Objective-Interleukin (IL)-33 is the most recently described member of the IL-1 family of cytokines and it is a ligand of the ST2 receptor. While the effects of IL-33 on the immune system have been extensively studied, the properties of this cytokine in the cardiovascular system are much less investigated.

Interleukin-33 (IL-33) is a recently described member of the IL-1 family of cytokines, which was identified as a ligand for the ST2 receptor. Components of the IL-33/ST2 system were shown to be expressed in normal and pressure overloaded human myocardium, and soluble ST2 (sST2) has emerged as a prognostic biomarker in myocardial infarction and heart failure. However, expression and regulation of IL-33 in human adult cardiac myocytes and fibroblasts was not tested before. In this study we found that primary human adult cardiac fibroblasts (HACF) and human adult cardiac myocytes (HACM) constitutively express nuclear IL-33 that is released during cell necrosis. Tumor necrosis factor (TNF)-α, interferon (IFN)-γ and IL-1β significantly increased both IL-33 protein and IL-33 mRNA expression in HACF and HACM as well as in human coronary artery smooth muscle cells (HCASMC). The nuclear factor-κB (NF-κB) inhibitor dimethylfumarate inhibited TNF-α- and IL-1β-induced IL-33 production as well as nuclear translocation of p50 and p65 NF-κB subunits in these cells. Mitogen-activated protein/extracellular signal-regulated kinase inhibitor U0126 abrogated TNF-α-, IFN-γ-, and IL-1β-induced and Janus-activated kinase inhibitor I reduced IFN-γ-induced IL-33 production. We detected IL-33 mRNA in human myocardial tissue from patients undergoing heart transplantation (n = 27) where IL-33 mRNA levels statistically significant correlated with IFN-γ (r = 0.591, p = 0.001) and TNF-α (r = 0.408, p = 0.035) mRNA expression. Endothelial cells in human heart expressed IL-33 as well as ST2 protein. We also reveal that human cardiac and vascular cells have different distribution patterns of ST2 isoforms (sST2 and transmembrane ST2L) mRNA expression and produce different amounts of sST2 protein. Both human macrovascular (aortic and coronary artery) and heart microvascular endothelial cells express specific mRNA for both ST2 isoforms (ST2L and sST2) and are a source for sST2 protein, whereas cardiac myocytes, cardiac fibroblasts and vascular SMC express only minor amounts of ST2 mRNA and do not secrete detectable amounts of sST2 antigen. In accordance with the cellular distribution of ST2 receptor, human cardiac fibroblasts and myocytes as well as HCASMC did not respond to treatment with IL-33, as recombinant human IL-33 did not induce NF-κB p50 and p65 subunits nuclear translocation or increase IL-6, IL-8, and monocyte chemoattractant protein (MCP-1) level in HACF, HACM and HCASMC. In summary, we found that endothelial cells seem to be the source of sST2 and the target for IL-33 in the cardiovascular system. IL-33 is expressed in the nucleus of human adult cardiac fibroblasts and myocytes and released during necrosis. Proinflammatory cytokines TNF-α, IFN-γ and IL-1β increase IL-33 in these cells in vitro, and IL-33 mRNA levels correlated with TNF-α and IFN-γ mRNA expression in human myocardial tissue.

AimsRecent data indicate that right ventricular systolic dysfunction (RVSD) by cardiac magnetic resonance imaging (CMR) is a strong predictor of outcome in heart failure. However, the prognostic significance of RVSD by CMR in heart failure with preserved ejection fraction (HFpEF) Methods and resultsWe prospectively enrolled 171 HFpEF patients who underwent CMR in addition to invasive and non-invasive testing. RVSD, defined as right ventricular (RV) EF <45% by CMR, was present in 33 (19.3 %) patients. Patients were followed for 573 ± 387 days, during which 41 had a cardiac event. Patients with RVSD presented with more frequent history of AF (P = 0.038), significantly higher resting heart rate (P = 0.009), shorter 6-min walk distance (P = 0.036), and higher NT-pro BNP serum levels (P < 0.001), and were more symptomatic (P < 0.001). With respect to haemodynamic parameters, RVSD was associated with respect to haemodynamic parameters, RVSD was associated with higher diastolic pulmonary artery pressure (P = 0.045), with higher pulmonary vascular resistance (P = 0.048), higher transpulmonary gradient (P = 0.042), and higher diastolic pulmonary vascular pressure gradient (P = 0.007). In the multivariable Cox analysis, RVSD (P < 0.001) remained significantly associated with cardiac events, in addition to diabetes (P = 0.011), 6-min walk distance (P = 0.018), and systolic pulmonary artery pressure (P = 0.003).

Background— The underlying pathophysiology of heart failure with preserved ejection fraction (HFPEF) is incompletely understood, but myocardial extracellular matrix accumulation is thought to play a major role. Our aims were to estimate myocardial extracellular matrix using cardiac magnetic resonance T1 mapping and to assess the relationship between pathobiology/pathophysiology and prognosis. Methods and Results— Patients with suspected HFPEF (n=100) were enrolled in this prospective, observational study. Confirmatory diagnostic tests, cardiac magnetic resonance imaging including T1 mapping, and invasive hemodynamic assessments were performed at baseline. Sixty-one patients with confirmed HFPEF entered a longitudinal outcome-monitoring phase (mean, 22.9±5.0 months), during which 16 had a cardiac event. Cardiac magnetic resonance T1 time (hazard ratio, 0.99; 95% confidence interval, 0.98–0.99; P =0.046), left atrial area (hazard ratio, 1.08; 95% confidence interval, 1.03–1.13; P <0.01), and pulmonary vascular resistance (hazard ratio, 1.01; 95% confidence interval, 1.00–1.01; P =0.03) were significantly associated with cardiac events. Patients with T1 times below the median (<388.3 ms) were at greater risk of cardiac events than the rest of the group ( P <0.01). Extracellular matrix of left ventricular biopsies (n=9), quantified by TissueFAXS technology correlated with T1 time ( R =0.98; P <0.01). T1 time also correlated with right ventricular–pulmonary arterial coupling (pulmonary vascular resistance: R =−0.36; P <0.01; right ventricular ejection fraction: R =0.28; P =0.01). Conclusions— In the present preliminary study, cardiac magnetic resonance postcontrast T1 time is associated with prognosis in HFPEF, suggesting postcontrast T1 as possible biomarker for HFPEF.

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Background-Therapeutic decisions in cardiology are determined frequently by cardiac chamber size. To decide whether cardiac dimensions are still in the normal range, reliable reference values are needed. However, published reference values mostly refer to historical cohorts using motion-mode measurements and have not been adjusted for sex or age. The impact of body size was only vaguely addressed. The importance of such adjustments is illustrated by studies, which show that smaller individuals and women are at risk of delayed treatment and impaired outcome when currently used reference values are applied. The aim of the present study was to assess the impact of body size, sex, and age on the normal heart size. Methods and Results-We prospectively studied 622 individuals (52.7% women; 17-91 years; 143-200 cm; 32-240 kg) without cardiac disease by standard transthoracic echocardiography. Multivariable linear regression analyses of the impact of sex, age, height, and weight on cardiac chamber size were performed. By multivariable regression analysis (n=500), all 4 variables independently influenced cardiac chamber size. The validity of cardiac dimensions predicted by the regression model was tested prospectively in a validation cohort (n=122). A calculator is proposed that estimates cardiac dimensions on the basis of the regression analysis. Conclusions-Sex, height, weight, and age significantly affect the normal heart size. These parameters need to be considered when cutoff values indicating the need for treatment or even surgery are established. The present prospective study was intended to assess the impact of body size, sex, and age on the normal heart size. We, furthermore, provide a calculation tool that facilitates the application of the results of our statistical analysis in the individual patient. MethodsBetween November 2008 and June 2012, we prospectively included 622 consecutive individuals (52.7% women) who were referred to our outpatient clinic for a standard transthoracic echocardiogram. Age was limited to ≥17 years.Exclusion criteria comprised a cardiac murmur at auscultation, a history of cardiac disease, such as coronary artery disease, cardiomyopathy, rheumatic disease with cardiac involvement, valvular or congenital heart disease, and hypertension. If more than mild valvular heart disease was present, participants were also excluded from this protocol.Study participants were weighed on a calibrated scale without shoes, jacket, or coat, and height was determined.The ethical committee of the Medical University of Vienna approved the study protocol. All patients gave written informed consent. Echocardiographic MeasurementsStudy participants underwent a comprehensive echocardiographic examination by board-certified physicians in the echocardiographic laboratory of the Medical University of Vienna using high-end scanners, such as Siemens Acuson Sequoia C512 and GE (General Electric) Vivid 7. All measurements were obtained according to current recommendations for cardiac chamber quantification. 29 ...

Objectives— It is believed that adipose tissue acts as an endocrine organ by producing inflammatory mediators and thereby contributes to the increased cardiovascular risk seen in obesity. A link between adipose tissue mass and angiogenesis has been suggested. Vascular endothelial growth factor (VEGF) seems to be implicated in this process. Members of the glycoprotein (gp)130 ligand family regulate VEGF expression in other cells. Methods and Results— We used tissue explants as well as primary cultures of preadipocytes and adipocytes from human subcutaneous and visceral adipose tissue to investigate whether the gp130 ligands oncostatin M (OSM), interleukin-6 (IL-6), leukemia inhibitory factor (LIF), and cardiotrophin-1 (CT-1) regulate VEGF expression in human adipose tissue. Human subcutaneous and visceral adipose tissue responded to treatment with IL-6 and OSM with a significant increase in VEGF production. Human preadipocytes were isolated from subcutaneous and visceral adipose tissue. Adipocyte-differentiation was induced by hormone-supplementation. All cell types responded to IL-6 and OSM with a robust increase in VEGF protein production and a similar increase in VEGF-specific mRNA. Furthermore, IL-1β synergistically enhanced the effect of OSM on VEGF production. AG-490, a JAK/STAT inhibitor, abolished the OSM-dependent VEGF induction almost completely. In mice, IL-6 and OSM increased serum levels of VEGF and VEGF mRNA and vessel density in adipose tissue. Conclusion— We speculate that the inflammatory cytokines IL-6 and OSM might support angiogenesis during adipose tissue growth by upregulating VEGF.

CMR T1 mapping allows accurate noninvasive quantification of ECV and is independently associated with event-free survival among imaging parameters. Its prognostic value on top of established clinical risk factors warrants further investigation in long-term studies.