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This volume contains lectures on leading-edge research in methods and tools for use in computer system engineering; at the 4th International School on Engineering Trustworthy Software Systems, SETSS 2018, held in April 2018 at Southwest University in Chongqing, China. The five chapters in this volume provide an overview of research in the frontier of theories, methods, and tools for software modelling, design, and verification. The topics covered in these chapter include Software Verification with Whiley, Learning Büchi Automata and Its Applications, Security in IoT Applications, Programming in Z3, and The Impact of Alan Turing: Formal Methods and Beyond. The volume provides a useful resource for postgraduate students, resarchers, academics, and engineers in industry, who are interested in theory, methods, and tools for the development of trustworthy software.

Fibrosis is the abnormal deposition of extracellular matrix, which can lead to organ dysfunction, morbidity, and death. The disease burden caused by fibrosis is substantial, and there are currently no therapies that can prevent or reverse fibrosis. Metabolic alterations are increasingly recognized as an important pathogenic process that underlies fibrosis across many organ types. As a result, metabolically targeted therapies could become important strategies for fibrosis reduction. Indeed, some of the pathways targeted by antifibrotic drugs in development — such as the activation of transforming growth factor-β and the deposition of extracellular matrix — have metabolic implications. This Review summarizes the evidence to date and describes novel opportunities for the discovery and development of drugs for metabolic reprogramming, their associated challenges, and their utility in reducing fibrosis. Fibrotic therapies are potentially relevant to numerous common diseases such as cirrhosis, non-alcoholic steatohepatitis, chronic renal disease, heart failure, diabetes, idiopathic pulmonary fibrosis, and scleroderma.

Key Points Cardiac injury can lead to cardiomyocyte death, intense inflammation, scar formation and, over time, adverse cardiac remodelling. Following injury, cardiac inflammation is triggered by the release of conserved endogenous molecules and the production of pro-inflammatory cytokines and chemokines that lead to cellular infiltration. Early activation of mast cells leads to neutrophil recruitment, a robust inflammatory response and tissue damage. Recruited monocytes and resident macrophages modulate both tissue injury and tissue healing. Macrophage origin may dictate function in the heart. Primitive embryonically derived macrophages mediate cardiac tissue repair, whereas bone marrow-derived monocytes contribute to inflammation following cardiac injury. Lymphocytes and macrophages are involved in the complex transition from initial cardiac tissue inflammation to wound healing. This Review describes the immune responses that occur in the heart, explaining how different innate and adaptive immune cell populations can have beneficial or detrimental roles during cardiac tissue injury. In particular, the authors focus on the unique macrophage subsets that are found in the heart and their roles in regenerating damaged cardiac tissue. Despite the advances that have been made in developing new therapeutics, cardiovascular disease remains the leading cause of worldwide mortality. Therefore, understanding the mechanisms underlying cardiovascular tissue injury and repair is of prime importance. Following cardiac tissue injury, the immune system has an important and complex role in driving both the acute inflammatory response and the regenerative response. This Review summarizes the role of the immune system in cardiovascular disease — focusing on the idea that the immune system evolved to promote tissue homeostasis following injury and/or infection, and that the inherent cost of this evolutionary development is unwanted inflammatory damage.

Key Points Medical 3D printing refers to the fabrication of anatomical structures, typically derived from volumetric medical image data, and enables visual inspection and direct manipulation of hand-held models of human anatomy and pathology In cardiovascular 3D printing, advanced modern imaging such CT and MR is combined with dedicated 3D printing software and hardware Cardiovascular 3D printing enhances the diagnostic work-up of complex cardiovascular diseases, as well as surgical and interventional procedural planning and simulation 3D printing improves patient engagement in understanding their own diseases and participating in their own decision-making, and improves communication with patients and their families Widespread adoption of 3D printing is currently limited by the lack of robust evidence that systematically demonstrates effectiveness, and by the high costs and workflow complexity Cardiovascular 3D bioprinting and molecular 3D printing — which combine advanced manufacturing, cell biology, molecular biomarkers, and materials science — have not yet translated into clinical practice, but hold great promise for the future 3D printing applications for cardiovascular care range from models for education to planning and simulation of interventions and the generation of implantable devices. This Review summarizes the current cardiovascular 3D printing strategies and applications, including the workflow from image acquisition to the generation of a hand-held model, and highlights the future perspectives of cardiovascular 3D printing. 3D-printed models fabricated from CT, MRI, or echocardiography data provide the advantage of haptic feedback, direct manipulation, and enhanced understanding of cardiovascular anatomy and underlying pathologies. Reported applications of cardiovascular 3D printing span from diagnostic assistance and optimization of management algorithms in complex cardiovascular diseases, to planning and simulating surgical and interventional procedures. The technology has been used in practically the entire range of structural, valvular, and congenital heart diseases, and the added-value of 3D printing is established. Patient-specific implants and custom-made devices can be designed, produced, and tested, thus opening new horizons in personalized patient care and cardiovascular research. Physicians and trainees can better elucidate anatomical abnormalities with the use of 3D-printed models, and communication with patients is markedly improved. Cardiovascular 3D bioprinting and molecular 3D printing, although currently not translated into clinical practice, hold revolutionary potential. 3D printing is expected to have a broad influence in cardiovascular care, and will prove pivotal for the future generation of cardiovascular imagers and care providers. In this Review, we summarize the cardiovascular 3D printing workflow, from image acquisition to the generation of a hand-held model, and discuss the cardiovascular applications and the current status and future perspectives of cardiovascular 3D printing.

Myocarditis is an underdiagnosed cause of acute heart failure, sudden death, and chronic dilated cardiomyopathy. In developed countries, viral infections commonly cause myocarditis; however, in the developing world, rheumatic carditis, Trypanosoma cruzi, and bacterial infections such as diphtheria still contribute to the global burden of the disease. The short-term prognosis of acute myocarditis is usually good, but varies widely by cause. Those patients who initially recover might develop recurrent dilated cardiomyopathy and heart failure, sometimes years later. Because myocarditis presents with non-specific symptoms including chest pain, dyspnoea, and palpitations, it often mimics more common disorders such as coronary artery disease. In some patients, cardiac MRI and endomyocardial biopsy can help identify myocarditis, predict risk of cardiovascular events, and guide treatment. Finding effective therapies has been challenging because the pathogenesis of chronic dilated cardiomyopathy after viral myocarditis is complex and determined by host and viral genetics as well as environmental factors. Findings from recent clinical trials suggest that some patients with chronic inflammatory cardiomyopathy have a progressive clinical course despite standard medical care and might improve with a short course of immunosuppression.

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter–defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment. Dilated cardiomyopathy (DCM) is characterized by ventricular enlargement and impaired contractility without an underlying ischaemic origin. DCM has heterogeneous aetiologies (including gene mutations, infections and inflammation) and clinical presentations and can eventually result in heart failure.

Angiotensin converting enzyme 2 (ACE2) is a negative regulator of the renin-angiotensin system (RAS), catalyzing the conversion of Angiotensin II to Angiotensin 1-7. Apelin is a second catalytic substrate for ACE2 and functions as an inotropic and cardioprotective peptide. While an antagonistic relationship between the RAS and apelin has been proposed, such functional interplay remains elusive. Here we found that ACE2 was downregulated in apelin-deficient mice. Pharmacological or genetic inhibition of angiotensin II type 1 receptor (AT1R) rescued the impaired contractility and hypertrophy of apelin mutant mice, which was accompanied by restored ACE2 levels. Importantly, treatment with angiotensin 1-7 rescued hypertrophy and heart dysfunctions of apelin-knockout mice. Moreover, apelin, via activation of its receptor, APJ, increased ACE2 promoter activity in vitro and upregulated ACE2 expression in failing hearts in vivo. Apelin treatment also increased cardiac contractility and ACE2 levels in AT1R-deficient mice. These data demonstrate that ACE2 couples the RAS to the apelin system, adding a conceptual framework for the apelin-ACE2-angiotensin 1-7 axis as a therapeutic target for cardiovascular diseases.

The development of cardiac hypertrophy in response to increased hemodynamic load and neurohormonal stress is initially a compensatory response that may eventually lead to ventricular dilation and heart failure. Regulator of G protein signaling 5 (Rgs5) is a negative regulator of G protein-mediated signaling by inactivating Gα(q) and Gα(i), which mediate actions of most known vasoconstrictors. Previous studies have demonstrated that Rgs5 expresses among various cell types within mature heart and showed high levels of Rgs5 mRNA in monkey and human heart tissue by Northern blot analysis. However, the critical role of Rgs5 on cardiac remodeling remains unclear. To specifically determine the role of Rgs5 in pathological cardiac remodeling, we used transgenic mice with cardiac-specific overexpression of human Rgs5 gene and Rgs5⁻ / ⁻ mice. Our results demonstrated that the transgenic mice were resistant to cardiac hypertrophy and fibrosis through inhibition of MEK-ERK1/2 signaling, whereas the Rgs5⁻ / ⁻ mice displayed the opposite phenotype in response to pressure overload. These studies indicate that Rgs5 protein is a crucial component of the signaling pathway involved in cardiac remodeling and heart failure.

To date, treatment strategies for heart failure have focused on the symptomatic stage of disease, often after irreversible remodeling and functional impairment have occurred. Early identification of cardiac dysfunction would allow implementation of early intervention strategies to delay the progression or to prevent the onset of heart failure altogether. This Review highlights the utility of a staged approach for patients with predisposing risk factors, which uses serological biomarkers followed by noninvasive imaging techniques. The impact of cardiac dysfunction and heart failure is continuing to escalate in the developed world. Treatment of this heterogeneous condition has focused on the symptomatic stage, often after irreversible remodeling and functional impairment have occurred. Early identification of cardiac dysfunction would allow implementation of early intervention strategies to delay the progression or to prevent the onset of heart failure altogether. Although screening methods for asymptomatic cardiac dysfunction have yet to be optimized, a staged approach for patients with predisposing risk factors using serological biomarkers followed by noninvasive imaging techniques may be useful. Existing biomarkers for cardiac dysfunction include B-type natriuretic peptide, troponins, and C-reactive protein. Novel markers such as protein ST2, galectin-3, and various prohormones are emerging and may provide prognostic information that is incremental to conventional clinical evaluation. Monitoring myocardial mechanics and molecular processes through three-dimensional speckle tracking and hybrid imaging modalities, such as PET–CT, may provide insight into disease manifestation before overt structural and physiological abnormalities. Key Points The increase in the prevalence of heart failure and its late symptomatic presentation require novel approaches to assist in the early detection of myocardial dysfunction Novel serological biomarkers are emerging as independent predictors of adverse outcomes and contribute incremental prognostic information to traditional risk factors and B-type natriuretic peptide levels in heart failure Imaging tools that assess myocardial mechanics and molecular processes provide improved sensitivity and specificity for disease identification and progression A tandem approach using multiple representative biomarkers with molecular or multimodal imaging tools may provide additional risk stratification and evaluation of disease

Heart failure (HF) is a rising global cardiovascular epidemic driven by aging and chronic inflammation. As elderly populations continue to increase, precision treatments for age-related cardiac decline are urgently needed. Here we report that cardiac and blood expression of IGFBP7 is robustly increased in patients with chronic HF and in an HF mouse model. In a pressure overload mouse HF model, Igfbp7 deficiency attenuated cardiac dysfunction by reducing cardiac inflammatory injury, tissue fibrosis and cellular senescence. IGFBP7 promoted cardiac senescence by stimulating IGF-1R/IRS/AKT-dependent suppression of FOXO3a, preventing DNA repair and reactive oxygen species (ROS) detoxification, thereby accelerating the progression of HF. In vivo, AAV9-shRNA-mediated cardiac myocyte Igfbp7 knockdown indicated that myocardial IGFBP7 directly regulates pathological cardiac remodeling. Moreover, antibody-mediated IGFBP7 neutralization in vivo reversed IGFBP7-induced suppression of FOXO3a, restored DNA repair and ROS detoxification signals and attenuated pressure-overload-induced HF in mice. Consequently, selectively targeting IGFBP7-regulated senescence pathways may have broad therapeutic potential for HF.