Summary of the Original Article
Background
We are facing variability in therapeutic outcomes as a response of therapeutic treatments, resulting from different patients’ phenotypes. Therefore, incorporation of molecular profiling into clinical decision-making is an important tool for tailored therapy based on an understanding of the patient’s molecular characteristics. The use of biomarkers to tailor medical treatment, could assist in: selection of therapy, evaluation of efficacy, optimal dose selection, and recognition and avoidance of side-effects. This would lead to improved treatment response and clinical outcome. In this context, utilizing biomarkers to objectively assist in individualized treatment has gained attention in recent years.
Non-coding RNAs in disease and therapy
Around 80% of the human genome is transcribed, however only 1–3% is further translated into proteins, while most of the human transcriptome represents non-coding RNAs (ncRNAs), which play key regulatory functions. ncRNAs participate in various cellular processes and play a causative role in several diseases, leading to the idea that manipulation of ncRNA expression can serve as a therapeutic approach. ncRNAs could give insights in both physiological and pathological states of a patient, and transcriptome-originating biomarkers may provide characterization of disease phenotypes. From a clinical perspective, microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) have biochemical properties to serve as excellent biomarkers (they are stable against degradation, have a long half-life in biological samples and can be obtained by standard laboratory techniques). The scope of this review is miRNAs and lncRNAs application in medical management (treatment selection and monitoring). MiRNAs can be intracellular and extracellular. Extracellular miRNAs are protected from degradation by packaging in lipid vesicles and by binding to proteins or lipoproteins. They play a role in the prediction of therapeutic response and monitoring of the treatment effectiveness in biomarker-guided cardiovascular therapy. Results from studies suggest the potential of circulating miRNA levels as surrogate biomarkers of the efficacy of antithrombotic therapy. Plasma levels of miR-126, miR-191, miR-223 and several others, decrease proportionally to the platelet inhibition.
Circulating miRNAs can also serve as biomarkers that can predict the response to CRT (cardiac resynchronisation therapy), left ventricular assist devices (LVADs), and response to antihypertensive therapy. Likewise, long non-coding RNAs demonstrate the effect of pioglitazone on diastolic function.
Limitations
Although there are promising results, present implementation of circulating ncRNAs is not feasible in clinical laboratories, and there are no automated standardized assays for clinical application. ncRNA quantification, given current technology, is highly dependent on specimen collection, storage, and handling, making ncRNAs quantification highly variable between studies. Secondly, the addition of ncRNA testing to clinical practice in this phase would be time-consuming and may delay commencement of therapy.
Summary: A blood testing of circulating ncRNAs is a promising tool to assist physicians in decision-making regarding cardiovascular therapy. Nevertheless, at the present, most of the studies are in pre-clinical phases, requiring additional research to clinically adopt the non-coding transcriptome for personalized medicine.
Comments to the article
Cardiovascular diseases (CVD) are one of the leading causes of mortality, as such, there is a constant need to identify new diagnostic and prognostic biomarkers that will serve as diagnostic and prognostic biomarkers, as well as therapeutic treatment targets, and markers of therapeutic treatment efficacy. Advances in precision medicine enable measurement of microRNAs (miRNAs), and their identification as novel cardiac biomarkers. miRNAs are endogenous, small (~22 nucleotides), non-coding RNAs that influence most biological processes. miRNAs regulate cardiovascular function and play an important role in almost all aspects of cardiovascular biology. [1]
Changes in the levels of miRNAs can be used in the diagnosis and prognosis of several CV diseases. Changes, both increases and decreases, in the levels of almost 30 circulating miRNAs have been associated with heart failure (HF). Declining levels of circulating miRNAs, including: miR-18a, miR-27a, miR30e, miR-26b, miR-199a, miR-106a and miR-652, are found in patients with HF. Reductions in circulating miRNAs, such as: let-7i, miR-18b, miR-18a, miR-223, miR-301a, miR-652 and miR-423 have been reported within 48 h after acute HF admission, and are associated with an increased risk of 180-day mortality. miR-21 is upregulated and miR-1 is downregulated in patients with symptomatic HF, where the level of decrease is proportional to the severity of the New York Heart Association Class. [1]
In patients with acute myocardial infarction (AMI) with ischemia-related HF, increased levels of miR-1, miR-133, miR-21, miR-29b, miR-192, miR194, miR-34a, miR-208, miR-499, miR-423, miR-126, miR-134, miR-328 and miR-486, and decreased levels of miR-106, miR-197 and miR-223 are described. Temporal changes in miRNAs are related to LV structural remodelling post MI. [1] Patients with arrhythmia also demonstrate changes in the levels of several miRNAs. Deregulation of miR-29 (which targets mRNAs encoding fibrosis-promoting proteins), has been found to contribute to apoptosis. The risk of post-operative AF can be predicted from elevated serum levels of miR483. [1] Over 30 circulating miRNAs have been associated with the development and progression of pulmonary arterial hypertension. [1]
Changes in the levels of miRNAs circulating in the serum suggest that they may be potential therapeutic targets. In recent years, numerous miRNA mimics and anti-miRs synthetic oligonucleotides that block miRNA function have been evaluated in animal models for the treatment of different CV diseases, by targeting different processes in cardiac pathology: apoptosis, autophagy or hypertrophy. [1] Twelve miRNAs showed significant variation and underwent validation, as candidate biomarkers in patients treated with left ventricular assist devices (LVADs). miR-1202 and miR-483-3p were identified as biomarkers that have the potential to predict response to LVAD therapy. [2] Circulating miR-30c is significantly, positively correlated with total- and LDL-cholesterol, implicating regulatory functions in lipid homeostasis. miR-30c is transported in both exosomes and on HDL3, and pravastatin therapy significantly increased circulating miR-30c expression, adding to the pleiotropic dimensions of statins. [3]
The discovery of circulating miRNAs has opened new windows for novel drug development by administrating extracellular miRNAs. Several studies have shed light on the role of miRNAs in the maladaptive processes involved in heart failure and pointed to the potential of miRNA-based therapies to inhibit or reverse these processes. However, at the present time there are difficulties moving towards clinical application of miRNA mimics and antimirs in heart failure patients. [4]
During the past decade numerous studies highlighted the importance not only of miRNAs, but also of long non-coding RNAs (lncRNAs), in orchestrating cardiovascular cell signalling. A vast number of lncRNAs are dynamically regulated upon initiation and progression of CVDs. Cardiac lncRNAs play an important role in pathological cardiac remodelling and myocardial infarction, and as such in the development and progression of cardiac diseases. Having important biological functions, they have the potential to serve as a novel class of circulating biomarkers. [5]
Several in vivo experiments have revealed that modulation of lncRNAs offers a promising new therapeutic approach to treat cardiovascular diseases, with the potential to ameliorate cardiac dysfunction and diminish pathological progression in the diseased heart. However, the silencing or overexpression approaches still require further refinements. At the present moment, the field of lncRNAs as potential therapeutic targets is still in its infancy, however it is not unlikely that in the near future lncRNAs will emerge as valuable new tools for the treatment of CV diseases. [5]
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