Volume Loops Research Articles

Non-invasive pressure volume loops provide incremental value to age, sex, and infarct size for predicting adverse cardiac remodeling after ST-elevation myocardial infarction

Abstract Aims This study aimed to assess the predictive value of non-invasive pressure volume (PV)-loop variables by cardiovascular magnetic resonance (CMR) for determining development of adverse remodeling 3-months after primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI). Methods and results In total, 181 STEMI-patients examined with CMR during the index admission (baseline) after primary PCI and at 3-months follow-up in The Third DANish Study of Optimal Acute Treatment of Patients with STEMI (DANAMI-3) study were retrospectively analyzed. A time-varying elastance model for generating PV-loops from CMR volumetry and brachial blood-pressure was used to calculate contractility, arterial elastance, stroke work, potential energy, efficiency, external power, ventriculoarterial coupling, and energy per ejected volume. Adverse remodeling was seen in 28 patients (15%), defined as a concomitant increase in end-diastolic- and end-systolic volume of ≥12% from baseline to follow-up. Pressure volume loop variables measured at baseline showed predictive value for adverse remodeling, independent of age, sex and infarct size (IS) by a logistic regression analysis: contractility (OR 4.6, 95% CI 1.8-12.4), and efficiency (OR 1.05, 95% CI 1.00-1.11). Furthermore, females showed a higher increase in contractility between the timepoints (ΔContractility=0.4±0.4mmHg/mL vs 0.1±0.4mmHg/mL, p<0.0001). A higher energy expenditure was seen at baseline in LAD-infarctions compared to LCx- and RCA-infarctions. Conclusion Non-invasive PV-loop variables by CMR have incremental predictive value to age, sex, and IS for determining development of adverse cardiac remodeling in STEMI patients treated with primary PCI. Furthermore, the PV-loop variables show significant differences in post-infarct cardiovascular adaptation between sexes and culprit vessels.

Structural and Functional Remodeling for Elite Cyclists During Exercise; Pressure Volume Loops and Hemodynamic Forces Analysis.

The study was designed to investigate the pattern of intraventricular Hemo-Dynamic Forces (HDF) and myocardial performance during exercise in Elite Cyclists (EC). Transthoracic stress echocardiography was performed on nineteen EC and thirteen age-matched sedentary controls (SC) at three incremental exercise intensities based on Heart Rate Reserve (HRR). Left Ventricular (LV) HDF were computed from echocardiography long-axis data sets using a novel technique based on endocardial boundary tracking, both in apex-base and latero-septal directions. Pressure Volume (PV) loops were non-invasively investigated using the single-beat approach. Differences between groups were investigated using mixed model analysis. At PV loops EC showed a steeper increase in stroke work compared to SC, without acute changes in ventricular capacity (EDVI20). Contractility, measured as Ventricular Elastance (Ees), increased during exercise with no difference between groups (P=0.625). At rest, EC had significantly lower heart rates and generated lower HDF than SC. However, during exercise the pressure gradient developed by EC in systole, and therefore systolic HDF, was significantly higher than that developed by SC (P<0.009), also showing greater elastic rebound in late systole compared to SC (P<0.032). Importantly, during early diastolic filling, EC showed lower HDF deceleration than SC (P<0.043), indicating a facilitated relaxation of the left ventricle. Analysis of the HDF pattern during exercise shows the functional changes that occur in EC, characterized by increased HDF generation in systole, and facilitated relaxation in early diastole. This is the first time LV structural and functional remodeling is reported for elite cyclists during exercise.

Non-invasive pressure volume loops by cardiovascular magnetic resonance offer incremental prognostic information to blood pressure and stroke volume in patients with ST-elevation myocardial infarction

Non-invasive pressure volume loops by cardiovascular magnetic resonance offer incremental prognostic information to blood pressure and stroke volume in patients with ST-elevation myocardial infarction

Conductance catheterization compared to cardiac MRI environment in acquisition of pressure and volume loops for the physiological assessment of ventricular functionality

Conductance catheterization compared to cardiac MRI environment in acquisition of pressure and volume loops for the physiological assessment of ventricular functionality

Utility of Simultaneous Left Atrial Strain–Volume Relationship During Passive Leg Lift to Identify Elevated Left Ventricular Filling Pressure—A Proof-of-Concept Study

Background: The assessment of left ventricular (LV) filling pressure in heart failure (HF) poses a diagnostic challenge, as HF patients may have normal LV filling pressures at rest but often display elevated LV filling pressures during exercise. Rapid preload increase during passive leg lift (PLL) may unmask HF in such challenging scenarios. We explored the dynamic interplay between simultaneous left atrial (LA) function and volume using LA strain/volume loops during rest and PLL and compared its diagnostic performance with conventional echocardiographic surrogates to detect elevated LV filling pressure. Methods: We retrospectively reviewed 35 patients with clinical HF who underwent simultaneous echocardiography and right heart catheterization before and immediately after PLL. Patients with atrial fibrillation (n = 4) were excluded. Twenty age-matched, healthy controls were added as controls. LA reservoir strain (LASr) was analyzed using speckle-tracking echocardiography. LA strain–volume loops were generated, including the best-fit linear regression line employing simultaneous LASr and LA volume. Results: LA strain–volume slope was lower for HF patients when compared with controls (0.71 vs. 1.22%/mL, p &lt; 0.001). During PLL, the LA strain–volume slope displayed a moderately strong negative correlation with invasive pulmonary arterial wedge pressure (PAWP) (r = −0.71, p &lt; 0.001). At a 0.74%/mL cut-off, the LA strain–volume slope displayed 88% sensitivity and 86% specificity to identify elevated PAWP (AUC 0.89 [0.76–1.00]). In comparison, LASr demonstrated strong but numerically lower diagnostic performance (AUC 0.82 [0.67–0.98]), and mitral E/e’ showed poor performance (AUC 0.57 [0.32–0.82]). Conclusions: In this proof-of-concept study, LA strain–volume characteristics provide incremental diagnostic value over conventional echocardiographic measures in the identification of elevated LV filling pressure.

A self-regulated expiratory flow device for mechanical ventilation: a bench study

IntroductionUnregulated expiratory flow may contribute to ventilator-induced lung injury. The amount of energy dissipated into the lungs with tidal mechanical ventilation may be used to quantify potentially injurious ventilation. Previously reported devices for variable expiratory flow regulation (FLEX) require, either computer-controlled feedback, or an initial expiratory flow trigger. In this bench study we present a novel passive expiratory flow regulation device.MethodsThe device was tested using a commercially available mechanical ventilator with a range of settings (tidal volume 420 ml and 630 ml, max. inspiratory flow rate 30 L/min and 50 L/min, respiratory rate 10 min−1, positive end-expiratory pressure 5 cmH2O), and a test lung with six different combinations of compliance and resistance settings. The effectiveness of the device was evaluated for reduction in peak expiratory flow, expiratory time, mean airway pressure, and the reduction of tidal dissipated energy (measured as the area within the airway pressure–volume loop).ResultsMaximal and minimal reduction in peak expiratory flow was from 97.18 ± 0.41 L/min to 25.82 ± 0.07 L/min (p < 0.001), and from 44.11 ± 0.42 L/min to 26.30 ± 0.06 L/min, respectively. Maximal prolongation in expiratory time was recorded from 1.53 ± 0.06 s to 3.64 ± 0.21 s (p < 0.001). As a result of the extended expiration, the maximal decrease in I:E ratio was from 1:1.15 ± 0.03 to 1:2.45 ± 0.01 (p < 0.001). The greatest increase in mean airway pressure was from 10.04 ± 0.03 cmH2O to 17.33 ± 0.03 cmH2O. Dissipated energy was significantly reduced with the device under all test conditions (p < 0.001). The greatest reduction in dissipated energy was from 1.74 ± 0.00 J to 0.84 ± 0.00 J per breath. The least reduction in dissipated energy was from 0.30 ± 0.00 J to 0.16 ± 0.00 J per breath. The greatest and least percentage reduction in dissipated energy was 68% and 33%, respectively.ConclusionsThe device bench tested in this study demonstrated a significant reduction in peak expiratory flow rate and dissipated energy, compared to ventilation with unregulated expiratory flow. Application of the device warrants further experimental and clinical evaluation.

Sacubitril/Valsartan Combination Partially Improves Cardiac Systolic, but Not Diastolic, Function through β-AR Responsiveness in a Rat Model of Type 2 Diabetes

Cardiovascular complications are the major cause of diabetes mellitus-related morbidity and mortality. Increased renin–angiotensin–aldosterone system activity and decreased β-adrenergic receptor (β-AR) responsiveness contribute to diabetic cardiac dysfunction. We evaluated the effect of sacubitril/valsartan (neprilysin inhibitor plus angiotensin receptor antagonist combination) and valsartan treatments on the diabetic cardiac function through β-AR responsiveness and on protein expression of diastolic components. Six-week-old male Sprague Dawley rats were divided into control, diabetic, sacubitril/valsartan (68 mg/kg)-, and valsartan-treated (31 mg/kg) diabetic groups. Diabetes was induced by a high-fat diet plus low-dose streptozotocin (30 mg/kg, intraperitoneal). After 10 weeks of diabetes, rats were treated for 4 weeks. Systolic/diastolic function was assessed by in vivo echocardiography and pressure–volume loop analysis. β-AR-mediated responsiveness was assessed by in vitro papillary muscle and Langendorff heart experiments. Protein expression of sarcoplasmic reticulum calcium ATPase2a, phospholamban, and phosphorylated phospholamban was determined by Western blot. Sacubitril/valsartan improved ejection fraction and fractional shortening to a similar extent as valsartan alone. None of the treatments affected in vivo diastolic parameters or the expression of related proteins. β1-/β2-AR-mediated responsiveness was partially restored in treated animals. β3-AR-mediated cardiac relaxation (an indicator of diastolic function) responses were comparable among groups. The beneficial effect of sacubitril/valsartan on systolic function may be attributed to improved β1-/β2-AR responsiveness.

Intraoperative right ventricular end-systolic pressure–volume loop analysis in patients undergoing cardiac surgery: A proof-of-concept methodology

BackgroundPerioperative right ventricular (RV) dysfunction is associated with increased morbidity and mortality in cardiac surgery patients. This study aimed to demonstrate proof of concept in generating intraoperative RV pressure–volume (PV) loops and conducting an end-systolic PV relationship (ESPVR) analysis using data obtained from routinely used intraoperative monitors. MethodsAdult patients undergoing cardiac surgery with the placement of a pulmonary artery catheter (PAC) between May 2023 and March 2024 were included prospectively. The PV loops were generated using 3-dimensional echocardiographic RV volume data and continuous RV pressure data obtained from a PAC. The volume–time and pressure–time curves were digitized using the semiautomatic WebPlotDigitizer program and synchronized to reconstruct an RV PV loop and analyze ESPVR using the previously validated single-beat method. ResultsIntraoperative RV PV loops were generated for 25 patients, including 17 patients with preserved RV systolic function (group 1) and 8 patients with reduced systolic function (group 2). Mean Ees, Ea, and Ees/Ea ratio were 0.63 ± 0.25 mm Hg/mL, 0.60 ± 0.23 mm Hg/mL, and 1.0 8 ± 0.31 mm Hg/mL, respectively, by the Pmax method and 0.56 ± 0.32 mm Hg/mL, 0.60 ± 0.23 mm Hg/mL, and 0.91 ± 0.21 mm Hg/mL, respectively, by the V0 method. Group 1 had a significantly higher Ees compared to group 2 regardless of the calculation method and a larger Ees/Ea ratio calculated by the V0 method. ConclusionsIt is clinically feasible to derive RV PV loops from routine hemodynamic and echocardiographic data. With further validation and technological support, this can be a potential real-time intraoperative RV function monitoring tool.

Phase-Resolved Functional Lung MRI for Pulmonary Ventilation and Perfusion (V/Q) Assessment.

Fourier decomposition is a contrast agent-free 1H MRI method for lung perfusion (Q) and ventilation (V) assessment. After image registration, the time series of each voxel is analyzed with regard to the cardiac and breathing frequency components. Using a standard 2D spoiled gradient-echo sequence with a temporal resolution of ~300 ms, an image-sorting algorithm was developed to produce phase-resolved functional lung imaging (PREFUL) with an increased temporal resolution. Thus, it is feasible to evaluate regional flow volume loops (FVL) during tidal volume breathing and depict the propagation of the pulse wave during the cardiac cycle. This method can be applied at 1.5T or 3T with standard MR hardware without the necessity for sequence programming, as the described protocol can be implemented with the default SPGRE sequence on most systems. PREFUL ventilation MRI has been validated using 129Xe and 19F gas imaging with good regional agreement. Perfusion-weighted PREFUL MRI has been validated using SPECT as well as dynamic contrast enhanced (DCE) MRI. PREFUL has been tested in a dual center dual vendor setting and is currently applied in several ongoing multicenter trials. Furthermore, it is feasible across a range of field strengths (0.55T-3T) and different age groups, including newborns. Quantitative V/Q PREFUL MRI has been used in patients with cystic fibrosis, chronic obstructive pulmonary disease, chronic thromboembolic pulmonary hypertension, and corona virus disease-2019 to quantify disease and monitor treatment change after therapy. Furthermore, PREFUL V/Q imaging has been shown to predict transplant loss due to chronic lung allograft dysfunction in patients after lung transplantation. In summary, PREFUL MRI is a validated technique for quantitative ventilation and pulmonary pulse wave/perfusion imaging for regional pulmonary disease detection, quantification, and treatment monitoring with potential added value to the current clinical routine.

Active decompression during automated head-up cardiopulmonary resuscitation

BackgroundThe combination of active compression-decompression cardiopulmonary resuscitation (ACD-CPR) with an impedance threshold device (ITD) and controlled head-up positioning (AHUP-CPR) is associated with improved outcomes compared with conventional CPR (C-CPR). This study focused on the role of active decompression (AD) during AHUP-CPR. MethodsFarm pigs (n = 10, ∼40 kg) were anesthetized, intubated and ventilated. Physiological parameters and right ventricular pressure–volume loops were recorded continuously. Ventricular fibrillation was induced and left untreated for 10 mins, followed by automated C-CPR (2 min), ACD + ITD CPR in the flat position (2 min), and then AHUP-CPR with 3 cm of lift above the neutral chest position. After 15 min of CPR, AD was discontinued and then restarted incrementally to 4 cm. Data were analyzed with a linear mixed-effects model, using random intercepts for individual pigs. ResultsUpon cessation of AD during AHUP-CPR, decompression right atrial pressure (+59%) increased (p < 0.01), whereas multiple hemodynamic parameters positively associated with perfusion, including coronary (−25%) and cerebral perfusion pressures (−11%), end-tidal CO2 (−13%), stroke volume and cardiac output (−26%), decreased immediately and significantly with p < 0.05. Restoration of AD reduced right atrial pressure and increased positive perfusion parameters in an incremental manner. Only with ≥ 3 cm of AD were all hemodynamic parameters restored to ≥ 90% of pre-AD discontinuation levels. ConclusionFull chest wall lift, achieved with ≥ 3 cm of AD, was needed to maintain and optimize hemodynamics during AHUP-CPR in pigs. These findings should be considered when optimizing care with this new approach.

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension.

Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance have emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen cross-linking enzyme lysyl oxidase like 2 (LOXL2) in this study. Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from the pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe pulmonary hypertension (PH). Similarly, LOXL2 protein and mRNA levels were increased in the pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from the rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in vivo with PAT-1251. Importantly, PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Hypoxia-induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH and pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 could be a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH.NEW & NOTEWORTHY Pulmonary arterial stiffening contributes to the progression of PAH and the deterioration of right heart function. This study shows that LOXL2 is upregulated in rat models of PH. LOXL2 inhibition halts pulmonary vascular remodeling and improves PA contractility, endothelial function, and PA pressure, resulting in prolonged survival. Thus, LOXL2 is an important mediator of PA remodeling and stiffening in PH and a promising target to improve PA pressures and survival in PH.

Hemodynamics with mechanical circulatory support devices using a cardiogenic shock model

Mechanical circulatory support (MCS) devices, including veno-arterial extracorporeal membrane oxygenation (VA-ECMO) and Impella, have been widely used for patients with cardiogenic shock (CS). However, hemodynamics with each device and combination therapy is not thoroughly understood. We aimed to elucidate the hemodynamics with MCS using a pulsatile flow model. Hemodynamics with Impella CP, VA-ECMO, and a combination of Impella CP and VA-ECMO were assessed based on the pressure and flow under support with each device and the pressure–volume loop of the ventricle model. The Impella CP device with CS status resulted in an increase in aortic pressure and a decrease in end-diastolic volume and end-diastolic pressure (EDP). VA-ECMO support resulted in increased afterload, leading to a significant increase in aortic pressure with an increase in end-systolic volume and EDP and decreasing venous reservoir pressure. The combination of Impella CP and VA-ECMO led to left ventricular unloading, regardless of increase in afterload. Hemodynamic support with Impella and VA-ECMO should be a promising combination for patients with severe CS.

Salidroside modulates repolarization through stimulating Kv2.1 in rats

BackgroundVoltage-gated potassium (Kv) channel growth is strongly associated with the development of arrhythmia. Salidroside (Sal), an active component from Rhodiola crenulata, has been shown to exert protective effects against heart disease. The present study was conducted to investigate the effects of Sal on Kv2.1 channel, and to explore the ionic mechanism of anti-arrhythmic. MethodsIn this study, we utilized cisapride (Cis., A stimulant that prolongs the QT interval and causes cardiac arrhythmias) by intravenous injection to establish an arrhythmia model, and detected the effects of Sal on electrocardiography (ECG) and pressure volume loop (P–V loop) in SD rats. The effect of Sal on ECG of citalopram (Cit., a Kv2 channel inhibition)-evoked arrhythmia rat models was further evaluated by monitoring the dynamic changes of multiple indicators of ECG. Then, we detected the effect of Sal on the viability of hypoxic H9c2 cells using CCK-8 assay. After that, the effect of Sal on Kv channel currents (IKv) and Kv2.1 channel currents (IKv2.1) in H9c2 cells under normal and hypoxic conditions was examined using whole-cell patch clamp technique. In addition, the effect of Sal on IKv and IKv2.1 in H9c2 cells was determined under the inhibition of Kv and Kv2.1 channels. HEK293 cells stably transfected with Kv2.1 plasmids were also used to investigate the IKv2.1 changes under Sal pre-treated and co-incubated conditions. In addition, potential interactions of Sal with Kv2.1 protein were predicted and tested by molecular docking, molecular dynamics simulation (MDS), localized surface plasmon resonance (LSPR), and cellular thermal shift assay (CETSA) techniques, respectively. Furthermore, gene and protein levels of Kv2.1 in Sal-treated H9c2 cell were estimated by qRT-PCR, Western blot (WB) and immunofluorescence (IF) analysis. ResultsSal shortened the prolongated QT interval and ameliorated the cardiac impairment associated with arrhythmia in SD rats caused by Cis., as reflected in the ECG and P–V loop data. And Sal was also protective against arrhythmia in rats caused by Kv2 channel inhibition. At the cellular level, Sal increased cell viability after CoCl2-induced hypoxic injury in H9c2 cells. Whole-cell patch clamp assay confirmed that Sal inhibited both IKv and IKv2.1 in normal H9c2 cells, while enhanced IKv and IKv2.1 in cardiomyocytes after hypoxic injury. And Sal enhanced IKv inhibited by 1.5 mM 4-AP and upregulated all inhibition of Kv2 channels induced by 20 mM 4-AP administration, antagonized the IKv2.1 inhibitory effect of Cit. Moreover, Sal pre-administration for 24 h and immediate administration increased IKv2.1 in HEK293 cells stably transfected with Kv2.1 plasmids. Molecular docking demonstrated the potential binding of Sal to the Kv2.1 protein, with calculated binding energy of −5.4 kcal/mol. MDS test illustrated that the average hydrogen bonding of the Sal-Kv2.1 complexes was 30.89%. LSPR results verified the potential binding of Sal to Kv2.1 protein with an affinity value of 9.95 × 10−4 M. CETSA assay confirmed Sal can enhance the expression of Kv2.1 protein in H9c2 cells treated with heat, which suggests that Sal may bind to Kv2.1 protein. The results of WB, qRT-PCR, and IF further argued that Sal pre-administration for 24 h enhanced the levels of the Kv2.1 gene and protein (with no effects on the Kv2.1 gene and protein for H9c2 cells co-incubated with Sal for 6 h and 12 h). ConclusionOverall, our findings indicate that Sal can resist drug-induced arrhythmias in SD rats, partially by modulating repolarization through stimulating Kv2.1.

Correlation of Noninvasive Cardiac MRI Measures of Left Ventricular Myocardial Function and Invasive Pressure-Volume Parameters in a Porcine Ischemia-Reperfusion Model.

Purpose To assess the correlation between noninvasive cardiac MRI-derived parameters with pressure-volume (PV) loop data and evaluate changes in left ventricular function after myocardial infarction (MI). Materials and Methods Sixteen adult female swine were induced with MI, with six swine used as controls and 10 receiving platelet-derived growth factor-AB (PDGF-AB). Load-independent measures of cardiac function, including slopes of end-systolic pressure-volume relationship (ESPVR) and preload recruitable stroke work (PRSW), were obtained on day 28 after MI. Cardiac MRI was performed on day 2 and day 28 after infarct. Global longitudinal strain (GLS) and global circumferential strain (GCS) were measured. Ventriculo-arterial coupling (VAC) was derived from PV loop and cardiac MRI data. Pearson correlation analysis was performed. Results GCS (r = 0.60, P = .01), left ventricular ejection fraction (LVEF) (r = 0.60, P = .01), and cardiac MRI-derived VAC (r = 0.61, P = .01) had a significant linear relationship with ESPVR. GCS (r = 0.75, P < .001) had the strongest significant linear relationship with PRSW, followed by LVEF (r = 0.67, P = .005) and cardiac MRI-derived VAC (r = 0.60, P = .01). GLS was not significantly correlated with ESPVR or PRSW. There was a linear correlation (r = 0.82, P < .001) between VAC derived from cardiac MRI and from PV loop data. GCS (-3.5% ± 2.3 vs 0.5% ± 1.4, P = .007) and cardiac MRI-derived VAC (-0.6 ± 0.6 vs 0.3 ± 0.3, P = .001) significantly improved in the animals treated with PDGF-AB 28 days after MI compared with controls. Conclusion Cardiac MRI-derived parameters of MI correlated with invasive PV measures, with GCS showing the strongest correlation. Cardiac MRI-derived measures also demonstrated utility in assessing therapeutic benefit using PDGF-AB. Keywords: Cardiac MRI, Myocardial Infarction, Pressure Volume Loop, Strain Imaging, Ventriculo-arterial Coupling Supplemental material is available for this article. © RSNA, 2024.

LOXL2 inhibition ameliorates pulmonary artery remodeling in pulmonary hypertension

Background: Conduit pulmonary arterial stiffening and the resultant increase in pulmonary vascular impedance has emerged as an important underlying driver of pulmonary arterial hypertension (PAH). Given that matrix deposition is central to vascular remodeling, we evaluated the role of the collagen crosslinking enzyme lysyl oxidase like 2 (LOXL2) in this study. Methods and Results: Human pulmonary artery smooth muscle cells (PASMCs) subjected to hypoxia showed increased LOXL2 secretion. LOXL2 activity and expression were markedly higher in primary PASMCs isolated from pulmonary arteries of the rat Sugen 5416 + hypoxia (SuHx) model of severe PH. Similarly, LOXL2 protein and mRNA levels were increased in pulmonary arteries (PA) and lungs of rats with PH (SuHx and monocrotaline (MCT) models). Pulmonary arteries (PAs) isolated from rats with PH exhibited hypercontractility to phenylephrine and attenuated vasorelaxation elicited by acetylcholine, indicating severe endothelial dysfunction. Tensile testing revealed a a significant increase in PA stiffness in PH. Treatment with PAT-1251, a novel small-molecule LOXL2 inhibitor, improved active and passive properties of the PA ex vivo. There was an improvement in right heart function as measured by right ventricular pressure volume loops in-vivo with PAT-1251. Importantly PAT-1251 treatment ameliorated PH, resulting in improved pulmonary artery pressures, right ventricular remodeling, and survival. Conclusion: Hypoxia induced LOXL2 activation is a causal mechanism in pulmonary artery stiffening in PH, as well as pulmonary artery mechanical and functional decline. LOXL2 inhibition with PAT-1251 is a promising approach to improve pulmonary artery pressures, right ventricular elastance, cardiac relaxation, and survival in PAH. This work was supported by a NHLBI grant R01HL105296 (to D.E.B.), a NHLBI grant R01HL148112 01 (to L.S.), two Stimulating and Advancing ACCM Research (StAAR) grants from the Department of Anesthesiology and Critical Care Medicine, JHU (to L.S. and J.S.), NHLBI grants R01HL073859 and R01HL126514 (to L.A.S) and a NHLBI K08 grant K08HL145132 (to J.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiomyocyte Specific MLK3 Deletion Opposes LV Dysfunction and Cardiac Fetal Gene Re-Expression

Study Objective: To determine the cardiac myocyte (CM) and blood pressure-independent effects of Mixed lineage kinase 3 (MLK3) in the regulation of left ventricular (LV) function at baseline and in response to pathological stress. Background: MLK3 functions as a direct substrate effector of cGMP-dependent protein kinase 1α (PKG1α). Whole-body MLK3 deletion in mice increases cardiac dysfunction and remodeling after pressure overload and prevents the therapeutic effect of cGMP augmentation on LV function. However, MLK3 deletion also causes hypertension, which may confound these findings. Hypothesis: MLK3 opposes LV dysfunction through a blood pressure-independent function in the cardiac myocyte (CM). Methods: We generated mice harboring LoxP sites flanking the MAP3K11 gene encoding MLK3 (MLK3fl/fl) and crossed them with αMHC-Cre transgenic mice, enabling constitutive postnatal cardiac myocyte-specific MLK3 deletion (CMKO). Male and female 3- and 6-month-old MLK3 CMKO and control MLK3 intact (MLK3fl/fl Cre-) littermates were studied in the basal state. We also performed transaortic constriction (TAC) or sham surgery for 4 weeks on 3-month-old male mice. We assessed LV structure and function by organ mass, echocardiography, pressure volume loop analysis, qPCR, and immunoblot. In basal and TAC studies, we used age-matched αMHC-Cre x MLK3+/+ (non-floxed) mice as additional controls. Results: MLK3 gene excision in CMs was confirmed by PCR. By 6 months of age, MLK3 CMKO mice displayed: progressive reduction in LV ejection fraction; increase in LV internal diameter; and LV hypertrophy, indicating LV dysfunction and pathological remodeling, compared with littermate controls or with αMHC-Cre x MLK3+/+ non-floxed mice. This effect was more prominent in females than in males. LV fetal gene expression did not differ between genotypes at 3 months. At 6 months of age, however, the fetal genes nppa, RCAN, and CTGF were significantly upregulated in both male and female MLK3 CMKO mice, compared with MLK3 intact, indicating pathological remodeling. After 4-week TAC, MLK3 CMKO LVs developed more severe reduction in LV systolic function compared with MLK3 intact littermates as assayed by echocardiographic measures of LV ejection fraction; and invasive hemodynamic indices of preload recruitable stroke work, maximum LV pressure and LV developed pressure. The MLK3 CMKO LVs also demonstrated a more eccentric remodeling phenotype in which LV mass/tibia length, LV end diastolic and end systolic diameters increased more severely in CMKO mice, with corresponding reduced LV wall thicknesses. Finally, lung mass/tibia length was elevated in the MLK3 CMKO TAC mice compared to MLK3 intact TAC littermates, indicating overt heart failure. Conclusion: (1) MLK3 functions as a tonic inhibitor of LV dysfunction and pathological remodeling through a role in the CM, possibly through sex-specific mechanisms. (2) Intact MLK3 is required for normal LV compensation and concentric remodeling in response to pressure overload. These findings have important clinical implications, as drugs which activate PKG1 in heart failure improve outcomes but are limited by excess hypotension. As a myocardial PKG1 substrate which opposes pathological LV remodeling through blood pressure-independent mechanisms, MLK3 may represent a candidate therapeutic target for heart failure. NIH 1R01HL162919. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Oxidative stress: A driving force in CKD induced heart failure

Background: Several clinical investigations have shown that individuals with renal impairment are more likely to experience heart failure. Cardiac remodeling happens relatively early in the course of kidney injury, yet research into identification of common markers of cardiorenal signaling remains insuffcient. This may be because studies conducted in small animal models do not accurately reflect the complexity of the disease. To bridge the translational gap, we developed a swine model for chronic kidney disease (CKD) Aim: We employed proteome studies to clarify the pathophysiological impact of chronic kidney disease (CKD) on the heart and correlate to cardiac function and perfusion in order to offer mechanistic insights. Methods: We used microspheres to embolise both kidneys of swine at 10-12 weeks of age while sham operated swine served as controls. Post 6 months, we performed pressure volume loops to assess cardiac function, while coronary flow reserve (CFR) was measured by intracoronary infusion of adenosine in control and CKD. (LC-MS-MS based proteomic analyses of left ventricular tissue was performed. Paraffn embedded myocardium and kidney tissues were histologically examined for interstitial fibrosis and oxidative stress. Results: Renal embolization resulted in mild chronic kidney injury as evidenced by increased fibrosis staining and urinary NGAL (24±4 vs 48±9 pg/ml). Hemodynamic parameters showed increased wall stress (20±3 vs 40±7 ml*mmHg/g) as well as increase of end diastolic volume (1.5±0.1 vs 1.9±0.1 ml/kg) indicating dilation of the left ventricle in CKD. Quantitative proteomic analysis detected significant differences in the left ventricle of the controls when compared to those with CKD and STRING pre-ranked functional analysis showed enrichments in pathways related to reactive oxygen species. Furthermore, we detected alterations of pathways associated with remodeling of the extracellular matrix (ECM), Oxidative stress and ECM remodeling were confirmed histologically. Interestingly, in CKD we found that mitochondrial proteins like cytochrome oxidase (MT-CO2) and ATP5 synthase subunit were downregulated suggesting mitochondrial dysfunction which was associated with higher basal coronary blood flow (0.48±0.05 vs 0.87±0.11 ml/min/g). Conclusions: Our proteomic data in swine model provides strong evidence that mild CKD can induce early alterations in mitochondrial function along with oxidative stress and ECM remodeling. Thus, we aim to further our understanding by applying our proteomic findings in conjunction with functional hemodynamic data in this swine model of cardiorenal disease. German Center for Cardiovascular Research (DZHK81Z0600207 to D.M. and P.S.). This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Intrinsic mechanisms of right ventricular autoregulation

To elucidate the adaptation of the right ventricle to acute and intermittently sustained afterload elevation, targeted preload reductions and afterload increases were implemented in a porcine model involving 12 pigs. Preload reduction was achieved via balloon occlusion of the inferior vena cava before, immediately and 5 min after acute afterload elevation induced by pulmonary artery occlusion or thromboxane A2 analog (U46619) infusion. Ventricular response was monitored by registration of pressure–volume (PV) loops using a conductance catheter. The end-systolic pressure–volume relationship (ESPVR) during pure preload reduction was adequately described by linear regression (mean and SEM slope of ESPVR (Ees) 0.414 ± 0.064 mmHg/ml), reflecting the classical Frank-Starling mechanism (FSM). The ESPVR during acute afterload elevation exhibited a biphasic trajectory with significantly distinct slopes (mean and SEM Ees bilin1: 1.256 ± 0.066 mmHg ml; Ees bilin2: 0.733 ± 0.063 mmHg ml, p < 0.001). The higher slope during the first phase in the absence of ventricular dilation could be explained by a reduced amount of shortening deactivation (SDA). The changes in PV-loops during the second phase were similar to those observed with a preload intervention. The persistent increase in afterload resulted in an increase in the slopes of ESPVR and preload recruitable stroke work (PRSW) with a slight decrease in filling state, indicating a relevant Anrep effect. This effect became more pronounced after 5 min or TXA infusion. This study demonstrates, for the first time, the relevance of intrinsic mechanisms of cardiac autoregulation in the right ventricle during the adaptation to load. The SDA, FSM, and Anrep effect could be differentiated and occurred successively, potentially with some overlap. Notably, the Anrep effect serves to prevent ventricular dilation.

Diagnostic utility of spirometry for children with induced laryngeal obstruction or chronic non-specific cough

PurposeTo determine the diagnostic utility of spirometry in distinguishing children with Induced Laryngeal Obstruction (ILO) or chronic non-specific cough (a.k.a. tic cough) from those with mild or moderate to severe asthma. MethodsRetrospective cross sectional design. Children diagnosed with ILO (N = 70), chronic non-specific cough (N = 70), mild asthma (N = 60), or moderate to severe asthma (N = 60) were identified from the electronic medical record of a large children's hospital. Spirometry was completed before ILO, non-specific cough, or asthma diagnoses were made by pediatric laryngologists or pulmonologists. Spirometry was performed following American Thoracic Society guidelines and was interpreted by a pediatric pulmonologist. Forced Vital Capacity (FVC), Forced Expiratory Volume in 1 Second (FEV1), FEV1/FVC Ratio (FEV1/FVC), Forced Mid-Expiratory Flow 25‐–75 % (FEF25–75%), pulmonologist interpretation of flow volume loops, and overall exam findings were extracted from the medical record. ResultsNinety seven percent of children with ILO or chronic non-specific cough presented with spirometry values within normative range. Patients with ILO, non-specific cough, and mild asthma presented with FVC, FEV1, FEV1/FVC, and FEF25–75% values in statistically similar range. Children with moderate to severe asthma presented with significantly reduced FVC (p < .001), FEV1 (p < .001), FEV1/FVC (p < .001), and FEF25–75% (p < .001) values when compared with patients in the other groups. Flow volume loops were predominantly normal for children with ILO and non-specific cough. ConclusionsFindings indicate that ILO and chronic non-specific cough can neither be diagnosed nor differentiated from mild asthma using spirometry alone. Spirometry should therefore be used judiciously with this population, bearing in mind the limitations of the procedure. Future research should determine the most effective and efficient ways of delineating ILO and non-specific cough from other respiratory conditions in children.

Determinants of lung function development from birth to age 5 years: an interrupted time series analysis of a South African birth cohort

Early life is a key period that determines long-term health. Lung development in childhood predicts lung function attained in adulthood and morbidity and mortality across the life course. We aimed to assess the effect of early-life lower respiratory tract infection (LRTI) and associated risk factors on lung development from birth to school age in a South African birth cohort. We prospectively followed children enrolled in a population-based cohort from birth (between March 5, 2012 and March 31, 2015) to age 5 years with annual lung function assessment. Data on multiple early-life exposures, including LRTI, were collected. The effect of early-life risk factors on lung function development from birth to age 5 years was assessed using the Generalised Additive Models for Location, Scale and Shape and Interrupted Time Series approach. 966 children (475 [49·2%] female, 491 [50·8%] male) had lung function measured with oscillometry, tidal flow volume loops, and multiple breath washout. LRTI occurred in 484 (50·1%) children, with a median of 2·0 LRTI episodes (IQR 1·0-3·0) per child. LRTI was independently associated with altered lung function, as evidenced by lower compliance (0·959 [95% CI 0·941-0·978]), higher resistance (1·028 [1·016-1·041]), and higher respiratory rate (1·018 [1·063-1·029]) over 5 years. Additional impact on lung function parameters occurred with each subsequent LRTI. Respiratory syncytial virus (RSV) LRTI was associated with lower expiratory flow ratio (0·97 [0·95-0·99]) compared with non-RSV LRTI. Maternal factors including allergy, smoking, and HIV infection were also associated with altered lung development, as was preterm birth, low birthweight, female sex, and coming from a less wealthy household. Public health interventions targeting LRTI prevention, with RSV a priority, are vital, particularly in low-income and middle-income settings. UK Medical Research Council Grant, The Wellcome Trust, The Bill & Melinda Gates Foundation, US National Institutes of Health Human Heredity and Health in Africa, South African Medical Research Council, Hungarian Scientific Research Fund, and European Respiratory Society.