Acute Coronary Syndrome, Heart Failure
Conditions
Keywords
long noncoding RNA, heart failure, acute coronary syndrome, biomarkers
Brief summary
The objective of this project is 1) to explore the clinical relevance of BACE1-AS and BACE1 as therapeutic targets and 2) to evaluate their potentiality as biomarkers in ischemic heart failure (HF). The first aim will be studied by validating in left ventricle biopsies in patients with post-ischemic heart failure the transcriptome and DNA methylation status data obtained in cell lines where the expression of BACE1-AS has been modulated. The investigation of BACE1-AS and BACE1 as biomarkers will be obtained by using peripheral blood mononuclear cells (PBMCs) from patients with acute coronary syndrome (ACS) treated with percutaneous angioplasty (PCI) procedure and undergoing to left ventricular remodeling. Furthermore, PBMCs from patients with chronic ischemic HF recruited from the Istituti Clinici Scientifici Maugeri Pavia will be also used. From the data obtained from these patients and from non-decompensated subjects, the levels of BACE1-AS and BACE1 in the blood will be measured and correlated with each other and with β-amyloid levels (βA), as well as with clinically relevant parameters.
Detailed description
1.1) Validation of transcriptomic data obtained in vitro: The transcriptome of the AC16 cardiomyocyte cell line in which the expression of BACE1-AS was induced by lentivirus vectors will be analyzed, thus identifying the transcripts specifically modulated by BACE1-AS. The data obtained in vitro will be validated by analyzing the RNAs extracted from 20 HF patients and 20 controls. These RNA samples are already available thanks to the RNA\_HF\_AS project Study of the transcriptome in heart failure and aortic stenosis (San Raffaele Hospital - Milan, Ethics Committee CE 85/int/2016). 1.2) Validation of epigenetic data: The effect of BACE1-AS on the state of DNA methylation will be studied in the AC16 cardiomyocyte cell line. In over-expressing BACE1-AS cells, DNA hypomethylation will be evaluated by MS-HRM and pyrosequencing studies of bisulfite-modified genomic DNA of 69 enhancer sequences identified by us as candidates in preliminary studies. The data thus obtained will be validated in 20 cardiac biopsies from patients with post-ischemic HF and in 20 controls. Left ventricular biopsies will be taken after obtaining informed consent from 20 patients suffering from non-terminal dilated cardiomyopathy (DCM) undergoing left ventricular reconstruction (SVR) surgery at the San Donato Policlinico. A sufficient number of samples with these characteristics have already been obtained from IRCCS Policlinico San Donato as part of the RNA\_HF\_AS project (San Raffaele Hospital - Milan, Ethics Committee CE 85/int/2016). and not completely used for the study. 1.3) Study of the expression levels of BACE1-AS, BACE1 in PBMC of patients with ischemic cardiomyopathy. The expression levels of BACE1 and BACE1-AS will be measured in PBMCs from the following groups: Group 1: 130 ACS patients with left ventricular systolic dysfunction (left ventricular ejection fraction (LVEF) \< 45%) at 12 months follow-up after PCI, as well as 100 control subjects, recruited from the Interventional Cardiology Unit of the IRCCS Policlinico San Donato. The measurements of BACE1, BACE1-AS and βA will be carried out at the Molecular Cardiology Laboratory of the IRCCS Policlinico San Donato. These activities are included among those approved in the RNA\_ACS protocol (Ethics Committee of the San Raffaele Hospital - Milan 14/int/2020) RNA as prognostic biomarkers in patients with acute coronary syndrome Group 2: 240 patients with chronic post-ischemic HF and 120 age/sex-matched healthy controls. The recruitment of this group and measurements of BACE1, BACE1-AS and βA will be carried out at the Istituti Clinici Scientifici Maugeri Pavia.
Interventions
DIAGNOSTIC_TESTmeasurement of RNAs
RNAs will be measured in heart tissues and in peripheral blood mononuclear cells
Sponsors
Istituti Clinici Scientifici Maugeri di Pavia
IRCCS Policlinico S. Donato
Study design
Observational model
CASE_CONTROL
Time perspective
RETROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
Yes
Inclusion criteria
1. Left ventricular biopsies from patients with post-ischemic HF Inclusion Criteria: * left ventricular reconstruction surgery (SVR) * ESVI \>35 ml/m2 * EF\<40% * previous anterior transmural infarction * age 40-75 years
Exclusion criteria
* ESVI \<35 ml/m2 * EF\>40% * Tempo from E unknown * Pregnant women * Patients with genetic diseases * Patients suffering from malignant neoplasm * Subjects with collagenopathies * Subjects undergoing chemo/radiotherapy * Subjects undergoing prolonged steroid therapy * Subjects with known active infectious diseases * Subjects with positive serology for HIV, HBV (not vaccinated), HCV. 2. Patients with ACS and left ventricular dysfunction 12 months after percutaneous angioplasty Inclusion criteria: * Age \>18 years * Patients with ACS (first episode), defined according to the ESC 2017 guidelines \[19\] * Informed consent to enrollment in the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cardiac tissutal RNAs expression | From year 1 to year 3 | The RNAs cardiac tissutal expression of non- and end-stage heart failure patients compared to controls |
| Peripheral blood RNAs expression in ACS | From year 1 to year 3 | The RNAs expression in peripheral blood mononuclear cells of acute coronary syndrome patients treated with percutaneous angioplasty and remodelling compared to controls |
| Peripheral blood RNAs expression in heart failure | From year 1 to year 3 | The RNAs expression in peripheral blood mononuclear cells of heart failure patients compared to controls |
Countries
Italy
Outcome results
None listed