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Plasma volume and especially plasma volume excess is a relevant predictor for the clinical outcome of heart failure patients. In recent years, estimated plasma volume based on anthropometric characteristics and blood parameters has been used whilst direct measurement of plasma volume has not entered clinical routine. It is unclear whether the estimation of plasma volume can predict a true plasma volume excess. Plasma volume was measured in 47 heart failure patients (CHF, 10 female) using an abbreviated carbon monoxide rebreathing method. Plasma volume and plasma volume status were also estimated based on two prediction formulas (Hakim, Kaplan). The predictive properties of the estimated plasma volume status to detect true plasma volume excess > 10% were analysed based on logistic regression and receiver operator characteristics. The area under the curve (AUC) to detect plasma volume excess based on calculation of plasma volume by the Hakim formula is 0.65 (with a positive predictive value (PPV) of 0.62 at a threshold of − 16.5%) whilst the AUC for the Kaplan formula is 0.72 (PPV = 0.67 at a threshold of − 6.3%). Only the estimated plasma volume status based on prediction of plasma volume by the Kaplan formula formally appears as an acceptable predictor of true plasma volume excess, whereas calculation based on the Hakim formula does not sufficiently predict a true plasma volume excess. The low positive predictive values for both methods suggest that plasma volume status estimation based on these formulas is not suitable for clinical decision making.

Background Diet-induced obesity can result in the development of a diverse spectrum of cardiovascular and metabolic diseases, including type 2 diabetes, dyslipidemia, non-alcoholic liver steatosis and atherosclerotic disease. MicroRNAs have been described to be important regulators of metabolism and disease development. Methods In the current study, we investigated the effects of ubiquitous miR-100 overexpression on weight gain and the metabolic phenotype in a newly generated transgenic mouse strain under normal chow and high fat diet and used microarray expression analysis to identify new potential target genes of miR-100. Results While transgenic overexpression of miR-100 did not significantly affect weight and metabolism under a normal diet, miR-100 overexpressing mice showed a reduced weight gain under a high fat diet compared to wildtype mice, despite an equal calorie intake. This was accompanied by less visceral and subcutaneous fat development and lover serum LDL cholesterol. In addition, transgenic miR-100 mice were more glucose tolerant and insulin sensitive and demonstrated increased energy expenditure under high fat diet feeding. A comprehensive gene expression profiling revealed the differential expression of several genes involved in lipid storage- and metabolism, among them CD36 and Cyp4A14. Our data showed a direct regulation of CD36 by miR-100, leading to a reduced fatty acid uptake in primary hepatocytes overexpressing miR-100 and the downregulation of several downstream mediators of lipid metabolism such as ACC1, FABP4, FAS and PPARγ in the liver. Conclusions Our findings demonstrate a protective role of miR-100 in high fat diet induced metabolic syndrome and liver steatosis, partially mediated by the direct repression of CD36 and attenuation of hepatic lipid storage, implicating miR-100 as a possible therapeutic target in liver steatosis.

Systemic inflammation is a major feature of the post-cardiac arrest syndrome. The three monocyte subpopulations are thought to play an important role in this inflammatory state because they are endowed with numerous pattern recognition receptors, such as CD14, that have been associated with ischemia–reperfusion injury. By contrast, an exaggerated antiinflammatory response has also been described following cardiac arrest, which may be mediated by downregulation of antigen presentation receptor HLA-DR. We report the composition of monocyte subpopulations and the expression of CD14 and HLA-DR following cardiac arrest. Blood specimens were collected from 32 patients at three timepoints in the first 48 h after cardiac arrest. Monocyte subset composition was determined by flow cytometry based on the expression of CD14, CD16, and HLA-DR. Monocyte subset composition and the expression of CD14 and HLA-DR were correlated with patient outcomes. The results were compared to 19 patients with coronary artery disease. Cardiac arrest patients showed a significant decline in the percentage of nonclassical monocytes. Monocyte CD14 expression was upregulated after 24 h and correlated with the time to return of spontaneous circulation. Downregulation of HLA-DR expression was observed mainly among classical monocytes and significantly correlated with the dose of norepinephrine used to treat shock. Downregulation of HLA-DR among nonclassical and intermediate monocytes was significantly associated with disease severity. Our data demonstrate the disturbance of monocyte subset composition with a significant decline in nonclassical monocytes at an early stage following cardiac arrest. Our findings suggest the simultaneous presence of hyperinflammation, as evidenced by upregulation of CD14, and monocyte deactivation, characterized by downregulation of HLA-DR. The extent of monocyte deactivation was significantly correlated with disease severity.

We comprehensively studied morphological and functional aortic aging in a population study using modern three-dimensional MR imaging to allow future comparison in patients with diseases of the aortic valve or aorta. We followed 80 of 126 subjects of a population study (20 to 80 years of age at baseline) using the identical methodology 6.0 ± 0.5 years later. All underwent 3 T MRI of the thoracic aorta including 3D T1 weighted MRI (spatial resolution 1 mm 3 ) for measuring aortic diameter and plaque thickness and 4D flow MRI (spatial/temporal resolution = 2 mm 3 /20 ms) for calculating global and regional aortic pulse wave velocity (PWV) and helicity of aortic blood flow. Mean diameter of the ascending aorta (AAo) decreased and plaque thickness increased significantly in the aortic arch (AA) and descending aorta (DAo) in females. PWV of the thoracic aorta increased (6.4 ± 1.5 to 7.0 ± 1.7 m/s and 6.8 ± 1.5 to 7.3 ± 1.8 m/s in females and males, respectively) over time. Local normalized helicity volumes (LNHV) decreased significantly in the AAo and AA (0.33 to 0.31 and 0.34 to 0.32 in females and 0.34 to 0.32 and 0.32 to 0.28 in males). By contrast, helicity increased significantly in the DAo in both genders (0.28 to 0.29 and 0.29 to 0.30, respectively). 3D MRI was able to characterize changes in aortic diameter, plaque thickness, PWV and helicity during six years in our population. Aortic aging determined by 3D multi-parametric MRI is now available for future comparisons in patients with diseases of the aortic valve or aorta.

Background Swine are frequently used as animal model for cardiovascular research, especially in terms of representativity of human anatomy and physiology. Reference values for the most common species used in research are important for planning and execution of animal testing. Transesophageal echocardiography is the gold standard for intraoperative imaging, but can be technically challenging in swine. Its predecessor, epicardial echocardiography (EE), is a simple and fast intraoperative imaging technique, which allows comprehensive and goal-directed assessment. However, there are few echocardiographic studies describing echocardiographic parameters in juvenile swine, none of them using EE. Therefore, in this study, we provide a comprehensive dataset on multiple geometric and functional echocardiographic parameters, as well as basic hemodynamic parameters in swine using EE. Methods The data collection was performed during animal testing in ten female swine (German Landrace, 104.4 ± 13.0 kg) before left ventricular assist device implantation. Hemodynamic data was recorded continuously, before and during EE. The herein described echocardiographic measurements were acquired according to a standardized protocol, encompassing apical, left ventricular short axis and long axis as well as epiaortic windows. In total, 50 echocardiographic parameters and 10 hemodynamic parameters were assessed. Results Epicardial echocardiography was successfully performed in all animals, with a median screening time of 14 min (interquartile range 11–18 min). Referring to left ventricular function, ejection fraction was 51.6 ± 5.9% and 51.2 ± 6.2% using the Teichholz and Simpson methods, respectively. Calculated ventricular mass was 301.1 ± 64.0 g, as the left ventricular end-systolic and end-diastolic diameters were 35.3 ± 2.5 mm and 48.2 ± 3.5 mm, respectively. The mean heart rate was 103 ± 28 bpm, mean arterial pressure was 101 ± 20 mmHg and mean flow at the common carotid artery was 627 ± 203 mL/min. Conclusion Epicardial echocardiography allows comprehensive assessment of most common echocardiographic parameters. Compared to humans, there are important differences in swine with respect to ventricular mass, size and wall thickness, especially in the right heart. Most hemodynamic parameters were comparable between swine and humans. This data supports study planning, animal and device selection, reinforcing the three R principles in animal research. Graphical Abstract

Background Increased aortic stiffness is an independent predictor of cardiovascular disease. Optimal measurement is highly beneficial for the detection of atherosclerosis and the management of patients at risk. Thus, it was our purpose to selectively measure aortic stiffness using a novel imaging method and to provide reference values from a population-based study. Methods One hundred twenty six inhabitants of Freiburg, Germany, between 20 and 80 years prospectively underwent 3 Tesla cardiovascular magnetic resonance (CMR) of the thoracic aorta. 4D flow CMR (spatial/temporal resolution 2mm 3 /20ms) was executed to calculate aortic pulse wave velocity (PWV) in m/s using dedicated software. In addition, we calculated distensibility coefficients (DC) using 2D CINE CMR imaging of the ascending (AAo) and descending aorta (DAo). Segmental aortic diameter and thickness of aortic plaques were determined by 3D T1 weighted CMR (spatial resolution 1mm 3 ). Results PWV increased from 4.93 ± 0.54 m/s in 20–30 year-old to 8.06 ± 1.03 m/s in 70–80 year-old subjects. PWV was significantly lower in women compared to men ( p  < 0.0001). Increased blood pressure (systolic r  = 0.36, p  < 0.0001; diastolic r  = 0.33, p  = 0.0001; mean arterial pressure r  = 0.37, p  < 0.0001) correlated with PWV after adjustment for age and gender. Finally, PWV increased with increasing diameter of the aorta (ascending aorta r  = 0.20, p  = 0.026; aortic arch r  = 0.24, p  = 0.009; descending aorta r  = 0.26, p  = 0.004). Correlation of PWV and DC of the AAo and DAo or the mean of both was high ( r  = 0.69, r  = 0.68, r  = 0.73; p  < 0.001). Conclusions 4D flow CMR was successfully applied to calculate aortic PWV and thus aortic stiffness. Findings showed a high correlation with distensibility coefficients representing local compliance of the aorta. Our novel method and reference data for PWV may provide a reliable biomarker for the identification of patients with underlying cardiovascular disease and optimal guidance of future treatment in studies or clinical routine.

Background Whole body ischemia-reperfusion injury (IRI) after cardiopulmonary resuscitation (CPR) induces a generalized inflammatory response which contributes to the development of post-cardiac arrest syndrome (PCAS). Recently, pattern recognition receptors (PRRs), such as toll-like receptors (TLRs) and inflammasomes, have been shown to mediate the inflammatory response in IRI. In this study we investigated monocyte PRR signaling and function in PCAS. Methods Blood samples were drawn in the first 12 hours, and at 24 and 48 hours following return of spontaneous circulation in 51 survivors after cardiac arrest. Monocyte mRNA levels of TLR2, TLR4, interleukin-1 receptor-associated kinase (IRAK)3, IRAK4, NLR family pyrin domain containing (NLRP)1, NLRP3, AIM2, PYCARD, CASP1, and IL1B were determined by real-time quantitative PCR. Ex vivo cytokine production in response to stimulation with TLR ligands Pam 3 CSK 4 and lipopolysaccharide (LPS) was assessed in both whole blood and monocyte culture assays. Ex vivo cytokine production of peripheral blood mononuclear cells (PBMCs) from a healthy volunteer in response to stimulation with patients’ sera with or without LPS was assessed. The results were compared to 19 hemodynamically stable patients with coronary artery disease. Results Monocyte TLR2, TLR4, IRAK3, IRAK4, NLRP3, PYCARD and IL1B were initially upregulated in patients following cardiac arrest. The NLRP1 and AIM2 inflammasomes were downregulated in resuscitated patients. There was a significant positive correlation between TLR2, TLR4, IRAK3 and IRAK4 expression and the degree of ischemia as assessed by serum lactate levels and the time until return of spontaneous circulation. Nonsurvivors at 30 days had significantly lower mRNA levels of TLR2, IRAK3, IRAK4, NLRP3 and CASP1 in the late phase following cardiac arrest. We observed reduced proinflammatory cytokine release in response to both TLR2 and TLR4 activation in whole blood and monocyte culture assays in patients after CPR. Sera from resuscitated patients attenuated the inflammatory response in cultured PBMCs after co-stimulation with LPS. Conclusions Successful resuscitation from cardiac arrest results in changes in monocyte pattern recognition receptor signaling pathways, which may contribute to the post-cardiac arrest syndrome. Trial registration The trial was registered in the German Clinical Trials Register ( DRKS00009684 ) on 27/11/2015.

Arteriogenesis is a complicated process induced by increased local shear‐and radial wall‐stress, leading to an increase in arterial diameter. This process is enhanced by growth factors secreted by both inflammatory and endothelial cells in response to physical stress. Although therapeutic promotion of arteriogenesis is of great interest for ischaemic diseases, little is known about the modulation of the signalling cascades via microRNAs. We observed that miR‐132/212 expression was significantly upregulated after occlusion of the femoral artery. miR‐132/212 knockout (KO) mice display a slower perfusion recovery after hind‐limb ischaemia compared to wildtype (WT) mice. Immunohistochemical analysis demonstrates a clear trend towards smaller collateral arteries in KO mice. Although Ex vivo aortic ring assays score similar number of branches in miR‐132/212 KO mice compared to WT, it can be stimulated with exogenous miR‐132, a dominant member of the miR‐132/212 family. Moreover, in in vitro pericyte‐endothelial co‐culture cell assays, overexpression of miR‐132 and mir‐212 in endothelial cells results in enhanced vascularization, as shown by an increase in tubular structures and junctions. Our results suggested that miR‐132/212 may exert their effects by enhancing the Ras‐Mitogen‐activated protein kinases MAPK signalling pathway through direct inhibition of Rasa1, and Spred1. The miR‐132/212 cluster promotes arteriogenesis by modulating Ras‐MAPK signalling via direct targeting of its inhibitors Rasa1 and Spred1.

Background To assess age-related changes of blood flow and geometry of the caval veins and right atrium (RA) using 4D flow cardiovascular magnetic resonance (CMR) data obtained in a population-based study. Methods An age-stratified sample ( n  = 126) of the population of the city of Freiburg, Germany, underwent transthoracic echocardiography and electrocardiogram-triggered and navigator-gated 4D flow CMR at 3 Tesla covering the caval veins and right heart. Study participants were divided into three age groups (1:20–39; 2:40–59; and 3:60–80 years of age). Analysis planes were placed in the superior and inferior caval vein. Subsequently, RA morphology and three-dimensional blood inflow pattern was assessed. Results Blood flow of the RA showed a clockwise rotating helix without signs of turbulence in younger subjects. By contrast, such rotation was absent in 12 subjects of group 3 and turbulences were significantly more frequent ( p  < 0.001). We observed an age-related shift of the caval vein axis. While the outlets of the superior and inferior caval veins were facing each other in group 1, lateralization occurred in older subjects ( p  < 0.001). A convergence of axes was observed from lateral view with facing axes in older subjects ( p  = 0.004). Finally, mean and peak systolic blood flow in the caval veins decreased with age (group 3 < 2 < 1). Conclusions We have provided reference values of 4D CMR blood flow for different age groups and demonstrated the significant impact of age on hemodynamics of the RA inflow tract. This effect of aging should be taken into account when assessing pathologic conditions of the heart in the future.

Aims Heart failure (HF) is a systemic inflammatory disorder with infections being an important cause of morbidity and mortality. We asked if HF patients have a higher susceptibility to infections compared with the general population and if a subtle secondary immunodeficiency facilitates infectious complications. Methods and results In a cohort of 92 patients with HF with reduced ejection fraction, we analysed recirculating lymphocyte subpopulations, serum immunoglobulin levels, and specific antibody titres against pneumococcal antigens. We quantified susceptibility to infections of the respiratory tract with a validated questionnaire and compared it to the general population. Susceptibility to infections of the respiratory tract was comparable in HF patients and the general population. Hypogammaglobulinaemia was present in 16% of HF patients, but anti‐pneumococcal titres showed no evidence of specific secondary antibody deficiency. Relative lymphopaenia in our HF cohort was due to B lymphocytopenia with a relative reduction in naive B‐cells and expansion of memory B‐cells while CD4+ and CD8+ T‐lymphocytes as well as NK‐cell counts were comparable between HF and healthy donors. The intake of the angiotensin receptor neprilysin (CD10) inhibitor (ARNI) sacubitril/valsartan was associated with increased B‐lymphocyte counts, possibly by an increased output of CD10+ transitional B lymphocytes from the bone marrow. Conclusion Despite a reduction of B lymphocytes in HF and mild hypogammaglobulinaemia, patients showed no evidence of secondary immunodeficiency or increased susceptibility to infections. The relevance of B‐cell lymphopenia in HF patients and modulation of B‐cell counts under ARNI treatment remains to be investigated.