Fluid-based assays and precision medicine of cardiovascular diseases: the 'hope' for Pandora's box?

Progresses in liquid-based assays may provide novel useful non-invasive indicators of cardiovascular (CV) diseases. By analysing circulating cells or their products in blood, saliva and urine samples, we can investigate molecular changes present at specific time points in each patient allowing sequential monitoring of disease evolution. For example, an increased number of circulating endothelial cells may be a diagnostic biomarker for diabetic nephropathy and heart failure with preserved ejection fraction. The assessment of circulating cell-free DNA (cfDNA) levels may be useful to predict severity of acute myocardial infarction, as well as diagnose heart graft rejection. Remarkably, circulating epigenetic biomarkers, including DNA methylation, histone modifications and non-coding RNAs are key pathogenic determinants of CV diseases representing putative useful biomarkers and drug targets. For example, the unmethylated FAM101A gene may specifically trace cfDNA derived from cardiomyocyte death providing a powerful diagnostic biomarker of apoptosis during ischaemia. Moreover, changes in plasma levels of circulating miR-92 may predict acute coronary syndrome onset in patients with diabetes. Now, network medicine provides a framework to analyse a huge amount of big data by describing a CV disease as a result of a chain of molecular perturbations rather than a single defect (reductionism). We outline advantages and challenges of liquid biopsy with respect to traditional tissue biopsy and summarise the main completed and ongoing clinical trials in CV diseases. Furthermore, we discuss the importance of combining fluid-based assays, big data and network medicine to improve precision medicine and personalised therapy in this field.

Benincasa G ，Mansueto G ，Napoli C 《-》

Liquid Biopsy in Coronary Heart Disease.

Cardiovascular disease (CVD) remains the major cause of morbidity and mortality globally. Accumulating evidence indicates that coronary heart disease (CHD) contributes to the majority of cardiovascular deaths. With the development of precision medicine, the diagnosis and treatment of coronary heart disease are becoming more refined and individualized. Molecular diagnosis technology and individualized treatment are gradually applied to the clinical diagnosis and treatment of CHD. It is great significance to seek sensitive biological indicators to help early diagnosis and improve prognosis of CHD. Liquid biopsy is a minimally invasive technique, which is widely used to detect molecular biomarkers of tumors without invasive biopsy. Compared with the field of oncology, it is not easy to get the diseased tissue in CVD, especially CHD. Therefore, the idea of "fluid biopsy" is very attractive, and its progress may provide new and useful noninvasive indicators for CHD. By analyzing circulating cells or their products in blood, saliva, and urine samples, we can investigate the molecular changes that occur in each patient at a specific point in time, thus continuously monitoring the evolution of CHD. For example, the assessment of cell-free DNA (cfDNA) levels may help predict the severity of acute myocardial infarction and diagnose heart transplant rejection. Moreover, the unmethylated FAM101A gene may specifically track the cfDNA derived from cardiomyocyte death, which provides a powerful diagnostic biomarker for apoptosis during ischemia. In addition, the changes of plasma circulating miR-92 levels may predict the occurrence of acute coronary syndrome (ACS) onset in patients with diabetes. Liquid biopsy can reflect the disease state through patients' body fluids and may noninvasively provide dynamic and rich molecular information related to CHD. It has great application potential in early warning and auxiliary diagnosis, real-time monitoring of curative effect, medication guidance and exploration of drug resistance mechanism, prognosis judgment, and risk classification of CHD. This chapter will review the latest progress of liquid biopsy in accurate diagnosis and treatment of CHD, meanwhile explore the application status and clinical prospect of liquid biopsy in CHD, in order to improve the importance of precision medicine and personalized treatment in this field.

Zhu W ，Li X 《-》

Epigenetic-sensitive liquid biomarkers and personalised therapy in advanced heart failure: a focus on cell-free DNA and microRNAs.

Dilated cardiomyopathy (DCM) represents a common genetic cause of mechanical and/or electrical dysfunction leading to heart failure (HF) onset for which truncating variants in titin (TTN) gene result in the most frequent mutations. Moreover, myocyte and endothelial cell apoptosis is a key endophenotype underlying cardiac remodelling. Therefore, a deeper knowledge about molecular networks leading to acute injury and apoptosis may reveal novel circulating biomarkers useful to better discriminate HF phenotypes, patients at risk of heart transplant as well as graft reject in order to improve personalised therapy. Remarkably, increased plasma levels of cell-free DNA (cfDNA) may reflect the extent of cellular damage, whereas circulating mitochondrial DNA (mtDNA) may be a promising biomarker of poor prognosis in patients with HF. Furthermore, some panels of circulating miRNAs may improve the stratification of natural history of disease. For example, a combination of miR-558, miR-122* and miR-520d-5p, as well as miR-125a-5p, miR-550a-5p, miR-638 and miR-190a, may aid to discriminate different phenotypes of HF ranging from preserved to reduced ejection fraction. We give update on the most relevant genetic determinants involved in DCM and discuss the putative role of non-invasive biomarkers to overcome current limitations of the reductionist approach in HF management.

Mansueto G ，Benincasa G ，Della Mura N ，Nicoletti GF ，Napoli C ... -  《-》

Strengths and Opportunities of Network Medicine in Cardiovascular Diseases.

Benincasa G ，Marfella R ，Della Mura N ，Schiano C ，Napoli C ... -  《-》

Differential epigenetic factors in the prediction of cardiovascular risk in diabetic patients.

Hyperglycaemia can strongly alter the epigenetic signatures in many types of human vascular cells providing persistent perturbations of protein-protein interactions both in micro- and macro-domains. The establishment of these epigenetic changes may precede cardiovascular (CV) complications and help us to predict vascular lesions in diabetic patients. Importantly, these epigenetic marks may be transmitted across several generations (transgenerational effect) and increase the individual risk of disease. Aberrant DNA methylation and imbalance of histone modifications, mainly acetylation and methylation of H3, represent key determinants of vascular lesions and, thus, putative useful biomarkers for prevention and diagnosis of CV risk in diabetics. Moreover, a differential expression of some micro-RNAs (miRNAs), mainly miR-126, may be a useful prognostic biomarker for atherosclerosis development in asymptomatic subjects. Recently, also environmental-induced chemical perturbations in mRNA (epitranscriptome), mainly the N6-methyladenosine, have been associated with obesity and diabetes. Importantly, reversal of epigenetic changes by modulation of lifestyle and use of metformin, statins, fenofibrate, and apabetalone may offer useful therapeutic options to prevent or delay CV events in diabetics increasing the opportunity for personalized therapy. Network medicine is a promising molecular-bioinformatic approach to identify the signalling pathways underlying the pathogenesis of CV lesions in diabetic patients. Moreover, machine learning tools combined with tomography are advancing the individualized assessment of CV risk in these patients. We remark the need for combining epigenetics and advanced bioinformatic platforms to improve the prediction of vascular lesions in diabetics increasing the opportunity for CV precision medicine.

Napoli C ，Benincasa G ，Schiano C ，Salvatore M ... -  《-》