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Science, Technology and Medicine open access publisher.Publish, read and share novel research. 2008 Colony-stimulating factor-1 transfection of myoblasts improves the repair of failing myocardium following autologous myoblast transplantation. 2008 Myocardial regenerative therapy: immunologic basis for the potential universal donor cells. 1994 Efficient catheter-mediated gene transfer into the heart using replication-deficient adenovirus. 2008 AAV9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. 2009 In vivo remote delivery of DNA encoding for hypoxia-inducible factor 1 alpha reduces myocardial infarct size. 2009 Cardioprotection by hypoxia-inducible factor 1 alpha transfection in skeletal muscle is critically dependent on heme oxygenase activity in mice. 2011 Remote delivery of DNA encoding for hypoxia-inducible factor 1 alpha is protective against in vivo myocardial ischemia-reperfusion injury. 2008 Cardiac-targeted RNA interference mediated by an AAV9 vector improves cardiac function in coxackievirus B3 cardiomyopathy.
2009 Enhancement of myocardial regeneration through genetic engineering of cardiac progenitor cells expressing Pim-1 kinase.
2004 Helper-dependent adenovirus vectors devoid of all viral genes cause less myocardial inflammation compared with first-generation adenovirus vectors. 1994 Direct in vivo transfer to porcine myocardium using replication-deficient adenoviral vectors. 2010 Low invasive angiogenic therapy for myocardial infarction by retrograde transplantation of mononuclear cells expressing the VEGF gene. 2005 Catheter-based antegrade intracoronary viral gene delivery with coronary Venous blockade. 2010 Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engratfment, and capillary density in the injured myocardium. 2006 Robust systemic transduction with AAV9 vectors in mice; Efficient global cardiac gene transfer superior to that of AAV8. 2004 Inhibition of matrix metalloproteinase activity by TIMP-1 gene transfer effectively treats ischemic cardiomyopathy. 2007 Transplantation of genetically engineered mesenchymal stem cells improves cardiac function in rats with myocardial infarction: benefit of a nonviral vector, cationized dextran. 1996 Long-term gene transfer in porcine myocardium after coronary infusion of an adeno-associated virus vector. 2005 Myocardial gene transfer and long-term expression following intracoronary delivery of adeno-associated virus. 2011 Hypoxia-inducible vascular endothelial growth factor-engineered mesenchymal stem cells prevent myocardial ischemic injury.
2004 Local delivery of marrow-derived stromal cells augments collateral perfusion through paracrine mechanisms. 2001 Neovascularization of ischemic myocardium by human bone-marrow-derived angioblasts prevents cardiomyocyte apoptosis, reduces remodeling and improves cardiac function. 2010 Distinct roles for cell-autonomous Notch signalling in cardiomyocytes of the embryonic and adult heart. Like other insulin pump systems, OneTouch® Ping™ frees you from multiple daily injections and gives you the ability to quickly and easily adjust your insulin based on your body’s immediate needs. The OneTouch Ping meter-remote and the OneTouch Ping insulin pump communicate and share information wirelessly.
The meter-remote can store the nutritional values of 500 of your favorite foods, via CalorieKing®, for easy and accurate carb counting on the go. The OneTouch Ping insulin pump has a flat panel color screen that uses the same screen technology as the latest televisions and digital cameras. The primary objective of the present study was to analyse the advantages of insulin pump therapy and real time glucose monitoring systems as the tools for reducing the frequency of hypoglycemic episodes. Donnelly LA, Morris AD, Frier BM, Ellis JD, Donnan PT, Durrant R, Band MM, Reekie G, Leese GP. Seaquist ER, Anderson J, Childs B, Cryer P, Dagogo-Jack S, Fish L, Heller SR, Rodriguez H, Rosenzweig J, Vigersky R. This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License. GLP-1 agonists (for example, Byetta, Victoza, and Bydureon) were first approved in 2005 and stimulate the body to produce insulin only when blood glucose levels become too high.
The second piece of news this month came from GlaxoSmithKline, which announced positive clinical trial results for its new once-weekly GLP-1 agonist (albiglutide) when used in combination with basal insulin therapy. Finally, even further down the road, we also heard an update from Sanofi and Zealand Pharma on their novel pen device that will allow users to inject both Lyxumia (the companies’ once-daily GLP-1 agonist) and Lantus at the same time, eliminating one extra shot per day. If a bald eagle loses a feather on one wing, it will drop a matching feather on the other side to maintain balance.
The talking cure describes relief from psychological disorders with the help of talk therapy. When it comes to treating depression, the talking cure has a major advantage over medication.
Unlike some other forms of therapy, like medication, the talking cure puts the power of change into the hands of the patient. I always thought that my depression was mostly chemical and that I was a generally well adjusted person. The cartoon depicts possible routes of delivery of either stem cells or DNA with or without a vector to the heart. The advantages of using genetically engineered stem cells versus naive stem cells are illustrated. The cartoon depicts the principle of remote gene therapy delivering plasmid DNA into the skeletal muscle, increasing nuclear uptake by electroporation, and achieving myocardial protection. IntroductionTo combat ischemic heart disease in the clinical scenarios of open heart surgery, unstable coronary syndromes, percutaneous coronary interventions, or thrombolysis, different research approaches are used to improve clinical treatments.
The pump is packed with unique capabilities that may be accessed both wirelessly (by using the meter-remote) and manually. Using ezManager® Max software, you can even customize the database or enter your own favorites (like Mom’s chicken soup). The screen is also self-illuminating and high contrast for readability and viewable from a wide angle. The study included 190 children and adolescents at the age varying from 1 to 18 years suffering from type 1 diabetes mellitus. The e?ect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus.
Hypoglycemia in type 1 diabetes: a still unresolved problem in the era of insulin analogs and pump therapy. E?ect of intensive diabetes treatment on the development and progression of long-termcomplications in adolescents with insulin-dependent diabetes mellitus: Diabetes Control and Complications Trial. The impact of a decade of changing treatment on rates of severe hypoglycemia in a population-based cohort of children with type 1 diabetes. Prevalence of Nocturnal Hypoglycemia in Pediatric Type 1 Diabetes: A Pilot Study Using Continuous Glucose Monitoring.
Hypoglycemia prevalence in prepubertal children with type 1 diabetes on standard insulin regimen: use of continuous glucose monitoring system.
Hypoglycemia and diabetes: a report of a workgroup of the American Diabetes Association and the Endocrine Society. Fear of hypoglycaemia in mothers and fathers of children with type 1 diabetes is associated with poor glycaemic control and parental emotional distress: a population-based study. Neurocognitive functioning in children with type-1 diabetes with and without episodes of severe hypoglycaemia.
E?ects of prior hypoglycemia and hyperglycemia on cognition in children with type 1 diabetes mellitus. Sensoraugmented pump therapy from diagnosis of childhood type 1 diabetes: results of the Paediatric Onset Study (ONSET) after 12 months of treatment. Use of Insulin Pump Therapy in the Pediatric Age-Group: Consensus statement from the European Society for Paediatric Endocrinology, the Lawson Wilkins Pediatric Endocrine Society, and the International Society for Pediatric and Adolescent Diabetes, endorsed by the American Diabetes Association and the European Association for the Study of Diabetes. Establishing glycaemic control with continuous subcutaneous insulin infusion in children and adolescents with type 1 diabetes: experience of the PedPump Study in 17 countries. Characteristics of basal insulin requirements by age and gender in Type-1 diabetes patients using insulin pump therapy.
Lately, the concept of using a GLP-1 agonist with a basal insulin (such as Levemir and Lantus) has received more attention; the use of this combination to treat type 2 diabetes offers a number of advantages. The first announcement was that the GLP-1 agonist Victoza was finally approved for use with any basal insulin in the US.
In the trial, 500 people with type 2 diabetes received either a weekly injection of albiglutide in combination with a daily injection of Lantus or a daily injection of Lantus in combination with mealtime injections of the prandial insulin Humalog.
Notably, the companies announced that their pen device will allow users to adjust their Lantus dose while receiving the same dose of Lyxumia every time. Talk therapy is a time-tested methodology for treating disorders, such as depression, anxiety, and even schizophrenia, among others.
Anti-depressant medications typically take at least a couple of weeks to begin having a noticeable effect on mood. Mirror neurons in the brain, also called the premotor cortex and the somatosensory cortex, respond to the feelings and behaviors of others. It is often the case that people suffering from psychological disorders, such as depression, are not aware of the root causes behind their feelings. The compulsive nature of thoughts and behaviors in people with depression, anxiety, and other mental health disorders can be very overwhelming. The therapist and patient work together to develop a tool kit for the patient to take with him or her when therapy is complete. There are a lot of people who don't get the same benefits from talking about their problems, particularly if they don't have someone they trust to talk to. My dad spoke very insultingly about the talking cure and especially Freud and his theories. So it took me a while to decide that I wanted to try counseling as well. I finally ended up having some counseling after a breakdown last year and I never realized how beneficial it could be for me. The most dreaded long term consequence of ischemic heart disease – heart failure – is another clinical diagnosis where the treatment we have to offer is less than optimal.
And the meter-remote, with its full set of functions, is designed to make your life with diabetes easier and more discreet. All the patients were hospitalized at the Endocrinological Research Centre for the treatment the disease using different modalities of insulin therapy, such as multiple injections of insulin (MII) and its continuous subcutaneous infusion (CSII).
Frequency and predictors of hypoglycaemia in type 1 and insulin-treated type 2 diabetes: a population-based study. One advantage is that GLP-1 agonists and basal insulins act in complementary ways to lower blood glucose, meaning that the use of both therapies together may well improve blood glucose control more effectively than either therapy alone. The approval was based upon a study that looked at the safety and effectiveness of treating people with Levemir, a basal insulin, who were already using Victoza and metformin.


Over 26 weeks, those receiving albiglutide achieved significantly greater reductions in A1c than those receiving Humalog (0.82% vs. The device is currently under development, and Sanofi has indicated that trials will begin in early 2013. The social nature of talking to a therapist can trigger instant neurological connections, which can help the patient better understand and change his or her problematic thoughts or behaviors. Medication can be a necessary and very helpful treatment plan, but because it works on a chemical level, the changes are subtle and take a while to work into the system. When a person sees someone smiling, it triggers a response in the observer's own smile-controlling neurons.
Talking to an objective, empathetic, and psychologically knowledgeable third party can trigger neurological connections that may not have otherwise been experienced. Talking to a therapist who is not stuck in compulsive patterns can be an incredibly refreshing and healing experience, showing patients that things can be seen with a different perspective than the ones that automatically flood their minds. Talk therapy helps the patient identify, understand, and ultimately change behavior and thought patterns that have become problematic. Some researchers are attempting to omit the reason for cardiovascular disease through targeting the process of atherosclerosis.
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The blood glucose level was monitored during 72 hours making use of the continuous blind and real time monitoring protocols (blind-CGM and RT-CGM respectively). Over 52 weeks, those treated with Levemir achieved an additional A1c reduction of 0.5% over those who were not. These new connections may be in the form of experiencing empathy for the self or learning new coping mechanisms. The effectiveness of talk therapy, like most therapy, lies with the patient and how much work he or she is willing to do. I always feel like I'm trying to figure out what they want me to say, and that ends up making me feel worse in the long run. Others adress the pathophysiology of restenosis, which may occurr after balloon dilatation of atherosclerotic lesions. All the patients were divided into 4 groups depending on the therapeutic modality and the mode of blood glucose monitoring. Moreover, basal insulins act slowly and over a long period of time to cover background insulin needs, while GLP-1 agonists stimulate insulin secretion only when blood glucose levels are high.
The risk for hypoglycemia was higher among those receiving Levemir, although the risk was still low (0.228 episodes per patient year vs. Neuroscientists give the credit of this instant reaction to the fact that humans are social animals and talk therapy is a type of social connection. If a person sees a friend or even a stranger stub a toe, that person will likely feel sympathy pain in his or her own toe, controlled by the mirror neurons. Yet others adress improved treatment of the myocardium which has undergone an infarction, where the building of new blood vessels, strengthening of the contractile apparatus, and recruitment of new cells to areas of necrosis may be therapeutical end-points.
Group 1 was comprised of the patients given multiple insulin injections in combination with blind glucose monitoring ("blind-CGM + MII"), group 2 included the patients undergoing blind glucose monitoring in conjunction with continuous insulin infusion ("blind-CGM + CSII"), group 3 contained the patients treated by multiple insulin injections followed by real-time blood glucose monitoring ("RT-CGM + MII"), and group 4 was composed of the patients undergoing continuous subcutaneous infusion of insulin combined with real-time blood glucose monitoring ("RT-CGM + CSII").
This makes GLP-1 agonists effective therapies f0r post-meal glucose spikes without increasing the risk for hypoglycemia.
As expected, the most common side effects among those receiving albiglutide were nausea (13.0% with albiglutide vs.
Instead of allowing users to adjust their insulin dose separately from their GLP-1 dose, the drugs (Victoza and the company’s latest basal insulin called degludec) will always be injected together at a fixed ratio to one another. The psychologist and I just try to understand what is going on in my head and how we can make it easier to be happy. Arrthythmias may occur due to reperfusion injury, after long-term morphological changes in the heart, or due to endogenous causes related to changes of the conduction system; new therapies are required for improved treatment. In all the cases, the blood glucose levels were measured and the occurrence of hypoglycemia during the period of monitoring time was evaluated. In other words, if a user reduces the amount of degludec they wish to inject, the amount of Victoza they will receive will be reduced as well. Novel treatments for dysfunctional, calsified heart valves are subject to other lines of investigations. It was shown that the highest frequency of hypoglycemia during 72 hours was recorded in the "blind-CGM" group and the lowest one in the RT-CGM groups. Novo Nordisk has indicated that this approach will still allow over 80% of people to receive the right amount of basal insulin and enough Victoza to be effective in the body. Gene therapy and cell therapy using genetic engineering of stem cells will be the focus of this chapter, in particular the current status of treatments directed towards the myocardium itself in ischemic heart disease will be discussed. Despite adequate self-control, almost half of the patients in the "blind-CGM + MII" group reported at least one hypoglycemic episode either at the daytime or at night ; the duration of such episode was more than 1 hour on the average. In comparison to Byetta, Victoza offers the convenience of fewer injections (once per day vs. The use of albiglutide in combination with a basal insulin could reduce the number of required injections per week by 13 versus Byetta and six versus Victoza. Two phase two trials for this device are underway, which are expected to complete in the second half of this year. Gene therapy and to a lesser extend cell therapy have been used both clinically and experimentally to combat acute ischemia, remodeling and heart failure. GlaxoSmithKline has not yet revealed when it might apply for approval for albiglutide as a therapy for type 2 diabetes, but we believe it will likely be in 2013, placing a possible approval in early 2014. Assuming the trials complete as expected, approval may be possible as early as the end of 2013.
However, the protected location of the heart of the heart inside the thoracic cavity, the nature of cardiac cells with minimal ability of entering cell cycle, and the electrophysiological properties of the heart render this organ with some particular challenges for gene therapy.2. To date, no trials have compared the effectiveness of Victoza and Byetta when used with a basal insulin, although some scientists have argued that shorter acting GLP-1 agonists (like Byetta) may offer greater effectiveness because of their greater effects on post-meal glucose levels. Gene therapy for myocardial protectionDelivery of DNA to hearts as well as other organs has been performed in animal experiments, and clinical studies in “no-option” patients have been conducted. Nonetheless, this approval for Victoza is certainly exciting, and we expect reimbursement and access to this treatment option to improve in the months ahead. One alternative is intravascular delivery, which can be directed through coronary arteries or retrogradely into the coronary sinus. An arterial approach which requires open coronary arteries may not be suitable for patients with coronary artery disease if the target is treating cardiomyocytes rather than vascular cells. Pericardial gene delivery has been attempted, but there are rather few publications with that particular route of delivery. Another option is direct intracardiac delivery, which has been tried clinically and experimentally (Isner, 2002, Semenza, 2004, Vinge et al., 2008).
In general it is difficult to achieve a lasting transfection through this invasive approach, which may be delivery of naked DNA or DNA ligated to a vector.
Viral vectors used for cardiovascular therapy are most commonly adenovirus, adenoasscociated virus, and to a lesser extent lentivirus.
The “something” in question may be adenovirus or adenoassociated virus, which have been most extensively used for genetic correction of cardiovascular disorders.
Adenovirus have the advantage of being easy to manipulate, can be produced in high titers, and have a large transgene cloning capacity (Vinge et al., 2008).
Development of so-called “gutted or gutless” adenovirus, where the immunogenic viral epitopes are removed, may become an option in the future (Vinge et al., 2008). Adenoassociated virus are not associated with any human disease, produce a stable and long-lasting gene expression, and easily transfect cardiac muscle cells.
A disadvantage is that only small constructs (less than 5 kb) can be packed into adenoassociated virus (AAV).
Further considerations in cardiac gene therapy are which cells are to be treated and what do we want to overexpress or silence (Vinge et al., 2008). The possibilities range from targeting the vasculature to stabilize atherosclerotic plaques, prevent neointima formation, reduce atherosclerosis, induce angiogenesis, to improve survival of cardiomyocytes, improve function of cardiomyocytes, to reduce pathologic remodelling, and to prevent arrhythmia generation.
Genes encoding for factors which have intracellular effects should be delivered to a large population of cells to correct the underlying pathology, while genes encoding for secretory factors require fewer successfully transfected cells provided gene expression lasts (Isner, 2002).
RNA interference or silencing, a possibility for gene knockdown, is predominantly at an animal experimental level.
Experimentally, RNA interference though short hairpin RNA silencing the RNA polymerase of Coxsackie B3 virus packed into AAV2 successfully treated cardiac dysfunction in mice with coxsackieB cardiomyopathy (Fechner et al., 2008).
The same group have also used phospholamban silencing in short hairpin RNA delivered systemically through a AAV9 vector to normalize left ventricular remodelling after phenylephrine-induced hypertrophy (Suckau et al., 2009). Although those studies were successful in the terms of being able to cause transgene expression up to six months later in cardiomyocytes, the number of transfected myocytes was estimated to be as low as 60-100 cells (Ascadi et al., 1991). This lead to the search for vectors to enhance nuclear uptake, where viral vectors have been most extensively studied. Guzman and coworkers injected an adenoviral vector containing ?-galactosidase (1993) into the myocardium, and was able to see a stronger signal than that evoked by plasmid containing the same molecular marker. However, the expression lasted only one week, and was accompanied by an inflammatory response (Guzman et al.
For instance, adenoviral based delivery of DNA encoding for ?2-adrenoceptors enhanced cardiac function in hamsters with cardiomyopathy (Tomiyasu et al., 2000). However, although adenovirus was the first vector to be used for cardiac gene therapy and has been useful for “proof of concept” as well as some initial clinical trials (Lavu et al., 2010), it may not be of large scale therapeutic use for the future.
Adenovirus are double-stranded DNA viruses, with a high effeciency of delivery and expression of their genome in nuclei of dividing and non-dividing cells (Voplers & Kochanek, 2004).
They are relatively large viral structures, with the capacity to carry constructs of up to 30 kB (Lyon et al., 2011). However, despite the fact that they are relatively cheap to produce in high titers and with a reasonably high purity, a major issue is that they evoke an immune response. Thus immune responses leading to destruction of cells containing adenovirus in the heart is a likely outcome. The latter factor also limits the time frame of therapeutic gene expression (Lyon et al., 2011).
However, since work on gene therapy of the heart started with adenoviral vectors, the experience in use of this vector is high, and it is an excellent tool for basic science studies to evaluate the therapuetic potential of novel genes.
Attempts are being made to reduce the immunogenicity of adenoviruses, removing the viral genome and viral proteins. The third generation of “gutless” adenovirus have low immunogenicity, and longer transgene expression (Chen et al., 1997). Direct myocardial delivery of gutless adenovirus resulted in less inflammation than the first generation virus, but the gene expression was not high and it was short-lasting (Fleury et al., 2004).
Adenoassociated viruses (AAV) are currently without comparison the most suitable vectors for cardiovascular gene transfer.
AAVs are not associated with any human pathology although 20-40% of all humans may have antibodies to them, making them attractive and safe for clinical treatment. The most recent serotyope, AAV9, is more cardiotropic than any other known virus and will transfect nearly 100% of all heart cells (Vandendriessche et al., 2007). AAV1, 6, and 8 also have relatively high tropism to the heart, and since they have been around for a longer time, they have come further into clinical studies.


Hitherto more than 20 clinical trials using AAV vectors have delivered the vectors to hundreds of patients without observing any adverse effects (Lyon et al. A major advantage of AAV9 is that a systemic approach to gene delivery can be used, thus avoiding some of the challenges of the other viral vectors.Retroviruses are RNA viruses which integrate into the host cell chromosome after enzymatic conversion to DNA.
Retroviral vectors are modified to retain the part of the genome which is neccessary to initiate reverse transcription into the target cell, while the rest of the viral genome is removed (Lyon et al., 2011).
Integration of virus into the cell requires cell division, which is why this vector can be suitable for therapies against endothelial or smooth muscle cells such as in avoiding atherosclerosis or restenosis, but less suitable for cardiomyocytes which have a low division rate. However, the insertion of retrovirus into the host genome may cause mutations, potentially leading to malignancies which can be passed on into the germline to offspring.Lentiviruses belong to the retroviridae family, and include vectors derived from the human immunodeficiency virus type I (HIV-1). Wild-type HIV-1 have an affinity for T-cell subpopulations, limiting their usability for cardiovascular purposes. Hybrid “pseudotyped” lentivirus have been produced to expand their tropism for other cell types. In the context of transfecting cardiomyocytes, lentiviral-based vectors are as effecient as adenoviruses, with transgene expression lasting longer (Yoshimitsu 2006). Lentivirurses are especially favoured in studies targeting transfection of endothelial cells or smooth muscle cells (Sakoda et al., 2007). The major obstacle towards a large-scale employment of lentivirus is currently uncertainties regarding safety. Modifications of the virus to avoid any risk of human disease are being performed, and may in the future lead to a larger therapeutic potential (Lyon et al. Intrapericardial gene deliveryIn theory, injection of DNA into the intrapericardial space may offer an environment which is relatively constant (no blood flow), and would be a relatively non-invasive approach for getting DNA to the heart. However, an intrapericardial injection can not lead to directed gene delivery, in the sense that there is no control over uptake in a specific type of cell or a specific area of the heart such as into the border zone of myocardial infarction. Zhang and coworkers delivered adenoviral based LacZ into the pericardium of neonatal mice through a percutaneous puncture, and three days later found LacZ activity in the endocardium, epicardium, and myocardium (Zhang et al., 1999). However, the same regimen did not lead to wide-spread expression in adult hearts, in which hepatic transduction was found in high levels (Zhang et al., 1999). Mixing the virus with proteolytic enzymes increased transgene expression intramyocardially within a short time later, but the expression did not last, and there was leakage to other organs (Fromes et al., 1999). In the canine myocardium, March and coworkers (1999) delivered adenovirus based LacZ through a penetrating catheter. Regardless of whether the injection is of plasmid DNA or DNA ligated to a vector, intramyocardial injections are invasive and do not have a clinical appeal.
One can envision injection of DNA during open heart surgery when the heart is exposed anyway, or catheter-based delivery when a patient is undergoing invasive arterial procedures.
However, except for open heart surgery with direct visualization the accuracy of such an approach is not high - if the intention is delivery of genes i.e. The approach has, however, given us invaluable research information on the therapeutic potential and limitations of genes thought to correct underlying pathologies.
Delivery of the transcription factor GATA-4 ligated to an adenoviral vector before coronary artery ligation resulted in improved left ventricular function and reduced infarct size (Rysa et al., 2010).
This was due to increased angiogenesis, decreased apoptosis, and mobilization of cardiac stem cells in GATA-4 treated hearts. AAV-based transfection with angiogenin in an in vivo infarction model reduced remodelling, induced angiogenesis, and attenuated cardiac dysfunction four weeks later (Zhao et al., 2006).
Therapeutic use of AAV9-vascular endothelial growth factor-B is cardioprotective in canine pacing-induced dilated cardiomyopathy, but not due to formation of new vessels (Pepe et al., 2010). Delivery of adenoviral vector-ligated vascular endothelial growth factor B to rats with angiotensin II-induced hypertrophy leads to reduction of diastolic dysfunction, increasing capillary area but not density (Serpi et al., 2011).
In a chronic ischemia model in rats, AAV2-based delivery of both vascular endothelial growth factor A and – B were protective (Zentilin et al., 2010). Vascular endothelial growth factor B was more protective than A, reducing apoptosis and remodelling and preserving heart function in the abscence of angiogenesis.
Hepatocyte growth factor delivered by adenovirus into the myocardium following myocardial infarction preserved cardiac function, reduced remodelling and apoptosis, and induced angiogenesis (Jayasankar et al., 2003).
Other studies have used antiinflammatory agents injected into the myocardium to combat ischemic heart disease and its consequences. Adenoviral-based expression of inhibitory kappa B-alpha in a rat infarction model improved heart function six weeks later (Trescher et al., 2004). AAV9 based delivery of heme oxygenase-1 into the myocardium before myocardial infarction had infarct reducing, anti-inflammatory, and antiapoptotic effects (Melo et al., 2002).
Intramyocardial injection with inducible nitric oxide synthase ligated to adenovirus had an infarct-reducing effect both short-term and long-term (Li et al., 2006). This effect was mediated by inducible cyclooxygenase and nuclear factor kappa B (Liet al., 2007). Thus, a major insight into possible therapeutic genes has been provided by this gene delivery route. Intramyocardial gene delivery is likely to remain a powerful research tool for testing the therapeutic potiential of genes in experimental models in the future.
Intravascular deliveryCardiac intravascular gene delivery has been performed through antegrade coronary artery delivery, non-selective intracoronary delivery (i.e.
Common for these approaches is the need to occlude the coronary circulation temporarily to allow virus to migrate into cells.
The attractive aspect of this approach is the possibility of a minimally invasive delivery procedure through a catheter well within established clinical procedures (at least the antegrade technique) and the possibility to deliver into all four heart chambers. With a recombinant AAV2 vector ligated to deliver enhanced green fluorescent protein, Kaspar and collegues (2005) used rats for indirect intracoronary delivery.
Rats had transgene expression lasting up to 12 months, with a gradient of expression across the left ventricular wall, the epicardium expressing much more than the endocardium.
There was evidence of AAV2 vector genome in liver and lungs of injected animals (Kaspar et al., 2005). Lai and coworkers (2004) delivered DNA encoding for adenylyl cyclase 6 ligated to an adenoviral vector into all three major coronary arteries of pigs with heart failure, using a vasodilator at the time of delivery, and compared with delivery of saline. Three weeks later left ventricular function was improved in the pigs recieving adenylyl cyclase 6. Gene expression in left ventricular biopsies evaluated with PCR was increased, although in which cells was not adressed (Lai et al., 2004). The success of intravascular gene delivery may depend on the target cell; if it is vascular, the chance of success may increase compared with a cardiac cell target. However, anything that enters the coronary circulation must enter the general circulation, reducing the clinical appeal of this approach.
Gene therapy using non-viral vectorsAlthough improvements are made in modifying viral vectors, reducing immunogenicity and increasing duration and amount of gene expression and narrowing the expression to target cells, researchers are travelling on alternative routes to deliver genes to the heart. Several non-viral techniques are used to improve the transfection efficacy of plasmids such as liposomes, polymers, electroporation, and nanotechnology (Holladay et al. These types of cells include multipotent bone marrow or adipose tissue derived mesenchymal stem cells and embryonic stem cells. Commited progenitor cells are more differentiated, and include endothelial progenitor cells, fetal cardiomyocytes, and autologous skeletal myoblasts. Experimental studies have successfully been able to induce neovascularization, increase cardiomyocyte survival, and improve postinfarct function through using cell transplantation. Possibly there is a fusion between the transplanted cells and the endogenous cardiomyocytes (Beeres et al., 2008).
As transplanted cells have a short life span in their new environment, these effects will be transitory. Some suggested mechanisms of action are autocrine or paracrine release of cytokines and growth factors that will stimulate new vessel formation, inhibit apoptosis, rescue injured cardiomyocytes, and reduce pathologic remodelling.
Recently, endogenous cardiac stem cells are reported to have even more promising potential for correcting cardiac pathologies. These cells are a large topic beyond the scope of this chapter (Bolli & Chaudrey, 2010). Therapeutic use of stem cells is now a clinical reality, but there is need for more laboratory work before this field can become useful in patients at a large scale.
At the moment we do not know the optimal cell for delivery, the optimal amount of cells, or which route of delivery (as for gene therapy, intramyocardial, intravascular through artery or vein, pericardial and other approaches have all been performed) that will give the best outcome. Genetically modifed cells may act as transgene carriers and be used to deliver therapeutic targets to cardiac tissue. Genetically engineered stem cells as cardioprotective agentsBased on the assumption that the major effect of stem cells is through their paracrine effects, quite a few works have focused on genetically engineered stem cells to produce angiogenic factors, with the perspective to both increase survival of the transplanted cell and to enhance the formation of new blood vessels in the infarcted heart.
For instance, bone-marrow derived endothelial progenitor cells were expanded and transduced with AAV to overexpress insulin-like growth factor 1. Then the autologous cells were transplanted into the infarct area of rats (Sen et al., 2010).
Three months later rats receiving insulin-like growth factor 1 transduced cells as opposed to LacZ-transduced cells had improved myocardial function, reduced apoptosis, increased number of capillaries, and increased cardiomyocyte proliferation in the infarct area. In a model of neointima formation in hypercholesterolemic rats, endothelial progenitor cells transduced to overexpress hepatocyte growth factor were delivered. The transduced cells homed to the vascular site of injury more than untreated cells, and this caused a decreased neointima formation and increased endothelialization (Song et al., 2009).
Colony stimulating factor-1 was used to transfect primary autologous rat myoblasts, which were transplanted into the myocardium of rats with postinfarction heart failure (Aharinejad et al., 2008).
Left ventricular function evaluated by echocardiography was improved in hearts of rats treated with with autologous colony stimulating factor myoblasts. This protection was not found after delivery of untransduced myoblasts or plasmid DNA encoding for colony stimulating factor. In a similar model myoblasts transduced with human growth factor were able to improve heart function, increase capillary density, and reduced apoptosis (Rong et al., 2008). Mesenchymal stem cells engineered to overexpress adrenomedullin transplanted after myocardial infarction improved cardiac function more than naive mesenchymal stem cells (Jo et al., 2007). The growth factor angiopoietin-1 in modified mesenchymal stem cells has reduced ischemic damage when injected shortly after ischemia in rat hearts (Sun et al., 2007). In pigs, mononuclear cells were extracted from peripheral blood and induced to overexpress vascular endothelial growth factor retrogradely delivered through the coronary sinus.
The transduced cells induced angiogenesis and reduced postischemic ventricular dysfunction four weeks later (Hagikura et al., 2010). Vascular endothelial growth factor ligated to mesenchymal stem cells under the control of a hypoxia response element induced ischemia-responsive production of vascular endothelial growth factor when transplanted into the ischemic myocardium (Kim et al., 2010).
This caused an increased retainment of genetically altered mesenchymal stem cells in the infarcted heart compared with naive cells, reduction of apoptosis, and reduced remodelling. Treatment of mesenchymal stem cells to overexpress connexin 43 followed by injection into infarcted myocardium improves left ventricular function and reduces cell death (Wang et al., 2010).



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