in the plaque can precipitate the thrombotic complications of atherosclerosis, including the obstruction of flow in the culprit coronary artery by thrombus followed by myocardial ischemia and necrosis. In our study, all ACS patients displayed >90% percent obstruction in the culprit coronary artery.

MPC is generally evaluated and treated as acute pericarditis. One of the key challenges in managing MPC is excluding the presence of an ACS in the ER setting. Pericarditis and myocarditis features commonly exist together, and recently growing number of cases present with over- lapping signs and symptoms of both conditions in clinical practice [3-5]. Guidelines define pericarditis with known or clinically suspected con- comitant myocardial involvement as MPC, on the other hand, if patients present with predominant myocarditis symptoms with pericardial involvement, in this case, the diagnosis is referred as perimyocarditis [17]. In our study, all patients presented with elevated cTn level, and left ventricular function was preserved. Recent history of viral infections and emotional stress was present in most of the patients. The diagnosis was assumed to be MPC, in the absence of significant coronary artery disease.

Currently, cTn is used as the universal biomarker for myocardial in- jury. However, cTn can be elevated in both MPC and ACS. Novel surrogate biomarkers are needed to identify MPC.

The clinical significance of sLRP-1 level is poorly understood. The finding of high levels of sLRP-1 in the ER, therefore needs to be confirmed with larger studies with long term follow up. To date, no other data exists on the human serum sLRP-1 levels in MPC vs ACS. Yet, LRP-1 plays a role in diverse processes including lipid metabolism, inflammation, Cardiac damage, immune system, cell growth, migration, tissue invasion and re- generation [17-24]. In humans, circulating sLRP-1 has been widely stud- ied in atherosclerosis and vascular disorders [18-20].

Clinical studies report limited data about the causes of MPC. Viral in- fections are given as the most common cause, with tuberculosis and other infections listed as potential etiologies in certain countries. While, none of these patients had any history or evidence of tuberculo- sis, nearly 1/3 reported a history of upper respiratory tract infection, and 1 reported diarrhea prior to admission. LRP-1 expression is likely a de- fense response to viral infection [21-24]. In response to viral infection, protein expression is altered to adjust cellular functions and limit viral replication. LRP-1 modulates cholesterol hemostasis in infected cells. LRP-1 initiates a signalling cascade to regulate and integrate cellular cholesterol homeostasis through the expression of the major cholesterol exporter ABCA1 with apoptotic cell removal and inflamma- tory responses [21-24].

Recent Sar-Cov-2 pandemia brought MPC into clinical focus because Covid19 cases present with a high prevalence of MPC [25,26]. Myocardi- tis and pericarditis have been potential mechanisms of cardiac injury during SARS-CoV-2 infection. Our study patients were all seen in 2018 and none of the patients displayed any clinical eveidence for COVID-

19. Future studies are needed to consider the clinical significance for elevated sLRP-1 level as a biomarker of myocardial damage after viral infections. The present study aims to describe the potential role of di- verse biomarkers to help the clinician in the ER for differential diagnosis of MPC and ACS.

  1. Conclusion

MPC is a disease of exaggerated inflammation after viral infection. The study reports that sLRP-1 levels are significantly higher in patients

with MPC, compared to ACS or healthy controls. Future studies are needed to test the utility of sLRP-1 as a diagnostic and prognostic bio- marker in MPC versus ACS.

Funding

This work is supported by the Research Fund of Istanbul Medeniyet University. Project number is 1358.

CRediT authorship contribution statement

Mehmet Agirbasli: Funding acquisition, Methodology, Project administration, Writing – original draft, Supervision. Furkan Bolen: Data curation, Formal analysis, Investigation, Methodology, Visualiza- tion. Oguz Konal: Data curation, Investigation, Writing – original draft. Rabia Korkmaz: Investigation, Resources, Writing – original draft. Ayse Ismihan Onur: Data curation, Investigation, Resources. Ilkay Kartal: Data curation, Investigation. Ferruh Isman: Investigation, Supervision.

Declaration of Competing Interest

The authors report no conflict of interest.

References

  1. Azar RR, Sarkis A, Giannitsis E. A practical approach for the use of high-sensitivity cardiac troponin assays in the evaluation of patients with chest pain. Am J Cardiol. 2021;139:1-7.
  2. Gibbs J, McCord J. Chest pain evaluation in the emergency department: risk scores and high-sensitivity cardiac troponin. Curr Cardiol Rep. 2020;22:49. https://doi. org/10.1007/s11886-020-01294-1.
  3. Lazarou E, Tsioufis P, Vlachopoulos C, Tsioufis C, Lazaros G. Acute pericarditis: up- date. Curr Cardiol Rep. 2022;20:1-9. https://doi.org/10.1007/s11886-022-01710-8.
  4. Farzad A, Schussler JM. Acute myopericardial syndromes. Cardiol Clin. 2018;36: 103-14.
  5. Imazio M, Trinchero R. Myopericarditis: etiology, management, and prognosis. Int J Cardiol. 2008 Jun 23;127(1):17-26.
  6. Nakashima H, Honda Y, Katayama T. Serial electrocardiographic findings in acute myo- carditis. Intern Med. 1994;33:659-66. https://doi.org/10.2169/internalmedicine.33. 659. [PMID: 7849377].
  7. Potere N, Del Buono MG, Mauro AG, Abbate A, Toldo S. Low density lipoprotein receptor-related Protein-1 in cardiac inflammation and infarct healing. Front Cardiovasc Med. 2019 Apr 26;6:51. https://doi.org/10.3389/fcvm.2019.00051. PMID: 31080804; PMCID: PMC6497734.
  8. Lillis AP, Van Duyn LB, Murphy-Ullrich JE, Strickland DK. LDL receptor-related pro- tein 1: unique tissue-specific functions revealed by selective gene knockout studies. Physiol Rev. 2008;2007(88):887-918. https://doi.org/10.1152/physrev.00033.2007.
  9. Mineo C. Lipoprotein receptor signalling in atherosclerosis. Cardiovasc Res. 2020 Jun 1;116(7):1254-74. https://doi.org/10.1093/cvr/cvz338.
  10. Herz J, Strickland DK. LRP: a multifunctional scavenger and signaling receptor. J Clin Invest. 2001;108:779-84. https://doi.org/10.1172/JCI13992.
  11. Herz J, Kowal RC, Goldstein JL, Brown MS. Proteolytic processing of the 600 kd low density lipoprotein receptor-related protein (LRP) occurs in a trans-Golgi compart- ment. EMBO J. 1990;9:1769-76.
  12. Cal R, Juan-Babot O, Brossa V, Roura S, Galvez-Monton C, Portoles M, et al. Low den- sity lipoprotein receptor-related protein 1 expression correlates with cholesteryl ester accumulation in the myocardium of ischemic cardiomyopathy patients. J Transl Med. 2012;10:160. https://doi.org/10.1186/1479-5876-10-160Crossre.
  13. Gudleski-O’Regan N, Greco TM, Cristea IM, Shenk T. Increased expression of LDL receptor-related protein 1 during human cytomegalovirus infection reduces virion cholesterol and infectivity. Cell Host Microbe. 2012;12:86-96. https://doi.org/10. 1016/j.chom.2012.05.012.
  14. Batu Oto B, Aykut V, Gunes M, Korkmaz R, Isman FK, Agirbasli M. Low levels of sol- uble low-density lipoprotein receptor-related protein 1 in patients with type 2 dia- betes mellitus and diabetic retinopathy. Exp Eye Res. 2022 Feb;215:108921. https:// doi.org/10.1016/j.exer.2022.108921.
  15. Brophy ML, Dong Y, Tao H, Yancey PG, Song K, Zhang K, et al. Myeloid-specific dele- tion of Epsins 1 and 2 reduces atherosclerosis by preventing LRP-1 downregulation. Circ Res. 2019;15(124):e6-19. https://doi.org/10.1161/CIRCRESAHA.118.313028.
  16. Giannitsis E, Katus HA. Cardiac troponin level elevations not related to acute coro- nary syndromes. Nat Rev Cardiol. 2013 Nov;10(11):623-34. https://doi.org/10. 1038/nrcardio.2013.129. Epub 2013 Aug 27. PMID: 23979214.
  17. Adler Yehuda, Charron Philippe, Imazio Massimo, Badano Luigi, Baron-Esquivias Gonzalo, Bogaert Jan, et al. 2015 ESC guidelines for the diagnosis and management of pericardial diseases: the task force for the diagnosis and Management of Pericar- dial Diseases of the European Society of Cardiology (ESC) endorsed by: the European

Association for Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2015;36:2921-64. https://doi.org/10.1093/eurheartj/ehv318.

  1. Potere N, Del Buono MG, Mauro AG, Abbate A, Toldo S. Low density lipoprotein receptor-related Protein-1 in cardiac inflammation and infarct healing. Front Cardiovasc Med. 2019;6:51.
  2. Actis Dato V, Chiabrando GA. The role of low-density lipoprotein receptor-related protein 1 in lipid metabolism, glucose homeostasis and inflammation. Int J Mol Sci. 2018;19(6):1780. https://doi.org/10.3390/ijms19061780.
  3. Xian X, Ding Y, Dieckmann M, Zhou L, Plattner F, Liu M, et al. LRP1 integrates murine macrophage cholesterol homeostasis and inflammatory responses in atherosclero- sis. Elife. 2017 Nov 16;6:e29292. https://doi.org/10.7554/eLife.29292. PMID: 29144234; PMCID: PMC5690284.
  4. Tree MO, Londono-Renteria B, Troupin A, Clark KM, Colpitts TM, Conway MJ. Dengue virus reduces expression of low-density lipoprotein receptor-related protein 1 to fa- cilitate replication in Aedes aegypti. Sci Rep. 2019 Apr 23;9(1):6352. https://doi.org/ 10.1038/s41598-019-42803-9. PMID: 31015516; PMCID: PMC6478881.
  5. Ganaie SS, Schwarz MM, CM McMillen, Price DA, Feng AX, Albe JR, et al. Lrp1 is a host entry factor for Rift Valley fever virus. Cell. 2021 Sep 30;184(20):5163-78. e24.

https://doi.org/10.1016/j.cell.2021.09.001.. Epub 2021 Sep 23. PMID: 34559985; PMCID: PMC8786218.

  1. Lee SY, Choi BS, Yoon CH, Kang C, Kim K, Kim KC. Selection of biomarkers for HIV-1 latency by integrated analysis. Genomics. 2019 May;111(3):327-33. https://doi.org/ 10.1016/j.ygeno.2018.02.007. Epub 2018 Feb 14. PMID: 29454027.
  2. Congote LF. Serpin A1 and CD91 as host instruments against HIV-1 infection: are ex- tracellular antiviral peptides acting as intracellular messengers? Virus Res. 2007 May;125(2):119-34. https://doi.org/10.1016/j.virusres.2006.12.018. [Epub 2007 Jan].
  3. Santoso A, Pranata R, Wibowo A, Al-Farabi MJ, Huang I, Antariksa B. Cardiac injury is associated with mortality and critically ill pneumonia in COVID-19: a meta-analysis. Am J Emerg Med. 2021;44:352-7. https://doi.org/10.1016/j.ajem.2020.04.052.
  4. Rafaniello C, Gaio M, Zinzi A, Sullo MG, Liguori V, Ferraro M, et al. Disentangling a thorny issue: myocarditis and pericarditis post COVID-19 and following mRNA COVID-19 vaccines. Pharmaceuticals (Basel). 2022 Apr 25;15(5):525. https://doi. org/10.3390/ph15050525.

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