Sost Haploinsufficiency Provokes Peracute Lethal Cardiac Tamponade without Rescuing the Osteopenia in a Mouse Model of Excess Glucocorticoids.

Glucocorticoid-induced secondary osteoporosis is the most predictable side effect of this anti-inflammatory. One of the main mechanisms by which glucocorticoids achieve such deleterious outcome in bone is by antagonizing Wnt/ß-catenin signaling. Sclerostin, encoded by Sost gene, is the main negative regulator of the proformative and antiresorptive role of the Wnt signaling pathway in the skeleton. It was hypothesized that the partial inactivation of sclerostin function by genetic manipulation will rescue the osteopenia induced by high endogenous glucocorticoid levels. Sost-deficient mice were crossed with an established mouse model of excess glucocorticoids, and the effects on bone mass and structure were evaluated. Sost haploinsufficiency did not rescue the low bone mass induced by high glucocorticoids. Intriguingly, the critical manifestation of Sost deficiency combined with glucocorticoid excess was sporadic, sudden, unprovoked, and nonconvulsive death. Detailed histopathologic analysis in a wide range of tissues identified peracute hemopericardium and cardiac tamponade to be the cause. These preclinical studies reveal outcomes with direct relevance to ongoing clinical trials that explore the use of antisclerostin antibodies as a treatment for osteoporosis. They particularly highlight a potential for increased cardiovascular risk and may inform improved stratification of patients who might otherwise benefit from antisclerostin antibody treatment.

Cardiac tamponade as an initial presentation of papillary carcinoma with psammoma bodies and intranuclear grooves-A diagnostic dilemma.

Involvement of body fluids by adenocarcinoma is a common phenomenon. However, metastasis to the pericardial fluid by adenocarcinoma is a rare occurrence. The most common malignancies associated with malignant pericardial effusion are carcinoma of the lung, breast, esophagus, melanoma, lymphoma, and leukemia. Here, we discuss a case of a 36-year-old female with hemorrhagic pericardial effusion presenting with cardiac tamponade and psammoma bodies which was suspected and reported as metastatic papillary carcinoma of thyroid on cytomorphology; however, the immunocytochemical and radiological features confirmed metastatic papillary adenocarcinoma of lung contrary to the thyroid which is more common and expected.

Sodium nitroprusside does not influence tissue oxygen extraction capabilities during a critical reduction in oxygen delivery.

By its regulating effects on blood vessel tone, nitric oxide (NO) may play an important role in the coupling of oxygen delivery (DO2) to metabolic rate. We reasoned that if endogenous NO synthesis is an important modulator of oxygen extraction ratio (O2ER), then administration of a NO donor will alter oxygen extraction capabilities during a fall in blood flow. We studied the effects of the NO donor, nitroprusside, on the relationship between DO2 and oxygen uptake (VO2) during an acute reduction in DO2 induced by cardiac tamponade. Twenty-one healthy, anaesthetised, mechanically ventilated dogs were randomly divided into 3 groups. Group 1 (n = 7) served as control; Groups 2 and 3 were given sodium nitroprusside at 1.0 microgram/kg.min (n = 7), and 2.5 micrograms/kg.min intravenously (n = 7), respectively. All animals were given normal saline i.v. at a rate of 20 ml/kg.h throughout the study. Cardiac tamponade was induced by bolus injections of normal saline into the pericardial space. In the control animals the critical DO2 (DO2crit) was found at 10.1 +/- 1.5 ml/kg.min and critical O2ER (O2ERcrit) at 63.3 +/- 10.9%. Nitroprusside at the lower dose decreased systemic vascular resistance but did not significantly influence arterial pressure, cardiac output, DO2 or VO2; neither DO2crit nor O2ERcrit was altered (9.3 +/- 2.9 ml/kg.min and 70.4 +/- 20.9%). Nitroprusside at the higher dose induced significant decreases in mean arterial pressure and systemic vascular resistance, but had no significant effect on cardiac output. DO2crit (9.2 +/- 2.0 ml/kg.min) and O2ERcrit (59.8 +/- 13.2%) were similar to the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

An evaluation of the pericardial sac as a safety factor during tamponade.

Studies were conducted in vitro to determine the permeability characteristics of the rabbit and dog pericardium. The hydraulic conductance (Lp), which was significantly higher than other tissue, was 1.6 +/- 0.19 X 10(-4) and 1.78 +/- 0.18 X 10(-4) g-cm-2-min-1-cm H2O-1 (mean +/- SEM), respectively, for the rabbit and dog pericardium. For various solutes, the permeability coefficient (P) of the pericardium for the rabbit was: 1.40 +/- 0.10 X 10(-4) cm-s-1 for water, 0.50 +/- 0.03 X 10(-4) cm-s-1 for glucose, and 0.73 +/- 0.005 X 10(-4) cm-s-1 for albumin. The reflection coefficient, sigma, for various solutes was: glucose 8.89 +/- 0.86 X 10(-4), sucrose 15.7 +/- 1.5 X 10(-4), dextran (molecular weight 40 000) 0.39 +/- 0.03, albumin 0.42 +/- 0.05, and for haemoglobin 0.58 +/- 0.06. These results, which indicate that the pericardium offers little resistance to the bulk transfer of liquids and to the passage of large molecules, are discussed as possible safety factors during pericardial effusion.

Interleukin-1beta alters the oxygen delivery-oxygen consumption relationship in rabbits by increasing the slope of the supply-independent line.

When systemic oxygen delivery (DO2) is reduced, oxygen consumption (VO2) is maintained until a critical level is reached (DO2crit). Sepsis is thought to shift DO2crit to the right and lengthen the supply-dependent portion. We tested the effect of interleukin (IL)-1beta, which is one of the key cytokines related to sepsis, on the DO2-VO2 relationship. Fifteen rabbits were subjected to stepwise cardiac tamponade to reduce DO2 to 10% by inflating a handmade balloon placed into the pericardial sac. Seven rabbits were given 10 microg/kg of IL-1beta intravenously (IL-1beta group) prior to the graded cardiac tamponade. The remainder received saline alone (control group). The DO2-VO2 relationship was analyzed by the dual-line method. IL-1beta significantly decreased mean arterial pressure (65 +/- 11 mmHg from baseline 85 +/- 7 mmHg) without altering cardiac output. The IL-1beta group showed significantly steeper supply-independent line slopes than did the control group (0.19 +/- 0.02 vs. 0.11 +/- 0.02, respectively), which resulted in a DO2crit shift to the left (IL-1beta group, 8.7 +/- 1.7 ml/kg x min vs. control, 11.7 +/- 0.7 ml/kg x min). The IL-1beta group also showed greater PO2 and plasma lactate levels in the portal vein than did the control group. These results indicate that IL-1beta impairs systemic oxygen uptake even before VO2 becomes supply-dependent, presumably due to maldistribution of the blood flow including the splanchnic circulation.

Jejunal luminal microdialysate lactate in cardiac tamponade--effect of low systemic blood flow on gut mucosa.

OBJECTIVE: To assess gut mucosal metabolic response and susceptibility to dysoxia during low systemic blood flow induced by cardiac tamponade. DESIGN: A randomized, controlled animal experiment. SETTING: National laboratory animal center. INTERVENTIONS: Cardiac tamponade was induced in six pigs, while six additional pigs served as controls. In the tamponade group, fluid was injected into the pericardial space to reduce aortic flow, aiming first at a flow of 50 ml/kg per min and then at 30 ml/kg per min. Each step lasted for 60 min. MEASUREMENTS AND RESULTS: We measured luminal lactate by microdialysis and mucosal PCO(2) by tonometry in the mid-jejunum. Aortic and superior mesenteric artery blood flow, arterial and mesenteric venous lactate, pyruvate and ketone bodies and regional lactate exchange were measured. The distribution of aortic blood flow to superior mesenteric artery remained unchanged (baseline 14 (12-16)%; median (interquartile range), stepwise flow reduction 11 (10-17)% and 13 (12-19)%, NS) during reduction of aortic blood flow from 81 (61-95) ml/kg per min to 49 (47-49) ml/kg per min and 23 (21-27) ml/kg per min. Systemic hyperlactatemia developed early, whereas gut luminal lactate increased only after 60 min of hypoperfusion and could be largely explained by arterial hyperlactatemia. Mesenteric venous lactate-to-pyruvate (L/P) ratio increased after 30 min of tamponade, but both venous-arterial lactate and pyruvate gradients turned negative (gut lactate and pyruvate uptake). Mesenteric venous ss-hydroxybutyrate to acetoacetate ratio increased after 60 min. No changes were observed in the controls. CONCLUSIONS: Jejunal mucosal dysoxia and anaerobic metabolism occurs late during low systemic blood flow induced by experimental cardiac tamponade.

Diaphragmatic energetics and blood flow during pulmonary edema and hypotension.

We studied the role of O2 supply and demand factors for producing diaphragmatic failure in a canine model of cardiogenic shock with pulmonary edema. We produced pulmonary edema with oleic acid and then hypotension with cardiac tamponade and followed the animals until respiratory failure began, which was defined by a 50% fall in frequency of breathing and diaphragmatic pressure-time index (PTI; cmH2O.s-1.min-1) with no decrease in the diaphragmatic electromyogram. Regional blood flows were measured with radiolabeled microspheres. Diaphragmatic O2 consumption (VO2 di) (ml.min-1.100 g-1) was determined from the diaphragmatic blood flow (Qdi) and the arterial and phrenic venous O2 contents. With oleic acid-induced pulmonary edema, PTI Qdi, and VO2 di increased from control of 101.7 +/- 31.7, 17 +/- 1.8, and 0.81 +/- 0.11, respectively, to 187.2 +/- 27.6, 42.2 +/- 7.2, and 3.32 +/- 0.35 (P less than 0.05). With tamponade, PTI did not change (186.7 +/- 60.0), whereas VO2 di increased further to 3.98 +/- 0.98 (P less than 0.05) due to increased O2 extraction and no significant change in Qdi (32.8 +/- 4.0). As fatigue developed, VO2 di decreased to 2.30 +/- 0.23 due to the combined effects of small declines in Qdi and the arterial O2 content but remained higher than control even though the energy demands returned to control values. In conclusion, when cardiogenic shock is added to pulmonary edema VO2 di and energy output do not increase further and eventually fall.

Effects of nitric oxide on blood flow distribution and O2 extraction capabilities during endotoxic shock.

The effects of the nitric oxide (NO) synthase inhibitor NG-monomethyl-L-arginine (L-NMMA) and the NO donor 3-morpholinosydnonimine (SIN-1) were tested in 18 endotoxic dogs. L-NMMA infusion (10 mg . kg-1 . h-1) increased arterial and pulmonary artery pressures and systemic and pulmonary vascular resistances but decreased cardiac index, left ventricular stroke work index, and blood flow to the hepatic, portal, mesenteric, and renal beds. SIN-1 infusion (2 microg . kg-1 . min-1) increased cardiac index; left ventricular stroke work index; and hepatic, portal, and mesenteric blood flow. It did not significantly influence arterial and pulmonary artery pressures but decreased renal blood flow. The critical O2 delivery was similar in the L-NMMA group and in the control group (13.3 +/- 1.6 vs. 12.8 +/- 3.3 ml . kg-1 . min-1) but lower in the SIN-1 group (9.1 +/- 1.8 ml . kg-1 . min-1, both P < 0.05). The critical O2 extraction ratio was also higher in the SIN-1 group than in the other groups (58.7 +/- 10.6 vs. 42.2 +/- 7.6% in controls, P < 0.05; 43.0 +/- 15.5% in L-NMMA group, P = not significant). We conclude that NO is not implicated in the alterations in O2 extraction capabilities observed early after endotoxin administration.

Systemic oxygen extraction can be improved during repeated episodes of cardiac tamponade.

We used a tamponade model to study the relationship between oxygen uptake (VO2) and oxygen delivery (DO2) during successive, reversible decreases in blood flow. In 7 pentobarbital-anesthetized and mechanically ventilated dogs, a catheter was introduced via a left thoracotomy into the pericardium to inject and to withdraw saline. Each experiment consisted of three steps. First, cardiac output was reduced by successive pericardial fluid injections until 4 to 6 data points were obtained in the dependent region of the VO2/DO2 plot (step 1). Second, cardiac output was restored by progressive withdrawal of pericardial fluid (step 2). Third, cardiac output was lowered again by reinjection of fluid into the pericardium until death (step 3). Expired gases were collected for determination of VO2. In each animal, critical DO2 (DO2crit), below which VO2 became DO2 dependent, was determined from a plot of VO2 versus DO2. When releasing tamponade, VO2 was restored to baseline. For the 3 steps, DO2crit were 10.5 +/- 2.2 mL/kg/min in step 1, 9.8 +/- 1.8 mL/kg/min in step 2, and 8.3 +/- 1.9 mL/kg/min in step 3 (P < .01 v step 1; P < .05 v step 2, respectively). There was no significant difference in VO2 at DO2crit for the three steps. Hence, critical oxygen extraction ratio (ERO2crit) increased from 60% +/- 12% in step 1 to 64% +/- 11% in step 2 (not significant) and to 73% +/- 12% in step 3 (P < .01). The VO2/DO2 dependency slope was also steeper in step 3 than in step 1 (0.77 +/- 0.31 v 0.54 +/- 0.20, P < .05).(ABSTRACT TRUNCATED AT 250 WORDS)

Chylous pericardial effusion after aortic valve replacement.

Chylous pericardial effusion after open-heart surgery is a rare complication. We report a case of chylous pericardial effusion following aortic valve replacement, which presented as cardiac tamponade, and its subsequent management.

Coronary artery hemodynamics in conscious dog during cardiac tamponade.

We tested the hypothesis that coronary artery blood flow is sufficient to meet myocardial requirements throughout cardiac tamponade in a conscious euvolemic canine model recovered from surgery. Seven mongrel dogs were chronically instrumented to measure ascending aortic blood flow (electromagnetic flowmeter); intrapericardial, right atrial, and aortic blood pressures; regional myocardial blood flow (radionuclide labelled microspheres); and myocardial consumption of lactate, pyruvate, and oxygen. Data were collected during progressive cardiac tamponade induced by intrapericardial saline infusion to the point of hemodynamic decompensation. Decompensated cardiac tamponade (DCT) was defined as a decline in mean aortic blood pressure to 70% of the level present when the pericardial space was drained of fluid (baseline) and was produced in all animals within 25 minutes. Cardiac tamponade caused a continuous decline in coronary artery blood flow from 1.26 +/- 0.35 (baseline, mean +/- SD) to 0.53 +/- 0.15 ml/min/g (DCT, p less than 0.01), which was associated with a decrease in myocardial oxygen consumption from 1.26 +/- 0.35 (baseline) to 0.74 +/- 0.27 ml/min/g (DCT, p less than 0.05) and a slight increase in myocardial oxygen extraction from 71 +/- 3 (baseline) to 81 +/- 4% (DCT, p less than 0.05). This change in oxygen extraction occurred because of both an increase in arterial and a decrease in coronary venous oxygen content. At all degrees of cardiac tamponade, the lactate-pyruvate ratio did not change significantly from baseline (7.56 +/- 2.31), there was no evidence of lactate production, and the normal endocardial to epicardial blood flow ratio present at baseline (1.41 +/- 0.23) was preserved.(ABSTRACT TRUNCATED AT 250 WORDS)

Pericardial tamponade and excessive secretion of antidiuretic hormone.

We have described a case of presumed excessive antidiuretic hormone (ADH) secretion due to pericardial effusion and tamponade. Pericardiotomy and drainage produced dramatic resolution of the antidiuresis. In the setting of pericardial tamponade, increased antidiuretic hormone secretion may be "appropriate" in response to overriding stimuli from the left atrial stretch receptors and carotid sinus baroreceptors.

Oxygen extraction is altered by endotoxin during tamponade-induced stagnant hypoxia in the dog.

The present study used a model of cardiac tamponade to investigate the effects of endotoxin on the oxygen extraction capabilities of the body during an acute reduction in blood flow, when blood volume and arterial oxygen content were maintained. In 21 pentobarbital anesthetized, mechanically ventilated dogs, two catheters were introduced into the pericardial space to induce cardiac tamponade, and simultaneously to measure the intrapericardial pressure. Oxygen uptake (VO2) was determined from the expired gases. Oxygen delivery (DO2) was calculated by the product of the thermodilution cardiac index and the arterial oxygen content. Eleven dogs received 2 mg/kg Escherichia coli endotoxin, followed by generous saline infusion (20 ml/kg.hr). Ten dogs served as a control group. In each dog, DO2 was progressively reduced by pericardial saline infusion at a rate of 40 ml/hr for the first hour and 30 ml/hr thereafter. Critical O2 delivery (DO2crit) and critical O2 extraction ratio (O2ERcrit) were determined from a plot of VO2/DO2 for each individual dog. The DO2crit was greater in the endotoxic than in the control group (12.1 +/- 3.1 ml/kg.min vs. 9.6 +/- 1.6 ml/kg.min; P < 0.05). Endotoxin at the dose used did not alter VO2 (or critical VO2). Accordingly, O2ERcrit was significantly lower in the endotoxic than in the control animals (47.2% +/- 5.7% vs. 60.3% +/- 10.6%; P < 0.01). The mixed venous PO2 levels at DO2crit were higher in the endotoxic than in the control group (30.6 +/- 6.1 mm Hg vs. 25.4 +/- 5.2 mm Hg; P < 0.05). Arterial blood lactate concentration was higher in the endotoxic than in the control dogs.(ABSTRACT TRUNCATED AT 250 WORDS)