A Simulation-Based Comparison of Human, Porcine and Ovine Pulmonary Artery Hemodynamics. Evaluating the Suitability of Large Animal Models for Endopulmonary Device Evaluation from a Hemodynamics Point of View.

To study the pulmonary artery (PA) hemodynamics in patients with systemic sclerosis (SSc) using 4D flow MRI (4D-flow). Twenty-three patients with SSc (M/F: 2/21, 57 ± 15years, 3 manifest PA hypertension (PAH) by right heart catheterization) and 10 control subjects (M/F: 1/9, 55 ± 17years) underwent 4D-flow for the in vivo measurement of 3D blood flow velocities in the PA. Data analysis included area-averaged flow quantification at the main PA, 3D wall shear stress (WSS), oscillatory shear index (OSI) calculation along the PA surface, and Reynolds number. The composite outcome of all-cause death and major adverse cardiac events was also investigated. The maximum PA flow at the systole did not differ, but the minimum flow at the diastole was significantly greater in patients with SSc compared with that in control subjects (7.7 ± 16.0ml/s vs. ‑13.0 ± 17.3ml/s, p < 0.01). The maximum WSS at the peak systole was significantly lower and OSI was significantly greater in patients with SSc compared with those in control subjects (maximum WSS: 1.04 ± 0.20Pa vs. 1.33 ± 0.34Pa, p < 0.01, OSI: 0.139 ± 0.031 vs. 0.101 ± 0.037, p < 0.01). The cumulative event-free rate for the composite event was significantly lower in patients with minimum flow in main PA ≤ 9.22ml/s (p = 0.012) and in patients with Reynolds number ≤ 2560 (p < 0.001). 4D-flow has the potential to detect changes of PA hemodynamics noninvasively and predict the outcome in patients with SSc at the stage before manifest PAH. • The WSS at the peak systolic phase was significantly lower (p < 0.05), whereas OSI was greater (p < 0.01) in patients with SSc without manifest PAH than in controls. • The hemodynamic change detected by 4D-flow may help patient management even at the stage before manifest PAH in SSc. • The minimum PA flow and Reynolds number by 4D-flow will serve as a predictive marker for SSc.

Obstructive sleep apnea and pulmonary hypertension: the pendulum swings again.

Chronic thromboembolic pulmonary hypertension (CTEPH) develops due to the accumulation of blood clots in the lung vasculature that obstructs flow and increases pressure. The mechanobiological factors that drive progression of CTEPH are not understood, in part because mechanical and hemodynamic changes in the small pulmonary arteries due to CTEPH are not easily measurable. Using previously published hemodynamic measurements and imaging from a large animal model of CTEPH, we applied a subject-specific one-dimensional (1D) computational fluid dynamic (CFD) approach to investigate the impact of CTEPH on pulmonary artery stiffening, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) in extralobar (main, right, and left) pulmonary arteries and intralobar (distal to the extralobar) arteries. Our results demonstrate that CTEPH increases pulmonary artery wall stiffness and decreases TAWSS in extralobar and intralobar arteries. Moreover, CTEPH increases the percentage of the intralobar arterial network with both low TAWSS and high OSI, quantified by the novel parameter φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document}, which is related to thrombogenicity. Our analysis reveals a strong positive correlation between increases in mean pulmonary artery pressure (mPAP) and φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} from baseline to CTEPH in individual subjects, which supports the suggestion that increased φ\\documentclass[12pt]{minimal} \\usepackage{amsmath} \\usepackage{wasysym} \\usepackage{amsfonts} \\usepackage{amssymb} \\usepackage{amsbsy} \\usepackage{mathrsfs} \\usepackage{upgreek} \\setlength{\\oddsidemargin}{-69pt} \\begin{document}$$\\varphi$$\\end{document} drives disease severity. This subject-specific experimental–computational framework shows potential as a predictor of the impact of CTEPH on pulmonary arterial hemodynamics and pulmonary vascular mechanics. By leveraging advanced modeling techniques and calibrated model parameters, we predict spatial distributions of flow and pressure, from which we can compute potential physiomarkers of disease progression. Ultimately, this approach can lead to more spatially targeted interventions that address the needs of individual CTEPH patients.

Chronic thromboembolic pulmonary hypertension (CTEPH) develops due to the accumulation of blood clots in the lung vasculature that obstruct flow and increase pressure. The mechanobiological factors that drive progression of CTEPH are not understood, in part because mechanical and hemodynamic changes in the pulmonary vasculature due to CTEPH are not easily measurable. Using previously published hemodynamic measurements and imaging from a large animal model of CTEPH, we developed a subject-specific one-dimensional (1D) computational fluid dynamic (CFD) models to investigate the impact of CTEPH on pulmonary artery stiffening, time averaged wall shear stress (TAWSS), and oscillatory shear index (OSI). Our results demonstrate that CTEPH increases pulmonary artery wall stiffness and decreases TAWSS in extralobar (main, right and left pulmonary arteries) and intralobar vessels. Moreover, CTEPH increases the percentage of the intralobar arterial network with both low TAWSS and high OSI. This subject-specific experimental-computational framework shows potential as a predictor of the impact of CTEPH on pulmonary arterial hemodynamics and pulmonary vascular mechanics. By leveraging advanced modeling techniques and calibrated model parameters, we predict spatial distributions of flow and pressure, from which we can compute potential physiomarkers of disease progression, including the combination of low mean wall shear stress with high oscillation. Ultimately, this approach can lead to more spatially targeted interventions that address the needs of individual CTEPH patients.

HighlightsWhat are the main findings?This study demonstrated that ultrasound-facilitated catheter-directed fibrinolysis for the treatment of 45 patients with intermediate high-risk pulmonary embolism was associated with significant improvements in hemodynamics and low major bleeding events as demonstrated in previous trials (Ultima and Seattle II). However, this protocol used a lower dose and shorter duration of t-PA. The third arm of Optalyse PE-Trial used the same regime (6 mg/6 h/lung) for the treatment of 24 patients.It focuses on pulmonary artery hemodynamics as a primary precise surrogate marker for therapy effectiveness in addition to RV/LV ratio that was used in previous trials (Ultima and Seattle II), which has a bias of interobserver variability.What is the implication of the main finding?It assessed pulmonary artery hemodynamics for the first time by fibrinolysis delivery catheter, without additional need for a right heart catheterization. The results matched the right heart catheter results in EKOS and Heparin arm of Ultima trial, thereby confirming the validity of these diagnostic tools.It’s a valid and precise diagnostic tool to assess therapy effectiveness and reduce additional procedure-related complications, hospital residency, and economics. It gives this therapy additional diagnostic potential. It stressed the importance of interdisciplinary teams in the management of PE and evaluated the quality of life of these patients. This protocol shortens ICU stay to 6 h.Background: Ultrasound-facilitated and catheter-directed low-dose fibrinolysis (EKOS) has shown favorable hemodynamic and safety outcomes in intermediate- to high-risk pulmonary embolism (PE) cases. Objectives: This prospective single-arm monocentric study assessed the effects of using a delivery catheter for fibrinolysis as a novel approach for acute intermediate- to high-risk patients on pulmonary artery hemodynamics PE. Methods: Forty-five patients (41 intermediate–high and 4 high risk) with computer tomography (CT)-confirmed PE underwent EKOS therapy. By protocol, a total of 6 mg of tissue-plasminogen activator (t-PA) was administered over 6 h in the pulmonary artery (unilateral 6 mg or bilateral 12 mg). Unfractionated heparin was provided periprocedurally. The primary safety outcome was death, as well as major and minor bleeding within 48 of procedure initiation and at 90 days. The primary effectiveness outcomes were: 1. to assess the difference in pulmonary artery pressure from baseline to 6 h post-treatment as a primary precise surrogate marker, and 2. to determine the echocardiographic RV/LV ratio from baseline to 48 h and at 90 days post-delivery. Results: Pulmonary artery pressure decreased by 15/6/10 mmHg (p < 0.001). The mean RV/LV ratio decreased from 1.2 ± 0.85 at baseline to 0.85 ± 0.12 at 48 and to 0.76 ± 0.13 at 90 days (p < 0.001). Five patients (11%) died within 90 days of therapy. Conclusions and Highlights: Pulmonary artery hemodynamics were assessed using a delivery catheter for fibrinolysis, which is reproducible for identifying PE at risk of adverse outcomes. The results matched the right heart catheter results in EKOS and Heparin arm of Ultima trial, thereby confirming the validity of this potential diagnostic tool to assess therapy effectiveness and thereby reduce additional procedure-related complications, hospital residency, and economics. These results stress the importance of having an interdisciplinary team involved in the management of PE to evaluate the quality of life of these patients and this protocol shortens ICU admission to 6 h.

Citation:Mesarwi O, Malhotra A. Obstructive sleep apnea and pulmonary hypertension: a bidirectional relationship. J Clin Sleep Med. 2020;16(8):1223–1224.

Summary In an effort to better understand the role of vasodilators in the management of pulmonary hypertension associated with chronic heartworm disease (hwd), pulmonary hemodynamic measurements were obtained from 7 experimentally infected, anesthetized dogs before and after hydralazine administration (mean dose, 1.96 mg/kg of body weight). Five dogs were maintained on room air, while 2 were maintained on 100% oxygen during the hydralazine study. The hemodynamic effect of hydralazine in dogs with hwd was evaluated, using heart rate, cardiac index, mean pulmonary artery pressure, mean arterial pressure, total pulmonary resistance, total systemic resistance, total systemic resistance/total pulmonary resistance, left ventricular dP/dtmax, left ventricular end diastolic pressure, and left and right ventricular double products ([mean arterial pressure × heart rate] and [mean pulmonary artery pressure × heart rate], respectively). Responders were defined as those in which total pulmonary resistance decreased ≥ 20% without an increase in mean pulmonary arterial pressure and in which heart rate increase was ≤ 10%. Comparison was also made between maximal hemodynamic effect of hydralazine with that after 100% oxygen administration for 15 minutes to previously normoxemic dogs (n = 5). Significance was determined if P &lt; 0.05, using the paired t-test. Hydralazine induced significant reductions in mean pulmonary and systemic arterial pressures and total pulmonary resistance, with no significant change in heart rate, cardiac index, total systemic resistance, left ventricular dP/dtmax, left ventricular end diastolic pressure, or right and left ventricular double products. Four (57%) of the 7 dogs studied were considered responders. Pretreatment cardiac index, mean pulmonary artery pressure, and total pulmonary resistance did not allow differentiation of responders from nonresponders. However, pretreatment right ventricular end diastolic pressure was significandy less in responders than in nonresponders. Two dogs sustained hypotension after hydralazine administration, but no dogs had significant tachycardia. In dogs with experimentally induced hwd, treatment with hydralazine had significantly greater effect on cardiac index and mean pulmonary and systemic arterial pressures and resistance than did administration of 100% oxygen. These data indicate that further study of vasodilators for treatment of hwd-induced pulmonary hypertension may be warranted.

Cardiac magnetic resonance (CMR) imaging allows for multiparametric assessment of healthy pulmonary artery (PA) hemodynamics. Gender- and aging-associated PA stiffness and pressure alterations have remained clinically unestablished, however may demonstrate epidemiological differences in disease development. The aim of this study is to evaluate the role of CMR as a surrogate for catheter examinations by providing a comprehensive CMR assessment of sex- and age-related reference values for PA stiffness, flow, and pressure. PA hemodynamics were studied between gender and age groups (>/<50 years) using phase-contrast CMR. Corresponding correlation analyses were performed. 179 healthy volunteers with a median age of 32.6 years (range 11.3-68.2) were examined. Males demonstrated increased PA compliance (median [interquartile range] or mean ± standard deviation) (20.8 mm2/mmHg [16.6; 25.8] vs. 19.2 ± 7.1 mm2/mmHg; P < 0.033), higher pulse wave velocity (2.00 m/s [1.35; 2.87] vs. 1.73 m/s [1.19; 2.34]; P = 0.018) and a reduced full width half maximum (FWHM) (219 ± 22 ms vs. 235 ± 23 ms; P < 0.001) than females. Mean, systolic, diastolic PA pressure and pulmonary proportional pulse pressure were significantly elevated for males compared to females (P < 0.001). Older subjects (>50 years) exhibited reduced PA elasticity (41.7% [31.0; 52.9] vs. 66.4% [47.7; 83.0]; P < 0.001), reduced PA compliance (15.4 mm2/mmHg [12.3; 20.7] vs. 21.3 ± 6.8 mm2/mmHg; P < 0.001), higher pulse wave velocity (2.59 m/s [1.57; 3.59] vs. 1.76 m/s [1.24; 2.34]; P < 0.001) and a reduced FWHM (218 ± 29 ms vs. 231 ± 21 ms; P < 0.001) than younger subjects. Velocity-time profiles are dependent on age and gender. PA stiffness indices deteriorate with age. CMR has potential to serve as a surrogate for right heart catheterization.

This study created 3D CFD models of the Norwood procedure for hypoplastic left heart syndrome (HLHS) using standard angiography and echocardiogram data to investigate the impact of shunt characteristics on pulmonary artery (PA) hemodynamics. Leveraging routine clinical data offers advantages such as availability and cost-effectiveness without subjecting patients to additional invasive procedures. Patient-specific geometries of the intrathoracic arteries of two Norwood patients were generated from biplane cineangiograms. "Virtual surgery" was then performed to simulate the hemodynamics of alternative PA shunt configurations, including shunt type (modified Blalock-Thomas-Taussig shunt (mBTTS) vs. right ventricle-to-pulmonary artery shunt (RVPAS)), shunt diameter, and pulmonary artery anastomosis angle. Left-right pulmonary flow differential, Qp/Qs, time-averaged wall shear stress (TAWSS), and oscillatory shear index (OSI) were evaluated. There was strong agreement between clinically measured data and CFD model output throughout the patient-specific models. Geometries with a RVPAS tended toward more balanced left-right pulmonary flow, lower Qp/Qs, and greater TAWSS and OSI than models with a mBTTS. For both shunt types, larger shunts resulted in a higher Qp/Qs and higher TAWSS, with minimal effect on OSI. Low TAWSS areas correlated with regions of low flow and changing the PA-shunt anastomosis angle to face toward low TAWSS regions increased TAWSS. Excellent correlation between clinically measured and CFD model data shows that 3D CFD models of HLHS Norwood can be developed using standard angiography and echocardiographic data. The CFD analysis also revealed consistent changes in PA TAWSS, flow differential, and OSI as a function of shunt characteristics.

Pulmonary artery hemodynamics with varying degrees of valvular stenosis: an in vitro study

Hyperthyroidism is a common endocrinopathy affecting middle-aged to elderly cats, with multisystemic repercussions. Hyperthyroid humans show decreased lung compliance and increased cardiac output with subsequent left heart failure leading to pulmonary capillary congestion. Prognosis worsens with the development of increased pulmonary vascular pressures (ie, pulmonary hypertension [PH]) in hyperthyroid humans. The effect of excess thyroid hormone concentration on pulmonary arterial hemodynamics is unknown in cats. Assessing pulmonary vascular pressures in veterinary medicine relies heavily on echocardiographic measurements performed at the level of the heart and pulmonary trunk. This study investigated right-sided cardiac and pulmonary arterial hemodynamics in hyperthyroid cats using echocardiography. Echocardiographic examinations of hyperthyroid cats identified through a bi-institutional database search were reviewed for the determination of systolic pulmonary arterial pressure (PAP) and 20 other metrics. Values were compared with those of a healthy cat group using non-parametric statistical analyses. Systolic PAP could not be determined in 23/26 hyperthyroid and 13/14 healthy cats owing to unmeasurable tricuspid regurgitation flow velocity. Hyperthyroid cats were roughly twice as old (P <0.001) and had 2-4-fold higher respiratory rates (P <0.001) than healthy cats. Hyperthyroid cats showed an increase in acceleration time-to-ejection time ratio of pulmonary flow (1.4-fold, P = 0.001), pulmonary artery velocity time integral (1.2-1.6-fold, P = 0.001), maximal pulmonary velocity (1.3-1.7-fold, P = 0.002), stroke volume (1.5-fold, P = 0.001) and cardiac output (1.6-fold, P <0.001) vs healthy cats. None of the other echocardiographic metrics reached statistical significance. Systolic PAP estimation proved unsuitable as a sole measurement for the assessment of PH in hyperthyroid cats owing to the frequent inability to interrogate tricuspid regurgitant flow velocity. Hyperthyroid cats have altered echocardiographic measures of pulmonary hemodynamics dissimilar to those reported in hyperthyroid humans. Differential effects of thyrotoxic cardiomyopathy on ventricular systolic function may underlie species differences.

Staged ascent (SA), temporary residence at moderate altitude en route to high altitude, reduces the incidence and severity of noncardiopulmonary altitude illness such as acute mountain sickness. To date, the impact of SA on pulmonary arterial pressure (PAP) is unknown. We tested the hypothesis that SA would attenuate the PAP increase that occurs during rapid, direct ascent (DA). Transthoracic echocardiography was used to estimate mean PAP in 10 healthy males at sea level (SL, P(B) approximately 760 torr), after DA to simulated high altitude (hypobaric chamber, P(B) approximately 460 torr), and at 2 times points (90 min and 4 days) during exposure to terrestrial high altitude (P(B) approximately 460 torr) after SA (7 days, moderate altitude, P(B) approximately 548 torr). Alveolar oxygen pressure (Pao(2)) and arterial oxygenation saturation (Sao(2)) were measured at each time point. Compared to mean PAP at SL (mean +/- SD, 14 +/- 3 mmHg), mean PAP increased after DA to 37 +/- 8 mmHg (Delta = 24 +/- 10 mmHg, p < 0.001) and was negatively correlated with both Pao(2) (r(2) = 0.57, p = 0.011) and Sao(2) (r(2) = 0.64, p = 0.005). In comparison, estimated mean PAP after SA increased to only 25 +/- 4 mmHg (Delta = 11 +/- 6 mmHg, p < 0.001), remained unchanged after 4 days of high altitude residence (24 +/- 5 mmHg, p = not significant, or NS), and did not correlate with either parameter of oxygenation. SA significantly attenuated the PAP increase associated with continuous direct ascent to high altitude and appeared to uncouple PAP from both alveolar hypoxia and arterial hypoxemia.

Most centers consider medically unresponsive pulmonary hypertension an absolute contraindication to orthotopic cardiac transplantation because the alternative surgical therapy, heterotopic graft placement, is associated with decreased survival, although most patients normalize their pulmonary hemodynamics postoperatively. Orthotopic transplantation in patients with elevated, but responsive pulmonary pressures, also is associated with an increased operative mortality rate and decreased long-term survival. The authors present the case of a patient with medically unresponsive pulmonary hypertension who was mechanically supported in an effort to improve his orthotopic transplant candidacy and decrease his risk. After informed consent, a Heart Mate left ventricular assist device (LVAD) was inserted and the pulmonary hemodynamic response was monitored. Immediately before LVAD insertion, the pulmonary artery pressure (PA) was 74/28 mmHg with a transpulmonary gradient (TPG) of 28 mmHg, and a pulmonary vascular resistance (PVR) of 6.6 Wood units, despite prolonged dobutamine, milrinone, and prostaglandin E1 infusions. After 10 weeks of LVAD support, pressure and resistance improved; pulmonary artery pressure was 28/15 mmHg, transpulmonary gradient was 15 mmHg, and pulmonary vascular resistance was 2.8 Wood units. This patient subsequently underwent an uneventful orthotopic heart transplant. At 1 year after transplantation, pulmonary artery hemodynamics were normal (PA 34/14 mmHg, TPG at 8 mmHg, and PVR at 1.5 Wood units). The authors recommend the consideration of LVAD placement in patients with medically unresponsive pulmonary artery hypertension to assess PA responsiveness and improve the patient's orthotopic cardiac transplant candidacy and decrease the operative risk. However, several weeks may be needed for normalization of pressure and resistance.

Most centers consider medically unresponsive pulmonary hypertension an absolute contraindication to orthotopic cardiac transplantation because the alternative surgical therapy, heterotopic graft placement, is associated with decreased survival, although most patients normalize their pulmonary hemodynamics postoperatively. Orthotopic transplantation in patients with elevated, but responsive pulmonary pressures, also is associated with an increased operative mortality rate and decreased long-term survival. The authors present the case of a patient with medically unresponsive pulmonary hypertension who was mechanically supported in an effort to improve his orthotopic transplant candidacy and decrease his risk. After informed consent, a HeartMate left ventricular assist device (LVAD) was inserted and the pulmonary hemodynamic response was monitored. Immediately before LVAD insertion, the pulmonary artery pressure (PA) was 74/28 mmHg with a transpulmonary gradient (TPG) of 28 mmHg, and a pulmonary vascular resistance (PVR) of 6.6 Wood units, despite prolonged dobutamine, milrinone, and prostaglandin E1 infusions. After 10 weeks of LVAD support, pressure and resistance improved; pulmonary artery pressure was 28/15 mmHg, transpulmonary gradient was 15 mmHg, and pulmonary vascular resistance was 2.8 Wood units. This patient subsequently underwent an uneventful orthotopic heart transplant. At 1 year after transplantation, pulmonary artery hemodynamics were normal (PA 34/14 mmHg, TPG at 8 mmHg, and PVR at 1.5 Wood units). The authors recommend the consideration of LVAD placement in patients with medically unresponsive pulmonary artery hypertension to assess PA responsiveness and improve the patient's orthotopic cardiac transplant candidacy and decrease the operative risk. However, several weeks may be needed for normalization of pressure and resistance.

IntroductionWall shear stress (WSS) and oscillatory shear index (OSI) are associated with atherosclerotic disease. Both parameters are derived from blood velocities, which can be measured with phase-contrast MRI (PC-MRI). Limitations in spatiotemporal resolution of PC-MRI are known to affect these measurements. Our aim was to investigate the effect of spatiotemporal resolution using a carotid artery phantom.MethodsA carotid artery phantom was connected to a flow set-up supplying pulsatile flow. MRI measurement planes were placed at the common carotid artery (CCA) and internal carotid artery (ICA). Two-dimensional PC-MRI measurements were performed with thirty different spatiotemporal resolution settings. The MRI flow measurement was validated with ultrasound probe measurements. Mean flow, peak flow, flow waveform, WSS and OSI were compared for these spatiotemporal resolutions using regression analysis. The slopes of the regression lines were reported in %/mm and %/100ms. The distribution of low and high WSS and OSI was compared between different spatiotemporal resolutions.ResultsThe mean PC-MRI CCA flow (2.5±0.2mL/s) agreed with the ultrasound probe measurements (2.7±0.02mL/s). Mean flow (mL/s) depended only on spatial resolution (CCA:-13%/mm, ICA:-49%/mm). Peak flow (mL/s) depended on both spatial (CCA:-13%/mm, ICA:-17%/mm) and temporal resolution (CCA:-19%/100ms, ICA:-24%/100ms). Mean WSS (Pa) was in inverse relationship only with spatial resolution (CCA:-19%/mm, ICA:-33%/mm). OSI was dependent on spatial resolution for CCA (-26%/mm) and temporal resolution for ICA (-16%/100ms). The regions of low and high WSS and OSI matched for most of the spatiotemporal resolutions (CCA:30/30, ICA:28/30 cases for WSS; CCA:23/30, ICA:29/30 cases for OSI).ConclusionWe show that both mean flow and mean WSS are independent of temporal resolution. Peak flow and OSI are dependent on both spatial and temporal resolution. However, the magnitude of mean and peak flow, WSS and OSI, and the spatial distribution of OSI and WSS did not exhibit a strong dependency on spatiotemporal resolution.