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

NCT04533282 | Unknown

• 1 other identifier: IHD-EPITRAN
• Study Type: observational
• Target: 200
• Locations: 1 country
• Sites: 1

Brief 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

Keywords

Ischemic heart disease; Coronary artery disease; Epitranscriptomics; Blood Biomarkers; Biomarkers; Direct long-read nanopore sequencing; RNA editing

Outcome Measures

Primary Outcomes (1)

• Blood leukocyte RNA's epitranscriptomic changes specifically attributable for IHD

  Primary outcome measure for this prospective observational study with multiple cohorts design, representing the diverse clinical continuum of IHD, is to identify blood leukocyte RNA's epitranscriptomic alterations attributable to IHD that are both specific as well as sensitive enough for acting as biomarker candidates for further clinical diagnostic studies.

  2020-2023

Secondary Outcomes (1)

• Blood cell-free RNA's epitranscriptomic alterations specifically attributable for IHD.

  2020-2023

Study Arms (4)

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.

Diagnostic Test: Blood samples.; Diagnostic Test: Health Survey, Clinical symptom scaling; Diagnostic Test: Transthoracic echocardiography (TTE)

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.

Diagnostic Test: Blood samples.; Diagnostic Test: Collection of right atrial appendage tissue sample.; Diagnostic Test: Health Survey, Clinical symptom scaling; Diagnostic Test: Transthoracic echocardiography (TTE)

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.

Diagnostic Test: Blood samples.; Diagnostic Test: Collection of right atrial appendage tissue sample.; Diagnostic Test: Health Survey, Clinical symptom scaling; Diagnostic Test: Transthoracic echocardiography (TTE)

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).

Diagnostic Test: Blood samples.

Interventions

Blood samples. DIAGNOSTIC_TEST

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).

Acute IHD with STEMI and PCI; Chronic IHD and elective CABG; Elective aortic valve stenosis (AVS) replacement therapy; IHD-negative healthy controls verified by coronary CT

Collection of right atrial appendage tissue sample. DIAGNOSTIC_TEST

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.

Chronic IHD and elective CABG; Elective aortic valve stenosis (AVS) replacement therapy

Health Survey, Clinical symptom scaling DIAGNOSTIC_TEST

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.

Acute IHD with STEMI and PCI; Chronic IHD and elective CABG; Elective aortic valve stenosis (AVS) replacement therapy

Transthoracic echocardiography (TTE) DIAGNOSTIC_TEST

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.

Acute IHD with STEMI and PCI; Chronic IHD and elective CABG; Elective aortic valve stenosis (AVS) replacement therapy

Eligibility Criteria

• Age: 18 Years - 80 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)
• Sampling Method: Non-Probability Sample

Study Population

Cohort I; Acute IHD (STEMI+PCI): Patients presenting with ST-elevation myocardial infarction to the CCU and admitted for PCI Intervention. Cohort II; Chronic IHD (elective CABG): Stable IHD patients with angina pectoris or dyspnea destined to undergo an elective CABG operation based on preceding angiography. Cohort III; Aortic valve stenosis (elective AVR): Stable patients with angina pectoris or dyspnea destined to undergo an elective open surgery AVR due to aortic valve calcification and stenosis without recorded comorbid IHD in preceding angiography. Cohort IV; IHD-negative controls (coronary CT): Patients referred to Heart Unit's coronary CT angiogram in order to investigate the possibility of IHD for symptoms such as pressing chest pain or dyspnea provoked by exertion with negative results.

You may qualify if:

• 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.

You may not qualify if:

• Condition that limits life expectancy.
• Combination procedures (i.e. CABG+valve).
• Chronic renal insufficiency (KDIGO scale Pt-GFR \< 45/min).
• Active inflammatory/infectious process.
• Known disease affecting either blood or bone marrow.
• Structural or functional congenital heart disease.
• Recorded atrial fibrillation.
• Other comorbidities in poor clinical control (i.e. uncontrolled severe hypertension \>170-180/100 and for diabetes HbA1c \> 60 mmol/l).
• Insulin treated diabetes.

Sponsors & Collaborators

• Hospital District of Helsinki and Uusimaa: lead
• University of Helsinki: collaborator
• Tays Heart Hospital: collaborator
• Middle East Technical University: collaborator
• Folkhälsan Researech Center: collaborator
• Karolinska Institutet: collaborator
• University of Tartu: collaborator

Study Sites (1)

Hospital District of Helsinki and Uusimaa, Helsinki University Hospital, Heart and Lung Center & Cardiac Unit

Helsinki, Uusimaa, 00029, Finland

RECRUITING

Related Publications (20)

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Biospecimen

Retention: SAMPLES WITH DNA

Based on a priori power analysis, N=25 for each cohort would suffice for achieving statistical significance for anticipated epitranscriptomic changes with the parameter values specified in study description. N=50/cohort was selected and possible residue blood samples and atrial appendage tissue samples (= IHD-EPITRAN's biospecimen samples) will be stored, if not needed for the study itself or its validation or follow-up analyses, for later use. The usage of the study samples in the other future projects requires new supporting decision from the respective ethics board for the new study protocol intending to use the residue study samples from the IHD-EPITRAN.

MeSH Terms

Conditions

Myocardial Ischemia; Coronary Artery Disease; Aortic Valve Stenosis

Interventions

Blood Specimen Collection; Echocardiography

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Coronary Disease; Arteriosclerosis; Arterial Occlusive Diseases; Aortic Valve Disease; Heart Valve Diseases; Ventricular Outflow Obstruction

Intervention Hierarchy (Ancestors)

Specimen Handling; Clinical Laboratory Techniques; Diagnostic Techniques and Procedures; Diagnosis; Punctures; Surgical Procedures, Operative; Investigative Techniques; Cardiac Imaging Techniques; Diagnostic Imaging; Ultrasonography; Heart Function Tests; Diagnostic Techniques, Cardiovascular

Study Officials

• Antti E Vento, Docent

  Helsinki University Central Hospital, Heart and Lung Center

  STUDY DIRECTOR

• Esko Kankuri, Docent

  University of Helsinki, Faculty of Medicine, Department of Pharmacology

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Antti E Vento, Docent

CONTACT

09 471 72200; antti.vento@hus.fi

Esko Kankuri, Docent

CONTACT

040 7037338; esko.kankuri@helsinki.fi

Study Design

• Study Type: observational
• Observational Model: COHORT
• Time Perspective: PROSPECTIVE
• Target Duration: 6 Months
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Docent (adjunct professor) in Cardiac and Thoracic surgery, Director, Physician-in-Chief at the Heart and Lung Center (Helsinki University Central Hospital)

Study Record Dates

• First Submitted: August 26, 2020
• First Posted: August 31, 2020
• Study Start: November 10, 2020
• Primary Completion: December 31, 2023
• Study Completion: December 31, 2025
• Last Updated: November 12, 2020

Record last verified: 2020-11

Locations

FI (1)