Enhanced external counterpulsation: A unique treatment for the "No-Option" refractory angina patient.

WHAT IS KNOWN AND OBJECTIVES: Coronary artery disease (CAD) is the leading cause of death in the United States. For patients on whom guideline-driven measures have been tried, enhanced external counterpulsation (EECP) is the only truly noninvasive and safe intervention for which a reduction of angina symptoms and nitrate use, increased exercise tolerance, and improvement in myocardial ischaemia have been shown. The objective of this study was to demonstrate, by way of literature review, the efficacy of EECP as a treatment modality for the relief of refractory angina and improvement in quality of life in CAD patients. METHODS: This article reviewed the safety and efficacy of EECP in patients with refractory angina, by conducting a sweeping search and analysis of existing published literature. RESULTS AND DISCUSSION: Critical review of a multitude of studies revealed that EECP consistently reduces angina pectoris, extends time to exercise-induced ischaemia, decreases dependency on nitroglycerine for frequent chest pain, increases maximum workload, and improves the quality of life in patients with symptomatic stable angina. The literature reviewed also indicated that EECP is well-tolerated by the vast majority of patients, with relatively few adverse events reported. CONCLUSION: The present study suggests that EECP is a safe and likely best available method of treatment for patients presenting with symptomatic CAD not amenable to further revascularization.

Journeying together: A visual exploration of "engagement" as a journey in HIV programming and service delivery.

The experiences of people living with, or impacted by HIV, who participate in research and programming are relatively-well documented. However, how stakeholders within the HIV sector understand engagement, or how it functions discursively, is undertheorized. We used a comparative case study design and photovoice to explore engagement in three community-based organizations providing HIV programs or services in Toronto, Canada. We invited stakeholders to photograph their subjective understandings of engagement. We employ a visual and thematic analysis of our findings, by focusing on participants' use of journey metaphors to discuss engagement within and across sites. Visual metaphors of journey were employed by participants to make sense of their experience, and demonstrated that for many, engagement was a dynamic, affective and relational process. Our findings illustrate how journey may be an apt metaphor to explore the relational, contingent and socio-spatial/political specificities of engagement within and across HIV organizations. We conclude with a discussion on implications for practice.

Comparison of the Kansas City Cardiomyopathy Questionnaire and Minnesota Living With Heart Failure Questionnaire in Predicting Heart Failure Outcomes.

Patient-reported outcome measures (PROMs) are relevant independent outcomes in heart failure (HF) care and are predictive of subsequent hospitalization and death in HF. The Kansas City Cardiomyopathy Questionnaire (KCCQ) and the Minnesota Living with Heart Failure Questionnaire (MLHFQ) are the 2 most widely adopted PROMs specific to HF. We compared their prognostic abilities in a prospective cohort of HF patients. A prospective cohort of subjects from a single-center registry was analyzed with regard to baseline KCCQ and MLHFQ scores and the outcomes of death, transplant, or left ventricular assist device implantation and hospitalization. A total of 516 subjects with reduced left ventricular ejection fraction (HFrEF) and 151 subjects with preserved left ventricular ejection fraction (HFpEF) were included. Discrimination was assessed using c-statistics based on time-to-event analyses and receiver-operator curves. The additive contribution of MLHFQ was assessed through the change in c-statistic, incremental discrimination index, and category-free net reclassification index. Overall, KCCQ was superior to MLHFQ for predicting death/transplant/ventricular assist device (c-statistic 0.702 [0.666 to 0.738] and 0.658 [0.621 to 0.695] respectively, p value for difference <0.001) and hospitalization (c-statistic 0.640 [0.613 to 0.666] and 0.624 [0.597 to 0.651], respectively, p value for difference 0.022). However, this difference was statistically nonsignificant in the HFpEF group alone. When analyzing the additional prognostic information afforded by adding MLHFQ to KCCQ in the overall, HFrEF, and HFpEF groups there was no significant improvement, although adding KCCQ to MLHFQ did significantly improve risk stratification. Scoring based upon the abbreviated KCCQ-12 did not reduce the prognostic accuracy of KCCQ. In conclusion, KCCQ is more prognostic of death/transplant/left ventricular assist device and hospitalization than MLHFQ in a combined cohort of patients with HFrEF and HFpEF, although the effect in HFpEF was less pronounced. KCCQ should be the preferred PROM for patients with HF if prognostication is a desired goal of using the PROMs.

Trehalose-Induced Activation of Autophagy Improves Cardiac Remodeling After Myocardial Infarction.

BACKGROUND: Trehalose (TRE) is a natural, nonreducing disaccharide synthesized by lower organisms. TRE exhibits an extraordinary ability to protect cells against different kinds of stresses through activation of autophagy. However, the effect of TRE on the heart during stress has never been tested. OBJECTIVES: This study evaluated the effects of TRE administration in a mouse model of chronic ischemic remodeling. METHODS: Wild-type (WT) or beclin1+/- mice were subjected to permanent ligation of the left anterior descending artery (LAD) and then treated with either placebo or trehalose (1 mg/g/day intraperitoneally for 48 h, then 2% in the drinking water). After 4 weeks, echocardiographic, hemodynamic, gravimetric, histological, and biochemical analyses were conducted. RESULTS: TRE reduced left ventricular (LV) dilation and increased ventricular function in mice with LAD ligation compared with placebo. Sucrose, another nonreducing disaccharide, did not exert protective effects during post-infarction LV remodeling. Trehalose administration to mice overexpressing GFP-tagged LC3 significantly increased the number of GFP-LC3 dots, both in the presence and absence of chloroquine administration. TRE also increased cardiac LC3-II levels after 4 weeks following myocardial infarction (MI), indicating that it induced autophagy in the heart in vivo. To evaluate whether TRE exerted beneficial effects through activation of autophagy, trehalose was administered to beclin 1+/- mice. The improvement of LV function, lung congestion, cardiac remodeling, apoptosis, and fibrosis following TRE treatment observed in WT mice were all significantly blunted in beclin 1+/- mice. CONCLUSIONS: TRE reduced MI-induced cardiac remodeling and dysfunction through activation of autophagy.

A Review of the Molecular Mechanisms Underlying the Development and Progression of Cardiac Remodeling.

Pathological molecular mechanisms involved in myocardial remodeling contribute to alter the existing structure of the heart, leading to cardiac dysfunction. Among the complex signaling network that characterizes myocardial remodeling, the distinct processes are myocyte loss, cardiac hypertrophy, alteration of extracellular matrix homeostasis, fibrosis, defective autophagy, metabolic abnormalities, and mitochondrial dysfunction. Several pathophysiological stimuli, such as pressure and volume overload, trigger the remodeling cascade, a process that initially confers protection to the heart as a compensatory mechanism. Yet chronic inflammation after myocardial infarction also leads to cardiac remodeling that, when prolonged, leads to heart failure progression. Here, we review the molecular pathways involved in cardiac remodeling, with particular emphasis on those associated with myocardial infarction. A better understanding of cell signaling involved in cardiac remodeling may support the development of new therapeutic strategies towards the treatment of heart failure and reduction of cardiac complications. We will also discuss data derived from gene therapy approaches for modulating key mediators of cardiac remodeling.

Towards a Cognitive Radar: Canada's Third-Generation High Frequency Surface Wave Radar (HFSWR) for Surveillance of the 200 Nautical Mile Exclusive Economic Zone.

Canada's third-generation HFSWR forms the foundation of a maritime domain awareness system that provides enforcement agencies with real-time persistent surveillance out to and beyond the 200 nautical mile exclusive economic zone (EEZ). Cognitive sense-and-adapt technology and dynamic spectrum management ensures robust and resilient operation in the highly congested High Frequency (HF) band. Dynamic spectrum access enables the system to simultaneously operate on two frequencies on a non-interference and non-protected basis, without impacting other spectrum users. Sense-and-adapt technologies ensure that the system instantaneously switches to a new vacant channel on the detection of another user or unwanted jamming signal. Adaptive signal processing techniques mitigate against electrical noise, interference and clutter. Sense-and-adapt techniques applied at the detector and tracker stages maximize the probability of track initiation whilst minimizing the probability of false or otherwise erroneous track data.

Functional Role of Nox4 in Autophagy.

Accumulating lines of evidence suggest that reactive oxygen species (ROS) may act as intracellular signaling molecules under cellular stress conditions, activating several molecular pathways. Autophagy, the intracellular mechanism by which cells digest and recycle unfolded proteins and dysfunctional organelles, is emerging as a major target of ROS and NADPH oxidase (Nox) enzymes, the major generators of ROS. While autophagy represents an important self-defense mechanism in promoting cell survival, it may be maladaptive in some conditions. In particular, in the cardiovascular system, moderate activation of autophagy has been shown to be protective, while excessive or insufficient activation of autophagy may be deleterious. Thus, modulating ROS-dependent autophagy may represent a novel strategy to keep autophagy within the therapeutic range. Among the Nox isoforms, Nox4 in particular plays a pivotal role in autophagy regulation. This appears to be due to its intracellular localization and its ability to produce hydrogen peroxide, a stable signaling molecule. In this chapter we review the studies relating to the functional role of Nox4 in autophagy, with particular emphasis on the heart and cardiovascular system.

An overview of the inflammatory signalling mechanisms in the myocardium underlying the development of diabetic cardiomyopathy.

Heart failure is a highly morbid and mortal clinical condition that represents the last stage of most cardiovascular disorders. Diabetes is strongly associated with an increased incidence of heart failure and directly promotes cardiac hypertrophy, fibrosis, and apoptosis. These changes, in turn, contribute to the development of ventricular dysfunction. The clinical condition associated with the spectrum of cardiac abnormalities induced by diabetes is termed diabetic cardiomyopathy. Myocardial inflammation has recently emerged as a pathophysiological process contributing to cardiac hypertrophy, fibrosis, and dysfunction in cardiac diseases. Myocardial inflammation is also implicated in the development of diabetic cardiomyopathy. Several molecular mechanisms link diabetes to myocardial inflammation. The NF-κB signalling pathway and the renin-angiotensin-aldosterone system are strongly activated in the diabetic heart, thereby promoting myocardial inflammation. Advanced glycation end-products and damage-associated molecular pattern molecules also represent strong triggers for inflammation. The mediators resulting from this inflammatory process modulate specific intracellular signalling mechanisms in cardiac cells that promote the development of diabetic cardiomyopathy. This review article will provide an overview of the signalling molecular mechanisms linking diabetic cardiomyopathy to myocardial inflammation.

Tibial Osteomyelitis Following Prehospital Intraosseous Access.

Intraosseous (IO) access is a lifesaving alternative to peripheral or central venous access in emergency care. However, emergency physicians and prehospital care providers must be aware of the potential for infectious complications associated with this intervention. We describe the case of a HIV-negative, otherwise immunocompetent adult patient who underwent prehospital insertion of a tibial IO device. Following successful resuscitation, the patient developed tibial osteomyelitis requiring multiple operative debridements, soft tissue coverage, and several courses of prolonged antimicrobial therapy. Skin antisepsis prior to device insertion followed by early device removal are important strategies for reducing the risk of infection associated with IO access.

mTORC2 regulates cardiac response to stress by inhibiting MST1.

The mTOR and Hippo pathways have recently emerged as the major signaling transduction cascades regulating organ size and cellular homeostasis. However, direct crosstalk between two pathways is yet to be determined. Here, we demonstrate that mTORC2 is a direct negative regulator of the MST1 kinase, a key component of the Hippo pathway. mTORC2 phosphorylates MST1 at serine 438 in the SARAH domain, thereby reducing its homodimerization and activity. We found that Rictor/mTORC2 preserves cardiac structure and function by restraining the activity of MST1 kinase. Cardiac-specific mTORC2 disruption through Rictor deletion leads to a marked activation of MST1 that, in turn, promotes cardiac dysfunction and dilation, impairing cardiac growth and adaptation in response to pressure overload. In conclusion, our study demonstrates the existence of a direct crosstalk between mTORC2 and MST1 that is critical for cardiac cell survival and growth.

Role of NADPH oxidase in the regulation of autophagy in cardiomyocytes.

In the past several years, it has been demonstrated that the reactive oxygen species (ROS) may act as intracellular signalling molecules to activate or inhibit specific signalling pathways and regulate physiological cellular functions. It is now well-established that ROS regulate autophagy, an intracellular degradation process. However, the signalling mechanisms through which ROS modulate autophagy in a regulated manner have only been minimally clarified. NADPH oxidase (Nox) enzymes are membrane-bound enzymatic complexes responsible for the dedicated generation of ROS. Different isoforms of Nox exist with different functions. Recent studies demonstrated that Nox-derived ROS can promote autophagy, with Nox2 and Nox4 representing the isoforms of Nox implicated thus far. Nox2- and Nox4-dependent autophagy plays an important role in the elimination of pathogens by phagocytes and in the regulation of vascular- and cancer-cell survival. Interestingly, we recently found that Nox is also important for autophagy regulation in cardiomyocytes. We found that Nox4, but not Nox2, promotes the activation of autophagy and survival in cardiomyocytes in response to nutrient deprivation and ischaemia through activation of the PERK (protein kinase RNA-like endoplasmic reticulum kinase) signalling pathway. In the present paper, we discuss the importance of Nox family proteins and ROS in the regulation of autophagy, with a particular focus on the role of Nox4 in the regulation of autophagy in the heart.

The importance of autophagy in cardioprotection.

Autophagy is an intracellular lysosomal-mediated catabolic process in which senescent or damaged proteins and organelles are sequestered by double membrane-limited vesicles called autophagosomes, and then degraded by lysosomes. While the role of autophagy in different pathological states is context-dependent, it has been shown that during cardiac ischemia, autophagy is upregulated as a cardioprotective adaptation. We recently demonstrated that Rheb, a small GTP-binding protein that directly activates the complex 1 of the mechanistic target of rapamycin, is a critical regulator of autophagy during cardiac ischemia. We found that cardiac Rheb/mTORC1 signaling is activated in a deregulated manner during ischemia in obesity and metabolic syndrome. This uncontrolled activation of the Rheb/mTORC1 pathway leads to autophagy inhibition and to a reduction of myocardial tolerance to ischemia. This data further supports the relevance of autophagy as a fundamental protective mechanism during myocardial ischemia and suggests that reactivation of autophagy, in particular through the inhibition of Rheb/mTORC1 signaling may represent a promising therapeutic option to treat subjects with an acute myocardial infarction, particularly those affected by metabolic derangements. This review will deal with the biological significance of autophagy in cardioprotection.

Hyaluronic Acid hydrogels support cord-like structures from endothelial colony-forming cells.

The generation of functional vascular networks has the potential to improve treatment for vascular diseases and to facilitate successful organ transplantation. Endothelial colony-forming cells (ECFCs) have robust proliferative potential and can form vascular networks in vivo. ECFCs are recruited from a bone marrow niche to the site of vascularization, where cues from the extracellular matrix instigate vascular morphogenesis. Although this process has been elucidated using natural matrix, little is known about vascular morphogenesis by ECFCs in synthetic matrix, a xeno-free scaffold that can provide a more controllable and clinically relevant alternative for regenerative medicine. We sought to study hyaluronic acid (HA) hydrogels as three-dimensional scaffolds for capillary-like structure formation from ECFCs, and to determine the crucial parameters needed to design such synthetic scaffolds. We found that ECFCs express HA-specific receptors and that vascular endothelial growth factor stimulates hyaluronidase expression in ECFCs. Using a well-defined and controllable three-dimensional HA culture system, we were able to decouple the effect of matrix viscoelasticity from changes in adhesion peptide density. We determined that decreasing matrix viscoelasticity, which corresponds to a loose ultrastructure, significantly increases ECFC vascular tube length and area, and that the effect of local delivery of vascular endothelial growth factor within the hydrogel depends on the makeup of the synthetic environment. Collectively, these results set forth initial design criteria that need to be considered in developing vascularized tissue constructs.

Vascular endothelial growth factor and substrate mechanics regulate in vitro tubulogenesis of endothelial progenitor cells.

Endothelial progenitor cells (EPCs) in the circulatory system have been suggested to maintain vascular homeostasis and contribute to adult vascular regeneration and repair. These processes require that EPCs break down the extracellular matrix (ECM), migrate, differentiate and undergo tube morphogenesis. Evidently, the ECM plays a critical role by providing biochemical and biophysical cues that regulate cellular behaviour. Using a chemically and mechanically tunable hydrogel to study tube morphogenesis in vitro, we show that vascular endothelial growth factor (VEGF) and substrate mechanics co-regulate tubulogenesis of EPCs. High levels of VEGF are required to initiate tube morphogenesis and activate matrix metalloproteinases (MMPs), which enable EPC migration. Under these conditions, the elasticity of the substrate affects the progression of tube morphogenesis. With decreases in substrate stiffness, we observe decreased MMP expression while increased cellular elongation, with intracellular vacuole extension and coalescence to open lumen compartments. RNAi studies demonstrate that membrane type 1-MMP (MT1-MMP) is required to enable the movement of EPCs on the matrix and that EPCs sense matrix stiffness through signalling cascades leading to the activation of the RhoGTPase Cdc42. Collectively, these results suggest that coupled responses for VEGF stimulation and modulation of substrate stiffness are required to regulate tube morphogenesis of EPCs.