A Review on the Evolving Roles of MiRNA-Based Technologies in Diagnosing and Treating Heart Failure

MiRNA-regulated processes are pivotal in cardiovascular homeostasis and disease. These short non-coding RNAs have ideal properties that could be utilized as potential biomarkers; moreover, their functions as post-transcriptional regulators of mRNA make them interesting therapeutic targets. In this review, we summarize the current state of miRNA-based biomarkers in a variety of diseases leading to heart failure, as well as provide an outlook on developing miRNA-based therapies in the heart failure field

Human Induced Pluripotent Stem Cell as a Disease Modeling and Drug Development Platform—A Cardiac Perspective

A comprehensive understanding of the pathophysiology and cellular responses to drugs in human heart disease is limited by species differences between humans and experimental animals. In addition, isolation of human cardiomyocytes (CMs) is complicated because cells obtained by biopsy do not proliferate to provide sufficient numbers of cells for preclinical studies in vitro. Interestingly, the discovery of human-induced pluripotent stem cell (hiPSC) has opened up the possibility of generating and studying heart disease in a culture dish. The combination of reprogramming and genome editing technologies to generate a broad spectrum of human heart diseases in vitro offers a great opportunity to elucidate gene function and mechanisms. However, to exploit the potential applications of hiPSC-derived-CMs for drug testing and studying adult-onset cardiac disease, a full functional characterization of maturation and metabolic traits is required. In this review, we focus on methods to reprogram somatic cells into hiPSC and the solutions for overcome immaturity of the hiPSC-derived-CMs to mimic the structure and physiological properties of the adult human CMs to accurately model disease and test drug safety. Finally, we discuss how to improve the culture, differentiation, and purification of CMs to obtain sufficient numbers of desired types of hiPSC-derived-CMs for disease modeling and drug development platform

Mitochondrial Homeostasis Mediates Lipotoxicity in the Failing Myocardium

Heart failure remains the most common cause of death in the industrialized world. In spite of new therapeutic interventions that are constantly being developed, it is still not possible to completely protect against heart failure development and progression. This shows how much more research is necessary to understand the underlying mechanisms of this process. In this review, we give a detailed overview of the contribution of impaired mitochondrial dynamics and energy homeostasis during heart failure progression. In particular, we focus on the regulation of fatty acid metabolism and the effects of fatty acid accumulation on mitochondrial structural and functional homeostasis

Plasma proteome correlates of lipid and lipoprotein: biomarkers of metabolic diversity and inflammation in children of rural Nepal.

Proteins involved in lipoprotein metabolism can modulate cardiovascular health. While often measured to assess adult metabolic diseases, little is known about the proteomes of lipoproteins and their relation to metabolic dysregulation and underlying inflammation in undernourished child populations. The objective of this population study was to globally characterize plasma proteins systemically associated with HDL, LDL, and triglycerides in 500 Nepalese children. Abnormal lipid profiles characterized by elevated plasma triglycerides and low HDL-cholesterol (HDL-C) concentrations were common, especially in children with subclinical inflammation. Among 982 proteins analyzed, the relative abundance of 11, 12, and 52 plasma proteins was correlated with LDL-cholesterol (r = -0.43∼0.70), triglycerides (r = -0.39∼0.53), and HDL-C (r = -0.49∼0.79) concentrations, respectively. These proteins included apolipoproteins and numerous unexpected intracellular and extracellular matrix binding proteins, likely originating in hepatic and peripheral tissues. Relative abundance of two-thirds of the HDL proteome varied with inflammation, with acute phase reactants higher by 4∼40%, and proteins involved in HDL biosynthesis, cholesterol efflux, vitamin transport, angiogenesis, and tissue repair lower by 3∼20%. Untargeted plasma proteomics detects comprehensive sets of both known and novel lipoprotein-associated proteins likely reflecting systemic regulation of lipoprotein metabolism and vascular homeostasis. Inflammation-altered distributions of the HDL proteome may be predisposing undernourished populations to early chronic disease

Kinetic Monte Carlo Simulations of Quantum Dot Self-Assembly

In the Stranski–Krastanov growth mode for heteroepitaxial systems, layer-by-layer growth is followed by the formation and growth of three-dimensional (3D) islands. In this paper, we use a kinetic Monte Carlo method to simulate this growth mode behavior. We present a detailed and systematic investigation into the effects of key model parameters including strain, growth temperature, and deposition rate on this phenomenon. We show that increasing the strain lowers the apparent critical thickness that is defined by the onset of 3D island formation. Similarly, increasing the growth temperature lowers the apparent critical thickness, until intermixing, and the resulting relevance of entropic contributions, become more significant. We also report the impact on Stranski–Krastanov growth of more model-specific parameters, such as bond strengths between constituent atoms of the system, and surface energy anisotropies

Efficacy and safety of intravenous iron repletion in patients with heart failure : a systematic review and meta-analysis

Introduction AFFIRM-AHF and IRONMAN demonstrated lower rates of the combined endpoint recurrent heart failure (HF) hospitalizations and cardiovascular death (CVD) using intravenous (IV) ferric carboxymaltose (FCM) and ferric derisomaltose (FDI), respectively in patients with HF and iron defciency (ID) utilizing prespecifed COVID-19 analyses. Material and methods We meta-analyzed efcacy, between trial heterogeneity and data robustness for the primary endpoint and CVD in AFFIRM-AHF and IRONMAN. As sensitivity analysis, we analyzed data from all eligible exploratory trials investigating FCM/FDI in HF. Results FCM/FDI reduced the primary endpoint (RR=0.81, 95% CI 0.69–0.95, p=0.01, I 2=0%), with the number needed to treat (NNT) being 7. Power was 73% and fndings were robust with fragility index (FI) of 94 and fragility quotient (FQ) of 0.041. Efects of FCM/FDI were neutral concerning CVD (OR=0.88, 95% CI 0.71–1.09, p=0.24, I 2=0%). Power was 21% while fndings were fragile with reverse FI of 14 and reversed FQ of 0.006. The sensitivity analysis from all eligible trials (n=3258) confrmed positive efects of FCM/FDI on the primary endpoint (RR=0.77, 95% CI 0.66–0.90, p=0.0008, I 2=0%), with NNT being 6. Power was 91% while fndings were robust (FI of 147 and FQ of 0.045). Efect on CVD was neutral (RR=0.87, 95% CI 0.71–1.07, p=0.18, I 2=0%). Power was 10% while fndings were fragile (reverse FI of 7 and reverse FQ of 0.002). Rate of infections (OR=0.85, 95% CI 0.71–1.02, p=0.09, I 2=0%), vascular disorder (OR=0.84, 95% CI 0.57–1.25, p=0.34, I 2=0%) and general or injection-site related disorders (OR=1.39, 95% CI 0.88–1.29, p=0.16, I 2=30%) were comparable between groups. There was no relevant heterogeneity (I 2>50%) between the trials for any of the analyzed outcomes. Conclusions Use of FCM/FDI is safe and reduces the composite of recurrent HF hospitalizations and CVD, while efects on CVD alone are based on available level of data indeterminate. Findings concerning composite outcomes exhibit a high level of robustness without heterogeneity between trials with FCM and FDI

Predicting the need for renal replacement therapy using a vascular occlusion test and tissue oxygen saturation in patients in the early phase of multiorgan dysfunction syndrome

Background: Acute kidney injury (AKI) is associated with an increased mortality in critically ill patients, especially in patients with multiorgan dysfunction syndrome (MODS). In daily clinical practice, the grading of AKI follows the Kidney Disease: Improving Global Outcomes (KDIGO) criteria. In most cases, a relevant delay occurs frequently between the onset of AKI and detectable changes in creatinine levels as well as clinical symptoms. The aim of the present study was to examine whether a near infrared spectroscopy (NIRS)-based, non-invasive ischemia–reperfusion test (vascular occlusion test (VOT)) together with unprovoked (under resting conditions) tissue oxygen saturation (StO 2 ) measurements, contain prognostic information in the early stage of MODS regarding the developing need for renal replacement therapy (RRT). Methods: Within a period of 18 months, patients at the medical intensive care unit of a tertiary university hospital with newly developed MODS (≤24 h after diagnosis, APACHE II score ≥20) were included in our study. The VOT occlusion slope (OS) and recovery slope (RS) were recorded in addition to unprovoked StO 2 . StO 2 was determined non-invasively in the area of the thenar muscles using a bedside NIRS device. The VOT was carried out by inflating a blood pressure cuff on the upper arm. AKI stages were determined by the changes in creatinine levels, urinary output, and/or the need for RRT according to KDIGO. Results: 56 patients with MODS were included in the study (aged 62.5 ± 14.4 years, 40 men and 16 women, APACHE II score 34.5 ± 6.4). Incidences of the different AKI stages were: no AKI, 16.1% ( n = 9); AKI stage I, 19.6% ( n = 11); AKI stage II, 25% ( n = 14); AKI stage III, 39.3% ( n = 22). Thus, 39.3% of the patients ( n = 22) developed the need for renal replacement therapy (AKI stage III). These patients had a significantly higher mortality over 28 days (RRT, 72% ( n = 16/22) vs. no RRT, 44% ( n = 15/34); p = 0.03). The mean unprovoked StO 2 of all patients at baseline was 81.7 ± 11.1%, and did not differ between patients with or without the need for RRT. Patients with RRT showed significantly weaker negative values of the OS (−9.1 ± 3.7 vs. −11.7 ± 4.1%/min, p = 0.01) and lower values for the RS (1.7 ± 0.9 vs. 2.3 ± 1.6%/s, p = 0.02) compared to non-dialysis patients. Consistent with these results, weaker negative values of the OS were found in higher AKI stages (no AKI, −12.7 ± 4.1%/min; AKI stage I, −11.5 ± 3.0%/min; AKI stage II, −11.1 ± 3.3%/min; AKI stage III, −9.1 ± 3.7%/min; p = 0.021). Unprovoked StO 2 did not contain prognostic information regarding the AKI stages. Conclusions: The weaker negative values of the VOT parameter OS are associated with an increased risk of developing AKI and RRT, and increased mortality in the early phase of MODS, while unprovoked StO 2 does not contain prognostic information in that regard

Abnormal nuclear shape and impaired mechanotransduction in emerin-deficient cells

Emery-Dreifuss muscular dystrophy can be caused by mutations in the nuclear envelope proteins lamin A/C and emerin. We recently demonstrated that A-type lamin-deficient cells have impaired nuclear mechanics and altered mechanotransduction, suggesting two potential disease mechanisms (Lammerding, J., P.C. Schulze, T. Takahashi, S. Kozlov, T. Sullivan, R.D. Kamm, C.L. Stewart, and R.T. Lee. 2004. J. Clin. Invest. 113:370–378). Here, we examined the function of emerin on nuclear mechanics and strain-induced signaling. Emerin-deficient mouse embryo fibroblasts have abnormal nuclear shape, but in contrast to A-type lamin-deficient cells, exhibit nuclear deformations comparable to wild-type cells in cellular strain experiments, and the integrity of emerin-deficient nuclear envelopes appeared normal in a nuclear microinjection assay. Interestingly, expression of mechanosensitive genes in response to mechanical strain was impaired in emerin-deficient cells, and prolonged mechanical stimulation increased apoptosis in emerin-deficient cells. Thus, emerin-deficient mouse embryo fibroblasts have apparently normal nuclear mechanics but impaired expression of mechanosensitive genes in response to strain, suggesting that emerin mutations may act through altered transcriptional regulation and not by increasing nuclear fragility