Lipotoxicity in the heart

Obesity and insulin resistance are associated with ectopic lipid deposition in multiple tissues, including the heart. Excess lipid may be stored as triglycerides, but are also shunted into non-oxidative pathways that disrupt normal cellular signaling leading to organ dysfunction and in some cases apoptosis, a process termed lipotoxicity. Various pathophysiological mechanisms have been proposed to lead to lipotoxic tissue injury, which might vary by cell type. Specific mechanisms by which lipotoxicity alter cardiac structure and function are incompletely understood, but are beginning to be elucidated. This review will focus on mechanisms that have been proposed to lead to lipotoxic injury in the heart and will review the state of knowledge regarding potential causes and correlates of increased myocardial lipid content in animal models and humans. We will seek to highlight those areas where additional research is warranted.     

Regenerating cardiac cells: insights from the bench and the clinic

A major challenge in cardiovascular regenerative medicine is the development of novel therapeutic strategies to restore the function of cardiac muscle in the failing heart. The heart has historically been regarded as a terminally differentiated organ that does not have the potential to regenerate. This concept has been updated by the discovery of cardiac stem and progenitor cells that reside in the adult mammalian heart. Whereas diverse types of adult cardiac stem or progenitor cells have been described, we still do not know whether these cells share a common origin. A better understanding of the physiology of cardiac stem and progenitor cells should advance the successful use of regenerative medicine as a viable therapy for heart disease. In this review, we summarize current knowledge of the various adult cardiac stem and progenitor cell types that have been discovered. We also review clinical trials presently being undertaken with adult stem cells to repair the injured myocardium in patients with coronary artery disease.     

Are heart valves from donors over 65 years of age morphologically suitable for transplantation?

Since there is no upper age limit for general organ donation, unlike heart valve donation, and since a quarter of all organ donors are 65 years and older, we examined whether the heart valves from these donors are suitable as allografts. In the period 1999–2004 the aortic valve and pulmonary valve of 100 organ donors above 65 years of age were examined to establish whether they would have been suitable as valve grafts. To compare the valve grafts above and below the age limit of 65 years, we used data on the aortic and pulmonary valves of 380 organ donors below the age limit in the same time period. Examination of the 200 heart valves showed that – just like valves from donors below the age limit – 100 of them would have met the medical quality standards for transplantation, which discriminate among optimal, suitable and unsuitable tissue morphology. The morphological suitability of the aortic valves decreases rapidly during the 4th decade of life and near to the age limit only 6% of them are accepted as grafts. The rate of potentially acceptable aortic valve grafts from organ donors aged over 65 years of 15% is also small. By contrast, the pulmonary valves are not affected by age-related tissue changes that might reduce their transplantability. The predominant majority (85%) of potential pulmonary valve grafts from organ donors over 65 years of age fulfilled the acceptance criteria, half of them (48%) even showing good tissue quality. In light of these results the age limit was raised to 70 years in 2005.     

Effects of d‐galactose‐induced ageing on the heart and its potential interventions

Ageing is a strong independent risk factor for disability, morbidity and mortality. Post‐mitotic cells including those in the heart are a particular risk to age‐related deterioration. As the occurrence of heart disease is increasing rapidly with an ageing population, knowledge regarding the mechanisms of age‐related cardiac susceptibility and possible therapeutic interventions needs to be acquired to prevent advancing levels of heart disease. To understand more about the ageing heart, numerous aged animal models are being used to explore the underlying mechanisms. Due to time‐consuming for investigations involving naturally aged animals, mimetic ageing models are being utilized to assess the related effects of ageing on disease occurrence. d ‐galactose is one of the substances used to instigate ageing in various models, and techniques involving this have been widely used since 1991. However, the mechanism through which d ‐galactose induces ageing in the heart remains unclear. The aim of this review was to comprehensively summarize the current findings from in vitro and in vivo studies on the effects of d ‐galactose‐induced ageing on the heart, and possible therapeutic interventions against ageing heart models. From this review, we hope to provide invaluable information for future studies and based on the findings from experiments involving animals, we can inform possible therapeutic strategies for the prevention of age‐related heart diseases in clinical settings.     

Glucocorticoids produce whole body insulin resistance with changes in cardiac metabolism

Insulin resistance is viewed as an insufficiency in insulin action, with glucocorticoids being recognized to play a key role in its pathogenesis. With insulin resistance, metabolism in multiple organ systems such as skeletal muscle, liver, and adipose tissue is altered. These metabolic alterations are widely believed to be important factors in the morbidity and mortality of cardiovascular disease. More importantly, clinical and experimental studies have established that metabolic abnormalities in the heart per se also play a crucial role in the development of heart failure. Following glucocorticoids, glucose utilization is compromised in the heart. This attenuated glucose metabolism is associated with altered fatty acid supply, composition, and utilization. In the heart, elevated fatty acid use has been implicated in a number of metabolic, morphological, and mechanical changes and, more recently, in "lipotoxicity". In the present article, we review the action of glucocorticoids, their role in insulin resistance, and their influence in modulating peripheral and cardiac metabolism and heart disease.     

From ABC genes to regulatory networks,epigenetic landscapes and flower morphogenesis: Making biological sense of theoretical approaches

The ABC model postulates that expression combinations of three classes of genes (A, B and C) specify the four floral organs at early stages of flower development. This classic model provides a solid framework to study flower development and has been the foundation for multiple studies in different plant species, as well as for new evolutionary hypotheses. Nevertheless, it has been shown that in spite of being necessary, these three gene classes are not sufficient for flower organ specification. Rather, flower organ specification depends on complex interactions of several genes, and probably other non-genetic factors. Being useful to study systems of complex interactions, mathematical and computational models have enlightened the origin of the A, B and C stereotyped and robust expression patterns and the process of early flower morphogenesis. Here, we present a brief introduction to basic modeling concepts and techniques and review the results that these models have rendered for the particular case of the Arabidopsis thaliana flower organ specification. One of the main results is the uncovering of a robust functional module that is sufficient to recover the gene configurations characterizing flower organ primordia. Another key result is that the temporal sequence with which such gene configurations are attained may be recovered only by modeling the aforementioned functional module as a noisy or stochastic system. Finally, modeling approaches enable testable predictions regarding the role of non-genetic factors (noise, mechano-elastic forces, etc.) in development. These predictions, along with some perspectives for future work, are also reviewed and discussed.     

Atrial natriuretic peptide in the granular cells of the snail heart

Cardiomyocytes of vertebrates combine contractile and endocrine functions. They synthesize and secrete atrial natriuretic peptide (ANP), which is localized in their specific granules. The presence of ANP has been shown in some tissues of invertebrates, including the heart of molluscs. We have studied localization of ANP in cells of the snail heart. METHOD: The atrial and ventricular tissues of the snail Helix pomatia were studied by electron microscope immunocytochemistry, using anti-ANP antibodies. ANP-immunoreactivity has been detected in granules of granular cells located on the luminal surface of the snail myocardium. These cells are abundant in the atrium being very rare in the ventricle. Granular cells at different stages of maturation were revealed. Immature granular cells have light granules of moderate size with homogeneous tight content, while mature granular cells are huge in size and all their granules are fused together. The material of these granules loosens up and almost completely fills up the cytoplasm. No ANP-immunoreactivity was observed in muscle cells or nerve fibers. A possible origin of granular cells from the cardiac endothelial cells is discussed. The molluscan heart, similar to that of vertebrates, is a bifunctional organ. However, contrary to the heart of vertebrates, in the molluscan heart contractile and endocrine functions are separated between different types of cells.     

Bioinformatics, multiscale modeling and the IUPS Physiome Project

Multiscale modeling is required for linking physiological processes operating at the organ and tissue levels to signal transduction networks and other subcellular processes. Several XML markup languages, including CellML, have been developed to encode models and to facilitate the building of model repositories and general purpose software tools. Progress in this area is described and illustrated with reference to the heart Physiome Project which aims to understand cardiac arrhythmias in terms of structure-function relations from proteins up to cells, tissues and organs.     

ARGUMENTS AGAINST PROMOTING ORGAN TRANSPLANTS FROM BRAIN‐DEAD DONORS,AND VIEWS OF CONTEMPORARY JAPANESE ON LIFE AND DEATH

As of 2009, the number of donors in Japan is the lowest among developed countries. On July 13, 2009, Japan's Organ Transplant Law was revised for the first time in 12 years. The revised and old laws differ greatly on four primary points: the definition of death, age requirements for donors, requirements for brain‐death determination and organ extraction, and the appropriateness of priority transplants for relatives. In the four months of deliberations in the National Diet before the new law was established, various arguments regarding brain death and organ transplantation were offered. An amazing variety of opinions continue to be offered, even after more than 40 years have elapsed since the first heart organ transplant in Japan. Some are of the opinion that with the passage of the revised law, Japan will finally become capable of performing transplants according to global standards. Contrarily, there are assertions that organ transplants from brain‐dead donors are unacceptable because they result in organs being taken from living human beings. Considering the current conditions, we will organize and introduce the arguments for and against organ transplants from brain‐dead donors in contemporary Japan. Subsequently, we will discuss the primary arguments against organ transplants from brain‐dead donors from the perspective of contemporary Japanese views on life and death. After introducing the recent view that brain death should not be regarded as equivalent to the death of a human being, we would like to probe the deeply‐rooted views on life and death upon which it is based.     

Capillaries within compartments: microvascular interpretation of dynamic positron emission tomography data

Measurement of exchange of substances between blood and tissue has been a long-lasting challenge to physiologists, and considerable theoretical and experimental accomplishments were achieved before the development of the positron emission tomography (PET). Today, when modeling data from modern PET scanners, little use is made of earlier microvascular research in the compartmental models, which have become the standard model by which the vast majority of dynamic PET data are analysed. However, modern PET scanners provide data with a sufficient temporal resolution and good counting statistics to allow estimation of parameters in models with more physiological realism. We explore the standard compartmental model and find that incorporation of blood flow leads to paradoxes, such as kinetic rate constants being time-dependent, and tracers being cleared from a capillary faster than they can be supplied by blood flow. The inability of the standard model to incorporate blood flow consequently raises a need for models that include more physiology, and we develop microvascular models which remove the inconsistencies. The microvascular models can be regarded as a revision of the input function. Whereas the standard model uses the organ inlet concentration as the concentration throughout the vascular compartment, we consider models that make use of spatial averaging of the concentrations in the capillary volume, which is what the PET scanner actually registers. The microvascular models are developed for both single- and multi-capillary systems and include effects of non-exchanging vessels. They are suitable for analysing dynamic PET data from any capillary bed using either intravascular or diffusible tracers, in terms of physiological parameters which include regional blood flow.     

Multi-scale modelling and the IUPS physiome project

We review the development of models of cellular and tissue function and in particular address issues of multi-scale modelling, including the transition from stochastic models to continuum models and the incorporation of cell and tissue structure. The heart is used as an example of linking models at the molecular level to cell, tissue and organ level function.     

Testing Drugs on Human Osteoarthritic Articular Cartilage

New drugs are generally developed against animal models of the human disease. Before they are subjected to clinical trials it might be helpful to be able to test whether they are as effective against the disease in human tissue as they were in animals. It is proposed that this can be achieved by the use of organ maintenance culture of the human diseased tissue, the relevant biochemical parameters being measured by quantitative cytochemistry. In the present studies differences between the effect of indomethacin and of the ‘chondroprotective’ drug diclofenac sodium, on human osteoarthritic cartilage, have been measured.     

Cardiac regeneration in non-mammalian vertebrates

The heart is a robust organ, capable of pumping nutrients and transferring oxygen throughout the body via a network of capillaries, veins and arteries, for the entirety of a human's life. However, the fragility of mammalian hearts is also evident when it becomes damaged and parts of the organ fail to function. This is due to the fact that rather than replenishing the damaged areas with functional cellular mass, fibrotic scar tissue is the preferred replacement, resulting in an organ with functional deficiencies. Due to the mammalian hearts incapability to regenerate following damage and the ever-increasing number of people worldwide suffering from heart disease, tireless efforts are being made to discover ways of inducing a regenerative response in this most important organ. One such avenue of investigation involves studying our distantly related non-mammalian vertebrate cousins, which over the last decade has proved to us that cardiac regeneration is possible. This review will highlight these organisms and provide insights into some of the seminal discoveries made in the heart regeneration field using these amazing chordates.     

Combinatorial signaling in the heart orchestrates cardiac induction, lineage specification and chamber formation

The complexity of mammalian cardiogenesis is compounded, as the heart must function in the embryo whilst it is still being formed. Great advances have been made recently as additional cardiac progenitor cell populations have been identified. The induction and maintenance of these progenitors, and their deployment to the developing heart relies on combinatorial molecular signalling, a feature also of cardiac chamber formation. Many forms of congenital heart disease in humans are likely to arise from defects in the early stages of heart development; therefore it is important to understand the molecular pathways that underlie some of the key events that shape the heart during the early stages of it development.     

Experience of a Canadian multi-organ transplant service.

Organ transplantation has become the treatment of choice for selected patients with end-stage failure of the heart, liver or kidneys. The expanding role for organ transplantation, however, has led to a corresponding increase in the complexity of patient management. In response to these changes, University Hospital, London, Ont., has established an interdisciplinary multi-organ transplant service (MOTS). MOTS coordinates donor organ procurement and patient management. Donor organs have been retrieved from as far south as Dalton, Georgia, as far west as Calgary and as far east as Halifax. As of Dec. 31, 1985, 485 transplants had been performed, including 387 kidney transplants, 51 heart transplants, 3 heart/lung transplants, 43 liver transplants (in adults and children) and 1 pancreas transplant. With current immunosuppressive protocols MOTS projects 1-year patient survival rates of 95% after kidney transplantation, 88% after heart transplantation and 81% after liver transplantation. Patient rehabilitation has been excellent.     

Hidden phenotypes of PINK1/Parkin knockout mice

PINK1, a serine/threonine ubiquitin kinase, and Parkin, an E3 ubiquitin ligase, work in coordination to target damaged mitochondria to the lysosome in a process called mitophagy. This review will cover what we have learned from PINK1 and Parkin knockout (KO) mice. Systemic PINK1 and Parkin KO mouse models haven’t faithfully recapitulated early onset forms of Parkinson’s disease found in humans with recessive mutations in these genes. However, the utilization of these mouse models has given us insight into how PINK1 and Parkin contribute to mitochondrial quality control and function in different tissues beyond the brain such as in heart and adipose tissue. Although PINK1 and Parkin KO mice have been generated over a decade ago, these models are still being used today to creatively elucidate cell-type specific functions. Recently, these mouse models have uncovered that these proteins contribute to innate immunity and cancer phenotypes.     

The gravitropic set-point angle (GSA): the identification of an important developmentally controlled variable governing plant architecture*

The angle at which an organ is maintained by gravit-ropism is characteristic of the organ, its developmental state and the prevailing environmental conditions. We propose that this angle be called the gravitropic set-point angle (GSA), defined as the angle with respect to the gravity vector (with a vertically downward orientation being 0°) at which an organ is maintained as a consequence of gravitropism. Studies of the gravitropic behaviour of organs from trailing plants show that the GSA is subject to developmental regulation. Depending on the developmental age and prevailing environmental conditions, the GSA of an organ can he set at any value between 0° and 180° The previously reported reversal of the sign of the gravitropic response in such organs, whether this is brought about developmentally or induced by light, represents the change from one common extreme (GSA = 180°, conventionally referred to as negative orthogravitropism) to another (GSA = 0°, or positive orthogravitropism). The concept of a variable gravitropic set-point offers a more unified view of all forms of gravitropic behaviour than has been advanced previously, and places a new constraint on models of gravitropism. Current models of gravitropism appear to be unable to explain either the ability of organs to change their orientation with respect to gravity as they develop, or the re-orientation that can be observed when some organs are exposed to new environmental conditions.     

Cytomegalovirus-mediated upregulation of chemokine expression correlates with the acceleration of chronic rejection in rat heart transplants

Cytomegalovirus (CMV) infections have been shown to dramatically affect solid organ transplant graft survival in both human and animal models. Recently, it was demonstrated that rat CMV (RCMV) infection accelerates the development of transplant vascular sclerosis (TVS) in both rat heart and small bowel graft transplants. However, the mechanisms involved in this process are still unclear. In the present study, we determined the kinetics of RCMV-accelerated TVS in a rat heart transplant model. Acute RCMV infection enhances the development of TVS in rat heart allografts, and this process is initiated between 21 and 24 days posttransplantation. The virus is consistently detected in the heart grafts from day 7 until day 35 posttransplantation but is rarely found at the time of graft rejection (day 45 posttransplantation). Grafts from RCMV-infected recipients had upregulation of chemokine expression compared to uninfected controls, and the timing of this increased expression paralleled that of RCMV-accelerated neointimal formation. In addition, graft vessels from RCMV-infected grafts demonstrate the increased infiltration of T cells and macrophages during periods of highest chemokine expression. These results suggest that CMV-induced acceleration of TVS involves the increased graft vascular infiltration of inflammatory cells through enhanced chemokine expression.