Epitranscriptomic Biomarkers for Ischemic Heart Disease (IHD-EPITRAN) - A Prospective Cohort Study

Status: Recruiting
Location: See location...
Intervention Type: Diagnostic test
Study Type: Observational
SUMMARY

Despite advancements in medical care, ischemic heart disease (IHD) remains the leading global cause of death. IHD develops through lipid accumulation into the coronary arteries with subsequent formation of larger atherogenic plaques. During myocardial infarction (MI), a plaque ruptures and subsequent occlusion leads to a death of the heart muscle. The tissue is rapidly replaced with a scar, which may later lead to heart failure (HF). Optimally, disease biomarkers are analyzed from blood, provide insight into the disease progression and aid the evaluation of therapy efficacy. Unfortunately, no optimal biomarkers have been identified for IHD. The vast but uncounted number of patients with undiagnosed IHD, benefitting from an early diagnosis, underscore the dire need for an IHD biomarker. Epitranscriptomics, the study of posttranscriptional modifications on RNA, has recently been properly re-established. This expanding field is uncovering a new layer of regulation, controlling processes ranging from cell division to cell death. Over 170 modifications have been identified as posttranscriptional marks in RNA species. These modifications influence RNA metabolism, including export, stability, and translation. One the most common and intensively studied RNA modification is the N6-methyladenosine (m6A), the abundance and effects of which are determined by the interplay between its writers, readers and erasers. Recent findings suggest a local dysregulation of the m6A dynamics in the myocardium, coalescing in signalling pathway and contractility related RNA transcripts during hypertrophy, MI and HF. While these early reports have focused on the myocardium, the role of the m6A in the circulation during IHD remains unexplored. We hypothesize the IHD pathophysiology to be reflected in the epitranscriptome of the circulating RNA. The objective of the IHD-EPITRAN is to identify new IHD biomarkers via cohort comparison of the blood epitranscriptomes from patients with: (1) MI related with coronary angioplasty, (2) IHD treated with elective coronary artery bypass grafting, (3) aortic valve stenosis treated with valve replacement and (4) IHD-healthy controls verified with computerized tomography imaging. The RNA fractionation is followed by the quantitative modifications analysis with mass spectrometry. Ultimately, nanopore RNA sequencing with simultaneous m6A identification in their native sequences is carried out using recently published artificial intelligence-based algorithm.

Eligibility
Participation Requirements
Sex: All
Minimum Age: 18
Maximum Age: 80
Healthy Volunteers: f
View:

• Cohort I, STEMI + PCI:

‣ Earlier PCIs and silent infarctions eligible.

⁃ ECG confirmed STEMI with Troponin I elevation and pressing chest pain.

⁃ ECG-indicated local damage correlates with recorded dyskinesia in TTE.

⁃ During acute PCI and angiography, only one clear occlusion.

⁃ Successful initial coronary artery reperfusion during PCI.

• Cohort II, Chronic IHD + elective CABG:

‣ Chronic and either CCS or NYHA II-IV symptoms for at least one month.

⁃ First and elective operation. Only heart operation to be performed.

⁃ In transthoracic echocardiogram (TTE):

• No indication of cardiomyopathy other than ischemic.

∙ No pathological remodelling (valves, ventricles and atrias).

∙ No clear indication of significant heart failure (i.e. LVEF \> 25%)

• Cohort III, elective aortic replacement therapy (AVR) for stenosis:

‣ Chronic and either CCS or NYHA II-IV symptoms for at least one month.

⁃ Operated as an open heart surgery (either prosthetic or biovalves)

⁃ No signs of IHD in coronary angiography.

⁃ Both bicuspid and tricuspid valves eligible.

• Cohort IV, IHD-negative healthy controls defined by coronary CT:

‣ Computerized tomography angiogram results are categorized as negative for coronary artery disease.

⁃ No known heart disease.

Locations
Other Locations
Finland
Hospital District of Helsinki and Uusimaa, Helsinki University Hospital, Heart and Lung Center & Cardiac Unit
RECRUITING
Helsinki
Contact Information
Primary
Antti E Vento, Docent
antti.vento@hus.fi
09 471 72200
Backup
Esko Kankuri, Docent
esko.kankuri@helsinki.fi
040 7037338
Time Frame
Start Date: 2020-11-10
Estimated Completion Date: 2025-12-31
Participants
Target number of participants: 200
Treatments
Acute IHD with STEMI and PCI
Acute ischemia in IHD is represented by the recruitment of patients presenting with ST-elevation myocardial infarction (STEMI patients) to the Meilahti Cardiac Care Unit (CCU) and admitted for Percutaneous Coronary Intervention (PCI) revascularization. The informed consent and blood samples from these patients will be collected during the first 72 hours after PCI, during their stay either in CCU or medical ward.~Inclusion of this cohort to the IHD-EPITRAN opens the possibility to identify novel circulative epitranscriptomic biomarkers representing acute ischemic myocardial damage as well as particularly insightful comparison of acute and chronic states of IHD when compared against the second study cohort.
Chronic IHD and elective CABG
The second study cohort composes of patients with stable IHD phenotype with angina pectoris or exertional dyspnea provoked by either moderate or severe physical exertion, corresponding either NYHA or CCS classes II to IV, respectively, destined to undergo an elective coronary artery bypass grafting (CABG) operation as method for revascularization. The duration of stable symptoms must exceed a month in order to exclude acute events.~The obtained blood samples from this main cohort of the IHD-EPITRAN project provides insightful overview into the circulation-borne RNAs' epitranscriptomic landscape for identification of novel biomarkers for stable IHD. Furthermore, availability of right atrial appendage tissue pieces following CABG surgery from this patient cohort gives invaluable organ-specific information in its own right as well as a crucial reference point, against of which the alterations observed in circulation can be compared.
Elective aortic valve stenosis (AVS) replacement therapy
The third study cohort consists of patients admitted for surgical (open heart surgery) valve replacement due to aortic valve calcification and critical stenosis with no IHD as a comorbidity. As to elective CABG patients, here patients are also required to be either moderately or severely symptomatic equaling NYHA or CCS II to IV classes, respectively.~This cohort will provide insights into how the pathological pressure overloaded left ventricular remodelling is reflected to the epitranscriptomes of the supposedly relatively spared right atrial appendage tissue and blood RNA. Comparison of this data to the data of the first two IHD study cohorts opens the window to assess the possible differences for these differing pathologies, thus functioning as an active control cohort.
IHD-negative healthy controls verified by coronary CT
The fourth study cohort shall consist of patients referred to Meilahti Heart Unit's Coronary Artery Computerised Tomography (CT) Angiogram imaging in order to investigate the possibility of atherosclerotic coronary artery disease (i.e. IHD) behind symptoms such as pressing chest pain (i.e. angina pectoris) or abnormal dyspnea provoked by exertion. Based on the results from CT angiogram, only those patients' blood samples are selected for further study that show negative results for IHD (no visualisation of either atherosclerotic strands or plaques in coronary arteries). This patient cohort functions as a critical IHD-healthy control group in the IHD-EPITRAN project (i.e. negative control).
Sponsors
Collaborators: Tays Heart Hospital, Karolinska Institutet, Folkhälsan Researech Center, University of Tartu, University of Helsinki, Middle East Technical University
Leads: Hospital District of Helsinki and Uusimaa

This content was sourced from clinicaltrials.gov