Development Of Cardiovascular Dysfunction Research Articles

Doxorubicin Dose-Dependent Impact on Physiological Balance-A Holistic Approach in a Rat Model.

Doxorubicin (DOX) is commonly used in several chemotherapies to treat various cancers, but it is known to cause cardiotoxicity and cardiac symptoms. Autonomic dysfunction is thought to contribute to the cardiotoxic effects of DOX, but the specific dose required to disrupt homeostatic processes is still unclear and is influenced by numerous factors. This study aimed to investigate how the DOX dosage affects autonomic function and physiological parameters, to elucidate the neurocardiac mechanisms underlying the observed cardiovascular side effects. Wistar rats were treated with DOX for four weeks and divided into three dosing groups: DOX8 (2 mg/kg/week), DOX16 (4 mg/kg/week), and DOX20 (5 mg/kg/week). A control group received NaCl 0.9% saline (1 mL/kg/week). In an acute experiment, we recorded blood pressure (BP), electrocardiogram, heart rate (HR), and respiratory rate (RF). Baroreflex gain and chemoreflex sensitivity were calculated, and cardiac tissue was analyzed with picrosirius histochemistry to measure collagen content. Our results showed that the LF/HF ratio, indicative of autonomic activity, was altered along with hypotension and bradycardia at a cumulative DOX dose threshold of 16 mg/kg. We observed a positive correlation between DOX dose and BP, HR, urinary norepinephrine, LF/HF ratio, and fibrotic heart area. Lower LF/HF ratios were associated with high DOX doses, reflecting drug-induced impairment of autonomic control of HR. This study provides valuable insights into the dose-dependent effects of DOX on physiological parameters and the development of cardiovascular dysfunction. These findings are critical, which is important for optimizing the management and therapeutic strategies for patients undergoing DOX-based chemotherapy.

Peculiarities of changes in the cardiovascular system in the course of sepsis in newborns

The issues of early diagnostics of cardiovascular disorders in neonates with sepsis using up-to-date methods of examination are relevant today and will remain so in the future. They can be used as screening methods with the purpose to verify the possible development of cardiovascular dysfunction. Aim of the study: The study aimed to investigate the peculiarities of possible changes in the cardiovascular system and physiological electrical heart activity in neonates with signs of generalised infectious-inflammatory process, and to assess possible diagnostic methods and use of electrocardiography to verify cardiovascular disorders in newborns with neonatal sepsis. Materials and methods: To achieve the study objective, we followed up a total of 69 neonates with signs of generalised infectious-inflammatory process. Group I (32 patients – 46.4%) included neonates with a term of gestation of 37–42 weeks, and group II included 37 preterm neonates (53.6%) with a term of gestation under 36 weeks inclusive. Results: Generalised infectious-inflammatory process during the neonatal period of term infants is accompanied by electrocardiographic signs of left ventricular overload associated with the female sex (r = 0.30), delivery by cesarean section (r = 0.27), and assessment of neonatal condition by a 5-minute Apgar score (r = −0.33). The study demonstrates that increased values of lactate dehydrogenase activity in the blood plasma both in the term and preterm neonates are associated with left ventricular overload among the former, and the right ventricular overload among the latter, that is, preterm neonates. Conclusions: Increased values of lactate dehydrogenase activity in the blood serum of both term and preterm neonates are associated with left ventricular overload in term neonates, while right ventricular overload in preterm infants thus can be considered as a marker of cardiovascular dysfunction caused by neonatal sepsis, especially in the subpopulation of term patients considering its diagnostic value. Changes found in electrophysiological heart activity promote the necessity of routine use of electrocardiography in neonates with signs of the septic process.

Nitrotyrosine, Nitrated Lipoproteins, and Cardiovascular Dysfunction in Patients with Type 2 Diabetes: What Do We Know and What Remains to Be Explained?

Diabetes mellitus (DM) is a strong risk factor for the development of cardiovascular diseases (CVDs), which are the most important cause of morbidity and mortality in the population of patients living with DM. DM is associated with lipid metabolism disorders characterized by a decrease in the high-density lipoprotein blood concentration, an increase in the triglyceride blood concentration, and the presence of modified lipoproteins not routinely measured in clinical practice. Nitrated lipoproteins are produced by the nitration of the tyrosyl residues of apolipoproteins by myeloperoxidase. There is some evidence from the research conducted showing that nitrated lipoproteins may play a role in the development of cardiovascular dysfunction, but this issue requires further investigation. It was found that the nitration of HDL particles was associated with a decrease in caspase-3 and paraoxonase-1 activity, as well as a decrease in the activity of cholesterol transport via ABCA1, which reduces the protective effect of HDL particles on the cardiovascular system. Less information has been collected about the role of nitrated LDL particles. Thus far, much more information has been obtained on the relationship of nitrotyrosine expression with the presence of cardiovascular risk factors and the development of cardiovascular dysfunction. The purpose of this paper is to provide an extensive review of the literature and to present the most important information on the current state of knowledge on the association between nitrotyrosine and nitrated lipoproteins with dysfunction of the cardiovascular system, especially in patients living with DM. Moreover, directions for future research in this area were discussed.

SURGICAL TREATMENT OF ACUTE SMALL BOWEL OBSTRUCTION: CLINICAL AND LABORATORY PARAMETERS ASSOCIATED WITH STRANGULATION AND EARLY MORTALITY AFTER SURGERY

The aim: The study aimed to evaluate some criteria for preoperative diagnosis of strangulation and significant indicators of the prognosis of short-term outcomes in patients with small bowel obstruction. Materials and methods: The results of the treatment of 123 patients aged 18-70 years with SBO were evaluated. Results: All of these patients underwent emergency surgery, and 22 patients (17.9%) have died. It has been shown that four lab parameters (blood leukocytes, lactate, intestinal fatty acid-binding protein, and C-reactive protein levels) and one instrumental (involving the mesentery of the small intestine, free fluid in the abdomen during CT) with 80% probability or more were associated with the strangulation type of SBO (Λ=0.276, p = 0.000). Three lab indicators (WBC count, serum lactate, and intestinal fatty acid-binding protein levels) and two clinical parameters (abdominal perfusion pressure level and the presence of abdominal sepsis) were associated with early mortality after surgery (Λ=0.626, p = 0.000) with the same probability. Immediate results of the treatment in these patients depended on the development of intra-abdominal complications after surgery (P = 0.024) and the need for early reoperation (P = 0.006) as well as the development of cardiovascular dysfunction (P = 0.000) and respiratory dysfunction (P = 0.000). Conclusions: There were confirmed parameters that were significantly associated with strangulation before surgery and short-term in-hospital mortality with an 80% probability or more. This made it possible to develop new mathematical models for the diagnosis of strangulated bowel obstruction and early postoperative mortality with an accuracy of 84.5% and 84.2%, respectively.

Щодо окремих клініко-параклінічних маркерів сепсис-індукованої міокардіальної дисфункції в новонароджених

The problem of neonatal sepsis continues to be one of the leading places in neonatal practice. The issues of early diagnostics of cardiovascular disorders in neonates with sepsis by means of up-to-date methods of examination remain relevant. They can be used as screening methods with the purpose to verify possible development of cardiovascular dysfunction. Purpose — to study the meaning of certain clinical and paraclinical markers of myocardial dysfunction in neonates with sepsis. Materials and methods. In order to realize the objective we have observed 69 neonates with signs of generalized infectious-inflammatory process. Group I (32 patients — 46,4%) included neonates with the term of gestation 37–42 weeks, group II included 37 preterm neonates (53,6%) with the term of gestation under 36 week inclusive. Results. It was found that in mothers who gave birth prematurely, compared to mothers of newborns of group I, premature rupture of membranes occurred more often, but 1.5 times less often — indications of infectious diseases of the genitourinary system of the pregnant woman. Generalized infectious-inflammatory process during the neonatal period of term infants is accompanied by electrocardiographic signs of left ventricular overload associated with female sex (r=0,30), delivery by cesarean section (r=0,27), and assessment of neonatal condition by a 5=minute Apgar score (r=-0,33). Conclusions. Increased values of lactate dehydrogenase activity in the blood serum of both term and preterm neonates are associated with left ventricular over-load in the term ones, and right ventricular overload in the preterm infants. Changes found in electrophysiological heart activity promote the necessity of a routine use of electrocardiography in neonates with signs of septic process. The research was carried out in accordance with the principles of the Helsinki declaration. The study protocol was approved by the Local Ethics Committee of all participating institution. The informed consent of the patient was obtained for conducting the studies. No conflict of interest was declared by the authors. Key words: neonatal sepsis; myocardial dysfunction.

Peri‐renal Adipose Tissue Inflammation Possibly Underlies Mild Renal Dysfunction in Early Metabolic Challenge

Cardiovascular disease remains a primary cause of morbidity and mortality in patients with diabetes. Cardiovascular complications in those patients are independent of glycemic control; intensive antihyperglycemic therapy was found to be ineffective in improving the prognosis of these complications. Evidence of vascular function deterioration in prediabetic patients implicates the involvement of mechanisms other than hyperglycemia in the development of cardiovascular dysfunction. Adipose inflammation constitutes a possible mechanism that is involved in the pathogenesis of diabetes and metabolic syndrome. We developed a rat model of mild hypercaloric (HC) stress with a delayed development of hyperglycemia to investigate the mechanism of cadiovascular dysfunction in early stages of metabolic challenge. We previously reported that prior to the development of hyperglycemia, perivascular adipose tissue inflammation was associated with cardiovascular structural and functional anomalies. No changes in blood glucose, body weight or blood pressure levels were observed in this rat model. Systemic inflammation was not detected in this rat model, however following 12 weeks of HC feeding, peri‐renal adipose tissue showed increased oxidative stress and inflammatory cytokine expression (IL‐1b). Moreover, proteinuria and hyperfiltration indicated an early stage of renovascular dysfunction. This renovascular dysfunction manifested as (1) loss of proper endothelial feedback, (2) loss of prostaglandin and nitric oxide activity, and (3) an uncontrolled vasodilation induced by upregulation of epoxyeicosatrienoic acid effect. Moreover, the renovascular dysfunction was associated with significant increases in renal oxidative stress, inflammatory mediators (IL‐1b and TGF‐b1) and culminated in renal structural damage. Glomerulosclerosis was increased following HC feeding as well as significant increases in the expression of a‐smooth muscle actin in proximal tubular cells suggesting possible epithelial to mesenchymal transformation. Ameliorating adipose inflammation by a two‐week treatment with non‐hypoglycemic doses of metformin (100 mg/Kg/day) or pioglitazone (2.5 mg/Kg/day), improved renovascular function and structural nephrotoxicity. These results provide evidence of an early progressive renal damage induced by localized perirenal adipose tissue inflammation in prediabetes.Support or Funding InformationResearch support: AUB‐FM grant #320186

JAK2V617F-Mediated Endothelial Dysfunction Promotes Congestive Heart Failure in a Murine Model of Myeloproliferative Neoplasm

No relevant conflicts of interest to declare.

Prognostic Risk Models for the Development of Cardiovascular Dysfunction in Adolescents with Essential Hypertension.

We present prognostic risk models for structural and functional cardiovascular disorders in Caucasian adolescents (Russians) with essential hypertension aged 14-17 years (15.92±1.12) taking into account biochemical (catecholamines and cortisol) and genetic parameters (carriage of polymorphic variants of α2A-adrenergic receptor gene ARA2A (-1291С>G), norepinephrine transporter NET (-1287G>A), and D2-dopamine receptor DRD2 (-141C Ins/Del) and the data of psychological testing. Prognostically significant risk factors for increased specific peripheral vascular resistance and variability of daytime systolic BP were a combination of [CC+AA] genotypes of ADRA2A -1291C>G and NET -1287G>A polymorphisms, cortisol level, anxiety, and proneness to conflict. The combination of genotypes [CC+GG+II] of polymorphisms -1291C>G ADRA2A, -1287G>A NET and -141C Ins/Del DRD is prognostically significant, with the GG genotype NET being epistatic.

Development of Cardiovascular Dysfunction in a Rat Spinal Cord Crush Model and Responses to Serotonergic Interventions.

Selection of a proper spinal cord injury (SCI) rat model to study therapeutic effects of cell transplantation is imperative for research in cardiovascular functional recovery, due to the local harsh milieu inhibiting cell growth. We recently found that a crushed spinal cord lesion can minimize fibrotic scarring and grafted cell death compared with open-dura injuries. To determine if this SCI model is applicable for studying cardiovascular recovery, we examined hemodynamic consequences following crushed SCI and tested cardiovascular responses to serotonin (5-HT) or dopamine (DA) receptor agonists. Using a radio-telemetric system, multiple cardiovascular parameters were recorded prior to, 2, and 4 weeks after SCI, including resting mean arterial pressure (MAP) and heart rate (HR), as well as spontaneous or colorectal distension (CRD)-induced autonomic dysreflexia (AD). The results showed that this injury caused tachycardia at rest as well as the occurrence of spontaneous or artificially induced dysreflexic events. Four weeks post-injury, specific activation of 5-HT2A receptors by subcutaneous (s.c.) or intrathecal (i.t.) delivery of Dimethoxy-4-iodoamphetamine (DOI) remarkably increased resting MAP levels in a dose-dependent fashion. During CRD-induced autonomic dysreflexia, systemic administration of DOI alleviated the severity of bradycardia responsive to episodic hypertension. In contrast, selective stimulation of 5-HT1A receptors with 8-OH-DPAT or non-selective activation of DA receptors with apomorphine did not affect cardiovascular performance. Thus, crush injuries induce cardiovascular abnormalities in rats that are sensitive to 5-HT2A receptor stimulation, indicating a reliable SCI model to study how cell-based approaches impact the severity of autonomic dysreflexia and identify a possible target for pharmacological interventions.

Development of cardiac dysfunction in sepsis‐surviving rats

ObjectivesSepsis is a life‐threatening syndrome induced by an infection and is associated with physiological, pathological and biochemical systemic changes. It is one of the major causes of death in critical care units and a public health concern around the world. A particular occurrence in sepsis is the development of cardiovascular dysfunction. Notably, cardiovascular diseases have been described as an important risk factor among those who survived sepsis (ANNANE et al., 2007; YENDE et al., 2014). We have hypothesized that depressed cardiac function is one of the long‐lasting effects in sepsis.Material and methodsTo investigate our hypothesis, we evaluated the cardiac function from male Wistar rats subjected to the cecal ligation puncture (CLP) model at 6, 24, 72 h, and 30 days after the surgery. Age matched sham‐operated animals were used as control. For this, the animals were maintained under anesthesia and a pressure‐volume catheter was inserted into the left ventricle chamber through the carotid artery. This approach allowed the assess of thirteen volume dependent cardiac parameters: cardiac output, CO; heart rate, HR; stroke volume, SV; end diastolic volume, EDV; end diastolic pressure, EDP; ventricular stroke work, SW; the rate of ventricle pressure rise and decrease, dP/dtmax and dP/dtmin, respectively; the pressure at dP/dtmax, P@dP/dtmax, relaxation time constant, TAU; ejection fraction, EF; the rate of ventricle volume rise, dV/dtmax; and end systolic volume; ESV. These parameters were analyzed before and after intravenous injection of 30 nmol/Kg dobutamine.ResultsAt 6 h and 24 h after the CLP surgery, the CO, EF, and SW were significantly reduced in the CLP groups when compared with control animals. For instance, the CO, EF, and SW were reduced from 30.4 ± 1.9 mL/min, 43.6 ± 2.2%, and 6097 ± 469 mmHg*μl in sham‐operated animals to 12.4 ± 1.2 mL/min, 24.4 ± 3.1%, and 2561 ± 597 mmHg*μl in the CLP 24 h group, respectively. Importantly, as measured under basal condition, all cardiac parameters at 72 h after the CLP were back to levels found in sham‐operated animals or even increased (i.e. both dV/dtmax and SW were around 70 and 57% higher in the CLP group). Nevertheless, when evaluated at 30 days after the CLP, the sepsis‐surviving animals presented decreased CO (20.85 ± 5.01 mL/min), EF (41.3 ± 4.8%), SW (6481 ± 1252 mmHg*μl), and EDV (169.3 ± 7.7 μl), compared with control animals (38.4 ± 4.1 mL/min, 57.8 ± 2.3%, 10551 ± 725 mmHg*μl, and 226.6 ± 12.0 μl, respectively). On the other hand, both EDP and Tau were increased in sepsis‐surviving rats around 57 and 70% respectively, compared with control animals. In addition, dobutamine, an inotropic adrenergic agent, had its effect on intraventricular pressure of sepsis‐surviving animals reduced aroud 58% compared with control animals.DiscussionAltogether these data indicate that cardiac injury, characterized by both diastolic and systolic dysfunction is present in early (6 and 24 h), but not late (72 h) sepsis, and reappeared in the sepsis‐surviving rats at 30 days after the CLP surgery. The translation of our results for humans may allow the development of new strategies for the management of cardiac function in those who survived the septic insult.Support or Funding InformationFAPESC, SC, Brazil (TR2012000367) and CNPq, Brazil (448738/2014)This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

CARD9 knockout ameliorates myocardial dysfunction associated with high fat diet-induced obesity

Obesity is associated with chronic inflammation which plays a critical role in the development of cardiovascular dysfunction. Because the adaptor protein caspase recruitment domain-containing protein 9 (CARD9) in macrophages regulates innate immune responses via activation of pro-inflammatory cytokines, we hypothesize that CARD9 mediates the pro-inflammatory signaling associated with obesity en route to myocardial dysfunction.C57BL/6 wild-type (WT) and CARD9−/− mice were fed normal diet (ND, 12% fat) or a high fat diet (HFD, 45% fat) for 5months. At the end of 5-month HFD feeding, cardiac function was evaluated using echocardiography. Cardiomyocytes were isolated and contractile properties were measured. Immunofluorescence was performed to detect macrophage infiltration in the heart. Heart tissue homogenates, plasma, and supernatants from isolated macrophages were collected to measure the concentrations of pro-inflammatory cytokines using ELISA kits. Western immunoblotting analyses were performed on heart tissue homogenates and isolated macrophages to explore the underlying signaling mechanism(s). CARD9 knockout alleviated HFD-induced insulin resistance and glucose intolerance, prevented myocardial dysfunction with preserved cardiac fractional shortening and cardiomyocyte contractile properties. CARD9 knockout also significantly decreased the number of infiltrated macrophages in the heart with reduced myocardium-, plasma-, and macrophage-derived cytokines including IL-6, IL-1β and TNFα. Finally, CARD9 knockout abrogated the increase of p38 MAPK phosphorylation, the decrease of LC3BII/LC3BI ratio and the up-regulation of p62 expression in the heart induced by HFD feeding and restored cardiac autophagy signaling.In conclusion, CARD9 knockout ameliorates myocardial dysfunction associated with HFD-induced obesity, potentially through reduction of macrophage infiltration, suppression of p38 MAPK phosphorylation, and preservation of autophagy in the heart.

Endothelial relaxation mechanisms and nitrative stress are partly restored by Vitamin D3 therapy in a rat model of polycystic ovary syndrome

AimsIn polycystic ovary syndrome (PCOS), metabolic and cardiovascular dysfunction is related to hyperandrogenic status and insulin resistance, however, Vitamin D3 has a beneficial effect partly due to its anti-oxidant capacity. Nitrative stress is a major factor in the development of cardiovascular dysfunction and insulin resistance in various diseases. Our aim was to determine the effects of vitamin D3 in a rat model of PCOS, particularly the pathogenic role of nitrative stress. Main methodsFemale Wistar rats weighing 100–140g were administered vehicle (C), dihydrotestosterone (DHT) or dihydrotestosterone plus vitamin D3 (DHT+D) (n=10 per group). On the 10th week, acetylcholine (Ach) induced relaxation ability of the isolated thoracic aorta rings was determined. In order to examine the possible role of endothelial nitric oxide synthase (eNOS) and cyclooxygenase-2 (COX-2) pathways in the impaired endothelial function, immunohistochemical labeling of aortas with anti-eNOS and anti-COX-2 antibodies was performed. Leukocyte smears, aorta and ovary tissue sections were also immunostained with anti-nitrotyrosine antibody to determine nitrative stress. Key findingsRelaxation ability of aorta was reduced in group DHT, and vitamin D3 partly restored Ach induced relaxation. eNOS labeling was significantly lower in DHT rats compared to the other two groups, however COX-2 staining showed an increment. Nitrative stress showed a significant increase in response to dihydrotestosterone, while vitamin D3 treatment, in case of the ovaries, was able to reverse this effect. SignificanceNitrative stress may play a role in the pathogenesis of PCOS and in the development of the therapeutic effect of vitamin D3.

PRENATAL EXPOSURE TO ZYMOSAN RESULTS IN HYPERTENSION IN ADULT OFFSPRING RATS

1. Events in utero appear to have a significant role in the development of cardiovascular dysfunction in adulthood. In the present study, we evaluated the effects of prenatal exposure to zymosan, a non-infectious and non-bacterial agent capable of inducing inflammation, on mean systolic arterial pressure (MSAP) in rat offspring at 6-66 weeks of age. 2. Pregnant rats were divided into three groups: (i) a control group, administered 0.5 mL, i.p., saline on gestation Days 8, 10 and 12; (ii) a zymosan-treated group, given 2.37 mg/kg, i.p., zymosan on gestation Days 8, 10 and 12; and (iii) a pyrrolidine dithiocarbamate (PDTC) + zymosan-treated group, which was given 100 mg/kg, i.p., PDTC 1 h before zymosan. At 6, 16, 26, 36, 56 and 66 weeks of age, MSAP was determined in rat offspring from all three groups. Serum levels of tumour necrosis factor (TNF)-alpha were determined in dams, as well as in offspring at 24 and 56 weeks of age. In addition, protein levels of nuclear factor (NF)-kappaB (p65) in the myocardium and kidney of offspring were determined at 24 weeks of age. 3. The results showed that MSAP and NF-kappaB (p65) levels in the myocardium and kidney of offspring from the zymosan-treated group were increased significantly compared with control. This increase was inhibited by concomitant treatment with PDTC. Serum TNF-alpha levels in dams exposed to zymosan and in their offspring at 56 weeks of age (but not at 24 weeks of age) were significantly increased compared with levels in the control group. Following lipopolysaccharide treatment (1 mg/kg, i.p.) of adult rat offspring at 24 weeks of age, there was a further increase in serum TNF-alpha levels in offspring in the zymosan-treated group compared with the other two groups. 4. The findings of the present study suggest that non-bacterial inflammation during gestation can lead to hypertension in offspring and that NF-kappaB signalling may play a critical role in this process.

Inhibition of Ras-GTPase signaling by FPTIII ameliorates development of cardiovascular dysfunction in diabetic–hypertensive rats

We studied the effect an inhibitor of Ras-GTPase (FPTIII, 1.5 mg/kg alt diem for 4 weeks) on mean arterial pressure (MAP), urine protein, vascular reactivity and cardiac function in streptozotocin (STZ)-induced diabetes in control normotensive (WKY) and spontaneously hypertensive rats (SHR). The increased urinary protein in STZ-treated WKY (D-WKY) and STZ-treated SHR (D-SHR) were significantly lower in FPTIII treated D-WKY and D-SHR. The abnormal vascular responsiveness to endothelin-1, angiotensin II, carbachol or histamine in isolated carotid artery from D-WKY and D-SHR was improved by chronic treatment with FPTIII. In isolated perfused hearts, recovery of left ventricular function from 40 min of global ischemia was significantly improved in FPTIII treated D-WKY and D-SHR. These results show that treatment with FPTIII can attenuate development of abnormal vascular reactivity and renal/cardiac dysfunction during simultaneous occurrence of hypertension and diabetes.

Anti-Inflammatory Effects of Intravenous Anesthetics on Endotoxemia

Endotoxemia and endotoxin shock are common problems in the intensive care unit and carry a very high mortality rate. Endotoxemia increases production of endogenous cytokines, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 (IL-1), IL-6, and IL-8. Not only endotoxin but also cytokines have been implicated as important factors in the pathophysiology of endotoxic shock and the development of cardiovascular dysfunction in endotoxemia. Recently, it has been shown both in vitro and in vivo that several intravenous anesthetics have anti-inflammatory effects. Thiopental and ketamine inhibit the endotoxin-induced TNF-alpha, IL-1 and IL-8 responses and increase IL-10 release in vitro. Ketamine prevent the pro-inflammatory cytokine (TNF-alpha, IL-1, and IL-6) responses to endotoxemia in vivo. Moreover, thiopental and ketamine suppress the activation of nuclear factor-kappa B induced by endotoxin. Propofol have been proven its anti-inflammatory effects on endotoxemia both in vitro and in vivo, but several studies have shown that propofol does not have any anti-inflammatory effects and deteriorates the inflammatory response to endotoxemia. This article reviews the anti-inflammatory effects of intravenous anesthetics on endotoxemia and endotoxic shock.

Human coronary endothelial cell activation by endotoxin is characterized by NF-kappa B activation and TNF-alpha synthesis.

Tumor necrosis factor-alpha (TNF-alpha), an early inflammatory mediator typically regulated by nuclear factor kappa B (NF-kappa B), plays a critical role in the development of cardiovascular dysfunction in sepsis. While several myocardial cell types synthesize TNF-alpha, the importance of the myocardial endothelium in sepsis-related cardiac cytokine production is unclear. To determine the role of the human coronary artery endothelial cell (HCA-EC) in the cytokine response to endotoxin we measured in vitro TNF-alpha synthesis, TNF-alpha mRNA, and the associated NF-kappa B response to LPS. To determine the magnitude of the HCA-EC response we assessed the TNF-alpha and NF-kappa B response to LPS in a human monocytic cell line (THP-1) as well. We observed an increase in supernatant TNF-alpha from LPS-stimulated HCA-EC (12 h) that was ablated by the proteosome inhibitor, ALLN (N-acetyl-Leu-Leu-norleucinal). Similarly, ALLN-sensitive TNF-alpha was produced by monocytes following LPS, although at concentrations 100-fold higher than HCA-EC. TNF-alpha mRNA from HCA-EC was detected at 60 min in LPS-stimulated cells, but not in unstimulated cells or cells pretreated with ALLN. NF-kappa B p50/p65 subunits were detectable in endothelial nuclear protein 60 min following LPS. In contrast, NF-kappa B subunits from monocytes were detected at 15 min. Also, while ALLN only attenuated endothelial NF-kappa B translocation, monocyte NF-kappa B translocation was completely inhibited. These data suggest endotoxin-stimulated human coronary endothelial cells express TNF-alpha, which is regulated in part by NF-kappa B activation, in a manner and degree distinct from human monocytes.

Anaemia in chronic renal disease: lessons learned since Seville 1994.

Cardiovascular disease is the major cause of death among patients with end-stage renal disease, accounting for almost half of all fatalities. In recent years much progress has been made in understanding the pathogenesis of cardiovascular disease in the uraemic population. Anaemia is a consistent finding in chronic renal disease, affecting up to 90% of patients, and the central role of anaemia in the development of cardiovascular dysfunction is now well established. A significant proportion of patients have established cardiovascular complications on initiation of dialysis, raising the possibility of early correction of anaemia as a strategy for preventing cardiovascular co-morbidities among renal patients. Randomized, controlled trials have shown that normalization of haemoglobin (Hb) with recombinant erythropoietin (rh-Epo) is of no cardiovascular benefit in haemodialysis patients with symptomatic heart failure, ischaemic heart disease, or severe left ventricular dilatation, although suggestive evidence exists for benefits at earlier stages of cardiac disease. Results from large-scale clinical trials are required to clarify the effects of early anaemia correction on mortality and cardiovascular function, as well as appropriate treatment targets in different patient populations. The potential exists for higher Hb levels to extend patient survival through cardioprotective effects.

The Influences of Obstructive Apneas on Changes of Cardiovascular Function in Anesthetized Dogs with alpha-chloralose

Background : Patients with obstructive sleep apnea syndrome are known to have high long-term mortality compared to healthy subjects because of their cardiovascular dysfunction. The observation of hemodynamic changes by obstructive apneas is helpful when attempting to understand the pathophysiological mechanism of the development of cardiovascular dysfunction in those patients. Therefore, we studied the changes in cardiovascular function with an animal model and tried to obtain the basic data for an ideal experimental model (this phrase is unclear), a requirement for a more advanced study. Methods : Sixteen anesthetized dogs with -chloralose delete were divided into two groups : 8 dogs of room air breathing group and 8 dogs of oxygen breathing group. We measured , , heart rate, cardiac output, mean femoral artery pressure, and mean pulmonary artery pressure at specified times during the apnea-breathing cycle before endotracheal tube occlusion (baseline), 25 seconds after endotracheal tube occlusion (apneic period), 10 seconds (early phase of postapneic period, EPA) and 25 seconds (late phase of postapneic period, LPA) after spontaneous breathing. Results : In room air breathing group, the heart rate significantly decreased during the apneic period compared to that at baseline (P