Somatic Mosaicism in Biology and Disease.

Contrary to earlier beliefs, every cell in the individual is genetically different due to somatic mutations. Consequently, tissues become a mixture of cells with distinct genomes, a phenomenon termed somatic mosaicism. Recent advances in genome sequencing technology have unveiled possible causes of mutations and how they shape the unique mutational landscape of the tissues. Moreover, the analysis of sequencing data in combination with clinical information has revealed the impacts of somatic mosaicism on disease processes. In this review, we discuss somatic mosaicism in various tissues and its clinical implications for human disease.

The Cancer Therapy-Related Clonal Hematopoiesis Driver Gene Ppm1d Promotes Inflammation and Non-Ischemic Heart Failure in Mice.

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Neuron-derived neurotrophic factor protects against dexamethasone-induced skeletal muscle atrophy.

Skeletal muscle atrophy caused by various conditions including aging, nerve damage, and steroid administration, is a serious health problem worldwide. We recently reported that neuron-derived neurotrophic factor (NDNF) functions as a muscle-derived secreted factor, also known as myokine, which exerts protective actions on endothelial cell and cardiomyocyte function. Here, we investigated whether NDNF regulates skeletal muscle atrophy induced by steroid administration and sciatic denervation. NDNF-knockout (KO) mice and age-matched wild-type (WT) mice were subjected to continuous dexamethasone (DEX) treatment or sciatic denervation. NDNF-KO mice exhibited decreased gastrocnemius muscle weight and reduced cross sectional area of myocyte fiber after DEX treatment or sciatic denervation compared with WT mice. Administration of an adenoviral vector expressing NDNF (Ad-NDNF) or recombinant NDNF protein to gastrocnemius muscle of WT mice increased gastrocnemius muscle weight after DEX treatment. NDNF-KO mice showed increased expression of ubiquitin E3-ligases, including atrogin-1 and MuRF-1, in gastrocnemius muscle after DEX treatment, whereas Ad-NDNF reduced expression of atrogin-1 and MuRF-1 in gastrocnemius muscle of WT mice after DEX treatment. Pretreatment of cultured C2C12 myocytes with NDNF protein reversed reduced myotube diameter and increased expression of atrogin-1 and MuRF-1 after DEX stimulation. Treatment of C2C12 myocytes increased Akt phosphorylation. Pretreatment of C2C12 myotubes with the PI3-kinase/Akt inhibitor reversed NDNF-induced increase in myotube fiber diameter after DEX treatment. In conclusion, our findings indicated that NDNF prevents skeletal muscle atrophy in vivo and in vitro through reduction of ubiquitin E3-ligases expression, suggesting that NDNF could be a novel therapeutic target of muscle atrophy.

Myonectin Is an Exercise-Induced Myokine That Protects the Heart From Ischemia-Reperfusion Injury.

RATIONALE: Physical exercise provides benefits for various organ systems, and some of systemic effects of exercise are mediated through modulation of muscle-derived secreted factors, also known as myokines. Myonectin/C1q (complement component 1q)/TNF (tumor necrosis factor)-related protein 15/erythroferrone is a myokine that is upregulated in skeletal muscle and blood by exercise. OBJECTIVE: We investigated the role of myonectin in myocardial ischemic injury. METHODS AND RESULTS: Ischemia-reperfusion in myonectin-knockout mice led to enhancement of myocardial infarct size, cardiac dysfunction, apoptosis, and proinflammatory gene expression compared with wild-type mice. Conversely, transgenic overexpression of myonectin in skeletal muscle reduced myocardial damage after ischemia-reperfusion. Treadmill exercise increased circulating myonectin levels in wild-type mice, and it reduced infarct size after ischemia-reperfusion in wild-type mice, but not in myonectin-knockout mice. Treatment of cultured cardiomyocytes with myonectin protein attenuated hypoxia/reoxygenation-induced apoptosis via S1P (sphingosine-1-phosphate)-dependent activation of cAMP/Akt cascades. Similarly, myonectin suppressed inflammatory response to lipopolysaccharide in cultured macrophages through the S1P/cAMP/Akt-dependent signaling pathway. Moreover, blockade of S1P-dependent pathway reversed myonectin-mediated reduction of myocardial infarct size in mice after ischemia-reperfusion. CONCLUSIONS: These data indicate that myonectin functions as an endurance exercise-induced myokine which ameliorates acute myocardial ischemic injury by suppressing apoptosis and inflammation in the heart, suggesting that myonectin mediates some of the beneficial actions of exercise on cardiovascular health.

C1q/TNF-related protein-1 functions to protect against acute ischemic injury in the heart.

Obesity is associated with an increased risk of cardiovascular disease. C1q/TNF-related protein (CTRP)-1 is a poorly characterized adipokine that is up-regulated in association with ischemic heart disease. We investigated the role of CTRP1 in myocardial ischemia injury. CTRP1-knockout mice showed increased myocardial infarct size, cardiomyocyte apoptosis, and proinflammatory gene expression after I/R compared with wild-type (WT) mice. In contrast, systemic delivery of CTRP1 attenuated myocardial damage after I/R in WT mice. Treatment of cardiomyocytes with CTRP1 led to reduction of hypoxia-reoxygenation-induced apoptosis and lipopolysaccharide-stimulated expression of proinflammatory cytokines, which was reversed by inhibition of sphingosine-1-phosphate (S1P) signaling. Treatment of cardiomyocytes with CTRP1 also resulted in the increased production of cAMP, which was blocked by suppression of S1P signaling. The antiapoptotic and anti-inflammatory actions of CTRP1 were cancelled by inhibition of adenylyl cyclase or knockdown of adiponectin receptor 1. Furthermore, blockade of S1P signaling reversed CTRP1-mediated inhibition of myocardial infarct size, apoptosis, and inflammation after I/R in vivo. These data indicate that CTRP1 protects against myocardial ischemic injury by reducing apoptosis and inflammatory response through activation of the S1P/cAMP signaling pathways in cardiomyocytes, suggesting that CTRP1 plays a crucial role in the pathogenesis of ischemic heart disease.

Role of Adipokines in Cardiovascular Disease.

Cardiovascular disease (CVD) is the greatest cause of death, accounting for nearly one-third of all deaths worldwide. The increase in obesity rates over 3 decades is widespread and threatens the public health in both developed and developing countries. Obesity, the excessive accumulation of visceral fat, causes the clustering of metabolic disorders, such as type 2 diabetes, dyslipidemia, and hypertension, culminating in the development of CVD. Adipose tissue is not only an energy storage organ, but an active endocrine tissue producing various biologically active proteins known as adipokines. Since leptin, a central regulator of food intake and energy expenditure, was demonstrated to be an adipose-specific adipokine, attention has focused on the identification and characterization of unknown adipokines to clarify the mechanisms underlying obesity-related disorders. Numerous adipokines have been identified in the past 2 decades; most adipokines are upregulated in the obese state. Adipokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-1ß, and resistin are pro-inflammatory, and exacerbate various metabolic and cardiovascular diseases. However, a small number of adipokines, including adiponectin, are decreased by obesity, and generally exhibit antiinflammatory properties and protective functions against obesity-related diseases. Collectively, an imbalance in the production of pro- and antiinflammatory adipokines in the obese condition results in multiple complications. In this review, we focus on the pathophysiologic roles of adipokines with cardiovascular protective properties.

Adipose-derived protein omentin prevents neointimal formation after arterial injury.

Obesity is highly linked with the development of vascular diseases. Omentin is a circulating adipokine that is downregulated in patients with cardiovascular diseases. In this study, we investigated the role of omentin in regulation of vascular remodeling in response to injury. Wild-type (WT) mice were treated intravenously with adenoviral vectors encoding human omentin (Ad-OMT) or control ß-gal and subjected to arterial wire injury. Ad-OMT treatment reduced the neointimal thickening and the frequencies of bromodeoxyuridine-positive proliferating cells in injured arteries. Treatment of vascular smooth muscle cells (VSMCs) with human omentin protein at a physiologic concentration led to suppression of growth and ERK phosphorylation after stimulation with various growth factors. Omentin stimulated AMPK signaling in VSMCs, and blockade of AMPK reversed omentin-mediated inhibition of VSMC growth and ERK phosphorylation. Furthermore, fat-specific human omentin transgenic (OMT-TG) mice exhibited reduced neointimal thickening and vascular cell growth following vascular injury. AMPK activation was enhanced in injured arteries in OMT-TG mice, and administration of AMPK inhibitor reversed the reduction of neointimal hyperplasia in OMT-TG mice. These data indicate that omentin attenuates neointimal formation after arterial injury and suppresses VSMC growth through AMPK-dependent mechanisms. Thus, omentin can represent a novel target molecule for the prevention of vascular disorders.

Cardiac myocyte-derived follistatin-like 1 prevents renal injury in a subtotal nephrectomy model.

Heart disease contributes to the progression of CKD. Heart tissue produces a number of secreted proteins, also known as cardiokines, which participate in intercellular and intertissue communication. We recently reported that follistatin-like 1 (Fstl1) functions as a cardiokine with cardioprotective properties. Here, we investigated the role of cardiac Fstl1 in renal injury after subtotal nephrectomy. Cardiac-specific Fstl1-deficient (cFstl1-KO) mice and wild-type mice were subjected to subtotal (5/6) nephrectomy. cFstl1-KO mice showed exacerbation of urinary albumin excretion, glomerular hypertrophy, and tubulointerstitial fibrosis after subtotal renal ablation compared with wild-type mice. cFstl1-KO mice also exhibited increased mRNA levels of proinflammatory cytokines, including TNF-α and IL-6, NADPH oxidase components, and fibrotic mediators, in the remnant kidney. Conversely, systemic administration of adenoviral vectors expressing Fstl1 (Ad-Fstl1) to wild-type mice with subtotal nephrectomy led to amelioration of albuminuria, glomerular hypertrophy, and tubulointerstitial fibrosis, accompanied by reduced expression of proinflammatory mediators, NADPH oxidase components, and fibrotic markers in the remnant kidney. In cultured human mesangial cells, treatment with recombinant FSTL1 attenuated TNF-α-stimulated expression of proinflammatory cytokines. Treatment of mesangial cells with FSTL1 augmented the phosphorylation of AMP-activated protein kinase (AMPK), and inhibition of AMPK activation abrogated the anti-inflammatory effects of FSTL1. These data suggest that Fstl1 functions in cardiorenal communication and that the lack of Fstl1 production by myocytes promotes glomerular and tubulointerstitial damage in the kidney.

Omentin functions to attenuate cardiac hypertrophic response.

Cardiac hypertrophy occurs in many obesity-related conditions. Omentin is an adipose-derived plasma protein that is downregulated under obese conditions. Here, we investigated whether omentin modulates cardiac hypertrophic responses in vivo and in vitro. Systemic administration of an adenoviral vector expressing human omentin (Ad-OMT) to wild-type (WT) mice led to the attenuation of cardiac hypertrophy, fibrosis and ERK phosphorylation induced by transverse aortic constriction (TAC) or angiotensin II infusion. In cultured cardiomyocytes, stimulation with phenylephrine (PE) led to an increase in myocyte size, which was prevented by pretreatment with human omentin protein. Pretreatment of cardiomyocytes with omentin protein also reduced ERK phosphorylation in response to PE stimulation. Ad-OMT enhanced phosphorylation of AMP-activated protein kinase (AMPK) in the heart of WT mice after TAC operation. Blockade of AMPK activation by transduction with dominant-negative mutant forms of AMPK reversed the inhibitory effect of omentin on myocyte hypertrophy and ERK phosphorylation following PE stimulation. Moreover, fat-specific transgenic mice expressing human omentin showed reduced cardiac hypertrophy and ERK phosphorylation following TAC surgery compared to littermate controls. These data suggest that omentin functions to attenuate the pathological process of myocardial hypertrophy via the activation of AMPK in the heart, suggesting that omentin may represent a target molecule for the treatment of cardiac hypertrophy.

FGF21 attenuates pathological myocardial remodeling following myocardial infarction through the adiponectin-dependent mechanism.

Ischemic heart disease is one of the leading causes of death. Fibroblast growth factor 21 (FGF21) is a circulating factor with an anti-diabetic property. Skeletal muscle is an important source of FGF21 production. Here, we investigated whether skeletal muscle-derived FGF21 modulates cardiac remodeling in a murine model of myocardial infarction. Myocardial infarction was produced in C57BL/6J wild-type (WT) mice by the permanent ligation of the left anterior descending coronary artery (LAD). Adenoviral vectors expressing FGF21 (Ad-FGF21) or control ß-galactosidase were intramuscularly injected into mice at 3 days before permanent LAD ligation. Intramuscular injection of Ad-FGF21 increased plasma FGF21 levels in WT mice compared with control. Treatment of WT mice with Ad-FGF21 led to improvement of left ventricular systolic dysfunction and dilatation at 2 weeks after LAD ligation. Ad-FGF21 administration to WT mice also led to enhancement of capillary density in the infarct border zone, and reduction of myocyte apoptosis in the remote zone, which were accompanied by decreased expression of pro-inflammatory cytokines. Furthermore, treatment of WT mice with Ad-FGF21 increased plasma levels of adiponectin, which is a cardioprotective adipokine. The beneficial effects of Ad-FGF21 on cardiac dysfunction and inflammatory response after myocardial infarction were diminished in adiponectin-knockout mice. These data suggest that muscle-derived FGF21 ameliorates adverse cardiac remodeling after myocardial infarction, at least in part, through an adiponectin-dependent mechanism.

High revivability of vitrified-warmed bovine mature oocytes after recovery culture with α-tocopherol.

The objective of this study was to investigate whether developmental competence of vitrified-warmed bovine oocytes can be improved by antioxidant treatment during recovery culture. In experiment 1, one of the two antioxidants (either l-ascorbic acid or α-tocopherol) was added as a supplement to the recovery culture medium to which postwarming oocytes were exposed for 2 h before IVF. The exposure to α-tocopherol had a positive effect on rescuing the oocytes as assessed by the blastocyst yield 8 days after the IVF (35.1-36.3% vs 19.2-25.8% in untreated postwarming oocytes). Quality of expanding blastocysts harvested on Day 8 was comparable between α-tocopherol-treated vitrification group and fresh control group in terms of total cell number and chromosomal ploidy. In experiment 2, level of reactive oxygen species, mitochondrial activity, and distribution of cortical granules in α-tocopherol-treated postwarming oocytes were assessed. No obvious differences from the control data were found in these parameters. However, the treatment with α-tocopherol increased the percentage of zygotes exhibiting normal single aster formation (90.3% vs 48.0% in untreated postwarming oocytes; 10 h post-IVF). It was concluded that α-tocopherol treatment of vitrified-warmed bovine mature oocytes during recovery culture can improve their revivability, as shown by the high blastocyst yield and the higher mean total cell number in the blastocysts.

Long-term effects of tolvaptan in patients requiring recurrent hospitalization for heart failure.

Although reports suggest that tolvaptan does not reduce survival or subsequent hospitalization rates in heart failure patients, its continuous use has shown good outcomes in some patients who cannot be effectively managed with high doses of loop diuretics. Therefore, we investigated the association of patient characteristics and continued tolvaptan use in heart failure patients with changes in the frequency and annual duration of patient hospitalization due to heart failure. We carefully reviewed the medical records of patients hospitalized due to heart failure who began tolvaptan therapy and continued with outpatient treatment between December 2010 and November 2013 (tolvaptan group); patients hospitalized for heart failure between May 2008 and March 2009 served as controls. We set the reference dates as the start of tolvaptan therapy (tolvaptan group) or as the date of admission (control group). The changes in hospitalization frequency and total hospitalization time due to heart failure, before and after the reference dates, were not significantly different between the tolvaptan and control groups. In the tolvaptan group, a high estimated glomerular filtration rate was a predictor of decreased hospitalization. Continuous tolvaptan use did not decrease hospitalization duration in all heart failure patients, but good renal function was predictive of a good response.

Omentin Modulates Chronic Cardiac Remodeling After Myocardial Infarction.

Background: Omentin, a circulating adipokine, is downregulated in complications of obesity, including heart disease. Here, we investigated whether omentin modulates adverse cardiac remodeling in mice after myocardial infarction (MI). Methods and Results: Transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg) and wild-type (WT) mice were subjected to permanent ligation of the left anterior descending coronary artery (LAD) to induce MI. OMT-Tg mice had a higher survival rate after permanent LAD ligation than WT mice. Moreover, OMT-Tg mice had lower heart weight/body weight (HW/BW) and lung weight/body weight (LW/BW) ratios at 4 weeks after coronary artery ligation compared with WT mice. OMT-Tg mice also showed decreased left ventricular diastolic diameter (LVDd) and increased fractional shortening (%FS) following MI. Moreover, an increase in capillary density in the infarct border zone and a decrease in myocardial apoptosis, myocyte hypertrophy, and interstitial fibrosis in the remote zone following MI, were more prevalent in OMT-Tg than WT mice. Finally, intravenous administration of adenoviral vectors expressing human omentin to WT mice after MI resulted in decreases in HW/BW, LW/BW, and LVDd, and an increase in %FS. Conclusions: Our findings document that human omentin prevents pathological cardiac remodeling after chronic ischemia, suggesting that omentin represents a potential therapeutic molecule for the treatment of ischemic heart disease.

Adipolin protects against renal injury via PPARα-dependent reduction of inflammasome activation.

Although chronic kidney disease (CKD) is a major health problem worldwide, its underlining mechanism is incompletely understood. We previously identified adipolin as an adipokine which provides benefits for cardiometabolic diseases. Here, we investigated the role of adipolin in the development of CKD. Adipolin-deficiency exacerbated urinary albumin excretion, tubulointerstitial fibrosis and oxidative stress of remnant kidneys in mice after subtotal nephrectomy through inflammasome activation. Adipolin positively regulated the production of ketone body, ß-hydroxybutyrate (BHB) and expression of a catalytic enzyme producing BHB, HMGCS2 in the remnant kidney. Treatment of proximal tubular cells with adipolin attenuated inflammasome activation through the PPARα/HMGCS2-dependent pathway. Furthermore, systemic administration of adipolin to wild-type mice with subtotal nephrectomy ameliorated renal injury, and these protective effects of adipolin were diminished in PPARα-deficient mice. Thus, adipolin protects against renal injury by reducing renal inflammasome activation through its ability to induce HMGCS2-dependent ketone body production via PPARα activation.

Analysis of the biological activity of a novel 24-membered macrolide JBIR-19 in Saccharomyces cerevisiae by the morphological imaging program CalMorph.

To investigate the biological activity of a novel 24-membered macrolide compound, JBIR-19, isolated from the culture broth of the entomopathogenic fungus Metarhizium sp. fE61, morphological changes in yeast cells were examined using the automated image-processing program CalMorph. Principal components analysis was used to elucidate dynamic changes in the phenotypes, revealing two independent effects of JBIR-19 in yeast cells: bud elongation and increased size of the actin region. Using a fitness assay, we identified the genes required for robust growth in the presence of JBIR-19. Among these were CCW12, YLR111W, and DHH1, which are also involved in abnormal bud morphology. Based on these results and others, we predict intracellular targets of JBIR-19 and its functional interactions.

Murine models of clonal haematopoiesis to assess mechanisms of cardiovascular disease.

Clonal haematopoiesis (CH) is a phenomenon whereby somatic mutations confer a fitness advantage to haematopoietic stem and progenitor cells (HSPCs) and thus facilitate their aberrant clonal expansion. These mutations are carried into progeny leucocytes leading to a situation whereby a substantial fraction of an individual's blood cells originate from the HSPC mutant clone. Although this condition rarely progresses to a haematological malignancy, circulating blood cells bearing the mutation have the potential to affect other organ systems as they infiltrate into tissues under both homeostatic and disease conditions. Epidemiological and clinical studies have revealed that CH is highly prevalent in the elderly and is associated with an increased risk of cardiovascular disease and mortality. Recent experimental studies in murine models have assessed the most commonly mutated 'driver' genes associated with CH, and have provided evidence for mechanistic connections between CH and cardiovascular disease. A deeper understanding of the mechanisms by which specific CH mutations promote disease pathogenesis is of importance, as it could pave the way for individualized therapeutic strategies targeting the pathogenic CH gene mutations in the future. Here, we review the epidemiology of CH and the mechanistic work from studies using murine disease models, with a particular focus on the strengths and limitations of these experimental systems. We intend for this review to help investigators select the most appropriate models to study CH in the setting of cardiovascular disease.

Factor Xa inhibitor, edoxaban ameliorates renal injury after subtotal nephrectomy by reducing epithelial-mesenchymal transition and inflammatory response.

Chronic kidney disease (CKD) is an increasing and life-threatening disease worldwide. Recent evidence indicates that blood coagulation factors promote renal dysfunction in CKD patients. Activated factor X (FXa) inhibitors are safe and first-line drugs for the prevention of thrombosis in patients with atrial fibrillation. Here, we investigated the therapeutic effects of edoxaban on CKD using the mouse 5/6 nephrectomy model. Eight-week-old wild-type mice were subjected to 5/6 nephrectomy surgery and randomly assigned to two groups, edoxaban or vehicle admixture diet. Edoxaban treatment led to reduction of urinary albumin excretion and plasma UN levels compared with vehicle group, which was accompanied with reduced glomerular cross-sectional area and cell number. Edoxaban treatment also attenuated fibrinogen positive area in the remnant kidneys after subtotal nephrectomy. Moreover, edoxaban treatment resulted in attenuated tubulointerstitial fibrosis after 5/6 nephrectomy, which was accompanied by reduced expression levels of epithelial-mesenchymal transition (EMT) markers, inflammatory mediators, and oxidative stress markers in the remnant kidneys. Treatment of cultured proximal tubular cells, HK-2 cells, with FXa protein led to increased expression levels of EMT markers, inflammatory mediators, and oxidative stress markers, which were abolished by pretreatment with edoxaban. Treatment of HK-2 cells with edoxaban attenuated FXa-stimulated phosphorylation levels of extracellular signal-regulated kinase (ERK) and NF-κB. Our findings indicate that edoxaban can improve renal injury after subtotal nephrectomy by reducing EMT and inflammatory response, suggesting that FXa inhibition could be a novel therapeutic target for CKD patients with atrial fibrillation.

Omentin attenuates angiotensin II-induced abdominal aortic aneurysm formation in apolipoprotein E-knockout mice.

AIMS: Abdominal aortic aneurysm (AAA) is an increasing and life-threatening disease. Obesity contributes to an increased risk of AAA. Omentin is a circulating adipokine, which is downregulated in obese complications. Here, we examined whether omentin could modulate angiotensin (Ang) II-induced AAA formation in apolipoprotein E-knockout (apoE-KO) mice. METHODS AND RESULTS: apoE-KO mice were crossed with transgenic mice expressing the human omentin gene in fat tissue (OMT-Tg mice) to generate apoE-KO/OMT-Tg mice. apoE-KO/OMT-Tg and apoE-KO mice were subjected to continuous Ang II infusion by using osmotic mini pumps. apoE-KO/OMT-Tg mice exhibited a lower incidence of AAA formation and a reduced maximal diameter of AAA compared with apoE-KO mice. apoE-KO/OMT-Tg mice showed attenuated disruption of medial elastic fibres in response to Ang II compared with apoE-KO mice. apoE-KO/OMT-Tg mice also displayed reduced expression levels of matrix metalloproteinase (MMP) 9, MMP2, and pro-inflammatory genes in aortic walls compared with apoE-KO mice. Furthermore, systemic administration of omentin also attenuated AAA formation and disruption of medial elastic fibres in response to Ang II in apoE-KO mice. Treatment of human monocyte-derived macrophages with omentin protein attenuated expression of MMP9 and pro-inflammatory mediators, and MMP9 activation after stimulation with lipopolysaccharide. Treatment of human vascular smooth muscle cells (VSMCs) with omentin protein reduced expression and activation of MMP2 after stimulation with tumour necrosis factor α. Omentin treatment increased phosphorylation levels of Akt in human macrophages and VSMCs. The suppressive effects of omentin on MMP9 and MMP2 expression were reversed by inhibition of integrin-αVß3/PI3-kinase/Akt signalling in macrophages and VSMCs, respectively. CONCLUSION: These data suggest that omentin acts as an adipokine that can attenuate Ang II-induced development of AAA through suppression of MMP9 and MMP2 expression and inflammatory response in the vascular wall.

Hematopoietic loss of Y chromosome leads to cardiac fibrosis and heart failure mortality.

Hematopoietic mosaic loss of Y chromosome (mLOY) is associated with increased risk of mortality and age-related diseases in men, but the causal and mechanistic relationships have yet to be established. Here, we show that male mice reconstituted with bone marrow cells lacking the Y chromosome display increased mortality and age-related profibrotic pathologies including reduced cardiac function. Cardiac macrophages lacking the Y chromosome exhibited polarization toward a more fibrotic phenotype, and treatment with a transforming growth factor ß1-neutralizing antibody ameliorated cardiac dysfunction in mLOY mice. A prospective study revealed that mLOY in blood is associated with an increased risk for cardiovascular disease and heart failure-associated mortality. Together, these results indicate that hematopoietic mLOY causally contributes to fibrosis, cardiac dysfunction, and mortality in men.

Donor screening algorithm for exclusion of thrombophilia during evaluation of living donor liver transplantation.

Living donor liver transplantation (LDLT) has evolved based on the premise that donor safety is most important. In 2005, we encountered a donor who developed a pulmonary embolism during the early post-operative period. As it is important for donors to be healthy, most risk factors related to perioperative thrombosis, such as obesity, age, and malignancy are used as exclusion criteria during the evaluation process. We speculated that thrombophilia not detected by conventional laboratory examinations may cause post-operative thrombotic complications and should be investigated by application of additional parameters, including protein S, protein C, antithrombin III, anti-ß2-glycoprotein I antibodies (anti-ß2GPI), and lupus anticoagulant. From July 2005 to June 2007, we evaluated 44 donor candidates for LDLT using our novel algorithm for screening of thrombophilia, which revealed two suspected candidates (one with low protein S, one with low protein C, and positive anti-ß2GPI findings), who were subsequently excluded from the donor pool. Thereafter, all donor hepatectomies, which included two borderline donors given anticoagulants perioperatively, were performed without complications. Four donors (two suspected, two borderline) would not have been recognized without additional screening. In conclusion, we were able to detect thrombophilia and avoid donor thrombosis using additional screening criteria and our novel algorithm.