Mediator Of Renin-angiotensin System Research Articles

Gastrodin regulates the expression of renin-angiotensin system-SIRT3 and proinflammatory mediators in reactive astrocytes via activated microglia.

Gastrodin, an anti-inflammatory herbal agent, is known to suppress microglia activation. Here, we investigated whether it would exert a similar effect in reactive astrocytes and whether it might act through the renin-angiotensin system (RAS) and sirtuin 3 (SIRT3). Angiotensinogen (ATO), angiotensin-converting enzyme (ACE), angiotensin II type 1 (AT1) and type 2 (AT2) receptor and SIRT3 expression was detected in TNC-1 astrocytes treated with BV-2 microglia conditioned medium (CM) with or without gastrodin and lipopolysaccharide (LPS) pre-treatment by RT-PCR, immunofluorescence and western blotting analysis. Expression of C3 (A1 astrocyte marker), S100A10 (A2 astrocyte marker), proinflammatory cytokines and neurotrophic factors was then evaluated. The results showed a significant increase of ATO, ACE, AT1, SIRT3, C3, proinflammatory cytokines and neurotrophic factors expression in TNC-1 astrocytes incubated in CM + LPS when compared with cells incubated in the CM, but AT2 and S100A10 expression was reduced. TNC-1 astrocytes responded vigorously to BV-2 CM treated with gastrodin + LPS as compared with the control. This was evident by the decreased expression of the abovementioned protein markers, except for AT2 and S100A10. Interestingly, SIRT3, IGF-1 and BDNF expression was enhanced, suggesting that gastrodin inhibited the expression of RAS and proinflammatory mediators but promoted the expression of neurotrophic factors. And gastrodin regulated the phenotypic changes of astrocytes through AT1. Additionally, azilsartan (a specific inhibitor of AT1) inhibited the expression of C3 and S100A10, which remained unaffected in gastrodin and azilsartan combination treatment. These findings provide evidence that gastrodin may have a therapeutic effect via regulating RAS-SIRT3.

Lymphatic Vessels and the Renin-Angiotensin-System.

The lymphatic system is an integral part of the circulatory system and plays an important role in the fluid homeostasis of the human body. Accumulating evidence has recently suggested the involvement of lymphatic dysfunction in the pathogenesis of cardio-reno-vascular (CRV) disease. However, how the sophisticated contractile machinery of lymphatic vessels is modulated, and possibly impaired in CRV disease, remains largely unknown. In particular, little attention has been paid to the effect of the renin-angiotensin-system (RAS) on lymphatics, despite the high concentration of RAS mediators that these tissue-draining vessels are exposed to and the established role of the RAS in the development of classic microvascular dysfunction and overt CRV disease. We herein review recent studies linking RAS to lymphatic function and/or plasticity, and further highlight RAS-specific signaling pathways - previously shown to drive adverse arterial remodeling and CRV organ damage - that have potential for direct modulation of the lymphatic system.

Gastrodin Regulates the Notch-1 Signal Pathway via Renin-Angiotensin System in Activated Microglia.

Notch-1 and renin angiotensin system (RAS) are involved in microglia activation. It has been reported that gastrodin inhibited inflammatory responses mediated by activated microglia. This study explored the possible interaction between this two pathways, and to determine whether gastrodin would exert its effects on both of them. Expression of RAS, Notch-1 signaling and proinflammatory mediators in lipopolysaccharide (LPS) activated BV-2 microglia subjected to various treatments was determined by Western blot and immunofluorescence. The protein expression of RAS, Notch-1 pathway and TNF-α and IL-1β was significantly increased in activated microglia. Exogenous Ang II markedly enhanced the expression of these biomarkers. Meanwhile, Azilsartan [a specific inhibitor of AT1 (AT1I)] inhibited the expression of Notch-1 pathway and proinflammatory cytokines. When Notch-1 signaling was inhibited with DAPT, ACE and AT1 expression remained unaffected, indicating that RAS can regulate the Notch-1 pathway in activated microglia but not reciprocally. Additionally, we showed here that gastrodin inhibited the RAS, Notch-1 pathway and inflammatory response. Remarkably, gastrodin did not exert any effect on expression of Notch-1 signaling when RAS was blocked by AT1I, suggesting that gastrodin acts on the RAS directly, not through the Notch-1 pathway. Furthermore, TNF-α and IL-1β expression was significantly increased in activated microglia treated with exogenous Ang II; the expression, however, was suppressed by gastrodin. Of note, expression of proinflammatory cytokines was further decreased in gastrodin and AT1I combination treatment. The results suggest that gastrodin acts via the RAS which regulates the Notch-1 signaling and inflammation in LPS-induced microglia.

Local Renin-Angiotensin System Signaling Mediates Cellular Function of Aortic Valves.

The renin-angiotensin system (RAS) is activated in aortic valve disease, yet little is understood about how it affects the acute functional response of valve interstitial cells (VICs). Herein, we developed a gelatin-based valve thin film (vTF) platform to investigate whether the contractile response of VICs can be regulated via RAS mediators and inhibitors. First, the impact of culture medium (quiescent, activated, and osteogenic medium) on VIC phenotype and function was assessed. Contractility of VICs was measured upon treatment with angiotensin I (Ang I), angiotensin II (Ang II), angiotensin-converting enzyme (ACE) inhibitor, and Angiotensin II type 1 receptor (AT1R) inhibitor. Anisotropic cell alignment on gelatin vTF was achieved independent of culture conditions. Cells cultured in activated and osteogenic conditions were found to be more elongated than in quiescent medium. Increased α-SMA expression was observed in activated medium and no RUNX2 expression were observed in cells. VIC contractile stress increased with increasing concentrations (from 10-10 to 10-6 M) of Ang I and Ang II. Moreover, cell contraction was significantly reduced in all ACE and AT1R inhibitor-treated groups. Together, these findings suggest that local RAS is active in VICs, and our vTF may provide a powerful platform for valve drug screening and development.

Interactions of the Brain Renin-Angiotensin-System (RAS) and Inflammation in the Sensitization of Hypertension.

Mounting evidence indicates that the renin-angiotensin (RAS) and immune systems interact with one another in the central nervous system (CNS) and that they are importantly involved in the pathogenesis of hypertension. Components comprising the classic RAS were first identified in the periphery, and subsequently, similar factors were found to be generated de novo in many different organs including the brain. There is humoral-neural coupling between the systemic and brain RASs, which is important for controlling sympathetic tone and the release of endocrine factors that collectively determine blood pressure (BP). Similar to the interactions between the systemic and brain RASs is the communication between the peripheral and brain immune systems. Systemic inflammation activates the brain’s immune response. Importantly, the RAS and inflammatory factors act synergistically in brain regions involved in the regulation of BP. This review presents evidence of how such interactions between the brain RAS and central immune mechanisms contribute to the pathogenesis of hypertension. Emphasis focuses on the role of these interactions to induce neuroplastic changes in a central neural network resulting in hypertensive response sensitization (HTRS). Neuroplasticity and HTRS can be induced by challenges (stressors) presented earlier in life such as a low-dose of angiotensin II or high fat diet (HFD) feeding in adults. Similarly, the offspring of mothers with gestational hypertension or of mothers ingesting a HFD during pregnancy are reprogrammed and manifest HTRS when exposed to new stressors as adults. Consideration of the actions and interactions of the brain RAS and inflammatory mediators in the context of the induction and expression of HTRS will provide insights into the etiology of high BP that may lead to new strategies for the prevention and treatment of hypertension.

Impact of the Renin-Angiotensin System on the Endothelium in Vascular Dementia: Unresolved Issues and Future Perspectives.

The effects of the renin–angiotensin system (RAS) surpass the renal and cardiovascular systems to encompass other body tissues and organs, including the brain. Angiotensin II (Ang II), the most potent mediator of RAS in the brain, contributes to vascular dementia via different mechanisms, including neuronal homeostasis disruption, vascular remodeling, and endothelial dysfunction caused by increased inflammation and oxidative stress. Other RAS components of emerging significance at the level of the blood–brain barrier include angiotensin-converting enzyme 2 (ACE2), Ang(1–7), and the AT2, Mas, and AT4 receptors. The various angiotensin hormones perform complex actions on brain endothelial cells and pericytes through specific receptors that have either detrimental or beneficial actions. Increasing evidence indicates that the ACE2/Ang(1–7)/Mas axis constitutes a protective arm of RAS on the blood–brain barrier. This review provides an update of studies assessing the different effects of angiotensins on cerebral endothelial cells. The involved signaling pathways are presented and help highlight the potential pharmacological targets for the management of cognitive and behavioral dysfunctions associated with vascular dementia.

Angiotensin II and angiotensin 1-7: which is their role in atrial fibrillation?

Atrial fibrillation (AF) is a significant cause of morbidity and mortality as well as a public health burden considering the high costs of AF-related hospitalizations. Pre-clinical and clinical evidence showed a potential role of the renin angiotensin system (RAS) in the etiopathogenesis of AF. Among RAS mediators, angiotensin II (AII) and angiotensin 1-7 (A1-7) have been mostly investigated in AF. Specifically, the stimulation of the pathway mediated by AII or the inhibition of the pathway mediated by A1-7 may participate in inducing and sustaining AF. In this review, we summarize the evidence showing that both RAS pathways may balance the onset of AF through different biological mechanisms involving inflammation, epicardial adipose tissue (EAT) accumulation, and electrical cardiac remodeling. EAT is a predictor for AF as it may induce its onset through direct (infiltration of epicardial adipocytes into the underlying atrial myocardium) and indirect (release of inflammatory adipokines, the stimulation of oxidative stress, macrophage phenotype switching, and AF triggers) mechanisms. Classic RAS blockers such as angiotensin converting enzyme inhibitors (ACE-I) and angiotensin receptor blockers (ARB) may prevent AF by affecting the accumulation of the EAT, representing a useful therapeutic strategy for preventing AF especially in patients with heart failure and known left ventricular dysfunction. Further studies are necessary to prove this benefit in patients with other cardiovascular diseases. Finally, the possibility of using the A1-7 or ACE2 analogues, to enlarge current therapeutic options for AF, may represent an important field of research.

Effects of angiotensin-(1–7) and angiotensin II on vascular tone in human cirrhotic splanchnic vessels

Evidence suggests that the renin angiotensin system (RAS) may play a role in the pathological splanchnic vasodilatation that leads to a hyperdynamic circulation in cirrhosis. An impaired contractile response to the angiotensin II peptide of the classical RAS system has been described in animal models of cirrhosis and in vivo in cirrhotic subjects. Furthermore, in experimental cirrhosis, the so-called alternate arm of the RAS was found to be upregulated and its effector peptide, angiotensin-(1–7) was shown to attenuate splanchnic vascular tone. The aim of this study was to explore the relevance of these findings to human disease.Omental arteries from cirrhotic and controls subjects were studied in isolation using a wire myograph. Varied protocols to evaluate the vasoactivity of RAS mediators were enacted.The contractile response to angiotensin II was comparable in cirrhotic vs control splanchnic arteries (61 ± 9 vs 68 ± 11% KPSS, respectively). Despite this, however, arterial contractility of the cirrhotic vessels correlated negatively with Child Pugh score (p = 0.0003, r=-0.83) and there was evidence that angiotensin II-induced contractility was increased in early cirrhosis. Angiotensin II-induced contractility was attenuated by angiotensin-(1–7) in cirrhotic and control arteries, however, adrenergic responses were not affected by angiotensin-(1–7).Contractile responses to angiotensin II are preserved in narrow lumen human cirrhotic splanchnic arteries and are comparatively augmented in early disease. Angiotensin-(1–7) had no vasodilatory effect on adrenergic tone, however, attenuated angiotensin II-induced contractility, possibly through an Ang-(1–7)-AT1R interaction, and thus may contribute to pathological vasodilatation in human cirrhosis.

Gastrodin attenuates microglia activation through renin-angiotensin system and Sirtuin3 pathway

Microglia activation and its mediated production of proinflammatory mediators play important roles in different neurodegenerative diseases; hence, modulation of microglia activation has been considered a potential therapeutic strategy to ameliorate neurodegeneration. This study was aimed to determine whether Gastrodin, a common herbal agent known to possess neuroprotective property, can attenuate production of proinflammatory mediators in activated microglia through the renin-angiotensin system (RAS) and Sirtuin3 (SIRT3). Expression of various members of the RAS including ACE, AT1, AT2, and SIRT3 in activated microglia was assessed by immunofluorescence and Western blot in hypoxic-ischemia brain damage (HIBD) in postnatal rats, and in BV-2 microglia in vitro challenged with lipopolysaccharide (LPS) with or without Gastrodin treatment. Expression of NOX-2, a subunit of NADPH oxidase, and proinflammatory mediators including iNOS and TNF-α, was also evaluated. The present results showed that expression of ACE, AT1, NOX-2, iNOS and TNF-α was markedly increased in activated microglia in the corpus callosum of HIBD rats, and in LPS stimulated BV-2 microglia. Remarkably, the expression was markedly attenuated following Gastrodin treatment. Conversely, Gastrodin enhanced AT2 and SIRT3 protein expression. In BV-2 microglia treated with Azilsartan, a specific inhibitor of AT1 (AT1I group), NOX-2 expression was decreased whereas that of SIRT3 in LPS + AT1I and LPS + Gastrodin group was increased when compared with the controls. In LPS + AT1I + Gastrodin group, SIRT3 expression was further augmented. More importantly, Gastrodin effectively reduced caspase 3 protein expression level in the HIBD rats coupled with a significant decrease in caspase 3 positive cells. We conclude that Gastrodin can exert its protective effects against the hypoxic-ischemia brain damage in the present experimental HIBD model. It is suggested that this is mainly through suppression of expression of RAS (except for AT2 and SIRT3) and proinflammatory mediators e.g. TNF-α in activated microglia.

Boldine Improves Kidney Damage in the Goldblatt 2K1C Model Avoiding the Increase in TGF-β.

Boldine, a major aporphine alkaloid found in the Chilean boldo tree, is a potent antioxidant. Oxidative stress plays a detrimental role in the pathogenesis of kidney damage in renovascular hypertension (RVH). The activation of the renin-angiotensin system (RAS) is crucial to the development and progression of hypertensive renal damage and TGF-β is closely associated with the activation of RAS. In the present study, we assessed the effect of boldine on the progression of kidney disease using the 2K1C hypertension model and identifying mediators in the RAS, such as TGF-β, that could be modulated by this alkaloid. Toward this hypothesis, rats (n = 5/group) were treated with boldine (50 mg/kg/day, gavage) for six weeks after 2K1C surgery (pressure ≥ 180 mmHg). Kidney function was evaluated by measuring of proteinuria/creatininuria ratio (U prot/U Crea), oxidative stress (OS) by measuring thiobarbituric acid reactive substances (TBARS). The evolution of systolic blood pressure (SBP) was followed weekly. Alpha-smooth muscle actin (α-SMA) and Col III were used as markers of kidney damage; ED-1 and osteopontin (OPN) were used as markers of inflammation. We also explored the effect in RAS mediators, such as ACE-1 and TGF-β. Boldine treatment reduced the UProt/UCrea ratio, plasma TBARS, and slightly reduced SBP in 2K1C hypertensive rats, producing no effect in control animals. In 2K1C rats treated with boldine the levels of α-SMA, Col III, ED-1, and OPN were lower when compared to 2K1C rats. Boldine prevented the increase in ACE-1 and TGF-β in 2K1C rats, suggesting that boldine reduces kidney damage. These results suggest that boldine could potentially be used as a nutraceutic.

Local bone marrow renin–angiotensin system in primitive, definitive and neoplastic haematopoiesis

The locally active ligand peptides, mediators, receptors and signalling pathways of the haematopoietic BM (bone marrow) autocrine/paracrine RAS (renin-angiotensin system) affect the essential steps of definitive blood cell production. Haematopoiesis, erythropoiesis, myelopoiesis, formation of monocytic and lymphocytic lineages, thrombopoiesis and other stromal cellular elements are regulated by the local BM RAS. The local BM RAS is present and active even in primitive embryonic haematopoiesis. ACE (angiotensin-converting enzyme) is expressed on the surface of the first endothelial and haematopoietic cells, forming the marrow cavity in the embryo. ACE marks early haematopoietic precursor cells and long-term blood-forming CD34(+) BM cells. The local autocrine tissue BM RAS may also be active in neoplastic haematopoiesis. Critical RAS mediators such as renin, ACE, AngII (angiotensin II) and angiotensinogen have been identified in leukaemic blast cells. The local tissue RAS influences tumour growth and metastases in an autocrine and paracrine fashion via the modulation of numerous carcinogenic events, such as angiogenesis, apoptosis, cellular proliferation, immune responses, cell signalling and extracellular matrix formation. The aim of the present review is to outline the known functions of the local BM RAS within the context of primitive, definitive and neoplastic haematopoiesis. Targeting the actions of local RAS molecules could represent a valuable therapeutic option for the management of neoplastic disorders.

Postpartum Assessment of the Renin Angiotensin System in Women with Previous Severe, Early-Onset Preeclampsia

Women with a history of severe preeclampsia are at an increased risk for the development of vascular disease. We hypothesized that abnormalities in the renin-angiotensin system (RAS) may be a predisposing factor. Physiological assessments were conducted at an academic center. Sixteen women with previous severe preeclampsia (PPE) were compared with nine previously pregnant controls (PPC) and 11 never-pregnant controls (NPC). Baseline circulating components of the RAS and expression of angiotensin (ANG) II type I (AT1) and type II (AT2) receptors in the skin were assessed along with the response to simulated orthostatic stress using incremental lower-body negative pressure (LBNP: -15, -25, and -40 mm Hg) and a graded ANG II infusion (1 and 3 ng/kg · min). Response to LBNP and ANG II was evaluated. RAS components were not different between previously pregnant groups, but were decreased compared with NPC subjects. In response to LBNP, there were significant increases in RAS components in all three groups, but the response to this stimulus was significantly lower and delayed in PPE subjects. Despite the blunted rise in circulating RAS mediators in PPE subjects, their blood pressure was maintained in 88% compared with only 33 and 55% in the PPC and NPC groups, respectively (P = 0.014). All three groups responded to the graded ANG II infusion with an increase in blood pressure that was significantly more pronounced in PPE subjects (P = 0.037) correlating with AT1/AT2 receptor expression. Alterations in the RAS in formerly preeclamptic patients may contribute to future vascular disease.

Angiotensin (1‐7) into rostral ventrolateral medulla is enhanced in spontaneously hypertensive rats

BackgroundAngiotensin‐(1‐7) (Ang‐(1‐7)) is recognized as an important mediator of renin angiotensin system. Ang‐(1‐7) is a peptide of ligand for Ang‐(1‐7)‐Mas receptor, and has opposite actions of angiotensin II in the vasculature. In the central nervous system, however, it has been shown that microinjection of Ang‐(1‐7) into rostral ventrolateral medulla (RVLM), one of vasomotor centers of brainstem increased blood pressure in normotensive rats. The aim of the present study was to determine the possible involvement of Ang‐(1‐7) in the RVLM in hypertension.Methods and ResultsIn anesthetized Wistar‐Kyoto (WKY) rats and spontaneously hypertensive rats (SHR), we microinjected Ang‐(1‐7) (100 pmol) and a Mas receptor antagonist (A‐779: 100 pmol) into the RVLM. Microinjection of Ang‐(1‐7) increased blood pressure in both strains. The changes were, however, significantly greater in SHR than WKY rats (13.3 ± 1.3 mmHg, n=7 vs. 6.6 ± 0.8 mmHg, n=5; p<0.05). In contrast, microinjection of a Mas receptor antagonist (A‐779) deceased blood pressure significantly greater in SHR than WKY rats (‐26.4 ± 1.7 mmHg, n=5 vs. ‐13.7 ± 0.8 mmHg, n=5; p<0.05).ConclusionBoth exogenous and endogenous Ang‐(1‐7) in the RVLM are enhanced in spontaneously hypertensive rats. The Ang‐(1‐7)‐Mas receptor pathway in RVLM may contribute to the mechanisms of blood pressure elevation in spontaneously hypertensive rats.

Renin-angiotensin system activation correlates with microvascular dysfunction in a prospective cohort study of clinical sepsis

IntroductionMicrovascular dysregulation characterized by hyporesponsive vessels and heterogeneous bloodflow is implicated in the pathogenesis of organ failure in sepsis. The renin-angiotensin system (RAS) affects the microvasculature, yet the relationships between RAS and organ injury in clinical sepsis remain unclear. We tested our hypothesis that systemic RAS mediators are associated with dysregulation of the microvasculature and with organ failure in clinical severe sepsis.MethodsWe studied 30 subjects with severe sepsis, and 10 healthy control subjects. Plasma was analyzed for plasma renin activity (PRA) and angiotensin II concentration (Ang II). Using near-infrared spectroscopy, we measured the rate of increase in the oxygen saturation of thenar microvascular hemoglobin after five minutes of induced forearm ischemia. In so doing, we assessed bulk microvascular hemoglobin influx to the tissue during reactive hyperemia. We studied all subjects 24 hours after the development of organ failure. We studied a subset of 12 subjects at an additional timepoint, eight hours after recognition of organ failure (early sepsis).ResultsAfter 24 hours of resuscitation to clinically-defined endpoints of preload and arterial pressure, Ang II and PRA were elevated in septic subjects and the degree of elevation correlated negatively with the rate of microvascular reoxygenation during reactive hyperemia. Early RAS mediators correlated with microvascular dysfunction. Early Ang II also correlated with the extent of organ failure realized during the first day of sepsis.ConclusionsRAS is activated in clinical severe sepsis. Systemic RAS mediators correlate with measures of microvascular dysregulation and with organ failure.

Renin-angiotensin system in the pathogenesis of liver fibrosis

Hepatic fibrosis is considered a common response to many chronic hepatic injuries. It is a multifunctional process that involves several cell types, cytokines, chemokines and growth factors leading to a disruption of homeostatic mechanisms that maintain the liver ecosystem. In spite of many studies regarding the development of fibrosis, the understanding of the pathogenesis remains obscure. The hepatic tissue remodeling process is highly complex, resulting from the balance between collagen degradation and synthesis. Among the many mediators that take part in this process, the components of the Renin angiotensin system (RAS) have progressively assumed an important role. Angiotensin (Ang) II acts as a profibrotic mediator and Ang-(1-7), the newly recognized RAS component, appears to exert a counter-regulatory role in liver tissue. We briefly review the liver fibrosis process and current aspects of the RAS. This review also aims to discuss some experimental evidence regarding the participation of RAS mediators in the pathogenesis of liver fibrosis, focusing on the putative role of the ACE2-Ang-(1-7)-Mas receptor axis.

The renin–angiotensin system and diabetes: An update

In the past few years the classical concept of the renin-angiotensin system (RAS) has experienced substantial conceptual changes. The identification of the renin/prorenin receptor, the angiotensin-converting enzyme homologue ACE2 as an angiotensin peptide processing enzyme, Mas as a receptor for Ang-(1-7) and the possibility of signaling through ACE, have contributed to switch our understanding of the RAS from the classical limited-proteolysis linear cascade to a cascade with multiple mediators, multiple receptors, and multi-functional enzymes. In this review we will focus on the recent findings related to RAS and, in particular, on its role in diabetes by discussing possible interactions between RAS mediators, endothelium function, and insulin signaling transduction pathways as well as the putative role of ACE2-Ang-(1-7)-Mas axis in disease pathogenesis.

Effect of propranolol on the splanchnic and peripheral renin angiotensin system in cirrhotic patients

To evaluate the effect of beta-blockade on angiotensins in the splanchnic and peripheral circulation of cirrhotic patients and also to compare hemodynamic parameters during liver transplantation according to propranolol pre-treatment or not. Patients were allocated into two groups: outpatients with advanced liver disease(LD) and during liver transplantation(LT). Both groups were subdivided according to treatment with propranolol or not. Plasma was collected through peripheral venipuncture to determine plasma renin activity(PRA), Angiotensin(Ang) I, Ang II, and Ang-(1-7) levels by radioimmunoassay in LD group. During liver transplantation, hemodynamic parameters were determined and blood samples were obtained from the portal vein to measure renin angiotensin system(RAS) components. PRA, Ang I, Ang II and Ang-(1-7) were significantly lower in the portal vein and periphery in all subgroups treated with propranolol as compared to non-treated. The relationships between Ang-(1-7) and Ang I levels and between Ang II and Ang I were significantly increased in LD group receiving propranolol. The ratio between Ang-(1-7) and Ang II remained unchanged in splanchnic and peripheral circulation in patients under beta-blockade, whereas the relationship between Ang II and Ang I was significantly increased in splanchnic circulation of LT patients treated with propranolol. During liver transplantation, cardiac output and index as well systemic vascular resistance and index were reduced in propranolol-treated subgroup. In LD group, propranolol treatment reduced RAS mediators, but did not change the ratio between Ang-(1-7) and Ang II in splanchnic and peripheral circulation. Furthermore, the modification of hemodynamic parameters in propranolol treated patients was not associated with changes in the angiotensin ratio.

Modeling a hydropic recipient twin in twin-twin transfusion syndrome

We developed a mathematical model of twin-twin transfusion syndrome (TTTS) that includes a hydropic recipient twin, adding interstitial and intracellular fluid compartments, fetal congestive cardiac failure, and the dynamics of renin-angiotensin system (RAS) mediators to our previous TTTS model. Ten differential equations for each twin, coupled by the net fetofetal transfusion of blood and blood components, i.e., colloids, osmoles, and RAS mediators, describe the development of fetal arterial and venous blood volumes, blood osmolality and colloid osmotic pressure (COP), interstitial fluid volume and COP, intracellular fluid volume, amniotic fluid volume and osmolality, and RAS mediator concentration. We included varying placental anastomoses, placental sharing, and amnionicity. The 20 differential equations were solved numerically from 0 to 40 wk with a 0.6-s time step. Consistent with clinical experience, model predictions are as follows. Unidirectional arteriovenous anastomoses and arteriovenous anastomoses inadequately compensated by oppositely directed anastomoses cause severe TTTS that includes a hydropic recipient. Adequately compensated arteriovenous anastomoses simulated TTTS without hydrops. The probability that oppositely directed anastomoses prevent onset of a hydropic recipient after TTTS onset, i.e., the largest interval between onset of TTTS and onset of hydrops in the recipient, was best for a venovenous anastomosis, closely followed by an arterioarterial and finally an oppositely directed arteriovenous anastomosis. Hydropic recipients have decreased amniotic fluid volume. Unequal placental sharing and amnionicity modify hydrops onset. In conclusion, our model simulates a sequence of events that results in a hydropic recipient twin in severe TTTS. The model may allow an assessment of the efficacy of current therapeutic interventions for TTTS cases that include a hydropic recipient twin.