Gene and cell therapies for the failing heart to prevent sudden arrhythmic death

Current therapies for treatment and prevention of sudden cardiac death have certain limitations, and a search for new therapeutic approaches is desirable to reduce the burden of sudden arrhythmic death. Gene therapy and stem cell therapy have been investigated as new, valuable tools in treating cardiac diseases such as arrhythmias. In this review, the basics of each modality, important related experimental and clinical studies, and potential advantages and limitations of these treatments will be discussed. The future success of gene and cell therapy to become practical clinical tools greatly depends on our understanding of the mechanisms of ventricular arrhythmia and the mechanisms of action of gene and cell therapy.     

Diastolic heart failure in the elderly: underlying mechanisms and clinical relevance

Diastolic heart failure (DHF) is now firmly established as a significant contributor to the heart failure syndrome. However, compared to the better studied systolic dysfunction heart failure relatively little is known about this form of the syndrome. Epidemiological data have demonstrated that it is particularly important in the elderly likely reflecting the combination of several changes occurring in the myocardium occurring with advancing years, including progressive fibrosis and stiffening of the myocardium, the impact of hypertension over the years and the increased likelihood of ischaemic heart disease. This review will focus on the relevant aetiological factors in DHF, possible pathophysiological mechanisms and outline new and evolving therapeutic strategies for this problem.     

Cardiomyocyte apoptosis in the failing heart — A critical review from definition and classification of cell death

It has been suggested that apoptosis may be responsible for a significant amount of the cardiomyocyte death that contributes to the development and progression of heart failure. However, studies of actual heart disease and in vivo experimental models have provided little or no direct morphological evidence that cardiomyocyte apoptosis occurs at any stage of heart failure, despite the availability of much indirect evidence that includes detection of DNA fragmentation and apoptosis-related factors. The Nomenclature Committee on Cell Death (NCCD), an international organization consulting on cell death, proposed an international standard for the definition and classification of cell death, in which cell death was defined based purely on morphological criteria. This is because there is no clear-cut equivalence between ultrastructural alterations and biochemical cell death characteristics. This review will first introduce the NCCD definition and classification of cell death and, based on this classification, survey the available data from both animals and humans to critically assess the impact of cardiomyocyte apoptosis during the progression of heart failure of various etiologies. Particularly noteworthy is the wide variation in the reported rates of apoptosis – e.g., the difference was > 1000-fold in one heart failure model – but even more importantly, no morphological (ultrastructural) data has ever been shown definitively demonstrating apoptosis of a cardiomyocyte. We conclude from our survey that even the existence of cardiomyocyte apoptosis in heart failure remains controversial.     

Programmed cell death: new thoughts and relevance to aging

Cell death is a common phenomenon in developmental biology, and recent data suggest that it is as tightly regulated as mitosis. For numerous systems endocrine and neuronal factors are required to maintain viability of cells, as are specific diffusible and other unknown factors deriving from intimate cell-to-cell contact; and, in some instances, specific hormones or other circulating factors induce spontaneous self-destruction by the targeted cells. Some cells such as thymocytes may be primed to self-destruct and hence activate specific enzymes. In others, the doomed cell up-regulates a limited number of genes just before it dies. Of these genes, several are known but are not considered to cause cell death; others are under investigation. Although the situation is clearest for developmental biology, it appears that the presumptively random loss of cells in senescence results from invocation of the same mechanisms. Understanding and control of these mechanisms could conceivably lead either to protection against cell loss or specific induction of lysis in malignant cells.     

Cell death signalling mechanisms in heart failure

Cardiac disease is a global epidemic that is on the rise, despite the recent advances in cardiovascular research. Once the myocardium is injured, it has a limited capacity to activate reparative mechanisms to restore proper cardiac function, leading to the development of systemic heart failure. Autophagy, under certain conditions, may result in cell death, further emphasizing the controversial issues regarding the autophagic process as an adaptive or maladaptive biological response. Although significant progress in understanding the signalling mechanisms of cell death in myocytes has been made, the role of apoptotic cell death and programmed necrosis during heart failure is not completely understood. Insight to how myocytes determine whether to activate apoptotic or programmed necrosis signalling machinery remains under current investigation because it is a major problem for both scientists and clinicians in treating heart failure patients. Herein, the different modes of cell death implicated in heart failure are highlighted, as well as the role of B-cell lymphoma-2 family members and how mitochondria act as central organelles in directing such cell death mechanisms.     

The AR dependent cell cycle: mechanisms and cancer relevance

Prostate cancer cells are exquisitely dependent on androgen receptor (AR) activity for proliferation and survival. As these functions are critical targets of therapeutic intervention for human disease, it is imperative to delineate the mechanisms by which AR engages the cell cycle engine. More than a decade of research has revealed that elegant intercommunication between AR and the cell cycle machinery governs receptor-dependent cellular proliferation, and that perturbations in this process occur frequently in human disease. Here, AR-cell cycle interplay and associated cancer relevance will be reviewed.     

Apoptosis: mechanisms and relevance in cancer

Apoptosis or programmed cell death is a process with typical morphological characteristics including plasma membrane blebbing, cell shrinkage, chromatin condensation and fragmentation. A family of cystein-dependent aspartate-directed proteases, called caspases, is responsible for the proteolytic cleavage of cellular proteins leading to the characteristic apoptotic features, e.g. cleavage of caspase-activated DNase resulting in internucleosomal DNA fragmentation. Currently, two pathways for activating caspases have been studied in detail. One starts with ligation of a death ligand to its transmembrane death receptor, followed by recruitment and activation of caspases in the death-inducing signalling complex. The second pathway involves the participation of mitochondria, which release caspase-activating proteins into the cytosol, thereby forming the apoptosome where caspases will bind and become activated. In addition, two other apoptotic pathways are emerging: endoplasmic reticulum stress-induced apoptosis and caspase-independent apoptosis. Naturally occurring cell death plays a critical role in many normal processes like foetal development and tissue homeostasis. Dysregulation of apoptosis contributes to many diseases, including cancer. On the other hand, apoptosis-regulating proteins also provide targets for drug discovery and new approaches to the treatment of cancer.     

Crosstalk of liver immune cells and cell death mechanisms in different murine models of liver injury and its clinical relevance

BACKGROUND: Liver inflammation or hepatitis is a result of pluripotent interactions of cell death molecules, cytokines, chemokines and the resident immune cells collectively called as microenvironment. The interplay of these inflammatory mediators and switching of immune responses during hepatotoxic, viral, drug-induced and immune cell-mediated hepatitis decide the fate of liver pathology. The present review aimed to describe the mechanisms of liver injury, its relevance to human liver pathology and insights for the future therapeutic interventions.DATA SOURCES: The data of mouse hepatic models and relevant human liver diseases presented in this review are systematically collected from Pub Med, Science Direct and the Web of Science databases published in English. RESULTS: The hepatotoxic liver injury in mice induced by the metabolites of CCl4, acetaminophen or alcohol represent necrotic cell death with activation of cytochrome pathway, formation of reactive oxygen species(ROS) and mitochondrial damage. The Fas or TNF-α induced apoptotic liver injury was dependent on activation of caspases, release of cytochrome c and apoptosome formation. The Con A-hepatitis demonstrated the involvement of TRAIL-dependent necrotic/necroptotic cell death with activation of RIPK1/3. The α-Gal Cer-induced liver injury was mediated by TNF-α. The LPS-induced hepatitis involved TNF-α, Fas/Fas L, and perforin/granzyme cell death pathways. The MHV3 or Poly(I:C) induced liver injury was mediated by natural killer cells and TNF-α signaling. The necrotic ischemia-reperfusion liver injury was mediated byhypoxia, ROS, and pro-inflammatory cytokines; however, necroptotic cell death was found in partial hepatectomy. The crucial role of immune cells and cell death mediators in viral hepatitis(HBV, HCV), drug-induced liver injury, non-alcoholic fatty liver disease and alcoholic liver disease in human were discussed.CONCLUSIONS: The mouse animal models of hepatitis provide a parallel approach for the study of human liver pathology. Blocking or stimulating the pathways associated with liver cell death could unveil the novel therapeutic strategies in the management of liver diseases.     

Arrhythmogenic mechanisms for the sudden death in heart failure

Introduction
Heart failure （HF） is a major clinical manifestation of many cardiac disease processes when the cardiovascular compensatory mechanisms fail. Five million patients suffer from HF with an additional 555,000 new patients diagnosed HF annually. Moreover, there are an estimated 400,000 to 460,000 deaths attributable to sudden cardiac death （SCD） in the United States each year.1 Mortality in the heart failure population is about six to seven times higher than that of the agematched general population.     

Study of the normal and failing isolated human heart: decreased response of failing heart to isoproterenol

We evaluated the effects of isoproterenol in right ventricular papillary muscles derived from normal and failing isolated human hearts. Basal values for the peak force developed, rate of force development (dF/dt), and time to peak tension (TPT) were similar in both groups. Isoproterenol produced a significantly smaller (p less than 0.05) increase in peak force developed and dF/dt in failing papillary muscles. The half equivalent dose (ED50) of isoproterenol was fivefold higher in failing muscle as compared to normal muscle. We conclude that failing cardiac muscle demonstrates decreased responsiveness to beta-receptor mediated stimulation.     

Mitochondrial dynamics and cell death in heart failure

The highly regulated processes of mitochondrial fusion (joining), fission (division) and trafficking, collectively called mitochondrial dynamics, determine cell-type specific morphology, intracellular distribution and activity of these critical organelles. Mitochondria are critical for cardiac function, while their structural and functional abnormalities contribute to several common cardiovascular diseases, including heart failure (HF). The tightly balanced mitochondrial fusion and fission determine number, morphology and activity of these multifunctional organelles. Although the intracellular architecture of mature cardiomyocytes greatly restricts mitochondrial dynamics, this process occurs in the adult human heart. Fusion and fission modulate multiple mitochondrial functions, ranging from energy and reactive oxygen species production to Ca²⁺ homeostasis and cell death, allowing the heart to respond properly to body demands. Tightly controlled balance between fusion and fission is of utmost importance in the high energy-demanding cardiomyocytes. A shift toward fission leads to mitochondrial fragmentation, while a shift toward fusion results in the formation of enlarged mitochondria and in the fusion of damaged mitochondria with healthy organelles. Mfn1, Mfn2 and OPA1 constitute the core machinery promoting mitochondrial fusion, whereas Drp1, Fis1, Mff and MiD49/51 are the core components of fission machinery. Growing evidence suggests that fusion/fission factors in adult cardiomyocytes play essential noncanonical roles in cardiac development, Ca²⁺ signaling, mitochondrial quality control and cell death. Impairment of this complex circuit causes cardiomyocyte dysfunction and death contributing to heart injury culminating in HF. Pharmacological targeting of components of this intricate network may be a novel therapeutic modality for HF treatment.     

Exercise and the failing heart

In summary, patients with chronic heart failure are frequently limited during exercise, even if they are asymptomatic at rest. Maximal exercise testing, preferably coupled with respiratory gas analysis, provides an objective method of assessing this functional limitation. Exercise testing also offers an objective method of noninvasively evaluating circulatory function in patients and, potentially, of monitoring responses to therapeutic interventions.