This pilot study, which, for the ﬁrst time, applied constant electrical signals chronically to a beating heart with the intention of treating impaired cardiacfunction, achieved extremely bene ﬁcial results that raise more questions than they answer. Our intent with this experiment was to con ﬁrm our hypothesis that microcurrent can in ﬂuence the in ﬂammation of the components of the extracellular matrix and can affect organ function. We focused on certain components of the extracellular matrix, because existing evidence from studies of mechanical circulatory support and left ventricular unloading has shown that normalization of the extracellular matrix is an important precursor to a reverse remodelling of cardiacfunction. 15,16 The duration of application of the microcurrent was derived (i) from our own clinical experience of a reverse remodelling process induced by mechanical unloading of the heart, a process that achieved optimal improvement of function within 4 to 8 weeks; (ii) from studies using cardiomyocytes exposed to microcurrent under culture conditions, with ﬁndings showing
Only limited data exist on heart function and the pre- valence of heart failure in patients suffering from primary AI. Animal models nicely demonstrate the necessity of GC and MC replacement to maintain proper cardiacfunction in adrenalectomized rats [ 25 ]. In humans, older, cross- sectional studies in 22 patients with AI and long-term dis- ease duration, heart failure was found in almost one-third of the patients [ 26 ]. This is in contrast to our study, in which systolic heart function was normal in all patients, despite a long disease duration of 19 ± 10 years. Systolic heart function was better in matched healthy controls compared with patients with primary AI. This difference was espe- cially marked, when patients were divided according to their previous median renin concentrations, showing sig- ni ﬁcantly worse ejection fraction in the group of Median- Renin low . Therefore, optimizing MC replacement therapy
Magnetic resonance imaging was performed using a 7-T Bruker NMR spectrometer and 18 F- ﬂuorodeoxyglucose posi- tron emission tomography on a high-resolution small-animal camera (quadHIDAC; Oxford Positron), respectively. High- resolution echocardiography with quantitative 3-dimensional assessment of cardiacfunction was performed on an ultrasound device with frame rates up to 280 Hz (Philips Medical Systems). Left ventricular (LV) catheterization was performed in closed-chest anesthetized mice, as described previously, 19 with dobutamine administered via the cannu- lated left jugular vein accompanied by measurements of heart rate, maximal LV pressure, and the ﬁrst derivative of LV pressure.
Levosimendan improves cardiacfunction in heart failure populations; however, its exact mechanism is not well defined. We analysed the short-term impact of levosimendan in heart failure patients with ischemic and non-ischemic cardiomyopathy (CMP) using multiparametric cardiac magnetic resonance (CMR). We identified 33 patients with ischemic or non-ischemic CMP who received two consecutive CMR scans prior to and within one week after levosimendan administration. Changes in LV ejection fraction (LVEF) and LV volumes, as well as changes in strain rates, were measured prior to and within one week after levosimendan infusion. LV scarring, based on late gadolinium enhancement (LGE), was correlated to changes in LV size and strain rates. Both LV endiastolic (EDV) and endsystolic volumes (ESV) significantly decreased (EDV: p=0,001; ESV: p=0,002) after levosimendan administration, with no significant impact on LVEF (p=0.41), cardiac output (p=0.61), and strain rates. Subgroup analyses of ischemic or non-ischemic CMP showed no significant differences between the groups in terms of short-term LV reverse remodeling. The presence and extent of scarring in LGE did not correlate with changes in LV size and strain rates. CMR is able to monitor cardiac effects of levosimendan infusion. Short-term follow-up of a single levosimendan infusion using CMR shows a significant decrease in LV size, but no impact on LVEF or strain measurements. There was no difference between patients with ischemic or non-ischemic CMP. Quantification of LV scarring in CMR is not able to predict changes in LV size and strain rates in response to levosimendan.
which reported an increase of hypertension rate every ten years in women more than three- times the increase of that in men (69% vs. 15%) (421). In our study, hypertension rates at age under 65 was higher in men than in women, in age group 65-74 appeared a double rate of increase of hypertension in females with the noticeable result of almost similar rates between men and women over the age of 65 years (74.5% in men versus 72.6% in women). These observational findings indicate an interfering role of female hormones, or their decrease, in pathogenesis of hypertension. This observation, although the prevalence of hypertension in women was not higher than that of men as suggested by Kannel et al. (278), agrees with Roger et al. (7), who reported a discreet increase of hypertension rates in female objects of age over 55 years with the result that more than almost 75% postmenopausal women present hypertension. Hypertension, consists a pressure overload situation, which can consequently trigger the cardiac remodeling of the left ventricle (422) and therefore result to diastolic disorder and even diastolic heart failure (279, 280), sequence which occurs principally postmenopausal when estrogen are detrimentally reduced and women are no longer under their protecting effect (92, 423). Indeed, investigations of the possible association of menopausal status of the female population to the symptomatic or asymptomatic diastolic disorders, independently from the systolic cardiacfunction, it was clearly confirmed the significant role of the estrogen loss in the concentric cardiac remodeling. The crucial role of hypertension, among other factors, in the diastolic dysfunction, in a way other than RAAS-activation, is also supported from our results. Particularly, our analysis presented that the initial significant association of renin and aldosterone to the HFpEF in women in the unadjusted model lost its statistical strength when adjusted for age and CVRF (model 2).
The comprehensive analysis of heart morphology and cardiacfunction revealed some intriguing insights into the role of BMP9 and BMP10. Cardiac failure can be defined by a decrease in SV, due to systolic or diastolic dysfunction, where the heart has problems with contractility (systolic dysfunction) or problems with chamber filling due to stiffness of the heart (diastolic dysfunction) leading to a decrease in EF 209 . These changes result in an increase in ventricular end diastolic pressure. To normalize this increase in preload, the heart dilates which over time can lead to cardiomyopathy and ultimately HF 209 . Although the DKO hearts show clear signs of cardiac hypertrophy, via MRI analysis, heart: tibia comparison and histochemistry, by 1 month of age they do not show a severe reduction in EF. However by 6 months of age these DKO animals display a higher increase in LVM and a significant reduction in EF but these symptoms did not progressively get worse, suggesting the system was able to stabilize and cope with these adverse effects hence why these mice survived. What causes the observed increase in LVM in the DKO mice can be explained by the increase detected in SV along with EDV, which in known to increase preload exerted on the heart 210 . Preload is defined as the stretching of CMs before contraction and according to the Frank Starling mechanism, an rise in SV increases the volume of blood in the heart, by stretching the ventricles which expand during diastole 211 . This increase in blood volume enhances the force of contraction and therefore also increases the blood pumped out during diastole 211 . Normally a significant decrease in EF is a hallmark of cardiac failure. However in the case of the DKO mice, the reduction in EF did not significantly worsen over time suggesting that this adaptation was more physiological rather than pathological. Overall loss of BMP9 and BMP10 results in a decrease in EF and increases in LVM, SV and wall thickness. This concludes that although the EF is lower, the SV is higher and the heart functional as there are no signs of a thinner ventricle wall, though the LVM is significantly increased, meaning a sufficient amount of blood is being pumped around the system and is not detrimental to the animal.
There is a connection between increased UCP levels, derangement of myocardial energetics and cardiac dysfunction. The contractile function of the heart is dependent on a sufficient energy supply that has to be continuously adapted to the energy demand. The required energy is brought by constant re- synthesis of ATP by oxidative phosphorylation in the mitochondria. In spite of this, cardiac energy metabolism involves three components: substrate utilization, oxidative phosphorylation, and ATP transfer and utilization (Neubauer 2007). A significant step in the latter component is the transfer of a phosphoryl group from ATP to the high-energy phosphate compound, phosphocreatine (PCr), by creatine kinase. The creatine kinase reaction equilibrium favors ATP synthesis over PCr synthesis by a factor of ~100. Thus, when the energy demand outstrips the energy supply, PCr levels decline, whereas ATP levels remain unchanged, and free ADP levels rise. A reduction in the ATP transfer capacity through creatine kinase leads to an insufficient transport of high-energy phosphate bonds from the mitochondria to the myofibrils, resulting in contractile dysfunction (Neubauer 2007). UCPs are believed to play a critical role in this context, as they uncouple oxygen consumption from ATP synthesis and thus impair myocardial energy metabolism.
Six weeks post-MI mice were anesthesized with isoflurane 1,5% via a respiration cone and cardiac MRI was performed on Medspec 3T MR system (Bruker, Biospin, Rheinstetten, Germany) by Ass.-Prof. Priv.-Doz. Martin Krššák, PhD (Centre of Excellence High Field MR, Department of Radiology, Medical University of Vienna, Austria) The system worked with a BGA-12 microgradient insert (200mT/m) and a 38 mm 1 H tuned resonator. Hemodynamic analyses were performed under spontaneous breathing and steady control of vital parameters (breathing rate, temperature, ECG) by a 1025 MR-compatible Small Animal Monitoring & Gating System (SA Instruments Inc., Stony Brook, NY, USA). Body temperature was kept stable at 37°C with a constant stream of heated air. Cardiacfunction was visualized with a prospective ECG-gated cine gradient echo based flow compensated MR sequence as implemented in ParaVision 3.1 (Bruker Biospin, Ettlingen, Germany) in a long (TE= 4.5 ms, TR= 15 ms, slice thickness= 1.5 mm, NA= 4, FOV= 50 x 30 mm, matrix 128 x 96, 7-10 frames) and short (TE= 3.8 ms, TR= 14 ms, slice thickness= 1.5 mm, NA= 4, FOV= 25 x 35 mm, matrix 64 x 96, 7-10 frames) axes orientation, with 4-5 imaging levels across the short axes from the apex to the base of the heart. Each imaging session lasted less than 40mins per animal. All mice survived this procedure.
The transcriptional regulator JDP2 (Jun dimerization protein 2) has been identified as a prognostic marker for patients to develop heart failure after myocardial infarction. We now performed in vivo studies on JDP2-overexpressing mice, to clarify the impact of JDP2 on heart failure progression. Therefore, during birth up to the age of 4 weeks cardiac-specific JDP2 overexpression was prevented by doxycycline feeding in transgenic mice. Then, JDP2 overexpression was started. Already after 1 week, cardiacfunction, determined by echocardiography, decreased which was also resembled on the cardiomyocyte level. After 5 weeks blood pressure declined, ejection fraction and cardiac output was reduced and left ventricular dilatation developed. Heart weight/body weight, and mRNA expression of ANP, inflammatory marker genes, collagen and fibronectin increased. Collagen 1 protein expression increased, and fibrosis developed. As an additional sign of elevated extracellular matrix remodeling, matrix metalloproteinase 2 activity increased in JDP2 mice. Thus, JDP2 overexpression is deleterious to heart function in vivo. It can be concluded that JDP2 overexpression provokes cardiac dysfunction in adult mice that is accompanied by hypertrophy and fibrosis. Thus, induction of JDP2 is a maladaptive response contributing to heart failure development.
dysfunction but rather improved systolic function under fasted conditions (179). MGL-/- mice demonstrated decreased cardiac MAG hydrolase activity and an accumulation of cardiac MAG (11,51,52). Yet, the functional consequences of MGL- deficiency on cardiacfunction have not been investigated. Cardiomyocytes lack perilipin 1, which plays a central role in adipocyte lipolysis. Instead, they express high levels of perilipin 5 (71-73) as well as perilipin 2, 3, and 4 (71,180). Perilipin 5 and perilipin 1 share the ability to bind and regulate members of the lipolytic proteome such as HSL and CGI-58. In contrast to perilipin 1, these interactions are not modulated by increasing cAMP levels although the phosphorylation of perilipin 5 is promoted under these conditions (67,181). Rather, perlipin 5 recruits lipolytic proteins to the lipid droplet surface in the basal state (49,181,182). Perilipin 5 interacts also with ATGL and was proposed to facilitate the lipolytic action of the ATGL/CGI-58 complex (67,181). Yet, overexpression of perilipin 5 in cells is associated with lipid droplet accumulation and impaired TAG catabolism suggesting a barrier function of perilipin 5 similar to perilipin 1 (72,181,183). This concept was recently confirmed in vivo by the characterization of transgenic mouse models. Cardiomyocyte-specific overexpression of perilipin 5 resulted in cardiac TAG accumulation, which was linked to impaired TAG ata olis a d de reased β-oxidation (180,184). Conversely, perilipin 5-deficiency resulted in increased cardiac TAG catabolism, reduced cardiac TAG levels and i reased ardia β-oxidation (76). However, how perilipin 5 regulates cardiac lipolysis in response to metabolic signals such as hormones or metabolites remains to be elucidated.
brain natriuretic peptide (NT-proBNP), a marker of hemodynamic stress characterizing myocardial function. To date, comprehensive analyses of the relation between lung function and mortality and the role of systemic inflammation and cardiac impairment therein are still rare for the general older population. Therefore, we investigated the relation of various lung function parameters with all-cause mortality in a large cohort study of community dwelling older adults and analysed whether this relation is independent of biomarkers of inflam- mation, cardiacfunction and myocardial injury.
Magnetic resonance imaging (MRI) is a well-established imaging technique and is increasingly used to follow up cardiac transplant patients to noninvasively evaluate cardiacfunction and myocardial tissue composition. 4,5 In particular, the differen- tiation of ischemic or nonischemic patterns of late gadolinium enhancement (LGE) can help to differentiate scars from cardiac allograft vasculopathy (CAV) or ﬁbrotic remnants from prior rejection episodes. 6 With the introduction of T 1 mapping tech- niques using modiﬁed Look–Locker inversion recovery (MOLLI) sequences, the evaluation and quanti ﬁcation of diffuse cardiac diseases also became possible. 7 In this setting an elevation of the native T 1 values represents changes in the myocardial com- position, mainly ﬁbrosis, amyloid deposition, or inﬂammation. On the other hand, a reduction of the T 1 value represents myo- cardial fat depositions (eg, Fabry’s disease). 8 Postcontrast T
i transient amplitude as well as accelerated relaxation and SR Ca 2+ uptake (Roof et al. 2017). Interestingly, this study also demonstrated that the effects of CXL-1020 on ventricular relaxation in failing rat hearts and shortening of single failing cardiac myocytes are more pronounced than in response to the inotrope milrinone. In line with independence from β-AR signaling, incubation with CXL-1020 did not affect cAMP and cGMP levels of murine ventricular myocardium (Zhu et al. 2015). CXL-1020 was further tested in two canine models of ischemic cardiomyopathy (ICM) and heart failure. Under both disease conditions, improved cardiacfunction and beneficial effects on parameters that affect cardiac afterload were obtained for the compound. Consequently, CXL-1020 was the first HNO donor to be tested in patients suffering from ADHF. The clinical study revealed that CXL-1020 induced an increase in cardiac and stroke volume indices, reflecting improved contractile function. Simultaneously, systemic vascular resistance and mean arterial pressure declined, indicating vasorelaxation and reduced cardiac afterload. CXL-1020-mediated vasorelaxation, but not its inotropic property, was shown to depend on sGC and, unlike AS and NCA, does not seem to involve direct oxidation and activation of PKGIα (Zhu et al. 2015). While vasorelaxation was blunted in mice that lacked the β subunit of sGC, it remained unchanged in mice which expressed a PKGIα mutant that was unable to dimerize. At present, the development of CXL-1020-successor compounds with improved suitability for therapeutic application, e.g. reduced injection site-inflammation, are being developed by Cardioxyl Pharmaceuticals in order to soon allow patients to benefit from the positive inotropic, lusitropic and vasorelaxing properties of HNO donor compounds (Hartman et al. 2018).
After its introduction by Wundrak et al.(Wundrak et al., 2016) in 2016, tyGRASP has been applied in few studies. Haris et al.(Haris et al., 2017) investigated fetal cardiac data of five volunteers at 1.5T by using tyGRASP combined with self-gated cardiac cine MRI. Further, they developed a free-breathing method for retrospective fetal cine MRI using Dopper ultrasound cardiac gating and tyGRASP for accelerated acquisition capable of detecting fetal movements for motion compensation(Haris et al., 2019). Haji-Valiyadeh et al.(Haji-Valizadeh et al., 2018) validate an optimal 12-fold accelerated real-time cine MRI pulse sequence using tyGRASP to produce accurate LV functional parameters in patients at 1.5T and 3T. Jan et al.(Paul et al., 2016) test tyGRASP combine with compressed sensing in real-time imaging to evaluate cardiacfunction. These experiments certified the feasibility of tyGRASP in cardiac real-time imaging in the clinical application. Due to the property of radial trajectory and real- time imaging, it could enable free-breathing acquisitions and imaging, such as in highly arrhythmic patients or fetal cardiovascular MRI.
43 pythons and crocodiles, both known for their long fasting periods and large meal sizes. Campen and Starck (2012) reviewed the studies that indicate a tight connection between digestion and the cardiovascular system: (1) Starck and Wimmer (2005) and Secor (2008) both measured increased blood flow volume into the gastrointestinal tract in pythons. Starck and Wimmer (2005) measured significantly increased blood flow in the liver portal vein (3-fold increase) and the mesenteric artery (ca. 30% increase) compared to predigesting values in pythons. Secor (2008) measured only the superior mesenteric artery and reported an 11-fold increase in blood flow volume in pythons. From the results of these studies it remains unclear whether this increase in blood supply of the digestive tract is a result of pulmonary bypass or of generally increased cardiac output, because blood flow measurements were performed on peripheral blood vessels. (2) Jones and Shelton (1993) suggested that bypass might play a role for digestion balancing blood pH during the crocodilian alkaline tide, but unfortunately they did not test this idea. (3) Axelsson and Fritsche (1991) could not explain the significant permanent pulsatile blood flow they measured in the coeliac artery in fasting Crocodylus porosus, because blood flow in the left aorta was very low. They concluded that right aortic blood enters the left aorta through the Foramen
In cardiac xenotransplantation, the advancement of IS regimens and genetical modifications have improved outcomes over recent years. Many studies have emphasized that the strategy of anti-inflammatory agents is increasingly important for postoperative survival [64, 89]. But before we draw any conclusion, administration of IS and other treatments cannot be ignored. To study this more thoroughly, single variable research would be a good choice. For example, monitoring inflammatory response while changing the anti-inflammatory drug or dose in a xenograft in which immunological tolerance has been obtained. In preclinical baboon experiments this approach is difficult to realize and other models might be needed.
substantially represented in cohorts investigating a cTNI elevation without obvious cardiac involvement. The dis- tribution of risk factors in these studies complies well with our findings. In stroke cohorts, a vascular burden per se could be assumed [25,26]. In studies investigating a cTNI elevation in critical illness in a high percentage of patients vascular risk factors were evident: diabetes 33%, hypertension 53% and hypercholesterolemia 37% . Even analyses within heterogeneous cohorts dem- onstrated a considerable vascular burden . Our find- ings might also support the hypothesis of vascular risk profile being a prerequisite for cTNI elevation in other conditions then ACS. In this context there is no pre- dominating risk factor; the hypertension seems to pos- sess the strongest association with increased cTNI levels. There is evidence supporting the hypothesis that CK levels directly correlate with seizure duration [27,28]. Increased CK levels could therefore be interpreted as a result of extended phases of global ischemia. In our study, patients with cTNI release presented more fre- quently with elevated CK values. This is in line with findings depicted by Eskandarian and co-workers, who demonstrated on average higher troponin levels after complicated seizers as indicated by different heart
In this paper, we propose an analytical and methodological comparison between two of the most known distance-based methods in the evaluation of the geographic concentration of economic activity. These two methods are Ripley’s K function, a cumulative function popularised by Marcon and Puech (2003) that counts the average number of neighbours of each point within a circle of a given radius, and K density function, a probability density function of point-pair distances introduced by Duranton and Overman (2005), which considers the distribution of bilateral distances between pairs of points. To carry out this comparison, we first apply both methodologies to an exhaustive database containing Spanish manufacturing establishments and we evaluate the spatial location patterns obtained from both analysis. After an initial analysis, we realise that although these functions have always been treated as substitutes they should be considered as complementary, as both cumulative function and probability density function provide relevant and necessary information about the distribution of activity in space. Therefore, our next step will be to assess what are the advantages and disadvantages of each methodology from a descriptive and analytical way.
Heutzutage sind kardiochirurgische Operationen mit komplettem kardiopulmonalem Bypass zum Standardverfahren geworden. Trotz verbesserter operativer Techniken und gewissenhaftem Myokardschutz kommt es bei knapp 3 % aller Patienten zu einer postoperativen myokardialen Pumpschwäche (Low Cardiac Output) des Herzens während oder nach dem Weaning von der Herz-Lungen-Maschine (Smedira et al., 2001). Die Gründe hierfür sind vielschichtig und oft nicht klar abgrenzbar; dazu gehören: lange Ischämiezeit des Myokards während des Abklemmens, Reperfusionsschäden, Dysfunktion des Myokards nach Kardioplegie, Aktivierung der Gerinnungskaskade und/oder des Immunsystems und vorbestehende Krankheiten des Herzens. (Doll et al., 2004) Oft werden diese Faktoren noch durch begleitenden Co-Morbiditäten insbesondere bei älteren Patienten verkompliziert.
1 Severtsov Institute of Ecology and Evolution, Moscow, Russia, email@example.com 2 Research Institute of Human Morphology, Moscow, Russia
It is well documented that immune function varies substantially on a seasonal basis. The autumn–winter season is the most critical period for animals. Non-tropical animals have evolved specific adaptations to cope with winter energy shortages. Animals can overcome periods of unfavorable environmental conditions by physiological hypothermia (daily torpor/ hibernation), characterized by strongly reduced metabolic rate and body temperature. Studies from mammals indicate that hibernation affects both the innate and adaptive immune systems. During winter representatives of subfamily Cricetinae demonstrate different types of hypothermia: (a) long-term hibernation (e.g. Cricetus