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

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ClinicalTrials.gov Identifier: NCT04533282
Recruitment Status : Recruiting
First Posted : August 31, 2020
Last Update Posted : November 12, 2020
Sponsor:
Collaborators:
University of Helsinki
Tays Heart Hospital
Middle East Technical University
Folkhälsan Researech Center
Karolinska Institutet
University of Tartu
Information provided by (Responsible Party):
Antti Vento, Hospital District of Helsinki and Uusimaa

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.


Condition or disease Intervention/treatment
Ischemic Heart Disease Coronary Artery Disease Aortic Valve Stenosis Acute Myocardial Infarction 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)

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Study Type : Observational [Patient Registry]
Estimated Enrollment : 200 participants
Observational Model: Cohort
Time Perspective: Prospective
Target Follow-Up Duration: 6 Months
Official Title: Epitranscriptomic Biomarkers for Ischemic Heart Disease (IHD-EPITRAN) - A Prospective Cohort Study
Actual Study Start Date : November 10, 2020
Estimated Primary Completion Date : December 31, 2023
Estimated Study Completion Date : December 31, 2025


Group/Cohort Intervention/treatment
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.
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: 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.

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.
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.

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.
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.

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.
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).




Primary Outcome Measures :
  1. Blood leukocyte RNA's epitranscriptomic changes specifically attributable for IHD [ Time Frame: 2020-2023 ]
    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.


Secondary Outcome Measures :
  1. Blood cell-free RNA's epitranscriptomic alterations specifically attributable for IHD. [ Time Frame: 2020-2023 ]
    Secondary outcome for this prospective observational study with multiple cohorts design, representing the diverse clinical continuum of IHD, is to identify epitranscriptomic alterations attributable to IHD from the blood cell-free plasma that are both specific as well as sensitive enough for acting as biomarker candidates for further clinical diagnostic studies.


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.


Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Criteria

Inclusion Criteria:

  1. Cohort I, STEMI + PCI:

    1. Earlier PCIs and silent infarctions eligible.
    2. ECG confirmed STEMI with Troponin I elevation and pressing chest pain.
    3. ECG-indicated local damage correlates with recorded dyskinesia in TTE.
    4. During acute PCI and angiography, only one clear occlusion.
    5. Successful initial coronary artery reperfusion during PCI.
  2. Cohort II, Chronic IHD + elective CABG:

    1. Chronic and either CCS or NYHA II-IV symptoms for at least one month.
    2. First and elective operation. Only heart operation to be performed.
    3. 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%)
  3. Cohort III, elective aortic replacement therapy (AVR) for stenosis:

    1. Chronic and either CCS or NYHA II-IV symptoms for at least one month.
    2. Operated as an open heart surgery (either prosthetic or biovalves)
    3. No signs of IHD in coronary angiography.
    4. Both bicuspid and tricuspid valves eligible.
  4. Cohort IV, IHD-negative healthy controls defined by coronary CT:

    1. Computerized tomography angiogram results are categorized as negative for coronary artery disease.
    2. No known heart disease.

Exclusion Criteria:

  • 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04533282


Contacts
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Contact: Antti E Vento, Docent 09 471 72200 ext +358 antti.vento@hus.fi
Contact: Esko Kankuri, Docent 040 7037338 ext +358 esko.kankuri@helsinki.fi

Locations
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Finland
Hospital District of Helsinki and Uusimaa, Helsinki University Hospital, Heart and Lung Center & Cardiac Unit Recruiting
Helsinki, Uusimaa, Finland, 00029
Contact: Antti E Vento, Docent    09 471 72200 ext +358    antti.vento@hus.fi   
Sponsors and Collaborators
Hospital District of Helsinki and Uusimaa
University of Helsinki
Tays Heart Hospital
Middle East Technical University
Folkhälsan Researech Center
Karolinska Institutet
University of Tartu
Investigators
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Study Director: Antti E Vento, Docent Helsinki University Central Hospital, Heart and Lung Center
Principal Investigator: Esko Kankuri, Docent University of Helsinki, Faculty of Medicine, Department of Pharmacology
Publications:

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Responsible Party: Antti Vento, Docent (adjunct professor) in Cardiac and Thoracic surgery, Director, Physician-in-Chief at the Heart and Lung Center (Helsinki University Central Hospital), Hospital District of Helsinki and Uusimaa
ClinicalTrials.gov Identifier: NCT04533282    
Other Study ID Numbers: IHD-EPITRAN
First Posted: August 31, 2020    Key Record Dates
Last Update Posted: November 12, 2020
Last Verified: November 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Antti Vento, Hospital District of Helsinki and Uusimaa:
Ischemic heart disease
Coronary artery disease
Epitranscriptomics
Blood Biomarkers
Biomarkers
Direct long-read nanopore sequencing
RNA editing
Additional relevant MeSH terms:
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Coronary Artery Disease
Myocardial Ischemia
Coronary Disease
Myocardial Infarction
Heart Diseases
Aortic Valve Stenosis
Ischemia
Infarction
Pathologic Processes
Necrosis
Cardiovascular Diseases
Arteriosclerosis
Arterial Occlusive Diseases
Vascular Diseases
Aortic Valve Disease
Heart Valve Diseases
Ventricular Outflow Obstruction