Cardiovascular diseases (CVD) are the leading cause of morbidity and mortality in the world. Although considerable progress has been made in the diagnosis, treatment and prognosis of CVD, there is still a critical need for novel diagnostic biomarkers and new therapeutic interventions to decrease the incidence of this disease. Recently, there is increasing evidence that circulating miRNAs (miRNAs), i.e. endogenous, stable, single-stranded, short, non-coding RNAs, can be used as diagnostic biomarkers for CVD. Furthermore, miRNAs represent potential novel therapeutic targets for several cardiovascular disorders. In this review we provides an overview of the effects of several CVD; including heart failure, acute myocardial infarction, arrhythmias and pulmonary hypertension; on levels of circulating miRNAs. In addition, the use of miRNA as therapeutic targets is also discussed, as well as challenges and recommendations in their use in the diagnosis of CVD.

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miRNAS in cardiovascular diseases: potential biomarkers, therapeutic targets and challenges

The discovery of thousands of noncoding RNAs (ncRNAs) has expanded our view on mammalian genomes and transcriptomes, as well as their organization and regulation. Accumulating evidence on aberrantly regulated ncRNAs, including short microRNAs, long ncRNAs and circular RNAs, across various heart diseases indicates that ncRNAs are critical contributors to cardiovascular pathophysiology. In addition, ncRNAs are released into the circulation where they are present in concentration levels that differ between healthy subjects and diseased patients. Although little is known about the origin and function of such circulating ncRNAs, these molecules are increasingly recognized as noninvasive and readily accessible biomarker for risk stratification, diagnosis and prognosis of cardiac injury, and multiple forms of cardiovascular disease. In this review, we summarize recent findings on biological characteristics of circulating ncRNAs and highlight their value as potential biomarker in selected pathologies of cardiovascular disease.

Circulating Noncoding RNAs as Biomarkers of Cardiovascular Disease and Injury.

Cardiovascular diseases are the number one cause of death worldwide and have a great impact on quality of life and medical costs. Enormous efforts are being made in research to obtain new tools for an efficient and quick diagnosis and prognosis of these diseases. Discoveries in epigenetic mechanism have related several pathologies, including cardiovascular diseases, with epigenetic dysregulation. This have implications on disease progression and opens new preventive strategies. Advances in methodology and big data analysis have identified novel mechanisms and targets involved in numerous diseases, making possible a more individualize epigenetic maps that would lead to a personalized diagnosis and treatment. This pave the way to what is called pharmacoepigenetics, which consider differences in epigenetic basis of each patient to predict drug response and develop a tailored therapy. Likewise, epigenetic biomarkers have emerged as a promising instrument for a consistent diagnosis and prognosis of cardiovascular disease. Their good accessibility and feasible methodology of detection make them suitable for implantation in clinical practice. However, it is a major requirement to perform multicenter studies with a large sample population to determine confidently which epigenetic biomarkers are reliable to be implanted in clinical routine. This review, therefore, focuses on epigenetic therapies in cardiovascular diseases, current discoveries and controversy in epigenetic biomarkers aimed to improve the diagnosis, disease prognosis and therapy in cardiovascular patients.

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Epigenetic Biomarkers in Cardiovascular Diseases

Cardiovascular diseases are one of the most common causes of death in both developing and developed countries worldwide. Even though there have been improvements in primary prevention, the prevalence of cardiovascular diseases continues to increase in recent years. Hence, it is crucial to both investigate the molecular pathophysiology of cardiovascular diseases in-depth and find novel biomarkers regarding the early and proper prevention and diagnosis of these diseases. MicroRNAs, or miRNAs, are endogenous, conserved, single-stranded non-coding RNAs of 21-25 nucleotides in length. miRNAs have important roles in various cellular events such as embryogenesis, proliferation, vasculogenesis, apoptosis, cell growth, differentiation, and tumorigenesis. They also have potential roles in the cardiovascular system, including angiogenesis, cardiac cell contractility, control of lipid metabolism, plaque formation, the arrangement of cardiac rhythm, and cardiac cell growth. Circulating miRNAs are promising novel biomarkers for purposes of the diagnosis and prognosis of cardiovascular diseases. Cell or tissue specificity, stability in serum or plasma, resistance to degradative factors such as freeze-thaw cycles or enzymes in the blood, and fast-release kinetics, provide the potential for miRNAs to be surrogate markers for the early and accurate diagnosis of disease and for predicting middle- or long-term prognosis. Moreover, it may be a logical approach to combine miRNAs with traditional biomarkers to improve risk stratification and long-term prognosis. In addition to their efficacy in both diagnosis and prognosis, miRNA-based therapeutics may be beneficial for treating cardiovascular diseases using novel platforms and computational tools and in combination with traditional methods of analysis. microRNAs are promising, novel therapeutic agents, which can affect multiple genes using different signaling pathways. miRNAs therapeutic modulation techniques have been used in the settings of atherosclerosis, acute myocardial infarction, restenosis, vascular remodeling, arrhythmias, hypertrophy and fibrosis, angiogenesis and cardiogenesis, aortic aneurysm, pulmonary hypertension, and ischemic injury. This review presents detailed information about miRNAs regarding structure and biogenesis, stages of synthesis and functions, expression profiles in serum/plasma of living organisms, diagnostic and prognostic potential as novel biomarkers, and therapeutic applications in various diseases.

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MicroRNA and Cardiovascular Diseases

Micro-RNAs (miRNAs) play a pivotal role in the development and physiology of the cardiovascular system while they have been associated with multiple cardiovascular diseases (CVDs). Several cardiac miRNAs are detectable in circulation (circulating miRNAs; c-miRNAs) and are emerging as diagnostic and therapeutic biomarkers for CVDs. c-miRNAs exhibit numerous essential characteristics of biomarkers while they are extremely stable in circulation, their expression is tissue-/disease-specific, and they can be easily detected using sequence-specific amplification methods. These features of c-miRNAs are helpful in the development of non-invasive assays to monitor the progress of CVDs. Despite significant progress in the detection of c-miRNAs in serum and plasma, there are many contradictory publications on the alterations of cardiac c-miRNAs concentration in circulation. The aim of this review is to examine the pre-analytical and analytical factors affecting the quantification of c-miRNAs and provide general guidelines to increase the accuracy of the diagnostic tests in order to improve future research on cardiac c-miRNAs.

Challenges in using circulating micro-rnas as biomarkers for cardiovascular diseases

Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: Preliminary results.

INTRODUCTION Left ventricular hypertrophy (LVH) is known as an independent risk factor for coronary heart disease, heart failure (HF), stroke, and sudden cardiac arrest. LVH implicates changes in the architecture of myocardial tissue, which consist of perivascular and myocardial fibrosis, as well as medial thickening of intramyocardial coronary arteries, in addition to cardiomyocyte hypertrophy [1–3]. The impact of miR-1 level on cardiac hypertrophy and cardiomyocyte apoptosis has been recently suggested [3, 4]. Also, the association between miR-21 and galectin-3 (gal-3) levels and maladaptive cardiac remodelling, fibrosis, and inflammation has been described [5, 6]. Nevertheless, the synergistic role of these molecules in LVH has not been explained to date. We analysed the expressions of miR-1, miR-21, and gal-3 concentration in patients with symptomatic HF (SHF) and a history of hypertension and LVH revealed in echocardiography.

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miR-1, miR-21, and galectin-3 in hypertensive patients with symptomatic heart failure and left ventricular hypertrophy

INTRODUCTION Left ventricular (LV) adverse remodelling represents a major feature of systolic heart failure (SHF). It has been identified as a risk factor for impaired cardiac function [1]. A potential role of miR-1 and miR-21 in adverse cardiac remodelling in HF has been recognised [2, 3]. Increased concentration of galectin-3 (gal-3) in HF patients has also been observed [4, 5]. We aimed to explore the serum expression of miR-1 and miR-21, and the concentration of gal-3 in SHF patients with different degrees of LV dilatation. The concentration of N-terminal pro-B-type natriuretic peptide (NT-proBNP) was measured and compared with new, potentially clinically useful HF biomarkers.

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Olga Błaszczyk

Papers

Circulating microribonucleic acids miR-1, miR-21 and miR-208a in patients with symptomatic heart failure: Preliminary results.

miR-1, miR-21, and galectin-3 in hypertensive patients with symptomatic heart failure and left ventricular hypertrophy

Dysregulations of miRNAs and galectin-3 may underlie left ventricular dilatation in patients with systolic heart failure.