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Sunitinib malate is a multi-targeted receptor tyrosine kinase inhibitor used in the treatment of human malignancies. A substantial number of sunitinib-treated patients develop cardiac dysfunction, but the mechanism of sunitinib-induced cardiotoxicity is poorly understood. We show that mice treated with sunitinib develop cardiac and coronary microvascular dysfunction and exhibit an impaired cardiac response to stress. The physiological changes caused by treatment with sunitinib are accompanied by a substantial depletion of coronary microvascular pericytes. Pericytes are a cell type that is dependent on intact PDGFR signaling but whose role in the heart is poorly defined. Sunitinib-induced pericyte depletion and coronary microvascular dysfunction are recapitulated by CP-673451, a structurally distinct PDGFR inhibitor, confirming the role of PDGFR in pericyte survival. Thalidomide, an anti-cancer agent that is known to exert beneficial effects on pericyte survival and function, prevents sunitinib-induced pericyte cell death in vitro and prevents sunitinib-induced cardiotoxicity in vivo in a mouse model. Our findings suggest that pericytes are the primary cellular target of sunitinib-induced cardiotoxicity and reveal the pericyte as a cell type of concern in the regulation of coronary microvascular function. Furthermore, our data provide preliminary evidence that thalidomide may prevent cardiotoxicity in sunitinib-treated cancer patients.

Obesity is a major risk factor for diabetes and heart disease. We previously reported that the inactivation of the gene for perilipin (plin), an adipocyte lipid droplet surface protein, produced lean and obesity-resistant mice. To dissect the underlying mechanisms involved, we used oligonucleotide microarrays to analyze the gene-expression profile of white adipose tissue (WAT), liver, heart, skeletal muscle, and kidney of plin ؊/؊ and plin ϩ/ϩ mice. As compared with wild-type littermates, the WAT of plin ؊/؊ mice had 270 and 543 transcripts that were significantly up-or downregulated. There was a coordinated upregulation of genes involved in ␤-oxidation, the Krebs cycle, and the electron transport chain concomitant with a downregulation of genes involved in lipid biosynthesis. There was also a significant downregulation of the stearoyl CoA desaturase-1 gene, which has been associated with obesity resistance. Thus, in response to the constitutive activation of lipolysis associated with absence of perilipin, WAT activated pathways to rid itself of the products of lipolysis and activated pathways of energy expenditure that contribute to the observed obesity resistance. The biochemical pathways involved in obesity resistance in plin ؊/؊ mice identified in this study may represent potential targets for the treatment of obesity. Diabetes 52:2666 -2674, 2003 P erilipin (plin) is a member of a family of proteins that coat the surfaces of intracellular neutral lipid storage droplets, mainly in adipocytes and in steroidogenic cells (1,2). Perilipin, in the basal state, prevents access of hormone-sensitive lipase to the lipid droplet (3) and is a major substrate of cAMPdependent protein kinase in adipocytes (4). Specific hormonal or cytokine stimuli, such as catecholamines and tumor necrosis factor-␣, activate lipolysis by phosphorylating perilipin, thereby allowing hormone-sensitive lipase to access the lipid droplet and initiate its lipolytic action (5,6).Plin Ϫ/Ϫ mice are characterized by constitutive lipolysis, normal body weight despite an increase in food consumption, a lean body habitus, and smaller fat depots composed of small adipocytes (7,8). These mice display increased oxygen consumption and are resistant to diet-induced and genetic obesity (7).To explain this phenotype, we hypothesized that there had to be significant changes in the expression of genes involved in pathways for substrate and energy metabolism. We further reasoned that although perilipin is expressed in adipocytes, there should be concomitant changes in other tissues that are important in whole-body metabolism, such as the liver, skeletal muscle, heart, and kidney, to explain the profound changes seen in plin Ϫ/Ϫ mice. To test these hypotheses, we performed oligonucleotide microarray analysis of the above tissues of plin Ϫ/Ϫ mice and compared the data with those obtained from their wild-type littermates. We show a concomitant and coordinated upregulation of multiple genes involved in oxidative catabolic pathways along with downregulation of gene...

The addition of glutamine as a major nutrient to cultured neonatal rat cardiomyocytes produced an increase in myocyte size and the organization of actin into myofibrillar arrays. The cellular response was associated with increased abundance of the mRNAs encoding the contractile proteins, ␣-myosin heavy chain and cardiac ␣-actin, and the metabolic enzymes, muscle carnitine palmitoyl transferase I and muscle adenylosuccinate synthetase (ADSS1). Adss1 gene expression was induced ϳ5-fold in glutamine-treated rat neonatal cardiac myocytes. The induction was mediated through the protein kinase A and mammalian target of rapamycin signaling pathways and required a cyclic AMP response element associated with the promoter region of the Adss1 gene. These results highlight glutamine as a major nutrient regulator of cardiac gene expression and identify protein kinase A and mammalian target of rapamycin signaling pathways as mediators of the cardiomyocyte transcriptional response.

Innate lymphoid cells (ILC) are a subset of leukocytes with lymphoid properties that lack antigen specific receptors. They can be stimulated by and exert their effect via specific cytokine axes, whereas Natural Killers (NK) cells are the only known cytotoxic member of this family. ILCs are considered key in linking the innate and adaptive response in physiologic and pathologic environments. In this study, we investigated the properties of non-cytotoxic cardiac ILCs in physiologic, inflammatory, and ischemic conditions. We found that in healthy humans and mice, non-cytotoxic cardiac ILCs are predominantly a type 2-committed population with progenitor-like features, such as an absence of type-specific immunophenotype, intermediate GATA3 expression, and capacity to transiently express Pro-myelocytic Leukemia Zinc Finger protein (PLZF) upon activation. During myocarditis and ischemia, in both human and mice, cardiac ILCs differentiated into conventional ILC2s. We found that cardiac ILCs lack IL-25 receptor and cannot become inflammatory ILC2s. We found a strong correlation between IL-33 production in the heart and the ability of cardiac ILCs to become conventional ILC2s. The main producer of IL-33 was a subset of CD29+Sca-1+ cardiac fibroblasts. ILC2 expansion and fibroblast-derived IL-33 production were significantly increased in the heart in mouse models of infarction and myocarditis. Despite its progenitor-like status in healthy hearts, cardiac ILCs were unable to become ILC1 or ILC3 in vivo and in vitro . Using adoptive transfer and parabiosis, we demonstrated that the heart, unlike other organs such as lung, cannot be infiltrated by circulating ILCs in adulthood even during cardiac inflammation or ischemia. Thus, the ILC2s present during inflammatory conditions are derived from the heart-resident and quiescent steady-state population. Non-cytotoxic cardiac ILCs are a resident population of ILC2-commited cells, with undifferentiated progenitor-like features in steady-state conditions and an ability to expand and develop pro-inflammatory type 2 features during inflammation or ischemia.

Background: Although the use of a left-ventricular assist system (LVAS) provides circulatory support for end-stage heart failure patients awaiting heart transplantation, this procedure is accompanied by a relatively high perioperative mortality. The aim of this retrospective study was to identify those patients preoperatively which have the highest perioperative mortality. Methods and Results: Forty-five consecutive patients undergoing LVAS implantation were evaluated for preoperative risk factors, including body mass index, hemodynamic data, and blood chemistry studies by multivariate analysis. They were divided into (1) patients who were successfully transplanted (n = 25) and (2) patients who died before transplantation (n = 20). The nonsurvivors were subclassified into patients who died within 14 days after surgery (n = 11) and patients who died after 2 weeks of device implantation (n = 9). Hemodynamic parameters were the same in both groups, but total cholesterol was significantly lower in the nonsurvivors than in the survivors (90 ± 7 vs. 144 ± 8 mg/dl, respectively, p < 0.0001). The sensitivity of predicting perioperative death with a serum cholesterol below 100 mg/dl was 100%, the specificity of predicting survival with a serum cholesterol above 120 mg/dl was 87%. Conclusion: In this small retrospective study, there was a correlation between total cholesterol levels and survival of patients with advanced heart failure on mechanical support. A cholesterol level below 100 mg/dl was accompanied by a high perioperative mortality. In contrast, a cholesterol level above 120 mg/dl was accompanied by a 87% chance of survival. The results suggest a predictive value of cholesterol which is independent of the hemodynamic status.

Background: Genomic duplications involving the smooth muscle myosin heavy chain gene, MYH11, are associated with increased risk for acute aortic dissections. Results: MYH11 overexpression causes increased turnover of contractile proteins through increased autophagy. Conclusion: MYH11 duplications may predispose to aortic disease through increased turnover of contractile proteins and disruption of contractile signaling. Significance: Increased protein turnover may be an important mechanism by which genomic duplications cause human disease.

ObjectiveMortality in heart failure (AHF) remains high, especially during the first days of hospitalization. New prognostic biomarkers may help to optimize treatment. The aim of the study was to determine metabolites that have a high prognostic value.MethodsWe conducted a prospective study on a training cohort of AHF patients (n = 126) admitted in the cardiac intensive care unit and assessed survival at 30 days. Venous plasmas collected at admission were used for 1H NMR – based metabonomics analysis. Differences between plasma metabolite profiles allow determination of discriminating metabolites. A cohort of AHF patients was subsequently constituted (n = 74) to validate the findings.ResultsLactate and cholesterol were the major discriminating metabolites predicting 30-day mortality. Mortality was increased in patients with high lactate and low total cholesterol concentrations at admission. Accuracies of lactate, cholesterol concentration and lactate to cholesterol (Lact/Chol) ratio to predict 30-day mortality were evaluated using ROC analysis. The Lact/Chol ratio provided the best accuracy with an AUC of 0.82 (P < 0.0001). The acute physiology and chronic health evaluation (APACHE) II scoring system provided an AUC of 0.76 for predicting 30-day mortality. APACHE II score, Cardiogenic shock (CS) state and Lact/Chol ratio ≥ 0.4 (cutoff value with 82% sensitivity and 64% specificity) were significant independent predictors of 30-day mortality with hazard ratios (HR) of 1.11, 4.77 and 3.59, respectively. In CS patients, the HR of 30-day mortality risk for plasma Lact/Chol ratio ≥ 0.4 was 3.26 compared to a Lact/Chol ratio of < 0.4 (P  =  0.018). The predictive power of the Lact/Chol ratio for 30-day mortality outcome was confirmed with the independent validation cohort.ConclusionThis study identifies the plasma Lact/Chol ratio as a useful objective and simple parameter to evaluate short term prognostic and could be integrated into quantitative guidance for decision making in heart failure care.