Increase In Pulmonary Resistance Research Articles

Characterization of heart disease in mucopolysaccharidosis type II mice

Mucopolysaccharidosis type II (MPSII) is a progressive lysosomal storage disease caused by mutations in the IDS gene, that leads to iduronate 2-sulfatase (IDS) enzyme deficiency. The enzyme catalyzes the first step of degradation of two glycosaminoglycans (GAGs), heparan sulfate (HS) and dermatan sulfate (DS). The consequences of MPSII are progressively harmful and can lead to death by cardiac failure. The aim of this study was to characterize the cardiovascular disease in MPSII mice. Thus, we evaluated the cardiovascular function of MPSII male mice at 6, 8, and 10 months of age, through functional, histological, and biochemical analyzes. Echocardiographic analyses showed a progressive loss in cardiac function, observed through parameters such as reduction in ejection fraction (46% in control versus 28% in MPS II at 10 months, P < .01) and fractional area change (31% versus 23%, P < .05). Similar results were found in parameters of vascular competence, obtained by echo Doppler. Both aortic dilatation and an increase in pulmonary resistance were observed at all time points in MPSII mice. The histological analyses showed an increase in the thickness of the heart valves (2-fold thicker than control values at 10 months). Biochemical analyzes confirmed GAG storage in these tissues, with a massive elevation of DS in the myocardium. Furthermore, an important increase in the activity of proteases such as cathepsin S and B (up to 5-fold control values) was found and could be related to the progressive loss of cardiac function observed in MPSII mice. In this work, we demonstrated that loss of cardiac function in MPSII mice started at 6 months of age, although its global cardiac capacity was still preserved at this time. Disease progressed at later time points leading to heart failure. The MPSII mice at later times reproduce many of the cardiovascular events found in patients with Hunter's disease.

Anaesthesia in Patients with Pulmonary Hypertension

The perioperative management of patients with pulmonary hypertension requires an in-depth knowledge of the underlying disease, its related pathophysiology, effects of anaesthesia and surgery, as well as the appropriate pharmacotherapy. With respect to preoperative assessment, it is essential to review all available diagnostic findings, evaluate the patient's physical state, and to plan the anaesthetic procedure. Intraoperatively, the prevention of increases in pulmonary resistance and right ventricular decompensation appears essential. For this purpose, stress, hypothermia, decreased systemic perfusion, hypercapnia, hypoxemia, acidosis, and invasive mechanical ventilation should be avoided. If the pulmonary artery pressure exacerbates, application of inhaled nitric oxide or prostacyclins (iloprost), phosphodiesterase-III-inhibitors (milrinone) and phosphodiesterase-V-inhibitors (sildenafil), reflect first-line treatment options. In order to support the right ventricle, inotropes (adrenalin, dobutamine, levosimendan) or inodilators (milrinone) increase its contractility. Dependent on severity of disease and the magnitude of surgical intervention, patients with pulmonary hypertension require a specific continuous monitoring as well as trained staff in the postoperative period.

Efficacy of an Inhaled IL-13 Antibody Fragment in a Model of Chronic Asthma.

IL-13 is an important cytokine implicated in the pathogenesis of allergic asthma and is an attractive target for an inhaled therapeutic. To investigate the efficacy of CDP7766, a nebulized inhaled anti-IL-13 monoclonal antibody Fab fragment, in a model of allergic asthma in cynomolgus macaques naturally sensitized to Ascaris suum. CDP7766 was nebulized using a vibrating-membrane nebulizer on the basis of eFlow technology. The aerosol generated was analyzed to determine the particle size profile and the biophysical and functional properties of CDP7766. Nebulized CDP7766 (0.1-60 mg/animal, once daily for 5 d) was delivered via the inhaled route. The investigational eFlow nebulizer used in this study generated a respirable aerosol of CDP7766 with no evidence of degradation, loss of potency, aggregation, or formation of particulates. Inhaled CDP7766 was well tolerated in the model (no adverse effects related to local irritation) and significantly inhibited BAL allergen-induced cytokine and chemokine upregulation (60 mg vs. vehicle: eotaxin-3, P < 0.0008; MIP [macrophage inflammatory protein]-1β, IL-8, IFN-γ, P ≤ 0.01). CDP7766 significantly inhibited the increase in pulmonary resistance stimulated by inhaled allergen, measured 15 minutes and 24 hours after allergen challenge. Inhaled CDP7766 potently inhibited the function of IL-13 generated during the airway response to inhaled allergen in cynomolgus macaques, demonstrating the potential of inhaled anti-IL-13 therapeutics for the treatment of allergic asthma.

Regulatory respiratory data refinement with reduced animal usage

IntroductionAssessment of effects of potential drug candidates on the respiratory system is part of the regulatory preclinical safety assessment conducted prior to first in human trials (FTIH). Commonly, this is carried out utilizing head out plethysmography (HOP) or whole body plethysmography (WBP) which record only ventilatory parameters. When dosing via the inhaled route a more thorough respiratory assessment, including a direct measure of airway mechanics, is desirable. The aim of the present work was to improve the strategy for respiratory safety testing by a) evaluating a telemetered pleural pressure – HOP (PP-HOP) model and b) evaluating a crossover study design protocol in the WBP model to reduce variability and animal usage. MethodsFor the PP- HOP model, rats were surgically implanted with a telemetry device for measurement of pleural pressure. Animals were placed in HOP tubes and respiratory function assessed when exposed to methacholine at doses of 0 (saline only), 0.42, 1.6 and 3.8 mg/kg. WBP assessment was performed in rats in a crossover study design when treated with theophylline at doses of 0 (saline only), 3, 10 and 30 mg/kg. ResultsData from the PP-HOP study confirmed the expected changes in ventilatory parameters and airway mechanics in response to inhaled methacholine, including an increase in pulmonary resistance and decrease in tidal volume.Data from the WBP crossover study demonstrated similar sensitivity and statistical power to detect changes in respiratory rate and tidal volume to a standard parallel group design. ConclusionMeasurement of PP-HOP in a stand-alone safety pharmacology study in conjunction with HOP assessment conducted as part of a toxicology study, represents an improved respiratory testing strategy for inhaled drugs. For compounds administered by other routes, we conclude that use of WBP using a crossover dosing design is a suitable alternative to parallel dosing groups, with a significant reduction in animal numbers and no loss of statistical power.

Food allergen-sensitized CCR9+ lymphocytes enhance airways allergic inflammation in mice.

The mechanisms of the atopic march, characterized by a natural progression from food and cutaneous allergies to rhinitis and asthma, are still unknown. However, as several organs can be involved, chemokines and their receptors might be implicated in this process and may be instrumental factors. We hypothesized that the T-cell gut-homing receptor CCR9 could be implicated in the evolution of allergic diseases. We characterized the immune response and the role of CCR9 in a murine model combining food allergy to wheat gliadin and a model of acute airways inflammation in response to house dust mite. Compared with solely asthmatic-like mice, we demonstrated that the aggravation of pulmonary symptoms in consecutive food and respiratory allergies, characterized by an increase in pulmonary resistance and a higher Th17/Treg ratio, was abrogated in CCR9 knockout mice. Moreover, transfer of food-allergic CD4+ T cells from wild-type but not from CCR9-/- aggravated airways inflammation demonstrating that CCR9 is involved in food allergy-enhanced allergic airway inflammation to unrelated allergens. Taken together, our results demonstrated a crucial role of the T-cell homing receptor CCR9 in this model and validated its potential for use in the development of therapeutic strategies for allergic diseases.

Transgelin-2 as a therapeutic target for asthmatic pulmonary resistance.

There is a clinical need for new bronchodilator drugs in asthma, because more than half of asthmatic patients do not receive adequate control with current available treatments. We report that inhibition of metallothionein-2 protein expression in lung tissues causes the increase of pulmonary resistance. Conversely, metallothionein-2 protein is more effective than β2-agonists in reducing pulmonary resistance in rodent asthma models, alleviating tension in tracheal spirals, and relaxing airway smooth muscle cells (ASMCs). Metallothionein-2 relaxes ASMCs via transgelin-2 (TG2) and induces dephosphorylation of myosin phosphatase target subunit 1 (MYPT1). We identify TSG12 as a nontoxic, specific TG2-agonist that relaxes ASMCs and reduces asthmatic pulmonary resistance. In vivo, TSG12 reduces pulmonary resistance in both ovalbumin- and house dust mite-induced asthma in mice. TSG12 induces RhoA phosphorylation, thereby inactivating the RhoA-ROCK-MYPT1-MLC pathway and causing ASMCs relaxation. TSG12 is more effective than β2-agonists in relaxing human ASMCs and pulmonary resistance with potential clinical advantages. These results suggest that TSG12 could be a promising therapeutic approach for treating asthma.

Right heart impairement in cirrhotic patients

Right ventricular dysfunction in cirrhotic patients is not well described, we suggest that cirrhosis will result in an increase of pulmonary resistance and the post-charge of RV, we aim to assess ventricle function in cirrhotic patients and the correlation between the severity of cirrhosis and the RV dysfunction. We assessed echocardiographic RV systolic function in 80 patients with cirrhosis. We compared compensated ( n = 39) and uncompensated patients ( n = 41) to controls ( n = 80). The severity of cirrhotic disease was assessed by Child and Mild scores. RV was significantly enlarged in cirrhotic patients compared to controls and in uncompensated patients compared to compensated patients (RV diastolic area = 16.7 ± 5 cm 2 , 14.5 ± 4 cm 2 , P = 0.01). The TAPSE and the S wave were significantly lower in cirrhotic patients ( P = 0.007) compared to controls but there were no difference between the sub-groups. Longitudinal peak systolic speckle tracking of lateral RV wall was significantly decreased in cirrhotic patients ( P < 0.001). There was no correlation between the different parameters of the RV and Child as well as Mild scores. The present study illustrated RV systolic function impairment in cirrhotic patients. The lack of correlation between the right ventricle dysfunction and the severity of cirrhosis suggest a complex mechanism. Right ventricular dysfunction in cirrhotic patients is not well described, we suggest that cirrhosis will result in an increase of pulmonary resistance and the post-charge of RV, we aim to assess ventricle function in cirrhotic patients and the correlation between the severity of cirrhosis and the RV dysfunction. We assessed echocardiographic RV systolic function in 80 patients with cirrhosis. We compared compensated ( n = 39) and uncompensated patients ( n = 41) to controls ( n = 80). The severity of cirrhotic disease was assessed by Child and Mild scores. RV was significantly enlarged in cirrhotic patients compared to controls and in uncompensated patients compared to compensated patients (RV diastolic area = 16.7 ± 5 cm 2 , 14.5 ± 4 cm 2 , P = 0.01). The TAPSE and the S wave were significantly lower in cirrhotic patients ( P = 0.007) compared to controls but there were no difference between the sub-groups. Longitudinal peak systolic speckle tracking of lateral RV wall was significantly decreased in cirrhotic patients ( P < 0.001). There was no correlation between the different parameters of the RV and Child as well as Mild scores. The present study illustrated RV systolic function impairment in cirrhotic patients. The lack of correlation between the right ventricle dysfunction and the severity of cirrhosis suggest a complex mechanism.

Mechanistic Basis for Obesity-related Increases in Ozone-induced Airway Hyperresponsiveness in Mice.

Obesity is a risk factor for asthma, especially nonallergic asthma. Ozone, a common air pollutant, is a nonallergic asthma trigger. Importantly, ozone-induced decrements in lung function are greater in obese and overweight human subjects than in lean individuals. Obese mice also exhibit exaggerated pulmonary responses to ozone. Ozone causes greater increases in pulmonary resistance, in bronchoalveolar lavage neutrophils, and in airway hyperresponsiveness in obese than in lean mice. Our data indicate that IL-33 plays a role in mediating these events. Ozone causes greater release of IL-33 into bronchoalveolar lavage fluid in obese than in lean mice. Furthermore, an antibody blocking the IL-33 receptor, ST2, attenuates ozone-induced airway hyperresponsiveness in obese but not in lean mice. Our data also indicate a complex role for tumor necrosis factor (TNF)-α in obesity-related effects on the response to ozone. In obese mice, genetic deficiency in either TNF-α or TNF-α receptor 2 augments ozone-induced airway hyperresponsiveness, whereas TNF-α receptor 2 deficiency virtually abolishes ozone-induced airway hyperresponsiveness in lean mice. Finally, obesity is known to alter the gut microbiome. In female mice, antibiotics attenuate obesity-related increases in the effect of ozone on airway hyperresponsiveness, possibly by altering microbial production of short-chain fatty acids. Asthma control is often difficult to achieve in obese patients with asthma. Our data suggest that therapeutics directed against IL-33 may ultimately prove effective in these patients. The data also suggest that dietary manipulations and other strategies (prebiotics, probiotics) that alter the microbiome and/or its metabolic products may represent a new frontier for treating asthma in obese individuals.

Pulmonary Arterial Hypertension Associated With Congenital Heart Disease

The management of patients with congenital heart disease (CHD) and pulmonary arterial hypertension (PAH) has changed dramatically with the development of targeted therapy with selective pulmonary vasodilators. It is important to develop evidence-based guidelines for the management of these patients, and to achieve this, a register of adult Bangladeshi patients with PAH associated with CHD should be established. At the World Symposium in Nice, France, in 2013, the consensus was reached that patients with a pulmonary resistance of &lt; 4 Wood Units (WU)û0m2 have operable disease, and patients with a pulmonary resistanceof &gt; 8 WUû0m2 have inoperable disease. However, these criteria are conservative. Some patients with a pulmonary resistance of &gt; 8 WUû0m2 and a good response to a pulmonary vasodilator test have operable disease and a favorable clinical course long after repair of CHD. The criteria determining operability in patients with PAH associated with CHD in the era of pulmonary vasodilators should be established using data obtained from patient registers and/or multicenter studies. The optimal management of Eisenmenger syndrome should also be established using data obtained from patient registers. Prospective studies should be conducted to determine the life expectancy of patients with Eisenmenger syndrome in the era of targeted therapy. A relatively mild increase in pulmonary resistance may result in failure of a Fontan circulation. The effects of pulmonary vasodilators on the long-term prognosis of patients who have undergone the Fontan operation are still unclear. (Int Heart J 2015; 56: S1-S3).University Heart Journal Vol. 12, No. 1, January 2016; 31-33

High Cardiac Output By Microfistulas: A New Pulmonary Hypertension Mechanism in Patients with Myelofibrosis and the Impact of the Treatment with Ruxolitinib

Background: Pulmonary Hypertension (PH) is a well-known complication of the advanced phase of Myeloproliferative Diseases (MPD) such as Polycythemia Vera (PV), Essential Thrombocytopenia (ET) and Myelofibrosis (MF). Although initially attributed to increased pulmonary vascular resistance (group 1 PH of the WHO classification), this entity was classified in 2009 in group 5 PH (unknown mechanism and miscellaneous PH). Our aim was to describe the prevalence and possible causes of PH in a series of patients with MF.Methods: We studied a series of patients with Primary MF or Secondary MF to other MPD with cardiac ultrasound, right heart catheterization and scintigraphy after intraarterial infusion of Tc99-labeled albumin macroaggregates.Results: We studied 11 consecutive patients with MF (7 male, mean age 58 years, 4 with MF post-PV, 4 post-TE and 3 Primary MF) during the period 2009-2014. All of them had mutations of JAK-2 gene, fibrosis in bone marrow biopsy and visceromegaly (all with intermediate-2 or higher IPSS). Median NTproBNP levels were 4597 pg/ml (range 175-5700). Echocardiogram showed high systolic pulmonary pressure in most cases, with a mean of 54 ± 17 mmHg (range 35-80). Right heart catheterization showed high cardiac output (HCO) in all patients (table 1).After ruling out other causes of HCO, a scintigraphy was performed after administration of Tc99-labeled albumin macroaggregates in descending thoracic aorta. In every case, a percentage of the labeled macroaggregates (6.1 ± 2.0% of the radioactivity) were plugged in the pulmonary capillary bed, what is diagnostic of the presence of microfistulas in infradiaphragmatic territory.In two of these patients, scintigraphies were performed at diagnosis and after been treated with the anti-JAK drug Ruxolitinib (Novartis Pharma). A favourable impact of this drug was obtained in the two cases, probably due to a reduction of spleen volume.Conclusion: Most patients with MF show pulmonary hypertension associated with high cardiac output caused by microfistulas, without significant increase in pulmonary resistance. This finding has important clinical implications, because pulmonary vasodilators (once recommended) should be contraindicated, since they could cause worsening of the clinical picture. Ruxolitinib could resolve PH in MF and a prospective study in this sense could be indicated.Table 1Patient1234567891011Pulmonary Artery Pres. (S/D/Mean)58/38/ 4269/41/ 5048/29/ 4084/26/ 4557/17/ 3022/17 / 1951/16 / 2822/9 / 1325/8 / 1471/23 / 3930/7 / 15Pulmonary wedge pres.28372713971378126Cardiac output (l/min)12.58.0117.187.38.76.77.4567.8Cardiac index (l/m/m2)5.54.06.63.6544.84.04.53.95.1Pulmonary vascular resistance (Wood U.)1.21.41.24.52.631.70.90.84.51.1 DisclosuresOjeda:Alexion Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fores:Alexion Pharmaceuticals: Consultancy, Speakers Bureau.

Absence of inflammatory lung injury in rabbits challenged intravascularly with complement-derived chemotactic factors.

Systemic activation of the complement system results in the generation of chemotactic factors that have been suggested to play a role in the pathogenesis of inflammatory pulmonary diseases such as the adult respiratory distress syndrome. This led us to ask whether systemic complement activation by cobra venom factor (CVF) or intravascularly administered zymosan-activated rabbit plasma (ZAP) or rabbit C5a would result in lung injury. As had been described previously for CVF and ZAP, intravenously administered rabbit C5a also caused an acute neutropenia along with sequestration of neutrophils within the pulmonary vasculature. However, no significant lung inflammation as measured by neutrophil emigration or increased vascular permeability occurred with any of the three stimuli. Only when these agents were combined with anesthesia, surgical manipulation, and intubation did significant neutrophil emigration into alveoli occur, but again without any change in vascular permeability. After administration of ZAP, a decrease in dynamic compliance and an increase in pulmonary resistance as well as a transient period of hypoxemia occurred that was not observed after CVF or rabbit C5a treatment. Thus, our studies suggest that changes in lung function after ZAP instillation may not represent changes from complement activation alone in that they are not reproduced with CVF or rabbit C5a. We conclude that complement activation, as an isolated event, may be an insufficient insult in the lung to produce significant lung injury.

Pulmonary arterial hypertension associated with congenital heart disease. Personal perspectives.

The management of patients with congenital heart disease (CHD) and pulmonary arterial hypertension (PAH) has changed dramatically with the development of targeted therapy with selective pulmonary vasodilators. The number of adult Japanese patients with PAH associated with CHD is increasing. It is important to develop evidence-based guidelines for the management of these patients, and to achieve this, a register of adult Japanese patients with PAH associated with CHD should be established. At the World Symposium in Nice, France, in 2013, the consensus was reached that patients with a pulmonary resistance of < 4 Wood Units (WU)·m(2) have operable disease, and patients with a pulmonary resistance of > 8 WU·m(2) have inoperable disease. However, these criteria are conservative. Some patients with a pulmonary resistance of > 8 WU·m(2) and a good response to a pulmonary vasodilator test have operable disease and a favorable clinical course long after repair of CHD. The criteria determining operability in patients with PAH associated with CHD in the era of pulmonary vasodilators should be established using data obtained from patient registers and/or multicenter studies. The optimal management of Eisenmenger syndrome should also be established using data obtained from patient registers. Prospective studies should be conducted to determine the life expectancy of patients with Eisenmenger syndrome in the era of targeted therapy. A relatively mild increase in pulmonary resistance may result in failure of a Fontan circulation. The effects of pulmonary vasodilators on the long-term prognosis of patients who have undergone the Fontan operation are still unclear.

Impaired preload reserve during exercise limits exercise capacity in the better Fontan patients

Background: Factors controlling cardiac output in a Fontan circulation are still poorly understood. This study aimed at evaluating changes in exercise hemodynamics using a novel cardiac magnetic resonance (CMR) methodology during mild, moderate and high intensity exercise. Methods: Ten Fontan patients (6 male, age 20±4 years, NYHA I-II) underwent CMR at rest and during supine exercise on a programmable cycle ergometer. Systemic ventricular volumes were obtained at rest (heart rate 72±14 bpm) and during mild (100±10 bpm), moderate (122±15 bpm) and high intensity (144±15 bpm) exercise. Images were acquired using an ungated, free-breathing real-time CMR sequence (12-18 contiguous 8mm slices). Software was developed to allow for synchronization of short and long-axis images with compensation for respiratory phase translation. Endocardial borders were delineated using a bi-plane model. Simultaneously, radial and pulmonary artery pressures were measured. Results: Cardiac output (CO) increased from rest to moderate intensity exercise, but failed to increase further during high intensity exercise (6.8±1.6 vs 10.0±3.2 vs 11.8±3.2 vs 12.5±3.1 l/min; P<0.0001). The increase in CO depended on a 106±49% increase in heart rate as stroke volume (SV) decreased during high intensity exercise (95±19 vs 100±21 vs 96±20 vs 87±16 ml; P<0.0001). End-diastolic volume (EDV) decreased during high intensity exercise (169±38 vs 174±39 vs 170±38 vs 162±36 ml; P=0.002), whereas end-systolic volume (ESV) did not change during exercise (74±31 vs 74±31 vs 73±32 vs 75±32 ml; P=0.715). Ejection fraction (EF) decreased during exercise (57±10 vs 58±10 vs 59±11 vs 55±11%, P=0.037). Pulmonary artery pressures (9±3 vs 14±4 vs 17±4 vs 21±5 mmHg; P<0.0001) and mean arterial pressures (81±7 vs 92±7 vs 100±6 vs 106±4 mmHg; P<0.0001) increased during exercise. Total pulmonary resistance increased during high intensity exercise (P=0.004) whereas systemic vascular resistance decreased during exercise (P=0.003). Arteriovenous oxygen difference increased from 5.5±1.2 to 9.6±1.9 ml/100ml (P=0.001). Conclusions: A decreasing SV and EDV despite a blunted heart rate response during exercise reflect a limited ventricular preload which is presumably related to the increase in total pulmonary resistance. The decreased preload reserve in a Fontan circuit is an important determinant limiting exercise capacity.

Analysis of cardiovascular dynamics in pulmonary hypertensive C57BL6/J mice

A computer model was used to analyze data on cardiac and vascular mechanics from C57BL6/J mice exposed to 0 (n = 4), 14 (n = 6), 21 (n = 8) and 28 (n = 7) days of chronic hypoxia and treatment with the VEGF receptor inhibitor SUGEN (HySu) to induce pulmonary hypertension. Data on right ventricular pressure and volume, and systemic arterial pressure obtained before, during, and after inferior vena cava occlusion were analyzed using a mathematical model of realistic ventricular mechanics coupled with a simple model of the pulmonary and systemic vascular systems. The model invokes a total of 26 adjustable parameters, which were estimated based on least-squares fitting of the data. Of the 26 adjustable parameters, 14 were set to globally constant values for the entire data set. It was necessary to adjust the remaining 12 parameters to match data from all experimental groups. Of these 12 individually adjusted parameters, three parameters representing pulmonary vascular resistance, pulmonary arterial elastance, and pulmonary arterial narrowing were found to significantly change in HySu-induced remodeling. Model analysis shows a monotonic change in these parameters as disease progressed, with approximately 130% increase in pulmonary resistance, 70% decrease in unstressed pulmonary arterial volume, and 110% increase in pulmonary arterial elastance in the 28-day group compared to the control group. These changes are consistent with prior experimental measurements. Furthermore, the 28-day data could be explained only after increasing the passive elastance of the right free wall compared to the value used for the other data sets, which is likely a consequence of the increased RV collagen accumulation found experimentally. These findings may indicate a compensatory remodeling followed by pathological remodeling of the right ventricle in HySu-induced pulmonary hypertension.

Respiratory responses to exercise in the horse

Horses are elite athletes when compared with other mammalian species. In the latter, performance is limited by cardiovascular or musculoskeletal performance whereas in athletic horses it is the respiratory system that appears to be rate limiting and virtually all horses exercising at high intensities become hypoxaemic and hypercapnoeic. This is due to both diffusion limitation and a level of ventilation inadequate for the metabolic level that enables horses to exercise at these intensities. In conjunction with these blood gas changes, total pulmonary resistance increases and the work of breathing rises exponentially and airflow eventually plateaus despite increases in inspiratory and expiratory intrapleural pressures. Horses breathe at comparatively high frequencies when galloping due to the tight 1:1 coupling of strides to breathing. Whether this effects gas exchange and, if so, to what extent, has not been fully elucidated.

Clinical detection and monitoring of acute pulmonary embolism: proof of concept of a computer-based method

BackgroundThe diagnostic ability of computer-based methods for cardiovascular system (CVS) monitoring offers significant clinical potential. This research tests the clinical applicability of a newly improved computer-based method for the proof of concept case of tracking changes in important hemodynamic indices due to the influence acute pulmonary embolism (APE).MethodsHemodynamic measurements from a porcine model of APE were used to validate the method. Of these measurements, only those that are clinically available or inferable were used in to identify pig-specific computer models of the CVS, including the aortic and pulmonary artery pressure, stroke volume, heart rate, global end diastolic volume, and mitral and tricuspid valve closure times. Changes in the computer-derived parameters were analyzed and compared with experimental metrics and clinical indices to assess the clinical applicability of the technique and its ability to track the disease state.ResultsThe subject-specific computer models accurately captured the increase in pulmonary resistance (Rpul), the main cardiovascular consequence of APE, in all five pigs trials, which related well (R2 = 0.81) with the experimentally derived pulmonary vascular resistance. An increase in right ventricular contractility was identified, as expected, consistent with known reflex responses to APE. Furthermore, the modeled right ventricular expansion index (the ratio of right to left ventricular end diastolic volumes) closely followed the trends seen in the measured data (R2 = 0.92) used for validation, with sharp increases seen in the metric for the two pigs in a near-death state. These results show that the pig-specific models are capable of tracking disease-dependent changes in pulmonary resistance (afterload), right ventricular contractility (inotropy), and ventricular loading (preload) during induced APE. Continuous, accurate estimation of these fundamental metrics of cardiovascular status can help to assist clinicians with diagnosis, monitoring, and therapy-based decisions in an intensive care environment. Furthermore, because the method only uses measurements already available in the ICU, it can be implemented with no added risk to the patient and little extra cost.ConclusionsThis computer-based monitoring method shows potential for real-time, continuous diagnosis and monitoring of acute CVS dysfunction in critically ill patients.

Effects of adenosine on NANC bronchoconstriction in anaesthetized guinea-pigs.

The present work assesses the effects of the acute administration of adenosine on tachykinergic bronchoconstriction induced in different ways (exogenously administered capsaicin or substance P and vagal electrical stimulation) in anaesthetized and curarized guinea-pigs. Adenosine (30-3000 micrograms kg-1, i.v.) enhanced significantly and dose-relatedly the airway narrowing induced by a single dose of capsaicin (0.5-2 micrograms kg-1, i.v.), both in normal and in vagotomized animals. A smaller and less dose-dependent enhancement by the nucleoside of the pulmonary resistance increase induced by substance P (5-15 micrograms kg-1, i.v.) was observed. This effect was almost completely prevented by the H1 antagonist diphenhydramine (1 mg kg-1, i.v.), which also unmasked an inhibitory action of adenosine at the highest doses. Diphenhydramine, on the contrary, did not significantly modify the potentiation by adenosine of capsaicin-mediated bronchoconstriction. Finally, the nucleoside dose-dependently inhibited the atropine-resistant bronchospasm following vagal electrical stimulation. The use of the selective adenosinic agonists R-N6-[2-phenylisopropyl]adenosine (1-100 micrograms kg-1, i.v.) and 5'-N-methylcarboxamidoadenosine (1-100 micrograms kg-1, i.v.) before the administration of capsaicin, revealed the ability of the first to reproduce the enhancement induced by adenosine, while the second had an inhibitory effect. It is concluded that adenosine has both excitatory and inhibitory modulatory effects on airway responsiveness to excitatory non-adrenergic non-cholinergic (e-NANC) stimuli. The excitatory effects, revealed with substance P and capsaicin, support the hypothesis that adenosine may play a role as an asthma mediator.

Brain-derived neurotrophic factor enhances histamine-induced airway responses and changes levels of exhaled nitric oxide in guinea pigs in vivo

The neurotrophin brain-derived neurotrophic factor (BDNF) occurs in elevated levels during airway inflammation, including asthma and hypoxic lung injury, and has been suggested to be associated with airway hyperresponsiveness in these conditions. The aim of the present study was to examine whether airway responses to histamine challenge and levels of exhaled nitric oxide (NO) in vivo might be altered upon BDNF treatment. Pulmonary resistance, lung compliance, insufflation pressure, and levels of exhaled NO were measured in anaesthetized guinea pigs exposed to BDNF prior to challenge with histamine and with intact or inhibited endogenous NO production. BDNF pretreatment significantly enhanced histamine-evoked increase in pulmonary resistance and insufflation pressure, as well as the decrease in lung compliance. BDNF markedly accentuated the reduction in exhaled NO following histamine challenge. In animals with inhibited endogenous NO production BDNF induced a significantly earlier histamine-evoked increase in airway responses. The present data show that BDNF can induce an augmentation of histamine-evoked airway responses and reduce levels of NO in exhaled air in vivo. Endogenous NO seems to exert a braking action on BDNF-induced enhancement of airway responses and a reduced ability to release NO may be one mechanism for increased airway response during elevated BDNF levels. Taken together this indicates that BDNF may be of importance for airway hyperresponsiveness in vivo. The interaction between BDNF and airway NO formation, and its relation to airway responses, merit further investigation.

Comparison of Enantiomers of SPFF, a Novel .BETA.2-Adrenoceptor Agonist, in Bronchodilating Effect in Guinea Pigs

Previous study on racemic SPFF [2-(4-amino-3-chloro-5-trifluomethyl-phenyl)-2-tert-butylamino-ethanol hydrochloride], a novel beta2-adrenoceptor agonist, has validated that it is a potent, long-acting bronchodilator with relative higher beta2-adrenoceptor selectivity. On the basis of this study, we compared the pharmacological properties of SPFF and its enantiomers ((-)-SPFF and (+)-SPFF) in guinea pigs taking isoprenaline or salbutamol (SAB) as referenced drugs. For the relaxation of both normal and precontracted trachea strips in vitro, (-)-SPFF was found more potent than (+/-)-SPFF or (+)-SPFF. Moreover, we confirmed that the bronchodilator effect of (-)- and (+)-enantiomers were due to activation of the beta2-adrenoceptor because this effect was antagonized by a specific beta2-adrenoceptor antagonist, ICI-118551, with similar pA2 values to those of (+/-)-SPFF. Radioligand binding assay revealed that affinity of (-)-enantiomer to beta2-adrenoceptor was 6 and 164 fold greater than that of (+/-)- and (+)-SPFF, respectively. In addition, isomeric difference of overall selectivity between (-)-SPFF and (+)-SPFF was 10.7 fold for lung versus atria. (-)-SPFF displayed almost the same protective effect against bronchospasm induced by histamine-acetylcholine aerosol in conscious guinea pigs as (+/-)-SPFF did. However, the latent time of (+)-SPFF (1 mg.kg(-1)) was significantly shorter than that of (+/-)- and (-)-SPFF at the same doses. Finally, in the inhibition of histamine-induced increase of pulmonary resistance (RL) in anesthetized guinea pigs, (-)-SPFF was 1.3 and 3.5 times more potent than (+/-)- and (+)-SPFF. Correspondingly, in inhibiting the decrease of pulmonary compliance (CL) , the potencies of (-)- and (+)-enantiomers were approximately equivalent to that of (+/-)-SPFF. Furthermore, a study on the long-lasting action of the test drugs had shown that the effects of (-)-SPFF (30 microg.kg(-1)), (+/-)-SPFF (30 microg.kg(-1)) and (+)-SPFF (100 microg.kg(-1)) in inhibiting the increase of RL all lasted for 4 h. Nevertheless, the effects of (-)- and (+)-enantiomers were slightly lower 4 h after intraduodenal administration in inhibiting the decrease of CL. In conclusion, (-)-SPFF may be beneficial for the treatment of asthma because of its more potent efficacy and higher adrenoceptor affinity than (+/-)- or (+)-SPFF.

Hypertension pulmonaire des affections respiratoires chroniques

Pulmonary hypertension of chronic respiratory disease is defined as elevation of the mean resting pulmonary artery pressure to over 20 mm Hg. It is the commonest cause of pre-capillary pulmonary hypertension on account of the high prevalence of chronic obstructive pulmonary disease. It is primarily due to alveolar hypoxia that leads to remodelling of the distal pulmonary vasculature and consequently to an increase in pulmonary resistance. It is not as severe as idiopathic pulmonary hypertension. The mean pulmonary artery pressure is usually moderately increased (20-35 mm Hg) when patients are seen during a stable period of the disease. There are, however, more severe cases of pulmonary hypertension called, in some cases, disproportionate but these are uncommon. Increased right ventricular afterload can lead to the development of right ventricular failure that is a definite prognostic factor. The clinical symptoms of pulmonary hypertension are at a secondary level compared with those of the causal disease. Non-invasive diagnosis depends on Doppler echocardiography. Currently the most effective treatment is long term oxygen therapy (16-18 hr/24 hr). This improves or, at least stabilises, the pulmonary hypertension.