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

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Effect of vItamin K2 on Calciummetabolism on 18F-NaF PET/MRI Endothelial Progenitors in Aortic Stenosis: Association With Aortic Stenosis Progression and Severity Outcomes of Transcatheter Aortic Valve Implantation in Oncology Patients With Severe Aortic Stenosis Evaluation of BAV in Different Hemodynamic Entities of Severe AS Intravenous Iron Supplement for Iron Deficiency in Patients With Severe Aortic Stenosis The SAPIEN 3 Ultra System in Intermediate Risk Patients With Symptomatic Severe Aortic Stenosis Clinical Value of Stress Echocardiography in Moderate Aortic Stenosis CENTERA THV System in Intermediate Risk Patients Who Have Symptomatic, Severe, Calcific, Aortic Stenosis Requiring Aortic Valve Replacement Outcomes of Transcatheter Aortic Valve Implantation in Management of Severe Symptomatic Aortic Stenosis Safety and Efficacy of Lotus Valve For TAVI In Patients With Severe Aortic Stenosis In Chinese Population Rehabilitation in Aortic Stenosis Patients Aortic Stenosis Evaluated Via Modern Ballistocardiography and Seismocardiography Study of Platelet Activation by Severe Aortic Stenosis and Its Correction by Transcatheter Aortic Valve Implantation Sizing-sTrategy of Bicuspid AoRtic Valve Stenosis With Transcatheter Self-expandable Valve The Plasma Serotonin and Aortic Stenosis: a Pilot Study. 18F-NaF Uptake and Aortic Stenosis Progression Cardiovascular Rehabilitation in Patients With Severe Aortic Stenosis Submitted to Valvar Correction Aortic Stenosis and PhosphodiEsterase Type 5 iNhibition (ASPEN): A Pilot Study Clinical Outcome of Patients With Low-gradient Severe Aortic Stenosis Ultrasonic Markers for Myocardial Fibrosis and Prognosis in Aortic Stenosis Fetal Intervention for Aortic Stenosis and Evolving Hypoplastic Left Heart Syndrome The PARTNER 3 – Trial – The Safety and Effectiveness of the SAPIEN 3 Transcatheter Heart Valve in Low Risk Patients With Aortic Stenosis Ventricular Remodeling In Patients With Aortic Stenosis Assessed Echocardiography Podocan and Wnt Pathway in Left Ventricular Remodeling of Aortic Stenosis Preoperative Assessment of Aortic Valve Stenosis and Coronary Artery Disease Statin Therapy in Asymptomatic Aortic Stenosis Validation of the “TASQ” in Patients Undergoing SAVR or TF-TAVI Analysis and Comparative Evaluation of Aortic Calcium by Computed Tomography and Histopathology in Patients With Aortic Stenosis Improving Echo Measurements in the Diagnosis of Aortic Stenosis accuRate Evaluation of Benefit With Optimal Medical Treatment With or With-Out Transcatheter Valve Repair of PARADOXical Low Flow Low Gradient Aortic Stenosis – REBOOT-PARADOX Aortic Stenosis: Determinants and Prognostic Value of Preoperative Left Ventricular Remodeling After Valvular Replacement Randomized Study for the Optimal Treatment of Symptomatic Patients With Low Gradient Severe Aortic Valve Stenosis and Preserved Left Ventricular Ejection Fraction Microvascular Dysfunction in Aortic Stenosis Percutaneous Aortic 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Surgery in Patients With Native Aortic Valve Stenosis Measurement of Myocardial Stiffness Using Elastometry in Patients With Aortic Stenosis Study to Improve Outcomes in Aortic Stenosis Multicenter Prospective Study of Low-Flow Low-Gradient Aortic Stenosis (TOPAS Study) Severe Aortic Stenosis in Patients Referred for Valve Surgery Frailty and Mortality in Older Old With Severe Aortic Stenosis Myocardial Efficiency of the Left Ventricle in Asymptomatic Patients With Aortic Valve Stenosis – a Prognostic Marker and a Target for Intervention? PCSK9 Inhibitors in the Progression of Aortic Stenosis Early Surgery Versus Conventional Treatment in Very Severe Aortic Stenosis Randomized Study to Evaluate the Efficacy of Fluvastatin on Inflammatory Markers in Patients With Aortic Stenosis. 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Brief Title

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

Official Title

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

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.
    

Detailed Description

      Background - Ischemic Heart Disease

      With a global prevalence of 126.5 million people and a yearly mortality of 8.9 million,
      ischemic heart disease (IHD) is the leading cause of death (GBD Collaborators 2017). IHD
      develops as a result of an ongoing atherogenesis, a process of lipid buildup into the walls
      of the coronary arteries. Eventually, the accumulation of cholesterol and calcium form
      deposits, i.e. plaques, that narrow down the vessel lumina. At the onset of myocardial
      infarction (MI), such a plaque ruptures, which leads to anoxic death of the myocardium
      relying on the blood supply of the vessel. In the short term, the heart's function is rescued
      by the formation of a stiff scar. Over time, the pumping function typically deteriorates with
      ensuing heart failure (HF).

      Optimally, disease biomarkers are analyzed from blood and provide both insight into disease
      progression, severity and aid the evaluation of therapy efficacy. Unfortunately, optimal
      biomarkers for IHD have not been identified to date. The vast but uncounted number of those
      living with undiagnosed IHD, benefitting from an early diagnosis, underscore the need for an
      IHD biomarker.

      Background - Epitranscriptomics

      Epitranscriptomics, the field of the posttranscriptional modifications of RNA, analogous to
      DNA epigenetics, has recently gained more scientific remark (Saletore 2012). This expanding
      field is uncovering a new layer of biological regulation that controls processes ranging from
      cell proliferation to death.

      Although more than 170 RNA modifications have been identified in RNA species (Yang 2018),
      adenosine methylation at the nitrogen-6 position (m6A) stands out as one the most common and
      intensively studied (Liu 2020). Following the initial findings of m6A methylated mRNAs in
      1970s (Desrosiers 1974), epitranscriptomics has only reignited during the last decade with
      the development of reliable in vivo methods to assess m6A (Dominissini 2012). These early
      immunoprecipitation-based methodologies (i.e. meRIP-seq) facilitated the discoveries of the
      specific m6A punctuation patterns and the specifically denoted writers (methyltransferases;
      METTL3/14/WTAP1 complex and METTL16), readers (binding proteins; e.g. YTH-protein family),
      and erasers (demethylases; ALKBH5; Zaccara 2019).

      Multiple readers mediating the m6A effects from the YTH domain family have been identified.
      YTHDF1-3 promote mRNA translation, degradation or both, respectively. YTHDC1-2, eIF2, METTL3
      and ribosomes recognize m6A as well and promote translation and cytoplasmic
      compartmentalization (Zaccara 2019).

      Changes in m6A levels have been associated with numerous pathologies, including cancers,
      cardiovascular and neurological disorders (Frye 2016). Studies using both knockout and
      overexpression of the m6A writers and erasers have revealed their role in driving immune
      reactivity, cell proliferation, migration and apoptosis (Delaunay 2019).

      Background - Epitranscriptomics & heart

      A recently published set of studies suggest a role for both the m6A and A-to-I editing
      (adenosine-to-inosine, another common modification diversifying the transcriptome by altering
      base pairing) during hypertension (Jain 2018), neovascularization (Kwast 2019), myocardial
      hypertrophy (Dorn 2019, Kmietczyk 2019), ischemia (Mathiyalagan 2019) and HF (Berulava 2020).
      While a body of evidence indicate epitranscriptomics as a contributor in cardiac health and
      disease, all of the initial studies have focused on the myocardium.

      Rationale, objectives and significance

      We hypothesize that the pathophysiology of IHD is reflected in the epitranscriptome of the
      circulating RNA. For example, ribosomal RNA has a long half-life and its modifications in the
      coronary circulation can respond to the state of the heart.

      The objectives of the IHD-ERPITRAN project are: (1) to establish screening protocols for
      epitranscriptomic biomarkers, (2) provide epitranscriptomic insight into the IHD
      pathophysiology, (3) identify a set of IHD biomarker candidates and (4) open avenues for
      therapeutic development that were previously disregarded due to lack of research and
      methodological limitations. For example, our research group has reported a discovery of small
      molecule ligands for RNA methyltransferases (Selberg 2019).

      Since epitranscriptomics has been suggested to play a regulatory role in heart and the
      IHD-EPITRAN is among the first to evaluate epitranscriptomic blood biomarkers in IHD, the
      project holds keys for a scientific breakthrough with expectable global clinical benefits.

      Methods

      Study cohorts - 200 patients are recruited into four cohorts, counting 50 patients each.
      First cohort consists of patients presenting to Heart Unit with an acute MI revascularized
      with percutaneous coronary intervention (PCI), a cohort that gives valuable insight to the
      way the acute IHD phenotype is mirrored to the blood epitranscriptomes. Second, the main
      study cohort of the project will be formed from patients with stable IHD phenotype treated
      with coronary artery bypass grafting (CABG) and offers critical information in respect to
      chronic ischemia and coronary atherogenesis, both ongoing processes in the silent, i.e.
      undiagnosed, IHD. Third, patients destined for an aortic valve replacement (AVR) therapy due
      to stenosis with no IHD provide the positive control group with a differing cardiac
      pathology, and, fourth, together with the healthy non-IHD patients verified with the coronary
      computed tomography (CT), form the control cohorts of the project.

      Study samples - The IHD-EPITRAN uncovers blood cellular and cell-free RNA epitranscriptomes
      from the twice collected TEMPUS(TM) and EDTA blood samples, respectively. In addition, for MI
      and CABG cohorts, the epitranscriptomes from the right atrial appendage tissue samples are
      deciphered for a reference point. Finally, a set of supplementary HF and IHD biomarkers:
      NT-proBNP, hsCRP, sST2 and TMAO (Aimo 2019, Ahmadmehrabi 2017 and Tibaut 2019) are measured.

      RNA methods - The RNA isolation and fractionation with in-lab-validated methods is followed
      by the quantitative analysis of seven base modifications utilizing an UHPLC-triple quadrupole
      liquid chromatography-tandem mass spectrometry (LC-MS/MS) system (Selberg 2019). Following
      the quantitative analysis, anti-m6A antibody-based RNA pre-selection rich in m6A marks in
      tandem with sequencing, i.e. meRIP-seq, is performed. Ultimately, after the UHPLC-LC-MS/MS
      and meRIP-seq, direct nanopore long-read sequencing enabling identification of the m6A marks
      in their native sequences is carried out using the novel and recently developed algorithm by
      Liu et al. (2019). The algorithm bases on the recognition of the characteristic disruptions
      of electrical current by the m6A flowing through specific protein nanopores.

      DNA sequencing - In order to identify the A-to-I RNA editing events, a whole genome next
      generation sequencing is performed for all study participants to enable a matched DNA-to-RNA
      base comparison (Park et al., 2012).

      Bioinformatics - In order to interpret the massive datasets yielded from the sequencing,
      bioinformatics protocols are developed in collaboration with the bioinformatics teams from
      Folkhälsan (Karolinska Institutet, Dr. Shintaro Katayma) and Middle East Technical University
      (professor Nurcan Tuncbag). The sequences are evaluated against known transcript libraries.

      Clinical methods - The echocardiography gives insight into the functional state of the heart
      and is performed with pre-specified parameters both during the initial hospitalization and 3
      months after either PCI, CABG or AVR. These cardiologists' appointments include the severity
      assessment of angina pectoris and exertional dyspnea with CCS and NYHA gradings,
      respectively. In addition, morbidity self-assessment with the standardized Short Form 36
      Health Survey is included. Moreover, a patient record system search including hospital
      admissions, deaths and medication changes associable to cardiovascular health are collected 6
      months prior and after operation.

      Power analysis - The cohort sizes were determined with RNAseqPS web tool designed for
      evaluating statistical power for RNAseq experiments (Guo et al., 2014). Parameter values used
      (false discovery rate [FDR] <0.05, total number of genes for testing 20 000, predicted
      prognostic genes 1500, minimum fold change threshold 2 for differential expression and
      average read counts of 10 for prognostic genes) were derived from an applicable report
      concerning epitranscriptomics during HF (Berulava et al., 2020). Prognostic gene dispersion
      value of 0,215 was applied based on the article focusing on the issue by Yoon & Nam 2017,
      which analysed dispersions from ten publicly available RNA-seq datasets, four of which
      reflected unrelated replicates applicable for the IHD-EPITRAN with the dispersions ranging
      between 0.15 and 0.28.

      Based on the power analysis described above, n=25 per cohort provides sufficient power
      (P≥0,95). To fluently tackle possible preanalytical errors, perform subsequent validation and
      follow-up analyses, the cohorts were doubled.

      Patient registries

      Individual participant identification information data collected during the IHD-EPITRAN will
      be mainly stored in electrical form on HUS's and Tays's network hard drives that are
      protected by role-based access rights. Two separate registries are created for the
      IHD-EPITRAN: (1) A Key Registry, which contains all participant identification information
      and links between pseudonymization codes that are used in the (2) Research Registry (fully
      pseudonymized) that contains all other collected study information from the participants.
      Antti Vento, the director of the IHD-EPITRAN, has the accession rights to the Key Registry.
      The registries are stored for 10 years to enable possible later follow-up projects.

      Processing description documents for both registries, alongside self assessment document for
      the risks of the study, have been created for the IHD-EPITRAN in Finnish. These documents has
      been reviewed and approved by the Ethics Board of the Hospital District of Helsinki and
      Uusimaa (Dnr. HUS/1211/2020).

      Research group

      Docent Antti Vento is the director of both the IHD-EPITRAN project and the HUS Heart and Lung
      Center. The interdisciplinary team composed of clinicians, basic researchers and analytical
      experts enables the IHD-EPITRAN to synergistically perform recruitment, sample collection and
      preparation followed by the bioinformatic analyses of the epitranscriptomic landscape of
      circulating RNA in IHD. Docents Mika Laine, Pasi Karjalainen, Helena Rajala and Satu Suihko,
      all cardiologists from HUS heart station, will carry out the CT patients' recruitment,
      imaging analyses, treatment of the MI patients and, thirdly, MI, CABG and AVR patients'
      control appointments. Heart and vascular surgeon Kari Teittinen from the HUS Heart and Lung
      Center, together with the cardiothoracic surgeon Jahangir Khan PhD and professor Jari
      Laurikka, both from Tays Heart Hospital, carry out the recruitment of the CABG and AVR
      patients and their operations. Research nurses Kati Oksaharju and Kati Helleharju, from HUS
      Heart and Lung Center and Tays Heart Hospital, respectively, coordinate patient recruitment
      and, in close collaboration with laborant Lahja Eurajoki, the sample collection, transport
      and prompt storage after freezing. The project will be carried out in the laboratory of
      docent Esko Kankuri and professor Eero Mervaala (University of Helsinki, CardioReg Group,
      Department of Pharmacology). B.M. Vilbert Sikorski and MSc Daria Blokhina, will
      collaboratively perform RNA isolation, fractionation, UHPLC-LC-MS/MS analysis and protocol
      article formulation. Additionally, Sikorski has collaboratively planned study protocol with
      the other IHD-EPITRAN co-authors, applied study permissions and continues to coordinate
      information exchange between collaborators and carries out results article writing with the
      co-authors.

      Ethics

      This study will be conducted in compliance with the protocol approved by the HUS Ethics Board
      (Dnr. HUS/1211/2020). Respective regional and national boards will evaluate the protocol
      subsequently for the multicenter sample collection. Care will be taken so that each study
      participant has enough time to familiarize himself/herself with the study protocol.
      Thereafter, an informed consent discussion will be held and written informed consent obtained
      from the participant.
    


Study Type

Observational [Patient Registry]


Primary Outcome

Blood leukocyte RNA's epitranscriptomic changes specifically attributable for IHD

Secondary Outcome

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

Condition

Ischemic Heart Disease

Intervention

Blood samples.

Study Arms / Comparison Groups

 Acute IHD with STEMI and PCI
Description:  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.

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Diagnostic Test

Estimated Enrollment

200

Start Date

August 26, 2020

Completion Date

December 31, 2025

Primary Completion Date

December 31, 2023

Eligibility 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.
      

Gender

All

Ages

18 Years - 80 Years

Accepts Healthy Volunteers

No

Contacts

Antti E Vento, Docent, 09 471 72200, [email protected]



Administrative Informations


NCT ID

NCT04533282

Organization ID

IHD-EPITRAN


Responsible Party

Principal Investigator

Study Sponsor

Hospital District of Helsinki and Uusimaa

Collaborators

 University of Helsinki

Study Sponsor

Antti E Vento, Docent, Study Director, Helsinki University Central Hospital, Heart and Lung Center


Verification Date

August 2020