No abstract

Cardiovascular disease is a leading cause of death worldwide. Loss of function or death of cardiomyocytes is a major contributing factor to these diseases. Cell death in conditions such as heart failure and myocardial infarction is associated with apoptosis. Apoptotic pathways have been well studied in non-myocytes and it is thought that similar pathways exist in cardiomyocytes. These pathways include death initiated by ligation of membrane-bound death receptors, release of pro-apoptotic factors from mitochondria or stress at the endoplasmic reticulum. The key regulators of apoptosis include inhibitors of caspases (IAPs), the Bcl-2 family of proteins, growth factors, stress proteins, calcium and oxidants. The highly organized and predictive nature of apoptotic signaling means it is amenable to manipulation. A thorough understanding of the apoptotic process would facilitate intervention at the most suitable points, alleviating myocardium decline and dysfunction. This review summarizes the mechanisms underlying apoptosis and the mediators/regulators involved in these signaling pathways. We also discuss how the potential therapeutic value of these molecules could be harnessed.

Chronic kidney disease (CKD) affects over 10% of the global population and poses significant challenges for societies and health care systems worldwide. To illustrate these challenges and inform cost-effectiveness analyses, we undertook a comprehensive systematic scoping review that explored costs, health-related quality of life (HRQoL) and life expectancy (LE) amongst individuals with CKD. Costs were examined from a health system and societal perspective, and HRQoL was assessed from a societal and patient perspective. Papers published in English from 2015 onward found through a systematic search strategy formed the basis of the review. All costs were adjusted for inflation and expressed in US$ after correcting for purchasing power parity. From the health system perspective, progression from CKD stages 1-2 to CKD stages 3a-3b was associated with a 1.1-1.7 fold increase in per patient mean annual health care cost. The progression from CKD stage 3 to CKD stages 4-5 was associated with a 1.3-4.2 fold increase in costs, with the highest costs associated with end-stage renal disease at $20,110 to $100,593 per patient. Mean EuroQol-5D index scores ranged from 0.80 to 0.86 for CKD stages 1-3, and decreased to 0.73-0.79 for CKD stages 4-5. For treatment with renal replacement therapy, transplant recipients incurred lower costs and demonstrated higher HRQoL scores with longer LE compared to dialysis patients. The study has provided a comprehensive updated overview of the burden associated with different CKD stages and renal replacement therapy modalities across developed countries. These data will be useful for the assessment of new renal services/ therapies in terms of cost-effectiveness.

Long QT syndrome (LQTS) is an inherited primary arrhythmia syndrome that may present with malignant arrhythmia and, rarely, risk of sudden death. The clinical symptoms include palpitations, syncope, and anoxic seizures secondary to ventricular arrhythmia, classically torsade de pointes. This predisposition to malignant arrhythmia is from a cardiac ion channelopathy that results in delayed repolarization of the cardiomyocyte action potential. The QT interval on the surface electrocardiogram is a summation of the individual cellular ventricular action potential durations, and hence is a surrogate marker of the abnormal cellular membrane repolarization. Severely affected phenotypes administered current standard of care therapies may not be fully protected from the occurrence of cardiac arrhythmias. There are 17 different subtypes of LQTS associated with monogenic mutations of 15 autosomal dominant genes. It is now possible to model the various LQTS phenotypes through the generation of patient-specific induced pluripotent stem cell-derived cardiomyocytes. RNA interference can silence or suppress the expression of mutant genes. Thus, RNA interference can be a potential therapeutic intervention that may be employed in LQTS to knock out mutant mRNAs which code for the defective proteins. CRISPR/Cas9 is a genome editing technology that offers great potential in elucidating gene function and a potential therapeutic strategy for monogenic disease. Further studies are required to determine whether CRISPR/Cas9 can be employed as an efficacious and safe rescue of the LQTS phenotype. Current progress has raised opportunities to generate in vitro human cardiomyocyte models for drug screening and to explore gene therapy through genome editing.

Since the discovery of Endothelial Progenitor Cells (EPC) by Asahara and colleagues in 1997, an increasing number of preclinical studies have shown that EPC based therapy is feasible, safe, and efficacious in multiple disease states. Subsequently, this has led to several, mainly early phase, clinical trials demonstrating the feasibility and safety profile of EPC therapy, with the suggestion of efficacy in several conditions including ischemic heart disease, pulmonary arterial hypertension and decompensated liver cirrhosis. Despite the use of the common term “EPC,” the characteristics, manufacturing methods and subset of the cell type used in these studies often vary significantly, rendering clinical translation challenging. It has recently been acknowledged that the true EPC is the endothelial colony forming cells (ECFC). The objective of this review was to summarize and critically appraise the registered and published clinical studies using the term “EPC,” which encompasses a heterogeneous cell population, as a therapeutic agent. Furthermore, the preclinical data using ECFC from the PubMed and Web of Science databases were searched and analyzed. We noted that despite the promising effect of ECFC on vascular regeneration, no clinical study has stemmed from these preclinical studies. We showed that there is a lack of information registered on www.clinicaltrials.gov for EPC clinical trials, specifically on cell culture methods. We also highlighted the importance of a detailed definition of the cell type used in EPC clinical trials to facilitate comparisons between trials and better understanding of the potential clinical benefit of EPC based therapy. We concluded our review by discussing the potential and limitations of EPC based therapy in clinical settings.

Tendon injuries are prevalent and problematic, especially among young and otherwise healthy individuals. The inherently slow innate healing process combined with the inevitable scar tissue formation compromise functional recovery, imposing the need for the development of therapeutic strategies. The limited number of low activity/reparative capacity tendon-resident cells has directed substantial research efforts towards the exploration of the therapeutic potential of various stem cells in tendon injuries and pathophysiologies. Severe injuries require the use of a stem cell carrier to enable cell localisation at the defect site. The present study describes advancements that injectable carriers, tissue grafts, anisotropically orientated biomaterials, and cell-sheets have achieved in preclinical models as stem cell carriers for tendon repair.

Diabetes mellitus (DM) commonly leads to progressive chronic kidney disease despite current best medical practice. The pathogenesis of diabetic kidney disease (DKD) involves a complex network of primary and secondary mechanisms with both intra-renal and systemic components. Apart from inhibition of the renin angiotensin aldosterone system, targeting individual pathogenic mediators with drug therapy has not, thus far, been proven to have high clinical value. Stem or progenitor cell therapies offer an alternative strategy for modulating complex disease processes through suppressing multiple pathogenic pathways and promoting pro-regenerative mechanisms. Mesenchymal stem cells (MSCs) have shown particular promise based on their accessibility from adult tissues and their diverse mechanisms of action including secretion of paracrine anti-inflammatory and cyto-protective factors. In this review, the progress toward clinical translation of MSC therapy for DKD is critically evaluated. Results from animal models suggest distinct potential for systemic MSC infusion to favourably modulate DKD progression. However, only a few early phase clinical trials have been initiated and efficacy in humans remains to be proven. Key knowledge gaps and research opportunities exist in this field. These include the need to gain greater understanding of in vivo mechanism of action, to identify quantifiable biomarkers of response to therapy and to define the optimal source, dose and timing of MSC administration. Given the rising prevalence of DM and DKD worldwide, continued progress toward harnessing the inherent regenerative functions of MSCs and other progenitor cells for even a subset of those affected has potential for profound societal benefits.

Chronic kidney disease (CKD) affects up to 15% of the adult population and is strongly associated with other non-communicable chronic diseases including diabetes. However, there is limited information on a population basis of the relationship between CKD and health-related quality of life (HRQoL) and the consequent economic cost. We investigated this relationship in a representative sample in England using the 2010 Health Survey for England. Multivariable Tobit models were used to examine the relationship between HRQoL and CKD severity. HRQoL was converted to quality adjusted life year (QALY) measures by combining decrements in quality of life with reductions in life expectancy associated with increased disease severity. QALYs were adjusted for discounting and monetised using the UK threshold for reimbursement of £30,000. The QALYs were then used in conjunction with forecasted prevalence to estimate the HRQoL burden associated with CKD among individuals with diabetes up to 2025. Individuals with more severe CKD had lower HRQoL compared to those with better kidney function. Compared to those with normal/low normal kidney function and stage 1 CKD, those with stage 2, stage 3 with albuminuria and stage 4/5 CKD experienced a decrement of 0.11, 0.18 and 0.28 in their utility index, respectively. Applying the UK reimbursement threshold for a QALY, the monetised lifetime burden of reduced HRQoL due to stage 2, stage 3 with albuminuria and stage 4/5 CKD were £103,734; £83,399; £125,335 in males and £143,582; £70,288; £203,804 in females, respectively. Utilizing the predicted prevalence of CKD among individuals with diabetes mellitus, the economic burden of CKD per million of individuals with diabetes is forecasted at approximately £11.4 billion in 2025. In conclusion, CKD has a strong adverse impact on HRQoL in multiple domains. The estimated economic burden of CKD among individuals with diabetes mellitus in the UK is projected to rise markedly over time.