Left ventricular venting during extracorporeal membrane oxygenation; the effects on cardiac performance in a porcine model of critical post-cardiotomy failure

Introduction Left ventricular distension is a major concern with postcardiotomy veno-arterial extracorporeal membrane oxygenation (VA-ECMO) supporting a critical heart failure after cardiac surgery. This porcine study evaluates the effects of left ventricular venting on cardiac function during ECMO-supported circulation and after weaning from ECMO. Methods Twenty anaesthetised open-chest pigs were put on cardiopulmonary bypass with aortic cross-clamping and suboptimal cardioplegic arrest for 40 min. After declamping and defibrillation, the animals were supported by VA-ECMO for 180 min either with or without additional left ventricular venting. Continuous haemodynamic evaluations were performed at baseline and at cardiac arrest, during VA-ECMO and for 120 min after weaning from circulatory support. Left ventricular perfusion and function were evaluated with microspheres, pressure-volume loops and epicardial echocardiography at baseline and after 1 and 2 h with unsupported circulation. Results In vented animals both mean aortic and left ventricular peak systolic pressure increased at the end of the ECMO-supported period compared to those not vented and remained increased also after weaning. Both at 60 min and 120 min after weaning from circulatory support, left ventricular stroke work and pressure-volume area were increased in vented compared to not vented animals. At 120 min left ventricular stroke volume was increased in vented compared to not vented animals, myocardial perfusion did not differ. The left ventricular mechanical efficiency, defined as the ratio between pressure volume area and myocardial perfusion, was increased (53.2 ± 5 vs 36.2 ± 2.1 J/mL/g, p = 0.011) in vented- compared to not vented hearts. Conclusion This experimental study demonstrate that left ventricular venting during post-cardiotomy veno-arterial ECMO for 3 h attenuates deterioration of left ventricular function and haemodynamics early after weaning from circulatory support.publishedVersio

Mitral annular dynamics are influenced by left ventricular load and contractility in an acute animal model

The purpose of this study was to investigate the effects of loading conditions and left ventricular (LV) contractility on mitral annular dynamics. In 10 anesthetized pigs, eight piezoelectric transducers were implanted equidistantly around the mitral annulus. High-fidelity catheters measured left ventricular pressures and the slope of the end-systolic pressure-volume relationship (Ees) determined LV contractility. Adjustments of pre- and afterload were done by constriction of the inferior caval vein and occlusion of the descending aorta. Mitral annulus area indexed to body surface area (MAAi ), annular circularity index (ACI), and nonplanarity angle (NPA) were calculated by computational analysis. MAAi was more dynamic in response to loading interventions than ACI and NPA. However, MAAi maximal cyclical reduction (−Δr) and average deformational velocity (−v) did not change accordingly (p=0.31 and p=0.22). Reduced Ees was associated to attenuation in MAAi -Δr and MAAi -v (r 2=0.744; p=0.001 and r 2=0.467; p=0.029). In conclusion, increased cardiac load and reduced LV contractility may cause deterioration of mitral annular dynamics, likely impairing coaptation and increasing susceptibility to valvular incompetence.publishedVersio

Seleenityöryhmän raportti 2016

Suomessa 1970–luvulla tehdyissä tutkimuksissa havaittiin elintarvikkeiden seleenipitoisuuksien olevan erittäin pieniä ja väestön seleeninsaanti jäi selvästi alle saantisuositusten. Taustalla oli seleenin ja erityisesti liukoisen, kasveille käyttökelpoisen seleenin pieni määrä viljelymaissa. Tilanteen korjaamiseksi natriumselenaattia on lisätty moniravinteisiin lannoitteisiin vuodesta 1984 lähtien. Seleenilannoituksen avulla epäorgaaninen lannoiteseleeni muuttuu kasveissa orgaanisiksi seleeniyhdisteiksi, joita ihmiset ja eläimet pystyvät hyödyntämään tehokkaammin kuin epäorgaanista seleeniä. Seleenilannoituksen myötä kotimaisten viljelykasvien ja rehujen ja sitä kautta elintarvikkeiden seleenipitoisuudet ovat kasvaneet. Liukoisen seleenin määrä viljelymaissa ei ole kuitenkaan kasvanut 30 vuoden aikana, sillä Suomen olosuhteissa seleeni muuttuu nopeasti niukkaliukoiseen muotoon. Lannoitteiden kautta maahan vuosittain tuleva seleenilisä tarvitaan kasvien seleenitason ylläpitämiseksi. Viljelykasvien seleenipitoisuus riippuu täysin lannoitteiden seleenitasosta ja seleenipitoisten lannoitteiden käyttömääristä. Väestön keskimääräinen seleeninsaanti on nykyisin sekä koti- että ulkomaisten saantisuositusten mukaista. Tärkeimmät saantilähteet ovat maitotuotteet ja liha, mutta myös kasvisruokavaliosta voidaan saada riittävästi seleeniä. Ihmisen veren seerumin seleenipitoisuus on 2000-luvulla ollut keskimäärin 1,4 µmol l-1, mikä on 60 % suurempi kuin ennen lannoitteiden seleenilisäystä vuonna 1984. Vuonna 2007 tehty lannoittei-den seleenipitoisuuden nosto (10→15 mg kg-1) näkyy seerumista mitatun seleenitason vakiintumi-sena >1,4 µmol l-1 pitoisuuksiin. Seleenilannoitustasoa on muutettu kolme kertaa vuosina 1990, 1998 ja 2007. Muutokset ovat pohjautuneet seleeninsaannissa tapahtuneisiin muutoksiin. Seleenilannoitus on tehokas, turvallinen, edullinen ja toimiva tapa vaikuttaa tuotantoeläinten ja väestön seleeninsaantiin ja sitä kautta kansanterveyteen. Se parantaa eläinten hyvinvointia vähentämällä tarvetta lisätä seleeniä rehuihin sekä vähentämällä tarvetta eläinten seleenilääkintään ja se ehkäisee seleeninpuutossairauksia kuten esim. lihasrappeumaa. Suomen olosuhteissa toimenpide on osoittautunut hyväksi ja turvalliseksi keinoksi vaikuttaa kotieläinten ja väestön seleeninsaantiin. Suunnitelmallisen ja tarkkaan kohdennetun seurannan myötä systeemi on kontrolloitavissa ja seleeninsaannissa tapahtuviin muutoksiin pystytään reagoimaan nopeasti.201

Human organotypic airway and lung organoid cells of bronchiolar and alveolar differentiation are permissive to infection by influenza and SARS-CoV-2 respiratory virus

The ongoing coronavirus disease 2019 (COVID-19) pandemic has led to the initiation of unprecedented research efforts to understand the pathogenesis mediated by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2). More knowledge is needed regarding the cell type-specific cytopathology and its impact on cellular tropism. Furthermore, the impact of novel SARS-CoV-2 mutations on cellular tropism, alternative routes of entry, the impact of co-infections, and virus replication kinetics along the respiratory tract remains to be explored in improved models. Most applied virology models are not well suited to address the remaining questions, as they do not recapitulate the histoarchitecture and cellular composition of human respiratory tissues. The overall aim of this work was to establish from single biopsy specimens, a human adult stem cell-derived organoid model representing the upper respiratory airways and lungs and explore the applicability of this model to study respiratory virus infection. First, we characterized the organoid model with respect to growth pattern and histoarchitecture, cellular composition, and functional characteristics. Next, in situ expression of viral entry receptors, including influenza virus-relevant sialic acids and SARS-CoV-2 entry receptor ACE2 and TMPRSS2, were confirmed in organoids of bronchiolar and alveolar differentiation. We further showed successful infection by pseudotype influenza A H7N1 and H5N1 virus, and the ability of the model to support viral replication of influenza A H7N1 virus. Finally, successful infection and replication of a clinical isolate of SARS-CoV-2 were confirmed in the organoids by TCID50 assay and immunostaining to detect intracellular SARS-CoV-2 specific nucleocapsid and dsRNA. The prominent syncytia formation in organoid tissues following SARS-CoV-2 infection mimics the findings from infected human tissues in situ. We conclude that the human organotypic model described here may be particularly useful for virology studies to evaluate regional differences in the host response to infection. The model contains the various cell types along the respiratory tract, expresses respiratory virus entry factors, and supports successful infection and replication of influenza virus and SARS-CoV-2. Thus, the model may serve as a relevant and reliable tool in virology and aid in pandemic preparedness, and efficient evaluation of antiviral strategies.publishedVersio

Is strain by Speckle Tracking Echocardiography dependent on user controlled spatial and temporal smoothing? An experimental porcine study

Background Speckle Tracking Echocardiography (STE) strain analysis relies on both spatial and temporal smoothing. The user is often allowed to adjust these smoothing parameters during analysis. This experimental study investigates how different degrees of user controllable spatial and temporal smoothing affect global and regional STE strain values in recordings obtained from normal and ischemic myocardium. Methods In seven anesthetized pigs, left ventricular short- and long-axis B-mode cineloops were recorded before and after left anterior descending coronary artery occlusion. Peak- and postsystolic global STE strain in the radial, circumferential and longitudinal direction as well as corresponding regional strain in the anterior and posterior walls were measured. During post-processing, strain values were obtained with three different degrees of both spatial and temporal smoothing (minimum, factory default and maximum), resulting in nine different combinations. Results All parameters for global and regional longitudinal strain were unaffected by adjustments of spatial and temporal smoothing in both normal and ischemic myocardium. Radial and circumferential strain depended on smoothing to a variable extent, radial strain being most affected. However, in both directions the different combinations of smoothing did only result in relatively small changes in the strain values. Overall, the maximal strain difference was found in normal myocardium for peak systolic radial strain of the posterior wall where strain was 22.0 ± 2.2% with minimal spatial and maximal temporal smoothing and 30.9 ± 2.6% with maximal spatial and minimal temporal smoothing (P < 0.05). Conclusions Longitudinal strain was unaffected by different degrees of user controlled smoothing. Radial and circumferential strain depended on the degree of smoothing. However, in most cases these changes were small and would not lead to altered conclusions in a clinical setting. Furthermore, smoothing did not affect strain variance. For all strain parameters, variance remained within the corresponding interobserver variance

Reperfusion Therapy with Low-Dose Insulin or Insulin-Like Growth Factor 2; Myocardial Function and Infarct Size in a Porcine Model of Ischaemia and Reperfusion

In an open-chest porcine model, we examined whether myocardial pharmacological conditioning at the time of reperfusion with low-dose insulin or insulin-like growth factor 2 (IGF2), not affecting serum glucose levels, could reduce infarct size and improve functional recovery. Two groups of anaesthetized pigs with either 60 or 40 min. of left anterior descending artery occlusion (total n = 42) were randomized to receive either 0.9% saline, insulin or IGF2 infusion for 15 min., starting 5 min. before a 180-min. reperfusion period. Repeated fluorescent microsphere injections were used to confirm ischaemia and reperfusion. Area at risk and infarct size was determined with Evans blue and triphenyltetrazolium chloride staining. Local myocardial function was evaluated with multi-layer radial tissue Doppler strain and speckle-tracking strain from epicardial echocardiography. Western blotting and TUNEL staining were performed to explore apoptosis. Infarct size did not differ between treatment groups and was 56.7 ± 6.8%, 49.7 ± 9.6%, 56.2 ± 8.0% of area at risk for control, insulin and IGF2 group, respectively, in the 60-min. occlusion series. Corresponding values were 45.6 ± 6.0%, 48.4 ± 7.2% and 34.1 ± 5.8% after 40-min. occlusion. Global and local cardiac function did not differ between treatment groups. No differences related to treatment could be found in myocardial tissue cleaved caspase-3 content or the degree of TUNEL staining. Reperfusion therapy with low-dose insulin or with IGF2 neither reduced infarct size nor improved function in reperfused myocardium in this in vivo porcine model

The influence of acute unloading on left ventricular strain and strain rate by speckle tracking echocardiography in a porcine model

Noninvasive measurements of myocardial strain and strain rate by speckle tracking echocardiography correlate to cardiac contractile state but also to load, which may weaken their value as indices of inotropy. In a porcine model, we investigated the influence of acute dynamic preload reductions on left ventricular strain and strain rate and their relation to the pressure-conductance catheter-derived preload recruitable stroke work (PRSW) and peak positive first derivative of left ventricular pressure (LV-dP/dtmax). Speckle tracking strain and strain rate in the longitudinal, circumferential, and radial directions were measured during acute dynamic reductions of end-diastolic volume during three different myocardial inotropic states. Both strain and strain rate were sensitive to unloading of the left ventricle (P < 0.001), but the load dependency for strain rate was modest compared with strain. Changes in longitudinal and circumferential strain correlated more strongly to changes in end-diastolic volume (r = −0.86 and r = −0.72) than did radial strain (r = 0.35). Longitudinal, circumferential, and radial strain significantly correlated with LV-dP/dtmax (r = −0.53, r = −0.46, and r = 0.86), whereas only radial strain correlated with PRSW (r = 0.55). Strain rate in the longitudinal, circumferential and radial direction significantly correlated with both PRSW (r = −0.64, r = −0.58, and r = 0.74) and LV-dP/dtmax (r = −0.95, r = −0.70, and r = 0.85). In conclusion, the speckle tracking echocardiography-derived strain rate is more robust to dynamic ventricular unloading than strain. Longitudinal and circumferential strain could not predict load-independent contractility. Strain rates, and especially in the radial direction, are good predictors of preload-independent inotropic markers derived from conductance catheter

Esmolol added in repeated, cold, oxygenated blood cardioplegia improves myocardial function after cardiopulmonary bypass

Objective: This study investigated if the β-receptor blocking agent esmolol, added to standard oxygenated blood cardioplegia, improved myocardial function after weaning from bypass. Design: A block-randomized, blinded study. Setting: A university laboratory. Participants: Twenty anesthetized pigs, Norwegian Landrace. Interventions: After cardiopulmonary bypass, cardiac arrest was induced with cold (12°C), oxygenated blood cardioplegia, enriched with either esmolol or vehicle, repeated every 20 minutes. After 100 minutes the heart was reperfused and weaned. Measurements and Main Results: Left ventricular function was evaluated with pressure-volume loops, local myocardial function with multilayer strain and strain rate by epicardial short-axis tissue Doppler imaging. One hour after declamping, preload recruitable stroke work did not differ between groups, but increased to 72±3 mmHg in esmolol-treated animals v 57±4 mmHg (p<0.001) in controls after 3 hours. Radial peak ejection strain rate also was increased by esmolol; 6.0±1.0 $s^{-1}$ v 2.9±0.3 $s^{-1}$ (p<0.001) in subendocardium and 3.9±0.5 $s^{-1}$ v 2.3±0.2 $s^{-1}$ (p<0.005) in the midmyocardium. Cardiac index was increased, 4.0±0.2 L/min/$$m^2\) by esmolol v 3.3±0.1 L/min/m2 for controls (p<0.05). Isovolumetric relaxation time constant was reduced by esmolol, 23±1 ms v 26±1 ms (p<0.025). Troponin-T did not differ and was 339±48 ng/L for the esmolol group and 357±55 ng/L for the control group (p = 0.81). Conclusions: Esmolol added to blood cardioplegia preserved systolic cardiac function during the first 3 hours after reperfusion in a porcine model with 100 minutes of cardioplegic arrest