Ischaemic cardiomyopathy. Pathophysiological insights,diagnostic management and the roles of revascularisation and device treatment. Gaps and dilemmas in the era of advanced technology

Ischaemic cardiomyopathy (ICM) represents an important cardiovascular condition associated with substantially increased morbidity and mortality. It is characterised from a broad spectrum of clinical manifestations and pathophysiological substrates and its diagnosis is based on the demonstration of significant left ventricular dysfunction in the context of significant epicardial coronary artery disease. Contemporary management aims at improving prognosis through evidence‐based pharmacotherapy and device therapy, where indicated. Whilst the beneficial role of revascularisation remains clear in patients with strong indications such as those with symptoms and/or acute coronary syndromes, for those patients that are asymptomatic and suffer from stable ischaemic heart disease the impact of revascularisation on hard outcomes remains less well defined and currently its adoption is hampered by the lack of robust randomised data. The aim of this review is therefore to provide a constructive appraisal on the pathophysiology of ICM, the role of the various non‐invasive imaging techniques in the diagnosis of ICM and the differentiation between viable and non‐viable myocardium and finally discourse the potential role of revascularisation and contemporary device therapy in the management of patients with ICM.     

Cathepsin E Promotes Pulmonary Emphysema via Mitochondrial Fission

Emphysema is characterized by loss of lung elasticity and irreversible air space enlargement, usually in the later decades of life. The molecular mechanisms of emphysema remain poorly defined. We identified a role for a novel cathepsin, cathepsin E, in promoting emphysema by inducing mitochondrial fission. Unlike previously reported cysteine cathepsins, which have been implicated in cigarette smoke-induced lung disease, cathepsin E is a nonlysosomal intracellular aspartic protease whose function has been described only in antigen processing. We examined lung tissue sections of persons with chronic obstructive pulmonary disease, a clinical entity that includes emphysematous change. Human chronic obstructive pulmonary disease lungs had markedly increased cathepsin E protein in the lung epithelium. We generated lung epithelial-targeted transgenic cathepsin E mice and found that they develop emphysema. Overexpression of cathepsin E resulted in increased E3 ubiquitin ligase parkin, mitochondrial fission protein dynamin-related protein 1, caspase activation/apoptosis, and ultimately loss of lung parenchyma resembling emphysema. Inhibiting dynamin-related protein 1, using a small molecule inhibitor in vitro or in vivo, inhibited cathepsin E-induced apoptosis and emphysema. To the best of our knowledge, our study is the first to identify links between cathepsin E, mitochondrial fission, and caspase activation/apoptosis in the pathogenesis of pulmonary emphysema. Our data expand the current understanding of molecular mechanisms of emphysema development and may provide new therapeutic targets.Emphysema is a major subset of chronic obstructive pulmonary disease (COPD) and is defined anatomically as the destruction of the distal lung parenchyma and enlargement of the air spaces. Pulmonary emphysema is one of the main causes of morbidity and death worldwide. The most studied factor in developing COPD has long been recognized to be cigarette smoking. However, only 10% to 20% of heavy smokers develop clinically significant COPD.^1,2 Importantly, recent studies indicate that complementary pathogenic mechanisms, such as proteolytic/antiproteolytic imbalance, oxidative stress, apoptosis, or altered innate immunity, are involved in the development and progression of alveolar destruction.^3–6Cathepsins have been implicated in mediating alveolar destruction via their proteolytic activity. Cathepsins are intracellular hydrolases and include serine proteases (cathepsins A and G), aspartic proteases (cathepsins D and E), and cysteine cathepsins (cathepsins B, C, F, H, K, L, O, S, V, X, and W). Cathepsin E (Cat E), a nonlysosomal intracellular aspartic protease, is homologous to aspartic protease cathepsin D, a major proteolytic activity in the lysosomal component.⁷ Recent studies have reported that Cat E plays an important role in antigen processing via the major histocompatibility complex class II pathway, host defense against cancer cells and invading microorganisms, gastric differentiation, and development of signet-ring cell carcinoma.^8–12 However, Cat E has not been linked to lung disease.Human lung sections from persons with COPD indicated increased expression of Cat E protein in the lung epithelial cells. To investigate if increased expression of lung epithelial Cat E could lead to emphysema, we generated lung-targeted constitutive and inducible Cat E transgenic (Tg) mice. Our data indicated that inducible Cat E Tg mice developed emphysema-like lung changes as early as 1 week. We noted robust caspase 3 activation, and, when mice were administered a caspase inhibitor, emphysema was prevented. To our surprise, we did not find changes in caspases usually associated with caspase 3 activation, such as caspases 8 and 9, in Cat E Tg mice. Instead, we found significant induction of a mitochondrial fission protein, dynamin-related protein 1 (Drp1). When we inhibited Drp1 in Cat E Tg mice with Mdivi-1, a small molecule Drp1 inhibitor, we completely abolished the development of emphysema. Collectively, our data indicate that increased Cat E is a clinically relevant finding in human COPD and invoke a novel role for Cat E in mitochondrial fission-induced emphysema.     

Managing Uncertainty: Healthcare Professionals' Meanings Regarding the HPV Vaccine

Background

New preventive technologies such as vaccines offer insight into psychological, social, and cultural landscapes. Providers have a key role in parents' decisions for vaccinating their children. Yet, perspectives from providers regarding the human papillomavirus (HPV) vaccine, or vaccination in general, are rarely sought

Purpose

Our objective in this paper is to understand how the HPV vaccine is perceived by health care providers and the multiple contextual meanings it elicits.

Methods

We conducted interviews with 20 health care professionals in Bulgaria about their attitudes and practices related to HPV vaccination and their recommendations for policies. The verbatim-transcribed interviews were analyzed through narrative analysis, with a special focus on language.

Results

We illustrate providers' contradictory and contextualized constructions of the vaccine and the narrative strategies they use to manage any uncertainty it elicits. These include being advocates and missionaries for preventive health, confirming their trust in the medical profession and professional organizations, challenging patients' concerns with rational explanations, normalizing the risk of medical innovations, and avoiding the sexual nature of HPV transmission.

Conclusions

The introduction of a vaccine to prevent HPV infection, and by implication, possibly cervical and other cancers, created hope, and at the same time, intensified confusion and uncertainty. Providers have been frustrated for years with the rising mortality from cervical cancer in Bulgaria, and their perceived powerlessness in affecting this. HPV vaccination, on the other hand, seems relatively simple and “taming uncertainty” positions them as instrumental in limiting (or even eliminating) morbidity and mortality in future generations.     

Increased lipolysis and altered lipid homeostasis protect γ-synuclein–null mutant mice from diet-induced obesity

Synucleins are a family of homologous proteins principally known for their involvement in neurodegeneration. γ-Synuclein is highly expressed in human white adipose tissue and increased in obesity. Here we show that γ-synuclein is nutritionally regulated in white adipose tissue whereas its loss partially protects mice from high-fat diet (HFD)–induced obesity and ameliorates some of the associated metabolic complications. Compared with HFD-fed WT mice, HFD-fed γ-synuclein–null mutant mice display increased lipolysis, lipid oxidation, and energy expenditure, and reduced adipocyte hypertrophy. Knockdown of γ-synuclein in adipocytes causes redistribution of the key lipolytic enzyme ATGL to lipid droplets and increases lipolysis. γ-Synuclein–deficient adipocytes also contain fewer SNARE complexes of a type involved in lipid droplet fusion. We hypothesize that γ-synuclein may deliver SNAP-23 to the SNARE complexes under lipogenic conditions. Via these independent but complementary roles, γ-synuclein may coordinately modulate lipid storage by influencing lipolysis and lipid droplet formation. Our data reveal γ-synuclein as a regulator of lipid handling in adipocytes, the function of which is particularly important in conditions of nutrient excess.Understanding the link between increased adiposity and the development of metabolic disease may reveal novel therapeutic targets to counter the rising pandemic of obesity. Inhibiting adipose tissue expansion alone is likely to worsen metabolic outcome, as evidenced by human syndromes of lipodystrophy, whereby inappropriately decreased adipose mass causes severe metabolic disorders (1). Indeed, adipose tissue dysfunction and/or exceeded adipose storage capacity may underlie ectopic lipid accumulation and lipotoxicity in obesity (2). Therefore, a major challenge is to identify pathways via which adiposity can be reduced without concomitant increases in circulating lipids and attendant metabolic disease. Achieving this goal requires a better understanding of the molecular mechanisms that regulate lipid metabolism and storage in adipocytes, particularly in times of energy surplus.γ-Synuclein belongs to the synuclein family of proteins, whose founder member α-synuclein is best known for its links with neurodegenerative diseases, most notably Parkinson disease (3). To date, no clear cellular role is attributed to γ-synuclein, and ablation of γ-synuclein causes only minor changes in the nervous system (4–7). Recently, we and others have reported high levels of γ-synuclein expression in adipose tissue of humans and other mammals (8, 9). Moreover, expression of γ-synuclein is increased in the adipose tissue of obese humans and decreased during caloric restriction (8).Here we demonstrate that γ-synuclein–null mice display significantly reduced adiposity and fewer metabolic derangements compared with WT mice following high-fat feeding. This appears to result from increased adipocyte lipolysis coupled to enhanced whole-body lipid oxidation and energy expenditure. At a molecular level, we identify dual roles for γ-synuclein independently regulating lipid droplet fusion and adipocyte lipolysis to coordinately regulate triglyceride (TG) storage in adipocytes. Together, our observations reveal that γ-synuclein is a regulator of lipid metabolism and, hence, a potential therapeutic target for treatment of obesity and associated metabolic diseases.