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Pre‐clinical studies aimed at treating ischemic heart disease (i.e. stem cell‐ and growth factor therapy) often consider restoration of the impaired microvascular circulation as an important treatment goal. However, serial in vivo measurement hereof is often lacking. The purpose of this study was to evaluate the applicability of intracoronary pressure and flow velocity as a measure of microvascular resistance in a large animal model of chronic myocardial infarction (MI). Myocardial infarction was induced in Dalland Landrace pigs (n = 13; 68.9 ± 4.1 kg) by a 75‐min. balloon occlusion of the left circumflex artery (LCX). Intracoronary pressure and flow velocity parameters were measured simultaneously at rest and during adenosine‐induced hyperemia, using the Combowire (Volcano) before and 4 weeks after MI. Various pressure‐ and/or flow‐derived indices were evaluated. Hyperemic microvascular resistance (HMR) was significantly increased by 28% in the infarct‐related artery, based on a significantly decreased peak average peak flow velocity (pAPV) by 20% at 4 weeks post‐MI (P = 0.03). Capillary density in the infarct zone was decreased compared to the remote area (658 ± 207/mm2 versus 1650 ± 304/mm2, P = 0.017). In addition, arterioles in the infarct zone showed excessive thickening of the alpha smooth muscle actin (αSMA) positive cell layer compared to the remote area (33.55 ± 4.25 μm versus 14.64 ± 1.39 μm, P = 0.002). Intracoronary measurement of HMR successfully detected increased microvascular resistance that might be caused by the loss of capillaries and arteriolar remodelling in the chronic infarcted pig heart. Thus, HMR may serve as a novel outcome measure in pre‐clinical studies for serial assessment of microvascular circulation.

This chapter contains sections titled: Introduction CMR for Evaluation of Morphology and Function Sarcoidosis Congenital Heart Diseases Cardiovascular Magnetic Resonance Myocardial Perfusion Imaging CMR Perfusion Imaging Using First Pass of Contrast Agent Techniques Used in Clinical Studies CMR Myocardial Perfusion Imaging: The Future Myocardial Viability Using Cardiovascular Magnetic Resonance Imaging Future Applications of Contrast Enhanced CMR Myocardial CMR Spectroscopy: Introduction Conclusions References

In this phase 3 study involving patients with HCV genotype 1, 2, 4, 5, or 6 infection, including those with compensated cirrhosis, treatment with 12 weeks of sofosbuvir and velpatasvir resulted in a sustained virologic response in 99% of patients. The hepatitis C virus (HCV), a single-stranded RNA virus of the family Flaviviridae with six major genotypes, infects up to 150 million people worldwide. 1 , 2 Chronic HCV infection causes progressive liver fibrosis, which can lead to cirrhosis, hepatic decompensation, and hepatocellular carcinoma. 3 , 4 As many as half a million people die annually from liver disease associated with chronic HCV infection. 5 In recent years, the development of drugs that directly interfere with HCV replication has revolutionized HCV treatment. There are now effective combinations of direct-acting antiviral agents for most patients, but in choosing an appropriate regimen, clinicians must take into account . . .

Key Points Heart failure (HF) interacts with kidney disease via numerous pathophysiological pathways in both the acute and chronic setting Mounting data indicate that the complex interplay between the heart and the kidneys involves haemodynamic, (neuro)homonal and cardiovascular disease-associated mechanisms Acceleration of HF or kidney dysfunction is driven by impairment of either the heart or kidneys via mechanisms including induction of inflammation, activation of the cellular immune system, metabolic disorders, anaemia and mineral and bone disorder In an effort to differentiate respective underlying pathologies and to assess acute and/or chronic organ dysfunction over time, five subtypes of cardio-renal syndromes were proposed The absence of a standardized terminology database and the lack of studies specific to cardio-renal syndrome has hampered efforts to develop novel treatments Heart failure and kidney disease share a number of pathophysiological pathways. Here, Stefan Anker and colleagues discuss crosstalk between the heart and the kidneys, the epidemiology of heart failure and kidney dysfunction, and the treatment of cardio-renal syndromes. Heart failure (HF) is a major health-care problem and the prognosis of affected patients is poor. HF often coexists with a number of comorbidities of which declining renal function is of particular importance. A loss of glomerular filtration rate, as in acute kidney injury (AKI) or chronic kidney disease (CKD), independently predicts mortality and accelerates the overall progression of cardiovascular disease and HF. Importantly, cardiac and renal diseases interact in a complex bidirectional and interdependent manner in both acute and chronic settings. From a pathophysiological perspective, cardiac and renal diseases share a number of common pathways, including inflammatory and direct, cellular immune-mediated mechanisms; stress-mediated and (neuro)hormonal responses; metabolic and nutritional changes including bone and mineral disorder, altered haemodynamic and acid–base or fluid status; and the development of anaemia. In an effort to better understand the important crosstalk between the two organs, classifications such as the cardio-renal syndromes were developed. This classification might lead to a more precise understanding of the complex interdependent pathophysiology of cardiac and renal diseases. In light of exceptionally high mortality associated with coexisting HF and kidney disease, this Review describes important crosstalk between the heart and kidney, with a focus on HF and kidney disease in the acute and chronic settings. Underlying molecular and cellular pathomechanisms in HF, AKI and CKD are discussed in addition to current and future therapeutic approaches.

Key Points Traumatic brain injury (TBI) is caused by an external mechanical force that injures the brain parenchyma; however, most patients with mild TBI show no signs of injury on a CT scan Given that mild TBI cannot usually be diagnosed objectively, accurate fluid biomarkers would be a welcome addition to the diagnostic toolbox Repetitive mild TBI can cause progressive neurodegeneration, known as chronic traumatic encephalopathy (CTE); however, estimating the risk of CTE is difficult, and the condition cannot be diagnosed in living patients In future, biomarkers for mild TBI, postconcussive syndrome and CTE might help us predict the risk of long-term sequelae and improve our understanding of the underlying pathophysiology Brain specificity or brain-enhanced expression is an important characteristic of blood-based biomarkers for mild TBI and related conditions, as extracerebral sources for biomarker molecules can compromise the interpretability of the test results In mild TBI, fluid biomarkers for axonal injury and astroglial activation show the greatest promise at the moment, and several other promising biomarker candidates exist Owing to a lack of objective diagnostic tools, the diagnosis of mild traumatic brain injury (TBI) and related conditions, such as postconcussive syndrome and chronic traumatic encephalopathy must be made on clinical grounds. Here, Zetterberg and Blennow review the most recent developments in search for biomarkers for mild TBI and related conditions. Diagnostic and prognostic biomarkers for mild traumatic brain injury (TBI), also known as concussion, remain a major unmet clinical need. Moderate to severe TBI can be diagnosed definitively by clinical assessment and standard neuroimaging techniques that detect the gross damage to the brain parenchyma. Diagnostic tools for mild TBI are lacking and, currently, the diagnosis has to be made on clinical grounds alone, because most patients show no gross pathological changes on CT. Most patients with mild TBI recover quickly, but about 15% develop an ill-defined condition called postconcussive syndrome (PCS). Repeated concussions have been associated with a chronic neurodegenerative disorder called chronic traumatic encephalopathy (CTE), which can only currently be diagnosed post mortem . Fluid biomarkers are needed to better define and detect mild TBI and related conditions. Here, we review the literature on fluid biomarkers for neuronal, axonal, oligodendrocytic, astroglial and blood–brain barrier injury, as well as markers for neuroinflammation and metabolic dysregulation, in the context of mild TBI, PCS and CTE. We also discuss technical and standardization issues and potential pathways to advance the most promising biomarker candidates into clinical laboratory practice.

Key Points Circulating alkaline phosphatase (ALP) is a robust and independent predictor of all-cause mortality in the general population and in patients with chronic kidney disease (CKD) Tissue-nonspecific ALP (TNALP) is the most abundant ALP isozyme in the body, comprising >90% of circulating ALP; functional differences between bone ALP (BALP) and liver TNALP are the result of post-translational glycosylation BALP promotes tissue mineralization by inactivating calcification inhibitors and by supplying phosphate Liver ALP and intestinal ALP (IALP) contribute to the immune response through dephosphorylation of circulating endotoxins Modulation of ALP is a potential novel treatment strategy that might reduce vascular calcification and improve cardiovascular outcomes in patients with CKD or diabetes mellitus type 2 Alkaline phosphatase (ALP) drives skeletal mineralization and has a role in vascular calcification and resulting cardiovascular disease in patients with CKD. Here, the authors describe the mechanisms of ALP-mediated vascular calcification and discuss the therapeutic potential of targeting ALP to improve cardiovascular outcomes in these patients. Cardiovascular disease is the main cause of early death in the settings of chronic kidney disease (CKD), type 2 diabetes mellitus (T2DM), and ageing. Cardiovascular events can be caused by an imbalance between promoters and inhibitors of mineralization, which leads to vascular calcification. This process is akin to skeletal mineralization, which is carefully regulated and in which isozymes of alkaline phosphatase (ALP) have a crucial role. Four genes encode ALP isozymes in humans. Intestinal, placental and germ cell ALPs are tissue-specific, whereas the tissue-nonspecific isozyme of ALP (TNALP) is present in several tissues, including bone, liver and kidney. TNALP has a pivotal role in bone calcification. Experimental overexpression of TNALP in the vasculature is sufficient to induce vascular calcification, cardiac hypertrophy and premature death, mimicking the cardiovascular phenotype often found in CKD and T2DM. Intestinal ALP contributes to the gut mucosal defence and intestinal and liver ALPs might contribute to the acute inflammatory response to endogenous or pathogenic stimuli. Here we review novel mechanisms that link ALP to vascular calcification, inflammation, and endothelial dysfunction in kidney and cardiovascular diseases. We also discuss new drugs that target ALP, which have the potential to improve cardiovascular outcomes without inhibiting skeletal mineralization.

Macrophages (Mø) are integral in ischemia/reperfusion injury-incited (I/R-incited) acute kidney injury (AKI) that leads to fibrosis and chronic kidney disease (CKD). IL-34 and CSF-1 share a receptor (c-FMS), and both cytokines mediate Mø survival and proliferation but also have distinct features. CSF-1 is central to kidney repair and destruction. We tested the hypothesis that IL-34-dependent, Mø-mediated mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD. In renal I/R, the time-related magnitude of Mø-mediated AKI and subsequent CKD were markedly reduced in IL-34-deficient mice compared with controls. IL-34, c-FMS, and a second IL-34 receptor, protein-tyrosine phosphatase ζ (PTP-ζ) were upregulated in the kidney after I/R. IL-34 was generated by tubular epithelial cells (TECs) and promoted Mø-mediated TEC destruction during AKI that worsened subsequent CKD via 2 distinct mechanisms: enhanced intrarenal Mø proliferation and elevated BM myeloid cell proliferation, which increases circulating monocytes that are drawn into the kidney by chemokines. CSF-1 expression in TECs did not compensate for IL-34 deficiency. In patients, kidney transplants subject to I/R expressed IL-34, c-FMS, and PTP-ζ in TECs during AKI that increased with advancing injury. Moreover, IL-34 expression increased, along with more enduring ischemia in donor kidneys. In conclusion, IL-34-dependent, Mø-mediated, CSF-1 nonredundant mechanisms promote persistent ischemia-incited AKI that worsens subsequent CKD.

The microbial metabolite Trimethylamine-N-oxide (TMAO) has been linked to adverse cardiovascular outcome and mortality in the general population. To assess the contribution of TMAO to inflammation and mortality in chronic kidney disease (CKD) patients ranging from mild-moderate to end-stage disease and 1) associations with glomerular filtration rate (GFR) 2) effect of dialysis and renal transplantation (Rtx) 3) association with inflammatory biomarkers and 4) its predictive value for all-cause mortality. Levels of metabolites were quantified by a novel liquid chromatography/tandem mass spectrometry-based method in fasting plasma samples from 80 controls and 179 CKD 3-5 patients. Comorbidities, nutritional status, biomarkers of inflammation and GFR were assessed. GFR was the dominant variable affecting TMAO (β = -0.41; p<0.001), choline (β = -0.38; p<0.001), and betaine (β = 0.45; p<0.001) levels. A longitudinal study of 74 CKD 5 patients starting renal replacement therapy demonstrated that whereas dialysis treatment did not affect TMAO, Rtx reduced levels of TMAO to that of controls (p<0.001). Following Rtx choline and betaine levels continued to increase. In CKD 3-5, TMAO levels were associated with IL-6 (Rho = 0.42; p<0.0001), fibrinogen (Rho = 0.43; p<0.0001) and hsCRP (Rho = 0.17; p = 0.022). Higher TMAO levels were associated with an increased risk for all-cause mortality that remained significant after multivariate adjustment (HR 4.32, 95% CI 1.32-14.2; p = 0.016). Elevated TMAO levels are strongly associated with degree of renal function in CKD and normalize after renal transplantation. TMAO levels correlates with increased systemic inflammation and is an independent predictor of mortality in CKD 3-5 patients.

Imatinib therapy, which targets the oncogene product BCR-ABL, has transformed chronic myeloid leukemia (CML) from a life-threatening disease into a chronic condition. Most patients, however, harbor residual leukemia cells, and disease recurrence usually occurs when imatinib is discontinued. Although various mechanisms to explain leukemia cell persistence have been proposed, the critical question from a therapeutic standpoint--whether disease persistence is BCR-ABL dependent or independent--has not been answered. Here, we report that human CML stem cells do not depend on BCR-ABL activity for survival and are thus not eliminated by imatinib therapy. Imatinib inhibited BCR-ABL activity to the same degree in all stem (CD34+CD38-, CD133+) and progenitor (CD34+CD38+) cells and in quiescent and cycling progenitors from newly diagnosed CML patients. Although short-term in vitro imatinib treatment reduced the expansion of CML stem/progenitors, cytokine support permitted growth and survival in the absence of BCR-ABL activity that was comparable to that of normal stem/progenitor counterparts. Our findings suggest that primitive CML cells are not oncogene addicted and that therapies that biochemically target BCR-ABL will not eliminate CML stem cells.

Imatinib-insensitive leukemia stem cells (LSCs) are believed to be responsible for resistance to BCR-ABL tyrosine kinase inhibitors and relapse of chronic myelogenous leukemia (CML). Identifying therapeutic targets to eradicate CML LSCs may be a strategy to cure CML. In the present study, we discovered a positive feedback loop between BCR-ABL and protein arginine methyltransferase 5 (PRMT5) in CML cells. Overexpression of PRMT5 was observed in human CML LSCs. Silencing PRMT5 with shRNA or blocking PRMT5 methyltransferase activity with the small-molecule inhibitor PJ-68 reduced survival, serial replating capacity, and long-term culture-initiating cells (LTC-ICs) in LSCs from CML patients. Further, PRMT5 knockdown or PJ-68 treatment dramatically prolonged survival in a murine model of retroviral BCR-ABL-driven CML and impaired the in vivo self-renewal capacity of transplanted CML LSCs. PJ-68 also inhibited long-term engraftment of human CML CD34+ cells in immunodeficient mice. Moreover, inhibition of PRMT5 abrogated the Wnt/β-catenin pathway in CML CD34+ cells by depleting dishevelled homolog 3 (DVL3). This study suggests that epigenetic methylation modification on histone protein arginine residues is a regulatory mechanism to control self-renewal of LSCs and indicates that PRMT5 may represent a potential therapeutic target against LSCs.