Pulmonary Vascular Impedance Research Articles

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.

Assessment of Pulmonary Arterial Vascular Impedance in Fetuses With Tetralogy of Fallot.

To evaluate the vascular impedance of the pulmonary arteries in fetuses with tetralogy of Fallot (TOF) by Doppler echocardiography. A total of 42 fetuses with TOF (TOF group) and 84 gestational age-matched normal fetuses (control group) were prospectively collected from the Second Xiangya Hospital of Central South University from August 2022 to January 2023. The severity of TOF was classified into mild TOF (z score ≥-2), moderate TOF (-4 < z score < -2), or severe TOF (z score ≤-4) according to the z score value of the pulmonary annulus diameter. The pulsatility index (PI) of the main pulmonary artery (MPA), distal left pulmonary artery (DLPA), and distal right pulmonary artery (DRPA) were measured by pulsed-wave Doppler. The differences in clinical data and echocardiographic parameters between TOF group, control group, and TOF subgroups were compared. Compared with the control group, MPA-PI increased significantly, whereas DLPA-PI and DRPA-PI decreased in TOF group (all P < .001). There were no significant differences in MPA-PI and DRPA-PI among mild TOF, moderate TOF, and severe TOF (all P > .05). However, DLPA-PI decreased significantly in severe TOF compared with mild TOF (P < .05). Fetuses with TOF presented increased vascular impedance in the pulmonary trunk and decreased impedance in distal pulmonary artery branches. Further large and follow-up studies are needed to demonstrate the associations between those changed vascular impedances and the development of PA in patients with TOF.

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.

Feasibility of a Composite Measure of Pulmonary Vascular Impedance and Application to Patients with Chronic RV Failure Post LVAD Implant.

Pulmonary vascular impedance (PVZ) describes RV afterload in the frequency domain and has not been studied extensively in LVAD patients. We sought to determine (1) feasibility of calculating a composite (c)PVZ using standard of care (SoC), asynchronous, pulmonary artery pressure (PAP) and flow (PAQ) waveforms; and (2) if chronic right ventricular failure (RVF) post-LVAD implant was associated with changes in perioperative cPVZ.PAP and PAQ were obtained via SoC procedures at three landmarks: T(1), Retrospectively, pre-operative with patient conscious; and T(2) and T(3), prospectively with patient anesthetized, and either pre-sternotomy or chest open with LVAD, respectively. Additional PAP's were taken at T(4), following chest closure; and T(5), 4-24h post chest closure. Harmonics (z) were calculated by Fast Fourier Transform (FFT) with cPVZ(z) = FFT(PAP)/FFT(PAQ). Total pulmonary resistance Z(0); characteristic impedance Zc, mean of cPVZ(2-4); and vascular stiffness PVS, sum of cPVZ(1,2), were compared at T(1,2,3) between +/-RVF groups.Out of 51 patients, nine experienced RVF. Standard hemodynamics and changes in cPVZ-derived parameters were not significant between groups at any T.In conclusion, cPVZ calculated from SoC measures is possible. Although data that could be obtained were limited it suggests no difference in RV afterload for RVF patients post-implant. If confirmed in larger studies, focus should be placed on cardiac function in these subjects.

Beraprost Sodium for Pulmonary Hypertension in Dogs: Effect on Hemodynamics and Cardiac Function.

Simple SummaryPulmonary hypertension is a potentially life-threatening disease among dogs that is characterized by increased pulmonary arterial pressure and pulmonary vascular resistance. In veterinary medicine, a phosphodiesterase-5 inhibitor such as sildenafil is the most common drug used to treat pulmonary hypertension. However, the availability of sildenafil is limited because of its high cost, difficulty in obtaining the drug in some areas, and potential inter-individual variability in the response to sildenafil therapy. Beraprost sodium is one of the most common drugs used to treat pulmonary hypertension in humans. However, little is known about its efficacy in dogs with pulmonary hypertension. In this study, beraprost sodium showed significant pulmonary and systemic vasodilation without any adverse effects in sixteen dogs with pulmonary hypertension. Additionally, echocardiographic improvements in cardiac function and pulmonary and systemic circulation were observed. These results emphasize the potential efficacy of beraprost sodium in treating canine pulmonary hypertension.Pulmonary hypertension (PH) is a fatal condition that affects many dogs. In humans, PH is often treated with beraprost sodium (BPS). However, the effectiveness of BPS for canine PH has not been established. This study aimed to evaluate the clinical and cardiovascular response of BPS in canine patients with PH of various causes. Sixteen dogs with PH (post-capillary PH, n = 8; pre-capillary PH, n = 8) were included. BPS was continuously administered twice daily at 15 µg/kg. All dogs underwent echocardiography, including speckle-tracking analysis and blood pressure measurement, before and after BPS administration. Continuous BPS administration (range: 13.2–22.0 µg/kg) significantly decreased the pulmonary and systemic vascular impedance and increased left and right ventricular myocardial strain. In dogs with post-capillary PH, BPS administration caused no significant worsening of the left atrial pressure indicators. No side effects of BPS were observed in any dog. BPS also improved cardiac function and pulmonary circulation through pulmonary vasodilation, suggesting that BPS may be an additional treatment option for canine PH of various causes. Particularly, BPS increased left ventricular function and systemic circulation without worsening the left heart loading condition in dogs with post-capillary PH.

Investigation of Beraprost Sodium on Cardiac Function and Hemodynamics in Canine Models of Chronic Pulmonary Hypertension.

Pulmonary hypertension (PH) is a life-threatening disease in dogs characterized by increased pulmonary arterial pressure (PAP) and/or pulmonary vascular resistance. No study has evaluated the utility of Beraprost sodium (BPS) in dogs with PH. This study aimed to evaluate the effect of BPS on cardiac function and hemodynamics and examine the optimal dose of BPS in canine models of chronic embolic PH. In this prospective crossover study, three doses of BPS (5, 15, and 25 μg/kg, twice a day) were examined in eight canine models of chronic embolic PH. All model dogs underwent invasive PAP measurement, echocardiography, and non-invasive systemic blood pressure measurement before and after continuous administration of oral BPS for 1 week. No side effects of BPS were observed in any dog during the study. All doses of BPS significantly decreased systolic PAP and pulmonary vascular impedance. Additionally, systemic vascular impedance significantly decreased with 15 and 25 μg/kg of BPS. The right ventricular stroke volume and longitudinal strain significantly decreased with all doses of BPS. The left ventricular stroke volume and circumferential strain decreased with 15 μg/kg BPS. BPS was well-tolerated in this study. A dose-dependent vasodilating effect on pulmonary vessels was observed in canine models of chronic PH. Additionally, 15 μg/kg BPS showed a balanced vasodilating effect on systemic and pulmonary vessels. Furthermore, with a decrease in systemic and pulmonary vascular impedance, the left and right ventricular functions were significantly improved. Our results suggest that BPS may be useful in the treatment of canine PH.

Arterial load and right ventricular-vascular coupling in pulmonary hypertension

Right ventricular (RV) functional adaptation to afterload determines outcome in pulmonary hypertension (PH). RV afterload is determined by the dynamic interaction between pulmonary vascular resistance (PVR), characteristic impedance (Zc), and wave reflection. Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of RV afterload; however, there is an unmet need for an easier bedside measurement of this complex variable. Although a recent study showed that Zc and wave reflection can be estimated from RV pressure waveform analysis and cardiac output, this has not been validated. Estimations of Zc and wave reflection coefficient (λ) were validated relative to conventional spectral analysis in an animal model. Zc, λ, and the single-beat ratio of end-systolic to arterial elastance (Ees/Ea) to estimate RV-pulmonary arterial (PA) coupling were determined from right heart catheterization (RHC) data. The study included 30 pulmonary artery hypertension (PAH) and 40 heart failure with preserved ejection fraction (HFpEF) patients [20 combined pre- and postcapillary PH (Cpc-PH) and 20 isolated postcapillary PH, (Ipc-PH)]. Also included were 10 age- and sex-matched controls. There was good agreement with minimal bias between estimated and spectral analysis-derived Zc and λ. Zc in PAH and Cpc-PH groups exceeded that in the Ipc-PH group and controls. λ was increased in Ipc-PH (0.84 ± 0.02), Cpc-PH (0.87 ± 0.05), and PAH groups (0.85 ± 0.04) compared with controls (0.79 ± 0.03); all P values were <0.05. λ was the only afterload parameter associated with RV-PA coupling in PAH. In the PH-HFpEF group, RV-PA uncoupling was independent of RV afterload. Our findings indicate that Zc and λ derived from an RV pressure curve can be used to improve estimation of RV afterload. λ is the only afterload measure associated with RV-PA uncoupling in PAH, whereas RV-PA uncoupling in PH-HFpEF appears to be independent of afterload consistent with an inherent abnormality of the RV myocardium.NEW & NOTEWORTHY Pulmonary vascular impedance (PVZ) represents the most comprehensive measure of right ventricle (RV) afterload; however, measurement of this variable is complex. We demonstrate that characteristic impedance (Zc) and a wave reflection coefficient, λ, can be derived from RV pressure waveform analysis. In addition, RV dysfunction in left heart disease is independent of its afterload. The current study provides a platform for future studies to examine the pharmacotherapeutic effects and prognosis of different measures of RV afterload.

Semi-Automated Graphical System for Calculating Pulmonary Vascular Impedances in a Clinical Setting

Goal: Create a semi-automated, graphical, stand-alone application that uses clinically available asynchronous pressure and Doppler velocity captures to rapidly calculate, display, and interpret the pulmonary vascular impedance (PVZ) spectra. Methods: MATLAB-based software was written to analyze PVZ by creating a composite PVZ (cPVZ) spectra comprised of asynchronous screen captures of pulmonary arterial pressure and pulmonary arterial pulsed-wave Doppler velocity waveforms obtained during standard of care procedures. The pressure waveform, Doppler frequency envelopes, and ECG signals were re-digitized via automated border detection. cPVZ of averaged representative beats was calculated in the frequency domain via Fast Fourier Transform, and plotted vs harmonic z. Results: Successful generation of impedance spectra (PVZ(z)), where z is the harmonic, and additional parameters for characteristic impedance (Zc) and stiffness (Zs) were calculated as the mean of PVZ(2-4), and the sum of PVZ (1, 2), respectively. Conclusions: A graphically driven analysis of PVZ, calculated from standard of care right heart catheterization and echocardiography is possible. This system can help characterize both the steady and pulsatile components of right ventricular (RV) afterload in the clinical setting.

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients With Pulmonary Hypertension Associated with Heart Failure With Preserved Ejection Fraction

BackgroundThe severity of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance, which is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV). Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile forces, and thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with heart failure with preserved ejection fraction who were administered inhaled sodium nitrite to better understand the acute effects on afterload. Methods and ResultsFourteen patients with PH associated with heart failure with preserved ejection fraction underwent right heart catherization and were administered inhaled sodium nitrite. A Fourier transform was used to calculate PVZ for both before and after nitrite for comparison. Inhaled sodium nitrite decreased characteristic impedance (inversely related to proximal pulmonary artery compliance) and total work performed by the RV. RV efficiency improved, defined by a reduction in the total work divided by cardiac output. There was a mild decrease in pulmonary steady-state resistance after the administration of inhaled sodium nitrite, but this effect was not significant. ConclusionsPVZ analysis showed administration of inhaled sodium nitrite was associated with an improvement in pulmonary vascular compliance via a decrease in characteristic impedance, more so than pulmonary steady-state resistance. This effect was associated with improved RV efficiency and total work.

Pulmonary hemodynamics and wave reflections in adults with atrial septal defects.

Using high-fidelity micromanometers and flow velocity sensors at right heart catheterization, we compared pulmonary hemodynamics and wave reflections in age-matched normal adults and those with atrial septal defects, separated into three subgroups based on levels of mean pulmonary artery pressure: low (<17 mmHg), intermediate (17-26 mmHg), high (>26 mmHg). We made baseline measurements in all groups and after intravenous sodium nitroprusside in the subgroups. All of the subgroups had higher than normal baseline pulmonary flows and corresponding power that did not differ among the subgroups. The pulmonary vascular resistance, input resistance, and characteristic impedance in the subgroups did not differ from normal. Aside from the elevated flow and power, the hemodynamics in the low subgroup did not differ from normal. The intermediate subgroup had significantly higher than normal right ventricular and pulmonary artery pressures, wave reflections, and shorter wave reflection time, which all reverted to normal after nitroprusside. The high subgroup had similar changes as the intermediate subgroup. Unlike that subgroup, however, the pressures, wave reflections, and reflection return time did not revert to normal after nitroprusside. Hence, elevated wave reflections, but not resistance or characteristic impedance, are the hallmark of pulmonary hypertension in adults with atrial septal defects. Our results demonstrate that detailed measurements of hemodynamics and assessment of responsiveness to vasodilators provide important information about the pulmonary circulation in atrial septal defect. Coupled with studies after defect closure, those results may be a better foundation than current ones for clinical decisions.

Increased Pulmonary Vascular Impedance in Patients with Severe Pulmonary Arterial Hypertension

IntroductionPulmonary arterial hypertension (PAH) is characterized by increased pulmonary artery (PA) pressure and resistance due to pulmonary vascular remodeling. The functional effect of this vascular remodeling on the pulsatile pulmonary hemodynamics has not been well studied. Pulmonary vascular impedance (PVZ) represents the relationship between pulsatile pressure and flow in the pulmonary artery (PA) and provides a more comprehensive view of pulmonary arterial function. We hypothesized that decreased pulmonary vascular compliance and increased pulmonary vascular resistance (PVR) would significantly alter the pulsatile pulmonary hemodynamics in severe PAH.MethodsGroup 1 PAH patients (mean pulmonary arterial pressure (mPAP) ≥ 25 mmHg, pulmonary capillary wedge pressure ≤ 15 mmHg) and control patients (without pulmonary hypertension (PH), mPAP &lt; 25 mmHg) with both an echocardiogram including right ventricular outflow tract (RVOT) images and a right heart catheterization (RHC) within three months were identified from the University of Arizona PH registry. The PAH patients were divided into those with mild PH (PVR &lt; 7 mmHg*min/L) and severe PH (PVR ≥ 7 mmHg*min/L). RVOT Doppler flow velocity profiles were first traced using a custom MATLAB program. Flow velocity profiles were multiplied by the average PA diameter (ratio of thermodilution cardiac output and mean RVOT flow velocity) to determine PA flow profiles. PVZ was calculated in the frequency domain using RHC measured PA pressure and PA flow profiles. Characteristic Impedance (ZC) was calculated as the mean of Z2–4. Data is presented as mean ± standard error or median [interquartile range].ResultsFourteen subjects were identified (Control: n = 2, 2 female, 70 ± 3 yrs; Mild PAH: n = 6, 2 female, 63 ± 11 yrs; and Severe PAH: n = 6, 4 female, 45 ± 13 yrs, p = 0.05). The median time between the RHC and echo was 8 [1 − 15] days. Severe PAH patients have increased mPAP (60 ± 19 vs 38 ± 17 mmHg, p = 0.04) and end‐diastolic elastance (1.05 ± 0.43 vs 0.39 ± 0.3 mmHg/mL, p = 0.2), decreased stroke volume (61 ± 7 vs 91 ± 20 mL, p = 0.01) and no change in cardiac output (5.16 ± 0.81 vs 6.23 ± 1.3 L/min) compared to controls. Severe PAH showed increased 0 Hz impedance (Z0, 966 ± 138 dynes/sec/cm−5) compared to controls (288 ± 34 dynes/sec/cm−5, p = 0.02) and mild PAH (538 ± 64 dynes/sec/cm−5, p = 0.03, Figure 1). ZC in severe PAH had a non‐significant increase compared to controls (139 ± 23 vs 69 ± 19 dynes/sec/cm−5, respectively). Z1 was significantly increased in severe PAH compared to controls (52 ± 91 vs 5 ± 43 dynes/sec/cm−5, p = 0.02) but not compared to mild PAH (52 ± 91 vs 64 ± 54 dynes/sec/cm−5, p = 0.09).ConclusionPulmonary vascular impedance analysis in a small PAH cohort demonstrated that vascular resistance (Z0) and global vascular stiffness (Z1) are increased in severe PAH patients and that there is a non‐significant increase in proximal vascular stiffness (ZC).Support or Funding InformationThis work was supported in part by grants from the Arizona Biomedical Research Commission (ABRC NIA ADHS18‐198871 (RRV))This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

The Effects of Inhaled Sodium Nitrite on Pulmonary Vascular Impedance in Patients with Pulmonary Hypertension Associated with HFpEF

Purpose The severity and clinical response of pulmonary hypertension (PH) is monitored by measuring pulmonary vascular resistance (PVR). However, PVR is a steady-state measurement and ignores the pulsatile load encountered by the right ventricle (RV), which may be one-third of the total afterload. Pulmonary vascular impedance (PVZ) can depict both steady-state and pulsatile loads, thus may better predict clinical outcomes. We sought to calculate PVZ in patients with PH associated with HFpEF (PH-HFpEF), who were administered inhaled sodium nitrite to better understand the acute effects on afterload. Methods Patients with PH-HFpEF underwent right heart catherization (RHC) to obtain standard hemodynamics, and if eligible, were administered two doses of inhaled sodium nitrite at 45 and 90 mg. Concurrently, transthoracic Doppler spectral imaging was used to measure pulmonary artery velocity. A Fourier transform was used via MATLAB to calculate PVZ at the first ten harmonics for both pre and post-nitrite for comparison. Results Fourteen patients underwent RHC with simultaneous Doppler imaging and received at least one dose of inhaled sodium nitrite. Inhaled sodium nitrite decreased characteristic impedance (Zc, inversely related to compliance), and total work (WT) performed by the RV (Table 1). RV efficiency improved, defined by a reduction in the total work divided by cardiac output (WT/CO). There were trends towards decreases in pulmonary vascular resistance (Z0), first harmonic impedance (Z1), steady state work (Ws), and pulmonary vascular stiffness (Zs) after administration of this drug. Conclusion PVZ analysis showed inhaled sodium nitrite acutely improves pulmonary vascular compliance by reducing characteristic impedance (Zc) more so than PVR (Z0). This was associated with improved RV efficiency and total work. These results suggest inhaled sodium nitrite preferentially acts on the larger proximal compliance vessels to reduce the load on the RV.

An efficient parallel simulation of unsteady blood flows in patient-specific pulmonary artery.

Simulation of blood flows in the pulmonary artery provides some insight into certain diseases by examining the relationship between some continuum metrics, eg, the wall shear stress acting on the vascular endothelium, which responds to flow-induced mechanical forces by releasing vasodilators/constrictors. V. Kheyfets, in his previous work, studies numerically a patient-specific pulmonary circulation to show that decreasing wall shear stress is correlated with increasing pulmonary vascular impedance. In this paper, we develop a scalable parallel algorithm based on domain decomposition methods to investigate an unsteady model with patient-specific pulsatile waveforms as the inlet boundary condition. The unsteady model offers tremendously more information about the dynamic behavior of the flow field, but computationally speaking, the simulation is a lot more expensive since a problem which is similar to the steady-state problem has to be solved many times, and therefore, the traditional sequential approach is not suitable anymore. We show computationally that simulations using the proposed parallel approach with up to 10 000 processor cores can be obtained with much reduced compute time. This makes the technology potentially usable for the routine study of the dynamic behavior of blood flows in the pulmonary artery, in particular, the changes of the blood flows and the wall shear stress in the spatial and temporal dimensions.

Cardiovascular mechanics in the early stages of pulmonary hypertension: a computational study.

We formulate and study a new mathematical model of pulmonary hypertension. Based on principles of fluid and elastic dynamics, we introduce a model that quantifies the stiffening of pulmonary vasculature (arteries and arterioles) to reproduce the hemodynamics of the pulmonary system, including physiologically consistent dependence between compliance and resistance. This pulmonary model is embedded in a closed-loop network of the major vessels in the body, approximated as one-dimensional elastic tubes, and zero-dimensional models for the heart and other organs. Increasingly severe pulmonary hypertension is modeled in the context of two extreme scenarios: (1) no cardiac compensation and (2) compensation to achieve constant cardiac output. Simulations from the computational model are used to estimate cardiac workload, as well as pressure and flow traces at several locations. We also quantify the sensitivity of several diagnostic indicators to the progression of pulmonary arterial stiffening. Simulation results indicate that pulmonary pulse pressure, pulmonary vascular compliance, pulmonary RC time, luminal distensibility of the pulmonary artery, and pulmonary vascular impedance are much better suited to detect the early stages of pulmonary hypertension than mean pulmonary arterial pressure and pulmonary vascular resistance, which are conventionally employed as diagnostic indicators for this disease.

Composite indices of upstream pulmonary vascular impedance and capacitance do not help in identifying patients who should undergo pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension.

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially curable by surgical pulmonary endarterectomy (PEA). Patient selection for PEA is crucial and depends mainly on discri...

Pediatric Artificial Lung: A Low-Resistance Pumpless Artificial Lung Alleviates an Acute Lamb Model of Increased Right Ventricle Afterload.

Lung disease in children often results in pulmonary hypertension and right heart failure. The availability of a pediatric artificial lung (PAL) would open new approaches to the management of these conditions by bridging to recovery in acute disease or transplantation in chronic disease. This study investigates the efficacy of a novel PAL in alleviating an animal model of pulmonary hypertension and increased right ventricle afterload. Five juvenile lambs (20-30 kg) underwent PAL implantation in a pulmonary artery to left atrium configuration. Induction of disease involved temporary, reversible occlusion of the right main pulmonary artery. Hemodynamics, pulmonary vascular input impedance, and right ventricle efficiency were measured under 1) baseline, 2) disease, and 3) disease + PAL conditions. The disease model altered hemodynamics variables in a manner consistent with pulmonary hypertension. Subsequent PAL attachment improved pulmonary artery pressure (p = 0.018), cardiac output (p = 0.050), pulmonary vascular input impedance (Z.0 p = 0.028; Z.1 p = 0.058), and right ventricle efficiency (p = 0.001). The PAL averaged resistance of 2.3 ± 0.8 mm Hg/L/min and blood flow of 1.3 ± 0.6 L/min. This novel low-resistance PAL can alleviate pulmonary hypertension in an acute animal model and demonstrates potential for use as a bridge to lung recovery or transplantation in pediatric patients with significant pulmonary hypertension refractory to medical therapies.

Pulmonary vascular collagen content, not cross-linking, contributes to right ventricular pulsatile afterload and overload in early pulmonary hypertension.

The present study found an important role for collagen content, but not collagen cross-linking, in the pulsatile right ventricular (RV) afterload, which is correlated with RV hypertrophy. These results uncover a new collagen-mediated mechanical mechanism of RV dysfunction in early pulmonary hypertension progression. Furthermore, our results suggest that measures and metrics of pulsatile hemodynamics such as pulse pressure and pulse wave velocity are potentially important to cardiovascular mortality in patients with pulmonary hypertension.

Reduced haemodynamic coupling and exercise are associated with vascular stiffening in pulmonary arterial hypertension

ObjectiveInadequate right ventricular (RV) and pulmonary arterial (PA) functional responses to exercise are important yet poorly understood features of pulmonary arterial hypertension (PAH). This study combined invasive catheterisation with echocardiography...

Composite indices of upstream pulmonary vascular impedance and capacitance do not help in identifying patients who should undergo pulmonary endarterectomy in chronic thromboembolic pulmonary hypertension

Background Chronic thromboembolic pulmonary hypertension (CTEPH) is potentially curable by surgical pulmonary endarterectomy (PEA). Patient selection for PEA is crucial and depends mainly on discriminating between those with proximal accessible disease and distal disease. In this study we evaluated the value of composite indices such as upstream resistance (Zup) and capacitance (Cp) for partitioning of pulmonary vascular resistance and surgical outcome.Methods We retrospectively reviewed data from 30 patients who underwent PEA between 2007 and 2012. Zup, defined as the ratio between the mean pulmonary artery pressure (PAPm) minus diastolic pulmonary artery pressure (PAPd) and PAPm minus pulmonary artery occlusion pressure (POAP), was computed preoperatively as was the Cp, defined as the ratio of stroke volume over pulse pressure. We assessed the use of these indices to predict pulmonary haemodynamics after PEA.Results Postoperatively, total pulmonary vascular resistance (tPVR) was > 400 dynes•s•cm-5 in 11 patients (37%); nine patients were treated with an endothelin receptor antagonist (ERA) and had unsatisfactory surgical results. Preoperative Cp was identical in both groups (0.9945 ± 0.06867 vs. 1.348 ± 0.1961, P= 0.14). Zup was higher in the group with better haemodynamic outcomes (50.29% ± 3.266) than in the ERA group (38.59% ± 2.86) (P < 0.05). In multivariate analysis, the relation of Zup and outcome was not statistically significant when adjusted for tPVR.Conclusions The composite indices Cp and Zup were not useful for distinguishing between CTEPH patients who were good candidates for PEA versus patients with substantial distal vasculopathy with PVR values that remained elevated after surgery.

Increased Red Blood Cell Stiffness Increases Pulmonary Vascular Resistance and Pulmonary Arterial Pressure.

Patients with sickle cell anemia (SCD) and pulmonary hypertension (PH) have a significantly increased risk of sudden death compared to patients with SCD alone. Sickled red blood cells (RBCs) are stiffer, more dense, more frequently undergo hemolysis, and have a sixfold shorter lifespan compared to normal RBCs. Here, we sought to investigate the impact of increased RBC stiffness, independent of other SCD-related biological and mechanical RBC abnormalities, on the hemodynamic changes that ultimately cause PH and increase mortality in SCD. To do so, pulmonary vascular impedance (PVZ) measures were recorded in control C57BL6 mice before and after ∼50 μl of blood (Hct = 45%) was extracted and replaced with an equal volume of blood containing either untreated RBCs or RBCs chemically stiffened with glutaraldehyde (Hct = 45%). Chemically stiffened RBCs increased mean pulmonary artery pressure (mPAP) (13.5 ± 0.6 mmHg at baseline to 23.2 ± 0.7 mmHg after the third injection), pulmonary vascular resistance (PVR) (1.23 ± 0.11 mmHg*min/ml at baseline to 2.24 ± 0.14 mmHg*min/ml after the third injection), and wave reflections (0.31 ± 0.02 at baseline to 0.43 ± 0.03 after the third injection). Chemically stiffened RBCs also decreased cardiac output, but did not change hematocrit, blood viscosity, pulmonary arterial compliance, or heart rate. The main finding of this study is that increased RBC stiffness alone affects pulmonary pulsatile hemodynamics, which suggests that RBC stiffness plays an important role in the development of PH in patients with SCD.