Heart Failure with Reduced Ejection Fraction (HFrEF) and Preserved Ejection Fraction (HFpEF): The Diagnostic Value of Circulating MicroRNAs

Circulating microRNAs offer attractive potential as epigenetic disease biomarkers by virtue of their biological stability and ready accessibility in liquid biopsies. Numerous clinical cohort studies have revealed unique microRNA profiles in different disease settings, suggesting utility as markers with diagnostic and prognostic applications. Given the complex network of microRNA functions in modulating gene expression and post-transcriptional modifications, the circulating microRNA landscape in disease may reflect pathophysiological status, providing valuable information for delineating distinct subtypes and/or stages of complex diseases. Heart failure (HF) is an increasingly significant global health challenge, imposing major economic liability and health care burden due to high hospitalization, morbidity, and mortality rates. Although HF is defined as a syndrome characterized by symptoms and findings on physical examination, it may be further differentiated based on left ventricular ejection fraction (LVEF) and categorized as HF with reduced ejection fraction (HFrEF) and HF with preserved ejection fraction (HFpEF). The presenting clinical syndromes in HFpEF and HFrEF are similar but mortality differs, being somewhat lower in HFpEF than in HFrEF. However, while HFrEF is responsive to an array of therapies, none has been shown to improve survival in HFpEF. Herein, we review recent HF cohort studies focusing on the distinct microRNA profiles associated with HF subtypes to reveal new insights to underlying mechanisms and explore the possibility of exploiting these differences for diagnostic/prognostic applications

Differential MicroRNA Expression Profile in Myxomatous Mitral Valve Prolapse and Fibroelastic Deficiency Valves

Myxomatous mitral valve prolapse (MMVP) and fibroelastic deficiency (FED) are two common variants of degenerative mitral valve disease (DMVD), which is a leading cause of mitral regurgitation worldwide. While pathohistological studies have revealed differences in extracellular matrix content in MMVP and FED, the molecular mechanisms underlying these two disease entities remain to be elucidated. By using surgically removed valvular specimens from MMVP and FED patients that were categorized on the basis of echocardiographic, clinical and operative findings, a cluster of microRNAs that expressed differentially were identified. The expressions of has-miR-500, -3174, -17, -1193, -646, -1273e, -4298, -203, -505, and -939 showed significant differences between MMVP and FED after applying Bonferroni correction (p < 0.002174). The possible involvement of microRNAs in the pathogenesis of DMVD were further suggested by the presences of in silico predicted target sites on a number of genes reported to be involved in extracellular matrix homeostasis and marker genes for cellular composition of mitral valves, including decorin (DCN), aggrecan (ACAN), fibromodulin (FMOD), α actin 2 (ACTA2), extracellular matrix protein 2 (ECM2), desmin (DES), endothelial cell specific molecule 1 (ESM1), and platelet/ endothelial cell adhesion molecule 1 (PECAM1), as well as inverse correlations of selected microRNA and mRNA expression in MMVP and FED groups. Our results provide evidence that distinct molecular mechanisms underlie MMVP and FED. Moreover, the microRNAs identified may be targets for the future development of diagnostic biomarkers and therapeutics

MicroRNA expression profiles of human left ventricle derived cardiac cells in normoxic and hypoxic conditions

Studies in the cardiovascular research field have demonstrated the vital roles of microRNAs for proper cardiovascular development and functional maintenance. The involvement of aberrant microRNA expression leading to ontogenesis of cardiovascular diseases lends further support of the regulatory role of microRNAs in heart function. Hypoxic insult is one of the major factors that trigger downstream signal cascades which contribute to the pathogenesis of hypoxic/ischemic-related heart diseases. Here, we report the microRNA expression profile in human cardiac-derived cells subjected to 120-h hypoxic treatment. By comparing with the normoxic control state, we identified microRNAs differentially expressed in cardiac cells subjected to hypoxic challenge. MicroRNA microarray data are available at NCBI under the GEO accession number, GSE55387

Deficits in Motor Coordination with Aberrant Cerebellar Development in Mice Lacking Testicular Orphan Nuclear Receptor 4

Since testicular orphan nuclear receptor 4 (TR4) was cloned, its physiological function has remained largely unknown. Throughout postnatal development, TR4-knockout (TR4(−/−)) mice exhibited behavioral deficits in motor coordination, suggesting impaired cerebellar function. Histological examination of the postnatal TR4(−/−) cerebellum revealed gross abnormalities in foliation; specifically, lobule VII in the anterior vermis was missing. Further analyses demonstrated that the laminations of the TR4(−/−) cerebellar cortex were changed, including reductions in the thickness of the molecular layer and the internal granule layer, as well as delayed disappearance of the external granule cell layer (EGL). These lamination irregularities may result from interference with granule cell proliferation within the EGL, delayed inward migration of postmitotic granule cells, and a higher incidence of apoptotis. In addition, abnormal development of Purkinje cells was observed in the postnatal TR4(−/−) cerebellum, as evidenced by aberrant dendritic arborization and reduced calbindin staining intensity. Expression of Pax-6, Sonic Hedgehog (Shh), astrotactin (Astn), reelin, and Cdk-5, genes correlated with the morphological development of the cerebellum, is reduced in the developing TR4(−/−) cerebellum. Together, our findings suggest that TR4 is required for normal cerebellar development

Overview of MicroRNAs in Cardiac Hypertrophy, Fibrosis, and Apoptosis

MicroRNAs (miRNAs) are non-coding RNAs that play essential roles in modulating the gene expression in almost all biological events. In the past decade, the involvement of miRNAs in various cardiovascular disorders has been explored in numerous in vitro and in vivo studies. In this paper, studies focused upon the discovery of miRNAs, their target genes, and functionality are reviewed. The selected miRNAs discussed herein have regulatory effects on target gene expression as demonstrated by miRNA/3′ end untranslated region (3′UTR) interaction assay and/or gain/loss-of-function approaches. The listed miRNA entities are categorized according to the biological relevance of their target genes in relation to three cardiovascular pathologies, namely cardiac hypertrophy, fibrosis, and apoptosis. Furthermore, comparison across 86 studies identified several candidate miRNAs that might be of particular importance in the ontogenesis of cardiovascular diseases as they modulate the expression of clusters of target genes involved in the progression of multiple adverse cardiovascular events. This review illustrates the involvement of miRNAs in diverse biological signaling pathways and provides an overview of current understanding of, and progress of research into, of the roles of miRNAs in cardiovascular health and disease

MicroRNA and Heart Failure

Heart failure (HF) imposes significant economic and public health burdens upon modern society. It is known that disturbances in neurohormonal status play an important role in the pathogenesis of HF. Therapeutics that antagonize selected neurohormonal pathways, specifically the renin-angiotensin-aldosterone and sympathetic nervous systems, have significantly improved patient outcomes in HF. Nevertheless, mortality remains high with about 50% of HF patients dying within five years of diagnosis thus mandating ongoing efforts to improve HF management. The discovery of short noncoding microRNAs (miRNAs) and our increasing understanding of their functions, has presented potential therapeutic applications in complex diseases, including HF. Results from several genome-wide miRNA studies have identified miRNAs differentially expressed in HF cohorts suggesting their possible involvement in the pathogenesis of HF and their potential as both biomarkers and as therapeutic targets. Unravelling the functional relevance of miRNAs within pathogenic pathways is a major challenge in cardiovascular research. In this article, we provide an overview of the role of miRNAs in the cardiovascular system. We highlight several HF-related miRNAs reported from selected cohorts and review their putative roles in neurohormonal signaling

A Study of the Production and Combustion Characteristics of Pyrolytic Oil from Sewage Sludge Using the Taguchi Method

Sewage sludge is a common form of municipal solid waste, and can be utilized as a renewable energy source. This study examines the effects of different key operational parameters on sewage sludge pyrolysis process for pyrolytic oil production using the Taguchi method. The digested sewage sludge was provided by the urban wastewater treatment plant of Tainan, Taiwan. The experimental results indicate that the maximum pyrolytic oil yield, 10.19% (18.4% on dry ash free (daf) basis) by weight achieved, is obtained under the operation conditions of 450 °C pyrolytic temperature, residence time of 60 min, 10 °C/min heating rate, and 700 mL/min nitrogen flow rate. According to the experimental results, the order of sensitivity of the parameters that affect the yield of sludge pyrolytic oil is the nitrogen flow rate, pyrolytic temperature, heating rate and residence time. The pyrolysis and oxidation reactions of sludge pyrolytic oil are also investigated using thermogravimetric analysis. The combustion performance parameters, such as the ignition temperature, burnout temperature, flammability index and combustion characteristics index are calculated and compared with those of heavy fuel oil. For the blend of sludge pyrolytic oil with heavy fuel oil, a synergistic effect occurs and the results show that sludge pyrolytic oil significantly enhances the ignition and combustion of heavy fuel oil