Reduction In Cardiac Output Research Articles

Organ blood flow and O2 transport during hypothermia (27°C) and rewarming in a pig model.

What is the central question of this study? Absence of hypothermia-induced cardiac arrest is a strong predictor for a favourable outcome after rewarming. Nevertheless, detailed knowledge of preferences in organ blood flow during rewarming with spontaneous circulation is largely unknown. What is the main finding and its importance? In a porcine model of accidental hypothermia, we find, despite a significantly reduced cardiac output during rewarming, normal blood flow and O2 supply in vital organs owing to patency of adequate physiological compensatory responses. In critical care medicine, active rewarming must aim at supporting the spontaneous circulation and maintaining spontaneous autonomous vascular control. The absence of hypothermia-induced cardiac arrest is one of the strongest predictors for a favourable outcome after rewarming from accidental hypothermia. We studied temperature-dependent changes in organ blood flow and O2 delivery ( ) in a porcine model with spontaneous circulation during 3h of hypothermia at 27°C followed by rewarming. Anaesthetized pigs (n=16, weighing 20-29kg) were randomly assigned to one of two groups: (i) hypothermia/rewarming (n=10), immersion cooled to 27°C and maintained for 3h before being rewarmed by pleural lavage; and (ii) time-matched normothermic (38°C) control animals (n=6), immersed for 6.5h, the last 2h with pleural lavage. Regional blood flow was measured using a neutron-labelled microsphere technique. Simultaneous measurements of and O2 consumption ( ) were made. During hypothermia, there was a reduction in organ blood flow, and . After rewarming, there was a 40% reduction in stroke volume and cardiac output, causing a global reduction in ; nevertheless, blood flow to the brain, heart, stomach and small intestine returned to prehypothermic values. Blood flow in the liver and kidneys was significantly reduced. Cerebral and returned to control values. After hypothermia and rewarming there is a significant lowering of owing to heart failure. However, compensatory mechanisms preserve O2 transport, blood flow and in most organs. Nevertheless, these results indicate that hypothermia-induced heart failure requires therapeutic intervention.

Investigating the ability of non-invasive measures of cardiac output to detect a reduction in blood volume resulting from venesection in spontaneously breathing subjects

BackgroundMonitoring cardiac output (CO) in shocked patients provides key etiological information and can be used to guide fluid resuscitation to improve patient outcomes. Previously this relied on invasive monitoring, restricting its use in the Emergency Department (ED) setting. The development of non-invasive devices (such as LiDCOrapidv2 with CNAP™ and USCOM 1A), and ultrasound based measurements (Transthoracic echocardiography, inferior vena cava collapsibility index (IVCCI), carotid artery blood flow (CABF) and carotid artery corrected flow time (FTc)) enables stroke volume (SV) and CO to be measured non-invasively in the ED. We investigated the ability of these techniques to detect a change in CO resulting from a 500 ml reduction in circulating blood volume (CBV) following venesection in spontaneously breathing subjects. Additionally, we investigated if using incentive spirometry to standardise inspiratory effort improved the accuracy of IVC based measurements in spontaneously breathing subjects.MethodsWe recorded blood pressure, heart rate, IVCCI, CABF, FTc, transthoracic echocardiographic (TTE) SV and CO, USCOM 1A SV and CO, LIDCOrapidv2 SV, CO, Stroke volume variation (SVV) and pulse pressure variation (PPV) in 40 subjects immediately before and after venesection. The Log-Odds and coefficient of variation of the difference between pre- and post-venesection values for each technique were used to compare their ability to consistently detect CO changes resulting from a reduction in CBV resulting from venesection.ResultsTTE consistently detected a reduction in CO associated with venesection with an average decrease in measured CO of 0.86 L/min (95% CI 0.61 to 1.12) across subjects. None of the other investigated techniques changed in a consistent manner following venesection. The use of incentive spirometry improved the consistency with which IVC ultrasound was able to detect a reduction in CBV.ConclusionsIn a population of spontaneously breathing patients, TTE is able to consistency detect a reduction in CO associated with venesection.

Splanchnic Circulation and Intraabdominal Metabolism in Two Porcine Models of Low Cardiac Output

The impact of acute cardiac dysfunction on the gastrointestinal tract was investigated in anesthetized and instrumented pigs by sequential reductions of cardiac output (CO). Using a cardiac tamponade (n = 6) or partial inferior caval vein balloon inflation (n = 6), CO was controllably reduced for 1 h each to 75% (CO75%), 50% (CO50%), and 35% (CO35%) of the baseline value. Cardiac output in controls (n = 6) was not manipulated and maintained. Mean arterial pressure, superior mesenteric arterial blood flow, and intestinal mucosal perfusion started to decrease at CO50% in the intervention groups. The decrease in superior mesenteric arterial blood flow was non-linear and exaggerated at CO35%. Systemic, venous mesenteric, and intraperitoneal lactate concentrations increased in the intervention groups from CO50%. Global and mesenteric oxygen uptake decreased at CO35%. In conclusion, gastrointestinal metabolism became increasingly anaerobic when CO was reduced by 50%. Anaerobic gastrointestinal metabolism in low CO can be detected using intraperitoneal microdialysis.

Correlación clínica y ecocardiográfica en la disfunción miocárdica en el shock séptico en la Unidad de Cuidados Intensivos Pediátricos Hospital Uyapar, Venezuela

Septic shock is a situation of acute circulatory failure with tissue hypoperfusion and cellular hypoxia that affects anaerobic metabolism. During septic shock, tachycardia, and reduction of afterload increase cardiac output. Sepsis continues to be the main cause of death in the hospital environment, and is more frequent in patients of extreme ages. Materials and methodsThe study was carried out prospectively in a period of 1 year with a sample of 13 patients. The data as regards admission and haemodynamic parameters were recorded. Two-dimensional echocardiography was used to measure left ventricular ejection fraction (LVEF) at the time of admission without use of dobutamine, and subsequently 1, 3, 5, and 7days after the use of dobutamine. The results are presented in frequency distribution tables, the arithmetic mean calculated and the Pearson correlation test was applied. ResultsThe patients included 61.5% infants and the sex most affected was male. A respiratory system infection was observed in 38.5%. Cardiovascular dysfunction was present in 61.5% in the first 72hours after admission, with an initial mean LVEF of 41%. There was a recovery at 72hours after the use of dobutamine (P=.89). The heart rate was the clinical variable that showed the greatest statistical significance (P=.96). ConclusionsEchocardiography is a useful tool for non-invasive monitoring and has a high prognostic value. Objectively, heart rate monitoring offers a direct relationship with the improvement of left ventricular function.

Abstract 17077: Acute Hemodynamic Effects of Oral Nitrite in Pulmonary Hypertension Related to Heart Failure With Preserved Ejection Fraction (PH-HFpEF)

Introduction: Pulmonary hypertension (PH) occurs in 35-83% of patients with heart failure with preserved ejection fraction (HFpEF) and is associated with worse outcomes. There are no effective therapeutic options for these patients. Oral nitrite has demonstrated promise in pre-clinical models of PH-HFpEF. Recently, a phase 2 clinical trial showed that a single dose of inhaled nitrite significantly lowered pulmonary, right atrial, and pulmonary artery wedge pressures and substantially increased pulmonary artery compliance in patients with PH-HFpEF. We are currently evaluating the efficacy of chronic oral nitrite as a novel therapeutic agent in PH-HFpEF. We report, for the first time, our initial findings of the acute hemodynamic effects of a single dose of oral nitrite. Methods: This is part of an ongoing blinded 10-week cross-over treatment trial of oral nitrite in PH-HFpEF (NCT03015402). Patients were defined as having PH-HFpEF based on an ejection fraction > 40% and right heart catheterization (RHC) with a mPAP≥ 25 mmHg, PAWP ≥15 mmHg and TPG ≥ 12 mmHg. Patients who met criteria based on a screening RHC were given a single open label dose of 40 mg of sodium nitrite. Cardiopulmonary hemodynamics were obtained by RHC at baseline and after a single dose of oral nitrite. We are actively enrolling patients with the intent to provide open label oral sodium nitrite to ten patients. Results: Eight patients have currently been enrolled in the cross-over trial, of which four have required a screening RHC and have been given open label oral nitrite. Oral nitrite was well tolerated in all patients without any adverse events. Acute cardiopulmonary hemodynamic are presented in Figure 1. Conclusion: Administration of oral nitrite acutely results in an improvement of right ventricular and left ventricular filling pressures without any significant reduction in cardiac output, cardiac index, or mean arterial pressure. Oral nitrite may be a novel therapeutic agent for patients with PH-HFpEF.

Abstract 330: LDK378 Attenuates Macro and Microcirculation in a Sepsis Rat Model Induced by Cecal Ligation and Puncture

Background: Sepsis is a systemic inflammatory response syndrome caused by severe infections. Myocardial dysfunction has been associated with increased mortality in septic patients. Previous studies have demonstrated that LDK378, a second-generation ALK inhibitor, is a potential anti-inflammatory mediator. We investigated the effects of LDK378 on macro and microcirculation in a rat model of cecal ligation and puncture (CLP) induced sepsis. Hypothesis: LDK378 attenuates the deleterious effects of sepsis on macro- and micro- circulation in CLP induced septic rats. Method: Fifteen male rats weighing between 450-550g were randomized into three groups: Sham, CLP, and CLP+LDK378. Our rat sepsis model was induced by 50% cecum ligation and two punctures with a 20-gauge needle. LDK378 (20mg/kg) was administered intraperitoneal (IP) to animals at 0h, 24h and 48 hours after CLP operation in the CLP+LDK378 group. Cardiac output (CO), mean arterial pressure (MAP); sublingual microcirculation including perfused small vessel density (PVD) and microcirculatory flow index (MFI) were measured at 6h, 30h and 54h after CLP. Results: Significant reduction in CO, MAP, MFI and PVD were observed in both CLP and CLP+LDK378 groups at 6h, 30h and 54h. However, the levels of CO, MAP, MFI and PVD reduction were significantly better in the CLP+LDK378 group when compared with the CLP group at 30h and 54h after CLP. Conclusion: LDK378 attenuates macro and microcirculation parameters in our rat model of sepsis.

Abstract 16737: Cardiopulmonary Fitness and Cardiac Reserve 12-Months Following the Completion of Anthracycline-Based Chemotherapy With or Without Concurrent Exercise Training

Introduction: Anthracycline chemotherapy (AC) has been associated with reductions in cardiac function that increases long-term risk of heart failure. We have previously shown that AC is associated with a reduction in cardiopulmonary fitness (VO 2 peak) that occurs alongside a subtle reduction in the heart’s contractile response to exercise. However the degree to which these changes recover following the completion of AC is unknown. Hypothesis. We sought to determine whether change in cardiopulmonary fitness (VO 2 peak) and cardiac function persisted at 12-months post-AC completion. Methods: 28 women with breast cancer who had self-selected to undergo 12-weeks of aerobic and resistance training twice per week during AC (ET; n=14) or usual care during AC (UC; n=14) were followed up at 12-months from AC completion. Prior to AC and at 12-months, participants completed a cardiopulmonary exercise test (VO 2 peak) and cardiac MRI with exercise to assess the stroke volume (SV), heart rate (HR) and cardiac output (CO) response to exercise (measured at rest, and during high-intensity supine cycling). Results: Seventeen women (UC: n=8; ET: n=9) have completed follow-up evaluation. AC was associated with reductions in fitness at 12-months in both the UC (22.4±6.8 to 19.1±6.9 ml/kg/min; 15%) and ET (28.5±6.0 to 26.5±5.4 ml/kg/min; 6%, P<0.01), and these declines were not attenuated by ET (interaction, P=0.42). Peak CO was reduce by 13% as compared with pre-AC values (14.0 ± 2.5L/min vs 12.2 ± 2.6 L/min, P<0.01). The reduction in CO was due to a 14% reduction in the SV response to exercise (98.3 ± 12.1 ml vs 84.6 ± 14.5 ml, P<0.01), whereas the HR response was similar (146 ± 16 bpm vs 151 ± 17bpm, P=0.70). No differences were found between resting CO and SV from pre-AC to 12-months (P=0.25 and P=0.27 respectively). Conclusion: Cardiopulmonary fitness reductions persisted 12-months following AC-based chemotherapy, which was not attenuated by exercise during AC. Reductions in fitness coincided with reductions in peak cardiac output during exercise.

High intensity interval training protects the heart during increased metabolic demand in patients with type 2 diabetes: a randomised controlled trial

AimThe present study assessed the effect of high intensity interval training on cardiac function during prolonged submaximal exercise in patients with type 2 diabetes.MethodsTwenty-six patients with type 2 diabetes were randomized to a 12 week of high intensity interval training (3 sessions/week) or standard care control group. All patients underwent prolonged (i.e. 60 min) submaximal cardiopulmonary exercise testing (at 50% of previously assess maximal functional capacity) with non-invasive gas-exchange and haemodynamic measurements including cardiac output and stroke volume before and after the intervention.ResultsAt baseline (prior to intervention) there was no significant difference between the intervention and control group in peak exercise oxygen consumption (20.3 ± 6.1 vs. 21.7 ± 5.5 ml/kg/min, p = 0.21), and peak exercise heart rate (156.3 ± 15.0 vs. 153.8 ± 12.5 beats/min, p = 0.28). During follow-up assessment both groups utilized similar amount of oxygen during prolonged submaximal exercise (15.0 ± 2.4 vs. 15.2 ± 2.2 ml/min/kg, p = 0.71). However, cardiac function i.e. cardiac output during submaximal exercise decreased significantly by 21% in exercise group (16.2 ± 2.7–12.8 ± 3.6 L/min, p = 0.03), but not in the control group (15.7 ± 4.9–16.3 ± 4.1 L/min, p = 0.12). Reduction in exercise cardiac output observed in the exercise group was due to a significant decrease in stroke volume by 13% (p = 0.03) and heart rate by 9% (p = 0.04).ConclusionFollowing high intensity interval training patients with type 2 diabetes demonstrate reduced cardiac output during prolonged submaximal cardiopulmonary exercise testing. Ability of patients to maintain prolonged increased metabolic demand but with reduced cardiac output suggests cardiac protective role of high intensity interval training in type 2 diabetes.Trial registrationISRCTN78698481. Registered 23 January 2013, retrospectively registered.

Dead space in acute respiratory distress syndrome.

Dead space is the portion of each tidal volume that does not take part in gas exchange and represents a good global index of the efficiency of the lung function. Dead space is not routinely measured in critical care practice, because the difficulties in in interpreting capnograms and the different methods of calculations. Different dead space indices can provide useful information in acute lung injury (ALI) and acute respiratory distress syndrome (ARDS) patients, where changes in microvasculature are the main determinants for the increase in dead space and consequently a worsening of the outcome. Lung recruitment is a dynamic process that combines recruitment manoeuvres (RMs) with positive end expiratory pressure (PEEP) and low Vt to recruit collapsed alveoli. Dead space guided recruitment allows avoiding regional overdistension or reduction in cardiac output in critical care patients with ALI or ARDS. Different patterns of ventilation affect also CO2 elimination; in fact, end-inspiratory pause prolongation reduces dead space, increasing respiratory system compliance; plateau pressure and consequently driving pressure increase accordingly. Dead space measurement is a reliable method that provides important clinical and prognostic information. Different capnographic indices can be useful to evaluate therapeutic interventions or setting mechanical ventilation.

Celosia argentea L. (Amaranthaceae) a vasodilator species from the Brazilian Cerrado – An ethnopharmacological report

Ethnopharmacological relevanceCelosia argentea L. (Amaranthaceae), popularly known as “crista de galo”, is used in folk medicine due to its diuretic and hypotensive effects. However, there are no reports in the literature regarding its pharmacological effects on the cardiovascular system as well as no data proving the safety of this species. AimTo perform a detailed ethnopharmacological investigation of the ethanol soluble fraction from C. argentea (ESCA) using male and female Wistar rats. Material and methodsFirstly, a morpho-anatomical characterization was performed to determine the quality control parameters for the identification of the species under investigation. Then, the ethanol extract was obtained and chemically characterized by LC-DAD-MS. Furthermore, an oral acute toxicity study was performed in female Wistar rats. Finally, the possible diuretic and hypotensive effects of three different doses of ESCA (30, 100 and 300 mg/kg) were evaluated in male Wistar rats. Besides, the vasodilatory response of ESCA in mesenteric vascular beds (MVBs) and its involvement with nitric oxide/cGMP and prostaglandin/cAMP pathways as well as potassium channels were evaluated. ResultsThe main secondary metabolites present in ESCA were phenolic compounds, megastigmanes and triterpenoid saponins. ESCA caused no toxic effects in female rats nor increased urinary excretion in male rats after acute administration. However, ESCA significantly increased the renal elimination of potassium and chloride, especially at the end of 24 h after administration. Intermediary dose (100 mg/kg) of ESCA was able to promote significant acute hypotension and bradycardia. Moreover, its cardiovascular effects appear to be involved with the voltage-dependent K+ channels activation in MVBs. ConclusionThis study has brought new scientific evidence of preclinical efficacy of C. argentea as a hypotensive agent in normotensive rats. Apparently, these effects are involved with the activation of the voltage-sensitive K+ channels contributing to the reduction of peripheral vascular resistance and cardiac output.

Experimental assessment of a myocyte-based multiscale model of cardiac contractile dysfunction

Cardiac contractile dysfunction (CD) is a multifactorial syndrome caused by different acute or progressive diseases which hamper assessing the role of the underlying mechanisms characterizing a defined pathological condition. Mathematical modeling can help to understand the processes involved in CD and analyze their relative impact in the overall response. The aim of this study was thus to use a myocyte-based multiscale model of the circulatory system to simulate the effects of halothane, a volatile anesthetic which at high doses elicits significant acute CD both in isolated myocytes and intact animals. Ventricular chambers built using a human myocyte model were incorporated into a whole circulatory system represented by resistances and capacitances. Halothane-induced decreased sarco(endo)plasmic reticulum Ca2+ (SERCA2a) reuptake pump, transient outward K+ (Ito), Na+-Ca2+ exchanger (INCX) and L-type Ca2+ channel (ICaL) currents, together with ryanodine receptor (RyR2) increased open probability (Po) and reduced myofilament Ca2+ sensitivity, reproduced equivalent decreased action potential duration at 90% repolarization and intracellular Ca2+ concentration at the myocyte level reported in the literature. In the whole circulatory system, model reduction in mean arterial pressure, cardiac output and regional wall thickening fraction was similar to experimental results in open-chest sheep subjected to acute halothane overdose. Effective model performance indicates that the model structure could be used to study other changes in myocyte targets eliciting CD.

Reduced blood volume decreases cerebral blood flow in preterm piglets.

Preterm infants often have poor cardiovascular function that is associated with adverse neurodevelopmental outcomes. Preterm infants may be vulnerable to hypovolaemia due to excessive vasodilatation and leaky capillaries. Following reduction in blood volume, cardiac output and mean arterial pressure were reduced to the same extent in term and preterm piglets. Cerebral blood flow was maintained following blood volume reduction in term but not in preterm piglets. Effective detection and treatment of functional hypovolaemia may reduce the risk of brain injury in preterm infants. Preterm infants often have impaired cardiovascular function that may contribute to poor neurodevelopmental outcomes. The study aimed to determine the effects of reduced blood volume on cardiovascular function, including cerebral blood flow, in preterm and term piglets. In preterm (97/115days) and term piglets, up to 10% of the estimated blood volume was removed. Removal of blood was stopped if MAP dropped below 20mmHg. Heart rate, cardiac contractility and relaxation, cardiac output, mean arterial pressure (MAP), and cerebral blood flow were measured at baseline and again after blood volume reduction. The volume of blood removed was less in preterm piglets than in term piglets (5.1±1.8vs. 7.7±0.9mLkg-1 , mean±SD, P<0.001). Cardiac output and MAP decreased to the same extent in term and preterm piglets. Cerebral blood flow decreased in preterm but not term piglets and cerebral vascular conductance increased in term piglets only. Compensatory responses to maintain cerebral blood flow after blood volume reduction are active in term piglets but not in preterm piglets. As a result, even a small reduction in blood volume, or an increase in the capacity of the circulatory system leading to functional hypovolaemia, may lead to a significant reduction in cerebral blood flow and contribute to brain injury in preterm neonates.

Postural Hyperventilation as a Cause of Postural Tachycardia Syndrome: Increased Systemic Vascular Resistance and Decreased Cardiac Output When Upright in All Postural Tachycardia Syndrome Variants.

BackgroundPostural tachycardia syndrome (POTS) is a heterogeneous condition. We stratified patients previously evaluated for POTS on the basis of supine resting cardiac output (CO) or with the complaint of platypnea or “shortness of breath” during orthostasis. We hypothesize that postural hyperventilation is one cause of POTS and that hyperventilation‐associated POTS occurs when initial reduction in CO is sufficiently large. We also propose that circulatory abnormalities normalize with restoration of CO 2.Methods and ResultsFifty‐eight enrollees with POTS were compared with 16 healthy volunteer controls. Low CO in POTS was defined by a resting supine CO <4 L/min. Patients with shortness of breath had hyperventilation with end tidal CO 2 <30 Torr during head‐up tilt table testing. There were no differences in height or weight between control patients and patients with POTS or differences between the POTS groups. Beat‐to‐beat blood pressure was measured by photoplethysmography, and CO was measured by ModelFlow. Systemic vascular resistance was defined as mean arterial blood pressure/CO. End tidal CO 2 and cerebral blood flow velocity of the middle cerebral artery were only reduced during head‐up tilt in the hyperventilation group, whereas blood pressure was increased compared with control. We corrected the reduced end tidal CO 2 in hyperventilation by addition of exogenous CO 2 into a rebreathing apparatus. With added CO 2, heart rate, blood pressure, CO, and systemic vascular resistance in hyperventilation became similar to control.ConclusionsWe conclude that all POTS is related to decreased CO, decreased central blood volume, and increased systemic vascular resistance and that a variant of POTS is consequent to postural hyperventilation.

The effect of supine positioning on maternal hemodynamics during late pregnancy

Introduction: Recent studies have demonstrated an association between maternal supine sleep position and an increased risk of late stillbirth. During late pregnancy, the gravid uterus compresses the inferior vena cava (IVC) when a woman lies in the supine position. The azygos system of veins is the dominant pathway of collateral venous return back to the heart in the event of acute obstruction of the IVC. It is suggested that this pathway provides adequate collateral venous circulation in the event of IVC compression in the supine position during late pregnancy.Objective: Investigate the effect of supine positioning on maternal hemodynamics during late pregnancy and the role of collateral venous circulation.Methods: Ethics approval was obtained and 12 women with singleton pregnancies between 35- and 38-week gestation underwent magnetic resonance imaging in the supine and left lateral decubitus positions using a Skyra 3T system (Siemens). Phase-contrast images were evaluated to measure cardiac output, blood flow through the azygos vein, and blood flow through the abdominal aorta (AA) and IVC at two levels: at the level of aortic bifurcation and immediately above the renal veins.Results: The supine position was associated with a 16.4% reduction in cardiac output when compared to the left lateral position. In addition, blood flow through the IVC decreased at its origin by 85.3% and by 44.4% at the level of the renal veins. Blood flow through the azygos vein increased in the supine position by 220%. Blood flow through the AA at the level of the renal veins did not differ significantly; however, it is reduced by 32.3% at the level of the aortic bifurcation.Conclusions: Women in late pregnancy experience an increase in collateral venous blood flow when lying supine, likely as a response to marked compression of the IVC in this position. However, cardiac output and aortic blood flow were found to decrease while in the supine position.

Syncope

Syncope is a frequent condition, owing to a transient global cerebral hypoperfusion, that may depend on a reduction of vascular total peripheral resistance and/or cardiac output. Cardiac syncope doubled the risk of death from any cause and increased the risk of nonfatal and fatal cardiovascular events. Arrhythmias are the most common cardiac causes of syncope. Both bradyarrhythmias and tachyarrhythmias may predispose to syncope. The first line evaluation relies on clinical history, physical examination, active standing test, 12-lead echocardiogram. The diagnostic yield of electrophysiological study in detecting the cause of syncope depends highly on the pretest probability.

3,5-Diiodo-l-Thyronine Increases Glucose Consumption in Cardiomyoblasts Without Affecting the Contractile Performance in Rat Heart.

3,5-diiodo-l-thyronine (T2) is an endogenous derivative of thyroid hormone that has been suggested to regulate energy expenditure, resting metabolic rate and oxygen consumption with a mechanism that involves the activation of mitochondrial function. In this study, we focused on the cardiac effects of T2, which have been poorly investigated so far, by using both in vitro and ex vivo models. As a comparison, the response to T3 and T4 was also determined. Rat cardiomyoblasts (H9c2 cells) were used to determine T2, T3, and T4 uptake by high-performance liquid chromatography–tandem mass spectrometry. In the same experimental model, MTT test, crystal violet staining, and glucose consumption were investigated, using T2 concentrations ranging from 0.1 to 10 µM. To assess cardiac functional effects, isolated working rat hearts were perfused with T2, T3, or T4 in Krebs-Ringer buffer, and the hemodynamic variables were recorded. T2 was taken up by cardiomyoblasts, and in cell lysate T2 levels increased slowly over time, reaching higher concentrations than in the incubation medium. T2 significantly decreased MTT staining at 0.5–10 µM concentration (P < 0.05). Crystal violet staining confirmed a reduction of cell viability only upon treatment with 10 µM T2, while equimolar T3 and T4 did not share this effect. Glucose consumption was also significantly affected as indicated by glucose uptake being increased by 24 or 35% in cells exposed to 0.1 or 1.0 µM T2 (P < 0.05 in both cases). On the contrary, T3 did not affect glucose consumption which, in turn, was significantly reduced by 1 and 10 µM T4 (−24 and −41% vs control, respectively, P < 0.05 and P < 0.01). In the isolated perfused rat heart, 10 µM T2 produced a slight and transient reduction in cardiac output, while T3 and T4 did not produce any hemodynamic effect. Our findings indicate that T2 is taken up by cardiomyoblasts, and at 0.1–1.0 µM concentration it can modulate cardiac energy metabolism by increasing glucose consumption. Some evidence of toxicity and a transient impairment of contractile performance are observed only at 10 µM concentration. These effects appear to be specific for T2, since they are not reproduced by T3 or T4.

IMPACT OF LEVOSIMENDAN ON RENAL FUNCTION IN COMPLEX TREATMENT OF ACUTE DECOMPENSATED HEART FAILURE

Background. Levosimendan infusion can be used in the treatment of patients with acute decompensated heart failure (ADHF) with a reduction in cardiac output and signs of severe congestion/pulmonary edema. Aim. To study impact of levosimendan on renal function in patients with ADHF with reduced systolic function. Material and methods. The study was a prospective, randomized trial. We enrolled 30 men (age 62.5 [55.8-69.3] years) hospitalized with ADHF with reduced systolic function (left ventricular ejection fraction 500 pg/mL) and systolic blood pressure >125 mmHg. All patients were randomized into 2 groups of 15 people each. In the first group, the patients received an intravenous infusion of levosimendan 0.1 μg/kg/min for 24 hour added to standard therapy. The second group received standard therapy. Results. 24-hour levosimendan infusion significantly increased the glomerular filtration rate levels from 65.4 [45.2-99.2] mL/min/1.73m2 at baseline to 79.0 [66.3-93.1] mL/min/1.73m2 at discharge (p= 0.011), greatly decreased serum creatinine from 1.17 [0.90-1.55] mg/dL at baseline to 1.01 [0.89-1.14] mg/dL at discharge (p = 0.009) and blood urea nitrogen and at the same time improved renal blood flow in patients with ADHF while there were no clinically significant changes in the studied parameters in the standard therapy group. Conclusion. Levosimendan had a positive effect on renal function in patients with ADHF with reduced systolic function.

BALB/cJBom Treated with Angiotensin II and High Salt Diet Develop Pulmonary Hypertension and Right Sided Heart Failure while C57BL/6J Mice do not

Pulmonary arterial hypertension (PAH) is caused by increased pulmonary vascular resistance that can develop as part of other pathologies such as pulmonary embolism and heart failure, or because of pulmonary vascular remodeling. Right ventricle failure is the primary cause of death in patients with pulmonary hypertension. Interestingly, despite similar right ventricle systolic pressure and degree of hypertrophy, some patients rapidly develop right ventricle failure while others show prolonged periods of stability. Here we present a new mouse model of acute decompensated pulmonary hypertension displaying genetic predisposition to right‐sided heart failure.In a previous study we have seen that BALB/cJBom mice are more sensitive to a combination treatment of angiotensin II and high salt diet (AngII+Salt) compared to C57BL/6J. During the treatment BALB/cJBom mice develop massive edema and display very high mortality. The aim of present study was to elucidate the physiological and genetic mechanism responsible for the increased sensitivity in BALB/cJBom. BALB/cJBom and C57BL/6J mice were treated with AngII (0.5 μg/min/kg) and high salt diet (3%) and cardiac function was measured with echocardiography every day for seven days. BALB/cJBom treated with AngII+Salt display an increased pulmonary vascular resistance and right ventricle systolic pressure 24 hours following treatment initiation, assessed with Pulsed wave Doppler measurement of pulmonary artery flow. Increased pulmonary vascular resistance precedes diastolic dysfunction and reduced cardiac output, that is seen at day two and three respectively. Ejection fraction is not affected by AngII+Salt treatment. AngII+Salt does not affect cardiac function in C57BL/6J except increasing heart rate. This indicates a genetic susceptibility to pulmonary hypertension and right‐sided heart failure in BALB/cJBom. Linkage analysis identified a quantitative trait loci (QTL) at chromosome 3 which could explain the variation in change in cardiac output. Urine and sodium excretion, measured with metabolic cages when reduced cardiac output was established, was lower in BALB/cJBom mice treated with AngII+Salt than in C57BL/6J. Some BALB/cJBom mice did not excrete any urine during the 24‐hour measurement period, indicating acute kidney injury. QTLs on chromosome 2 and 3 were linked to changes in water and sodium regulation.In conclusion, BALB/cJBom treated with AngII+Salt develop decompensated pulmonary hypertension which is genetically predisposed. A QTL on chromosome 3 is linked to reduction in cardiac output during the setting of decompensated pulmonary hypertension. BALB/cJBom treated with AngII+Salt may work as an animal model to study the adaptive capacity of the right ventricle in pulmonary hypertension.Support or Funding InformationRegional Health Authority in Western NorwayÅke Wiberg foundationSwedish heart‐lung foundationSwedish Society of MedicineMarcus Borgström foundationSwedish Society for Medical ResearchThis abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Oxygen in the critically ill: friend or foe?

To examine the potential harmful effects of hyperoxia and summarize the results of most recent clinical studies evaluating oxygen therapy in critically ill patients. Excessive oxygen supplementation may have detrimental pulmonary and systemic effects because of enhanced oxidative stress and inflammation. Hyperoxia-induced lung injury includes altered surfactant protein composition, reduced mucociliary clearance and histological damage, resulting in atelectasis, reduced lung compliance and increased risk of infections. Hyperoxemia causes vasoconstriction, reduction in coronary blood flow and cardiac output and may alter microvascular perfusion. Observational studies showed a close relationship between hyperoxemia and increased mortality in several subsets of critically ill patients. In absence of hypoxemia, the routine use of oxygen therapy in patients with myocardial infarction, stroke, traumatic brain injury, cardiac arrest and sepsis, showed no benefit but rather it seems to be harmful. In patients admitted to intensive care unit, a conservative oxygen therapy aimed to maintain arterial oxygenation within physiological range has been proved to be well tolerated and may improve outcome. Liberal O2 use and unnecessary hyperoxia may be detrimental in critically ill patients. The current evidence supports the use of a conservative strategy in O2 therapy to avoid patient exposure to unnecessary hyperoxemia.

Clinical Biomarkers of Congestive Heart Failure Significantly Correlate with Pancreatic Trypsin and Lipase Levels in Human Blood Plasma

We recently have shown that pancreatic enzymes entering the circulation after a rise in intestinal permeability may cause multiple organ dysfunctions. Increased intestinal permeability occurs in congestive heart failure (CHF), for example due to reduction of cardiac output with hypoperfusion of the small intestine. We hypothesize that elevated intestinal permeability during CHF allows digestive enzymes, such as pancreatic trypsin and lipase, typically found in the lumen of the small intestine, to enter the systemic circulation. Our goal is to determine the levels of pancreatic trypsin and lipase and their correlation with clinical biomarkers of inflammation, and functional measurements of the heart and sympathetic nervous system. Blood from 35 (19 CHF and 16 non‐CHF Controls) patients at rest and analyzed by Western Blot for pancreatic lipase and trypsin and for inflammatory markers by ELISA assays for TNF‐a, IL‐6, BNP, ICAM, p‐Selectin, CRP, differential leukocyte counts and adrenergic sensitivity assays using isoproterenol. Clinical measurements such as age, body weight, BMI, and cardiac ejection fraction were recorded. The results showed significantly higher levels of trypsin, lipase, as well as TNF‐a, IL‐6, BNP, p‐Selectin, CRP, and neutrophil count. No change in monocyte, eosinophil, and basophil counts of CHF patients were seen when compared to Control. There were significant correlations between pancreatic trypsin levels and TNF‐a, BNP, and neutrophil count, and also between pancreatic lipase and TNF‐a, IL‐6, BNP, CRP, p‐Selectin, ejection fraction, neutrophil count, and Isoproterenol response. These results suggest that the protein levels of pancreatic digestive enzymes in the systemic circulation are elevated. The levels correlate with functional metrics of CHF and potentially play key roles as CHF biomarkers and in the analysis of the loss of cardiac function.Support or Funding InformationNational Institutes of Health Grant GM 85072This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.