Epitranscriptomic Blood Biomarkers for Coronary Artery Disease - A Prospective Cohort Study (IHD-EPITRAN)

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.

Conditions

• Ischemic Heart Disease
• Coronary Artery Disease
• Aortic Valve Stenosis
• Acute Myocardial Infarction

Interventions

DIAGNOSTIC_TEST

Blood samples.

Peripheral blood samples (TEMPUS(TM) whole blood samples, EDTA plasma and heparin plasma, total volume 40ml) taken during (1) initial hospitalisation and (2) three month follow-up visit after hospital stay (follow-up samples are not taken from coronary CT healthy control patients).

DIAGNOSTIC_TEST

Collection of right atrial appendage tissue sample.

Collection of the clinically insignificant small piece of heart's right atrial appendage tissue during either standard cannulation of the right atrium for the installation of the heart-lung machine in the beginning of the operation or additionally for routine surgical protocol.

DIAGNOSTIC_TEST

Health Survey, Clinical symptom scaling

Patients in the study CABG and AVR cohorts are invited to both pre- and postoperative (3-month time-point), and in the case of PCI cohort only to postoperative, appointments led by experienced clinical cardiologists. The appointments will include clinical anamnesis, status and assessment of morbidity level with combined use of Canadian Cardiovascular Society grading of Angina Pectoris (CCS), New York Heart Association Classification for Heart Failure (NYHA) classification systems and Short Form 36 (SF36) Health Survey. The CT imaging control cohort is not invited to these appointments.

DIAGNOSTIC_TEST

Transthoracic echocardiography (TTE)

In order to acquire comprehensive insight into the patients' functional heart status, all appointments are supplemented with echocardiographic evaluation for both functional as well as structural parameters. Detailed echocardiographic analysis criteria for the IHD-EPITRAN study are prespecified in the research plan.

Sponsors & Collaborators

• University of Helsinki

  collaborator OTHER

• Tays Heart Hospital

  collaborator UNKNOWN

• Middle East Technical University

  collaborator OTHER

• Folkhälsan Researech Center

  collaborator OTHER

• Karolinska Institutet

  collaborator OTHER

• University of Tartu

  collaborator OTHER

• Hospital District of Helsinki and Uusimaa

  lead OTHER

Principal Investigators

• Antti E Vento, Docent · Helsinki University Central Hospital, Heart and Lung Center

• Esko Kankuri, Docent · University of Helsinki, Faculty of Medicine, Department of Pharmacology

Eligibility

Min Age

18 Years

Max Age

80 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2020-11-10

Primary Completion

2023-12-31

Completion

2025-12-31

Countries

• Finland

Study Locations