Immunometabolic cross-talk in the inflamed heart.

Inflammatory processes underlie many diseases associated with injury of the heart muscle, including conditions without an obvious inflammatory pathogenic component such as hypertensive and diabetic cardiomyopathy. Persistence of cardiac inflammation can cause irreversible structural and functional deficits. Some are induced by direct damage of the heart muscle by cellular and soluble mediators but also by metabolic adaptations sustained by the inflammatory microenvironment. It is well established that both cardiomyocytes and immune cells undergo metabolic reprogramming in the site of inflammation, which allow them to deal with decreased availability of nutrients and oxygen. However, like in cancer, competition for nutrients and increased production of signalling metabolites such as lactate initiate a metabolic cross-talk between immune cells and cardiomyocytes which, we propose, might tip the balance between resolution of the inflammation versus adverse cardiac remodeling. Here we review our current understanding of the metabolic reprogramming of both heart tissue and immune cells during inflammation, and we discuss potential key mechanisms by which these metabolic responses intersect and influence each other and ultimately define the prognosis of the inflammatory process in the heart

Naked mole-rats have distinctive cardiometabolic and genetic adaptations to their underground low-oxygen lifestyles.

The naked mole-rat Heterocephalus glaber is a eusocial mammal exhibiting extreme longevity (37-year lifespan), extraordinary resistance to hypoxia and absence of cardiovascular disease. To identify the mechanisms behind these exceptional traits, metabolomics and RNAseq of cardiac tissue from naked mole-rats was compared to other African mole-rat genera (Cape, Cape dune, Common, Natal, Mahali, Highveld and Damaraland mole-rats) and evolutionarily divergent mammals (Hottentot golden mole and C57/BL6 mouse). We identify metabolic and genetic adaptations unique to naked mole-rats including elevated glycogen, thus enabling glycolytic ATP generation during cardiac ischemia. Elevated normoxic expression of HIF-1α is observed while downstream hypoxia responsive-genes are down-regulated, suggesting adaptation to low oxygen environments. Naked mole-rat hearts show reduced succinate levels during ischemia compared to C57/BL6 mouse and negligible tissue damage following ischemia-reperfusion injury. These evolutionary traits reflect adaptation to a unique hypoxic and eusocial lifestyle that collectively may contribute to their longevity and health span

Algorithmic Complexity for Short Binary Strings Applied to Psychology: A Primer

Since human randomness production has been studied and widely used to assess executive functions (especially inhibition), many measures have been suggested to assess the degree to which a sequence is random-like. However, each of them focuses on one feature of randomness, leading authors to have to use multiple measures. Here we describe and advocate for the use of the accepted universal measure for randomness based on algorithmic complexity, by means of a novel previously presented technique using the the definition of algorithmic probability. A re-analysis of the classical Radio Zenith data in the light of the proposed measure and methodology is provided as a study case of an application.Comment: To appear in Behavior Research Method

Ischaemic accumulation of succinate controls reperfusion injury through mitochondrial ROS.

Ischaemia-reperfusion injury occurs when the blood supply to an organ is disrupted and then restored, and underlies many disorders, notably heart attack and stroke. While reperfusion of ischaemic tissue is essential for survival, it also initiates oxidative damage, cell death and aberrant immune responses through the generation of mitochondrial reactive oxygen species (ROS). Although mitochondrial ROS production in ischaemia reperfusion is established, it has generally been considered a nonspecific response to reperfusion. Here we develop a comparative in vivo metabolomic analysis, and unexpectedly identify widely conserved metabolic pathways responsible for mitochondrial ROS production during ischaemia reperfusion. We show that selective accumulation of the citric acid cycle intermediate succinate is a universal metabolic signature of ischaemia in a range of tissues and is responsible for mitochondrial ROS production during reperfusion. Ischaemic succinate accumulation arises from reversal of succinate dehydrogenase, which in turn is driven by fumarate overflow from purine nucleotide breakdown and partial reversal of the malate/aspartate shuttle. After reperfusion, the accumulated succinate is rapidly re-oxidized by succinate dehydrogenase, driving extensive ROS generation by reverse electron transport at mitochondrial complex I. Decreasing ischaemic succinate accumulation by pharmacological inhibition is sufficient to ameliorate in vivo ischaemia-reperfusion injury in murine models of heart attack and stroke. Thus, we have identified a conserved metabolic response of tissues to ischaemia and reperfusion that unifies many hitherto unconnected aspects of ischaemia-reperfusion injury. Furthermore, these findings reveal a new pathway for metabolic control of ROS production in vivo, while demonstrating that inhibition of ischaemic succinate accumulation and its oxidation after subsequent reperfusion is a potential therapeutic target to decrease ischaemia-reperfusion injury in a range of pathologies

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

The potential for ischemic preconditioning to reduce infarct size was first recognized more than 30 years ago. Despite extension of the concept to ischemic postconditioning and remote ischemic conditioning and literally thousands of experimental studies in various species and models which identified a multitude of signaling steps, so far there is only a single and very recent study, which has unequivocally translated cardioprotection to improved clinical outcome as the primary endpoint in patients. Many potential reasons for this disappointing lack of clinical translation of cardioprotection have been proposed, including lack of rigor and reproducibility in preclinical studies, and poor design and conduct of clinical trials. There is, however, universal agreement that robust preclinical data are a mandatory prerequisite to initiate a meaningful clinical trial. In this context, it is disconcerting that the CAESAR consortium (Consortium for preclinicAl assESsment of cARdioprotective therapies) in a highly standardized multi-center approach of preclinical studies identified only ischemic preconditioning, but not nitrite or sildenafil, when given as adjunct to reperfusion, to reduce infarct size. However, ischemic preconditioning—due to its very nature—can only be used in elective interventions, and not in acute myocardial infarction. Therefore, better strategies to identify robust and reproducible strategies of cardioprotection, which can subsequently be tested in clinical trials must be developed. We refer to the recent guidelines for experimental models of myocardial ischemia and infarction, and aim to provide now practical guidelines to ensure rigor and reproducibility in preclinical and clinical studies on cardioprotection. In line with the above guideline, we define rigor as standardized state-of-the-art design, conduct and reporting of a study, which is then a prerequisite for reproducibility, i.e. replication of results by another laboratory when performing exactly the same experiment

Is rate-pressure product of any use in the isolated rat heart? Assessing cardiac "effort' and oxygen consumption in the Langendorff-perfused heart

This work was supported by a British Heart Foundation Programme Grant (RG/12/4/29426) to M.J.S. and a British Heart Foundation 4 year MRes/PhD studentship (FS/13/55/30643) toH.R.L

Senescence and Type 2 Diabetic Cardiomyopathy: How Young Can You Die of Old Age?

Inflammation is well understood to be a physiological process of ageing however it also underlies many chronic diseases, including conditions without an obvious pathogenic inflammatory element. Recent findings have unequivocally identified type 2 diabetes (T2D) as a chronic inflammatory disease characterized by inflammation and immune senescence. Immunosenescence is a hallmark of the prolonged low-grade systemic inflammation, in particular associated with metabolic syndrome and can be a cause as well as a consequence of T2D. Diabetes is a risk factor for cardiovascular mortality and remodelling and with particular changes to myocardial structure, function, metabolism and energetics collectively resulting in diabetic cardiomyopathy. Both cardiomyocytes and immune cells undergo metabolic remodelling in T2D and as a result become trapped in a vicious cycle of lost metabolic flexibility, thus losing their key adaptive mechanisms to dynamic changes in O(2) and nutrient availability. Immunosenescence driven by metabolic stress may be both the cause and key contributing factor to cardiac dysfunction in diabetic cardiomyopathy by inducing metabolic perturbations that can lead to impaired energetics, a strong predictor of cardiac mortality. Here we review our current understanding of the cross-talk between inflammaging and cardiomyocytes in T2D cardiomyopathy. We discuss potential mechanisms of metabolic convergence between cell types which, we hypothesize, might tip the balance between resolution of the inflammation versus adverse cardiac metabolic remodelling in T2D cardiomyopathy. A better understanding of the multiple biological paradigms leading to T2D cardiomyopathy including the immunosenescence associated with inflammaging will provide a powerful target for successful therapeutic interventions

Artificial intelligence in cardiology: Hope for the future and power for the present

Cardiovascular disease (CVD) is the principal cause of mortality and morbidity globally. With the pressures for improved care and translation of the latest medical advances and knowledge to an actionable plan, clinical decision-making for cardiologists is challenging. Artificial Intelligence (AI) is a field in computer science that studies the design of intelligent agents which take the best feasible action in a situation. It incorporates the use of computational algorithms which simulate and perform tasks that traditionally require human intelligence such as problem solving and learning. Whilst medicine is arguably the last to apply AI in its everyday routine, cardiology is at the forefront of AI revolution in the medical field. The development of AI methods for accurate prediction of CVD outcomes, non-invasive diagnosis of coronary artery disease (CAD), detection of malignant arrythmias through wearables, and diagnosis, treatment strategies and prediction of outcomes for heart failure (HF) patients, demonstrates the potential of AI in future cardiology. With the advancements of AI, Internet of Things (IoT) and the promotion of precision medicine, the future of cardiology will be heavily based on these innovative digital technologies. Despite this, ethical dilemmas regarding the implementation of AI technologies in real-world are still unaddressed