Epitranscriptomic Biomarkers for Ischemic Heart Disease (IHD-EPITRAN) - A Prospective Cohort Study
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 发起方
- 入组人数
- 200
- 试验地点
- 1
- 主要终点
- Blood leukocyte RNA's epitranscriptomic changes specifically attributable for IHD
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Cohort
- 时间视角
- Prospective
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •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.
排除标准
- •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.
结局指标
主要结局
Blood leukocyte RNA's epitranscriptomic changes specifically attributable for IHD
时间窗: 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.
次要结局
- Blood cell-free RNA's epitranscriptomic alterations specifically attributable for IHD.(2020-2023)
研究者
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