Distinct morphologies of arterial waveforms reveal preload-, contractility-, and afterload-deficient hemodynamic instability: An in silico simulation study.

Hemodynamic instability is frequently present in critically ill patients, primarily caused by a decreased preload, contractility, and/or afterload. We hypothesized that peripheral arterial blood pressure waveforms allow to differentiate between these underlying causes. In this in-silico experimental study, a computational cardiovascular model was used to simulate hemodynamic instability by decreasing blood volume, left ventricular contractility or systemic vascular resistance, and additionally adaptive and compensatory mechanisms. From the arterial pressure waveforms, 45 features describing the morphology were discerned and a sensitivity analysis and principal component analysis were performed, to quantitatively investigate their discriminative power. During hemodynamic instability, the arterial waveform morphology changed distinctively, for example, the slope of the systolic upstroke having a sensitivity of 2.02 for reduced preload, 0.80 for reduced contractility, and -0.02 for reduced afterload. It was possible to differentiate between the three underlying causes based on the derived features, as demonstrated by the first two principal components explaining 99% of the variance in waveforms. The features with a high correlation coefficient (>0.25) to these principal components are describing the systolic up- and downstroke, and the anacrotic and dicrotic notches of the waveforms. In this study, characteristic peripheral arterial waveform morphologies were identified that allow differentiation between deficits in preload, contractility, and afterload causing hemodynamic instability. These findings are confined to an in silico simulation and warrant further experimental and clinical research in order to prove clinical usability in daily practice.

Long-term Extracorporeal Membrane Oxygenation Bridge to Lung Transplantation After COVID-19.

This report describes a patient with severe acute respiratory syndrome coronavirus 2 infection and irreversible lung destruction who underwent successful lung transplantation after 138 days of bridging with extracorporeal membrane oxygenation support. The case exemplifies that lung transplantation may be a possibility after very long-term coronavirus disease 2019 care, even if the patient is initially an unsuitable candidate.

Right-Left Ventricular Interaction in Left-Sided Heart Failure With and Without Venoarterial Extracorporeal Membrane Oxygenation Support-A Simulation Study.

Left ventricular (LV) dilatation is commonly seen with LV failure and is often aggravated during venoarterial extracorporeal membrane oxygenation (VA ECMO). In this context, the intricate interaction between left and right heart function is considered to be of pivotal importance, yet mechanistically not well understood. We hypothesize that a preserved or enhanced right heart contractility causes increased LV loading both with and without VA ECMO. A closed-loop in-silico simulation model containing the cardiac chambers, the pericardium, septal interactions, and the pulmonary and systemic vascular systems with an option to connect a simulated VA ECMO circuit was developed. Right ventricular contractility was modified during simulation of severe LV failure with and without VA ECMO. Left atrial pressures increased from 14.0 to 23.8 mm Hg without VA ECMO and from 18.4 to 27.0 mm Hg under VA ECMO support when right heart contractility was increased between end-systolic elastance 0.1 and 1.0 mm Hg/ml. Left-sided end-diastolic volumes increased from 125 to 169 ml without VA ECMO and from 150 to 180 ml with VA ECMO. Simulations demonstrate that increased diastolic loading of the LV may be driven by increased right ventricular contractility and that left atrial pressures cannot be interpreted as a reflection of the degree of LV dysfunction and overload without considering right ventricular function. Our study illustrates that modelling and computer simulation are important tools to unravel complex cardiovascular mechanisms underlying the right-left heart interdependency both with and without mechanical circulatory support.

Hydraulic force is a novel mechanism of diastolic function that may contribute to decreased diastolic filling in HFpEF and facilitate filling in HFrEF.

A hydraulic force generated by blood moving the atrioventricular plane is a novel mechanism of diastolic function. The direction and magnitude of the force is dependent on the geometrical relationship between the left atrium and ventricle and is measured as the short-axis atrioventricular area difference (AVAD). In short, the net hydraulic force acts from a larger area toward a smaller one. It is currently unknown how cardiac remodeling affects this mechanism. The aim of the study was therefore to investigate this diastolic mechanism in patients with pathological or physiological remodeling. Seventy subjects [n = 11 heart failure with preserved ejection fraction (HFpEF), n = 10 heart failure with reduced ejection fraction (HFrEF), n = 7 signs of isolated diastolic dysfunction, n = 10 hypertrophic cardiomyopathy, n = 10 cardiac amyloidosis, n = 18 triathletes, and n = 14 controls] were included. Subjects underwent cardiac MR, and short-axis images of the left atrium and ventricle were delineated. AVAD was calculated as ventricular area minus atrial area and used as an indicator of net hydraulic force. At the onset of diastole, AVAD in HFpEF was -9.2 cm2 (median) versus -4.4 cm2 in controls, P = 0.02. The net hydraulic force was directed toward the ventricle for both but was larger in HFpEF. HFrEF was the only group with a positive median value (11.6 cm2), and net hydraulic force was throughout diastole directed toward the atrium. The net hydraulic force may impede cardiac filling throughout diastole in HFpEF, worsening diastolic dysfunction. In contrast, it may work favorably in patients with dilated ventricles and aid ventricular filling.NEW & NOTEWORTHY It is a previously unrecognized physiological mechanism of the heart that diastolic filling occurs with the help of hydraulics. In patients with heart failure with preserved ejection fraction, atrial dilatation may cause the net hydraulic force to work against cardiac filling, thus further augmenting diastolic dysfunction. In contrast, it may work favorably in patients with dilated ventricles, as in heart failure with reduced ejection fraction.

A Missense Variant in ALDH5A1 Associated with Canine Succinic Semialdehyde Dehydrogenase Deficiency (SSADHD) in the Saluki Dog.

Dogs provide highly valuable models of human disease due to the similarity in phenotype presentation and the ease of genetic analysis. Seven Saluki puppies were investigated for neurological abnormalities including seizures and altered behavior. Magnetic resonance imaging showed a diffuse, marked reduction in cerebral cortical thickness, and symmetrical T2 hyperintensity in specific brain regions. Cerebral cortical atrophy with vacuolation (status spongiosus) was noted on necropsy. Genome-wide association study of 7 affected and 28 normal Salukis revealed a genome-wide significantly associated region on CFA 35. Whole-genome sequencing of three confirmed cases from three different litters revealed a homozygous missense variant within the aldehyde dehydrogenase 5 family member A1 (ALDH5A1) gene (XM_014110599.2: c.866G>A; XP_013966074.2: p.(Gly288Asp). ALDH5A1 encodes a succinic semialdehyde dehydrogenase (SSADH) enzyme critical in the gamma-aminobutyric acid neurotransmitter (GABA) metabolic pathway. Metabolic screening of affected dogs showed markedly elevated gamma-hydroxybutyric acid in serum, cerebrospinal fluid (CSF) and brain, and elevated succinate semialdehyde in urine, CSF and brain. SSADH activity in the brain of affected dogs was low. Affected Saluki dogs had striking similarities to SSADH deficiency in humans although hydroxybutyric aciduria was absent in affected dogs. ALDH5A1-related SSADH deficiency in Salukis provides a unique translational large animal model for the development of novel therapeutic strategies.

The hemodynamic effect of different left ventricular unloading techniques during veno-arterial extracorporeal life support: a systematic review and meta-analysis.

BACKGROUND: Pulmonary edema and left ventricular thrombosis may arise during veno-arterial extracorporeal life support due to an increase in cardiac load. This mechanical stress can be reduced through different left ventricular unloading techniques. We set out to quantitatively summarize the hemodynamic effects of available methods in patients treated with veno-arterial extracorporeal life support. METHODS: Literature was systematically searched for studies reporting left ventricular unloading during veno-arterial extracorporeal life support as reflected by changes in left atrial pressure, pulmonary capillary wedge pressure, diastolic pulmonary artery pressure, or left ventricular end-diastolic pressure. For studies including ⩾10 patients per group, changes in these parameters were pooled using (1) standardized mean differences and (2) ratio of means. Assessment of potential bias was performed for all studies. RESULTS: Eight studies met the inclusion criteria. Reported techniques included use of intra-aortic balloon pump (n = 1), micro-axial blood pump (Impella®, n = 2), left ventricular venting (n = 1), and atrial septostomy (n = 4). Overall, left ventricular unloading was associated with a statistically significant reduction in preload parameters (standardized mean differences = -1.05 (95% confidence interval = -1.24 to -0.86) and ratio of means = 0.60 (0.47 to 0.76)). Effect sizes were strongest for micro-axial blood pump and atrial septostomy (standardized mean differences = -1.11 (-1.55 to -0.68) and -1.22 (-1.47 to -0.96), and ratio of means = 0.58 (0.39 to 0.86) and 0.54 (0.36 to 0.83), respectively). CONCLUSION: Left ventricular unloading was associated with a significant reduction in left ventricular preload parameters in the setting of veno-arterial extracorporeal life support. This effect may be most pronounced for micro-axial blood pump and atrial septostomy.

Extended use of extra corporeal membrane oxygenation as bridge to lung transplantation in two patients.

BACKGROUND: We have previously reported our outcome after extra-corporeal membrane oxygenation as bridge-to-lung transplantation, which initially was considered controversial, but over time have gained acceptance and now is performed in most high-volume institutions. CASE PRESENTATION: We now report two "extreme" extra-corporeal membrane oxygenation (ECMO) bridge-to-lung transplantation cases, on ECMO > 200 days prior to lung transplantation. One patient survived long-term and the other one did not, and clinical cause and morbidity is outlined in this case-report. CONCLUSION: We believe these two cases highlight the medical, ethical and resource allocation difficulties involved with saving patients in very dire circumstances. We have shown that a patient can survive extremely long duration of ECMO bridge to lung transplantation, but selection remains crucial to achieve a reasonable cost-benefit.

Differential hypoxemia during venoarterial extracorporeal membrane oxygenation.

Venoarterial extracorporeal membrane oxygenation, indicated for severe cardio-respiratory failure, may result in anatomic regional differences in oxygen saturation. This depends on cannulation, hemodynamic state, and severity of respiratory failure. Differential hypoxemia, often discrete, may cause clinical problems in peripheral femoro-femoral venoarterial extracorporeal membrane oxygenation, when the upper body is perfused with low saturated blood from the heart and the lower body with well-oxygenated extracorporeal membrane oxygenation blood. The key is to diagnose and manage fulminant differential hypoxemia, that is, a state that may develop where the upper body is deprived of oxygen. We summarize physiology, assessment of diagnosis, and management of fulminant differential hypoxemia during venoarterial extracorporeal membrane oxygenation. A possible solution is implantation of an additional jugular venous return cannula. In this article, we propose an even better solution, to drain the venous blood from the superior vena cava. Drainage from the superior vena cava provides superiority to venovenoarterial configuration in terms of physiological rationale, efficiency, safety, and simplicity in clinical circuit design.

Cardiac remodeling in aortic and mitral valve disease: a simulation study with clinical validation.

Remodeling is an important long-term determinant of cardiac function throughout the progression of heart disease. Numerous biomolecular pathways for mechanosensing and transduction are involved. However, we hypothesize that biomechanical factors alone can explain changes in myocardial volume and chamber size in valve disease. A validated model of the human vasculature and the four cardiac chambers was used to simulate aortic stenosis, mitral regurgitation, and aortic regurgitation. Remodeling was simulated with adaptive feedback preserving myocardial fiber stress and wall shear stress in all four cardiac chambers. Briefly, the model used myocardial fiber stress to determine wall thickness and cardiac chamber wall shear stress to determine chamber volume. Aortic stenosis resulted in the development of concentric left ventricular hypertrophy. Aortic and mitral regurgitation resulted in eccentric remodeling and eccentric hypertrophy, with more pronounced hypertrophy for aortic regurgitation. Comparisons with published clinical data showed the same direction and similar magnitudes of changes in end-diastolic volume index and left ventricular diameters. Changes in myocardial wall volume and wall thickness were within a realistic range in both stenotic and regurgitant valvular disease. Simulations of remodeling in left-sided valvular disease support, in both a qualitative and quantitative manner, that left ventricular chamber size and hypertrophy are primarily determined by preservation of wall shear stress and myocardial fiber stress. NEW & NOTEWORTHY Cardiovascular simulations with adaptive feedback that normalizes wall shear stress and fiber stress in the cardiac chambers could predict, in a quantitative and qualitative manner, remodeling patterns seen in patients with left-sided valvular disease. This highlights how mechanical stress remains a fundamental aspect of cardiac remodeling. This in silico study validated with clinical data paves the way for future patient-specific predictions of remodeling in valvular disease.

Left Ventricular Unloading During Veno-Arterial ECMO: A Simulation Study.

Veno-arterial extracorporeal membrane oxygenation (VA ECMO) is widely used in cardiogenic shock. It provides systemic perfusion, but left ventricular (LV) unloading is suboptimal. Using a closed-loop, real-time computer model of the human cardiovascular system, cardiogenic shock supported by peripheral VA ECMO was simulated, and effects of various adjunct LV unloading interventions were quantified. After VA ECMO initiation (4 L/min) in cardiogenic shock (baseline), hemodynamics improved (increased to 85 mm Hg), while LV overload occurred (10% increase in end-diastolic volume [EDV], and 5 mm Hg increase in pulmonary capillary wedge pressure [PCWP]). Decreasing afterload (65 mm Hg mean arterial pressure) and circulating volume (-800 mL) reduced LV overload (12% decrease in EDV and 37% decrease in PCWP) compared with baseline. Additional intra-aortic balloon pumping only marginally decreased cardiac loading. Instead, adjunct Impella™ enhanced LV unloading (23% decrease in EDV and 41% decrease in PCWP). Alternative interventions, for example, left atrial/ventricular venting, yielded substantial unloading. We conclude that real-time simulations may provide quantitative clinical measures of LV overload, depending on the degree of VA ECMO support and adjunct management. Simulations offer insights into individualized LV unloading interventions in cardiogenic shock supported by VA ECMO as a proof of concept for potential future applications in clinical decision support, which may help to improve individualized patient management in complex cardiovascular disease.

Left ventricular unloading during veno-arterial ECMO: a review of percutaneous and surgical unloading interventions.

Short-term mechanical support by veno-arterial extracorporeal membrane oxygenation (VA ECMO) is more and more applied in patients with severe cardiogenic shock. A major shortcoming of VA ECMO is its variable, but inherent increase of left ventricular (LV) mechanical load, which may aggravate pulmonary edema and hamper cardiac recovery. In order to mitigate these negative sequelae of VA ECMO, different adjunct LV unloading interventions have gained a broad interest in recent years. Here, we review the whole spectrum of percutaneous and surgical techniques combined with VA ECMO reported to date.

Echocardiography in extracorporeal life support: A key player in procedural guidance, tailoring and monitoring.

Extracorporeal life support (ECLS) is a mainstay of current practice in severe respiratory, circulatory or cardiac failure refractory to conventional management. The inherent complexity of different ECLS modes and their influence on the native pulmonary and cardiovascular system require patient-specific tailoring to optimize outcome. Echocardiography plays a key role throughout the ECLS care, including patient selection, adequate placement of cannulas, monitoring, weaning and follow-up after decannulation. For this purpose, echocardiographers require specific ECLS-related knowledge and skills, which are outlined here.

Hydraulic forces contribute to left ventricular diastolic filling.

Myocardial active relaxation and restoring forces are known determinants of left ventricular (LV) diastolic function. We hypothesize the existence of an additional mechanism involved in LV filling, namely, a hydraulic force contributing to the longitudinal motion of the atrioventricular (AV) plane. A prerequisite for the presence of a net hydraulic force during diastole is that the atrial short-axis area (ASA) is smaller than the ventricular short-axis area (VSA). We aimed (a) to illustrate this mechanism in an analogous physical model, (b) to measure the ASA and VSA throughout the cardiac cycle in healthy volunteers using cardiovascular magnetic resonance imaging, and (c) to calculate the magnitude of the hydraulic force. The physical model illustrated that the anatomical difference between ASA and VSA provides the basis for generating a hydraulic force during diastole. In volunteers, VSA was greater than ASA during 75-100% of diastole. The hydraulic force was estimated to be 10-60% of the peak driving force of LV filling (1-3 N vs 5-10 N). Hydraulic forces are a consequence of left heart anatomy and aid LV diastolic filling. These findings suggest that the relationship between ASA and VSA, and the associated hydraulic force, should be considered when characterizing diastolic function and dysfunction.

Venous Cannula Positioning in Arterial Deoxygenation During Veno-Arterial Extracorporeal Membrane Oxygenation-A Simulation Study and Case Report.

Venoarterial extracorporeal membrane oxygenation (VA-ECMO) is indicated in reversible life-threatening circulatory failure with or without respiratory failure. Arterial desaturation in the upper body is frequently seen in patients with peripheral arterial cannulation and severe respiratory failure. The importance of venous cannula positioning was explored in a computer simulation model and a clinical case was described. A closed-loop real-time simulation model has been developed including vascular segments, the heart with valves and pericardium. ECMO was simulated with a fixed flow pump and a selection of clinically relevant venous cannulation sites. A clinical case with no tidal volumes due to pneumonia and an arterial saturation of below 60% in the right hand despite VA-ECMO flow of 4 L/min was described. The case was compared with simulation data. Changing the venous cannulation site from the inferior to the superior caval vein increased arterial saturation in the right arm from below 60% to above 80% in the patient and from 64 to 81% in the simulation model without changing ECMO flow. The patient survived, was extubated and showed no signs of hypoxic damage. We conclude that venous drainage from the superior caval vein improves upper body arterial saturation during veno-arterial ECMO as compared with drainage solely from the inferior caval vein in patients with respiratory failure. The results from the simulation model are in agreement with the clinical scenario.

Contribution of the Arterial System and the Heart to Blood Pressure during Normal Aging - A Simulation Study.

During aging, systolic blood pressure continuously increases over time, whereas diastolic pressure first increases and then slightly decreases after middle age. These pressure changes are usually explained by changes of the arterial system alone (increase in arterial stiffness and vascular resistance). However, we hypothesise that the heart contributes to the age-related blood pressure progression as well. In the present study we quantified the blood pressure changes in normal aging by using a Windkessel model for the arterial system and the time-varying elastance model for the heart, and compared the simulation results with data from the Framingham Heart Study. Parameters representing arterial changes (resistance and stiffness) during aging were based on literature values, whereas parameters representing cardiac changes were computed through physiological rules (compensated hypertrophy and preservation of end-diastolic volume). When taking into account arterial changes only, the systolic and diastolic pressure did not agree well with the population data. Between 20 and 80 years, systolic pressure increased from 100 to 122 mmHg, and diastolic pressure decreased from 76 to 55 mmHg. When taking cardiac adaptations into account as well, systolic and diastolic pressure increased from 100 to 151 mmHg and decreased from 76 to 69 mmHg, respectively. Our results show that not only the arterial system, but also the heart, contributes to the changes in blood pressure during aging. The changes in arterial properties initiate a systolic pressure increase, which in turn initiates a cardiac remodelling process that further augments systolic pressure and mitigates the decrease in diastolic pressure.

EVALUATION OF QUANTITATIVE THYROID SCINTIGRAPHY FOR DIAGNOSIS AND STAGING OF DISEASE SEVERITY IN CATS WITH HYPERTHYROIDISM: COMPARISON OF THE PERCENT THYROIDAL UPTAKE OF PERTECHNETATE TO THYROID-TO-SALIVARY RATIO AND THYROID-TO-BACKGROUND RATIOS.

Thyroid scintigraphy is commonly used for evaluation of cats with hyperthyroidism, with the thyroid-to-salivary ratio (T/S) being the most common method to quantify the degree of thyroid activity and disease. Calculation of thyroid-to-background ratios (T/B) or percent thyroidal uptake of (99m) TcO(-) 4 (TcTU) has only been reported in a few studies. The purpose of this prospective, cross-sectional study was to evaluate a number of quantitative scintigraphic indices as diagnostic tests for hyperthyroidism, including the T/S, three different T/B, TcTU, and estimated thyroid volume. Of 524 cats referred to our clinic for evaluation of suspected hyperthyroidism, the diagnosis was confirmed (n = 504) or excluded (n = 20) based on results of a serum thyroid panel consisting of thyroxine (T4 ), triiodothyronine (T3 ), free T4 (fT4 ), and thyroid-stimulating hormone (TSH) concentrations. In the hyperthyroid cats, median values for TcTU, T/S, and three T/B ratios were all significantly higher (P < 0.001) than values in euthyroid suspect cats or clinically normal cats. All scintigraphic parameters were relatively sensitive and specific as diagnostic tests for hyperthyroidism, but the T/S ratio had the highest test accuracy. The T/S ratio correlated strongly with the TcTU (r = 0.85). However, the TcTU had a higher and more significant correlation (P < 0.01) with serum T4 (r = 0.76 vs. 0.64), T3 (r = 0.77 vs. 0.64), and estimated thyroid volume (r = 0.62 vs. 0.38). Overall, calculation of TcTU is an accurate diagnostic test, but also appears to be the best parameter to predict the functional volume and metabolic activity of the feline adenomatous thyroid gland.

Individualized real-time clinical decision support to monitor cardiac loading during venoarterial ECMO.

Veno-arterial extracoporeal membrane oxygenation (VA ECMO) is increasingly used for acute and refractory cardiogenic shock. Yet, in clinical practice, monitoring of cardiac loading conditions during VA ECMO can be cumbersome. To this end, we illustrate the validity and clinical applicability of a real-time cardiovascular computer simulation, which allows to integrate hemodynamics, cardiac dimensions and the corresponding degree of VA ECMO support and ventricular loading in individual patients over time.

Prevalence and degree of thyroid pathology in hyperthyroid cats increases with disease duration: a cross-sectional analysis of 2096 cats referred for radioiodine therapy.

OBJECTIVES: Hyperthyroidism is common in cats, but there are no reports that evaluate its severity or underlying thyroid tumor disease based on disease duration (ie, time from original diagnosis). The objective of this study was to compare serum thyroxine (T4) concentrations and thyroid scintigraphic characteristics of cats referred for radioiodine treatment based on disease duration. METHODS: This was a cross-sectional study of 2096 cats with hyperthyroidism. Cats were divided into five groups based on time from diagnosis: ⩽1 year (n = 1773); >1-2 years (n = 169); >2-3 years (n = 88); >3-4 years (n = 35); and >4-6.1 years (n = 31). Methimazole, administered to 996 (47.5%) cats, was stopped at least 1 week prior to examination to allow for serum T4 testing. Each thyroid scintiscan was evaluated for pattern (unilateral, bilateral, multifocal), location (cervical, thoracic inlet, chest) and size (small, medium, large, huge) of the thyroid tumor, as well as features suggesting malignancy. RESULTS: Median serum T4 concentration increased with increasing disease duration from 100 nmol/l (⩽1 year) to 315 nmol/l (>4-6.1 years) (P <0.001). Prevalence of unilateral thyroid disease decreased, whereas multifocal disease (three or more tumor nodules) increased (P <0.001) with increasing disease duration. Median tumor volume in the five groups increased from 1.6 cm(3) (⩽1 year) to 6.4 cm(3) (>4-6.1 years). Prevalence of large (4-8 cm(3)) and huge (>8 cm(3)) thyroid tumors increased from 5.1% (⩽1 year) to 88.6% (>4-6.1 years), while the prevalence of intrathoracic tumor tissue increased from 3.4% (⩽1 year) to 32.3% (>4-6.1 years). Prevalence of suspected thyroid carcinoma (characterized by severe hyperthyroidism; huge, intrathoracic, multifocal tumors; refractory to methimazole treatment) increased with increasing disease duration from 0.4% (⩽1 year) to 19.3% (>4-6.1 years). CONCLUSIONS AND RELEVANCE: Our results indicate that the prevalence of severe hyperthyroidism, large thyroid tumors, multifocal disease, intrathoracic thyroid masses and suspected malignant disease all increase with disease duration in cats referred for radioiodine therapy.